Principles and Practice of
SLEEP MEDICINE
Fifth
Edition
Principles and Practice of
SLEEP MEDICINE Meir H. Kryger, MD, FRCPC
Clinical Professor of Medicine University of Connecticut Director of Research and Education Gaylord Sleep Medicine Wallingford, Connecticut
Thomas Roth, PhD
Professor, Department of Psychiatry Wayne State University School of Medicine Director and Division Head Sleep Disorders and Research Center Henry Ford Hospital Detroit, Michigan Clinical Professor, Department of Psychiatry University of Michigan Medical School Ann Arbor, Michigan
William C. Dement, MD, PhD
Lowell W. and Josephine Q. Berry Professor of Psychiatry and Behavioral Sciences, and Director Sleep Disorders and Research Center Stanford University School of Medicine Palo Alto, California
3251 Riverport Lane St. Louis, Missouri 63043 PRINCIPLES AND PRACTICE OF SLEEP MEDICINE
Basic Edition: 978-1-4160-6645-3 Premium Edition: 978-1-4377-0731-1 Copyright © 2011, 2005, 2000, 1994, 1989 by Saunders, an imprint of Elsevier Inc. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, or any information storage and retrieval system, without permission in writing from the publisher. Details on how to seek permission, further information about the Publisher’s permissions policies and our arrangements with organizations such as the Copyright Clearance Center and the Copyright Licensing Agency, can be found at our website: www.elsevier.com/permissions. This book and the individual contributions contained in it are protected under copyright by the Publisher (other than as may be noted herein).
Notices Knowledge and best practice in this field are constantly changing. As new research and experience broaden our understanding, changes in research methods, professional practices, or medical treatment may become necessary. Practitioners and researchers must always rely on their own experience and knowledge in evaluating and using any information, methods, compounds, or experiments described herein. In using such information or methods they should be mindful of their own safety and the safety of others, including parties for whom they have a professional responsibility. With respect to any drug or pharmaceutical products identified, readers are advised to check the most current information provided (i) on procedures featured or (ii) by the manufacturer of each product to be administered, to verify the recommended dose or formula, the method and duration of administration, and contraindications. It is the responsibility of practitioners, relying on their own experience and knowledge of their patients, to make diagnoses, to determine dosages and the best treatment for each individual patient, and to take all appropriate safety precautions. To the fullest extent of the law, neither the Publisher nor the authors, contributors, or editors, assume any liability for any injury and/or damage to persons or property as a matter of products liability, negligence or otherwise, or from any use or operation of any methods, products, instructions, or ideas contained in the material herein. Library of Congress Cataloging-in-Publication Data Principles and practice of sleep medicine / [edited by] Meir H. Kryger, Thomas Roth, William C. Dement.—5th ed. p. ; cm. Includes bibliographical references and index. ISBN 978-1-4160-6645-3 1. Sleep disorders. 2. Sleep. I. Kryger, Meir H. II. Roth, T. (Tom) III. Dement, William C., 1928 [DNLM: 1. Sleep Disorders. 2. Sleep–physiology. WM 188 P957 2011] RC547.P75 2011 616.8′498–dc22 2010002721
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But the tigers come at night, With their voices soft as thunder, As they tear your hope apart, As they turn your dream to shame. From I Dreamed a Dream, LES MISÉRABLES, with permission, Cameron Mackintosh, producer © 1985 Alain Boublil Music Ltd. Used by permission 1991, CMI.
Blessings on him who first invented sleep.—It covers a man all over, thoughts and all, like a cloak.—It is meat for the hungry, drink for the thirsty, heat for the cold, and cold for the hot.—It makes the shepherd equal to the monarch, and the fool to the wise.—There is but one evil in it, and that is that it resembles death, since between a dead man and a sleeping man there is but little difference. From DON QUIXOTE By Saavedra M. de Cervantes
“To sleep! To forget!” he said to himself with the serene confidence of a healthy man that if he is tired and sleepy, he will go to sleep at once. And the same instant his head did begin to feel drowsy and he began to drop off into forgetfulness. The waves of the sea of unconsciousness had begun to meet over his head, when all at once—it was as though a violent shock of electricity had passed over him. He started so that he leapt up on the springs of the sofa, and leaning on his arms got in a panic on to his knees. His eyes were wide open as though he had never been asleep. The heaviness in his head and the weariness in his limbs that he had felt a minute before had suddenly gone. From ANNA KARENINA, Part IV, Chapter XVIII By Leo Tolstoy
Contributors ix
Contributors
Peter Achermann, PhD Professor, Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland
Sleep Homeostasis and Models of Sleep Regulation
Alon Y. Avidan, MD, MPH Associate Professor of Neurology; Associate Director, Sleep Disorders Program; Director, UCLA Neurology Residency Program; Director, UCLA Neurology Clinic, Department of Neurology, University of California, Los Angeles, Los Angeles, California Physical Examination in Sleep Medicine
Torbjörn Åkerstedt, PhD Head Professor, Stress Research Institute, Stockholm University; Affiliated Professor, Department of Clinical Neuroscience, Karolinska Institute, Stockholm, Sweden Introduction Sleep, Stress, and Burnout
Ravi Allada, MD Associate Professor, Neurobiology and Physiology, Associate Director, Center for Sleep and Circadian Biology, Northwestern University, Evanston, Illinois
Genetic Basis of Sleep in a Simple Model Organism: Drosophila
Richard P. Allen, PhD, FAASM Associate Professor, Department of Neurology, School of Medicine, Johns Hopkins University, Baltimore, Maryland Restless Legs Syndrome and Periodic Limb Movements during Sleep
Sonia Ancoli-Israel, PhD Professor of Psychiatry, University of California, San Diego, La Jolla, California Sleep and Fatigue in Cancer Patients Insomnia in Older Adults Actigraphy
Roseanne Armitage, PhD Professor of Psychiatry, Adjunct Professor of Psychology, Director, Sleep and Chronophysiology Laboratory, University of Michigan Medical School, Ann Arbor, Michigan Sex Differences and Menstrual-Related Changes in Sleep and Circadian Rhythms
Isabelle Arnulf, MD, PhD Sleep Disorders Unit, Pitié-Salpêtrière Hospital, Paris, France Parkinsonism
Charles W. Atwood, Jr., MD Associate Professor and Director, Sleep Medicine Fellowship, Department of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh School of Medicine; Assistant Chief of Medicine and Sleep Laboratory Director, Department of Medicine, Pulmonary and Sleep Medicine Section, VA Pittsburgh Healthcare System, Pittsburgh, Pennsylvania Medical Therapy for Obstructive Sleep Apnea
Fiona C. Baker, PhD Honorary Senior Research Fellow, Brain Function Research Group, School of Physiology, University of the Witwatersrand, Johannesburg, South Africa; Sleep Physiologist, Center for Health Sciences, SRI International, Menlo Park, California Sex Differences and Menstrual-Related Changes in Sleep and Circadian Rhythms
Thomas J. Balkin, PhD Director, Behavioral Biology Branch Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland Performance Deficits during Sleep Loss: Effects of Time Awake, Time of Day, and Time on Task
Bilgay Izci Balserak, BA, MA, PhD Division of Sleep Medicine and Center for Sleep and Respiratory Neurobiology, Department of Medicine, School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania Sleep Disturbances and Sleep-Related Disorders in Pregnancy
Siobhan Banks, PhD Research Fellow, Centre for Sleep Research, University of South Australia, Adelaide, Australia Chronic Sleep Deprivation
Steven R. Barczi, MD, FAASM Associate Professor of Medicine, Department of Medicine, Division of Geriatrics and Gerontology, University of Wisconsin School of Medicine and Public Health; Associate Director, Education and Evaluation, Madison VA Geriatric Research, Education & Clinical Center, Wm. S. Middleton Veterans Memorial Hospital, Director of Education, University of Wisconsin Center for Sleep Medicine and Sleep Research, Madison, Wisconsin Medical and Psychiatric Disorders and the Medications Used to Treat Them
ix
x Contributors
Joseph T. Bass, MD, PhD Associate Professor, Department of Medicine and Neurology, Northwest University, Evanston, Illinois
Animal Models for Disorders of Chronobiology: Cell and Tissue
Claudio L. Bassetti, MD Director, Neurocenter of Southern Switzerland, Lugano; Chairman, Neurology Department, Professor of Neurology, University Hospital, Zürich, Switzerland Idiopathic Hypersomnia Sleep and Stroke
Gregory Belenky, MD Research Professor and Director, Sleep and Performance Research Center, Washington State University, Spokane, Washington Introduction Fatigue Risk Management Sleep and Performance Monitoring in the Workplace: The Basis for Fatigue Risk Management
Ruth M. Benca, MD, PhD Professor, Department of Psychiatry, University of Wisconsin-Madison School of Medicine, Madison, Wisconsin Mood Disorders
Kathleen L. Benson, PhD Brain Imaging Center, McLean Hospital, Belmont, Massachusetts; Associate Clinical Professor (retired), Department of Psychiatry and Behavioral Sciences, Stanford University School of Medicine, Stanford, California; Director, Sleep Disorders Program (retired), Psychiatry Service, VA Palo Alto Health Care System, Palo Alto, California Schizophrenia
Donald L. Bliwise, PhD Professor of Neurology, Psychiatry, Behavioral Sciences and Nursing; Director, Program in Sleep, Aging and Chronobiology, Emory University School of Medicine, Atlanta, Georgia Normal Aging Sleep in Independently Living and Institutionalized Elderly
Bradley F. Boeve, MD Professor of Neurology, Mayo College of Medicine, Department of Neurology, Mayo Clinic, Rochester, Minnesota Alzheimer’s Disease and Other Dementias
Michael H. Bonnet, PhD Professor, Department of Neurology, Wright State University, Director of Sleep Laboratory; Neurology, Dayton Department of Veterans Affairs Medical Center, Dayton, Ohio Acute Sleep Deprivation Shift Work, Shift Work Disorder, and Jet Lag
Alexander A. Borbély, MD Professor Emeritus of Pharmacology, Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland Sleep Homeostasis and Models of Sleep Regulation
Michel A. Cramer Bornemann, MD, D-ABSM, FAASM Director, Minnesota Regional Sleep Disorders Center; Lead Investigator, Sleep Forensics Associates, Hennepin County Medical Center; Assistant Professor, Department of Neurology, Department of Medicine, University of Minnesota School of Medicine; Faculty Instructor, Department of Biomedical Engineering, Bakken/MIND Laboratory, University of Minnesota Graduate School, Minneapolis, Minnesota Sleep Forensics Non-REM Arousal Parasomnias
Peter Buchanan, MB, ChB, MD, FRACP Senior Clinical Research Fellow, Sleep & Circadian Group, Woolcock Institute of Medical Research; Senior Staff Specialist, Department of Respiratory Medicine, Liverpool Hospital; Consultant Sleep Medicine Physician, St. Vincent’s Clinic, Sydney, Australia
Positive Airway Pressure Treatment for Obstructive Sleep Apnea-Hypopnea Syndrome
Orfeu M. Buxton, PhD Instructor in Medicine, Division of Sleep Medicine, Harvard Medical School; Associate Neuroscientist, Department of Medicine, Brigham and Women’s Hospital, Boston Massachusetts
The Human Circadian Timing System and Sleep−Wake Regulation
Daniel J. Buysse, MD Professor, Psychiatry, Clinical, and Translational Science, University of Pittsburgh School of Medicine; Director, Neuroscience Clinical and Translational Research Center, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Clinical Pharmacology of Other Drugs Used as Hypnotics Insomnia: Recent Developments and Future Directions Treatment Guidelines for Insomnia
Georgina Cano, PhD Research Assistant Professor, Neuroscience, University of Pittsburgh, Pittsburgh, Pennsylvania Models of Insomnia
Michelle T. Cao, DO Clinical Instructor, Division of Sleep Medicine, Stanford University School of Medicine, Palo Alto, California. Narcolepsy: Diagnosis and Management Sleep Neuromuscular Diseases Clinical Features and Evaluation of Obstructive Sleep Apnea and Upper Airway Resistance Syndrome
Colleen E. Carney, PhD Assistant Professor, Department of Psychology, Ryerson University, Toronto, Ontario, Canada Psychological and Behavioral Treatments for Insomnia II: Implementation and Specific Populations
Contributors xi
Mary A. Carskadon, PhD Professor, Psychiatry and Human Behavior, Alpert Medical School of Brown University; Director of Chronobiology and Sleep Research, Child and Adolescent Psychiatry, E.P. Bradley Hospital, Providence, Rhode Island Normal Human Sleep: An Overview Daytime Sleepiness and Alertness
Rosalind Cartwright, PhD, FAASM Professor Emeritus, Neuroscience Program, Graduate College, Rush University Medical Center, Chicago, Illinois Dreaming as a Mood-Regulation System
Chien Lin Chen, MD Lecturer, Department of Medicine, Tzu Chi University, School of Medicine; Director, Gastrointestinal Motility, Laboratory; Attending Physician, Division of Gastroenterology and Hepatology, Tzu Chi General Hospital, Hualien, Taiwan Gastrointestinal Monitoring Techniques
Ronald D. Chervin, MD, MS Professor of Neurology, Michael S. Aldrich Collegiate Professor of Sleep Medicine, Department of Neurology and Sleep Disorders Center, University of Michigan Medical School; Director, Sleep Disorders Center; Co-Director, Center for Sleep Science, University of Michigan Health System, Ann Arbor, Michigan Use of Clinical Tools and Tests in Sleep Medicine
Peter A. Cistulli, MBBS, PhD, MBA, FRACP, FCCP Professor, Respiratory Medicine, Head of Discipline of Sleep Medicine, Sydney Medical School, University of Sydney; Director, Centre for Sleep Health & Research, Department of Respiratory Medicine, Royal North Shore Hospital; Research Leader, Sleep & Circadian Group, Woolcock Institute of Medical Research, Sydney, Australia Oral Appliances for Sleep-Disordered Breathing
Anita P. Courcoulas, MD, MPH, FACS Chief, Minimally Invasive Bariatric and General Surgery; Associate Professor of Surgery, University of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania Obstructive Sleep Apnea, Obesity, and Bariatric Surgery
Yves Dauvilliers, MD, PhD Professor, Neurology, Guide Chauliac Hospital, Montpellier, France Idiopathic Hypersomnia
Alec J. Davidson, PhD Assistant Professor, Department of Neurobiology, Morehouse School of Medicine, Atlanta, Georgia
Animal Models for Disorders of Circadian Functions: Whole Organism
O’Neill F. D’Cruz, MD, MBA Medical Director, Neurology, UCB Pharma, Raleigh, North Carolina Cardinal Manifestations of Sleep Disorders
Tom de Boer, PhD Assistant Professor, Molecular Cell Biology, Leiden University Medical Center, Leiden, The Netherlands Body Temperature, Sleep, and Hibernation
William C. Dement, MD, PhD Lowell W. and Josephine Q. Berry Professor of Psychiatry and Behavioral Sciences; Director, Sleep Disorders and Research Center, Stanford University School of Medicine, Palo Alto, California History of Sleep Physiology and Medicine Normal Human Sleep: An Overview Daytime Sleepiness and Alertness Sleep Medicine, Public Policy, and Public Health
Ronald Denis, MD Faculty of Dental Medicine, Université de Montréal, Montréal, Québec, Canada Pain and Sleep
Derk-Jan Dijk, PhD Professor of Sleep and Physiology, Surrey Sleep Research Centre, University of Surrey, Guildford, United Kingdom Genetic Basis of Sleep in Healthy Humans
David F. Dinges, PhD Professor and Chief, Division of Sleep and Chronobiology, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Chronic Sleep Deprivation Circadian Rhythms in Sleepiness, Alertness, and Performance Sleep Medicine, Public Policy, and Public Health
Antonio Culebras, MD, FAAN, FAHA Professor, Neurology, SUNY Upstate Medical University; Consultant, The Sleep Center, Community General Hospital, Syracuse, New York.
G. William Domhoff, PhD Research Professor of Psychology, Department of Psychology, University of California, Santa Cruz, Santa Cruz, California
Charles A. Czeisler, PhD, MD, FRCP Baldino Professor of Sleep Medicine and Director, Division of Sleep Medicine, Harvard Medical School; Chief, Division of Sleep Medicine, Senior Physician, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts
Neil J. Douglas, Kt, MD, DSc, FRCP, FRCPE Professor of Respiratory and Sleep Medicine, Respiratory Medicine, University of Edinburgh; Consultant Physician, Sleep Department, Royal Infirmary of Edinburgh, United Kingdom
Other Neurological Disorders
The Human Circadian Timing System and Sleep−Wake Regulation
Dream Content: Quantitative Findings
Respiratory Physiology: Understanding the Control of Ventilation Sleep in Patients with Asthma and Chronic Obstructive Pulmonary Disease
xii Contributors
Christopher L. Drake, PhD Bioscientific Staff Investigator, Sleep Disorders and Research Center, Henry Ford Hospital; Associate Professor, Department of Psychiatry and Behavioral Neuroscience, Wayne State University, Detroit, Michigan Shift Work, Shift-Work Disorder, and Jet Lag
Jack D. Edinger, PhD Clinical Professor, Department of Psychiatry and Behavioral Sciences, Duke University School of Medicine; Senior Psychologist, Durham VA Medical Center, Durham, North Carolina Psychological and Behavioral Treatments for Insomnia II: Implementation and Specific Populations
Mark W. Elliott, MD, FRCP Senior Lecturer, Clinical Medicine, University of Leeds, Department of Respiratory Medicine, St. James’s University Hospital, Leeds, West Yorkshire, England Noninvasive Ventilation to Treat Chronic Ventilatory Failure
Colin A. Espie, MappSci, PhD FBPsS, CPsychol Director, University of Glasgow Sleep Centre; Head, Section of Psychological Medicine, Section of Psychological Medicine, Faculty of Medicine, University of Glasgow; Professor, Clinical Psychology, University of Glasgow Sleep Centre, Sackler Institute of Psychobiological Research, Southern General Hospital, Glasgow, Scotland, United Kingdom Models of Insomnia
Juliette H. Faraco, PhD Senior Research Scientist, Stanford Center for Narcolepsy Research, Stanford University, Palo Alto, California Genetics of Sleep and Sleep Disorders in Humans
Irwin Feinberg, MD Psychiatry and Behavioral Sciences, University of California, Davis, Davis, California Schizophrenia
Kathleen A. Ferguson, BSc, MD, FRCPC Associate Professor of Medicine, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, Canada Oral Appliances for Sleep-Disordered Breathing
Luigi Ferini-Strambi, MD Associate Professor, General Psychology, Universita Vita-Salve San Raffaele; Director, Sleep Disorders Center, Department of Neuroscience, Milan, Italy Restless Legs Syndrome and Periodic Limb Movements during Sleep
Paul Franken, PhD Maître d’Enseignement et de Recherche, Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland Genetic Basis of Sleep in Rodents
Karl A. Franklin, MD Associate professor, Surgery and Respiratory Medicine, Umeå University, Umeå, Sweden Coronary Artery Disease and Obstructive Sleep Apnea
Philippa Gander, PhD Professor and Centre Director, Sleep/Wake Research Centre, Massey University, Wellington, New Zealand Fatigue Risk Management
Charles F.P. George, MD, FRCPC Professor of Medicine, University of Western Ontario; Director, Sleep Medicine Clinic and Laboratory, London Health Sciences Centre, London, Ontario, Canada Sleep and Stroke Cognition and Performance in Patients with Obstructive Sleep Apnea
Rachel Givelber, MD Assistant Professor of Medicine, Division of Pulmonary, Allergy, and Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania Medical Therapy for Obstructive Sleep Apnea
Shelagh K. Gleeson, MD Staff Physician, Pulmonary, Critical Care & Sleep Disorders, Sentara Pulmonary and Critical Care Specialists, Norfolk, Virginia
Wake-Promoting Medications: Efficacy and Adverse Effects
Paul B. Glovinsky, PhD Clinical Director, St. Peter’s Sleep Center, St. Peter’s Hospital, Albany, New York Assessment Techniques for Insomnia
Namni Goel, PhD Research Assistant Professor, Division of Sleep and Chronobiology, Department of Psychiatry, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania Circadian Rhythms in Sleepiness, Alertness, and Performance
Joshua J. Gooley, PhD Assistant Professor, Neuroscience and Behavioral Disorders, Duke-NUS Graduate Medical School, Singapore; Instructor of Medicine, Harvard Medical School, Boston, Massachusetts Anatomy of the Mammalian Circadian System
R. Curtis Graeber, PhD President, The Graeber Group, Ltd., Kirkland, Washington Fatigue Risk Management
Contributors xiii
Ronald Grunstein, MB, BS, MD, PhD, FRACP Professor of Sleep Medicine, Woolcock Institute of Medical Research, The University of Sydney Medical School; Head and Senior Staff Specialist, Centre for Respiratory Failure and Sleep Disorders, Department of Respiratory and Sleep Medicine, Royal Prince Alfred Hospital, Camperdown, Australia; Chief Investigator, NHMRC, Centre for Integrated Research and Understanding of Sleep (CIRUS), The University of Sydney, Glebe, Sydney, Australia Positive Airway Pressure Treatment for Obstructive Sleep Apnea-Hypopnea Syndrome Endocrine Disorders
Béatrice Guardiola-Lemaître, PhD Scientific Director, R & D, Scientific Direction, ADIR, Servier International Research Institute, Courbevoie, France
Melatonin and the Regulation of Sleep and Circadian Rhythms
Christian Guilleminault, MD, DM, DBiol Professor, Division of Sleep Medicine, Stanford University School of Medicine, Palo Alto, California
Narcolepsy: Diagnosis and Management Sleep and Neuromuscular Diseases Clinical Features and Evaluation of Obstructive Sleep Apnea and Upper Airway Resistance Syndrome
Ronald M. Harper, PhD Department of Neurobiology and the Brain Research Institute, David Geffen School of Medicine University of California, Los Angeles, Los Angeles, California Cardiovascular Physiology: Central and Autonomic Regulation
Allison G. Harvey, PhD Professor of Clinical Psychology, Department of Psychology; Director, Golden Bear Sleep and Mood Clinic, University of California, Berkeley, Berkeley, California Insomnia: Diagnosis, Assessment, and Outcomes
Jan Hedner, MD, PhD Professor, Sleep Medicine, Department of Internal Medicine, Gothenburg University, Gothenburg, Sweden
Coronary Artery Disease and Obstructive Sleep Apnea
Raphael C. Heinzer, MD, MPH Senior Lecturer and Researcher, Pulmonary Department; Co-Director, Center for Investigation and Research in Sleep, Lausanne University Hospital, Lausanne, Switzerland Normal Physiology of the Upper and Lower Airways
John H. Herman, PhD Professor, Departments of Psychiatry and Pediatrics, University of Texas Southwestern Medical Center at Dallas; Director, Sleep Disorders Center for Children, Children’s Medical Center, Dallas, Texas; Associate Professor, Departments of Psychiatry and Medicine, Baylor College of Medicine; Director, Sleep Disorders and Research Center, Michael E. DeBakey VA Medical Center; Clinical Director, Methodist Hospital Diagnostic Sleep Laboratory, VA Medical Center Sleep Center, Houston, Texas Chronobiologic Monitoring Techniques
Victor Hoffstein, PhD, MD, FRCP(C), FCCP Professor of Medicine, Department of Medicine, University of Toronto; Staff Respirologist, Department of Medicine, St. Michael’s Hospital, Toronto, Canada Snoring
Max Hirshkowitz, PhD Tenured Associate Professor, Medicine, Baylor College of Medicine, Houston, Texas; Sleep Center Director, Sleep Disorders and Research Center, Michael E. DeBakey VA Medical Center, Houston, Texas Monitoring and Staging Human Sleep Monitoring Techniques for Evaluating Suspected Sleep-Disordered Breathing Evaluating Sleepiness
Richard L. Horner, PhD Canada Research Chair in Sleep and Respiratory Neurobiology, Associate Professor, Departments of Medicine and Physiology, University of Toronto, Toronto, Canada Respiratory Physiology: Central Neural Control of Respiratory Neurons and Motoneurons during Sleep
Christer Hublin, MD, PhD Adjunct Professor, Neurology, Helsinki University; Assistant Chief Medical Officer, Brain@Work Research Center, Finnish Institute of Occupational Health, Helsinki, Finland Epidemiology of Sleep Disorders
Steven R. Hursh, PhD Adjunct Professor, Department of Psychiatry and Behavioral Sciences, Johns Hopkins University School of Medicine; President, Institutes for Behavior Resources, Inc., Baltimore, Maryland Fatigue and Performance Modeling Fatigue, Performance, Errors, and Accidents
Nelly T. Huynh, PhD Faculty of Dentistry, Université de Montréal, Centre d’Etude du Sommeil, Hôpital du Sacré-Coeur, Montréal, Québec, Canada Sleep Bruxism
xiv Contributors
Shahrokh Javaheri, MD Professor Emeritus of Medicine, University of Cincinnati College of Medicine; Medical Director of Sleepcare Diagnostics, Cincinnati, Ohio Sleep and Cardiovascular Disease: Present and Future Cardiovascular Effects of Sleep-Related Breathing Disorders Systemic and Pulmonary Hypertension in Obstructive Sleep Apnea Heart Failure
Mark E. Josephson, MD Herman Dana Professor of Medicine, Department of Medicine, Harvard Medical School; Chief, Division of Cardiovascular Medicine; Director, HarvardThorndike Electrophysiology Institute and Arrhythmia Service, Beth Israel Deaconess Medical Center, Boston, Massachusetts Jonathan Jun, MD Post-Doctoral Fellow, Medicine, Pulmonary and Critical Care, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Baltimore, Maryland Obstructive Sleep Apnea and Metabolic Dysfunction
Göran Kecklund, PhD National Institute for Psychosocial Medicine, Department of Public Health Sciences, Karolinska Institute, Stockholm, Sweden Sleep, Stress, and Burnout
Sharon Keenan, PhD, REEGT, RPSGT, D-ABSM Director, The School of Sleep Medicine, Inc., Palo Alto, California Monitoring and Staging Human Sleep
Kurt Kräuchi Head, Thermophysiological Chronobiology, Centre for Chronobiology, Psychiatric Hospital of the University of Basel, Basel, Switzerland Body Temperature, Sleep, and Hibernation
James M. Krueger, PhD, MDHC Regents Professor, Sleep and Performance Research Center, Washington State University, Pullman, Washington Sleep and Host Defense
Meir H. Kryger, MD, FRCPC Clinical Professor of Medicine, University of Connecticut; Director of Research and Education, Gaylord Hospital, Sleep Medicine, Wallingford, Connecticut
Management of Obstructive Sleep Apnea-Hypopnea Syndrome Restrictive Lung Disorders Monitoring Techniques for Evaluating Suspected Sleep-Disordered Breathing
Andrew D. Krystal, MD, MS Professor, Psychiatry and Behavioral Sciences, Duke University School of Medicine, Durham, North Carolina Pharmacologic Treatment: Other Medications
Samuel T. Kuna, MD Associate Professor of Medicine, Pulmonary, Allergy and Critical Care, Department of Medicine, University of Pennsylvania; Chief, Pulmonary, Critical Care and Sleep Section, Philadelphia VA Medical Center Sleep Center, Philadelphia, Pennsylvania Anatomy and Physiology of Upper Airway Obstruction
Clete A. Kushida, MD, PhD, RPSGT Professor, Division of Sleep Medicine; Acting Medical Director, Stanford Sleep Medicine Center; Director, Stanford Center for Human Sleep Research, Palo Alto, California Clinical Features and Evaluation of Obstructive Sleep Apnea and Upper Airway Resistance Syndrome
Hans-Peter Landolt, PhD Professor, Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland Genetic Basis of Sleep in Healthy Humans
Paola A. Lanfranchi, MD Assistant Professor, Medicine, Université de Montréal; Cardiologist, Department of Medicine, Division of Cardiology, Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada Cardiovascular Physiology: Autonomic Control in Health and in Sleep Disorders
Gilles Lavigne, DMD, FRCD, PhD, HC Dean, Faculty of Dental Medicine, Université de Montreal; Scientist Clinician, Surgery, Trauma and Sleep, Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada Relevance of Sleep Physiology for Sleep Medicine Clinicians Sleep Bruxism Pain and Sleep
Kathryn Lee, RN, PhD, FAAN, CBSM Professor and Associate Dean for Research; James & Marjorie Livingston Endowed Chair; Director, T32 Nurse Research Training in Symptom Management, School of Nursing, University of California, San Francisco Department of Family Health Care Nursing, San Francisco, California Sleep Disturbances and Sleep-Related Disorders in Pregnancy Menopause
Patrick Leger, MD, FCCP Laboratoire du Sommeil, Service de Pneumologie, Pierre Bénite, Lyon, France Noninvasive Ventilation to Treat Chronic Ventilatory Failure
Christopher Li, MD, FRCP (C), DABSM Assistant Professor, Department of Medicine, University of Toronto; Staff Respirologist, Medicine, St. Michael’s Hospital, Toronto, Ontario, Canada Snoring
Contributors xv
Kenneth L. Lichstein, PhD Professor, Department of Psychology, The University of Alabama, Tuscaloosa, Alabama Insomnia: Epidemiology and Risk Factors
Alan A. Lowe, DMD, PhD, FRCD(C) Professor and Chair, Division of Orthodontics, Faculty of Dentistry, The University of British Columbia, Vancouver, British Columbia, Canada Oral Appliances for Sleep-Disordered Breathing
James G. MacFarlane, PhD Assistant Professor of Pediatrics and Psychiatry, University of Toronto; Research Associate (Neurology), The Hospital for Sick Children; Director of Education, MedSleep (Network of Clinics), Toronto, Ontario, Canada Fibromyalgia and Chronic Fatigue Syndromes
Mark W. Mahowald, MD Professor, Neurology, University of Minnesota Medical School; Co-Director, Minnesota Regional Sleep Disorders Center, Hennepin County Medical Center, Minneapolis, Minnesota Sleep Forensics Epilepsy, Sleep, and Sleep Disorders Non-REM Arousal Parasomnias REM Sleep Parasomnias Other Parasomnias
Jeannine A. Majde, PhD Adjunct Professor, College of Veterinary Medicine, Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology, Washington State University, Pullman, Washington Sleep and Host Defense
Beth A. Malow, MD, MS Professor and Director, Sleep Disorders Division, Neurology; Director, Vanderbilt Sleep Disorders Center, Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee Approach to the Patient with Disordered Sleep Neurologic Monitoring Techniques Physical Examination in Sleep Medicine
Juan F. Masa, MD Head of Respiratory Research in Centro de Investigación Biomédica en Red de Enfermedades Respiratorias; (CIBERES); Head of Pulmonary Division, Pulmonary Unit, San Pedro de Alcántara Hospital, Cáceres, Spain Restrictive Lung Disorders
Christina S. McCrae, PhD Associate Professor, Department of Clinical and Health Psychology, University of Florida, Gainesville, Florida Insomnia: Epidemiology and Risk Factors
Jennifer McDonald, PhD Postdoctoral Fellow, Center for Behavioral Health Research and Services, University of Alaska Anchorage, Anchorage, Alaska
Sleep and Performance Monitoring in the Workplace: The Basis for Fatigue Risk Management
Dennis McGinty, PhD Adjunct Professor, University of California Los Angeles; Chief, Neurophysiology Research, VA Greater Los Angeles Healthcare System, Los Angeles, California Neural Control of Sleep in Mammals
Melanie K. Means, PhD Staff Psychologist, Veterans Affairs Medical Center; Assistant Professor, Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, Durham, North Carolina Psychological and Behavioral Treatments for Insomnia II: Implementation and Specific Populations
Thomas A. Mellman, MD Professor, Psychiatry, Howard University, Washington, DC Dreams and Nightmares in Posttraumatic Stress Disorder Anxiety Disorders
Wallace Mendelson, MD Professor of Psychiatry and Clinical Pharmacology, University of Chicago, Chicago, Illinois
Hypnotic Medications: Mechanisms of Action and Pharmacologic Effects
Rachel Manber, PhD Professor, Psychiatry and Behavioral Science, Stanford Sleep Medicine Center, Stanford School of Medicine, Stanford University, Palo Alto, California
Emmanuel Mignot, MD, PhD Director, Center for Sleep Sciences and Medicine, Stanford University, Palo Alto, California
Christiane Manzini Research Assistant, University of Montreal Faculty of Medicine and Dentistry; Center for the Study of Sleep and Biological Rhythms, Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada
Ralph E. Mistlberger, PhD Professor, Psychology, Simon Fraser University, Burnaby, British Columbia, Canada
Psychological and Behavioral Treatments for Insomnia II: Implementation and Specific Populations
Sleep Bruxism
Pierre Maquet, MD, PhD Research Director FNRS, Cyclotron Research Centre, University of Liège, Liège, Belgium
What Brain Imaging Reveals about Sleep Generation and Maintenance
Genetics of Sleep and Sleep Disorders in Humans Wake-Promoting Medications: Basic Mechanisms and Pharmacology Narcolepsy: Pathophysiology and Genetic Predisposition
Circadian Rhythms in Mammals: Formal Properties and Environmental Influences
xvi Contributors
Murray A. Mittleman, MD, DrPH Associate Professor of Medicine and Epidemiology, Harvard Schools of Medicine and Public Health; Director, Cardiovascular Epidemiology Research Unit, Medicine, Cardiology, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Seiji Nishino, MD Professor, Psychiatry and Behavioral Sciences, Stanford University School of Medicine; Director, Sleep and Circadian Neurobiology Laboratory, Stanford University School of Medicine, Palo Alto, California
Karen E. Moe, PhD Research Associate Professor and Assistant Vice Provost for Research, Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington
Eric A. Nofzinger, MD Director, Sleep Neuroimaging Research Program, Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Sleep-Related Cardiac Risk
Menopause
Harvey Moldofsky, MD, Dip Psych, FRCPC Professor Emeritus, Department of Psychiatry; Member Emeritus, Institute of Medical Science, School of Graduate Studies, University of Toronto; Honorary Staff, Department of Psychiatry, Toronto Western Hospital, University Health Network; President and Medical Director, Sleep Disorders Clinics, Centre for Sleep and Chronobiology, Toronto, Ontario, Canada Fibromyalgia
Jacques Montplaisir, MD, PhD, CRCP Professor, Psychiatry and Neuroscience, Université de Montréal; Director, Center for Advanced Studies in Sleep Medicine, Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada Restless Legs Syndrome and Periodic Limb Movements during Sleep Alzheimer’s Disease and Other Dementias
Charles M. Morin, PhD Professor, Psychology, Université Laval; Director, Sleep Research Center, Centre de Recherche Université Laval Robert-Giffard, Québec, Québec, Canada Psychological and Behavioral Treatments for Insomnia I: Approaches and Efficacy
Tore Nielsen, PhD Professor, Psychiatry, Université de Montréal; Director, Dream & Nightmare Laboratory, Sleep Research Center, Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada Introduction: The Changing Historical Context of Dream Research Ultradian, Circadian, and Sleep-Dependent Features of Dreaming Dream Analysis and Classification: The Reality Simulation Perspective Idiopathic Nightmares and Dream Disturbances Associated with Sleep−Wake Transitions Disturbed Dreaming as a Factor in Medical Conditions
F. Javier Nieto, MPH, MD, PhD Helfaer Professor of Public Health; Professor and Chair of Population Health Sciences, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin
Systemic and Pulmonary Hypertension in Obstructive Sleep Apnea
Wake-Promoting Medications: Basic Mechanisms and Pharmacology
What Brain Imaging Reveals about Sleep Generation and Maintenance
Louise M. O’Brien, PhD Assistant Professor, Sleep Disorders Center, Department of Neurology; Assistant Research Scientist, Department of Oral and Maxillofacial Surgery, University of Michigan, Ann Arbor, Michigan Sex Differences and Menstrual-Related Changes in Sleep and Circadian Rhythms
Bruce F. O’Hara, PhD Associate Professor, Biology, University of Kentucky, Lexington, Kentucky Genetic Basis of Sleep in Rodents
Eric J. Olson, MD Associate Professor, Medicine, College of Medicine; Co-Director, Center for Sleep Medicine, Division of Pulmonary and Critical Care Medicine, Mayo Clinic, Rochester, Minnesota Obstructive Sleep Apnea, Obesity, and Bariatric Surgery
Mary B. O’Malley, MD, PhD Private Practice Great Barrington, Massachusetts
Wake-Promoting Medications: Efficacy and Adverse Effects
William C. Orr, PhD President and CEO, Lynn Health Science Institute; Clinical Professor of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma Gastrointestinal Physiology in Relation to Sleep Gastrointestinal Disorders Gastrointestinal Monitoring Techniques
Edward F. Pace-Schott, PhD Postdoctoral Fellow, Psychology, University of Massachusetts, Amherst, Massachusetts; Associate Researcher, Psychiatry, Massachusetts General Hospital; Faculty, Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts The Neurobiology of Dreaming
Markku Partinen, MD, PhD Adjunct Professor, Department of Clinical Neurosciences, University of Helsinki; Director, Helsinki Sleep Clinic, Vitalmed Research Center, Helsinki, Finland Epidemiology of Sleep Disorders
Contributors xvii
Dipali Patel, BSc (Hons)
Sleep and Performance Monitoring in the Workplace: The Basis for Fatigue Risk Management
John H. Peever, PhD Associate Professor, Cell and Systems Biology, University of Toronto, Toronto, Ontario, Canada Sensory and Motor Processing during Sleep and Wakefulness
Philippe Peigneux, PhD Professor, Chair Clinical Neuropsychology, Neuropsychology and Functional Neuroimaging Research Unit, Université Libre de Bruxelles, Bruxelles, Belgium; Scientific Collaborator, Cyclotron Research Centre, Université de Liège, Liège, Belgium Memory Processing in Relation to Sleep
Yüksel Peker, MD, PhD Associate Professor, Pulmonary Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; Medical Doctor, Neurology, Rehabilitation and Sleep Medicine, Skaraborg County Hospital, Skövde, Sweden Coronary Artery Disease and Obstructive Sleep Apnea
Michael Perlis, PhD Associate Professor, Psychiatry; Director, Behavioral Sleep Medicine Program, University of Pennsylvania, Philadelphia, Pennsylvania Models of Insomnia
Aleksander Perski, PhD Assistant Professor, Stress Research Institute, Stockholm University, Stockholm, Sweden Sleep, Stress, and Burnout
Michael J. Peterson, MD, PhD Assistant Professor, Psychiatry, University of Wisconsin, School of Medicine and Public Health; Director of Consultation and Liaison Psychiatry, University of Wisconsin Hospital and Clinics, Madison, Wisconsin Mood Disorders
Dominique Petit, PhD Research Assistant, Psychiatry, Université de Montréal; Senior Research Assistant, Center for Advanced Studies in Sleep Medicine, Hôpital du Sacré-Coeur de Montréal, Montreal, Quebec, Canada Alzheimer’s Disease and Other Dementias
Pierre Philip, MD, PhD Université Bordeaux 2, GENPPHASS, Clinique du Sommeil, Centre Hospitalier Universitaire Pellegrin, Bordeaux, France Drowsy Driving
Barbara A. Phillips, MD, MSPH, FCCP Professor, Division of Pulmonary, Critical Care and Sleep Medicine; Internal Medicine, University of Kentucky College of Medicine; Medical Director, University of Kentucky Good Samaritan Sleep Center, Lexington, Kentucky Management of Obstructive Sleep Apnea-Hypopnea Syndrome Obstructive Sleep Apnea in the Elderly
Wilfred R. Pigeon, PhD, CBSM Assistant Professor; Director, Sleep and Neurophysiology Research Laboratory, Psychiatry, University of Rochester Medical Center, Rochester, New York Dreams and Nightmares in Posttraumatic Stress Disorder
Vsevolod Y. Polotsky, MD, PhD Associate Professor, Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland Obstructive Sleep Apnea and Metabolic Dysfunction
Nelson B. Powell, MD, DDS, FACS Department of Otolaryngology Head and Neck Surgery and Department of Psychiatry and Behavioral Science, Stanford University School of Medicine, Palo Alto, California Surgical Management for Obstructive SleepDisordered Breathing
Naresh M. Punjabi, MD, PhD Associate Professor of Medicine and Epidemiology, Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins University, Baltimore, Maryland Obstructive Sleep Apnea and Metabolic Dysfunction
Maria Antonia Quera-Salva, MD Director of Sleep Unit, Hôpital Raymond Poincaré APHP, Paris Ouest University, Paris, France
Melatonin and the Regulation of Sleep and Circadian Rhythms
Holly Ramsawh, PhD Assistant Project Scientist, Psychiatry, University of California, San Diego, La Jolla, California Anxiety Disorders
Kathryn Moynihan Ramsey, PhD Post Doctoral Fellow, Departments of Neurobiology & Physiology and Medicine, Northwestern University, Evanston, Illinois Animal Models for Disorders of Chronobiology: Cell and Tissue
Susan Redline, MD, MPH Professor, Medicine and Center of Clinical Investigation, Case Western Reserve University, Cleveland, Ohio Genetics of Obstructive Sleep Apnea
Kathryn J. Reid, PhD Research Assistant Professor, Department of Neurology, Northwestern University Feinberg School of Medicine, Chicago, Illinois Circadian Disorders of the Sleep–Wake Cycle
xviii Contributors
John E. Remmers, MD Professor, Internal Medicine and of Physiology and Biophysics, University of Calgary Faculty of Medicine; Physician, Foothills Hospital, Calgary, Alberta, Canada Anatomy and Physiology of Upper Airway Obstruction
Robert W. Riley, DDS, MD, FACS Adjunct Clinical Professor, Surgery, Department of Otolaryngology Head and Neck Surgery; Adjunct Clinical Associate Professor, Sleep Disorders Medicine, Department of Psychiatry and Behavioral Science, Stanford University School of Medicine, Stanford University Sleep and Research Center, Palo Alto, California Surgical Management for Obstructive SleepDisordered Breathing
Dominique Robert, PUPH Professor, Claude Bernard University; Medical Doctor, Intensive Care, Hospices Civils de Lyon; President, Home Care Program, Association Lyonnaise de Logistique Post-hospitalière, Lyon, France
Noninvasive Ventilation to Treat Chronic Ventilatory Failure
Timothy Roehrs, PhD Professor, Department of Psychiatry and Behavioral Neuroscience, Wayne State University, School of Medicine; Director of Research, Sleep Disorders of Research Center, Henry Ford Hospital, Detroit, Michigan Daytime Sleepiness and Alertness Medication and Substance Abuse
Alan M. Rosenwasser, PhD Professor, Department of Psychology, University of Maine; Cooperating Professor, School of Biology and Ecology, University of Maine, Orono, Maine Physiology of the Mammalian Circadian System
Thomas Roth, PhD Professor, Department of Psychiatry, Wayne State University School of Medicine; Director and Division Head, Sleep Disorders and Research Center, Henry Ford Hospital, Detroit, Michigan; Clinical Professor, Department of Psychiatry, University of Michigan Medical School, Ann Arbor, Michigan Daytime Sleepiness and Alertness Pharmacologic Treatment of Insomnia: Benzodiazepine Receptor Agonists Medication and Substance Abuse
Megan E. Ruiter, MA Graduate Student, Department of Psychology, The University of Alabama, Tuscaloosa, Alabama Insomnia: Epidemiology and Risk Factors
Benjamin Rusak, PhD, FRSC Professor and Director of Research, Psychiatry, Dalhousie University; Director, Chronobiology and Sleep Program, Capital District Health Authority; Professor, Psychology, Pharmacology, Dalhousie University, Halifax, Nova Scotia, Canada
Circadian Rhythms in Mammals: Formal Properties and Environmental Influences
Patricia Sagaspe, PhD Genpphass, Centre Hospitalier Universitaire Pellegrin, Bordeaux, France; Laboratoire Exploitation, Perception, Simulateurs et Simulations; Institut National de Recherche sur les Transports et leur Sécurité; Laboratoire Central des Ponts et Chaussées, Paris, France Drowsy Driving
Charles Samuels, MD Medical Director, Centre for Sleep and Human Performance; Clinical Assistant Professor, Faculty of Medicine, University of Calgary, Calgary, Alberta, Canada
Sleep Problems in First Responders and the Military
Mark H. Sanders, MD, FCCP, D’ABSM Professor of Medicine (retired), Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Sleep in Chronic Kidney Disease
Clifford B. Saper, MD, PhD James Jackson Putnam Professor, Department of Neurology, Program in Neuroscience, and Division of Sleep Medicine, Harvard Medical School; Chairman, Department of Neurology, Beth Israel Deaconess Medical Center, Boston, Massachusetts Anatomy of the Mammalian Circadian System
Aliya Sarwar, MD Assistant Professor of Neurology, Baylor College of Medicine; Associate Director, Clinical Care, Parkinson’s Disease Research, Education and Clinical Center (PADRECC), Michael E. DeBakey VA Medical Center, Houston, Texas Evaluating Sleepiness
Michael J. Sateia, MD Professor of Psychiatry, Sleep Medicine, Dartmouth Medical School; Chief, Section of Sleep Medicine, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire Treatment Guidelines for Insomnia
Josée Savard, PhD Professor, School of Psychology, Université Laval; Researcher, Laval University Cancer Research Center, Québec, Québec, Canada Sleep and Fatigue in Cancer Patients
Carlos H. Schenck, MD Professor, Department of Psychiatry, University of Minnesota Medical School; Staff Psychiatrist, Minnesota Regional Sleep Disorders Center, Hennepin County Medical Center, Minneapolis, Minnesota REM Sleep Parasomnias
Michael Schredl, PhD Head of Research, Sleep Laboratory, Central Institute of Mental Health; Associate Professor, Department of Psychology, Fakultät für Sozialwissenschaften, University of Mannheim, Mannheim, Germany Dreams in Patients with Sleep Disorders
Contributors xix
Richard J. Schwab, MD Professor, Department of Medicine, Division of Sleep Medicine, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania Medical Center, Philadelphia, Pennsylvania
Carlyle Smith, PhD Lifetime Professor Emeritus, Psychology, Trent University, Peterborough, Ontario, Canada; Adjunct Professor, Centre for Neuroscience Studies, Queen’s University, Kingston, Ontario, Canada
Paula K. Schweitzer, PhD Director of Research, Sleep Medicine and Research Center, St. Luke’s Hospital, St. Louis, Missouri
Michael T. Smith, PhD Associate Professor, Psychiatry and Behavioral Sciences; Director, Behavioral Sleep Medicine Program, The Johns Hopkins Bayview Medical Center, Baltimore, Maryland
Anatomy and Physiology of Upper Airway Obstruction
Drugs That Disturb Sleep and Wakefulness
Frédéric Sériès, MD Professor, Department of Medicine, Laval University; Director, Sleep Laboratory, Pneumology, Institut de Cardiologie et de Pneumologie de Québec, Québec, Québec, Canada
Normal Physiology of the Upper and Lower Airways
Barry J. Sessle, MDS, PhD, DSc(hc), FRSC Professor, Canada Research Chair, Faculty of Dentistry, University of Toronto; Consultant, Wasser Pain Management Centre, Mount Sinai Hospital, Toronto, Ontario, Canada; Adjunct Professor of Dentistry, School of Medicine and Dentistry, University of Rochester, Rochester, New York Sensory and Motor Processing during Sleep and Wakefulness
Amir Sharafkhaneh, MD, PhD, DABSM Associate Professor of Medicine, Baylor College of Medicine, Baylor University; Medical Director, Sleep Disorders and Research Center, Michael E. DeBakey VA Medical Center, Houston, Texas Evaluating Sleepiness
Paul J. Shaw, PhD Assistant Professor, Anatomy and Neurobiology, Washington University in St. Louis School of Medicine, St. Louis, Missouri Models of Insomnia
Tamar Shochat, DSc Associate Professor, Nursing, University of Haifa, Haifa, Israel Insomnia in Older Adults
Margaret Shouse, PhD Professor, Neurobiology, School of Medicine, University of California, Los Angeles, Los Angeles, California Epilepsy, Sleep, and Sleep Disorders
Jerome M. Siegel, PhD Professor, Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, California; Chief, Neurobiology Research, VA Greater Los Angeles Healthcare System-Sepulveda, Center for Sleep Research, North Hills, California REM Sleep Sleep in Animals: A State of Adaptive Inactivity
Memory Processing in Relation to Sleep
Pain and Sleep
Virend K. Somers, MD, PhD Professor of Medicine, Cardiovascular Division, Department of Internal Medicine; Consultant, Division of Cardiology Department of Medicine, Mayo Clinic and Mayo Foundation, Rochester, Minnesota
Cardiovascular Physiology: Autonomic Control in Health and in Sleep Disorders Cardiovascular Effects of Sleep-Related Breathing Disorders
Arthur J. Spielman, PhD Professor, Psychology, The City College of the City University of New York; Associate Director, Center for Sleep Medicine, Weill Cornell Medical College, Cornell University, New York, New York; Director of Research, Center for Sleep Disorders Medicine and Research, New York Methodist Hospital, Brooklyn, New York Assessment Techniques for Insomnia Insomnia: Diagnosis, Assessment, and Outcomes
Murray B. Stein, MD, MPH Professor, Psychiatry and Family and Preventive Medicine, University of California, San Diego, La Jolla, California; Staff Psychiatrist, Psychiatry, VA San Diego Healthcare System, San Diego, California Anxiety Disorders
Robert Stickgold, PhD Associate Professor, Psychiatry, Harvard Medical School; Associate Professor, Psychiatry, Beth Israel-Deaconess Medical Center, Boston, Massachusetts Why We Dream
Katie L. Stone, MA, PhD Senior Scientist, Research Institute, California Pacific Medical Center, San Francisco, California Actigraphy
Robyn Stremler, RN, PhD Assistant Professor, Lawrence S. Bloomberg Faculty of Nursing, University of Toronto; Adjunct Scientist, The Hospital for Sick Children, Toronto, Ontario, Canada The Postpartum Period
xx Contributors
Patrick J. Strollo, Jr., MD Associate Professor, Medicine and Clinical and Translational Research, Division of Pulmonary Allergy and Critical Care Medicine, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Medical Therapy for Obstructive Sleep Apnea
Ronald Szymusiak, PhD Adjunct Professor, Departments of Medicine and Neurobiology, David Geffen School of Medicine at UCLA; Research Scientist, VA Greater Los Angeles Healthcare System, Los Angeles, California Neural Control of Sleep in Mammals
J. Taillard, MD, PhD Université Bordeaux 2, GENPPHASS, Clinique du Sommeil, Centre Hospitalier Universitaire Pellegrin, Bordeaux, France Drowsy Driving
Esra Tasali, MD Assistant Professor, Medicine, Pulmonary & Critical Care Medicine, University of Chicago Medical Center, Chicago, Illinois Endocrine Physiology in Relation to Sleep and Sleep Disturbances
Daniel J. Taylor, PhD Associate Professor, Department of Psychology, University of North Texas, Denton, Texas Insomnia: Epidemiology and Risk Factors
Mihai Teodorescu, MD Clinical Assistant Professor of Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin Medical and Psychiatric Disorders and the Medications Used to Treat Them
Jiuan Su Terman, PhD Clinical Coordinator, Center for Light Treatment and Biological Rhythms, Columbia University Medical Center, New York, New York Light Therapy
Michael Terman, PhD Professor, Psychiatry, College of Physicians & Surgeons, Columbia University; Research Scientist VI, Clinical Chronobiology, New York State Psychiatric Institute; Director, Center for Light Treatment and Biological Rhythms, New York Presbyterian Hospital, Columbia University Medical Center; President, Center for Environmental Therapeutics, New York, New York Light Therapy
Michael J. Thorpy, MD Director, Sleep/Wake Disorders Center, Montefiore Medical Center, and Albert Einstein College of Medicine New York, New York Classification of Sleep Disorders
Irene Tobler, PhD Professor, Institute of Pharmacology and Toxicology, University of Zurich, Zurich, Switzerland Phylogeny of Sleep Regulation
Claudia Trenkwalder, MD Paracelsus Elena Hospital Kassel, Professor of Neurology, Department of Clinical Neurophysiology, University of Gottingen, Gottingen, Germany; Chair, Paracelsus-Elena Hospital, Center of Parkinsonism and Movement Disorders, Kassel, Germany Parkinsonism
Fred W. Turek, PhD Charles E. and Emma H. Mison Professor, Biology, Center for Sleep and Circadian Biology, Northwestern University, Evanston, Illinois Introduction, Section 3 Circadian Clock Genes Genetic Basis of Sleep in Rodents Introduction: Master Circadian Clock and Master Circadian Rhythm Gastrointestinal Physiology in Relation to Sleep Physiology of the Mammalian Circadian System Animal Models for Disorders of Circadian Functions: Whole Organism
Mark L. Unruh, MD, MSc Assistant Professor, Medicine, Renal-Electrolyte Division, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania Sleep in Chronic Kidney Disease
Eve Van Cauter, PhD Professor, Department of Medicine, Chicago, Illinois
Endocrine Physiology in Relation to Sleep and Sleep Disturbances
Hans P.A. Van Dongen, MS, PhD Research Professor and Assistant Director, Sleep and Performance Research Center, Washington State University, Spokane, Washington Circadian Rhythms in Sleepiness, Alertness, and Performance Fatigue and Performance Modeling Fatigue, Performance, Errors, and Accidents
Bradley V. Vaughn, MD Professor, Neurology and Biomedical Engineering, University of North Carolina School of Medicine, Chapel Hill, North Carolina Cardinal Manifestations of Sleep Disorders
Richard L. Verrier, PhD, FACC Associate Professor of Medicine, Harvard Medical School, Department of Medicine, Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Boston, Massachusetts
Cardiovascular Physiology: Central and Autonomic Regulation Sleep-Related Cardiac Risk Cardiac Arrhythmogenesis during Sleep: Mechanisms, Diagnosis, and Therapy
Contributors xxi
Bryan Vila, PhD Professor and Director, Simulated Hazardous Operational Tasks Laboratory, Sleep and Performance Research Center, Washington State University, Spokane, Washington Sleep Problems in First Responders and the Military
Martha Hotz Vitaterna, PhD Research Associate Professor, Center for Functional Genomics, Northwestern University Center for Functional Genomics, Evanston, Illinois Circadian Clock Genes
James K. Walsh, PhD Visiting Professor, Department of Psychiatry, Stanford University School of Medicine, Palo Alto, California; Executive Director and Senior Scientist, Sleep Medicine and Research Center, St. Luke’s Hospital; Adjunct Professor, Department of Psychology, Saint Louis University, St. Louis, Missouri Sleep Medicine, Public Policy, and Public Health Pharmacologic Treatment of Insomnia: Benzodiazepine Receptor Agonists
Arthur S. Walters, MD Professor and Associate Director, Sleep Medicine, Neurology, Vanderbilt University School of Medicine, Nashville, Tennessee Restless Legs Syndrome and Periodic Limb Movements during Sleep
Erin J. Wamsley, PhD Instructor, Psychiatry, Harvard Medical School; Instructor, Psychiatry, Beth Israel Deaconess Medical Center, Boston, Massachusetts Why We Dream
Terri E. Weaver, PhD, RN, FAAN Professor and Dean, University of Illinois at Chicago College of Nursing, Chicago, Illinois Cognition and Performance in Patients with Obstructive Sleep Apnea
John V. Weil, MD Emeritus Professor, Medicine, University of Colorado School of Medicine, Denver, Colorado Respiratory Physiology: Sleep at High Altitudes
Ian D. Weir, DO Associate Director, the Sleep Disorders Center; Director of the Insomnia Center, Norwalk Hospital, Norwalk, Connecticut Wake-Promoting Medications: Efficacy and Adverse Effects
Andrew Wellman, MD Instructor, Medicine, Division of Sleep Medicine, Harvard Medical School, Boston, Massachusetts Central Sleep Apnea and Periodic Breathing
Nancy J. Wesensten, PhD Behavioral Biology Branch, Center for Military Psychiatry and Neuroscience, Walter Reed Army Institute of Research, Silver Spring, Maryland
Pharmacologic Management of Performance Deficits Resulting from Sleep Loss and Circadian Desynchrony
David P. White, MD Clinical Professor, Medicine, Harvard Medical School; Clinical Professor of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts Central Sleep Apnea and Periodic Breathing
Amy R. Wolfson, PhD Professor of Psychology; Associate Dean for Faculty Development, Office of the Dean, College of the Holy Cross, Worcester, Massachusetts The Postpartum Period
Kenneth P. Wright, Jr., PhD Assistant Professor, University of Colorado, Boulder, Colorado Shift Work, Shift-Work Disorder, and Jet Lag
Chien-Ming Yang, PhD Assistant Professor, Department of Psychology, National Chengchi University, Taipei, Taiwan Assessment Techniques for Insomnia
Terry Young, MS, PhD Professor, Department of Population Health Sciences, Epidemiology Section, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin Systemic and Pulmonary Hypertension in Obstructive Sleep Apnea
Antonio Zadra, PhD Professor, Psychology, Université de Montréal; Research Professor, Centre d’Etude du Sommeil et des Rythmes Biologiques, Hôpital du Sacré-Coeur de Montréal, Montréal, Québec, Canada Dream Content: Quantitative Findings Idiopathic Nightmares and Dream Disturbances Associated with Sleep−Wake Transitions
Phyllis C. Zee, MD, PhD Professor, Neurology; Director, Sleep Disorders Center, Northwestern University Feinberg School of Medicine, Chicago, Illinois Circadian Disorders of the Sleep−Wake Cycle
Marco Zucconi, MD Professor, Department of Neurology, Sleep Disorders Center, H San Raffaele Scientific Institute and Hospital, Università Vita-Salute San Raffaele, Milan, Italy Pain and Sleep
Foreword xxiii
Foreword
Medicine has only recently discovered the importance of sleep, and how sleep symptoms can be the canary in the mine of serious medical and psychiatric problems that can affect all people. I can attest firsthand about the importance of sleep, and how symptoms affecting sleep can impact a person’s life. I was the Canadian Force Commander of the United Nations Assistance Mission for Rwanda between October 1993 and August 1994. During that time, a genocide resulted in the deaths of 800,000 people and I was an eyewitness having heard, smelled, seen, and touched thousands and thousands of mutilated bloated bodies of innocent civilians while trying to arrange a peace during a civil war while much of the world stood idly by. My sleep suffered, my health suffered, and I developed the symptoms of posttraumatic stress disorder. As the mission was winding down … “After prayers, I climbed into my vehicle and took off without telling anyone. It wasn’t the first time. I had begun to suffocate in the headquarters, with its endless stream of problems and demands. I had been inventing trips to get me away from it, deciding that I had to see the troops in the field or just tour the country. In every village, along every road, in every church, in every school were unburied corpses. My dreams at night became my reality of the day, and increasingly I could not distinguish between the two. By this point, I wasn’t bothering to make excuses anymore to disguise my quest for solitude. I would just sneak away and then drive around thinking all manner of black thoughts that I couldn’t permit myself to say to anyone for fear of the effect on the morale of my troops. Without my marking the moment, death became a desired option. I hoped I would hit a mine or run into an ambush and just end it all. I think some part of me wanted to join the legions of the dead, whom I felt I had failed. I could not face the thought of leaving Rwanda alive after so many people had died. On my travels around the country, whole roads and villages were empty, as if they’d been hit by a nuclear bomb or the bubonic plague. You could drive for miles without seeing a single human being or a single living creature. Everything seemed so dead.” From, Roméo A. Dallaire, Shake Hands with the Devil: The Failure of Humanity in Rwanda. Carroll & Graf Publishers, New York. 2003. pp 499-500. This is the first medical textbook that focuses on the sleep disorders that affect everyone, and that also includes the problems of first responders and the military and teaches doctors about how post traumatic stress disorder impacts sleep. I congratulate the editors.
It is an honor for us, representing the Sleep Research Society, to help introduce the 5th edition of Principles and Practice of Sleep Medicine. This volume appears nearly fifty years after the first professional sleep research meeting in the United States on March 25 and 26, 1961, a meeting which directly led to the formation of the Sleep Research Society. According to records of Al Rechtschaffen, maintained in the University of Chicago Library, the first meeting was titled the “Conference on Research in EEG, Sleep and Dreams.” Two days of scientific sessions included topics such as: “Methods and Merits of Various Systems of Scoring,” “Equipment and Technical Problems” and “The Relation of EEG to Verbal Report.” As the session titles suggest, in 1961 sleep scientists were necessarily focused upon some of the most basic tenants of research: observation, measurement, standardization, and tech nology. It seems very unlikely that any of the thirty-six scientists in attendance, including Bill Dement, would have envisioned the exponential growth of knowledge about sleep and its disorders represented in the many pages of the current volume. Sleep research has evolved to include the breadth of modern scientific approaches, and sleep medicine is germane to most medical specialties and public health concerns. In the 149 chapters of this text (including more than 50 new chapters and new sections on Genetics, Occupational Sleep Medicine, Sleep Medicine in Older People) experts describe the intricate mechanisms of biological timing, the genetic polymorphisms conferring risk for sleep disorders, sleep-immune interactions, the morbidity and mortality risks of sleep apnea, and the impact of sleep disturbance on workplace and transportation safety, just to highlight as few areas. We commend the authors on their excellent contributions which will serve to educate and inspire practitioners, researchers and students for years to come. The Sleep Research Society congratulates Drs. Kryger, Roth, and Dement on the publication of this very impressive 5th edition of Principles and Practice of Sleep Medicine and thanks them for undertaking the important service of identifying the latest advances in the field and compiling the body of knowledge represented herein.
—Lt. Gen the Hon. Roméo Dallaire, OC, CMM,
—Clifford B. Saper, MD, PhD
GOQ, MSC, CD, (Ret’d), Senator, Canada
—James K. Walsh, PhD President, Sleep Research Society Executive Director and Senior Scientist Sleep Medicine and Research Center St. Luke’s Hospital Chesterfield, Missouri Past-president, Sleep Research Society James Jackson Putnam Professor of Neurology and Neuroscience, Harvard Medical School and Beth Israel Deaconess Medical Center Boston, Massachusetts
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xxiv Foreword
The success of any field of medicine is often directly proportional to the scope and comprehensiveness of the knowledge base available to physicians, scientists, trainees, and the general public. For the field of sleep medicine, we are fortunate in that there continues to be dramatic growth in this knowledge, derived from both patient care and clinical/basic research. It is revealing when we step back and reflect on how this knowledge base has developed in so short a time: It has been less than 60 years since the discovery of rapid eye movement (REM) sleep, which initiated the organized, scientific study of sleep, and barely 25 years since the invention of continuous positive airway pressure (CPAP), which comprised the first effective treatment for obstructive sleep apnea. In this short time, the sleep field has expanded to the point where we have almost 1,900 accredited sleep centers and laboratories in the United States and over 9,000 members of the American Academy of Sleep Medicine. Our field has blossomed to the point where it is truly interdisciplinary, comprising specialists from the areas of pulmonary medicine, neurology, psychiatry, internal and family medicine, pediatrics, psychology, otolaryngology, and others. Exciting breakthroughs in sleep research have impacted other disciplines of science and research as well, and it is not unusual for sleep medicine specialists to collaborate with other diverse fields of medicine such as cardiology, endocrinology, and immunology. Despite our amazing growth, there are still many questions yet to be answered, including the holy grail of our field: the function of sleep. To explore these questions, the field requires a continued supply of dedicated and talented researchers in both the clinical and basic sciences. In addition, funding from the government, industry, and foundations; support from institutions; and strong mentorship by experienced investigators are important cornerstones to a successful independent research career. As members of the field, we must collectively strive to ensure that funding, support, and mentorship continues in order to ensure success of our field, even in times of economic downturns and increased competition from other fields. For without breakthroughs in research, there won’t be new diagnostic tools, medications, or treatments to help us manage the nearly 90 different sleep disorders that we have identified thus far. The growth of our field and the exploration of critical research areas cannot exist without adequate education and training of our young clinicians and investigators. We are indeed privileged that we have excellent resources available that enable trainees to learn more about sleep and sleep medicine. For countless numbers of students, Principles and Practice of Sleep Medicine has served as the primary textbook, study material for the sleep medicine board certification examination, and/or the basic resource for any sleep-related condition or question about sleep. Often fondly referred to simply as “P&P”, it continues to rise in prominence and demand. I’ve had the great pleasure to learn from and collaborate with Drs. Kryger, Roth, and Dement, and not only are they among the top clinicians and scientists within our field, but they have continued to produce a sleep medicine reference that has remained the
gold standard over the span of 20 years. Our field is deeply indebted to their dedication, hard work, and diligence. —Clete A. Kushida, MD, PhD, RPSGT
President, American Academy of Sleep Medicine Director, Stanford Center for Human Sleep Research Stanford University, California
The American Sleep Apnea Association (ASAA) congratulates the editors of the Principles and Practice of Sleep Medicine on the publication of the fifth edition of this invaluable guide for those practicing sleep medicine. As the field evolves, it has become a key resource for those responsible for diagnosing and treating those with sleep disorders like sleep apnea. The long-term management of patients requires a partnership between the doctor who will learn from this volume the scientific basis of the field and the patient with a chronic illness who must also learn about their condition. For the patient and their families seeking to understand sleep apnea prior to diagnosis, and often once they are treated, they frequently turn to the ASAA, since 1990 the only patient interest organization in the USA dedicated to sleep apnea education, support and advocacy. The ASAA produces educational materials and includes support groups for sleep apnea patients and their families operating under the name A.W.A.K.E. that stands for Alert, Well, And Keep Energetic. The network of the more than 300 A.W.A.K.E. groups has locations around the United States, Canada and overseas. As elucidated in this book sleep apnea is associated with several important comorbidities and thus the ASAA will expand contacts with other patient groups concerned such as heart disease and type 2 diabetes. The fifth edition of Practice and Principles of Sleep Medicine is for the education and support of the caregiver and the American Sleep Apnea Association for the education and support of the apnea patient and their family. —Edward Grandi
Executive Director American Sleep Apnea Association
On behalf of the National Sleep Foundation, it is my pleasure and honor to help introduce the fifth edition of Principles and Practice of Sleep Medicine, the latest update to what has over the past 21 years properly come to be regarded as the preeminent reference text on sleep medicine. I congratulate the editors, Drs. Kryger, Roth, and Dement, for this new edition – representing as it does their long-standing and continuing commitment to the expansion of the field of sleep medicine and science, and their collective talent for presentation and dissemination of sleep-related knowledge. When the first edition was published, the discipline of sleep medicine was in its infancy. Today, perusing previous editions of PPSM is akin to marveling over the growth of a child by leafing through old family photo albums: Although it is understood on an intellectual level that growth and maturation have been occurring continuously, the intermittent nature of the photographic record serves to crystallize those changes in startlingly sharp relief. So it
Foreword xxv
is with PPSM and the history of our field. Each successive edition of PPSM has faithfully reflected the progress made in the intervening years, in a narrative manner that makes clear the process by which high-quality scientific research on sleep and its disorders accrues and is translated into the practice of sleep medicine. Perusal of the current edition will, I think, make it apparent that our field has now grown past infancy, spurted through childhood, and entered its adolescence: to be sure,
a phase of high energy and escalating complexity with a few early hints of maturity, but a phase primarily characterized by the exhilaration of a future that still seems horizonless. For those wishing an understanding of the roots of sleep science, desiring a comprehensive overview of the current ‘state of the art’ of sleep medicine, or yearning for a glimpse of what the future of sleep science holds, just start turning the pages. … —Thomas J. Balkin, Ph.D.
Chairman of the Board of Directors National Sleep Foundation Washington, DC
Preface It has been a quarter century since we started work on the first edition of Principles and Practice of Sleep Medicine. At that time there was a great deal of concern from colleagues that there simply wasn’t enough information available for a book, and there simply wasn’t enough of a market to justify all that effort. In fact, several colleagues whom we respect a great deal tried to talk us out of a textbook because they felt it would have been a waste of time. At that time there were roughly 2000 members of the American Sleep Disorders Association (now the American Academy of Sleep Medicine). Information about sleep medicine was transmitted and shared via telephone (almost everybody knew everybody practicing sleep medicine), articles, scientific meetings and one or two journals that regularly published articles about sleep. How things have changed. In the United States of America, within about 25 miles of anybody’s home there are about 5 to 10 accredited sleep disorders centers, and also some unaccredited centers. There are about 1900 accredited sleep disorders centers. The American Academy of Sleep medicine has approximately 9000 members and counting. The number of doctors who practice sleep medicine is unknown, but there are 3,445 who have specialty certification in sleep awarded by the American Board of Sleep Medicine. This has been supplanted by a new certification exam administered by the American Board of Medical Specialties. The first time the exam was given, 724 physicians passed the examination. In addition, doctors from other specialties who may not have had any training in sleep medicine (for example those trained in pulmonary, neurology, otolaryngology) frequently evaluate and manage patients with sleep disorders. There are now eleven journals that publish articles exclusively about sleep. Whereas in 1985 there were about
Thomas Roth
400 articles published using the keywords “sleep apnea” or “sleep apnoea,” by 2010 about 4000 articles are being published per year. Entirely new fields now have important sleep components including geriatrics, occupational health, women’s health, and there has been an explosion of knowledge just in the past few years in the genetics, molecular biology, and neuroanatomy and neurochemistry of sleep. To ensure that the information is up-to-date, this edition has five entirely new sections (“Sleep Medicine in the Elderly,” “Occupational Sleep Medicine,” “Physiology in Sleep,” “Genetics of Sleep,” and “Sleep Mechanisms and Phylogeny”). There are more than 50 brand new chapters and the remaining chapters have all been updated. There are new sleep stage and respiratory event scoring rules and this is perhaps the first major sleep textbook that incorporates these rules. A companion volume, Atlas of Clinical Sleep Medicine, contains hundreds of examples of polysomnographic data, and videos of interviews with patients with sleep disorders. Besides the dramatic increase in content, we had to deal with the changes in the delivery of information. Books were the way to go in the 1980s, content on CDs were the rage in the 1990s, but web-enabled books appear to be what people want beyond 2010. The third edition almost came out solely on a CD. It turned out that CDs were a passing trend and people hated reading large amounts of text on a computer screen. What doctors want now is a book that they can access in their library, via the internet and even on their handheld device and tablet. We have been listening to caregivers who use this content to help them better care for their patients and hope that you will continue to provide feedback.
Meir H. Kryger
William C. Dement
xxvii
Acknowledgments
This is now about the 25th year since the editors started to work on the first edition of the Principles and Practice of Sleep Medicine. Twenty-five years is a generation and during that time it is safe to say that thousands of professionals and editorial staff have worked on this book, and it is impossible to thank each and every one, as much as we would love to. We would like to thank the current and previous section editors. They are the leaders in their fields and they bring their vision to the book. They fashioned the content so it is of greatest value and relevance to the reader, and ultimately the patient. We would like to thank all the chapter contributors for their hard work. Producing a new chapter or refreshing and updating a previous one is not easy because scientific papers on sleep are published daily and it is a difficult task to remain completely up-to-date.
We would also like to thank the staff at Elsevier who have been so supportive of sleep medicine. Dolores Meloni has been fabulous and supportive of the book. Angela Norton and Anne Snyder shepherded the production of content for the book and Bob Browne has quietly and efficiently managed the web content. We especially wish to thank Sarah Wunderly who took over production of the book at the home stretch and calmly, expertly, and patiently delivered it to the printers. We want to thank the book designers and the production staff for producing such an elegant volume. Finally, we want to thank the many people, readers, who have given us such excellent ideas and feedback. —Meir H. Kryger, Thomas Roth, and William C. Dement
xxix
Abbreviations xxxi
Abbreviations
AASM: American Academy of Sleep Medicine ACC: anterior cingulate cortex Ach: acetylcholine ACTH: adrenocorticotropic hormone AD-ACL: Activation-Deactivation Adjective Check List ADHD: attention-deficit-hyperactivity disorder AHI: apnea-hypopnea index AIM: ancestry informative marker AMPA: α-amino-3hydroxy-5-methylisozazole-4propionic acid AMPK: adenosine-monophosphate-activated protein kinase AMS: acute mountain sickness ANS: autonomic nervous system ASPS: advanced sleep phase syndrome ASPT: advanced sleep phase type AW: active wakefulness BA: Brodman area BAC: blood alcohol content BCOPS: Buffalo Cardio-Metabolic occupational Police Stress BF: basal forebrain BMAL1: brain and muscle ARNT-like BMI: body mass index BNST: bed nucleus of the stria terminalis BPD: biliopancreatic diversion BPDDS: Biliopancreatic diversion with duodenal switch BzRA: benzodiazepine receptor agonist CAD: coronary artery disease CAPS: cyclic alternating pattern sequence(s) CBT: cognitive behavior therapy CHF: congestive heart failure CI: confidence interval CPS/HHPRI: Calgary Police Service Health and Human Performance Research Initiative COMT: catechol-O-methyltransferase COPD: chronic obstructive pulmonary disease CPAP: continuous positive airway pressure CRP: C-reactive protein CRY: cryptochrome CSN: cold-sensitive neuron CYP: cytochrome P-450 DA: dopamine DAT: dopamine transporter DBP: D-element binding protein DD: constant dark DIM: digital integration mode DLMO: dim-light melatonin onset DLPFC: dorsolateral prefrontal cortex DMD: Duchenne’s muscular dystrophy DSISD: Duke Structured Interview for Sleep Disorders
DSM-IV: Diagnostic and Statistical Manual of Mental Disorders, 4th Edition DSPS: delayed sleep phase syndrome DSPT: delayed sleep phase type DTs: delirium tremens DU: duodenal ulcer ECG: electrocardiogram/electrocardiographic EDS: excessive daytime sleepiness EEG: electroencephalogram, electroencephalographic EMG: electromyogram ENS: enteric nervous system EOG: electrooculogram EPS: extrapyramidal side effects (s) EPSP: excitatory postsynaptic potential ERP: event-related potential ESS: Epworth Sleepiness Scale FAID: Fatigue Audit InterDyne 18 FDG: 2-deoxy-2-[18F]fluoro-d-glucose F-DOPA: 6-[18F]fluoro-l-dopa FEV1: forced expiratory volume in 1 second FIRST: Ford Insomnia Response to Stress Test fMRI: functional magnetic resonance imaging FOQA: flight operations quality assurance FOSQ: Functional Outcomes of Sleep Questionnaire FRA: Federal Railroad Administration FRC: functional residual capacity FSIVGTT: frequently sampled intravenous glucose tolerance test GABA: gamma-aminobutyric acid GAD: generalized anxiety disorder GAHMS: genioglossus advancement, hyoid myotomy, and suspension GCD: global cessation of dreaming GER: gastroesophageal reflux GHB: gamma-hydroxybutyrate GHRH: growth hormone-releasing hormone GWA: genome wide association 5-HIAA: 5-hydroxyindole acetic acid 5-HT: hydroxytryptamine (serotonin) HAPE: high-altitude pulmonary edema Hcrt: hypocretin HDI: hypnotic-dependent insomnia HDL: high density lipoprotein HIF: hypoxia inducible factor HIV: human immunodeficiency virus HLA: human leukocyte antigen HOMA: homeostasis model assessment HPA: hypothalamic-pituitary-adrenal axis HRV: heart rate variability HVA: homovanillic acid HWHSGPS: Harvard Work Hours and Safety Group Police Study xxxi
xxxii Abbreviations
ICD: International Classification of Diseases ICD-9-CM: International Classification of Diseases, 9th revision, Clinical Modification ICS-10: International Classification of Diseases, 10th revision ICSD-2: International Classification of Sleep Disorders, Revised ICV: intracerebroventricular IEG: immediate early gene IGL: intergeniculate leaflet IL: interleukin ILD: interstitial lung disease IPSP: inhibitory postsynaptic potential ISI: Insomnia Severity Index kd: kilodalton KSS: Karolinska Sleepiness Scale LAUP: laser-assisted uvulopalatoplasty LD: light-dark LDL: low density lipoprotein l-dopa: l-dihydroxyphenylalanine, levodopa LG: lateral geniculate LL: constant light LOC: left outer canthus LPA (or LPOA): lateral preoptic area LSAT: lowest oxyhemoglobin saturation LTIH: long-term intermittent hypoxia MAO: monoamine oxidase MAOI: monamine oxidase inhibitor MDA: methylenedioxyamphetamine MDD: major depressive disorder MDMA: methylenedioxymethamphetamine (“ecstasy”) MDP-LD: muramyl dipeptide N-actyl-muramyl-l-alanyl-d-isoglutamine MEG: magnetoencephalography MI: myocardial infarction MMC: migrating motor complex MMO: maxillary and mandibular osteotomy MnPN: median preoptic nucleus MNSA: muscle nerve sympathetic vasomotor activity MPA or (MPOA): medial preoptic area MPA: medroxyprogesterone acetate MRA: mandibular repositioning appliance MSLT: Multiple Sleep Latency Test MWT: Maintenance of Wakefulness Test NAD: nicotinamide adenine nucleotide NAMPT: nicotinamide phosphoribosyltransferase NASH: nonalcoholic steatohepatitis NCEP: National Cholesterol Education Program NCSDR: National Center on Sleep Disorders Research NE: norepinephrine NET: norepinephrine transporter NFLD: nonalcoholic fatty liver disease NFκB: nuclear factor kappa B NHANES: national Health and Nutrition Examination Survey NIH: National Institutes of Health NIPPV: nasal intermittent positive-pressure ventilation NK: natural killer [cell] NMDA: N-methyl-d-aspartate NO: nitric oxide NPPV: noninvasive positive-pressure ventilation NPT: nocturnal penile tumescence
NREM: non–rapid eye movement, non-REM OCD: obsessive-compulsive disorder OFC: orbitofrontal cortex 6-OHDA: 6-hydroxydopamine OHS: obesity-hypoventilation syndrome OR: odds ratio OSA: obstructive sleep apnea OSAHS: obstructive sleep apnea–hypopnea syndrome OSAS: obstructive sleep apnea syndrome PACU: postanesthesia care unit PCOS: polycystic ovary syndrome PEEP: positive end-expiratory pressure PER: period PET: positron emission tomography PGO: ponto-geniculo-occipital [spike] PIA: pontine inhibitory area PLMS: periodic limb movements during sleep (or PLM) PMDD: premenstrual dysphoric disorder PNI: people not having insomnia POA: preoptic area POMS: Profile of Mood States POSSR: Patrol Officers Shift Schedule Review PR: prevalence ratio PRC: phase–response curve PSG: polysomnography, polysomnographic PSQI: Pittsburgh Sleep Quality Index PTSD: posttraumatic stress disorder PVN: paraventricular nucleus PVT: psychomotor vigilance test PWI: people with insomnia PWOP: people who did not report having the medical problem PWP: people who reported have the medical problem QTL: quantitative trait loci (or locus) QW: quiet wakefulness RBD: REM sleep behavior disorder RDC: research diagnostic criteria RDI: respiratory disturbance index REM: rapid eye movement RERA: respiratory effort related arousal RFA: radiofrequency ablation RHT: retinohypothalamic tract RI: recombinant inbred Rin: membrane input resistance RIP: respiratory inductive plethysmography RLS: restless legs syndrome RMMA: rhythmic masticatory motor activity ROC: right outer canthus ROS: reactive oxygen species (sing. and pl.) RR: risk ratio RT: reaction time RYGB: Roux-en-Y gastric bypass SAFTE: Sleep, Activity, Fatigue, and Task Effectiveness (model) SCD: stearoyl coenzyme A desaturase SCID: Structured Clinical Interview for Diagnosis SCN: suprachiasmatic nucleus SCT: sleep compression therapy SDB: sleep-disordered breathing SE%: sleep efficiency percentage SEMs: small eye movements SIDS: sudden infant death syndrome
Abbreviations xxxiii
SIT: suggested immobilization test SND: synucleinopathic disorders SNP: single nucleotide polymorphism SOL: sleep-onset latency SOREM: sleep-onset REM SOREMP: sleep-onset REM period SP: sleep paralysis SPM: statistical parametric mapping SRE: sleep-related erection SREBP: sterol regulatory element binding proteinSRED: sleep-related eating disorder SRT: sleep restriction therapy SSEP: somatosensory evoked potential SSS: Stanford Sleepiness Scale SSRI: selective serotonin reuptake inhibitor SWA: slow wave activity SWD: shift work disorder/shift work sleep disorder SWS: slow wave sleep Ta: ambient temperature
TAT: time above threshold TCA: tricyclic antidepressant THH: terrifying hypnagogic hallucination TLR: Toll-like receptor TMJ: temporomandibular joint TNF: tumor necrosis factor TRD: tongue-retaining device UARS: upper airway resistance syndrome UNS: Ullanlinna Narcolepsy Scale UPF: uvulopalatal flap UPPP: uvulopalatopharyngoplasty VIP: vasoactive intestinal peptide VLDL: very low density lipoprotein VLPO: ventrolateral POA (preoptic area) VMAT2: vascular monoamine transporter-2 VTA: ventral tegmental area WASO: wake after sleep onset WSN: warm-sensitive neuron ZCM: zero crossing mode
Normal Sleep and Its Variations
Section
1
Timothy Roehrs 1 History of Sleep Physiology and Medicine 2 Normal Human Sleep: An Overview 3 Normal Aging
4 Daytime Sleepiness and Alertness 5 Acute Sleep Deprivation 6 Chronic Sleep Deprivation
History of Sleep Physiology and Medicine William C. Dement Abstract There has been great scientific interest in sleep for well over a century, with the discoveries of the electrical activity of the brain, the arousal systems, the circadian system, and rapid eye movement sleep. In spite of these discoveries, the field of sleep medicine has existed for only about 4 decades. The evolution of the field required clinical research, development of clinical services, and changes in society and public policy that recognized the impact of sleep disorders on society. The field is still evolving as new disorders are being discovered, new treatments are being delivered, and basic science is helping us understand the complexity of sleep and its disorders. Interest in sleep and dreams has existed since the dawn of history. Perhaps only love and human conflict have received
SLEEP AS A PASSIVE STATE “Sleep is the intermediate state between wakefulness and death; wakefulness being regarded as the active state of all the animal and intellectual functions, and death as that of their total suspension.”2 The foregoing is the first sentence of The Philosophy of Sleep, a book by Robert MacNish, a member of the faculty of physicians and surgeons of Glasgow; the first American edition was published in 1834 and the Scottish edition somewhat earlier. This sentence exemplifies the overarching historical conceptual dichotomy of sleep research and sleep medicine, which is sleep as a passive process versus sleep as an active process. Until the discovery of rapid eye movements and the duality of sleep, sleep was universally regarded as an inactive state of the brain. With one or two exceptions, most thinkers regarded sleep as the inevitable result of reduced sensory input with the consequent diminishment of brain activity and the occurrence of sleep. Waking up and being awake were considered a reversal of this process, mainly as a result of bombardment of the brain by stimulation from the envi-
Chapter
1
more attention from poets and writers. Some of the world’s greatest thinkers, such as Aristotle, Hippocrates, Freud, and Pavlov, have attempted to explain the physiologic and psychological bases of sleep and dreaming. However, it is not the purpose of this chapter to present a scholarly review across the ages about prehistoric, biblical, and Elizabethan thoughts and concerns regarding sleep or the history of man’s enthrallment with dreams and nightmares. This has been reviewed by others.1 What is emphasized here for the benefit of the student and the practitioner is the evolution of the key concepts that define and differentiate sleep research and sleep medicine, crucial discoveries and developments in the formative years of the field, and those principles and practices that have stood the test of time.
ronment. No real distinction was seen between sleep and other states of quiescence such as coma, stupor, intoxication, hypnosis, anesthesia, and hibernation. The passive to active historical dichotomy is also given great weight by the modern investigator J. Allan Hobson.3 In the first sentence of his book, Sleep, published in 1989, he stated that “more has been learned about sleep in the past 60 years than in the preceding 6,000.” He went on, “In this short period of time, researchers have discovered that sleep is a dynamic behavior. Not simply the absence of waking, sleep is a special activity of the brain, controlled by elaborate and precise mechanisms.” Dreams and dreaming were regarded as transient, fleeting interruptions of this quiescent state. Because dreams seem to occur spontaneously and sometimes in response to environmental stimulation (e.g., the well-known alarm clock dreams), the notion of a stimulus that produces the dream was generalized by postulating internal stimulation from the digestive tract or some other internal source. Some anthropologists have suggested that notions of spirituality and the soul arose from primitive peoples’ need to 3
4 PART I / Section 1 • Normal Sleep and Its Variations
explain how their essence could leave the body temporarily at night in a dream and permanently at death. In addition to the mere reduction of stimulation, a host of less popular theories were espoused to account for the onset of sleep. Vascular theories were proposed from the notion that the blood left the brain to accumulate in the digestive tract, and from the opposite idea that sleep was due to pressure on the brain by blood. Around the end of the 19th century, various versions of a “hypnotoxin” theory were formulated in which fatigue products (toxins and the like) were accumulated during the day, finally causing sleep, during which they were gradually eliminated. It had, of course, been observed since biblical times that alcohol would induce a sleeplike state. More recently, these observations included other compounds such as opium. Finally, it was noted that caffeine had the power to prevent sleep. The hypnotoxin theory reached its zenith in 1907 when French physiologists, Legendre and Pieron,4 did experiments showing that blood serum from sleep-deprived dogs could induce sleep in dogs that were not sleep deprived. The notion of a toxin causing the brain to sleep has gradually given way to the notion that there are a number of endogenous “sleep factors” that actively induce sleep by specific mechanisms. In the 1920s, the University of Chicago physiologist Nathaniel Kleitman carried out a series of sleep-deprivation studies and made the simple but brilliant observation that individuals who stayed up all night were generally less sleepy and impaired the next morning than in the middle of their sleepless night. Kleitman argued that this observation was incompatible with the notion of a continual buildup of a hypnotoxin in the brain or blood. In addition, he felt that humans were about as impaired as they would get, that is, very impaired, after about 60 hours of wakefulness, and that longer periods of sleep deprivation would produce little additional change. In the 1939 (first) edition of his comprehensive landmark monograph “Sleep and Wakefulness” Kleitman5 summed up by saying, “It is perhaps not sleep that needs to be explained, but wakefulness, and indeed, there may be different kinds of wakefulness at different stages of phylogenetic and ontogenetic development. In spite of sleep being frequently designated as an instinct, or global reaction, an actively initiated process, by excitation or inhibition of cortical or subcortical structures, there is not a single fact about sleep that cannot be equally well interpreted as a let down of the waking activity.”
THE ELECTRICAL ACTIVITY OF THE BRAIN As the 20th century got under way, Camillo Golgi and Santiago Ramón y Cajal had demonstrated that the nervous system was not a mass of fused cells sharing a common cytoplasm but rather a highly intricate network of discrete cells that had the key property of signaling to one another. Luigi Galvani had discovered that the nerve cells of animals produce electricity, and Emil duBois-Reymond and Hermann von Helmholtz found that nerve cells use their electrical capabilities for signaling information to one another. In 1875, the Scottish physiologist Richard Caton
demonstrated electrical rhythms in the brains of animals. The centennial of his discovery was commemorated at the 15th annual meeting of the Association for the Psychophysiological Study of Sleep convening at the site of the discovery, Edinburgh, Scotland. However, it was not until 1928 when the German psychiatrist Hans Berger6 recorded electrical activity of the human brain and clearly demonstrated differences in these rhythms when subjects were awake or asleep that a real scientific interest commenced. Berger correctly inferred that the signals he recorded, which he called “electroencephalograms,” were of brain origin. For the first time, the presence of sleep could be conclusively established without disturbing the sleeper, and, more important, sleep could be continuously and quantitatively measured without disturbing the sleeper. All the major elements of sleep brain wave patterns were described by Harvey, Hobart, Davis, and others7-9 at Harvard University in a series of extraordinary papers published in 1937, 1938, and 1939. Blake, Gerard, and Kleitman10,11 added to this from their studies at the University of Chicago. On the human electroencephalogram (EEG), sleep was characterized by high-amplitude slow waves and spindles, whereas wakefulness was characterized by low-amplitude waves and alpha rhythm. The image of the sleeping brain completely “turned off ” gave way to the image of the sleeping brain engaged in slow, synchronized, “idling” neuronal activity. Although it was not widely recognized at the time, these studies were some of the most critical turning points in sleep research. Indeed, Hobson3 dated the turning point of sleep research to 1928, when Berger began his work on the human EEG. Used today in much the same way as they were in the 1930s, brain wave recordings with paper and ink, or more recently on computer screens, have been extraordinarily important to sleep research and sleep medicine. The 1930s also saw one series of investigations that seemed to establish conclusively both the passive theory of sleep and the notion that it occurred in response to reduction of stimulation and activity. These were the investigations of Frederick Bremer,12,13 reported in 1935 and 1936. These investigations were made possible by the aforementioned development of electroencephalography. Bremer studied brain wave patterns in two cat preparations. One, which Bremer called encéphale isolé, was made by cutting a section through the lower part of the medulla. The other, cerveau isolé, was made by cutting the midbrain just behind the origin of the oculomotor nerves. The first preparation permitted the study of cortical electrical rhythms under the influence of olfactory, visual, auditory, vestibular, and musculocutaneous impulses; in the second preparation, the field was narrowed almost entirely to the influence of olfactory and visual impulses. In the first preparation, the brain continued to present manifestations of wakeful activity alternating with phases of sleep as indicated by the EEG. In the second preparation, however, the EEG assumed a definite deep sleep character and remained in this condition. In addition, the eyeballs immediately turned downward with a progressive miosis. Bremer concluded that in sleep there occurs a functional (reversible, of course) deafferentation of the cerebral
cortex. The cerveau isolé preparation results in a suppression of the incessant influx of nerve impulses, particularly cutaneous and proprioceptive, which are essential for the maintenance of the waking state of the telencephalon. Apparently, olfactory and visual impulses are insufficient to keep the cortex awake. It is probably misleading to assert that physiologists assumed the brain was completely turned off, whatever this metaphor might have meant, because blood flow and, presumably, metabolism continued. However, Bremer and others certainly favored the concept of sleep as a reduction of activity-idling, slow, synchronized, “resting” neuronal activity.
THE ASCENDING RETICULAR SYSTEM After World War II, insulated, implantable electrodes were developed, and sleep research on animals began in earnest. In 1949, one of the most important and influential studies dealing with sleep and wakefulness was published: Moruzzi and Magoun’s classic paper “Brain Stem Reticular Formation and Activation of the EEG.”14 These authors concluded that “transitions from sleep to wakefulness or from the less extreme states of relaxation and drowsiness to alertness and attention are all characterized by an apparent breaking up of the synchronization of discharge of the elements of the cerebral cortex, an alteration marked in the EEG by the replacement of high voltage, slow waves with low-voltage fast activity” (p. 455). High-frequency electrical stimulation through electrodes implanted in the brainstem reticular formation produced EEG activation and behavioral arousal. Thus, EEG activation, wakefulness, and consciousness were at one end of the continuum; sleep, EEG synchronization, and lack of consciousness were at the other end. This view, as can be seen, is hardly different from the statement by MacNish quoted at the beginning of this chapter. The demonstration by Starzl and coworkers15 that sensory collaterals discharge into the reticular formation suggested that a mechanism was present by which sensory stimulation could be transduced into prolonged activation of the brain and sustained wakefulness. By attributing an amplifying and maintaining role to the brainstem core and the conceptual ascending reticular activating system, it was possible to account for the fact that wakefulness outlasts, or is occasionally maintained in the absence of, sensory stimulation. Chronic lesions in the brainstem reticular formation produced persisting slow waves in the EEG and immobility. The usual animal for this research was the cat because excellent stereotaxic coordinates of brain structures had become available in this model.16 These findings appeared to confirm and extend Bremer’s observations. The theory of the reticular activating system was an anatomically based passive theory of sleep or an active theory of wakefulness. Figure 1-1 is from the published proceedings of a symposium entitled Brain Mechanisms and Consciousness, which published in 1954 and is probably the first genuine neuroscience bestseller.17 Horace Magoun had extended his studies to the monkey, and the illustration represents the full flowering of the ascending reticular activating system theory.
CHAPTER 1 • History of Sleep Physiology and Medicine 5
EARLY OBSERVATIONS OF SLEEP PATHOLOGY Insomnia has been described since the dawn of history and attributed to many causes, including a recognition of the association between emotional disturbance and sleep disturbance. Scholars and historians have a duty to bestow credit accurately. However, many discoveries lie fallow for want of a contextual soil in which they may be properly understood and in which they may extend the understanding of more general phenomena. Important early observations were those of von Economo on “sleeping sickness” and of Pavlov, who observed dogs falling asleep during conditioned reflex experiments. Two early observations about sleep research and sleep medicine stand out. The first is the description in 1880 of narcolepsy by Jean Baptiste Edouard Gélineau (18591906), who derived the name narcolepsy from the Greek words narkosis (a benumbing) and lepsis (to overtake). He was the first to clearly describe the collection of components that constitute the syndrome, although the term cataplexy for the emotionally induced muscle weakness was subsequently coined in 1916 by Richard Henneberg. Obstructive sleep apnea syndrome (OSAS), which may be called the leading sleep disorder of the 20th century, was described in 1836, not by a clinician but by the novelist Charles Dickens. In a series of papers entitled the “Posthumous Papers of the Pickwick Club,” Dickens described Joe, a boy who was obese and always excessively sleepy. Joe, a loud snorer, was called Young Dropsy, possibly as a result of having right-sided heart failure. Meir Kryger18 and Peretz Lavie19,20 published scholarly accounts of many early references to snoring and conditions that were most certainly manifestations of OSAS. Professor Pierre Passouant21 provided an account of the
Figure 1-1 Lateral view of the monkey’s brain, showing the ascending reticular activating system in the brainstem receiving collaterals from direct afferent paths and projecting primarily to the associational areas of the hemisphere. (Redrawn from Magoun HW: The ascending reticular system and wakefulness. In Adrian ED, Bremer F, Jasper HH [eds]. Brain mechanisms and consciousness. A symposium organized by the Council for International Organizations of Medical Sciences, 1954. (Courtesy of Charles C Thomas, Publisher, Springfield, Ill.)
6 PART I / Section 1 • Normal Sleep and Its Variations
life of Gélineau and his landmark description of the narcolepsy syndrome.
SIGMUND FREUD AND THE INTERPRETATION OF DREAMS By far the most widespread interest in sleep by health professionals was engendered by the theories of Sigmund Freud, specifically about dreams. Of course, the interest was really in dreaming, with sleep as the necessary concomitant. Freud developed psychoanalysis, the technique of dream interpretation, as part of his therapeutic approach to emotional and mental problems. As the concept of the ascending reticular activating system dominated behavioral neurophysiology, so the psychoanalytic theories about dreams dominated the psychological side of the coin. Dreams were thought to be the guardians of sleep and to occur in response to a disturbance in order to obviate waking up, as exemplified in the classic alarm clock dream. Freud’s concept that dreaming discharged instinctual energy led directly to the notion of dreaming as a safety valve of the mind. At the time of the discovery of rapid eye movements during sleep (circa 1952), academic psychiatry was dominated by psychoanalysts, and medical students all over America were interpreting one another’s dreams. From the vantage point of today’s world, the dream deprivation studies of the early 1960s, engendered and reified by the belief in psychoanalysis, may be regarded by some as a digression from the mainstream of sleep medicine. On the other hand, because the medical–psychiatric establishment had begun to take dreams seriously, it was also ready to support sleep research fairly generously under the guise of dream research. CHRONOBIOLOGY Most, but not all, sleep specialists share the opinion that what has been called chronobiology or the study of biologic rhythms is a legitimate part of sleep research and sleep medicine. The 24-hour rhythms in the activities of plants and animals have been recognized for centuries. These biologic 24-hour rhythms were quite reasonably assumed to be a direct consequence of the periodic environmental fluctuation of light and darkness. However, in 1729, Jean Jacques d’Ortous de Mairan described a heliotrope plant that opened its leaves during the day even after de Mairan had moved the plant so that sunlight could not reach it. The plant opened its leaves during the day and folded them for the entire night even though the environment was constant. This was the first demonstration of the persistence of circadian rhythms in the absence of environmental time cues. Figure 1-2, which represents de Mairan’s original experiment, is reproduced from The Clocks That Time Us by Moore-Ede and colleagues.22 Chronobiology and sleep research developed separately. The following three factors appear to have contributed to this: 1. The long-term studies commonly used in biologic rhythm research precluded continuous recording of brain wave activity. Certainly, in the early days, the latter was far too difficult and not really necessary. The measurement of wheel-running activity was a conve-
Figure 1-2 Representation of de Mairan’s original experiment. When exposed to sunlight during the day (upper left), the leaves of the plant were open; during the night (upper right), the leaves were folded. De Mairan showed that sunlight was not necessary for these leaf movements by placing the plant in total darkness. Even under these constant conditions, the leaves opened during the day (lower left) and folded during the night (lower right). (Redrawn from Moore-Ede MC, Sulzman FM, Fuller CA. The clocks that time us: physiology of the circadian timing system. Cambridge, Mass: Harvard University Press; 1982. p. 7.)
nient and widely used method for demonstrating circadian rhythmicity. 2. The favorite animal of sleep research from the 1930s through the 1970s was the cat, and neither cats nor dogs demonstrate clearly defined circadian activity rhythms. 3. The separation between chronobiology and sleep research was further maintained by the tendency for chronobiologists to know very little about sleep, and for sleep researchers to remain ignorant of such biological clock mysteries as phase response curves, entrainment, and internal desynchronization.
THE DISCOVERY OF REM SLEEP The characterization of rapid eye movement (REM) sleep as a discrete organismic state should be distinguished from the discovery that rapid eye movements occur during sleep. The historical threads of the discovery of rapid eye movements can be identified. Nathaniel Kleitman (Fig. 1-3, Video 1-1), a professor of physiology at the University of Chicago, had long been interested in cycles of activity and inactivity in infants and in the possibility that this cycle ensured that an infant would have an opportunity to
Figure 1-3 Nathaniel Kleitman (circa 1938), Professor of Physiology, University of Chicago, School of Medicine.
respond to hunger. He postulated that the times infants awakened to nurse on a self-demand schedule would be integral multiples of a basic rest-activity cycle. The second thread was Kleitman’s interest in eye motility as a possible measure of “depth” of sleep. The reasoning for this was that eye movements had a much greater cortical representation than did almost any other observable motor activity, and that slow, rolling, or pendular eye movements had been described at the onset of sleep with a gradual slowing and disappearance as sleep “deepened.”23 In 1951, Kleitman assigned the task of observing eye movement to a graduate student in physiology named Eugene Aserinsky. Watching the closed eyes of sleeping infants was tedious, and Aserinsky soon found that it was easier to designate successive 5-minute epochs as “periods of motility” if he observed any movement at all, usually a writhing or twitching of the eyelids, versus “periods of no motility.” After describing an apparent rhythm in eye motility, Kleitman and Aserinsky decided to look for a similar phenomenon in adults. Again, watching the eyes during the day was tedious, and at night it was even worse. Casting about, they came upon the method of electrooculography and decided (correctly) that this would be a good way to measure eye motility continuously and would relieve the human observer of the tedium of direct observations. Sometimes in the course of recording electrooculograms (EOGs) during sleep, they saw bursts of electrical potential changes that were quite different from the slow movements at sleep onset. When they were observing infants, Aserinsky and Kleitman had not differentiated between slow and rapid movements. However, on the EOG, the difference between the slow eye movements at sleep onset and the newly discovered rapid motility was obvious. Initially, there was a
CHAPTER 1 • History of Sleep Physiology and Medicine 7
great deal of concern that these potentials were electrical artifacts. With their presence on the EOG as a signal, however, it was possible to watch the subject’s eyes simultaneously, and when this was done, the distinct rapid movement of the eyes beneath the closed lids was extremely easy to see. At this point, Aserinsky and Kleitman made two assumptions: 1. These eye movements represented a “lightening” of sleep. 2. Because they were associated with irregular respiration and accelerated heart rate, they might represent dreaming. The basic sleep cycle was not identified at this time, primarily because the EOG and other physiologic measures, notably the EEG, were not recorded continuously but rather by sampling a few minutes of each hour or halfhour. The sampling strategy was done to conserve paper (there was no research grant) and because there was not a clear reason to record continuously. Also, the schedule made it possible for the researcher to nap between sampling episodes. Aserinsky and Kleitman initiated a small series of awakenings, both when rapid eye movements were present and when rapid eye movements were not present, for the purpose of eliciting dream recall. They did not apply sophisticated methods of dream content analysis, but the descriptions of dream content from the two conditions were generally quite different with REM awakenings yielding vivid complex stories and non-REM (NREM) awakenings often yielding nothing at all or very sparse accounts. This made it possible to conclude that rapid eye movements were associated with dreaming. This was, indeed, a breakthrough in sleep research.24,25 The occurrence of the eye movements was quite compatible with the contemporary dream theories that dreams occurred when sleep lightened in order to prevent or delay awakening. In other words, dreaming could still be regarded as the “guardian” of sleep. However, it could no longer be assumed that dreams were fleeting and evanescent.
ALL-NIGHT SLEEP RECORDINGS AND THE BASIC SLEEP CYCLE The seminal Aserinsky and Kleitman paper was published in 1953. It attracted little attention, and no publications on the subject appeared from any other laboratory until 1959. Staying up at night to study sleep remained an undesirable occupation by anyone’s standards. In the early 1950s, most previous research on the EEG patterns of sleep, like most approaches to sleep physiology generally, had either equated short periods of sleep with all sleep or relied on intermittent time sampling during the night. The notion of obtaining continuous records throughout typical nights of sleep would have seemed highly extravagant. However, motivated by the desire to expand and quantify the description of rapid eye movements, then graduate student William Dement and Kleitman26 did just this over a total of 126 nights with 33 subjects and, by means of a simplified categorization of EEG patterns, scored the paper recordings in their entirety. When they examined these 126 records, they found that there was a predictable
8 PART I / Section 1 • Normal Sleep and Its Variations
sequence of patterns over the course of the night, such as had been hinted at by Aserinsky’s study but entirely overlooked in all previous EEG studies of sleep. Although this sequence of regular variations has now been observed tens of thousands of times in hundreds of laboratories, the original description remains essentially unchanged. The usual sequence was that after the onset of sleep, the EEG progressed fairly rapidly to stage 4, which persisted for varying amounts of time, generally about 30 minutes, and then a “lightening” took place. Whereas the progression from wakefulness to stage 4 at the beginning of the cycle was almost invariable through a continuum of change, the lightening was usually abrupt and coincident with a body movement or series of body movements. After the termination of stage 4, there was generally a short period of stage 2 or stage 3 which gave way to stage 1 and rapid eye movements. When the first eye movement period ended, the EEG again progressed through a continuum of change to stage 3 or 4, which persisted for a time and then lightened, often abruptly, with body movement to stage 2, which again gave way to stage 1 and the second rapid eye movement period (see p. 679 of Dement and Kleitman26). Dement and Kleitman found that this cyclical variation of EEG patterns occurred repeatedly throughout the night at intervals of 90 to 100 minutes from the end of one eye movement period to the end of the next. The regular occurrences of REM periods and dreaming strongly suggested that dreams did not occur in response to chance disturbances. At the time of these observations, sleep was still considered to be a single state. Dement and Kleitman characterized the EEG during REM periods as “emergent stage 1” as opposed to “descending stage 1” at the onset of sleep. The percentage of the total sleep time occupied by REM sleep was between 20% and 25%, and the periods of REM sleep tended to be shorter in the early cycles of the night. This pattern of all-night sleep has been seen over and over in normal humans of both sexes, in widely varying environments and cultures, and across the life span.
REM SLEEP IN ANIMALS The developing knowledge of the nature of sleep with rapid eye movements was in direct opposition to the ascending reticular activating system theory and constituted a paradigmatic crisis. The following observations were crucial: • Arousal thresholds in humans were much higher during periods of REM sleep that had a low-amplitude, relatively fast (stage 1) EEG pattern than during similar “light sleep” periods at the onset of sleep. • Rapid eye movements during sleep were discovered in cats; the concomitant brain wave patterns (lowamplitude, fast) were indistinguishable from active wakefulness. • By discarding the sampling approach and recording continuously, a basic 90-minute cycle of sleep without rapid eye movements, alternating with sleep with rapid eye movements, was discovered. This basic sleep-cycle characterized all episodes of nocturnal sleep. Continuous recording also revealed a consistent, low-amplitude
EEG pattern during a precise interval of sleep always associated with bursts of REM, which were additionally established as periods of vivid dreaming. • Observations of motor activity in both humans and animals revealed the unique occurrence of an active suppression of spinal motor activity and muscle reflexes. Thus, sleep consists not of one state but rather of two distinct organismic states, as different from one another as both are from wakefulness. It had to be conceded that sleep could no longer be thought of as a time of brain inactivity and EEG slowing. By 1960, this fundamental change in our thinking about the nature of sleep was well established; it exists as fact that has not changed in any way since that time. The discovery of rapid eye movements during sleep in humans, plus the all-night sleep recordings that revealed the regular recurrence of lengthy periods during which rapid eye movements occurred and during which brain wave patterns resembled light sleep, prepared the way for the discovery of REM sleep in cats, in spite of the extremely powerful bias that an “activated” EEG could not be associated with sleep. In the first study of cats, maintaining the insulation and, therefore, the integrity of implanted electrodes had not yet been solved, so an alternative, small pins in the scalp, was used. With this approach, the waking EEG was totally obscured by the electromyogram from the large temporal muscles of the cat. However, when the cat fell asleep, slow waves could be seen, and the transition to REM sleep was clearly observed because muscle potentials were completely suppressed. The cat’s rapid eye movements and also the twitching of the whiskers and paws could be directly observed. It is very difficult today, in 2010, to understand and appreciate the exceedingly controversial nature of these findings. The following note from a more personal account27 illustrates both the power and the danger of scientific dogma. “I wrote them [the findings] up, but the paper was nearly impossible to publish because it was completely contradictory to the totally dominant neurophysiological theory of the time. The assertion by me that an activated EEG could be associated with unambiguous sleep was considered to be absurd. As it turned out, previous investigators had observed an activated EEG during sleep in cats28,29 but simply could not believe it and ascribed it to arousing influences during sleep. A colleague who was assisting me was sufficiently skeptical that he preferred I publish the paper as sole author. After four or five rejections, to my everlasting gratitude, Editor-in-Chief Herbert Jasper accepted the paper without revision for publication in Electroencephalography and Clinical Neurophysiology.” (see p. 23 of Dement30) It is notable, however, that I did not appreciate the significance of the absence of muscle potentials during the REM periods in cats. It remained for Michel Jouvet, working in Lyon, France, to insist on the importance of electromyographic suppression in his early papers,31,32 the first of which was published in 1959. Hodes and Dement began to study the “H” reflex in humans in 1960, finding complete suppression of reflexes during REM sleep,33 and Octavio Pompeiano and others in Pisa, Italy, worked out the basic mechanisms of REM atonia in the cat.34
THE DUALITY OF SLEEP Even though the basic NREM sleep cycle was well established, the realization that REM sleep was qualitatively different from the remainder of sleep took years to evolve. Jouvet35 and his colleagues performed an elegant series of investigations on the brainstem mechanisms of sleep that forced the inescapable conclusion that sleep consists of two fundamentally different organismic states. Among his many early contributions were clarification of the role of pontine brainstem systems as the primary anatomic site for REM sleep mechanisms and the clear demonstration that electromyographic activity and muscle tonus are completely suppressed during REM periods and only during REM periods. These investigations began in 1958 and were carried out during 1959 and 1960. It is now an established fact that atonia is a fundamental characteristic of REM sleep and that it is mediated by an active and highly specialized neuronal system. The pioneering microelectrode studies of Edward Evarts36 in cats and monkeys, and observations on cerebral blood flow in the cat by Reivich and Kety37 provided convincing evidence that the brain during REM sleep is very active. Certain areas of the brain appear to be more active in REM sleep than in wakefulness. By now, the notion of sleep as a passive process was totally demolished although for many years there was a lingering attitude that NREM sleep was essentially inactive and quiet. By 1960, it was possible to define REM sleep as a completely separate organismic state characterized by cerebral activation, active motor inhibition, and, of course, an association with dreaming. The fundamental duality of sleep was an established fact. PREMONITIONS OF SLEEP MEDICINE Sleep research, which emphasized all-night sleep recordings, burgeoned in the 1960s and was the legitimate precursor of sleep medicine and particularly of its core clinical test, polysomnography. Much of the research at this time emphasized studies of dreaming and REM sleep and had its roots in a psychoanalytic approach to mental illness which strongly implicated dreaming in the psychotic process. After sufficient numbers of all-night sleep recordings had been carried out in humans to demonstrate a highly characteristic “normal” sleep architecture, investigators noted a significantly shortened REM latency in association with endogenous depression.38 This phenomenon has been intensively investigated ever since. Other important precursors of sleep medicine were the following: 1. Discovery of sleep-onset REM periods in patients with narcolepsy 2. Interest in sleep, epilepsy, and abnormal movement– primarily in France 3. Introduction of benzodiazepines and the use of sleep laboratory studies in defining hypnotic efficacy SLEEP-ONSET REM PERIODS AND CATAPLEXY In 1959, a patient with narcolepsy came to the Mount Sinai Hospital in New York City to see Dr. Charles Fisher. At
CHAPTER 1 • History of Sleep Physiology and Medicine 9
Fisher’s suggestion, a sleep recording was begun. Within seconds after he fell asleep, the patient was showing the dramatic, characteristic rapid eye movements of REM sleep, and sawtooth waves as well, in the EEG. The first paper documenting sleep-onset REM periods in a single patient was published in 1960 by Gerald Vogel.39 In a collaborative study between the University of Chicago and the Mount Sinai Hospital, nine patients were studied, and the important sleep-onset REM periods at night were described in a 1963 paper.40 Subsequent research showed that sleepy patients who did not have cataplexy did not have sleep-onset REM periods (SOREMPs), and those with cataplexy always had SOREMPs.41 It was clear that the best explanation for cataplexy was the normal motor inhibitory mechanisms of REM sleep occurring during wakefulness in a precocious or abnormal way.
THE NARCOLEPSY CLINIC: A FALSE START In January 1963, after moving to Stanford University, Dement was eager to test the hypothesis of an association between cataplexy and SOREMPs. However, not a single narcoleptic patient could be identified. A final attempt was made by placing a “want ad,” a few words about an inch high, in a daily newspaper, the San Francisco Chronicle. More than 100 people responded! About 50 of these patients were bona fide narcoleptics having both sleepiness and cataplexy. The response to the ad was a noteworthy event in the development of sleep disorders medicine. With one or two exceptions, none of the narcoleptics had ever been diagnosed correctly. A responsibility for their clinical management had to be assumed in order to facilitate their participation in the research. The late Dr. Stephen Mitchell, who had completed his neurology training and was entering a psychiatry residency at Stanford University, joined Dement in creating a narcolepsy clinic in 1964, and they were soon managing well over 100 patients. Mostly, this involved seeing the patients at regular intervals and adjusting their medication. Nonetheless, the seeds of the typical sleep disorders clinic were sowed because at least one daytime polygraphic sleep recording was performed on all patients to establish the presence of SOREMPs, and patients were questioned exhaustively about their sleep. If possible, an all-night sleep recording was carried out. Unfortunately, most of the patients were unable to pay cash to cover their bills, and insurance companies declared that the recordings of narcoleptic patients were experimental. Because the clinic was unable to generate sufficient income, it was discontinued and most of the patients were referred back to local physicians with instructions about treatment. EUROPEAN INTEREST In Europe, a genuine clinical interest in sleep problems had arisen, and it achieved its clearest expression in a 1963 symposium held in Paris, organized by Professor H. Fischgold, and published as La Sommeil de Nuit Normal et Pathologique in 1965.42 The primary clinical emphasis in this symposium was the documentation of sleep-related
10 PART I / Section 1 • Normal Sleep and Its Variations
epileptic seizures and a number of related studies on sleepwalking and night terrors. Investigators from France, Italy, Belgium, Germany, and the Netherlands took part.
BENZODIAZEPINES AND HYPNOTIC EFFICACY STUDIES Benzodiazepines were introduced in 1960 with the marketing of chlordiazepoxide (Librium). This compound offered a significant advance in terms of safety over barbiturates for the purpose of tranquilizing and sedating. It was quickly followed by diazepam (Valium) and the first benzodiazepine introduced specifically as a hypnotic, flurazepam (Dalmane). Although a number of studies had been done on the effects of drugs on sleep, usually to answer theoretical questions, the first use of the sleep laboratory to evaluate sleeping pills was the 1965 study by Oswald and Priest.43 An important series of studies establishing the role of the sleep laboratory in the evaluation of hypnotic efficacy was carried out by Anthony Kales and his colleagues at the University of California, Los Angeles.44 The group also carried out studies of patients with hypothyroidism, asthma, Parkinson’s disease, and somnambulism.45-48 THE DISCOVERY OF SLEEP APNEA One of the most important events in the history of sleep disorders medicine occurred in Europe. Sleep apnea was discovered independently by Gastaut, Tassinari, and Duron49 in France and by Jung and Kuhlo in Germany.50 Both these groups reported their findings in 1965. As noted earlier, scholars have found references to this pheno menon in many places, but this was the first clear-cut recognition and description that had a direct causal continuity to sleep disorders medicine as we know it today. Peretz Lavie has detailed the historical contributions made by scientists and clinicians around the world in helping to describe and understand this disorder.20 These important findings were widely ignored in America (Video 1-2). What should have been an almost inevitable discovery by either the otolaryngologic surgery community or the pulmonary medicine community did not occur because there was no tradition in either specialty for carefully observing breathing during sleep. The wellknown and frequently cited study of Burwell and colleagues51—although impressive in a literary sense in its evoking of the somnolent boy, Joe, from the “Posthumous Papers of the Pickwick Club”—erred badly in evaluating their somnolent obese patients only during waking and attributing the cause of the somnolence to hypercapnia. The popularity of this paper further reduced the likelihood of discovery of sleep apnea by the pulmonary community. To this day, there is no evidence that hypercapnia causes true somnolence, although, of course, high levels of PCO2 are associated with impaired cerebral function. Nonetheless, the term “pickwickian” became an instant success as a neologism and may have played a role in stimulating interest in this syndrome by the European neurologists who were also interested in sleep. A small group of French neurologists who specialized in clinical neurophysiology and electroencephalography were in the vanguard of sleep research. One of the collaborators
in the French discovery of sleep apnea, C. Alberto Tassinari, joined the Italian neurologist Elio Lugaresi in Bologna in 1970. These clinical investigators along with Giorgio Coccagna and a host of others over the years performed a crucial series of clinical sleep investigations and, indeed, provided a complete description of the sleep apnea syndrome, including the first observations of the occurrence of sleep apnea in nonobese patients, an account of the cardiovascular correlates, and a clear identification of the importance of snoring and hypersomnolence as diagnostic indicators. These studies are recounted in Lugaresi’s book, Hypersomnia with Periodic Apneas, published in 1978.52
ITALIAN SYMPOSIA In 1967, Henri Gastaut and Elio Lugaresi (Fig. 1-4) organized a symposium, published as The Abnormalities of Sleep in Man,53 which encompassed issues across a full range of pathologic sleep in humans. This meeting took place in Bologna, Italy, and the papers presented covered many of what are now major topics in the sleep medicine field: insomnia, sleep apnea, narcolepsy, and periodic leg movements during sleep. It was an epic meeting from the point of view of the clinical investigation of sleep; the only major issues not represented were clear concepts of clinical practice models and clear visions of the high population prevalence of sleep disorders. However, the event that may have finally triggered a serious international interest in sleep apnea syndromes was organized by Lugaresi in 1972 and took place in Rimini, a small resort on the Adriatic coast.54 BIRTH PANGS In spite of all the clinical research, the concept of all-night sleep recordings as a clinical diagnostic test did not emerge unambiguously. It is worth considering the reasons for this failure, partly because they continue to operate today as impediments to the expansion of the field, and partly to understand the field’s long overdue development. The first important reason was the unprecedented nature of an all-night diagnostic test, particularly if it was conducted on outpatients. The cost of all-night
Figure 1-4 Elio Lugaresi, Professor of Neurology, University of Bologna, at the 1972 Rimini symposium.
polygraphic recording, in terms of its basic expense, was high enough without adding the cost of hospitalization although hospitalization would have legitimized a patient’s spending the night in a testing facility. To sleep in an outpatient clinic for a diagnostic test was a totally unprecedented, time-intensive, and labor-intensive enterprise and completely in conflict with the brief time required to go to the chemistry laboratory to give a blood sample, to breathe into a pulmonary function apparatus, to undergo a radiographic examination, and so forth. A second important barrier was the reluctance of nonhospital clinical professionals to work at night. Although medical house staff are very familiar with night work, they do not generally enjoy it; furthermore, clinicians could not work 24-hour days, first seeing patients and ordering tests, and then conducting the tests themselves. Finally, only a very small number of people understood that complaints of daytime sleepiness and nocturnal sleep disturbance represented something of clinical significance. Even narcolepsy, which was by the early 1970s fully characterized as an interesting and disabling clinical syndrome requiring sleep recordings for diagnosis, was not recognized in the larger medical community and had too low a prevalence to warrant creating a medical subspecialty. A study carried out in 1972 documented a mean of 15 years from onset of the characteristic symptoms of excessive daytime sleepiness and cataplexy to diagnosis and treatment by a clinician. The study also showed that a mean of 5.5 different physicians were consulted without benefit throughout that long interval.55
THE EARLY DEVELOPMENT OF SLEEP MEDICINE CLINICAL PRACTICE The practice of sleep medicine developed in many centers in the 1970s, often as a function of the original research interests of the center. The sleep disorders clinic at Stanford University is in many ways a microcosm of how sleep medicine evolved throughout the world. Patients complaining of insomnia were enrolled in hypnotic efficacy research studies. This brought the Stanford group into contact with many insomnia patients and demolished the notion that the majority of such patients had psychiatric problems. An early question was how reliable the descriptions of their sleep by these patients were. The classic all-night sleep recording gave an answer and yielded a great deal of information. Throughout the second half of the 1960s, as a part of their research, the Stanford group continued to manage patients with narcolepsy. As the group’s reputation for expertise in narcolepsy grew, it began to receive referrals for evaluation from physicians all over the United States. Although sleep apnea had not yet been identified (or treated) as a frequent cause of severe daytime sleepiness, it was clear that a number of patients referred with the presumptive diagnosis of narcolepsy certainly did not possess narcolepsy’s two cardinal signs, SOREMPs and cataplexy, and actually suffered from obstructive sleep apnea. True pickwickians were an infrequent referral at this time. In January 1972, Christian Guilleminault, a French neurologist and psychiatrist, joined the Stanford group. He
CHAPTER 1 • History of Sleep Physiology and Medicine 11
had extensive knowledge of the European studies of sleep apnea. Until his arrival, the Stanford group had not routinely used respiratory and cardiac sensors in their allnight sleep studies. Starting in 1972, these measurements became a routine part of the all-night diagnostic test. This test was given the permanent name of polysomnography in 1974 by Dr. Jerome Holland, a member of the Stanford group. Publicity about narcolepsy and excessive sleepiness resulted in a small flow of referrals to the Stanford sleep clinic, usually with the presumptive diagnosis of narcolepsy. During the first year or two, the goal for the Stanford practice was to see at least five new patients per week. To foster financial viability, the group did as much as possible (within ethical limits) to publicize its services. As a result, there was also a sprinkling of patients, often self-referred, with chronic insomnia. The diagnosis of obstructive sleep apnea in patients with profound excessive daytime sleepiness was nearly always completely unambiguous. During 1972, the search for sleep abnormality in patients with sleep-related complaints continued; an attempt was made as well to conceptualize the pathophysiologic process both as an entity and as the cause of the presenting symptom. With this approach, a number of phenomena seen during sleep were rapidly linked to the fundamental sleep-related presenting complaints. Toward the end of 1972, the basic concepts and formats of sleep disorders medicine were sculpted to the extent that it was possible to offer a daylong course through Stanford University’s Division of Postgraduate Medicine. The course was titled “The Diagnosis and Treatment of Sleep Disorders.” The topics covered were normal sleep architecture; the diagnosis and treatment of insomnia with drug-dependent insomnia, pseudoinsomnia, central sleep apnea, and periodic leg movement as diagnostic entities; and the diagnosis and treatment of excessive daytime sleepiness or hypersomnia, with narcolepsy, NREM narcolepsy, and obstructive sleep apnea as diagnostic entities. The disability and cardiovascular complications of severe sleep apnea were severe and alarming. Unfortunately, the treatment options at this time were limited to usually ineffective attempts to lose weight and chronic tracheostomy. The dramatic results of chronic tracheostomy in ameliorating the symptoms and complications of obstructive sleep apnea had been reported by Lugaresi and coworkers56 in 1970. However, the notion of using such a treatment was strongly resisted at the time by the medical community, both in the Stanford University medical community and elsewhere. One of the first patients referred to the Stanford sleep clinic for investigation of this severe somnolence and who eventually had a tracheostomy was a 10-year-old boy. The challenges that were met to secure the proper management of this patient can be seen in this account by Christian Guilleminault (personal communication, 1990). In addition to medical skepticism, a major obstacle to the practice of sleep disorders medicine was the retroactive denial of payment by insurance companies, including the largest one in the United States. A 3-year period of educational efforts directed toward third-party carriers finally culminated in the recognition of polysomnography as a reimbursable diagnostic test in 1974. Another issue was
12 PART I / Section 1 • Normal Sleep and Its Variations
that outpatient clinics that offered overnight testing in polysomnographic testing bedrooms needed to obtain state licensure in order to avoid the licensing requirements of hospitals. This, too, was finally accomplished in 1974.
CLINICAL SIGNIFICANCE OF EXCESSIVE DAYTIME SLEEPINESS Christian Guilleminault, in a series of studies, had clearly shown that excessive daytime sleepiness was a major presenting complaint of several sleep disorders as well as a pathologic phenomenon unto itself.57 However, it was recognized that methods to quantify this symptom and the underlying condition were not adequate to document the degree of improvement as a result of treatment. The subjective Stanford Sleepiness Scale, developed by Hoddes and colleagues,58 did not give reliable results. The problem was not a crisis, however, because patients with severe apnea and overwhelming daytime sleepiness improved dramatically after tracheostomy, and the reduction in daytime sleepiness was unambiguous. Nonetheless, the less urgent need to document the pharmacologic treatment of narcolepsy and the objective improvement of sleepiness in patients with less severe sleep apnea continued to be a problem. The apparent lack of interest in daytime sleepiness by individuals who were devoting their careers to the investigation of sleep at that time has always been puzzling. There is no question but that the current active investigation of this phenomenon is the result of the early interest of sleep disorders specialists. The early neglect of sleepiness is all the more difficult to understand because it is now widely recognized that sleepiness and the tendency to fall asleep during the performance of hazardous tasks is one of the most important problems in our society. A number of reasons have been put forward. One is that sleepiness and drowsiness are negative qualities. A second is that the societal failure to confront the issue was fostered by language ambiguities in identifying sleepiness. A third is that the early sleep laboratory studies focused almost exclusively on REM sleep and other nighttime procedures with little concern for the daytime except for psychopathology. Finally, the focus with regard to sleep deprivation was on performance from the perspective of human factors rather than on sleepiness as representing a homeostatic response to sleep reduction. An early attempt to develop an objective measure of sleepiness was that of Yoss and coworkers59 who observed pupil diameter directly by video monitoring and described changes in sleep deprivation and narcolepsy. Subsequently designated pupillometry, this technique has not been widely accepted. Dr. Mary Carskadon deserves most of the credit for the development of the latter-day standard approach to the measurement of sleepiness called the Multiple Sleep Latency Test (MSLT). She noted that subjective ratings of sleepiness made before a sleep recording not infrequently predicted the sleep latency. In the spring of 1976, she undertook to establish sleep latency as an objective measurement of the state of sleepiness-alertness by measuring sleep tendency before, during, and after 2 days of total sleep deprivation.60 The protocol designed for this study has become the standard protocol for the MSLT.
The choices of a 20-minute duration of a single test and a 2-hour interval between tests were essentially arbitrary and dictated by the practical demands of that study. This test was then formally applied to the clinical evaluation of sleepiness in patients with narcolepsy61 and, later, in patients with OSAS.62 Carskadon and her colleagues then undertook a monumental study of sleepiness in children by following them longitudinally across the second decade of life, which happens to also be the decade of highest risk for the development of narcolepsy. Using the new MSLT measure, she found that 10-year-old children were completely alert in the daytime, but by the time they reached sexual maturity, they were no longer fully alert even though they obtained almost the same amount of sleep at night as at age ten. Results of this remarkable decade of work and other studies are summarized in an important review.63 Early MSLT research established the following important advances in thinking: 1. Daytime sleepiness and nighttime sleep are an inter active continuum, and the adequacy of nighttime sleep absolutely cannot be understood without a complementary measurement of the level of daytime sleepiness or its antonym, alertness. 2. Excessive sleepiness, also known as impaired alertness, was sleep medicine’s most important symptom.
FURTHER DEVELOPMENT OF SLEEP MEDICINE As the decade of the 1970s drew to a close, the consolidation and formalization of the practice of sleep disorders medicine was largely completed. What is now the American Academy of Sleep Medicine was formed and provided a home for professionals interested in sleep and, particularly, in the diagnosis and treatment of sleep disorders. This organization began as the Association of Sleep Disorders Centers with five members in 1975. The organization then was responsible for the initiation of the scientific journal Sleep, and it fostered the setting of standards through center accreditation and an examination for practitioners by which they were designated Accredited Clinical Polysomnographers. The first international symposium on narcolepsy took place in the French Languedoc in the summer of 1975, immediately after the Second International Congress of the Association for the Physiological Study of Sleep in Edinburgh. The former meeting, in addition to being scientifically productive, had landmark significance because it produced the first consensus definition of a specific sleep disorder,64 drafted, revised, and unanimously endorsed by 65 narcoleptologists of international reputation. The first sleep disorders patient volunteer organization, the American Narcolepsy Association, was also formed in 1975. The ASDC/APSS Diagnostic Classification of Sleep and Arousal Disorders was published in fall 1979 after 3 years of extraordinary effort by a small group of dedicated individuals who composed the “nosology” committee chaired by Howard Roffwarg.65 Before the 1980s, the only effective treatment for severe OSAS was chronic tracheostomy. This highly effective but personally undesirable approach was replaced by two new
CHAPTER 1 • History of Sleep Physiology and Medicine 13
procedures—one surgical,66 the other mechanical.67 The first was uvulopalatopharyngoplasty, which is giving way to more complex and effective approaches. The second was the widely used and highly effective continuous positive nasal airway pressure technique introduced by the Australian pulmonologist Colin Sullivan (Video 1-3). The combination of the high prevalence of OSAS and effective treatments fueled a strong expansion of centers and individuals offering the diagnosis and treatment of sleep disorders to patients. The decade of the 1980s was capped by the publication of sleep medicine’s first textbook, Principles and Practice of Sleep Medicine.68 For many years there was only one medical journal devoted to sleep; by 2004 there were seven: Sleep, Journal of Sleep Research, Sleep and Biological Rhythms, Sleep & Breathing, Sleep Medicine, Sleep Medicine Reviews, and Sleep Research Online. Articles about sleep are now routinely published in the major pulmonary, neurology, and psychiatric journals. The 1990s saw an acceleration in the acceptance of sleep medicine throughout the world.69 In spite of that, adequate sleep medicine services are still not readily available everywhere.70 In the United States, the National Center on Sleep Disorders Research (NCSDR) was established by statute as part of the National Heart, Lung, and Blood Institute of the National Institutes of Health.71,72 The mandate of NCSDR is to support research, promote educational activities, and coordinate sleep-related activities throughout various branches of the U.S. government. This initiative led to the development of large research projects dealing with various aspects of sleep disorders and the establishment of awards to develop educational materials at all levels of training. The 1990s also saw the establishment of the National Sleep Foundation73 as well as other organizations for patients. This foundation points out to the public the dangers of sleepiness, and sponsors the annual National Sleep Awareness Week. As the Internet increases exponentially in size, so does the availability of sleep knowledge for physicians, patients, and the general public. The average
person today knows a great deal more about sleep and its disorders than the average person did at the end of the 1980s.
THE TURN OF THE CENTURY AND BEYOND Chapter 62 of this volume deals with public policy and public health issues. From today’s vantage, the greatest challenge for the future is the cost-effective expansion of sleep medicine so that its benefits will be readily available. The major barrier to this availability is the continuing failure of sleep research and sleep medicine to effectively penetrate the educational system at any level. As a consequence, the majority of individuals remain unaware of important facts of sleep and wakefulness, biologic rhythms, and sleep disorders, and particularly of the symptoms that suggest a serious pathologic process. The management of sleep deprivation and its serious consequences in the workplace, particularly in those industries that depend on sustained operations, continue to need increased attention. Finally, the education and training of all health professionals, including nurses, has far to go. This situation was highlighted by the recently published report of the Institute of Medicine.74 Take heart! These problems are grand opportunities. Sleep medicine has come into its own (Videos 1-4 and 1-5). It has made concern for health a truly 24-hours-a-day enterprise, and it has energized a new effort to reveal the secrets of the healthy and unhealthy sleeping brain. ❖ Clinical Pearl Recent advances in sleep science, sleep medicine, public policy, and communications will foster an educated public that will know a great deal about sleep and its disorders. Clinicians should expect that their patients may have already learned about their sleep disorders from the information sources that are readily available.
Case History Raymond M. was a 10 12 -year-old boy referred to the pediatrics clinic in 1971 for evaluation of unexplained hypertension, which had developed progressively over the preceding 6 months. There was a positive family history of high blood pressure, but never so early in life. Raymond was hospitalized and had determination of renin, angiotensin, and aldosterone, renal function studies including contrast radiographs, and extensive cardiac evaluation. All results had been normal except that his blood pressure oscillated between 140-170/90100. It was noticed that he was somnolent during the daytime and Dr. S. suggested that I see him for this “unrelated” symptom. I reviewed Raymond’s history with his mother. Raymond had been abnormally sleepy “all his life.” However, during the past 2 to 3 years, his schoolteachers were complaining that he would fall asleep in class and was at times a “behavioral problem” because he
was not paying attention and was hyperactive and aggressive. His mother confirmed that he had been a very loud snorer since he was very young, at least since age 2, perhaps before. Physical examination revealed an obese boy with a short neck and a very narrow airway. I recommended a sleep evaluation, which was accepted. An esophageal balloon and measurement of end-tidal CO2 was added to the usual array. His esophageal pressure reached 80 to 120 cm H2O, he had values of 6% end-tidal CO2 at end of apnea, apneic events lasted between 25 and 65 seconds, and the apnea index was 55. His SaO2 [oxygen saturation, arterial] was frequently below 60%. I called the pediatric resident and informed him that the sleep problem was serious. I also suggested that the sleep problem might be the cause of the unexplained hypertension. The resident could not make Continued
14 PART I / Section 1 • Normal Sleep and Its Variations sense of my information and passed it to the attending physician. I was finally asked to present my findings at the pediatric case conference, which was led by Dr. S. I came with the recordings, showed the results, and explained why I believed that there was a relationship between the hypertension and the sleep problem. There were a lot of questions. They simply could not believe it. I was asked what treatment I would recommend, and I suggested a tracheostomy. I was asked how many patients had this treatment in the United States, and how many children had ever been treated with tracheostomy. When I had to answer “zero” to both questions, the audience was somewhat shocked. It was decided that such an approach was doubtful at best, and com-
REFERENCES 1. Thorpy M. History of sleep and man. In: Thorpy M, Yager J, editors. The encyclopedia of sleep and sleep disorders. New York: Facts on File; 1991. 2. MacNish R. The philosophy of sleep. New York: D Appleton; 1834. 3. Hobson J. Sleep. New York: Scientific American Library; 1989. 4. Legendre R, Pieron H. Le probleme des facteurs du sommeil: resultats d’injections vasculaires et intracerebrales de liquides insomniques. C R Soc Biol 1910;68:1077-1079. 5. Kleitman N. Sleep and wakefulness. Chicago: University of Chicago Press; 1939. 6. Berger H. Ueber das Elektroenkephalogramm des Menschen. J Psychol Neurol 1930;40:160-179. 7. Davis H, Davis PA, Loomis AL, et al. Changes in human brain potentials during the onset of sleep. Science 1937;86:448-450. 8. Davis H, Davis PA, Loomis AL, et al. Human brain potentials during the onset of sleep. J Neurophysiol 1938;1:24-38. 9. Harvey EN, Loomis AL, Hobart GA. Cerebral states during sleep as studied by human brain potentials. Science 1937;85:443-444. 10. Blake H, Gerard RW. Brain potentials during sleep. Am J Physiol 1937;119:692-703. 11. Blake H, Gerard RW, Kleitman N. Factors influencing brain potentials during sleep. J Neurophysiol 1939;2:48-60. 12. Bremer F. Cerveau “isolé” et physiologie du sommeil. C R Soc Biol 1935;118:1235-1241. 13. Bremer F. Cerveau. Nouvelles recherches sur le mecanisme du sommeil. C R Soc Biol 1936;122:460-464. 14. Moruzzi G, Magoun H. Brain stem reticular formation and activation of the EEG. Electroencephalogr Clin Neurophysiol 1949;1:455-473. 15. Starzl TE, Taylor CW, Magoun HW. Collateral afferent excitation of reticular formation of brain stem. J Neurophysiol 1951;14:479. 16. Jasper H, Ajmone-Marsan C. A Stereotaxic Atlas of the Diencephalon of the Cat. Ottawa, Ontario, Canada: The National Research Council of Canada; 1954. 17. Magoun HW. The ascending reticular system and wakefulness. In: Adrian ED, Bremer F, Jasper HH, editors. Brain mechanisms and consciousness: a symposium organized by the council for international organizations of medical sciences. Springfield, Ill: Charles C Thomas; 1954. 18. Kryger MH. Sleep apnea: From the needles of Dionysius to continuous positive airway pressure. Arch Intern Med 1983;143:2301-2308. 19. Lavie P. Nothing new under the moon: historical accounts of sleep apnea syndrome. Arch Intern Med 1986;144:2025-2028. 20. Lavie P. Restless Nights: Understanding Snoring and Sleep Apnea. New Haven, Conn: Yale University Press; 2003. 21. Passouant P. Doctor Gélineau (1828-1906): narcolepsy centennial. Sleep 1981;3:241-246. 22. Moore-Ede M, Sulzman F, Fuller C. The clocks that time us: Physiology of the circadian timing system. Cambridge, Mass: Harvard University Press; 1982. 23. de Toni G. I movimenti pendolari dei bulbi oculari dei bambini durante il sonno fisiologico, ed in alcuni stati morbosi. Pediatria 1933;41:489-498.
pletely unacceptable in a child. However, they did concede that if no improvement was achieved by medical management, Raymond would be reinvestigated, including sleep studies. That was spring 1972. In the fall, he was, if anything, worse in spite of vigorous medical treatment. At the end of 1972, Raymond finally had his tracheostomy. His blood pressure went down to 90/60 within 10 days, and he was no longer sleepy. During the 5 years we were able to follow Raymond, he remained normotensive and alert, but I had to fight continuously to prevent outside doctors from closing his tracheostomy. I do not know what has happened to him since then.
24. Aserinsky E, Kleitman N. Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science 1953;118: 273-274. 25. Aserinsky E, Kleitman N. Two types of ocular motility occurring in sleep. J Appl Physiol 1955;8:11-18. 26. Dement W, Kleitman N. Cyclic variations in EEG during sleep and their relation to eye movements, body motility, and dreaming. Electroencephalogr Clin Neurophysiol 1957;9:673-690. 27. Dement W. A personal history of sleep disorders medicine. J Clin Neurophysiol 1990;1:17-47. 28. Derbyshire AJ, Rempel B, Forbes A, et al. The effects of anesthetics on action potentials in the cerebral cortex of the cat. Am J Physiol 1936;116:577-596. 29. Hess R, Koella WP, Akert K. Cortical and subcortical recordings in natural and artificially induced sleep in cats. Electroencephalogr Clin Neurophysiol 1953;5:75-90. 30. Dement W. The occurrence of low voltage, fast electroencephalogram patterns during behavioral sleep in the cat. Electroencephalogr Clin Neurophysiol 1958;10:291-296. 31. Jouvet M, Michel F, Courjon J. Sur un stade d’activite electrique cerebrale rapide au cours du sommeil physiologique. C R Soc Biol 1959;153:1024-1028. 32. Jouvet M, Mounier D. Effects des lesions de la formation reticulaire pontique sur le sommeil du chat. C R Soc Biol 1960;154:2301-2305. 33. Hodes R, Dement W. Depression of electrically induced reflexes (“H-reflexes”) in man during low voltage EEG “sleep.” Electroencephalogr Clin Neurophysiol 1964;17:617-629. 34. Pompeiano O. Mechanisms responsible for spinal inhibition during desynchronized sleep: Experimental study. In: Guilleminault C, Dement WC, Passouant P, editors. Advances in Sleep Research, vol 3: Narcolepsy. New York: Spectrum; 1976. p. 411-449. 35. Jouvet M. Recherches sur les structures nerveuses et les mecanismes responsales des differentes phases du sommeil physiologique. Arch Ital Biol 1962;100:125-206. 36. Evarts E. Effects of sleep and waking on spontaneous and evoked discharge of single units in visual cortex. Fed Proc 1960;4 (Suppl.):828-837. 37. Reivich M, Kety S. Blood flow and metabolism in the sleeping brain. In: Plum F, editor. Brain Dysfunction in Metabolic Disorders. New York: Raven Press; 1968. p. 125-140. 38. Kupfer D, Foster F. Interval between onset of sleep and rapid eye movement sleep as an indicator of depression. Lancet 1972;2:684686. 39. Vogel G. Studies in psychophysiology of dreams, III: The dream of narcolepsy. Arch Gen Psychiatry 1960;3:421-428. 40. Rechtschaffen A, Wolpert E, Dement W, et al. Nocturnal sleep of narcoleptics. Electroencephalogr Clin Neurophysiol 1963;15: 599-609. 41. Dement W, Rechtschaffen A, Gulevich G. The nature of the narcoleptic sleep attack. Neurology 1966;16:18-33. 42. Fischgold H, editor. La Sommeil de Nuit Normal et Pathologique: Etudes Electroencephalographiques. Paris, France: Masson et Cie; 1965. 43. Oswald I, Priest R. Five weeks to escape the sleeping pill habit. Br Med J 1965;2:1093-1095.
44. Kales A, Malmstrom EJ, Scharf MB, et al. Psychophysiological and biochemical changes following use and withdrawal of hypnotics. In: Kales A, editor. Sleep: Physiology and Pathology. Philadelphia: JB Lippincott; 1969. p. 331-343. 45. Kales A, Beall GN, Bajor GF, et al. Sleep studies in asthmatic adults: Relationship of attacks to sleep stage and time of night. J Allergy 1968;41:164-173. 46. Kales A, Heuser G, Jacobson A, et al. All night sleep studies in hypothyroid patients, before and after treatment. J Clin Endocrinol Metab 1967;27:1593-1599. 47. Kales A, Ansel RD, Markham CH, et al. Sleep in patients with Parkinson’s disease and normal subjects prior to and following levodopa administration. Clin Pharmacol Ther 1971;12:397-406. 48. Kales A, Jacobson A, Paulson NJ, et al. Somnambulism: Psychophysiological correlates, I: All-night EEG studies. Arch Gen Psychiatry 1966;14:586-594. 49. Gastaut H, Tassinari C, Duron B. Etude polygraphique des manifestations episodiques (hypniques et respiratoires) du syndrome de Pickwick. Rev Neurol 1965;112:568-579. 50. Jung R, Kuhlo W. Neurophysiological studies of abnormal night sleep and the pickwickian syndrome. Prog Brain Res 1965;18: 140-159. 51. Burwell CS, Robin ED, Whaley RD, et al. Extreme obesity associated with alveolar hypoventilation: a pickwickian syndrome. Am J Med 1956;21:811-818. 52. Lugaresi E, Coccagna G, Mantovani M. Hypersomnia with Periodic Apneas. New York: Spectrum; 1978. 53. Gastaut H, Lugaresi E, Berti-Ceroni G, et al, editors. The Abnormalities of Sleep in Man. Bologna, Italy: Aulo Gaggi Editore; 1968. 54. Gastaut H, Lugaresi E, Berti-Ceroni G, et al. Pathophysiological, clinical, and nosographic considerations regarding hypersomnia with periodic breathing. Bull Physiopathol Resp 1972;8:12491256. 55. Dement W, Guilleminault C, Zarcone V, et al. The narcolepsy syndrome. In: Conn H, Conn R, editors. Current diagnosis, vol. 2. Philadelphia: WB Saunders; 1974. p. 917-921. 56. Lugaresi E, Coccagna G, Mantovani M, et al. Effects de la trachéotomie dans les hypersomnies avec respiration periodique. Rev Neurol 1970;123:267-268. 57. Guilleminault C, Dement W. 235 cases of excessive daytime sleepiness: Diagnosis and tentative classification. J Neurol Sci 1977;31: 13-27. 58. Hoddes E, Zarcone V, Smythe H, et al. Quantification of sleepiness: A new approach. Psychophysiology 1973;10:431-436.
CHAPTER 1 • History of Sleep Physiology and Medicine 15 59. Yoss R, Moyer N, Hollenhorst R. Pupil size and spontaneous pupillary waves associated with alertness, drowsiness, and sleep. Neurology 1970;20:545-554. 60. Carskadon M, Dement W. Effects of total sleep loss on sleep tendency. Percept Mot Skills 1979;48:495-506. 61. Richardson G, Carskadon M, Flagg W, et al. Excessive daytime sleepiness in man: Multiple sleep latency measurements in narcoleptic and control subjects. Electroencephalogr Clin Neurophysiol 1978;45:621-627. 62. Dement W, Carskadon M, Richardson G. Excessive daytime sleepiness in the sleep apnea syndromes. In: Guilleminault C, Dement W, editors. Sleep Apnea Syndromes. New York: Alan R Liss. 1978. p. 23-46. 63. Carskadon M, Dement W. Daytime sleepiness: Quantification of a behavioral state. Neurosci Biobehav Rev 1987;11:307-317. 64. Guilleminault C, Dement W, Passouant P, editors. Narcolepsy. New York: Spectrum; 1976. 65. Sleep Disorders Classification Committee. Diagnostic classification of sleep and arousal disorders, 1st ed. Association of Sleep Disorders Centers and the Association for the Psychophysiological Study of Sleep. Sleep 1979;2:1-137. 66. Fujita S, Conway W, Zorick F, et al. Surgical correction of anatomic abnormalities in obstructive sleep apnea syndrome: Uvulopalatopharyngoplasty. Otolaryngol Head Neck Surg 1981; 89:923-934. 67. Sullivan CE, Issa FG, Berthon-Jones M, et al. Reversal of obstructive sleep apnea by continuous positive airway pressure applied through the nares. Lancet 1981;1:862-865. 68. Kryger M, Roth T, Dement WC. Principles and Practice of Sleep Medicine. Philadelphia: WB Saunders; 1989. 69. International Sleep Medicine Societies. Available at http://dev.ersnet. org/uploads/Document/15/WEB_CHEMIN_743_11654189 26.pdf, accessed September 2010. 70. Flemons WW, Douglas NJ, Kuna ST, et al. Access to diagnosis and treatment of patients with suspected sleep apnea. Am J Respir Crit Care Med 2004;169:668-672. 71. Lefant C, Kiley JP. Sleep research: Celebration and opportunity. Sleep 1998;21:665-669. 72. National Heart, Lung, and Blood Institute. Sleep Disorders Information. Available at http://www.nhlbi.nih.gov/about/ncsdr/. Accessed September 2010. 73. National Sleep Foundation. Available at http://www.sleepfound ation.org. Accessed September 2010. 74. Colten H, Altevogt B, editors. Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem. Washington DC: National Academies Press; 2006.
Normal Human Sleep: An Overview Mary A. Carskadon and William C. Dement Abstract Normal human sleep comprises two states—rapid eye movement (REM) and non–REM (NREM) sleep—that alternate cyclically across a sleep episode. State characteristics are well defined: NREM sleep includes a variably synchronous cortical electroencephalogram (EEG; including sleep spindles, Kcomplexes, and slow waves) associated with low muscle tonus and minimal psychological activity; the REM sleep EEG is desynchronized, muscles are atonic, and dreaming is typical. A nightly pattern of sleep in mature humans sleeping on a regular schedule includes several reliable characteristics: Sleep begins in NREM and progresses through deeper NREM stages (stages 2, 3, and 4 using the classic definitions, or stages N2 and N3 using the updated definitions) before the first episode of REM sleep occurs approximately 80 to 100 minutes later. Thereafter, NREM sleep and REM sleep cycle with a period of approximately 90 minutes. NREM stages 3 and 4 (or stage N3) concentrate in the early NREM cycles, and REM sleep episodes lengthen across the night. Age-related changes are also predictable: Newborn humans enter REM sleep (called active sleep) before NREM (called quiet sleep) and have a shorter sleep cycle (approximately 50
SLEEP DEFINITIONS According to a simple behavioral definition, sleep is a reversible behavioral state of perceptual disengagement from and unresponsiveness to the environment. It is also true that sleep is a complex amalgam of physiologic and behavioral processes. Sleep is typically (but not necessarily) accompanied by postural recumbence, behavioral quiescence, closed eyes, and all the other indicators one commonly associates with sleeping. In the unusual circumstance, other behaviors can occur during sleep. These behaviors can include sleepwalking, sleeptalking, teeth grinding, and other physical activities. Anomalies involving sleep processes also include intrusions of sleep—sleep itself, dream imagery, or muscle weakness—into wakefulness, for example (Box 2-1). Within sleep, two separate states have been defined on the basis of a constellation of physiologic parameters. These two states, rapid eye movement (REM) and non-REM (NREM), exist in virtually all mammals and birds yet studied, and they are as distinct from one another as each is from wakefulness. NREM (pronounced “non-REM”) sleep is conventionally subdivided into four stages defined along one measurement axis, the electroencephalogram (EEG). The EEG pattern in NREM sleep is commonly described as synchronous, with such characteristic waveforms as sleep spindles, K-complexes, and high-voltage slow waves (Fig. 2-1). The four NREM stages (stages 1, 2, 3, and 4) roughly parallel a depth-of-sleep continuum, with arousal thresholds generally lowest in stage 1 and highest in stage 4 sleep. NREM 16
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minutes); coherent sleep stages emerge as the brain matures during the first year. At birth, active sleep is approximately 50% of total sleep and declines over the first 2 years to approximately 20% to 25%. NREM sleep slow waves are not present at birth but emerge in the first 2 years. Slow-wave sleep (stages 3 and 4) decreases across adolescence by 40% from preteen years and continues a slower decline into old age, particularly in men and less so in women. REM sleep as a percentage of total sleep is approximately 20% to 25% across childhood, adolescence, adulthood, and into old age except in dementia. Other factors predictably alter sleep, such as previous sleep-wake history (e.g., homeostatic load), phase of the circadian timing system, ambient temperature, drugs, and sleep disorders. A clear appreciation of the normal characteristics of sleep provides a strong background and template for understanding clinical conditions in which “normal” characteristics are altered, as well as for interpreting certain consequences of sleep disorders. In this chapter, the normal young adult sleep pattern is described as a working baseline pattern. Normative changes due to aging and other factors are described with that background in mind. Several major sleep disorders are highlighted by their differences from the normative pattern.
sleep is usually associated with minimal or fragmentary mental activity. A shorthand definition of NREM sleep is a relatively inactive yet actively regulating brain in a movable body. REM sleep, by contrast, is defined by EEG activation, muscle atonia, and episodic bursts of rapid eye movements. REM sleep usually is not divided into stages, although tonic and phasic types of REM sleep are occasionally distinguished for certain research purposes. The distinction of tonic versus phasic is based on short-lived events such as eye movements that tend to occur in clusters separated by episodes of relative quiescence. In cats, REM sleep phasic activity is epitomized by bursts of ponto-geniculooccipital (PGO) waves, which are accompanied peripherally by rapid eye movements, twitching of distal muscles, middle ear muscle activity, and other phasic events that correspond to the phasic event markers easily measurable in human beings. As described in Chapter 141, PGO waves are not usually detectable in human beings. Thus, the most commonly used marker of REM sleep phasic activity in human beings is, of course, the bursts of rapid eye movements (Fig. 2-2); muscle twitches and cardiorespiratory irregularities often accompany the REM bursts. The mental activity of human REM sleep is associated with dreaming, based on vivid dream recall reported after approximately 80% of arousals from this state of sleep.1 Inhibition of spinal motor neurons by brainstem mechanisms mediates suppression of postural motor tonus in REM sleep. A shorthand definition of REM sleep, therefore, is an activated brain in a paralyzed body.
CHAPTER 2 • Normal Human Sleep: An Overview 17
Box 2-1 Sleep Medicine Methodology and Nomenclature In 2007, the American Academy of Sleep Medicine (AASM) published a new manual (see reference 50) for scoring sleep and associated events. This manual recommends alterations to recording methodology and terminology that the Academy will demand of clinical laboratories in the future. Although specification of arousal, cardiac, movement, and respiratory rules appear to be value added to the assessment of sleep-related events, the new rules, terminology, and technical specifications for recording and scoring sleep are not without controversy. The current chapter uses the traditional terminology and definitions, upon which most descriptive and experimental research has been based since the 1960s.17 Hence, where the AASM terminology uses the term N for NREM sleep stages and R for REM sleep stages, N1 and N2 are used instead of stage 1 and stage 2; N3 is used to indicate the sum of stage 3 and stage 4 (often called slow-wave sleep in human literature); R is used to name REM sleep. Another change is to the nomenclature for the recording placements. Hence, calling the auricular placements M1 and M2 (rather than A1 and A2) is unnecessary and places the sleep EEG recording terminology outside the pale for EEG recording terminology in other disciplines. Although these are somewhat trivial changes, changes in nomenclature can result in confusion when attempting to compare to previous literature and established data sets and are of concern for clinicians and investigators who communicate with other fields. Of greater concern are changes to the core recording and scoring recommendations that the AASM manual recommends. For example, the recommended scoring montage requires using a frontal (F3 or F4) EEG placement for use with visual scoring of the recordings, rather than the central (C3 or C4) EEG placements recommended in the standard manual. The rationale for the change is that the frontal placements pick up more slow-wave activity during sleep. The consequence, however, is that sleep studies performed and scored with the frontal EEG cannot be compared to normative or clinical data and the frontal placements also truncate the ability to visualize sleep spindles. Furthermore, developmental changes to the regional EEG preclude the universal assumption that sleep slow-wave activity is a frontal event. Other issues are present in this new AASM approach to human sleep; however, this is not the venue for a complete description of such concerns. In summary, the AASM scoring manual has not yet become the universal standard for assessing human sleep and might not achieve that status in its current form. Specifications for recording and scoring sleep are not without controversy.51-56
SLEEP ONSET The onset of sleep under normal circumstances in normal adult humans is through NREM sleep. This fundamental principle of normal human sleep reflects a highly reliable finding and is important in considering normal versus pathologic sleep. For example, the abnormal entry into
Stage 1
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100 µV 5 sec Figure 2-1 The stages of non–rapid eye movement sleep. The four electroencephalogram tracings depicted here are from a 19-year-old female volunteer. Each tracing was recorded from a referential lead (C3/A2) recorded on a Grass Instruments Co. (West Warwick, R.I.) Model 7D polygraph with a paper speed of 10 mm/sec, time constant of 0.3 sec, and 12 -amplitude highfrequency setting of 30 Hz. On the second tracing, the arrow indicates a K-complex and the underlining shows two sleep spindles.
C3/A2 ROC/A1 LOC/A2 50 µV
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Figure 2-2 Phasic events in human rapid eye movement (REM) sleep. On the left side is a burst of several rapid eye movements (out-of-phase deflections in right outer canthus [ROC]/A1 and left outer canthus [LOC]/A2). On the right side, there are additional rapid eye movements as well as twitches on the electromyographic (EMG) lead. The interval between eye movement bursts and twitches illustrates tonic REM sleep.
sleep through REM sleep can be a diagnostic sign in adult patients with narcolepsy. Definition of Sleep Onset The precise definition of the onset of sleep has been a topic of debate, primarily because there is no single measure that is 100% clear-cut 100% of the time. For example, a change in EEG pattern is not always associated with a person’s perception of sleep, yet even when subjects report that they are still awake, clear behavioral changes can indicate the presence of sleep. To begin a consideration of this issue, let us examine the three basic polysomnographic measures of sleep and how they change with sleep onset. The electrode placements are described in Chapter 141. Electromyogram The electromyogram (EMG) may show a gradual diminution of muscle tonus as sleep approaches, but rarely does
18 PART I / Section 1 • Normal Sleep and Its Variations
C3/A2
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Figure 2-3 The transition from wakefulness to stage 1 sleep. The most marked change is visible on the two electroencephalographic (EEG) channels (C3/A2 and O2/A1), where a clear pattern of rhythmic alpha activity (8 cps) changes to a relatively low-voltage, mixed- frequency pattern at about the middle of the figure. The level of electromyographic (EMG) activity does not change markedly. Slow eye movements (right outer canthus [ROC]/left outer canthus [LOC]) are present throughout this episode, preceding the EEG change by at least 20 seconds. In general, the change in EEG patterns to stage 1 as illustrated here is accepted as the onset of sleep.
a discrete EMG change pinpoint sleep onset. Furthermore, the presleep level of the EMG, particularly if the person is relaxed, can be entirely indistinguishable from that of unequivocal sleep (Fig. 2-3). Electrooculogram As sleep approaches, the electrooculogram (EOG) shows slow, possibly asynchronous eye movements (see Fig. 2-3) that usually disappear within several minutes of the EEG changes described next. Occasionally, the onset of these slow eye movements coincides with a person’s perceived sleep onset; more often, subjects report that they are still awake. Electroencephalogram In the simplest circumstance (see Fig. 2-3), the EEG changes from a pattern of clear rhythmic alpha (8 to 13 cycles per second [cps]) activity, particularly in the occipital region, to a relatively low-voltage, mixed-frequency pattern (stage 1 sleep). This EEG change usually occurs seconds to minutes after the start of slow eye movements. With regard to introspection, the onset of a stage 1 EEG pattern may or may not coincide with perceived sleep onset. For this reason, a number of investigators require the presence of specific EEG patterns—the K-complex or sleep spindle (i.e., stage 2 sleep)—to acknowledge sleep onset. Even these stage 2 EEG patterns, however, are not unequivocally associated with perceived sleep.2 A further complication is that sleep onset often does not occur all at once; instead, there may be a wavering of vigilance before “unequivocal” sleep ensues (Fig. 2-4). Thus, it is difficult to accept a single variable as marking sleep onset. As Davis and colleagues3 wrote many years ago (p. 35): Is “falling asleep” a unitary event? Our observations suggest that it is not. Different functions, such as sensory awareness, memory, self-consciousness, continuity of logical thought, latency of response to a stimulus, and alterations in the pattern of brain potentials all go in parallel in a general way, but there are exceptions to every rule. Nevertheless, a reasonable consensus exists that the EEG change to stage 1, usually heralded or accompanied by slow eye movements, identifies the transition to sleep, provided
50 µV
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Figure 2-4 A common wake- to-sleep transition pattern. Note that the electroencephalographic pattern changes from wake (rhythmic alpha) to stage 1 (relatively low-voltage, mixedfrequency) sleep twice during this attempt to fall asleep. EMG, electromyogram; LOC, left outer canthus; ROC, right outer canthus.
C3/A2 ROC/A1
SEMs
Asleep
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Figure 2-5 Failure to perform a simple behavioral task at the onset of sleep. The volunteer had been deprived of sleep overnight and was required to tap two switches alternately, shown as pen deflections of opposite polarity on the channel labeled SAT. When the electroencephalographic (EEG; C3/A2) pattern changes to stage 1 sleep, the behavior stops, returning when the EEG pattern reverts to wakefulness. LOC, left outer canthus; ROC, right outer canthus; SEMs, slow eye movements. (From Carskadon MA, Dement WC. Effects of total sleep loss on sleep tendency. Percept Mot Skills 1979;48:495-506. © Perceptual and Motor Skills, 1979.)
that another EEG sleep pattern does not intervene. One might not always be able to pinpoint this transition to the millisecond, but it is usually possible to determine the change reliably within several seconds. Behavioral Concomitants of Sleep Onset Given the changes in the EEG that accompany the onset of sleep, what are the behavioral correlates of the wake-tosleep transition? The following material reviews a few common behavioral concomitants of sleep onset. Keep in mind that “different functions may be depressed in different sequence and to different degrees in different subjects and on different occasions” (p. 35).3 Simple Behavioral Task In the first example, volunteers were asked to tap two switches alternately at a steady pace. As shown in Figure 2-5, this simple behavior continues after the onset of slow eye movements and may persist for several seconds after the EEG changes to a stage 1 sleep pattern.4 The behavior then ceases, usually to recur only after the EEG reverts to a waking pattern. This is an example of what one may think of as the simplest kind of “automatic” behavior pattern. Because such simple behavior can persist past sleep onset
and as one passes in and out of sleep, it might explain how impaired, drowsy drivers are able to continue down the highway. Visual Response A second example of behavioral change at sleep onset derives from an experiment in which a bright light is placed in front of the subject’s eyes, and the subject is asked to respond when a light flash is seen by pressing a sensitive microswitch taped to the hand.5 When the EEG pattern is stage 1 or stage 2 sleep, the response is absent more than 85% of the time. When volunteers are queried afterward, they report that they did not see the light flash, not that they saw the flash but the response was inhibited. This is one example of the perceptual disengagement from the environment that accompanies sleep onset. Auditory Response In another sensory domain, the response to sleep onset is examined with a series of tones played over earphones to a subject who is instructed to respond each time a tone is heard. One study of this phenomenon showed that reaction times became longer in proximity to the onset of stage 1 sleep, and responses were absent coincident with a change in EEG to unequivocal sleep.6 For responses in both visual and auditory modalities, the return of the response after its sleep-related disappearance typically requires the resumption of a waking EEG pattern. Olfactory Response When sleeping humans are tasked to respond when they smell something, the response depends in part on sleep state and in part on the particular odorant. In contrast to visual responses, one study showed that responses to graded strengths of peppermint (strong trigeminal stimulant usually perceived as pleasant) and pyridine (strong trigeminal stimulant usually perceived as extremely unpleasant) were well maintained during initial stage 1 sleep.7 As with other modalities, the response in other sleep stages was significantly poorer: Peppermint simply was not consciously smelled in stages 2 and 4 NREM sleep or in REM sleep; pyridine was never smelled in stage 4 sleep, and only occasionally in stage 2 NREM and in REM sleep.7 On the other hand, a tone successfully aroused the young adult participants in every stage. One conclusion of this report was that the olfactory system of humans is not a good sentinel system during sleep. Response to Meaningful Stimuli One should not infer from the preceding studies that the mind becomes an impenetrable barrier to sensory input at the onset of sleep. Indeed, one of the earliest modern studies of arousability during sleep showed that sleeping human beings were differentially responsive to auditory stimuli of graded intensity.8 Another way of illustrating sensory sensitivity is shown in experiments that have assessed discriminant responses during sleep to meaningful versus nonmeaningful stimuli, with meaning supplied in a number of ways and response usually measured as evoked K-complexes or arousal. The following are examples. • A person tends to have a lower arousal threshold for his or her own name versus someone else’s name.9 In light
CHAPTER 2 • Normal Human Sleep: An Overview 19
sleep, for example, one’s own name spoken softly will produce an arousal; a similarly applied nonmeaningful stimulus will not. Similarly, a sleeping mother is more likely to hear her own baby’s cry than the cry of an unrelated infant. • Williams and colleagues10 showed that the likelihood of an appropriate response during sleep was improved when an otherwise nonmeaningful stimulus was made meaningful by linking the absence of response to punishment (a loud siren, flashing light, and the threat of an electric shock). From these examples and others, it seems clear that sensory processing at some level does continue after the onset of sleep. Indeed, one study has shown with functional magnetic resonance imaging that regional brain activation occurs in response to stimuli during sleep and that different brain regions (middle temporal gyrus and bilateral orbitofrontal cortex) are activated in response to meaningful (person’s own name) versus nonmeaningful (beep) stimuli.11 Hypnic Myoclonia What other behaviors accompany the onset of sleep? If you awaken and query someone shortly after the stage 1 sleep EEG pattern appears, the person usually reports the mental experience as one of losing a direct train of thought and of experiencing vague and fragmentary imagery, usually visual.12 Another fairly common sleep-onset experience is hypnic myoclonia, which is experienced as a general or localized muscle contraction very often associated with rather vivid visual imagery. Hypnic myoclonias are not pathologic events, although they tend to occur more commonly in association with stress or with unusual or irregular sleep schedules. The precise nature of hypnic myoclonias is not clearly understood. According to one hypothesis, the onset of sleep in these instances is marked by a dissociation of REM sleep components, wherein a breakthrough of the imagery component of REM sleep (hypnagogic hallucination) occurs in the absence of the REM motor inhibitory component. A response by the individual to the image, therefore, results in a movement or jerk. The increased frequency of these events in association with irregular sleep schedules is consistent with the increased probability of REM sleep occurring at the wake-to-sleep transition under such conditions (see later). Although the usual transition in adult human beings is to NREM sleep, the REM portal into sleep, which is the norm in infancy, can become partially opened under unusual circumstances. Memory Near Sleep Onset What happens to memory at the onset of sleep? The transition from wake to sleep tends to produce a memory impairment. One view is that it is as if sleep closes the gate between short-term and long-term memory stores. This phenomenon is best described by the following experiment.13 During a presleep testing session, word pairs were presented to volunteers over a loudspeaker at 1-minute intervals. The subjects were then awakened either 30 seconds or 10 minutes after the onset of sleep (defined as EEG stage 1) and asked to recall the words presented before sleep onset. As illustrated in Figure 2-6, the
20 PART I / Section 1 • Normal Sleep and Its Variations
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Figure 2-7 The progression of sleep stages across a single night in a normal young adult volunteer is illustrated in this sleep histogram. The text describes the ideal or average pattern. This histogram was drawn on the basis of a continuous overnight recording of electroencephalogram, electrooculogram, and electromyogram in a normal 19-year-old man. The record was assessed in 30-second epochs for the various sleep stages. REM, rapid eye movement.
Figure 2-6 Memory is impaired by sleep, as shown by the study results illustrated in this graph. See text for explanation.
30-second condition was associated with a consistent level of recall from the entire 10 minutes before sleep onset. (Primacy and recency effects are apparent, although not large.) In the 10-minute condition, however, recall paralleled that in the 30-second group for only the 10 to 4 minutes before sleep onset and then fell abruptly from that point until sleep onset. In the 30-second condition, therefore, both longer-term (4 to 10 minutes) and shorter-term (0 to 3 minutes) memory stores remained accessible. In the 10-minute condition, by contrast, words that were in longer-term stores (4 to 10 minutes) before sleep onset were accessible, whereas words that were still in shorter-term stores (0 to 3 minutes) at sleep onset were no longer accessible; that is, they had not been consolidated into longer-term memory stores. One conclusion of this experiment is that sleep inactivates the transfer of storage from short- to long-term memory. Another interpretation is that encoding of the material before sleep onset is of insufficient strength to allow recall. The precise moment at which this deficit occurs is not known and may be a continuing process, perhaps reflecting anterograde amnesia. Nevertheless, one may infer that if sleep persists for approximately 10 minutes, memory is lost for the few minutes before sleep. The following experiences represent a few familiar examples of this phenomenon: • Inability to grasp the instant of sleep onset in your memory. • Forgetting a telephone call that had come in the middle of the night. • Forgetting the news you were told when awakened in the night. • Not remembering the ringing of your alarm clock. • Experiencing morning amnesia for coherent sleeptalking. • Having fleeting dream recall. Patients with syndromes of excessive sleepiness can experience similar memory problems in the daytime if sleep becomes intrusive.
Learning and Sleep In contrast to this immediate sleep-related “forgetting,” the relevance for sleep to human learning—particularly for consolidation of perceptual and motor learning—is of growing interest.14,15 The importance of this association has also generated some debate and skepticism.16 Nevertheless, a spate of recent research is awakening renewed interest in the topic, and mechanistic studies explaining the roles of REM and NREM sleep more precisely are under examination (see Chapter 29).
PROGRESSION OF SLEEP ACROSS THE NIGHT Pattern of Sleep in a Normal Young Adult The simplest description of sleep begins with the ideal case, the normal young adult who is sleeping well and on a fixed schedule of about 8 hours per night (Fig. 2-7). In general, no consistent male versus female distinctions have been found in the normal pattern of sleep in young adults. In briefest summary, the normal human adult enters sleep through NREM sleep, REM sleep does not occur until 80 minutes or longer thereafter, and NREM sleep and REM sleep alternate through the night, with an approximately 90-minute cycle (see Chapter 141 for a full description of sleep stages). First Sleep Cycle The first cycle of sleep in the normal young adult begins with stage 1 sleep, which usually persists for only a few (1 to 7) minutes at the onset of sleep. Sleep is easily dis continued during stage 1 by, for example, softly calling a person’s name, touching the person lightly, quietly closing a door, and so forth. Thus, stage 1 sleep is associated with a low arousal threshold. In addition to its role in the initial wake-to-sleep transition, stage 1 sleep occurs as a transitional stage throughout the night. A common sign of severely disrupted sleep is an increase in the amount and percentage of stage 1 sleep. Stage 2 NREM sleep, signaled by sleep spindles or K-complexes in the EEG (see Fig. 2-1), follows this brief
episode of stage 1 sleep and continues for approximately 10 to 25 minutes. In stage 2 sleep, a more intense stimulus is required to produce arousal. The same stimulus that produced arousal from stage 1 sleep often results in an evoked K-complex but no awakening in stage 2 sleep. As stage 2 sleep progresses, high-voltage slow-wave activity gradually appears in the EEG. Eventually, this activity meets the criteria17 for stage 3 NREM sleep, that is, high-voltage (at least 75 µV) slow-wave (2 cps) activity accounting for more than 20% but less than 50% of the EEG activity. Stage 3 sleep usually lasts only a few minutes in the first cycle and is transitional to stage 4 as more and more high-voltage slow-wave activity occurs. Stage 4 NREM sleep—identified when the high-voltage slowwave activity comprises more than 50% of the record— usually lasts approximately 20 to 40 minutes in the first cycle. An incrementally larger stimulus is usually required to produce an arousal from stage 3 or 4 sleep than from stage 1 or 2 sleep. (Investigators often refer to the combined stages 3 and 4 sleep as slow-wave sleep [SWS], delta sleep, or deep sleep.) A series of body movements usually signals an “ascent” to lighter NREM sleep stages. A brief (1- or 2-minute) episode of stage 3 sleep might occur, followed by perhaps 5 to 10 minutes of stage 2 sleep interrupted by body movements preceding the initial REM episode. REM sleep in the first cycle of the night is usually short-lived (1 to 5 minutes). The arousal threshold in this REM episode is variable, as is true for REM sleep throughout the night. Theories to explain the variable arousal threshold of REM sleep have suggested that at times, the person’s selective attention to internal stimuli precludes a response or that the arousal stimulus is incorporated into the ongoing dream story rather than producing an awakening. Certain early experiments examining arousal thresholds in cats found highest thresholds in REM sleep, which was then termed deep sleep in this species. Although this terminology is still often used in publications about sleep in animals, it should not be confused with human NREM stages 3 plus 4 sleep, which is also often called deep sleep. One should also note that SWS is sometimes used (as is synchronized sleep) as a synonym for all of NREM sleep in other species and is thus distinct from SWS (stages 3 plus 4 NREM) in human beings. NREM-REM Cycle NREM sleep and REM sleep continue to alternate through the night in cyclic fashion. REM sleep episodes usually become longer across the night. Stages 3 and 4 sleep occupy less time in the second cycle and might disappear altogether from later cycles, as stage 2 sleep expands to occupy the NREM portion of the cycle. The average length of the first NREM-REM sleep cycle is approximately 70 to 100 minutes; the average length of the second and later cycles is approximately 90 to 120 minutes. Across the night, the average period of the NREM-REM cycle is approximately 90 to 110 minutes. Distribution of Sleep Stages across the Night In the young adult, SWS dominates the NREM portion of the sleep cycle toward the beginning of the night (the
CHAPTER 2 • Normal Human Sleep: An Overview 21
first one third); REM sleep episodes are longest in the last one third of the night. Brief episodes of wakefulness tend to intrude later in the night, usually near REM sleep transitions, and they usually do not last long enough to be remembered in the morning. The preferential distribution of REM sleep toward the latter portion of the night in normal human adults is thought to be linked to a circadian oscillator, which can be gauged by the oscillation of body temperature.18,19 The preferential distribution of SWS toward the beginning of a sleep episode is not thought to be mediated by circadian processes but shows a marked response to the length of prior wakefulness.20 The SWS pattern reflects the homeostatic sleep system, highest at sleep onset and diminishing across the night as sleep pressure wanes. Thus, these aspects of the normal sleep pattern highlight features of the two-process model of sleep as elaborated on in Chapter 37. Length of Sleep The length of nocturnal sleep depends on a great number of factors—of which volitional control is among the most significant in human beings—and it is thus difficult to characterize a “normal” pattern. Most young adults report sleeping approximately 7.5 hours a night on weekday nights and slightly longer, 8.5 hours, on weekend nights. The variability of these figures from person to person and from night to night, however, is quite high. Sleep length also depends on genetic determinants,21 and one may think of the volitional determinants (staying up late, waking by alarm, and so on) superimposed on the background of a genetic sleep need. Length of prior waking also affects how much sleeps, although not in a one-for-one manner. Indeed, the length of sleep is also determined by processes associated with circadian rhythms. Thus, when one sleeps helps to determine how long one sleeps. In addition, as sleep is extended, the amount of REM sleep increases, because REM sleep depends on the persistence of sleep into the peak circadian time in order to occur. Generalizations about Sleep in the Normal Young Adult A number of general statements can be made regarding sleep in the normal young adult who is living on a conventional sleep-wake schedule and who is without sleep complaints: • Sleep is entered through NREM sleep. • NREM sleep and REM sleep alternate with a period near 90 minutes. • SWS predominates in the first third of the night and is linked to the initiation of sleep and the length of time awake. • REM sleep predominates in the last third of the night and is linked to the circadian rhythm of body temperature. • Wakefulness in sleep usually accounts for less than 5% of the night. • Stage 1 sleep generally constitutes approximately 2% to 5% of sleep. • Stage 2 sleep generally constitutes approximately 45% to 55% of sleep. • Stage 3 sleep generally constitutes approximately 3% to 8% of sleep.
22 PART I / Section 1 • Normal Sleep and Its Variations
• Stage 4 sleep generally constitutes approximately 10% to 15% of sleep. • NREM sleep, therefore, is usually 75% to 80% of sleep. • REM sleep is usually 20% to 25% of sleep, occurring in four to six discrete episodes. Factors Modifying Sleep Stage Distribution Age The strongest and most consistent factor affecting the pattern of sleep stages across the night is age (Fig. 2-8). The most marked age-related differences in sleep from the patterns described earlier are found in newborn infants. For the first year of life, the transition from wake to sleep is often accomplished through REM sleep (called active sleep in newborns). The cyclic alternation of NREM-REM sleep is present from birth but has a period of approximately 50 to 60 minutes in the newborn compared with approximately 90 minutes in the adult. Infants also only gradually acquire a consolidated nocturnal sleep cycle, and the fully developed EEG patterns of the NREM sleep stages are not present at birth but emerge over the first 2 to 6 months of life. When brain structure and function achieve a level that can support high-voltage slowwave EEG activity, NREM stages 3 and 4 sleep become prominent. SWS is maximal in young children and decreases markedly with age. The SWS of young children is both qualitatively and quantitatively different from that of older adults. For example, it is nearly impossible to wake youngsters in the SWS of the night’s first sleep cycle. In one study,22 a 123-dB tone failed to produce any sign of arousal in a group of children whose mean age was 10 years. In addition, children up to midadolescence often “skip” their first REM episode, perhaps due to the quantity and inten-
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Figure 2-8 Changes in sleep with age. Time (in minutes) for sleep latency and wake time after sleep onset (WASO) and for rapid eye movement (REM) sleep and non-REM (NREM) sleep stages 1, 2, and slow wave sleep (SWS). Summary values are given for ages 5 to 85 years. (Ohayon M, Carskadon MA, Guilleminault C, et al. Meta-analysis of quantitative sleep parameters from childhood to old age in healthy individuals: developing normative sleep values across the human lifespan. Sleep 2004;27:1255-1273.)
sity of slow-wave activity early in the night. A similar, although less profound qualitative difference distinguishes SWS occurring in the first and later cycles of the night in a given person. The quantitative change in SWS may best be seen across adolescence, when SWS decreases by nearly 40% during the second decade, even when length of nocturnal sleep remains constant.23 Feinberg24 hypothesized that the age-related decline in nocturnal SWS might parallel loss of cortical synaptic density. By midadolescence, youngsters no longer typically skip their first REM, and their sleep resembles that described earlier for young adults. By age 60 years, SWS might no longer be present, particularly in men. Women appear to maintain SWS later into life than men. REM sleep as a percentage of total sleep is maintained well into healthy old age; the absolute amount of REM sleep at night has been correlated with intellectual functioning25 and declines markedly in the case of organic brain dysfunctions of the elderly.26 Arousals during sleep increase markedly with age. Extended wake episodes of which the individual is aware and can report, as well as brief and probably unremembered arousals, increase with aging.27 The latter type of transient arousals may occur with no known correlate but are often associated with occult sleep disturbances, such as periodic limb movements during sleep (PLMS) and sleeprelated respiratory irregularities, which also become more prevalent in later life.28,29 Perhaps the most notable finding regarding sleep in the elderly is the profound increase in interindividual variability,30 which thus precludes generalizations such as those made for young adults. Prior Sleep History A person who has experienced sleep loss on one or more nights shows a sleep pattern that favors SWS during recovery (Fig. 2-9). Recovery sleep is also usually prolonged and deeper—that is, having a higher arousal threshold throughout—than basal sleep. REM sleep tends to show a rebound on the second or subsequent recovery nights after an episode of sleep loss. Therefore, with total sleep loss, SWS tends to be preferentially recovered compared with REM sleep, which tends to recover only after the recuperation of SWS. Cases in which a person is differentially deprived of REM or SWS—either operationally, by being awakened each time the sleep pattern occurs, or pharmacologically (see later)—show a preferential rebound of that stage of sleep when natural sleep is resumed. This phenomenon has particular relevance in a clinical setting, in which abrupt withdrawal from a therapeutic regimen can result in misleading diagnostic findings (e.g., sleep-onset REM periods [SOREMPs] as a result of a REM sleep rebound) or could conceivably exacerbate a sleep disorder (e.g., if sleep apneas tend to occur preferentially or with greater intensity in the rebounding stage of sleep). Chronic restriction of nocturnal sleep, an irregular sleep schedule, or frequent disturbance of nocturnal sleep can result in a peculiar distribution of sleep states, most commonly characterized by premature REM sleep, that is, SOREMPs. Such episodes can be associated with hypnagogic hallucinations, sleep paralysis, or an increased
CHAPTER 2 • Normal Human Sleep: An Overview 23
circadian body temperature phase position shows that sleep onset is likeliest to occur on the falling limb of the temperature cycle. A secondary peak of sleep onsets, corresponding to afternoon napping, also occurs; the offset of sleep occurs most often on the rising limb of the circadian body temperature curve.34
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Figure 2-9 The upper histogram shows the baseline sleep pattern of a normal 14-year-old female volunteer. The lower histogram illustrates the sleep pattern in this volunteer for the first recovery night after 38 hours without sleep. Note that the amount of stage 4 sleep on the lower graph is greater than on baseline, and the first rapid eye movement (REM) sleep episode is markedly delayed.
incidence of hypnic myoclonia in persons with no organic sleep disorder. Although not strictly related to prior sleep history, the first night of a laboratory sleep evaluation is commonly associated with a disruption of the normal distribution of sleep states, characterized chiefly by a delayed onset of REM sleep.31 Often this delay takes the form of skipping the first REM episode of the night. In other words, the NREM sleep stages progress in a normal fashion, but the first cycle ends with an episode of stage 1 or a brief arousal instead of the expected brief REM sleep episode. In addition, REM sleep episodes are often disrupted, and the total amount of REM sleep on the first night in the sleep laboratory is also usually reduced from the normal value. Circadian Rhythms The circadian phase at which sleep occurs affects the distribution of sleep stages. REM sleep, in particular, occurs with a circadian distribution that peaks in the morning hours coincident with the trough of the core body temperature rhythm.18,19 Thus, if sleep onset is delayed until the peak REM phase of the circadian rhythm—that is, the early morning—REM sleep tends to predominate and can even occur at the onset of sleep. This reversal of the normal sleep-onset pattern is commonly seen in a normal person who acutely undergoes a phase shift, either as a result of a work shift change or as a change resulting from jet travel across a number of time zones. Studies of persons sleeping in environments free of all cues to time have shown that the timing of sleep onset and the length of sleep occur as a function of circadian phase.32,33 Under these conditions, sleep distribution with reference to the
Temperature Extremes of temperature in the sleeping environment tend to disrupt sleep. REM sleep is commonly more sensitive to temperature-related disruption than is NREM sleep. Accumulated evidence from human beings and other species suggests that mammals have only minimal ability to thermoregulate during REM sleep; in other words, the control of body temperature is virtually poikilothermic in REM sleep.35 This inability to thermoregulate in REM sleep probably affects the response to temperature extremes and suggests that such conditions are less of a problem early during a night than late, when REM sleep tends to predominate. It should be clear, as well, that such responses as sweating or shivering during sleep under ambient temperature extremes occur in NREM sleep and are limited in REM sleep. Drug Ingestion The distribution of sleep states and stages is affected by many common drugs, including those typically prescribed in the treatment of sleep disorders as well as those not specifically related to the pharmacotherapy of sleep dis orders and those used socially or recreationally. Whether changes in sleep stage distribution have any relevance to health, illness, or psychological well-being is unknown; however, particularly in the context of specific sleep dis orders that differentially affect one sleep stage or another, such distinctions may be relevant to diagnosis or treatment. A number of generalizations regarding the effects of certain of the more commonly used compounds on sleep stage distribution can be made. • Benzodiazepines tend to suppress SWS and have no consistent effect on REM sleep. • Tricyclic antidepressants, monoamine oxidase inhibitors, and certain selective serotonin reuptake inhibitors tend to suppress REM sleep. An increased level of motor activity during sleep occurs with certain of these compounds, leading to a pattern of REM sleep without motor inhibition or an increased incidence of PLMS. Fluoxetine is also associated with rapid eye movements across all sleep stages (“Prozac eyes”). • Withdrawal from drugs that selectively suppress a stage of sleep tends to be associated with a rebound of that sleep stage. Thus, acute withdrawal from a benzodiazepine compound is likely to produce an increase of SWS; acute withdrawal from a tricyclic antidepressant or monoamine oxidase inhibitor is likely to produce an increase of REM sleep. In the latter case, this REM rebound could result in abnormal SOREMPs in the absence of an organic sleep disorder, perhaps leading to an incorrect diagnosis of narcolepsy. • Acute presleep alcohol intake can produce an increase in SWS and REM sleep suppression early in the night, which can be followed by REM sleep rebound in the latter portion of the night as the alcohol is metabolized.
24 PART I / Section 1 • Normal Sleep and Its Variations Wake
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Figure 2-10 These sleep histograms depict the sleep of a 64-year-old male patient with obstructive sleep apnea syndrome. The let graph shows the sleep pattern before treatment. Note the absence of slow-wave sleep, the preponderance of stage 1 (S1), and the very frequent disruptions. The right graph shows the sleep pattern in this patient during the second night of treatment with continuous positive airway pressure (CPAP). Note that sleep is much deeper (more SWS) and more consolidated, and rapid eye movement (REM) sleep in particular is abnormally increased. The pretreatment REM percentage of sleep was only 10%, versus nearly 40% with treatment. (Data supplied by G. Nino-Murcia, Stanford University Sleep Disorders Center, Stanford, Calif.)
Low doses of alcohol have minimal effects on sleep stages, but they can increase sleepiness late at night.36,37 • Acute effects of marijuana (tetrahydrocannabinol [THC]) include minimal sleep disruption, characterized by a slight reduction of REM sleep. Chronic ingestion of THC produces a long-term suppression of SWS.38
have indicated a relatively high prevalence of REM sleep onsets in young adults40 and in adolescents with early rise times.41 In the latter, the REM sleep onsets on morning (8:30 am and 10:30 am) naps were related to a delayed circadian phase as indicated by later onset of melatonin secretion.
Pathology Sleep disorders, as well as other nonsleep problems, have an impact on the structure and distribution of sleep. As suggested before, these distinctions appear to be more important in diagnosis and in the consideration of treatments than for any implications about general health or illness resulting from specific sleep stage alterations. A number of common sleep-stage anomalies are commonly associated with sleep disorders.
S LEEP APNEA SYNDROMES Sleep apnea syndromes may be associated with suppression of SWS or REM sleep secondary to the sleep-related breathing problem. Successful treatment of this sleep disorder, as with nocturnal continuous positive airway pressure, can produce large rebounds of SWS or REM sleep (Fig. 2-10).
N ARCOLEPSY Narcolepsy is characterized by an abnormally short delay to REM sleep, marked by SOREMPs. This abnormal sleep-onset pattern occurs with some consistency, but not exclusively; that is, NREM sleep onset can also occur. Thus, the preferred diagnostic test consists of several opportunities to fall asleep across a day (see Chapter 143). If REM sleep occurs abnormally on two or more such opportunities, narcolepsy is extremely probable. The occurrence of this abnormal sleep pattern in narcolepsy is thought to be responsible for the rather unusual symptoms of this disorder. In other words, dissociation of components of REM sleep into the waking state results in hypnagogic hallucinations, sleep paralysis, and, most dramatically, cataplexy. Other conditions in which a short REM sleep latency can occur include infancy, in which sleep-onset REM sleep is normal; sleep reversal or jet lag; acute withdrawal from REM-suppressant compounds; chronic restriction or disruption of sleep; and endogenous depression.39 Reports
S LEEP FRAGMENTATION Fragmentation of sleep and increased frequency of arousals occur in association with a number of sleep disorders as well as with medical disorders involving physical pain or discomfort. PLMS, sleep apnea syndromes, chronic fibrositis, and so forth may be associated with tens to hundreds of arousals each night. Brief arousals are prominent in such conditions as allergic rhinitis,42,43 juvenile rheumatoid arthritis,44 and Parkinson’s disease.45 In upper airway resistance syndrome,46 EEG arousals are important markers because the respiratory signs of this syndrome are less obvious than in frank obstructive sleep apnea syndrome, and only subtle indicators may be available.47 In specific situations, autonomic changes, such as transient changes of blood pressure,48 can signify arousals; Lofaso and colleagues49 indicated that autonomic changes are highly correlated with the extent of EEG arousals. Less well studied is the possibility that sleep fragmentation may be associated with subcortical events not visible in the cortical EEG signal. These disorders also often involve an increase in the absolute amount of and the proportion of stage 1 sleep.
CHAPTER 2 • Normal Human Sleep: An Overview 25
Acknowledgments The authors thank Joan Mancuso for preparing the figures.
❖ Clinical Pearls The clinician should expect to see less slow-wave sleep (stages 3 and 4) in older persons, particularly men. Clinicians or colleagues might find themselves denying mid-night communications (nighttime calls) because of memory deficits that occur for events proximal to sleep onset. This phenomenon might also account for memory deficits in excessively sleepy patients. Many medications (even if not prescribed for sleep) can affect sleep stages, and their use or discontinuation alters sleep. Thus, REM-suppressant medications, for example, can result in a rebound of REM sleep when they are discontinued. Certain patients have sleep complaints (insomnia, hypersomnia) that result from attempts to sleep or be awake at times not in synchrony with their circadian phase. Patients who wake with events early in the night might have a disorder affecting NREM sleep; patients who wake with events late in the night may have a disorder affecting REM sleep. When using sleep restriction to build sleep pressure, treatment will be more effective if sleep is scheduled at the correct circadian phase. The problem of napping in patients with insomnia is that naps diminish the homeostatic drive to sleep.
REFERENCES 1. Dement W, Kleitman N. The relation of eye movements during sleep to dream activity: an objective method for the study of dreaming. J Exp Psychol 1957;53:339-346. 2. Agnew HW, Webb WB. Measurement of sleep onset by EEG criteria. Am J EEG Technol 1972;12:127-134. 3. Davis H, Davis PA, Loomis AL, et al. Human brain potentials during the onset of sleep. J Neurophysiol 1938;1:24-38. 4. Carskadon MA, Dement WC. Effects of total sleep loss on sleep tendency. Percept Mot Skills 1979;48:495-506. 5. Guilleminault C, Phillips R, Dement WC. A syndrome of hypersomnia with automatic behavior. Electroencephalogr Clin Neurophysiol 1975;38:403-413. 6. Ogilvie RD, Wilkinson RT. The detection of sleep onset: behavioral and physiological convergence. Psychophysiology 1984;21:510-520. 7. Carskadon MA, Herz R. Minimal olfactory perception during sleep: why odor alarms will not work for humans. Sleep 2004;27:402-405. 8. Williams HL, Hammack JT, Daly RL, et al. Responses to auditory stimulation, sleep loss and the EEG stages of sleep. Electroencephalogr Clin Neurophysiol 1964;16:269-279. 9. Oswald I, Taylor AM, Treisman M. Discriminative responses to stimulation during human sleep. Brain 1960;83:440-453. 10. Williams HL, Morlock HC, Morlock JV. Instrumental behavior during sleep. Psychophysiology 1966;2:208-216. 11. Portas CM, Krakow K, Allen P, et al. Auditory processing across the sleep-wake cycle: simultaneous EEG and fMRI monitoring in humans. Neuron 2000;28:991-999. 12. Foulkes D. The psychology of sleep. New York: Charles Scribner’s Sons; 1966. 13. Wyatt JK, Bootzin RR, Anthony J, et al. Does sleep onset produce retrograde amnesia? Sleep Res 1992;21:113. 14. Maquet P. The role of sleep in learning and memory. Science 2001;294:1048-1052.
15. Stickgold R, Hobson JA, Fosse R, et al. Sleep, learning and dreams: Off-line memory reprocessing. Science 2001;294:1052-1057. 16. Siegel J. The REM sleep-memory consolidation hypothesis. Science 2001;294:1058-1063. 17. Rechtschaffen A, Kales A, editors. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Los Angeles: UCLA Brain Information Service/Brain Research Institute; 1968. 18. Czeisler CA, Zimmerman JC, Ronda JM, et al. Timing of REM sleep is coupled to the circadian rhythm of body temperature in man. Sleep 1980;2:329-346. 19. Zulley J. Distribution of REM sleep in entrained 24 hour and freerunning sleep-wake cycles. Sleep 1980;2:377-389. 20. Weitzman ED, Czeisler CA, Zimmerman JC, et al. Timing of REM and stages 3 + 4 sleep during temporal isolation in man. Sleep 1980;2:391-407. 21. Karacan I, Moore CA. Genetics and human sleep. Psychiatr Ann 1979;9:11-23. 22. Busby K, Pivik RT. Failure of high intensity auditory stimuli to affect behavioral arousal in children during the first sleep cycle. Pediatr Res 1983;17:802-805. 23. Carskadon MA, Dement WC. Sleepiness in the normal adolescent. In: Guilleminault C, editor. Sleep and its disorders in children. New York: Raven Press; 1987. p. 53-66. 24. Feinberg I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res 1983; 17:319-334. 25. Prinz P. Sleep patterns in the healthy aged: relationship with intellectual function. J Gerontol 1977;32:179-186. 26. Prinz PN, Peskind ER, Vitaliano PP, et al. Changes in the sleep and waking EEGs of nondemented and demented elderly subjects. J Am Geriatr Soc 1982;30:86-93. 27. Carskadon MA, Brown ED, Dement WC. Sleep fragmentation in the elderly: relationship to daytime sleep tendency. Neurobiol Aging 1982;3:321-327. 28. Ancoli-Israel S, Kripke DF, Mason W, et al. Sleep apnea and nocturnal myoclonus in a senior population. Sleep 1981;4:349-358. 29. Carskadon MA, Dement WC. Respiration during sleep in the aging human. J Gerontol 1981;36:420-423. 30. Williams RL, Karacan I, Hursch CJ. EEG of human sleep: clinical applications. New York: John Wiley & Sons; 1974. 31. Agnew HW, Webb WB, Williams RL. The first-night effect: an EEG study of sleep. Psychophysiology 1966;2:263-266. 32. Czeisler CA, Weitzman ED, Moore-Ede MC, et al. Human sleep: Its duration and organization depend on its circadian phase. Science 1980;210:1264-1267. 33. Zulley J, Wever R, Aschoff J. The dependence of onset and duration of sleep on the circadian rhythm of rectal temperature. Pflugers Arch 1981;391:314-318. 34. Strogatz SH. The mathematical structure of the human sleep-wake cycle. New York: Springer-Verlag; 1986. 35. Parmeggiani PL. Temperature regulation during sleep: a study in homeostasis. In Orem J, Barnes CD, editors. Physiology in sleep. New York: Academic Press; 1980. p. 98-143. 36. Van Reen E, Jenni O, Carskadon MA. Effects of alcohol on sleep and the sleep electroencephalogram in healthy young women. Alcohol Clin Exp Res 2006;30(6):974-981. 37. Rupp TL, Acebo C, Van Reen E, Carskadon MA. Effects of a moderate evening dose of alcohol. I. Sleepiness. Alcohol Clin Exp Res 2007;31(8):1358-1364. 38. Freemon FR. The effect of chronically administered delta-9-tetrahydrocannabinol upon the polygraphically monitored sleep of normal volunteers. Drug Alcohol Depend 1982;10:345-353. 39. Kupfer DJ. REM latency: a psychobiologic marker for primary depressive disease. Biol Psychiatry 1976;11:159-174. 40. Bishop C, Rosenthal L, Helmus T, et al. The frequency of multiple sleep onset REM periods among subjects with no excessive daytime sleepiness. Sleep 1996;19:727-730. 41. Carskadon MA, Wolfson AR, Acebo C, et al. Adolescent sleep patterns, circadian timing, and sleepiness at a transition to early school days. Sleep 1998;21:871-881. 42. Lavie P, Gertner R, Zomer J, et al. Breathing disorders in sleep associated with “microarousals” in patients with allergic rhinitis. Acta Otolaryngol 1981;92:529-533. 43. Craig TJ, Teets S, Lehman EB, et al. Nasal congestion secondary to allergic rhinitis as a cause of sleep disturbance and daytime fatigue
26 PART I / Section 1 • Normal Sleep and Its Variations and the response to topical nasal corticosteroids. J Allergy Clin Immunol 1998;101:633-637. 44. Zamir G, Press J, Tal A, et al. Sleep fragmentation in children with juvenile rheumatoid arthritis. J Rheumatol 1998;25:1191-1197. 45. Stocchi F, Barbato L, Nordera G, et al. Sleep disorders in Parkinson’s disease. J Neurol 1998;245(Suppl. 1):S15-S18. 46. Guilleminault C, Stoohs R, Clerk A, et al. From obstructive sleep apnea syndrome to upper airway resistance syndrome—consistency of daytime sleepiness. Sleep 1992;15(6 Suppl.):S13-S16. 47. Hosselet JJ, Norman RG, Ayappa I, et al. Detection of flow limitation with a nasal cannula/pressure transducer system. Am J Respir Crit Care Med 1998;157:1461-1467. 48. Pitson DJ, Stradling JR. Autonomic markers of arousal during sleep in patients undergoing investigation for obstructive sleep apnoea, their relationship to EEG arousals, respiratory events and subjective sleepiness. J Sleep Res 1998;7:53-59. 49. Lofaso F, Goldenberg F, Dortho MP, et al. Arterial blood pressure response to transient arousals from NREM sleep in nonapneic snorers with sleep fragmentation. Chest 1998;113:985-991. 50. Iber C, Ancoli-Israel S, Quan SF, for the American Academy of Sleep Medicine. The AASM manual for the scoring of sleep and associated events: rules, terminology, and technical specifications.
1st ed. Westchester, Ill: American Academy of Sleep Medicine, 2007. 51. Moser D, Anderer P, Gruber G, et al. Sleep classification according to AASM and Rechtschaffen & Kales: effects on sleep scoring parameters. Sleep 2009;32:139-149. 52. Danker-Hopfe H, Anderer P, Zeitlhofer J, et al. Interrater reliability for sleep scoring according to the Rechtschaffen & Kales and the new AASM standard. J Sleep Res 2009;18:74-84. 53. Parrino L, Ferri R, Zucconi M, Fanfulla F. Commentary from the Italian Association of Sleep Medicine on the AASM manual for the scoring of sleep and associated events: for debate and discussion. Sleep Med 2009;10:799-808. 54. Grigg-Damberger MM. The AASM scoring manual: a critical appraisal. Curr Opin Pulm Med 2009;15:540-549. 55. Novelli L, Ferri R, Bruni O. Sleep classification according to AASM and Rechtschaffen and Kales: effects on sleep scoring parameters of children and adolescents. J Sleep Res 2010;19:238-247. 56. Miano S, Paolino MC, Castaldo R, Villa MP. Visual scoring of sleep: A comparison between the Rechtschaffen and Kales criteria and the American Academy of Sleep Medicine criteria in a pediatric population with obstructive sleep apnea syndrome. Clin Neurophysiol 2010;121:39-42.
Normal Aging Donald L. Bliwise Abstract Numerous factors challenge the integrity of sleep in the older human. Intrinsic lightening and fragmentation of sleep, reflecting changes in circadian and, even more so, homeostatic processes characterize aging, as do numerous medical and psychiatric comorbidities. Specific disorders such as sleep-disordered breathing and restless legs syndrome can
As the populations of industrialized societies age, knowledge of defining how sleep is affected by age will assume greater importance. Within the United States, the average current life expectancy of 77 years means that 80% of residents now live to be at least 65; the fastest growing segment of the population is those who are 85 years and older. These huge numbers force the sleep medicine specialist to confront the definition of what is normal. Researchers often use the term to connote a variety of meanings. In sleep medicine, confusion often occurs because the term is used descriptively, to indicate representativeness, as well as clinically, to indicate absence of disease. Aging is also subject to semantic confusion. Chronologic age has been shown repeatedly only to approximate physiologic (biological) age. The decline in slow-wave sleep, for example, can occur at a chronological age (at least in men) far earlier than most age-related declines in other biological functions. Some researchers in gerontology have noted that distance from death may be a far better approximation of the aging process, but too few longitudinal sleep studies in humans exist to yield these types of findings. However, studies of invertebrates and have shed new light on relationships between physiologic age and sleep that can affect the functional significance of age-dependent changes (see Basic Science Considerations, later). In addition to the issue of physiologic age, subjective age must be considered. Because the practice of sleep disorders medicine in geriatrics relies heavily on the increased self-reports of sleep disturbance seen in aging, subjective appraisal of the older person’s symptoms must be considered. Whether an aged person views 75% sleep efficiency as insomnia or merely accepts this as a normal part of aging may depend largely on that person’s perspective on growing old and what that means to him or her. It has been reported that older people are more likely to perceive themselves as having sleep problems if they have difficulty falling asleep rather than staying asleep, even though the latter continues to be a generally more commonly endorsed symptom.(See reference 1 for review) In addition, some have suggested that self-reports of sleep measured by polysomnography (PSG) are inherently less accurate and valid in older relative to younger subjects, although evidence for such age differences in other studies is decidedly mixed and varies according to the variables under consideration or the subject’s sex. Finally, normal aging must be viewed in counterpoint to pathologic aging (see Chapter 136). Although the preva-
Chapter
3
demonstrate age-dependence and contribute to sleep problems. Descriptive data continue to accrue to suggest that sleep disturbance in late life might carry its own morbidity and should not be dismissed by the sleep medicine specialist. New data suggest that the breakdown of sleep in the aged organism might reflect physiologic age and reflect alterations in function present at the genomic level.
lence of dementing illnesses is high in late life, determination of the number of normal elderly persons who may be in incipient stages of dementia has seldom been addressed. Additionally, recognition of mental impairments in the more limited domains of memory, executive function, language, attention, and visuospatial ability characterized as of lesser severity has led to the use of an intermediate diagnostic category termed mild cognitive impairment (MCI).2 Few sleep studies of normal aging rely on extensive diagnostic work to eliminate persons in the earliest stages of mental impairment, and polysomnographic studies in well-defined MCI patients have yet to occur. The point here is not to dismiss all that is known about sleep patterns in normal aging as inadequate but rather to point out the complexities of defining normal aging. Normal aging can never be defined without some arbitrary criteria. Throughout this chapter I will refer to aging across several species, encompassing both what in humans may be considered “middle-aged” (approximately 40 to 65 years) and “elderly” (older than 65 years). We recognize fully the otherwise arbitrary nature of these verbal and numeric descriptors of processes that are most assuredly gradual, are continuous, and vary widely across individuals. It is also important to recognize that the age-dependent alterations in sleep may simply be secondary manifestations of senescence.
SLEEP ARCHITECTURE Although age-dependent alterations in sleep architecture have been described for many years,3 only recently have attempts been made to summarize this large body of crosssectional data using meta-analytic techniques.4,5 Results from the first of these analyses4 indicated that although sleep efficiency showed clear age-dependent declines up to and beyond age 90 years, the vast majority of agedependent changes in sleep architecture occurred before age of 60 years, with few changes in slow-wave sleep (SWS, now referred to as N3 sleep in the revised American Academy of Sleep Medicine [AASM] nomenclature6; see later), rapid eye movement (REM) sleep, and stage 1 percentage (N1) occurring after that.4 Some variables (total sleep time, REM) appeared best characterized as linear decline, whereas others (SWS, wake after sleep onset) followed a more exponential course. Sleep latency showed no clear age effect after age 60 years, although it increased up 27
28 PART I / Section 1 • Normal Sleep and Its Variations Table 3-1 Sleep Architecture as a Function of Age Percentage of Time Spent in Stage—Mean (95% CI) STAGE 1 AGE (YR)
STAGE 2
STAGE 3 + 4
REM SLEEP
MEN
WOMEN
MEN
WOMEN
MEN
WOMEN
MEN
WOMEN
37-54
5.8 (5.2-6.5)
4.6 (4.1-5.3)
61.4 (60.0-62.8)
58.5 (57.1-60.0)
11.2 (9.9-12.6)
14.2 (12.7-15.9)
19.5 (18.8-20.2)
20.9 (20.0-21.8)
55-60
6.3 (5.6-7.0)
5.0 (4.4-5.7)
64.5 (63.2-65.9)
56.2 (54.5-57.8)
8.2 (7.1-9.5)
17.0 (15.2-18.9)
19.1 (18.4-19.8)
20.2 (19.3-21.1)
61-70
7.1 (6.4-7.9)
5.0 (4.4-5.7)
65.2 (63.9-66.5)
57.3 (55.7-58.9)
6.7 (5.7-7.7)
16.7 (14.8-18.6)
18.4 (17.8-19.1)
19.3 (18.4-20.2)
>70
7.6 (6.8-8.5)
4.9 (4.3-5.6)
66.5 (65.1-67.8)
57.1 (55.6-58.7)
5.5 (4.5-6.5)
17.2 (15.5-19.1)
17.8 (17.1-18.5)
18.8 (18.0-19.6)
CI, confidence interval; REM, rapid eye movement. From Redline S, Kirchner HL, Quan SF, et al. The effects of age, sex, ethnicity, and sleep-disordered breathing on sleep architecture. Arch Intern Med 2004;164:406-418.
to that point. A second meta-analysis focused only on REM percentage and noted a cubic trend, with REM apparently increasing after age 75 years and then demonstrating an even steeper drop after age 90 years.5 The meaning of the latter data is unclear and raises many questions as to the extent of the precision of chronologic age to capture biological processes in these upper age ranges. Published population-based longitudinal data on sleep architecture would assist in addressing many of these uncertainties. Although meta-analyses can provide cumulative information on age-dependent values across many laboratories, enormous variability in parameter values exists across studies,4 and much of the sleep architecture was not scored blindly to the patient’s chronologic age or sex. This might limit the value of meta-analytic approaches for extrapolation of readily usable, age-dependent laboratory norms. By contrast, the systematically collected, rigorously acquired data derived from the centralized scoring center for the Sleep Heart Health Study (SHHS), although subject to survivor effects and based on single-night data derived from composite cohorts, offer detailed appreciation of how comorbidities, demographics, and sleep-disordered breathing (SDB) can affect observed sleep architecture values employing traditional Rechtschaffen and Kales rules.7 Some have viewed the SHHS sleep architecture data as broadly representative of the elderly population generally because persons with a wide variety of medical conditions were not excluded.8 Percentage of Time Spent in Each Sleep Stage Table 3-1 provides sleep architecture values for 2685 SHHS participants ages 37 to 92 years, excluding persons who use psychotropic medications and who have high alcohol intake, restless legs syndrome symptoms and systemic pain conditions. About a third of these participants were hypertensive and about 10% had histories of cardiovascular disease or chronic pulmonary disease. Results clearly show that although age effects are apparent in some measures, gender occupied a far more dramatic role in sleep architecture, in some cases showing considerable
divergence when comparing women and men. Most notable in this regard is percentage of time spent in sleep stages 3 plus 4, which shows enormous gender differences at every age and, in fact, shows no appreciable decline with aging in women, relative to men. Men demonstrate a marked cross-sectional decline with aging, as well as huge individual differences in every age group. In fact, the extent of these individual differences is emphasized by the fact that even within men as a group, coefficients of variation (ratio of variance to mean) in percentage of time spent in sleep stages 3 plus 4 far exceeded those for all other sleep variables in both men and women. Although gender differences in SWS have been noted previously (see reference 3 for review), the fact that the agedependent decline may be confined only to men suggests a more limited utility of this often-characterized aging biomarker for women. In contrast to the results of the SHHS, these gender differences in SWS were not confirmed meta-analytically.4 At least one study has proposed that gender differences in delta activity are more likely to be a function of overall lower EEG amplitude in men relative to women.9 When corrected for overall amplitude, the decreased growth hormone secretion seen in postmenopausal women was accompanied by lower delta amplitude than in comparably aged men.10 A decline in the amplitude and the incidence of the evoked K-complex over the age range of 19 to 78 years has been reported in both women and men, suggesting that similar deficits in delta synchronization processes operate equally in both sexes.11 Gender did not play a significant role when assessed as the homeostatic response of nighttime delta power to daytime napping in either young or elderly subjects.12 Percentage of time spent in sleep stage 1 also showed similar gender-related effects in SHHS, and agedependent increases in this sleep stage, usually considered to represent a feature of fragmented, transitional sleep, were confined only to men. By contrast, percentage of time spent in REM sleep showed a modest decline with age, but the effect was detected in both men and women. REM percentages of 18% to 20% in 75- to 85-year-olds were derived from curve smoothing in another meta-analysis
focused on only REM sleep measures in normal aging,5 which were slightly lower than, but essentially similar to, SHHS data (see Table 3-1). In SHHS, sleep efficiency also declined with age, with mean values of 85.7 (standard deviation [SD] = 8.3) in the 37- to 54-year-old group, 83.3 (SD = 8.9) in the 55- to 60-year-old group, 80.6 (SD = 11.7) in the 61- to 70-year-old group, and 79.2 (SD = 10.1), in the over-70-year-old group, but without differential effects of gender, findings corroborated metaanalytically in persons older than 60 years.4 However, the declines in percentage of time spent in REM sleep and the (male-specific) increases in percentage of time spent in sleep stage 1 seen in SHHS were not confirmed metaanalytically in persons older than 60 years.4 The density of eye movements in REM is reduced with aging,13 but lack of standardization across laboratories precludes examination of this aspect of REM using meta-analytic techniques. Arousals during Sleep Brief arousals during sleep, representing one component of the microarchitecture of sleep, continues to attract considerable interest as a metric, with particular relevance for the aged population. When examined in the laboratory, healthy older persons wake up from sleep more frequently than younger persons do, regardless of circadian phase, but they have no greater difficulty falling back to sleep.14 Failure to maintain continuous sleep has, as its basic science counterpart, short bout lengths, a feature highly characteristic of sleep in many aged mammalian species.3 In elderly humans without SDB, arousal indices from 18 to 27 events per hour have been reported.15 Among the predominantly elderly subjects (mean age, 61 years) in SHHS, the mean (SD) Arousal Index showed significant but relatively small increases with age: 16.0 (8.2) for 37- to 54-year-olds, 18.4 (10.0) for 55- to 61-year-olds, 20.3 (10.5) for 62- to 70-year-olds, and 21.0 (11.6) for subjects older than 70 years.7 Values approximating these have been reported16 in another group of subjects without sleep apnea or periodic leg movements, thus further corroborating these SHHS values. Other phasic events of non-REM (NREM) sleep, such as K-complex and spindle density, also decrease with age.17 Spindle density is thought to reflect, at least partially, the corticothalamic functional integrity of gammaaminobutyric acid–ergic (GABAergic) systems. Although, like other metrics of impaired sleep quality, brief arousals show a male predominance (also seen metaanalytically using Wake after Sleep Onset4), the influences of age and gender are not as pronounced as the effects of breathing events (Table 3-2). In fact, when accounting for the presence of brief arousals in the elderly, the Respiratory Disturbance Index (RDI) predicts 10-fold more variance than age and 5-fold more variance than gender. Higher levels of RDI were also associated with slightly lower percentage of time spent in REM sleep in both men and women and with lower percentages of time spent in sleep stages 3 plus 4 in men. The latter result is consistent with the hypothesis that at least some SDB in both elderly men and women might reflect ventilatory control instability and that SWS may be protective (see the later section on SDB).
CHAPTER 3 • Normal Aging 29
Table 3-2 Brief Arousal Index in Elderly Subjects as a Function of Sleep-Disordered Breathing Arousal Index: Brief Arousals per Hour of Sleep (±SD) RDI
MEN
WOMEN
≤5
16.7 (7.7)
14.7 (7.1)
>5 to 15
20.5 (8.7)
17.9 (7.8)
>15 to 30
25.2 (10.3)
23.2 (10.4)
>30*
39.4 (14.7)
29.7 (13.6)
*Estimated weighted values. RDI, respiratory disturbance index (apneas plus hypopneas per hour of sleep), a measure of sleep-disordered breathing; SD, standard deviation. From Redline S, Kirchner HL, Quan SF, et al. The effects of age, sex, ethnicity, and sleep-disordered breathing on sleep architecture. Arch Intern Med 2004;164:406-418.
Comorbidities Insofar as comorbidities are concerned, SHHS sleep architecture data showed substantial convergence with metaanalytically derived data. In SHHS, selected medical comorbidities (a positive history of cardiovascular disease, hypertension, and stroke) were associated with disturbed sleep architecture, as was smoking, although, curiously, these results were not seen with chronic obstructive pulmonary disease. Consistent with results suggesting that reduced sleep amounts or quality might predispose to the metabolic syndrome in old age, diabetic patients had smaller percentages of time in stages 3 plus 4 sleep, lower sleep efficiencies, and higher numbers of brief arousals and percentage of time spent in sleep stage 1. In most cases, however, these effects appeared to less salient (i.e., predicted less variance) for sleep architecture than demographic variables such as gender, age (to a lesser extent), and, in some cases, ethnicity,7 except for the arousal index, where RDI was by far the single most powerful predictor. Less-disease-specific moderator effects from meta-analytic approaches also suggested that across the entire life span, age effects were reduced substantially when persons with medical and psychiatric conditions were included.4 The inclusion of persons with sleep apnea showed some evidence of reducing the effects of age in sleep efficiency, wake after sleep onset, and SWS when considered across the entire adult life span,4 data that are compatible with SHHS. Slow-Wave Sleep The gender differences in SWS reported by SHHS notwithstanding, several aspects of these data must be viewed in the context of prior literature on age-dependent changes in architecture. When analyzed with period-amplitude analyses, the major change in SWS ascribed to aging has been a decline in delta wave amplitude rather than wavelength (Fig. 3-1).(See reference 3 for review) The decrease in delta amplitude simply may be a more readily identifiable visual change of the sleep EEG, which is present at frequencies up to about 10 Hz, though it is difficult to see above this.18 When scored visually using central derivations and
30 PART I / Section 1 • Normal Sleep and Its Variations
Delta activity of a 15-year-old male
Well-preserved delta activity, 65-year-old male
Typical delta activity of older men (age 64)
50 µV 1 sec
Figure 3-1 Age differences in delta activity. The top tracing shows typically abundant high-amplitude delta in an adolescent. The middle tracing shows particularly well-preserved delta in an older man. Note the marked decrease in amplitude relative to the adolescent. The bottom tracing is a more typical example of delta activity in an older man. Note the number of waves failing to meet the 75-µV amplitude criterion. (From Zepelin H. Normal age related change in sleep. In: Chase MH, Weitzman ED, editors. Sleep disorders: basic and clinical research. New York: Spectrum; 1983. pp. 431-445.)
employing a 75-µV threshold, typical figures for the amount stages 3 plus 4 sleep in the elderly have often been considered to fall in the 5% to 10% range. Thus, the figures reported by SHHS, particularly for women, are somewhat higher than these conventionally accepted figures. Whether these values represent a more precise rendering of delta activity within sleep, perhaps engendered by the visual analyses of EEG waveforms on digital display or the simultaneous availability of precise calibration of the 75 microvolt criterion for delta waves stipulated by the Rechtschaffen and Kales guidelines, is unclear. Nonetheless, the strictly controlled and exquisitely refined visual analyses conducted by SHHS are likely to represent a standard of polysomnographic technology aspired to by the field of sleep medicine, thus arguing that these newly published metrics may well replace existing data and supplant our current understanding of how sleep architecture measures should be benchmarked. Given the new AASM guidelines for sleep stage scoring,6 much of the foregoing normative data on sleep architecture may have limited relevance for laboratories that elect to adopt such changes. For example, slow-wave activity has higher amplitude when recorded from frontal derivations relative to central derivations. This would be expected to result in increased levels of visually scored slow-wave (i.e., N3) sleep. Indeed a recent study comparing recordings scored with both revised AASM and traditional Rechtschaffen and Kales criteria have shown a number of significant differences in resulting measures.19 Predictably, particularly in older persons, the revised scoring system resulted in higher percentages in N3 sleep. Beyond creating the need to establish new normative data, the mechanistic and functional significance or the diagnostic and
therapeutic importance of such a revisionary approach remain obscure. Much the same effect could be obtained by adopting alternative scoring thresholds of less than 75 µV for defining delta wave activity. Such proposals were put forth in the 1990s(See reference 3 for review) but have not led to enhanced understanding of the age-dependent changes in SWS. Eventually, digitized indices of delta activity (e.g., fast Fourier transform, zero-crossing, or hybrid techniques) might come to replace such conventional measures; however, considerable controversy regarding filtering, sampling rates, and data-storage formatting leaves formal adoption of such approaches dubious for routine clinical purposes at this time,20 though such efforts at signal processing are yielding important new clues regarding the significance of sleep-related delta activity for aging. Slow-wave activity during sleep is thought to represent synaptic downscaling, which is viewed as critical for forming memories.21 Broadly viewed, given at least some data suggesting decreased SWS with age, such findings might fit with mild impairments in cognition that characterize normal aging. Extremely low frequency (<1.0 Hz) slow wave activity in NREM sleep has been thought to hold particular significance as a more immediate reflection of cellular processes than conventionally defined delta activity.22 In dementia, the integrity of the normal auditory evoked response (K-complex) may be impaired,23 whereas in normal aging, there is some suggestion that spectral power at frequencies below 0.7 Hz might demonstrate fewer age differences than at between 0.7 and 3.0 Hz.24 Other attempts to examine NREM sleep in old age using nonlinear, dynamic EEG approaches yield broadly compatible findings. The sleep EEG of healthy older adults in the first NREM period may resemble patterns of compensatory activation similar to those seen in young adults during sleep subsequent to sleep deprivation.25 Whether such phenomenological parallels of altered functional connectivity in sleep deprivation and aging hold prognostic or practical significance at the individual case level is unknown but certainly plausible. Nonlinearity of the NREM sleep EEG increases with normal aging25 and sample entropy, a novel measure reflecting dynamic probabilities of state,26 also changes with age.
CIRCADIAN RHYTHMS IN AGING In humans, most descriptive data collected under entrained conditions have suggested that the amplitude of the sleepwake rhythm, body temperature (Fig. 3-2),27 and some hormones decrease with aging. Sex differences in such phenomena have also been reported (see reference 28 for review). However, in exceptionally healthy older adults such differences might not always appear,29 and a study of centenarians indicated relatively robust neuroendocrine profiles.30 A phase advance of aging has often been ascribed to the timing of sleep patterns in older adults. Many sleep medicine specialists use this designation as an abbreviation for indicating that older persons go to bed earlier in the evening and wake up earlier in the morning than younger persons, findings corroborated in age differences in the timing of bedtimes and wakeup times in dozens of crosssectional surveys(See reference 3 for review) and even longitudinally.31
CHAPTER 3 • Normal Aging 31
Mean oral body temperature (°C)
37.0 36.8 36.6 36.4 36.2 36.0 09:30 13:30 17:30 21:30 01:30 05:30 09:30 Time Figure 3-2 Oral temperatures in young (open circles) and old (dark circles) subjects, showing apparent decreased amplitude and earlier phase in body temperature cycle as a function of aging. Data were obtained under entrained conditions. (From Richardson GS, Carskadon MA, Orav EJ. Circadian variation of sleep tendency in elderly and young adult subjects. Sleep 1982;5[Suppl. 2]:S82-S94.)
However, the reader should be aware that fundamental changes in phase relationships in human circadian rhythms might not always substantiate the notion of such an advance. For example, in the constant routine protocol, older subjects’ typical earlier bedtimes and wakeup times relative to younger subjects actually were more phase delayed, rather than phase advanced, relative to their peaks in melatonin.32 The implication of this finding is that the earlier bedtimes and wakeup times may be due to homeostatic factors. Studies using 28-hour forced desynchrony, an experimental protocol that requires subjects to sleep on a 2 : 1 wake-to-sleep ratio outside the limits of entrainment of the circadian system, have shown absence of age differences in estimates of tau, the endogenous period length of the human core temperature rhythm.33 Again, these results implicate factors other than circadian ones that may be responsible for the earlier bedtimes of older humans. Further evidence of interaction between circadian and homeostatic factors comes from a study of age differences in the melatonin rhythm under the constant routine protocol, during which younger subjects showed elevated melatonin levels during the higher homeostatic pressure induced by this procedure, whereas older subjects did not.34 The interaction between homeostatic and circadian influences in older humans has been described elegantly in the forced desynchrony protocol, which has shown that throughout the assigned (9.33-hour) sleep period, elderly subjects awakened more frequently than younger subjects, regardless of circadian phase.35 The duration of awakenings was virtually identical in young and old subjects, but the largest differences in the frequency of awakenings between young and older subjects were detected early, rather than late, in the sleep period. These results appear incompatible with the broadly defined phase-advanced hypothesis of sleep in the elderly, in which differences in sleep consolidation would be predicted to be most pro-
nounced late in the sleep period (corresponding to early morning awakening) and least pronounced just after sleep onset (corresponding to early evening sleepiness). This study also analyzed sleep structure immediately before awakenings from consolidated periods of sleep. With circadian phase controlled, older subjects were far less likely to awaken from stage 1 and far more likely to awaken from stage 2 than were young subjects, suggesting that awakenings in the older subjects probably represented abrupt transitions from NREM sleep rather than gradual lightening of sleep.35 These findings can be interpreted as an indication of a reduced homeostatic pressure for continuous bouts of sleep independent of circadian phase in the sleep of older persons. A well-described feature of the circadian system in the aged organism is the relative impairment in the ability to phase shift. This may in part reflect loss of rhythmic function within the suprachiasmatic nucleus.36 In humans, the sleep-wake system appears particularly vulnerable to such changes in phase shifting37 and might account for the some of the apparent self-selection out of shift work typically seen in older people (see reference 38 for review). In rodents, such impairments in phase shifting have also been described.39 Although both photic and nonphotic influences on impaired phase-shifting ability have been described in aging,(See reference 38 for review) the ability to phase shift and entrain to light in old age might be expected to be particularly impaired because of challenges to the visual system that occur as a part of human aging (e.g., cataracts, macular degeneration). Perhaps as a consequence, in epidemiologic studies, elderly persons with visual impairments were 30% to 60% more likely to have impaired nighttime sleep relative to visually unimpaired elderly subjects.40 In the laboratory setting, however, disagreement exists as to whether, among persons without visual impairment, responsiveness of the circadian system, as indexed by melatonin rhythms, is decreased41 or unchanged42 by light exposure. Finally, another study examined the ability of a nonphotic stimulus (evening exercise) to phase shift melatonin onset in young and elderly humans and found comparable phase delays subsequent to exercise in both groups, arguing for the importance of entraining factors other than bright light to affect rhythms in the elderly.43 Invertebrate models in studies of sleep and aging have been broadly confirmatory for many of the changes described in mammals, such as the decline in nocturnal sleep durations.44 Several studies in the fruit fly (Drosophila melanogaster)45 and in the honeybee (Apis mellifera)46 have indicated a dispersal of sleep around the 24-hour day occurring with aging. Perhaps more noteworthy is that these studies have also implied that total amount of sleep per 24 hours does not merely redistribute (via shorter bout length and increased number of bouts) but might also increase in quantity with advanced physiologic age. These changes appeared particularly pronounced in male fruit flies45 and female honeybees46 near the end of life. Because an avowed function of the mammalian master clock, located in the suprachiasmatic nucleus, is to provide clockdependent alerting, these data are consistent with early studies that demonstrated such a role for the suprachiasmatic nucleus in primates using lesion models.47 Although studies involving neurodegenerative disease in aged
32 PART I / Section 1 • Normal Sleep and Its Variations
humans have shown increased sleep per 24 hours consistent with level of dementia (see Chapter 136), the invertebrate data imply that increased rather than decreased sleep-durations hours would be likely to occur in aged humans normatively on a population-wide basis. In this regard, it is noteworthy that the largest single compilation of human sleep durations ever published (more than 1 million subjects), shows that reported sleep durations increase, rather than decrease, with age.48 Taken together, these data broadly suggest that increased sleep durations in aged humans might fundamentally represent biological rather than sociocultural factors. Among lower vertebrates, aged zebrafish (Danio rerio) have been shown to demonstrate reduced rest-activity rhythm and shorter nocturnal sleep durations across the lifespan (from 1 to 4 years), and these were associated with decreased brain melatonin during the dark period.49 Melatonin administration was shown to partially restore sleep durations and simple measures of learning in this species. Zebrafish aging was also shown to be associated with gene expression in several clock genes (Bmal1, PER 1),49 although the translation of this finding back to older humans might not be clear.50 Additionally, in rodents, age-effects in the expression of several clock genes may occur equally in both wild-type and mutant lines.51
CAUSES AND CONSEQUENCES OF POOR SLEEP IN OLD AGE Causes The prevalence of insomnia in the aged varies across studies, but figures between approximately 20% and 40% are typically reported. In one of the largest surveys of an American population (the Established Populations for Epidemiologic Studies of the Elderly [EPESE], with more than 9000 participants), 29% of the over-65 population had difficulty maintaining sleep.52 Relative to sleep maintenance, sleep latency is less likely to be problematic for the elderly population, with prevalence figures on the order of 10% to 19% typically seen, although one study53 reported a relatively high prevalence of sleep latency problems (36.7%) in a largely rural aged population. In nearly all studies, elderly women have a greater probability of sleep complaints and sedative-hypnotic use than elderly men do (see reference 1 for review). Conflicting data exist on racial differences in sleep complaints,54 though health disparities in sleep durations did not appear to depend on age.55 Figures for regular use of sedative-hypnotics in elderly populations range from as low as 5% per year to as high as 16% over 4.5 years, 29% over 8 years, 34% over 1 year and 62% over 3 years.(See reference 1 for review) Although subjective reports of poor sleep invariably increased with age and numerous changes in sleep architecture have been frequently noted (see earlier), the relationship between these two domains are significant, though relatively weak, with women showing slightly higher levels of association relative to men.56 Disturbed sleep is thought to both contribute to and reflect allostatic load of illness in old age and might reflect physiologic age of the organism. When other causes of poor sleep are taken into account, chronological age might explain little of the observed higher prevalence in the
elderly. Psychiatric conditions have always been considered to play a major role in the insomnia of old age. A study of more than 3000 older men reported that depressive symptoms were associated with difficulties in falling asleep, but not lower sleep efficiency or total sleep time.57 Among women, although the caregiving role per se was not associated with poor sleep, for women who were depressed, caregiving was associated with reported sleep problems.58 Regardless of caregiving status, anxiety appeared to play a larger role in predicting poor sleep quality in these older women, even relative to depressed mood per se.59 However, poor sleep, left untreated, appears to be a risk factor for incident depression in the elderly.60 Limitations in mobility, visual impairment, lack of regular exercise, alcohol use, and smoking all contribute to declining sleep quality in older persons, as do chronic pain conditions, such as arthritis, hip fracture, fibromyalgia, headache, and back pain; cardiovascular diseases such as hypertension, myocardial infarction, stroke, congestive heart failure, and angina; respiratory conditions such as asthma and bronchitis; and other systemic diseases such as diabetes, gastroesophageal reflux, and duodenal ulcer (see reference 61 for review). When persons with such comorbidities are eliminated from consideration, the resulting insomnia prevalence in elderly populations may be only 1% to 3%,62 reiterating the decreased significance of chronologic age per se in predicting poor sleep. In women, some evidence suggests that menopause may also be associated with declining sleep quality (see Chapter 140). Additionally, in both women and men, the otherwise mundane occurrence of nocturia (nightly awakenings to void) appears to be associated with poor sleep,63 even when other factors such as pain and medical comorbidity are taken into account. In fact, nocturia may be the single most common factor associated with poor sleep in the elderly.63 The role of SDB as a cause for insomnia in older adults has been debated over the years. Although a carefully performed case-control study suggested that SDB frequency was no higher (and might even have been lower) in older persons with poor sleep than in those who slept well, there was evidence that for persons who demonstrated both SDB and poor-quality sleep, the impact on day-to-day function was quite substantial,64 even exceeding those in persons with comparable levels of SDB but no insomnia. Several longitudinal studies examining the incidence (development of new cases) of insomnia over periods of up to 10 years have been reported. The single best predictor of insomnia continuing longer than 10 years was insomnia at a previous time, although cardiovascular and pulmonary comorbidities conferred risk as well in the over-65 population.65 Reported remissions were less likely in older subjects than in younger ones.66 The EPESE data indicated a yearly incidence of insomnia complaints in the aged population of about 5%, with a spontaneous remission rate of about 50% over 3 years.67 In these data, incident insomnia was related to heart disease, stroke, hip fracture, and newonset depression. Spontaneous remission of insomnia was related to the resolution of depression, physical illness, and physical disability affecting activities of daily living,67 whereas in the Cardiovascular Health Study, persistence of insomnia was associated with unresolved depression.68 Important from the standpoint of prevention, another
study reported that higher levels of physical activity were protective for incident insomnia over an 8-year period.69 Potential Consequences A major question regarding the frequent complaints of poor sleep among the elderly involves whether these have an impact on the health of older persons. If the poor sleep of old age, although annoying and distressing for many, represents primarily a quality-of-life issue, albeit one modifiable by medical or behavioral interventions, it might cast a different perspective on this problem, than for a medical disorder such as SDB, where negative outcomes may be better defined and quantified. There is no question that almost universally, poor nocturnal sleep is distressing and related to lower quality of life of many older persons. This has been demonstrated in elderly populations in the United States,70 in Canada,71 across Europe72 and in Asia.73 Interestingly, some have questioned the extent to which such observations may be tempered by older persons’ qualitative perceptions of sleep satisfaction74 or sleep insufficiency,75 which might not change with aging. Most work relating poor sleep quality or duration to putative adverse outcomes has been observational, which, although often provocative, lacks the definitive element of proof of causation that is afforded by randomized clinical trials. Unfortunately, with few exceptions, most pharmacologic and nonpharmacologic randomized clinical trials attempting to treat poor sleep in elderly persons seldom rely on outcomes other than conventional subjective and polysomnographic measures of nocturnal sleep per se. Rare exceptions to the latter have been several insomnia treatment studies among older adults that have demonstrated increases in selected quality-of-life measures such as the SF-3676 or decreased daytime napping.77 Interventional data relevant for other medical outcomes in old age (e.g., hypertension, insulin resistance) have yet to be published. Among observational studies, the association between nocturia and insomnia has led to speculation that the more likely a person is to rise from bed during the night to use the bathroom, the more likely the person is to fall.63 Considerable evidence for this association exists at the population level, where studies have shown associations between insomnia and falls.78 Sleep durations of less than 5 hours were associated with an increased risk for falls of more than 50%.79 Risk for increased falls with short duration of sleep or poor quality of sleep (or both) is also consistent with data suggesting that insomnia is associated with impaired physical function. For example, lower sleep efficiencies were associated with lower grip strength and slower walking speed in a population of elderly men.80 Short sleep durations were associated with a slightly different set of markers of physical impairment in elderly women, primarily consisting of chair-to-stand speed.81 Although the increased risk for falls in the older populations has been typically ascribed to psychotropic and sedative-hypnotic medications, reanalyses of some of these databases have suggested that poor sleep per se may be a more relevant predictive factor.82 Population-based studies also have suggested that poor sleep may be linked to lower cognition in old age. In the Study of Osteoporotic Fractures, a population of older
CHAPTER 3 • Normal Aging 33
women were noted to have scored lower on the Mini Mental State Examination, a general examination of mental function and orientation, and take more time to complete the Trail Making Test, part B, a paper-and-pencil test of psychomotor speed, as sleep efficiencies decreased and sleep latencies increased.83 In another report from that same population, cognitive decline over 15 years was more likely to be associated with sleep efficiency of less than 70% at follow-up.84 In the Nurses’ Health Study cohort, poorer performances on a more-comprehensive battery of cognition, including immediate and delayed verbal memory, category fluency, and attention, were associated with sleep durations of less than 5 hours.85 In an older French population, the likelihood of cognitive problems derived on a self-reported telephone-derived questionnaire was increased by 50% for those reporting 4.5 to 6.0 hours of sleep, and it more than doubled in respondents reporting less than 4.5 hours of sleep.86 Relative to poor-quality sleep, at least some data suggest adverse outcomes associated with short sleep durations in older populations. Gangwisch and colleagues87 reported that sleep durations of less than 5 hours were associated with higher rates of all-cause mortality in subjects 60 years and older, a finding that was not present in persons ages 32 to 59 years. Sleep durations of less than 5 hours per night in even older populations (67 to 99 years old) were associated with obesity as well,88 a finding otherwise well acknowledged in populations younger than 65 years in women in one study89 and in men and women in another.90 Hypertension has also been associated with short sleep durations in elderly persons,91 but other studies of older populations indicated that neither short sleep durations92 nor complaints of poor sleep93 were associated with this morbidity. Diabetes and impaired glycemic control were associated with sleep durations of less than 6 hours (but not insomnia complaints) across the age range 53 to 93 years94 and were independent of age across an even broader age range.95 As mentioned earlier, these are all observational studies, which, although impressive by size of the samples studied and control over confounding variables, did not manipulate sleep quality or sleep duration to demonstrate improvement in any of these putative adverse outcomes in older persons.
RESTLESS LEGS SYNDROME AND PERIODIC LIMB MOVEMENTS IN SLEEP One specific cause of insomnia in the elderly is restless legs syndrome (RLS) (see Chapter 90). This condition, characterized by an urge to move the legs, which is usually accompanied by sensations of discomfort, aggravation of symptoms by rest and temporary relief of symptoms by movement, and worsening during the evening or nocturnal hours, is exceedingly common in elderly populations. Estimates vary, but the condition appears to be more prevalent in northern European96 relative to Asian populations,97 and several genotypes have been identified (see Chapter 90). Peak prevalence was noted in the group ages 60 to 69 years for women (16.3%) and 50 to 59 years for men (7.8%),96 though the population sampled included persons up to age 90 years. Another European study including subjects up to
Number of cases
34 PART I / Section 1 • Normal Sleep and Its Variations
n ale Combined prev
SDB as an age-related disorder
40
50
ce
SDB as an age-dependent disorder
60 Age
70
80
Figure 3-3 Heuristic model suggesting that sleep-disordered breathing (SDB) is both an age-related and an age-dependent condition with potential overlap of distributions in the 60- to 70-year-old age range. Cross-sectionally, note that the number of cases observed can remain high and increase with age, despite a presumed decrease in age-related SDB.
their 80s also showed similar gender differences (14.7% in women; 6.8% in men) with peak prevalence for both genders in the 50- to 59-year-old range.98 Thus, in some respects, RLS prevalence appears to be more age related than age dependent (see later and Fig. 3-3), although at least one study of a Dutch population noted that prevalence was highest in the oldest subjects (80 to 100 years of age).99 Periodic limb movements in sleep (PLMS) are stereotypic, repetitive, nonepileptiform movements of the legs usually consisting of dorsiflexion of the ankle but occasionally limited to flexion of the great toe or incorporating flexion at the level of knee or hip. They often, but not invariably, occur in conjunction with RLS. The intermovement interval has been reported to decrease with age from about 24 to 28 seconds before the age of 55 years to about 14 to 16 seconds after the age of 65 years.100 Agedependent increases in the occurrence of PLMS have been noted cross-sectionally in series without a drop in the oldest (e.g., older than 80 years) groups.101 Curiously, longitudinal follow-up of elderly subjects did not show increases consistently,102 perhaps owing to inherent variability in PLMS. Prevalence, defined as a PLM Index of 15 movements or more per hour, has been estimated as high as 52% in a population of older women.103 When measured with wrist actigraphy in that population, the presence of PLMS was associated with sleep durations of less than 5 hours of sleep,104 though earlier populationbased studies have presented conflicting data as to whether PLMS, in the absence of frank RLS symptoms, were associated with poor sleep.101 One study of men ages 40 to 60 years noted poorer sleep quality when the PLM index exceeded 10.105 Other studies demonstrating the mixed pattern of results correlating PLMS with sleep complaints have been reviewed elsewhere.106 One possible explanation for the variability of results across studies is that PLMS may vary considerably from
night to night. A 15-night study suggested that estimated prevalence for PLMS might stabilize only after multiple nights of measurement.107 The discrepancy between the higher prevalence of PLMS relative to RLS and the failure of a number of studies to show associations between their presence and specific symptoms suggests that in many elderly persons, PLMS may be an incidental finding.106 The worsening of RLS and PLMS with aging suggests that this syndrome may be associated with other conditions known to be common in older populations. Given the likelihood of anemia among the elderly, current attention has focused largely on iron transport and storage deficiencies.108 Elderly RLS patients with serum ferritin levels of less than 45 mg/mL showed subjective improvement following use of ferrous sulfate, although their total iron levels were no different.108 These findings were later replicated by the same research group.109 Because iron represents a key component of production of dopamine, it could play a role in presence of RLS in some elderly subjects. One population-based study could not confirm the ferritin finding,110 although another report indicated that higher serum-soluble transferrin-receptor levels (often characteristic of early-stage anemia) and lower serum iron were associated with RLS.96 An interesting perspective on iron metabolism and aging was based on examination of ferritin levels in the cerebrospinal fluid of elderly RLS patients. Older patients had higher CSF ferritin levels than did younger patients; however, for elderly patients whose RLS had been long-standing, lower levels were associated with a more-severe condition.111
SLEEP-DISORDERED BREATHING Specific considerations related to diagnosis and treatments of SDB in the elderly are covered in Chapter 134. This section deals with more general issues involving age-dependence. The previously proposed heuristic model for SDB (Fig. 3-3) posits that SDB represents both an age-related phenomenon (with a specific vulnerability confined to middle age) and an age-dependent phenomenon (with a prevalence that steadily increases throughout the human life course).1 The articulation and differentiation of these two presumably separate, but chronologically overlapping, distributions represents a major challenge to clinicians. Practically, if the health consequences of SDB in elderly populations are diminished, the necessity to treat the enormous numbers of elderly persons who have the condition is reduced. Age dependence implies that SDB risk factors might be best considered markers of physiologic or biological age.112 Chronologic age may thus serve only as a proxy for other risk factors that are themselves age-dependent. Risk Factors Risk factors for SDB in the older population may differ to some extent from those in middle-aged populations. In SHHS, several markers of obesity that were significant cross-sectional predictors of SDB in middle-aged populations (neck circumference and waist-to-hip ratio), were no longer significant predictors by age 70 years and 80 years,
CHAPTER 3 • Normal Aging 35
respectively,113 although body mass index continued to be correlated with SDB, even past age 80 years, albeit with a somewhat diminished effect. Although the male predominance in SDB is thought to equalize in old age, this was not the case within SHHS.113 Other cohort studies including older subjects suggested roughly equal prevalence in elderly men and women.114,115 The prevailing view for many decades was that most SDB in the elderly consisted of central (i.e., diaphragmatic) events, whereas in the middle-aged population obstructive events predominated; however this is unsubstantiated by both descriptive studies, showing the predominance of obstructive apneas, and by pathophysiologic studies, which show increased tendency for upper airway collapse with aging (see reference 116 for review). Upper airway resistance has been reported to be higher in both REM and NREM sleep in older men relative to younger men,117 and closing pressures during sleep were higher in older subjects in N2 sleep relative to younger subjects.118 Aging has been associated with lengthening of the soft palate and with upper airway fat pad deposition, both of which may contribute to oropharygeal collapse during sleep.119 Lower lung volumes have been shown to predict incident SDB in elderly persons over time,120 perhaps by providing less caudal traction on the trachea and hastening upper airway collapse during sleep. In older animals, the pharyngeal muscles appear to have a worse profile for endurance relative to the diaphragm, which may enhance susceptibility to collapse,121 and a shift from type IIa to IIb fibers occurred in the genioglossus in 24-month-old rats, a finding interpreted as conferring susceptibility to fatigue.122 Predisposing influences on SDB in elderly human populations are not limited to neuromuscular factors. Ventilatory control instability,123 which may be accentuated by the decrease of N3 sleep with age, might also predispose to SDB in the elderly, though not all studies report high loop gain in older subjects.124 These and other potential age-dependent risk factors for SDB are shown in Figure 3-4. Outcomes Potential outcomes relevant to SDB in old age include mortality, cardiovascular and neurobehavioral morbidities,
POTENTIAL AGE-DEPENDENT RISK FACTORS ↑ Body weight ↓ Lung capacity ↓ Ventilatory control ↑ Upper airway collapsibility ↓ Muscular endurance ↓ Thyroid function ↑ Sleep fragmentation ↓ Slow-wave sleep
POTENTIAL AGE-DEPENDENT OUTCOMES
SDB as a marker of physiologic aging
Mortality Neurobehavioral morbidity Cardiovascular morbidity Other endorgan damage (e.g., renal)
Figure 3-4 Sleep-disordered breathing (SDB) in older adults as an age-dependent condition. Other potentially associated agedependent risk factors and outcomes are shown.
and morbidities related to other potential end-organ damage (see Fig. 3-4). In the absence of large-scale prospective randomized clinical trials specifically targeting SDB treatments in geriatric populations, definitive causal associations with adverse outcomes in the aged remain uncertain. The prevailing viewpoint in sleep medicine has been that SDB demonstrates weakened associations with morbidities in elderly, relative to middle-aged, persons. Offered here is a brief description of studies in older populations suggesting otherwise. In the elderly, SDB has been associated cross-sectionally with clinically defined hypertension,125 a nondipping blood pressure pattern,126 composite cardiovascular disease history (in men),127 stroke,128 reduced kidney function (in men),129 poorer physical function (in men),80 nocturia,130 overactive bladder,131 and impaired cognition (in women).132 Longitudinal data have shown a relationship between declining mental status test scores and the development of SDB.133 Additionally, higher health care costs were associated with sleep apnea in both middle-aged and elderly persons.134 An important association between SDB and frailty has also been noted in older women,135 which is particularly important given the fact that, as a wellacknowledged geriatric syndrome, frailty is highly predictive of other morbidities and of mortality.136 In SHHS, when subjects with prevalent cardiovascular disease were excluded, relationships between SDB (as measured by quartiles of the apnea-hypopnea index) and various morbidities (including diabetes and hyperlipidemia) were clearly lower in the over-65-year-old population than in the under-65-year-old population, but only in men, not women, where the associations were similar.137 By contrast, Haas and colleagues138 reported that isolated systolic hypertension was unrelated to SDB in any age range, but that systolic and diastolic hypertension were related to SDB in only those younger than 60 years. In another report examining associations between multi ple measures of SDB and more broadly defined cardiovascular disease (including coronary heart disease, congestive heart failure, and stroke), relationships with SDB, although reduced to some extent by age, were still age-independent.139 Despite this suggestive evidence, other studies continue to minimize the significance of SDB for elderly populations. For example, it has been contended that sleep apnea has little impact upon quality of life in the elderly,140 and others have argued that ischemic preconditioning essentially renders the SDB of old age innocuous, because some component of protective adaptation is likely to have occurred.141 Goff and colleagues142 have shown that cardiovascular responses (elevations in heart rate and blood pressure) to auditory stimulation are reduced in older relative to younger persons, and they have interpreted this as consistent with the reduced associations between SDB and systemic hypertension that has been reported in older persons. Because the study was performed in older persons without SDB, the results are difficult to reconcile with the ischemic preconditioning hypothesis, and it remains unclear whether such presumed sympathetic downregulation might underlie the presumably reduced impact of SDB in the elderly. The consequences of SDB in older
36 PART I / Section 1 • Normal Sleep and Its Variations
populations thus remain an area of considerable controversy, and the sleep medicine specialist should be cognizant of these issues. For further discussion, the reader is directed elsewhere(See references 1 and 116 for review) and to other chapters in this volume (Chapters 134 and 136).
WHY DO OLDER PEOPLE NAP? A time-honored question, asked by both professionals and the lay public, involves the significance of napping in old age. From the layperson’s perspective the question is most typically: “Is it normal to nap?” or “Are naps good or bad for my health?” The sleep medicine specialist may ask fundamentally similar, though more diagnostically inclined questions such as: “What is the probability that daytime naps in a 75-year-old indicate SDB?” “Does excessive sleepiness during the day in an older person portend dementia?” or “To what extent does daytime napping adversely effect sleep at night?” These are highly relevant questions that are made even more difficult to answer by cultural issues related to napping, the complexities in relying on self-reports to derive estimates of the physiologic tendency of sleep during the daytime hours, and the fact that, overarching all other issues, sleeping during the daytime hours in old age is most assuredly a multidetermined phenomenon. Elsewhere I have reviewed the complex matrix of results that suggest that napping is both a beneficial and potentially protective event in the life of an older person as well as an identifiable risk factor for numerous morbidities and even mortality.1 Perhaps the most direct approach to answer the question of why older persons are sleepy during the day is a case-control design that compares otherwise demographically well-matched, communitydwelling elderly persons, some of whom are sleepy during the day and some of whom are not.143 Key to such a design is the incorporation of a diverse array for variables that have been thought to account for sleepiness in older persons, including subjective and polysomnographically defined measures of nocturnal sleep fragmentation, careful assessment of comorbid medical disease, psychopathology, medication use that might induce sleepiness, alcohol use, smoking status, measurements of SDB and PLMS, and specific conditions known to disrupt nocturnal sleep, such as nocturia and physical pain. Results from such a study indicated that male sex, poor sleep quality, sleep interruptions due to nocturnal pain or bathroom trips, and medications known to induce sleepiness differentiated cases and controls. Only severe SDB (more than 30 events per hour) predicted sleepiness, but PLMS did not.143 Several unanticipated findings (positive relationship to percentage of time spent in REM sleep, negative relationship to alcohol consumption) were also noted. Taken together, these findings suggest there are many factors that predict why an older person may be sleepy during the day. Napping has also been associated with falls144 and incipient cognitive decline84 in a population of older women and with depression,145 nocturia,146 diabetes,147 and lower quality of life148 in both men and women. On the other hand, evidence continues to accrue that naps may be protective for cardiovascular events,149 might improve daytime
function,150 do not adversely affect nocturnal sleep,151 and might even be associated with longer sleep duration the previous night.152 Other studies suggest that naps and hypersomnolence portend mortality153 or ischemic heart disease154 and that daytime fatigue or anergy predict diverse morbidities155 or all-cause mortality.156 Again, however, not all population-based studies concur, and some suggest absence of excess mortality risk associated with napping,157 particularly in elderly persons.149 Clearly, the many reasons for daytime napping and sleepiness in older populations continue to be elusive and outcomes associated with the phenomenon are disparate.(See reference 1 for review) Additionally, the methodologic issues involved in defining napping are substantial and undoubtedly effect lack of comparability across studies.158
BASIC SCIENCE CONSIDERATIONS Beyond the aforementioned rich description of the complex and interrelated changes in human sleep with advancing years outlined in this chapter, the ultimate significance of such alterations remains enigmatic. If one views such changes in sleep merely as epiphenomenal to components of the aging process, they may be merely a consequence of more fundamental changes in the biology of the organism operating at the system, cellular, or molecular levels. On the other hand, might age-dependent alterations in sleep and rhythms themselves be potential influences on physiologic aging per se? If that is indeed the case, then manipulations or interventions that alter sleep might modify disease course, change fundamental processes of aging, or perhaps even contribute to the longevity of the organism. Research in this exciting area is only just beginning, but certain provocative clues are emerging, particularly as we learn more about sleep function. Invertebrate models have proved invaluable in understanding more about how sleep is related to the aging process. The relative strength of the sleep–wake cycle and the length of sleep bouts have been shown to breakdown with age in Drosophila, and the extent of the disruption was magnified under higher temperatures (29 °C) relative to more moderate (25 °C) or cooler (18 °C) temperatures,45 an important observation because Drosophila are known to have a longer life span in cooler temperatures. Additionally, incorporation of paraquat, an herbicide known to induce oxidative stress, into the flies’ food supply produced similar results. Examination of sleep in Drosophila mutants with exceedingly short sleep durations and rapid physiologic aging (i.e., shortened life span) also suggested that sleep may indeed play a vital role in survival.158a In the first of these, the minisleep (MNS) line, derived from an exhaustive search of 9000 mutant lines, homozygous flies showed reductions in sleep durations of 37% of female flies and 32% of male flies relative to wild-type flies.159 Genotyping suggested that the MNS line was characterized by a point mutation in the Shaker gene, thought to regulate potassium channel repolarization and broadly defined neuronal excitability. Perhaps most importantly from the standpoint of aging, survivorship to very old age in these flies (defined in this study as 56 days), was substantially lower than in flies with other Shaker locus mutations or in wild-type controls; in
some cases the effects approached a fivefold reduction in life span.159 A different fly line, called sleepless (sss), which overexpresses another Shaker-related protein involved in the downregulation of potassium influx, has been shown to be associated with even more dramatic reductions in sleep amount (85% for males, 80% for females).160 In this mutant, reductions in survivorship were even more profound, with virtually none of the sss flies surviving beyond 50 days (median about 30 days) relative to the median survival of control flies (about 70 days).160 These data certainly imply that absence of sleep is associated with more rapid aging, though they do not suggest what function ascribed to sleep may be related to acceleration of such aging processes. By contrast, studies of sleep deprivation in mammals might afford a broader perspective on such issues. Sleep deprivation studies in humans over the last 25 years have shown repeatedly that sleep loss interacts with aging in several key ways. Homeostatic pressure for sleep may be somewhat diminished in humans and in some rodent species, particularly when recovery sleep is characterized by changes in both sleep duration and delta activity pressure. In humans, the behavioral consequences of sleep loss, framed in terms of both greater daytime sleepiness and more impaired waking performances, appear diminished, rather than enhanced, with aging (see references 1 and 28 for reviews of this area). These facts imply, but cannot prove, that sleep might have less significance and, as a corollary, loss of sleep may be of less consequence—or at very least, no more consequence—as the organism ages. The data presented throughout this chapter notwithstanding, such results might be interpreted hastily as suggesting less of a need to intervene in the sleep of older persons. By contrast, important new molecular evidence suggests that at the subcellular level, sleep deprivation may be more detrimental for function in aging animals than in young animals. More specifically, the unfolded protein response within the endoplasmic reticulum occurring after sleep deprivation161 may be modified substantially by aging. Protein aggregation is a well-acknowledged feature of many neurodegenerative conditions in late life and appears to occur as one of the earliest signs of impending neuronal death. The unfolded protein response, which consists of a host of molecular changes involving attenuation of translation of adverse proteins, degradation of misfolded proteins, and promotion of factors (chaperones) protective for normal function of the endoplasmic reticulum, shows synergistic age and sleep-deprivation effects. For example, expression of a major chaperone, BiP/GRP78, is known to be downregulated in both brain and liver of aged animals, but it showed major upregulation following sleep deprivation in young, but not old, mice.161,162 Perhaps even more relevant were changes in proapoptotic proteins (e.g., caspase-12). Aging was associated with greater expression of these markers of apoptosis, and sleep deprivation in the mouse activated this pathway as well. Strikingly, sleep deprivation in the older animal further accentuated such markers of preprogrammed cell death beyond those seen in normal aging and beyond those in sleep deprivation.162 If these findings are in any way translatable to the human condition, they would suggest a greater, rather than lesser,
CHAPTER 3 • Normal Aging 37
necessity to attend to the myriad number of sleep problems in old age.163
SUMMARY Defining normality in elderly populations remains a challenging task. However, an ever-increasing database informs the sleep medicine specialist about potential morbidities that may be associated with poor sleep and various sleep disorders in old age. Multiple factors contribute to poor sleep at night and excessive sleepiness during the day in the aged human. Although most studies have been observational and descriptive, the examination of sleep in lower animals might allow greater understanding of agedependent changes in sleep as an indicator of biological or physiologic age and sheds new light on the importance of treating sleep problems in human aging. Acknowledgment This work is supported by National Institute on Aging grants AG-020269 and AG-025688 and National Institute of Neurological Disorders and Stroke grant NS-050595.
❖ Clinical Pearls In old age, in particular, the sleep medicine specialist should always remember that there are numerous overlapping and contributing reasons why the elderly patient has disrupted sleep at night or may be sleepy during the day. Napping should never be assumed to be innocuous, nor should excessive sleepiness during the day be attributed unequivocally to active or subclinical disease. Sleep-disordered breathing may be associated with adverse outcomes in elderly populations as well as middle-aged populations and might warrant treatment. Poor sleep might not only reduce the quality of life of the older person, it might also portend adverse health consequences.
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42 PART I / Section 1 • Normal Sleep and Its Variations
Daytime Sleepiness and Alertness Timothy Roehrs, Mary A. Carskadon, William C. Dement, and Thomas Roth Abstract Sleepiness is a problem reported by 10% to 25% of the population, depending on the definition of sleepiness used and the population sampled. It is more frequent in young adults and elderly people. Sleepiness is a physiological need state with its intensity evident by how rapidly sleep onset occurs, how easily sleep is disrupted, and how long sleep endures. Validated self-rated scales and physiological measures are available to assess the presence and degree of sleepiness. Relative to sleepy, healthy adults, the chronicity and irreversibility of sleepiness is indicative of its clinical and pathological
INTRODUCTION Scientific and clinical attention to sleepiness arose from the recognition of excessive daytime sleepiness (EDS) as a symptom associated with serious life-threatening medical conditions. In the late 1960s, this symptom—which earlier had been ignored, attributed to lifestyle excesses, viewed as a sign of laziness and malingering, or at best, seen as a sign of narcolepsy–began to be seriously studied by scientist–clinicians. Methods to detect and quantify sleepiness were developed. The result has been a growing scientific literature on the nature of sleepiness and its determinants in clinical populations, selected populations of healthy volunteers, and the general population. This chapter will review information regarding the prevalence of sleepiness in the population. The various methods used to measure sleepiness in the population and laboratory will be described and guidelines regarding clinical assessment of sleepiness will be offered. The nature and neurobiological substrates of sleepiness will be discussed and the known determinants of sleepiness will be described. Finally, the clinical and public health significance of persistent complaints of sleepiness will be discussed.
EPIDEMIOLOGY OF SLEEPINESS Prevalence estimates of sleepiness in the population vary widely depending on the definition of sleepiness used and the type of population sampled. Surveys and questionnaires have queried regarding the experience of a mood or feeling state of sleepiness, fatigue, or tiredness; about falling asleep unintentionally; or about struggling to stay awake and fighting sleep onset. New developments in the epidemiology of sleepiness have included the use of standardized sleepiness scales and physiological assessments of sleepiness that measure the behavior of falling asleep, its estimated likely occurrence or the speed of its actual occurrence. While another important focus has been on sleepiness in children and adolescents, this chapter only will address sleepiness in adults. 42
Chapter
4
significance. Sleepiness is caused by reduced sleep time as often seen in otherwise healthy adults, by fragmented and disrupted sleep as found in patients with primary sleep disorders, by administration of sedating drugs and discontinuation of alerting drugs, and by various neurological disorders. Sleepiness has a normal circadian rhythm that is increased in circadian rhythm misalignments such as those occurring in shift work or jet lag. Excessive and persistent sleepiness is life-threatening, but when its presence is recognized and its etiology identified, it can be successfully treated or at least minimized.
Sleepiness in Limited Populations or Populations of Convenience In surveys of relatively small, selected populations, 0.3% to 36% of respondents reported excessive sleepiness. Surveys with reported excessive sleepiness rates of less than 3% generally are from earlier studies that focused on hypersomnia.1 In later studies, in which 4% to 9% rates were reported, more specific questions about excessive sleepiness during the day or relative to one’s peers were asked.2 In some surveys, postprandial, or midday, sleepiness was distinguished from sleepiness at other times of the day, a distinction discussed later in regard to the circadian correlates of sleepiness. Somewhat higher rates are reported in other selected populations using sleepiness scales. For example, the Epworth Sleepiness Scale (ESS), a scale that requires one to estimate the likelihood of falling asleep in different situations, was completed by 740 day workers in 8 industrial plants in Israel and 23% of respondents had ESS scores indicative of excessive sleepiness (i.e., scores >10).3 Prevalence rates for sleepiness of 15% and greater also have been found for specific age groups that are consistent with smaller laboratory studies using the physiological measure of sleepiness, the Multiple Sleep Latency Test (MSLT), which is described later. Young adults were sleepier, on average, than a comparison group of middle-aged adults, and about 20% of the young adults had mean daily sleep latencies of less than 5 minutes, a level of sleepiness considered pathological.4 Healthy elderly also were found to be physiologically sleepier than middle-aged adults.5 In surveys of the work force engaged in shift or night work, complaints of excessive sleepiness during waking hours are more frequent than among day workers, and continuous ambulatory electroencephalographic (EEG) field monitoring has confirmed the sleepiness.6 Sleepiness in Representative Populations Representative survey studies of national populations have been done. In a study representative of the Finnish
CHAPTER 4 • Daytime Sleepiness and Alertness 43
population, 11% of women and 7% of men reported daytime sleepiness almost every day.7 In another survey, representative of a large geographical area in Sweden, 12% of respondents thought their sleep was insufficient.8 In that survey, insufficient sleep, and not its consequent daytime sleepiness, was the focus of the questions. Two studies representative of the United States population used the MSLT to assess sleepiness. Given the necessary time commitment required of participants in MSLT studies, the representative integrity of study results is critically dependent on the recruitment response rate. From a large southeastern Michigan random sample (n = 1648) representative of the U.S. population, a subsample (n = 259) with a 68% response rate was recruited to undergo a nocturnal polysomnogram (NPSG) and MSLT the following day. The prevalence of excessive sleepiness, defined as a MSLT average sleep latency of less than 6 minutes, was 13%.9 In another probability sample of 6,947 Wisconsin state employees, a subsample (n = 632), collected with a 52% response rate, slept at home and then completed a MSLT in the laboratory the next day. Twenty-five percent had an average sleep latency of less than 5 minutes.10 These two studies also used the ESS to assess sleepiness; in the Michigan study 20% had ESS scores greater than 10, and in the Wisconsin study 25% had scores greater than 11. The higher prevalence in the Wisconsin study, despite the more stringent definition of sleepiness (MSLT of 5 vs. 6 minutes and ESS of 11 vs. 10), could be attributed to an age difference in the samples (51 vs. 42 yr on average) or the previous night’s sleep time and circumstances (habitual
at home, on average 7.1 hr vs. standard laboratory 8.5 hr). In Figure 4-1 the distribution of sleepiness, defined as average sleep latency on the MSLT, is illustrated for the Michigan population representative sample. The average sleep latency of various clinical samples and experimental sleep time manipulations is provided for comparisons. Risk Factors for Sleepiness The risk factors for sleepiness identified in the various surveys includes hours of daily sleep, employment status, marital status, snoring, and depression. Among 26- to 35-year-old members of a large health maintenance organization in Michigan, respondents reported 6.7 hours of sleep on weekdays and 7.4 hours on weekend days, on average.11 The hours of sleep were inversely related to daytime sleepiness scores on the Sleep–Wake Activity Inventory (SWAI). Both these variables were related to employment and marital status, with full employment and being single predictive of less sleep time and more sleepiness. Self-reported snoring and depression, as measured by a structured diagnostic interview, were also associated with increased sleepiness. In the Finnish study cited earlier, sleepiness was associated with moderate to severe depression and with snoring more than three times per week.7
NATURE OF SLEEPINESS Physiological Need State Sleepiness, according to a consensus among sleep researchers and clinicians, is a basic physiological need state.12
7.7%
29.0%
Excessive daytime sleepiness
Moderate sleepiness
10%
Anesthesia Residents Sleep apnea
Mean = 11.4
8 hr TIB x 5 nights
6 hr TIB x 4 nights
0 hr TIB x 1 night 7.5%
10 hr TIB x 14 nights (full alertness) Narcolepsy
5%
2.5%
0% 0
5
10
15
20
MSLT mean sleep latency (min) Figure 4-1 The distribution of mean daily sleep latency (min) on the multiple sleep latency test in a subsample (n = 259) recruited (68% response rate) from a large Southeastern Michigan random sample (N = 1648) representative of the U.S. population. The population mean is 11.4 minutes and this is compared to means reported for various patient groups60,70,71 and the means found in healthy normals after various bedtime manipulations.23,62 TIB, time in bed.
44 PART I / Section 1 • Normal Sleep and Its Variations
It may be likened to hunger or thirst, which are physiological need states basic to the survival of the individual organism. The presence and intensity of this state can be inferred by how readily sleep onset occurs, how easily sleep is disrupted, and how long sleep endures. Deprivation or restriction of sleep increases sleepiness, and as hunger or thirst is reversible by eating or drinking, sleep reverses sleepiness. In the organism’s daily homeostatic economy, severe deprivation states do not normally occur and hence are not routinely responsible for regulating eating or drinking; other factors (i.e., taste, smell, time-of-day, social factors, biological variables) modulate these behaviors before severe deprivation states develop. Similarly, routine consumption of sleep is not purely homeostatic, but is greatly influenced by social (i.e., job, family, and friends) and environmental (i.e., noise, light, and bed) factors. The subjective experience of sleepiness and its behavioral indicators (yawning, eye rubbing, nodding) can be reduced under conditions of high motivation, excitement, exercise, and competing needs (e.g., hunger, thirst); that is, physiological sleepiness may not necessarily be manifest. The expression of mild to moderate sleepiness can be masked by any number of factors that are alerting, including motivation, environment, posture, activity, light, or food intake. Studies have shown that average sleep latency on the MSLT is increased by 6 minutes when sitting versus lying in bed and also by 6 minutes when immediately preceded by a 5-minute walk.13 However, when physiological sleepiness is most severe and persistent, the ability to reduce its impact on overt behavior wanes. The likelihood of sleep onset increases and the intrusion of microsleeps into ongoing behavior occurs. On the other hand, a physiologically alert (sleepiness and alertness are used here as antonyms) person does not experience sleepiness or appear sleepy even in the most soporific situations. Heavy meals, warm rooms, boring lectures, and the monotony of longdistance automobile driving unmask physiological sleepiness when it is present, but they do not cause it. Within a conventional 24-hour sleep and wake schedule, maximum sleepiness ordinarily occurs in the middle of the night when the individual is sleeping, and consequently this sleepiness typically is not experienced or remembered. When forced to be awake in the middle of the night, one experiences loss of energy, fatigue, weariness, difficulty concentrating, and memory lapses. When significant physiological sleepiness (as a result of reduced sleep quantity or quality) intrudes on one’s usual waking activities during the day, similar symptoms are experienced. Adaptation to the chronic experience of sleepiness most probably occurs. Clinicians have reported anecdotally that successfully treated patients will frequently comment that they had forgotten the experience of complete alertness. Reduced sensitivity to chronic sleepiness is a likely explanation for the disparities between subjective assessments, even when done with validated scales and the MSLT.5,14 Typically, it is the most sleepy individuals that show the greatest disparity in subjective versus objective assessments.5,14 Such individuals deny sleepiness despite significant objective indicators of sleepiness. On the other hand, basally alert individuals (ESS mean 5.6, SEM 0.3) after a one night acute sleep restriction were quite accurate in estimating their sleepiness relative to the increases in EEG
theta activity shown during a simulated driving task.15 Studies have also shown that compensation occurs to the cognitive and behavioral effects of experimental sleep restriction and increased sleepiness, particularly when the sleep loss is mild and accumulates at a slow rate.16 The absence of a readily apparent behavioral deficiency probably also contributes to the subjective-objective disparity seen in chronically sleepy individuals. Finally, findings from a general population study suggest that subjective sleepiness has multiple dimensions, beyond an increased tendency to fall asleep.17 Consequently, patients often mistake chronic debilitating fatigue for sleepiness.18 The specific nature of this physiological need state is unclear. Whether sleepiness is one-dimensional, varying only in severity, or multidimensional, varying as to etiology or chronicity, has been discussed.19 If it is one-dimensional, whether or not sleepiness and alertness are at opposite poles of the dimension is also an issue. Earlier, it was noted that sleepiness and alertness are being used as antonyms, which suggests a unipolar state. However, it is possible that sleepiness varies from presence to absence and is distinct from alertness. It was noted that sleepiness may be multidimensional, and among the different types of sleepiness cited are rapid eye movement (REM) versus non–rapid eye movement (NREM) and core versus optional sleepiness.19 A complete discussion of the heuristic value and evidence to support these distinctions is beyond the scope of this chapter. Nonetheless, the point must be made that these theoretical perspectives may be colored by different measures, experimental demands, populations studied, and subject or patient motivations (i.e., sensitivity to and capacity to counteract sleepiness). Neural Substrates of Sleepiness The substrates of sleepiness have yet to be determined. It is assumed that sleepiness is a central nervous system (CNS) phenomenon with identifiable neural mechanisms and neurochemical correlates. Various electrophysiological events suggestive of incipient sleep processes appear in behaviorally awake organisms undergoing sleep deprivation. In sleep-deprived animals, ventral hippocampal spike activity, which normally is a characteristic of NREM sleep, increases during behavioral wakefulness and in the absence of the usual changes in cortical EEG indicative of sleep.20 Human beings deprived, or restricted, of sleep show identifiable microsleep episodes (brief intrusions of EEG indications of sleep) and increased amounts of alpha and theta activity while behaviorally awake.21 The evidence suggests that these electrophysiological events are indicants of sleepiness. An emerging literature of neuroimaging studies, both structural and functional, have suggested specific brain systems that may be involved in sleepiness. Sleep deprivation in young healthy volunteers reduced regional cerebral glucose metabolism, as assessed by positron emission tomography, in thalamic, basal ganglia, and limbic regions of the brain.22 Functional magnetic resonance imaging (fMRI) after chlorpheniramine (a sedating antihistamine) compared with placebo showed increased frontal and temporal activation.23 Because fMRI was conducted while the subject was performing cognitive tasks, the authors interpreted the observed brain activation to have resulted from
the increased mental effort, due to sleepiness, required to perform the task. Two groups of patients with severe or slight hypersomnia associated with paramedian thalamic stroke on an MRI showed lesions involving dorso- and centromedial thalamic nuclei, bilateral lesions in the severe group and unilateral in the slight group.24 As yet, these imaging data are not conclusive. They do suggest it may be possible to identify brain regions and functions that vary with sleepiness. But the nature of the alteration may depend on the behavioral load imposed on the sleepy subject as well as the cause of the sleepiness. The neurochemistry of sleepiness and alertness involves critical and complex issues that have not yet been fully untangled (see Chapters 18, 37, 42, and 44). First, a basic issue concerns whether sleepiness and alertness have a neurochemistry specific and unique from that associated with the sleep process, per se. Second, it is not clear whether sleepiness and alertness are controlled by separate neurochemicals or by a single substance or system. Third, the relation of the neurochemistry of sleepiness and alertness to circadian mechanisms has not yet been determined. Given the number of questions, it should be of no surprise that these are areas of active research. Neurophysiological studies of sleep and wake mechanisms have implicated histamine, serotonin, the catecholamines, and acetylcholine in control of wake and gamma-aminobutyric acid (GABA) for sleep.25 Evidence from animal studies is emerging that suggests extracellular adenosine is the homeostatic sleep factor, with brain levels accumulating during prolonged wakefulness and declining during sleep.26 The peptide hypocretin/orexin has received much attention for its role in the pathophysiology of narcolepsy.27 It is considered to be a major wake-promoting hypothalamic neuropeptide and a hypocretin/orexin deficiency has been found in human narcolepsy. Its interactive role in the homeostatic control of sleep and sleepiness has yet to be determined. It is discussed in greater detail in Chapters 18, 37, 42, and 44. Pharmacological studies provide other interesting hypotheses regarding the neurochemistry of sleepinessalertness. For example, the benzodiazepines induce sleepiness and facilitate GABA function at the GABAA receptor complex, thus implicating this important and diffuse inhibitory neurotransmitter.25 Another example involves histamine, which is now considered to be a CNS neurotransmitter and is thought to have CNS-arousing activity.25 Antihistamines that penetrate the CNS produce sleepiness.28 A functional neuroimaging study of histamine H1 receptors in human brain found that the degree of sleepiness associated with cetirizine (20 mg) was correlated to the degree of H1 receptor occupancy.29 Stimulant drugs suggest several other transmitters and neuromodulators. The mechanism of action of one class of drugs producing psychomotor stimulation and arousal, the amphetamines, is blockade of catecholamine uptake.30 Another class of stimulants, the methylxanthines, which include caffeine and theophylline, are adenosine receptor antagonists. Adenosine, considered the key neurochemical in the homeostatic regulation of sleep, has inhibitory activity on the two major excitatory neurotransmitters acetylcholine and glutamate. It may be a biomarker of sleepiness.26 On the other hand, some contradictory evi-
CHAPTER 4 • Daytime Sleepiness and Alertness 45
dence limits making definitive conclusions. The space here is too limited to discuss all the evidence in detail. In conclusion, although it is widely held that sleepiness is a physiological state, its physiological substrates are as yet not fully defined.
ASSESSMENT OF SLEEPINESS Quantifying Sleepiness The behavioral signs of sleepiness include yawning, ptosis, reduced activity, lapses in attention, and head nodding. An individual’s subjective report of his or her level of sleepiness also can be elicited. As noted earlier, a number of factors such as motivation, stimulation, and competing needs can reduce the behavioral manifestation of sleepiness. Thus, behavioral and subjective indicators often underestimate physiological sleepiness. Assessment problems were evident early in research on the daytime consequences of sleep loss. Sleep loss compromises daytime functions; virtually everyone experiences dysphoria and reduced performance efficiency when not sleeping adequately. But a majority of the tasks used to assess the effects of sleep loss are insensitive.31 In general, only long and monotonous tasks are reliably sensitive to changes in the quantity and quality of nocturnal sleep. An exception is a 10-minute visual vigilance task, completed repeatedly across the day, during which lapses (response times greater than or equal to 500 milliseconds) and declines in the best response times are increasingly observed as sleep is lost, either during total deprivation or cumulatively over nights of restricted bedtimes.32 In various measures of mood, including factor analytic scales, visual analogue scales, and scales for specific aspects of mood, subjects have shown increased fatigue or sleepiness with sleep loss. Among the various subjective measures of sleepiness, the Stanford Sleepiness Scale (SSS) is the best validated.33 Yet clinicians have found that chronically sleepy patients may rate themselves alert on the SSS even while they are falling asleep behaviorally.34 Such scales are state measures that query individuals about how they feel at the present moment. Another perspective is to view sleepiness behaviorally, as in the likelihood of falling asleep, and thus ask individuals to rate that likelihood in different social circumstances and over longer periods. The Epworth Sleepiness Scale (ESS) has been validated in clinical populations showing a 74% sensitivity and 50% specificity relative to the MSLT in a study of sleep disorders patients.35 It asks about falling asleep in settings in which patients typically report falling asleep (e.g., while driving, at church, in social conversation). The time frame over which ratings are to be made is 2 to 4 weeks. The standard physiological measure of sleepiness, the MSLT, similarly conceptualizes sleepiness as the tendency to fall asleep by measuring the speed of falling asleep. The MSLT has gained wide acceptance within the field of sleep and sleep disorders as the standard method of quantifying sleepiness.36 Using standard polysomnographic techniques, this test measures, on repeated opportunities at 2-hour intervals throughout the day, the latency to fall asleep while lying in a quiet, dark bedroom. The MSLT is based on the assumption, as outlined earlier, that sleepiness is a
46 PART I / Section 1 • Normal Sleep and Its Variations
physiological need state that leads to an increased tendency to fall asleep. The metric typically used to express sleepiness has been average daily sleep latency (i.e., mean of the four or five tests conducted), but survival analyses have also been successfully used.37 The reliability and validity of this measure have been documented in a variety of experimental and clinical situations.38 In contrast to tests of performance, motivation does not seem to reduce the impact of sleep loss as measured by the MSLT. After total sleep deprivation, subjects can compensate for impaired performance, but they cannot stay awake long while in bed in a darkened room, even if they are instructed to do so.39 An alternative to the MSLT, suggested by some clinical investigators, is the Maintenance of Wakefulness Test (MWT). This test requires that subjects lie in bed or sit in a chair in a darkened room and try to remain awake.40 Like the MSLT, the measure of ability to remain awake is the latency to sleep onset. The test has not been standardized: there are 20-minute and 40-minute versions, and the subject is variously sitting upright in a chair, lying in bed, or semirecumbent in bed. The reliability of the MWT has not been established either. One study reported sensitivity to the therapeutic effects of continuous positive airway pressure (CPAP) in patients with sleep apnea,41 and several studies reported sensitivity to the therapeutic effects of stimulants in narcolepsy.42 A study attempted to tease apart the critical factors being measured by the MWT and concluded that, unlike the MSLT which measures level of sleepiness, the MWT measures the combined effects of level of sleepiness and the degree of arousal as defined by heart rate.43 The rationale for the MWT is that clinically the critical issue for patients is how long wakefulness can be maintained. A basic assumption underlying this rationale, however, may not be valid: it assumes that a set of circumstances can be evaluated in the laboratory that will reflect an individual’s probability of staying awake in the real world. Such a circumstance is not likely because environment, motivation, circadian phase, and any competing drive states all affect an individual’s tendency to remain awake. Stated simply, an individual crossing a congested intersection at midday is more likely to stay awake than an individual driving on an isolated highway in the middle of the night. The MSLT, on the other hand, addresses the question of the individual’s risk of falling asleep by establishing a setting to maximize the likelihood of sleep onset: all factors competing with falling asleep are removed from the test situation. Thus, the MSLT identifies sleep tendency or clinically identifies maximum risk for the patient. Obviously, the actual risk will vary from individual to individual, from hour to hour, and from environment to environment. Relation of Sleepiness to Behavioral Functioning Given that the MSLT is a valid and reliable measure of sleepiness, the question arises as to how this measure relates to an individual’s capacity to function. Direct correlations of the MSLT with other measures of performance under normal conditions have not been too robust. Several studies have found, however, that when sleepiness is at maximum levels, correlations with performance are
high. For example, MSLT scores after sleep deprivation,44 after administration of sedating antihistamines,45 and after benzodiazepine administration46 correlate with measures of performance and even prove to be the most sensitive measure. Studies also have compared levels of sleepiness to the known performance-impairing effects of alcohol.47 A study relating performance lapses on a vigilance task to the cumulative effects of sleep restriction found a function comparable to that of the MSLT under a similar cumulative sleep restriction (Fig. 4-2).48 The reason many studies have found weak correlations between performance and MSLT at normal or moderate levels of sleepiness is that laboratory performance and MSLT are differentially affected by variables such as age, education, and motivation. For the most part, the literature relating sleepiness and behavioral functioning has focused on psychomotor and attention behaviors with the major outcomes being response slowing and attentional lapses. These impairments can be attributed to slowed processing of information and microsleeps, that is intrusion of sleep preparation and sleep onset behaviors. Research has focused on other behavioral domains not as clearly associated with sleepmediated behaviors, including decision-making and pain sensation. Several studies have shown that increased sleepiness is associated with poor risk-taking decisions.49 Sleep loss and its associated sleepiness have also been shown to increase pain sensitivity.50
16 14 12 10 8 6 4 PVT lapses 2
Sleep latency (min)
0 B
P1
P2
P3
P4
P5
P6
P7
Day Figure 4-2 Similar functions relating mean daily sleep latency on the multiple sleep latency test (MSLT) and mean daily lapses on the visual psychomotor vigilance test (PVT) to the cumulative effects of sleep restriction (about 5 hours of bedtime nightly) across 7 consecutive nights (P1 to P7). (Redrawn from Dinges DF, Pack F, Williams K, et al. Cumulative sleepiness, mood disturbance, and psychomotor vigilance performance decrements during a week of sleep restricted to 4-5 hours per night. Sleep 1997;20:275.)
CHAPTER 4 • Daytime Sleepiness and Alertness 47
Clinical Assessment of Sleepiness Assessing the clinical significance of a patient’s complaint of excessive sleepiness can be complex for an inexperienced clinician. The assessment depends on two important factors: chronicity and reversibility. Chronicity can be explained simply. Although a healthy normal individual may be acutely sleepy, the patient’s sleepiness is persistent and unremitting. As to reversibility, unlike the healthy normal person, increased sleep time may not completely or consistently ameliorate a patient’s sleepiness. Patients with excessive sleepiness may not complain of sleepiness per se, but rather its consequences: loss of energy, fatigue, lethargy, weariness, lack of initiative, memory lapses, or difficulty concentrating. To clarify the patient complaint, it is important to focus on soporific situations in which physiological sleepiness is more likely to be manifest, as was discussed earlier. Such situations might include watching television, reading, riding in a car, listening to a lecture, or sitting in a warm room. Table 4-1 presents the commonly reported “sleepinducing” situations for a large sample of patients with sleep apnea syndrome. After clarifying the complaint, one should ask the patient about the entire day: morning, midday, and evening. In the next section, it will become clear that most adults experience sleepiness over the midday. However, patients experience sleepiness at other times of the day as well, and often throughout the day. Whenever possible, objective documentation of sleepiness and its severity should be sought. As indicated earlier, the standard and accepted method to document sleepiness objectively is the MSLT. Guidelines for interpreting the results of the MSLT are available (see Fig. 4-1).36 A number of case series of patients with disorders of excessive sleepiness have been published with accompanying MSLT data for each diagnostic classification.51 These data provide the clinician with guidelines for evaluating the clinical significance of a given patient’s MSLT results. Although these data cannot be considered norms, a scheme for ranking MSLT scores to indicate degree of pathology has been suggested.41 An average daily MSLT score of 5 minutes or fewer suggests pathological sleepiness, a score of more than 5 minutes but fewer than 10 minutes is considered a diagnostic gray area,
Table 4-1 Sleep-Inducing Situations for Patients with Apnea* SITUATION
PERCENTAGE OF PATIENTS
Watching television
91
Reading
85
Riding in a car
71
Attending church
57
Visiting friends and relatives
54
Driving
50
Working
43
Waiting for a red light
32
*N = 384 patients.
and a score of more than 10 minutes is considered to be in the normal range (see Fig. 4-1 for MSLT results in the general population). The MSLT is also useful in identifying sleep-onset REM periods (SOREMPs), which are common in patients with narcolepsy.52 The American Academy of Sleep Medicine Standards of Practice Committee has concluded that the MSLT is indicated in the evaluation of patients with suspected narcolepsy.52 MSLT results, however, must also be evaluated with respect to the conditions under which the testing was conducted. Standards have been published for administering the MSLT, which must be followed to obtain a valid, interpretable result.36
DETERMINANTS OF SLEEPINESS Quantity of Sleep The degree of daytime sleepiness is directly related to the amount of nocturnal sleep. The performance effects of acute and chronic sleep deprivation are discussed in Chapters 5 and 6. As to sleepiness, partial or total sleep deprivation in healthy normal subjects is followed by increased daytime sleepiness the following day.38 Therefore, modest nightly sleep restriction accumulates over nights to progressively increase daytime sleepiness and performance lapses (see Fig. 4-1).53 However, the speed at which sleep loss is accumulated is critical, as studies have shown adaptation to a slow accumulation of 1 to 2 hours nightly occurs, which then increases the duration of the subsequent recovery process.23 Increased sleep time in healthy, but sleepy, young adults by extending bedtime beyond the usual 7 to 8 hours per night produces an increase in alertness (i.e., reduction in sleepiness).54 Further, the pharmacological extension of sleep time by an average of 1 hour in elderly people produces an increase in mean sleep latency on the MSLT (i.e., increased alertness).55 Reduced sleep time explains the excessive sleepiness of several patient and nonpatient groups. For example, a subgroup of sleep clinic patients has been identified whose excessive daytime sleepiness can be attributed to chronic insufficient sleep.56 These patients show objectively documented excessive sleepiness, “normal” nocturnal sleep with unusually high sleep efficiency (time asleep–time in bed), and report about 2 hours more sleep on each weekend day than each weekday. Regularizing bedtime and increasing time in bed produces a resolution of their symptoms and normalized MSLT results.57 The increased sleepiness of healthy young adults also can be attributed to insufficient nocturnal sleep. When the sleepiest 25% of a sample of young adults is given extended time in bed (10 hours) for as long as 5 to 14 consecutive nights, their sleepiness is reduced to a level resembling the general population mean.54 Individual differences in tolerability to sleep loss have been reported.58 These differences can be attributed to a number of possible factors. A difference in the basal level of sleepiness at the start of a sleep time manipulation is quite possible given the range of sleepiness in the general population (see Fig. 4-1). The basal differences may reflect insufficient nightly sleep relative to ones’ sleep need.54 There also may be differences in the sensitivity and responsivity of the sleep homeostat to sleep loss, that is how large
48 PART I / Section 1 • Normal Sleep and Its Variations
a sleep deficit the system can tolerate and how robustly the sleep homeostat produces sleep when detecting deficiency. Finally, genetic differences in sleep need, the set point around which the sleep homeostat regulates daily sleep time, have long been hypothesized and one study has suggested a gene polymorphism may mediate vulnerability to sleep loss.59 These all are fertile areas for research. Quality of Sleep Daytime sleepiness also relates to the quality and the continuity of a previous night’s sleep. Sleep in patients with a number of sleep disorders is punctuated by frequent, brief arousals of 3 to 15 second durations. These arousals are characterized by bursts of EEG speeding or alpha activity and, occasionally, transient increases in skeletal muscle tone. Standard scoring rules for transient EEG arousals have been developed.60 A transient arousal is illustrated in Figure 4-3. These arousals typically do not result in awakening by either Rechtschaffen and Kales sleep staging criteria or behavioral indicators, and the arousals recur in some conditions as often as 1 to 4 times per minute. The arousing stimulus differs in the various disorders and can be identified in some cases (apneas, leg movements, pain) but not in others. Regardless of etiology, the arousals generally do not result in shortened sleep but rather in fragmented or discontinuous sleep, and this fragmentation produces daytime sleepiness.61 Correlational evidence suggests a relation between sleep fragmentation and daytime sleepiness. Fragmentation, as indexed by number of brief EEG arousals, number of shifts from other sleep stages to stage 1 sleep or wake, and the percentage of stage 1 sleep correlates with EDS in various patient groups.61 Treatment studies also link sleep fragmentation and excessive sleepiness. Patients with sleep apnea syndrome who are successfully treated by surgery (i.e., number of apneas are reduced) show a reduced frequency of arousals from sleep as well as a reduced level of sleepiness, whereas those who do not benefit from the
surgery (i.e., apneas remain) show no decrease in arousals or sleepiness, despite improved sleeping oxygenation.62 Similarly, CPAP, by providing a pneumatic airway splint, reduces breathing disturbances and consequent arousals from sleep and reverses EDS.63 The reversal of daytime sleepiness following CPAP treatment of sleep apnea syndrome is presented in Figure 4-4. The hours of nightly CPAP use predicts both subjective and objective measures of sleepiness.64 Experimental fragmentation of the sleep of healthy normal subjects has been produced by inducing arousals with an auditory stimulus. Several studies have shown that subjects awakened at various intervals during the night demonstrate performance decrements and increased sleepiness on the following day.65 Studies have also fragmented sleep without awakening subjects by terminating the stimulus on EEG signs of arousal rather than on behavioral response. Increased daytime sleepiness (shortened latencies on the MSLT) resulted from nocturnal sleep fragmentation in one study,66 and in a second study, the recuperative effects (measured as increased latencies on the MSLT) of a nap following sleep deprivation were compromised by fragmenting the sleep on the nap.67 One nonclinical population in which sleep fragmentation is an important determinant of excessive sleepiness is the elderly. Many studies have shown that even elderly people without sleep complaints show an increased number of apneas and periodic leg movements during sleep.68 As noted earlier, the elderly as a group are sleepier than other groups.5 Furthermore, it has been demonstrated that elderly people with the highest frequency of arousal during sleep have the greatest daytime sleepiness.69 Circadian Rhythms A biphasic pattern of objective sleep tendency was observed when healthy, normal young adult and elderly subjects were tested every 2 hours over a complete 24-hour day.70 During the sleep period (11:30 pm to 8:00 am) the latency
15 Latency to sleep (min)
LE – A1 RE – A1 EMG (submental) C4 – A1 Oz – A1 V5 50 µV
12 9
1 night 14 nights
*,**
*,**
42 nights *
6 3
1 sec
Figure 4-3 A transient arousal (on right side of figure) fragmenting sleep. The preexistence of sleep is evident by the K-complex at second 9 of the epoch preceding the arousal. LE-A1, Left electrooculogram referenced to A1; RE-A1, right electrooculogram referenced to A1; EMG, electromyogram from submental muscle; C4-A1, electroencephalogram referenced to A1 from C4 placement; Oz-A1, electroencephalogram referenced to A1 from Oz placement; V5, electrocardiogram from V5 placement. (Redrawn from American Sleep Disorders Association. EEG arousals: scoring rules and examples. Sleep 1992; 15:173-184.)
0 Pre
Post CPAP treatment
Figure 4-4 Mean daily sleep latency on the multiple sleep latency test (MSLT) in patients with obstructive sleep apnea syndrome before (pre) and after (post) 1, 14, and 42 nights of continuous positive airway pressure (CPAP) treatment. *, P < .05; **, P < .01. (Redrawn from Lamphere J, Roehrs T, Wittig R, et al. Recovery of alertness after CPAP in apnea. Chest 1989;96:1364-1367.)
Mean latency to sleep onset (min)
CHAPTER 4 • Daytime Sleepiness and Alertness 49
25 20 15 10 5
Elderly
Young adult
0 0930
1330
1730
2130
0130
0530
0930
Time of day Figure 4-5 Latency to sleep at 4-hour intervals across the 24-hour day. Testing during the daytime followed standard multiple sleep latency test (MSLT) procedures. During the night, from 11:30 PM to 8:00 AM (shaded area), subjects were awakened every 2 hours for 15 minutes, and latency of return to sleep was measured. Elderly subjects (n = 10) were 60 to 83 years old; young subjects (n = 8) were 19 to 23 years old. (Redrawn from Carskadon MA, Dement WC: Daytime sleepiness: Quantification of a behavioral state. Neurosci Biobehav Rev 1987;111:307-317. Copyright 1987, Elsevier Science.)
testing was accomplished by awakening subjects for 15 minutes and then allowing them to return to sleep. Two troughs of alertness—one during the nocturnal hours (about 2:00 to 6:00 am) and another during the daytime hours (about 2:00 to 6:00 pm)—were observed. Figure 4-5 shows the biphasic pattern of sleepiness–alertness. Other research protocols have yielded similar results. In constant routine studies, where external environmental stimulation is minimized and subjects remain awake, superimposed on the expected increase in self-rated fatigue resulting from the deprivation of sleep is a biphasic circadian rhythmicity of self-rated fatigue similar to that seen for sleep latency.71 In another constant routine study in which EEG was continuously monitored, a biphasic pattern of “unintentional sleep” was observed.72 In studies with sleep scheduled at unusual times, the duration of sleep periods has been used as an index of the level of sleepiness. A pronounced circadian variation in sleep duration is found with the termination of sleep periods closely related to the biphasic sleep latency function in the studies cited earlier.73 If individuals are permitted to nap when they are placed in time-free environments, this biphasic pattern becomes quite apparent in the form of a midcycle nap.74 This circadian rhythm in sleepiness is part of a circadian system in which many biological processes vary rhythmically over 24 hours. The sleepiness rhythm parallels the circadian variation in body temperature, with shortened latencies occurring in conjunction with temperature troughs.70 But these two functions, sleep latency and body temperature, are not mirror images of each other; the midday body temperature decline is relatively small compared with that of sleep latency. Furthermore, under freerunning conditions, the two functions become dissociated.75 However, no other biological rhythm is as closely associated with the circadian rhythm of sleepiness as is body temperature.
Earlier, it was noted that shift workers are unusually sleepy, and jet travelers experience sleepiness acutely in a new time zone. The sleepiness in these two conditions results from the placement of sleep and wakefulness at times that are out of phase with the existing circadian rhythms. Thus, not only is daytime sleep shortened and fragmented but also wakefulness occurs at the peak of sleepiness or trough of alertness. Several studies have shown that pharmacological extension and consolidation of out-of-phase sleep can improve daytime sleepiness (see Chapters 42, 73, and 81 for more detail).76 Yet, the basal circadian rhythm of sleepiness remains, although the overall level of sleepiness has been reduced. In other words, the synchronization of circadian rhythms to the new sleep– wake schedule is not hastened. CNS Drugs Sedating Drug Effects Central nervous system (CNS) depressant drugs, as expected, increase sleepiness. Most of these drugs act as agonists at the GABAA receptor complex. The benzodiazepine hypnotics hasten sleep onset at bedtime and shorten the latency to return to sleep after an awakening during the night (which is their therapeutic purpose), as demonstrated by a number of objective studies.77 Long-acting benzodiazepines continue to shorten sleep latency on the MSLT the day following bedtime administration.77 Finally, ethanol administered during the daytime (9:00 am) reduces sleep latency in a dose-related manner as measured by the MSLT.78 Second generation antiepileptic drugs, including gabapentin, tiagabine, vigabatrin, pregabalin, and others, enhance GABA activity through various mechanisms that directly or indirectly involve the GABAA receptor.79 The sedating effects of these various drugs have not been thoroughly documented, but some evidence indicates they do have sedative activity. GABAB receptor agonists are being investigated as treatments for drug addictions and the preclinical animal research suggests these drugs may have sedative activity as well.80 Antagonists acting at the histamine H1 receptor also have sedating effects. One of the most commonly reported side effects associated with the use of H1 antihistamines is daytime sleepiness. Several double-blind, placebo-controlled studies have shown that certain H1 antihistamines, such as diphenhydramine, increase sleepiness using sleep latency as the objective measure of sleepiness, whereas others, such as terfenadine or loratadine do not.81 The difference among these compounds relates to their differential CNS penetration and binding. Others of the H1 antihistamines (e.g., tazifylline) are thought to have a greater peripheral compared with central H1 affinity, and, consequently, effects on daytime sleep latency are found only at relatively high doses.81 Antihypertensives, particularly beta adrenoreceptor blockers, are also reported to produce sedation during the daytime.82 These CNS effects are thought to be related to the differential liposolubility of the various compounds. However, we are unaware of any studies that directly measure the daytime sleepiness produced by beta-blockers; the information is derived from reports of side effects. As noted earlier, it is important to differentiate sleepiness
50 PART I / Section 1 • Normal Sleep and Its Variations
from tiredness or fatigue. Patients may be describing tiredness or fatigue resulting from the drugs’ peripheral effects (i.e., lowered cardiac output and blood pressure), not sleepiness, a presumed central effect. Sedative effects of dopaminergic agonists used in treating Parkinson’s disease have been reported as adverse events in clinical trials and in case reports as “sleep attacks” while driving.83 It is now clear these “sleep attacks” are not attacks per se, but are the expression of excessive sleepiness. Whereas the dose-related sedative effect of these drugs has been established, the mechanism by which the sedative effects occur is unknown. The dopaminergic agonists are also known to disrupt and fragment sleep.84 Thus, the excessive sleepiness may be secondary to disturbed sleep, or to a combination of disturbed sleep and direct sedative effects. Alerting Drug Effects Stimulant drugs reduce sleepiness and increase alertness. The drugs in this group differ in their mechanisms of action. Amphetamine, methylphenidate, and pemoline block dopamine reuptake and to a lesser extent enhance the release of norepinephrine, dopamine, and serotonin. The mechanism of modafinil is not established; some evidence suggests that modafinil has a mechanism distinct from the classical stimulants. Amphetamine, methylphenidate, pemoline, and modafinil are used to treat the EDS associated with narcolepsy and some have been studied as medications to maintain alertness and vigilance in normal subjects under conditions of sustained sleep loss (e.g., military operations). Studies in patients with narcolepsy using MSLT or MWT have shown improved alertness with amphetamine, methylphenidate, modafinil, and pemoline.85 There is dispute as to the extent to which the excessive sleepiness of narcoleptics is reversed and the comparative efficacy of the various drugs. In healthy normal persons restricted or deprived of sleep, both amphetamine and methylphenidate increase alertness on the MSLT and improve psychomotor performance.86,87 Caffeine is an adenosine receptor antagonist. Caffeine, in doses equivalent to 1 to 3 cups of coffee, reduced daytime sleepiness on the MSLT in normal subjects after 5 hours of sleep the previous night.88 Influence of Basal Sleepiness The preexisting level of sleepiness–alertness interacts with a drug to influence the drug’s behavioral effect. In other words, a drug’s effect differs when sleepiness is at its maximum compared to its minimum. As noted previously, the basal level of daytime sleepiness can be altered by restricting or extending time in bed58; this in turn alters the usual effects of a stimulating versus a sedating drug. A study showed comparable levels of sleepiness–alertness during the day following 5 hours in bed and morning (9:00 am) caffeine consumption compared to 11 hours in bed and morning (9:00 am) ethanol ingestion. Follow-up studies explored the dose relations of ethanol’s interaction with basal sleepiness.89 Dose-related differences in daytime sleepiness following ethanol and 8 hours of sleep were diminished after even 1 night of 5 hour sleep, although the measured levels of ethanol in breath were consistent day to day. In other words, sleepiness enhanced the sedative
effects of ethanol. In contrast, caffeine and methylphenidate produced a similar increase in alertness, regardless of the basal level of sleepiness. Clinically, these findings imply, for example, that a sleepy driver with minimal blood ethanol levels may be as dangerous as an alert driver who is legally intoxicated.89 The basal state of sleepiness also influences drug-seeking behavior. The likelihood that a healthy normal person without a drug abuse history will self-administer methylphenidate is greatly enhanced after 4 hours of sleep the previous night compared to 8 hours of sleep (see Fig. 4-4). Though not experimentally demonstrated as yet, self administration of caffeine also is probably influenced by basal state of sleepiness. The high volume of caffeine use in the population probably relates to the high rate of self medication for sleepiness due to chronic insufficient sleep in the population. CNS Pathologies Pathology of the CNS is another determinant of daytime sleepiness. The previously noted hypocretin/orexin deficiency is thought to cause excessive sleepiness in patients with narcolepsy.90 Another sleep disorder associated with excessive sleepiness due to an unknown pathology of the CNS is idiopathic CNS hypersomnolence. A report of a series of rigorously diagnosed cases (n = 77) found moderate MSLT scores (8.5 minutes mean latency) relative to narcoleptics (4.1 minutes mean latency).91 As yet hypocretin/orexin deficiency has not been shown in this disorder. These two conditions are described in detail in Chapters 84 and 86. Excessive sleepiness is reported in other neurological diseases. A study in patients with myotonic dystrophy, type 1 reported excessive sleepiness on the MSLT and reduced cerebrospinal levels of hypocretin/orexin.92 “Sleep attacks” have been reported in Parkinson’s disease and assessment with the MSLT suggests these attacks are the expression of excessive daytime sleepiness.93 What remains unresolved in the excessive sleepiness of Parkinson’s disease is the relative contribution of the disease itself, the fragmentation of sleep due to periodic leg movement or apnea , and the dopaminergic drugs used in treating Parkinson’s disease.94 The previously cited study found no differences in sleepiness as a function of prescribed drug or sleep fragmentation, although further assessment in larger samples is necessary to confirm this finding. Sleepiness may be prominent after traumatic brain injury.94a,94b
CLINICAL AND PUBLIC HEALTH SIGNIFICANCE OF SLEEPINESS Although the patients at sleep disorders centers are not representative of the general population, they do provide some indications regarding the clinical significance of sleepiness. Their sleep–wake histories directly indicate the serious impact excessive sleepiness has on their lives.95 Nearly half the patients with excessive sleepiness report automobile accidents; half report occupational accidents, some life threatening; and many have lost jobs because of their sleepiness. In addition, sleepiness is considerably disruptive of family life.96 An elevated automobile accident rate (i.e., sevenfold) among patients with excessive sleepi-
ness has been verified through driving records obtained from motor vehicle agencies.97 Population-based information regarding traffic and industrial accidents also suggests a link between sleepiness and life-threatening events. Verified automobile accidents occurred more frequently in a representative sample of people with MSLT scores of 5 minutes or less.98 The highest rate of automobile accidents occurs in the early morning hours, which is notable because the fewest automobiles are on the road during these hours. Also during these early morning hours, the greatest degree of sleepiness is experienced.99 Long-haul truck drivers have accidents most frequently (even corrected for hours driving before the accident) during the early morning hours, again when sleepiness reaches its zenith.100 Workers on the graveyard shift were identified as a particularly sleepy subpopulation. In 24-hour ambulatory EEG recordings of sleep and wakefulness, workers (20% in one study) were found to actually fall asleep during the night shift.8 Not surprisingly, the poorest job performance consistently occurs on the night shift, and the highest rate of industrial accidents is usually found among workers on this shift.101 Medical residents are another particularly sleepy subpopulation. In surveys those reporting five or fewer hours of sleep per night were more likely to make medical errors, report serious accidents, and were two times more likely to be named in medical malpractice suits.102,103 In a survey of medical house-staff, 49% reported falling asleep while driving and 90% of the episodes occurred postcall compared to 13% fall-asleep episodes reported by the medical faculty and 20 of the 70 housestaff were involved in automobile accidents compared to 11 of the 85 faculty.104 Cognitive function is also impaired by sleepiness. Adults with various disorders of excessive sleepiness have cognitive and memory problems.105 The memory deficiencies are not specific to a certain sleep disorder but rather specific to the sleepiness associated with the disorder. When treated adequately, sleepiness is rectified and the memory and cognitive deficits similarly improve.106 Results of sleep deprivation studies in healthy normal patients support the relation between sleepiness and memory deficiency. Even modest reductions of sleep time are associated with cognitive deficiencies.107 Sleepiness also depresses arousability to physiological challenges: 24-hour sleep deprivation decreases upper airway dilator muscle activity108 and decreases ventilatory responses to hypercapnia and hypoxia.109 In a canine model of sleep apnea, periodic disruption of sleep with acoustic stimuli (i.e., sleep fragmentation, in contrast to sleep deprivation) resulted in lengthened response times to airway occlusion, greater oxygen desaturation, increases in inspiratory pressures, and surges in blood pressure.110 Depressed physiological responsivity due to sleepiness is clinically significant for patients with sleep apnea and other breathing disorders as they are all exacerbated by sleepiness. The emerging data on sleepiness and pain threshold, cited earlier, is also clinically significant in the management of both acute and chronic pain conditions. Finally, life expectancy data directly link excessive sleep (not specifically sleepiness) and mortality. A 1976 study found that men and women who reported sleeping more
CHAPTER 4 • Daytime Sleepiness and Alertness 51
than 10 hours of sleep a day were about 1.8 times more likely to die prematurely than those sleeping between 7 and 8 hours daily.111 This survey, however, associated hypersomnia and increased mortality and not necessarily EDS, for which the relation is currently unknown. ❖ Clinical Pearl Sleepiness, when most excessive and persistent, is a signal to the individual to stop operating because it is dangerous and life-threatening to continue without sleep. It is also a signal to the clinician that there may be some underlying pathology that can be successfully treated, or in the very least minimized, as to its vital, life-threatening impact.
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editors. Sleep 1976. Basel, Switzerland: Karger; 1977. pp. 95- 100. 96. Broughton R, Ghanem Q, Hishikawa Y, et al. Life effects of narcolepsy in 180 patients from North America, Asia and Europe compared to matched controls. J Can Sci Neurol 1981;8: 299-304. 97. Findley LJ, Unverzagt ME, Suratt PM. Automobile accidents involving patients with obstructive apnea. Am Rev Respir Dis 1988;138:337-340. 98. Drake C, Scofield H, Jefferson C, et al. MSLT defined sleepiness predicts verified automotive crashes in the general population. Sleep 2007;30:A131 [abstract]. 99. Mitler MM, Carskadon MA, Czeisler CA, et al. Catastrophes, sleep, and public policy: consensus report. Sleep 1988;11:100-109. 100. Mackie RR, Miller JC. Effects of hours of service, regularity of schedules, and cargo loading on truck and bus driver fatigue. Washington, DC: US Government Printing Office; 1978. Technical Report 1765-F DOT-HS-5-01142. 101. Dorrian J, Tolley C, Lamond N, et al. Sleep and errors in a group of Australian hospital nurses at work and during the commute. App Ergon 2008;39:605-613. 102. Baldwin DC, Daugherty SR. Sleep deprivation and fatigue in residency training: results of a national survey of first- and second-year residents. Sleep 2004;27:217-223. 103. Marcus CL, Loughlin GM. Effect of sleep deprivation on driving safety in housestaff. Sleep 1996;19:763-766. 104. Roehrs TA, Merrion M, Pedrosi B, et al. Neuropsychological function in obstructive sleep apnea syndrome (OSAS) compared to chronic obstructive pulmonary disease (COPD). Sleep 1995;18: 382-388. 105. Rao V, Spiro J, Samus QM, et al. Insomnia and anytime sleepiness in people with dementia residing in assisted living: finding from the Maryland Assisted Living Study. Int J Ger Psychiat 2008;23:199- 206. 106. Aguirre M, Broughton RJ, Stuss D. Does memory impairment exist in narcolepsy-cataplexy? J Clin Exp Neuropsychol 1985;7: 14-24. 107. Blagrove M, Alexander C, Horne JA. The effects of chronic sleep reduction on the performance of cognitive tasks sensitive to sleep deprivation. Appl Cogn Psychol 1994;9:21-40. 108. Leiter JC, Knuth SL, Barlett D. The effect of sleep deprivation on activity of the genioglossus muscle. Am Rev Respir Dis 1985; 132:1242-1245. 109. White DP, Douglas NJ, Pickett CK, et al. Sleep deprivation and control of ventilation. Am Rev Respir Dis 1983;128:984-986. 110. Brooks D, Horner RL, Kimoff RJ, et al. Effect of obstructive sleep apnea versus sleep fragmentation on responses to airway occlusion. Am J Respir Crit Care Med 1997;155:1609-1617. 111. Kripke DF, Simons NR, Garfinkel L, et al. Short and long sleep and sleeping pills. Is increased mortality associated? Arch Gen Psychiatry 1979;36:103-116.
Acute Sleep Deprivation Michael H. Bonnet Abstract Sleep deprivation is extremely common in modern society. Sleep loss is accompanied by significant and increasingly apparent alterations in mood, alertness, and performance. This chapter reviews the behavioral effects of sleep deprivation, including both sleep/circadian influences and arousal system influences such as activity, light, noise, posture, motivation, and drugs. The effects of sleep loss are broad, and numerous systems are affected. Work showing similar changes after alcohol ingestion provides one means of comparatively describing the effects of sleep loss. A number of relatively mild physiologic changes accompany total sleep deprivation in
Sleep deprivation is both extremely common and critically relevant in our society. As a clinical entity, sleep deprivation is recognized by the diagnosis of insufficient sleep syndrome (International Classification of Diseases [ICD]2, #307.44). As an experimental methodology, sleep deprivation serves as a major tool in understanding the function of sleep. A broad range of physiologic responses and behavioral abilities have been examined after varying periods without sleep, and lawful relationships have been described. These relationships and the theory they represent are important in their own right, but the findings also serve as an extensive guide to symptoms associated with insufficient sleep. Furthermore, methods developed to lessen the impact of sleep deprivation also serve as possible clinical treatments for disorders related to insufficient sleep or excessive sleepiness. This chapter will review behavioral, physiologic, and theoretical implications of acute sleep deprivation. Chronic partial sleep deprivation is examined in Chapter 6. Studies of sleep deprivation can suffer from some common methodological problems that require consideration. The most important control issue is that one cannot perform a blinded sleep deprivation study. Both experimenter and subject motivation can have an impact on results, particularly in the behavioral and subjective domains. Motivation effects are frequently apparent near the end of sleep deprivation studies (where performance improvement is sometimes found) and may account for the difficulty in showing early decrements. Animal studies are less susceptible to subject expectation effects, but they may contain additional elements of stress that may interact with sleep loss, so these studies may not be directly comparable with stress control conditions. In addition, almost all sleep loss experiments involve more than simple loss of sleep. Maintenance of wakefulness usually includes upright posture, light, movement, cognition, and all the underlying physiologic processes implied by these activities. The experimental setting itself is usually far from routine. Some studies have attempted to control some of these factors during sleep loss, but trying to control all variables in a single experiment is daunting. 54
Chapter
5
man. However, several new means of assessing sleep deprivation effects, including brain scans, genetic assessment, and animal models, show promise for a better understanding of sleep and sleep loss. Studies have also shown that highfrequency periodic sleep fragmentation produces nonrestorative sleep that results in a state of sleepiness and decreased performance that is similar in many dimensions to sleepiness after total sleep deprivation. Recovery sleep after sleep loss or sleep fragmentation shows a characteristic pattern of elevated slow-wave sleep (SWS) with elevated sensory thresholds followed by elevated rapid eye movement (REM) sleep.
Over a thousand studies of sleep deprivation have been published during the past 10 years, and the resulting knowledge database has been remarkably consistent. However, new techniques and increasingly sensitive tests continue to add both theoretical and practical understanding of the impact of sleep loss. This review includes sections on total sleep deprivation, sleep fragmentation, and recovery from sleep deprivation.
TOTAL SLEEP DEPRIVATION The first published studies of total sleep loss date to 1894 for puppies1 and 1896 for humans.2 The puppy study indicated that prolonged sleep loss in animals could be fatal, an idea reinforced by numerous, more recent animal studies. The human study included a range of physiologic and behavioral measurements and remains a model study. Behavioral Effects The most striking effect of sleep loss is sleepiness, and this can be inferred from subjective reports, the multiple sleep latency test (MSLT), electroencephalographic (EEG) change, or simply looking at the face of the participant. The variables that determine the impact of sleep loss can be divided into four categories: sleep/circadian influences, arousal system influences, individual characteristics, and test characteristics (Box 5-1). Sleep/Circadian Influences Sleep deprivation, like nutritional status, is a relative concept. How an individual responds to sleep loss depends on the prior sleep amount and distribution. Performance during a period of sleep loss is also directly dependent on the length of time awake and the circadian time, and predictive models support these factors. Experiments usually try to control prior wakefulness and sleep amount by requiring “normal” nights of sleep before initiation of a sleep loss episode. Data from multiple regression analyses of behavioral and EEG data during 64 hours of sleep loss3 suggest that time awake accounts for 25% to 30% of the variance in alertness, and that circadian time
CHAPTER 5 • Acute Sleep Deprivation 55
1.3
Sleep/Circadian Influences • Prior sleep amount and distribution • Length of time awake • Circadian time
1.1
Individual Characteristics • Age • Individual sensitivity • Personality and psychopathology Test Characteristics and Types • Length of test • Knowledge of results • Test pacing • Proficiency level • Difficulty or complexity of test • Memory requirement • Executive function measures • Subjective (versus objective) measures • Electroencephalographic measures—multiple sleep latency test (MSLT)
accounts for about 6% of the variance. When prophylactic naps of varying length were interjected early in a period of sleep loss, it was found that the prophylactic nap sleep accounted for about 5% of the variance in alertness during the sleep deprivation period. In terms of reducing the effect of sleep loss, the overall effect of increasing the prophylactic nap period was linear for additional sleep amounts ranging up to 8 hours in length. Figure 5-1 displays the effects of time awake and the circadian rhythm on objective alertness as measured by the MSLT and the ability to complete correct symbol substitutions during 64 hours of sleep loss. Arousal Influences Environmental and emotional surroundings have a large impact on the course of a period of sleep loss. In early stages of sleep deprivation, many intervening variables can easily reverse all measurable sleep loss decrements. These influences include activity, bright light, noise, temperature, posture, stress, and drugs. A CTIVITY A 5-minute walk immediately preceding MSLT evaluations had a large impact (about 6 minutes) on MSLT values, which masked the impact of a 50% reduction of nocturnal sleep (about a 2-minute reduction on MSLT) and continued for at least 90 minutes.4 Exercise before
MSLT DSST
0.9 0.7 0.5 0.3
:0 1: 0 0 4: 0 0 7: 0 0 10 0 :0 13 0 : 16 00 :0 19 0 :0 22 0 :0 1: 0 0 4: 0 0 7: 0 0 10 0 :0 13 0 :0 16 0 :0 19 0 :0 0
0.1
22
Arousal Influences • Activity • Bright light • Noise • Temperature • Posture • Motivation or interest • Drugs • Group effects • Repeated exposure to sleep loss
Proportion of baseline
Box 5-1 Determinants of the Impact of Sleep Loss
Time of day Figure 5-1 Latency to stage 2 sleep (boxes) and number of correctly completed symbol substitutions in repeated 5-minute test sessions (dots) over a period of 64 hours of sleep deprivation, both expressed as a proportion of baseline values. (Data from Bonnet MH, Gomez S, Wirth O, et al. The use of caffeine versus prophylactic naps in sustained performance. Sleep 1995;18:97-104.) DSST, digit symbol substitution task; MSLT multiple sleep latency test.
performing tasks provided transient reversal of some psychomotor decrements resulting from sleep loss. However, more ambitious studies comparing high activity and low activity that continued over 40 to 64 hours of sleep deprivation have shown no beneficial effects of exercise on overall performance.5 Perhaps, arousing stimuli act for only a discrete period of time that is decreased by increasing sleep loss.6 There may also be a trade-off between production of arousal and production of physical fatigue. B RIGHT LIGHT Bright light can shift circadian rhythms. Some controversy exists concerning whether bright light can also act as a source of stimulation during a sleep-loss state to help to maintain alertness. Two of five studies found that periods of bright light immediately before sleep onset significantly increased sleep latencies. Other studies found improved nocturnal performance during bright light conditions, with elevated heart rate as a probable correlate.7 N OISE Noise, despite complex and occasionally negative effects on the performance of well-rested individuals, may produce small beneficial effects during sleep deprivation.8 It is generally assumed that noise increases arousal level, and this may provide maximal benefit during sleep loss. T EMPERATURE Although temperature variation is commonly used as an acute stimulus to maintain alertness, little research supports ambient temperature as a large modulator of alertness. One study has shown that heat (92° F) was effective in improving performance during the initial minutes of a vigilance task during sleep deprivation.9 However, another
56 PART I / Section 1 • Normal Sleep and Its Variations
study10 showed only a small decrease in subjectively rated sleepiness for about 15 minutes after a car air-conditioner was turned on during simulated driving. P OSTURE One study has shown a significant increase in sleep latency, as a measure of alertness, when subjects were asked to fall asleep in the sitting position (60-degree angle) as opposed to lying down.11 Such a difference could be accounted for by increasing sympathetic nervous system activity, which occurs as one moves to the upright posture. D RUGS Many drugs have been studied in conjunction with sleep loss, and an extensive review by the American Academy of Sleep Medicine has been published.12 Most studies have examined stimulants, including amphetamine, caffeine, methylphenidate, modafinil, armodafinil, nicotine, and cocaine. Numerous studies have shown that caffeine (dosages of 200 to 600 mg), modafinil (100 to 400 mg), and amphetamine (5 to 20 mg) can improve objective alertness and psychomotor performance for periods of time related to dosage, half-life, and hours of total sleep deprivation. However, head-to-head studies often provide the clearest comparison of compounds. One study13 examined alertness and response speed hourly for 12 hours during the first night of sleep deprivation after administration of modafinil (100, 200, and 400 mg) in comparison with caffeine 600 mg. In that study, modafinil dosages of 200 and 400 mg were shown to be equivalent to caffeine (600 mg) in maintaining response speed consistently above placebo levels for 12 hours. The same group compared modafinil (400 mg), caffeine (600 mg), and dextroamphetamine (20 mg) given just before midnight of the second night of total sleep loss.14 In this study, caffeine and dextroamphetamine significantly improved response speed only at midnight, 2:00 am, and 4:00 am, whereas modafinil improved response speed through 10 am. The decreased sensitivity to caffeine probably reflects both the half-life of caffeine and the increased sleep pressure from the second night of deprivation. Side effects were fewest after modafinil at 400 mg. However, the authors concluded that (1) these stimulants all provided some benefits and had some associated costs, (2) caffeine, with efficacy, availability, and low cost, can be a first choice for alertness, and (3) modafinil, with good efficacy and few side effects, would be a good substitute if caffeine were ineffective (related to time course of available administration, tolerance, side effects, or degree of sleep loss). Effects of stimulants can be enhanced by the use of naps or other sources of arousal. The beneficial effect of caffeine (300 mg) during periods of sleep loss was approximately equivalent to that seen after a 3- to 4-hour prophylactic nap before the sleep loss period.15 The combination of a 4-hour prophylactic nap followed by 200 mg of caffeine at 1:30 am and 7:30 am resulted in significantly improved performance (remaining at baseline levels) compared with the nap alone, for 24 hours.16 The combination of naps and caffeine was additive16 and superior to the provision of 4 hours of nocturnal naps. The combination of 200 mg of caffeine administered at 10:00 pm and 2:00 am and expo-
sure to 2500-lux bright light had no impact beyond the effect of caffeine alone on the maintenance of wakefulness test but did provide significant benefit above caffeine alone on a vigilance task.17 Recent work has shown that armodafinil (the levorotatory R-enantiomer of modafinil), which has a 10- to 14-hour half-life, is effective in maintaining alertness and performance throughout 1 night of sleep deprivation.18 Results with armodafinil (200 mg) appeared to be similar to those with modafinil (200 mg) but may have provided some additional benefit 11 to 13 hours after administration.18 Nicotine, infused intravenously at dosages of 0.25, 0.37 and 0.5 mg after 48 hours of wakefulness, had no significant impact on MSLT or psychomotor performance.19 Cocaine (96 mg), like amphetamine, did not improve performance in subjects before sleep loss. However, reaction time and alertness, as measured by the Profile of Mood States, was improved after 24 and 48 hours of sleep loss.20 Alcohol use has been found to consistently reduce alertness.21 Subjects were tested with the MSLT and simulated driving after 0.6 g/kg alcohol or placebo following normal sleep or 4 hours of sleep. There was a significant main effect for condition, and MSLT latencies were 10.7, 6.3, 6.1, and 4.7 minutes after placebo (normal sleep), placebo (4 hours sleep), ethanol (normal sleep), and ethanol (4 hours sleep), respectively. Similar results were found in the driving simulator, where there were three “crashes”— all in the reduced-sleep-with-ethanol condition. One difficulty in assessing the magnitude of performance effects associated with sleep loss is the lack of a clear standard of pathology for most measures. The fact that society has established very specific rules for blood alcohol content with respect to driving has led to the use of impairment associated with blood alcohol level as a standard reference for sleep deprivation as well. Several studies of alcohol use in direct comparison with sleep deprivation have shown decrements on different tasks. Response speed on the Mackworth task was reduced by approximately half a second by 3:45 am (i.e., with sleep loss) and to a similar extent by a blood alcohol content (BAC) of 0.1%. Also, hand–eye coordination (in a visual tracking task) declined in a linear fashion during sleep loss and with increasing BAC, such that performance was equivalent at 3:00 am to a blood alcohol level of 0.05% and equivalent at 8:00 am (after a full night of sleep loss) to a blood alcohol level of 0.1%. In a third study,22 performance was measured in a driving simulator after alcohol use or sleep deprivation. After a night of sleep deprivation (at 7:30 am), subjects averaged one off-road (i.e., vehicle driving off the road) incident every 5 minutes. This same level of off-road driving was reached with a BAC of 0.08%. These studies suggest that the changes in response speed, visual tracking, and driving commonly found during the first night of total sleep deprivation are equivalent to changes associated with legal intoxication. Such metrics provide useful understanding of the consequences associated with short periods of sleep loss. M OTIVATION OR INTEREST Motivation is relatively easy to vary by paying subjects and has therefore received attention. In one study, monetary
rewards for “hits” on a vigilance task and “fines” for false alarms23 resulted in performance being maintained at baseline levels for the first 36 hours of sleep loss in the highincentive group. Performance began to decline during the following 24 hours but remained significantly better than in the “no incentive” group. However, the incentive was ineffective in maintaining performance at a higher level during the third day of sleep loss. Knowledge of results— for example, the publication of daily test results—was sufficient to remove the effects of 1 night of sleep loss. In another variation, simple knowledge that a prolonged episode of sleep deprivation was going to end in a few hours was sufficient for performance to improve by 30% in a group of soldiers.24 G ROUP EFFECTS There are few studies, but interest is growing in how groups perform during sleep deprivation. Such studies are difficult because groups of individuals interact in many ways. One early study suggested that, if all group members were working at a similar task, greater deficits were seen as sleep deprivation progressed, compared with individual work. However, a more recent study that distributed work so that each individual added a unique component to task completion found that the deficits that accumulated during sleep deprivation were less pronounced in the group task.25 R EPEATED PERIODS OF SLEEP LOSS Studies of repeated episodes of sleep loss have agreed that the magnitude of performance loss increases as a function of the number of exposures to sleep loss.26 Increasingly poor performance may be secondary to decreased motivation or to familiarity with the sleep deprivation paradigm (resulting in decreased arousal). Individual Characteristics The impact of sleep loss on a given individual depends on characteristics that each participant brings to the sleep loss situation. For example, age and personality represent differences in physiologic or psychological function that may interact with the sleep loss event. A GE Tests of performance and alertness in older subjects undergoing sleep loss reveal a decrease in performance and alertness similar to that seen in younger individuals. If anything, older men had a smaller decrease in psychomotor performance ability at nocturnal times during sleep loss27,28 than younger men. Older individuals perform more poorly than young adults on a broad range of tasks, but, because of decreased amplitude of the circadian body temperature rhythm, this relationship may not be maintained across the night or during sleep loss.27 The same flattened curve associated with lower temperatures and decreased performance during the day also produces relatively elevated temperatures that could be related to improved performance at night. S ENSITIVITY TO SLEEP LOSS A number of studies have now demonstrated consistent individual differences in both alertness and performance during sleep deprivation.29 The studies have also shown
CHAPTER 5 • Acute Sleep Deprivation 57
that the reliable changes in subjective alertness, objective alertness, and performance are not related to one another. Performance consistently declined in the same subjects when sleep loss was repeated, but decrements did not generalize across performance tasks. This has led some to speculate that different brain areas could be responsible for different tasks. Some studies have begun to look for central predictors of performance loss. Early functional magnetic resonance imaging (fMRI) studies showed that subjects with higher levels of global brain activation (consistent at both baseline and during sleep loss) maintained better performance on a working memory task,30 and a more recent study linked working memory during sleep loss with left frontal and parietal brain areas.31 Other studies have shown that extroverts and caffeine-sensitive individuals were more sensitive to sleep loss.32 Such findings imply individual trait ability to maintain higher levels of arousal in specific brain areas or systems to help to maintain performance during sleep loss. In another approach, over 400 potential subjects were screened genetically, and groups were formed on the basis of the PER3 polymorphism (PER3[5/5] versus PER3[4/4]) before a 40-hour constant routine. The PER3(5/5) group appeared sleepier by all measures (significantly shorter sleep latency, more slow-wave sleep (SWS), greater slow eye movements during sleep loss, and significantly worse performance during sleep loss, particularly on executive tasks done early in the morning [0600 to 0800]).33,34 P ERSONALITY AND PSYCHOPATHOLOGY Mood changes, including increased sleepiness, fatigue, irritability, difficulty in concentrating, and disorientation, are commonly reported during periods of sleep loss. Perceptual distortions and hallucinations, primarily of a visual nature, occur in up to 80% of normal individuals, depending on work load, visual demands, and length of deprivation.35 Such misperceptions are normally quite easy to differentiate from the primarily auditory hallucinations of a schizophrenic patient, but normal individuals undergoing sleep loss may express paranoid thoughts. Two percent of 350 individuals sleep deprived for 112 hours experienced temporary states resembling acute paranoid schizophrenia. Some predisposition toward psychotic behavior existed in individuals who experienced significant paranoia during sleep loss, and the paranoid behavior tended to become more pronounced during the night, with partial recovery during the day and disappearance after recovery sleep. In a review of the area, Johnson concluded, “Each subject’s response to sleep loss will depend on his age, physical condition, the stability of his mental health, expectations of those around him, and the support he receives.”36, p. 208 At a more general level, normal adults undergoing sleep deprivation typically express some increase in somatic complaints, anxiety, depression, and paranoia that do not reach clinical levels.37 In view of the commonly reported effects of sleep deprivation, it seems quite unusual that one would seek to treat depression by sleep deprivation. However, sleep deprivation has been used as a successful treatment for depression in 40% to 60% of cases for over 30 years. Imaging studies have shown that depressed patients have elevated metabolism in the prefrontal cortex and ventral anterior cingulate
58 PART I / Section 1 • Normal Sleep and Its Variations
cortex (possibly related to reduced transmission of dopamine and serotonin) that is normalized by sleep deprivation.38 One theory proposes that sleep deprivation is more effective in depressed patients with high levels of activation or high central noradrenergic activity because it limits the effects of chronic hyperarousal. As a result, patients felt tired but also had improved mood and energy. Test Characteristics and Types Two meta-analyses of subtopics of sleep deprivation have been published.39 Both analyses indicated that sleep deprivation has a significant impact on psychomotor performance. In general, longer periods of sleep loss had greater impact on performance, and decrements in speed of performance were greater than decreases in accuracy. Also, mood measures were more sensitive than cognitive tasks, which were more sensitive than motor tasks,39 during sleep loss. Therefore, the measured response to sleep deprivation is critically dependent on the characteristics of the test used. To some extent, the type of test has also been used to infer specific brain area dysfunction. Sleep-deprived individuals appear most sensitive to the following dimensions. L ENGTH OF TEST Individuals undergoing sleep loss can usually rally momentarily to perform at their non–sleep-deprived levels, but their ability to maintain that performance decreases as the length of the task increases. For example, subjects attempted significantly fewer addition problems than baseline after 10 minutes of testing following 1 night of sleep loss but reached the same criterion after 6 minutes of testing following the second night of sleep loss. It took 50 minutes of testing to show a significant decrease in percentage of correct problems after 1 night of sleep loss, and 10 minutes of testing to reach that criterion after the second night.40 It is frequently difficult to show reliable differences during short-term sleep loss from almost any test that is shorter than 10 minutes in duration. Momentary arousal, even as minor as an indication that 5 minutes remained on a task, was sufficient to reverse 75% of the decrement accumulated over 30 minutes of testing. K NOWLEDGE OF RESULTS Immediate performance feedback, possibly acting through motivation, has been shown to improve performance during sleep deprivation.41 Simply not giving knowledge of results to subjects with normal sleep doubled their number of very long responses (“gaps”) on a serial-reaction time test. One night of total sleep loss increased the number of gaps by 9.3 times the baseline level, but provision of immediate knowledge of results decreased the number of gaps back to baseline levels.41 T EST PACING Self-paced tasks are usually more resistant to the effects of sleep loss than tasks that are timed or in which items are presented by the experimenter. In a self-paced task, the subject can concentrate long enough to complete items correctly and not be penalized for lapses in attention that occur between items. When tasks are externally
paced, errors occur if items are presented during lapses in attention. P ROFICIENCY LEVEL Sleep loss is likely to affect newly learned skills more than well-known activities, as long as arousal level remains constant. For example, in a study of the effects of sleep loss on doctors in training, significant performance decrements were found in postgraduate year (PGY)-1 surgical residents but not in PGY-2 to -5 surgical residents.42 D IFFICULTY OR COMPLEXITY Performance on simple tasks such as monitoring a light on a control panel (on/off) declines less than performance on more complex tasks such as mental subtraction43 during sleep loss. Task difficulty can also be adjusted by increasing the speed at which the work must be performed. When 2 seconds was allowed to complete mental arithmetic problems, no significant performance decline was found after 2 nights of sleep loss, but when the rate of presentation was increased to 1.25 seconds, significant performance decline was found. M EMORY REQUIREMENT Impairment of immediate recall for elements placed in short-term memory is a classic finding in sleep deprivation studies. Because subjects are usually required to write down each item as presented, the observed decrements, which can usually be seen after 1 night of sleep loss, do not result from impaired sensory registration of items. Observed decrements may result from decreased ability to encode,44 from an increasing inability to rehearse old items (due to lapses) while the items are being presented, or from a combination of memory effects with reduced ability to respond. Deficits have been shown in both explicit/declarative memory and procedural/implicit memory.44 E XECUTIVE FUNCTION Increasing behavioral and physiologic data implicate loss of function in prefrontal brain areas during sleep loss. Prefrontal areas are heavily involved in divergent thinking, temporal memory (planning, prioritization, organization), and novelty. Numerous studies have shown deficits on these tasks during sleep loss. One study45 has shown decreased ability to make emotional judgments after total sleep loss. Another aspect of prefrontal behavior is related to risk taking. Studies have shown a shift toward accepting short-term rewards even when long-term consequences were more severe after sleep loss.46 S UBJECTIVE (VERSUS OBJECTIVE) MEASURES Measures of mood such as sleepiness, fatigue, and ability to think or concentrate are inversely correlated with performance and body temperature during sleep loss. Mood changes occur early, are easy to measure, and are prominent. E EG MEASURES Clear EEG changes are seen during sleep loss (see Neurologic Changes, later). The MSLT, a standard test developed as an objective measure of sleepiness, was validated,
in part, by being shown to be sensitive to several types of partial and total sleep loss.47 That the MSLT is more sensitive than psychomotor tasks can be seen in Figure 5-1, which displays performance changes in terms of the number of symbol substitutions correctly completed in 5-minute test periods and MSLT data.15 Summary Tasks most affected by sleep loss are long, monotonous, without feedback, externally paced, newly learned, and have a memory component. One example of a task containing many of these elements is driving, which was discussed earlier in reference to the effects of alcohol. Since 1994, more than 20 studies have examined the impact of reduced sleep on various measures of driving ability or safety. One study,48 for example, found that 49% of medical residents who worked on call and averaged 2.7 hours of sleep reported falling asleep at the wheel (90% of the episodes were after being on call). The residents also had 67% more citations for moving violations and 82% more car accidents than the control group.48
PHYSIOLOGIC EFFECTS OF SLEEP DEPRIVATION Physiologic changes that occur during sleep loss can be categorized into neurologic (including EEG), autonomic, genetic, biochemical, and clinical changes. Physiologic and biochemical effects of sleep deprivation were extensively reviewed by Horne.49 Neurologic Changes Although it is easy to identify a sleep-deprived individual by appearance and to demonstrate obvious behavioral changes, measurable neurologic changes during sleep loss are relatively minor and quickly reversible. In extended sleep loss studies (205 or more hours), mild nystagmus, hand tremor, intermittent slurring of speech, and ptosis have been noted.50 Sluggish corneal reflexes, hyperactive gag reflex, hyperactive deep tendon reflexes, and increased sensitivity to pain were reported after deprivation that is more extensive. All of these changes reversed immediately after recovery sleep. Sleep loss is consistently accompanied by characteristic EEG changes.51 In careful studies, subjects have been required to stand or to be involved in tasks in an attempt to stabilize arousal level. Several studies have reported a generally linear decrease in alpha activity during sleep loss. Subjects were unable to sustain alpha activity for longer than 10 seconds after 24 hours of sleep loss, and this ability continued to decline to 4 to 6 seconds after 72 hours, and 1 to 3 seconds after 120 hours of sleep loss.52 After 115 hours of sleep loss, eye closure failed to produce alpha activity. In another study, in which individuals were recorded standing with their eyes closed, the percentage of time spent with an alpha pattern in the EEG decreased from 65% in the early deprivation period to about 30% after 100 hours of sleep loss.53 Delta and theta activity in the waking EEG were increased from 17% and 12% of the time to 38% and 26% of the time, respectively.53 The increase in delta activity was most pronounced in frontal areas in younger subjects. Performance errors during sleep
CHAPTER 5 • Acute Sleep Deprivation 59
loss were usually accompanied by a slowing of the EEG54 that was labeled a “microsleep.” Imaging Studies Global decreases in brain activation correlated with increasing sleep loss have been found using positron emission tomography (PET). Larger decreases were found in prefrontal, parietal, and thalamic areas.55 Several fMRI studies have examined the activity in prefrontal cortex and parietal lobes after sleep loss56 that was measured while subjects performed various tasks. In some studies of verbal tasks, activity in these areas increases with task difficulty and after sleep loss as long as performance level is maintained, which has been interpreted as representing increased effort after sleep loss.56 However, studies that have found declines in performance or examined subjects with poor performance after sleep loss have reported decreases in parietal activation during the performance.31,57 These fMRI results suggest that imaging patterns could predict performance deficits during sleep loss. Clinical EEG Although the neurologic changes associated with significant sleep loss are relatively minor in normal young adults, sleep loss has repeatedly been shown to be a highly activating stress in individuals suffering seizure disorders, perhaps by reduction of central motor inhibition.58 Using a period of sleep loss as a “challenge” to elicit abnormal EEG events is currently a standard neurologic test.58 Autonomic Changes In humans, autonomic changes, even during prolonged periods of sleep loss, are relatively minor. Individual studies have reported either increases or decreases in systolic blood pressure, diastolic blood pressure, finger pulse volume, heart rate, respiration rate, and tonic and phasic skin conductance. However, the majority of 10 to 15 studies have reported no change in these variables during sleep loss in humans.49 It has been suggested that these variable findings could be explained in part by measurement circumstances. Those studies that have had more strict activity controls and have made measurements from recumbent subjects have been more likely to find evidence for decreased or no change in activation, whereas studies of sitting or more active participants have tended to find increases in these parameters.59 There may be about a 20% reduction in response to hypoxia and hypercapnia60 during sleep deprivation. However, this reduction was suggestive of a transient setpoint change rather than system failure. Sleep deprivation has been associated with small decreases in forced expiratory volume in 1 second (FEV1) and forced vital capacity (FVC) in patients with pulmonary disease.61 Both a study of infants61a and one of adults62 have shown more apneic events61a and longer apneic events after sleep loss. Brooks and colleagues63 have shown that apneas become longer as a function of the sleep fragmentation produced by the apneas (as opposed to the respiratory pathology). Several studies in humans have found a small overall decrease (0.3° to 0.4° C) in body temperature during sleep loss.2,64 Changes in thermoregulation have been described as heat retention deficits. Much larger changes
60 PART I / Section 1 • Normal Sleep and Its Variations
in thermoregulation producing huge increases in energy expenditure have been found in rats after longer periods of sleep deprivation (see Chapter 28).65 No sleep deprivation–related changes in whole-body metabolism were found at normal temperatures and in a cold-stress situation.66 This finding in humans is of particular interest because a series of elegant studies in rats has shown that after a week of sleep loss, metabolic levels are greatly increased, increased food consumption is accompanied by significant weight loss, and significant difficulty with thermoregulation is apparent.65 Several studies have examined aspects of brain metabolism in animals during short periods of sleep deprivation. Direct measures of brain metabolic rate were not different after a short period of sleep deprivation,67 although several related enzymes did differ. However, some of the noted differences could have been related to stress rather than sleep deprivation. Biochemical Changes Several studies (10 or more for some variables) have examined various biochemical changes in humans during sleep loss. There is generally no significant change in cortisol,68 adrenaline and related compounds, catecholamine output,66,69 hematocrit,70 plasma glucose,70 creatinine,66 or magnesium66 during sleep loss. Results from analyses of blood components largely parallel the results found in urine components. None of the adrenal or sex hormones (including cortisol, adrenaline, noradrenaline, luteinizing hormone, follicle-stimulating hormone, variants of testosterone, and progesterone) rises during sleep deprivation in humans.68 Some of these hormones actually decreased somewhat during sleep loss, perhaps as a result of sleepiness and decreased physiologic activation. Thyroid activity, as indexed by thyrotropin, thyroxine, and triiodothyronine, was increased, probably as a result of the increased energy requirements of continuous wakefulness.71 Studies appear about equally divided between those showing an increase in melatonin and no change in melatonin during sleep deprivation.72 A finding of decreased melatonin in young adults after sleep deprivation suggested that earlier findings of increased melatonin may have been related to lack of control for posture, activity, and light.73 Most studies have concluded that there is no significant change in hematocrit levels,66 erythrocyte count, or plasma glucose during total sleep deprivation in humans.70 As would be expected, hormones such as noradrenaline, prolactin, ghrelin, and growth hormone, which are dependent on sleep for their circadian rhythmicity or appearance, lose their periodic pattern of excretion during sleep loss (see reference 74 for review). Rebounds in growth hormone and adrenocorticotropic hormone (ACTH) during recovery sleep are seen after sleep loss or SWS deprivation.75 Gene Studies A recent review of gene expression has described a number of changes that occur during wakefulness and extended wakefulness76 (see Chapter 15). A number of genes expressed during wakefulness that regulate mitochondrial activity and glucose transport probably reflect increased energy use while awake. However, as sleep
deprivation progresses, one gene, for the enzyme arylsulfotransferase (AST), showed stronger induction as a function of length of sleep deprivation. AST induction could reflect a homeostatic response to continuing central noradrenergic activity during sleep loss,76 and this might imply a role for sleep in reversing activity of brain catecholaminergic systems.77 In another approach, a gene named Sleepless was identified as required for sleep in Drosophila. Flies with significant reduction in Sleepless protein had reduced sleep and sleepiness before and after sleep deprivation.78 Clinical Changes Immune Function A number of studies in humans have examined various aspects of immune function after varying periods of partial or total sleep loss (see Chapter 25). Several studies have found decreases in natural killer (NK) cell numbers after short periods of sleep deprivation,79 but increases after longer periods of sleep loss. Some studies have shown increases in interleukin (IL)-179 and IL-680 during total sleep loss. In general, immune function studies are difficult to compare because parameters measured, time and number of blood draws, and degree of sleep deprivation vary across studies. At a more macroscopic level, one study reported the development of respiratory illness or asthma in three subjects after a 64-hour sleep deprivation protocol,81 whereas another reported no incidence of illness after a similar protocol.79 In longer studies involving strenuous exercise and other factors along with sleep loss, increased infection rates are reported about 50% of the time.82 One animal study has suggested that mice immunized against a respiratory influenza virus responded to that virus as if they had never been immunized, only when exposed after sleep loss.83 However, in another study,84 total sleep loss actually slowed the progression of a viral infection in mice. An extensive study of sleep loss in rats (7 to 49 days) was unable to show significant changes in spleen cell numbers, mitogen responses, or in vivo or in vitro splenic antibody-secreting cell responses.85 Pain Increased sensitivity to pain has been an incidental finding in sleep deprivation research for many years, but 10 studies have now made specific pain measurements in several conditions of partial, sleep stage, or total sleep deprivation. Initial studies linked increased pain to SWS but not rapid eye movement (REM) deprivation. Later studies showed that total sleep deprivation decreased pressure pain or heat pain tolerance. However, the most recent studies86,87 found effects for REM-stage deprivation not found earlier, and they split on the effectiveness of total sleep deprivation. One study,87 which found increased pain sensitivity after disturbed sleep compared with reduced sleep, suggested that all of the pain findings associated with sleepstage deprivation may actually have been caused by the sleep fragmentation necessary to produce sleep-stage deprivation. Another study has reported increased pain sensitivity to esophageal acid perfusion, specifically in patients with gastroesophageal reflux disease (but not controls) after sleep reduced to 3 hours or less for 1 night.88
Weight Control and Insulin There are numerous reports of increased sympathetic activity, impaired glucose tolerance, and weight gain associated with chronic partial sleep deprivation (see Chapter 6), but, remarkably, these effects have not been replicated following total sleep deprivation. One study, in a small group of subjects, before and after 1 night of total sleep deprivation found no increase in cortisol, blood glucose, insulin, ACTH, catecholamines, or lactate.90 This study did report a decrease in basal glucagon, possibly linked to pancreatic islet secretion and increased hunger. From such reports, it is unclear whether the results reported from chronic partial sleep deprivation are related to increased or chronic stress or whether time of sampling may play a role. Exercise Effects of sleep loss on the ability to perform exercise are subtle. Animal studies have consistently shown that sleep deprivation decreases spontaneous activity by up to 40%,91 but most human studies have focused on maximal exercise ability, where large differences as a function of sleep loss are more difficult to demonstrate. For example, one study92 reported a 7% decrease in maximum oxygen O 2max ) during 64 hours of sleep loss. This uptake ( V change was not associated with heart rate, respiratory exchange ratio, or blood lactate, which remained unchanged. Recovery from exercise may be slowed by sleep loss. Studies are evenly divided between claims that the amplitude of the circadian rhythm of temperature is increased, decreased, or unchanged during sleep loss.49 Summary A large number of studies have reported autonomic, biochemical, and immune function variables during sleep loss. Many of the older studies were based on single observation points before and after sleep loss. Many studies suffer from poor activity controls (use of activity to maintain wakefulness may produce or mask changes in underlying variables of interest). More recent studies have been able to make use of sampling as often as once per hour and have begun to consider circadian and activity effects. For example, NK cell numbers were increased93 during the night when subjects remained awake (compared with a sleep control) but were then decreased on the following afternoon, with the result that numbers averaged across the entire study were the same in sleep loss and baseline conditions. This means that a study could find an increase, a decrease, or the same number of NK cells based on the time of sampling. In a similar manner, it has been found that IL-6 was decreased during a night of sleep deprivation compared with the sleep control but increased compared with control during the next day, so that numbers averaged across the entire study were, again, about the same.
SLEEP FRAGMENTATION Sleep is a time-based cumulative process that can be impeded both by deprivation and by systematic disturbance. A number of studies have shown that very brief periodic arousals from sleep reduce the restorative power of sleep and leave deficits similar to those seen after total sleep deprivation.94 Experimental Sleep Fragmentation Many studies have examined the relationship between various empiric schedules of sleep fragmentation and residual sleepiness on the following day. Data from eight studies are plotted in Figure 5-2. There is a strong relationship (r = .775, P < .01) between rate of fragmentation (plotted as minutes of sleep allowed between disturbances) and decrease in sleep latency on the following day as measured by MSLT.94 As expected, increased sleepiness after sleep fragmentation was also associated with decreased psychomotor performance on a broad range of tasks,95 and with degraded mood.94 Studies have been carefully designed to produce brief EEG arousals or even “nonvisible” EEG sleep disturbance, with the result that there are few96 in standard sleep EEG parameters despite the periodic sleep fragmentation. With preservation of normal-EEG sleep amounts, participants were still significantly sleepier on the day after sleep fragmentation. In another approach, fragmentation rates, consolidated sleep periods, and SWS amounts were experimentally varied in participants in an attempt to tease out sleep stage versus fragmentation effects, with similar
1.1 1.0 Proportion of baseline MSLT
This suggests that individual differences could also play a role in the modulation of pain. Animal studies have replicated findings of increasing pain sensitivity after REM deprivation and showed that pain sensitivity remained elevated even after low dosages of morphine and 24 hours of recovery sleep.89
CHAPTER 5 • Acute Sleep Deprivation 61
0.9 0.8 0.7 0.6 0.5 0.4 0.3 0
2
4
6
8
10
12
14
16
18
20
Length of sleep allowed (min) Figure 5-2 Proportion of baseline multiple sleep latency test (MSLT) value (i.e., sleep latency after fragmentation nights divided by sleep latency after baseline) in eight sleep fragmentation studies (two separate fragmentation conditions were identified in three studies), plotted as a function the amount of sleep time allowed until disturbance (e.g., “2” means that subjects were aroused briefly after each 2 minutes of sleep). (From Bonnet MH, Arand DL. Clinical effects of sleep fragmentation versus sleep deprivation. Sleep Med Rev 2003;7:297-310.)
62 PART I / Section 1 • Normal Sleep and Its Variations
conclusions—residual sleepiness was more related to the sleep fragmentation than to sleep-stage parameters.94 Other studies have directly compared the impact of relatively high rates of sleep fragmentation (usually disturbance every 1 to 2 minutes) with the effect of total sleep deprivation in the same study. In one study, profiles of cortisol and ACTH were similar during total sleep deprivation and sleep fragmentation.97 In other studies,94 MSLT was decreased to similar low values after both total sleep deprivation and high-frequency sleep fragmentation. A significant increase in apnea-hypopnea index was found after both sleep fragmentation and sleep deprivation, and this increase was actually greater after sleep fragmentation.94 These findings of similar impacts on hormones, respiratory parameters, psychomotor performance, and objective sleepiness after similar periods of sleep deprivation and sleep fragmentation indicate that there is much in common between the high-frequency sleep fragmentation and total sleep deprivation. Clearly, the restorative function of sleep is impaired by high rates of sleep fragmentation. However, as indicated by Figure 5-2, the impact of periodic sleep fragmentation decreases rapidly as the intervals between arousals increase, and this may imply that normal restoration during sleep requires periods of consolidated sleep of 10 to 20 minutes.94 Recovery sleep following high rates of sleep fragmentation is characterized by rebounds of SWS and REM sleep like that seen after total sleep deprivation. In addition, recovery sleep after sleep fragmentation and sleep deprivation is notable for decreased arousals.98 A broad range of physiologic indices have been examined as possible measures of sleep fragmentation.94 A number of respiratory, cardiac, and alternative EEG measures have been examined, with the general conclusion that most of these physiologic measures, including traditional arousals, are moderately correlated with daytime sleepiness. However, much empirical work needs to be done to determine the extent to which these other physiologic measures are simply correlates of EEG arousals rather than new measures of sleep continuity. A physiologic event more specific than the EEG arousal remains to be identified. New animal models of sleep fragmentation in rats have revealed decreases in hippocampal neurogenesis and increases in basal forebrain adenosine to levels found after similar amounts of total sleep deprivation.99 Sleep Disorders and Fragmentation The earliest study of sleep fragmentation in dogs documented impaired arousal responses to hypercapnia and hypoxia during sleep.100 Further studies following dogs with experimentally produced apnea or sleep fragmentation for periods of more than 4 months showed that both the sleep fragmentation procedure and the experimentally produced apnea produced increased time to arousal as well as greater oxygen desaturation, greater peak inspiratory pressure, and greater surges in blood pressure in response to airway occlusion. It was concluded that the sleep fragmentation alone was responsible for the sleepiness symptoms associated with sleep apnea, and “the changes in the acute responses to airway occlusion resulting from OSA (obstructive sleep apnea) are
primarily the result of the associated sleep fragmentation.”63, p. 1609 Other clinical studies have documented that the number of brief arousals is significantly correlated with the magnitude of daytime sleepiness in groups of patients.94 Traditional sleep-stage rebounds (see Recovery Sleep, next) are seen when the pathology is corrected. After effective treatment of sleep apnea and the corresponding decrease in frequency of arousals during sleep, alertness was improved as measured by either MSLT or reduction in traffic accidents.101 There are many other instances of sleep fragmentation as a component in both medical illnesses (such as fibrositis, intensive-care-unit syndrome, chronic movement disorders, and chronic pain disorders) and life requirements (infant care, medical residents). Some of these impositions may not produce the critical number of arousals required for significant decrements in the apnea patients and in sleep fragmentation studies. However, most of these situations are a combination of chronic partial sleep loss and chronic sleep fragmentation.
RECOVERY SLEEP Sleep is all that is required to reverse the effects of sleep deprivation in almost all circumstances. The EEG characteristics of recovery sleep depend on the amount of prior wakefulness and the circadian time. These effects have been successfully modeled (see Chapter 37). Performance Effects Several efforts have been made to assess recovery of performance after sleep deprivation. It is commonly reported that recovery from periods of sleep loss of up to 10 days and nights is rapid and can occur within 1 to 3 nights. Several studies have reported recovery of performance after a single night (usually 8 hours) of sleep following anywhere from 40 to 110 hours of continuous wakefulness.5 Such experiments suggest that an equal amount of sleep is not required to recover from sleep lost. However, sleep deprivation itself was typically the main concern of these studies and, therefore, recovery was given minimal attention. One study specifically examined the rate of performance recovery during sleep in young adults, normal older subjects, and insomniacs after 40- and 64-hour sleep loss periods.27 Participants were awakened from stage 2 sleep for 20-minute test batteries approximately every 2 hours during baseline and recovery nights. Therefore, it was possible to follow the time course of return to baseline performance during recovery sleep in the three groups. In normal young adults, reaction time returned to levels not significantly less than baseline after 4 hours of sleep during recovery sleep following 40 hours of sleep loss. However, reaction time remained significantly slower than baseline in young adults throughout the first night of recovery sleep (including the postsleep morning test) following 64 hours of sleep loss. In contrast, reaction time in both older normal sleeper and insomniac groups was significantly slower than baseline at 5:30 am but had returned to baseline levels by 8:00 am after the first recovery night after 64 hours of sleep loss. The young adults not only recovered more slowly from sleep loss on the initial recovery night
CHAPTER 5 • Acute Sleep Deprivation 63
Table 5-1 Effects of Sleep Loss on Stages of Recovery Sleep SLEEP LOSS: 40 HR YOUNG ADULTS (SD) Sleep latency
0.38 (0.09)
OLDER ADULTS (SD) —
DEPRESSED ADULTS
DEMENTED ADULTS
0.22
0.14
SLEEP LOSS: 64 HR SHORT SLEEPERS —
LONG SLEEPERS —
OLDER NORMAL SUBJECTS —
OLDER INSOMNIAC PATIENTS —
Wake time
0.44 (0.19)
0.51 (0.11)
—
—
0.13
0.48
—
—
Stage 1
0.42 (0.12)
0.59 (0.14)
0.61
0.68
0.98
0.60
0.56
0.52 1.20
Stage 2
0.87 (0.10)
0.95 (0.07)
1.06
1.08
1.38
0.99
1.07
Stage 3
0.98
1.32 (0.25)
1.14
1.16
—
—
2.36
3.00
Stage 4
2.40
2.06 (0.45)
1.35
1.12
—
—
7.00
5.25
Slow-wave sleep stage
1.53 (0.11)
1.56 (0.23)
1.23
1.15
1.37
1.52
2.56
3.30
REM sleep stage
0.89 (0.13)
1.04 (0.09)
0.84
0.78
1.26
1.03
0.26
0.92
REM sleep latency
1.01 (0.20)
0.77 (0.20)
2.2
2.0
1.13
1.26
0.35
0.96
The values presented in this table are the mean percentages of baseline levels of the indicated sleep stages for the indicated groups during the first sleep recovery night. Where sufficient studies were available, the standard deviation around the mean percentage is also given (SD). For example, on their recovery night after 1 night of sleep loss, young adults have a sleep latency that is 38% ± 9% of their baseline sleep latency. (See text for references.)
but also had some decrease in their reaction times that extended into the second recovery night. This result is consistent with other data showing that older subjects had daytime MSLT values at baseline levels following sleep loss and a single night of recovery sleep, whereas shorterthan-normal latencies continued in young adults.102 EEG Effects A large number of studies have reported consistent effects on sleep EEG when totally sleep deprived individuals are finally allowed to sleep. If undisturbed, young adults typically sleep only 12 to 15 hours, even after 264 hours of sleep loss.103 If sleep times are held to 8 hours on recovery nights, effects on sleep stages may be seen for 2 or more nights. The effects of 40 and 64 hours of sleep loss on recovery sleep stages during the initial recovery night are summarized in Table 5-1 for normal young adults,47,104-107 young adult short sleepers,108 young adult long sleepers,108 60- to 80-year-old normal sleepers,102,109,110 60- to 70-year-old chronic insomniacs,109,111 and 60- to 80-year-old depressed and demented patients.112,113 The table presents percentage change from baseline data, with an indication of studyto-study variability where the number of studies allowed computation. The table is presented as a summary device so that EEG effects of sleep deprivation can be predicted (roughly by multiplying population baseline values by figures presented in the table), and so that the potential differential effects of sleep deprivation on EEG recovery sleep as a function of group can be more clearly seen. The results of these several studies indicate that recovery sleep EEG changes that occur as a function of sleep deprivation are remarkably consistent across studies and across several experimental groups including men, women, older subjects, and older insomniacs. Significant deviations from population recovery values are seen primarily in REM latency changes in depressed and demented patients, and
secondarily in some less robust differences found in small groups of long and short sleepers. These latter findings might be related to differential sleep-stage distributions secondary to long or short sleep times. On the first recovery night after total sleep loss, there is a large increase in SWS over baseline amounts.70,111 As would be expected, wake time and stage 1 sleep are usually reduced. Stage 2 and REM sleep may both be decreased on the first recovery night after 64 hours of sleep loss,27,47 at least in young adults, as a function of increased SWS. In older normal sleepers and insomniacs, there is less absolute increase in SWS than in young adults on the first recovery night, although the percentage increase in SWS may be as great. Because there is less SWS rebound, there may be no change (geriatric normals) or even an increase in stage 2.27,113 Normal older individuals had a decrease in REM latency during recovery sleep102,109,113 rather than the increased REM latency common in young adults. It was found that REM latency in the older population was positively correlated with baseline SWS amounts109,113 and that sleep-onset REM periods occurred in about 20% of those carefully screened normal subjects.109,113 These REM changes were interpreted to be the result of decreased pressure for SWS in older humans. The REM latency findings did not apply to older depressed or demented individuals. REM rebound effects appear to be related to the amount of lost SWS, so that REM rebound is more likely on an early recovery night when there is less SWS loss as a function of either a shorter period of sleep loss or age. On the second recovery night after total sleep loss, SWS amounts approached normal values, and an increase in REM sleep was found in young adults.47 Total sleep time was still elevated. By the third recovery night, all sleep EEG values approached baseline. In situations where REM rebounds on the first sleep-recovery night, sleep EEG values may normalize by the second recovery night.
64 PART I / Section 1 • Normal Sleep and Its Variations
Exceptions to these general rules may include older insomniacs, who have increased total sleep for at least 3 nights after 64 hours of sleep loss27 and individuals who have had significant selective REM deprivation. Relationship between EEG and Psychomotor Performance Recovery Effects The increase in SWS during recovery from sleep loss leads to the speculation that SWS is implicated in the sleep recovery process. Unfortunately, human studies designed to test this hypothesis directly by experimentally varying the amount of SWS during the recovery sleep period or during a sleep fragmentation period have not implicated any sleep stages as central in the recovery process.114 However, these studies were not designed to look for more subtle effects that might have occurred in the initial recovery night. Studies have also examined recovery of alertness and performance after total sleep deprivation for 1 or 2 nights. An early study that examined performance recovery in the sleep period found recovery of response speed to baseline levels after 1 night of recovery sleep following 40 hours of sleep loss and recovery to baseline levels during the second night of recovery sleep following 64 hours of sleep loss.115 More recent studies with larger groups of subjects have reported that simple response speed had recovered to baseline levels after 1 night of recovery sleep following 64 hours of sleep loss in one study116 but did not recover to baseline levels even after 5 recovery nights in a second study.117 MSLT was still significantly shorter after 1 night of recovery sleep following both 1 and 2 nights of total sleep loss.116,117 One study reported recovery for the MSLT after a second night of recovery sleep following 64 hours of sleep loss,116 but the second study did not.117
CONCLUSIONS The physiologic and behavioral effects of sleep loss in humans are consistent and well defined. There is a physiologic imperative to sleep in man and other mammals, and the drive to sleep can be as strong as the drive to breathe. Future work should (1) examine in more detail the physiologic microstructure of the sleep process and its relationship to sleep restoration, (2) reconcile response differences among species, (3) examine differences in response to sleep deprivation in normal and depressed humans, and (4) further explore the interaction of the sleep and the arousal systems, (5) examine impact in specific occupations.118
❖ Clinical Pearl The impact of sleep deprivation on performance and physiology has been examined in thousands of studies for over a hundred years. These findings might not seem directly relevant in a clinical sense, but it should be remembered that the clinical diagnosis of insufficient sleep syndrome is based on sleep deprivation. Sleepiness symptoms secondary to sleep apnea and periodic limb movements (sleep fragmentation) also evolve from sleep deprivation.
Acknowledgements Supported by the Medical Research Service of the Dayton Department of Veterans Affairs Medical Center and Wright State University, Dayton, Ohio. Literature searches were supported by the Sleep-Wake Disorders Research Institute, Dayton, Ohio. REFERENCES 1. Manaceine M. Quelques observations experimentales sur l’influence de l’insomnie absolue. Arch Ital Biol 1894;21:322-325. 2. Patrick GTW, Gilbert JA. On the effect of loss of sleep. Psychol Rev 1896;3:469-483. 3. Mikulincer M, Babkoff H, Caspy T, Sing H. The effects of 72 hours of sleep loss on psychological variables. Br J Psychol 1989;80: 145-162. 4. Bonnet MH, Arand DL. Sleep latency testing as a time course measure of state arousal. J Sleep Res 2005;14:387-392. 5. Lubin A, Hord DJ, Tracy ML, et al. Effects of exercise, bedrest and napping on performance decrement during 40 hours. Psychophysiology 1976;13:334-339. 6. Bonnet MH, Arand DL. Level of arousal and the ability to maintain wakefulness. J Sleep Res 1999;8:247-254. 7. Yokoi M, Aoki K, Shimomura Y, et al. Exposure to bright light modifies HRV responses to mental tasks during nocturnal sleep deprivation. J Physiol Anthropol 2006;25:153-161. 8. Wilkinson RT. Interaction of noise with knowledge of results and sleep deprivation. J Exp Psychol 1963;66:332-337. 9. Poulton EC, Edwards RS, Colquhoun WP. The interaction of the loss of a night’s sleep with mild heat: task variables. Ergonomics 1974;17:59-73. 10. Reyner LA, Horne JA. Evaluation of “in-car” countermeasures to sleepiness: cold air and radio. Sleep 1998;21:46-50. 11. Bonnet MH, Arand DL. Arousal components which differentiate the MWT from the MSLT. Sleep 2001;24:441-450. 12. Bonnet MH, Balkin TJ, Dinges DF, et al. The use of stimulants to modify performance during sleep loss: a review by the Sleep Deprivation and Stimulant Task Force of the American Academy of Sleep Medicine. Sleep 2005;28:1163-1187. 13. Wesensten J, Belenky G, Kautz MA, et al. Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine. Psychopharmacology 2002;159:238-247. 14. Wesensten NJ, Killgore WD, Balkin TJ. Performance and alertness effects of caffeine, dextroamphetamine, and modafinil during sleep deprivation. J Sleep Res 2005;14:255-266. 15. Bonnet MH, Gomez S, Wirth O, et al. The use of caffeine versus prophylactic naps in sustained performance. Sleep 1995;18:97-104. 16. Bonnet MH, Arand DL. The use of prophylactic naps and caffeine to maintain performance during a continuous operation. Ergonomics 1994;37:1009-1020. 17. Wright KP, Badia P, Myers BL, et al. Combination of bright light and caffeine as a countermeasure for impaired alertness and performance during extended sleep deprivation. J Sleep Res 1997; 6:26-35. 18. Dinges DF, Arora S, Darwish M, et al. Pharmacodynamic effects on alertness of single doses of armodafinil in healthy subjects during a nocturnal period of acute sleep loss. Curr Med Res Opin 2006;22:159-167. 19. Newhouse PA, Penetar DM, Fertig JB, et al. Stimulant drug effects on performance and behavior after prolonged sleep deprivation: a comparison of amphetamine, nicotine, and deprenyl. Mil Psychology 1992;4:207-233. 20. Fischman MW, Schuster CR. Cocaine effects in sleep-deprived humans. Psychopharmacology 1980;72:1-8. 21. Roehrs T, Beare D, Zorick F, et al. Sleepiness and ethanol effects on simulated driving. Alcohol Clin Exp Res 1994;18:154-158. 22. Arnedt JT, Wilde GJ, Munt PW, et al. How do prolonged wakefulness and alcohol compare in the decrements they produce on a simulated driving task? Accid Anal Prev 2001;33:337-344. 23. Horne JA, Pettitt AN. High incentive effects on vigilance performance during 72 hours of total sleep deprivation. Acta Psychologica 1985;58:123-139. 24. Haslam DR. The incentive effect and sleep deprivation. Sleep 1983;6:362-368.
CHAPTER 5 • Acute Sleep Deprivation 65 25. Baranski JV, Thompson MM, Lichacz FM, et al. Effects of sleep loss on team decision making: motivational loss or motivational gain? Hum Factors 2007;49:646-660. 26. Webb WB, Levy CM. Effects of spaced and repeated total sleep deprivation. Ergonomics 1984;27:45-58. 27. Bonnet MH, Rosa RR. Sleep and performance in young adults and older insomniacs and normals during acute sleep loss and recovery. Biol Psychol 1987;25:153-172. 28. Adam M, Retey JV, Khatami R, et al. Age-related changes in the time course of vigilant attention during 40 hours without sleep in men. Sleep 2006;29:55-57. 29. Leproult R, Colecchia EF, Berardi AM, et al. Individual differences in subjective and objective alertness during sleep deprivation are stable and unrelated. Am J Physiol Regul Integr Comp Physiol 2003;284:R280-R290. 30. Mu Q, Mishory A, Johnson KA, et al. Decreased brain activation during a working memory task at rested baseline is associated with vulnerability to sleep deprivation. Sleep 2005;28:433-446. 31. Chee MW, Chuah LY, Venkatraman V, et al. Functional imaging of working memory following normal sleep and after 24 and 35 h of sleep deprivation: correlations of fronto-parietal activation with performance. Neuroimage 2006;31:419-428. 32. Retey JV, Adam M, Gottselig JM, et al. Adenosinergic mechanisms contribute to individual differences in sleep deprivation-induced changes in neurobehavioral function and brain rhythmic activity. J Neurosci 2006;26:10472-10479. 33. Viola AU, Archer SN, James LM, et al. PER3 Polymorphism predicts sleep structure and waking performance. Curr Biol 2007; 17:613-618. 34. Groeger JA, Viola AU, Lo JCY, et al. Early morning executive functioning during sleep deprivation is compromised by a PERIOD3 polymorphism. Sleep 2008;31:1159-1167. 35. Mullaney DJ, Kripke DF, Fleck PA, et al. Sleep loss and nap effects on sustained continuous performance. Psychophysiol 1983;20: 643-651. 36. Johnson LC. Physiological and psychological changes following total sleep deprivation. In: Kales A, editor. Sleep physiology and pathology. Philadelphia: JB Lippincott; 1969. p. 206-220. 37. Kahn-Greene ET, Killgore DB, Kamimori GH, et al. The effects of sleep deprivation on symptoms of psychopathology in healthy adults. Sleep Med 2007;8:215-221. 38. Wu JC, Buchsbaum M, Bunney W, et al. Antidepressant effects. In: Kushida CA, editor. Sleep deprivation: basic science, physiology, and behavior. New York: Marcel Dekker; 2005. p. 421-430. 39. Pilcher JJ, Huffcutt AI. Effects of sleep deprivation on performance: a meta-analysis. Sleep 1996;19:318-326. 40. Donnell JM. Performance decrement as a function of total sleep loss and task duration. Percept Mot Skills 1969;29:711-714. 41. Wilkinson RT. Interaction of lack of sleep with knowledge of results, repeated testing, and individual differences. J Exp Psychol 1961;62:263-271. 42. Light AI, Sun JH, McCool C, et al. The effects of acute sleep deprivation on level of resident training. Curr Surg 1989;46:29-30. 43. Alluisi EA, Coates GD, Morgan BBJ. Effects of temporal stressors on vigilance and information processing. In: Mackie RR, editor. Vigilance: theory, operational performance, and physiological correlates. New York: Plenum Press; 1977. p. 361-421. 44. Forest G, Godbout R. Attention and memory changes. In: Kushida CA, editor. Sleep deprivation: basic science, physiology, and behavior. New York: Marcel Dekker; 2005. p. 199-222. 45. Killgore WD, Killgore DB, Day LM, et al. The effects of 53 hours of sleep deprivation on moral judgment. Sleep 2007;30:345-352. 46. McKenna BS, Dicjinson DL, Orff HJ, Drummond SP. The effects of one night of sleep deprivation on known-risk and ambiguous-risk decisions. J Sleep Res 2007;16:245-252. 47. Carskadon MA, Dement WC. Effects of total sleep loss on sleep tendency. Percept Mot Skill 1979;48:495-506. 48. Marcus CL, Loughlin GM. Effect of sleep deprivation on driving safety in housestaff. Sleep 1996;19:763-766. 49. Horne JA. A review of the biological effects of total sleep deprivation in man. Biol Psychol 1978;7:55-102. 50. Kollar EJ, Namerow N, Pasnau RO, et al. Neurological findings during prolonged sleep deprivation. Neurology 1968;18:836-840. 51. Finelli LA. Cortical and electroencephalographic changes. In: Kushida CA, editor. Sleep deprivation: basic science, physiology, and behavior. New York: Marcel Dekker; 2005. p. 223-264.
52. Rodin EA, Luby ED, Gottleib JS. The EEG during prolonged experimental sleep deprivation. Electroencephalogr Clin Neurophysiol 1962;14:544-551. 53. Naitoh P, Pasnau RO, Kollar EJ. Psychophysiological changes after prolonged deprivation of sleep. Biol Psychiatry 1971;3:309-320. 54. Williams HL, Granda AM, Jones RC, et al. EEG frequency and finger pulse volume as predictors of reaction time during sleep loss. Electroencephalogr Clin Neurophysiol 1962;14:64-70. 55. Thomas M, Sing H, Belenky G, et al. Neural basis of alertness and cognitive performance impairments during sleepiness. I. Effects of 24 h of sleep deprivation on waking human regional brain activity. J Sleep Res 2000;9:335-352. 56. Drummond SP, Brown GG, Salamat JS, et al. Increasing task difficulty facilitates the cerebral compensatory response to total sleep deprivation. Sleep 2004;27:445-451. 57. Lim J, Choo WC, Chee MW. Reproducibility of changes in behaviour and fMRI activation associated with sleep deprivation in a working memory task. Sleep 2007;30:61-70. 58. Scalise A, Desiato MT, Gigli GL, et al. Increasing cortical excitability: a possible explanation for the proconvulsant role of sleep deprivation. Sleep 2006;29:1595-1598. 59. Zhong X, Hilton HJ, Gates GJ, et al. Increased sympathetic and decreased parasympathetic cardiovascular modulation in normal humans with acute sleep deprivation. J Appl Physiol 2005;98: 2024-2032. 60. White DP, Douglas NJ, Pickett CK, et al. Sleep deprivation and the control of ventilation. Am Rev Respir Dis 1983;128:984-986. 61. Phillips BA, Cooper KR, Burke TV. The effect of sleep loss on breathing in chronic obstructive pulmonary disease. Chest 1987; 91:29-32. 61a. Canet E, Gaultier C, D’Allest AM, et al. Effects of sleep deprivation on respiratory events during sleep in healthy infants. J Appl Physiol 1989;66:1158-1163. 62. Persson HE, Svanborg E. Sleep deprivation worsens obstructive sleep apnea. Comparison between diurnal and nocturnal polysomnography. Chest 1996;109:645-650. 63. Brooks D, Horner RL, Kimoff RJ, et al. Effect of obstructive sleep apnea versus sleep fragmentation on responses to airway occlusion. Am J Respir Crit Care Med 1997;155:1609-1617. 64. Minors D, Waterhouse J, Akerstedt T, et al. Effect of sleep loss on core temperature when movement is controlled. Ergonomics 1999;42:647-656. 65. Shaw PJ. Thermoregulaory changes. In: Kushida CA, editor. Sleep deprivation: basic science, physiology, and behavior. New York: Marcel Dekker; 2005. p. 319-338. 66. Fiorica V, Higgins EA, Iampietro PF, et al. Physiological responses of men during sleep deprivation. J Appl Physiol 1968;24:167-176. 67. Van Den Noort S, Brine K. Effect of sleep on brain labile phosphates and metabolic rate. Am J Physiol 1970;218:1434-1439. 68. Akerstedt T, Palmblad J, de la Torre B, et al. Adrenocortical and gonadal steroids during sleep deprivation. Sleep 1980;3:23-30. 69. Froberg JE. Twenty-four-hour patterns in human performance, subjective and physiological variables and differences between morning and evening active subjects. Biol Psychol 1977;5:119-134. 70. Kollar EJ, Slater GG, Palmer JO, et al. Stress in subjects undergoing sleep deprivation. Psychosom Med 1966;28:101-113. 71. Gary KA, Winokur A, Douglas SD, et al. Total sleep deprivation and the thyroid axis: effects of sleep and waking activity. Aviat Space Environ Med 1996;67:513-519. 72. Goh VH, Tong TY, Lim C, et al. Effects of one night of sleep deprivation on hormone profiles and performance efficiency. Mil Med 2001;166:427-431. 73. Zeitzer JM, Duffy JF, Lockley SW, et al. Plasma melatonin rhythms in young and older humans during sleep, sleep deprivation, and wake. Sleep 2007;30:1437-1443. 74. Spiegel K, Leproult R, Van Cauter E. Metabolic and endocrine changes. In: Kushida CA, editor. Sleep deprivation: basic science, physiology, and behavior. New York: Marcel Dekker; 2005. p. 293-318. 75. Schussler P, Uhr M, Ising M, et al. Nocturnal ghrelin, ACTH, GH and cortisol secretion after sleep deprivation in humans. Psychoneuroendocrinology 2006;31:915-923. 76. Cirelli C. Functional genomic of sleep and circadian rhythm Invited review: how sleep deprivation affects gene expression in the brain: a review of recent findings. J Appl Physiol 2002;92: 394-400.
66 PART I / Section 1 • Normal Sleep and Its Variations 77. Cirelli C. Changes in gene expression. In: Kushida CA, editor. Sleep deprivation: basic science, physiology, and behavior. New York: Marcel Dekker; 2005. p. 387-397. 78. Koh K, Joiner WJ, Wu MN, et al. Identification of SLEEPLESS, a sleep-promoting factor. Science 2008;321:372-376. 79. Dinges DF, Douglas SD, Zaugg L, et al. Leukocytosis and natural killer cell function parallel neurobehavioral fatigue induced by 64 hours of sleep deprivation. J Clin Invest 1994;93:1930-1939. 80. Irwin MR, Wang M, Campomayor CO, et al. Sleep deprivation and activation of morning levels of cellular and genomic markers of inflammation. Arch Intern Med 2006;166:1756-1762. 81. Moldofsky H. Central nervous system and peripheral immune functions and the sleep-wake system. J Psychiatr Neurosci 1994;19: 368-374. 82. Boyum A, Wiik P, Gustavsson E, et al. The effect of strenuous exercise, calorie deficiency and sleep deprivation on white blood cells, plasma immunoglobulins and cytokines. Scand J Immunol 1996;43:228-235. 83. Brown R, Pang G, Husband AJ, et al. Suppression of immunity to influenza virus infection in the respiratory tract following sleep disturbance. Regional Immunology 1989;2:321-325. 84. Renegar KB, Crouse D, Floyd RA, et al. Progression of influenza viral infection through the murine respiratory tract: the protective role of sleep deprivation. Sleep 2000;23:859-863. 85. Benca RM, Kushida CA, Everson CA, et al. Sleep deprivation in the rat: VII. Immune function. Sleep 1989;12:47-52. 86. Roehrs T, Hyde M, Blaisdell B, et al. Sleep loss and REM sleep loss are hyperalgesic. Sleep 2006;29:145-151. 87. Smith MT, Edwards RR, McCann UD, et al. The effects of sleep deprivation on pain inhibition and spontaneous pain in women. Sleep 2007;30:494-505. 88. Schey R, Dickman R, Parthasarathy S, et al. Sleep deprivation is hyperalgesic in patients with gastroesophageal reflux disease. Gastroenterology 2007;133:1787-1795. 89. Nascimento DC, Andersen ML, Hipolide DC, et al. Pain hypersensitivity induced by paradoxical sleep deprivation is not due to altered binding to brain mu-opioid receptors. Behav Brain Res 2007;178:216-220. 90. Schmid SM, Hallschmid M, Jauch-Chara K, et al. Sleep loss alters basal metabolic hormone secretion and modulates the dynamic counterregulatory response to hypoglycemia. J Clin Endocrinol Metab 2007;92:3044-3051. 91. Tobler I, Sigg H. Long-term motor activity recording of dogs and the effect of sleep deprivation. Experientia 1986;42:987991. 92. Plyley MJ, Shephard RJ, Davis GM, et al. Sleep deprivation and cardiorespiratory function. Influence of intermittent submaximal exercise. Eur J Appl Physiol 1987;56:338-344. 93. Born J, Lange T, Hansen K, et al. Effects of sleep and circadian rhythm on human circulating immune cells. J Immunol 1997; 158:4454-4464. 94. Bonnet M. Sleep fragmentation. In: Kushida CA, editor. Sleep deprivation: basic science, physiology, and behavior. New York: Marcel Dekker; 2005. p. 503-513. 95. Stepanski E. The effect of sleep fragmentation on daytime function. Sleep 2002;25:268-276. 96. Martin SE, Wraith PK, Deary IJ, et al. The effect of nonvisible sleep fragmentation on daytime function. Am J Respir Crit Care Med 1997;155:1596-1601.
97. Spath-Schwalbe E, Gofferje M, Kern W, et al. Sleep disruption alters nocturnal ACTH and cortisol secretory patterns. Biol Psychiatry 1991;29:575-584. 98. Sforza E, Chapotot F, Pigeau R, et al. Effects of sleep deprivation on spontaneous arousals in humans. Sleep 2004;27:1068-1075. 99. Guzman-Marin R, Bashir T, Suntsova N, et al. Hippocampal neurogenesis is reduced by sleep fragmentation in the adult rat. Neuroscience 2007;148:325-333. 100. Phillipson EA, Bowes G, Sullivan CE, et al. The influence of sleep fragmentation on arousal and ventilatory responses to respiratory stimuli. Sleep 1980;3:281-288. 101. Cassel W, Ploch T, Becker C, et al. Risk of traffic accidents in patients with sleep-disordered breathing: reduction with nasal CPAP. Eur Respir J 1996;9:2606-2611. 102. Carskadon MA, Dement WC. Sleep loss in elderly volunteers. Sleep 1985;8:207-221. 103. Johnson LC, Slye ES, Dement WC. Electroencephalographic and autonomic activity during and after prolonged sleep deprivation. Psychosom Med 1965;27:415-423. 104. Bonnet MH. The effect of varying prophylactic naps on performance, alertness and mood throughout a 52-hour continuous operation. Sleep 1991;14:307-315. 105. Borbely AA, Baumann F, Brandeis D, et al. Sleep deprivation: effect on sleep stages and EEG power density in man. Electroencephalogr Clin Neurophysiol 1981;51:483-495. 106. Moses J, Lubin A, Naitoh P, et al. Exercise and sleep loss: effects on recovery sleep. Psychophysiol 1977;14:414-416. 107. Nakazawa Y, Kotorii M, Ohshima M, et al. Changes in sleep pattern after sleep deprivation. Folia Psychiatr Neurol Jpn 1978;32: 85-93. 108. Benoit O, Foret J, Bouard G, et al. Habitual sleep length and patterns of recovery sleep after 24 hour and 36 hour sleep deprivation. Electroencephalogr Clin Neurophysiol 1980;50:477-485. 109. Bonnet MH. Effect of 64 hours of sleep deprivation upon sleep in geriatric normals and insomniacs. Neurobiol Aging 1986;7:89-96. 110. Reynolds CFd, Kupfer DJ, Hoch CC, et al. Sleep deprivation in healthy elderly men and women: effects on mood and on sleep during recovery. Sleep 1986;9:492-501. 111. Bonnet MH, Arand DL. Sleep loss in aging. In: Roth T, Roehrs T, editors. Clinics in geriatric medicine. 1989. p. 405-420. 112. Reynolds CFd, Kupfer DJ, Hoch CC, et al. Sleep deprivation effects in older endogenous depressed patients. Psychiatry Res 1987;21: 95-109. 113. Reynolds CF 3rd, Kupfer DJ, Hoch CC, et al. Sleep deprivation as a probe in the elderly. Arch Gen Psychiatry 1987;44:982-990. 114. Bonnet MH. Performance and sleepiness following moderate sleep disruption and slow wave sleep deprivation. Physiol Behav 1986; 37:915-918. 115. Rosa RR, Bonnet MH, Warm JS. Recovery of performance during sleep following sleep deprivation. Psychophysiol 1983;20:152-159. 116. Beaumont M, Batejat D, Coste O, et al. Recovery after prolonged sleep deprivation: residual effects of slow-release caffeine on recovery sleep, sleepiness and cognitive functions. Neuropsychobiology 2005;51:16-27. 117. Lamond N, Jay SM, Dorrian J, et al. The dynamics of neurobehavioural recovery following sleep loss. J Sleep Res 2007;16:33-41. 118. Malmberg B, Kecklund G, Karlson B, et al. Sleep and recovery in physicians on night call: a longitudinal field study. BMC Health Serv Res 2010;10(1):239.
Chronic Sleep Deprivation Siobhan Banks and David F. Dinges Abstract Chronic sleep deprivation, also referred to as chronic sleep restriction, is common, with a wide range of causes including shift work and other occupational and economic demands, medical conditions and sleep disorders, and social and domestic responsibilities. Sleep dose–response experiments have found that chronic sleep restriction to less than 7 hours per night resulted in cognitive deficits that (1) accumulate (i.e., become progressively worse over time as sleep restriction persists), (2) are sleep-dose sensitive (i.e., the less sleep that is obtained, the faster the rate at which deficits develop), and
Chronic sleep restriction occurs frequently and results from a number of factors, including medical conditions (e.g., pain), sleep disorders, work demands (including extended work hours and shift work), and social and domestic responsibilities. Adverse effects on neurobehavioral functioning accumulate as the magnitude of sleep loss escalates, and the result is an increased risk of on-the-job errors, injuries, traffic accidents, personal conflicts, health complaints, and drug use. Chronic sleep restriction, or partial sleep deprivation, has been thought to occur when one fails to obtain a usual amount of sleep.1,2 Half a century ago, Kleitman first used the phrase sleep debt to describe the circumstances of delaying sleep onset time while holding sleep termination time constant.3 He described the increased sleepiness and decreased alertness in individuals on such a sleep–wake pattern, and proposed that those subjects who were able to reverse these effects by extending their sleep on weekends were able to “liquidate the debt.”3, p. 317 The term sleep debt is usually synonymous with chronic sleep restriction because it refers to the increased pressure for sleep that results from an inadequate amount of physiologically normal sleep.4 To determine the effects of chronic sleep loss on a range of neurobehavioral and physiologic variables, a variety of paradigms have been used, including controlled, restricted time in bed for sleep opportunities in both continuous and distributed schedules,5 gradual reductions in sleep duration over time,6 selective deprivation of specific sleep stages,7 and limiting the time in bed to a percentage of the individual’s habitual time in bed.8 These studies have ranged from 24 hours9 to 8 months6 in length. Many reports published before 1997 concluded that chronic sleep restriction in the range commonly experienced by the general population (i.e., sleep durations of less than 7 hours per night but greater than 4 hours per night) resulted in some increased subjective sleepiness but had little or no effect on cognitive performance capabilities. Consequently, there was a widely held belief that individuals could “adapt” to chronic reductions in sleep duration, down to 4 to 5 hours per day. However, nearly all of these reports of adaptation to sleep loss were limited
Chapter
6
(3) do not result in profound subjective sleepiness or full selfawareness of the cumulative deficits from sleep restriction. The mechanisms underlying the sleep dose–response cumulative neurobehavioral and physiologic alterations during chronic sleep restriction remain unknown. Individual variability in neurobehavioral responses to sleep restriction appear to be as large as those in response to total sleep deprivation and as stable over time, suggesting a traitlike (possibly genetic) differential vulnerability to the effects of chronic sleep restriction or differences in the nature of compensatory brain responses to the growing sleep loss.
by problems in experimental design.8 Since 1997, experiments that have corrected for these methodological weaknesses have found markedly different results from those earlier studies, and have documented cumulative objective changes in neurobehavioral outcomes as sleep restriction progressed.10 This chapter reviews the cognitive and neurobehavioral consequences of chronic sleep restriction in healthy individuals.
INCIDENCE OF CHRONIC SLEEP RESTRICTION Human sleep need, or, more precisely, the duration of sleep needed to prevent daytime sleepiness, elevated sleep propensity, and cognitive deficits, has been a long-standing controversy central to whether chronic sleep restriction may compromise health and behavioral functions. Selfreported sleep durations are frequently less than 8 hours per night. For example, approximately 20% of more than 1.1 million Americans indicated that they slept 6.5 hours or less each night.11 Similarly, in polls of 1000 American adults by the National Sleep Foundation, 15% of subjects (aged 18 to 84 years) reported sleeping less than 6 hours on weekdays, and 10% reported sleeping less than 6 hours on weekends over the past year.12 Scientific perspectives on the duration of sleep that defines chronic sleep restriction have come from a number of theories. THEORETICAL PERSPECTIVES ON SLEEP NEED AND SLEEP DEBT Basal Sleep Need The amount of sleep habitually obtained by an individual is determined by a variety of factors. Epidemiologic and experimental studies point to a high between-subjects variance in sleep duration, influenced by environmental, genetic, and societal factors. Although not clearly defined in the literature, the concept of basal sleep need has been described as habitual sleep duration in the absence of preexisting sleep debt.13 Sleep restriction has been defined as the fundamental duration of sleep below which waking deficits begin to accumulate.14 Given these definitions, the 67
68 PART I / Section 1 • Normal Sleep and Its Variations
basal need for sleep appears to be between 7.5 and 8.5 hours per day in healthy adult humans. This number was based on a study in which prior sleep debt was completely eliminated through repeated nights of long-duration sleep that stabilized at a mean of 8.17 hours.15 A similar value was obtained from a large-scale dose–response experiment on chronic sleep restriction that statistically estimated daily sleep need to average 8.16 hours per night to avoid detrimental effects on waking functions.4 Core Sleep versus Optional Sleep In the 1980s, it was proposed that a normal nocturnal sleep period was composed of two types of sleep relative to functional adaptation: core and optional sleep.16,17 The initial duration of sleep in the sleep period was referred to as core, or “obligatory,” sleep, which was posited to “repair the effects of waking wear and tear on the cerebrum.”16, p. 57 Initially, the duration of required core sleep was defined as 4 to 5 hours of sleep per night, depending on the duration of the sleep restriction.16 The duration of core sleep has subsequently been redefined as 6 hours of (good-quality, uninterrupted) sleep for most adults.14 Additional sleep obtained beyond the period of core sleep was considered to be optional, or luxury, sleep, which “fills the tedious hours of darkness until sunrise.”16, p. 57 This core versus optional theory of sleep need is often presented as analogous to the concept of appetite: Hunger drives one to eat until satiated, but additional food can still be consumed beyond what the body requires. It is unknown whether the so-called optional sleep serves any function. According to the core sleep theory, only the core portion of sleep—which is dominated by slow-wave sleep (SWS) and slow-wave activity (SWA) on an electroencephalogram (EEG)—is required to maintain adequate levels of daytime alertness and cognitive functioning.16 The optional sleep does not contribute to this recovery or maintenance of neurobehavioral capability. This theory was strengthened by results from a mathematical model of sleep and waking functions (the three-process model) that predicted that waking neurobehavioral functions were primarily restored during SWS,18 which makes up only a portion of total sleep time. However, if only the core portion of sleep is required, it would be reasonable to predict that there would be no waking neurobehavioral consequences of chronically restricting sleep to 6 hours per night, and that cognitive deficits would be evident only when sleep durations were reduced below this amount. Experimental data have not supported this prediction.10 For example, findings from the largest sleep dose–response study to date, which examined the effects of sleep chronically restricted to 4, 6, or 8 hours of time in bed per night,4 found that cognitive performance measures were stable across 14 days of sleep restriction to 8 hours time in bed, but when sleep was reduced to either 6 or 4 hours per night, significant cumulative (dose-dependent) decreases in cognitive performance functions and increases in sleepiness were observed.4 It appears, therefore, that the “core” sleep needed to maintain stable waking neurobehavioral functions in healthy adults aged 22 to 45 years is in the range of 7 to 8 hours on average.18 Moreover, because extended sleep is thought to dissipate sleep debt caused by chronic sleep restriction,3 it is not clear that there is such a thing as
“optional” sleep. There is, instead, recovery sleep, which may or may not be optional, although there have very few studies of the sleep needed to recover from varying degrees of chronic sleep restriction. Adaptation to Sleep Restriction One popular belief is that subjects may be acutely affected after initial restriction of sleep length and may then be able to adapt to the reduced sleep amount, with waking neurocognitive functions unaffected further or returned to baseline levels. Although several studies have suggested that this is the case when sleep duration is restricted to approximately 4 to 6 hours per night for up to 8 months,6,9 there is also evidence indicating that the adaptation is largely confined to subjective reports of sleepiness but not objective cognitive performance parameters.4 This suggests that the presumed adaptation effect is actually a misperception on the part of chronically sleep-restricted people regarding how sleep restriction has affected their cognitive capability. One factor thought to be important in adaptation to chronic sleep restriction is the abruptness of the sleep curtailment. One study examined the relationship between rate of accumulation of sleep loss, to a total of 8 hours, and neurobehavioral performance levels.19 After 1 night of total sleep deprivation (i.e., a rapid accumulation of 8 hours of sleep loss), neurobehavioral capabilities were significantly reduced. When the accumulation of sleep loss was slower, achieved by chronically restricting sleep to 4 hours per night for 2 nights or 6 hours per night for 4 nights, neurobehavioral performance deficits were evident, but they were of a smaller magnitude than those following the night of total sleep loss. A greater degree of neurobehavioral impairment was evident in those subjects restricted to 4 hours for 2 nights than in those subjects allowed 6 hours per night, leading to the conclusion that during the slowest accumulation of sleep debt (i.e., 6 hours per night for 4 nights), there was evidence of a compensatory adaptive mechanism.19 It is possible but not scientifically resolved that different objective neurobehavioral measures may show different degrees of sensitivity and adaptation to chronic sleep restriction. For example, in the largest controlled study to date with statistical modeling of adaptation curves, cognitive performance measures showed little adaptation across 14 days of sleep restriction to 4 or 6 hours per night, compared with 8 hours per night,4 whereas waking EEG measures of alpha and theta frequencies showed no systematic sleep dose–dependent changes over days.14 Consequently, different neurobehavioral outcomes showed markedly different responses to chronic sleep restriction, with neurocognitive functions showing the least adaptation, subjective sleepiness measures showing more adaptation, and waking EEG measures as well as non–rapid eye movement (nonREM), SWS measures showing little or no response.4,14 The reliability of the latter findings may depend on the dose of restricted sleep and other factors. Two-Process Model Predictions of Sleep Restriction Biomathematical models of sleep–wake regulation have been used to make predictions about recovery in response
to various sleep durations. The basis of almost all current biomathematical models of sleep–wake regulation is the two-process model of sleep regulation.20 This model proposes that two primary components regulate sleep: (1) a homeostatic process that builds up exponentially during wakefulness and declines exponentially during sleep (as measured by slow-wave energy or delta power in the non-REM sleep EEG), and (2) a circadian process, with near–24-hour periodicity. Since its inception, the two-process model has gained widespread acceptance for its explanation of the timing and structure of sleep. Its use has extended to predictions of waking alertness and neurobehavioral functions in response to different sleep–wake scenarios.21 This extension of the two-process model was based on observations that as sleep pressure accumulated with increasing time awake, so did waking neurobehavioral or neurocognitive impairment, and as sleep pressure dissipated with time asleep, performance capability improved during the following period of wakefulness. In addition, forced-desynchrony experiments revealed that the sleep homeostatic and circadian processes interacted to create periods of stable wakefulness and consolidated sleep during normal 24-hour days.22 Hence, it was postulated that waking cognitive function (alertness variable A) could be mathematically modeled as the difference between the quantitative state for the homeostatic process (S) and the quantitative state for the circadian process (C), and thus A = S − C. Accordingly, predictions for changes in the neurobehavioral recovery afforded by chronically restricted sleep of varying durations could be made on the basis of sleep–wake times and circadian phase estimates, using the quantitative version of the two-process model. The validity of the various biomathematical models based on the two-process model, and their ability to predict actual experimental results of the neurobehavioral effects of chronic sleep restriction have been evaluated in a blind test.23 Because all current models are based on the same underlying principles as the two-process model, all yielded comparable predictions for neurobehavioral functioning in scenarios involving total sleep deprivation or chronic partial sleep restriction. All models accurately predicted waking neurobehavioral responses to total sleep deprivation. However, they all failed to adequately predict sleepiness and cognitive performance responses during chronic sleep restriction.4,23 Hence, it appears that the extension of the two-process model to prediction of waking alertness21 does not account for the results of chronic sleep restriction. Because the two-process model has had a profound theoretical influence on predictions of sleepiness based on total sleep deprivation data, its failure to capture the dynamic changes in neurobehavioral measures during chronic sleep restriction suggests that additional biological factors are relevant to the brain’s response to chronic sleep restriction.
EFFECTS OF CHRONIC SLEEP RESTRICTION The effects of sleep loss may be quantified in a number of different ways, using a wide range of physiologic, neurocognitive, behavioral, and subjective tools. Many early
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studies examining the effects of chronic sleep restriction on cognitive performance were conducted outside a controlled laboratory setting, with little or no control over potentially contaminating factors, such as the level of napping, extension of sleep periods, diet, stimulant use (e.g., caffeine, nicotine), activity, or exposure to zeitgebers (environmental time cues). The majority of these studies concluded that there were few or no detrimental effects on waking neurobehavioral capabilities, or subjective effects of the sleep restriction. For example, restriction of nocturnal sleep periods to between approximately 4 and 6 hours per night for up to 8 months produced no significant effects on a range of cognitive outcomes, including vigilance performance,9 psychomotor performance,6 logical reasoning, addition, or working memory.9 In addition, few effects on subjective assessments of sleepiness or mood were reported.9 Later studies, however, with far greater experimental control and appropriate control groups, have demonstrated significant cumulative sleep dose–response effects on a wide range of physiologic and neurobehavioral functions, which we summarize here. Sleep Architecture Sleep restriction alters sleep architecture, but it does not affect all sleep stages equally. Depending on the timing and duration of sleep, and the number of days it is reduced, some aspects of sleep are conserved, occur sooner, or intensify, and other aspects of sleep time are diminished. For example, studies examining sleep architecture during chronic periods of sleep restriction have demonstrated a consistent conservation of SWS at the expense of other non-REM and REM sleep stages.4,24,25 In addition, elevations in SWA, derived from spectral analysis of the sleep EEG in the range of 0.5 to 4.5 Hz, during non-REM sleep have also been reported during and after chronic sleep restriction.4,25 Because of the conservation of the amount of SWS and SWA during restricted sleep protocols, independent of sleep duration (e.g., 8 hours of time in bed or 4 hours of time in bed), it has been proposed that, with regard to behavioral and physiologic outcomes, these phenomena provide the recovery aspects of sleep. It remains to be determined whether the lack of SWS and SWA response to chronic restriction of sleep to 4 hours a night, relative to steady increases in physiologic and neurobehavioral measures of sleepiness,4 can account for the latter deficits. Consequently, although SWS and non-REM SWA may be conserved in chronic sleep restriction (to 4 to 7 hours per night), they do not appear to reflect the severity of daytime cognitive deficits or to protect against these deficits, raising serious doubts about SWS and non-REM SWA being the only aspects of sleep critical to waking functions in chronic sleep restriction.4 Sleep Propensity With the development and validation of sleep latency measures as sensitive indices of sleep propensity,26 the effects of chronic sleep restriction could be evaluated physiologically. Objective EEG measures of sleep propensity, such as the multiple sleep latency test26 (MSLT) and the
70 PART I / Section 1 • Normal Sleep and Its Variations
maintenance of wakefulness test27 (MWT), are frequently used to evaluate sleepiness (see Chapters 4 and 143). The daytime MSLT26 has been shown to vary linearly after 1 night of sleep restricted to between 1 and 5 hours of time in bed.26 Progressive decreases in daytime sleep latency have been documented (i.e., increases in sleep propensity) across 7 days of sleep restricted to 5 hours per night in healthy young adults,28 a finding confirmed in a later study using the psychomotor vigilance test (PVT).8 Dose–response effects of chronic sleep restriction on daytime MSLT values have been reported in a controlled laboratory study in commercial truck drivers.24 A significant increase in sleep propensity across 7 days of sleep restricted to either 3 or 5 hours per night was observed, with no increase in sleep propensity found when sleep was restricted to 7 or 9 hours per night.24 Similarly, sleep propensity (as measured by the MWT29) during 7 days of sleep restriction to 4 hours per night was reported to increase, especially in subjects whose sleep was restricted by advancing sleep offset.30 An epidemiologic study of predictors of objective sleep tendency in the general population31 also found a dose– response relationship between self-reported nighttime sleep duration and objective sleep tendency as measured by the MSLT. Persons reporting more than 7.5 hours of sleep had significantly less probability of falling asleep on the MSLT than those reporting between 6.75 and 7.5 hours per night (27% risk of falling asleep), and than those reporting sleep durations less than 6.75 hours per night (73% risk of falling asleep).31 Although the MWT has been used less in experimental settings than the MSLT, it has also been found to increase in experiments in which adults were restricted to 4 hours for sleep for 7 nights,30 and for 5 nights.32 All of these studies suggest that chronic curtailment of nocturnal sleep increases daytime sleep propensity. Oculomotor responses have also been reported to be sensitive to sleep restriction.33 Eyelid closure and slow rolling eye movements are part of the initial transition from wakefulness to drowsiness. Eye movements and eye closures have been studied during sleep-loss protocols, under the premise that changes in the number and rate of movements and eyelid closures are a reflection of increased sleep propensity and precursors of the eventual onset of sleep.34 It has been demonstrated experimentally that slow eyelid closures during performance are associated with vigilance lapses and are sensitive indices of sleep deprivation, and slow eyelid closures have been found to be a sign of drowsiness while driving.33 Increased slow eye movements attributed to attentional failures have been reported to be increased by reduced sleep time in medical residents.35 Sleep restriction has also been found to decrease saccadic velocity and to increase the latency to pupil constriction in subjects allowed only 3 or 5 hours of time in bed for sleep over 7 nights.36 These changes in ocular activity were positively correlated with sleep latency, subjective sleepiness measures, and accidents on a simulated driving task.36 Waking Electroencephalogram Slowing in certain waking EEG frequencies has been thought to reflect the increased homeostatic pressure for
sleep during sleep restriction. EEG frequencies in the slower range (0.5 to 14 Hz)—in sleep-deprived individuals in particular—may herald an increased tendency for microsleeps. Significant increases in power densities in the delta range (3.75 to 4.5 Hz) and decreases in the alpha range (9.25 to 10 Hz) have been reported in subjects exposed to 4 hours of sleep restriction for 4 nights.25 In contrast, no effect on waking alpha power (8 to 12 Hz) across days of restriction was evident in subjects restricted to 4 or 6 hours of time in bed for sleep per night for 14 nights.14 An increase in theta power (4 to 8 Hz) across days of the sleep restriction protocol was evident; however, there was no significant difference in theta power changes between restriction conditions. It has been suggested that these changes in waking EEG frequency during sleep loss reflect “spectral leakage” indicative of elevated sleep pressure manifesting in wakefulness.37 Few studies have investigated the “leakage” of slower EEG activity in humans, but animal studies suggest that this process may enable the brain to discharge some of the accumulated homeostatic sleep drive without actually going to sleep.37 Cognitive Effects Reduced sleep time can adversely affect different aspects of waking cognitive performance, especially behavioral alertness, which is fundamental to many cognitive tasks. Behavioral alertness can be measured with the PVT, which requires vigilant attention and has proved to be very sensitive to any reduction in habitual sleep time.38,39 Studies have consistently shown that sleep restriction increases PVT response slowing40 and lapses,38 which are thought to reflect microsleeps.3,41 As loss of sleep accumulates, relatively brief lapses of a half second can increase to well over 10 seconds and longer.3,41,42 It is suggested that lapses produced by sleep loss involve shifts in neuronal activity in frontal, thalamic, and secondary sensory processing areas of the brain.43 Lapses of attention occur unpredictably throughout cognitive performance in sleep-restricted subjects, and they increase in frequency and duration as a function of the severity of sleep restriction, which has led to the idea that they reflect underlying “wake state instability.”38,42,43 This instability appears to involve moment-tomoment fluctuations in the relationship between neurobiological systems mediating wake maintenance and sleep initiation.43 One early study of chronic sleep restriction effects on cognitive performance examined the effects of reducing habitual sleep time by 40% for 5 nights.44 Decreases in performance on a vigilance and simple reaction time performance task were observed across the protocol with sleep restriction. Interestingly, however, there was no effect of sleep restriction on a choice reaction time task, suggesting that not all measures of performance are equally sensitive to chronic sleep restriction. This could result from any of a number of aspects of the psychometric properties of cognitive tests (e.g., learning curves) or from their neurobiological substrates; negative findings provide no insight into the reason for lack of sensitivity. Two large-scale experimental studies published in 2003 described dose-related effects of chronic sleep restriction on neurobehavioral performance measures.4,24 In one study, truck drivers were randomized to 7 nights of 3, 5,
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7, or 9 hours of time in bed for sleep per night.24 Cognitive performance was assessed using the PVT. Subjects in the 3- and 5-hour time-in-bed groups experienced a decrease in performance across days of the sleep restriction protocol, with increases in the mean reaction time, in the number of lapses, and in the speed of the fastest reaction on the PVT.24 In the subjects who were allowed 7 hours of time in bed per night, a significant decrease in mean response speed was also evident, although no effect on lapses was evident. Performance in the group allowed 9 hours of time in bed was stable across the 7 days. In an equally large experiment,4 young adults had their sleep duration restricted to 4, 6, or 8 hours of time in bed per night for 14 nights, and daytime deficits in cognitive functions were observed for lapses on the PVT (Fig. 6-1), for a memory task, and for a cognitive throughput task. These performance deficits accumulated across the experimental protocol in those subjects allowed less than 8 hours of sleep per night.4 Data from this study demonstrate that sleep restriction–induced deficits continued to accumulate beyond the 7 nights of restriction used in other experiments,8,24 with performance deficits still increasing at day 14 of the restricted sleep schedule. By the end of the 14-day chronic partial-sleep restriction period, the level of cognitive impairments recorded in subjects in the 4-hour sleep restriction condition was equivalent to the level of impairment seen after 1 to 2 nights without any sleep (see Fig. 6-1). To understand the relationship between the different sleep-loss conditions and the equivalence in performance impairment observed, the amount of cumulative sleep loss for subjects in each condition was calculated.4 The degree of sleep loss was greater in subjects allowed 4 hours of sleep each night for 14 nights (i.e., losing approximately 55 hours of sleep) than in subjects who remained awake for 88 hours (i.e., losing approximately 25 hours of sleep) (Fig. 6-2A), suggesting that impairments in waking performance should have been much worse in the 4-hour condition. However, this was not the case (see Fig. 6-1). To reconcile this paradox, wake time was defined as the difference between the duration of each continuous wake period and the duration of habitual wake time. Accordingly, cumulative wake-time extension was calculated as the sum of all consecutive hours of wakefulness extending beyond the habitual duration of wakefulness that each subject was accustomed to at home. In the 4-, 6-, and 8-hour sleep restriction conditions, this yielded the same results as for cumulative sleep loss, because the definitions of cumulative wake extension and cumulative sleep loss were arithmetically equivalent. However, for the 0-hour total sleep deprivation condition, each day without sleep added 24 hours to the cumulative wake extension. Thus, over 3 days with 0 hours of sleep, cumulative wake extension was equal to 72 hours for each subject (see Fig. 6-2B), whereas cumulative sleep loss was only 23 hours (see Fig. 6-2A). These results illustrate that cumulative sleep loss and cumulative wake extension are different constructs that can have different quantitative values, depending on the manner in which sleep loss occurs. They also suggest that sleep debt can also be understood as resulting in additional wakefulness beyond an average of approximately 16 hours a day, which has a neurobiological cost that accumulates over time.4
CHAPTER 6 • Chronic Sleep Deprivation 71
Effect sizes 4 hr vs. 8 hr: 1.45 6 hr vs. 8 hr: 0.71 4 hr vs. 6 hr: 0.43
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Figure 6-1 Psychomotor vigilance task (PVT) performance lapses under varying dosages of daily sleep. Displayed are group averages for subjects in the 8-hour (diamond), 6-hour (light blue square), and 4-hour (circle) chronic sleep period time in bed (TIB) across 14 days, and in the 0-hour (green square) sleep condition across 3 days. Subjects were tested every 2 hours each day; data points represent the daily average (07:30 to 23:30) expressed relative to baseline (BL). The curves through the data points represent statistical nonlinear model-based best-fitting profiles of the response to sleep deprivation for subjects in each of the four experimental conditions. The ranges (mean ± SE) of neurobehavioral functions for 1 and 2 days of 0 hours of sleep (total sleep deprivation) are shown as light and dark bands, respectively, allowing comparison of the 3-day total sleep deprivation condition and the 14-day chronic sleep restriction conditions. (Redrawn from Van Dongen HP, Maislin G, Mullington JM, et al. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 2003;26:117-126.)
It appears that the neurocognitive effects of restricting nocturnal sleep to 6 or 4 hours per night on a chronic basis are fundamentally the same as when sleep is chronically restricted but split each day between a nighttime sleep and a daytime nap.45 Cognitive performance deficits also accumulate across consecutive days in which the restricted sleep occurs during the daytime and wakefulness occurs at night.46 The primary difference between the nocturnally4 and diurnally46 placed restricted sleep periods is that the magnitude of neurobehavioral impairment is significantly greater with daytime sleep compared with nighttime sleep, reflecting a combined influence of the homeostatic and circadian systems. In another experiment, when recovery periods after total sleep time were restricted to 6 hours versus 9 hours time in bed for sleep per night, neither PVT performance nor sleepiness recovered to baseline levels, suggesting that restricting sleep can also reduce its recovery potential.47 All these studies suggest that when time in bed for sleep is chronically restricted to less than 7 hours per night in healthy adults (aged 21 to 64 years), cumulative deficits in a variety of cognitive performance functions become evident. These deficits can accumulate to levels of impairment equivalent to those observed after 1 or even 2 nights of total sleep deprivation. These cognitive performance findings are consistent with those on the effects of sleep restriction on physiologic
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72 PART I / Section 1 • Normal Sleep and Its Variations
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Figure 6-2 Cumulative buildup of sleep loss and wake time extension across days of sleep restriction and total sleep loss. A, Cumulative sleep loss relative to habitual sleep duration—that is, all hours of sleep habitually obtained (as measured at home during the 5 days prior to the experiment) but not received in the experiment because of sleep restriction. B, Cumulative wake extension relative to habitual wake duration—that is, all consecutive hours of wakefulness in excess of the habitual duration of a wakefulness period. Daily means are shown for subjects in the 8-hour (diamond), 6-hour (light blue square), 4-hour (circle), and 0-hour (green square) sleep period conditions. A also shows the range (orange band) of cumulative sleep loss (relative to habitual sleep duration) after 3 days in the 0-hour sleep condition, which was 23.1 ± 2.6 hours (mean ± SD). This was significantly less than the cumulative sleep loss after 14 days in the 4-hour sleep period condition (t20 = 10.58, P < .001). (Redrawn from Van Dongen HP, Maislin G, Mullington JM, et al. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 2003;26:117-126.)
sleep propensity measures (MSLT, MWT).24,28,30,32 Collectively, they suggest that there is a neurobiological integrator that accumulates either homeostatic sleep drive or the neurobiological consequences of excess wakefulness.4,24 There has as yet been no definitive evidence of what causes this destabilization of cognitive functions, but one intriguing line of evidence suggests that it may involve extracellular adenosine in the basal forebrain.48 Driving Performance There is an increased incidence of sleep-related motor vehicle crashes in drivers reporting less than 7 hours of sleep per night on average.49 Additional contributing factors to these sleep- or sleepiness-related crashes included poor sleep quality, dissatisfaction with sleep duration (i.e., undersleeping), daytime sleepiness, previous instances of driving drowsy, and time driving and time of day (driving late at night). It has been found that after 1 night of restricted sleep (5 hours), a decrease in performance on a driving simulator, with a concurrent increase in subjectively reported sleepiness, was found.50 In addition, during chronic sleep restriction in a controlled laboratory, with sleep durations reduced to between 4 and 6 hours per 24 hours, placed either nocturnally or diurnally, significant increases in the rate of accidents on a driving simulator occurred with decreased sleep durations, independent of the timing of the sleep period.51 Subjective Sleepiness and Mood In contrast to the continuing accumulation of cognitive performance deficits associated with nightly restriction of sleep to below 8 hours, subjective ratings of sleepiness, fatigue, and related factors repeatedly made by subjects on standardized sleepiness scales did not parallel performance deficits.4 As a consequence, after 2 weeks of sleep restricted to 4 or 6 hours per night, subjects were markedly impaired
and behaviorally less alert, but they thought themselves only moderately sleepy. This suggests that individuals frequently underestimate the actual cognitive impact of sleep restriction and believe themselves fit to perform. Experiments using driving simulators have found similar results, with drivers unable to accurately perceive their level of fatigue and cognitive impairment.50 Individual Differences in Responses to Chronic Sleep Restriction Although the majority of healthy adults develop cumulative cognitive deficits and sleepiness with chronic sleep restriction, interindividual variability in the neurobehavioral and physiologic responses to sleep restriction is substantial.3,38,39,42 Sleep restriction increases neurobehavioral performance variability in subjects,38,39,41 and it also reveals clear neurobehavioral differences between subjects. This interindividual variability is quite apparent in sleep restriction studies. For example, not everyone was affected to the same degree when sleep duration was limited to less than 7 hours per day in the studies described earlier.4,24 Some people experience very severe impairments even with modest sleep restriction, whereas others show little effect until sleep restriction is severe. However, this difference is not always apparent to the individual. It has been postulated that these individual differences are a result of state (basal level of sleepiness/alertness and basal differences in circadian phase) and trait differences (optimal circadian phase for sleep/wakefulness, sensitivity/responsiveness of sleep homeostat, and compensatory mechanisms),52 but these factors have not been widely researched. For studies of the possible genetic contributors to differential vulnerability to sleep loss, it is significant that the neurobehavioral responses to sleep deprivation have been found to be stable and consistent within subjects,23 suggesting they are traitlike.23
PHYSIOLOGIC EFFECTS There is increasing evidence of physiologic and healthrelated consequences of chronic sleep restriction. Alterations in other physiologic parameters, such as endocrine (see Chapter 125) and immune function (see Chapters 25 and 26), have been recognized and have implications for health status and risk. Several anecdotal and longitudinal studies have reported an increased incidence and risk of medical disorders and health dysfunction related to shift work schedules, which have been attributed to both circadian disruption and sleep disturbance. Further links between sleep disturbance and health effects have been reported in studies examining insomniac patients and patients with other sleep disorders and medical disorders that disturb sleep.53 In addition, an elevated mortality risk in those individuals who reported sleeping less than 6.5 hours per night has been found.11 One provocative discovery from this study was the finding that individuals sleeping more than 7.4 hours per night were also at an elevated risk of all-cause mortality. This finding is similar to that reported from the Nurses’ Health Study,54 where subjects reporting greater than 9 hours of sleep per night on average were at a higher risk for coronary events than those sleeping 8 hours per night. In addition, an increased risk of coronary events in women obtaining 7 hours of sleep or less per night was observed.55 Also, increasing epidemiologic, cross-sectional, and longitudinal data suggest that reduced sleep duration is associated with larger body mass index (BMI). A meta-analysis study found a consistent, increased risk of obesity among short sleepers—both children (sleeping less than 10 hours per night) and adults (sleeping less than 5 hours per night)—but, as the authors pointed out, causal inference was difficult because of the lack of control of confounders and inconsistency in the methodologies used.56 Endocrine and Metabolic Effects A number of studies have examined the effects of sleep loss on a range of neuroendocrine factors.57,57a Comparison of sleep restriction (4 hours per night for 6 nights) with sleep extension (12 hours per night for 6 nights) revealed an elevation in evening cortisol, increased sympathetic activation, decreased thyrotropin activity, and decreased glucose tolerance in the restricted as opposed to the extended sleep condition.55 Similarly, an elevation in evening cortisol levels and an advance in the timing of the morning peak in cortisol, so that the relationship between sleep termination and cortisol acrophase was maintained, were found after 10 nights of sleep restricted to 4.2 hours of time in bed for sleep each night compared with baseline measures and a control group allowed 8.2 hours of time in bed for sleep for 10 nights.58 Changes in the timing of the growth hormone secretory profile associated with sleep restriction to 4 hours per night for 6 nights, with a bimodal secretory pattern evolving, have also been reported.59 Immune and Inflammatory Effects The majority of studies examining sleep loss and immune function have concentrated on total sleep deprivation or 1 night of sleep restriction. Changes in natural killer cell activity,60,61 lymphokine-activated killer cell activity,60
CHAPTER 6 • Chronic Sleep Deprivation 73
interleukin-6,62 and soluble tumor necrosis factor–alpha receptor 161 have all been reported with total sleep deprivation and sleep restriction. One study reported that antibody titers were decreased by more than 50% after 10 days in subjects who were vaccinated for influenza immediately after 6 nights of sleep restricted to 4 hours per night, compared with those who were vaccinated after habitual sleep duration.63 But by 3 to 4 weeks after the vaccination, there was no difference in antibody level between the two subject groups. Therefore, sleep loss appeared to alter the acute immune response to vaccination. Cardiovascular Effects Increased cardiovascular events and cardiovascular morbidity have been reported with reduced sleep durations.11,54 Additionally, this relationship has been found in a casecontrol study examining insufficient sleep resulting from work demands.64 In the Nurses’ Health Study, Ayas and colleagues54 reported that coronary events were increased in female subjects obtaining 7 hours of sleep or less per night compared with those averaging 8 hours per night, and Liu and associates64 reported a twofold to threefold increase in risk of cardiovascular events with an average sleep duration of 5 hours or less per night. Shift workers who typically experience chronic reductions in sleep time as well as circadian disruption have been found to have reduced cardiovascular health.65 The mechanism that links chronic sleep restriction and increased cardiovascular risk is unknown, but one potential pathway may be via activation of inflammatory processes during sleep loss. C-reactive protein (CRP) is a predictive inflammatory marker of increased risk for cardiovascular disease. Increased CRP levels have been found in patients with obstructive sleep apnea, who commonly experience reduced sleep time as well as hypoxia,66 and an increase in CRP levels was reported after both total sleep deprivation and sleep restriction (4 hours in bed for sleep per night) in healthy subjects.67 ❖ Clinical Pearl Chronic sleep deprivation can be caused by sleep disorders, work schedules, and modern lifestyles. Regardless of its cause, chronic sleep deprivation results in cumulative adverse effects in daytime awake functions, including sleep propensity, cognitive performance, driving safety, mood, and physiologic conditions.
Acknowledgments The substantive evaluation on which this chapter was based was supported by National Institutes of Health grants NR04281 and CTRC UL1RR024134, and by the National Space Biomedical Research Institute through NASA NCC 9-58. REFERENCES 1. Webb WB. Partial and differential sleep deprivation. In: Kales A, editor. Sleep: physiology and pathology—a symposium. Philadelphia: JB Lippincott; 1969. p. 221-231.
74 PART I / Section 1 • Normal Sleep and Its Variations 2. Dement WC, Vaughan C. The promise of sleep. New York: Dell; 1999. 3. Kleitman N. Sleep and wakefulness. 2nd ed. Chicago: University of Chicago Press; 1963. 4. Van Dongen HPA, Maislin G, Mullington JM, Dinges DF. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 2003;26(2):117-126. 5. Hartley LR. Comparison of continuous and distributed reduced sleep schedules. Q J Exp Psychol 1974;26:8-14. 6. Friedmann J, Globus G, Huntley A, Mullaney D, et al. Performance and mood during and after gradual sleep reduction. Psychophysiology 1977;14:245-250. 7. Ferrara M, De Gennaro L, Bertini M. The effects of slow-wave sleep (SWS) deprivation and time of night on behavioral performance upon awakening. Physiol Behav 1999;68(1-2):55-61. 8. Dinges DF, Pack F, Williams K, Gillen KA, et al. Cumulative sleepiness, mood disturbance, and psychomotor vigilance performance decrements during a week of sleep restricted to 4-5 hours per night. Sleep 1997;20(4):267-277. 9. Webb WB, Agnew HW. Effects of a chronic limitation of sleep length. Psychophysiology 1974;11(3):265-274. 10. Dinges DF. Sleep debt and scientific evidence. Sleep 2004;27(6): 1050-1052. 11. Kripke DF, Garfinkel L, Wingard DL, Klauber MR, et al. Mortality associated with sleep duration and insomnia. Arch Gen Psychiatry 2002;59(2):131-136. 12. 2002 Sleep in America Poll—National Sleep Foundation. Washington DC: 2002. 13. Dement W, Greenber S. Changes in total amount of stage 4 sleep as a function of partial sleep deprivation. Electroencephalogr Clin Neurophysiol 1966;20(5):523-526. 14. Van Dongen HPA, Rogers NL, Dinges DF. Understanding sleep debt: Theoretical and empirical issues. Sleep and Biol Rhythms 2003; 1:4-12. 15. Wehr TA, Moul DE, Barbato G, Giesen HA, et al. Conservation of photoperiod-responsive mechanisms in humans. Am J Physiol 1993;265(4):R846-R857. 16. Horne J, editor. Why we sleep: the functions of sleep in humans and other mammals. Oxford: Oxford University Press; 1988. 17. Horne JA. Sleep function, with particular reference to sleepdeprivation. Ann Clin Res 1985;17(5):199-208. 18. Akerstedt T, Folkard S. The three-process model of alertness and its extension to performance, sleep latency, and sleep length. Chronobiol Int 1997;14(2):115-123. 19. Drake CL, Roehrs TA, Burduvali E, Bonahoom A, et al. Effects of rapid versus slow accumulation of eight hours of sleep loss. Psychophysiology 2001;38(6):979-987. 20. Borbely AA. A two process model of sleep regulation. Hum Neurobiol 1982;1(3):195-204. 21. Borbely AA, Achermann P. Sleep homeostasis and models of sleep regulation. J Biol Rhythms 1999;14(6):557-568. 22. Dijk DJ, Czeisler CA. Paradoxical timing of the circadian-rhythm of sleep propensity serves to consolidate sleep and wakefulness in humans. Neurosci Let 1994;166(1):63-68. 23. Van Dongen HPA. Comparison of mathematical model predictions to experimental data of fatigue and performance. Aviat Space Environ Med 2004;75(3):A15-A36. 24. Belenky G, Wesensten NJ, Thorne DR, Thomas ML, et al. Patterns of performance degradation and restoration during sleep restriction and subsequent recovery: a sleep dose-response study. J Sleep Res 2003;12(1):1-12. 25. Brunner DP, Dijk DJ, Borbely AA. Repeated partial sleep-deprivation progressively changes the EEG during sleep and wakefulness. Sleep 1993;16(2):100-113. 26. Carskadon MA Dement WC. The multiple sleep latency test—what does it measure. Sleep 1982;5:S67-S72. 27. Mitler MM, Gujavarty KS, Browman CP. Maintenance of wakefulness test—a polysomnographic technique for evaluating treatment efficacy in patients with excessive somnolence. Electroencephalogr Clin Neurophysiol 1982;53(6):658-661. 28. Carskadon MA, Dement WC. Cumulative effects of sleep restriction on daytime sleepiness. Psychophysiology 1981;18(2):107-113. 29. Banks S, Barnes M, Tarquinio N, Pierce RJ, et al. The maintenance of wakefulness test in normal healthy subjects. Sleep 2004;27(4): 799-802.
30. Guilleminault C, Powell NB, Martinez S, Kushida C, et al. Preliminary observations on the effects of sleep time in a sleep restriction paradigm. Sleep Med 2003;4(3):177-184. 31. Punjabi NM, Bandeen-Roche K, Young T. Predictors of objective sleep tendency in the general population. Sleep Med 2003;26(6):678683. 32. Banks S, Van Dongen H, Dinges DF. How much sleep is needed to recover from sleep debt?—the impact of sleep dose on recovery. Sleep 2005;28:A138. 33. Dinges DF, Mallis M, Maislin G, Powell JW. Evaluation of techniques for ocular measurement as an index of fatigue and the basis for alertness management. Final report for the U.S. Department of Transportation, National Highway Traffic Safety Administration. 1998;1-112. 34. Mallis MM, Dinges DF. Monitoring alertness by eyelid closure. In: Stanton N, Hedge A, Brookhuis K, Salas E, editors. The handbook of human factors and ergonomics methods. New York: CRC Press; 2005. p. 25. 35. Lockley SW, Cronin JW, Evans EE, Cade BE, et al. Effect of reducing interns’ weekly work hours on sleep and attentional failures. N Eng J Med 2004;351(18):1829-1837. 36. Russo M, Thomas M, Thorne D, Sing H, et al. Oculomotor impairment during chronic partial sleep deprivation. Clin Neurophysiol 2003;114(4):723-736. 37. Cirelli C, Tononi G. Is sleep essential? PLoS Biol 2008;6(8):e216. 38. Dorrian J, Dinges DF. Sleep deprivation and its effects on cognitive performance. In: Dorrian JS, Dinges DF, editors. Encyclopedia of sleep medicine. Hoboken, NJ:1 John Wiley & Sons; 2005. 39. Durmer JS, Dinges DF. Neurocognitive consequences of sleep deprivation. Semin Neurol 2005;25:117-129. 40. Lim J, Dinges DF. Sleep deprivation and vigilant attention. Molecular and biophysical mechanisms of arousal, alertness, and attention. Ann N Y Acad Sci 2008;1129:305-322. 41. Dinges DF, Kribbs NB. Performing while sleepy: effects of experimentally-induced sleepiness. In: Monk TH, editor. Sleep, sleepiness and performance. Chichester: John Wiley & Sons; 1991. p. 97-128. 42. Doran SM, Van Dongen HPA, Dinges DF. Sustained attention performance during sleep deprivation: evidence of state instability. Arch Ital Biol 2001;139:253-267. 43. Chee MW, Tan JC, Zheng H, Parimal S, et al. Lapsing during sleep deprivation is associated with distributed changes in brain activation. J Neurosci 2008;28(21):5519-5528. 44. Herscovitch J, Broughton R. Performance deficits following shortterm partial sleep-deprivation and subsequent recovery oversleeping. Can J Psychol 1981;35(4):309-322. 45. Mollicone DJ, Van Dongen HPA, Rogers NL, Dinges DF. Response surface mapping of neurobehavioral performance: testing the feasibility of split sleep schedules for space operations. Acta Astronautica 2008;63(7):833-840. 46. Rogers NL, Van Dongen HPA, Powell JW, Carlin MM, et al. Neurobehavioural functioning during chronic sleep restriction at an adverse circadian phase. Sleep 2002;25(Abstract Suppl.):A126-A127. 47. Lamond N, Jay SM, Dorrian J, Ferguson SA, et al. The dynamics of neurobehavioural recovery following sleep loss. J Sleep Res 2007; 16(1):33-41. 48. Porkka-Heiskanen T, Strecker RE, Thakkar M, Bjorkum AA, et al. Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science 1997;276(5316):1265-1268. 49. Stutts JC, Wilkins JW, Osberg JS, Vaughn BV. Driver risk factors for sleep-related crashes. Accid Anal Prev 2003;35(3):321-331. 50. Banks S, Catcheside P, Lack L, Grunstein RR, et al. Low levels of alcohol impair driving simulator performance and reduce perception of crash risk in partially sleep deprived subjects. Sleep 2004; 27(6):1063-1067. 51. Dorrian J, Dinges DF, Rider RL, Price NJ, et al. Simulated driving performance during chronic partial sleep deprivation. Sleep 2003; 26:A182-A183. 52. Roth T, Roehrs T. The timing of sleep opportunities in a seven-night sleep restriction. Sleep Med 2003;4(3):169-170. 53. Bonnet MH. Sleep deprivation. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. Philadelphia: Saunders; 1994. p. 50-67. 54. Ayas NT, White DP, Manson JE, Stampfer MJ, et al. A prospective study of sleep duration and coronary heart disease in women. Arch Int Med 2003;163(2):205-209.
55. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999;354(9188):1435-1439. 56. Cappuccio FP, Taggart FM, Kandala NB, Currie A, et al. Metaanalysis of short sleep duration and obesity in children and adults. Sleep 2008;31(5):619-626. 57. Knutson KL, Van Cauter E. Associations between sleep loss and increased risk of obesity and diabetes. Ann N Y Acad Sci 2008; 1129:287-304. 57a. Leproult R, Van Cauter E. Role of sleep and sleep loss in hormonal release and metabolism. Endocr Dev 2010;17:11-21. 58. Rogers NL, Price NJ, Mullington JM, Szuba MP, et al. Plasma cortisol changes following chronic sleep restriction. Sleep 2000;23: A70-A71. 59. Spiegel K, Leproult R, Colecchia EF, L’Hermite-Baleriaux M, et al. Adaptation of the 24-h growth hormone profile to a state of sleep debt. Ame J Physiol Regul Integr Comp Physiol 2000;279(3): R874-R883. 60. Irwin M, McClintick J, Costlow C, Fortner M, et al. Partial night sleep deprivation reduces natural killer and cellular immune responses in humans. FASEB J 1996;10(5):643-653. 61. Shearer WT, Reuben JM, Mullington JM, Price NJ, et al. Soluble TNF alpha receptor 1 and IL-6 plasma levels in humans subjected
CHAPTER 6 • Chronic Sleep Deprivation 75 to the sleep deprivation model of spaceflight. J Allergy Clin Immunol 2001;107(1):165-170. 62. Redwine L, Hauger RL, Gillin JC, Irwin M. Effects of sleep and sleep deprivation on interleukin-6, growth hormone, cortisol, and melatonin levels in humans. J Clin Endocrinol Metab 2000; 85(10):3597-3603. 63. Spiegel K, Sheridan JF, Van Cauter E. Effect of sleep deprivation on response to immunization. JAMA 2002;288(12):1471-1472. 64. Liu Y, Tanaka H, the Fukuoka Heart Study Group. Overtime work, insufficient sleep, and risk of non-fatal acute myocardial infarction in Japanese men. Occup Environ Med 2002;59:447-451. 65. Knutsson A, Hallquist J, Reuterwall C, Theorell T, et al. Shiftwork and myocardial infarction: a case-control study. Occup Environ Med 1999;56(1):46-50. 66. Lee LA, Chen NH, Huang CG, et al. Patients with severe obstructive sleep apnea syndrome and elevated high-sensitivity C-reactive protein need priority treatment. Otolaryngol Head Neck Surg 2010;143(1):72-77. 67. van Leeuwen WM, Lehto M, Karisola P, et al. Sleep restriction increases the risk of developing cardiovascular diseases by augmenting proinflammatory responses through IL-17 and CRP. PLoS One 2009;4(2):e4589.
Sleep Mechanisms and Phylogeny
Section
2
Jerome M. Siegel 7 Neural Control of Sleep in Mammals 8 REM Sleep 9 Phylogeny of Sleep Regulation 10 Sleep in Animals: A State of Adaptive Inactivity
Neural Control of Sleep in Mammals Dennis McGinty and Ronald Szymusiak Abstract Mammalian sleep and wake states are facilitated by multiple brain regions. The lower brainstem is sufficient to generate wake, non–rapid eye movement (NREM)-like, and REM sleep states, but lesions in several brain regions, including sites in the medulla, mesencephalon, preoptic area (POA) of the hypothalamus, thalamus, and neocortex, all markedly reduce the amounts of NREM and REM sleep. Similarly, arousal and waking are facilitated by several chemically distinct neuronal groups localized in the midbrain, the posterior and lateral hypothalamus, and the basal forebrain. These include histaminergic, orexinergic, serotonergic, cholinergic, dopaminergic, and noradrenergic neurons. These arousal systems share the property of having long axons and extensive projections to widespread brain regions, including the diencephalon, limbic system, and neocortex. These widespread projections can account for the global aspect of arousal from sleep, characterized by concurrent changes in electroencephalographic (EEG), motor, sensory, autonomic, and integrative functions. Arousal systems also control the neuronal membrane potentials in thalamocortical neurons; these potentials, in turn, regulate the oscillatory mechanisms intrinsic to thalamocortical networks that underlie NREM or “synchronized” EEG patterns. Inhibition of arousal systems permits the emergence of synchronized EEG patterns.
DIVERSE BRAIN REGIONS MODULATE WAKING AND NREM SLEEP Isolated Forebrain The capacity of various brain regions to generate sleep and wake states was first studied by isolating or removing major regions. The physiology of the chronically maintained isolated forebrain or chronic cerveau isolé preparation can be examined in dogs and cats.1 Acutely after complete midbrain transections, the isolated forebrain exhibits continuous EEG slow waves and spindles. Thus, structures below the midbrain must normally facilitate awake-like EEG states. However, if a brainstem transection is made lower, at the 76
Chapter
7
Although several brain regions modulate sleep, the POA has a critical role in the control of NREM sleep. Groups of neurons in the POA exhibit increased activity during NREM and REM sleep and respond to physiologic signals, such as warming, that increase sleep. Several putative neurochemical sleep factors promote sleep through actions in the POA or adjacent basal forebrain. Signals from the circadian clock originating in the hypothalamic suprachiasmatic nucleus regulate the circadian timing of sleep through connections in this brain region. POA sleep-active neurons send inhibitory gamma-aminobutyric acid (GABA)ergic projections to the histaminergic, orexinergic, serotonergic, and noradrenergic arousal systems. Through coordinated inhibition of these arousal systems, the key elements of NREM sleep onset are enabled, including EEG synchronization and suppression of motor activity. We take it for granted that the brain controls sleep and waking, and this has been confirmed. Research spanning the past 80 years has identified specific groups of neurons and neurochemical mechanisms that carry out the control of sleep and waking and generate core aspects of the phenomena of sleep and waking, such as the electroencephalographic (EEG) patterns that define these states. Many methods have been used. The story is complex, but a surprisingly coherent picture of sleep–wake control has emerged.
mid-pontine level, an activated or wakelike forebrain EEG state becomes predominant immediately after the transection, but with some residual episodes of EEG slow-wave activity.2 In this preparation, the forebrain exhibits evidence of conditioning, and other signs of an integrated waking state. These studies argue that neuronal groups localized between the midpons and upper midbrain are important for generating a waking-like state. After 5 to 9 days of recovery from surgery, the chronic cerveau isolé rat preparation exhibits a circadian pattern of EEG activation and synchronization.3 In this preparation, preoptic area (POA) lesions are followed by a continuously activated EEG, abolishing the circadian facilitation of synchronization. Thus, the isolated forebrain can generate a sustained wake-
like state, and the POA must play a critical role in initiating the sleeplike EEG state of the isolated forebrain (see later). Wakelike and sleeplike EEG states appear to depend on a balance between wake-promoting and sleep-promoting systems. Diencephalon Chronic diencephalic cats, whose neocortex and striatum have been removed, exhibit behavioral waking with persistent locomotion and orientation to auditory stimuli, a quiet sleeplike or non–rapid eye movement (NREM)-like state with typical cat sleeping postures, and a REM-like state including antigravity muscle atonia, rapid eye movements, muscle twitches, and pontine EEG spikes.4 EEG patterns recorded in the thalamus showed increased amplitude in conjunction with the NREM-sleep–like state, although true spindles and slow waves are absent. The thalamic EEG exhibits desynchronization during the REM-like state. In summary, at least in the cat, the neocortex and striatum are not required for any behaviorally defined sleep– wake states, and an NREM-like state occurs in the absence of sleep spindles and slow waves. Thalamus Cats subjected to complete thalamectomy (athalamic cats) continue to exhibit episodes of EEG and behavioral sleep and waking, although there is an absence of spindles in the NREM sleep EEG,4 and they exhibit chronic insomnia, with reductions in both NREM and REM sleep. Fatal familial insomnia,5 a neurodegenerative disease characterized by progressive autonomic hyperactivation, motor disturbances, loss of sleep spindles, and severe NREM sleep insomnia, typically begins after age 40 years. Neuropathologic findings reveal initial severe cell loss and gliosis in the anterior medial thalamus, including the dorsomedial nucleus. However, patients with paramedian thalamic stroke, with magnetic resonance imaging (MRI)-verified damage to the dorsomedial and centromedial nuclei, present with either severe hypersomnolence or increased daytime sleepiness, not insomnia.6 In summary the thalamus plays a critical role in regulating cortical EEG patterns during waking and sleep, and portions of this structure appear to have hypnogenic functions. Lower Brainstem After recovery from the acute effects of the complete midbrain transections (described earlier), the lower brainstem can generate rudimentary behavioral waking, a NREMlike state, and a REM-like state.4 The behavior of the midbrain-transected cats could be characterized as having three states, including “waking” (identified by crouching, sitting, attempts to walk, dilated pupils, and head orientation to noises), and two sleeplike states. In the first sleeplike state, cats lay down in a random position, pupils exhibited reduced but variable miosis, and eyes exhibited slow and nonconjugate movements, and they could be aroused by auditory or other stimuli. If this stage is not disturbed, cats enter another stage, characterized by complete pupillary miosis, loss of neck muscle tone, and rapid eye movements, identifying a REM-like state. Additional studies support the hypothesis that the lower brainstem contains sleep-facilitating processes. Low-frequency electrical stimulation of the dorsal medullary reticular forma-
CHAPTER 7 • Neural Control of Sleep in Mammals 77
tion in the nucleus of the solitary track produced neocortical EEG synchronization.7 Lesions or cooling of this site were followed by EEG activation.8 In summary, widespread structures in the mammalian nervous system, from the neocortex to the lower brainstem, have the capacity to facilitate both sleeplike and waking-like states and to modulate the amounts of sleep.
RETICULAR ACTIVATING SYSTEM AND DELINEATION OF AROUSAL SYSTEMS The transection studies just reviewed support the concept of a pontomesencephalic wake-promoting or arousal system. No discovery was historically more significant than the description of the reticular activating system (RAS) by Moruzzi.9 Large lesions of the core of the rostral pontine and mesencephalic tegmentum are followed by persistent somnolence and EEG synchronization, and electrical stimulation of this region induces arousal from sleep. Interruption of sensory pathways does not affect EEG activation. It was hypothesized that cells in the RAS generated forebrain activation and wakefulness. The concept of the RAS has been superseded by the finding that arousal is facilitated not by a single system but instead by several discrete neuronal groups localized within and adjacent to the pontine and midbrain reticular formation and its extension into the hypothalamus (Fig. 7-1). These discrete neuronal groups are identified and differentiated by their expression of molecular machinery that synthesizes and releases specific neurotransmitters and neuromodulators. These include neuronal groups that synthesize serotonin, noradrenalin, histamine, acetylcholine, and orexin/hypocretin (herein called orexin). Each of these systems has been studied extensively in the context of the control of specific aspects of waking behaviors. Here we will give only a brief overview of each, focusing on their contribution to generalized brain arousal or activation. Before proceeding, we point out certain general properties of these neuronal systems. 1. Arousal is a global process, characterized by concurrent changes in several physiologic systems, including autonomic, motor, endocrine, and sensory systems, and in EEG tracings. Thus, it is intriguing that most arousal systems share one critical property: the neurons give rise to long, projecting axons with extensive terminal fields that impinge on multiple regions of the brainstem and forebrain. These diffuse projections enable the systems to have multiple actions, as might be expected of arousal systems. In this review, we emphasize the ascending projections—that is, projections from the brainstem and hypothalamus to the diencephalon, limbic system, and neocortex, as these are particularly germane to the generation of cortical arousal. Some arousal systems also give rise to descending projections, which are also likely to play a role in regulating certain properties of sleep–wake states, such as changes in muscle tone. 2. The release of neurotransmitters and neuromodulators at nerve terminals is initiated by the propagation of action potentials to the terminals. Thus, neurotransmitter release is correlated with the discharge rate of
78 PART I / Section 2 • Sleep Mechanisms and Phylogeny
Thalamus
BF (ACh)
TMN (HA) SN Raphe VTA (5-HT) (DA)
PPT (ACh) LDT LC (NE)
Reticular formation
A
Cortex Orexin BF TMN
SN VTA
PPT LDT
Raphe LC
B Figure 7-1 A, Sagittal view of a generic mammalian brain providing an overview of the wake-control networks described in the text. The upper brainstem, posterior and lateral hypothalamus, and basal forebrain contain several clusters of neuronal phenotypes, with arousal-inducing properties. These clusters include neurons expressing serotonin (5-HT), norepinephrine (NE), acetylcholine (ACh) in both pontomesencephalic and basal forebrain clusters, dopamine (DA), and histamine (HA). B, Sagittal view of brainstem and diencephalon showing localization of orexin-containing neurons and their projections to both forebrain and brainstem. All of these groups facilitate EEG arousal (waking and REM) and/ or motor-behavioral arousal (waking). The arousal systems facilitate forebrain EEG activation both through the thalamus and the basal forebrain and through direct projections to neocortex. Arousal systems also facilitate motor-behavioral arousal through descending pathways.
neurons. Most arousal systems have been studied by recording the discharge patterns of neurons in “freely moving” animals, in relationship to spontaneously occurring wake and sleep states. Increased discharge during arousal or wake compared with sleep constitutes part of the evidence for an arousal system. 3. The actions of a neurotransmitter on a target system are determined primarily by the properties of the receptors in the target. The neurotransmitters and neuromodulators underlying arousal systems each act on several distinct receptor types, with diverse actions. In addition, postsynaptic effects are regulated by transmitter-specific “reuptake” molecules, which transport the neurotransmitter out of the synaptic space, terminating
its action. Pharmacologic actions are usually mediated by actions on specific receptor types or transporters (see examples later). 4. Chronic lesions of individual arousal systems or genetic knockout (KO) of critical molecules have only small or sometimes no effect on sleep–wake patterns (with the exception of serotonin and orexin KOs; see later), even though acute manipulations of these same systems have strong effects on sleep–wake. The absence of chronic lesions or KO effects is probably explained by the redundancy of the arousal systems, such that, over time, deficiency in one system is compensated for by other systems or by changes in receptor sensitivity. Electrophysiologic studies show that the arousal systems are normally activated and deactivated within seconds or minutes. Thus, effects of acute experimental manipulations of particular arousal-related neurotransmitters, as with administration of a drug, may better mimic the normal physiologic pattern and be more informative as to their function. 5. REM sleep is, on one hand, a sleep state, but, on the other hand, it is associated with neocortical EEG characteristics of wake. In parallel with these two sides of REM, it has been shown that arousal systems can be classified into two types, ones that are “off” in REM, befitting the sleeplike property of REM, and others that are “on” in REM, befitting the wakelike properties of REM. Some arousal-promoting systems (summarized later) also play a role in REM control. Detailed analyses of the control of the role of these systems in REM sleep can be found in Chapters 8 and 9.
WAKE-ON, REM-OFF AROUSAL SYSTEMS Serotonin Neurons containing serotonin, or 5-hydroxytryptamine (5-HT), innervate the forebrain and are found in the dorsal raphe (DR) and median raphe (MR) nuclei of the midbrain. These neurons project to virtually all regions of the diencephalon, limbic system, and neocortex. Although it was initially hypothesized that serotonin might be a sleeppromoting substance,10 much evidence shows that the immediate effect of release of serotonin is arousal (reviewed in reference 11). Although there is some heterogeneity, the discharge rates of most DR and MR neurons are highest during waking, lower during NREM, and there is minimal discharge in REM; release of serotonin in the forebrain is highest in waking. Because of the great diversity of serotonin receptors (there are at least 14 types), the effects of serotonin on target neurons are complex. Some receptor types are inhibitory, some are excitatory. At least one class of receptors (5-HT2A) appears to facilitate NREM sleep; 5-HT2A KO mice have less NREM.12 Another type (5-HT1A) is inhibitory to REM sleep, as 5-HT1A KO mice have increased REM.13 Selective serotonin reuptake inhibitors (SSRIs) and serotonin–norepinephrine reuptake inhibitors (SNRIs) are used to treat a variety of medical and psychiatric problems, and some drugs in this class have arousing or alerting properties. Serotonin has a wide range of functions in addition to the modulation of sleep–wake.
Norepinephrine Norepinephrine (NE)-containing neuronal groups in mammals are found throughout the brainstem, but the primary nucleus giving rise to ascending projections is the locus coeruleus (LC). NE neurons in the LC project throughout the diencephalon, forebrain, and cerebellum. LC neurons exhibit regular discharge during waking, reduced discharge during NREM sleep, and near-complete cessation of discharge in REM sleep, a pattern congruent with a role in behavioral arousal.14 Acute inactivation of the LC or a lesion in the ascending pathway from the LC increases slow-wave EEG activity during sleep.15 Distinct roles for alpha-1, alpha-2, and beta NE receptor types are established. Direct application of alpha-1 and beta agonists in preoptic area and adjacent basal forebrain sites induces increased wakefulness (reviewed in reference 16). The arousal-producing effects of psychostimulant drugs such as amphetamines depend partly on induction of increased NE release and inhibition of NE reuptake, as well as on enhanced dopamine action (see later). Histamine Histamine (HA)-containing neurons in mammals are discretely localized in the tuberomamillary nucleus (TMN) and adjacent posterior hypothalamus (PH). HA neurons project throughout the hypothalamus and forebrain, including the neocortex, as well as to the brainstem and spinal cord. Perhaps the most familiar evidence for an arousal-promoting action of central HA is that administration of histamine (H1)-receptor antagonists (antihistamines) that penetrate the blood–brain barrier cause sedation. Transient inactivation of the TMN region results in increased NREM sleep.17 HA neurons exhibit regular discharge during waking, greatly reduced discharge during NREM sleep, and cessation of discharge in REM sleep.18 HA neurons express the inhibitory H3-type autoreceptors. Administration of an antagonist of this receptor causes disinhibition and increased waking. Blockade of the critical HA-synthesizing enzyme increases NREM sleep.19 Orexin The loss of orexin neurons is known to underlie the human disease narcolepsy, whose major symptoms are cataplexy and excessive sleepiness.19-20a Orexin-containing neurons are localized in the midlateral hypothalamus, and like other arousal systems, they give rise to projections to all brain regions including the brainstem.21 Among the targets of orexin terminals are other arousal-promoting neurons including HA, 5-HT, and NE neurons. Orexin-containing neurons are active in waking, and they are “off” in both NREM and REM sleep.22,23 Local administration of orexin in several brain sites induces arousal.24 (See also Chapters 8 and 16.)
WAKE-ON, REM-ON AROUSAL SYSTEMS Acetylcholine Groups of acetylcholine (ACH)-containing neurons are localized in two regions: in the dorsolateral pontomesen-
CHAPTER 7 • Neural Control of Sleep in Mammals 79
cephalic reticular formation (RF) (the pedunculopontine tegmental [PPT] and laterodorsal tegmental [LDT] nuclei) and in the basal forebrain.25 The pontomesencephalic ACH neuronal group projects to the thalamus, hypothalamus, and basal forebrain; the basal forebrain group projects to the limbic system and neocortex. Neurons in both groups exhibit higher rates of discharge in both waking and REM than in NREM sleep,26 and release of ACH is also increased in these states.27 Pharmacologic blockade of ACH receptors induces EEG synchrony and reduces vigilance, and inhibition of the ACH-degrading enzyme cholinesterase enhances arousal.28 Dopamine Dopamine (DA)-containing neurons are primarily localized in the substantia nigra and the adjacent ventral tegmental area of the midbrain and the basal and medial hypothalamus.29 Putative dopaminergic neurons exhibit highest activity in waking and REM sleep. Release of DA in the frontal cortex is higher during wakefulness than during sleep.30 DA is inactivated primarily through reuptake by the dopamine transporter. Stimulant drugs such as amphetamines and modafinil act primarily through DA receptors, particularly by binding to and suppressing the dopamine transporter, reducing reuptake.31 The degeneration of the nigrostriatal DA system is the primary neuropathologic basis of Parkinson’s disease, and excessive daytime sleepiness is one manifestation of it.32 DA agonists used to treat periodic limb movement in sleep and restless leg syndrome do not usually induce arousal, probably because they have effects on both presynaptic and postsynaptic DA receptors; presynaptic receptors inhibit transmitter release, counteracting postsynaptic stimulation. Glutamate Glutamate (Glu)-containing neurons are found throughout the brain, including in the core of the pontine and midbrain RF.33 However, the projections of the brainstem Glu system have not been described. Glu is the primary excitatory neurotransmitter of the brain. Arousal is increased by application of Glu to many sites.34 Glu actions are mediated by receptors controlling membrane ion flux, including the N-methyl-d-aspartate (NMDA) receptor, and “metabotrophic” receptors controlling intracellular processes. Humans may be exposed to systemic administration of NMDA receptor antagonists in the form of anesthetics (e.g., ketamine) or recreational drugs (PCP). The effects are dosage dependent: low dosages produce arousal, and high dosages produce sedation. In rats, exposure to NMDA antagonists induces a potent long-lasting enhancement of NREM slow-wave activity.35
SLEEP-PROMOTING MECHANISMS We have reviewed evidence for multiple neurochemically specific arousal systems and noted that the activity of each of these neuronal groups is reduced during NREM sleep. In most groups, the reduction in neuronal discharge precedes EEG changes that herald sleep onset. How is the process of sleep onset orchestrated?
80 PART I / Section 2 • Sleep Mechanisms and Phylogeny
c-Fos Mapping Lesion and stimulation studies argue that the POA must contain sleep-active neurons. This has been confirmed in several species (reviewed in reference 38). The identification of sleep-active POA neurons was advanced by the application of the c-Fos immunostaining method.40 Rapid expression of the protooncogene c-fos has been identified as a marker of neuronal activation in many brain sites.41 Thus, c-Fos immunostaining permits functional mapping of neurons, identifying neurons that were activated in the preceding interval. After sustained sleep, but not waking, a discrete cluster of neurons exhibiting Fos immunoreactivity is found in the ventrolateral preoptic area (VLPO).40 The VLPO is located at the base of the brain, lateral to the optic chiasm. Sleep-related Fos immunoreactive neurons are also localized in the rostral and caudal median preoptic nucleus (MnPN).42 The MnPN is a midline cell group that widens to form a “cap” around the rostral end of the third ventricle. Examples of c-Fos immunostaining and the correlations between c-Fos counts and sleep amounts are shown in Figure 7-2. The number of sleeprelated Fos immunoreactive neurons in the MnPN is increased in rats exposed to a warm ambient temperature, in association with increased NREM sleep.42 The VLPO and the MnPN contain a high density of neurons with sleep-related discharge.43 Most sleep-active
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A POA Sleep-Promoting System Von Economo postulated a POA sleep-promoting area more than 70 years ago on the basis of his observation that postmortem examinations of patients who had had encephalitis and severe insomnia showed inflammatory lesions in this area of the brain.36 Patients with hypersomnia had lesions in the vicinity of the PH. To von Economo, this suggested the concept of opposing hypothalamic sleeppromoting and wake-promoting systems. In rats, symmetrical bilateral transections of the POA resulted in complete sleeplessness, and symmetrical bilateral transections of the PH caused continuous sleep.37 Rats with both POA and PH transections exhibited continuous sleep, as with PH transections alone. This was interpreted as showing that the POA normally inhibits the PH wakepromoting region. The PH wake-promoting system can now be understood as the rostral extension of arousalpromoting systems and pathways summarized earlier. The existence of a sleep-promoting mechanism in the POA has been confirmed by a variety of methods. Experimental lesions of this area result in insomnia. Bilateral lesions of the POA with diameters of 1 to 2 mm in rats and cats induce partial sleep loss. Larger bilateral lesions (3 to 5 mm in diameter) that extend into the adjacent basal forebrain yield more severe insomnia (reviewed in reference 38). After POA lesions that result in partial sleep loss, residual sleep is characterized by reduced slow-wave (delta) EEG activity.39 Delta EEG activity in NREM sleep is augmented by POA warming (see later). Because delta activity is recognized as a marker of enhanced sleep drive, this finding suggests that POA output contributes to the regulation of sleep drive. Electrical or chemical stimulation of the POA evokes EEG synchronization and behavioral sleep.
40 30 20
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r22 = 0.8 p2 <0.0001 r12 = 0.67 p1 = 0.0002 0 20 40 60 80 100 Sleep percentage (2 hours)
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Figure 7-2 Upper: Examples of c-Fos immunostaining of preoptic area (POA) neuronal nuclei, identified by dark spots after either sustained spontaneous sleep or wake. c-Fos immunostaining is a marker of neuronal activation and is a method for mapping the localization of sleep-active neurons in the brain. After sleep, increased staining was seen in the midline (A) or around the top of the third ventricle (B) compared with the wake samples (C and D). These sites correspond to the caudal and rostral median preoptic nucleus (MnPN). Similar results were seen in the ventrolateral preoptic area (VLPO). In other POA sites, c-Fos immunostaining was seen following both waking and sleep. Lower: Regression functions and correlations relating c-Fos counts and sleep amounts before sacrifice among individual animals. In all sites, high correlations were found between sleep amounts and c-Fos counts at a normal ambient temperature. Groups of animals were studied in both normal and warm ambient temperatures. In a warm ambient temperature, c-Fos counts after sleep and correlations between counts and sleep amounts were increased in MnPN sites (A and B), but they were suppressed in the VLPO (C). (From Gong H, Szymusiak R, King J, et al. Sleep-related c-Fos expression in the preoptic hypothalamus: effects of ambient warming. Am J Physiol Regul Integr Comp Physiol 2000;279:R2079-R2088.)
CHAPTER 7 • Neural Control of Sleep in Mammals 81
500 µV
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EMG 40 sec Figure 7-3 Example of sleep-active neurons in the median preoptic nucleus (MnPN). Shown is a continuous recording of discharge of an MnPN neuron during a wake-NREM-REM cycle (top). Discharge rate increased at the onset of sleep, as indicated by the increased amplitude of the EEG. Discharge rate increased further in association with REM sleep (right). Such sleep-active neurons were the majority of neurons encountered in the median preoptic nucleus (MnPN) and the ventrolateral preoptic area (VLPO). The presence of sleep-active neurons provides one critical piece of evidence for the importance of a brain region in the facilitation of sleep. (From Suntsova N, Szymusiak R, Alam MN, et al. Sleep-waking discharge patterns of median preoptic nucleus neurons in rats. J Physiol 2002;543:665-677.)
neurons in these nuclei are more activated during both NREM and REM sleep than in waking (Fig 7-3). A majority of VLPO neurons exhibit an increase in activity during the immediate transition periods between waking and sleep onset and display a progressive increase in discharge rate from light to deep NREM sleep. In response to 12 to 16 hours of sleep deprivation, VLPO neurons exhibit increased activation during sleep, but rates during waking remain the same as in control rats. Many MnPN neurons show a gradual increase in firing rates before sleep onset, elevated discharge rates during NREM sleep, and a small but significant additional increase in discharge rate during REM sleep. Other sites in the POA also exhibit sleep-related c-Fos immunoreactivity. Electrophysiologic studies describe sleep-active neurons throughout the POA, and lesions that do include the VLPO or MnPN are known to suppress sleep. This suggests that much of the diffuse sleep-related c-Fos immunoreactivity in the POA also labels neurons that are functionally important for sleep regulation.
THE ORCHESTRATION OF SLEEP BY THE POA HYPNOGENIC SYSTEM How do POA sleep-active neurons initiate and sustain sleep? VLPO neurons that exhibit c-Fos immunoreactivity following sleep express glutamic acid decarboxylase (GAD), the synthetic enzyme that produces the inhibitory neu-
rotransmitter, gamma-aminobutyric acid (GABA). The majority of MnPN neurons that exhibit sleep-related Fosimmunoreactivity also express GAD.44 VLPO neurons send anatomic projections to HA neurons in the TMN.45 Additional projections of the VLPO include the midbrain DR and the LC.46 The MnPN also projects to both the DR and LC.47 Both MnPN and VLPO also project to the perifornical lateral hypothalamic area, the location of cell bodies of the orexin arousal system.48 Thus, discharge of VLPO and MnPN GABAergic neurons during sleep is expected to release GABA at these sites. Indeed, GABA release is increased during NREM sleep and further increased in REM sleep in the PH, DR, and LC (reviewed in reference 38).49 Sleep-active neurons in VLPO and MnPN exhibit discharge-rate-change profiles across the wake-NREM-REM cycle that are reciprocal to those of wake-promoting HA, 5-HT, NE, and orexin neurons (Fig 7-4). These findings support a hypothesis that POA sleepactive neurons, through release of GABA, inhibit multiple arousal systems. The PH and LH areas also facilitate both motor and autonomic activation, and these processes are under GABAergic control.50 Sleep-related GABAergic inhibition of PH and LH provides a basis for sleep-related deactivation of autonomic and motor functions. POA lesions suppress REM as well as NREM sleep. REM sleep loss after POA damage may be a secondary consequence of NREM sleep disturbance. Alternatively, POA mechanisms may facilitate REM sleep as well as NREM sleep.
82 PART I / Section 2 • Sleep Mechanisms and Phylogeny
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Figure 7-4 Interactions of the preoptic area (POA) sleep-promoting neuronal system with arousal systems that can account for the orchestration of the sleep process. A, The neuronal discharge rates across the wake-NREM-REM cycle of sleep-active neurons from the ventrolateral preoptic area (VLPO) and the median preoptic nucleus (MnPN), and from arousal-related (wake-active) neurons in the perifornical lateral hypothalamus (PFLH) and tuberomammillary nucleus (TMN). These neuronal groups have generally reciprocal discharge patterns, although MnPN and VLPO neurons have peak activity at different times during NREM episodes. The wake-active, NREM-diminished, REM-off discharge pattern shown for TMN and a subgroup of PFLH neurons is also characteristic of putative serotoninergic neurons of the dorsal raphe nucleus (DR) and putative noradrenergic neurons of the locus coeruleus (see also C). B, Sagittal section of the diencephalon and upper brainstem of the rat showing anatomic interconnections of MnPN and VLPO neurons with arousal-related neuronal groups. The MnPN and VLPO distribute projections to sites of arousal-related activity including the (1) basal forebrain, (2) PFLH, which includes orexin-containing neurons, (3) histamine (HIST)-containing neurons of the tuberomammillary nucleus, (4) pontomesencephalic acetylcholine (ACH)-containing neurons, (5) pontomesencephalic serotonin (5-HT)-containing neurons, and (6) noradrenergic (NE)-containing neurons of the pons, particularly the locus coeruleus (LC). 5-HT, NE, and ACH arousal-related neurons provide inhibitory feedback to sleep-active neurons. The arousal-related neuronal groups also have widespread additional ascending and descending projections that control state-related functions throughout the brain. C, The sleep–wake switch or “flip-flop” model characterized by mutually inhibitory sleep-promoting and arousal-promoting neuronal groups, depicted as a seesaw, which can promote stable sleep or waking states. Activity of either sleep-promoting or wake-promoting neurons inhibits the neurons generating the opposing state. This network provides a mechanism for the global control of brain activity in the sleep–wake cycle. (Modified from McGinty D, Szymusiak R. Hypothalamic regulation of sleep and arousal. Front Biosci 2003;8:1074-1083.)
GABAergic neurons in the VLPO region are inhibited by ACH, 5-HT, and NE, transmitters of the arousal systems.51 MnPN neurons are inhibited by NE.52 Thus, POA sleep-active neurons inhibit arousal systems, and arousal systems inhibit POA sleep-active neurons. These mutually inhibitory processes are hypothesized to underlie a sleep-wake switch or “flip-flop” model (see Fig 7-4).53 Activation of arousal systems would inhibit sleep-active neurons, thereby removing inhibition from arousal systems, facilitating stable episodes of waking. On the other hand, activation of sleep-promoting neurons would inhibit arousal-related neurons, removing inhibition from sleeppromoting neurons and reinforcing consolidated sleep episodes. This model provides a mechanism for the stabilization of both sleep and waking states. Abnormalities in one or more of the components of this “flipflop” system could result in less stable sleep and wake states, a possible explanation for the fragmentation of sleep in sleep disorders in which insomnia is an element, and the fragmentation of waking in narcolepsy.
THALAMIC–CORTICAL INTERACTIONS AND THE GENERATION OF THE SLEEP EEG Changes in cortical EEG patterns are usually considered to be the defining feature of NREM sleep in mammals. Here we briefly review current understanding of thalamocortical mechanisms underlying NREM sleep EEG patterns, and of how modulation of thalamocortical circuits by arousal and sleep regulatory neuronal systems has an impact on key features of the sleep EEG. Thalamocortical circuits exhibit two fundamentally different modes of operation across the sleep–waking cycle: a state of tonic activation, or desynchrony, during waking and REM sleep, and a state of rhythmic, synchronized activity that is characteristic of NREM sleep.54 The two functional modes of thalamocortical activity are evident at the level of single neurons. During waking and REM sleep, thalamocortical neurons exhibit tonic firing of single action potentials (Fig. 7-5A) that are modulated by the levels of excitatory input from thalamic afferents, including specific sensory afferents.54,55 During NREM sleep, relay neurons discharge in high-frequency bursts of action potentials, followed by long pauses (see Fig. 7-5B). These two modes of action potential generation reflect the expression of intrinsic properties of thalamocortical neurons, and a specialized, voltage-sensitive Ca2+ current plays a critical role.56 This Ca2+ current, known as the lowthreshold or transient Ca2+ current (It), is inactivated (nonfunctional) when the membrane potential of thalamic relay neurons is relatively depolarized (less negative than −65 mV). Thus, when depolarizing input is delivered to a relay neuron that is resting at this level of membrane polarization, the cell responds with tonic single-spike firing (see Fig. 7-5C). When relay neurons are hyperpolarized (membrane potential more negative than −65 mV), It becomes activated, and depolarizing input evokes a slow Ca2+-mediated depolarization (100 to 200 msec in duration) that is crowned by a burst of three to eight fast Na+ action potentials (see Fig. 7-5D). There is a pause in the generation of fast action potentials after the burst, because
CHAPTER 7 • Neural Control of Sleep in Mammals 83
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Figure 7-5 Thalamic neurons exhibit distinct patterns of action potential generation during waking/REM sleep and during NREM sleep. A and B, Typical extracellularly recorded discharge patterns of a neuron in the cat lateral geniculate nucleus during waking and NREM sleep. Note the change from tonic, singlespike firing during waking (A), to high-frequency-burst firing during NREM sleep (B). Tonic versus burst firing reflects intrinsic, voltage-dependent properties of thalamic neurons, and it can be recorded in neurons from isolated slices of thalamus. C and D, In vitro intracellular recordings of a relay neuron from guinea pig thalamus. In C, note direct current (DC) injections (1 and 2) and recordings of intracellular voltage (3 and 4). Spontaneous resting potential for the cell is indicated by the dashed line. A depolarizing current step (1) delivered at resting potential (> −65 mV) evokes a tonic depolarizing response in the neuron (3) that is subthreshold for action potential generation. When membrane potential is rendered more positive by DC injection, the same depolarizing step (2) evokes tonic generation of fast action potentials (4) that persist for the duration of the depolarizing pulse. In D, the neuron has been hyperpolarized below resting potential (< −65 mV) by negative DC injection, and the low threshold Ca2+ current (It) is activated. When a depolarizing pulse is applied on the background of hyperpolarization, a slow Ca2+ spike is evoked (arrow), and it is crowned by a high-frequency burst of fast Na+ action potentials. It is inactivated in response to the Ca2+-mediated depolarization, and membrane potential sags toward the hyperpolarized level despite the continuance of the depolarizing current step. EOG, electrooculogram; LGN, lateral geniculate nucleus. (A and B modified from McCarley RW, Benoit O, Barrionuevo G. Lateral geniculate nucleus unitary discharge during sleep and waking: state- and rate-specific effects. J Neurophysiol 1983;50:798818; C and D modified from Jouvet M. Neurophysiology of the states of sleep. Physiol Rev 1967;47:117-177.)
It is self-inactivated by the Ca2+-mediated depolarization, and membrane potential falls below the threshold for action potential generation and back to the resting, hyperpolarized state (see Fig. 7-5D). Thus, the properties of It equip thalamocortical neurons with the ability to generate action potentials in two different modes: (1) tonic firing when stimulated from a relatively depolarized resting state, and (2) burst-pause firing from a hyperpolarized resting state.54,55 The major NREM sleep EEG rhythms, spindles, delta waves, and slow oscillations all arise through a combina-
RE
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Figure 7-6 Schematic representation of thalamic and cortical cell types involved in the generation of sleep EEG rhythms, and of the synaptic connectivity among the cell types. Four cell types are shown: thalamocortical relay (TC) cells, thalamic reticular (RE) neurons, cortical pyramidal (PY) cells, and cortical interneurons (IN). TC cells receive excitatory inputs from prethalamic afferent fibers (PRE) arising from specific sensory systems and from cholinergic and monoaminergic arousal systems located in the brainstem and posterior hypothalamus. Activity in sensory systems is relayed to the appropriate cortical area by ascending thalamocortical axons (up arrow). TC neurons also send an axon collateral that makes synaptic contact with RE neurons. RE neurons are GABAergic, and they send an inhibitory projection back to TC neurons. Corticothalamic feedback is mediated by layer VI, PY neurons that project back to the same relay neurons from which they derive thalamic input, and they send an axon collateral to RE neurons. Corticothalamic projections are excitatory on both RE and TC cells, but cortical stimulation can evoke net inhibitory effects on TC neurons because of activation of GABAergic RE neurons. (From Destexhe A, Sejnowski TJ. Interactions between membrane conductances underlying thalamocortical slow-wave oscillations. Physiol Rev 2003;83:1401-1453.)
tion of intrinsic neuronal properties (e.g., It) and the synaptic organization of cortical and thalamic circuits.57 A schematic of the core circuitry responsible for the generation of sleep rhythms in the EEG is shown in Figure 7-6. Thalamocortical relay neurons receive excitatory input from sensory neurons and from several of the brainstem arousal systems that function to promote depolarization and tonic firing in relay cells during waking. During waking, this excitation is faithfully conveyed by ascending thalamocortical axons to the functionally relevant area of
84 PART I / Section 2 • Sleep Mechanisms and Phylogeny
Sleep Spindles In humans, EEG spindles are waxing and waning, nearly sinusoidal waves with a frequency profile of 10 to 15 Hz. Spindles are generated in the thalamus, as evidenced by the fact that thalamectomy eliminates spindles in the sleep EEG.4 At the level of the thalamus, spindles are generated by an interplay between neurons in the RE and the relay nuclei.54,55,57 RE neurons also possess It calcium channels and exhibit high-frequency-burst firing from a hyperpolarized background. A high-frequency burst in RE neurons will produce strong inhibitory postsynaptic potentials (IPSPs) in relay neurons that are followed by rebound slow Ca2+ spikes and a high-frequency burst. This burst of firing in the relay neuron is conveyed back to the RE, evoking an excitatory postsynaptic potential (EPSP) that triggers a calcium spike and a burst in RE neurons. In thalamic slices that preserve connectivity between the RE and the adjacent relay nuclei, this disynaptic circuit can generate spontaneous spindle-like oscillations that can propagate across the slice.55 In the intact brain, the spindle oscillation in the thalamus is conveyed to the cortex by the pattern of burst firing in thalamic relay neurons.54,57,58 However, relay of specific sensory information through the thalamus to the cortex is severely compromised during spindle oscillations (Fig. 7-7), because of the combination of (1) disfacilitation of relay neurons resulting from loss of excitatory input from arousal systems and (2) the rhythmic IPSPs evoked by RE input. This sensory deafferentation of the cortex is believed to play an important role in maintaining NREM sleep continuity. Although the spindle oscillation originates in the thalamus, cortical feedback to the thalamus and cortico-cortical connections are important in synchronizing the occurrence of spindles over widespread thalamic and cortical areas.57,58 Phasic activation of layer VI pyramidal neurons excites neurons in the RE and synchronizes IPSP–rebound burst sequences in thalamic relay neurons with cortical activity.
r Wake t
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cortex for processing and integration. Thalamic relay neurons also send a collateral projection to the adjacent portion of the thalamic reticular nucleus (RE), which is a thin band of neurons that surrounds most thalamic relay nuclei. RE neurons are GABAergic and they send an inhibitory projection back to the relay neurons. These reciprocal connections between relay and RE neurons are thought to be important for aspects of waking thalamic function. The final critical piece of the basic circuitry for consideration is the feedback projection from layer VI pyramidal cells in cortex to both thalamic relay neurons and RE neurons. Corticothalamic projections are topographically organized, so that each cortical column has connectivity with the same relay neurons from which they derive thalamic inputs, and with the corresponding sector of the RE. In this anatomic/functional scheme, note the central location of RE neurons, which receive copies of thalamocortical and corticothalamic activity and sends an inhibitory projection back to the relay neurons. Although corticothalamic projections have excitatory effects on their postsynaptic targets in the thalamus, corticothalamic inputs to the RE are so powerful that the net response evoked in relay neurons by cortical stimulation is often inhibition.57
+ 2 msec Figure 7-7 Blockade of synaptic transmission in the thalamus during drowsiness and sleep in the cat. Field potentials are evoked in the ventrolateral thalamus by stimulation of the cerebellothalamic pathway. The evoked response consists of a presynaptic volley (t) and the postsynaptic response (r). Note the variability of the postsynaptic response during drowsiness compared with during waking, and the complete absence of a postsynaptic response during sleep. (Modified from Steriade M, Llinás RR. The functional states of the thalamus and the associated neuronal interplay. Physiol Rev 1988;68:649-742.)
Delta Waves The delta oscillation of NREM sleep appears to have both cortical and thalamic components. This is evidenced by the fact that cortical delta activity in the 1- to 4-Hz range persists after complete thalamectomy4 and by the demonstration that isolated thalamic relay neurons can generate a spontaneous clocklike delta oscillation resulting from the interplay of It and a hyperpolarization-activated cation current, known as the h-current.55 In the intact, sleeping brain, both sources of delta oscillation contribute to the frequency content of the cortical EEG. As discussed for spindles, corticothalamic and cortico-cortical connections function to synchronize delta oscillations over widespread cortical areas. Slow Oscillations Slow oscillations (less than 1 Hz) are a key aspect of the sleep EEG because they function to coordinate the occurrence of other synchronous EEG events (e.g., delta waves,
CHAPTER 7 • Neural Control of Sleep in Mammals 85 Slow wave sleep
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Figure 7-8 Slow oscillations in local cortical field potentials (LFP) and in the membrane potential of a cortical neuron during NREM sleep. A, Simultaneous intracellular, LFP, and EMG recording during sleep and wakefulness. the animal is in NREM sleep at the beginning of the recording with a transition to waking after about 70 seconds (arrows indicate EMG activation). Action potentials are truncated in the intracellular recording. B, Higher levels of delta power in the LFP are present during NREM sleep than during waking. Plotted are 10-second bins of the ratio of spectral power (<4 Hz/>4 Hz) recorded in the LFP. C, Intracellular activity and LFP recording from (A) shown at expanded timescale. Note clear fluctuations of the membrane potential between depolarized (up) and hyperpolarized (down) states during NREM sleep in association with the slow oscillation (<1 Hz) in the LFP. During wakefulness, cell is tonically depolarized and no sustained episodes of hyperpolarization are present. (From Mukovski M, Chauvette S, Timofeev I, Volgushev M. Detection of active and silent states in neocortical neurons from the field potential signal during slow-wave sleep. Cereb Cortex 2007;17:400-414.)
spindles, and K-complexes). Slow oscillations are entirely of cortical origin. They are absent from the thalamus in decorticate animals and are present in the cortex after thalamectomy as well as in isolated cortical slices.57 Underneath the slow oscillations, fluctuations occur between two states of activity in nearly all cortical neurons (Figs. 7-8 and 7-9).59,60 The “up” state is characterized by depolarization and generation of trains of action potentials. The up state occurs simultaneously in all cell types, including interneurons, and both fast IPSPs and EPSPs are characteristic of cortical neuronal activity during this state. Up states are followed by a prolonged period of hyperpolarization and quiescence, referred to as a “down” state (see Fig. 7-8). Generation of up states occurs through recurrent excitation in local cortical circuits and depends on excitatory transmission through α-amino-3-hydroxy-5-methyl-4isoxazole propionic acid (AMPA) and NMDA receptors.61 Transitions from up to down states involve a combination of activation of outward K+ currents and disfacilitation
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Figure 7-9 The cortical slow oscillation groups other sleeprelated EEG events in humans. A, Recordings of human EEG during NREM sleep from three bilateral derivations. Note the synchronous occurrence of K-complexes (KC) and of spindles (o) at multiple recording sites, and the regular recurrence of KC/delta waves with a periodicity of less than 1 Hz. B, Spectral decomposition from the C3 lead showing peaks in spectral power in the spindle frequency range (12 to 15 Hz), in the delta power range (1 to 4 Hz), and in the slow oscillation range (<1 Hz). (Modified from Sanchez-Vives MV, McCormick DA. Cellular and network mechanisms of rhythmic recurrent activity in neocortex. Nat Neurosci 2000;3:1027-1034.)
resulting from depression of excitatory synapses.61,62 Discharge of layer IV corticothalamic projection neurons during up phases can synchronize IPSPs in thalamic relay neurons through activation of RE neurons, causing the expression of EEG spindles and delta activity of thalamic origin on the background of the slow oscillation.58 Slow oscillations organize the synchronization and propagation of cortical delta activity through cortico-cortical connections. Frequency spectra of the human NREM sleep EEG reflect this dynamic, with prominent spectral peaks in the delta (1 to 4 Hz) and slow oscillation (less than 1 Hz) frequency ranges (see Fig. 7-9).63 By orchestrating the temporal and spatial coherence of rhythmic oscillations in thalamocortical circuits, slow oscillations are thought to be important in promoting the functional sensory deafferentation of the cortex during sleep, which in turn enhances sleep continuity and sleep depth. The transitions between up and down states in cortical neurons have been hypothesized to underlie changes in synaptic plasticity, or synaptic strength, during sleep, and to contribute to sleep-dependent changes in learning and memory.64
86 PART I / Section 2 • Sleep Mechanisms and Phylogeny
Spindle and delta oscillations are blocked by stimulation of the rostral brainstem, which activates cholinergic, monoaminergic, orexinergic, and glutamatergic inputs to the thalamus. Activity of cholinergic and monoaminergic neurons facilitates thalamic depolarization through inhibition of potassium channels.55 Thus, inhibition of these arousal systems facilitates hyperpolarization of thalamic neurons, permitting the activation of voltage-dependent membrane currents underlying spindles and slow waves. The POA sleep-promoting system can control EEG patterns through inhibitory modulation of these arousal systems, as described earlier.
INTEGRATION OF CIRCADIAN RHYTHMS AND SLEEP The suprachiasmatic nucleus (SCN) of the POA generates the signals that bring about the circadian patterns of sleep– waking.65 Direct projections from the SCN to areas of the POA implicated in sleep regulation are sparse, but multisynaptic pathways by which SCN signals can control of sleep-active neurons have been described. Lesions of a primary SCN projection target, the subparaventricular zone (SPVZ), also eliminate circadian rhythms of sleep– waking.66 The SPVZ projects directly to the MnPN and indirectly to the VLPO, MnPN, and other POA regions through the dorsomedial hypothalamic nucleus (DMH).67 Lesions of the DMH disrupt the circadian distribution of sleep–waking states in rats. In diurnal animals, activity of SCN neurons could inhibit sleep-promoting neurons during the light phase, or they may facilitate sleep-promoting neurons in the dark phase, with the reciprocal pattern occurring in nocturnal animals, or they may do both. THE POA, THERMOREGULATION, AND CONTROL OF SLEEP Several types of evidence support the hypothesis that sleep onset is coupled to body cooling. Depending on ambient conditions, sleep onset evokes heat loss–effector processes such as cutaneous vasodilation and sweating.68 In humans, sleep onset occurs soon after vasodilation of the hands and feet, which increases heat loss. Sleep in humans and animals is modulated by ambient temperature. Mild to moderate ambient temperature elevation increases coincident sleep as well as subsequent sleep (reviewed in reference 38). An increase in heat production by selective activation of brown adipose tissue using a beta3 adrenoreceptor agonist also increases NREM sleep.69 Thus, it is reasonable to hypothesize that one function of sleep is body cooling, particularly after increased body warming during wake. A circadian temperature rhythm is well documented. In humans, sleep normally occurs on the descending phase of the circadian temperature cycle, but sleep onset evokes a further decrease in temperature, even during continuous bed rest (reviewed in reference 38). Self-selected human bedtimes occur at the time of the maximal rate of decline of core body temperature.70 The association of sleep onset and the circadian temperature rhythm could represent two independent outputs of the circadian oscillator. However, under certain experimental conditions, including short
sleep–wake cycles, internal desynchronization, and forced desynchronization, the interactions of the temperature rhythm and sleep propensity can be studied and partially isolated from effects of prior waking (see Chapter 35). Although sleep may occur at any circadian phase, sleep propensity is increased on the late descending phase of the circadian temperature rhythm and is highest when temperature is low. Awakenings tend to occur as temperature increases, even if sleep time is short. This can be interpreted as evidence that the thermoregulatory mechanism that lowers body temperature also promotes sleep. The coupling of sleep propensity and body cooling is controlled by the POA. The POA is recognized as a thermoregulatory control site on the basis of the effects of local warming and cooling, lesions, local chemical stimulation, and neuronal unit recording studies (reviewed in reference 71). In vivo and in vitro studies have confirmed that the POA contains populations of warm-sensitive and coldsensitive neurons (WSNs and CSNs), which are identified by changes in neuronal discharge in response to locally applied mild thermal stimuli. Local POA warming promotes NREM sleep and EEG slow-wave activity in cats, rabbits, and rats (reviewed in reference 38). NREM sleep is increased for several hours during sustained POA warming.72 Local POA warming also increases EEG delta activity in sustained NREM. Because delta EEG activity in sustained sleep is considered to be a measure of sleep drive, this finding supports a hypothesis that sleep drive is modulated by POA thermosensitive neurons. Augmentation of sleep by ambient warming is prevented by coincident local POA cooling.72 Because POA cooling prevents activations of WSNs, this finding suggests that POA WSN activation mediates the sleep augmentation induced by ambient warming. Most POA WSNs exhibit increased discharge during NREM sleep compared with waking; most CSNs are wake-active (reviewed in reference 38). Increases in WSN discharge and decreases in CSN discharge anticipate EEG changes at sleep onset by several seconds. Thus, activity of WSNs and CSNs is likely to modulate spontaneous sleep– wake as well as sleep induced by local POA warming. As summarized earlier, POA sleep-active neurons send afferents to putative arousal systems. Local POA warming suppresses the discharge of arousal-related neurons in the PH, DR (5-HT neurons), LH orexin neuronal field, and basal forebrain cholinergic field (Fig. 7-10) (reviewed in reference 38). These studies demonstrate that functional inhibitory regulation of arousal-regulatory neurons originates in WSNs located in the POA, and they provide a mechanistic explanation for the coupling of sleep propensity to heat loss.
HIERARCHICAL CONTROL MODEL As reviewed in the beginning paragraphs of this chapter, there is evidence for the existence of sleep-promoting mechanisms at all levels of the neuraxis, including both forebrain and brainstem. Sleeplike behavior may be generated by an isolated lower brainstem, and sleep is facilitated by midbrain, thalamus, and neocortex. Lesions encompassing the ventral pontomesencephalic reticular formation and adjacent ventral structures, also produced severe sustained sleep reductions.73 Both NREM and REM sleep
1.4 1.2 Discharge rate (spikes/sec)
were reduced by about 50% a month after such lesions were created. However, a central role for the POA in the orchestration of sleep is supported by a variety of findings. To rationalize these diverse findings, it is useful to consider a hierarchical control concept, such as that applied previously to thermoregulation.74 In this conceptualization, a fundamental behavior such as rest–activity or sleep– waking is organized at all levels of the neuraxis, just as rest–activity cycles are found in all orders of animals. The POA may act as a master controller, integrating sleeppromoting circuitry with sleep homeostatic processes, other behavioral and hormonal regulatory systems, and circadian signals. The limbic system and neocortex are likely sources of additional controls, related to more complex behavioral contingencies including learning processes, instinctive behaviors, and sensory stimuli. These controls may be conveyed to the hypothalamus through projections from neocortex and limbic system.
CHAPTER 7 • Neural Control of Sleep in Mammals 87
1.0 0.8 0.6 0.4
*
0.2
* 0.0
A
Waking 1.66 Hz
NREM 0.59 Hz
REM 1.71 Hz
UNIT
Adenosine Adenosine is recognized as an inhibitory neuromodulator in the CNS, whose role in sleep is suggested by the potent arousal-producing effects of caffeine, an antagonist of adenosine A1 receptors. Adenosine and its analogues were found to promote sleep after systemic injection, intracerebroventricular (ICV) administration, and intra-POA microinjection, and particularly after administration by microdialysis in the basal forebrain (reviewed in reference 76). In the basal forebrain and, to a lesser extent, in neocortex, adenosine recovered through microdialysis increased during sustained waking in cats. No increase was found in thalamus, POA, or brainstem sites. Application in the basal forebrain of an antisense oligonucleotide to the adenosine A1 receptor mRNA, which blocks synthesis of receptor protein, slightly reduced spontaneous sleep, but it strongly reduced rebound after sleep deprivation.77 Adenosine A1 agonists delivered via microdialysis adjacent to basal forebrain neurons inhibited wake-active neurons during both waking and sleep.78 A current hypothesis is that the effects of adenosine on sleep–waking are mediated
100 µV
EMG
1 msec
EEG POA/BF temp. °C
SLEEP-PROMOTING NEUROCHEMICAL AGENTS Conceptions of sleep control based on neuronal circuitry, as outlined earlier, are deficient in that they do not provide explanations for quantitative features of sleep or sleep homeostasis. The control of neuronal activity by neurochemical mechanisms, including the release of GABA, occurs in a time frame of seconds. Sleep regulation and homeostasis has a time frame of days, not seconds. In addition, a complete description should account for biological variations in sleep such as the high daily sleep quotas in low-body-weight mammalian species and low quotas in very large species, higher sleep quotas in infants, sleep facilitation after body heating, and increased sleep propensity during acute infection. The investigation of biochemical mechanisms with sustained actions is needed to address these issues. Here we provide a brief overview of this approach, focusing on neurochemical agents with sleep-promoting properties. See Obal and Kreuger75 for a detailed and complete review of biochemical mechanisms of sleep–wake regulation.
B
38 36
50 sec
Figure 7-10 Effects of activation of preoptic area (POA) warmsensitive neurons (WSNs) by local warming on discharge of a putative serotoninergic neuron of the dorsal raphe nucleus (DRN) in the rat. A, Pattern of activity of DRN neurons across the sleep–wake cycle. Putative DRN serotoninergic neurons exhibit reduced discharge during NREM compared with waking, and very low discharge in REM sleep. The identification of this pattern of discharge as representing serotoninergic neurons is supported by several types of indirect evidence. B, Effects of POA warming on the discharge of a putative serotoninergic REM-off neuron during waking. A POA warming pulse was applied for about 100 seconds (bottom trace). During POA warming, the discharge was reduced by 64%, to a typical NREM sleep rate. A waking state was maintained during warning, as shown by electroencephalographic and electromyographic recordings. Increased discharge of POA WSNs during spontaneous NREM sleep is thought to contribute to the concurrent reduction of DRN discharge. The central role of temperaturesensitive neurons in sleep control provides a mechanistic basis for the coupling of sleep and the circadian temperature rhythm (see text). (From Guzman-Marin R, Alam MN, Szymusiak R, et al. Discharge modulation of rat dorsal raphe neurons during sleep and waking: effects of preoptic/basal forebrain warming. Brain Res 2000;875:23-34.)
by basal forebrain cholinergic neurons via A1 receptors.76 The proposed basal forebrain cholinergic neuronal site of action is problematic because destruction of these neurons has little effect on sleep.79 However, adenosine could act at multiple sites. Adenosine A2A receptors are also present in restricted brain regions and seem to mediate some sleep-promoting effects of adenosine. Brain adenosine levels rise when ATP production is reduced; under these conditions, inhibition of neuronal activity is neuroprotective. It has been proposed that
88 PART I / Section 2 • Sleep Mechanisms and Phylogeny
increased adenosine is a signal of reduced brain energy reserves that develop during waking, and that sleep is induced as an energy-restorative state.80 With respect to the brain energy restorative concept, some, but not all, studies show reduced cerebral glycogen, an energy-supply substrate, after sleep deprivation.81 There is no functional evidence that brain energy supply is compromised after sleep deprivation. This is a critical gap in the theory. Of course, adenosine could be a sleep-promoting signal based on functions other than energy supply limitation. Proinflammatory Cytokines Several proinflammatory cytokines have sleep-promoting properties. We summarize work on a well-studied and prototypic molecule, interleukin (IL)-1β. When administered intravenously, intraperitoneally, or into the lateral ventricles, IL-1β increases sleep, particularly NREM sleep, (reviewed in reference 82). Basic findings have been confirmed in several species. REM is usually inhibited by IL-1β. Much additional evidence supports a hypothesis that IL-1 modulates spontaneous sleep. Administration of agents that block IL-1 reduce sleep. In rats, IL-1 mRNA is increased in the brain during the light phase, when rat sleep is maximal. Sleep deprivation also increases IL-1 mRNA in brain. On the basis of these studies and others, it has been hypothesized that IL-1 plays a role in spontaneous sleep. Increased sleep associated with peripheral infection may also be mediated by responses to circulating IL-1, either through vagal afferents or via induction of central IL-1 or other hypnogenic signals. POA sleep-active neurons are activated by local application of IL-1, and wake-active neurons are inhibited.83 IL-1 fulfills many criteria for a sleep-promoting signal, and it is likely to be particularly important in facilitating sleep during infection. Prostaglandin D2 Administration of prostaglandin D2 (PGD2) by ICV infusion or by microinjection into the POA increases sleep, but the most potent site for administration is the subarachnoid space ventral to the POA and basal forebrain (reviewed in reference 84). Sleep induced by PGD2 administration is indistinguishable from normal sleep on the basis of EEG analysis. The synthetic enzyme lipocalin-PGD synthase (L-PGDS) is enriched in the arachnoid membrane and choroid plexus, but the receptor (the D-type prostanoid receptor) is localized more locally in the leptomeninges under the basal forebrain and the TMN. Knockout mice for L-PGDS had normal baseline sleep, but, unlike the controls, they had no rebound increase in NREM sleep after sleep deprivation. The PGD2 concentration was higher in the cerebrospinal fluid during NREM sleep than in waking and was higher in the light phase in the rat, when sleep amounts are high. Sleep deprivation increased the PGD2 concentration in the cerebrospinal fluid. On this basis, it was proposed that PGD2 plays a central role in sleep homeostasis. The hypnogenic action of PGD2 is hypothesized to be mediated by adenosine release acting on an adenosine A2A receptor. Administration of A2A antagonists blocked the effects of PGD2. A functional basis for the role of PGD2 in sleep homeostasis or its primary localization in the meninges has not been identified.
Growth Hormone–Releasing Hormone Growth hormone–releasing hormone (GHRH) is known primarily for its role in stimulating the release of growth hormone (GH). A surge in GH release occurs early in the major circadian sleep period in humans and in rats, specifically during the earliest stage 3/4 NREM sleep episodes in humans.85 GHRH is a peptide with a restricted localization in neurons in the hypothalamic arcuate nucleus and in the adjacent ventromedial and periventricular nuclei. Neurons in the latter location are thought to be the source of projections to the POA and basal forebrain. GHRH promotes NREM sleep after intraventricular, intravenous, intranasal, or intraperitoneal administration, or after direct microinjection into the POA (reviewed in reference 75). Blockade of GHRH by administration of a competitive antagonist or by immunoneutralization reduces baseline sleep and rebound sleep after short-term sleep deprivation. Mutant mice with GHRH signaling abnormalities have lower amounts of NREM sleep. GHRH stimulates cultured GABAergic hypothalamic neurons; these may constitute the GHRH target in the sleep-promoting circuit.86 It has been suggested that GHRH may elicit sleep onset in conjunction with release of GH as a coordinated process for augmenting protein synthesis and protecting proteins from degradation during the fasting associated with sleep. In brain, protein synthesis increases during sleep, and inhibition of protein synthesis augments sleep.87 GHRH is proposed to be one element of a multiple-element sleeppromoting system.75 Sleep as Detoxification or Protection from Oxidative Stress Oxidized glutathione (GSSR) was identified as one of four sleep-promoting substances in brain tissue extracted from sleep-deprived rats.88 Infusion of GSSR or its reduced form (GSH) into the lateral ventricle of rats during the dark phase increases both NREM and REM sleep (reviewed in reference 89). The sleep-enhancing effects of GSSR and GSH could be based on their antioxidant functions (see later) or on their functions as inhibitory regulators of glutamatergic transmission. Glutamatergic stimulation, in excess, has known neurotoxic functions mediated by NMDA receptors. Thus, GSSR and GSH could function to protect the brain against excess glutamatergic stimulation and potential neurotoxicity, inducing sleep through NMDA receptor blockade. Reactive oxygen species (ROS) include superoxide anion (O2−), hydrogen peroxide (H2O2), hydroxyl radical (OH−), nitric oxide (NO), and peroxynitrite (OONO−). ROS are generated during oxidation reactions or reactions between O2− and H2O2 or NO. ROS are normally reduced by constitutive antioxidants such as GSSR, GSH, and different forms of superoxide dismutase (SOD). GSH is lower in the hypothalamus of rats after 96 hours of sleep deprivation using the platform-over-water method.90 Five to 11 days of deprivation using the disk-over-water sleep deprivation method reduces Cu/Zn SOD (cytosolic SOD) as well as glutathione peroxidase in the hippocampus and brainstem.91 These studies suggest that, by reducing antioxidant availability, sleep deprivation can increase the risk of oxidative damage, and that sleep is protective against actions of
ROS. The possibility that sleep deprivation could cause neuronal damage was suggested by a finding that supraoptic nucleus neurons exhibited signs of subcellular damage after exposure to sleep deprivation.92 Supraoptic nucleus neurons may be sensitive to sleep deprivation because of their high rate of protein synthesis.92 What are the signaling molecules related to oxidative stress that increase as a function of sustained wakefulness and can promote sleep? One possible signal is NO production, which can be a response to glutamatergic stimulation, to cytokines and inflammation, and to oxidative stress.93 Activity of one NO synthetic enzyme, cytosolic nitric oxide synthase (NOS), is increased during the dark phase in rats, most strongly in the hypothalamus (reviewed in reference 94). Intravertebroventricular or IV administration of a NOS inhibitor strongly reduced sleep in rabbits and rats and suppressed NREM sleep response to sleep deprivation. Administration of NO donors increased sleep. NO inhibits oxidative phosphorylation and may stimulate the production of adenosine. NO production could, therefore, be a mediator of several sleep factors. ROS may play a role in the pathology associated with patients with obstructive sleep apnea. These patients exhibit signs of increased oxidative stress, including increased O2− production by neutrophils, monocytes, and granulocytes derived from patients (see Chapter 20). They also exhibit elevated levels of proteins, such as vascular endothelial growth factor, that are normally induced by ROS. These changes were reversed by treatment with continuous positive airway pressure. On the basis of these and several additional findings, it has been proposed that the increased cardiovascular disease in patients with obstructive sleep apnea results from oxidative damage to vascular walls. Oxidative stress is hypothesized to play a central role in both vascular disease and neurodegenerative disease. It is important to note that adenosine, ROS, glutamate, and NO have brief lives in the synaptic space—no more than a few seconds. If these molecules regulate sleep, they must have sustained release, or they may regulate the gene expression to generate sustained downstream effects. These mechanisms are the subject of current investigations.
SUMMARY There has been rapid progress in the elucidation of the neural circuitry underlying the facilitation of sleep and the orchestration of NREM sleep as well as the facilitation of arousal. We have detailed models that can explain many of the phenomena of sleep–wake. Wake and arousal are facilitated by several chemically distinct neuronal groups, including groups synthesizing and releasing acetylcholine, serotonin, norepinephrine, dopamine, histamine, orexin/ hypocretin, and glutamate. These neuronal groups distribute axons and terminal throughout the brain, providing a basis for concurrent changes in physiology associated with arousal. At the center of the sleep-promoting circuitry is the POA of the hypothalamus, confirming a hypothesis that is more than 70 years old. The POA sleep-promoting circuitry has reciprocal inhibitory connections with several arousal-promoting systems. A balance between the activities of sleep-promoting and arousal-promoting neuronal
CHAPTER 7 • Neural Control of Sleep in Mammals 89
systems would determine sleep–waking state. The circadian clock in the suprachiasmatic nucleus has direct and multisynaptic connections, with POA sleep-promoting neurons providing a mechanistic basis for generation of the daily rhythm of sleep–waking. Both sleep-promoting and arousal-promoting neuronal groups are modulated by a host of processes, including sensory, autonomic, endocrine, metabolic, and behavioral influences, accounting for the sensitivity of sleep to a wide range of centrally acting drugs and behavioral manipulations. The long-term regulation of sleep—sleep homeostasis—is the subject of competing and still incomplete hypotheses. Long-term sleep homeostasis may reflect the actions of several neurochemical processes that express “sleep factors.” Some of these sleep factors, including adenosine, PGD2, IL-1β, and GHRH, are known to act directly on the POA or adjacent basal forebrain neuronal targets. Sleep factors have been linked to distinct functional models of sleep homeostasis, including brain energy supply (adenosine), control of protein synthesis (GHRH), brain cell group “use” or temperature elevation (IL-1), or protection against oxidative or glutamatergic stress (NO, antioxidant enzymes). All of these factors may be involved in sleep homeostasis, but the relative importance of each factor for daily sleep is not established. ❖ Clinical Pearls Sleep is reduced by a wide variety of localized brain lesions. This may account for the association of insomnia with a variety of neuropathologies. Degeneration of the hypothalamic wake-promoting cell type that expresses the neuropeptide orexin is known to underlie narcolepsy.
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CHAPTER 7 • Neural Control of Sleep in Mammals 91 79. Bassant MH, Apartis E, Jazat-Poindessous FR, et al. Selective immunolesion of the basal forebrain cholinergic neurons: effects on hippocampal activity during sleep and wakefulness in the rat. Neurodegeneration 1995;4:61-70. 80. Benington JH, Heller HC. Restoration of brain energy metabolism as the function of sleep. Prog Neurobiol 1995;45:347-360. 81. Franken P, Gip P, Hagiwara G, et al. Changes in brain glycogen after sleep deprivation vary with genotype. Am J Physiol 2003; 285:P413-P419. 82. Kreuger JM, Rector DM, Churchill L. Sleep and cytokines. Sleep Med Clin 2007;2:161-169. 83. Alam MN, McGinty D, Imeri L, et al. Effects of interleukin-1 beta on sleep- and wake-active preoptic anterior hypothalamic neurons in unrestrained rats. Sleep 2001;24:A59. 84. Huang Z-L, Urade Y, Hayaishi O. Prostaglandins and adenosine in the regulation of sleep and wakefulness. Curr Opin Pharmacol 2007;7:33-38. 85. Mitsugi N, Kimura F. Simultaneous determination of blood levels of corticosterone and growth hormone in the male rat: relation to the sleep-wakefulness cycle. Neuroendocrinology 1985;41:125-130. 86. De A, Churchill L, Obal F Jr, et al. GHRH and IL1 beta increase cytoplasmic Ca2+ levels in cultured hypothalamic GABAergic neurons. Brain Res 2002;949:209-212. 87. Methippara MM, Alam MN, Kumar S, et al. Administration of the protein synthesis inhibitor, anisomycin, has distinct sleep-promoting effects in lateral preoptic and perifornical hypothalamic sites in rats. Neurosci 2008;151:1-11. 88. Inoue S, Honda K, Komoda Y. Sleep as neuronal detoxification and restitution. Behavi Brain Res 1995;69:91-95. 89. Ikeda M, Ikeda-Sagara M, Okada T, et al. Brain oxidation is an initial process in sleep induction. Neurosci 2005;130:1029-1040. 90. D’Almeida V, Lobo LL, Hipolide DC, et al. Sleep deprivation induces brain region-specific decreases in glutathione levels. Neuroreport 1998;9:2853-2856. 91. Ramanathan L, Gulyani S, Nienhuis R, et al. Sleep deprivation decreases superoxide dismutase activity in rat hippocampus and brainstem. Neuroreport 2002;13:1387-1390. 92. Eiland MM, Ramanathan LGS, Gilliland M, et al. Increases in amino-cupric-sliver staining of the supraoptic nucleus after sleep deprivation. Brain Res 2002;945:1-8. 93. Olivenza R, Mora MA, Lizasoain L, et al. Chronic stress induces the expression of inducible nitirc oxide synthase in rat brain cortex. J Neurochem 2000;74:785-791. 94. Gautier-Sauvigne S, Colas D, Parmantier P, et al. Nitric oxide and sleep. Sleep Med Rev 2005;9:101-113.
REM Sleep* Jerome M. Siegel Abstract Rapid eye movement (REM) sleep was first identified by its most obvious behavior: rapid eye movements during sleep. In most adult mammals, the electroencephalogram (EEG) of the neocortex exhibits low voltage during REM sleep. The hippocampus has regular high-voltage theta waves throughout REM sleep. The key brain structure for generating REM sleep is the brainstem, particularly the pons and adjacent portions of the midbrain. These areas and the hypothalamus contain cells that are maximally active in REM sleep, called REM-on cells, and cells that are minimally active in REM sleep, called REM-off cells. Subgroups of REM-on cells use the transmitter gammaaminobutyric acid (GABA), acetylcholine, glutamate, or glycine. Subgroups of REM-off cells use the transmitter norepinephrine, epinephrine, serotonin, histamine, or GABA. Destruction of large regions in the midbrain and pons can prevent the occurrence of REM sleep. Damage to portions of the brainstem can cause abnormalities in certain aspects of
Rapid eye movement, or REM, sleep was discovered by Aserinsky and Kleitman in 1953.1 In a beautifully written paper that has stood the test of time, they reported that REM sleep was characterized by the periodic recurrence of rapid eye movements, linked to a dramatic reduction in amplitude from the higher-voltage activity of the prior non-REM sleep period, as seen on the electroencephalogram (EEG). They found that the EEG of subjects in REM sleep closely resembled the EEG of alert–waking subjects, and they reported that subjects awakened from REM sleep reported vivid dreams. Dement identified a similar state of low-voltage EEG with eye movements in cats.2 Jouvet then repeated this observation, finding in addition a loss of muscle tone (i.e., atonia) in REM sleep and using the term paradoxical sleep to refer to this state. The paradox was that the EEG resembled that of waking, but behaviorally the animal remained asleep and unresponsive.3-5 Subsequent authors have described this state as activated sleep, or dream sleep. More recent work in humans has shown that some mental activity can be present in non-REM sleep but has supported the original finding that linked our most vivid dreams to the REM sleep state. However, we cannot assume that any person or animal who has REM sleep also dreams. Lesions of parietal cortex and certain other regions prevent dreaming in humans, even in individuals continuing to show normal REM sleep as judged by cortical EEG, suppression of muscle tone, and rapid eye movements.6 Children younger than 6 years, who have larger amounts of REM sleep than adults, do not *Supported by the Medical Research Service of the Department of Veterans Affairs, NIH grants NS14610, HL41370, HL060296, and MH64109. (Portions of this review have appeared elsewhere in another review by the author.)
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REM sleep. Of particular interest are manipulations that affect the regulation of muscle tone in REM sleep. Lesions of several regions in the pons and medulla can cause REM sleep to occur without the normal loss of muscle tone. In REM sleep without atonia, animals exhibit locomotor activity, appear to attack imaginary objects, and execute other motor programs during a state that otherwise resembles REM sleep. This syndrome may have some commonalties with the REM sleep behavior disorder seen in humans. Stimulation of portions of the REM sleep-controlling area of the pons can produce a loss of muscle tone in antigravity and respiratory musculature, even without eliciting all aspects of REM sleep. Narcolepsy is characterized by abnormalities in the regulation of REM sleep. Most cases of human narcolepsy are caused by a loss of hypocretin (orexin) neurons. Hypocretin neurons, which are located in the hypothalamus, contribute to the regulation of the activity of norepinephrine, serotonin, histamine, acetylcholine, glutamate, and GABA cell groups. These transmitters have potent effects on alertness and motor control and are normally activated in relation to particular emotions.
typically report dream mentation, perhaps because these cortical regions have not yet developed.7 The physiologic signs of REM sleep in both the platypus, the animal showing the most REM sleep,8 and a related monotreme, the short-nosed echidna,9 are largely restricted to the brainstem, in contrast to their propagation to the forebrain in adult placental and marsupial mammals. These findings make it questionable whether all or any nonhuman mammals that have REM sleep, all of which have cortical regions whose structure differs from that of adult humans, have dream mentation. This chapter will review the following: (1) the defining characteristics of REM sleep, including its physiology and neurochemistry, (2) the techniques used to investigate the mechanisms generating REM sleep and the conclusions of such investigations, (3) the mechanisms responsible for the suppression of muscle tone during REM sleep, and the pathologic effects of the disruption of these mechanisms, (4) narcolepsy and its link to mechanisms involved in REM sleep control, and especially to the peptide hypocretin, and (5) the functions of REM sleep.
CHARACTERISTICS OF REM SLEEP The principal electrical signs of REM sleep include a reduction in EEG amplitude, particularly in the power of its lower-frequency components (Fig. 8-1). REM sleep is also characterized by a suppression of muscle tone (atonia), visible in the electromyogram (EMG). Erections tend to occur in males.10 Thermoregulation (e.g., sweating and shivering) largely ceases in most animals, and body temperatures drift toward environmental temperatures, as in reptiles.11 Pupils constrict, reflecting a parasympathetic
CHAPTER 8 • REM Sleep* 93
WAKING
NON-REM
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EEG EOG OLF LGN HIPP 50 µV
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Figure 8-1 Top, Polygraph tracings of states seen in the intact cat. Bottom, States seen in the forebrain 4 days after transection at the pontomedullary junction. EEG, sensorimotor electroencephalogram; EMG, dorsal neck electromyogram; EOG, electrooculogram; HIPP, hippocampus; LGN, lateral geniculate nucleus; OLF, olfactory bulb; PGO, ponto-geniculo-occipital.
dominance in the control of the iris.12 These changes that are present throughout the REM sleep period have been termed its tonic features. Also visible are electrical potentials that can be most easily recorded in the lateral geniculate nucleus of the cat.13 These potentials originate in the pons, appear after a few milliseconds in the lateral geniculate nucleus, and can be observed with further delay in the occipital cortex, leading to the name ponto-geniculo-occipital (PGO) spikes. They occur as large-amplitude, isolated potentials 30 or more seconds before the onset of REM sleep as defined by EEG and EMG criteria. After REM sleep begins, they arrive in bursts of three to ten waves, usually correlated with rapid eye movements. PGO-linked potentials can also be recorded in the motor nuclei of the extraocular muscles, where they trigger the rapid eye movements of REM sleep. They are also present in thalamic nuclei other than the geniculate and in neocortical regions other than the occipital cortex. In humans, rapid eye movements are loosely correlated with contractions of the middle ear muscles of the sort that accompany speech generation and that are part of the protective response to loud noise.14 Other muscles also contract during periods of rapid eye movement, briefly breaking through the muscle atonia of REM sleep. There are periods of marked irregularity in respiratory and heart rates during REM sleep, in contrast to non-REM sleep, during which respiration and heart rate are highly regular. No single pacemaker for all of this irregular activity has been identified. Rather, the signals producing twitches of the peripheral or middle ear muscles may lead or follow PGO spikes and rapid eye movements. Bursts of brainstem neuronal activity may likewise lead or follow the activity of any particular recorded muscle.15-17 These changes that
occur episodically in REM sleep have been called its phasic features. As we will see later, certain manipulations of the brainstem can eliminate only the phasic events of REM sleep, whereas others can cause the phasic events to occur in waking; yet other manipulations can affect tonic components. These tonic and phasic features are also expressed to varying extents in different species, and not all of these features are present in all species that have been judged to have REM sleep.18
REM GENERATION MECHANISMS Technical Considerations The identification of sleep-generating mechanism can be achieved by inactivation or destruction of particular brain regions or neurons, by the activation of populations of neurons, or by recording the activity of neurons or measuring the release of neurotransmitters. Each approach has its advantages and limitations. Inactivation of Neurons by Lesions, Inhibition, Antisense Administration, or Genetic Manipulation More has been learned about brain function and about sleep control from brain damage caused by stroke, injury, or infection in patients, and by experimentally induced brain lesions in animals, than by any other technique. However, some basic principles need to be borne in mind when interpreting such data. Brain lesions can result from ischemia, pressure, trauma, and degenerative or metabolic changes. In animals, experimental lesions are most commonly induced by aspiration, transection of the neuraxis, electrolysis, local heating by radio frequency currents, or the injection of cytotoxins.
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The latter include substances such as N-methyl-d-aspartic acid (NMDA) and kainate that cause cell death by excitotoxicity, and targeted cytotoxins such as saporin coupled to particular ligands, which will kill only cells containing receptors for that ligand. Cytotoxic techniques have the considerable advantage of sparing axons passing through the region of damage, so that deficits will be attributable to the loss of local neurons rather than to interruption of these axons. If damage to a brain region causes the loss of a sleep state, it cannot be concluded that this is where a center for the state resides. Lesion effects are usually maximal immediately after the lesion is created. Swelling and circulatory disruption make the functional loss larger than will be apparent from standard postmortem histologic techniques. The loss of one brain region can also disrupt functions that are organized elsewhere. For example, spinal shock, a phenomenon in which severing the spinal cord’s connection to more rostral brain regions causes a loss of functions, is known to be mediated by circuits intrinsic to the spinal cord. On the other hand, with the passage of time, this sort of denervation-induced shock dissipates. In addition, adaptive changes occur that allow other regions to take over lost functions. This is mediated by sprouting of new connections to compensate for the loss. A striking phenomenon seen after placement of lesions aimed at identifying the brain regions responsible for REM and non-REM sleep is that even massive lesions targeted at putative sleepgenerating centers often produce only a transient disruption or reduction of sleep, presumably as a result of this compensation. A particularly useful approach to the understanding of REM sleep generation has been the transection technique. In this approach, the brain is cut at the spinomedullary junction, at various brainstem levels, or at forebrain levels by passing a knife across the coronal plane of the neuraxis. Regions rostral to the cut may be left in situ or may be removed. It might be expected that such a manipulation would completely prevent sleep phenomena from appearing on either side of this cut. However, to a surprising extent this is not the case. As we will review later, REM sleep reappears within hours after some of these lesions. When both parts of the brain remain, signs of REM sleep usually appear on only one side of the cut. This kind of positive evidence is much more easily interpreted than loss of function after lesions, because we can state with certainty that the removed regions are not essential for the signs of REM sleep that survive. It will soon be possible to acquire mutant mice in which any one, or several, of more than 20,000 genes are inactivated, to the extent that such deletions are not lethal. Investigation of two mutants19,20 led to major insights into the etiology of human narcolepsy.21-23 Techniques for the postnatal inactivation of genes permit investigation of gene deletions without the developmental effect of these deletions. They can also be used for investigation of the effects of gene inactivation in particular brain regions. A similar inactivation can be achieved by localized microinjections of antisense. Many if not most such mutants can be expected to have some sleep phenotype, such as increases or decreases in total sleep or REM sleep time, altered sleep
rebound, altered responses of sleep to environmental variables, and altered changes in sleep with development and aging. The same interpretive considerations long appreciated in lesion studies apply to the interpretation of manipulations that inactivate genes or prevent gene expression, with the additional possibility of direct effects of genetic manipulation on tissues outside the brain. Activation of Neurons by Electrical or Chemical Stimulation, Gene Activation, or Ion Channel Manipulation Sites identified by lesion or anatomic studies can be stimulated to identify their roles in sleep control. Older studies used electrical stimulation and were successful in identifying the medial medulla as a region mediating the suppression of muscle tone,24 and the basal forebrain as a site capable of triggering sleep.25 Electrical stimulation is clearly an aphysiologic technique, involving the forced depolarization of neuronal membranes by ion flow at a frequency set by the stimulation device, rather than by the patterned afferent impulses that normally control neuronal discharge. For this reason, it has been supplanted for many purposes by administration of neurotransmitter agonists, either by direct microinjection or by diffusion from a microdialysis membrane that is placed in the target area and perfused with high concentrations of agonists. One cannot assume that responses produced by such agonist administration demonstrate a normal role for the applied ligand. For example, many transmitter agonists and antagonists have been administered to the pontine regions thought to trigger REM sleep. In some cases, this administration has increased REM sleep. But we can only conclude from this that cells in the region of infusion have receptors for the ligand and have connections to REM sleep–generating mechanisms. Under normal conditions, these receptors may not have a role in triggering the state. Only by showing that the administration duplicates the normal pattern of release of the ligand in this area, and that blockade of the activated receptors prevents normal REM sleep, can a reasonable suspicion be raised that a part of the normal REM sleep control pathway has been identified. Because it is far easier to inject a substance than to collect and quantify physiologically released ligands, there have been many studies implying that various substances are critical for REM sleep control based solely on microinjection. These results must be interpreted with caution. For example, hypocretin is known to depolarize virtually all neuronal types. It should therefore not be surprising to find that hypocretin microinjection into arousal systems such as the locus coeruleus produces arousal,26 that microinjection of hypocretin into sites known to control feeding increases food intake,27 that injection into regions known to contain cells that are waking active increase waking,28 that injection into regions known to contain cells selectively active in REM sleep will increase the occurrence of this state,29,30 that injection into regions known to facilitate muscle tone will increase tone, that identical injections into regions known to suppress tone will decrease tone,31 and that intracerebroventricular injection of hypocretin can increase water intake32 and can activate other periventricular systems.29 Such types of findings do
not by themselves demonstrate a role for hypocretin (or any other neurotransmitter) in the observed behavior. It is necessary to obtain data on the effects of inactivation of, for example, hypocretin or hypocretin receptors, and to record evidence that indicates activity of hypocretin neurons at the appropriate times before seriously entertaining such conclusions. Genetic manipulations enable activation of neurons or nonneuronal cells of a particular type. A recent example of a genetic approach is the insertion of a light-sensitive ion channel into hypocretin cells using a lentivirus. Fiberoptic delivery of light could then be used to activate just these cells and determine the effect on sleep–waking transitions.33 Observation of Neuronal Activity Recording the activity of single neurons in vivo can provide a powerful insight into the precise time course of neuronal discharge. Unit activity can be combined with other techniques to make it even more useful. For example, electrical stimulation of potential target areas can be used to antidromically identify the axonal projections of the recorded cell. Intracellular or juxtacellular34 labeling of neurons with dyes, with subsequent immunolabeling of their transmitter, can be used to determine the neurotransmitter phenotype of the recorded cell. Combined dialysis and unit recording or iontophoresis of neurotransmitter from multiple-barrel recording and stimulating micropipettes can be used to determine the transmitter response of the recorded cell, although it cannot be easily determined whether the effects seen are the direct result of responses in the recorded cell or are mediated by adjacent cells projecting to the recorded cell. Such distinctions can be made in in vitro studies of slices of brain tissue by blocking synaptic transmission or by physically dissociating studied cells, but in this case their role in sleep may not be easily determined. Although the role of a neuron in fast, synaptically mediated events happening in just a few milliseconds can be traced by inspection of neuronal discharge and comparison of that discharge with the timing of motor or sensory events, such an approach may be misleading when applied to the analysis of sleep-state generation. The sleep cycle consists of a gradual coordinated change in EEG, EMG, and other phenomena over a period of seconds to minutes, as waking turns into non-REM sleep and then as non-REM sleep is transformed into REM sleep. Despite this mismatch of time courses, the tonic latency, a measure of how long before REM sleep–onset activity in a recorded cell changes, has been computed in some studies. Neurons purported to show a “significant” change in activity many seconds or even minutes prior to REM sleep onset have been reported. However, such a measure is of little usefulness, because at the neuronal level, the activity of key cell groups can best be seen as curvilinear over the sleep cycle, rather than changing abruptly in the way that activity follows discrete sensory stimulation. A major determinant of the tonic latency, computed as defined here, is the level of noise, or variability in the cell’s discharge, which affects the difficulty of detecting a significant underlying change in rate in a cell population. It is therefore not surprising that cell groups designated as
CHAPTER 8 • REM Sleep* 95
executive neurons for REM sleep control on the basis of their tonic latencies were later found to have no essential role in the generation of REM sleep.35-37 The more appropriate comparison of the unit activity cycle to state control is to compare two different cell types to see what the phase relationship of the peaks or troughs of their activity is, under similar conditions. This kind of study is difficult, involving the simultaneous long-term recording of multiple cells, and it is rarely performed. Even in this case, a phase lead does not by itself prove that the “lead” neuron is driving activity seen in the “following” neuron, but it does indicate that the reverse is not the case. However, awakening is a process that can be studied in this way, because it can be elicited by stimuli, and it appears to be preceded by abrupt changes in the activity of many neuronal groups.38 A major advantage of unit recording approaches in the intact animal to understand sleep and other behavioral processes is their high level of temporal resolution. Observation of the normal pattern of neurotransmitter release and neuronal activity can help determine the neurochemical correlates of sleep states. The natural release of neurotransmitters can be most easily determined by placing a tubular dialysis membrane 1 to 5 mm in length in the area of interest and circulating artificial cerebrospinal fluid through it. Neurotransmitters released outside the membrane will diffuse through the membrane and can be collected. Each sample is collected at intervals, typically ranging from 2 to 10 minutes. The collected dialysates can be analyzed by chromatography, radioimmunoassay, mass spectroscopy, or other means. The temporal resolution of this technique is typically on the order of a few minutes for each sample.39-41 Unit recording and dialysis approaches require a sharp research focus on a particular neurotransmitter or neuronal group. In contrast, histologic approaches can be used to measure the activity of the entire brain at cellular levels of resolution. The most popular such approach in animal studies labels the activation of immediate early genes. These genes are expressed when a neuron is highly active, and their expression is an early step in the activation of other downstream genes mobilizing the response of the cell to activation. The likelihood of such expression may vary between neuronal types and may not be detectable below some activity-dependent threshold. Activation of these genes can be detected by immunohistochemistry, most commonly by staining for the production of the Fos protein or the mRNA used to synthesize this protein.42 Neurons can be double-labeled to determine the transmitter they express, allowing investigators to determine, for example, whether histaminergic neurons in the posterior hypothalamus were activated in a particular sleep or waking state. Metabolic labels such as 2-deoxyglucose can also provide an indication of which neurons are active.42,43 Similar techniques using radioactive ligands in positron emission tomography (PET) studies can be used in living humans or animals. In vivo measurements of blood flow can be made throughout the brain with functional magnetic resonance imaging (fMRI). All of these techniques have in common an ability to make anatomically driven discoveries of brain region involvement in particular states, independent of specific hypotheses, thus leading to major
96 PART I / Section 2 • Sleep Mechanisms and Phylogeny
advances in understanding. However, another common feature of these types of recording techniques is their very poor temporal and spatial resolutions compared with neuronal recording approaches. Fos activation can take 20 minutes or more. PET takes a similar amount of time, and fMRI can be used to observe events lasting on the order of 1 to 15 seconds. It cannot be known whther areas active during a particular state caused the state or were activated because of the state. Summary Clearly, there is no perfect technique for determining the neuronal substrates of sleep states. Ideally, all three approaches are used in concert to reach conclusions. Next, we will explore the major findings derived from lesion, stimulation, and recording studies of REM sleep control mechanisms. Transection Studies The most radical types of lesion studies are those that slice through the brainstem, severing the connections between regions rostral and caudal to the cut. Sherrington43a discovered that animals, whose forebrain was removed after transecting the neuraxis in the coronal plane at the rostral border of the superior colliculus, showed tonic excitation of the “antigravity muscles” or extensors (Fig. 8-2, level A). This decerebrate rigidly was visible as soon as anesthesia was discontinued. Bard and Macht reported in 1958 that animals with decerebrate rigidity would show periodic limb relaxation.44 We now know that Bard was observing the periodic muscle atonia of REM sleep. After the discovery of REM sleep in the cat,2 Jouvet found that this state of EEG desynchrony was normally accompanied by muscle atonia.4 Jouvet then examined the decerebrate cat preparation used by Sherrington and Bard, now adding measures of muscle tone, eye movement and EEG. One might have expected that REM sleep originated
A
6
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Figure 8-2 Outline of a sagittal section of the brainstem of the cat drawn from level L = 1.6 of the Berman atlas, indicating the level of key brainstem transection studies. H (horizontal) and P-A (anteroposterior) scales are drawn from the atlas. IO, inferior olive; LC, locus coeruleus; RN, red nucleus; 6, abducens nucleus; 7, genu of the facial nerve. (Scales are drawn from Berman AL. The brain stem of the cat. Madison: University of Wisconsin Press; 1968.)
in the forebrain, but Jouvet found something quite different. When he recorded in the forebrain after separating the forebrain from the brainstem at the midbrain level (see Fig. 8-2, levels A or B), he found no clear evidence of REM sleep. In the first few days after transection, the EEG in the forebrain always showed high voltage, but when lowvoltage activity appeared, the PGO spikes that help identify REM sleep in the intact animal were absent from the thalamic structures, particularly the lateral geniculate where they can be most easily recorded. Thus it appeared that the isolated forebrain had slow-wave sleep states and possibly waking, but no clear evidence of REM sleep. In contrast, the midbrain and brainstem behind the cut showed clear evidence of REM sleep. Muscle atonia appeared with a regular periodicity and duration, like that of the intact cat’s REM-sleep periods. This atonia was accompanied by PGO spikes that had a morphology similar to that seen in the intact animal. The pupils were highly constricted during atonic periods, as in REM sleep in the intact cat. An interesting feature of REM sleep in the decerebrate animal is that its frequency and duration varied with the temperature of the animal. In the decerebrate animal, the forebrain thermoregulatory mechanisms are disconnected from their brainstem effectors. Shivering and panting do not occur at the relatively small temperature shifts that trigger them in the intact animal. For this reason, if the body temperature is not maintained by external heating or cooling, it will tend to drift toward room temperature. Arnulf and colleagues45 found that if body temperature was maintained at a normal level, little or no REM sleep appeared. But if temperature was allowed to fall, REM sleep amounts increased to levels well above those seen in the intact animal. This suggests that REM-sleep facilitatory mechanisms are, on balance, less impaired by reduced temperature than are REM-sleep inhibitory mechanisms. Another way of looking at this phenomenon is that brainstem mechanisms are set to respond to low temperatures by triggering REM sleep, perhaps to stimulate the brainstem, and that high brainstem temperatures inhibit REM sleep. It is unclear whether this mechanism is operative in the intact animal where temperature shifts are within a much narrower range. A further localization of the REM sleep control mechanisms can be achieved by examining the sleep of humans or animals in which the brainstem-to-spinal cord connection has been severed (see Fig. 8-2, level C). In this case, normal REM sleep in all its manifestations, except for spinally mediated atonia is present.46 Thus we can conclude that the region between the caudal medulla and the rostral midbrain is sufficient to generate REM sleep. This approach can be continued by separating the caudal pons from the medulla (see Fig. 8-2, level D or E). In such animals, no atonia is present in musculature controlled by the spinal cord, even though electrical or chemical stimulation of the medial medulla in the decerebrate animal suppresses muscle tone.47 Furthermore, neuronal activity in the medulla does not resemble that seen across the REM– non-REM sleep cycle, with neuronal discharge very regular for periods of many hours, in contrast to the periodic rate modulation that is linked to the phasic events of REM sleep in the intact animal (Fig. 8-3).48 This demonstrates
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QUIESCENT EMG ECG RESP PHASIC ACTIVATION EMG ECG RESP TONIC ACTIVATION EMG ECG RESP 30 sec Figure 8-3 States seen in the chronic medullary cat. Note the absence of periods of atonia. Calibration, 50 µV. RESP, thoracic strain gauge measuring respiration. EMG, electromyogram, ECG, electrocardiogram. (From Siegel JM, Tomaszewski KS, Nienhuis R. Behavioral states in the chronic medullary and mid-pontine cat. Electroencephalogr Clin Neurophysiol 1986;63:274-288.)
POSTTRANSECTION DAY 11 EEG EOG LGN
50 µV
Unit
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EEG EOG LGN Unit 5 sec Figure 8-4 Midbrain unit: EEG, electrooculographic (EOG), and lateral geniculate nucleus (LGN) activity rostral to chronic transections at the pontomedullary junction. Upper: The unit channel displays the output of an integrating digital counter resetting at 1-second intervals. Lower: One pulse is produced for each spike by a window discriminator. (From Siegel JM. Pontomedullary interactions in the generation of REM sleep. In: McGinty DJ, Drucker-Colin R, Morrison A, et al, editors. Brain mechanisms of sleep. New York: Raven Press; 1985. pp. 157-174.)
that the medulla and spinal cord together, although they may contain circuitry whose activation can suppress muscle tone, are not sufficient to generate this aspect of REM sleep when disconnected from more rostral brainstem structures. In contrast, the regions rostral to this cut show aspects of REM sleep (Fig. 8-4, and see Fig. 8-1, bottom).49 In these regions, we can see the progression from isolated to grouped PGO spikes and the accompanying reduction in PGO spike amplitude that occurs in the pre-REM sleep period and the REM sleep periods in the intact animal. We also see increased forebrain unit activity, with unit
spike bursts in conjunction with PGO spikes, just as in REM sleep.48,50 To summarize, this work shows that when pontine regions are connected to the medulla, atonia, rapid eye movements and the associated unit activity of REM sleep occur, whereas the medulla and spinal cord together, disconnected from the pons, are not sufficient to generate these local aspects of REM sleep. When the pons is connected to the forebrain, forebrain aspects of REM sleep are seen, but the forebrain without attached pons does not generate these aspects of REM sleep. Further confirmation of the importance of the pons and caudal midbrain comes
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from the studies of Matsuzaki,51 who found that when two cuts were placed, one at the junction of the midbrain and pons and the other at the junction of the pons and medulla, periods of PGO spikes could be seen in the isolated pons, but no signs of REM sleep in structures rostral or caudal to the pontine island. These transection studies demonstrate, by positive evidence, that the pons is sufficient to generate the pontine signs of REM sleep—that is, the periodic pattern of PGO spikes and irregular neuronal activity that characterizes REM sleep. One can conclude that the pons is the crucial region for the generation of REM sleep. Later, we will consider in more detail the structures in this region that synthesize the core elements of REM sleep. However, it is also clear that the pons alone does not generate all the phenomena of REM sleep. Atonia requires the activation of motor inhibitory systems in the medulla.52 In the intact animal, forebrain mechanisms interact with pontine mechanisms to regulate the amplitude and periodicity of PGO spikes,53 which in turn are linked to the twitches and rapid eye movements of REM sleep. We know from cases of human REM sleep behavior disorder that the motor activity expressed in dreams is tightly linked to the imagery of the dream.54 Extrapolating to dream imagery in normal humans, one can hypothesize that because the structure of REM sleep results from an interaction of forebrain and brainstem mechanisms, the dream itself is not just passively driven from the brainstem but rather represents the result of a dynamic interaction between forebrain and brainstem structures. Localized Lesion Studies The transection studies point to a relatively small portion of the brainstem—the pons and caudal midbrain—as being critical for REM sleep generation. Further specification of the core regions can be achieved by destroying portions of the pons in an otherwise intact animal and seeing which areas are necessary and which are unnecessary for REM sleep generation. An early systematic study by Carli and Zanchetti in the cat55 and other subsequent studies emphasized that lesions of locus coeruleus56 and the dorsal raphe57 nuclei, or of simultaneous lesions of locus coeruleus, forebrain cholinergic neurons, and histamine neurons,58 did not block REM sleep. Carli and Zanchetti concluded that lesions that destroyed the region ventral to the locus coeruleus, called the nucleus reticularis pontis oralis or the subcoeruleus region, produced a massive decrease in the amount of REM sleep. In their studies, Carli and Zanchetti used the electrolytic lesion technique, in which a current is passed, depositing metal that kills cells and axons of passage. As cytotoxic techniques that allowed poisoning of cell bodies without damage to axons of passage came into use, these initial conclusions were confirmed and refined. It was shown that neurons in medial pontine regions including the giant cell region were not important in REM sleep control,52,59,60 as near-total destruction of these cells was followed by normal amounts of REM sleep as soon as anesthesia dissipated.36,61 However, lesions of the subcoeruleus and adjacent regions with cytotoxins did cause a prolonged reduction in the amount of REM sleep. According to one study, the extent of this loss was pro-
portional to the percentage of cholinergic cells lost in subcoeruleus and adjacent regions of the brainstem of the cat.62 In rats, lesion or inactivation of the same region below the locus coeruleus (called the sublaterodorsal nucleus in the terminology of Swanson63) has been found to reduce REM sleep.64 Although large lesions may eliminate all aspects of REM sleep, small bilaterally symmetrical lesions in the pons can eliminate specific aspects of REM sleep. Lesions of lateral pontine structures allow muscle atonia during REM sleep. However, PGO spikes and the associated rapid eye movements are absent when lesions include the region surrounding the superior cerebellar peduncle of the cat (Fig. 8-5, top).65 This points to the role of this lateral region in the generation of PGO waves and some of the associated phasic activity of REM sleep. Small lesions confined to portions of the subcoeruleus regions identified as critical for REM sleep by Carli and Zanchetti, or to the medial medulla52 result in a very unusual syndrome. After non-REM sleep, these animals enter REM sleep, as indicated by lack of responsiveness to the environment, PGO spikes, EEG desynchrony, and pupil constriction. However, they lack the muscle atonia that normally characterizes this state (see Fig. 8-5, bottom).5,66 During REM sleep without atonia, these animals appear to act out dreams, attacking objects that are not visible, exhibiting unusual affective behaviors and ataxic locomotion. When they are awakened, normal behavior resumes. More recent studies have demonstrated that lesions of a system extending from the ventral midbrain to the medial medulla can cause REM sleep without atonia and that activation of this system can suppress muscle tone.52,67-69 This subcoeruleus region is under the control of midbrain regions. A midbrain region located just beneath and lateral to the periaqueductal gray (and called the dorsocaudal central tegmental field in the cat), appears to inhibit REM sleep by inhibiting the critical REM-on subcoeruleus neurons. Muscimol, a gamma-aminobutyric acid A (GABAA) receptor agonist, injected into this midbrain region, silences these cells and increases REM sleep, presumably by blocking the inhibition.70 The same phenomena have been observed when muscimol is injected into the corresponding region of the guinea pig71 and the rat (in the rat, this midbrain region has been called the deep mesencephalic nucleus).72 The midbrain region of the deep mesencephalic nucleus is the heart of the classic reticular activating system, shown to induce waking when electrically stimulated,73 and coma when lesioned.74 Both of these manipulations affect not only intrinsic neurons but also axons of passage. Increasing the levels of GABA in the subcoeruleus region (also called the pontine oralis nucleus in the rat and cat) produces an increase in waking, rather than the increase in REM sleep seen with GABA injection into the midbrain regions indicated previously.75,76 This is another reminder that, despite the sleep-inducing effect of systemic administration of hypnotic medications, local manipulation shows that the effect of GABA on sleep and waking states varies across brain regions. Blocking GABA in the subcoeruleus has been reported to increase REM sleep in the cat.77
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Motor cortex EOG LGN EMG 2 sec 50µV Figure 8-5 Twenty-second polygraph tracings of REM sleep before and after lesions, together with a coronal section through the center of the pontine lesions. EEG voltage reduction of REM sleep (recorded from motor cortex) was present after both lesions. Top, Radiofrequency lesions of the pedunculopontine region diminished ponto-geniculo-occipital (PGO) spikes and eye movement bursts during REM sleep. Bottom, Lesions in the region ventral to the locus coeruleus produced REM sleep without atonia without any diminution of PGO spike or REM frequency. (Reprinted from Shouse MN, Siegel JM. Pontine regulation of REM sleep components in cats: integrity of the pedunculopontine tegmentum [PPT] is important for phasic events but unnecessary for atonia during REM sleep. Brain Res 1992;571:50-63, copyright, with permission from Elsevier Science.) EEG, Electroencephalogram; EOG, electrooculogram; LGN, lateral geniculate nucleus; EMG, dorsal neck electromyogram.
Stimulation Studies The first study showing that stimulation could elicit REM sleep was carried our by George and colleagues.78 They found that application of the acetylcholine agonist carbachol to specific regions of the pons ventral to the locus coeruleus could elicit REM sleep in the cat. An impressive proof that a unique REM sleep–generation mechanism was being activated was the long duration of the elicited REM sleep periods. Microinjection of acetylcholine into this region in the decerebrate cat produces an immediate suppression of decerebrate rigidity. Later studies showed that, depending on the exact site, either REM sleep or just atonia in a waking state could be triggered by such stimulation.79-81 When stimulation was applied to the lateral regions whose lesion blocked PGO waves, continuous PGO spikes were generated even though the animal was not always behaviorally asleep. Increased REM sleep has been reported in the rat after microinjection of cholinergic agonists into the subcoeruleus region,82-84 although this effect is certainly not as robust as it is in the cat.85 The first study demonstrating a role for glutamate in the control of REM sleep was done in the cat. We found that a profound suppression of muscle tone could be elicited by the injection of glutamate into the subcoeruleus region or into the ventral medullary region.47,86,87 Further work has demonstrated that the pontine cells in this inhibitory region receiving this cholinergic input use glutamate as
their transmitter and project directly to glutamate-responsive regions of the medial medulla.86,88-90 Work in the rat has emphasized the strong triggering of REM sleep by glutamatergic excitation of this region.64,91 However, glutamatergic excitation of this region in the cat also increases REM sleep,92 suggesting that the difference in response in the two species does not indicate a fundamental difference in control features, although it does indicate species differences in the relative potency of these transmitters or perhaps in the pattern of distribution of receptors for them. Neuronal Activity, Transmitter Release The transection, lesion, and stimulation studies all point to the same regions of the pons and caudal midbrain as the critical region for the generation of the state of REM sleep as a whole, and smaller subregions in the brainstem and forebrain in the control of its individual components. The pons contains a complex variety of cells differing in their neurotransmitter, receptors, and axonal projections. Unit recording techniques allow an analysis of the interplay between these cell groups and their targets to further refine our dissection of REM sleep mechanisms. Medial Brainstem Reticular Formation Most cells in the medial brainstem reticular formation are maximally active in waking, greatly reduce discharge rate in non-REM sleep, and increase discharge rate back to
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waking levels in REM sleep.15,16,60,93,94 Discharge is most regular in non-REM sleep and is relatively irregular in both waking and REM sleep. The similarity of the waking and REM sleep discharge patterns suggests a similar role for these cells in both states. Indeed, most of these cells have been shown to be active in waking in relation to specific lateralized movements of the head, neck, tongue, face, or limbs. For example, a cell may discharge only with extension of the ipsilateral forelimb or abduction of the tongue. The twitches that are normally visible in facial and limb musculature during REM sleep and the phenomenon of REM sleep without atonia suggest that these cells command movements that are blocked by the muscle tone suppression of REM sleep. Lesion of these cells has little or no effect on REM sleep duration or periodicity,36,37 but it does dramatically prevent movements of the head and neck in waking.95 Cholinergic Cell Groups Cholinergic cell groups have an important role in REM sleep control in the cat. As was pointed out earlier, microinjection of cholinergic agonists into the pons of the cat reliably triggers long REM sleep periods that can last for minutes or hours. Microdialysis studies show that pontine acetylcholine release is greatly increased during natural REM sleep when compared with either non-REM sleep or waking.96 Recordings of neuronal activity in the cholinergic cell population demonstrate the substrates of this release. Certain cholinergic cells are maximally active in REM sleep (REM-on cells). Others are active in both waking and REM sleep.97 Presumably, the REM sleep–on cholinergic cells project to the acetylcholine-responsive region in the subcoeruleus area.98 Cells with Activity Selective for REM Sleep Cells with activity selective for REM sleep can be identified in the subcoeruleus area in both cats99 and rats.72 Anatomic studies using Fos labeling and tract tracing suggest that these neurons are glutamatergic, and that some of them project to the ventral medullary region involved in the triggering of the muscle atonia of REM sleep.47,64,72,86,88-90 Monoamine-Containing Cells Monoamine-containing cells have a very different discharge profile. Most if not all noradrenergic100,101 and serotonergic102 cells of the midbrain and pontine brainstem, and histaminergic103 cells of the posterior hypothalamus are continuously active during waking, decrease their activity during non-REM sleep, and further reduce or cease activity during REM sleep (Fig. 8-6). As pointed out earlier, these cell groups are not critical for REM sleep generation, but it is likely that they modulate the expression of REM sleep. The cessation of discharge in monoaminergic cells during REM sleep appears to be caused by the release of GABA onto these cells,104-107 presumably by REM sleep–active GABAergic brainstem neurons.108,109 Administration of a GABA agonist to the raphe cell group increases REM sleep duration,105 demonstrating a modulatory role for this cell group in REM sleep control. Some studies indicate that dopamine cells do not change discharge across sleep states,41,110,111 other work suggests that
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there is increased release of dopamine in REM sleep,112,113 other work shows decreased release in REM sleep,114 and still other work shows selective waking activity in these neurons.115 These findings may reflect heterogeneity of firing of different dopamine cell groups and presynaptic control of release in dopamine terminals. Other Cholinergic Cells in Lateral Pontine Regions Other cholinergic cells in lateral pontine regions discharge in bursts before each ipsilateral PGO wave.116,117 These cells may therefore participate in the triggering of these waves. We know from other studies that PGO waves are tonically inhibited in waking by serotonin input.118-120 Therefore, it is likely that certain groups of cholinergic cells receive direct or perhaps indirect serotonergic inhibition in waking, and that the decrease of this inhibition in non-REM sleep and REM sleep facilitates PGO wave and REM sleep generation. Fos Labeling A more global mapping of neurons active in REM sleep can be achieved by using the Fos labeling to identify neurons active within the 20 minutes or more before sacrifice. Quattrochi and colleagues demonstrated that microinjections of the cholinergic agonist carbachol triggered episodes of continuous PGO waves in waking-activated neurons in the laterodorsal and pedunculopontine nuclei. Destruction of these nuclei blocks these waves.120-122 More extensive Fos mapping has been done to identify neurons activated during REM sleep in the rat. Verret and associates123 found that only a few cholinergic neurons from the laterodorsal and pedunculopontine tegmental
nuclei were Fos-labeled after REM sleep. In contrast, a large number of noncholinergic Fos-labeled cells were observed in the laterodorsal tegmental nucleus, the subcoeruleus region, and the lateral, ventrolateral, and dorsal periaqueductal gray of the midbrain. In addition, other regions outside the brainstem regions critical for REM sleep control were labeled. These included the alpha and ventral gigantocellular reticular nuclei of the medulla, dorsal, and lateral paragigantocellular reticular124 nuclei and the nucleus raphe obscurus. Half of the cells in the latter nucleus were cholinergic, suggesting that these neurons might be a source of acetylcholine during REM sleep. In a second study, an effort was made to identify the source of the GABAergic input thought to cause the cessation of discharge in locus coeruleus cells during REM sleep.106 Verret and colleagues87 found that the dorsal and lateral paragigantocellular reticular nuclei of the medulla and regions of the periaqueductal gray of the midbrain— regions with large percentages of GABAergic cells—are active in REM sleep. Maloney and associates108 found GABAergic cells adjacent to the locus coeruleus that expressed Fos during periods of high REM sleep. Because the critical phenomena of REM sleep do not appear to require the medulla, it seems likely that the periaqueductal gray GABAergic neurons and GABAergic neurons adjacent to locus coeruleus and raphe nuclei are sufficient to suppress the activity of noradrenergic and serotonergic neurons,105,125 although medullary neurons may participate in the intact animal. Fos mapping has also been used to identify forebrain regions likely to control REM sleep. The preoptic region, important in non-REM sleep control (see Chapter 7), contains neurons that express Fos maximally in REM sleep–deprived animals, suggesting that these neurons may be related to the triggering or duration of REM sleep by brainstem systems.126 Fos studies also indicate that melanin-concentrating-hormone neurons, which are located in the hypothalamus, express Fos during periods with large amounts of REM sleep and that intracerebroventricular administration of melanin-concentrating hormone increases the amount of subsequent REM sleep.127,128 These results suggest that melanin-concentrating-hormone neurons are an additional source of forebrain modulation of REM sleep. It should be emphasized that the identity of the cells involved in triggering and controlling REM sleep is not easily determined. The Fos studies do not necessarily identify all the cells active during REM sleep, only those of a phenotype that allows them to express Fos during the tested manipulations. Certain cell types do not readily express Fos even when very active. In other words, cells not expressing Fos during periods of REM sleep may be involved and may even have a critical role in REM sleep control. On the other hand, cells expressing Fos because of their activity during REM sleep may be responding to the motor and autonomic changes characteristic of this state, rather than causing these changes. With neuronal activity recording, the identification of the cells responsible for starting the process of REM sleep triggering cannot be easily be determined without a complete profile of discharge across the sleep cycle and a direct comparison of candidate cell groups, for the reasons just reviewed.
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Finally, recording from neurons in head-restrained animals, while easier than in freely moving animals, can be misleading because it can lower the activity of movement-related cells in waking, making them appear to be selectively active in REM sleep.35 Nevertheless by comparing the results of multiple recording and stimulation techniques, with those of lesions, we gather evidence that helps identify the brainstem and forebrain neuronal groups that are the best candidates for controlling the REM sleep state.
CONTROL OF MUSCLE TONE Abnormalities of muscle tone control underlie many sleep disorders. During REM sleep, central motor systems are highly active, whereas motoneurons are hyperpolarized.129 The normal suppression of tone in the tongue and laryngeal muscles is a major contributing factor in sleep apnea (see Chapter 100). The failure of muscle tone suppression in REM sleep causes REM sleep behavior disorder (see Chapter 95). Triggering of the REM sleep muscle tone control mechanism in waking is responsible for cataplexy (see Chapter 100).130 Early work using intracellular recording and microiontophoresis had shown that motoneuron hyperpolarization during REM sleep was accompanied by the release of glycine onto motoneurons.129,131 Microdialysis sampling showed that both GABA and glycine are released onto motoneurons during atonia induced by carbachol in the cat.40 This release occurs in ventral horn motoneurons as well as in hypoglossal motoneurons. The glycinergic inhibition during a carbachol-elicited REM sleeplike state was investigated with immunohistochemistry and found to be caused by the activation of glycinergic neurons in the nucleus reticularis gigantocellularis and nucleus magnocellularis in the rostroventral medulla and the ventral portion of the nucleus paramedianus reticularis,131 regions whose activation has been shown to suppress muscle tone in the unanesthetized decerebrate animal.86 A second population was located in the caudal medulla adjacent to the nucleus ambiguus; these neurons may be responsible for the REM sleep–related inhibition of motoneurons that innervate the muscles of the larynx and pharynx. In related work, it has been shown that norepinephrine and serotonin release onto motoneurons is decreased during atonia.132 Because these monoamines are known to excite motoneurons, and GABA and glycine are known to inhibit them, it appears that the coordinated activity of these cell groups produces motoneuron hyperpolarization and hence atonia in REM sleep by a combination of inhibition and disfacilitation. The inhibitory and facilitatory systems are strongly and reciprocally linked. Electrical stimulation of the pontine inhibitory area (or PIA, located in the subcoeruleus region86) produces muscle tone suppression. Even though the pontine inhibitory area is within a few millimeters of the noradrenergic locus coeruleus, electrical stimulation in the pontine inhibitory area that suppresses muscle tone will always cause a cessation of activity in the noradrenergic neurons of the locus coeruleus and other facilitatory cell groups.133 Cells that are maximally active in REM sleep (REM-on cells) are present in the pontine inhibitory area
102 PART I / Section 2 • Sleep Mechanisms and Phylogeny
and also in the region of the medial medulla that receives pontine inhibitory area projections (Fig. 8-7). The release of GABA and glycine onto motoneurons during REM sleep atonia is most likely mediated by a pathway from the pontine inhibitory area to the medial medulla.89,90 The pontine region triggering this release not only is sensitive to acetylcholine but also responds to glutamate (Fig. 8-8).86,88 The medullary region with descending projections to motoneurons can be subdivided into a rostral portion responding to glutamate and a caudal portion responding to acetylcholine (see Fig. 8-8).47,134 The medullary interaction with pontine structures is critical for muscle tone suppression, because inactivation of pontine regions greatly reduces the suppressive effects of medullary stimulation on muscle tone.135,136 This ascending pathway from the medulla to the pons may mediate the inhibition of locus coeruleus during atonia and may also help recruit other active inhibitory mechanisms. Thus, damage anywhere in the medial pontomedullary region can block muscle atonia by interrupting ascending and descending portions of the pontomedullary inhibitory system, as can muscimol injection into the pons,135 again indicating that pontine activation is a key component of motor inhibition. The studies just reviewed focused largely on ventral horn and hypoglossal motoneurons. However, the control of jaw muscles is also a critical clinical issue. The success of jaw appliances indicates that reduced jaw muscle activity can contribute to closure of the airway in sleep apnea (see Chapter 109). Jaw muscle relaxation is a common initial sign of cataplexy, and tonic muscle activation underlies
bruxism. Investigation of the control of masseter motor neurons allows analysis of the regulation of muscle tone on one side of the face, while using the other side as a control for changes in behavioral state caused by application of neurotransmitter agonists and antagonists.137 Using this model, it was determined that tonic glycine release reduces muscle tone in both waking and non-REM sleep. However, blockade of glycine receptors did not prevent the suppression of muscle tone in REM sleep. In a similar manner, blockade of GABA receptors alone or in combination with glycine receptors increased tone in waking and non-REM sleep but did not prevent the suppression of masseter tone138 or of genioglossus tone in REM sleep.139
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Figure 8-8 Sagittal map of pontomedullary inhibitory areas. Electrical stimulation produced atonia at all the points mapped. All electrically defined inhibitory sites were microinjected with glutamate or cholinergic agonists. Filled symbols represent points at which microinjections decreased muscle tone (to less than 30% of baseline values or to complete atonia). Open circles indicate points at which injections increased or produced no change in baseline values. Top, Glutamate injections. Bottom, Acetylcholine (ACh; circles) and carbachol (Carb; triangles) injections. IO, inferior olivary nucleus; LC, locus coeruleus nucleus, NGC, nucleus gigantocellularis; NMC, nucleus magnocellularis; NPM, nucleus paramedianus; PG, pontine gray; PT, pyramid tract; SO, superior olivary nucleus; T, nucleus of the trapezoid body; TB, trapezoid body; 4V, fourth ventricle; 5ME, mesencephalic trigeminal tract; 6, abducens nucleus; 7G, genu of the facial nerve. (From Lai YY, Siegel JM. Medullary regions mediating atonia. J Neurosci 1988;8:4790-4796.)
However, both of these manipulations increased phasic masseter muscle activity in REM sleep. Further studies showed that a blockade of glutamate receptors reduces the normal enhancement of muscle tone in waking relative to the level in non-REM sleep. Glutamate also contributes to the phasic motor activity during REM sleep. However, reduction in glutamate alone is not sufficient to account for the suppression of muscle tone in REM sleep, because stimulation of NMDA and nonNMDA glutamate receptors does not appear to restore muscle tone in REM sleep.140 A study in the anesthetized rat suggested that activation of norepinephrine receptors, in combination with the activation of glutamate receptors, was sufficient to potently increased muscle tone in the masseter muscles.141 A study of the hypoglossal motor nucleus in the unanesthetized rat concluded that the suppression of muscle tone in REM sleep was mediated to a large extent by a reduction in norepinephrine release, but not by reduced serotonin release.142 Thus, this work in the context of prior microdialysis analysis of transmitter release suggests that the reduction of norepinephrine release may be a key factor regulating muscle tone, along with the changes in amino acid release described earlier. These conclusions are consistent with prior work indicating that cataplexy was linked to a reduction in the activity of noradrenergic neurons (see later).143 Although the current literature suggests that trigeminal, hypoglossal, and ventral horn motoneurons are subjected to similar neurochemical control across the sleep cycle, direct comparison of these systems has not been made, and it is likely that some aspects of control differ across systems as well as species. The role of reduced serotonin release in the suppression of muscle tone has been investigated in the hypoglossal nucleus of the rat. It was found that the modulation of genioglossus activity across natural sleep-wake states was not greatly affected by endogenous input from serotonergic neurons, although prior studies in vagotomized and anesthetized rats had shown an effect of serotonin on muscle tone under these aphysiologic conditions.144-146 Although same glycinergic inhibition clearly acts, at the level of the motoneuronal membrane, it remains to be determined to what extent norepinephrine, GABA, and glutamate effects are exerted directly at the motoneuronal membrane level. Some of the effects of these neurotransmitters on motoneurons may be mediated polysynaptically. Recent work suggests that inhibition of motor output is accompanied by a neurochemically similar inhibition of sensory relays during REM sleep.147 Such sensory inhibition may be important in preserving sleep and, in particular, in blocking the sensory input produced by twitches breaking through the motor inhibition of REM sleep. The failure of this inhibition may contribute to sleep disruption and increased motor activity in sleep in pathologic states. In contrast to norepinephrine, serotonin, and histamine cell groups, it was reported that mesencephalic dopaminergic neurons do not appear to alter their discharge rate across the sleep cycle.110 Dopamine release in the amygdala measured by dialysis does not significantly vary across the sleep cycle.148 In disagreement with this finding, a Fos study indicted that dopaminergic neurons in the ventral portion of the mesencephalic tegmentum were activated during periods of increased REM sleep.149 A unit recording
CHAPTER 8 • REM Sleep* 103
study indicated that dopaminergic neurons in the ventral tegmental area of the midbrain show maximal burst firing in both waking and REM sleep.112 Other work using the Fos labeling technique identified a wake-active dopaminergic cell population in the ventral periaqueductal gray.115 In dialysis measurements of dopamine release, we have seen reduced dopamine release in the dorsal horn of the spinal cord during the REM sleeplike state triggered by carbachol. We did not see such a decrease in the ventral horn or hypoglossal nucleus.132 These data suggest either heterogeneity in the behavior of sleep cycle activity of dopaminergic neurons or presynaptic control of dopamine release independent of action potentials in the cell somas. Figure 8-9 illustrates some of the anatomic and neurochemical substrates of the brainstem generation of REM sleep.
NARCOLEPSY AND HYPOCRETIN Narcolepsy has long been characterized as a disease of the REM sleep mechanism. Narcoleptic patients often have REM sleep within 5 minutes of sleep onset, in contrast to normal individuals, who rarely show such sleep-onset REM sleep. Most narcoleptic patents experience cataplexy, a sudden loss of muscle tone with the same reflex suppression that is seen in REM sleep. High-amplitude theta activity in the hippocampus, characteristic of REM sleep, is also prominent in cataplexy, as observed in dogs.143 Further evidence for links between narcolepsy and REM sleep comes from studies of neuronal activity during cataplexy. Many of the same cell populations in the pons and medulla that are tonically active only during REM sleep in normal subjects, become active during cataplexy in narcoleptic animals.17,150 Likewise, cells in the locus coeruleus, which cease discharge only in REM sleep in normal animals, invariably cease discharge in cataplexy.151 However, just as cataplexy differs behaviorally from REM sleep in its maintenance of consciousness, not all neuronal aspects of REM sleep are present during cataplexy. As was noted earlier, in the normal animal, noradrenergic, serotonergic, and histaminergic cell are all tonically active in waking, reduce discharge in non-REM sleep, and cease discharge in REM sleep.143,151 However, unlike noradrenergic cells, serotonergic cells do not cease discharge during cataplexy, reducing discharge only to quiet waking levels. Histaminergic cells actually increase discharge in cataplexy relative to quiet waking levels (Fig. 8-10).152 These findings allow us to identify some of the cellular substrates of cataplexy. Medullary inhibition and noradrenergic disfacilitation are linked to cataplexy’s loss of muscle tone. In contrast, the maintained activity of histamine neurons is a likely substrate for the maintenance of consciousness during cataplexy that distinguishes cataplexy from REM sleep. Thus, the study of neuronal activity in the narcoleptic animal provides an insight into both narcolepsy and the normal role of these cell groups across the sleep cycle. In 2001, it was discovered that most human narcolepsy was caused by a loss of hypothalamic cells containing the peptide hypocretin (Fig. 8-11).22,23 On average, 90% of these cells are lost in narcolepsy. Subsequently, it was discovered that a lesser reduction in the number of hypocretin cells was seen in Parkinson’s disease, with a loss of up to 60% of hypocretin cells.153,154 It was found that
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Figure 8-9 A, Anatomic relationship of REM sleep-on and sleep-off cells, carbachol-induced atonia sites, lesions blocking atonia but not preventing REM sleep, and lesions completely blocking REM sleep. B, Anatomic locations of REM on areas in cats, rat, and projected location in human, in sagittal and coronal views. (A from Siegel JM, Rogawski MA. A function for REM sleep: regulation of noradrenergic receptor sensitivity. Brain Res 1988;13:213-233; B from Siegel JM. The stuff dreams are made of: anatomical substrates of REM sleep. Nat Neurosci 2006;9:721-722.) CG, central gray; CST, corticospinal tract; DT, dorsal tegmental; IO, inferior olive; IC, inferior colliculus; L, locus colliculus; Mo5, motor nucleus of the trigeminal nerve (5M); PN, pontine nuclei; R, red nucleus; RO, reticularis oralis nucleus; SC, superior colliculus; SCP, superior cerebellar peduncle (brachium conjunctivum).
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Figure 8-10 Comparison of mean discharge rates in sleepwaking states and cataplexy of REM-off cells recorded from three brain regions. Posterior hypothalamic histaminergic neurons remain active, whereas dorsal raphe serotonergic neurons reduced discharge, and locus coeruleus noradrenergic neurons cease discharge during cataplexy. All of these cell types were active in waking, reduced discharge in NREM sleep, and were silent or nearly silent in REM sleep. (From John J, Wu M-F, Boehmer LN, Siegel JM. Cataplexy-active neurons in the posterior hypothalamus: implications for the role of histamine in sleep and waking behavior. Neuron 2004;42:619-634.) AW, active waking; QW, quiet waking; SWS, slow wave (non-REM) sleep; REM, REM sleep; CAT, cataplexy.
CHAPTER 8 • REM Sleep* 105 NORMAL
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Figure 8-11 Loss of hypocretin cells in human narcolepsy. Distribution of cells in perifornical and dorsomedial hypothalamic regions of normal and narcoleptic humans. (From Thannickal TC, Moore RY, Nienhuis R, et al. Reduced number of hypocretin neurons in human narcolepsy. Neuron 2000;27:469-474.)
administration of the peptide to genetically narcoleptic dogs reversed symptoms of the disorder,155 and that nasal administration reversed sleepiness in monkeys,156 suggesting that similar treatment could be uniquely effective for narcolepsy and perhaps for other disorders characterized by sleepiness. In further work in normal animals, it was determined that identified hypocretin neurons are maximally active during active waking.34,34a This discharge was reduced or absent during aversive waking situations, even if the EEG indicated high levels of alertness (Fig. 8-12).34 This is consistent with the hypothesis that release of hypocretin facilitates motor activity during emotionally charged activities of the sort that trigger cataplexy in narcoleptics, such as laughter.157-159 Even normal individuals experience weakness at these times, seen in the “doubling over” that often accompanies laughter, or the weakness that can result from
other sudden-onset, strong emotions. Mice engineered to lack hypocretin cannot maintain alertness when working for positive reinforcement, but they are unimpaired when working to avoid aversive stimuli.160 Studies of hypocretin release in the cat161 and preliminary studies in humans are also consistent with this hypothesis.162 In the absence of the hypocretin-mediated motor facilitation, muscle tone is lost at these times. Hypocretin cells also send ascending projections to cortical and basal forebrain regions. In the absence of hypocretin-mediated facilitation of forebrain arousal centers, waking periods are truncated, resulting in the sleepiness of narcolepsy.158 The functions of hypocretin have been investigated in knockout animals that do not have the peptide, using operant reinforcement tasks. Hypocretin knockout mice were deficient in the performance of bar presses to secure food or water reinforcement. However, they did not differ from their normal littermates in their performance when trained to bar press to avoid foot shock. Periods of poor performance on the positive reinforcement tasks were characterized by EEG deactivation. Fos labeling of normal mice showed that the positive reinforcement task used in this study was characterized by activation of hypocretin neurons. However, hypocretin neurons were not activated in the negative reinforcement task despite high levels of EEG activation, indicating that nonhypocretin systems mediate arousal during this behavior. This study led to the conclusion that hypocretin neurons are critically involved in arousal linked to positive reinforcement, and that in their absence such behaviors are impaired. However, they are not required to maintain arousal in conditions of negative reinforcement, indicating that other brain systems subserve this role. Hypocretin appears to act largely by modulating the release of amino acid neurotransmitters.163 Systemic injection of hypocretin causes a release of glutamate in certain hypocretin-innervated regions, producing a potent postsynaptic excitation.137,164 In other regions, it facilitates GABA release, producing postsynaptic inhibition.161,165 The loss of these competing inhibitory and facilitatory influences in narcolepsy appears to leave brain motor regulatory and arousal systems less stable than the tightly regulated balance that can be maintained in the presence of hypocretin (Fig. 8-13). According to this hypothesis, this loss of stability is the underlying cause of narcolepsy, with the result being inappropriate loss of muscle tone in waking and inappropriate increases of muscle tone during sleep resulting in a striking increased incidence of REM sleep behavior disorder in narcoleptics (see Chapter 84). In the same manner, although a principal symptom of narcolepsy is intrusions of sleep into the waking period, narcoleptics sleep poorly at night, with frequent awakenings.166-168 In other words, narcoleptics are not simply weaker and sleepier than normal subjects. Rather, their muscle tone and sleep-waking state regulation is less stable than that in normal subjects as a result of the loss of hypocretin function.
THE FUNCTIONS OF REM SLEEP Research into the control of REM sleep turns into a seemingly infinite regression, with REM-on cells inhibited
106 PART I / Section 2 • Sleep Mechanisms and Phylogeny AW (GROOMING) 10 sp/sec
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Figure 8-12 Firing rate of hypocretin cells in waking and sleep behaviors in freely moving rats. Left: The discharge pattern of a representative hypocretin neuron across the sleep-waking cycle in the freely moving rat. A, High firing rates are seen during AW (active waking—grooming). B, Reduced firing rate or cessation of activity is seen in QW (quiet waking) and drowsiness. C, A further decrease or cessation of firing is seen during slow wave [nonREM] sleep (SW) sleep. D, Minimal firing rate is seen during the tonic phase of REM sleep. Brief hypocretin (Hcrt) cell discharge bursts are correlated with muscle twitches during the phasic events of REM sleep. Right: Summary data from identified Hcrt cells: exploratory behavior (EB), grooming (Gr), eating (Ea), quiet wake (QW), slow wave sleep (SW), and tonic (REMt) and phasic (REMp) sleep. Maximal discharge is seen during exploration-approach behavior, sec, seconds. (From Mileykovskiy BY, Kiyashchenko LI, Siegel JM. Behavioral correlates of activity in identified hypocretin [orexin] neurons. Neuron 2005;46:787-798.)
by REM-off cells, which in turn may be inhibited by other REM-on cells. It is in fact very difficult to identify the sequence in which these cell groups are normally activated because the axonal condition and synaptic delays could not be more than a few milliseconds between these cell groups, yet REM sleep onset occurs over a period of minutes in man and cat and at least 30 or more seconds in the rat. It also does not completely enlighten us with respect to the ultimate functional question; what is REM sleep for? To answer this question, we need to determine what if any physiologic process is altered over REM sleep periods. Is some toxin excreted or some protein synthesized? If so, how do we account for the widely varying durations of the typical REM sleep? In the human, REM sleep typically lasts from 5 to 30 minutes, whereas in the mouse it typically lasts 90 seconds.169 What can be accomplished in 90 seconds in the mouse but requires an average of approximately 15 minutes in humans? If
a vital process is accomplished, why do drug treatments that abolish REM sleep have no discernable effect on any vital process, even when such drugs are taken continuously for many years? Why do some marine mammals have no apparent REM sleep (see Chapter 7)? Why is REM sleep present in homeotherms (i.e., birds and mammals) but apparently absent in the reptilian ancestors of homeotherms? Great progress has been made in localizing the mechanisms that generate REM sleep. As described earlier, we know many of the key neurotransmitters and neurons involved. The recent discovery of the role of hypocretin in narcolepsy serves as a reminder that there may still be key cell groups that need to be identified before we can gain fundamental insights into the generation, mechanism, and functions of REM sleep. Yet, despite this caveat, we already understand a substantial amount about what goes on in the brain during REM sleep.
CHAPTER 8 • REM Sleep* 107 ACH DA GABA
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Figure 8-13 Major identified synaptic interactions of hypocretin neurons. Lines terminated by perpendicular lines denote excitation; circular terminations indicate inhibition. Acb, nucleus accumbens; ACH, acetylcholine; AP, anterior pituitary; CBL, cerebellum; CC, corpus callosum; CM, centromedian nucleus of the thalamus; DA, dopamine; DR, dorsal raphe; f, fornix; GABA, gamma-aminobutyric acid; 5-HT, serotonin; IC, inferior colliculus; LC, locus coeruleus; LDT, laterodorsal tegmental and pedunculopontine; NE, norepinephrine; OB, olfactory bulb; OX, optic chiasm; PH, posterior hypothalamus; SC, superior colliculus; VM, ventral midbrain.
However, the mystery exposed by the discovery of REM sleep remains. We do not know the biological need that initiates REM sleep. We do not know the source of the REM sleep debt that accumulates during REM sleep deprivation.170 What is clear is that increased brain activity in REM sleep consumes considerable amounts of metabolic energy. The intense neuronal activity shown by most brain neurons, similar to or even more intense than that seen during waking, extracts a price in terms of energy consumption and wear and tear on the brain. It is unlikely that such a state would have produced a Darwinian advantage and remained so ubiquitous among mammals if it did not have benefits compensating for these costs. But what might the benefits be? One idea that has received much media attention is that REM sleep has an important role in memory consolidation. However, the evidence for this is poor.171 Although early animal work suggested that REM sleep deprivation interfered with learning, subsequent studies showed that it was the stress of the REM sleep deprivation procedure, rather than the REM sleep loss itself, that was critical. A leading proponent of a sleep and memory consolidation relationship has concluded that sleep has no role in the consolidation of declarative memory,172 which would exclude a role for sleep in rote memory, language memory, and conceptual memory, leaving only the possibility of a role in procedural memory, the sort of memory required for learning to ride a bicycle or play a musical instrument. However, studies supporting a role for sleep in the consolidation of human procedural learning have made contradictory claims about similar learning tasks, with some concluding that REM but not non-REM sleep is important, others stating just the reverse, and yet others claiming
that both sleep states are essential.171 Millions of humans have taken monoamine oxidase (MAO) inhibitors or tricyclic antidepressants, often for 10 to 20 years. These drugs profoundly depress, or in many cases completely eliminate, all detectable aspects of REM sleep. However, there is not a single report of memory deficits attributable to such treatment. Likewise, well-studied individuals with permanent loss of REM sleep resulting from pontine damage show normal learning abilities; the best-studied such individual completed law school after his injury173 and was last reported to be the puzzle editor of his city newspaper. Humans with multiple-system atrophy can have a complete loss of slow-wave sleep and disruption of REM sleep without manifesting any memory deficit.174 A recent wellcontrolled study showed that REM sleep suppression with selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors produced no significant decrement in memory consolidation on any task and even produced a small significant improvement in a motor learning task.175 Another idea that has been repeatedly suggested is that REM sleep serves to stimulate the brain.45,176,177 According to this theory, the inactivity of non-REM sleep causes metabolic processes to slow down to an extent that the animal would be unable to respond to a predator, capture prey, or meet other challenges on awakening. This would leave mammals functioning like reptiles, with slow response after periods of inactivity. This hypothesis explains the appearance of REM sleep after non-REM sleep under most conditions. It also explains the well-documented increased proportion of sleep time in REM sleep as the sleep period nears its end in humans and other animals. Humans are more alert when aroused from REM sleep than non-REM sleep, as are rats,178 consistent with this idea. The very low amounts or absence of REM sleep in dolphins, whose brainstem is continuously active and which never have bilateral EEG synchrony, can be explained by this hypothesis. If one hemisphere is always active, there is no need for the periodic stimulation of REM sleep to maintain the ability to respond rapidly. However, the brain-stimulation hypothesis of REM sleep function does not explain why waking does not substitute for REM sleep in terrestrial mammals. REM sleep– deprived individual have a REM sleep rebound even if they are kept in an active waking state for extended periods. One phenomenon that may explain REM sleep rebound is the cessation of activity of histamine, norepinephrine, and serotonin neurons during REM sleep. This cessation does not occur during waking, so waking would not be expected to substitute for this aspect of REM sleep.179 Therefore, REM sleep rebound may be caused by an accumulation of a need to inactivate these aminergic cell groups. Several cellular processes might benefit from the cessation of activity in aminergic cells. Synthesis of these monoamines and their receptors might be facilitated during this period of reduced release. The receptors for these substances might be resensitized in the absence of their agonist. The metabolic pathways involved in the reuptake and inactivation of these transmitters might also benefit from periods of inactivity. Some but not all studies have supported this hypothesis.180-184 Further investigation at the cellular level may lead to an inside-out explanation of REM sleep function, deriving a
108 PART I / Section 2 • Sleep Mechanisms and Phylogeny
functional explanation from a better understanding of the neuronal basis of REM sleep control. Further relevant literature can be found at http://www. semel.ucla.edu/sleepresearch.
❖ Clinical Pearls The loss of hypocretin neurons is responsible for most human narcolepsy. It is thought that this cell loss may be the result of an immune system attack on these neurons, but convincing evidence for this is lacking. Administration of hypocretin is a promising future avenue for the treatment of narcolepsy. Because the hypocretin system has potent effects on arousal systems, including the norepinephrine, serotonin, acetylcholine, and histamine systems, manipulation of the hypocretin system with agonists and antagonists is likely to be important in further pharmacotherapies for narcolepsy, insomnia, and other sleep disorders.
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119. Wu MF, Siegel JM. Facilitation of the acoustic startle reflex by ponto-geniculo-occipital waves: effects of PCPA. Brain Res 1990;532:237-241. 120. Brooks DC, Gershon MD. An analysis of the effect of reserpine upon ponto-geniculo-occipital wave activity in the cat. Neuropharmacol 1972;11:499-510. 121. Quattrochi JJ, Bazalakova M, Hobson JA. From synapse to gene product: prolonged expression of c-fos induced by a single microinjection of carbachol in the pontomesencephalic tegmentum. Brain Res Mol Brain Res 2005;136:164-176. 122. Datta S, Li G, Auerbach S. Activation of phasic pontine-wave generator in the rat: a mechanism for expression of plasticity-related genes and proteins in the dorsal hippocampus and amygdala. Eur J Neurosci 2008;27:1876-1892. 123. Verret L, Leger L, Fort P, et al. Cholinergic and noncholinergic brainstem neurons expressing Fos after paradoxical (REM) sleep deprivation and recovery. Eur J Neurosci 2005;21:2488-2504. 124. Goutagny R, Luppi PH, Salvert D, et al. Role of the dorsal paragigantocellular reticular nucleus in paradoxical (rapid eye movement) sleep generation: a combined electrophysiological and anatomical study in the rat. Neuroscience 2008;152:849-857. 125. Pompeiano O, Hoshino K. Tonic inhibition of dorsal pontine neurons during the postural atonia produced by an anticholinesterase in the decerebrate cat. Arch Ital Biol 1976;114:310-340. 126. Gvilia I, Xu F, McGinty D, et al. Homeostatic regulation of sleep: a role for preoptic area neurons. J Neurosci 2006;26:9426-9433. 127. Hanriot L, Camargo N, Courau AC, et al. Characterization of the melanin-concentrating hormone neurons activated during paradoxical sleep hypersomnia in rats. J Comp Neurol 2007;505: 147-157. 128. Verret L, Goutagny R, Fort P, et al. A role of melanin-concentrating hormone producing neurons in the central regulation of paradoxical sleep. BMC Neurosci 2003;4:19. 129. Chase MH, Morales FR. Control of motoneurons during sleep. In: Kryger MH, Roth T, Dement WC, editors. Principles of sleep medicine. 4th ed. Philadelphia: Elsevier Saunders; 2005. pp. 154168. 130. Scammell TE, Willie JT, Guilleminault C, et al. A consensus definition of cataplexy in mouse models of narcolepsy. Sleep 2009; 32:111-116. 131. Morales FR, Sampogna S, Rampon C, et al. Brainstem glycinergic neurons and their activation during active (rapid eye movement) sleep in the cat. Neuroscience 2006;142:37-47. 132. Lai YY, Kodama T, Siegel JM. Changes in monoamine release in the ventral horn and hypoglossal nucleus linked to pontine inhibition of muscle tone: an in vivo microdialysis study. J Neurosci 2001;21:7384-7391. 133. Mileykovskiy BY, Kiyashchenko LI, Siegel JM. Cessation of activity in red nucleus neurons during stimulation of the medial medulla in decerebrate rats. J Physiol 2002;545:997-1006. 134. Kodama T, Lai YY, Siegel JM. Enhancement of acetylcholine release during REM sleep in the caudomedial medulla as measured by in vivo microdialysis. Brain Res 1992;580:348-350. 135. Kohyama J, Lai YY, Siegel JM. Inactivation of the pons blocks medullary-induced muscle tone suppression in the decerebrate cat. Sleep 1998;21:695-699. 136. Siegel JM, Nienhuis R, Tomaszewski KS. Rostral brainstem contributes to medullary inhibition of muscle tone. Brain Res 1983;268:344-348. 137. Peever JH, Lai YY, Siegel JM. Excitatory effects of hypocretin-1 (orexin-A) in the trigeminal motor nucleus are reversed by NMDA antagonism. J Neurophysiol 2003;89:2591-2600. 138. Brooks PL, Peever JH. Glycinergic and GABAA-mediated inhibition of somatic motoneurons does not mediate rapid eye movement sleep motor atonia. J Neurosci 2008;28:3535-3545. 139. Morrison JL, Sood S, Liu H, et al. GABAA receptor antagonism at the hypoglossal motor nucleus increases genioglossus muscle activity in NREM but not REM sleep. J Physiol 2003;548: 569-583. 140. Burgess C, Lai D, Siegel J, et al. An endogenous glutamatergic drive onto somatic motoneurons contributes to the stereotypical pattern of muscle tone across the sleep-wake cycle. J Neurosci 2008;28: 4649-4660. 141. Schwarz PB, Yee N, Mir S, et al. Noradrenaline triggers muscle tone by amplifying glutamate-driven excitation of somatic motoneurones in anaesthetized rats. J Physiol 2008;586:5787-5802.
142. Chan E, Steenland HW, Liu H, et al. Endogenous excitatory drive modulating respiratory muscle activity across sleep-wake states. Am J Respir Crit Care Med 2006;174:1264-1273. 143. John J, Wu M-F, Boehmer LN, et al. Cataplexy-active neurons in the posterior hypothalamus: implications for the role of histamine in sleep and waking behavior. Neuron 2004;42:619-634. 144. Fenik VB, Davies RO, Kubin L. Noradrenergic, serotonergic and GABAergic antagonists injected together into the XII nucleus abolish the REM sleep-like depression of hypoglossal motoneuronal activity. J Sleep Res 2005;14:419-429. 145. Jelev A, Sood S, Liu H, et al. Microdialysis perfusion of 5-HT into hypoglossal motor nucleus differentially modulates genioglossus activity across natural sleep-wake states in rats. J Physiol 2001; 532:467-481. 146. Sood S, Raddatz E, Liu X, et al. Inhibition of serotonergic medullary raphe obscurus neurons suppresses genioglossus and diaphragm activities in anesthetized but not conscious rats. J Appl Physiol 2006;100:1807-1821. 147. Taepavarapruk N, Taepavarapruk P, John J, et al. State-dependent release of glycine in Clarke’s column of the upper lumbar spinal cord. Sleep 2003;26:A11-A12. 148. Shouse MN, Staba RJ, Saquib SF, et al. Monoamines and sleep: microdialysis findings in pons and amygdala. Brain Res 2000; 860:181-189. 149. Maloney KJ, Mainville L, Jones BE. c-Fos expression in dopaminergic and GABAergic neurons of the ventral mesencephalic tegmentum after paradoxical sleep deprivation and recovery. Eur J Neurosci 2002;15:774-778. 150. Siegel JM, Nienhuis R, Fahringer H, et al. Neuronal activity in narcolepsy: identification of cataplexy related cells in the medial medulla. Science 1991;252:1315-1318. 151. Wu MF, Gulyani S, Yao E, Mignot E, et al. Locus coeruleus neurons: cessation of activity during cataplexy. Neuroscience 1999;91:1389-1399. 152. John J, Wu MF, Maidment N, et al. Increased activity reduces cataplexy in canine narcolepsy: possible role of elevated hypocretin level. Sleep 2004;27:049. 153. Fronczek R, Overeem S, Lee SY, et al. Hypocretin (orexin) loss in Parkinson’s disease. Brain 2007;130(Pt. 6):1577-1585. 154. Thannickal TC, Lai YY, Siegel JM. Hypocretin (orexin) cell loss in Parkinson’s disease. Brain 2007;130:1586-1595. 155. John J, Wu MF, Siegel JM. Systemic administration of hypocretin-1. Sleep Res Online 2000;3:23-28. 156. Deadwyler SA, Porrino L, Siegel JM, et al. Systemic and nasal delivery of orexin-A (hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci 2007;27:14239-14247. 157. Gulyani S, Wu M-F, Nienhuis R, et al. Cataplexy-related neurons in the amygdala of the narcoleptic dog. Neuroscience 2002;112: 355-365. 158. Siegel JM. Hypocretin (orexin): role in normal behavior and neuropathology. Annual Rev of Psychol 2004;55:125-148. 159. Siegel JM, Boehmer LN. Narcolepsy and the hypocretin system— where motion meets emotion. Nat Clin Pract Neurol 2006;2: 548-556. 160. McGregor R, Wu M-F, Boehmer LN, et al. Reduced motivated behavior in hypocretin knockout mice. Abstract Viewer/Itinerary Planner Society for Neuroscience 2007;97.7. 161. Kiyashchenko LI, Mileykovskiy BY, Maidment N, et al. Release of hypocretin (orexin) during waking and sleep states. J Neurosci 2002; 22:5282-5286.
CHAPTER 8 • REM Sleep* 111 162. Blouin AM, Fried I, Staba RJ, et al. Hypocretin release during wake and sleep in the human brain. Abstract Viewer/Itinerary Planner Society for Neuroscience 2007. 163. van den Pol AN, Gao XB, Obrietan K, et al. Presynaptic and postsynaptic actions and modulation of neuroendocrine neurons by a new hypothalamic peptide, hypocretin/orexin. J Neurosci 1998;18: 7962-7971. 164. John J, Wu M-F, Kodama T, et al. Intravenously administered hypocretin-1 alters brain amino acid release: an in vivo microdialysis study in rats. J Physiol (Lond) 2003;548.2:557-562. 165. Liu RJ, van den Pol AN, Aghajanian GK. Hypocretins (orexins) regulate serotonin neurons in the dorsal raphe nucleus by excitatory direct and inhibitory indirect actions. J Neurosci 2002;22:94539464. 166. Siegel JM. Narcolepsy: A key role for hypocretins (orexins). Cell 1999;98:409-412. 167. Guilleminault C, Anognos A. Narcolepsy. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. 3rd ed. Philadelphia: Saunders; 2000. p. 676-686. 168. Siegel JM. Narcolepsy. Sci Am 2000;282:76-81. 169. Zhang S, Zeitzer JM, Sakurai T, et al. Sleep/wake fragmentation disrupts metabolism in a mouse model of narcolepsy. J Physiol (Lond) 2007;581:649-663. 170. Siegel JM. Why we sleep. Sci Am 2003;289:92-97. 171. Siegel JM. The REM sleep-memory consolidation hypothesis. Science 2001;294:1058-1063. 172. Smith C. Sleep states and memory processes in humans: procedural versus declarative memory systems. Sleep Med Rev 2001;5:491-506. 173. Lavie P, Pratt H, Scharf B, et al. Localized pontine lesion: nearly total absence of REM sleep. Neurology 1984;34:118-120. 174. Vetrugno R, Alessandria M, D’Angelo R, et al. Status dissociatus evolving from REM sleep behaviour disorder in multiple system atrophy. Sleep Med. 2009;10:247-252. 175. Rasch B, Pommer J, Diekelmann S, et al. Pharmacological REM sleep suppression paradoxically improves rather than impairs skill memory. Nat Neurosci 2009;12:396-397. 176. Ephron HS, Carrington P. Rapid eye movement sleep and cortical homeostasis. Psychol Rev 1966;73:500-526. 177. Wehr TA. A brain-warming function for REM sleep. Neurosci Biobehav Rev 1992;16:379-397. 178. Horner RL, Sanford LD, Pack AI, et al. Activation of a distinct arousal state immediately after spontaneous awakening from sleep. Brain Res 1997;778:127-134. 179. Mallick BN, Siegel JM, Fahringer H. Changes in pontine unit activity with REM sleep deprivation. Brain Res 1989;515:94-98. 180. Tsai L, Bergman B, Perry B, et al. Effects of chronic total sleep deprivation on central noradrenergic receptors in rat brain. Brain Res 1993;602:221-227. 181. Hipolide DC, Tufik S, Raymond R, et al. Heterogeneous effects of rapid eye movement sleep deprivation on binding to alpha- and beta-adrenergic receptor subtypes in rat brain. Neuroscience 1998; 86:977-987. 182. Hipolide DC, Wilson AA, Barlow K, et al. Effects of paradoxical sleep deprivation on serotonin transporter (SERT) binding. Sleep 2003;26:A176. 183. Troncone LRP, Braz S, Benedito MAC, et al. REM sleep deprivation induces a decrease in norepinephrine-stimulated 3H-cyclic AMP accumulation in slices from rat brain. Pharmacol Biochem Behav 1986;25:223-225. 184. Siegel JM, Rogawski MA. A function for REM sleep: Regulation of noradrenergic receptor sensitivity. Brain Res Rev 1988;13:213-233.
Phylogeny of Sleep Regulation Irene Tobler Abstract It is remarkable that the function of sleep is still unknown, despite the general acceptance that sleep leads to some form of recuperation. Making use of the diversity of animals in the investigation of sleep or sleeplike behavior is likely to yield insights into its origins and functional significance. In particular, representatives of different evolutionary stages could reveal at which stage sleep evolved and became necessary for survival. Tracing the evolution of sleep to its origins is a powerful approach that can provide clues to its mechanisms and functions. Comparative studies of sleep at different levels of its evolution centered on the presence of sleep and its stages in the higher vertebrates (e.g., mammals and birds), and less attention was given to the possibility that sleeplike states are
Sleep in mammals is finely regulated: a constant daily quota is maintained through a balance of sleep duration and sleep intensity, a phenomenon that was termed sleep homeostasis. The main measure for sleep intensity is the amount of EEG slow wave activity (SWA; defined as EEG waves in the frequencies between 0.5 and 4 Hz, also referred to as delta activity) within non–rapid eye movement (NREM) sleep. Additional measures such as arousal threshold, sleep continuity, motor activity, and heart rate also are useful indicators of sleep homeostasis. The regulatory property of sleep becomes evident when sleep pressure is enhanced, such as by sleep deprivation, an intervention that is applicable to many diverse species. Loss of sleep is expected to activate compensatory mechanisms. Comparative data addressing the presence of regulatory mechanisms in evolution indicate that a need for sleep has evolved. This need is derived from the increase in compensatory variables. An important condition is that compensation occurs as a function of the duration of waking and its dissipation during sleep. The regulatory property of sleep distinguishes it from merely rest, because its intensity component surpasses the constraints of the ubiquitous circadian rest–activity rhythm. This feature may be the essence of an adaptive value for sleep. Birds, perhaps because they are homeotherms, have NREM-REM sleep cycles very similar to those of mammals and also show compensatory mechanisms, including an increase in EEG sleep-intensity variables, when deprived of sleep. Species belonging to the lower vertebrates (reptiles and fish) and invertebrates (e.g., scorpions, cockroaches, and bees, with the exception of Drosophila melanogaster, where brain activity changes correlate with behavior) do not meet the electrophysiology criteria for the definition of sleep. Nevertheless, sleep deprivation in these species does elicit compensatory mechanisms. These evolutionarily simpler animals are useful for investigating basic mechanisms underlying compensatory activities at the molecular, neuroanatomic, and genetic level. Extensive studies in fruit flies convincingly show that their sleep exhibits many of the properties of mammalian 112
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present also in the lower vertebrates, reptiles, amphibians, and fish. The limitations were set by the narrow electrophysiologic definition of vigilance states and the behavioral correlates derived from mammals and were applied to nonmammalian species. After sleep deprivation in mammals, there is typically a compensatory rebound. This widely occurring phenomenon led to the proposal that the homeostatic aspect of sleep regulation is an essential property of sleep and should be included in a broader definition of sleep.1 This property sets it apart from the chronobiological definition of rest, with the important consequence that a relatively constant quota of sleep can be fulfilled by the interaction between sleep duration and intensity. This flexibility is especially important when animals are faced with situations in which the opportunity to sleep is limited.
sleep, demonstrating that sleep is not a phenomenon unique to the most highly evolved vertebrates—the homoeothermic mammals and birds—but is present also, in simpler manifestations, in arthropods. Drosophila is being used as a model organism to investigate the molecular regulation of vigilance states. Genes regulating their sleep have been identified, and these genes might have a similar function in more evolved species. There are indications suggesting sleeplike features in crayfish, octopus, and Caenorhabditis elegans, but its existence in these species and yet in lower vertebrates needs to be further clarified.
SLEEP REGULATION IN MAMMALS The Origins and Definition of Sleep Homeostasis The aim of early studies on sleep was to establish the presence of NREM sleep and especially of REM sleep in a diversity of species at different evolutionary stages. Particular emphasis was given to determining the amount of each of these states. Most data stem from animals recorded in the laboratory or in captivity. It can be assumed that such values are not necessarily representative for the sleep need of a species. The amount of sleep reported for animals bred and raised in the laboratory rather represents excess sleep. A typical example is the finding that sloths recorded by telemetry while living in the wild slept 6 hours less than animals of the same species recorded in a laboratory setting.2 The implementation of EEG spectral analysis and other methods of signal analysis to complement the traditional vigilance-state scoring led to the recognition that a continuous process underlies the NREM-REM sleep cycle. This process is reflected in the time course of SWA in NREM sleep across a sleep period. The principle of homeostasis was defined by W.B. Cannon in 1939 as “the coordinated physiologic processes which maintain most of the steady states in the organism.” Later, in 1980, the term sleep homeostasis was coined by Alexander Borbély,3 who posited that sleep strives to maintain a constant level by
16-hr SD 12-hr SD
300 SWA in NREMS (%)
variation of its duration and intensity. A vast amount of experimental data, especially from humans and rodents, shows that homeostatic mechanisms counteract the deviations of sleep from an average reference level. When waking is prolonged, sleep duration, and more importantly, EEG SWA during NREM sleep, is enhanced. In contrast, when sleep is prolonged or human subjects take a nap during the day, SWA in the subsequent night reaches a predictably lower level compared with a night preceded by a normal wakefulness period. In animals, it is more difficult to prolong sleep experimentally. Still, blocking access to a running wheel in rats induced excess sleep, which in turn was followed by decreased SWA levels.4 The two-process model of sleep regulation postulates that a homeostatic Process S rises during waking, and declines during sleep, interacting with Process C, which represents the output of the endogenous circadian clock, the nucleus suprachiasmaticus (SCN). SWA best reflects the prior history of sleep and waking and thus is an ideal quantitative marker of the dynamics of the homeostatic Process S in humans (see Chapter 37). The time course of the homeostatic variable S was derived from EEG SWA. The model accounts for the timing of human sleep5 and for the interaction of S and C, allowing predictions of the time course of daytime vigilance. In animals, sleep is polyphasic; thus, SWA is modulated by the alternation of sleep and waking bouts lasting from a few seconds up to several hours (their duration depends on the minimum criteria defining a sleep epoch). SWA turned out to be the best physiologic marker of sleep homeostasis in humans. Is this also true for animals? Strictly speaking, sleep homeostasis is fulfilled by a species when a (predictable) relationship is established between the degree of rebound and previous waking duration. It has been repeatedly shown for humans and in an increasing number of other mammals (squirrel monkey, rat, Syrian hamster, Djungarian hamster, cat, ground squirrel, and several mouse strains6-14) that SWA increases as a function of the duration of the sleep deprivation (Fig. 9-1; see Figs. 9-2 and 9-3). Can the original two-process model predict sleep regulation also in rodents? Attempts at simulating SWA in rodents on the basis of the original two-process model of sleep regulation showed that its tenets can be used to predict experimental results in animals, despite their polyphasic sleep pattern. The original formulation was based on an extensive data set derived from experiments in the laboratory rat.3 Experiments investigating the magnitude of the influence of Process C in animals are still scarce, and therefore Process C has yet to be incorporated in models of animal sleep. In rats, simulations of SWA closely resembled the data, demonstrating the validity of this simple model for a laboratory rodent.15 Because light exposure can affect both C and S,16-18 it was necessary to incorporate the SWA-reducing effect of light in order to optimize the correspondence between SWA data and its simulations. Simulations of SWA for inbred mouse strains enabled the investigation of mechanisms underlying sleep homeostasis at the genetic level.7,19-21 Strains differ considerably in the dynamics of the buildup of sleep pressure and subsequent SWA dissipation.6,7 It still remains to be examined whether sleep homeostasis as conceptualized in the two-process model can be applied to
CHAPTER 9 • Phylogeny of Sleep Regulation 113
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Hours SDD 6 hr (n = 8) SD 16 hr (n = 9) SD 12 hr (n = 9) SDL 6 hr (n = 8) Baseline (n=8) Figure 9-1 Effect of sleep deprivation (SD) by “gentle handling” on slow-wave activity (SWA) (electroencephalographic power density, 0.75 to 4.0 Hz) in non–rapid eye movement (NREM) sleep in the laboratory rat (Sprague Dawley). Mean values (n = 8 or 9 rats) of 2-hour intervals are expressed as a percentage of the corresponding 24-hour baseline value. SD duration was 6 hours beginning at either dark onset (6-hr SDD) or light onset (6-hr SDL), or 12 hours and 16 hours both beginning at dark onset (12-hr SD; 16-hr SD). SWA in NREM sleep during baseline is higher at light onset, after more wakefulness during the dark period than at dark onset, after the rats had slept considerable amounts. The experimental curves demonstrate the doseresponse relationship of the duration of wakefulness and the magnitude of SWA increase during recovery. The levels of SWA are similar when recovery begins at dark onset and at light onset, when recovery is expressed relative to the 24-hour baseline. A difference between the two recovery curves would become apparent when each of the 2-hour intervals would be plotted relative to their corresponding 2-hour intervals. After SDD, recovery is biphasic: An additional SWA peak occurs at the beginning of the subsequent light period. After all manipulations, SWA attained recovery levels after approximately 12 hours, and in some cases, falls below the baseline; that is, there is a negative rebound.
mammals other than rodents. In addition, a more-refined modeling approach must be developed to simulate the short-term changes in SWA. In rodents, SWA in NREM sleep reaches high values in a matter of seconds, whereas in humans the manifestation of slow waves at the transition to NREM sleep episodes is progressive, lasting 20 to 30 minutes. The comparison of the dynamics of Process S in different species and strains is a powerful method to identify the mechanisms underlying sleep regulation.6 Using a quantitative simulation of NREM sleep homeostasis in the rat and two mouse strains, the biphasic time course of SWA during baseline conditions, during the initial increase after sleep deprivation, and during the subsequent prolonged negative rebound was reproduced (see Chapter 37, Fig. 37-6).6,7,15 Sleep Duration and Sleep Intensity The hallmarks of sleep homeostasis in mammals are its duration, consolidation (i.e., brief awakenings and/or duration of consolidated NREM sleep and REM sleep epochs), and EEG SWA (also called delta power) in NREM sleep.
114 PART I / Section 2 • Sleep Mechanisms and Phylogeny
SWA (% of 2-hr interval)
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Duration of waking before sleep onset (hours) Figure 9-2 Top panel, slow-wave activity (SWA) (electroencephalographic [EEG] power density, 0.75 to 4.0 Hz) in non–rapid eye movement (NREM) sleep after spontaneous waking in the 12-hour baseline light period of an inbred mouse strain 129/ Ola (n = 9). The waking episodes were subdivided into three categories according to their duration (10 to 20 minutes, 20 to 30 minutes, and longer than 30 minutes). The SWA increase in the 10-minute NREM sleep interval immediately following the waking episode is expressed relative to SWA in NREM sleep in the corresponding 2-hour baseline interval. Even after the short waking interval, SWA increases above baseline, increasing progressively as a function of the duration of the waking episode. (Modified from Huber R, Deboer T, Tobler I. Effects of sleep deprivation on sleep and sleep EEG in three mouse strains: empirical data and simulations. Brain Res 2000;857:8-19.) Lower panels, scatter plots of correlations between the duration of spontaneous wakefulness episodes and subsequent EEG SWA in NREM sleep increase in the first 2-hour interval after sleep onset (% of mean) in the frontal and parietal derivation. Two days are shown: the day when a running wheel (RW) was provided and when access to the wheel was prevented (no RW). Each individual (n = 9) contributed with 2 values (RW and no RW; different symbols). The line depicts the linear regression. (Modified from Vyazovskiy VV, Ruijgrok G, Deboer T, Tobler I. Running wheel accessibility affects the regional electroencephalogram during sleep in mice. Cereb Cortex 2006;16:328-336.)
A homeostatic balance between sleep duration and sleep intensity strives to maintain a constant daily quota of sleep. An increase of total sleep time is restricted by the constraints imposed by the circadian pacemaker, the SCN, providing the frame for the circadian rest–activity rhythm and the limitations ensuing from the environmental conditions. For most animals, it is maladaptive to engage in long periods of sleep during the wrong circadian phase.
Generally, compensation of a sleep deficit occurs by a minor increase in total sleep. In rodents, NREM and REM sleep are little increased after waking epochs in the range of 3 to 24 hours. Instead, the most striking feature manifested early during recovery sleep is the remarkable increase of slow waves in the NREM sleep EEG; this was first demonstrated in the rabbit,22 extensively documented in the rat,23,24 and shown in a diversity of different mouse strains.6,7,19 The magnitude of the increase in sleep time or of SWA in NREM sleep depends on the species or strain, the duration of induced wakefulness, the efficacy of the deprivation, the quality of waking (behavior), and the circadian time point at which the deprivation ended. Apart from its clear relation to the duration of wakefulness, there is abundant evidence that the arousal threshold is consistently higher during NREM sleep with high amounts of slow waves, compared with more shallow NREM sleep with fewer slow waves.25-27 Therefore, it has become generally accepted that SWA reflects NREM sleep intensity.23,24 It is evident that the main factor determining the degree of increase of SWA during recovery sleep is the duration of the waking state (i.e., the absence of sleep), but early studies questioned whether the quality of wakefulness also might affect SWA, a notion that would be consistent with a recovery function of sleep. However, using forced locomotion to achieve sleep deprivation and comparing the effects of different cylinder rotation rates23,24 as well as voluntary running28 failed to elicit major differences in the magnitude of increase of slow waves during recovery sleep. However, stressful waking experiences can contribute to an increase of SWA (e.g., in rats exposed to a social conflict).29 An important aspect that has received much attention in the interpretation of changes in SWA levels is the potential stressful effect of sleep deprivation per se. The gentle handling procedure introduced in Zurich consists primarily of keeping the animal active by introducing objects such as tissue and cardboard rolls, by tapping on the cage, and, when necessary, by tilting the cage (the animals are never touched, despite the use of the term “handling”30,31). Our procedure entails constant observation of the animals to ensure that they are awake. Great care is taken to avoid stressing the animals (that is why they are never touched) and to avoid interference with spontaneous feeding and drinking bouts. A major influence of stress on the changes observed during recovery sleep appears unlikely because the forced locomotion procedure did not entail a significant increase in the level of plasma corticosterone,32 and the expression patterns of genes were similar after 3 hours of spontaneous wakefulness or enforced sleep deprivation.33 Moreover, in mice, corticosterone levels showed a negligible increase of this hormone after 6 hours of sleep deprivation compared to a massive increase after immobilization or spontaneous running activity.34 A more refined study provided mice with a running wheel, which induces vigorous spontaneous running during the active phase; this study showed that indeed the longer waking epochs are followed by higher SWA levels (Fig. 9-2).4 Studies in mice and ground squirrels found that SWA in NREM sleep also increased after spontaneous, undisturbed bouts of waking, and the magnitude of the increase depended on the duration of the
CHAPTER 9 • Phylogeny of Sleep Regulation 115
EFFECT OF TORPOR BOUT DURATION ON SUBSEQUENT SLOW-WAVE ACTIVITY
TORPOR AND SLEEP DEPRIVATION: SIMILAR EFFECTS ON SLOW-WAVE ACTIVITY
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Figure 9-3 Time course of slow-wave activity (SWA) (mean electroencephalographic power density, 0.75 to 4.0 Hz) within non– rapid eye movement (NREM) sleep during sleep after torpor episodes of three different durations (less than 3 hours, 3 to 6 hours, and 6 to 9 hours) (A), and during baseline, recovery from 1.5 and 4-hours sleep deprivation (SD), and after torpor (B) (mean torpor duration = 4.8 ± 0.3 hours SEM) in the Djungarian hamster, Phodopus sungorus. A, Mean 30-minute values (n = 6, 15, and 7, for less than 3 hours, 3 to 6 hours, and 6 to 9 hours of torpor, respectively) during recovery after the spontaneous end of torpor. SWA is expressed relative to the individuals’ 24-hour baseline day without torpor. A linear correlation between torpor bout duration and SWA increase was significant (n = 28, r = 0.42, P < .05). B, Time course of SWA after torpor and after 1.5 and 4-hour SD. Mean 30-minute values (n = 8, 8, and 7 for 1.5, 4-hour SD, and torpor, respectively). All recordings were performed in a short photoperiod, light–dark = 8:16, at 16° to 18° C. (Modified from Deboer T, Tobler I. Sleep regulation in the Djungarian hamster: Comparison of the dynamics leading to the slow-wave activity increase after sleep deprivation and daily torpor. Sleep 2003;26:567-572; and Deboer T, Tobler I. Slow waves in the sleep electroencephalogram after daily torpor are homeostatically regulated. Neuroreport 2000;11:881-885.)
previous waking bout (see Fig. 9-2).6,7,10 These studies support the argument that an increase of EEG slow waves that follows a wakefulness interval is not due to stress. It is unlikely that a global increase in metabolic rate during wakefulness is a critical variable contributing to the SWA increase after sleep deprivation. This possibility was rejected by the findings that changes induced by sleep deprivation performed either in a warm environment or at room temperature were similar, despite the higher levels of brain temperature in the warm condition.35 The fine regulatory property of sleep, especially the predictable changes in sleep intensity, and its so far ubiquitous manifestation, indicate that sleep must have an adaptive function, unless we postulate that sleep does not have a major function.36,37 Under natural conditions, animals need to be vigilant, forage for food, reproduce, and avoid long, continuous bouts of deep sleep with high arousal thresholds. Evidently, compensating for sleep loss by balancing sleep duration and sleep intensity, depending on the timing and the situation, has added flexibility to sleep.
Daily Time Course of Slow-Wave Activity and Its Sleep-Wake Dependence Having established that the main factor contributing to the initial level of EEG SWA in NREM sleep is the prior sleep and waking history, it follows that animals with a strong circadian amplitude of their rest–activity rhythm, which are awake preferably during the light or the dark period, therefore should exhibit high initial SWA values during the circadian preferred time for sleep. Moreover, as the need for sleep dissipates, SWA should decline progressively. This relationship is evident in nocturnal rodents (e.g. rat, hamster, and inbred mouse strains) and consistent in the diurnal chipmunk38 and in humans. The global progressive SWA decline, despite the intermittent waking bouts typical for most mammals, reveals a stable, continuous process underlying the sleep–wake pattern. In contrast, in species with a minor or no preference for sleep in the light or dark period (rabbit, guinea pig, cat, blind mole rat), the decline of SWA in the course of sleep is negligible.39-42
116 PART I / Section 2 • Sleep Mechanisms and Phylogeny
The Waking EEG Reflects Homeostatic Mechanisms The marker for Process S, EEG SWA, can only be measured during sleep, leaving us with the difficulty of quantifying the buildup of sleep pressure as wakefulness progresses. In humans, theta activity in the waking EEG as well as the ratio of alpha to theta have been demonstrated as markers of increasing sleep pressure (see Chapter 37). In animals, in the course of sleep deprivation, it becomes increasingly difficult to keep them awake; more and more slow waves appear in the EEG despite the evident waking behaviors the animals engage in. This SWA during waking is a potential spillover of the slow waves typical for sleep intensity. It remains to be demonstrated that this is the case. Another remarkable feature of increasing sleep pressure during sleep deprivation in rodents is an increase in EEG theta activity during wake-
Circadian versus Homeostatic Aspects of Sleep Regulation Several lines of evidence from animal experiments indicate that the homeostatic (Process S) and circadian (Process C) facets of sleep regulation are mediated by separate processes. Seminal experiments in the rat established that an intact circadian rhythm is not a necessary condition for sleep homeostasis. After the circadian facet of sleep regulation was disrupted by lesions of the SCN, and the rats became arrhythmic, a 24-hour sleep deprivation was followed by an intact ability to compensate for sleep loss.51-53 Both SWA in NREM sleep and the amount of REM sleep increased. Therefore, the homeostatic response to sleep deprivation persists despite the abolished circadian rhythm (Fig. 9-4A). Similarly, arrhythmic fruit fly mutants subjected to sleep deprivation still retain the capacity to compensate for sleep loss (see Fig. 9-4B). Neither the phase nor the period of the free-running rest–activity rhythm of intact rats was affected by sleep deprivation,54,55 but in the Syrian hamster it did lead to rapid resetting of the circadian clock.56
INCREASE OF SWA AFTER SLEEP DEPRIVATION IN THE RAT SWA in NREMS
Is REM Sleep Homeostatically Regulated? Both total sleep deprivation and selective REM sleep deprivation elicit a subsequent compensatory increase in the amount of REM sleep (e.g., in cat, dog, rat, mouse, cow). Despite the considerable focus on the evolutionary origin of REM sleep, its rebound after sleep deprivation has not been addressed from an evolutionary perspective. There is as yet little indication for an intensity dimension of REM sleep, although in the rat28,46 and rabbit40 EEG theta activity in REM sleep was enhanced after 24 hours of sleep deprivation, and it declined progressively in the course of recovery sleep. Perhaps theta activity does reflect REM sleep intensity.
fulness50 (EEG power between approximately 5 and 8 Hz). Such findings provide us with tools to quantify sleep pressure in animals under different conditions.
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Several experimental manipulations verified this relationship between the sleep-wake pattern and SWA. Changing the photoperiod from long to short days and vice versa in the rat and Djungarian hamster (Phodopus sungorus), or subjecting mice to short light–dark cycles over 24-hour intervals resulted in a dramatic redistribution of vigilance states, with no change in the total amount of sleep, but the time course of SWA followed the sleep–wake pattern as predicted.16,17,43,44 Similarly, mice with an estrogen deficiency had a lower 24-hour sleep–wake amplitude than normal mice, and this sleep pattern was again predictably accompanied by a dampened SWA amplitude.45 There are large differences in the magnitude of a sleep deprivation–induced SWA increase between different mammals and even within mouse strains. Simulations show that the rate of the increase of SWA pressure (Process S), reflected by the time constants of its increase, is faster in the rat and mouse than in human beings (see Chapter 37, Fig. 37-6).6,7,46 The remarkable difference in the increase of SWA elicited by 4 hours of sleep deprivation between two relatively small rodents, the Djungarian hamster and inbred mice6,47-49 (Fig. 9-3, and see Fig. 9-1) might reflect different levels of Process S during their baseline conditions. Such an interpretation is supported by the different magnitude of the SWA response to sleep deprivation in human long and short sleepers (see Chapter 37). It is difficult to interpret the meaning of the differences in these fundamental dynamics within sleep between related species and within inbred mouse strains, whose genetics should be very similar.
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Figure 9-4 Independence of the homeostatic aspect of sleep regulation from the circadian component in the rat and the fruit fly Drosophila melanogaster. A, Increase of slow-wave activity (SWA) in non–rapid eye movement sleep (NREMS) in the rat after bilateral lesion of the nucleus suprachiasmaticus. Mean 3-hour values of sliding averages of 1-hour intervals for the baseline day preceding the 24-hour sleep deprivation (dashed light blue line) and the recovery light period (n = 5) (dark blue curve). (Modified from Tobler I, Borbély AA, Groos G. The effect of sleep deprivation on sleep in rats with suprachiasmatic lesions. Neurosci Lett 1983;42:49-54.) B, Increase in duration of rest (minutes) in an arrhythmic Per 01 fly mutant recorded in constant darkness. Blue bar, 6 hours of deprivation of rest; light circles, amount of rest during baseline; dark squares, amount of rest during recovery. (From Greenspan RJ, Tononi G, Cirelli C, Shaw PJ. Sleep and the fruit-fly. Trends Neurosci 2001;24:142-145.)
INDEPENDENCE OF SLOW-WAVE ENERGY FROM CIRCADIAN FACTORS AFTER SLEEP DEPRIVATION
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Nevertheless, despite the predominance of the homeostasis aspect of sleep regulation, the vigilance states can affect the circadian process. Simultaneous recording of sleep stages and neuronal SCN activity of the rat demonstrated a feedback from sleep to the circadian pacemaker.57 Also, conflict experiments examined the relationship between the two processes. In the rat, the conflict was induced by ending a 24-hour sleep-deprivation period either at the onset or in the middle of the dark period, the circadian period in which rats are predominantly awake.23,58 SWA showed a two-stage rebound within the constraints of the circadian rhythm: an immediate increase followed by waking, and then a second, delayed increase at light onset. Because sleep in animals is largely polyphasic, short periods of sleep deprivation, such as 3 to 6 hours in rats or mice, theoretically can elicit considerable increases in sleep duration within the circadian constraint, but its magnitude depends on whether recovery is allowed within the light or the dark period. Thus, it is not that the capacity to sleep attained an upper threshold, as has been argued. Instead, 3 hours of sleep deprivation leads to a small but significant increase in SWA with no change in NREM or REM sleep, whereas after 6 hours of sleep deprivation, NREM sleep (and, with a few hours’ delay, also REM sleep) increases.13,35 However, two bouts of 6 hours of sleep deprivation, once at the beginning of the light period and once at the beginning of the dark period, resulted in a major difference in the amount of sleep loss, and the time course and amount of increase in NREM sleep and SWA were different.59 When the relationship between NREM sleep and SWA was analyzed by computing slow-wave energy (i.e., integrated SWA in NREM sleep), the compensation was identical under both sleep-deprivation conditions (Fig. 9-5). It is remarkable that even in cats, a species with a very small circadian sleep–wake modulation,9,42 the effect of a short 4-hour sleep deprivation, performed at two different phases of the light–dark cycle, depended on the phase at which recovery was allowed.9 Generally, the circadian influence becomes evident when recovery from sleep deprivation begins in the circadian phase of predominant waking. The increase in total sleep time is invariably larger than when recovery occurs during the phase where sleep is predominant, but the SWA increase is less dependent on circadian factors.58 A series of sleep-deprivation experiments in squirrel monkeys performed in constant light and initiated at the beginning of the subjective day, and therefore ending at different times of the circadian cycle,8 led to the conclusion that the homeostatic component is weaker than circadian factors in determining the amount and intensity of sleep in the monkeys. However, a generalization to primates is not possible. In human subjects undergoing a forced desynchrony protocol, SWA showed little circadian modulation (see Chapter 37). Also the results obtained in species lacking a natural distinct preference for sleep in a particular circadian phase (guinea pig, rabbit, and some mouse strains,40,60-62) support the notion that sleep homeostasis is largely independent of the circadian rhythm. The identification of clock genes in mice, humans, and fruit flies renewed the interest in the potential interaction between circadian and homeostatic aspects of sleep regula-
CHAPTER 9 • Phylogeny of Sleep Regulation 117
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Hours Figure 9-5 Time course of slow-wave energy (SWE) (cumulative electroencephalographic power density, 0.75 to 4.0 Hz in non– rapid eye movement [NREM] sleep) for the 18-hour recovery interval after 6 hours of sleep deprivation (SD) that began either at light onset (SDL) or dark onset (SDD). Curves connect 2-hour cumulative values of mean SWE (male Sprague-Dawley rats: SDL, n = 8; SDD, n = 8; male B1 mice [I/LnJ × C57BL/6]: SDL, n = 13; SDD, n = 15), expressed relative to mean SWE in NREM sleep in the corresponding individual 24-hour baseline. During recovery from 6 hours of sleep deprivation performed either at the beginning of the 12-hour light period (SDL) or at the beginning of the 12-hour dark period (SDD) in the rat (n = 8) and B1 mice (n = 13 to 15), NREM sleep and slow-wave activity in NREM sleep are significantly increased. The magnitude of the effect and its time course depend on the timing of the SD. The differences in time course become evident when SWE is computed. However, it is notable that in both species, SWE reaches identical values toward the end of the recovery period of both treatments. (Vyazovskiy V, Tobler I, unpublished data, 2007.)
tion. Studies using mouse mutants with deletions in circadian genes confirmed the presence of sleep homeostasis despite the absence of a circadian rhythm,63-65 but for some mutants the homeostatic response to sleep deprivation was weak.21,66 For state-of-the art knowledge on circadian genes affecting sleep homeostasis, see chapter 15). In summary, caution is warranted in interpreting the effects of sleep deprivation on sleep, because sleep can vary its duration and its intensity. Moreover, the efficacy of the sleep-deprivation procedure can differ between species, and the spillover of slow waves into the waking EEG can confound the results. Simulations based on the two-
118 PART I / Section 2 • Sleep Mechanisms and Phylogeny
process model, which accounts for the changes in duration of NREM sleep and its intensity, indicates that the considerable differences between strains are a consequence of different dynamics (i.e., of time constants) of the homeostatic process (see Chapter 37).6 Special Features Herbivores: Cows and Horses, Ruminants and Nonruminants The herbivores are a diverse group of animals encompassing ruminating and nonruminating species, some with considerably large body and brain weights; human-bred domesticated species; and animals living in the wild (giraffes, elephants, antelopes) (Videos 9-1 and 9-2). Therefore, the ungulates can help clarify whether sleep regulation is affected by these features. The impact of the specialization of nutrition, entailing many hours of rumination, on sleep is worth pursuing. The effects of prolonged wakefulness have been investigated in three species: cows, donkeys, and ponies. Recumbence was prevented in cows for 14 to 22 hours per day for 2 to 4 weeks. This intervention, a major REM sleep deprivation (although NREM sleep and drowsiness were also reduced), was followed by both NREM and REM sleep enhancement during recovery.67 Similarly, sleep time increased in a donkey that was sleep deprived for 48 hours.68 In ponies, recorded in a stall and outdoors and subjected to visual and auditory sensory deprivation for a 4-day period in the stall, the amount of NREM sleep increased from day to day at the cost of drowsiness, a lighter form of NREM sleep, and REM sleep was unchanged. On exposure to the more disturbed conditions outdoors, there was a threefold increase of REM sleep during the first 2 days indicating a relationship with the increased environmental stimuli.69,70 Taken together, at least some aspects of sleep are regulated in large herbivores. It remains to be clarified whether their NREM sleep has a strictly regulated intensity component. Sleep Regulation: Unihemispheric Sleep and Regional Aspects of Sleep One of the most remarkable specializations of sleep evolved in aquatic mammals belonging to the orders Cetacea, Pinnipedia, and Sirenia. Some species of each of these orders engage in episodes of unihemispheric deep sleep (i.e., with a predominance of delta waves) that can last from minutes to hours while the other hemisphere exhibits an EEG resembling waking.71 Although the invasive recordings with implanted electrodes, the restriction of the animals’ movement by the recording cables, and the constraints of the recording environment might have influenced these findings, Ridgway72 confirmed unihemispheric sleep in a bottle-nosed dolphin recorded by telemetry in a small pool. Refined recording equipment and conditions have been used to describe sleep in representatives of all orders of cetaceans. Unihemispheric sleep provides a unique opportunity to investigate whether sleep regulation occurs simultaneously in both brain hemispheres. Maintaining six bottle-nosed dolphins awake for 35 to 72 hours resulted in an increase in delta sleep in three individuals and, in an early study, in a more regular alternation of deep sleep between the brain
hemispheres,71 providing evidence that slow waves in NREM sleep represent sleep intensity also in dolphins. Further experiments targeting the arousal threshold during unihemispheric sleep are lacking. The most revealing experiment was the attempt to restrict sleep deprivation to a single brain hemisphere by intervening only when the EEG of one hemisphere showed delta waves. Although some variability was seen between individuals in the magnitude of changes, the unilateral intervention resulted in a larger compensation of delta sleep during recovery in the deprived hemisphere in seven of the nine deprivations.71 These findings show that sleep does not necessarily encompass the entire brain and led to the notion that sleep might have local aspects in other species. Several lines of evidence supported the notion of topographic EEG SWA differences between and within hemispheres in humans and rodents.31 Elaborate experiments manipulating the quality of waking revealed that specific aspects of the waking state can indeed induce SWA changes in the brain regions that were more active during waking.30,73 Such enhanced neuronal activity was attained experimentally in rats and mice by stimulation of whiskers or spontaneously by use of a preferred paw during feeding30,74 and unilateral sleep deprivation in dolphins.71 A function of slow waves during sleep could be to enable recuperation of neurons in those regions that were most active during waking.75 Sleep and Hibernation Hibernation and daily torpor, both characterized by a remarkable, physiologically regulated decrease in metabolism, as well as body and brain temperature, thereby showing similarity to the regulated decrease observed during sleep, have been used as models to understand sleep. Hibernation and daily torpor are specializations that reduce energy requirements most effectively in endothermic animals. In daily torpor, temperature is lowered to approximately 15° to 20° C for several hours during the circadian rest period.76 In contrast, during hibernation, body temperature is lowered to 5° C or less for several months,77 with short (less than 24-hour) euthermic interruptions.77,78 It is well established for several hibernators that they arouse from hibernation and, paradoxically, go to sleep. It is puzzling that animals arouse regularly from hibernation despite the high energy costs of the arousals.78 Their SWA is high at the initiation of the sleep episode and subsequently decreases, exhibiting dynamics that are comparable to recovery after sleep deprivation. In three species of ground squirrels, the initial values of SWA during euthermia were higher after long hibernation bouts than after short ones, which again is a typical feature for recovery from sleep deprivation.77,79,80 Thus hibernation, especially at low temperatures, and daily torpor seem to be incompatible with restorative processes that are expected to occur during sleep.77,79 The relationship of the torpid state, subsequent arousal, and sleep deprivation was extensively investigated in the Djungarian hamster (Phodopus sungorus sungorus). They alternate days with torpor with days at euthermic levels, enabling comparisons within the same individuals (for a review, see reference 48). As in the hibernating ground squirrels, during euthermia, the initial value of SWA in
NREM sleep was high and was followed by a progressive decline closely resembling the pattern during recovery from sleep deprivation (see Fig. 9-3). Similarly, as after sleep deprivation, the initial level of SWA was higher after long torpor bouts than after short bouts (see Fig. 9-3),81 and a better fit between the duration of torpor or sleep deprivation and the initial SWA values was attained by a saturating exponential function than by a linear function.82 The kinetics of the increase in sleep pressure during torpor was 2.75 times slower than after sleep deprivation in the same species (see Fig. 9-3),48 supporting the hypothesis that during hypothermia, the hamsters incur a sleep deficit that is recovered by returning to euthermia. Another similarity between recovery from torpor and sleep deprivation are the distinct regional differences between cortical areas in the degree of increase of EEG SWA, which invariably is higher above the frontal cortex compared to parietal or occipital regions. It still remains to be clarified whether the return to euthermia is triggered by a homeostatic need to recover. Other Measures for Sleep Regulation: Sleep or Rest Consolidation Abundant data document a compensatory increase of SWA and other EEG variables after prolonged wakefulness in species encompassing humans and rodents and many other mammals, including two nonhuman primates (the rhesus monkey [Macaca mulatta] and squirrel monkey),8,83-85 three carnivores (the cat,9,11,14,40,86 the dog,87 and the ferret88), and rabbits and dolphins. However, variables such as sleep state consolidation, or alternatively, when sleep data are lacking, the number and consolidation of epochs with little or no motor activity, also change as a function of the duration of previous wakefulness. Sleep consolidation might not merely reflect higher SWA pressure, but might also provide an organism with an additional means to enhance the recovery value of sleep. Indeed, the higher SWA levels encountered in long NREM sleep episodes compared to shorter episodes support the notion of a higher recovery value of long, consolidated epochs.59 Thus, the consolidation of sleep under increased sleep pressure by means of sleep-episode prolongation might be a powerful mechanism to achieve more-intense sleep. Sleep continuity can be defined also by the frequency of short wake episodes (brief awakenings). In the rat, the frequency of wake episodes shorter than 32 seconds was reduced after 24 hours of sleep deprivation, leading to a consolidation of sleep during recovery. In further similar experiments in the rat and other rodents (guinea pigs and laboratory mice), the reduction in the number of brief awakenings correlated with the increase of SWA.15,20,39,89 This inverse relationship indicates that brief awakenings might represent a behavioral correlate of sleep intensity.15 The decrease of brief awakenings under enhanced sleep pressure likely contributes to the reduced variability of the NREM-REM sleep cycle shown in the rat,89 bottle-nosed dolphin,71 and cat90 to the shortening of the sleep cycle, as well as to decrease in the duration of the single-cell activity discharge cycle in brainstem dorsal raphe nucleus.90 Motor activity is reduced during recovery from sleep deprivation in humans91 and in several other mammals. In dogs subjected to sleep deprivation, motor activity assessed
CHAPTER 9 • Phylogeny of Sleep Regulation 119
continuously by actigraphy was reduced by as much as 40% during recovery.92 Similarly, in the rat, activity was reduced to 84% of baseline when recovery from 24 hours of sleep deprivation coincided with dark onset.23 There are data showing that the amount of consecutive rest episodes as a marker for sleep intensity may be a useful measure to quantify sleep regulation in inbred mouse strains (e.g., 45). In summary, motor activity is a simple measure that can be recorded easily, allowing investigation of aspects of sleep regulation when invasive EEG interventions are not possible or in species where sleep cannot be defined by EEG criteria (see “Sleep Regulation in Invertebrates”).
SLEEP REGULATION IN NONMAMMALIAN VERTEBRATES Birds Sleep in birds is similar to sleep in mammals (for a review, see reference 93), but the limited number of species investigated relative to the large diversity of avian species does not allow generalization. The similarity applies especially to the uncontested presence of the two stages NREM sleep and REM sleep, although the duration of REM sleep epochs in birds is typically much shorter. Three vigilance states can be distinguished by spectral analysis of the EEG concomitant with electromyogram (EMG) and electrooculogram (EOG) measures. In birds, the differences between sleep stages are much smaller than in mammals,94 in which NREM sleep power density values in the low-frequency range (0.25 to 6.0 Hz) exceed those of REM sleep and waking by approximately one order of magnitude. It was important to clarify whether sleep in birds is homeostatically regulated, because specific aspects of sleep regulation may be related to homeothermy. An early study in pigeons showed no effect of 12-hour sleep deprivation on SWA in NREM sleep.94 Nevertheless, several other variables were affected by the sleep deprivation, which are consistent with a need for recovery. Sleep duration, the amount of REM sleep, and EOG activity in waking and NREM sleep were increased. In the meantime, a homeostatic SWA increase was documented in pigeons,95 and sparrows.96 It is still an open question whether SWA in birds affects the arousal threshold to stimuli, providing another measure to demonstrate the relation between their SWA and sleep intensity. Many birds exhibit unilateral eye-blinking, which in some species was correlated to a wakelike EEG over the contralateral hemisphere.97 In Barbary doves, frequency of eye blinking decreased substantially after 3- to 36-hour sleep deprivation (achieved by exposing the animals to a ferret on a leash).98 The level of vigilance estimated by the blinking frequency depended on the duration of the sleep deprivation, suggesting a need to compensate for sleep loss. There is a trade-off between the benefits of frequent eye blinking (e.g., optimizing predator detection by increasing vigilance) and sleep with few interruptions.98 The results imply that the birds benefited from sleep with closed eyes and that those benefits were reduced during sleep deprivation. This early finding was later complemented by EEG recordings in pigeons and mallard ducks. Both species had short epochs of EEG asymmetry during
120 PART I / Section 2 • Sleep Mechanisms and Phylogeny
sleep, resembling unihemispheric sleep in dolphins. However, in birds, these epochs were ultrashort, in the range of seconds. In addition, mallards exposed to laboratory surroundings had higher amounts of such eye-openings and concomitant unilateral sleep than the same birds placed in the more protected space between conspecifics rather than at the periphery of the group.97,99 This elegant experiment indicated that the lateralization might enhance survival, because it allows one hemisphere to scan the environment intermittently while the other remains in a sleeping state. The occurrence of such episodes may be the clue to “sleeping on the wing,” which was determined in frigate birds wearing altimeters100 and was postulated years ago on the basis of behavioral observations of swifts. The frigate birds were in constant motion day and night. Alternatively, birds might sleep while they are gliding100a or, as recordings in the laboratory in sparrows showing migratory behavior, drowsiness can be enhanced.101 Reptiles The sleep EEG in reptiles differs in many ways from that in mammals. In particular, the vigilance state–related changes in EEG patterns are different. It is therefore remarkable that elements in their EEG did respond to sleep deprivation. Considerable diversity in the appearance of high-voltage slow waves (sharp waves and spikes) superimposed on the waking and sleeping EEG was found, suggesting that this type of EEG activity may be a precursor or a correlate of the slow waves associated with sleep in mammals.102 A state-related change in firing rate of brainstem neurons (waking versus quiescence) was seen in box turtles.103 In the early 1970s, Flanigan104 performed a unique set of sleep-deprivation experiments in reptiles belonging to the orders Crocodilia (Caiman sclerops), Chelonia (box turtle [Terrapene carolina] and red-footed tortoise [Geochelone carbonaria]), and Squamata (iguanid lizards, green iguana [Iguana iguana], and spiny-tailed lizard, also called black lizard [Ctenosaura pectinata]). The animals were subjected to 24 or 48 hours of stimulation by stroking, handling, or gently tugging the animal’s leash when it showed signs of behavioral sleep. The increasing amount of interventions necessary to keep the turtles awake and the loss of muscle tone in the iguanas toward the last hours of sleep deprivation were clear signs of increasing sleepiness, indicating an accumulating need for sleep. Recovery consisted of a compensatory rebound: The latency to behavioral sleep shortened, the duration and amount of behavioral sleep increased, and EEG spikes and, importantly, arousal threshold (response to electrical stimulation of eye potentials or heart rate) were markedly enhanced. It is therefore possible that reptilian EEG spikes and sharp waves reflect sleep intensity. Their increase after prolonged wakefulness, similar to slow waves in mammals, suggests a functional similarity. Amphibians and Fish Data on sleep in amphibians and fish are scarce, although they show many behavioral aspects of sleep. Moreover, investigations of effects of sleep deprivation in amphibians are lacking. For example, a correlation between
arousal threshold and behavioral sleeplike states is not established. However, two early studies subjected two species of fish, carp and perch, to sleep deprivation, using behavioral measures to assess its effects.105 Activation of carp for up to 96 hours by continuous illumination induced decreased latency to sleep behavior during the reinstatement of the dark period,106 and in perch, the activation induced by exposure to 6 and 12 hours of light during the habitual rest period (i.e., the dark period) resulted in an increase of resting behavior during recovery.105 The effect depended on the length of the light exposure, confirming the notion that homeostatic mechanisms might underlie the regulation of rest in fish. The availability of the zebrafish (Danio rerio) genetic map makes this lower vertebrate an interesting candidate to screen for the genes involved in sleep regulation at the level of simpler vertebrates. Rest deprivation of larvae elicited behavioral sleep, or a rest rebound,107 and deprivation of rest by electrical stimulation of adults elicited a sleep rebound, albeit only when recovery began at dark onset,108 confirming the sleep-regulatory capacity in this species. Taken together the findings in fish demonstrate that a sleep regulatory system might have evolved across the vertebrate classes. Fish may be powerful models to investigate the molecular networks and mechanisms underlying sleep regulation.
SLEEP REGULATION IN INVERTEBRATES Simpler models are better suited than mammals and birds to dissect the molecular basis of sleep. Once it was established that in mammals and birds a series of additional variables other than the EEG could be used to define sleep and its homeostasis, the way was paved to investigate whether nonvertebrate organisms, such as arthropods, meet the behavioral criteria for sleep. The criteria have indeed been met, showing that arthropods evolved the capacity for a compensatory response after prolongation of the normal waking period. Initial evidence came from two species of cockroaches and the scorpion, the oldest living arthropod (marine scorpions can be traced back to the Silurian period of about 400 million years ago). The most compelling evidence for the existence of sleep in an invertebrate is available for the fruit fly, Drosophila, rendering this insect an ideal species to dissect the genetics of sleep and sleep regulation.109-113 Cockroaches (Leucophea maderae,114 Blaberus giganteus,115 and Periplaneta australasiae) (K. Sly and R. Brown, unpublished data, 1994) were prevented from resting for 3 hours at the end of the daily rest period; it was predicted that a compensatory increase of rest would best be manifested at the time of habitual activity. Rest exhibited a rebound after the intervention, whereas the control experiment, simply removing the insects from their home cages for 3 hours, elicited a smaller and shorter-lasting decrease of activity and an increase of immobile rest episodes. The data provided the first evidence for compensatory mechanisms in an invertebrate.114 In a more-refined approach, behavior was scored as “activity” or “rest,” but rest was subdivided on the basis of the position of the head, abdomen, and
CHAPTER 9 • Phylogeny of Sleep Regulation 121
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in the fly brain correlated with behavioral state.116 The definition of sleep and its regulatory capacity in Drosophila paved the way to screen thousands of fly mutants (see Fig. 9-6C), leading to the identification of the genetic components regulating their sleep. Several hundred fly mutants, including lines derived from single females collected in the wild, are being screened for short and long sleepers and for flies that lack a homeostatic response to the loss of sleep (reviewed by Cirelli109). Already, there is large variability in sleep homeostasis in flies. Drosophila mutants lacking an enzyme involved in the catabolism of monoamines, dopamine acetyltransferase, as well as the loss-of-circadian-function fly, cyc01, showed enhanced rest rebound after sleep deprivation, whereas male flies with a null mutation for cycle (BMAL1) showed no rebound or very little rebound (reviewed in references 117 and 118). Homeostasis was apparently impaired in flies mutant for the clock gene timeless, but this result was based on the lack of a rebound after only 6 hours of sleep deprivation.110 Longer periods of sleep deprivation should reveal whether a compensatory response can be induced in these mutants.
Arousal threshold (% of baseline)
antennae in order to clarify whether substates reflect different arousal thresholds. In one of the nine behavioral states, characterized by a horizontal body axis with the antennae touching the substrate, arousal was lower than in all other states. After disturbing the cockroaches for an entire 12-hour dark period, it was this behavioral state that showed a tendency to increase its duration and frequency during recovery; however, locomotion was also increased.115 The fruit fly (with its manifold mutants) has significantly contributed to our knowledge about the genetic basis of sleep regulatory mechanisms. Rest in this insect is not merely a state of inactivity but fulfills all the behavioral criteria for sleep.110,111,113 Correlates of sleep and waking were established: The rest activity pattern was quantified and the arousal thresholds to several types of stimuli were investigated. Preventing the flies from attaining rest for different periods of time elicited a corresponding increase of rest during recovery (Fig. 9-6A) that was associated with increased sleep continuity and arousal thresholds (see Fig. 9-6B). Thus, both factors contributing to sleep homeostasis in mammals, duration and intensity, are firmly established for the fruit fly. Moreover, electrical field potentials
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Figure 9-6 Sleep in the fruit fly. A, Left, Solid circles indicate the typical pattern of sleep in a population of about 100 female wild-type flies during baseline. Flies sleep mostly during the night. Open circles indicate sleep amount and distribution after 12 hours of sleep deprivation (SD). Time and duration of sleep deprivation are indicated by the light blue bar on the x-axis. The increase in sleep duration occurs mainly during the first 6 hours after sleep deprivation (paired t tests). Flies were maintained in a 12:12 light–dark cycle (light on at 8 AM). Right, Amount of sleep lost (during sleep deprivation) and of sleep recovered (after sleep deprivation) for the experiments shown at left. Sleep duration is significantly increased during the first 3 hours after sleep deprivation. *P < .05; O, P < .1, Duncan’s multiple range test. In flies, as in mammals, the amount of sleep recovered after sleep deprivation represents only a fraction of the sleep lost. B, Sleep intensity is increased after sleep deprivation. Left, The number of brief awakenings is reduced during the first 3 hours after SD. Right, The arousal threshold is increased during the first 6 hours after sleep deprivation. Values refer to the experiment shown in A. *P < .05, Duncan’s multiple range test. C, Left, Daily amount of sleep in 1547 mutant lines. Mean amount of sleep per 24 hours is 616 ± 169 (mean ± standard deviation; minimum, 131; maximum, 1155). Shaded areas show one (dark blue) and two (light blue) standard deviations from the mean. Only a very few mutant lines sleep less than 2 standard deviations from the mean (short sleepers). Right, Daily amount of sleep in female and male flies of a short-sleeper line (light blue lines). For comparison, the dark blue line in each panel represents the daily amount of sleep in wild-type flies. (From Cirelli C, Huber R, Tononi G. unpublished data, 2005.)
122 PART I / Section 2 • Sleep Mechanisms and Phylogeny
Sleep deprivation in bees led to compensatory changes including prolongation of rest and decreased antenna movements, complementing the early studies.119,120 Scorpions of the three species Heterometrus longimanus, Heterometrus spinnifer, and Pandinus imperator also show a clear daily rhythm of rest and activity, and on the basis of the reaction to a vibration stimulus, an intermediate alert state and a rest state could be defined. Deprivation of rest for 12 hours elicited an initial rise of activity and a significant increase in the resting state (Fig. 9-7).94 Among lower invertebrates, crayfish not only displayed most elements of behavioral sleep, including an enhanced arousal threshold to mechanical stimulation when in behavioral quiescence, but also a rest rebound after the quiescent state was prevented for 24 hours.121 A series of experiments in cuttlefish (octopus, Sephia pharaonis) resulted in similar rebound mechanisms after 12 hours of vibratory stimulation,122 thereby expanding the presence of a sleeplike state to mollusks. The evolutionary lowest organism in which the presence of sleep and sleep regulation was
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Figure 9-7 Effect of 12-hour rest deprivation on three vigilance states in the scorpion. Bars represent mean values ± SEM (standard error of the mean) (n = 7) for the 12-hour intervals of the control day and recovery after rest deprivation, ending at dark onset, separately for the 12-hour dark and 12-hour light period. *P < .05, Wilcoxon matched-pairs signed-rank test; differences between control and recovery. Dark and light conditions are indicated by the dark green and light green bar at the bottom of the figure. Note: The prolonged compensation of resting immobility at the cost of alert immobility, and note the initial activating effect of the intervention. (Modified from Tobler I, Stalder J: Rest in the scorpion—a sleep like state? J Comp Physiol [A] 1988;163:227-235.)
extensively investigated most recently is the nematode Cenorhabditis elegans.123 Many genes in Drosophila have a homologous counterpart in mice and humans. These genetic links mean that flies, zebrafish, mice, and perhaps also C. elegans can be used as models, which will eventually lead to our understanding of sleep in humans.
OUTLOOK Compensation for the loss of sleep has been found in many mammals. Similar phenomena were described in birds, reptiles, fish, and some invertebrates. Most notably, Drosophila exhibits homeostatic compensation of rest after rest deprivation, leading to its use as a model to investigate the underlying mechanisms at the genetic level. In natural environments, there are many disturbances that can prevent animals from obtaining their normal quota of sleep. A large variety of animals have developed mechanisms to compensate for the loss of sleep within the constraints of the circadian rest–activity rhythm by intensifying sleep. This is a powerful indication that there is a benefit to sleep that is reduced during sleep deprivation and is indispensable. Rest behavior may be a state from which sleep evolved. A more-detailed characterization of rest in different classes of animals is helping to clarify the origin of sleep and to identify the unique properties of sleep in comparison to rest. Sleep, as it is defined in mammals and birds, has many properties that can be identified in lower vertebrates and invertebrates. An important common feature is that sleep is not merely a function of the circadian rest–activity rhythm but is determined by additional regulatory mechanisms. Sleep deprivation in vertebrates and invertebrates elicits compensatory responses. This regulatory property of sleep, which can be considered the essence of sleep, can be used to examine rest in a broad range of animals that, because of the absence of EEG criteria, are not considered to manifest sleep. The effects of rest deprivation in invertebrates are, in some aspects, analogous to the compensation of sleep after sleep deprivation in mammals. Elementary properties of sleep may be found that will allow the investigation of the underlying mechanisms in less-complex organisms. Although these technologies allow the application of genetics to complex systems such as those encountered in mammals, the finding that Drosophila exhibits the criteria used to define sleep provides an interesting parallel avenue to clarify the involvement of genes in sleep regulation.124
❖ Clinical Pearl Hibernation and daily torpor, which are the most effective ways to reduce energy requirements, result in reduction of body temperature and other physiologic changes that protect organs that have a high metabolic rate. Lessons learned from understanding spontaneous or artificially induced hibernation might lead to new treatments to protect the brain in patients with stroke and traumatic brain injury.
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28. Hanagasioglu M, Borbély AA. Effect of voluntary locomotor activity on sleep in the rat. Behav Brain Res 1982;4:359-368. 29. Meerlo P, de Bruin EA, Strijkstra AM, et al. A social conflict increases EEG slow-wave activity during subsequent sleep. Physiol Behav 2001;73:331-335. 30. Vyazovskiy VV, Borbély AA, Tobler I. Unilateral vibrissae stimulation during waking induces interhemispheric EEG asymmetry during subsequent sleep in the rat. J Sleep Res 2000;9:367-371. 31. Vyazovskiy VV, Borbély AA, Tobler I. Interhemispheric sleep EEG asymmetry in the rat is enhanced by sleep deprivation. J Neurophysiol 2002;88:2280-2286. 32. Tobler I, Murison R, Ursin R, et al. The effect of sleep deprivation and recovery sleep on plasma corticosterone in the rat. Neurosci Lett 1983;35:297-300. 33. Cirelli C, Tononi G. Differences in brain gene expression between sleep and waking as revealed by mRNA differential display and cDNA microarray technology. J Sleep Res 1999;8(Suppl. 1):44-52. 34. Palchykova S, Winsky-Sommerer R, Meerlo P, et al. Sleep deprivation impairs object recognition in mice. Neurobiol Learn Mem 2006;85:263-271. 35. Tobler I, Franken P, Gao B, et al. Sleep deprivation in the rat at different ambient temperatures: effect on sleep, EEG spectra and brain temperature. Arch Ital Biol 1994;132:39-52. 36. Cirelli C, Tononi G. Is sleep essential? PLoS Biol 2008;6:e216. 37. Siegel JM. Do all animals sleep? Trends Neurosci 2008;31: 208-213. 38. Dijk DJ, Daan S. Sleep EEG spectral analysis in a diurnal rodent: Eutamias sibiricus. J Comp Physiol [A] 1989;165:205-215. 39. Tobler I, Franken P, Jaggi K. Vigilance states, EEG spectra, and cortical temperature in the guinea pig. Am J Physiol 1993;264: R1125-R1132. 40. Tobler I, Franken P, Scherschlicht R. Sleep and EEG spectra in the rabbit under baseline conditions and following sleep deprivation. Physiol Behav 1990;48:121-129. 41. Tobler I, Herrmann M, Cooper HM, et al. Rest-activity rhythm of the blind mole rat Spalax ehrenbergi under different lighting conditions. Behav Brain Res 1998;96:173-183. 42. Tobler I, Scherschlicht R. Sleep and EEG slow-wave activity in the domestic cat: effect of sleep deprivation. Behav Brain Res 1990;37:109-118. 43. Deboer T, Ruijgrok G, Meijer JH. Short light-dark cycles affect sleep in mice. Eur J Neurosci 2007;26:3518-3523. 44. Palchykova S, Deboer T, Tobler I. Seasonal aspects of sleep in the Djungarian hamster. BMC Neuroscience 2003;4:9. 45. Vyazovskiy VV, Kopp C, Wigger E, et al. Sleep and rest regulation in young and old oestrogen-deficient female mice. J. Neuroendocrinol 2006;18:567-576. 46. Franken P, Tobler I, Borbély AA. Sleep homeostasis in the rat: simulation of the time course of EEG slow-wave activity [published erratum appeared in Neurosci Lett 1991;132:279]. Neurosci Lett 1991;130:141-144. 47. Deboer T, Tobler I. Sleep EEG after daily torpor in the Djungarian hamster: similarity to the effects of sleep deprivation. Neurosci Lett 1994;166:35-38. 48. Deboer T, Tobler I. Sleep regulation in the Djungarian hamster: comparison of the dynamics leading to the slow-wave activity increase after sleep deprivation and daily torpor. Sleep 2003;26:567-572. 49. Tobler I, Deboer T, Fischer M. Sleep and sleep regulation in normal and prion protein-deficient mice. J Neurosci 1997;17:18691879. 50. Vyazovskiy VV, Tobler I. Theta activity in the waking EEG is a marker of sleep propensity in the rat. Brain Res 2005;1050:64-71. 51. Mistlberger RE, Bergmann BM, Waldenar W, et al. Recovery sleep following sleep deprivation in intact and suprachiasmatic nucleilesioned rats. Sleep 1983;6:217-233. 52. Tobler I, Borbély AA, Groos G. The effect of sleep deprivation on sleep in rats with suprachiasmatic lesions. Neurosci Lett 1983;42:49-54. 53. Trachsel L, Edgar DM, Seidel WF, et al. Sleep homeostasis in suprachiasmatic nuclei-lesioned rats: effects of sleep deprivation and triazolam administration. Brain Res 1992;589:253-261. 54. Beersma DGM, Daan S, Dijk DJ. Sleep intensity and timing: a model for their circadian control. In: Carpenter G, editor. Some mathematical questions in biology: circadian rhythms. Lectures on
124 PART I / Section 2 • Sleep Mechanisms and Phylogeny mathematics in life sciences. Providence, RI: American Mathematical Society; 1987. p. 39-62. 55. Borbély AA. Sleep regulation: circadian rhythm and homeostasis. Curr Top Neuroendocrinol 1982;1:83-103. 56. Antle MC, Mistlberger RE. Circadian clock resetting by sleep deprivation without exercise in the Syrian hamster. J Neurosci 2000;20:9326-9332. 57. Deboer T, Vansteensel MJ, Detari L, et al. Sleep states alter activity of suprachiasmatic nucleus neurons. Nat Neurosci 2003;6:1086-1090. 58. Trachsel L, Tobler I, Borbély AA. Sleep regulation in rats: effects of sleep deprivation, light, and circadian phase. Am J Physiol 1986;251:R1037-R1044. 59. Vyazovskiy VV, Achermann P, Tobler I. Sleep homeostasis in the rat in the light and dark period. Brain Res Bull 2007;74:37-44. 60. Franken P, Malafosse A, Tafti M. Genetic determinants of sleep regulation in inbred mice. Sleep 1999;22:155-169. 61. Pellet J, Béraud G. Organisation nycthémérale de la veille et du sommeil chez le cobaye (Cavia porcellus): comparaisons interspécifiques avec le rat et le chat. Physiol Behav 1967;2:131-137. 62. Tobler I, Franken P. Sleep homeostasis in the guinea pig: similar response to sleep deprivation in the light and dark period. Neurosci Lett 1993;164:105-108. 63. Franken P, Lopez-Molina L, Marcacci L, et al. The transcription factor DBP affects circadian sleep consolidation and rhythmic EEG activity. J Neurosci 2000;20:617-625. 64. Naylor E, Bergmann BM, Krauski K, et al. The circadian clock mutation alters sleep homeostasis in the mouse. J Neurosci 2000;20:8138-8143. 65. Wisor JP, O’Hara BF, Terao A, et al. A role for cryptochromes in sleep regulation. BMC Neurosci 2002;3:20. 66. Franken P, Tafti M. Genetics of sleep and sleep disorders. Front Biosci 2003;8:e381-e397. 67. Ruckebusch Y. Sleep deprivation in cattle. Brain Res 1974;78: 495-499. 68. Ruckebusch Y. Un problème controversé: la perte de vigilance chez le cheval et la vache au cours du sommeil. Cah Med Vet 1970; 39:210-225. 69. Dallaire A, Ruckebusch Y. Sleep patterns in the pony with observations on partial perceptual deprivation. Physiol Behav 1974; 12:789-796. 70. Ruckebusch Y. The hypnogram as an index of adaptation of farm animals to change in their environment. Appl Anim Ethol 1975;2:3-18. 71. Oleksenko AI, Mukhametov LM, Polyakova IG, et al. Unihemispheric sleep deprivation in bottlenose dolphins. J Sleep Res 1992;1:40-44. 72. Ridgway SH. Asymmetry and symmetry in brain waves from dolphin left and right hemispheres: some observations after anesthesia, during quiescent hanging behavior, and during visual obstruction. Brain Behav Evol 2002;60:265-274. 73. Huber R, Ghilardi MF, Massimini M, et al. Local sleep and learning. Nature 2004;430:78-81. 74. Vyazovskiy VV, Tobler I. Handedness leads to interhemispheric EEG asymmetry during sleep in the rat. J Neurophysiol 2008; 99:969-975. 75. Tononi G, Cirelli C. Sleep function and synaptic homeostasis. Sleep Med Rev 2006;10:49-62. 76. Heldmaier G, Steinlechner S. Seasonal pattern and energetics of short daily torpor duration in the Djungarian hamster, Phodopus sungorus. Oecologia 1981;48:265-270. 77. Barnes BM. Freeze avoidance in a mammal: body temperatures below 0 degree C in an Arctic hibernator. Science 1989;244: 1593-1595. 78. Wang L. Energetic and field aspects of mammalian torpor: the Richardson’s ground squirrel. In Wang LCH, Hudson JW, editors. Strategies in the cold. New York: Academic Press; 1978. p. 109-145. 79. Strijkstra AM, Daan S. Sleep during arousal episodes as a function of prior torpor duration in hibernating European ground squirrels. J Sleep Res 1997;6:36-43. 80. Trachsel L, Edgar DM, Heller HC. Are ground squirrels sleep deprived during hibernation? Am J Physiol 1991;260:R1123-R1129. 81. Deboer T, Franken P, Tobler I. Sleep and cortical temperature in the Djungarian hamster under baseline conditions and after sleep deprivation. J Comp Physiol [A] 1994;174:145-155.
82. Deboer T, Tobler I. Natural hypothermia and sleep deprivation: common effects on recovery sleep in the Djungarian hamster. Am J Physiol 1996;271:R1364-R1371. 83. Berger R, Meier G. The effects of selective deprivation states of sleep in the developing monkey. Psychophysiology 1966;2: 354-371. 84. Hsieh KC, Robinson EL, Fuller CA. Sleep architecture in unrestrained rhesus monkeys (Macaca mulatta) synchronized to 24-hour light-dark cycles. Sleep 2008;31:1239-1250. 85. Pegram G, Reite M, Stephens L, et al. Prolonged sleep deprivation in the monkey: effects on sleep patterns, brain temperature and performance. In: Laboratory SAR, editor: Holloman Air Force Base, NM; 1969. p. 51-53. 86. Kiyono S, Kawamoto T, Sakakura H, et al. Effects of sleep deprivation upon the paradoxical phase of sleep in cats. Electroencephalogr Clin Neurophysiol 1965;19:34-40. 87. Takahashi Y, Ebihara S, Nakamura Y, et al. Temporal distributions of delta wave sleep and REM sleep during recovery sleep after 12-hour forced wakefulness in dogs: similarity to human sleep. Neurosci Lett 1978;10:329-334. 88. Jha SK, Coleman T, Frank MG. Sleep and sleep regulation in the ferret (Mustela putorius furo). Behav Brain Res 2006;172: 106-113. 89. Trachsel L, Tobler I, Achermann P, et al. Sleep continuity and the REM-nonREM cycle in the rat under baseline conditions and after sleep deprivation. Physiol Behav 1991;49:575-580. 90. Lydic R, McCarley RW, Hobson JA. Forced activity alters sleep cycle periodicity and dorsal raphe discharge rhythm. Am J Physiol 1984;247:R135-R145. 91. Naitoh P, Muzet A, Johnson LC, et al. Body movements during sleep after sleep loss. Psychophysiology 1973;10:363-368. 92. Tobler I, Sigg H. Long-term motor activity recording of dogs and the effect of sleep deprivation. Experientia 1986;42:987-991. 93. Rattenborg NC, Martinez-Gonzalez D, Lesku JA. Avian sleep homeostasis: convergent evolution of complex brains, cognition and sleep functions in mammals and birds. Neurosci Biobehav Rev 2009;33:253-270. 94. Tobler I, Borbély AA. Sleep and EEG spectra in the pigeon (Columba livia) under baseline conditions and after sleep deprivation. J Comp Physiol [A] 1988;163:729-738. 95. Martinez-Gonzalez D, Lesku JA, Rattenborg NC. Increased EEG spectral power density during sleep following short-term sleep deprivation in pigeons (Columba livia): evidence for avian sleep homeostasis. J Sleep Res 2008;17:140-153. 96. Jones SG, Vyazovskiy VV, Cirelli C, et al. Homeostatic regulation of sleep in the white-crowned sparrow (Zonotrichia leucophrys gambelii). BMC Neurosci 2008;9:47. 97. Rattenborg NC, Amlaner CJ, Lima SL. Unilateral eye closure and interhemispheric EEG asymmetry during sleep in the pigeon (Columba livia). Brain Behav Evol 2001;58:323-332. 98. Lendrem D. Sleeping and vigilance in birds: II. An experimental study of the Barbary dove (Streptopelia risoria). Anim Behav 1984;32:243-248. 99. Rattenborg N, Lima S, Amlaner C. Half-awake to the risk of predation. Nature 1999:397-398. 100. Weimerskirch H, Chastel O, Barbraud C, et al. Flight performance: frigatebirds ride high on thermals. Nature 2003;421:333-334. 100a. Rattenborg NC. Do birds sleep in flight? Naturwissenschaften 2006;93:413-425. Review. 101. Rattenborg NC, Mandt BH, Obermeyer WH, et al. Migratory sleeplessness in the white-crowned sparrow (Zonotrichia leucophrys gambelii). PLoS Biol 2004;2:E212. 102. Hartse KM, Rechtschaffen A. The effect of amphetamine, nembutal, alpha-methyl-tyrosine, and parachlorophenylalanine on the sleep-related spike activity of the tortoise, Geochelone carbonaria, and on the cat ventral hippocampus spike. Brain Behav Evol 1982; 21:199-222. 103. Eiland MM, Lyamin OI, Siegel JM. State-related discharge of neurons in the brainstem of freely moving box turtles, Terrapene carolina major. Arch Ital Biol 2001;139:23-36. 104. Flanigan WF Jr. Sleep and wakefulness in iguanid lizards, Ctenosaura pectinata and Iguana iguana. Brain Behav Evol 1973;8:401436. 105. Tobler I, Borbély AA. Effect of rest deprivation on motor activity of fish. J Comp Physiol [A] 1985;157:817-822.
106. Shapiro CM, Hepburn HR. Sleep in a schooling fish, Tilapia mossambica. Physiol Behav 1976;16:613-615. 107. Zhdanova IV, Wang SY, Leclair OU, et al. Melatonin promotes sleep-like state in zebrafish. Brain Res 2001;903:263-268. 108. Yokogawa T, Marin W, Faraco J, et al. Characterization of sleep in zebrafish and insomnia in hypocretin receptor mutants. PLoS Biol 2007;5:e277. 109. Cirelli C. Searching for sleep mutants of Drosophila melanogaster. Bioessays 2003;25:940-949. 110. Hendricks JC, Finn SM, Panckeri KA, et al. Rest in Drosophila is a sleep-like state. Neuron 2000;25:129-138. 111. Huber R, Hill SL, Holladay C, et al. Sleep homeostasis in Drosophila melanogaster. Sleep 2004;27:628-639. 112. Shaw P. Awakening to the behavioral analysis of sleep in Drosophila. J Biol Rhythms. 2003;18:4-11. 113. Shaw PJ, Cirelli C, Greenspan RJ, et al. Correlates of sleep and waking in Drosophila melanogaster. Science 2000;287:1834-1837. 114. Tobler I. Effect of forced locomotion on the rest-activity cycle of the cockroach. Behav Brain Res 1983;8:351-360. 115. Tobler I, Neuner-Jehle M. 24-h variation of vigilance in the cockroach Blaberus giganteus. J Sleep Res 1992;1:231-239.
CHAPTER 9 • Phylogeny of Sleep Regulation 125 116. Nitz DA, van Swinderen B, Tononi G, et al. Electrophysiological correlates of rest and activity in Drosophila melanogaster. Curr Biol 2002;12:1934-1940. 117. Greenspan RJ, Tononi G, Cirelli C, et al. Sleep and the fruit fly. Trends Neurosci 2001;24:142-145. 118. Hendricks JC, Lu S, Kume K, et al. Gender dimorphism in the role of cycle (BMAL1) in rest, rest regulation, and longevity in Drosophila melanogaster. J Biol Rhythms 2003;18:12-25. 119. Kaiser W, Steiner-Kaiser J. Neuronal correlates of sleep, wakefulness and arousal in a diurnal insect. Nature 1983;301:707-709. 120. Sauer S, Herrmann E, Kaiser W. Sleep deprivation in honey bees. J Sleep Res 2004;13:145-152. 121. Ramon F, Hernandez-Falcon J, Nguyen B, Bullock TH. Slow wave sleep in crayfish. Proc Natl Acad Sci U S A 2004;101:11857-11861. 122. Brown ER, Piscopo S, De Stefano R, et al. Brain and behavioural evidence for rest-activity cycles in Octopus vulgaris. Behav Brain Res 2006;172:355-359. 123. Raizen DM, Zimmerman JE, Maycock MH, et al. Lethargus is a Caenorhabditis elegans sleep-like state. Nature 2008;451:569-572. 124. Crocker A, Sehgal A. Genetic analysis of sleep. Genes Dev 2010;24:1220-1235.
Sleep in Animals: A State of Adaptive Inactivity Jerome M. Siegel Abstract In most adult animals sleep is incompatible with mating and feeding. Animals are believed to be vulnerable to predation during sleep. Humans frequently see sleep as an obstacle to a productive life. Many people use alarm clocks to truncate sleep and take stimulants, such as caffeine, to maintain alertness after insufficient sleep. Why do animals devote from 2 to 20 hours of the day to sleep, in what appears to be a nonproductive state? Why has evolution preserved this state? It is often said that sleep must have some unknown vital function to have persisted in all humans and throughout much, though not necessarily all,1 of the animal kingdom. Without this so far undiscovered function, it has been said that sleep would be evolution’s greatest mistake. Sleep is not a maladaptive state that needs to be explained by undiscovered functions (which nevertheless undoubtedly exist). Rather, the major function of sleep is to increase behavioral efficiency. Greater waking activity does not necessarily lead to increased numbers of viable offspring and, hence, genetic success. Rather, genetic success is closely linked to the efficient use of resources and to the avoidance of risk. Thus, inactivity can reduce predation and injury. It also reduces brain and body energy consumption. It has often been stated that energy conservation is not a sufficient explanation for
ADAPTIVE INACTIVITY Sleep should be viewed in the context of other forms of “adaptive inactivity.” Most forms of life have evolved mechanisms that permit the reduction of metabolic activity for long periods of time when conditions are not optimal. In animals, this usually includes a reduction or cessation of movement and sensory response. The development of dormant states was an essential step in the evolution of life, and it continues to be essential for the preservation of many organisms. Many species have evolved seasonal dormancy patterns that allow them to anticipate periods that are not optimal for survival and propagation (predictive dormancy). In other species dormancy is triggered by environmental conditions (consequential dormancy). Many organisms spend most of their lifespan in dormancy. A continuum of states of adaptive inactivity can be seen in living organisms including plants, unicellular and multicellular animals, and animals with and without nervous systems.3a In the plant kingdom, seeds are often dormant until the correct season, heat, moisture and pH conditions are present. One documented example of this was a lotus seed that produced a healthy tree after 1300 years of dormancy.4 More recently it was found that a seed from a 2000-yearold palm tree seed produced a viable sapling. http://news. nationalgeographic.com/news/2005/11/1122_051122_ old_seed.html. Some forms of vegetation can germinate only after fires that may come decades apart. These include the giant sequoias native to the southwest United States as well as many other species of trees and grass. Most decidu126
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sleep because the energy saved in a night’s sleep in humans is only equivalent to that contained in a slice of bread, although to the extent that sleep prevents locomotor activity the energy savings are much greater. In the wild, most animals are hungry and are seeking food most of the time they are awake. The ability of sleep to conserve energy when food is scarce will produce a major survival benefit. Conversely, if food is available but is time consuming to acquire, then it is highly advantageous for animals to be able to reduce sleep time without behavioral impairment.2 Similarly, it is highly advantageous to reduce or eliminate sleep to allow migration and to respond to certain other needs. Many have assumed that predation risk is increased during sleep, that is, that more animals are killed per hour during sleep than during waking. However there is scant evidence to support this contention.1 Most animals seek safe sleeping sites, often underground, in trees, or in groups that provide communal protection. Those large herbivores that cannot find safe sleeping sites appear to have smaller amounts of sleep and sleep less deeply, making it difficult to see how they would get the unknown benefit that sleep supposedly confers. Large animals that are not at risk for predation, such as big cats and bears, can sleep for long periods, often in unprotected sites and appear to sleep deeply.3
ous trees and plants have seasonal periods of dormancy during which they cease photosynthesis, a process called abscission. These periods of dormancy enhance plant survival by synchronizing growth to optimal conditions. Clearly this mechanism has evolved to time germination to optimal conditions, that is, not in a dry clay pot or when growth conditions will not be optimal for survival. Energy savings is not the only reason for dormancy in plants or animals. Many unicellular organisms (protozoans) have evolved to live in environments that can only sustain them for portions of the year because of changes in temperature, water availability or other factors. Their survival requires that they enter dormant states that can be reversed when optimal conditions reappear. A tiny colony of yeast trapped inside a Lebanese weevil covered in ancient Burmese amber for up to 45 million years has been brought back to life and used to brew a modern beer (http://www.foodinthefort.com/tag/ raul-cano/). Rotifers, a group of small multicellular organisms of microscopic or submicroscopic size (up to 0.5 mm long) have extended dormant periods lasting from days to months in response to environmental stresses, including lack of water or food.5,6 Parasites can become dormant within an animal’s tissues for years, emerging during periods when the immune system is compromised.7 Some invertebrate parasites also have extended dormant periods, defending themselves by forming a protective cyst.8 In some cases the cyst can only be dissolved and the parasite activated by digestive juices. Many sponges have a similar dormant state which allows
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them to survive suboptimal conditions by being encased in “gemmules.” Insect dormancy or diapause can be seasonal lasting several months, and anecdotal reports indicate that it, under some conditions, can last for several years to as long as a century.9 This can occur in an embryological, larval, pupal, or adult stage. During diapause insects are potentially vulnerable to predation, as are some sleeping animals. Passive defense strategies are employed, such as entering dormancy underground or in hidden recesses, having hard shells and tenacious attachment to substrates. In a few cases insects have evolved a vibrational defensive response which is elicited when pupae are disturbed. Land snails and slugs can secrete a mucus membrane for protection and enter a dormant state when conditions are not optimal.10 Reptiles and amphibia that live in lakes that either freeze or dry seasonally and snakes that live in environments with periods of cold or extreme heat have the ability to enter dormant states (called brumination in reptiles). These dormant periods may occur just during the cool portion of the circadian cycle or may extend for months in winter.11 In the mammalian class, a continuum of states ranging from dormancy to continuous activity can be seen. Small animals that cannot migrate long distances and live in temperate or frigid environments often survive the winter by hibernating. Some bats, many species of rodents, marsupials and insectivores hibernate. This condition is entered from, and generally terminates in, sleep periods. During hibernation, body temperature can be reduced to below 10° C to as low as −3° C with greatly reduced energy consumption.12,13 Animals are quite difficult to arouse during hibernation, with arousal taking many minutes. Consequently, hibernators are vulnerable to predation and survive hibernation by seeking protected sites. Torpor12 is another form of dormancy which can be entered by mammals and birds daily. Torpor is entered and exited through sleep and can recur in a circadian rhythm or can last for weeks or months. Animals in shallow torpor are less difficult to arouse than hibernating animals but are still unable to respond quickly when stimulated. Some other mammals such as bears have extended periods of sleep in the winter during which their metabolic rate and body temperature are reduced by 4° to 5° C,14 but they remain more responsive than animals in torpor. Sleep can be seen as a form of adaptive inactivity lying on this continuum. What is most remarkable about sleep is not the unresponsiveness or vulnerability it creates, but rather its ability to reduce activity and body and brain metabolism, but still allow a high level of responsiveness relative to the states of dormancy described previously. The often cited example of a parent arousing at a baby’s whimper but sleeping through a thunderstorm illustrates the ability of the sleeping human brain to continuously process sensory signals during the sleep period and trigger complete awakening to significant stimuli within a few hundred milliseconds. This capacity is retained despite the great reduction in brain energy consumption achieved in sleep relative to quiet waking.14a,15,16 Adolescent humans are less responsive than adults to stimuli presented during sleep, as anyone who has raised teenagers can attest. This may have been selected for by evolution, because protection from predators is provided
by older members of the family group who also tend to the nocturnal needs of infants. The inactivity of children benefits the group by reducing their relatively large portion of the food needs of the family. The continuum from adaptive inactivity to high levels of activity can be seen within the life cycle of some animals. Thus, some animals that live in climates with a pronounced seasonal reduction in food or light availability or a periodic increase in threat from predators may need to migrate to survive. Many species of birds do this as do certain species of marine mammals (discussed later). Although some may maintain circadian rhythms of activity during migration, others remain continuously active for weeks or months. Some vertebrate species do not ever appear to meet the behavioral criteria for sleep, remaining responsive, or responsive and active, throughout their lifetime.1 Humans with insomnia, who are typically not sleepy during the day despite reduced sleep at night, may be viewed as falling closer to migrating animals or short sleeping animals, in contrast to humans with sleep disturbed by sleep deprivation, sleep apnea or pain, who are sleepy during the day.17 Individuals with restless legs syndrome are similarly unlikely to be sleepy during the day despite low levels of nightly sleep. Conversely, many individuals with hypersomnia appear to need more sleep and sleep more deeply, rather than being the victims of shallow or disrupted sleep that is compensated for by extended sleep time. To summarize, evolution has produced a wide range of forms of diurnal or seasonal adaptive inactivity, some of which are accompanied by a virtual cessation of metabolism and responsiveness. Clearly, evolution rewards judicious activity, not continuous activity. Sleep is often viewed as a liability because of its reduced alertness compared to quiet waking. However, seen in the context of adaptive inactivity shown by most species, what is most notable about sleep in humans is its intermediate status, between the highly inactive unresponsive states seen in rotifers, insects, and hibernating mammals (which show little neuronal activity during hibernation), and the virtually continuous periods of activity and waking that have been seen in migrating birds and cetaceans.
QUANTITATIVE ANALYSES OF THE CORRELATES OF SLEEP DURATION An increasing number of studies have attempted to correlate the data that has been collected on sleep duration in mammals with a number of physiological and behavioral variables in order to develop hypotheses as to the function of sleep. The data these studies are based on are not ideal. Only approximately 60 mammalian species have been studied with sufficient measurements to determine the amounts of rapid eye movement (REM) and non-REM (NREM) sleep over the 24-hour period. These species are by no means a random sample of the more than 5,000 mammalian species. Rather they are species that are viable and available for study in laboratories or in some instances for noninvasive (and less accurate) studies in zoos. In laboratories, animal subjects for sleep studies are typically fed ad libitum and are on artificial light cycles at thermoneutral temperatures. These environments differ greatly from
128 PART I / Section 2 • Sleep Mechanisms and Phylogeny
those in which they evolved. Digital recording and storage technologies now exist that will enable the collection of polygraphic data on animals in their natural environment18 but they have not yet been widely used. Such observations are necessary to determine the variation in sleep times caused by hunger, response to temperature changes, predation and other variables that have driven evolution. Very few of these animals have been tested for arousal threshold, the nature and extent of sleep rebound, and other aspects of sleep whose variation across species might contribute to an understanding of sleep evolution and function. An important issue in comparing sleep times in animals is determining sleep depth. In humans we know that sleep depth, as assessed by either arousal threshold or electroencephalogram (EEG) amplitude, increases after sleep deprivation and is often greater during early stages of development when total sleep time is greatest. Can sleep time be profitably compared across animals without incorporating information on sleep depth? Should we assume that animals that sleep for longer periods also sleep more deeply as is true across human development, or should we assume the reverse, that short sleeping animals sleep more deeply as has been hypothesized?19 One of the earliest studies comparing REM and NREM sleep durations with physiological variables, found that sleep duration was inversely correlated with body mass.20,21 A subsequent analysis found that this relationship applied only to herbivores, not to carnivores or omnivores.3 This study also showed that, as a group, carnivores slept more than omnivores, who in turn slept more than herbivores (Fig. 10-1). Significant negative correlations were found between brain weight and REM sleep time (but not total sleep time). It should be emphasized that this latter correlation was extremely small, accounting for only 4% of the variance in REM sleep time between species (Fig. 10-2). The largest correlation emerging from these early studies was that between body or brain mass and the duration of the sleep cycle, that is, the time from the start of one REM sleep period to the start of the next, excluding interposed waking. This correlation accounted for as much as 80% of the variance in sleep-cycle time between animals and has held up in subsequent studies in mammals. Sleep cycle time is about 10 minutes in mice, 90 minutes in humans, and 2 hours in elephants. Another robust correlation in the Zepelin study was between adult REM sleep time and immaturity at birth, that is, animals that are born in a relatively helpless state have greater amounts of REM sleep as adults than animals born in a more mature state. Because sleep is linked to a reduction in body temperature22 and a reduction in energy usage, it has been hypothesized that energy conservation may be a function of sleep.23 Several studies have reanalyzed the phylogenetic data set with the addition of the few more recently studied animals. These studies took a variety of strategies to extract relations from this data set. Lesku et al.24 used a method of “independent contrasts” in an attempt to control for the relatedness of species being compared. They confirmed prior findings of a negative relationship between basal metabolic rate (which is correlated with body mass) and sleep time. In contrast to earlier and subsequent studies of the same data set, they reported a positive correlation
between REM sleep and relative brain mass and a negative relationship between REM sleep time and predation risk. Another recent study, confining its analysis to studies that met what they felt were more rigorous criteria, found that metabolic rate correlates negatively rather than positively with sleep quotas,25 in contrast to earlier studies.21 This result is not inconsistent with some prior work.3 They also reported that neither adult nor neonatal brain mass correlates positively with adult REM or NREM sleep times, differing from earlier studies.21,25 They find, in agreement with prior analyses, that animals with high predation risk sleep less.3,26 In keeping with the concept that there is some fixed need for an unknown function preformed only during sleep, they propose that short-sleeping species sleep more intensely to achieve this function in less time, but they present no experimental evidence for this hypothesis. A notable feature of the Lesku et al. study and the Capellini et al. studies is that both excluded animals that they decided had unusual sleep patterns. So the echidna, which combines REM and NREM features in its sleep27 was eliminated from the analysis. The platypus, which has the largest amount of REM sleep of any animal yet studied28 was also excluded from this analysis as it was from another study focusing on brain size relations.29 The dolphin and three other cetacean species and two species of manatee were excluded from the Lesku et al. study because of their low levels of REM sleep and unihemispheric slow waves. Including these species in their analyses would undoubtedly negate or reverse the positive relationship they report between brain size and REM sleep, because the platypus has the largest amount of REM sleep time of any studied animal and one of the smallest brain sizes, and the dolphin, which appears to have little or no REM sleep, has a larger brain size than humans. As I will discuss hereafter, these “unusual” species that have been excluded from prior analyses may in fact hold the most important clues to the function of sleep across species. In considering the possibility of universal functions of sleep across species, from humans to drosophila, it is important to appreciate the presence of REM and NREM sleep in birds. A recent correlational analysis of sleep parameters in birds, which paralleled the studies done in mammals, found no relationship between brain mass, metabolic rate, relative metabolic rate, maturity at birth and total sleep time or REM sleep time.30 All values for these parameters were found to be “markedly nonsignificant.” The only significant relation found was a negative correlation between predation risk and NREM sleep time (but not REM sleep time), in contrast to the relation reported previously in mammals between predation risk and REM sleep time (but not NREM sleep time). This lone significant relation explained only 27% of the variance in avian NREM sleep time. To summarize, a variety of correlation studies reach disparate and often opposite conclusions about the physiological and functional correlates of sleep time. It should be emphasized that with the exception of the strong relationship between sleep cycle length and brain and body mass, all of the “significant” correlations reported explain only a small portion of the variance in sleep parameters, throwing into question whether the correlational approach as currently used is getting at the core
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Figure 10-1 Sleep time in mammals. A, Carnivores are shown in dark red; B, herbivores are in green and C, omnivores in grey. Sleep times in carnivores, omnivores and herbivores differ significantly, with carnivore sleep amounts significantly greater than those of herbivores. Sleep amount is an inverse function of body mass over all terrestrial mammals (black line). This function accounts for approximately 25% of the interspecies variance (D) in reported sleep amounts. Herbivores are responsible for this relation because body mass and sleep time were significantly and inversely correlated in herbivores, but were not in carnivores or omnivores. Small red box in the combined figure (lower right) indicates human data point. (From Siegel JM. Clues to the function of mammalian sleep. Nature 2005;437:1264-1271.)
issues of sleep function. Despite similar genetics, anatomy, cognitive abilities and physiological functioning, closely related species can have very different sleep parameters and distantly related species can have very similar sleep parameters. Many such examples exist despite the relatively small number of species in which REM and NREM sleep time have been determined (Fig. 10-3).
THE DIVERSITY OF SLEEP On the assumption that sleep satisfies an unknown, yet universal function in all animals, recent work has been carried out on animals whose genetics and neuroanatomy is better understood and more easily manipulated than that of mammals. Much of this work has focused on the fruit fly, Drosophila melanogaster. These animals appear to meet the behavioral definition of sleep. Their response thresh-
old is elevated during periods of immobility but will rapidly “awaken” when sufficiently intense stimuli are applied. They make up for “sleep” deprivation with a partial rebound of inactivity when left undisturbed. However, major differences between the physiology and anatomy of these organisms and mammals make it difficult to transfer insights gleaned from studies of drosophila sleep to human sleep. The Drosophila brain does not resemble the vertebrate brain. Octopamine, a major sleep regulating transmitter in drosophila does not exist in mammals. Hypocretin, a major sleep regulating transmitter in mammals does not exist in Drosophila.31 Drosophila are not homeotherms, whereas thermoregulation has been closely linked to fundamental aspects of mammalian sleep.3,22,32 There is no evidence for the occurrence of a state resembling REM sleep in Drosophila. Thus the neurochemistry, neuroanatomy, and neurophysiology of sleep must necessarily differ
130 PART I / Section 2 • Sleep Mechanisms and Phylogeny BUSHTAIL POSSUM Trichosaurus vulpecula
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Figure 10-2 Sleep amount is not proportional to the relative size of the cerebral cortex or to the degree of encephalization, as illustrated by these two examples. (From Siegel JM. Clues to the function of mammalian sleep. Nature 2005;437:1264-1271.)
among Drosophila, man, and other mammals. Any commonality of sleep phenomena would have to be restricted to cellular level processes. Two recent studies have shown that drosophila sleep and sleep rebound is markedly impaired by genetic alteration of a potassium current that regulates neuronal membrane excitability.33,34 Regulation of potassium currents may be a core function of sleep or it may instead affect the excitability of circuits regulating activity and quiescence, just as such currents affect seizure susceptibility.35,36 Caenorhabditis elegans, a roundworm with a nervous system much simpler than that of Drosophila, has also been investigated for sleeplike behavior.37 C. elegans reaches adulthood in 60 hours and has periods of inactivity during this maturation called “lethargus” occurring before each of the four molts it undergoes prior to reaching maturity. Stimulation of C. elegans during the lethargus period produced a small but significant decrease in activity during the remainder of the lethargus period, but did not delay the subsequent period of activity or increase quiescence overall, phenomena that differ from the effects of sleep deprivation in mammals. It is not clear if adult C. elegans show any aspect of sleep behavior.38 Fundamental species differences in the physiology and neurochemistry of sleep have been identified even within the mammalian line. Although there are many similarities, the EEG aspects of sleep also differ considerably between humans, rats, and cats, the most studied species.39-41 Human stage 4 NREM sleep is linked to growth hormone secretion. Disruption of stage 4 sleep in children is thought to cause short stature. However, in dogs, growth hormone secretion normally occurs in waking, not sleep.42 Melatonin release is maximal during sleep in diurnal animals, but is maximal in waking in nocturnal animals.43 Erections have been shown to be present during REM sleep in humans and rats,44 however the armadillo has erections only in NREM sleep.45 Blood flow and metabolism differ dramatically between neocortical regions in adult human REM sleep,46 although most animal sleep deprivation and
sleep metabolic studies treat the neocortex as a unit. Lesions of parietal cortex and certain other regions prevent dreaming in humans, even in individuals continuing to show normal REM sleep as judged by cortical EEG, rapid eye movements and suppression of muscle tone.47 Humans before age 6 do not have dream mentation, perhaps because these cortical regions have not yet developed.48 These findings make it questionable whether nonhuman mammals that have REM sleep, all of which have cortical regions whose structure differs from that of adult humans, have dream mentation.
SLEEP IN MONOTREMES The mammalian class can be subdivided into three subclasses: placentals, marsupials, and monotremes. There are just three extant monotreme species, the short beaked and long beaked echidna and the platypus (Video 10-1). Fossil and genetic evidence indicates that the monotreme line diverged from the other mammalian lines about 150 million years ago and that both echidna species are derived from a platypus-like ancestor.49-52 The monotremes have shown a remarkably conservative evolutionary course since their divergence from the two other mammalian lines. For example, fossil teeth from Steropodon galmani dated at 110 million years ago show many similarities to the vestigial teeth of the current day platypus, Ornithorhyncus anatinus.53 Analyses of fossilized skull remains indicate remarkably little change in platypus morphology over at least 60 million years.53,54 The low level of speciation throughout the fossil record is another indicator of the uniquely conservative lineage of monotremes. The 150 million years of platypus evolution has produced no species radiation, apart from the echidna line, and there are only two living and one extinct species of echidna. Although monotremes are distinctly mammalian, they do display a number of reptilian features, making study of their physiology a unique opportunity to determine the commonalities and divergences in mammalian evolution.50,55,56
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Same phylogenetic order, different sleep times
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Golden Manteled Ground Squirrel Degu Spermophilus lateralis Octodon de gu
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Figure 10-3 Mammalian phylogenetic order is not strongly correlated with sleep parameters. Despite similar genetics and physiology, sleep times within mammalian orders overlap extensively. On the left are three pairs of animals that are in the same order but have very different sleep parameters. On the right are three pairs of animals from different orders with similar sleep amounts. Mammalian sleep times are not strongly correlated with phylogenetic order. (From Allada R, Siegel JM. Unearthing the phylogenetic roots of sleep. Curr Biol 2008;18:R670-R679.)
This phylogenetic history led to an early study of the echidna to test the hypothesis that REM sleep was a more recently evolved sleep state. No clear evidence of the forebrain low-voltage EEG that characterizes sleep was seen in this study, leading to the tentative conclusion that REM sleep evolved in placentals and marsupials after the divergence of the monotreme line from the other mammals.57 We reexamined this issue using single neuron recording techniques, in addition to the EEG measures employed in the prior studies. REM sleep is generated in the mesopontine brainstem (see Chapter 8) and is characterized by highly variable burst pause
activity of brainstem neurons. This activity is responsible for driving the rapid eye movements, twitches, and other aspects of the REM sleep. We recorded from these brainstem regions in unrestrained echidnas to see if this activation was absent throughout sleep. We found that instead of the slow, regular activity that characterizes brainstem neurons in many nuclei during NREM sleep in placental mammals,58,59 the echidna showed the irregular activity pattern of REM sleep throughout most of the sleep period (Fig. 10-4).27,60 It appeared that the brainstem was in an REM sleeplike state, whereas the forebrain was in an NREM sleep state. Other investigators
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Figure 10-4 Brainstem activation during sleep in the echidna. Instantaneous compressed rate plots of representative units recorded in nucleus reticularis pontis oralis of the cat, dog, and echidna. Each point represents the discharge rate for the previous interspike interval. In cat QW and non-REM sleep, the discharge rate is low and relatively regular. The rate increases and becomes highly variable during REM sleep. A similar pattern can be seen in a unit recorded in the dog. In the echidna, sleep is characterized by variable unit discharge rates as is seen in REM sleep, but this occurs while the cortex is showing high-voltage activity. (From Siegel JM, Manger PR, Nienhuis R, et al. The echidna Tachyglossus aculeatus combines REM and non-REM aspects in a single sleep state: implications for the evolution of sleep. J Neurosci 1996;16:3500-3506.)
also concluded that the echidna had an REM sleeplike state.61 These findings encouraged us to perform electrophysiological studies of sleep in the platypus. We found that the platypus had pronounced phasic motor activity typical of that seen in REM sleep (see video on PPSM web-site and at http://www.npi.ucla.edu/sleepresearch/media.php). This intense motor activity could occur while the forebrain EEG exhibited high-voltage activity,28 similar to the phenomena seen in the echidna. Not only was the motor activity during sleep equal to or greater in intensity than that seen in REM sleep in other animals, but also the daily amount of this REM sleep state was greater than that in any other animal. However, unlike the condition in adult placental and marsupial mammals, the signs of REM sleep were largely confined to the brainstem (Fig. 10-5). This bears some resemblance to the conditions in most mammals that are born in an immature (altricial) state, which do not show marked forebrain EEG activation during REM sleep early in life. The tentative conclusion reached in the initial studies of the echidna, that the monotremes had no REM sleep and that REM sleep was a recently evolved state, had to be reversed. It appears that a brainstem manifestation of REM sleep was most likely present in the earliest mammals, perhaps in very large amounts. It may be the brainstem quiescence of NREM sleep, and likely reduction in brain energy consumption that is the most recently evolved aspect of sleep in the mammalian line.
REINDEER Reindeer are ruminants. Like other ruminants they appear to remain active over the entire circadian cycle to an extent not seen in most carnivores and omnivores. A recent study examined the activity of two species of reindeer living in polar regions where they experience periods of continuous darkness in the winter and continuous light in the summer. Activity was monitored for an entire year. This was the
first such study and contrasts with the constant conditions of light and temperature usually employed in laboratory studies. It was found that the circadian rhythm of melatonin and circadian rhythms of behavioral activity dissipated in winter and summer. It was also reported that activity time was from 22% to 43% greater in summer than in winter (calculated from Figure 4 in van Oort and Tyler62).63 EEG recording and arousal threshold tests were not done, however, the activity changes suggest that major changes in sleep duration occur seasonally.
BIRDS Birds have REM sleep that appears physiologically very similar to that seen in mammals, although REM sleep values tend to be lower in comparison to total sleep values than in mammals.30 Many bird species migrate over long distances. The effect of this migratory behavior on sleep has been studied in the white-crowned sparrow (Zonotrichia leucophrys gambelii). These birds, even when confined in the laboratory, decrease sleep time by two thirds during the periods when they would normally be migrating.64 It should be noted that this is a common feature of cycles of adaptive inactivity; for example, a ground squirrel that normally hibernates in the winter will enter a state of torpor at the appropriate season even when maintained in a laboratory under constant conditions.65 During the migratory period, the sparrow’s learning and responding was unimpaired or improved. Their sleep was not deeper by EEG criteria than that seen when they were not migrating, despite its greatly reduced duration. Their sleep latency did not differ from that during nonmigrating periods.64 The observations in monotremes and birds suggest that the reptilian common ancestor of both mammals and birds had REM sleep or a closely related precursor state, rather than the previously advanced speculation that REM sleep must have evolved twice based on the prior conclusion that monotremes did not have REM sleep. Although there
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terrestrial mammals, although they cannot be ruled out. Animals living in marine environments may not be as strongly affected by circadian variables because their evolution has been shaped by tidal and weather features that do not adhere to 24-hour cycles.
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Figure 10-5 Brainstem REM sleep state in the platypus. Rapid eye movements and twitches can occur while the forebrain is showing a slow-wave activity pattern. EEG, EOG, EMG and EEG power spectra of samples shown of sleep–wake states in the platypus. (From Siegel JM, Manger PR, Nienhuis R, Fahringer HM, et al. Sleep in the platypus. Neuroscience 1999; 91:391-400.)
were scattered early reports claiming to have seen REM sleep in reptiles, these have not been replicated.3 We applied the same recording techniques we had used in the echidna to the turtle in a search for evidence of REM sleep. We saw no evidence of phasic brainstem neuronal activity during quiescent states in this reptile.66
WALRUS A recent study of the walrus revealed that these animals frequently become continuously active for periods of several days even when fed ad libitum and under no apparent stress.67 Such behaviors have not been reported in
SLEEP IN CETACEANS (DOLPHINS AND WHALES) REM sleep is present in all terrestrial animals that have been studied, but signs of this state have not been seen in cetaceans, which are placental mammals. These animals show only unihemispheric slow waves (USW), which can be confined to one hemisphere for 2 hours or longer. The eye contralateral to the hemisphere with slow waves is typically closed, although covering the eye is not sufficient to produce slow waves in the contralateral hemisphere.28,68 They never show persistent high voltage waves bilaterally. Sometimes they float at the surface while showing USW. However, often they swim while USW are being produced (Fig. 10-6). When they swim while having USW, there is no asymmetry in their motor activity, in contrast to the behavior seen in the fur seal. Regardless of which hemisphere is showing slow wave activity, they tend to circle in a counterclockwise direction (in the northern hemisphere69). No evidence has been presented for elevated sensory response thresholds contralateral to the hemisphere that has slow waves. Indeed it seems that a substantial elevation of sensory thresholds on one side of the body would be quite maladaptive given the danger of collisions while moving. Similarly, brain motor systems must be bilaterally active to maintain the bilaterally coordinated movement. Therefore, forebrain and brainstem sensory and motor activity must differ radically during USW from that seen in terrestrial mammals during sleep (see Chapter 8).58,59 The one study of USW rebound after USW deprivation in dolphins produced very variable results, with little or no relation between the amount of slow waves lost in each hemisphere and the amount of slow waves recovered when the animals were subsequently left undisturbed.70 In another study it was shown that dolphins are able to maintain continuous vigilance for 5 days with no decline in accuracy. At the end of this period there was no detectable decrease of activity or evidence of inattention or sleep rebound such as would be expected of a sleep deprived animal.1,71 Unihemispheric slow waves would be expected to save nearly one half of the energy consumed by the brain that is saved during bilateral slow wave sleep (BSWS).15,16 Unihemispheric slow waves are well suited to the dolphins’ group activity patterns. Because dolphins and other cetaceans swim in pods, the visual world can be monitored by dolphins on each side of the pod and the remaining dolphins merely have to maintain contact with the pod. In routine “cruising” behavior this can be done with only one eye, allowing the other eye and connected portions of the brain to reduce activity as occurs in USW. This hypothesis needs to be explored by electroencephalographic observations of groups of cetaceans in the wild. In some smaller cetaceans, such as the harbor porpoise72 and Commerson’s dolphin,73 motor activity is essentially continuous from birth to death, that is, they never float or sink to the bottom and remain still. They move rapidly and
134 PART I / Section 2 • Sleep Mechanisms and Phylogeny
1 cm
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Figure 10-6 Cetacean sleep, unihemispheric slow waves in cetaceans. Top, photos of immature beluga, adult dolphin and section of adult dolphin brain. Electroencephalogram (EEG) of adult cetaceans, represented here by the beluga, during sleep are shown. All species of cetacean so far recorded have unihemispheric slow waves. Top traces show left and right EEG activity. The spectral plots show 1- to 3-Hz power in the two hemispheres over a 12-hour period. The pattern in the cetaceans contrasts with the bilateral pattern of slow waves seen under normal conditions in all terrestrial mammals, represented here by the rat (bottom traces). (From Siegel JM. Clues to the function of mammalian sleep [review]. Nature 2005;437:1264-1271.)
it is evident that they must have accurate sensory and motor performance and associated brain activation to avoid collisions. It is difficult to accept this behavior as “sleep” without discarding all aspects of the behavioral definition of sleep.1
All studied land mammals have been reported to show maximal sleep and maximal immobility at birth, leading to the conclusion that sleep is required for brain and body development. However, newborn killer whales and dolphins are continuously active. In captivity, they swim in
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tight formation and turn several times a minute to avoid conspecifics in the pool and pool walls. During this period the calves learn to nurse, breathe and swim efficiently. Although some USWs might be present at these times, the eyes are open bilaterally when they surface at average intervals of less than 1 minute, indicating that any slow wave pattern could not last longer than this period.74 Sleep interruption at such intervals can be lethal to rats,75 and human sleep is not restorative if interrupted on such a schedule.76 The cetacean mothers also cease eye closure at the surface and floating behavior and are continuously active during the postpartum period. No loss of alertness is apparent during the “migratory” period. In the wild, mother and calf migrate together, typically for thousands of miles from calving to feeding grounds. Sharks, killer whales, and other predatory animals target the migrating calves and a high level of continuous alertness is necessary for both mother and calf during migration. One could describe the maternal and neonatal pattern as “sleep” with well coordinated motor activity, accurate sensory processing, effective response to threats in the environment, and without the likelihood of any EEG slow waves or eye closure lasting more than 60 seconds.77,78 However, this does not comport with the accepted behavioral definition of sleep.79 Thus both cetaceans and migrating birds greatly reduce sleep time during migrations without any sign of degradation of physiological functions, sluggishness, loss of alertness, or impairment of cognitive function.
SLEEP IN OTARIIDS (EARED SEALS) On land, sleep in the fur seal generally resembles that in most terrestrial mammals. The EEG is bilaterally synchronized and the animal closes both eyes, appears unresponsive and cycles between REM and NREM sleep. In contrast, when the fur seal is in the water, it usually shows an asymmetrical pattern of behavior with one of the flippers being active in maintaining body position, while the other flipper is inactive. The fur seal can have slow waves in one hemisphere with the contralateral eye being closed. The other eye is generally open or partially open (Fig. 10-7). Therefore, it appears that half of the brain and body may be “asleep” and the other half “awake.” A microdialysis study showed that during asymmetrical sleep, the waking hemisphere has significantly higher levels of acetylcholine release than the sleeping hemisphere.80 SLEEP REBOUND Sleep rebound is not always seen. When the fur seal goes in the water for extended periods, as they do in winter, REM sleep time is greatly reduced. There is little or no rebound of lost REM sleep when the fur seal returns to land, even after several weeks in the water.81 In the cases of the dolphins and killer whales mentioned previously, a near total abolition of sleep for periods of several weeks during migration is followed by a slow increase back to baseline levels with no rebound. The same phenomenon is seen in migrating white sparrows, a species that has been carefully studied under laboratory conditions.64 Manic humans greatly reduce sleep time for extended periods, and there is no persuasive evidence for progressive degra-
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“Sleeping” “Waking” Figure 10-7 Fur seal sleep. On land fur seals usually sleep like terrestrial mammals, with bilateral EEG synchrony and REM sleep (not shown in the figure). However, when in water they typically show asymmetrical slow-wave sleep, with a sleeplike EEG in one hemisphere while the other hemisphere has a wakinglike EEG. Unlike the dolphin, the asymmetrical EEG of the fur seal is accompanied by asymmetrical posture and motor activity, with the flipper contralateral to the hemisphere with lowvoltage activity used to maintain the animal’s position in the water while the other flipper and its controlling hemisphere “sleep.”
dation of performance, physiological function, or sleep rebound during this period. Zebrafish can be completely deprived of sleep for three days by placing them in continuous light, but show no rebound when returned to a 12-12 light–dark cycle.82 On the other hand, when they are deprived by repetitive tactile stimulation they do show rebound. Typically 30% or less of lost sleep is recovered in the human and rodent studies, in which the phenomenon has been most extensively studied. A similar percent of rebound is seen in other species including some invertebrates (see Chapter 9). One may ask why, if sleep is essentially a maladaptive state, animals that have the ability to regain lost sleep in 30% of the time it would normally have taken have not evolved shorter sleep times to take advantage of the adaptive benefits of increased waking. However, if sleep is viewed as a form of “adaptive inactivity,” then this paradox vanishes. A small sleep rebound may be necessary to compensate for processes that can only occur, or occur optimally, in sleep, but most sleep time is determined in each species by the evolved trade-offs between active waking and adaptive inactivity. The variation in rebound within and across species needs to be more carefully studied. Some aspects of
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rebound have been shown to be due to the deprivation procedure rather than the sleep loss. For example stressing rats by restraint can produce increased REM sleep even when no sleep has been lost. This is mediated by the release of pituitary hormones.83,84 It is possible that in some species other aspects of rebound are driven by hormonal release linked to sleep rather than by some intrinsic property of sleep.
CONCLUSION Sleep can be seen as an adaptive state, benefiting animals by increasing the efficiency of their activity. Sleep does this by suppressing activity at times that have maximal predator risk and permitting activity at times of maximal food and prey availability and minimal predator risk. It also increases efficiency by decreasing brain and body metabolism. However, unlike the dormant states employed in plants, simple multicellular organisms, and ectothermic organisms, and the hibernation and torpor employed in some mammals and birds, sleep allows rapid arousal for tending to infants, dealing with predators, and responding to environmental changes. A major function of REM sleep may be to allow this rapid response by periodic brainstem activation. Many organisms can reduce sleep for long periods of time without rebound during periods of migration or other periods in which a selective advantage can be obtained by continuous waking. The big brown bat specializes in eating mosquitoes and moths that are active from dusk to early evening. The big brown bat typically is awake only about 4 hours a day.21 Not surprisingly, this waking is synchronized to the period when flies are active. It is not likely that this short waking period, one of the shortest yet observed, can be explained by the need for some time consuming unknown process that occurs only during sleep and requires 20 hours to complete. It can be more easily explained by the ecological specializations of this bat. Similarly sleep in ectothermic animals is most likely determined by temperature and other environmental variables, rather than any information processing or physiological maintenance requirement. An approach that takes the environmental conditions in which each species evolved into account can better explain the variance in sleep time between mammals. Many vital processes occur in both waking and sleep including recovery of muscles from exertion, control of blood flow, respiration, growth of various organs and digestion. Some may occur more efficiently in sleep, but can also occur in waking. It is highly probable that some functions have migrated into or out of sleep in various animals. Recent work has suggested that neurogenesis,85 synaptic downscaling,86 immune system activation87 and reversal of oxidative stress88,89 may be accomplished in sleep in mammals. It remains to be seen if these or any other vital functions can only be performed in sleep. However, this review of the phylogenetic literature suggests that such functions cannot explain the variation of sleep amounts and the evident flexibility of sleep physiology within and between animals. Viewing sleep as a period of well-timed adaptive inactivity that regulates behavior may better explain this variation.
Further relevant literature can be found at http://www. semel.ucla.edu/sleepresearch. ❖ Clinical Pearl Although sleep and sleep stages differ in amount between species, human sleep does not appear to be qualitatively unique. This factor makes animal models suitable for the investigation of many aspects of pharmacology and pathology.
Acknowledgment Supported by NIH, NSF, and the Department of Veterans Affairs. Portions of this review have appeared in prior reviews by the author. REFERENCES 1. Siegel JM. Do all animals sleep? Trends Neurosci 2008;31(4): 208-213. 2. Jacobs BL, McGinty DJ. Effects of food deprivation on sleep and wakefulness in the rat. Exp Neurol 1971;30:212-222. 3. Siegel JM. Clues to the functions of mammalian sleep [review]. Nature 2005;437:1264-1271. 3a. Siegel JM. Sleep viewed as a state of adaptive inactivity. Nat Rev Neurosci 2009;10:747-753. 4. Shen-Miller J, Schopf JW, Harbottle G, et al. Long-living lotus: germination and soil γ-irradiation of centuries-old fruits, and cultivation, growth, and phenotypic abnormalities of offspring. Am J Bot 2002;89:236-247. 5. Caprioli M, Santo N, Ricci C. Enhanced stress resistance of dormant bdelloids (rotifera). J Gravit Physiol 2002;9:235-236. 6. Ricci C, Caprioli M, Fontaneto D. Stress and fitness in parthenogens: is dormancy a key feature for bdelloid rotifers? BMC Evol Biol 2007;7(Suppl. 2):S9. 7. Di Cristina M, Marocco D, Galizi R, et al. Temporal and spatial distribution of toxoplasma gondii differentiation into bradyzoites and tissue cyst formation in vivo. Infect Immun 2008;76:3491-3501. 8. Pozio E. Foodborne and waterborne parasites. Acta Microbiol Pol 2003;52(Suppl):83-96. 9. Brusca RC, Brusca GJ. Invertebrates. Sunderland, Mass: Sinauer Associates; 1990. 10. Li D, Graham LD. Epiphragmin, the major protein of epiphragm mucus from the vineyard snail, Cernuella virgata. Comp Biochem Physiol B Biochem Mol Biol 2007;148:192-200. 11. Krohmer RW, Bieganski GJ, Baleckaitis DD, et al. Distribution of aromatase immunoreactivity in the forebrain of red-sided garter snakes at the beginning of the winter dormancy. J Chem Neuroanat 2002;23:59-71. 12. Swoap SJ. The pharmacology and molecular mechanisms underlying temperature regulation and torpor. Biochem Pharmacol 2008;76 (7):817-824. 13. Geiser F. Reduction of metabolism during hibernation and daily torpor in mammals and birds: temperature effect or physiological inhibition? J Comp Physiol 1988;158:25-37. 14. Hissa R, Siekkinen J, Hohtola E, et al. Seasonal patterns in the physiology of the European brown bear (Ursus arctos arctos) in Finland. Comp Biochem Physiol A Physiol 1994;109:781-791. 14a. Webb WB. Sleep as an adaptive response. Percep Motor Skills 1974;38:1023-1027. 15. Nofzinger EA, Nissen C, Germain A, et al. Regional cerebral metabolic correlates of WASO during NREM sleep in insomnia. J Clin Sleep Med 2006;2:316-322. 16. Raichle ME, Mintun MA. Brain work and brain imaging. Annu Rev Neurosci 2006;29:449-476. 17. Kryger MH, Roth T, Dement WC. Principles and practice of sleep Medicine. 4th ed. Philadelphia: Elsevier Saunders; 2005. 18. Rattenborg NC, Voirin B, Vyssotski AL, et al. Sleeping outside the box: electroencephalographic measures of sleep in sloths inhabiting a rainforest. Biol Lett 2008;4:402-405.
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19. Capellini I, Nunn CL, McNamara P, et al. Energetic constraints, not predation, influence the evolution of sleep patterning in mammals. Function Ecol 2008;22:847-853. 20. Zepelin H, Rechtschaffen A. Mammalian sleep, longevity and energy metabolism. Brain Behav Evol 1974;10:425-470. 21. Zepelin H, Siegel JM, Tobler I. Mammalian sleep. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. 4 ed. Philadelphia: Elsevier Saunders; 2005. p. 91-100. 22. McGinty D, Szymusiak R. Keeping cool: a hypothesis about the mechanisms and functions of slow-wave sleep. Trends Neurosci 1990;13:480-487. 23. Berger RJ, Phillips NH. Energy conservation and sleep. Behav Brain Res 1995;69:65-73. 24. Lesku JA, Roth TC, Amlaner CJ, et al. A phylogenetic analysis of sleep architecture in mammals: the integration of anatomy, physiology, and ecology. Am Nat 2006;168:441-453. 25. Capellini I, Barton RA, McNamara P, et al. Phylogenetic analysis of the ecology and evolution of mammalian sleep. Evolution 2008;62: 1764-1776. 26. Allison T, Cicchetti DV. Sleep in mammals: ecological and constitutional correlates. Science 1976;194:732-734. 27. Siegel JM, Manger P, Nienhuis R, et al. The echidna Tachyglossus aculeatus combines REM and nonREM aspects in a single sleep state: implications for the evolution of sleep. J Neurosci 1996;16: 3500-3506. 28. Siegel JM, Manger PR, Nienhuis R, et al. Sleep in the platypus. Neuroscience 1999;91(1):391-400. 29. Savage VM, West GB. A quantitative, theoretical framework for understanding mammalian sleep. Proc Natl Acad Sci U S A 2007; 104:1051-1056. 30. Roth TC, Lesku JA, Amlaner CJ, Lima SL. A phylogenetic analysis of the correlates of sleep in birds. J Sleep Res 2006;15(4): 395-402. 31. Allada R, Siegel JM. Unearthing the phylogenetic roots of sleep. Curr Biol 2008;18:R670-R679. 32. Rechtschaffen A, Bergmann BM, Everson CA, et al. Sleep deprivation in the rat. X. Integration and discussion of findings. Sleep 1989;12:68-87. 33. Cirelli C, Bushey D, Hill S, et al. Reduced sleep in Drosophila Shaker mutants. Nature 2005;434:1087-1092. 34. Koh K, Joiner WJ, Wu MN, et al. Identification of SLEEPLESS, a sleep-promoting factor. Science 2008;321:372-376. 35. Gargus JJ. Ion channel functional candidate genes in multigenic neuropsychiatric disease. Biol Psychiatry 2006;60:177-185. 36. Steinhäuser C, Seifert G. Glial membrane channels and receptors in epilepsy: impact for generation and spread of seizure activity. Eur J Pharmacol 2002;447:227-237. 37. Raizen DM, Zimmerman JE, Maycock MH, et al. Lethargus is a Caenorhabditis elegans sleep-like state. Nature 2008;451:569-572. 38. Zimmerman JE, Naidoo N, Raizen DM, et al. Conservation of sleep: insights from non-mammalian model systems. Trends Neurosci 2008;31(7):371-376. 39. Bergmann BM, Winter JB, Rosenberg RS, et al. NREM sleep with low-voltage EEG in the rat. Sleep 1987;10:1-11. 40. Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Public Health Service. Washington, DC: US Government Printing Service; 1968, p. 52. 41. Sterman MB, Knauss T, Lehmann D, et al. Circadian sleep and waking patterns in the laboratory cat. Electroencephalogr Clin Neurophysiol 1965;19:509-517. 42. Takahashi Y, Ebihara S, Nakamura Y, et al. A model of human sleeprelated growth hormone secretion in dogs: effects of 3, 6, and 12 hours of forced wakefulness on plasma growth hormone, cortisol, and sleep stages. Endocrinology 1981;109:262-272. 43. Redman JR. Circadian entrainment and phase shifting in mammals with melatonin. J Biol Rhythms 1997;12(6):581-587. 44. Hirshkowitz M, Schmidt MH. Sleep-related erections: clinical perspectives and neural mechanisms. Sleep Med Rev 2005;9:311-329. 45. Affanni JM, Cervino CO, Marcos HJ. Absence of penile erections during paradoxical sleep. Peculiar penile events during wakefulness and slow wave sleep in the armadillo. J Sleep Res 2001;10:219228. 46. Braun AR, Balkin TJ, Wesensten NJ, et al. Dissociated pattern of activity in visual cortices and their projections during human rapid eye movement sleep. Science 1998;279:91-95.
47. Solms M. Dreaming and REM sleep are controlled by different brain mechanisms. Behav Brain Sci 2000;23:843-850. 48. Foulkes D. Home and laboratory dreams: four empirical studies and a conceptual reevaluation. Sleep 1979;2:233-251. 49. Clemens WA. Diagnosis of the class mammalia. In: Walton DW, Richardson BJ, editors. Fauna of Australia. 1B ed. Canberra: Australian Government Publishing; 1989. p. 401-406. 50. Westerman M, Edwards D. DNA hybridization and the phylogeny of monotremes. In: Augee M, editor. Platypus and echidnas. Mosman: Royal Zoological Society of NSW; 1992. p. 28-34. 51. Flannery TF. Origins of the Australo-Pacific mammal fauna. Aust Zool Rev 1989;1:15-24. 52. Warren WC, Hillier LW, Marshall Graves JA, et al. Genome analysis of the platypus reveals unique signatures of evolution. Nature 2008;453:175-183. 53. Archer M, Jenkins F, Hand S, et al. Description of the skull and non-vestigial dentition of a miocene platypus (Obdurodon dicksoni n. sp.) from Riversleigh, Australia, and the problem of monotreme origins. In: Augee M, editor. Platypus and echidnas. Mosman, Australia: Royal Zoological Society of NSW; 1992. p. 15-27. 54. Pascual R, Archer M, Ortiz J, Hand S. The first non-Australian monotreme: an early paleocene South American platypus (monotremata, ornithorhynchidae). In: Augee M, editor. Platypus and echidnas. Mosman, Australia: Royal Zoological Society of NSW; 1992. p. 1-14. 55. Griffiths M. The biology of the monotremes. New York: Academic Press; 1978. p. 367. 56. Kemp T. Mammal-like reptile and the origin of mammals. London: Academic Press; 1982. pp. 1-363. 57. Allison T, Van Twyver H, Goff WR. Electrophysiological studies of the echidna, Tachyglossus aculeatus. I. Waking and sleep. Arch Ital Biol 1972;110:145-184. 58. Siegel JM, Tomaszewski KS. Behavioral organization of reticular formation: studies in the unrestrained cat. I. Cells related to axial, limb, eye, and other movements. J Neurophysiol 1983;50: 696-716. 59. Siegel JM, Tomaszewski KS, Wheeler RL. Behavioral organization of reticular formation: studies in the unrestrained cat. II. Cells related to facial movements. J Neurophysiol 1983;50:717-723. 60. Siegel JM, Manger P, Nienhuis R, et al. Novel sleep state organization in the echidna: implications for the evolution of REM and nonREM sleep. Soc Neurosci Abstr 1994;20:1218. 61. Nicol SC, Andersen NA, Phillips NH, et al. The echidna manifests typical characteristics of rapid eye movement sleep. Neurosci Lett 2000;283:49-52. 62. van Oort BE, Tyler NJ, Gerkema MP, et al. Where clocks are redundant: weak circadian mechanisms in reindeer living under polar photic conditions. Naturwissenschaften 2007;94(3):183-194. 63. van Oort BE, Tyler NJ, Gerkema MP, et al. Circadian organization in reindeer. Nature 2005;438:1095-1096. 64. Rattenborg NC, Mandt BH, Obermeyer WH, et al. Migratory sleeplessness in the white-crowned sparrow (Zonotrichia leucophrys gambelii). PLoS Biol 2004;2:E212. 65. O’Hara BF, Watson FL, Srere HK, et al. Gene expression in the brain across the hibernation cycle. J Neurosci 1999;19:37813790. 66. Eiland MM, Lyamin OI, Siegel JM. State-related discharge of neurons in the brainstem of freely moving box turtles, Terrapene carolina major. Arch Ital Biol 2001;139:23-36. 67. Lyamin OI, Kosenko P, Lapierre JL, et al. Study of sleep in a walrus. Sleep 2008;A24-A25. 68. Lyamin OI, Mukhametov LM, Siegel JM. Relationship between sleep and eye state in cetaceans and pinnipeds. Arch Ital Biol 2004;142:557-568. 69. Stafne GM, Manger PR. Predominance of clockwise swimming during rest in Southern Hemisphere dolphins. Physiol Behav 2004;82:919-926. 70. Oleksenko AI, Mukhametov LM, Polykova IG, et al. Unihemispheric sleep deprivation in bottlenose dolphins. J Sleep Res 1992;1: 40-44. 71. Ridgway S, Carder D, Finneran J, et al. Dolphin continuous auditory vigilance for five days. J Exp Biol 2006;209(Pt 18):3621-3628. 72. Mukhametov LM. Sleep in marine mammals. Exp Brain Res 2007;8:227-238. 73. Mukhametov LM, Lyamin OI, Shpak OV, et al. Swimming styles and their relationship to rest and activity states in captive Commerson’s
138 PART I / Section 2 • Sleep Mechanisms and Phylogeny dolphins. Proceedings of the 14th Biennial Conference on the Biology of Marine Mammals, Vancouver, British Columbia, Nov 27-Dec 3, 2002;152. 74. Lyamin O, Pryaslova J, Lance V, et al. Animal behaviour: continuous activity in cetaceans after birth. Nature 2005;435:1177. 75. Rechtschaffen A, Bergmann BM. Sleep deprivation in the rat: an update of the 1989 paper. Sleep 2002;25:18-24. 76. Bonnet MH: Sleep deprivation. In: Kryger MH, Roth T, Dement WC, editors. Principles and practices of sleep medicine. 3rd ed. Philadelphia: Saunders; 2000, p. 53-71. 77. Sekiguchi Y, Arai K, Kohshima S. Sleep behaviour: sleep in continuously active dolphins. Nature 2006;441:E9-E10. 78. Gnone G, Moriconi T, Gambini G. Sleep behaviour: activity and sleep in dolphins. Nature 2006;441:E10-E11. 79. Lyamin OI, Pryaslova J, Lance V, et al. sleep behaviour: sleep in continuously active dolphins. Activity and sleep in dolphins (Reply). Nature 2006;441:E11. 80. Lapierre JL, Kosenko PO, Lyamin OI, et al. Cortical acetylcholine release is lateralized during asymmetrical slow-wave sleep in northern fur seals. J Neurosci 2007;27:1999-2006. 81. Lyamin OI, Oleksenko AI, Polyakova IG, et al. Paradoxical sleep in northern fur seals in water and on land. J Sleep Res 1996;5 (Supp. l):130.
82. Yokogawa T, Marin W, Faraco J, et al. Characterization of sleep in zebrafish and insomnia in hypocretin receptor mutants. PLoS Biol 2007;5:2379-2397. 83. Zhang JX, Valatx JL, Jouvet M. Hypophysectomy in monosodium glutamate-pretreated rats suppresses paradoxical sleep rebound. Neurosci Lett 1988;86:94-98. 84. Rampin C, Cespuglio R, Chastrette N, et al. Immobilization stress induces a paradoxical sleep rebound in rat. Neurosci Lett 1991; 126:113-118. 85. Guzman-Marin R, Suntsova N, Bashir T, et al. Rapid eye movement sleep deprivation contributes to reduction of neurogenesis in the hippocampal dentate gyrus of the adult rat. Sleep 2008;31:167-175. 86. Vyazovskiy VV, Cirelli C, Pfister-Genskow M, et al. Molecular and electrophysiological evidence for net synaptic potentiation in wake and depression in sleep. Nat Neurosci 2008;11:200-208. 87. Opp MR. Sleep and psychoneuroimmunology. Neurol Clin 2006;24: 493-506. 88. Eiland MM, Ramanathan L, Gulyani S, et al. Increases in aminocupric-silver staining of the supraoptic nucleus after sleep deprivation. Brain Res 2002;945:1-8. 89. Ramanathan L, Gulyani S, Nienhuis R, et al. Sleep deprivation decreases superoxide dismutase activity in rat hippocampus and brainstem. Neuroreport 2002;13:1387-1390.
Genetics of Sleep Fred W. Turek 11 Introduction 12 Circadian Clock Genes 13 Genetics of Sleep in a Simple Model Organism: Drosophila
15 Genetic Basis of Sleep in Healthy
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Humans 16 Genetics of Sleep and Sleep Disorders in Humans
14 Genetic Basis of Sleep in Rodents
Introduction Fred W. Turek
The inclusion for the first time of a specific Section on genetics in Principles and Practice of Sleep Medicine is a heralding event as it signifies that the study of the genetic control of the sleep–wake cycle is becoming an important approach for understanding not only the regulatory mechanisms underlying the regulation of sleep and wake but also for elucidating the function of sleep. Indeed, as genetic approaches are being used for the study of sleep in diverse species from flies to mice to humans (see Chapters 13 to 16), the evolutionary significance for the many functions of sleep that have evolved over time are becoming a tractable subject for research, as many researchers are bringing the tools of genetics and genomics to the sleep field. The complexity of the sleep–wake phenotypes and the difficulty in collecting phenotypic data on a large enough number of animals and humans to begin to unravel genetic mechanisms has in part been responsible for why few comprehensive attempts have been made to identify “sleep genes” beyond the circadian clock genes regulating the timing of sleep (see Chapter 12). As noted by Landolt and Dijk (Chapter 15), sleep is a rich phenotype that can be broken down into a wide variety of sleep–wake traits based on the electroencephalogram (EEG) and the electromyogram (EMG).1 Furthermore, the genetic landscape for regulating multiple sleep–wake traits is clearly going to involve hundreds of genes and integrated molecular neurobiological networks.2 The fact that the environment also can have major effects on sleep– wake traits, particularly sleep duration in humans, also makes it difficult to uncover the underlying genetic control mechanisms. Indeed, while a large number of genomewide association studies in humans have identified multiple genetic loci and genes involved in regulating a wide variety of physiologic systems and disease states, only a single relatively small and inconclusive genome-wide association study has been undertaken for sleep–wake traits in humans.3 A great deal of progress has been made in elucidating a number of circadian clock genes that regulate the diurnal timing of the sleep–wake cycle as well as most, if not
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all, of 24-hour behavioral, physiologic, and cellular rhythms of the body. The simplicity and ease of monitoring a representative “output rhythm” of the central circadian clock from literally thousands of rodents in a single laboratory, such as the precise rhythm of wheel running in rodents, was a major factor in uncovering the molecular transcriptional and translational feedback loops that give rise to 24-hour output signals.4,5 There is now substantial evidence demonstrating that deletion or mutations in many canonical circadian clock genes can lead to fundamental changes in other sleep–wake traits including the amount of sleep and the response to sleep deprivation.6 Indeed, as discussed in the Chapter 14, one can argue that many circadian clock genes are also “sleep genes.” Another reason for the successful identification since the 1990s of the core clock genes in mammals is the remarkable conservation of the major clock genes from flies to mice to humans. Thus, core clock genes identified in flies, which involved mutagenesis and the screening of thousands of flies for mutant phenotypes, eventually led to finding the same genes in mice and humans. The relatively recent search for sleep genes in flies has been an active area of study since only about the turn of the century, and this approach is expected to uncover new sleep-related genes that will have mammalian orthologues. Indeed, the recent finding that different alleles of a core circadian gene, per, first indentified in flies, can affect the homeostatic response to sleep deprivation and the amount of slow-wave sleep (Chapter 15) argues that uncovering sleep genes in flies will directly lead to the genes underlying the changes in sleep–wake traits in mammals. Early studies by Valtex and colleagues on inbred strains of mice7 and early human twin studies8 provided considerable evidence for a strong genetic basis for some sleep– wake traits, but little has been done to unravel the complex network of genetic interactions that must underlie this universal behavior in mammals. Tafti, Franken, and colleagues pioneered the use of quantitative trait loci in 139
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recombinant inbred mouse strains, which has led to the identification of a small number of genes that are associated with specific sleep–wake properties.9 More recently, the first attempt to record sleep in a large genetically segregating population of mice revealed considerable complexity to the genetic landscape for multiple sleep–wake traits.2 Using 2310 informative single-nucleotide polymorphisms, and assessing 20 sleep–wake traits in 269 mice from a genetically segregating population, led to the identification of 52 significant quantitative trait loci representing a minimum of 20 distinct genomic regions.2 Because this study involved only two inbred mouse strains contributing to the genetic diversity, it can be expected that many other loci will be identified once sleep is recorded in the offspring of different crosses of inbred and outbred mouse strains. Uncovering these loci, and understanding how interactions between genes and environment contribute to different sleep–wake states, is expected to not only reveal the molecular events underlying the sleep–wake cycle but also to yield new targets for drug discovery. New therapies based on the genetic control of sleep may be particularly important for treating genetic-based disorders of sleep (Chapter 16).
REFERENCES 1. Tucker AM, Dinges DF, Van Dongen HPA. Trait interindividual differences in the sleep physiology of healthy young adults. J Sleep Res 2007;16:170-180. 2. Winrow CJ, Williams D, Kasarskis A, Millstein J, et al. Uncovering the genetic landscape for multiple sleep–wake traits. PLoS One 2009; 4(4):e5161. 3. Gottlieb DJ, O’Connor GT, Wilk JB. Genome-wide association of sleep and circadian phenotypes. BMC Med Genet 2007;8(Suppl 1:59). 4. Vitaterna MH, King DP, Chang AM, Kornhauser JM, et al. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 1994;264(5159):719-725. 5. King DP, Zhao Y, Sangoram AM, Wilsbacher LD, et al. Positional cloning of the mouse circadian clock gene. Cell 1997;89(4):641653. 6. Naylor E, Bergmann BM, Krauski K, Zee PC, et al. The circadian Clock mutation alters sleep homeostasis in the mouse. J Neuroscience 2000;20(21):8138-8143. 7. Valatx JL, Bugat R, Jouvet M. Genetic studies of sleep in mice. Nature 1972 ;238(5361):226-227. 8. Linkowski P, Spiegel K, Kerkhofs M, L’Hermite-Balériaux M, et al. Genetic and environmental influences on prolactin secretion during wake and during sleep. Am J Physiol 1998;274(5 Pt 1):E909E919. 9. Franken P, Chollet D, Tafti M. The homeostatic regulation of sleep need is under genetic control. J Neurosci 2001;21(8):2610-2621.
Circadian Clock Genes Martha Hotz Vitaterna and Fred W. Turek Abstract Circadian (near 24-hour) rhythms can be produced by individual mammalian cells in a self-sustaining manner. These rhythms result from coordinated daily oscillations in the transcription and translation of several clock-component genes. In mammals, central to the generation of these cycles are the levels of the proteins PER and CRY, which feed back to inhibit transcription of their own genes. This inhibition is exerted on the enhancement of transcription that results from binding of the CLOCK and BMAL1 proteins to E-box elements of the promoter regions of the Per and Cry genes. These four genes are thought to form the core feedback loop of the time-keeping mechanism. Additional interactions between the protein products of these genes, as well as other proteins, appear to add to the complexity of the circadian system. The phosphorylation of
Since the 1980s, remarkable progress has been made in elucidating the molecular substrates that underlie the generation of 24-hour rhythms in mammals. A major finding that has arisen since the turn of the 21st century is that most cells and tissues of the body contain and express the core 24-hour molecular clock mechanism. Although the circadian rhythm is normally coordinated, individual tissues and cells are capable of producing sustained rhythms in isolation. These rhythms are the result of oscillations of expression of a core set of interrelated circadian genes. This chapter describes the genes expressed in cells of the hypothalamic suprachiasmatic nucleus and other oscillators and our understanding of the roles they play in this daily rhythmicity. In addition, in view of the homology of mammalian clock genes with those in the fly, where appropriate, a discussion of the discovery of fly and mammalian genes is provided.
THE MAMMALIAN CELLULAR CIRCADIAN CLOCK Several lines of evidence pointed to the suprachiasmatic nucleus (SCN) as the site of the master circadian pacemaker beginning in the 1970s. Destruction of the SCN abolishes circadian oscillations in the plasma concentration of cortisol1 and in locomotion and drinking.2 These oscillations are independent of inputs from the eye,1 although an autonomous circadian clock has been demonstrated to exist within the eye that controls, among other functions, the shedding of rod outer segment disks.3 Normal circadian rhythms can be restored to an SCN-lesioned animal by transplantation of fetal SCN tissue but not by transplantation of fetal tissue from other regions of the brain.4 Transplant into an SCN-lesioned animal of fetal tissue from the SCN of a circadian mutant animal confers the short period of the donor,5 indicating that the properties of the rhythm are determined by the SCN rather than
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PER by casein kinase α (CKIα) can lead to its degradation, and the association with BMAL1 appears needed for CLOCK to be present in the nucleus. Rhythmic transcription of Bmal1 appears to result from regulation via the protein REV-ERBα, its transcription regulated by CLOCK-BMAL1 binding to E-box elements. Furthermore, Bmal1 and other clock genes are involved in the transcriptional regulation of important metabolic genes, such as Rev-erbα, providing direct molecular links between the circadian clock and metabolic regulatory pathways. Finally, it appears that rhythms in histone acetylation contribute to the circadian expression pattern of some core circadian genes, raising the intriguing possibility that circadian rhythms at other functional levels may contribute to the genetic clockwork. Additional genes have been identified based on altered circadian rhythms in mutants, although the precise roles of these genes in the circadian system remain to be determined.
other tissues or brain regions. Thus, several lines of evidence point to the SCN as the site driving or controlling circadian behavior for mammals. Recent studies of rhythms in gene expression have indicated that persistent rhythms can be observed in tissues throughout the organism, even in tissue explants kept in culture for extended periods of time.6,7 The phase of these peripheral tissue rhythms differs from that of the SCN, but nonetheless it appears to be coordinated by the SCN. In SCN-lesioned animals, these peripheral rhythms persist but no longer exhibit the consistent phase seen in unlesioned animals.7 Some environmental manipulations, such as temperature cycles or restricted feeding, can alter the phase of peripheral rhythms.8,9 In addition, studies confirm the presence of oscillations in gene expression throughout the body, with different phases in different tissues.10-13 Loss of many of these rhythms is reported with SCN lesions. However, these studies cannot discriminate between a loss of rhythmicity by individual animals and a loss of synchronicity among the individuals. Thus the roles of the SCN and of the peripheral oscillators in the mammalian circadian system continue to be defined.
CIRCADIAN CLOCK PROPERTIES AND CLOCK GENES Half a century ago, the formal properties of the circadian clock function had been well defined. Included among the 16 “empirical generalizations about circadian rhythms” defined by Colin Pittendrigh14 were that circadian rhythms are ubiquitous in living systems; they are endogenous; they are innate, they are not learned from or impressed by the environment; they occur autonomously at both cell and whole-organism levels of organization; the free-running period of circadian rhythms are so slightly temperaturedependent that it is proper to emphasize their near independence of temperature; and they are surprisingly 141
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intractable to chemical perturbation. These six observations already suggested what we now know to be the case: A cell-autonomous program of gene expression makes up the mammalian circadian clock that produces these rhythms. How do individual cells generate rhythmic activity with a period of about 1 day? Many pacemaker neurons generate oscillatory activity, such as rhythmic patterns of action potentials, and these relatively rapid oscillations can be explained by the concerted action of a small number of ion channels. However, the much slower oscillations of the individual SCN neurons are not likely to involve the same mechanisms. Pittendrigh’s observation that circadian rhythms are not sped up or slowed down by changes in temperature and that they are relatively impervious to chemical perturbations would similarly argue against such a neuronal mechanism underlying the generation of 24-hour oscillations. In fact, the finding that nonneuronal tissues (Pittendrigh’s cell–autonomy) can produce sustained circadian rhythms, as well as the prevalence of circadian rhythms in plants and unicellular organisms (Pittendrigh’s ubiquity), argue against a neural process underlying generation of circadian rhythm. Indeed, it appears that the synthesis of proteins by each oscillatory cell is central to the mechanism for the generation of 24-hour rhythms. The initial evidence for this is that application of protein synthesis inhibitors in the region of the SCN shifts the circadian phase of activity of animals by an amount and in a direction that depends upon the time when the inhibition is imposed.15,16 A similar shift in the phase of vasopressin release from explanted SCN also results from inhibition of protein synthesis.17 Thus, gene expression is central to the generation of circadian oscillations. Gene expression profile studies, in which expression levels are sampled at regular time points in constant darkness (free-running conditions) focusing on the SCN and on peripheral tissues reveal that approximately one third of the transcriptome is rhythmically expressed, even in peripheral tissues.10-13 Reporter gene constructs combining genes known to be rhythmically expressed with luciferase (thus allowing visualization of expression in culture via the luciferase’s glow) demonstrated in rats and in mice that peripheral tissues are capable of self-sustained rhythms.6,7 With so many genes exhibiting circadian expression, and competent oscillators present in such a variety of tissues, one cannot assume that either rhythmic expression or expression in the SCN are valid criteria for a clock gene. Identification of which genes are central to the generation and maintenance of circadian cycles thus represents a challenge. A potential solution to the challenge of identification of clock genes (as distinct from clock-controlled genes) is to refocus attention on the formal properties of the circadian system. Arnold Eskin and others promoted this conceptual framework in the late 1970s by characterizing rhythm properties as arising from the input pathway, the clock itself, or the output pathway (Fig. 12-1).18 As articulated for pharmacologic approaches (but equally valid for genetic ones), manipulations that produce phase-dependent shifts in the rhythm (a phase-response curve), or changes in the phase-response curve or the free-running period are likely
Input
Clock
Output
Period Phase Amplitude
Persistence Period Phase Amplitude
Persistence Phase Amplitude
Figure 12-1 Classic view of circadian system and circadian clock properties. At minimum, the circadian clock system would have an input pathway by which entraining signals are received (light is illustrated), a clock mechanism, and output pathways. No single property of observed circadian rhythms is necessarily determined by the clock mechanism; these properties may be affected by changes in the input or output. However, when a mutation is observed to affect multiple properties of circadian rhythms, then that genetic change may most parsimoniously be attributed to a change in the clock mechanism itself.
to be affecting the clock, or at least not affecting an output process.19 Applying this logic, a genetic perturbation that alters the free-running period in constant darkness, or the phase-response curve to light pulses, or the persistence of rhythmicity in constant conditions is likely to be a perturbation in a clock gene, although no one alteration alone is necessarily a clock change (rather than input or output). Zatz and others20,21 proposed more restrictive criteria: Null mutations should abolish rhythmicity, the gene’s protein product level or activity should oscillate and be reset by light pulses, changes in amount or activity should result in phase shifts, and prevention of oscillation of protein levels or activity should result in loss of rhythmicity.21 In the parlance of the field, these criteria would define a state variable—a rate-limiting element that itself defines the phase of the core oscillation. A self-sustaining clock would require at least two state variables,22 although more are clearly possible. To date, no single gene in the mammalian system has satisfied all the criteria for a state variable. Indeed a hallmark of the mammalian circadian clock seems to be the multiple homologues of many genes that appear to play related but nonredundant roles (Fig. 12-2). It may thus be that “state variable” status is actually shared by related groups of genes in the mammalian system.
POSITIVE ELEMENTS Clock In the early 1990s, no genes in mammals had been identified as even possible candidate circadian clock genes, leading us to undertake a mutagenesis and screening in mice in an effort to identify mammalian circadian clock genes. For this, we used the C57BL/6J mouse strain, in which wild-type mice show robust entrainment to a light– dark cycle and have a circadian period between 23.6 and 23.8 hours under free-running conditions in constant darkness (DD). In a screen for mutations of more than 300 progeny of mutagen-treated mice, we found one animal that had a free-running period of about 24.8 hours, more than six standard deviations longer than the mean.23 In the homozygous condition this mutation results in a dramatic lengthening of the period to about 28 hours, which is
CHAPTER 12 • Circadian Clock Genes 143
DBP Decs Npas2
FbxI3 Clock
Crys
Bmal1
Pers
Tim
Rev-erbα
ROR
CKI
Figure 12-2 Multiple gears are required to build a genetic clock. The central gear, composed of the positive elements Clock and Bmal1 and the negative elements period and Cryptochrome, constitutes a clear feedback oscillator, but several genetic elements have been identified that interact with each of these and are critical for determining the functional properties of the circadian clock.
usually followed by the eventual loss of circadian rhythmicity (i.e., arrhythmicity) after about 1 to 3 weeks in DD. The affected gene was mapped to mouse chromosome 5 and named Clock.23,24 We cloned the Clock gene by a combination of genetic rescue and positional cloning techniques. Clock/Clock mutant mice were phenotypically rescued by a bacterial artificial chromosome (BAC) transgene that contained the Clock gene, allowing functional identification of the gene.25 The Clock gene encodes a transcriptional regulatory protein having a basic helix-loop-helix DNA-binding domain, a PAS dimerization domain, and a Q-rich transactivation domain. The mutant form of the CLOCK protein (CLOCK Δ19) lacks a portion of the activation domain found in wild-type protein, and thus, although it is capable of protein dimerization, transcriptional activation is diminished or lost. The PAS domain is so named because of the genes originally identified with this protein dimerization domain, per, ARNT, and sim. Clock mRNA is expressed in the SCN as well as other tissues, but it has not been found to oscillate in a circadian fashion.26 Bmal1 The presence of the PAS dimerization domain in CLOCK protein suggested that it might form a heterodimer similar to that of PER and the protein product of another Drosophila clock gene, TIM.27 A screen for potential partners for the CLOCK protein using the yeast two-hybrid system revealed that a protein of unknown function, BMAL1 (Brain and Muscle ARNT-Like 1), was able to dimerize with the CLOCK protein.28 Creation of mice harboring a null allele of Bmal1 (also referred to as MOP3) demonstrated the critical role of this gene in generating circadian rhythm. These mutant mice, which display light–dark responsive differences in activity level, become arrhythmic immediately upon release in constant darkness.
Additional actions of the CLOCK:BMAL1 heterodimer have become clear. Although Clock mRNA does not oscillate, its protein’s nuclear versus cytoplasmic localization does.29 By studying the intracellular localization of CLOCK and BMAL1 in fibroblasts of mouse embryos with mutations in different clock genes, and ectopically expressing the proteins, it was found that nuclear accumulation of CLOCK depended on formation of the CLOCK:BMAL1 dimer, as was phosphorylation of the complex and its degradation.29 Other PAS domain–containing proteins failed to affect the localization of CLOCK, indicating that these posttranslational events are specific to the CLOCK:BMAL1 dimer.
NEGATIVE ELEMENTS Period Genes As described in Chapter 13, the first identified gene (defined as a mendelian gene as opposed to a sequenced, cloned gene) that encodes a clock component, period, denoted with the symbol per, was discovered in 1971 in Drosophila using a forward genetic approach consisting of chemically inducing random mutations in the genome and then detecting the mutations that affect circadian rhythms by screening the progeny of the mutagenized individuals for altered rhythmicity.30 This approach has the advantage that no assumptions are made about the nature of the genes or gene products involved, but it is based on the presumption that there exist genes that, when mutated, will alter rhythms in a detectable manner. At the time, this presumption of the existence of genes that regulate a complex behavior was considered radical, but it has proved to have been a field-defining moment. Initially, three alleles of the per gene were identified by the process of mutagenesis and screening. Flies carrying these alleles had either no apparent rhythm in eclosion (emergence from the pupal case) or locomotion, or they had either long (e.g., 29 hours) or short (e.g., 19 hours) periods for the rhythms of eclosion and locomotor activity.30 The finding of three alleles with three different phenotypes made it possible to have confidence in the conclusion that the per gene encodes a protein that is a clock component. Had only an arrhythmic mutant been found, then the alternative explanation could be proposed that the lack of circadian behavior was secondary to another primary defect that did not lie in a clock component. The approach of mutagenesis and screening has also been successful in identifying circadian clock genes in other organisms such as Neurospora crassa,31 plants31 and cyanobacteria.33 Confirmation of the importance of the per gene as a central circadian clock component was the rescue of the mutant phenotype after introduction of the wild-type allele of the per gene into mutant flies.34,35 The level of the mRNA transcript encoded by the per gene was shown to oscillate in a circadian fashion36 as a result of transcriptional regulation,37 and the levels of the PER protein were shown to lag the per mRNA levels.38 In fact, shifts in the circadian phase can be evoked by the induction of PER protein under the control of a noncircadian promoter.39 Thus, many lines of evidence indicate that the per gene encodes a protein that is a clock component.
144 PART I / Section 3 • Genetics of Sleep
Three orthologues of the per gene—mPer1, mPer2, and mPer3—have now been identified in the mouse, and the levels of their mRNA have also been shown to oscillate with a circadian period.40-44 Following the identification of CLOCK:BMAL1 dimerization, the ability of this heterodimer to regulate transcription was tested using a reporter construct based on the upstream regulatory elements of the per gene. The per gene of Drosophila contains an upstream regulatory element, the clock control region, within which is contained a sequence needed for positive regulation of transcription, the E-box element (CACGTG).45 CLOCK-BMAL1 heterodimers were found to activate transcription of the mPer gene in a process that requires binding to the E-box element.28 However, CLOCK Δ19 mutant protein was not able to activate transcription, consistent with the finding that exon 19, which is skipped in Clock mutant animals,26 is necessary for transactivation. Thus, CLOCK protein interacts with the regulatory regions of the per gene to allow transcription of the per mRNA and eventual translation of PER protein. A similar activation of transcription of the tim gene by the CLOCK-BMAL1 heterodimer also occurs in flies.46 However, this positive regulation alone does not produce an oscillation in per mRNA levels, which is known to be responsible for the oscillation in PER protein levels.37 Findings that the Clock mutation dramatically decreases per genes’ expression also confirms the positive regulation of CLOCK:BMAL1 on per transcription in situ.47,48 Mice with null mutations of mPer1, mPer2, or mPer3 alone display altered circadian periods,49,50 and mice with both mPer1 and mPer2 null mutations lose rhythmicity. mPer3 null mutant mice exhibit only a subtle alteration in rhythmicity, and mPer1/mPer3 or mPer2/mPer3 double mutants are not substantially distinct from the mPer1 or mPer3 single mutants. These findings suggest there may be some compensation of function among the different mammalian per genes, and raise the question of the significance of mPer3 for the generation of mammalian circadian rhythms. Cryptochromes Cryptochromes are blue light–responsive flavoprotein photopigments related to photolyases, so named because their function was cryptic when first identified. In mammals, two cryptochrome genes, Cry1 and Cry2, have been identified. They were found to be highly expressed in the ganglion cells and inner nuclear layer of the retina as well as the SCN,51 and their mRNA expression levels oscillate in these tissues. Targeted mutant mice lacking Cry2 exhibit a lengthened circadian period, and mice lacking Cry1 have shortened circadian period; mice with both mutations have immediate loss of rhythmicity upon transfer to constant darkness.52-54 Thus, like the mammalian period genes, the cryptochrome genes appear to have both distinct (given their opposite effects on circadian period) and compensatory (given that either gene can sustain rhythmicity in the absence of the other) functions. Because of their expression pattern, the cryptochromes were thought to be the long-unidentified mammalian circadian photoreceptors (see later), and thus light
responses were examined in characterizing the null mutants. Cry2 mutant mice exhibit altered phase shifting responses to light pulses.52 Cry1/Cry2 double mutants exhibit impaired light induction of mPer1 in the SCN, but light induction of mPer2 in double mutants remains.53,55 Neither mPer1 nor mPer2 exhibit persistent oscillations in expression in the SCN in constant conditions in Cry1/Cry2 double mutants.53,55 Thus, although the cryptochromes are not the mammalian circadian photoreceptor, they do appear to play a central role in the generation of circadian signals. Further evidence for a central clock function is the finding that the cryptochromes appear to share a number of regulatory features with the period genes. In Clock mutant mice, the mRNA levels of Cry1 and Cry2 are reduced in the SCN and in skeletal muscle,56 suggesting that the cryptochromes also are induced by CLOCK:BMAL1 transactivation. Using mammalian (NIH 3T3 or COS7) cell lines, CRY1 and CRY2 were found by co-immunoprecipitation to interact with mPER1, mPER2, and mPER3, leading to nuclear localization of the CRY:PER dimer as indicated by co-transfection assays with epitope-tagged proteins.56 Luciferase assays indicate that CRY:CRY or CRY:PER complexes were capable of inhibiting CLOCK:BMAL1 transactivation of mPer1 or vasopressin transcription.56 Thus, the CRYs as well as the PERs are capable of a negative feedback function, inhibiting CLOCK:BMAL1induced transcription.
MODULATORS OF Period Timeless How is the level of the PER protein regulated by the circadian clock? The first hint came from the identification of the timeless gene tim, which when mutated produces abnormal circadian rhythms in Drosophila.57 The levels of the mRNA encoded by the tim gene oscillate with a time course that is indistinguishable from those of per mRNA.58 The levels of the TIM protein lag behind those of tim mRNA by several hours,59 similar to the finding with per mRNA and PER protein. The PER and TIM proteins form heterodimers60 that are transported to the nucleus.61 The finding that the heterodimer is transported to the nucleus suggested that it might be involved in the regulation of transcription of the per or tim genes. Indeed, experiments have shown that the transcription of the per and tim genes is repressed by the PER-TIM protein heterodimer.46 This finding is very important because it demonstrates that the production of mRNA encoded by a clock component gene, the delayed accumulation of the encoded protein, and later feedback to the clock gene’s promoter in the nucleus can explain the basic features of the circadian clock in Drosophila. However, interactions between PER and TIM are not sufficient, and the basic mechanism does not become clear until one adds interactions with other clock genes. In experiments using a luciferase reporter assay, the luminescent luciferase protein was expressed under the control of the promoter regions of the Drosophila per and tim genes. It was found that the fly homologue of Clock, dClock,62 was capable of driving expression of luciferase46 in cells that have high endogenous levels of the Drosophila homologue
of BMAL1, CYC (cycle). The effect of the PER-TIM heterodimer on the ability of the dCLOCK-CYC heterodimer to drive the transcription of the per and tim genes was tested by co-transfecting the encoding genes into the cells that expressed the luciferase reporter gene. Indeed, it was found that the expression of both the per and tim genes were reduced by their own protein products. This negative feedback has recently been found for a mammalian heterodimer consisting of homologues of the TIMELESS and mPER1 proteins.63 Whether the mammalian tim homologue identified63,64 actually represents an orthologous gene has been called into question.65 This issue has been difficult to resolve, because gene targeting to create a null mutant resulted in early embryonic lethality. Differences in results obtained by different groups examining the oscillation of mTim expression could result from both a full-length and a truncated protein being expressed, with only the full-length form oscillating.66 Using antisense oligodeoxynucleotides directed against Timeless in rat SCN slice preparations results in a disruption of neuronal oscillations in vitro, suggesting a role in rhythmicity might exist.66 However, true functional homology of Timeless in mammals remains to be demonstrated. Casein Kinase 1 The tau mutation of the hamster arose spontaneously in a laboratory stock.67 The mutation is semidominant and shortens the period from 24 to 22 hours in heterozygotes and to 20 hours in homozygotes. This mutation has been of great importance for several reasons. The mutation predated the Clock mutation and demonstrated that singlegene mutations could profoundly alter the circadian clock in mammals, just as in flies and Neurospora. Tau mutants display several other physiologic phenotypes, such as alteration of the responses of males to photoperiod length68 and effects of the estrous cycles in females,69 which gave further insights into the importance of the circadian clock for other biological cycles. The evidence that the SCN is indeed the site of the master circadian oscillator (see earlier) was demonstrated unequivocally using transplantation of the SCN that employed the tau mutation. These manipulations also gave rise to the evidence necessary to conclude that the tau mutation encodes a protein that is a clock component. Unfortunately, the genetic tools needed for cloning this important and interesting gene were not available for the hamster, and thus its molecular identity could not be determined by conventional genetic mapping or positional cloning approaches. Lowrey and colleagues identified a genomic region of conserved synteny (a grouping of genes together on a chromosome) in hamsters, mice, and humans that encompassed the tau mutation.70 Tau was thus identified as being a mutation in the Casein Kinase 1 epsilon (CK1ε) gene, the mammalian orthologue of the Drosophila doubletime gene. Sequencing of the gene identified a point mutation that leads to altered enzyme dynamics and autophosphorylation state. In vitro assays demonstrated that CKIε can phosphorylate PER proteins and that the tau mutant enzyme is deficient in this ability. Thus, CKIε can lead to degradation of PERs, slowing the accumulation of PER in the nucleus and thus repression of CLOCK:BMAL1.
CHAPTER 12 • Circadian Clock Genes 145
Casein Kinase 1 delta (CKIδ) has also been implicated in mammalian circadian rhythmicity.
MODULATORS OF Bmal1 Rev-erbα and ROR The negative feedback of PER and CRY proteins on their own CLOCK:BMAL1-induced transcription constitutes a form of negative feedback, and it may be sufficient to explain the oscillations in expression of mPer and Cry genes, but the rhythmic expression of Bmal1 with an opposite phase is not explained by this feedback. What regulatory elements produce the rhythmic transcription of Bmal1, with an antiphase relationship to the Pers? Reverbα, an orphan nuclear receptor, may act as the missing link. Its promoter region contains 3 E-boxes, and transcription is thus positively regulated by CLOCK and BMAL1.71 Its transcription is negatively regulated by PER and CRYs and is at a minimum when mPER2 is at a maximum, and it is constitutively expressed at intermediate levels in Cry1/Cry2 or Per1/Per2 double knockouts. REV-ERBα protein appears to drive the circadian oscillation in Bmal1 transcription: The Bmal1 promoter includes two RORE sequences (enhancer sequences that recognize members of the REV-ERB and ROR orphan nuclear receptor families), and Bmal1 expression is drastically reduced in Rev-erbα null mutants.71 Thus Rev-erbα might act to link the positive and negative regulatory signals of other clock genes to the transcription of Bmal1. Given the importance of orphan nuclear receptors in regulating cellular metabolic properties,72 interaction with circadian clock genes might, at the molecular level, form the links between circadian clocks and metabolic regulation, with important implications for health and disease. See chapters in Section 5 for more detail. The differences between the phase of Cry1 mRNA rhythms relative to other clock genes whose transcription is enhanced by CLOCK:BMAL binding to E-boxes may also be attributable to Rev-erbα. The Cry1 gene has three candidate REV-ERB/ROR binding sites73; in vitro assays indicate that REV-ERBα binds to two of these sites. Luciferase reporter assays indicate that REV-ERBα protein can inhibit transcription of Cry1 through binding at these two sites. REV-ERBβ also appears to share some functional redundancy with REV-ERBα.74 MODULATORS OF Cry In addition to REV-ERB modulation of Cry, other genes appear to modulate the activity of the cryptochromes. Fbxl3 The Overtime mutation in mice was identified in a mutagenesis screen based on a lengthened free-running circadian period.75 The responsible mutation was ultimately identified as being in a known gene encoding the F-box protein Fbxl3, but a gene previously unknown to be involved in circadian rhythmicity. Fbxl3OVTM mutant appear to be functionally comparable to null mutants. FBXL3 protein leads to degradation of CRY1, but the OVTM mutant protein is less effective in this capacity. Thus, the period lengthening may be a direct result of a
146 PART I / Section 3 • Genetics of Sleep
delay in degradation of CRY, effectively preventing the core cycle from restarting. Other bHLH-PAS Family Members NPAS2 (neuronal PAS family member 2) shares the closest homology with CLOCK of all identified bHLH-PAS family members. Null mutants of this gene have altered circadian activity patterns, notably the absence of a “siesta” in later subjective night, but no dramatic alterations in circadian free-running period or persistence.76 However, when null mutants of the Clock had less-dramatic phenotypes than the Δ19 mutant,77 the role of NPAS2 was reexamined. In the absence of functioning CLOCK, NPAS2 appears to be able to partially compensate.78 The DBP gene has E-box elements in its promoter, and it exhibits robust oscillations in expression in the SCN and the liver. DBP-null mutant mice display alterations in circadian period as well.79 NPAS2 is another bHLH-PAS family member that forms heterodimers with BMAL1. Null mutant mice for this gene display alterations in the pattern of their activity rhythms.80 Dec1 and Dec2 Like other clock genes, Dec1 and Dec2 are basic helix-loophelix transcription factors that bind to E-boxes. DEC1 and DEC2 have been found to inhibit transactivation of Per by CLOCK and BMAL1.81 DEC1 and DEC2 form dimers.82 The inhibition of CLOCK and BMAL1 transactivation may be related to interactions with BMAL1, but it can also be attributed to binding to (and thus possibly competition for) E-boxes.83 A human allelic variant in Dec2 has been linked with total sleep time.84 This functional relationship has been confirmed in transgenic mice expressing the human Dec2 allele.
OUTPUT REGULATION Clock There also is evidence of regulation of clock gene transcription via rhythms in acetylation of H3 histone: CRY proteins might inhibit H3 acetylation,73 the Per1, Per2, and Cry1 promoters have rhythms in H3 acetylation, and the Per1, Per2, and Cry1 promoters have rhythms in RNA polymerase II binding. These promoter rhythms are in phase with mRNA levels. P300, a histone acetyltransferase, immunoprecipitates together with CLOCK in liver nuclear preparations, with a peak at CT (circadian time) 6 and minimum at CT 18.73 P300 may be part of the CLOCK:BMAL1 coactivator complex; a Per1 promoterdriven luciferase reporter assay indicates that CRY proteins can disrupt this. Hence, inhibition of histone acetylation by P300 provides a potential separate mechanism by which CRY proteins can preclude CLOCK:BMAL1 transactivation of Per and Cry genes. Prokineticin 2 Prokineticin 2 (PK2) is rhythmically expressed in the SCN,85 and infusion of PK2 into the cerebral ventricles inhibits locomotor activity. Mice with a null mutation in the PK2 gene exhibit dramatically reduced levels of activity86 with reduced circadian amplitude. These mice also
exhibit attenuated rebound in raid eye movement (REM) sleep, non-REM (NREM) sleep, and delta power following sleep deprivation.87 Transforming Growth Factor α The peptide transforming growth factor α (TGF-α) was identified in a screen for SCN factors that might inhibit locomotor activity; when infused into the third ventricle, this peptide inhibits locomotor activity. Mice with targeted mutations of the epidermal growth factor receptor (the receptor likely to bind TGF-α) also display disruption of activity rhythms.88 These effects are attributable to actions on the epidermal growth factor (EGF) receptors. VPAC2 Mice that lack the peptide receptor VPAC2 show abnormal entrainment and disrupted rhythms, indicating that vasoactive intestinal peptide (VIP) signaling in the SCN may be necessary for normal expression and coordination of rhythms.89 Cardiomyotrophin-like Cytokine Cardiomyotrophin-like cytokine (CLC) also is expressed in the SCN in a rhythmic manner in vasopressin neurons. Infusion of CLC into the third ventricle (near the SCN) dramatically inhibits locomotor activity, and infusion of antibodies to the CLC receptor increases activity.90
INPUT REGULATION Melanopsin The circadian rhythms of many humans who are blind, with no conscious perception of light, are nevertheless able to be entrained by light.91 This intriguing observation led to studies of the circadian light-input pathway and the photoreceptors and photopigments in mammals. In experiments employing mouse mutations that result in degeneration of rods92 or both rods and cones,93 light entrainment of the circadian rhythm was preserved.94 How ever, the eye must be the site of the light-entraining pathways in mammals because enucleated mammals are not capable of light entrainment.92 Indeed a morphologically distinct set of retinal ganglion cells projects to the SCN via the retinohypothalamic tract.95 Ablation of the SCN abolishes circadian rhythmicity, and ablation of the retinohypothalamic tract abolishes light entrainment.96 Thus, the light signal responsible for light entrainment enters the SCN via a unique axonal pathway from the eye. Melanopsin, a member of the opsin family of photopigments, was first found in the inner retina97 and later found to be expressed in the somata and dendrites of retinal ganglion cells of the retinohypothamamic tract.98 Neurons that contribute axons to the retinohypothalamic tract were found to express the marker pituitary adenylate cyclase– activating polypeptide (PACAP)98; when PACAP was used as a marker for rat retinohypothalamic tract neurons, every PACAP-positive neuron was found to express melanopsin, and every melanopsin-positive neuron was PACAP positive.98 Further evidence confirming the role of melanopsin as the phase-shifting pigment has come from genetically engineered mice in which the gene encoding melanopsin
CHAPTER 12 • Circadian Clock Genes 147
was disrupted.99,100 Two behavioral measures of the circadian rhythm’s responses to light were altered in these mice: the phase-shifting response to a discrete light pulse was of lesser amplitude in the knockout mice than in the wildtype mice, and the free-running periods of the knockout mice were lengthened less by exposure to constant light than the periods of wild-type mice. Hence, it appears that melanopsin represents a primary photopigment, with other photopigments also having input to the circadian system. Rab3a The Rab3a gene was identified in a mutagenesis screen (earlybird) based on an advanced phase angle of entrainment and shortened circadian period. Null mutant mice display a similar phenotype.101 Further, both the Rab3a null and earlybird mutants exhibit alterations in the homeostatic response to sleep deprivation101 as well as alterations in emotional behavior.102
CONCLUSIONS The core circadian oscillator is autonomous to individual neurons of the SCN and is the result of the daily oscillation in the levels of several clock component proteins. The basis for this oscillation in mammals, as in other organisms, lies in rhythmic feedback regulation of transcription of the genes encoding these proteins. The levels of the PER and CRY proteins alter the rate of transcription of their own genes. This alteration is achieved by inhibition of the enhancement of transcription that results from binding of the CLOCK-BMAL1 heterodimer to the E-box element of the promoter region of the Per and Cry genes. Additional interactions between circadian clock proteins may slow the time course of this feedback, achieving the near24-hour interval: The phosphorylation of PER by CKIα can lead to its degradation, and the association with BMAL1 appears needed for CLOCK to be present in the nucleus. Rhythmic transcription of Bmal1 appears to result from regulation via REV-ERBβ, itself regulated by E-box elements. Finally, it appears that rhythms in histone acetylation contribute to the circadian expression pattern of some core circadian genes. Additional genes have been identified based on altered circadian rhythms in mutants, although the roles of these genes in the circadian system remain to be determined.
The majority of the core genes have been identified in mice or in flies by forward genetics, in which mutations were induced in the genome randomly, and the mutations that specifically affect the circadian oscillator were identified with carefully crafted circadian phenotypic screens. Now that these clock-component proteins have been identified, it will be easier to find the proteins that serve the input and output pathways of the circadian oscillator and to identify the components that are out of order in disease states that affect circadian rhythms. It is fortuitous that the unraveling of the molecular basis for circadian rhythmicity is occurring at a time when the general public is becoming aware of the importance of normal circadian time keeping for human health, safety, performance, and productivity.
REMAINING QUESTION: CLOCK GENES AS SLEEP GENES? Are clock genes really sleep genes? As more and more circadian clock gene mutants are examined for other phenotypes, it becomes clear that the circadian system plays a role in the health and well-being of the organism in unanticipated ways. For example, the Clockd19 mutant mouse has now been shown to have alterations in emotional behavior,103 response to addictive psychostimulant drugs,103 metabolism,104 tolerance of cancer chemotherapeutic agents,105 reproduction,106 and, notably, sleep.107 Particularly noteworthy regarding the sleep phenotype is the finding that not only is the temporal pattern of sleep disrupted, but also the amount was drastically altered (Table 12-1). There may be additional sleep phenotypes not described in Table 12-1; many studies were focused on homeostatic sleep regulation only. Studies in mice and flies have found that deletion or mutation in core clock genes induces unexpected alterations in sleep amount, sleep architecture, and compensatory responses to sleep deprivation.107-115 These results have led to the hypothesis that circadian clock genes may also be central to sleep-regulatory processes beyond just the circadian timing of sleep. For example, mutation in the mammalian circadian gene, Clock, induces a decrease in NREM sleep time and an attenuated REM recovery following sleep deprivation.107 A mutation in the fly homologue of this gene, dClock, reduces consolidated rest time and leads to alterations in the response to rest
Table 12-1 Clock Genes and Clock-Related Genes That Have Already Been Examined for Sleep Phenotype in Mice GENE Clock
CHROMOSOME 5
Per1
11
Per2
1
Per3
4
Cry1
10
SLEEP PHENOTYPE ↓ Sleep, ↑ wake (Δ19 mutant)
REFERENCE 107
↓ Sleep, ↑ wake in dark (null)
108
↓ Sleep, ↑ wake in late light (PAS deletion)
108
No change reported, bouts and fragmentation not reported
109
↑ NREM in double null
110
Cry2
2
↑ NREM in double null
110
Bmal1
7
↑ Total sleep time, ↓ response to sleep deprivation (null)
111
Npas2
1
↓ Sleep in dark (null)
112
Dbp
7
↓ Circadian amplitude, ↑ fragmentation (null)
113
148 PART I / Section 3 • Genetics of Sleep
deprivation.114,115 Cryptochrome double-knockout (Cry1/ Cry2) mice have increases in baseline amounts of NREM sleep and consolidation of NREM episodes and NREM delta power over wild-type control levels, and they lack the normal compensatory response in sleep amount and NREM delta power following sleep deprivation.110 Interestingly, a mutation in the Drosophila gene timeless, which might function in a similar manner to the mammalian CRY gene, leads to an impaired recovery response to short-term rest deprivation in flies.114,115 In addition, deletion of Bmal1 in mice and the fly homologue, cycle, also leads to altered sleep–wake and rest–activity amounts under baseline conditions as well as after sleep deprivation.111,114,115 The finding that mutation or deletion of canonical circadian clock genes can induce major effects on the sleep–wake cycle that go beyond just the timing of this rhythm may be just the beginning of a new way of thinking about how the circadian clock regulates a multitude of physiologic and behavioral rhythms. It may well be that once the central circadian input to a particular output rhythmic system has been disrupted, that downstream rhythm may now be disrupted or altered in many different ways due to loss of normal temporal organization. Indeed, the recent discovery that Clock-mutant animals show a wide range of metabolic abnormalities supports the hypothesis that a disrupted molecular circadian clock can have far-reaching implications for physiology and pathophysiology.72 Whether such disruptions in physiology and behavior are due to altered circadian information from the SCN or are due to local tissue-specific changes in the molecular circadian clock are not known. Regardless of the mechanisms, such results point to a very central role of circadian clock genes in regulating biochemical, metabolic, and physiologic processes at many different levels of organization.116 ❖ Clinical Pearl Circadian clock genes have a central role in regulating biochemical, metabolic, and physiologic processes throughout the body. They may play a pivotal role in the linkage between circadian misalignment (e.g., shift work) and the increased risk of developing metabolic and other abnormalities such as the metabolic syndrome.
Acknowledgements Preparation of this manuscript was in part supported by NIH PO1 AG 11412. REFERENCES 1. Moore RY, Eichler VB. Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res 1972;42(1):201-206. 2. Stephan FK, Zucker I. Circadian rhythms in drinking behavior and locomotor activity of rats are eliminated by hypothalamic lesions. Proc Natl Acad Sci U S A 1972;69(6):1583-1586. 3. Tosini G, Menaker M. Circadian rhythms in cultured mammalian retina. Science 1996;272(5260):419-421. 4. Lehman MN, Silver R, Gladstone WR, et al. Circadian rhythmicity restored by neural transplant. Immunocytochemical characterization of the graft and its integration with the host brain. J Neurosci 1987;7(6):1626-1638.
5. Ralph MR, Foster RG, Davis FC, Menaker M. Transplanted suprachiasmatic nucleus determines circadian period. Science 1990;247(4945):975-978. 6. Yamazaki S, Numano R, Abe M, et al. Resetting central and peripheral circadian oscillators in transgenic rats. Science 2000;288(5466): 682-685. 7. Yoo SH, Yamazaki S, Lowrey PL, et al. PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc Natl Acad Sci U S A 2004;101(15):5339-5346. 8. Brown SA, Zumbrunn G, Fleury-Olela F, et al. Rhythms of mammalian body temperature can sustain peripheral circadian clocks. Curr Biol 2002;12(18):1574-1583. 9. Stokkan KA, Yamazaki S, Tei H, et al. Entrainment of the circadian clock in the liver by feeding. Science 2001;291(5503):490493. 10. Panda S, Antoch MP, Miller BH, et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 2002; 109(3):307-320. 11. Akhtar RA, Reddy AB, Maywood ES, et al. Circadian cycling of the mouse liver transcriptome, as revealed by cDNA microarray, is driven by the suprachiasmatic nucleus. Curr Biol 2002;12(7): 540-550. 12. Storch KF, Lipan O, Leykin I, et al. Extensive and divergent circadian gene expression in liver and heart. Nature 2002;417(6884): 78-83. 13. Duffield GE, Best JD, Meurers BH, et al. Circadian programs of transcriptional activation, signaling, and protein turnover revealed by microarray analysis of mammalian cells. Curr Biol 2002;12(7): 551-557. 14. Pittendrigh CS. Circadian rhythms and the circadian organization of living systems. Cold Spring Harb Symp Quant Biol 1960;25: 159-184. 15. Takahashi JS. Molecular neurobiology and genetics of circadian rhythms in mammals. Ann Rev Neurosci 1995;18:531-553. 16. Inouye SIT, Takahashi JS, Wollnik F, Turek FW. Inhibitor of protein synthesis phase shifts a circadian pacemaker in the mammalian SCN. Am J Physiol 1988;255:R1055-R1058. 17. Watanabe K, Katagai T, Ishida N, Yamaoka S. Anisomycin induces phase shifts of circadian pacemaker in primary cultures of rat suprachiasmatic nucleus. Brain Res 1995;684(2):179-184. 18. Eskin A. Circadian system of the Aplysia eye: properties of the pacemaker and mechanisms of its entrainment. Fed Proc 1979; 38(12):2573-2579. 19. Turek FW. Pharmacological probes of the mammalian circadian clock: use of the phase response curve approach. Trends Pharmac Sci 1987;8:212-217. 20. Aronson, BD, Johnson KA, Loros JJ, Dunlap JC. Negative feedback defining a circadian clock: autoregulation of the clock gene frequency. Science 1994;263:1578-1584. 21. Zatz M. Perturbing the pacemaker in the chick pineal. Discoveries Neurosci 1992;8:67. 22. Winfree AT. Integrated view of resetting a circadian clock. J Theoret Biol 1970;28:327-374. 23. Vitaterna MH, King DP, Chang AM, et al. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 1994;264(5159):719-725. 24. King DP, Vitaterna MH, Chang AM, et al. The mouse Clock mutation behaves as an antimorph and maps within the W19H deletion, distal of Kit. Genetics 1997;146(3):1049-1060. 25. Antoch MP, Song EJ, Chang AM, et al. Functional identification of the mouse circadian Clock gene by transgenic BAC rescue. Cell 1997;89(4):655-667. 26. King DP, Zhao Y, Sangoram AM, et al. Positional cloning of the mouse circadian clock gene. Cell 1997;89(4):641-653. 27. Huang ZJ, Edery I, Rosbash M. PAS is a dimerization domain common to Drosophila period and several transcription factors. Nature 1993;364(6434):259-262. 28. Gekakis N, Staknis D, Nguyen HB, et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science 1998; 280(5369):1564-1569. 29. Kondratov RV, Chernov MV, Kondratova AA, et al. BMAL1-dependent circadian oscillation of nuclear CLOCK: posttranslational events induced by dimerization of transcriptional activators of the mammalian clock system. Genes Dev 2003;17(15):19211932.
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55. Okamura H, Miyake S, Sumi Y, et al. Photic induction of mPer1 and mPer2 in cry-deficient mice lacking a biological clock. Science 1999;286(5449):2531-2534. 56. Kume K, Zylka MJ, Sriram S, et al. mCRY1 and mCRY2 are essential components of the negative limb of the circadian clock feedback loop. Cell 1999;98(2):193-205. 57. Sehgal A, Price JL, Man B, Young MW. Loss of circadian behavioral rhythms and per RNA oscillations in the Drosophila mutant timeless. Science 1994;263(5153):1603-1606. 58. Sehgal A, Rothenfluh-Hilfiker A, Hunter-Ensor M, et al. Rhythmic expression of timeless: a basis for promoting circadian cycles in period gene autoregulation. Science 1995;270(5237):808-810. 59. Hunter-Ensor M, Ousley A, Sehgal A. Regulation of the Drosophila protein timeless suggests a mechanism for resetting the circadian clock by light. Cell 1996;84(5):677-685. 60. Gekakis N, Saez L, Delahaye-Brown AM, et al. Isolation of timeless by PER protein interaction: defective interaction between timeless protein and long-period mutant PERL. Science 1995;270(5237): 811-815. 61. Saez L, Young MW. Regulation of nuclear entry of the Drosophila clock proteins period and timeless. Neuron 1996;17(5):911-920. 62. Allada R, White NE, So WV, et al. A mutant Drosophila homolog of mammalian Clock disrupts circadian rhythms and transcription of period and timeless. Cell 1998;93(5):791-804. 63. Sangoram AM, Saez L, Antoch MP, et al. Mammalian circadian autoregulatory loop: a Timeless ortholog and mPer1 interact and negatively regulate CLOCK-BMAL1-induced transcription. Neuron 1998;21(5):1101-1113. 64. Tischkau SA, Barnes JA, Lin FJ, et al. Oscillation and light induction of timeless mRNA in the mammalian circadian clock. J Neurosci 1999;19(12):RC15. 65. Gotter AL, Manganaro T, Weaver DR, et al. A time-less function for mouse timeless. Nat Neurosci 2000;3(8):755-756. 66. Barnes JW, Tischkau SA, Barnes JA, et al. Requirement of mammalian Timeless for circadian rhythmicity. Science 2003;302(5644): 439-442. 67. Ralph MR, Menaker M. A mutation of the circadian system in golden hamsters. Science 1988;241(4870):1225-1227. 68. Shimomura K, Menaker M. Light-induced phase shifts in tau mutant hamsters. J Biol Rhythms 1994;9(2):97-110. 69. Refinetti R, Menaker M. Evidence for separate control of estrous and circadian periodicity in the golden hamster. Behav Neural Biol 1992;58(1):27-36. 70. Lowrey PL, Shimomura K, Antoch MP, et al. Positional syntenic cloning and functional characterization of the mammalian circadian mutation tau. Science 2000;288(5465):483-492. 71. Preitner N, Damiola F, Lopez-Molina L, et al. The orphan nuclear receptor REV-ERBα controls circadian transcription within the positive limb of the mammalian circadian oscillator. Cell 2002; 110(2):251-260. 72. Laposky AD, Turek FW. Physiologic and health consequences of circadian disruption (in animal models). Sleep Med 2009;4: 127-142. 73. Etchegaray JP, Lee C, Wade PA, Reppert SM. Rhythmic histone acetylation underlies transcription in the mammalian circadian clock. Nature 2003;421(6919):177-182. 74. Liu AC, Tran HG, Zhang EE, et al. Redundant function of REVERBα and β and non-essential role for Bmal1 cycling in transcriptional regulation of intracellular circadian rhythms. PLOS Genetics 2008;4:e1000023. 75. Siepka SM, Yoo SH, Park J, et al. Circadian mutant Overtime reveals F-box protein FBXL3 regulation of cryptochrome and period gene expression. Cell 2007;129:1011-1023. 76. Reick M, Garcia JA, Dudley C, McKnight SL. NPAS2: an analog of Clock operative in the mammalian forebrain. Science 2001; 293:506-509. 77. Debruyne JP, Noton E, Lambert CM, et al. A clock shock: mouse CLOCK is not required for circadian oscillator function. Neuron 2006;50:465-477. 78. Debruyne JP, Weaver DR, Reppert SM. CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock. Nat Neurosci 2007;10:543-545. 79. Lopez-Molina L, Conquet F, Dubois-Dauphin M, Schibler U. The DBP gene is expressed according to a circadian rhythm in the suprachiasmatic nucleus and influences circadian behavior. Embo J 1997;16(22):6762-6771.
150 PART I / Section 3 • Genetics of Sleep 80. Dudley CA, Erbel-Sieler C, Estill SJ, et al. Altered patterns of sleep and behavioral adaptability in NPAS2-deficient mice. Science 2003;301(5631):379-383. 81. Honma S, Kawamoto T, Takagi Y, et al. Dec1 and Dec2 are regulators of the mammalian molecular clock. Nature 2002;419:841844. 82. Sato F, Kawamoto T, Fujimoto K, et al. Functional analysis of the basic helix-loop-helix transcription factor DEC1 in circadian regulation. Interaction with BMAL1. Eur J Biochem 2004;271:44094419. 83. Li Y, Song X, Ma Y, et al. DNA binding, but not interaction with Bmal1, is responsible for DEC1-mediated transcription regulation of the circadian gene mPer1. Biochem J 2004;382:895-904. 84. He Y, Jones CR, Fujiki N, et al. The transcriptional repressor DEC2 regulates sleep length in mammals. Science 2009;325(5942): 866-870. 85. Cheng MY, Bullock CM, Li C, et al. Prokineticin 2 transmits the behavioral circadian rhythm of the suprachiasmatic nucleus. Nature 2002;417:405-410. 86. Li J-D, Hu W-P, Boehmer L, et al. Attenuated circadian rhythms in mice lacking the Prokineticin 2 gene. J Neurosci 2006;26:1161511623. 87. Hu W-P, Li J-D, Zhang C, et al. Altered circadian and homeostatic sleep regulation in Prokineticin 2–deficient mice. Sleep 2007;30:247256. 88. Kramer A, Yang FC, Snodgrass P, et al. Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science 2001;294(5551):2511-2515. 89. Harmar AJ. An essential role for peptidergic signalling in the control of circadian rhythms in the suprachiasmatic nuclei. J Neuroendocrinol 2003;15(4):335-338. 90. Kraves S, Weitz CJ. A role for cardiotrophin-like cytokine in the circadian control of mammalian locomotor activity. Nat Neurosci 2006;9:212-219. 91. Czeisler CA, Shanahan TL, Klerman EB, et al. Suppression of melatonin secretion in some blind patients by exposure to bright light. N Engl J Med 1995;332(1):6-11. 92. Foster RG, Provencio I, Hudson D, et al. Circadian photoreception in the retinally degenerate mouse (rd/rd). J Comp Physiol (A) 1991;169(1):39-50. 93. Freedman MS, Lucas RJ, Soni B, et al. Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science 1999;284(5413):502-504. 94. von Schantz M, Provencio I, Foster RG. Recent developments in circadian photoreception: more than meets the eye. Invest Ophthalmol Vis Sci 2000;41(7):1605-1607. 95. Moore RY, Lenn NJ. A retinohypothalamic projection in the rat. J Comp Neurol 1972;146(1):1-14. 96. Johnson RF, Moore RY, Morin LP. Loss of entrainment and anatomical plasticity after lesions of the hamster retinohypothalamic tract. Brain Res 1988;460(2):297-313. 97. Provencio I, Jiang G, De Grip WJ, et al. Melanopsin: an opsin in melanophores, brain, and eye. Proc Natl Acad Sci U S A 1998;95(1): 340-345. 98. Hannibal J, Hindersson P, Knudsen SM, et al. The photopigment melanopsin is exclusively present in pituitary adenylate cyclase–
activating polypeptide-containing retinal ganglion cells of the retinohypothalamic tract. J Neurosci 2002;22(1):RC191. 99. Panda S, Sato TK, Castrucci AM, et al. Melanopsin (Opn4) requirement for normal light-induced circadian phase shifting. Science 2002;298(5601):2213-2216. 100. Ruby NF, Brennan TJ, Xie X, et al. Role of melanopsin in circadian responses to light. Science 2002;298(5601):2211-2213. 101. Kapfhamer D, Valladares O, Sun Y, et al. Mutations in Rab3a alter circadian period and homeostatic response to sleep loss in the mouse. Nat Genet 2002;32(2):290-295. 102. Yang S, Farias M, Kapfhamer D, et al. Biochemical, molecular and behavioral phenotypes of Rab3A mutations in the mouse. Genes Brain Beha 2007;6:77-96. 103. Roybal K, Theobold D, Graham A, et al. Mania-like behavior induced by disruption of CLOCK. Proc Natl Acad Sci U S A 2007; 104(15):6406-6411. 104. Turek FW, Joshu C, Kohsaka A, et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 2005;308(5724): 1043-1045. 105. Gorbacheva VY, Kondratov RV, Zhang R, et al. Circadian sensitivity to chemotherapeutic agent cyclophosphamide depends on the functional status of the CLOCK/BMAL1 transactivation complex. Proc Natl Acad Sci U S A 2005;102(9):3407-3412. 106. Miller BH, Olson SL, Turek FW, et al. Circadian clock mutation disrupts estrous cyclicity and maintenance of pregnancy. Curr Biol 2004;14(15):1367-1373. 107. Naylor E, Bergmann BM, Krauski K, et al. The circadian clock mutation alters sleep homeostasis in the mouse. J Neurosci 2000;20(21):8138-8143. 108. Kopp C, Albrecht U, Zheng B, Tobler I. Homeostatic sleep regulation is preserved in mPer1 and mPer2 mutant mice. Eur J Neurosci 2002;16(6):1099-1106. 109. Shiromani PJ, Xu M, Winston EM, et al. Sleep rhythmicity and homeostasis in mice with targeted disruption of mPeriod genes. Am J Physiol Regul Integr Comp Physiol 2004;287(1): R47-R57. 110. Wisor JP, O’Hara BF, Terao A, et al. A role for cryptochromes in sleep regulation. BMC Neurosci 2002;3(1):20. 111. Laposky AD, Easton AE, Bradfield CA, et al. Null allele mice for the MOP-3 gene have increased sleep time and altered sleep consolidation. Sleep 2003;26:A110. 112. Dudley CA, Erbel-Sieler C, Estill SJ, et al. Altered patterns of sleep and behavioral adaptability in NPAS2-deficient mice. Science 2003; 301(5631):379-383. 113. Franken P, Lopez-Molina L, Marcacci L, et al. The transcription factor DBP affects circadian sleep consolidation and rhythmic EEG activity. J Neurosci 2000;20(2):617-625. 114. Shaw PJ, Tononi G, Greenspan RJ, Robinson DF. Stress response genes protect against lethal effects of sleep deprivation in Drosophila. Nature 2002;417(6886):287-291. 115. Hendricks JC, Lu S, Kume K, et al. Gender dimorphism in the role of cycle (BMAL1) in rest, rest regulation, and longevity in Drosophila melanogaster. J Biol Rhythms 2003;18(1):12-25. 116. Duez H, Staels B. Nuclear receptors linking circadian rhythms and cardiometabolic control. Arterioscler Thromb Vasc Biol 2010;30: 1529-1534.
Genetics of Sleep in a Simple Model Organism: Drosophila Ravi Allada Abstract The complexity of sleep in mammals has led to a movement toward examining simpler model systems, such as nematodes, flies, and fish, that exhibit sleep (or sleeplike states) and harbor technical advantages not evident in more conventional rodent, feline, or primate models. One system is the fruit fly Drosophila melanogaster, best known for its use for genetic studies. Remarkably, the mammalian homologues of many Drosophila genes have been found to function in a manner similar to the way they do in flies. Indeed, most human disease genes have clear fly homologues. Given the notable similarity
In contrast to studies of naturally occurring genetic variation, one can attempt to induce mutations in animal models to test whether a given gene is important for sleep. One strategy to understand the molecular basis of complex behavior such as sleep is classic or forward genetics.1 Here a population of animals is randomly mutagenized using DNA alkylating agents such as ethyl methane sulfonate (EMS) or a mobile DNA transposable element. This mutagenized population is screened for a mutant phenotype of interest, such as altered sleep. Using molecular genetic approaches, one can then identify the mutant gene responsible for the mutant phenotype. Thus, forward genetics can be used to establish causal relationships between the function of individual genes and otherwise complex phenotypes. Forward genetics is unbiased and does not require any prior knowledge about the genetic basis of the phenotype of interest and is therefore an ideal approach for studying sleep. In contrast, reverse genetics starts with a disrupted gene in search of a phenotype. Nonetheless, the finding of a gene can provide insight into biochemical and cellular pathways that are important for sleep, perhaps even providing novel diagnostic tests or targets for drug development for sleep disorders.
DROSOPHILA AS A MODEL SYSTEM FOR GENETICS Many of the model organisms in genetics, such as zebrafish (Danio rerio) and the nematode Caenorhabditis elegans, have been adopted for sleep studies because they are highly suited to the forward genetics approach.2 Here I will focus on one of the premier model systems for genetics, the fruit fly Drosophila melanogaster (Fig. 13-1, Video 13-1). The fruit fly has been a workhorse for genetic studies since pioneering studies of Thomas Hunt Morgan in the early 20th century.3 A major advantage of Drosophila over many
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13
between Drosophila and mammals, it is not surprising that fruit flies exhibit many of the defining features of sleep, including immobility, reduced responsiveness to sensory stimuli, and homeostatic regulation. Furthermore, preliminary indications are that even the genetic and pharmacologic underpinnings of sleep are conserved between flies and mammals. Here I will address why the Drosophila model is used for sleep studies, information that has been garnered in the understanding the circadian regulation of behavior, and insights into sleep regulation. These insights could prove important in understanding the genetic basis of human sleep and ultimately in answering the question of why we sleep.
alternative model systems is the ability to grow and handle large numbers relatively easily and cheaply.1 A single female can produce hundreds of offspring. In addition, it has a short generation time, about 10 to 12 days from fertilized egg to fertile adult at room temperature. Because of these traits, Drosophila has been a model par excellence for high throughput screening of mutants with altered phenotypes. The facility of genetic mapping, gene disruption using transposable elements (mobile DNA), and the full genome sequence allows one to identify mutant genes responsible for mutant phenotypes.4 Remarkably (to some), the mammalian homologues of Drosophila genes have been found to function in a similar manner to their Drosophila counterparts. Indeed, entire signaling pathways are shared between Drosophila and their mammalian counterparts. For example, most human disease genes have clear fly homologues.5 Thus, genes identified in flies will likely serve comparable functions in more complex mammalian systems, including that of humans. The conservation between flies and mammals extends to the nervous system. Although flies have only about 1/1,000,000 the number of neurons as humans (about 105 versus 1011), the fly and human genomes are surprisingly similar in gene number (14,000 versus ~22,000), with differences largely due to gene duplication.6 In fact, the fly brain uses comparable neuronal machinery, including neurotransmitters, ion channels, receptors, and signal transduction pathways. Consequently, flies have been used as valuable nervous system models for olfaction,7 vision,8 hearing,9 sexual behavior,10 synaptic transmission, axon guidance,11 and learning and memory.12 Flies have also been exploited as models for numerous human diseases including diabetes,13 aging,14 pain,15 Alzheimer’s disease,11 Parkinson’s disease,11 epilepsy,16 and fragile X mental retardation.17 Finally, flies have been successfully used to study the response to clinically important drugs such as ethanol,18 cocaine,18 and general anesthetics.19 In many of 151
152 PART I / Section 3 • Genetics of Sleep
A
Figure 13-1 Drosophila melanogaster, a genetic model organism. Shown here is a fruit fly attached to a tether with recording electrodes implanted for measurement of electrical correlates. (Photo courtesy B. Van Swinderen, Queensland Brain Institute, Australia.)
these cases, genes identified in Drosophila serve similar functions in mammalian systems.
DROSOPHILA AS A MODEL FOR STUDIES OF SLEEP Studies of Drosophila sleep have been predicated on a small but noteworthy literature examining sleeplike states in other invertebrate models such as mollusks20 and in insects such as cockroaches21 and honey bees.22,23 These classical descriptions of sleep behavior formed the basis for pursuing similar studies in Drosophila. Sleep in the fruit fly is typically measured behaviorally using the Drosophila Activity Monitoring (DAM) System developed by Trikinetics (Waltham, MA; Fig. 13-2). Single flies are placed into a small transparent glass tube plugged on one end by agar food and the other end by a porous cap, allowing air passage. Each tube is placed into a monitor that contains a series of 32 infrared emitter-detector pair, one for each tube. An awake fly moves and back and forth in the tube, periodically breaking the infrared beam. Independent methods indicate a close correlation between infrared beam breaks and overall activity. A five-minute period of inactivity (no beam breaks) has been found to be a reliable indicator of sleep. Given the remarkable similarity between Drosophila and mammals, it is not surprising that fruit flies exhibit many of the defining features of sleep. Flies exhibit extended periods of behavioral quiescence that can last for hours, and the majority of sleep typically occurs in bouts greater than 30 minutes.24 In addition, sleeping flies exhibit
B Figure 13-2 The Drosophila activity monitoring system and rotating sleep depriving box. A, The Drosophila Activity Monitoring (DAM) system. A U.S. dime (diameter = ~1.5 cm) is shown for scale and is placed over the location of infrared emitter/ detectors. B, Drosophila sleep deprivation apparatus. A DAM monitor can be placed into a slot, and the box is rotated randomly to disrupt fly sleep. (Photo courtesy B. Chung, Northwestern University, Evanston, IL.)
reduced responsiveness to sensory stimuli and exhibit homeostatic regulation.2,24-27 Video-based monitoring has also been coupled to measurements of beam breaks to provide higher spatial resolution analysis of fly sleep behavior.24,28 Drosophila sleep studies do not solely rely on measures of spontaneous movement; they also rely on responsiveness to sensory stimuli. Arousal threshold is assayed by application of a stimulus and measuring a behavioral response, typically induction of locomotor activity. During periods of extended immobility, flies are less likely to respond to a range of sensory stimuli including social, mechanical, vibratory, thermal, and visual.24,25,29,30 Although this responsiveness is typically measured behaviorally, it can also be uncoupled from movement using electrophysiologic measures.31 The typical fly demonstrates an increase in arousal threshold reaching a plateau after 5 minutes.25,30 The 5-minute criterion for sleep is in part based on this observation. Thus, one can distinguish quiet wakefulness from sleep by assessing arousal threshold. Importantly, fly sleep is under homeostatic regulation: Flies deprived of sleep rebound the following day. Flies are typically deprived of sleep mechanically using automated
CHAPTER 13 • Genetics of Sleep in a Simple Model Organism: Drosophila 153
devices or by tapping the flies by hand (see Fig. 13-2).24,25,30,32 The former must be programmed to vary the stimulus to avoid adaptation, and the latter allows one (with great patience and stamina) to deliver the stimulus selectively to sleeping flies. If a fly is deprived of sleep, it exhibits increases in sleep duration and intensity (the latter as measured by sleep bout length) the following day. Sleep rebound is not observed or is much less evident if similar deprivation protocols are applied to flies that are already awake, arguing strongly against nonspecific stress effects of mechanical disruption.24,25,30 Continuous sleep deprivation ultimately results in premature death in about 2 to 3 days32 as it does in some mammals.33 Unperturbed flies can live for 1 to 2 months. Thus, sleep is essential for life in the fly. Although flies do not display the precise electroencephalographic signatures of mammalian sleep—the synchronous changes in neural activity seen as slow waves by electroencephalogram that are diagnostic of mammalian sleep have not been observed in Drosophila29—they do exhibit electrical correlates of sleep behavior providing behavior-independent state markers. In vivo electrical correlates in behaving flies have relied on the development of novel approaches to study the fly brain. In this approach, recording electrodes are inserted into the center of the Drosophila brain and into the optic lobes of a tethered fly (see Fig. 13-1).29 Local field potentials (LFPs) are measured, reflecting neural activity near the electrode. Leg movement in the tethered fly is simultaneously monitored. There is a general, but not perfect, correlation between spikelike potentials recorded from the central brain and waking movement. If flies are exposed to a rotating stripe, LFPs in the 20- to 30-Hz frequency are observed, reflecting attention to the stimulus, but these LFPs are reduced when the fly is asleep.31 In addition, periods of poor correlation between LFPs and movement are associated with increased arousal threshold and precede behavioral quiescence.31 These approaches clearly demonstrate that differences in arousal states can be characterized using electrophysiologic correlates as they are in more-complex organisms. The differences between fly and mammalian neuroanatomy could account for the differing electrical manifestation of sleep even if the underlying molecular and cellular mechanisms are similar. Studies of eye development provide some precedent for the idea that common genetic mechanisms can underlie anatomically distinct but functionally analogous structures.34 In addition to the core features of sleep, flies also display age-related changes in sleep architecture similar to those of aging mammals. Directly following emergence from the pupal case, young flies display elevated levels of sleep similar to their mammalian counterparts.25 With increasing age, sleep becomes more fragmented and less consolidated.35 In addition, drugs that increase oxidative stress can mimic these effects.35 Thus, the fruit fly has the potential to become a valuable model for the analysis of aging effects on sleep. Mammalian sleep has been demonstrated to influence various aspects of memory consolidation.36 Similarly, flies also display sleep-loss–related deficits in learning and memory, using a number of different learning paradigms. For example, flies normally exhibit phototaxis but can be
trained to avoid light using aversive stimuli. However, flies that have reduced sleep perform more poorly on this task.37 In courtship conditioning, male flies learn to stop courting females that have already mated. Under the appropriate conditions, males can remember this experience for over 24 hours; however, if flies are subjected to sleep deprivation after training (i.e., during the period of presumed memory consolidation), they fail to retain this memory.38 Finally, waking experience—in particular, social experience—can increase subsequent sleep amount, a process that might use dopamine and cyclic adenosine monophosphate (cAMP) pathways.38 Taken together, these data implicate a reciprocal relationship between sleep–wake regulation and synaptic plasticity memory in Drosophila, as is proposed in mammals.
DROSOPHILA CIRCADIAN BEHAVIOR REVEALS CONSERVED MECHANISMS BETWEEN FLIES AND HUMANS The best case for the argument that Drosophila genetics will illuminate the genetics of human sleep has emerged from studies of circadian behavior. As in many (but not all) organisms, sleep is under temporal control by a circadian clock in Drosophila.24,25 The first identified fly circadian mutants displayed short and long period rhythms in constant conditions and phase advanced and delayed activity in light–dark conditions, analogous to human advanced and delayed sleep phase syndromes.39,40 Cloning of the genes responsible for these fly phenotypes led to breakthroughs in our understanding of the core biochemical mechanisms of circadian timing. These studies also provide an experimental roadmap for elucidating basic mechanisms of sleep homeostasis. Although circadian clocks have often been viewed solely as timekeepers, both circadian genes and their accompanying neural circuits extensively regulate sleep–wake, perhaps independent of their timing functions (see later). Thus a deeper molecular understanding of the circadian system should provide insights into the control mechanisms for sleep. Most aspects of the fly molecular clockwork are conserved with mammals, including humans (Table 13-1).41,42 Persons affected by familial advanced sleep phase
Table 13-1 Drosophila Clock Genes and Their Highly Conserved Mammalian Homologues DROSOPHILA
MAMMALS
Period
Period1,2,3
Timeless
Timeless
Clock
Clock, NPAS2
Cycle
Bmal1
Doubletime
CK1δ/ε
CK2
CK2
Cryptochrome
Cryptochrome 1,2
Clockwork orange
Dec1, 2
Slimb
β-TRCP
154 PART I / Section 3 • Genetics of Sleep
syndrome (FASPS) exhibit an advanced phase of sleep– wake rhythms and shortened circadian period that is inherited in a mendelian dominant manner.40 Mutations in the human PER2 and CK1delta genes, orthologues of fly circadian genes period and doubletime, respectively, are responsible for this advanced sleep phase.43,44 These data argue that the basic architecture and core components of circadian clocks can be traced back to the shared ancestor of flies and humans hundreds of millions of years ago. Given the close association of circadian to sleep behavior, this suggests that the basic mechanisms of sleep homeostasis might also be conserved with flies.
CELLULAR AND MOLECULAR BASIS OF DROSOPHILA SLEEP As described earlier, considerable evidence indicates that fruit flies display the core characteristics of sleep. Substantial progress has been made in identifying discrete molecular and neural circuits that convey signals to time sleep and wake behavior. Here the neural circuits that contribute to sleep–wake behavior are described and the genes that are regulated by and that regulate sleep are discussed. The emerging picture (and take-home message) is that the molecular mechanisms governing Drosophila sleep may be shared with animals that have more complex nervous systems. SPECIFIC NEURAL CIRCUITS ARE IMPORTANT FOR SLEEP–WAKE REGULATION A theme of mammalian sleep studies is the notion that discrete neural circuits are important for initiating and maintaining sleep and wake states. Using gene-based tools to study neural circuit function in live animals, distinct neural circuits have been found that regulate sleep in Drosophila. Thus far, three anatomically defined loci have been implicated in sleep–wake regulation: the mushroom bodies (MBs), the pars intercerebralis, and the circadian pacemaker neurons: the large ventral lateral neurons (lLNv) (described earlier) (Fig. 13-3). In addition to these loci, additional circuits have been defined based on their transmitter identity (e.g., dopamine). These are discussed further later. To discover novel circuits involved in sleep regulation, an approach akin to forward genetics has been employed with the modification that, instead of screening for genes, circuits are screened in an unbiased manner for behavioral functions. A cornerstone of this approach is the binary GAL4/UAS system.45,46 In one parental strain, the yeast transcription factor GAL4 is placed under the control of a tissue-specific promoter. In the second strain, the upstream activating sequence (UAS) bearing GAL4 binding sites is fused to an effector gene of interest. In the progeny of these two strains, the effector gene is expressed in the distribution specified by the tissue or circuit-specific promoter driving GAL4. Fortunately for Drosophila geneticists, there is a plethora of GAL4 lines available that provide a nearly limitless display of temporal and spatial expression patterns. In addition to the multitude of GAL4 lines, numerous UAS effector lines have been generated, including
PI MB
A PI
ILNv OL sLNv
B Figure 13-3 Neuroanatomy of Drosophila sleep–wake circuits. A, The sleep-regulatory mushroom bodies (MB) and pars intercerebralis (PI) neurons are labeled with green fluorescent protein (GFP). B, Large and small ventral lateral neurons (lLNv, sLNv, respectively) are labeled with GFP. The arousal-promoting large subset sends projections to the ipsilateral and contralateral sLNv and optic lobes (OL). sLNv sends projections to the PI.
those that have been engineered to alter specific cellular properties such as membrane excitability or synaptic transmission. While these approaches are well developed in Drosophila, they have inspired even more sophisticated strategies in mammalian models.47 A number of cellular effectors have been successfully used for Drosophila sleep studies. One tool that has been used to conditionally block synaptic transmission is the UAS-driven shibirets1 (shits1) transgene.48 shi encodes for a multimeric GTPase homologous to mammalian dynamins. SHI is required for vesicle scission, a process that is required for synaptic vesicle recycling and thus the maintenance of fast synaptic transmission. UAS-driven expression of the shits1 allele in a wild-type neuron can block synaptic transmission at an elevated restrictive temperature (e.g., 29° C) but not at the permissive temperature (e.g., 21° C). Using the GAL4/UAS system and given the fact that flies are not homeotherms, one can specifically manipulate synaptic transmission in discrete neural circuits in a live behaving animal, using temperature acting as a remote control, and then assay the behavioral consequences of circuit modulation. Tools to manipulate cellular excitability have also been developed and applied. For example, a bacterial depolarization-activated sodium channel, NaChBac, has been used to increase cellular excitability.49 On the other hand, a non-inactivating mutant
CHAPTER 13 • Genetics of Sleep in a Simple Model Organism: Drosophila 155
form of the voltage-gated Shaker potassium channel, termed electrical knockout (eko) has been used to silence neuronal activity.50 The use of these transgenic tools in combination with various GAL4 drivers led to the discovery of a sleep-regulatory role for the mushroom bodies, a bilateral neuropil well known for its role in learning and memory.12,51,52 To discover novel sleep-promoting circuits, a series of adult neural GAL4 lines were crossed with UAS-driven shits1.51 Their progeny were exposed to 12-hour cycles at restrictive (29° C) and permissive (21° C) temperatures, and the sleep behavior was examined. Reduced sleep at 29° C could be attributed to reduced synaptic transmission in the relevant neural circuits. Of nearly 100 lines tested, only a handful exhibited this reduced-sleep phenotype, suggesting that perturbation of neural function did not generally affect sleep behavior and that there are specific circuits in the fly devoted to promoting sleep. All of these lines displayed MB expression. An independent method, chemical ablation of the MBs with hydroxyurea, was also used to assess MB sleep function. Hydroxyurea fed to larvae during the appropriate developmental time (first-instar) selectively ablates the neuroblasts that give rise to the large majority of the MBs.53 Like their shits1-expressing counterparts, flies fed hydroxyurea exhibited reduced sleep,51,52 and in both cases the reduced sleep was largely due to reduced sleep bout length—in other words, an inability to maintain sleep.51 In addition, flies with impaired or absent MBs exhibited a reduced lifespan consistent with a loss of restorative sleep.51 Thus, these flies are analogous to insomniac humans who are unable to maintain sleep and suffer adverse consequences as a result. Although these observations suggest a sleep-promoting role for the MBs, other data using a different MB-GAL4 line suggest that the MBs might also promote wakefulness. These studies made use of a modified version of GAL4 called Gene Switch, in which the GAL4 is fused to the ligand-binding domain (LBD) of the progesterone receptor.54 In the absence of the ligand RU-486, the LBD retains GAL4 in the cytoplasm, rendering it inactive. In the presence of ligand, the LBD-GAL4 fusion is released to the nucleus, where the GAL4 binds its target UAS DNA sites and transcription can be initiated. RU-486 can be selectively delivered to adult flies by feeding to avoid any developmental effects of GAL4-driven gene expression. Using a version of Gene Switch that is driven by an MBspecific promoter,55 the silencing transgene eko resulted in increased sleep while expression of the activating NachBac transgene reduced sleep, suggesting that MB neuron activity increases wake.52 One possibility is that different subsets of MB neurons play opposing roles in sleep regulation. The finding that a part of the brain important for learning and memory is also important for sleep further supports the idea that sleep and memory consolidation are closely linked in the fly. Flies that lack MBs demonstrate both spontaneous sleep (albeit reduced) and a robust homeostatic response, indicating that other brain loci promote sleep. One such locus is the pars intercerebralis (PI), a neuroendocrine cluster considered genetically analogous to the mammalian hypothalamus.56 Targeted decreases in epidermal growth factor
(EGF) function in the PI result in reduced sleep.57 The PI may be a direct target of circadian pacemaker neurons. The dorsal projections of a subset of circadian pacemaker neurons, the small ventral lateral neurons (sLNv), terminate in close proximity to the PI neuron soma (see Fig. 13-3), and loss of the key peptide transmitter of these neurons, pigment dispersing factor (PDF), affects molecular circadian rhythms in PI neurons.58 In addition to sleep–wake circuits in the MBs and PI, the circadian pacemaker lLNv neurons promote wake fulness (see Fig. 13-3). Excitation of the lLNv using NaChBac or a novel tool, TrpA1, reduces sleep, especially at night.59-61 TrpA1 encodes for a cation channel that is activated at elevated temperatures, allowing conditional temperature-dependent regulation similar to the shits1 system.62 Selective ablation of the lLNv results in increased sleep.60 The vigilance affect is similar to that observed in animals in which the mammalian circadian pacemaker, the suprachiasmatic nucleus, is ablated.63 An important molecular effector of PDF+ pacemaker neuron functions in sleep is the transcription factor ATF-2, a member of the ATF/ CREB (activating transcription factor/cAMP response element binding) family.64 The activity of these arousalpromoting neurons appears to be inhibited by gammaaminobutyric acid (GABA),61 a relationship that is reminiscent of a similar organization of mammalian sleep circuits.65
GENETICS AND PHARMACOLOGY OF SLEEP: WHICH MOLECULES REGULATE SLEEP? The power of the Drosophila system lies in the ability to identify genes whose function is important for sleep. One strategy is to manipulate the function of genes and assay the consequences on sleep. In addition, traditional pharmacologic approaches have complemented genetics to identify pathways whose function is important for sleep. Finally, genomic approaches have been applied to identify genes whose expression is regulated by sleep–wake state. The discovery of novel sleep genes in Drosophila using genetics has relied on a combination of candidate-gene approaches and classical forward genetics. Unbiased largescale screens are especially powerful because they tend to identify the strongest contributors to a process among thousands of mutagenized candidates. Not surprisingly, identified genes are involved in various aspects of neural function, including genes involved in stress and immune responses, signal transduction, neurotransmitter or neuromodulator function, and cellular excitability. These studies suggest that many sleep pathways are conserved between flies and mammals and support the notion that studies in Drosophila should yield insights into the molecular basis of sleep in more complex systems. Circadian Clock Pathway As in many mammalian species, sleep is under the control of a circadian clock in Drosophila.24,25 Mutations in the core clock transcription factors Clock (Clk) and cycle (cyc) result in reduced sleep.66 However, in certain arrhythmic mutants, such as per01, sleep homeostasis is intact consistent with the two-process model.24,25 Some of these clock gene effects
156 PART I / Section 3 • Genetics of Sleep
are likely mediated by the PDF neuropeptide through its function in the arousal promoting lLNv (see Fig. 13-3).60,61 Stress and Immune Pathways Studies of the role of the circadian clock gene cyc led to the discovery of a role for heat-shock stress-response genes in sleep homeostasis. Female, but not male, cyc mutants display an exaggerated sleep rebound.32,66 In addition, cyc mutants, both male and female, are hypersensitive to the lethal effects of sleep deprivation.32 These phenotypes are likely due to a noncircadian cyc function, because other clock mutants fail to display these phenotypes.32 They do not reflect a general impairment in stress response because cyc flies are not sensitive to other stressors. These effects appear to be due to inadequate expression of heat-shock proteins (HSPs), protein chaperones important in the cellular response to stresses, such as elevated temperature. Heat shocking flies before sleep deprivation, which induces hsp transcription, rescues the premature lethality due to sleep deprivation.32 Moreover, mutants of the heat-shock protein 83 (hsp83) gene also display hypersensitivity to the lethal effects of sleep deprivation.32 This study suggests that the heat-shock stress response is an important pathway for defending against the adverse consequences (i.e., death) of sleep loss. In addition to the heat-shock stress pathway, endoplasmic reticulum stress responses might also be crucial for sleep homeostasis. The endoplasmic reticulum (ER) stress pathway both is regulated by and regulates sleep. The ER chaperone, BiP, is upregulated during wake and during sleep deprivation.25,67 In addition, the amount of rebound sleep following sleep deprivation is dependent on BiP levels.67 BiP plays an important role in the stabilization and translocation of newly synthesized secretory proteins from the cytosol to the ER. BiP is also upregulated as part of the unfolded protein response (UPR), which is activated in response to an abundance of unfolded proteins in the ER. The UPR is also upregulated in mammals in response to sleep deprivation.68 These data suggest that the UPR response, and subsequent BiP activation, might occur as a consequence of extended wakefulness and suggest a central role for ER stress pathways in sleep homeostasis. Another important regulator of Drosophila sleep is the immune response. Infection resistance and immuneresponse genes, including the immune system master regulator NFκB Relish, are upregulated in response to sleep deprivation.69 Reductions in Relish function in the fat bodies, a key immune-response tissue in Drosophila, results in reduced sleep.69 Notably, the immune-related cytokines are important regulators of sleep in mammals.70 Membrane Excitability The role for membrane excitability in sleep regulation is evident from studies using engineered heterologous transgenes, such as eko and Nachbac (see earlier); however, these studies leave open the question of which specific channels normally underlie sleep function. Studies in Drosophila have highlighted the function of the voltage-gated potassium channel Shaker (Sh). The Sh mutant was discovered several decades ago as a mutant whose legs shake under ether anesthesia.71 Positional cloning of this mutant led to the identification of the first voltage-gated potassium
channel and subsequently several similar channels in mammals, highlighting the similarity in fly and mammalian nervous system components.72-74 Independent unbiased mutagenesis screens identified mutants in the SH potassium channel and a novel SH regulator, called SLEEPLESS (SSS), that exhibit dramatically reduced sleep amounts, losing as much as 80% of total sleep in an sss mutant.75,76 sss encodes a glycosylphosphatidyl-linked membrane protein that is potentially released into the extracellular space to promote SH expression.76 In addition, mutants of an SH regulatory subunit Hyperkinetic (Hk), also exhibit a reduced sleep phenotype.77 Both Sh and sss mutant flies fail to exhibit large changes in waking locomotor activity, suggesting a primary role in regulating the transition between sleep and waking states.75,76 Both Sh and sss mutants display reduced lifespan, although it is not clear if this is a primary consequence of their reduced sleep.75,76 Sh and sss mutant differ in that Sh mutants display intact sleep rebound after sleep deprivation but sss mutants exhibit reduced sleep rebound.75,76 It is not yet clear what the basis for this difference is. Shortsleeping Sh and Hk mutants display reduced memory in a short-term memory paradigm, providing a genetic link between reduced sleep and cognitive function.77 SH sleep function is highly conserved as genetic inactivation of mammalian SH orthologues also results in reduced sleep.78,79 The magnitude of the sleep-duration phenotypes in both Sh and sss mutants, coupled to their independent isolation in unbiased screens and conserved functions in mammals, highlights the central role of SH and membrane excitability in sleep regulation. Growth Factors and Signal Transduction Two other gene classes that have been implicated in sleepwake regulation are growth factors, which activate intracellular signaling pathways, and components of intracellular signal-transduction pathways. The growth factor most strongly and broadly relevant is epidermal growth factor (EGF). EGF, like other growth factors, is processed and then secreted to activate cell-surface receptors, which act as tyrosine protein kinases that autophosphorylate, leading to activation of intracellular signaling cascades. The function of EGF was uncovered by the combination of the GAL4/UAS system and RNA interference (RNAi).64,80 UAS-driven RNAi transgenes are constructed to express inverted repeats corresponding to a gene of interest. The inverted repeat RNAi base pairs with itself, forming a double-stranded hairpin RNA (hpRNA). The hpRNA is recognized by the cellular RNAi machinery and processed into small interfering RNAs (siRNAs). siRNAs in turn base pair with endogenous transcripts of a given gene, targeting them for degradation by the RNAi machinery. Genome-wide libraries of UAS-RNAi transgenic flies have been established, allowing one to knockdown virtually any gene in the Drosophila genome in a spatially and temporally targeted manner.81 rho and star encode two processing proteins important for EGF action.57 rho and star induction increases sleep, and rho knockdown using RNA interference reduces sleep.57 EGF appears to be released by the neuroendocrine cells of the pars intercerebralis, a potential fly analogue of the hypothalamus, to promote sleep.57 EGF and its related
CHAPTER 13 • Genetics of Sleep in a Simple Model Organism: Drosophila 157
set of ligands (e.g., transforming growth factor α) appear to serve similar functions in promoting sleep in C. elegans82 and mammals,83,84 suggesting an ancient sleep function for EGF. Components of the cAMP signaling pathway also play conserved roles in sleep regulation. Various neurotransmitters act at cell-surface G protein–coupled receptors (GPCR) to activate intracellular signal transduction cascades via metabotropic receptors (e.g., dopamine). Activation of the G protein–coupled receptors, such as dopamine receptors, leads to an increase or decrease in adenylate cyclase, which modulates cAMP levels. cAMP in turn activates protein kinase A (PKA), which phosphorylates a number of targets, including the transcription factor CREB (cAMP response element binding protein). Mutants affecting this pathway increase activity (e.g., increase cAMP or PKA activity) resulting in increased wake while mutants that decrease cAMP flux generally reduced wake.52,85 Furthermore, CREB activity is linked to sleep homeostasis as a CRE reporter gene is upregulated in response to sleep deprivation and reduced CREB activity results in an elevated sleep rebound.85 In addition to a wake-promoting role for this pathway in Drosophila, the cAMP pathway serves similar functions in both nematodes and mice.86,87 Many of the mutations that affect the cAMP pathway were originally isolated in unbiased genetic screens for mutations that disrupt learning and memory. Thus, signaling important for sleep and memory might intersect at cAMP pathways. Arousal Neurotransmitters: Monoaminergic Arousal Pathways A number of different neurotransmitters and neuromodulators have been shown to play important roles in sleep regulation. Although the anatomic organization of the Drosophila brain is distinct from that in mammals, flies use similar neurotransmitters and receptors. Indeed, it appears that flies use transmitters to regulate sleep similar to those used in mammals. In mammals, monoamine transmitters, such as dopamine, histamine, and norepinephrine, generally promote wake or arousal.88 Similarly in flies, these monoamines or their fly counterparts also promote wake, suggesting that the nervous system of the common ancestor of flies and mammals used similar arousal transmitters. The monoamine most strongly linked to arousal in Drosophila is dopamine. Mutants of the dopamine transporter fumin exhibit dramatically reduced sleep duration (about 50%).89,90 Mutants in this gene were also identified in a large-scale unbiased genetic screen for sleep mutants.90 The psychostimulant methamphetamine, which is thought to increase dopaminergic neurotransmission, also reduces sleep.91 When awake, flies treated with methamphetamine display increased spontaneous locomotor activity as well as hyperresponsiveness to mechanosensory stimuli, suggesting that these flies were hyperaroused.89-91 In addition, although its mechanism of action remains unclear, the clinically prescribed wake-promoting drug modafinil might operate by enhancing dopaminergic neurotransmission.92 Importantly, modafinil has similar wake-promoting properties in Drosophila.93 Dopamine, or other monoamines, might also play a role in the homeostatic response to sleep deprivation. The aryl
alkamine acetyltransferase gene (Dat), involved in monoamine catabolism, is upregulated in response to sleep deprivation, and Dat mutants exhibit an exaggerated sleep rebound.25 However, dopamine transporter mutants exhibit either normal90 or reduced rebound.89 Dopamine might exert its wake-promoting effects by acting at the MBs, a major locus for sleep–wake regulation (see earlier). Dopaminergic neurons densely innervate the MBs.94 In addition, dopamine D1 receptor (dDA1) activation in the MBs might mediate the wake-promoting effects of caffeine95 and can mitigate the effects of sleep loss in an MD-dependent learning paradigm.37 One possibility is that sleep and memory functions overlap in the MBs, an important site for the function of adenylate cyclase in short-term memory96 and PKA activity in sleep.52 The connection between sleep and memory is particularly intriguing given the proposed function of sleep in regulating synaptic plasticity. Taken together, these data indicate that dopamine is an important transmitter for arousal and cognitive function in Drosophila. Two other monoaminergic transmitters implicated in fly arousal are octopamine and histamine. Octopamine is thought to serve as a functional homologue of mammalian norepinephrine. Genetically reduced octopamine synthesis or octopamine neuron activity results in increased sleep, which can be rescued in the former case by pharmacologically restoring octopamine.97 These effects require PKA but do not operate through the MB.97 Histamine has been implicated principally by pharmacology. The H1 receptor antagonist hydroxyzine induces sleep and reduced sleep latency in flies,25 suggesting conserved functions for histamine. Not all monoamines promote arousal in Drosophila (e.g., serotonin98). In addition, the arousal-promoting orexin neuropeptide, which is important in human narcolepsy, has not yet been reported in Drosophila. Nonetheless, the role for monoamines in promoting arousal in mammals is largely preserved in Drosophila. Sleep Neurotransmitters: GABA and Adenosine Sleep Pathways A crucial neurotransmitter for sleep promotion in both flies and mammals is the inhibitory neurotransmitter GABA. Many of the most commonly prescribed hypnotics act at inotropic GABA receptors, promoting GABAergic neurotransmission.99 To test the role of GABAergic neurotransmission in Drosophila sleep, the hyperpolarizing Shaw potassium channel was expressed in GABAergic neurons to silence their activity.100 Targeted expression was accomplished using a GAL4 driven by the promoter glutamic acid decarboxylase, a key enzyme in GABA biosynthesis (GAD-GAL4). Shaw expression resulted in reduced sleep, consistent with a sleep-promoting role for these neurons.100 In Drosophila, a mutation in one GABA(A) receptor subunit gene is responsible for resistance to the dieldrin insecticide, hence its name: resistant to dieldrin (RDL). These receptors rapidly desensitize upon GABA activation, and this process is reduced in insecticide-resistant Rdl mutants, prolonging GABA-activated currents.100 Flies typically fall asleep soon after transfer from light to dark. In these Rdl mutants, this latency to sleep is reduced, consistent with an important role for GABA in promoting sleep in Drosophila.100 Rdl might promote sleep in part by
158 PART I / Section 3 • Genetics of Sleep
reducing the activity of PDF arousal-promoting neurons (see earlier, and see Fig. 13-3).61 Given the conserved role for inotropic GABA receptors in sleep regulation, it will be interesting to see if flies respond to many clinically used hypnotics that target this receptor class. Adenosine is thought to play a critical role in sleep homeostasis in mammals.101 Adenosine has been implicated in the promotion of sleep in Drosophila. Adenosine, a metabolic product of ATP, acts through specific G protein–coupled receptors.101 The stimulant effects of caffeine are thought to operate by antagonizing adenosine receptors. Flies fed caffeine exhibit reduced sleep, and flies administered cyclohexyladenosine, an adenosine agonist, exhibit increased sleep.24,25 As mentioned earlier, these effects may be mediated by dopamine receptor function in the MBs.95 The conservation of these central sleep-promoting pathways suggests an ancient function for GABA and adenosine.
WHICH GENES ARE REGULATED BY SLEEP–WAKE? Although the focus of classic genetics is to identify genes whose function is important for a process of interest, it is also of interest to determine how sleep–wake might in turn regulate gene function or expression. A number of sleep– wake-sensitive changes in gene expression have been described, including the activity of a CRE reporter,85 upregulation of the ER chaperone, BiP,67 and immunesystem genes.69 The most extensive attempts at identifying sleep–wake-regulated genes have used DNA microarrays to assess genome-wide gene expression under conditions of sleep, wake, and sleep deprivation.102,103 To control for circadian regulation of gene expression, sleep-deprived and spontaneously asleep animals are analyzed at the same circadian time. By identifying the genes that correlate with a behavioral state, one is presumably identifying factors that sustain or reflect that state. In addition, one can monitor gene expression linked to homeostatic drive by screening for genes whose expression increases with the duration of wakefulness. These changes in gene expression might provide clues to the molecular processes occurring during sleep and thus might reveal its underlying function. SUMMARY Since the turn of the 21st century, the fruit fly model of sleep has been validated as an important model for the study of sleep. The fly has many of the core features of sleep in common with mammalian systems. Many features of Drosophila sleep are independent of changes in spontaneous movement and include elevated arousal threshold, homeostatic regulation, electrophysiologic correlates, and conserved responses to sleep–wake regulatory drugs. In addition, genetic screens have identified shared genes and pathways of sleep control with their mammalian relations. Future work exploiting the power of genetics in this model organism promises to reveal the underlying molecular and cellular mechanisms of sleep regulation and ultimately provide some clues to the function of sleep.104
❖ Clinical Pearl Chronic sleep loss can lead to adverse health consequences. Indeed, sleep deprivation in the fruit fly leads to premature death.
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CHAPTER 13 • Genetics of Sleep in a Simple Model Organism: Drosophila 159 28. Zimmerman JE, Raizen DM, Maycock MH, Maislin G, et al. A video method to study Drosophila sleep. Sleep 2008;31(11): 1587-1598. 29. Nitz DA, van Swinderen B, Tononi G, Greenspan RJ. Electrophysiological correlates of rest and activity in Drosophila melanogaster. Curr Biol 2002;12(22):1934-1940. 30. Huber R, Hill SL, Holladay C, Biesiadecki M, et al. Sleep homeostasis in Drosophila melanogaster. Sleep 2004;27(4):628-639. 31. van Swinderen B, Nitz DA, Greenspan RJ. Uncoupling of brain activity from movement defines arousal states in Drosophila. Curr Biol 2004;14(2):81-87. 32. Shaw PJ, Tononi G, Greenspan RJ, Robinson DF. Stress response genes protect against lethal effects of sleep deprivation in Drosophila. Nature 2002;417(6886):287-291. 33. Rechtschaffen A, Gilliland MA, Bergmann BM, Winter JB. Physiological correlates of prolonged sleep deprivation in rats. Science 1983;221(4606):182-184. 34. Kumar JP, Moses K. Eye specification in Drosophila: perspectives and implications. Semin Cell Dev Biol 2001;12(6):469-474. 35. Koh K, Evans JM, Hendricks JC, Sehgal A. From the cover: a Drosophila model for age-associated changes in sleep:wake cycles. Proc Natl Acad Sci U S A 2006;103(37):13843-13847. 36. Stickgold R, Walker MP. Sleep-dependent memory consolidation and reconsolidation. Sleep Med 2007;8(4):331-343. 37. Seugnet L, Suzuki Y, Vine L, Gottschalk L, et al. D1 receptor activation in the mushroom bodies rescues sleep-loss-induced learning impairments in Drosophila. Curr Biol 2008;18(15):1110-1117. 38. Ganguly-Fitzgerald I, Donlea J, Shaw PJ. Waking experience affects sleep need in Drosophila. Science 2006;313(5794):17751781. 39. Konopka RJ, Benzer S. Clock mutants of Drosophila melanogaster. Proc Natl Acad Sci U S A 1971;68(9):2112-2116. 40. Jones CR, Campbell SS, Zone SE, Cooper F, et al. Familial advanced sleep-phase syndrome: a short-period circadian rhythm variant in humans. Nat Med 1999;5(9):1062-1065. 41. Zheng X, Sehgal A. Probing the relative importance of molecular oscillations in the circadian clock. Genetics 2008;178(3):11471155. 42. Takahashi JS, Hong HK, Ko CH, McDearmon EL. The genetics of mammalian circadian order and disorder: implications for physiology and disease. Nat Rev Genet 2008;9(10):764-775. 43. Toh KL, Jones CR, He Y, Eide EJ, et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 2001;291(5506):1040-1043. 44. Xu Y, Padiath QS, Shapiro RE, Jones CR, et al. Functional consequences of a CKIdelta mutation causing familial advanced sleep phase syndrome. Nature 2005;434(7033):640-644. 45. Brand AH, Perrimon N. Targeted gene expression as a means of altering cell fates and generating dominant phenotypes. Development 1993;118(2):401-415. 46. Phelps CB, Brand AH. Ectopic gene expression in Drosophila using GAL4 system. Methods 1998;14(4):367-379. 47. Zhang F, Aravanis AM, Adamantidis A, de Lecea L, et al. Circuitbreakers: optical technologies for probing neural signals and systems. Nat Rev Neurosci 2007;8(8):577-581. 48. Kitamoto T. Conditional modification of behavior in Drosophila by targeted expression of a temperature-sensitive shibire allele in defined neurons. J Neurobiol 2001;47(2):81-92. 49. Nitabach MN, Wu Y, Sheeba V, Lemon WC, et al. Electrical hyperexcitation of lateral ventral pacemaker neurons desynchronizes downstream circadian oscillators in the fly circadian circuit and induces multiple behavioral periods. J Neurosci 2006;26(2): 479-489. 50. White BH, Osterwalder TP, Yoon KS, Joiner WJ, et al. Targeted attenuation of electrical activity in Drosophila using a genetically modified K+ channel. Neuron 2001;31(5):699-711. 51. Pitman JL, McGill JJ, Keegan KP, Allada R. A dynamic role for the mushroom bodies in promoting sleep in Drosophila. Nature 2006;441(7094):753-756. 52. Joiner WJ, Crocker A, White BH, Sehgal A. Sleep in Drosophila is regulated by adult mushroom bodies. Nature 2006;441(7094): 757-760. 53. de Belle JS, Heisenberg M. Associative odor learning in Drosophila abolished by chemical ablation of mushroom bodies. Science 1994;263(5147):692-695.
54. Osterwalder T, Yoon KS, White BH, Keshishian H. A conditional tissue-specific transgene expression system using inducible GAL4. Proc Natl Acad Sci U S A 2001;98(22):12596-12601. 55. Mao Z, Roman G, Zong L, Davis R. Pharmacogenetic rescue in time and space of the rutabega memory impairment by using GeneSwitch. Proc Natl Acad Sci U S A 2004;101:198-203. 56. de Velasco B, Erclik T, Shy D, Sclafani J, et al. Specification and development of the pars intercerebralis and pars lateralis, neuroendocrine command centers in the Drosophila brain. Dev Biol 2007;302(1):309-323. 57. Foltenyi K, Greenspan RJ, Newport JW. Activation of EGFR and ERK by rhomboid signaling regulates the consolidation and maintenance of sleep in Drosophila. Nat Neurosci 2007;10(9):11601167. 58. Jaramillo AM, Zheng X, Zhou Y, Amado DA, et al. Pattern of distribution and cycling of SLOB, Slowpoke channel binding protein, in Drosophila. BMC Neurosci 2004;5(1):3. 59. Sheeba V, Fogle KJ, Kaneko M, Rashid S, et al. Large ventral lateral neurons modulate arousal and sleep in Drosophila. Curr Biol 2008;18(20):1537-1545. 60. Shang Y, Griffith LC, Rosbash M. Light-arousal and circadian photoreception circuits intersect at the large PDF cells of the Drosophila brain. Proc Natl Acad Sci U S A 2008;105(50):1958719594. 61. Parisky KM, Agosto J, Pulver SR, Shang W, et al. PDF cells are a GABA-responsive wake-promoting component of the Drosophila sleep circuit. Neuron 2008;60(4):672-682. 62. Hamada FN, Rosenzweig M, Kang K, Pulver SR, et al. An internal thermal sensor controlling temperature preference in Drosophila. Nature 2008;454(7201):217-220. 63. Edgar DM, Dement WC, Fuller CA. Effect of SCN lesions on sleep in squirrel monkeys: evidence for opponent processes in sleep-wake regulation. J Neurosci 1993;13(3):1065-1079. 64. Shimizu H, Shimoda M, Yamaguchi T, Seong KH, et al. Drosophila ATF-2 regulates sleep and locomotor activity in pacemaker neurons. Mol Cell Biol 2008;28(20):6278-6289. 65. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437(7063):1257-1263. 66. Hendricks JC, Lu S, Kume K, Yin JC, et al. Gender dimorphism in the role of cycle (BMAL1) in rest, rest regulation, and longevity in Drosophila melanogaster. J Biol Rhythms 2003;18(1):12-25. 67. Naidoo N, Casiano V, Cater J, Zimmerman J, et al. A role for the molecular chaperone protein BiP/GRP78 in Drosophila sleep homeostasis. Sleep 2007;30(5):557-565. 68. Naidoo N, Giang W, Galante RJ, Pack AI. Sleep deprivation induces the unfolded protein response in mouse cerebral cortex. J Neurochem 2005;92(5):1150-1157. 69. Williams JA, Sathyanarayanan S, Hendricks JC, Sehgal A. Interaction between sleep and the immune response in Drosophila: a role for the NFκB relish. Sleep 2007;30(4):389-400. 70. Majde JA, Krueger JM. Links between the innate immune system and sleep. J Allergy Clin Immunol 2005;116(6):1188-1198. 71. Kaplan WD, Trout WE 3rd. The behavior of four neurological mutants of Drosophila. Genetics 1969;61(2):399-409. 72. Tempel BL, Papazian DM, Schwarz TL, Yan YN, et al. Sequence of a probable potassium channel component encoded at Shaker locus of Drosophila. Science 1987;237(4816):770-775. 73. Papazian DM, Schwarz TL, Tempel BL, Yan YN, et al. Cloning of genomic and complementary DNA from Shaker, a putative potassium channel gene from Drosophila. Science 1987;237(4816): 749-753. 74. Tempel BL, Jan YN, Jan LY. Cloning of a probable potassium channel gene from mouse brain. Nature 1988;332(6167):837-839. 75. Cirelli C, Bushey D, Hill S, Yan YN, et al. Reduced sleep in Drosophila Shaker mutants. Nature 2005;434(7037):1087-1092. 76. Koh K, Joiner WJ, Wu MN, Yue Z, et al. Identification of SLEEPLESS, a sleep-promoting factor. Science 2008;321(5887):372-376. 77. Bushey D, Huber R, Tononi G, Cirelli C. Drosophila Hyperkinetic mutants have reduced sleep and impaired memory. J Neurosci 2007;27(20):5384-5393. 78. Douglas CL, Vyazovskiy V, Southard T, Chiu SY, et al. Sleep in Kcna2 knockout mice. BMC Biol 2007;5:42. 79. Espinosa F, Torres-Vega MA, Marks GA, Joho RH. Ablation of Kv3.1 and Kv3.3 potassium channels disrupts thalamocortical oscillations in vitro and in vivo. J Neurosci 2008;28(21):5570-5581.
160 PART I / Section 3 • Genetics of Sleep 80. Kavi HH, Fernandez H, Xie W, Birchler JA. Genetics and biochemistry of RNAi in Drosophila. Curr Top Microbiol Immunol 2008;320:37-75. 81. Dietzl G, Chen D, Schnorrer F, Su KC, et al. A genome-wide transgenic RNAi library for conditional gene inactivation in Drosophila. Nature 2007;448(7150):151-156. 82. Van Buskirk C, Sternberg PW. Epidermal growth factor signaling induces behavioral quiescence in Caenorhabditis elegans. Nat Neurosci 2007;10(10):1300-1307. 83. Kushikata T, Fang J, Chen Z, Wang Y, et al. Epidermal growth factor enhances spontaneous sleep in rabbits. Am J Physiol 1998;275(2 Pt 2):R509-R514. 84. Kramer A, Yang FC, Snodgrass P, Li X, et al. Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science 2001;294(5551):2511-2515. 85. Hendricks JC, Williams JA, Panckeri K, Kirk D, et al. A non-circadian role for cAMP signaling and CREB activity in Drosophila rest homeostasis. Nat Neurosci 2001;4(11):1108-1115. 86. Raizen DM, Zimmerman JE, Maycock MH, Ta UD, et al. Lethargus is a Caenorhabditis elegans sleep-like state. Nature 2008; 451(7178):569-572. 87. Graves LA, Hellman K, Veasey S, Blendy JA, et al. Genetic evidence for a role of CREB in sustained cortical arousal. J Neurophysiol 2003;90(2):1152-1159. 88. Saper CB, Lu J, Chou TC, Gooley J. The hypothalamic integrator for circadian rhythms. Trends Neurosci 2005;28(3):152-157. 89. Kume K, Kume S, Park SK, Hirsh J, et al. Dopamine is a regulator of arousal in the fruit fly. J Neurosci 2005;25(32):7377-7384. 90. Wu MN, Koh K, Yue Z, Joiner WJ, et al. A genetic screen for sleep and circadian mutants reveals mechanisms underlying regulation of sleep in Drosophila. Sleep 2008;31(4):465-472. 91. Andretic R, van Swinderen B, Greenspan RJ. Dopaminergic modulation of arousal in Drosophila. Curr Biol 2005;15(13):11651175.
92. Wisor JP, Nishino S, Sora I, Uhl GH, et al. Dopaminergic role in stimulant-induced wakefulness. J Neurosci 2001;21(5):1787-1794. 93. Hendricks JC, Kirk D, Panckeri K, Miller MS, et al. Modafinil maintains waking in the fruit fly Drosophila melanogaster. Sleep 2003;26(2):139-146. 94. Zhang K, Guo JZ, Peng Y, Xi W, et al. Dopamine-mushroom body circuit regulates saliency-based decision-making in Drosophila. Science 2007;316(5833):1901-1904. 95. Andretic R, Kim YC, Jones FS, Han KA, et al. Drosophila D1 dopamine receptor mediates caffeine-induced arousal. Proc Natl Acad Sci U S A 2008;105(51):20392-20397. 96. Zars T, Fischer M, Schulz R, Heisenberg M. Localization of a short-term memory in Drosophila. Science 2000;288(5466): 672-675. 97. Crocker A, Sehgal A. Octopamine regulates sleep in Drosophila through protein kinase A-dependent mechanisms. J Neurosci 2008;28(38):9377-9385. 98. Yuan Q, Joiner WJ, Sehgal A. A sleep-promoting role for the Drosophila serotonin receptor 1A. Curr Biol 2006;16(11):1051-1062. 99. Gottesmann C. GABA mechanisms and sleep. Neuroscience 2002;111(2):231-239. 100. Agosto J, Choi JC, Parisky KM, Stilwell G, et al. Modulation of GABA(A) receptor desensitization uncouples sleep onset and maintenance in Drosophila. Nat Neurosci 2008;11(3):354-359. 101. Basheer R, Strecker RE, Thakkar MM, McCarley RW. Adenosine and sleep-wake regulation. Prog Neurobiol 2004;73(6):379-396. 102. Zimmerman JE, Rizzo W, Shockley KR, Raizen DM, et al. Multiple mechanisms limit the duration of wakefulness in Drosophila brain. Physiol Genomics 2006;27(3):337-350. 103. Cirelli C, LaVaute TM, Tononi G. Sleep and wakefulness modulate gene expression in Drosophila. J Neurochem 2005;94(5):14111419. 104. Bushey D, Hughes KA, Tononi G, Cirelli C. Sleep, aging, and lifespan in Drosophila. BMC Neurosci 2010;11:56.
Genetic Basis of Sleep in Rodents Bruce F. O’Hara, Fred W. Turek, and Paul Franken Abstract This chapter explores the progress and various approaches toward identifying genes important for an understanding of sleep and sleep-related traits in rodents. Until the functions of sleep are more clearly defined, it may be difficult to uncover the core genetic basis for sleep and the core molecular events that underlie this fundamental behavior in most, if not all, animal species. However, similar to other areas of medicine, an understanding of the underlying genetics will become
As discussed throughout the genetics section of this volume, genes and their allelic variants are important for an understanding of sleep for various reasons. For example, genetic analyses can allow researchers to identify critical functions and the core molecular pathways involved in normal sleep or in sleep disorders. This includes genes that play a role in the possible functional restorations of sleep such as energy state, protein levels, or some types of synaptic optimization (including, but not limited to, learning and memory). Genes and gene regulation may or may not be directly critical to the regulation of sleep–wake transition traits; nevertheless, genes still code for the proteins that are critical to all biological functions, and genetic analyses might still provide the keys for finding these functions. For example, state-to-state transitions between non– rapid eye movement (NREM) sleep, rapid eye movement (REM) sleep, and wake are probably too rapid to be regulated directly by gene expression but more likely involve posttranslational changes in ion channels or other proteins that alter membrane potential. Such proteins and the kinases and other proteins that alter their status are encoded by genes, and these genes most likely have allelic variation in murine and human populations that contribute to variations in sleep behavior. As a remarkable example of this, see the story of the sleepless mutation in Drosophila1 discussed in Chapter 13, which supports the idea that hyperpolarization of neurons and ion channel regulation are a fundamental feature of sleep–wake regulation in all animals. This chapter addresses various approaches to finding genes and gene alleles that influence sleep behavior. The genes that regulate sleep might or might not be different from those that are involved in the functional restorations that sleep may provide. Similarly, some genes that alter electroencephalogram (EEG) traits might or might not be central to the understanding of the function of sleep. In addition, a large group of genes vary their expression across sleep and wake, some of which are probably important to downstream functions relevant to sleep and wake even if they themselves are not core sleep-regulating genes.
Chapter
14
increasingly important in sleep medicine. At this time, rodents represent the best animal models for such studies, especially the many genetically modified mouse lines that have been created and the mouse strains that form important genetic reference populations for a wide range of biomedical research. Given the similarities in physiology and genetics across eutherian mammals, it is likely that genes influencing sleep traits in mice also influence sleep traits in humans, or they can at least help identify the most critical molecular pathways and networks.
To help understand the current state of the art in these various approaches towards understanding sleep, this chapter is divided into sections based on the most important general methodologies used to identify genetic mechanisms: • Changes in gene expression, or more precisely changes in steady-state specific messenger RNA (mRNA) levels, during sleep and wake. The majority of these genes might simply be responding to arousal state, but some of these genes are likely to be critical components in the regulation of sleep–wake traits. • Identification of naturally occurring allelic variants that underlie individual differences or strain differences in sleep-related traits. Some of these genes are likely to be important in sleep regulation or functional aspects of sleep, although many might represent pleiotropic genes that only indirectly alter sleep. Nevertheless, such genes and associated gene networks might still be important for understanding the underlying physiologic and pathophysiologic mechanisms that underlie normal sleep as well as sleep disorders. We particularly emphasize the quantitative trait locus (QTL) approach in uncovering the allelic variants influencing sleep–wake phenotypes. • Identification of genes that regulate sleep or influence sleep-related traits using mutagenesis and transgenic strategies. These approaches artificially alter or knockout genes to find those that influence sleep.
GENE EXPRESSION, mRNAs, AND MICROARRAY STUDIES The first class of genes that was clearly shown to vary across sleep and wake were rapid response genes, often called immediate early genes (IEGs) such as Fos.2-4 Changes in expression of IEGs are of interest for at least two reasons. Because most IEG mRNAs and proteins increase with neuronal activity, they can be used to identify brain regions activated by changes in arousal state. Second, because most IEGs are transcription factors, they might represent 161
162 PART I / Section 3 • Genetics of Sleep
master-switch genes that initiate a complex of molecular signaling cascades.5 These pathways may be important for longer-term homeostatic control or restorative functions critical to sleep and wake. Most brain regions are more active during wake than during NREM sleep, and they thus show higher levels of expression of IEGs during wake.2-4 This includes virtually all of the cerebral cortex, although even here there is an interesting exception. A small subset of gamma-aminobutyric acid–ergic (GABAergic) neurons that express nNOS (neuronal nitric oxide synthase) increase Fos expression during NREM sleep.6 Consistent data (for the increased Fos expression) were obtained in three different rodent species (mouse, rat, and hamster). These sleep-active cortical neurons might play a critical role in some aspect of sleep homeostasis, such as the synchronous firing that underlies EEG delta power (slow-wave activity). Another interesting region where Fos is higher in sleep than wake is in the ventrolateral preoptic area (VLPO), consistent with the VLPOs being a sleep-active region.7 Neuroanatomic tracings linked this sleep-active region containing inhibitory GABA neurons to wake-active structures, including histaminergic neurons in the posterior hypothalamus, suggesting a reciprocal interaction between these two structures.8 Later, other hypothalamic nuclei were integrated into a model indicating that several hypothalamic regions combine to play a critical role in sleep– wake regulation.9 Among these other regions are the hypocretin-orexin neurons that are central to our growing understanding of narcolepsy. The exciting breakthrough that led to the elucidation of a critical role for the hypocretins in narcolepsy came from a combination of dog genetics,10 mouse knockouts,11 human pathology and pathophysiology,12,13 and, earlier, the use of subtractive hybridization and rat neuroanatomy.14 This research is described in detail in the last chapter of this section. Outside the hypothalamus, expression of IEGs has been used to support and extend our understanding of the dorsolateral pontine region in the control of REM sleep15 and the locus ceruleus in wake.16 Other studies have shown interesting regional differences throughout the brain for the expression of specific IEGs during sleep deprivation and recovery sleep,17 and similarly for some of the heatshock or stress-response genes.18 The results from studies in rats and mice are consistent with one another,19 suggesting an important generalizability across rodents and probably all mammals. In addition, diurnal squirrels have peaks of IEG expression and heat-shock protein 70 (Hspa1b) during the day (instead of during the night, as in nocturnal rodents), consistent with high levels of mRNA correlating with wake.20,21 Although it is still unclear what role these IEGs and heat-shock mRNAs and proteins play, their consistent increase during periods of wake and neuronal activity suggest the possibility of some restorative role or, more specifically with IEGs, the need for transcriptional activation during wake. It is possible that transcription is preferentially activated during wake and translation into proteins is increased during sleep. This is supported by some earlier protein work using 14C-Leu autoradiography in rat and monkey, which showed that the rate at which labeled leucine was incorporated into the brain was posi-
tively correlated with the occurrence of slow-wave sleep, suggesting the exciting possibility that one function of sleep might be the restoration of proteins through increased synthesis.22,23 In general, protein data across sleep and wake periods have been limited due in part to the greater difficulty of identifying and quantifying proteins (see reference 24 for review) compared to measuring mRNA levels. For example, microarray technology allows for hundreds or thousands of mRNAs to be compared across conditions, and has generally supported these results.19,25 The first large-scale microarray study investigating sleep versus wake was done in rats.25 Several interesting observations were made in this extensive survey that compared transcripts derived from sleeping (undisturbed) versus sleep-deprived rats killed at 6 pm (sleep deprivation was for 8 hours), as well as from rats sacrificed at 6 am that had spent the majority of the night awake. More than 15,000 transcribed sequences were found to be present in the cerebral cortex. Of these 15,000, about 10% differed between day and night, and about half of these (5% of the total) varied between sleep and wake regardless of time of day. The cerebellum, a structure not generally associated with sleep, had similar changes, and about 5% of the detectable transcripts were differentially expressed between sleep and wake. Although the cerebellum does not display the electrographic signs of sleep comparable to EEG recordings of the cerebral cortex, this result is consistent with the idea that all or most neurons in the brain might require similar cellular restoration during sleep. The few areas of the brain that have higher activity during sleep, such as the VLPO, could potentially perform these tasks during wake. Different brain regions are likely to express a different constellation of genes. As discussed earlier, the hypothalamus alone has many different nuclei that appear to play central and counterbalancing roles in sleep and sleep regulation during sleep and wake. In keeping with this diversity, the hypothalamus appears to be the most different in gene expression changes across sleep and wake (at least relative to the cerebral cortex and basal forebrain)19 and to have fewer significant mRNA changes,26 perhaps due to its functional diversity. The nature of the restorative or other useful processes occurring during sleep are not well understood. During wake, there is a notable increase in certain categories of mRNAs, including those involved in oxidative phosphorylation (e.g., mitochrondrial genes), and other energyrelated processes (e.g., Glut1). Other genes showing increased activity during wake involve transcription factors such as the IEGs noted earlier and some of the clockrelated genes (e.g., Per2, discussed in detail later), stress response factors (e.g., heat-shock proteins such as Hsp5), glutamatergic neurotransmission-related genes (e.g., Nptx2, Homer1), and mRNAs related to activity-dependent neural plasticity and long-term potentiation (e.g., Arc, Bdnf ).25 In contrast, during sleep, different categories of mRNAs appear to be upregulated (or downregulated with wakefulness), including those involved with translational machinery (e.g., Eif4a2), membrane trafficking (e.g., members of the Rab and Arf gene families), promoting hyperpolarization (potassium channels such as Kcnk2, Knck3), and synaptic plasticity related to memory consolidation (e.g., Camk4, Ppp3ca).
An issue in this and many other studies is how to define the sleep–wake state for each group of animals from which tissues are collected for microarray analysis. For example, although mice and rats spend the majority of the day sleeping and the majority of the night awake, they are often awake one third of the day and sleeping one third of the night (with sleep and wake periods typically alternating over periods of minutes or even seconds). In rats and mice one cannot assume that the animals are sleeping during the light or daytime, or are awake during the dark or nighttime at the time of sample collections. Also, some mRNAs can change rapidly, in which case the prior hour or two is paramount, whereas other mRNAs may be influenced over many more hours. Lastly, it is not clear in studies of sleep-deprived versus control animals whether a gene is sleep-induced or goes down with sleep deprivation. Incorporating recovery sleep periods following sleep deprivation can partially address this issue, especially if multiple recovery time points are examined (1 hour, 2 hours, 4 hours after sleep deprivation). This has been done for several clock-related genes such as Per1, Per2, and Dbp,27,28 which generally return to baseline levels following recovery sleep. Per1, Per2, and other clock genes are central to circadian pacemaker function in the SCN, as discussed in Chapter 12. However, in other brain regions, these genes appear to be more responsive to sleep, wake, and activity state rather than their internal clock time.27-29 Mutations and knockouts of these genes in mice produce not only the expected circadian disturbances but also, unexpectedly, fundamental changes to sleep homeostasis. This is discussed in detail later. One microarray study examined sleeping versus sleepdeprived mice across the entire day and found a large number of mRNAs involved in biosynthesis and transport to be higher in the sleeping condition.26 This was most apparent for genes involved with cholesterol synthesis and lipid transport. In general, this finding supports the hypothesis that one function of sleep may be the restoration of certain molecular components that are perhaps depleted during wake. Another microarray study compared sleep-deprived and control mice of three different inbred strains at four different time points over the 24-hour day.30 Out of more than 2000 brain transcripts found to vary as a function of time of day under control conditions, fewer than 400 remained rhythmic when mice were sleep deprived, suggesting that most diurnal changes in gene expression are, in fact, sleep–wake-dependent instead of being under direct circadian control. This study also demonstrated that many of the changes in gene expression were strain specific, and only a relatively small number of transcripts changed consistently in all three strains. Of these, Homer1a, showed the most consistent and dramatic changes. Homer1a is a truncated form of Homer1 which is involved in glutamate neurotransmission and probably in intercellular calcium homeostasis. Thus, it may be important for neuronal recovery or optimization following periods of wakefulness. The Homer1 gene is also in the middle of a chromosome region shown to influence recovery from sleep deprivation31 (see later), a finding that might lead to more definitive evidence of a role for this gene in sleep.
CHAPTER 14 • Genetic Basis of Sleep in Rodents 163
In summary, gene-expression studies have suggested that at least 5% of mRNAs vary across sleep and wake, but many of these changes might not be consistent across strains and species, and they may be dependent on the specific conditions of each experiment. It seems likely that an even higher percentage of transcripts vary slightly with arousal state, but the present methods are generally not sensitive enough to pick up small changes in steady-state mRNA levels. The roughly 5% of mRNAs with measurable changes over the sleep–wake cycle code for many different proteins that are likely to reflect specific functions of sleep and wake, but more data from different levels of organization are needed to document these specific functions. One concern raised by this kind of approach is the timecourse issue. This is perhaps most relevant with the changes in transcription factor mRNAs, which are among the most consistent and reliable changes documented thus far. Presumably, in order to produce a functional change in the brain, the mRNAs must first be made into proteins, return to the nucleus, activate or inactivate transcription of their target genes, and then, if activated, these mRNAs must be made into proteins and perform some function that ultimately alters a neuronal property (such as resting membrane potential) before there is any fundamental change in sleepiness or other sleep-related variables. In most cases, this will take several hours. Of course, other molecular changes such as phosphorylation of proteins can take place in seconds and alter many neuronal properties. However, this does not elucidate how changes in mRNA levels ultimately affect sleep and wake. As discussed earlier, sleep pressure can build up over many hours and days, and certainly these long-term processes could be both monitored and regulated by these relatively slow transcriptional and translational changes. However, it has been shown in mice that sleepiness begins to accumulate after as little as 1 hour of wake,31,32 raising the question of whether these slow mechanisms are fast enough to underlie the physiology of sleepiness. It is of course possible that there are both slower and faster homeostatic responses to different arousal states, as has been suggested for REM sleep,32 and changes in gene expression and mRNA levels might underlie only the longer ones. It is also important to consider that most changes in steady state mRNA levels are probably driven by sleep–wake changes and not the other way around. A final caveat in extrapolating from changes in gene expression across arousal state to a functional role of these genes in sleep–wake regulation is the finding that sleep deprivation results in more changes in mRNA levels in the liver than in the brain.30 If sleep is “of the brain, by the brain, and for the brain,”33 then how does one account for this observation? Perhaps the brain is protected in some way from changes in transcription during sleep deprivation, or perhaps the liver in fact needs these greater changes to respond to increased wake. Is it even possible that the liver or other tissues are in fact sleeping or awake in any meaningful way? Or, it could be a matter of statistics, with more probe sets reaching significance levels in the liver because it is a less heterogeneous tissue as compared to the brain, which is composed of many anatomically and functionally different structures and cell types expressing
164 PART I / Section 3 • Genetics of Sleep
different genes according to specific times of day (see the earlier example for sleep-active neurons in cerebral cortex and VLPO). Until we understand the functions of sleep with more certainty, it is difficult to define what sleep might mean for peripheral tissues. In any case, the numerous findings that now link sleep deprivation to profound changes in metabolism and the expression of genes in many peripheral tissues indicates that sleep is more than just for the brain and that sleep–wake states and durations have pronounced effects on gene expressions throughout the body.34
IDENTIFICATION OF ALLELES THAT INFLUENCE SLEEP OR SLEEPRELATED TRAITS Although gene-expression studies are likely to lead to a better understanding of certain aspects of sleep, as noted earlier, there are many limitations to this approach, especially the issue of causality. Therefore, it is important to use genetic approaches to better understand sleep and wake as complements to gene-expression studies. There is substantial evidence that allelic differences in sleep-related genes exist, and identifying these alleles, and the genes themselves, will likely lead to identifying important sleeprelated functions. Abundant evidence exists that many aspects of normal sleep as well as several sleep disorders have strong genetic components (reviewed in references 35 to 38). Results from twin studies make this especially clear (Fig. 14-1). First, brain architecture and regional activity are much more similar in monozygotic than in dizygotic twins (see Fig. 14-1A).39 Second, EEG patterns of monozygotic twins have a much higher concordance than those of dizygotic twins, with the patterns in monozygotic twins being nearly as similar as in the same subject recorded on two different occasions (see Fig. 14-1B and C).40-42 These results support the hypothesis that complex EEG traits are largely controlled by genes and that environmental factors play a lesser role. In fact, for many EEG traits, more than 80% of the variance appears to be accounted for by genetic factors, whereas for other sleep traits such as the amount or timing of sleep, the relative importance of genes and environment is probably closer to 50% each.35-38 Like twin studies in humans, genetic studies of sleep in the mouse, pioneered by Valatx, yielded substantial support for the genetic control of sleep. In the early 1970s, Valatx’s group initiated a series of crossing experiments and recorded sleep in hundreds of inbred, recombinant inbred, and hybrid mice mainly to follow the segregation of REM sleep.43-45 However, until very recently, none of the genes underlying these, or any other, sleep traits had been identified. The first significant breakthrough in the field occurred in 1999, with the discovery that a mutation of the hypocretin-2 receptor gene underlies canine narcolepsy10 (see Chapter 15). This gene was certainly not one that would have been predicted to have a role in narcolepsy, highlighting the strength of the genetic approach. In a genome-wide search for genes affecting a particular phenotype, no a priori assumptions on the gene systems involved are made. Although this approach might lead to already known physiologic mechanisms, its strength is that
systems previously not known to be involved in sleep may be uncovered. Going from variability in a reliable sleeprelated phenotype to the underlying genotypic variability of differing alleles (sometimes called forward genetics or traditional genetics) usually involves a generally standard approach.46-49 In the first step, the mode of inheritance for a trait of interest is determined in segregating offspring, although for most complex traits this does not appear as simple mendelian inheritance patterns. Next, the localization of the underlying gene or genes is mapped by examining the entire genome at regular intervals using polymorphic markers (e.g., RFLPs, SSLPs, SNPs). Traits generally cosegregate with the markers most closely linked to the underlying gene(s). For simple mendelian traits, initial mapping in a few hundred offspring can yield sub-centi morgan (cM) resolution (typically on the order of 1 million base pairs, with perhaps 10 genes in the defined genetically linked region). However, for non-mendelian complex traits, this initial step usually narrows the region to about 10 to 30 cM. Subsequent fine mapping, if feasible, can further reduce these regions. Positional cloning techniques can then be applied to find and characterize candidate gene sequences, with potential follow-up studies using gain- or loss-of-function knockout and transgenic mouse models to confirm the functional involvement of the candidate gene in affecting the trait under study (see later). This approach has been most successful with mendelian monogenic traits such as for canine narcolepsy, as discussed earlier, and for studies involving mutagenesis, as discussed later, where a single mutated gene usually accounts for the phenotype. However, positional cloning is becoming increasingly successful in even the more common and difficult cases where multiple genes and environmental influences interact to produce a wide phenotypic range of a quantitative trait, such as EEG power spectrum differences among inbred strains of mice. The standard approach toward mapping chromosomal regions that underlie quantitative traits is QTL analysis. QTL analysis is a good method to genetically dissect complex traits, like sleep, because naturally occurring allelic variations or gene mutations with smaller effects can be mapped.46-49 QTL analysis can be performed in segregating mouse populations that involve intercrosses, backcrosses, recombinant inbred (RI) strains, or heterogeneous stocks. Often, two inbred mouse strains differing in a trait of interest are crossed and their F1 offspring are then intercrossed to generate F2 offspring. To generate RI sets, F2 mice are inbred by brother-sister matings for 20 generations until essentially full homozygosity is achieved, thereby fixing a unique set of recombinations in each RI strain. Controversy exists concerning the efficacy of the QTL approach in identifying genes, and in the past, forward genetics by genome-wide mutagenesis has been favored due to greater ease of identifying the underlying gene once a genomic region of interest has been indentified.50 Nonetheless, more than 2000 QTLs have now been mapped in rodents with a high level of confidence, and although only about 100 of these have been identified at the gene level, improved methods are making QTL cloning tractable, even for genes that only mildly affect the quantitative phe-
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Figure 14-1 Basic brain structure and electroencephalogram (EEG) patterns are among the most highly heritable complex traits. A, Brain architecture is highly genetically determined. Genetically identical (monozygotic; MZ) twins are almost perfectly correlated in their gray matter distribution. Fraternal (dizygotic; DZ) twins are significantly less alike in frontal (F) cortices but are 90% to 100% correlated for gray matter in the perisylvian language-related cortex, including supramarginal and angular territories and Wernicke’s language area (W). The significance of these increased similarities, visualized in color, is related to the local intraclass correlation coefficents (r). (From Thompson PM, Cannon TD, Narr KL, et al. Genetic influences on brain structure. Nat Neurosci 2001;4(12):1253-1258.) B, The spectral composition of the EEG during non–rapid eye movement (NREM) sleep is highly genetically determined. Intraclass correlation coefficients (ICCs) of EEG power in various frequency bands indicate a much higher concordance in MZ compared to DZ twin pairs, especially for lower frequencies (delta, theta, and alpha). (From Ambrosius U, Lietzenmaier S, Wehrle R, et al. Heritability of sleep electroencephalogram. Biol Psychiatry 2008;64(4):344-348.) C, The spectral composition of the waking EEG is equally under strong genetic control, and twin studies identified heritabilities of up to 90%, indicating that 90% in the variance of the phenotype can be accounted for by additive genetic factors. Note the higher similarly in MZ versus DZ twins even when raised apart. MZ twins are nearly as similar as the same subject recorded on two different occasions. (From Stassen HH, Lykken DT, Propping P, Bomben G. Genetic determination of the human EEG. Survey of recent results on twins reared together and apart. Hum Genet 1988;80(2):165-176.)
notype. QTL approaches can find different sets of genes than those uncovered in mutagenesis experiments and these procedures are thus complementary.51 This has been shown to be the case in the circadian field. Although most of the circadian genes that constitute the molecular circadian clock have been discovered via direct molecular techniques and mutagenesis (see Chapter 12), these genes alone do not explain the complexity of the observed circadian behavior. For example, none of the known circadian genes have been shown to regulate the differences in circadian period length or other circadian variables between BALB/c and C57BL/6 or other inbred mouse strains. By contrast, QTL analysis in a BALB/c x C57BL/6 intercross panel revealed several new loci that influence variables such as the free-running period, phase angle of entrainment, and the amplitude of the circadian
rhythm of activity, as well as the total amount of activity.52 In addition, the first QTL studies of circadian period length used BXD RI strains (derived from C57BL/6 and DBA/2) and CXB RI lines (derived from BALB/c and C57BL/6) to identify multiple loci that contribute to this trait.53,54 To confirm these QTLs and identify new QTLs that influence circadian period, this same research group took one of the BXD strains (BXD19 with a period of 24.26 hours) and one of the CXB strains (CXB07 with a short period of 23.12 hours) and performed a standard intercross that did indeed confirm a major QTL on chromosome 1 and identified three additional QTLs.55 Future identification of the gene alleles that underlie the QTLs from all of these studies should provide new information regarding the regulation of circadian period, activity levels, and other clock variables.
166 PART I / Section 3 • Genetics of Sleep
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Figure 14-2 CAST/EiJ (CE) mice are early runners, with an advanced phase of activity relative to the light–dark cycle, and could thus provide a model for advanced sleep phase syndrome (ASPS). Typical mice such as C57BL/6J (B6) begin activity very close to dark onset (blue circles). Ten out of ten CE mice (green triangles) have this advanced phase, suggesting a strong genetic component. However, the variability in the activity onset suggests important environmental or random factors as well. Note that CE mice have a shorter free-running period than B6, but this does not account for the magnitude of the advance (see Wisor JP, Striz M, DeVoss J, et al. A novel quantitative trait locus on mouse chromosome 18, “era1,” modifies the entrainment of circadian rhythms. Sleep 2007;30(10):1255-1263).
Another example is the case of early-runner mice that show activity traits similar to those of humans with advanced sleep-phase syndrome (ASPS).56 Virtually all normal mice begin their peak activity very close to dark onset. In contrast, early-runner mice begin their activity 2 to 6 hours before dark onset (Fig. 14-2), similar to ASPS humans who wake up several hours earlier than normal. Early runner mice also have shorter free-running periods than B6 mice, but this does not fully account for the several-hour phase advance in activity onset observed in these mice. Some cases of human ASPS are clustered in families and are called familial ASPS or FASPS (see Chapter 15 for more details). Inheritance is in a close to mendelian fashion, with mutations in specific genes such as Per257 or CKI-delta.58 Alternatively, more subtle allelic variations, such as those occurring in human Per3, might influence morn ingness and eveningness59,60 along with environmental factors. At some point, extreme morning or evening preference can become ASPS or delayed sleep-phase syndrome (DSPS). The dramatic cases with known mutations are quite rare, and therefore are referred to as mutations rather than alleles. In contrast, the Per3 alleles are common. Early-runner mice are more like this latter example in humans in that the primary QTL on chromosome 18 accounts for only about 10% of the total variance in this trait,56 although it contributes a higher percentage of the genetic variance and the total variance in general daytime activity. Such mice may be useful in testing new pharmaceuticals or nonpharmaceutical approaches to treatment of ASPS.
Like circadian variables, many aspects of sleep and the EEG parameters measured during sleep differ dramatically among different inbred strains of mice,31,44,61-65 and these differences are likely due to genetic factors. QTL analysis can be simplified in sets of RI strains that are derived from two parental inbred strains. In its simplest form, this mapping entails point correlations between the straindistribution pattern (SDP) of the phenotype and the SDP of the genotype at each marker (Fig. 14-3 is an example of this approach). Polymorphic markers at a specific chromosomal locus that correlate significantly with the quantitative trait are presumably linked and co-segregate with the actual gene (or genes) whose differing alleles, derived from the two parental strains, contribute to the phenotypic variance. Quantitative trait locus analysis of inter- and backcross panels also follows these same principles, but with two primary disadvantages. First, each offspring from these crosses is unique and must be genetically mapped to determine contributions from each parent—unlike RI strains where the recombination pattern is fixed by inbreeding and has already been mapped. Also, because each individual offspring is unique in traditional crosses (and cannot be made again), it is not possible to average over multiple mice. By contrast, in RI strains, observations from multiple identical mice can be averaged. However, a major advantage of traditional crosses is that a large number can be generated, unlike the very limited number of RI strains derived from a particular strain combination such as C (BALB/c) and B (C57BL/6). The limitation in numbers of RIs is partially compensated by the increased number of recombinations in each strain during the inbreeding process that produces improved mapping power per animal (approximately fourfold). The limitations in the number of RIs are being addressed by extending existing RI panels by adding more strains, including a very large effort that could revolutionize complex genetics in mice for the study of almost any trait of interest, including sleep.66 This major project is referred to as the Collaborative Cross because it will necessarily involve many research scientists. The cross includes eight different parental strains chosen for both their high genetic diversity and high diversity in almost every tested phenotype from cancer susceptibility to behavior. With plans for more than 1000 strains, and each strain having a very large number of historical recombination events fixed by inbreeding, it should be possible to map many QTLs at millimorgan resolution (essentially down to individual genes). Because RI lines only have to be mapped once, in theory, one can look at any trait in these mice such as total sleep time, analyze the correlations with allelic distributions, and have a very good idea of the gene alleles contributing to this trait. In a few years, when these mice are available, complete sequences for all eight founder strains are likely to be available as well, and it might even be possible in some instances to immediately predict which nucleotide difference among strains is responsible for a given QTL (sometimes referred to as a QTN, for quantitative trait nucleotide). Currently, although only small sets of RI strains are available, these strains have nonetheless contributed significant advances to the understanding of genetic influ-
CHAPTER 14 • Genetic Basis of Sleep in Rodents 167
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Figure 14-3 Quantitative trait locus (QTL) analysis for a sleep recovery trait in BXD recombinant inbred (RI) mice. QTL analysis is illustrated for the chromosome 13 Dps1 QTL (see text and reference 31 for additional details). A, The strain-distribution pattern (SDP) of the sleep phenotype. In 25 BXD RI strains (BXD-1 to BXD-32) and their parentals C57Bl/6J (B6; green) and DBA/2J (D2; orange) the rebound in electroencephalogram (EEG) delta power was measured after 6 hours of sleep deprivation (bars indicate mean strain values; n = 128; 4-7/strain). B, BXD RI recombination pattern for chromosome 13 (B6 alleles in green; D2 alleles in orange). This pattern is based on the 24 Mit-markers polymorphic between B6 and D2 that were genotyped in the BXD RIs. Relative map positions in centimorgans (cM) from the centromere. For QTL mapping for each marker, the genotype SDP is correlated with the SDP of the phenotype. C, The SDP for markers D13Mit126, 106, and 193 (along the red horizontal bar in B) yielded the best correlation coefficient (r), which was highly significant (P) and translated into a LOD score of 3.6. D, Among all 788 Mitmarkers used, only for these three markers was a genome-wide significant level (P < .05) obtained. This QTL was named Dps1 (Delta power in sleep-1). The underlying assumption of the QTL approach is that a gene (or genes) within the Dsp1 region segregated with the three D13Mit-markers in this BXD RI panel and that the B6 and D2 alleles for this gene are functionally different and modify the rebound in delta power after sleep deprivation. Dsp1 has been confirmed for EEG delta power at sleep onset under baseline conditions, and refined mapping is in progress.
ences on sleep homeostasis. For example, the BXD RI strains were examined for sleep-related traits by EEG analysis to identify QTLs for the homeostatic regulation of NREM sleep.31,36 The trait of interest was defined as the level of EEG delta power in NREM sleep reached after a
6-hour sleep deprivation (see Fig. 14-3A for variance in this trait among the two parental strains D2 and B6 and the 25 BXD RI strains). Large interstrain differences were observed in this trait and about 37% of the total variance could be attributed to additive genetic factors
168 PART I / Section 3 • Genetics of Sleep
(i.e., heritability). The contribution of the chromosome 13 QTL to the total genetic variance amounted to 49%, suggesting the presence of a major gene. Confirmation of the chromosome 13 QTL was obtained in baseline recordings of the same animals. This QTL was designated Dps1 for delta-power-sleep-1. Two additional significant QTLs (Dps2,3) for sleep need at sleep onset in baseline were also identified. However, because EEG delta power is driven by the sleep–wake distribution, these genes presumably are more likely related to genotype-specific differences in the distribution of sleep and waking before sleep onset than to the homeostatic regulation of sleep itself. The basic assumption underlying the QTL analysis is that the identified chromosomal regions contain genes with functionally different alleles that somehow influence or regulate sleep homeostasis. As discussed in the prior section, Homer1 is an excellent candidate gene, whose allelic variants might account for this QTL. The same BXD RI lines also led to another QTL on chromosome 14 that contributes to the delta oscillations (1 to 4 Hz) that mark NREM sleep.67 Although the study began as a QTL analysis, the data suggested that a single locus accounted for the majority of the variance in this trait. In this study, to verify that a single gene was responsible for the EEG phenotype, a panel of 30 different inbred strains was analyzed with 10 Mit-markers in this region of chromosome 14 and identified a unique biallelic marker D14Mit78 such that all 30 strains had either the B or D type allele. Next, a subset of highly divergent unrelated strains with the D allele were analyzed to see if they also had the predicted D EEG spectral properties (specifically, the power in the theta band, 6 to 7 Hz, divided by the power in the delta band). By using other polymorphic markers across many of these strains, a 350-kb region was identified as the smallest genomic region associated with this trait. Within this region was retinoic acid receptor beta (Rarb), which contained a restriction fragment length polymorphism that co-segregated 100% with D14Mit78. Rarb has two different promoters that produce four different transcripts. Targeted deletion of these different transcripts, coupled with gene sequencing and real-time reverse transcriptase polymerase chain reaction (RT-PCR), clearly documented that alleles of Rarb did in fact underlie this EEG phenotype. Retinoic acid receptors and retinoid-X receptors are nuclear receptors that form heterodimers, are highly expressed in the brain, and are implicated in neuronal functions such as control of locomotion, longterm potentiation, and effects on dopaminergic and cholinergic neurotransmission.68 These latter effects might underlie the role of Rarb in regulating the cortical synchrony that determines this EEG phenotype. This same research group was able to use similar methods to identify another major gene, acyl-coenzyme A dehydrogenase (Acads), which, when mutated, dramatically alters the frequency of theta oscillations during REM sleep.69 Microarray analysis of gene expression in mice with mutations in Acads also implicated Glo1 (glyoxylase 1) as a key factor. This work suggested the surprising involvement of a metabolic pathway involving fatty acid β-oxidation in regulating theta oscillations during sleep. Since this work began as a QTL analysis, it would be fair to say that it
represented the first successful identification of a gene that underlies a sleep-related QTL, and it is one of the first for any brain or behavior phenotype. Apart from the above-mentioned studies, surprisingly few other QTL studies have investigated natural sleep and EEG traits. Despite decades of research in defining sleepwake properties in mammals, little is known about the nature or identity of genes that regulate sleep, a fundamental behavior that in humans occupies about one third of the entire lifespan. Although genome-wide association studies in humans and QTL analyses in mice have identified candidate genes for an increasing number of complex traits and genetic diseases, the resources and time-consuming process necessary for obtaining detailed quantitative data have made sleep seemingly intractable to similar large-scale genomic approaches. However, a study of natural sleep and EEG and EMG activity analyzed 20 different sleep–wake traits in 269 mice from a segregating population. The study revealed 52 significant QTLs, representing a minimum of 20 genomic loci, as being involved in the regulation of multiple and diverse sleep–wake traits.70 Although many (28) QTLs affected a particular sleep–wake trait (e.g., amount of wake) across the full 24-hour day, other loci only affected a trait in the light or dark period, and some loci had opposite effects on the trait during light versus dark. Analysis of a dataset for multiple sleep–wake traits led to previously undetected interactions (including the differential genetic control of number and duration of REM bouts), as well as possible shared genetic regulatory mechanisms for seemingly different unrelated sleep–wake traits (e.g., number of arousals and REM latency). Construction of a bayesian network for sleep–wake traits and loci led to the identification of sub-networks of linkage not detectable in smaller data sets or limited single-trait analyses. Taken together, the results from this QTL study revealed a complex genetic landscape underlying numerous sleep– wake traits, and they emphasize the need for a systems biology approach for elucidating the full extent of the genetic regulatory mechanisms of this complex and universal behavior.70
MUTAGENESIS AND KNOCKOUTS The QTL analysis aims at identifying naturally occurring allelic variants or gene mutations that modify sleep; in mutagenesis studies, however, gene function is assessed by randomly inducing mutations. Because mutagenesis studies involve a progression from phenotype to genotype (finding the mutation that alters the screened phenotype), it is also considered a forward genetics approach, similar to attempts to identify QTL associated with a particular phenotype or trait. In contrast, beginning with a gene of interest and using targeted deletion in mouse embryonic stem cells to knock it out, is a reverse genetics approach because the progression is from gene to phenotype (see later). As with other approaches, these distinctions can blur; for instance, if a study is initiated on a large collection of knockout mice, without identified genotypic effects, one might begin with phenotypic assessment, an approach that would have similarities to mutagenesis and forward genetics approaches. This is now becoming
feasible with the increasing number of knockout and other transgenic lines of mice and with high-throughput sleep analysis systems (see later). Whether it is forward or reverse genetics depends on whether one is screening more or less randomly or is selecting only genes with suspected roles in the traits under study. Mutagenesis has been a successful technique for identifying genes that regulate circadian rhythms. A mutagen like N-ethyl-N-nitrosourea (ENU) mutates spermatogonia at an average rate of 0.001 mutations per locus per gamete.49 With high-throughput screening of several hundreds or thousands of offspring for dominant, semidominant, or recessive mutations, a major effect on a given trait can be expected to be identified.71,72 The individual mouse, fruit fly, or other organism for which an aberrant phenotype has been recorded then has to be crossed (usually with wildtype animals) to establish the mode of inheritance of this trait. The feasibility of this approach in the mouse was demonstrated by the isolation of the canonical circadian gene Clock.73 Although some mutations produce dramatic phenotypic changes, as was the case for the mutant Clock gene, others produce only subtle effects that, in addition, can be confounded by epistatic interactions and genetic background (i.e., modifier genes).74 In general, mutagenesis is probably more successful for fully penetrant dominant or recessive mutations, whereas the QTL approach is more powerful in detecting natural allelic variations controlling complex traits. High-Throughput Screening The sleep field has been fortunate that gene alleles with very large effects on sleep–wake traits are present in the common inbred strains of mice. However, the challenge for the future is to identify more typical QTLs that might contribute 1% to 5% of the genetic variance. Whether using QTL analysis or mutagenesis, both techniques require large numbers of mice to be screened to cover a majority of the genome (i.e., to produce functional alterations in a majority of the estimated 30,000 or so genes).71 Although screening a thousand mice is currently quite cumbersome with traditional EEG recording, highthroughput methods to monitor sleep and wake in mice and other rodents might alleviate this problem.75,76 One high-throughput noninvasive technology uses piezoelectric films covering the cage floor that act as an extremely sensitive motion detector. During sleep, the primary movement is breathing and thus the system records a consistent periodicity of about 3 Hz, a rate representative of the respiratory rate in mice. During wake, a variety of movements produce a more erratic signal, because even during quiet wake, mice are grooming or making many more postural adjustments than during sleep. It might eventually be possible to distinguish REM versus NREM sleep because respiratory variability increases during REM sleep, but this has not yet been achieved.75 This method could make mutagenesis screening for sleep traits more feasible and could take advantage of the very large collaborative crosses planned for mice.66 It could also be used as an initial screen for sleep-promoting or wake-promoting drugs or could be used to screen the increasing number of available transgenic mice. Video methods for scoring sleep–wake traits are also showing
CHAPTER 14 • Genetic Basis of Sleep in Rodents 169
increasing promise as a high-throughput method,77 either in isolation or in combination with the piezo method. Targeted Gene Deletion Targeted gene deletion and other transgenic approaches have been exciting areas for sleep research and have been reviewed elsewhere,36,78 but here we will discuss a few of the highlights. As discussed earlier, the use of these mouse models generally begins with a gene of interest that might influence some sleep phenotype, and so this is generally considered a reverse genetics approach (from gene to phenotype), as opposed to mendelian or QTL genetic approaches or mutagenesis approaches, which assay phenotype first with the goal of identifying the salient genes. Reverse genetics approaches in mice have been made possible by the development of a range of techniques over the past several decades.79,80 The field of sleep and circadian biology has benefited from knockout technology in which the insertion of a DNA construct into an exon results in a nonfunctional protein in mice, which are then bred to homozygosity. Advances have also come from transgenic methodology or nonhomologous (illegitimate) recombination, in which one or more DNA-construct copies are inserted into the genome at undefined locations, typically following injection of naked DNA into one of the two pronuclei at the one-cell stage.79 These two techniques generally produce loss- or gain-of-function mutations, respectively. These models are also useful in confirming the role of genes that were identified by forward genetics approaches. Advantages and problems of these techniques have been addressed in other reviews.81 One important concern with respect to sleep regulation is developmental compensation, whereby other molecules, perhaps from the same gene family, could compensate for the lacking protein.82 Other concerns involve nonspecificity (the relevant protein is absent in all the cells of the organism instead of the tissue of interest) and genetic background (genes that co-segregate with the introduced gene might differ between the background strain, often C57BL/6, and the strain in which the altered embryonic stem cells were introduced, usually a 129 strain) that might affect the phenotype.83 Some of these issues can be overcome by developing (tissue-specific) conditional or inducible knockout models where the acute effects of loss-of-function can be studied in structures of interest84; however, most studies rely on the easier-to-construct general knockout mice or simple transgenic mice. Despite these limitations, considerable knowledge has been gained from the study of knockout and other genetically altered mice, implicating genes in sleep and sleeprelated traits in often unexpected ways. The first sleep studies using transgenic mice appeared in 1996.85,86 Most knockout studies focus on pathways with previously described roles in sleep regulation such as monoamine neurotransmitters,87 their receptors, and their transporters (reviewed in references 36 and 78). Additional studies have supported a role for cytokine pathways in the regulation of sleep, including interleukin-1, interleukin-10, tumor necrosis factor, and their receptors.88 Finally, considerable information on sleep effects has been discovered about genes that are regarded as canonical circadian genes such as Clock, Bmal1, Per1, Per2, Cry1, Cry2, and Npas2 (a
170 PART I / Section 3 • Genetics of Sleep
homologue of Clock expressed in the forebrain but rare in the suprachiasmatic nucleus [SCN]) and genes known to alter circadian rhythms such as Dbp and Rab3a. Genetic Regulation of Homeostasis The identification of genes involved in the homeostatic regulation of sleep has been advanced by the comparisons between baseline sleep and the responses to sleep deprivation. For instance, mice overexpressing growth hormone show more REM sleep under baseline conditions but show normal recovery patterns following sleep deprivation.89 Disruptions of Fos increase wakefulness, while Fos b deletion reduces REM sleep. In addition, Fos knockout mice respond to sleep deprivation primarily with an increased latency to sleep onset.90 In mice lacking the transcription factor Dbp, the circadian distribution of sleep was flatter and sleep was more fragmented. The NREM sleep response and the delta power response to sleep deprivation, however, did not differ from that in wild-type mice.91 Also, in Clockmutant mice the relative increase in NREM sleep after sleep deprivation was the same as in wild-type mice, although NREM sleep amount in baseline conditions was significantly reduced.92 Although a change in baseline sleep might reflect a change in sleep homeostasis, the lack of change following sleep deprivation raises the fundamental issue of what does qualify as a true change in the homeostatic response. For instance, mice lacking functional genes for the serotonin-2C receptor (Htr2c),93 or Rab3a94 all were reported to have an altered NREM sleep rebound after sleep deprivation. In these cases the difference was, however, attributable largely to NREM sleep differences under baseline conditions, because no differences in recovery sleep were observed. Ideally, claims regarding an altered homeostatic regulation should be substantiated by quantifying the relationship between wake duration and the subsequent response of the regulated variable. This can be achieved by either establishing a dose-response relationship, in which the duration of the sleep deprivation is varied, or by mathematical means where the effects of spontaneous and enforced periods of wakefulness on a regulated variable are quantified.31 Furthermore, especially where the regulation of NREM sleep is concerned, one cannot rely on only one aspect because changes in the duration and intensity or consolidation of sleep have to be taken into account. Changes in REM-sleep homeostasis have also been observed in several knockout models. In mice lacking serotonin-1A or -1B receptors (Htr1a, or -1b),95,96 Dbp,91 Cry1, or Cry228 and in Clock-mutant mice,92 loss of REM sleep was followed by a compensatory increase in REM sleep that was smaller than in wild-type animals or that was lacking altogether. Apart from Htr1a and Htr1b knockout mice that displayed increased REM sleep during baseline conditions,95,96 these changes in the REM sleep response after sleep deprivation could not be attributed to genotype differences in REM sleep during baseline. Genetic Regulation of Circadian Rhythm One rationale for studying sleep in mice with modified or deleted genes critical for circadian rhythm generation, such as Clock, Per1, Per2, Cry1, or Cry2,97 is that they provide a model in which sleep homeostasis can be studied
in the presence of an altered or absent circadian modulation of sleep–wake time. Previously, the interactions between circadian and homeostatic influences on sleep were studied after circadian rhythms were eliminated by lesions of the SCN98-101 or in studies in which subjects followed a forced-desynchrony protocol.102,103 SCN lesion studies in rats revealed that direct circadian effects on the sleep homeostatic process were small, if present at all.104 However, SCN-lesion studies in mice105 and in monkeys106 have found that SCN lesions can influence not only the timing of sleep but also the amount of sleep. Deletions or mutations in circadian genes also influence sleep–wake traits beyond just the timing of sleep, including alterations in the homeostatic regulation of sleep. A clear demonstration of this was observed in Cry1,Cry2 double knockout mice that under baseline conditions showed all the hallmarks of high NREM sleep pressure, including a higher amount of NREM sleep, increased NREM sleep consolidation, and higher NREM sleep delta power compared to wild-type controls.28 After 6 hours of sleep deprivation, there was no further increase in NREM sleep time or consolidation or in the reduced rebound in EEG delta power. This suggests that apart from their role in regulating circadian rhythms, Cry genes or genes regulated by CRY (such as Per1 and Per2) play a role in sleep homeostasis. Because Per1 and Per2 mRNA levels are responsive to sleep deprivation,25,28,107 knockouts of these genes might be expected to have effects on sleep homeostasis. In two independent sets of experiments examining mice with nonfunctional Per1, Per2, or Per3 and double knockouts of Per1 and Per2, the authors suggested that there were no substantial alterations in sleep homeostasis.108,109 However, in our view, these data might actually support an important role for Per genes in sleep homeostasis, because a number of sleep related changes were found in these mice. Results from these studies showed Per mutations affected total sleep time, the timing of sleep, as well as the effects of light and dark on sleep patterns, REM sleep, delta power during sleep recovery following sleep deprivation, and certain other parameters. The authors noted that the most clear-cut differences from wild-type animals were in sleep distribution, consistent with circadian alterations, with Per1 knockouts sleeping more at the dark-to-light transition and Per2 knockouts sleeping more at the light-to-dark transition. However, other sleep perturbations were also observed that do not appear to be primarily circadian in nature. Per1-knockouts and Per1/Per2-double knockouts spent a much longer time in elevated delta power following sleep deprivation, from 5 to 12 hours compared to 3 hours in the wild-type mice. This contrasts with results found in Cry1/Cry2-double knockouts, which seem to have a greater overall sleep drive under baseline conditions, including a higher delta power, but that have elevated delta power for only 1 hour following sleep deprivation. One possibility suggested for the reduced increase in delta power in sleepdeprived Cry1,2 knockout mice is that delta power is already so high it cannot be increased any further. Taken together, these results are consistent with the possibility that the Per genes are involved in the process that ultimately modulates the sleep–wake dependent changes in EEG delta power. The absence of a more dramatic change in sleep in response to deletion of the Per
genes is perhaps not surprising because there are three Per genes, and each may be able to compensate for a loss in one or two of these genes. Other genes in the molecular circadian clock network that perform similar functions might also be able to compensate for the loss of one member. This compensation might be even greater in regions of the brain outside the SCN where these genes may play greater roles in other processes. Further evidence that clock genes play a role in sleep homeostasis comes from work on Npas2-deficient mice. Npas2 is a paralogue of Clock that can also bind with Bmal1, widely expressed in the forebrain but difficult to detect in the SCN. Npas2-deficient mice have normal circadian rhythms, although a very small amount of Npas2 expression in the SCN appears to compensate for a complete loss of the Clock gene.110 In any event, the alterations in sleep behavior in Npas2deficient mice are not the result of a disruption in circadian rhythmicity. Npas2 knockout mice lack the typical nap found in the latter half of the dark period that is invariably present in wild-type mice of this strain.29 Following sleep deprivation, however, these mice were also incapable of initiating the appropriate compensatory sleep response during the circadian phase when mice are usually awake. Similarly, these mice do poorly or even die when food availability is restricted to the light portion of the diurnal cycle.111 These results suggest that the clock genes in the forebrain integrate behaviors such as sleep, wake, and feeding with physiologic cues, and when these cues are disrupted, the SCN-dependent circadian drive might dominate, limiting the expression of adaptive behaviors that can differ from the normal circadian peak for that behavior. These Npas2 knockout results may be of particular interest because NPAS2/BMAL1 and CLOCK/ BMAL1 heterodimers are redox sensitive, which might tie this gene network to basic energy metabolism.112,113 Because restoration of an optimal neural energy state has long been considered a possible function of sleep, as discussed earlier,114 this gene network might underlie a fundamental energy restorative aspect of sleep homeostasis. The suggestion that clock genes are fundamental to sleep homeostasis (in addition to their role in the circadian pacemaker) is strengthened by observations in the fruit fly, Drosophila, where mutants carrying loss-of-function mutations for the canonical circadian genes Per, Timeless, Clock, or Cycle (the Bmal1 orthologue) all show a more-pronounced sleep rebound after sleep deprivation than wildtype flies115 (as discussed in Chapter 13). Cycle-mutant flies were exceptional in this respect because they clearly overcompensated for the amount of sleep lost, and this increase in sleep seemed permanent. In addition, Cycle-mutant fruit flies died after sleep deprivations of 10 hours or more, whereas wild-type flies typically survive for about 50 hours. It has become increasingly accepted that rest and activity in flies share many features with sleep–wake states in mammals.116-123 Mice homozygous for the Bmal1 deletion showed an attenuated rhythm of sleep and wake distribution across the 24-hour period. In addition, these mice showed increases in total sleep time, sleep fragmentation, and EEG delta power under baseline conditions and an attenuated compensatory response to acute sleep deprivation.124 Therefore, lack of circadian genes in mice and flies
CHAPTER 14 • Genetic Basis of Sleep in Rodents 171
do not only affect circadian rhythms. In humans, as discussed in Chapter 15 and elsewhere, a simple repeat polymorphism in Per3 has been shown to significantly affect performance following sleep deprivation59,125,126 (in addition to the morningness-eveningness trait mentioned earlier). In retrospect, this might not be too surprising, because circadian genes are expressed throughout the brain and the body, not only in the SCNs of mammals or the small ventrolateral neurons of the fruit fly. In addition, many of the circadian clock genes are pleiotropic and affect a number of physiologic processes, not just timing. Therefore, the involvement of circadian genes in sleep homeostasis represents a new and intriguing molecular pathway for future research.116 ❖ Clinical Pearl An understanding of the genes and gene variants that influence sleep and wake quality and the susceptibility to sleep loss might suggest novel targets or approaches to improve sleep and wake, as well as for the treatment of sleep disorders. As in other areas of medicine, allelic differences in these genes might suggest different treatments for different patients with the same disorder, because the pathophysiology may be distinct. The combination of rodent studies using molecular, forward, and reverse genetic approaches, in combination with human studies, are likely to lead to novel insights into the regulation and function of sleep, which can then be translated into improved treatments for sleep–wake disorders as well as other mental and physical disorders associated with disrupted sleep.
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89. Hajdu I, Obal F Jr, Fang J, Krueger JM, et al. Sleep of transgenic mice producing excess rat growth hormone. Am J Physiol Regul Integr Comp Physiol 2002;282(1):R70-R76. 90. Shiromani PJ, Basheer R, Thakkar J, Wagner D, et al. Sleep and wakefulness in c-fos and fos B gene knockout mice. Brain Res Mol Brain Res 2000;80(1):75-87. 91. Franken P, Lopez-Molina L, Marcacci L, Schibler U, et al. The transcription factor DBP affects circadian sleep consolidation and rhythmic EEG activity. J Neurosci 2000;20(2):617-625. 92. Naylor E, Bergmann BM, Krauski K, Zee PC, et al. The circadian clock mutation alters sleep homeostasis in the mouse. J Neurosci 2000;20(21):8138-8143. 93. Frank MG, Stryker MP, Tecott LH. Sleep and sleep homeostasis in mice lacking the 5-HT2c receptor. Neuropsychopharmacology 2002;27(5):869-873. 94. Kapfhamer D, Valladares O, Sun Y, Nolan PM, et al. Mutations in Rab3a alter circadian period and homeostatic response to sleep loss in the mouse. Nat Genet 2002;32(2):290-295. 95. Boutrel B, Franc B, Hen R, Hamon M, et al. Key role of 5-HT1B receptors in the regulation of paradoxical sleep as evidenced in 5-HT1B knock-out mice. J Neurosci 1999;19(8):3204-3212. 96. Boutrel B, Monaca C, Hen R, Hamon M, et al. Involvement of 5-HT1A receptors in homeostatic and stress-induced adaptive regulations of paradoxical sleep: studies in 5-HT1A knock-out mice. J Neurosci 2002;22(11):4686-4692. 97. Reppert SM, Weaver DR. Coordination of circadian timing in mammals. Nature 2002;418(6901):935-941. 98. Tobler I, Borbely AA, Groos G. The effect of sleep deprivation on sleep in rats with suprachiasmatic lesions. Neurosci Lett 1983;42(1):49-54. 99. Mistlberger RE, Bergmann BM, Waldenar W, Rechtschaffen A. Recovery sleep following sleep deprivation in intact and suprachiasmatic nuclei–lesioned rats. Sleep 1983;6(3):217-233. 100. Trachsel L, Edgar DM, Seidel WF, Heller HC, et al. Sleep homeostasis in suprachiasmatic nuclei–lesioned rats: effects of sleep deprivation and triazolam administration. Brain Res 1992;589(2): 253-261. 101. Wurts SW, Edgar DM. Circadian and homeostatic control of rapid eye movement (REM) sleep: promotion of REM tendency by the suprachiasmatic nucleus. J Neurosci 2000;20(11):4300-4310. 102. Dijk DJ, Czeisler CA. Paradoxical timing of the circadian rhythm of sleep propensity serves to consolidate sleep and wakefulness in humans. Neurosci Lett 1994;166(1):63-68. 103. Dijk DJ, Czeisler CA. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci 1995;15(5 Pt 1):3526-3538. 104. Mendelson WB, Bergmann BM, Tung A. Baseline and postdeprivation recovery sleep in SCN-lesioned rats. Brain Res 2003; 980(2):185-190. 105. Easton A, Meerlo P, Bergmann B, Turek FW. The suprachiasmatic nucleus regulates sleep timing and amount in mice. Sleep 2004;27(7):1307-1318. 106. Edgar DM, Dement WC, Fuller CA. Effect of SCN lesions on sleep in squirrel monkeys: evidence for opponent processes in sleep-wake regulation. J Neurosci 1993;13(3):1065-1079. 107. Wisor JP, Pasumarthi RK, Gerashchenko D, Thompson CL, et al. Sleep deprivation effects on circadian clock gene expression in the cerebral cortex parallel electroencephalographic differences among mouse strains. J Neurosci 2008;28(28):7193-7201. 108. Shiromani PJ, Xu M, Winston EM, Shiromani SN, et al. Sleep rhythmicity and homeostasis in mice with targeted disruption of mPeriod genes. Am J Physiol Regul Integ Comp Physiol 2004; 287(1):R47-R57. 109. Kopp C, Albrecht U, Zheng B, Tobler I. Homeostatic sleep regulation is preserved in mPer1 and mPer2 mutant mice. Eur J Neurosci 2002;16(6):1099. 110. DeBruyne JP, Weaver DR, Reppert SM. CLOCK and NPAS2 have overlapping roles in the suprachiasmatic circadian clock. Nat Neurosci 2007;10(5):543-545. 111. Dudley CA, Erbel-Sieler C, Estill SJ, Reick M, et al. Altered patterns of sleep and behavioral adaptability in NPAS2-deficient mice. Science 2003;301(5631):379-383. 112. Rutter J, Reick M, Wu LC, McKnight SL. Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science 2001;293(5529):510-514.
174 PART I / Section 3 • Genetics of Sleep 113. Reick M, Garcia JA, Dudley C, McKnight SL. NPAS2: an analog of clock operative in the mammalian forebrain. Science 2001; 293(5529):506-509. 114. Benington JH, Heller HC. Restoration of brain energy metabolism as the function of sleep. Prog Neurobiol 1995;45(4):347-360. 115. Shaw PJ, Tononi G, Greenspan RJ, Robinson DF. Stress response genes protect against lethal effects of sleep deprivation in Drosophila. Nature 2002;417(6886):287-291. 116. Shaw PJ, Franken P. Perchance to dream: Solving the mystery of sleep through genetic analysis. J Neurobiol 2003;54(1):179-202. 117. Shaw PJ, Cirelli C, Greenspan RJ, Tononi G. Correlates of sleep and waking in Drosophila melanogaster. Science 2000;287(5459): 1834-1837. 118. Hendricks JC, Finn SM, Panckeri KA, Chavkin J, et al. Rest in Drosophila is a sleep-like state. Neuron 2000;25(1):129-138. 119. Hendricks JC, Sehgal A. Why a fly? Using Drosophila to understand the genetics of circadian rhythms and sleep. Sleep 2004;27(2): 334-342.
120. Huber R, Hill SL, Holladay C, Biesiadecki M, et al. Sleep homeostasis in Drosophila melanogaster. Sleep 2004;27(4):628-639. 121. Cirelli C, LaVaute TM, Tononi G. Sleep and wakefulness modulate gene expression in Drosophila. J Neurochem 2005;94(5):14111419. 122. Cirelli C. Searching for sleep mutants of Drosophila melanogaster. Bioessays 2003;25(10):940-949. 123. Greenspan RJ, Tononi G, Cirelli C, Shaw PJ. Sleep and the fruit fly. Trends Neurosci 2001;24(3):142-145. 124. Laposky A, Easton A, Dugovic C, Walisser J, et al. Deletion of the mammalian circadian clock gene BMAL1/Mop3 alters baseline sleep architecture and the response to sleep deprivation. Sleep 2005;28: 395-409. 125. Groeger JA, Viola AU, Lo JC, von Schantz M, et al. Early morning executive functioning during sleep deprivation is compromised by a PERIOD3 polymorphism. Sleep 2008;31(8):1159-1167. 126. Dijk DJ, Archer SN. PERIOD3, circadian phenotypes, and sleep homeostasis. Sleep Med Rev 2010;14(3):151-160.
Genetic Basis of Sleep in Healthy Humans Hans-Peter Landolt and Derk-Jan Dijk Abstract Sleep is a very rich phenotype, and many aspects of sleep differ considerably in the population of healthy individuals even when only a very narrow age range is considered. Interindividual variation in diurnal preference, sleep duration, and sleep structure, and variation in the electroencephalogram (EEG) during rapid eye movement (REM) sleep, non-REM sleep, and wakefulness, have all been shown to have a genetic basis. The response to challenges of sleep regulatory processes such as sleep deprivation and circadian misalignment has also been shown to vary between individuals. Some of the polymorphic variations in genes contributing to variation in sleep characteristics have now been identified. They include variations in
EVIDENCE FOR GENOTYPEDEPENDENT DIFFERENCES IN DIURNAL PREFERENCE, SLEEP TIMING, SLEEP DURATION, SLEEP ARCHITECTURE, AND SLEEP EEG Many aspects of sleep and sleep–wake regulation are highly variable between individuals, yet highly stable within individuals. Uncovering genetic factors contributing to these traitlike individual differences in healthy humans constitutes one of the most promising avenues for fostering our understanding of the neurobiology of sleep in health and disease. This chapter will summarize the current evidence for genotype-dependent differences in duration, timing, and structure of sleep, as well as the sleep EEG, in healthy individuals. Table 15-1 summarizes the genetic variations in candidate genes that have been investigated to date to determine whether they contribute to genotype-dependent differences in diurnal preference, sleep timing, sleep duration, sleep structure, and sleep EEG. We will also review how these differences may relate to the homeostatic and circadian regulation of sleep. Several sleep characteristics differ between the sexes and between ethnic groups, but these differences will not be discussed here. The manifestation and regulation of sleep and the sleep EEG reflect different aspects of complex behaviors. Each of these aspects is likely to be under the control of multiple genes, which may interact, and which are also influenced by the environment and other factors such as age. In humans, very little is currently known about the genes that contribute to the traitlike, individual sleep phenotypes. Similarly, very little is known about the genes that contribute to individual circadian-phenotypes, although a considerable number of genes that contribute to circadian rhythmicity have been discovered in animals. Two main techniques for the genetic dissection of normal human sleep are available. The first is to examine the impact of candidate genes—that is, genes for which evidence exists that they are involved in sleep and sleep–
Chapter
15
genes associated with the circadian system (CLOCK, PER1, PER2, PER3), the adenosine system (ADA, ADORA2A), and the catecholaminergic system (COMT, AA-NAT). For some of these genes, associations with only one aspect of sleep have so far been reported (e.g., for PER2 and sleep timing). Variations in other genes have been shown to affect multiple aspects of sleep and wakefulness, as well as the response to sleep loss or pharmacologic interventions. For example, PER3 and ADA affect the EEG and performance during prolonged waking, whereas ADORA2A and COMT modulate EEG and response to the stimulants caffeine and modafinil. All currently known polymorphic variations explain only a small part of the variation in healthy human sleep phenotypes, and many more genetic contributions remain to be discovered.
wake regulation. With this method, individuals with distinct genotypes of known genetic polymorphisms are prospectively studied in the sleep laboratory. This approach precludes discovery of novel “sleep genes,” but it may help us understand the consequences of these polymorphisms for sleep physiology. By contrast, genome-wide association studies may lead to the identification of novel “sleep genes,” which may lead to the discovery of novel sleep regulatory pathways. These studies, however, require very large sample sizes and multiple replications. The weaknesses and strengths of these strategies were recently discussed in detail.1 Large interindividual differences are observed in preferred time of day for completion of distinct cognitive tasks, sleep timing, sleep duration, sleep structure, and sleep EEG. Genes contribute to each of these phenotypes, and a high degree of heritability (i.e., the percentage of variance explained by overall genetic effects) has been demonstrated for these variables. For some of these variables, the magnitude of interindividual differences exceeds by far the size of the effects of manipulations of sleep regulatory processes, such as sleep deprivation.2
GENES CONTRIBUTING TO HUMAN MORNINGNESS–EVENINGNESS AND TIMING OF SLEEP Candidate Genes The timing of the peaks and troughs of daytime alertness and the timing of nocturnal sleep (i.e., diurnal preference) are highly variable among healthy individuals. Some of us go to sleep when others wake up. Self-rating scales such as the Horne-Östberg morningness–eveningness questionnaire (MEQ) and the diurnal type scale show normal distribution along a morningness–eveningness axis,3,4 indicating the contribution of additive, small effects of multiple genes in combination with the environment. Recent studies of large numbers of monozygotic (MZ) and dizygotic (DZ) twin pairs and of population- and family175
176 PART I / Section 3 • Principles of Sleep Medicine Table 15-1 Genes Investigated to Determine Their Contribution to Genotype-Dependent Differences NCBI SNP-ID NUMBER
CHROM.
GENE
BASE CHANGE
AMINO ACID SUBSTITUTION
ALLELE FREQUENCIES* (%)
rs1801260
4
CLOCK
c.3111T/C
n/a
73 : 27
rs2070062
4
CLOCK
c.257T/G
n/a
73 : 27
17
PER1
c.2548G/A
n/a
85 : 15
17
PER1
c.2434T/C
n/a
82.5 : 17.5
2
PER2
c.1984A/G
Ser662Gly
rs2304672
2
PER2
c.111G/C
n/a
84 : 16
rs57875989
1
PER3
del(3031-3084 nt)
del(1011-1028 aa)
66 : 34
17
AANAT
c.619G/A
Ala129Thr
17
AANAT
c.-263G/C
n/a
20
ADA
c.22G/A
Asp8Asn
rs5751876
22
ADORA2A
c.1083T/C
n/a
40 : 60
rs4680
22
COMT
c.472G/A
Val158Met
51 : 49
rs1799990
20
PRNP
c.385A/G
Met129Val
—
rs2735611
100 : 0
100 : 0
51 : 49
94.5 : 5.5
NCBI SNP-ID number, National Center for Biotechnology Information single nucleotide polymorphism reference number; chrom, human chromosome number; gene, NCBI gene symbol; base change, nucleotide substitution at indicated position of coding DNA; amino acid substitution, amino acid substitution associated with base change; n/a, no amino acid substitution (silent polymorphism); (√), possible contribution to phenotypic variation was investigated and reported; (*), allele and genotype frequencies may vary considerably among different ethnic populations. Values refer to published data from mainly white populations (except the values for c.263G/C polymorphism of AANAT, which are derived from a Japanese population).
based cohorts revealed roughly 50% heritability for diurnal preference5 and 22% to 25% for habitual bedtime.6,7 Morningness–eveningness and timing of sleep are thought to be determined in part by circadian oscillators. At the molecular level, these oscillators consist of a network of interlocked transcriptional or translational feedback loops, which involve several clock-related genes including the transcription regulators CLOCK, BMAL1, PER1-3, CRY1-2, TIM, and other genes. This knowledge has provided a rational basis for the search for associations between these genes and morningness–eveningness and altered sleep timing. The effect of a single nucleotide polymorphism (SNP) in the 3′-untranslated region (UTR) of the human “Circadian locomotor output cycles kaput” gene (CLOCK),
located on chromosome 4, on diurnal preference was first studied in middle-aged adults. This SNP may affect the stability and half-life of messenger RNA,8 and thus alter the protein level that is finally translated. Katzenberg and colleagues9 reported that homozygous carriers of the 3111C allele have increased evening preference for mental activities and sleep, with delays ranging from 10 to 44 minutes, when compared with individuals carrying the 3111T allele. A similar association with diurnal preference was found in a Japanese population, and MEQ scores were significantly correlated with sleep onset time and wake time.4 By contrast, studies in healthy European and Brazilian samples failed to confirm an association between genetic variation in CLOCK and diurnal preference.10,11 Interestingly, an almost complete linkage
CHAPTER 15 • Genetic Basis of Sleep in Healthy Humans 177
GENOTYPE FREQUENCIES* (%)
DIURNAL PREFERENCE
SLEEP TIMING
SLEEP DURATION
T/T = 40 T/C = 53 C/C = 7
√
√
√
T/T = 40 T/C = 53 C/C = 7
√
G/G = 72 G/A = 27 A/A = 1
√
T/T = 69 T/C = 27 C/C = 4
√
SLEEP STRUCTURE
SLEEP EEG
√
A/A = 100 A/G = 0 G/G = 0 C/C = 70 C/G = 28 G/G = 3
√
√
PER34/4 = 43 PER34/5 = 48 PER35/5 = 9
√
√
G/G = 100 G/A = 0 A/A = 0
√
√
√
G/G = 89 G/A = 11 A/A = 0
√
√
T/T = 13 T/C = 54 C/C = 33
√
√
√
√
√
G/G = 28 G/C = 47 C/C = 25
G/G = 25 G/A = 53 A/A = 22
√
A/A = 37 A/G = 51 G/G = 12
disequilibrium was shown between the 3111T→C and the 257T→G polymorphisms located in the other extremity of this gene.11 Full-length analysis of secondary mRNA structure revealed no interaction between the two polymorphisms. Mouse Per1 and Per2 are importantly involved in maintaining circadian rhythmicity,12 and possible associations between variation in these genes and diurnal preference were thus also investigated in humans. Screening for missense mutations and functional or synonymous polymorphisms in promoter, 5′- and 3′-UTR, and coding regions of the period-1 gene (PER1) in volunteers with extreme diurnal preference and patients with delayed sleep-phase syndrome (DSPS) remained initially unsuccessful.13,14 By contrast, the distribution of the C and T alleles of a silent polymorphism in exon 18 was found to differ between extreme morning and evening types.14 Thus, the frequency
√
√
of the 2434C allele was roughly double in subjects with extreme morning preference (24%) compared with subjects with extreme evening preference (12%). This polymorphism may be linked to another functional polymorphism, or it may directly affect PER1 expression at the translational level.14 A missense mutation in the human period-2 gene (PER2) currently provides the most striking example of a direct link with between genetic variation in a clock gene and changed circadian rhythms. Linkage analyses in families afflicted with familial advanced sleep-phase syndrome (FASPS) revealed associations with functional polymorphisms of PER2 that cause altered amino acid sequences in regions important for phosphorylation of this protein15 and a mutation in casein kinase delta (CKδ), which plays an important role in phosphorylation.16 The subsequent finding in a transgenic mouse model express-
178 PART I / Section 3 • Principles of Sleep Medicine
ing the human FASPS mutation that casein kinase I delta (CKIδ) can regulate circadian period through PER2 provided further evidence that this gene is importantly involved in the mechanisms of circadian rhythm regulation in humans.17 In accordance with this notion, a C111G polymorphism located in the 5′-UTR of PER2 modulates diurnal preference in healthy volunteers.18 Thus, the 111G allele is significantly more prevalent in subjects with extreme morning preference (14%) than in individuals with extreme evening preference (3%). Computer simulation predicted that the 111G allele has a secondary RNA structure different from that of the 111C allele, and that the two transcripts may be differently translated.18 Findings in mice suggest that Per3 functions outside the core circadian clock work.12 Nevertheless, a variablenumber tandem-repeat (VNTR) polymorphism in the human period-3 gene (PER3) also appears to modulate morning and evening preference. A 54-nucleotide sequence located in a coding region of this gene on human chromosome 1 is repeated in either four or five units. This difference may alter the dynamics in PER3 protein phosphorylation. The longer five-repeat allele was associated in European and Brazilian populations with morning preference, and the shorter four-repeat allele with evening preference, respectively.19,20 The gene encoding arylalkylamine N-acetyl-transferase (AANAT) is located on human chromosome 17q25. This enzyme plays a key role in melatonin synthesis and thus may be important for diurnal preference and circadian rhythm disturbances. Comparison in a Japanese population between 50 outpatients diagnosed with DSPS and 161 unrelated healthy controls suggested that the frequency of a seldom-occurring threonine allele at codon 129 is significantly higher in patients than in controls.21 This association was not confirmed in a Brazilian population, where virtually no allelic variation at this position was found.22 In a small study conducted in Singapore, it was suggested that a commonly occurring, silent 263G→C polymorphism of AANAT modulates sleep timing and sleep duration (also see later) in healthy students.23 Genome-Wide Association Study Only one genome-wide association study of sleep-related phenotypes is currently available in humans.6 In the Framingham Heart Study 100K Project, phenotypic and genetic analyses were conducted in 749 subjects and revealed a heritability estimate for habitual bedtime of 22%. This small study suggests that a nonsynonymous polymorphism in a coding region of the gene encoding neuropeptide S receptor 1 (NPSR1) is a possible modulator of usual bedtime as obtained from a self-completion questionnaire. This polymorphism leads to a gain-of-function mutation in the receptor protein by increasing the sensitivity for neuropeptide S receptor 10-fold.24 Although a possible association of NPSR1 to weekday bedtime is interesting, the statistical power of this pilot study is limited, and the necessary replication of this finding in independent samples is lacking. A recent analysis of a larger sample of the Framingham Offspring Cohort did not parallel the prior result.7
GENES CONTRIBUTING TO HABITUAL SLEEP DURATION Habitual sleep duration, like diurnal preference, shows large variation between healthy individuals, and the physiologic sleep and circadian correlates of habitual short and long sleepers have been identified in small groups of subjects.25-27 The temporal profiles of nocturnal melatonin and cortisol levels, body temperature, and sleepiness under constant environmental conditions and in the absence of sleep suggest that the circadian pacemaker programs a longer biological night in long sleepers than in short sleepers.27 Individual differences in this program may contribute to the large variation in habitual sleep duration, which shows a perfect normal distribution in the general population.28,29 Such a distribution is consistent with the influence of multiple, low-penetrance polymorphisms. Several oldertwin studies and one recent genome-wide association study reported for sleep duration moderate heritability estimates of 17% to 40%.6,30-32 The Framingham Heart Study 100K Project revealed a linkage peak to usual sleep duration on chromosome 3 including the gene encoding prokineticin 2 (PROK2).6 This neuropeptide may be an important output molecule from the suprachiasmatic nucleus (SCN), in particular in defining the onset and maintenance of the circadian night.33,34 Because the danger of false-positive inferences from small genome-wide association studies is high, the methodological limitations of this work discussed earlier also apply to this potential association. It was not corroborated in a larger sample of the Framingham Cohort.7 GENES CONTRIBUTING TO SLEEP ARCHITECTURE Many variables characterizing sleep architecture demonstrate large variation between individuals and high stability within individuals.2,35-37 For example, the intraclass correlation coefficients, which estimate the intraindividual stability of a variable across conditions (e.g., baseline versus sleep deprivation), was reported to be 0.73 for slow-wave sleep (SWS) and 0.48 for REM sleep.2 This observation suggests the presence of traitlike, interindividual differences in sleep physiology, which have a genetic basis. Indeed, twin studies show striking similarity and concordance in visually defined sleep variables in MZ twins, yet not in DZ twins. Already the first polysomnographic sleep studies in MZ twins have revealed almost complete concordance in the temporal sequence of sleep stages.38 Subsequent work showed that in particular those variables that most reliably reflect sleep need are under tight genetic control. Apart from total sleep time, they include duration of non-REM sleep stages, especially SWS, and density of rapid eye movements in REM sleep.39-41 Linkowski41 estimated that the heritability of REM density is up to 90%. Slow-Wave Sleep and REM Sleep A few studies have conducted polysomnographic assessment in defined genotypes. The CLOCK genotypes that were associated with diurnal preference9 did not signifi-
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Figure 15-1 High interindividual variation (left) and high intraindividual stability (right) in all-night EEG power spectra in non-REM sleep in 32 baseline nights of 8 young men (S1-S8). The largest interindividual variation is observed in theta, alpha and sigma frequencies (about 5-15 Hz). The spectra of all 4 baseline nights (BL1-BL4) of one individual (S8) are virtually superimposable. (Adapted and modified from Buckelmüller J, Landolt HP, Stassen HH, Achermann P. Trait-like individual differences in the human sleep electroencephalogram. Neuroscience 2006;138:351-356.)
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The Sleep EEG: Among the Most Heritable Traits in Humans Visual sleep-state scoring relies on arbitrarily defined criteria and can reveal only limited information about sleep physiology. To obtain more detailed insights, quantitative analyses of the EEG signal recorded during sleep have to be performed. A powerful approach to quantify amplitude and prevalence of EEG oscillations with distinct frequencies is power spectral analysis based on fast Fourier transform (FFT).36,45,46 Recent studies strongly suggest that especially the sleep EEG, but also the waking EEG, are highly heritable traits in humans. All-night sleep EEG spectra derived from multiple recordings in healthy individuals show large interindividual variation and high intraindividual stability.36,37 Buckelmüller and colleagues37 recorded in eight young men two pairs of baseline nights separated by 4 weeks. Although the spectra in non-REM sleep differed largely between individuals, the absolute power values and the shape of each subject’s spectra were impressively constant across all nights (Fig. 15-1). The largest differences among the subjects were present in the theta, alpha, and sigma (i.e., about 5 to 15 Hz) range. Hierarchical cluster analysis of Euclidean distances based on spectral values as feature vectors demonstrated that all four nights of each individual segregated into the same single cluster.37 Similar results were obtained in REM sleep, and by other researchers in men and women of older age.36 These data strongly suggest that the sleep EEG contains systematic and stable interindividual differences that are at least in part genetically determined. This conclusion is supported by two recent studies comparing for the first time the spectral composition of the sleep EEG between MZ and DZ twin pairs. In non-REM sleep, the within-pair concordance in spectral power in the
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cantly affect sleep variables derived from nocturnal polysomnography. Only two polymorphisms have been identified to date as affecting sleep architecture in humans. First, in one study, homozygous carriers of the long-repeat genotype in PER3 (PER35/5), which associates with morningness, fell asleep more rapidly (about 9 versus 18 minutes) and showed more SWS (about 23% versus 16% of total sleep time) compared with homozygous four-repeat individuals.42 In addition, during recovery sleep from sleep deprivation, REM sleep was reduced in PER35/5 individuals. Second, a functional variation in the gene on chromosome 20 encoding the enzyme adenosine deaminase (ADA) was found to have a profound impact on sleep architecture.43 Adenosine and adenosine receptors are thought to be involved in regulating distinct aspects of human sleep,44 and ADA plays an important role in regulating extracellular adenosine levels. Healthy individuals with the G/A genotype, associated with lower ADA activity in erythrocytes and leucocytes than in individuals with the G/G genotype, showed significantly more SWS in a baseline recording than subjects with the G/G genotype (about 93 versus 63 minutes). This difference is comparable to the difference between a baseline night and recovery night after one night without sleep. All other sleep variables were similar in both genotypes.
CHAPTER 15 • Genetic Basis of Sleep in Healthy Humans 179
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Figure 15-2 Heritability of non-REM sleep EEG is over 90%. Panels show color-coded similarity indices of 8- to 16-Hz activity in monozygotic (left) and dizygotic (right) twin pairs. The similarity index in each twin pair was scaled between minimal (0% similarity, white) and maximal (100% similarity, dark orange). Black lines, derivation Fz; blue lines, derivation Cz; red lines, derivation Pz (unipolar derivations referenced to averaged mastoid). (Modified from De Gennaro L, Marzano C, Fratello F, et al. The EEG fingerprint of sleep is genetically determined: a twin study. Ann Neurol 2008;64:455-460.)
2 to 13 Hz range is significantly higher in MZ twins than in DZ twins.47 Especially alpha/sigma frequencies appear to reflect particularly strong genetic influences. Heri tability in this frequency range may be as high as 96% (Fig. 15-2).48
180 PART I / Section 3 • Principles of Sleep Medicine PER3 del(3031–3084 ht)
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Frequency (Hz) Figure 15-3 The period-3 (PER3) variable-number tandem-repeat polymorphism (insertion of nucleotides 3031 to 3084), the adenosine deaminase (ADA) c.22G/A polymorphism, and the adenosine A2A receptor (ADORA2A) c.1083T/C polymorphism modulate the EEG in sleep and wakefulness. Relative EEG power density spectra (C3A2 derivation) in non-REM sleep (stages 2 to 4), REM sleep, and wakefulness. Triangles at the bottom of the panels indicate frequency bins, which differed significantly between the genotypes (P < .05, two-tailed paired t tests). (Adapted from Viola AU, Archer SN, James LM, et al. PER3 polymorphism predicts sleep structure and waking performance. Curr Biol 2007;17:613-618, and Rétey JV, Adam M, Honegger E, et al. A functional genetic variation of adenosine deaminase affects the duration and intensity of deep sleep in humans. Proc Natl Acad Sci U S A 2005; 102:15676-15681.)
GENES CONTRIBUTING TO THE SLEEP EEG Healthy carriers of the PER35/5 genotype have not only more SWS but also more delta activity in non-REM sleep, as well as higher theta/alpha activity in REM sleep and wakefulness, than individuals with the PER34/4 genotype (Fig. 15-3).42,49 Like the PER3 polymorphism, the 22G>A polymorphism of ADA not only affects duration of SWS but also the spectral composition of the EEG. Thus, in non-REM sleep and REM sleep, EEG activity within the 0.5 to
5.5 Hz range is higher in G/A allele carriers than in homozygous G allele carriers (see Fig. 15-3).43 On the basis of data in animals, it may be expected that G/A and G/G genotypes behave differently during prolonged wakefulness. More specifically, quantitative trait locus (QTL) analyses in inbred mouse strains revealed that a genomic region including Ada modifies the rate at which non-REM sleep need accumulates during wakefulness.50 A synonymous 1083T→C polymorphism located in the coding region of the human adenosine A2A receptor gene (ADORA2A) also affects the EEG in non-REM sleep and
REM sleep.43 This polymorphism is linked to a 2592C→Tins polymorphism in the 3′-UTR of ADORA2A. The latter may modulate protein expression.51 Rétey and colleagues43 observed that EEG spectral power in the range of approximately 7 to 10 Hz is higher in subjects with the 1083T→T genotype than in individually-matched subjects with the 1083C→C genotype (see Fig. 15-2). Because the difference is not sleep or wakefulness specific, this polymorphism may modulate EEG generating mechanisms rather than sleep–wake regulation. Moreover, the same genetic variation in ADORA2A contributes to subjective and objective responses to moderate caffeine intake on sleep.52 The gene encoding the important catecholaminemetabolizing enzyme catechol-O-methyltransferase (COMT) is located on human chromosome 22q11.2, in proximity to ADORA2A. Human COMT contains a common functional variation that alters the amino acid sequence of COMT protein at codon 158 from valine (Val) to methionine (Met).53 Individuals homozygous for the Val allele presumably show higher COMT activity and lower dopaminergic signaling in prefrontal cortex than Met/Met homozygotes.54-56 Sleep variables and their response to sleep deprivation do not differ between male carriers of Val/Val and Met/Met genotypes.57,57a In contrast, EEG power in non-REM sleep, REM sleep, and wakefulness is consistently lower in the upper-alpha (11 to 13 Hz) range in Val/Val compared with Met/Met homozygotes.58 This difference is present before and after sleep deprivation, and it persists after administration of the stimulant modafinil. The data demonstrate that a functional variation of the COMT gene is associated with robust interindividual differences in the sleep EEG. This polymorphism profoundly affects the efficacy of modafinil after sleep deprivation in young healthy men.57 Thus, two-time 100-mg modafinil potently improved vigor and well-being, and maintained baseline performance of executive functioning and vigilant attention throughout 40 hours of prolonged wakefulness in 10 Val/Val homozygotes, yet the same dosage was virtually ineffective in 12 Met/Met homozygotes. Interestingly, an opposite relationship between Val158Met genotype of COMT and measures of daytime sleepiness may be present in patients suffering from narcolepsy (see Clinical Pearl). A point mutation at codon 178 (in rare cases also a mutation at codon 200) of the prion protein gene (PRNP) has been identified as the cause underlying the devastating disease, fatal familial insomnia (FFI).59,60 Interestingly, although healthy relatives of FFI patients appear to have normal sleep EEG,61 the polymorphic codon 129 of the PRNP gene may influence EEG activity during sleep.62 Subjects with Met/Val genotype showed lower slow-wave activity and higher spindle frequency activity than individuals with the Val/Val genotype, independent of codon 178.
GENETIC BASIS OF SLEEP–WAKE REGULATION: INTERACTION BETWEEN HOMEOSTATIC AND CIRCADIAN SYSTEMS Many of the traits and genes described here concern sleep– wake characteristics as assessed under baseline conditions.
CHAPTER 15 • Genetic Basis of Sleep in Healthy Humans 181
How these alterations in sleep characteristics relate to sleep–wake regulation and how they may lead to functional consequences remains largely unexplored. The available data, however, already indicate that the effects cross boundaries between sleep and wakefulness, and between homeostatic and circadian aspects of sleep–wake regulation. For example, the polymorphisms in PER3, ADORA2A, and COMT affect the EEG in non-REM sleep, REM sleep, and wakefulness. To investigate whether these changes reflect changes in EEG generating mechanisms with or without a relationship to sleep regulatory processes requires these processes to be challenged by, for example, sleep deprivation. Comparing the response to sleep deprivation in PER35/5 individuals with that in PER34/4 individuals revealed that the increase in theta activity in the EEG during wakefulness was more rapid, and furthermore that the decline of cognitive performance was more rapid.42 This genotype-dependent differential susceptibility to the negative effects of sleep loss on waking performance was particularly pronounced in the second half of the circadian night and on tasks of executive functioning.63 One interpretation of these data is that the VNTR polymorphism in PER3 affects the dynamics of the homeostatic process, which then through its interaction with the circadian regulation of performance leads to differential susceptibility to the negative effects of sleep loss. Indeed, an fMRI study has shown that the changes in brain responses of PER35/5 individuals to a working memory task during sleep deprivation is very different from the changes in PER34/4 individuals. Whereas PER34/4 individuals maintained activation and recruited new brain areas to the task, brain responses were greatly diminished in PER35/5 individuals.64 These laboratory data suggest that clock and sleep genes could contribute to individual differences in tolerance to shift work and jet lag, which are highly prevalent in society.
CONCLUDING REMARKS Sleep is a complex behavior, and any functional genetic variation associated with changes in one of the many neurotransmitter or neuromodulator systems can be expected to affect sleep and the sleep EEG. Polymorphic variations in a number of genes have now been shown to affect several characteristics of sleep, and some of these genes may indeed be involved in sleep regulatory processes. Elucidating the signaling pathways that are affected will aid in our understanding of individual differences in sleep–wake behavior.
Acknowledgements The authors’ research is supported by Swiss National Science Foundation, Zürich Center for Integrative Human Physiology, and Novartis Foundation for Medical-Biological Research (to HPL), and Biotechnology and Biological Sciences Research Council, Wellcome Trust, the Air Force Office of Scientific Research, and the Higher Education Funding Council for England (to DJD).
182 PART I / Section 3 • Principles of Sleep Medicine ❖ Clinical Pearl Distinct alleles and genotypes in the genes of monoamine oxidase type A (MAO-A)65—but see Dauvilliers and colleagues66—and COMT66 are thought to be associated with the clinical manifestation of narcolepsy. The Val158Met polymorphism of COMT exerts a sexual dimorphism and a strong effect of genotype on disease severity.66 More specifically, women narcoleptics with high COMT activity fall asleep twice as fast during the multiple sleep latency test than those with low COMT activity. An opposite relationship, although less pronounced, is observed in men. Also the response to treatment with modafinil to control excessive daytime sleepiness differs between COMT genotypes. Patients (female and male) with the Val/ Val genotype need an almost 100-mg-higher daily dosage than patients with the Met/Met genotype.67 Intriguingly, in male healthy volunteers, the impact of the Val158Met polymorphism of COMT on modafinil’s efficacy to improve excessive sleepiness after sleep deprivation is opposite to that in narcolepsy patients.57
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CHAPTER 15 • Genetic Basis of Sleep in Healthy Humans 183 55. Chen JS, Lipska BK, Halim N, Ma QD, et al. Functional analysis of genetic variation in catechol-O-methyltransferase (COMT): effects on mRNA, protein, and enzyme activity in postmortem human brain. Am J Hum Genetics 2004;75:807-821. 56. Slifstein M, Kolachana B, Simpson EH, Tabares P, et al. COMT genotype predicts cortical-limbic D1 receptor availability measured with [C-11]NNC112 and PET. Mol Psychiatry 2008; 13:821-827. 57. Bodenmann S, Xu S, Luhmann UFO, Arand M, et al. Pharmacogenetics of modafinil after sleep loss: catechol-O-methyltransferase genotype modulates waking functions but not recovery sleep. Clin Pharmacol Ther 2009;85:296-304. 57a. Bodenmann S, Landolt HP. Effects of modafinil on the sleep EEG depend on Val158Met polymorphism of COMT. Sleep 2010;33: 1027-1035. 58. Bodenmann S, Rusterholz T, Dürr R, Stoll C, et al. The functional Val158Met polymorphism of COMT predicts individual differences in brain alpha oscillations. J Neurosci 2009;29:10855-10862. 59. Lugaresi E, Medori R, Montagna P, Baruzzi A, et al. Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med 1986;315:997-1003. 60. Montagna P, Gambetti P, Cortelli P, Lugaresi E. Familial and sporadic fatal insomnia. Lancet Neurol 2003;2:167-176. 61. Ferrillo F, Plazzi G, Nobili L, Beelke M, et al. Absence of sleep EEG markers in fatal familial insomnia healthy carriers: a spectral analysis study. Clin Neurophysiol 2001;112:1888-1892. 62. Plazzi G, Montagna P, Beelke M, Nobili L, et al. Does the prion protein gene 129 codon polymorphism influence sleep? Evidence from a fatal familial insomnia kindred. Clin Neurophysiol 2002; 113:1948-1953. 63. Groeger JA, Viola AU, Lo JCY, von Schantz M, et al. Early morning executive functioning during sleep deprivation is compromised by a PERIOD3 polymorphism. Sleep 2008;31:1159-1167. 64. Vandewalle G, Archer SN, Wuillaume C, Balteau E, et al. Functional magnetic resonance imaging–assessed brain responses during an executive task depend on interaction of sleep homeostasis, circadian phase, and PER3 genotype. J Neurosci 2009;29:7948-7956. 65. Koch H, Craig I, Dahlitz M, Denney R, et al. Analysis of the monoamine oxidase genes and the Norrie disease gene locus in narcolepsy. Lancet 1999;353:645-646. 66. Dauvilliers Y, Neidhart E, Lecendreux M, Billiard M, et al. MAO-A and COMT polymorphisms and gene effects in narcolepsy. Mol Psychiatry 2001;6:367-372. 67. Dauvilliers Y, Neidhart E, Billiard M, Tafti M. Sexual dimorphism of the catechol-O-methyltransferase gene in narcolepsy is associated with response to modafinil. Pharmacogenomics J 2002;2: 65-68.
Genetics of Sleep and Sleep Disorders in Humans Juliette Faraco and Emmanuel Mignot Abstract Sleep is an evolutionarily old and vital process, and behavioral sleep has been observed in all vertebrates investigated, as well as some invertebrates. Although the precise physiologic functions remain elusive, the conservation of the behavior argues that sleep fulfils important biological needs. Despite the complexities, it is clear that genetic factors underlie the process of normal sleep, and they inevitably underlie sleep disorders. Recent work in animal models and in humans has begun to
Behavioral sleep can be viewed as a complex phenotype. The process of sleep is initiated through interconnected drives responding to clock-dependent and sleep-debt– dependent cues. Two distinct forms of sleep, including five stages, are defined at the electrophysiologic level: non– rapid eye movement (NREM) sleep (stages 1 to 3) and rapid eye movement (REM) sleep. These stages are associated with distinctive physiologic changes affecting muscle tone, thermoregulation, endocrine function, gastrointestinal activity, and cardiorespiratory activity. Interaction with the environment at each of these stages adds additional complexity, and each of these aspects is potentially under the control of a wide variety of genes. A large number of studies have shown that specific set of neural systems, most notably aminergic and cholinergic systems in the brainstem and basal forebrain, as well as systems located in the posterior (hypocretin, histamine) and anterior hypothalamus (median and ventrolateral preoptic gamma-aminobutyric acid [GABA]-ergic systems), display changes across sleep stages and may be primarily important in orchestrating sleep stage and wake organization.1,2 Circadian rhythms drive a “clock-dependent” variation in sleep propensity, and they are observed throughout the animal kingdom, from unicellular organisms to mammals. These serve to coordinate the timing of important physiologic processes, including sleep, with the alternating photoperiod of the external environment. In mammals, circadian rhythms are primarily coordinated by the master clock in the suprachiasmatic nuclei (SCN) of the hypothalamus, and they are entrained by light through the retinohypothalamic tract, although it is now evident that many other tissues, notably peripheral tissues, have their own autonomous circadian clocks. The basis of these rhythms is a largely conserved transcriptional–translational feedback system plus a set of complex posttranscriptional regulatory steps (phosphorylation, targeted degradation) involving Clock, Bmal1, the Period genes, and the Cryptochrome genes.3 The elaborate nature of these loops provides many distinctive points at which single gene mutations can manifest with clearly observable phenotypes such as 184
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uncover the genetic underpinnings of various aspects of sleep, including circadian behavioral variation, homeostatic response, and numerous disorders affecting sleep. Many associations between observed human phenotypes and candidate loci have been published, but replications have been lacking. We present an overview of how genes regulate sleep and circadian processes, and we discuss what is known about how these relate to normal and disordered sleep in humans. We also provide a framework through which the numerous association studies published may be interpreted.
altered period, phase angle, or loss of rhythm, which have been identified in models such as Drosophila and rodents, and in humans. Sleep homeostasis, on the other hand, responds to accumulated sleep debt, increasing the intensity and propensity to initiate sleep according to cumulative time spent awake. Less is known about the genetic, neurochemical, and neuroanatomic bases of the homeostat than about the circadian process. The neuroanatomic basis is likely to be diffuse,1 but slow-wave activity in the delta frequency range, quantified as delta power, varies in proportion to prior sleep and wakefulness and thus serves as one measure of homeostatic sleep need.4,5 Changes in glutamatergic transmission in the cortex, possibly in reaction to synaptic plasticity changes that have occurred in wakefulness, and intracellular metabolic changes may be critical.6 Studies in rodents have demonstrated that the rate of accumulation of this sleep need is also under genetic control.7 More generally, several electroencephalographic (EEG) features have been found to be highly heritable traits in humans, based on studies comparing monozygotic (MZ) and dizygotic (DZ) twins. Indeed, differences between MZ twins were not larger than successive recordings from the same individual. Autosomal dominant inheritance for an array of EEG variants has also been demonstrated through numerous family studies.8 EEG frequency bands in the delta through sigma frequency ranges during wakefulness showed high heritabilities of 76% to 89% in a large study of MZ and DZ twins.9 More recently, a twin study has also showed strong genetic control of spectral composition of NREM sleep, particularly in the delta, theta, alpha, and sigma frequencies.10 Thus, although the process of sleep is clearly under genetic control, the process is highly robust, making single gene mutations specifically abolishing sleep unlikely. The temporal dynamics of sleep are quite fast, indicating that gene expression per se is not likely to govern the state-tostate changes observed on the EEG. Rather, the roles of genes may manifest through differentially available stores
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of neurotransmitters, or variations in activity of transmembrane channels.
GENETIC STUDIES OF HUMAN SLEEP: METHODOLOGICAL LIMITATIONS Identification of single gene mutations in animal models has proved quite successful in the areas of circadian rhythms and narcolepsy, demonstrating that single gene mutations can have dramatic effects on sleep patterns, although in relatively rare situations. Linkage studies of sleep phenotypes in human families have often resulted in unreproduced or controversial results, probably because of a combination of small family size (resulting in limited power), phenotypes that are not fully penetrant or susceptible to phenocopy, rare occurrence of families, and allelic or locus heterogeneity. Even in the best case, linkage studies result in broad peaks containing many potential candidate genes. Numerous association studies have also been published, based either on candidate gene screens or hypothesis-free genome-wide association (GWA) scans. Association studies in general have had a very poor replication rate, and one review showed that for 166 putative associations that were studied three or more times, only six were consistently replicated.11 Keeping in mind that spurious or nonreproducible findings outnumber replicated findings in the pub-
lished literature, it is critical to understand the inherent limitations of these studies (Box 16-1). Case-control designs are popular and practical for association studies but are susceptible to population stratification, which causes problems when patients and controls are unknowingly drawn from different ethnic groups or subgroups. If the disease is more prevalent in one of these groups, it can be overrepresented in patients and underrepresented in controls, and any polymorphism marking the higher-risk subgroup will appear to be associated with the disease. A typical example of this problem is illustrated by previously reported studies of the dopamine D4 receptor gene (DRD4) in relation to personality traits and drug of abuse phenotypes, which were later shown to mostly represent differences in African-American admixture across samples.12,13 In this particular case, hundreds of studies have been published, and even a recent metaanalysis could not clearly conclude whether this association was genuine or artifactual.12 Indeed, even when strict meta-analyses are performed, it is impossible to exclude bias toward publishing positive replications that could inflate the number of positive reports. As an example, in 1999, we found that the Clock 3111C polymorphism was associated with delayed phase in 410 subjects of the Wisconsin Sleep Cohort,14 a finding we could not replicate in 600 additional subjects and that was never published. When population stratification is a problem, alleles enriched in a sub-ethnicity will show differences for
Box 16-1 Common Issues in Published Association Studies Population stratification: An association is observed because cases and controls do not have the same ethnic or sub-ethnic composition (it may not be apparent). This is most problematic in candidate gene associations. Inclusion of phenotypes with poor test or retest reliability: In many cases, the phenotype under study is not robust or validated. Studies of multiple phenotypes without correction for multiple testing: It is common for a study to start with a clear a priori hypothesis, but, despite nonsignificant results, to explore other phenotypes without properly stating that these were exploratory analyses. In a variation of this strategy (“phenotype dredging”), a borderline P value is improved by testing correlated sub-phenotypes (for example, studying amount of sleep after sleep deprivation rather than SWS power after sleep deprivation), or subdividing the groups (e.g., by sex). In general, these additional testing strategies are acceptable if they are clearly indicated as exploratory in reporting the study. Pseudoreplication: Unfortunately, researchers often frown upon precisely replicating a protocol performed in a prior study, often using an “improved version.” This, together with phenotype dredging, leads to multiple studies “replicating” a similar effect, where in reality this was not the case. Report of gene–gene interactions or testing of multiallele differences without adequate control for multiple testing: The study of interactions, a reasonable idea by itself, is really problematic with respect to power. Most notably, the number of interactions that can be explored is infinite and difficult to control. Interactions should be studied only when there is a clear biological basis, and in general they should be presented as exploratory until replicated. Testing of multiple genetic models without control for multiple testing: In the study of any genetic association, multiple models are frequently tested: allelic association, dominance, recessiveness, and haplotype analysis. The accepted standard to date is to conduct an allelic association test, and to explore further genotypic models only if the allelic test is significant. Functional characterization: In the presence of weaker results, a standard in the field is to show functional effects of the associated polymorphism. This is especially important in cases with single occurrence of a mutation in a family when other families with a similar phenotype and a different mutation in the same gene are not available. Importantly, however, a high standard should be applied to these studies. It may, for example, be easy to find unrelated small changes in lymphocytic gene expression in relation to a polymorphism. Similarly, studies in animal models have limitations: A similar T44A mutation in CKIδ causes opposite circadian phenotypes in Drosophila and mice.
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markers located across the entire genome, and they can thus be more easily detected in GWA-related designs (see later, notes on QQ plots, for example) than in candidate gene studies. For this reason, GWA studies are generally less susceptible to this problem. False positives and nonreplications can also arise from a variety of other factors, including small study sizes, variable phenotype definition, insufficient correction for multiple testing, variable linkage disequilibrium (LD) between the polymorphism studied and the causal variant among
different populations, and population-specific gene–gene or gene–environment interactions. Following the recent explosion of GWA studies, a white paper was published proposing best practices for conducting and publishing initial association reports and replication studies,15 and it focused on assessment of validity of association reports and criteria for establishing replication (Box 16-2). Although recommendations were directed toward GWA designs, the key points also apply to candidate gene association studies. First, not only should a biologically meaningful report
Box 16-2 Key Recommendations for Finding and Replicating Associations Design and Methodology Case-Control Study Information • The source of cases and controls, and recruitment information • Method for determining and validating affected or unaffected status, and reproducibility of classification • Case-control selection flow chart including exclusion points for missing or erroneous data • Table comparing relevant characteristics (ethnic background, demographics, risk factors) Genotyping Quality-Control Procedures • Description of genotyping assays and genotype-calling algorithm • Genotyping quality-control procedure described • Analysis of call rates (by marker, by individual, by case-and-control status) • Analysis of Hardy-Weinberg proportions (cases, controls separately) to identify poor assays • Testing for cryptic relatedness in subjects • Assessment of population heterogeneity including the following: • Average chi-square values and full distribution • QQ plots of chi-square analysis Results • Description of pre-analysis scheme for selection of results suitable for replication • Evaluation of genotype clustering for key markers • Description of specific statistical tests used and genetic models tested • Discussion of choice of threshold for significance and statistical basis for multiple testing adjustment Considerations Regarding Validity of Initial Report • Suitably large sample size • Description of the study’s power to detect an effect • Phenotypes assessed according to standard definitions, and specified in report • Testing for underlying population structure differences between cases and controls • Strength of observed effect • Sufficiently stringent criteria for significance (small P values) • Single-locus and multimarker haplotype analysis • Significance of effect not dependant on altering established quality controls or inclusion criteria, or on unusual sub-phenotype • Appropriate correction for multiple comparisons performed • Description of local linkage disequilibrium; typing of markers in strong linkage disequilibrium (LD) shows similar results • Biological or functional explanations firmly based on available data • If replication not included, preliminary nature of report should be emphasized Replication Studies • Included in the initial association report • Description equivalent in detail to original sample • Sufficient size to distinguish between proposed effect and no effect • Uses independent sample, but similar population group and same phenotype as used for initial replication • Strong rationale for selection of additional markers to be studied in replication (from initial study, implicated through LD or function, implicated in published literature) • Discussion of choice of threshold for significance • Statistical significance obtained with same genetic model as initial study • Joint analysis (if possible) yields smaller P value than seen in initial study • Replication uses same marker allele or haplotype, shows similar effect in same direction as original study • Summary of replication attempts by authors and summary of known replication attempts, including nonreplications
provide evidence of an association supported by a substantial odds ratio (OR) and a statistically significant P value, but it should also report a systematic phenotype criterion, demonstration of adequate sample size and lack of stratification, demonstration of quality of assays, description of multiple testing correction, and a declaration a priori of any weighting schemes, including which markers warrant a reduced multiple testing threshold. Clean and well-defined phenotypes are more likely to result in robust associations, and phenotypic criteria need to be clearly described. Altering phenotype definitions to achieve greater statistical significance has resulted in unreplicated findings. Similarly, it is not uncommon to see reports of “pseudoreplications,” where either the replication is in the opposite direction or it uses a more or less modified definition of the phenotype. Associations that are significant only after post hoc selection for unusual or highly specific sub-phenotypes, or phenotypes representing only a small proportion of a sample study, warrant cautious interpretation. Small studies pose problems because of lack of power, they are prone to large variation in risk estimates, and they are especially susceptible to cryptic stratification effects. Multiple methods are available to demonstrate lack of stratification in GWAs, but most commonly QQ plots of chi-square analysis are used to demonstrate that the distribution of values obtained, with the exception of the positive hits, are close to those expected by chance. Systematic deviation from expected values is a measure of general difference between patients and controls. These methods rely on the availability of vast numbers of genotypes and are not applicable to candidate gene association approaches. Stratification may thus underlie the high rate of nonreplications in candidate gene studies. This will become less of an impediment as genotyping costs decrease and sets of ancestry informative markers (AIMs) become increasingly well characterized. Alternatively, it may be necessary to form collaborations, as combining multiple independent samples overcomes obstacles of insufficient power and improves the generalizability of the findings. The enormous numbers of genotype–phenotype comparisons made in GWA studies lead to correspondingly large numbers of spurious hits. Without rigorous correction for multiple testing and filtering of artifacts, any real results can become obscured. Extremely small P values often result from technical artifacts, and it is important to examine Hardy-Weinberg equilibrium and genotype clustering quality for these genotypes. Methods for multiple testing correction are evolving. Although Bonferroni correction is accepted, it is overly conservative in GWAs because, as a result of LD, many markers are not independent. Genomewide significance for a 900,000 single nucleotide polymorphism (SNP) chip is on the order of 10−8, a daunting hurdle. Lowering the threshold for selected markers that may be anticipated to have a functional role is acceptable, but these will be rare, and they must be declared before analysis has begun, because there is considerable temptation to create credible biological hypotheses post hoc. It is now recommended that any initial association report include a replication study, and this should be performed with the same phenotypic criteria and on an independent sample from a comparable population (preferably
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a collaboration, to avoid the temptation of splitting a wellpowered study into two smaller samples). It is essential to replicate the same markers, and findings should show similar magnitude of effect and in the same direction. Patterns of LD may vary considerably among different ethnic groups. Studying other populations in subsequent replications can add substantial credibility and significantly narrow the region, but failure to replicate in different ethnic groups does not necessarily negate the initial finding. Where replication is not possible, functional analysis can be used to support the validity of the association. In light of these issues, we have elected to primarily describe only findings that are supported by replication studies, or that have substantial functional biological evidence from model systems.
GENETIC FACTORS UNDERLYING THE CIRCADIAN CLOCK AND CIRCADIAN RHYTHM DISORDERS A wealth of information is now known regarding the genetic basis of circadian rhythmicity, which is coordinated by a network of transcriptional–translational feedback loops that drive expression of a series of core clock components with approximately a 24-hour cycle. Analysis of circadian mutants has now led to the discovery of clock protein mutations in fungi, plants, Drosophila, and rodents.1 There is an extensive body of work on the genetics, functional biology, and behavioral and metabolic phenotypic effects of circadian mutants in the mouse, which has been extensively reviewed (see reference 16). Animals carrying circadian clock mutations have phenotypes extending beyond alterations of rhythmic behavior (sleep homeostasis, response to sleep deprivation, metabolism, cancers), probably a reflection of the widespread distribution and activity of clock proteins and their targets. Mutations in human clock-related genes are now well established in the etiology of familial advanced sleep phase syndrome (FASPS). This disorder was first described in a large pedigree from Utah that was segregating an autosomal dominant allele associated with a lifelong tendency to wake up and to go to sleep at very early times. Affected family members had normal sleep quality and quantity, but their preferred sleep and wake times, melatonin, and temperature rhythms were all advanced by 4 to 6 hours.17 The free-running period of the proband was approximately 1 hour shorter than matched controls. The underlying mutation was a serine to glycine substitution (S662G) in the human PER2 gene, and in vitro data suggested this to be a potential phosphorylation site by CK1ε.18 A second FASPS pedigree was found to carry a threonine to alanine (T44A) mutation in the CK1δ gene, which reduced activity of the enzyme in vitro.19 These findings in humans correspond well with identification of a CK1ε mutation in tau mutant Syrian hamsters20 that leads to deficient phosphorylation of PER. Although these results demonstrate a key role for CK1δ/ε in the function of the clock, further studies in rodents have demonstrated complexity.21,22 Surprisingly, CK1ε does not phosphorylate PER2 at position 662 but instead acts to phosphorylate three serine residues nearby. Instead, phosphorylation at 662 by an unknown enzyme acts as a priming event leading to CK1ε activity elsewhere.
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Furthermore, the S662G mutation does not decrease PER stability, as had been anticipated, but instead resulted in decreased transcription at PER2,22 although this is debated.21 The results support a model in which CLOCK timing is regulated by expression, degradation, and nuclear entry and retention of PER2. In addition, there is modulation through multiple states of PER2 phosphorylation, some of which are not dependent on CK1δ/ε.23 The search for this unknown kinase is ongoing. Apart from the well-defined mendelian effect in FASPS, a study of 238 twin pairs found higher correlations for Horne-Ostberg (HO) diurnal preference scores among MZ twins, thus suggesting the presence of circadian factors in the general population.24 A number of association studies have recently examined a connection of the CLOCK gene with diurnal preference. The initial study of Katzenberg examined 410 white individuals of the Wisconsin Sleep Cohort.14 Individuals with the CLOCK 3111C allele in the 3′ untranslated region had lower HO scores, with a 10- to 44-minute delay in preferred timing of activity or sleep, suggesting that this SNP, or another SNP in tight LD, could underlie the effect. Further studies gave variable results, and the association was not found in a study of 105 normal subjects, 26 blind, or 16 delayed-sleep-phase patients,25 but it was identified in a larger study of 421 Japanese subjects.26 These results thus remain controversial, as indeed we could not replicate the association in an additional sample of the Wisconsin cohort (although overall results for the entire sample remain significant). Similarly problematic results have been reported in the study of human PER gene polymorphisms. A purported association between the human PER3 locus and delayed sleep phase remains provisional. Although two groups have reported this general association,27,28 the small samples (16 discordant sib pairs [DSPs], 48 DSPs) were from different ethnic groups (Japan, United Kingdom, and the Netherlands), and they found similar but not equivalent associations. In one case, a rare five-marker haplotype containing the major variable number of tandem repeat (VNTR) four-repeat allele (G647, P864, 4-repeat, T1037, R1158) but not the VNTR four-repeat allele alone was present on seven predicted DSPs chromosomes total (15% carrier frequency) versus 2% of control Japanese.28 In the other study, in England, the VNTR four-repeat allele was associated with HO scores and delayed sleep phase27 in 484 subjects, 75% of whom were homozygous, an effect later suggested to be significant only in younger subjects through the study of HO extremes in a bigger sample.29 Similarly, a T2434C polymorphism in HPER1 (rs2735611) was recently reported to be associated with extreme HO scores (80 individuals per group) drawn from 1590 British volunteers,30 whereas in another, earlier 1999 study, G2548A (rs2253820) in PER1 was not associated with HO in 463 individuals drawn from the Wisconsin Sleep Cohort.31 The more recently published study, however, did not mention that these two PER1 polymorphisms are located within 114 base pairs of each other and are in almost complete LD (r2 = 1), so that typing one is equivalent to typing the other. Considering the relatively small effect size and the broad spectrum of preferences reported in the general population, in contrast to the high penetrance and tight ranges of preferred activity in FASPS, a variety of combi-
nations of different alleles at a number of circadian genes probably underline diurnal preference in the general population. Clearly, the next step is to greatly increase sample size (to several thousand subjects) to have power to exclude or confirm these prior studies. Resequencing of candidate genes in extremes, and finding familial clustering of the phenotype in relatives, to identify other rare strong effect alleles are also viable strategies. It is also likely that the HO, like any subjective assessment instrument, is less amendable to genetic analysis than more objective physiologic measures of circadian phase.
GENETIC FACTORS REGULATING EEG AND THE SLEEP HOMEOSTAT The search for the genetic basis of selected EEG traits and the sleep homeostat is well underway using rodent models. Strong genetic effects are more clearly evident for spectral features of the EEG versus sleep architecture variability.32 Power in the delta and sigma frequency bands in slowwave sleep (SWS) is associated with genetic background, and a deficiency in a single enzyme (acyl–coenzyme A dehydrogenase) results in slowed theta activity during sleep.33 Quantitative trait locus (QTL) and mapping studies demonstrate that strong genetic effects on SWS-need (measured as rate of accumulation of delta power after extended wakefulness)7 may represent differences in synaptic plasticity mediated by the Homer1a gene through differential disruption of glutamatergic signaling complexes.34,35 These same studies show that other genes have greater effects on sleep need depending genetic background, highlighting an issue of QTL models: one locus may represent a major gene in the context of two specific inbred strains, but the effect size in a more outbred population may be difficult to ascertain. These can complicate extrapolation to potential human phenotypes. In humans, a PER3 genotype was recently reported to be associated with differences in EEG markers of sleep homeostasis after sleep deprivation (and behavioral consequences) (10 PER35/5 versus 14 PER34/4 individuals respectively). This remains tentative, as the sample size was small and it has not yet been replicated by other groups.36 It is also worth noting that multiple papers linking other phenotype differences to the PER35/5 genotype have all been made using the same initial sample37,38 and thus cannot be considered replications. The finding is interesting as it suggests that circadian genes may be involved in regulating not only circadian timing but also sleep homeostasis, consistent with studies in mice and Drosophila.1 We expect that GWA studies will explore the genetic basis of the EEG in the near future. GENETICS OF NARCOLEPSY Heritability Narcolepsy affects the control of sleep and wakefulness, and it is characterized by excessive daytime sleepiness, symptoms of dissociated REM sleep (sleep paralysis, hypnagogic hallucinations), disrupted nocturnal sleep, and cataplexy (brief episodes of muscle weakness triggered by emotions). Although most of these symptoms appear in the general population in the context of sleep deprivation or
other sleep disorders, cataplexy is highly specific to narcolepsy. Although narcolepsy is primarily sporadic, family and twin studies indicate a strong genetic basis for susceptibility to narcolepsy, as the prevalence of narcolepsy/cataplexy in first-degree relatives of probands is between 0.9% and 2.3%. Although this recurrence risk in siblings is low, it is considerably higher than the population prevalence and corresponds to a 20- to 40-fold increased risk.39 MZ twins show a concordance rate of only 35%, indicating that narcolepsy/cataplexy results from an interaction of environmental factors on a susceptible genetic background. Human Leukocyte Antigen in Narcolepsy An association between narcolepsy and specific class II human leukocyte antigen (HLA) antigens (DR2 and DQ1) was first noted in the Japanese population.40 HLA class II antigens are present on immune cells and function to present processed foreign peptides to T cells by engaging the T-cell receptor. The initial association was subsequently confirmed by many studies and further refined. DR2 and DQ1 are in complete disequilibrium in Japanese, but substantially less in African Americans. Using highresolution mapping in different ethnic groups allowed refinement of the susceptibility region by examining the frequency of alternative haplotypes, and demonstrated that DQB1*0602 is the most specific marker for narcolepsy in all ethnic groups. Although 90% of narcolepsy cases are associated with DQB1*0602, this is a common allele across ethnic groups, ranging from 12% in Japanese, to 38% in African Americans, and thus is not sufficient for the development of the disease. Other HLA alleles also influence susceptibility to narcolepsy. A study of 420 narcolepsycataplexy patients and 1087 controls41 identified additional predisposing alleles: DQB1*0301, DQA1*06, DRB1*04, DRB1*08, DRB1*11, and DRB1*12. Approximately 10% of narcolepsy-cataplexy patients are DQB1*0602 negative, but a large proportion of these carry the DQB1*0301 allele. Four protective alleles, DQB1*0601, DQB1*0501, DQB1*0603, and DQA1*01 (non-DQA1*0102), were also found. It is notable that whereas HLA DQB1*0602 confers susceptibility to narcolepsy, the very similar DQB1*0601 antigen is rather protective. Thus very minor changes in the peptide binding pockets of these molecules (where these differences localize) may determine disease risk. Protective DQA1 alleles41-41b may form transdimers, reducing formation of the susceptibility heterodimer DQα1*0102/ DQβ1*0602.41a It is clear that non-HLA genes also contribute to susceptibility, as the proportion of recurrence risk attributable to HLA is well below the relative risk observed in first-degree relatives.41 The tight association with DQB1*0602, the typical peripubertal onset, and the low concordance in MZ twins all suggest an autoimmune mechanism for narcolepsy. The association of MHC proteins, particularly class II antigens, is well recognized in a variety of autoimmune diseases, although narcolepsy shows the tightest such interaction (reviewed in reference 39). The interaction of HLA proteins with processed antigens determines the resulting immune response. However, some features of narcolepsy are not as consistent with a typical autoimmune mechanism, as females are not at increased risk. Surprisingly,
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there is little consistent direct evidence for humoral or cellular immunity in narcolepsy. The disease has not been transferred through injection of serum into mice, and activity of T-cell subsets, and natural killer cells were not altered in patients with narcolepsy.39,42,43 Increased autoantibodies against Tribbles homolog 2 (TRIB2) were recently identified by three groups, and were more prevalent close to onset of cataplexy.41c-e Hypocretin Deficiency in Narcolepsy The study of narcolepsy in canines led to our current understanding of the disease pathophysiology. As in humans, most cases of canine narcolepsy are sporadic, but the identification of dog pedigrees segregating an autosomal recessive form of narcolepsy with clear-cut cataplexy allowed identification of mutations of the hypocretin receptor-2 gene underlying the disease (Video 16-1).44 Subsequent studies quickly demonstrated a profound reduction in hypocretin gene expression and peptide content in postmortem narcoleptic brains, and low or undetectable levels of hypocretin-1 in the cerebrospinal fluid (CSF) of patients with narcolepsy.45-47 Mutation screening of the hypocretin ligand and receptor genes in narcolepsy cases was performed focusing on rare DQB1*0602-negative, and familial cases, which would be more likely to carry mutations. A single mutation was identified in a case of early-onset narcolepsy with cataplexy present at 6 months.46 The mutation introduced a highly charged arginine residue into the signal peptide of the prepro-hypocretin protein. Functional analysis suggested abnormal trafficking of the mutant peptide precursor, resulting in toxicity to the cells, supported by undetectable hypocretin in the CSF. Further studies failed to find mutations in, or SNP associations with, the hypocretin system genes in more typical cases of sporadic DQB1*0602-positive narcolepsy.46,48,49 Therefore, although narcolepsy-cataplexy is clearly associated with deficient hypocretin neurotransmission, this is not a result of hypocretin gene mutations or variants. The pattern of highly selective hypocretin cell loss together with the lack of identified mutations again points to an underlying autoimmune disease mechanism. Although hypocretin is only one of a number of neurotransmitters implicated in sleep regulation, it is notable that only deficiency in hypocretin leads such a highly specific sleep-related phenotype. Non-HLA, Non-Hypocretin Genes in Narcolepsy Several studies have attempted to map narcolepsy genes in human families through linkage, but regions of suggested linkage have not been replicated.50,51 More recent efforts have focused on genome-wide association studies using high-density SNP platforms. The first such study52 examined associations in a set of 222 narcolepsy patients and 389 Japanese controls. The top SNPS were submitted for replication in 159 narcolepsy patients and 190 controls. In each round, the smallest P value at rs5770917, an SNP located between CPT1B and CHKB, ranged from 1 to 6 × 10−4. Additional genotyping in small samples from three ethnic groups—from Korea (115 versus 309), European Americans (388 versus 397), and African Americans (86 versus 98)—showed differences in minor allele
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frequencies in the same direction. A significant replication P value was obtained in the Korean set (.03), but not in the American sets. Notably, this SNP had very unfavorable minor allele frequencies in white (4%) and African-American (2.6%) controls, underscoring the wide-ranging differences in allele frequencies among different populations. A second GWA recently published by our group53 identified an SNP variant strongly associated with narcolepsy across three ethnic groups, and was replicated in a third GWA focusing on Europeans.41b In our sample of 807 white narcolepsy patients versus 1074 HLA-DQB1*0602+ controls, three SNPS in the T-cell receptor alpha (TCRA) locus were associated, with the highest significance at rs1154155 in the J segment region (P = 1.9 × 10−13).53 This SNP showed significant association upon replication in whites (363 patients, 355 controls, P = 3.67 × 10−5) and Asians (from Japan and Korea; 561 patients, 605 controls, P = 2.30 × 10−7), and a similar OR but not formal significance in a small set of African Americans, in whom the allele is uncommon (133 patients, 144 controls, P = .39, allele frequency 10% in patients, 8% in controls). The homogeneity of OR and the strong replication in independent samples of multiple ethnic groups indicate that this is an important susceptibility factor for narcolepsy. In contrast to previous results in the Asian samples, the chromosome 22 locus showed no evidence for association in this large sample of whites, indicating that if real, that locus may have effects only in select narcolepsy subgroups. SNP rs1154155 was not identified in that study as it was not among the markers tested. Indeed the TCRA locus is an excellent biological candidate, as it interacts with HLA and a presented antigen, leading to an immune response. Like the immunoglobulin loci, the TCRA locus undergoes somatic cell recombination, which occurs between 46 functional variable (V) and 49 functional joining (J) segments. Precisely how a J segment region polymorphism (rs1154155C or another variant in tight LD) could increase the risk of narcolepsy is unknown, but it could involve nonrandom VJα choices in recombination. As narcolepsy is almost entirely associated with a single HLA allele, it may be hypothesized that the DQB1*0602/DQA1*0102 heterodimer could interact with a TCR idiotype with a specific VJα recombinant associated with the presence of rs1154155 (directly or indirectly). Unlike HLA, the TCR is expressed only in immune T cells, making it all but certain that narcolepsy is indeed an autoimmune disease. In the context of a selected antigenic trigger, this could then lead to further immune reaction, ending in the destruction of hypocretin-producing cells.
GENETICS OF RESTLESS LEGS SYNDROME Heritability Restless legs syndrome (RLS) is a quite common neurologic phenotype, with an age-dependent prevalence of up to 10% in individuals over 65 (reviewed in reference 54). The unique sensory–motor phenotype is characterized by an uncomfortable and intrusive urge to move the lower limbs. Symptoms typically manifest during rest or inactivity, are worse in the evening, improve with walking or
moving the extremities, and often result in insomnia and severely disrupted sleep. Approximately 80% of patients with RLS also have periodic leg movements in sleep (PLMS), which are involuntary, highly stereotypical leg movements occurring with regular periodicity.55 RLS has a strong genetic component with high concordance (83%) between MZ twins in one small study.56 High heritability (0.6) was estimated in another large study of more than 4503 twins.57 Up to 60% of idiopathic patients with RLS report that symptoms are present in at least one family member. Phenotypic variability can be quite large in families, ranging from severe and debilitating symptoms each night, with involvement of upper limbs, to mild symptoms experienced only occasionally. Familial cases are associated with an earlier age of disease onset (by 12 years), although clinical signs and symptoms were similar in familial and nonfamilial cases.58 RLS Linkage Studies Despite the high familial recurrence risk and prevalence, attempts to identify RLS genes in families have identified neither specific mutations nor specific genes. Three genomic regions have been identified and replicated in additional studies of unrelated pedigrees (reviewed in reference 54). The RLS1 locus (Ch 12q) displayed recessive inheritance and has been replicated in a number of independent French-Canadian, Icelandic, and Bavarian families. The RLS2 locus was identified on chromosome 14q in a North Italian RLS family showing dominant transmission, and it was later replicated in an independent French-Canadian family. RLS3, mapping to chromosome 9p, has been somewhat controversial but has been implicated in two U.S. and two German families. In all of these studies, the presence of phenocopies, nonpenetrants, and stratification according to early-onset age has made identification of specific candidate genes or risk haplotypes difficult. Family studies have also presented mysteries regarding intragenerational risk and genetic effect size. A striking feature of a subset of pedigrees is the presence of disease in up to 100% of siblings, well above the expected rate of 50% for autosomal dominant transmission. Although not inconsistent with dominant mendelian inheritance, this may reflect other factors such as high phenocopy rate, multiple dominant alleles co-segregating, ascertainment bias, or overdiagnosis. It is also notable that loci identified in family linkage studies had logarithm of odds (LOD) scores much lower than had been predicted on the basis of family structure. Together, these results indicate that inheritance is probably complex and not explained by a simple monogenic mendelian trait. Genome-Wide Associations Significant progress in the understanding of the genetics of RLS has been based on two large GWA studies, revealing a surprising role for developmental regulatory factors in the pathophysiology. Winkelmann and colleagues59 studied a large set of well-characterized RLS patients, totaling 1600 RLS patients and 2600 controls from Germany and Canada, in a two-stage design that included replication in two independent samples. Three genomic regions were identified that replicated, and that withstood genome-wide multiple testing correction, including Meis1 (Ch 2p), BTBD9 (Ch 6p), and a broad region between
MAP2K5 and LBXCOR1 (Ch 15q). An independent GWA study was concurrently published that studied a total of 429 Icelandic patients with RLS/PLMS versus 1233 controls, with replication in 188 patients versus 662 controls from the United States,60 that found an association signal between RLS and the same BTBD9 variant. MEIS1 as a Candidate and Its Symptomatology The highest significance hit from the Winkelmann study was on chromosome 2 in the MEIS1 homeobox gene, where the association is fully tagged by two SNPS (rs12469063, rs2300478) in an LD block containing exon 9. The region shows high interspecies conservation, and it has a striking effect, with a haplotype OR greater than 2. This association has subsequently been confirmed in an independent sample of 244 U.S. RLS patients and 497 controls,61 but it was not detected in the Icelandic study, reflecting differences in phenotyping (identified through clinic visits and emphasis on familial cases versus selfreport, and inclusion of patients with isolated PLMS), or potentially population-specific differences. MEIS1 is a member of the TALE homeobox gene family and forms heterodimers with PBX and HOS proteins, which augment the specificity and affinity of DNA binding by HOX proteins. MEIS1 has broad-ranging functions in development, including a critical role in hematopoiesis and endothelial cell development, vascular patterning, and retinal development in vertebrates.62-64 More relevant to RLS, MEIS1 is strongly expressed in dopaminergic neurons of the substantia nigra, where studies have reported lower iron levels in RLS patients, and is also high in the red nucleus, a region regulating coordination of limb movement as well as implicated in lower iron levels.65,66 MEIS1 is essential for proximodistal limb formation during development.67 MEIS1 is also part of a HOX transcriptional regulatory network that specifies motor neuron pool identity and thus the pattern of target-muscle connectivity, suggesting a key link to the pathophysiology of RLS. A growing body of evidence indicates a spinal origin of PLMS, potentially mediated by the dopaminergic A11 nucleus in the hypothalamus.68 These neurons project to local hypothalamic centers and the neocortex, but the also descend and serve as the sole source of spinal dopamine. As these projections are long, they may be unusually susceptible to age-related damage or cell loss. Patients with RLS/PLMS display sleep-specific spinal sensorimotor hyperexcitability, manifesting with a lower threshold flexor reflex and a greater spread to adjacent muscles than seen in controls.69 Thus MEIS1 is an excellent candidate in RLS, with potential roles in development and modulation of these circuits in adults. BTBD9 as a Candidate and Its Symptomatology Both genome-wide studies59,60 identified an association between SNPS in a large LD block containing intron 5 of the BTBD9 gene on chromosome 6p, with maximal association at rs3923809, and this was also confirmed in the subsequent U.S. study of RLS probands.61 Again, the effect was quite strong, with allelic OR between 1.5 and 1.8. Notably, in the Icelandic cohort, there was no association of rs3923809A in subjects with RLS without PLMS, whereas the OR increased when subjects with PLMs with or without RLS were studied. These results imply that this
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locus may confer risk specifically for the motor component (PLMS), but because these individuals with isolated PLMS were relatives of patients with RLS, it is unknown whether this will also be true in the general population. In addition, serum ferritin levels were found to be decreased by 13% per A allele, potentially underlying the iron deficiency associated with RLS. Little is known of the function of BTBD9 in mammals, but in Drosophila, proteins containing the BTB (POZ) domain have important roles in metamorphosis and limb pattern formation.70,71 These proteins have wide-ranging functions, making assignment of a specific function to BTBD9 difficult. LBXCOR as a Candidate and Symptomatology The third locus identified by Winkelmann and associates was defined by seven SNPs on chromosome 15q. This large LD block contains both MAP2K5 and LBXCOR1 genes, and it was not possible to differentiate the origin of the association signal. LBXCOR1 has appealing links to RLS, as it is expressed selectively in a subset of dorsal horn interneurons in the developing spinal cord, which relay pain and touch. Activity of the LBXcor1/Lbx1 pathway is essential to the generation of a gamma-aminobutyric acid (GABA)-ergic versus glutamatergic phenotype in these cells,72 and this locus may contribute to the sensory component of phenotype by affecting modulation of sensory/ pain inputs. PTPRD and Nitric Oxide Synthase as Candidates in RLS In addition to the three replicated loci identified in the initial study, a fourth locus showed suggestive association in the vicinity of RLS3 on chromosome 9p. After extending the sample size to a total of 2458 patients and 4749 controls and genotyping markers in this region, again using a two-stage design with replication, an association at protein tyrosine phosphatase receptor type delta (PTPRD) reached genome-wide significance, with signal identified in two separate haplotype blocks.73 Surprisingly, no coding mutations were identified among patients from RLS3 families, and the relative risk to siblings attributed to SNPs at this locus could explain only a minor portion of the original RLS3 linkage signal. Nevertheless, PTPRD is an excellent RLS candidate, with established roles in axon guidance and termination of motor neurons during embryonic development in the mouse.74 Similar studies have implicated a role for neuronal nitric oxide synthase (NOS1) in RLS. An exploratory casecontrol study was initiated in a large area (366 genes, 21 Mb) in the chromosome 12 RLS1 region.75 Three subregions were significant in the first tier of the study. After testing the most significant SNPs in a second sample, one SNP in the NOS1 locus showed significant allele frequency differences after multiple testing correction. These results remain provisional, however, as two SNPs showed significant association in the exploratory and replication samples, but the allele frequencies and direction of the effect differed in the two samples. In addition, no likely coding variants explaining the effect were identified in the NOS1 coding sequence of a series of homozygous cases. The association results were not explained by stratification, or by lack of adequate SNP coverage, and further
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testing in an even larger sample will be needed to confirm the finding. The NOS1 gene is an appealing candidate in the symptomatology of the syndrome, acting as an “atypical neurotransmitter” in the central nervous system with roles in pain perception, control of sleep–wake regulation, and modulation of dopaminergic regulation.
GENETICS OF OTHER HYPERSOMNIAS, INSOMNIA, AND PARASOMNIAS Many additional sleep disorders and parasomnias show genetic effects or familial clustering but so far have no established connections with specific genes. No studies have yet identified definitive loci selective for insomnia, and considering the frequency and the complexity of the phenotype, only using extremely large samples and a GWA approach, possibly using an EEG endophenotype,76 is likely to succeed. Studies have shown that insomnia, like many other conditions, runs in families77,78 and has higher concordance in MZ twins.79 Like insomnia, hypersomnia or isolated sleepiness in the general population is a poorly defined phenotype.80 Candidate association loci have been reported,81 using a lowdensity GWA study (100,000 markers, most of which were not significant after correction for multiple comparison), but they await confirmation. The distinction between narcolepsy without cataplexy (NWC) and idiopathic hypersomnia is difficult. Although presence (NWC) versus absence (hypersomnia) of two sleep-onset REM periods on the multiple sleep latency test is typically used to distinguish these, it is possible that they lie on a continuum with narcolepsy-cataplexy. There is evidence that this is the case for NWC, as rates of DQB1*0602 positivity (40%) are intermediate between the rates found in the general population (12% to 38%) and in narcolepsy cataplexy (70% to 100%). Although measures of cerebrospinal fluid (CSF) hypocretin are more typically within the normal range for NWC, some patients do show low levels in the narcolepsycataplexy range in association with DQB1*0602.82 Hypocretin levels were within normal range for idiopathic hypersomnia, with rare exceptions that showed decreased levels. Kleine-Levin syndrome (KLS) is a rare disorder characterized by recurring episodes of profound hypersomnia together with cognitive and behavioral changes. It affects primarily adolescent boys and typically mysteriously attenuates and disappears in adulthood. KLS was previously thought to be sporadic, but recent studies83,84 indicate that there are likely to be genetic factors conferring susceptibility. An excess of Ashkenazi Jewish origin is reported in KLS cases compared with that expected on the basis of the general population, suggesting that a founder effect is potentially acting in this subset. In addition, five out of 105 patients with KLS reported KLS in a family member, indicating a substantially increased risk among relatives and suggesting the action of a major susceptibility gene. A proposed HLA association in KLS was not replicated in a second, larger study.83,85 Features of dissociated REM sleep are known to be highly heritable. Both sleep paralysis and hypnagogic hallucinations, representing intrusion of REM atonia and
REM imagery into wakefulness, frequently occur in the general population, particularly in the context of insufficient sleep. Sleep paralysis is highly familial, with MZ twins showing higher concordance than DZ twins. Cases of autosomal dominant transmission have also been reported (reviewed in reference 86). There may be an increased prevalence in African Americans. In REM sleep behavior disorder (RBD), there is loss of inhibition of motor pathways in REM sleep, leading to robust and potentially dangerous motor activity in response to dream content. As with other features of dysregulated REM sleep, RBD is common in narcolepsy, but it also occurs in the general population and in patients with Parkinson’s disease. There is increasing consensus that idiopathic RBD is an early sign of evolution toward a neurodegenerative disorder, with particular risk for Parkinson’s disease.87 The extent of heredity in RBD has not been established, but a variety of single gene defects are implicated in the development of Parkinson’s disease. Non-REM sleep parasomnias including sleepwalking, sleep talking, and night terrors typically occur during slowwave sleep (stages III and IV). Prevalence of parasomnias in general is high in children, rarely requires medical intervention, and typically disappears during adulthood. Sleepwalking may be present in up to 20% of children, and it is present in up to 3% of adults,88 who report that the disorder has been lifelong. If a parent was a sleepwalker, then children have a sixfold increased risk for the disorder. Twin studies show that sleepwalking, sleep talking, enuresis, bruxism, and night terrors have substantial genetic effects, and that they also co-occur, suggesting that they share some common genetic susceptibilities (reviewed in references 86 and 89).
AUTOSOMAL DOMINANT FRONTAL LOBE EPILEPSY Nocturnal frontal lobe epilepsy (NFLE) can mimic parasomnia symptoms.90-92 This distinctive disorder occurs in sporadic and autosomal dominant NFLE familial forms, with the clinical presentations having no significant differences. Three characteristic seizures associated with the disorder arise during NREM sleep (reviewed in reference 93). Paroxysmal arousals (PAs) are brief (<20 seconds), consisting of abrupt and frequently recurring arousal from sleep. They are associated with stereotypical movements, and patients raise their heads and sit up, often screaming or showing fright. Dystonic posturing may occur in the upper and lower limbs. A nocturnal paroxysmal dystonia (NPD)91 type of seizure may develop from a PA and may last up to 2 minutes. These are associated with complex stereotypical movement sequences, with asymmetric tonic or dystonic posturing. Patients may also emit sounds, or nonsense words, and occasionally violent ballic movements with flailing of limbs. PA and NPD may recur with a periodic repetition at 30-second to 2-minute intervals. As observed in the EEG, these are often directly preceded by a K-complex, suggesting that they may trigger the epileptic seizures. Indeed, the periodic occurrence of K-complexes may act to trigger the onset of the seizures through modulating activity of frontal lobe foci. The third and longest form of seizure in NFLE is episodic nocturnal
wandering, which lasts up to 3 minutes. The associated somnambulism results in jumping from bed with agitated violent motor behaviors involving the head, trunk, and limbs. These are much less frequent but may cause severe injuries to the patient. Differentiation of these from more typical NREM parasomnias can be difficult, requiring polysomnography with video monitoring to document the stereotypy of the attacks and abnormal motor aspects of the seizures. Although NREM parasomnias such as sleep terrors arise earlier in childhood, the age of onset of NFLE is more typically 14 years (but with wide variability). In addition, whereas episodes of sleep walking or sleep terrors are rare and isolated (once in 1 to 4 months), NFLE seizures occur nearly nightly, and with many repetitions through the night. Certainly, the extrapyramidal motor patterns (ballic movements, dystonic posturing) are distinctly different in their origin from simple partial sudden arousals. Finally, whereas parasomnias fade with ageing, NFLE persists into adulthood. Mapping of autosomal dominant NFLE in families led to the identification of at least three loci causing the disease, with subsequent identification of dysfunction in alpha-4, alpha-2, and beta-2 subunits of the nicotinic acetylcholine receptor (nAChR) affecting the first, second, and third transmembrane domains of the receptor in familial and sporadic cases.94-97 An involvement of rare variants in the promoter of the corticotrophin-releasing hormone gene have also been proposed.98
GENETICS OF OBSTRUCTIVE SLEEP APNEA Obstructive sleep apnea syndrome (OSAS) is a complex and highly prevalent phenotype affecting 2% of middleaged women and 4% of middle-aged men in developed countries99 and more than 11% of older adults.99,100 Family studies have demonstrated increased aggregation of OSAS for individuals with characteristic craniofacial features.101 Incidence was not increased in families of very obese patients with OSA, suggesting that the obesity outweighed risk from morphologic predispositions. High rates of concordance were identified in MZ twins.57 Linkage was first performed using a set of 375 autosomal markers on a modest-sized set of 66 European-American families with probands, ascertained from a sample of 1349 subjects, and demonstrating an apnea-hypopnea index (AHI) of 20 or greater or severe symptoms warranting therapy. Families were further selected for members in the extremes of the sample’s AHI distribution (mean pedigree size, 5.3; range, 4 to 14).102 Variance component linkage analysis was performed using AHI and body mass index (BMI) as quantitative phenotypes, with several regions showing suggestive linkage to AHI and BMI after correction. An analogous study was also performed in 59 AfricanAmerican families showing suggestion of linkage to different genomic regions.103 Although extensively phenotyped, the relatively small numbers of pedigrees used in these studies had limited power to detect modest effects, and markers were spaced at 9-cm intervals, a low resolution in comparison with recently developed high-density platforms. The sample would be more amenable to study
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using a GWA design on a large scale. Indeed, this would also avoid the issue of the typically large physical distances underlying a linkage peak. Whereas linkage intervals are refined by the observation of recombinants on chromosomes in a family, associations reveal very small regions reflecting vast numbers of historical recombinations in the case-control sample. Associations thus often pinpoint a single gene, or even a subregion of a gene, as defined by the local haplotype block structure. A series of physiologic traits act together to determine the susceptibility to, and severity of OSA, through their individual or combined effects on the obstruction of the pharyngeal airway during sleep.104 Thus it may be particularly useful to consider distinct separate sub-phenotypes in a genetic analysis of patients with OSA, potentially including pharyngeal anatomy, airway collapsibility (Pcrit), upper airway muscle responsiveness during sleep, arousal threshold, reactivity of the airway, activation response of pharyngeal dilator muscles, and loop gain reactivity in response to hypoxia. The only potential candidate that has been replicated is apolipoprotein E (APOE). This gene was first suggested as a candidate gene for OSA in a study of 791 middle-aged subjects from the Wisconsin cohort.105 The probability of moderate to severe apnea significantly increased with dosage of the number of APOE ε4 alleles. This association was confirmed in 1775 subjects from the Sleep Heart Health Study, and an important effect of age was iden tified106; the effect was strongest in individuals younger than 65 years, and weaker in those older than 65. This association remains somewhat controversial, as two other association studies did not replicate the finding, although the samples studied differed by age, ethnicity, BMI, and screening methodology.107,108 In addition, a recent study of 666 white and 545 African-American subjects in approximately 300 families also found no association between APOE ε4 and risk for OSA (AHI ≥ 15), even when restricted to a young or middle-aged sample.109 Fine mapping suggested the presence of a susceptibility gene in the region but excluded an effect of APOE. These findings could suggest that susceptibility is conferred by another gene in LD with APOE. It is notable that this sample was multi racial, had a high BMI, and was ascertained through OSAprobands that were identified at clinic visits, potentially indicating more severe disease or more extensive comorbidity. Finally, two studies have suggested an association of APOE and linked polymorphisms with sleep apnea in children, although these findings were made in small samples.110,111 How APOE ε4 could predispose to sleep apnea is unknown, but multiple mechanisms are plausible, including an effect through lowering levels of choline acetyltransferase and reducing neuromuscular activation of the upper airway dilator muscles, or differential lipid binding to beta amyloid or tau proteins leading to plaque formation in the respiratory center.
CONGENITAL CENTRAL HYPOVENTILATION SYNDROME Congenital central hypoventilation syndrome (CCHS), formerly known as Ondine’s curse, is a congenital and severe form of central sleep apnea resulting from abnormal autonomic control of breathing with decreased sensitivity
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to hypercapnia and hypoxemia, particularly during sleep. In addition to the respiratory features, CCHS is also associated with Hirschsprung’s disease, tumors of neural crest origin, and diffuse autonomic dysregulation (reviewed in reference 112). Although primarily sporadic, genetic factors are indicated by dominant transmission and by an increased prevalence of symptoms of autonomic nervous system dysfunction (although a considerably milder spectrum of features) among relatives of CCHS probands.113 The recognition that the PHOX2B homeodomain protein is critical for the development of the autonomic system in mice, led to the identification of frequent heterozygous mutations in the PHOX2B (4q13) gene in individuals with CCHS.114 The most common form (90%) of mutation identified is expansion of a polyalanine repeat (from the normal 20 alanine repeats to 25 to 33) in the protein, which probably acts as a spacer domain between functional elements of the protein. The remaining 10% of mutations consist of heterozygous missense, nonsense, and frameshift mutations at the same locus. Although the majority of patients have onset during the neonatal period, later onset cases, remarkably, have also been noted, with onset in later infancy, childhood, and even adulthood, and this has been linked to the presence of a 24-repeat alanine tract, which was also identified in nonpenetrant adult carriers.115 Onset of symptoms in this form of the disease appears to require additional environmental factors (anesthetics, sedatives) to trigger symptoms in heterozygotes, but when it is homozygous, it may present in infancy. It is tempting to speculate that the variable autonomic nervous system (ANS) dysfunction in the extended families of patients with congenital CCHS is related to the presence of a “premutation” sized PHOX2B expansion (>20 and <24) with potential implications for diffuse ANS symptoms in the general population.
SLEEP DISORDERS IN ASSOCIATION WITH OTHER GENETIC DISORDERS Sleep problems are commonly associated with genetic disorders, even when these are not strictly sleep disorders. Fatal familial insomnia (FFI) was the first “sleep disorder” with an identified single gene mutation, although the phenotype extends well beyond sleep abnormalities and includes dysautonomia and ataxia, as well as subsequent rapid decline in cognitive function. FFI results from the combination of two abnormalities in the prion protein gene: a mutation from asparagine to aspartic acid at position 178 in the context of the presence of methionine at codon 129 (a normal polymorphism).116 In sporadic cases, the same phenotype can be induced through conformational changes in the prion protein that are not associated with detected mutations.117 In FFI, there is degeneration in the anterior ventral and mediodorsal thalamic nuclei. As the thalamus and its cortical projections are important in the generation of cortical synchronization in slow-wave sleep and generation of sleep spindles, these thalamic lesions probably underlie the insomnia in FFI.90 Patients with Smith-Magenis syndrome have characteristic sleep problems including excessive daytime sleepiness but frequent awakenings at night.118 The melatonin rhythm in these patients is severely phase shifted, and it
is speculated that haploinsufficiency for a circadian-related gene in the characteristic chromosome 17 deletion is responsible.119 Obstructive sleep apnea is prevalent in Down syndrome,120 very likely influenced by the typical flattened midface and upper airway dysmorphology as well as by low muscle tone and enlarged tonsils or tongue. There is major clinical relevance, as OSA could contribute to pulmonary hypertension in these individuals. OSA may also be uniquely tied to morbidity in Marfan syndrome (MS).121 This connective tissue disease is associated with specific craniofacial abnormalities (high arched palate with dental crowding, retrognathia), which predispose to the development of OSA,122 and a high rate of OSA was described in a consecutive series of patients with MS.123 More importantly, OSA has been proposed to contribute to aortic root dilation in patients with MS,124 which often progresses to aortic dissection, an important source of mortality. Neurodegenerative diseases are often associated with sleep abnormalities. Huntington’s disease is associated with excessive daytime sleepiness, disrupted nocturnal sleep, insomnia, and various REM abnormalities.125,126 Parkinson’s disease is associated with significant sleep disturbances. REM behavior disorder may precede motor and dementia symptoms by several years.127 Patients with Parkinson’s disease develop secondary narcolepsy symptoms, and this is supported by evidence of significant hypocretin cell loss in the disease. Excessive sleepiness is a common and disabling symptom of myotonic dystrophy. Short sleep latencies and sleep-onset REM periods were commonly seen, and decreased CSF hypocretin-1 levels have been reported in some but not all cases.128,129 Cataplexy has been reported in a number of patients with genetic diseases, although it is highly selective and almost pathognomonic for narcolepsy. Niemann-Pick disease type C (NPC) is a recessive lysosomal storage disorder. Clinical symptoms and severity vary and include hepatosplenomegaly and neurologic findings, such as abnormalities of the EEG in sleep.130 CSF hypocretin-1 levels in patients with NPC are repeatedly found to be significantly lower than in controls, suggesting that the lysosomal storage abnormalities have an impact on the hypocretin-producing cells of the hypothalamus. Norrie disease is primarily an X-linked eye disease, but other features are variably present depending on the size of the underlying chromosomal deletion, which can include deletion of the monoamine oxidase loci. Cataplexy and REM sleep abnormalities have been described in Norrie disease in association with absent monoamine oxidase activity and increased serotonin levels.131 Narcolepsy-like symptoms, including excessive daytime sleepiness and cataplexy, have also been reported in Prader-Willi syndrome (PWS),132 and several studies have reported reduced CSF hypocretin levels.82 These results and others indicate that the excessive daytime sleepiness seen in PWS is not simply secondary to obesity and OSA in these individuals.
CONCLUSION Thanks to the recently completed human genome sequence and the description of single nucleotide and copy number variation polymorphisms across the genome, gene
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identification has progressed rapidly in many areas of medicine. Focus is now shifting from the identification of very rare familial single gene disorders using linkage analysis to genome-wide approaches using high-density marker sets. These are leading in some cases to the identification of common polymorphisms in entirely new pathways, such as the developmental genes that act as predisposing factors for RLS, and, in other cases in other areas of medicine, to the identification of novel rare high-penetrance mutations—for example, deleterious duplications or deletions that may cause autism. Additional studies are focusing on finding rare phenotypes and rare mutations in selected genes in the population, followed by family analysis—for example, in the circadian rhythm disorder area. It is likely that these approaches will increasingly be applied to sleep disorders research, a promising area, as sleep is an innate behavior with measurable physiologic variables. Importantly, however, as these studies are only nascent in our field, we suggest strict criteria for publication, including robust effects, adequately powered sample sizes, and independent replication of findings (for genetic association studies) or strong functional analysis data (for singlefamily reports and, if possible, in genetic association). The literature currently contains many studies with variable and sometimes conflicting results. When interpreting these, it is important to evaluate not only statistical confidence (P value), but also sample size, reliability of phenotype, and size of the effect (i.e., odds ratio). On one hand, some studies report rare mutations with very large effects and clear functional effects (as in familial circadian disorders, and the complex congenital hypoventilation syndrome phenotype). In other studies (typically association studies), effects are small and the proof primarily lies with statistical confidence and independent replication (for example, in RLS). In genome-wide association studies, it is likely that most of the identified polymorphisms will be risk factors only for sleep disorders, many with small effects, and will thus warrant further studies either in basic research programs to better understand the pathophysiology of the corresponding sleep disorder and associated phenotypes, or as tools to subdivide groups of patients if the polymorphisms are shown to have predictive outcome value or are helpful in guiding therapy. ❖ Clinical Pearl A large number of publications have described associations between genetic polymorphisms and sleeprelated phenotypes, but most have not been replicated, and results should be considered preliminary. Results using new methods such as genomewide association studies have begun to flow in the sleep field, with exciting and robust results indicating novel pathways in sleep-related diseases.
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Physiology in Sleep Gilles Lavigne 17 Relevance of Sleep
Physiology for Sleep Medicine Clinicians 18 What Brain Imaging Reveals about Sleep Generation and Maintenance 19 Cardiovascular Physiology: Central and Autonomic Regulation 20 Cardiovascular Physiology: Autonomic Control in Health and in Sleep Disorders
21 Respiratory Physiology:
Central Neural Control of Respiratory Neurons and Motoneurons during Sleep 22 Respiratory Physiology: Understanding the Control of Ventilation 23 Normal Physiology of the Upper and Lower Airways 24 Respiratory Physiology: Sleep at High Altitudes 25 Sleep and Host Defense
26 Endocrine Physiology in
Abstract The physiology section of this volume covers a wide spectrum of very precise concepts from molecular and behavioral genetics to system physiology (temperature control, cardiovascular and respiratory physiology, immune and endocrine functions, sensory motor neurophysiology), integrating functions such as mental performance, memory, mood, and wake time physical functioning. An important focus has been to highlight the relevance of these topics to the practice of sleep medicine. A keener understanding of physiological dysfunction helps clinicians to explain to patients how to cope with a sleep disorder,
Why do doctors and scientists need to understand sleep physiology? A thorough knowledge of sleep physiology is central to improved accuracy and validity in the development of diagnostic tools, to making innovations in patient management, and to keeping abreast of leading edge developments in sleep medicine. For some clinicians, reading chapters in sleep physiology may recall early years of training, but these days physiology is an integral part of many advancements in clinical practice (e.g., breathing and cardiovascular measurements, brain imaging), and it forms the basis of translating genetics and proteomics into innovation in diagnosis and therapeutics. The impact of poor sleep and of several sleep disorders on societal and economic health is interrelated1; health governmental agencies are extremely sensitive to discoveries that may improve the population’s quality of life and reduce health care costs. A greater understanding of sleep
4
Relation to Sleep and Sleep Disturbances 27 Gastrointestinal Physiology in Relation to Sleep 28 Body Temperature, Sleep, and Hibernation 29 Memory Processing in Relation to Sleep 30 Sensory and Motor Processing during Sleep and Wakefulness
Relevance of Sleep Physiology for Sleep Medicine Clinicians Gilles Lavigne
Section
Chapter
17
a process that is integral to patient satisfaction and well being. A wider knowledge of physiology will also assist clinicians in clarifying new and relevant research priorities for basic scientists or public health investigators. Overall, the development of enhanced communication between health workforces will promote the rapid transfer of relevant clinical issues to scientists, of new findings to the benefit of patients. At the same time, good communication will keep clinicians in step with the expanding field of sleep medicine and will make them well prepared to face the growing challenges in public health issues.
physiology has resulted in innovations in the pharmaceutical industry and in the design of diagnostic and therapeutic devices (e.g., recording and scoring systems, continuous positive airway pressure, mandibular advancement appliances). But governmental agencies only grant permission to market a given product following epidemiological findings, explorations of physiological and pathological mechanisms, and randomized control trials demonstrating efficacy and safety. The absence of objective and valid measures to assess sleep improvement and safety can prevent developments and innovation from being integrated into sleep medicine practices. Although questionnaires are used to screen patients for many sleep disorders, it is the physiological (e.g., hormonal-endocrine release, heart rate by electrocardiogram, brain activity by electroencephalography) and psychophysiological (reaction time, multiple sleep latency test, sensory perception) 199
200 PART I / Section 4 • Physiology in Sleep
measures that confirm the accuracy and validity of the concepts. Clinical science progresses sequentially. For example, using questionnaires, the prevalence of nonrestorative sleep has been reported at 10% in the general population.2 With polygraphy, the consequences of that nonrestorative sleep consequences are characterized,3,4 interindividual trait differences may be identified,5 and phenotypic determinants of vulnerability also recognized.6 The identification of gene polymorphism related to specific sleep disorders is another domain of intense interest (see Section 3 of this volume). We are already in the postgenomic era with the advent of proteomics: the science of protein characterization in relation to biological activity or disorder/disease.7 Most sleep disorders, such as insomnia, sleep breathing disorders (e.g., sleep apnea), parasomnia (e.g., sleepwalking, enuresis, REM behavior disorder [RBD]), sleep-related movement disorders (e.g., restless leg syndrome/periodic limb movement), and circadian rhythm sleep disorders have genetic and/or molecular targets that provide possible new avenues in therapeutics.8,9 Genetic epidemiology is a growing field that integrates all aspects of physiology to further identify targets (gene loci), and variance related to individuals and environments.10,11 Physiology provides the tools with which sleep disorders may be phenotyped and genetics advances the clinical domain by identifying risk or vulnerability factors. The combination makes for innovative approaches to therapy. This section updates some chapters from the previous edition related to cardiovascular, respiratory, immune, endocrine, gastrointestinal, and thermoregulatory mechanisms. In addition there are new chapters on the contribution of brain imaging to the understanding of sleep physiology (Chapter 18), a description of the relevance of autonomic-cardiovascular measures and their meaning in sleep medicine (Chapter 20), the mechanisms that regulate breathing and the relevance of respiratory measures in sleep medicine (Chapters 21 and 23), the extension of endocrinology to obesity and women’s sleep issues (Chapter 26), the potential impact of thermoregulation on nonrestorative sleep management (Chapter 28), the circular relationship between sleep and memory-learning (Chapter 29), the role of sensory-motor integration on the control of breathing and sleep breathing disorders, on motor parasomnia or movement disorders, and on ways in which sensory feedback interferes with sleep in relation to periodic limb movement, RBD, pain, and bruxism (Chapter 30). These new chapters will prepare the reader to understand the pathophysiological mechanisms relevant in
understanding the clinical disorders described in this volume. In other words, we hope they will provide some answers about how disease affects physiology, how interventions work, why they do not work, and what remains to be done. Future editions of this volume will probably integrate more knowledge on the relevance of nano information, such as molecular and synaptic homeostasis,12 micro information, such as how tractography imaging is used to assess cortical and brainstem networking activity during sleep or using mathematical modelling,13 and macro information that integrates behavior with sleep disorders and addresses issues related to cognition and placebo influence on sleep.14-17 REFERENCES 1. Léger D, Pandi-Perumal SR, editors. Sleep disorders—their impact on public health. London, UK: Informa Healthcare; 2007. 2. Ohayon M. Prevalence and risk factors of morning headaches in the general population. Arch Intern Med 2004;164:97-102. 3. Bonnet MH, Arand DL. Clinical effects of sleep fragmentation versus sleep deprivation. Sleep Med Rev 2003;7:297-310. 4. Stone KC, Taylor DJ, McCrae CS, et al. Nonrestorative sleep. Sleep Med Rev 2008;12:275-288. 5. Tucker AM, Dinges DF, Van Dongen HP. Trait interindividual differences in the sleep physiology of healthy young adults. J Sleep Res 2007;16:170-180. 6. Galliaud E, Taillard J, Saqaspe P, et al. Sharp and sleepy: evidence for dissociation between sleep pressure and nocturnal performance. J Sleep Res 2008;17:11-15. 7. Choudhary J, Grant SG. Proteomics in postgenomic neuroscience: the end of the beginning. Nat Neurosci 2004;7(5):440-445. 8. Tafti M, Maret S, Dauvilliers Y. Genes for normal sleep and sleep disorders. Ann Med 2005;37:580-589. 9. Wisor JP, Kilduff TS. Molecular genetic advances in sleep research and their relevance to sleep medicine. Sleep 2005;28:357-367. 10. Hublin C, Kaprio J. Genetic aspects and genetic epidemiology of parasomnias. Sleep Med Rev 2003;7:413-421. 11. Koskenvuo M, Hublin C, Partinen M, et al. Heritability of diurnal type: a nationwide study of 8753 adult twin pairs. J Sleep Res 2007;16:156-162. 12. Tononi G, Cirelli C. Sleep function and synaptic homeostasis. Sleep Med Rev 2006;10:49-62. 13. Phillips AJK, Robinson PA. A quantitative model of sleep-wake dynamics based on the physiology of the brainstem ascending arousal system. J Biol Rhythms 2007;22:167-179. 14. Gagnon JF, Postuma RB, Mazza S, et al. Rapid-eye-movement sleep behaviour disorder and neurodegenerative diseases. Lancet Neurol 2006;5:424-432. 15. Boelmans K, Kaufmann J, Bodammer N, et al. Involvement of motor pathways in corticobasal syndrome detected by diffusion tensor tractography. Mov Disord 2009;24:168-175. 16. Scott DJ, Stohler CS, Egnatuk CM, et al. Placebo and nocebo effects are defined by opposite opioid and dopaminergic responses. Arch Gen Psychiatry 2008;65:220-231. 17. Laverdure-Dupont D, Rainville P, Montplaisir J, et al. Changes in rapid eye movement sleep associated with placebo-induced expectations and analgesia. J Neurosci 2009;29:11745-11752.
What Brain Imaging Reveals about Sleep Generation and Maintenance Eric A. Nofzinger and Pierre Maquet Abstract The development of neuroimaging techniques has made it possible to characterize regional cerebral function in humans under a variety of sleep-related conditions. These techniques were first used to characterize brain activity throughout the sleep−wake cycle in normal human subjects. It was shown that regional brain activity during sleep was segregated and integrated within cortical and subcortical areas differently in
Functional neuroimaging consists of all techniques that can generate images of brain activity. In humans, they usually include single photon emission computed tomography (SPECT), positron emission tomography (PET), functional magnetic resonance imaging (fMRI), optical imaging, multichannel electroencephalography (EEG), and magnetoencephalography (MEG). Each technique has its own advantages and drawbacks in terms of spatial and temporal resolutions, accessibility, safety, and cost. For instance, EEG and MEG record brain oscillations with an excellent temporal resolution (usually on the order of a millisecond) but their localizing capacity is limited by our ability to accurately model the electric or magnetic sources of the signal. In contrast, PET and MRI have an excellent spatial resolution (a few millimeters) but they are based on the measure of hemodynamic or metabolic parameters, which reduces their temporal resolution from a few seconds to many minutes. For this reason, a comprehensive understanding of brain function probably requires human brain function to be characterized using as many techniques as possible. In this review, we summarize the main advances made using functional neuroimaging in our understanding of human sleep and its intimate relationships with waking performance and cognition, both in normal healthy sleepers and in patients with sleep disorders. This chapter is organized in four sections that address the characterization of regional brain activity during normal human sleep, the neural correlates of the regulation of sleep–wake cycle by circadian influences and nonclassical photoreception, the regional brain function in conditions of increased sleep pressure, and some application to sleep disorders.
FUNCTIONAL SEGREGATION AND INTEGRATION DURING NORMAL HUMAN SLEEP Preclinical research has identified the basic circuits in the brain that are responsible for promoting arousal. In general, reduction in activity in these systems is essential for generating and maintaining sleep. A major component of this network is the brainstem reticular core, a diffuse network of predominantly glutamatergic long-projecting neurons and a smaller collection of presumed local circuit
Chapter
18
sleep than during wakefulness. Regional brain activity was also shown to be influenced by incoming stimuli as well as by previous waking experience. Functional neuroimaging also probed the neural correlates of sleep−wake regulation by homeostatic sleep pressure and the nonvisual effects of light. Finally, functional imaging of patients with sleep disorders indicated reliable changes in neural systems across the sleep−wake cycle in primary sleep disorders and in response to treatment interventions.
gamma-aminobutyric acid (GABA) neurons. Additional components include a collection of nuclei in the brainstem tegmentum dorsal to the reticular formation that include cholinergic and monoaminergic (serotoninergic, noradrenergic, and dopaminergic) neurons. These nuclei send rostral projections that parallel and are interconnected with those of the brainstem reticular core. Cholinergic nuclei are also clustered rostrally in the basal forebrain, including septal nuclei and the diagonal band of Broca. Research attention has focused on the hypothalamus playing a significant role in arousal and in regulating transitions between sleep and waking states. Specifically, the tuberomamillary histaminergic neurons and the perifornical hypocretin neurons in the posterior hypothalamus have extensive interconnections and interactions with the basic arousal systems (for more information see Chapters 7, 8, 21, and 33). Activity changes in these primary regulating areas result in profound modifications in activity patterns in thalamocortical circuits and associated structures, such as basal ganglia or cerebellum. A primary aim of functional imaging studies has been to characterize this reorganization of regional brain function during normal human sleep as well as the responses to external stimuli and the influence of previous waking experience on regional brain activity during sleep. The results detailed below are summarized in Table 18-1 (Fig. 18-1). NON–RAPID EYE MOVEMENT SLEEP Neurophysiologic recordings in sleeping animals indicate that during non–rapid eye movement (NREM) sleep, the neural activity of the brain is shaped by a slow rhythm (<1 Hz), characterized by a fundamental oscillation of membrane potential made up of a depolarizing phase, associated with important neuronal firing (up state), followed by a hyperpolarizing phase, during which cortical neurons remain silent for a few hundred milliseconds (down state).1,2 The slow oscillation occurs synchronously in large neuronal populations in such a way that it can be reflected on EEG recordings as high-amplitude lowfrequency waves.1,3-5 The slow rhythm entrains other sleep oscillations in a coalescence of multiple rhythms.6 Among the latter, spindles are associated with burst firing in thalamocortical populations. They arise from a cyclic inhibition 201
~= W
OXYGEN METABOLISM
~= W
BLOOD FLOW
↓relative to W
~= W
BLOOD FLOW
↑in response to slow waves
↓relative to W ↓relative to W ↓relative to W
Basal ganglia
Pons, midbrain
Cerebellum
↑relative to W or SWS
↑relative to W or SWS
↑relative to W or SWS
↑relative to W or SWS
↑, increase; ↓, decrease; ~=, about same activity; fMRI, functional magnetic resonance imaging; NREM, non–rapid eye movement; PET, positron-emission tomography; REM, rapid eye movement; SWS, slow-wave sleep; W, wakefulness.
↑in response to slow waves
↓relative to W
↑in response to slow waves
Thalamus
Medial temporal lobe (amygdala)
Medial temporal lobe (hippocampus, parahippocampus)
Anterior cingulate cortex
Temporo-occipital
↑relative to W
↑relative to W
~= W
GLUCOSE METABOLISM
↓relative to W
↑in response to slow waves
↑in response to slow waves
↑in response to slow waves
BOLD SIGNAL
↓relative to W
↓relative to W
↓relative to W and REM sleep
BLOOD FLOW
PET
Medial parietal (including precuneus) ↑relative to W
↓relative to W and REM sleep
GLUCOSE METABOLISM
KETY-SCHMIDT
↓relative to W
↓relative to W and REM sleep
BLOOD FLOW
fMRI
↓relative to W
↓relative to W and REM sleep
OXYGEN METABOLISM
PET
REM SLEEP
Lateral parietal
Medial prefrontal (including orbito-frontal)
Lateral frontal
Regional Changes
Global Changes
AREA
KETY-SCHMIDT
DEEP NREM SLEEP
Table 18-1 Summary of the Modifications in Global and Regional Hemodynamic or Metabolic Parameters during NREM and REM Sleep
202 PART I / Section 4 • Physiology in Sleep
← Low Glucose metabolism High →
CHAPTER 18 • What Brain Imaging Reveals about Sleep Generation and Maintenance 203
Wakefulness Slow-wave sleep
REM sleep
Figure 18-1 Schematic representation of the variations in global cerebral glucose metabolism in resting wakefulness, slow-wave sleep, and REM sleep. The images represent the cerebral glucose metabolism measured in a single subject during three different sessions with fluorodeoxyglucose F-18 positron emission tomography (18F-FDG PET). Functional images are displayed at the same brain level and using the same color scale. Similar rates of brain glucose metabolism are measured during wakefulness and REM sleep. Brain glucose metabolism is significantly decreased during slow-wave sleep relative to both wakefulness and REM sleep. Adapted from Maquet P, Dive D, Salmon E, et al. Cerebral glucose utilization during sleep–wake cycle in man determined by positron emission tomography and [18F]2-fluoro-2-deoxy-D-glucose method. Brain Res 1990;513:136-143.
of thalamocortical (TC) neurons by reticular thalamic (RT) neurons, which elicits postinhibitory rebound spike bursts in TC cells, which in turn entrain cortical populations in spindle oscillations.7 At the macroscopic systems level, the measure of brain metabolism or hemodynamics by PET usually requires the integration of the brain activity over extended time periods (from tens of seconds for H215O-PET to 45 minutes for fluorodeoxyglucose F-18 (18F-FDG) PET, resulting in the averaging of brain activity over the up and down states described earlier. Consequently, NREM sleep has systematically been associated with lower brain energy metabolism than has wakefulness.8 Relative to wakefulness, cerebral glucose and oxygen metabolisms, as well as cerebral blood flow, are decreased by 5% to 10% during stage 2 sleep9,10 and by 25% to 40% during slow-wave sleep (SWS, i.e., stage 3 to 4 NREM sleep).11-13 These decreases are not homogeneous but show a reproducible regional distribution. It is thought that brain areas with a high proportion of neurons committed in synchronous sleep oscillations are likely to have the lowest regional activity.8 During light NREM sleep, cerebral blood flow decreases in the pons and thalamic nuclei, as well as in frontal and parietal areas, but is maintained in the midbrain.14 Consistent with the implication of thalamic nuclei in the generation of spindles, thalamic blood flow during stage 2 sleep decreases in proportion to the power density within the sigma frequency range (12-15 Hz).15 During SWS, the most consistent decreases were observed in areas playing a permissive or active role in generating NREM
sleep and its characteristic oscillations: These areas are the dorsal pons and mesencephalon, thalami, basal forebrain, and hypothalamus. The topography of the decreases in cortical blood flow during NREM sleep is also very reproducible and encompasses the prefrontal cortex, anterior cingulate cortex, the precuneus, and the mesial aspect of the temporal lobe. The mechanisms that produce these diminutions in regional blood flow are not completely understood. The frontal and parietal polymodal associative cortices are among the most active brain structures during wakefulness.8 Consequently, it is usually believed that homeostatic sleep pressure locally accrued during a normal waking day is particularly important in these cortical areas, resulting during NREM sleep in a considerable amount of local slow waves and consequently a substantial decrease in local energy metabolism.8 Significant decreases in blood flow were also unexpectedly observed in the cerebellum and basal ganglia. It is currently not known whether these changes in blood flow indicate that these two areas have a role in generating and maintaining cortical oscillations or if they are merely entrained by the cortical slow rhythm. Advances in event-related EEG and fMRI have allowed a finer-grained characterization of brain activities associated with transient events, such as spindles16 or slow waves. In humans, some evidence suggests that there are two different types of spindles during sleep, slow and fast EEG spindles, which differ by their scalp topography and some aspects of their regulation.17 Both spindle types trigger significant activity in the thalami, the anterior cingulate and insular cortices, and superior temporal gyri. Beyond the common activation pattern, slow spindles (11-13 Hz) are associated with increased activity in the superior frontal gyrus. In contrast, fast spindles (13-15 Hz) recruit a set of cortical regions involved in sensorimotor processing and recruit the mesial frontal cortex and hippocampus. During SWS, human EEG recordings are characterized by high-voltage low-frequency oscillations whose the classification is not always clear. The power density in the 0.75- to 4-Hz frequency band, usually referred to as slowwave activity (SWA), has proved a very useful and popular parameter because it quantifies the dissipation of homeostatic sleep pressure during NREM sleep.18 However, its frequency bounds do not respect the dichotomy between slow (<1 Hz) and delta rhythms (1-4 Hz), which is based on differences in the respective cellular correlates of these oscillations in animals.6 In the temporal domain, the amplitude of SWS waves is classically larger than 75 µV.19 However, the largest waves (>140 µV) have been taken as realizations of the slow oscillation (<1 Hz).20,21 Transient increases in brain activity associated with slow (>140 µV) and delta EEG waves (75-140 µV) can be detected in the pontine tegmentum (in an area encompassing the locus coeruleus), midbrain, and cerebellum in several cortical areas including inferior frontal, medial prefrontal, precuneus, and posterior cingulate parahippocampal gyrus,22 areas that have been shown to be current sources underpinning human slow waves.23 As compared to baseline activity, slow waves are associated with significant activity in the parahippocampal gyrus,
204 PART I / Section 4 • Physiology in Sleep
PROCESSING OF EXTERNAL STIMULI DURING NREM SLEEP At present, only a few neuroimaging studies have investigated how the human brain processes external stimuli during sleep, and their results are controversial. In sedated young children, examined with fMRI, visual stimulation elicited a paradoxical decrease in response in the anterior aspect of the medial occipital cortex.25 Although the neurobiological significance of this enigmatic finding remains elusive, it has been replicated in naturally sleeping adults during SWS, using fMRI and PET.26 This response pattern does not seem specific to visual stimulations because it is also observed when auditory stimuli are delivered during NREM sleep.27 In sharp contrast with these results, other data suggest that the brain still processes auditory stimuli up to cortical areas during NREM sleep.28 Significant responses to audi-
1 X = –8
0.5
Z = –28
0 –0.5 0
20
Resp. ampl. (a.u.)
Resp. ampl. (a.u.)
cerebellum, and brainstem, whereas delta waves are related to frontal responses. These findings show that NREM sleep is not a state of brain quiescence but is an active state during which neural activity is consistently synchronized by sleep oscillations (spindles, slow rhythm) in specific cerebral regions. Electrophysiologic and computational evidence from the cortex and thalamus indicates that the tonic firing pattern and fluctuations of the membrane potential during slow-oscillation up states are similar to those that occur during the waking state, suggesting that the up state is a ubiquitous feature of neuronal dynamics in corticothalamic networks reproducing a micro-wakelike state that facilitate neuronal interactions.24 The partial overlap between the regional activity pattern related to SWS waves and the waking default mode network is consistent with the hypothesis that the brain responses synchronized by the slow oscillation restore micro-wakelike activity patterns (Fig. 18-2).22
0.6 0.4 0.2 0 –0.2
40
0
1
Y = –36
Y = 24
0.5 0 –0.5 0
20
0.5 0 –0.5 0
0 –0.5 0
20
40
Time (seconds)
20
40
Time (seconds) X = –6
X=8
Resp. ampl. (a.u.)
Resp. ampl. (a.u.)
Time (seconds)
0.5
40
1
40
1
20
Time (seconds) Resp. ampl. (a.u.)
Resp. ampl. (a.u.)
Time (seconds)
1 0.5 0 –0.5 0
20
40
Time (seconds)
Figure 18-2 Brain regions activated in relation to slow oscillation (both high-amplitude slow waves and delta waves), as observed with combined EEG and functional MRI. Center panels, Significant responses are associated with both slow and delta waves. Functional results are displayed on an individual structural image (display at P < .001, uncorrected) at different levels of the x, y, and z axes as indicated for each section. Side panels, Time course (in seconds) of fitted response amplitudes (in arbitrary units [a.u.]) during slow waves or delta waves in the corresponding circled brain area. All responses consisted in regional increases of brain activity. From left to right and top to bottom: Pontine tegmentum, cerebellum, right parahippocampal gyrus, inferior frontal gyrus, precuneus, posterior cingulate cortex. Adapted from Dang-Vu TT, Schabus M, Desseilles M, et al. Spontaneous neural activity during human slow wave sleep. Proc Natl Acad Sci U S A 2008;105:15160-15165.
CHAPTER 18 • What Brain Imaging Reveals about Sleep Generation and Maintenance 205
tory stimuli were detected in bilateral auditory cortex, thalamus, and caudate nuclei during wakefulness and light NREM sleep. In addition, the left amygdala and the left prefrontal cortex are recruited by stimuli having particular affective significance for the individual subject. (More information on how the brain process sensory input during sleep is found in Chapter 30). RAPID EYE MOVEMENT SLEEP Reorganization of Regional Brain Function during REM Sleep: Relation with Dream Characteristics The level of energy metabolism recorded during rapid eye movement (REM) sleep is similar to waking levels.12,13 However, the distribution of regional brain activity significantly differs from wakefulness. In addition to areas known to participate in generation and maintenance of REM sleep (e.g., pontine tegmentum, thalamic nuclei), significant activations of limbic and paralimbic areas (e.g., amygdaloid complexes, hippocampal formation, anterior cingulate cortex, and orbitofrontal cortex) are reported during REM sleep (Fig. 18-3).11,29,30
Although not reported in all studies, posterior cortices in temporooccipital areas are typically activated during REM sleep.11 In contrast, the dorsolateral prefrontal cortex, parietal cortex, posterior cingulate cortex, and precuneus are the least active brain regions.11,29 Although early animal studies had already mentioned the high limbic activity during REM sleep, functional neuroimaging in humans highlighted the contrast between the activation of limbic, paralimbic, and posterior cortical areas on the one hand and the relative quiescence of the associative frontal and parietal cortices on the other hand. Regional functional integration is also modified during REM sleep, relative to wakefulness. For instance, the functional interactions between striate and extrastriate cortices, which are positive during wakefulness, become negative during REM sleep.31 Likewise, the functional connectivity between the amygdala and temporooccipital areas is tighter during REM sleep than during resting wakefulness.32 The organization of human brain function during REM sleep somehow relates to some of the characteristics of dreaming activity.29,33,34 The perceptual aspects of dreams
F
P F T-O
–4 mm 10
A PH
0 mm
5 Cp
Ca
rCBF [16 –28 –2]
T-O
–2 mm
O
B Th A,H PT
A
0 –5 –10 –15 –20
B
0
20
40
60
REMs density
Figure 18-3 A, Schematic representation of the relative increases and decreases in neural activity associated with REM sleep, as observed with positron emission tomography. A,H, amygdala and hyppocampus; B, basal forebrain; Ca, anterior cingulate gyrus; Cp, posterior cingulate gyrus and precuneus; F, prefrontal cortex; H, hypothalamus; M, motor cortex; P, parietal supramarginal cortex; PH, parahippocampic gyrus; PT, pontine tegmentum; O, occipital-lateral cortex; Th, thalamus; T-O, temporooccipital extrastriate cortex; B, Cerebral areas more active in relation to rapid eye movements during paradoxical sleep than during wake. Transverse sections from 24 to 0 mm from the bicommissural plane. The functional data are displayed at P < .001 uncorrected, superimposed on the average MRI of the subjects, coregistered to the same reference space. Bottom panel, Plot of the adjusted regional cerebral blood flow (rCBF; arbitrary units) in the right geniculate body in relation to the rapid eye movement counts. The geniculate cerebral blood flow is correlated to the rapid eye movement counts more during REM sleep (in red) than during wake (in green). (A adapted from Schwartz S, Maquet P. Sleep imaging and the neuro-psychological assessment of dreams. Trends Cogn Sci 2002;6:23-30. B adapted from Peigneux P, Laureys S, Fuchs S, et al. Generation of rapid eye movements during paradoxical sleep in humans. Neuroimage 2001;14:701-708.)
206 PART I / Section 4 • Physiology in Sleep
would be related to the activation of posterior (occipital and temporal) cortices, whereas emotional features in dreams would be related to the activation of amygdalar complexes, orbitofrontal cortex, and anterior cingulate cortex. The recruitment of mesiotemporal areas would account for the memory content commonly observed in dreams. The relative hypoactivation of the prefrontal cortex might help to explain the alteration in logical reasoning, working memory, episodic memory, and executive functions characterizing dream reports collected from experimentally induced REM sleep awakenings. Activation of the anterior cingulate cortex and surrounding mesial prefrontal cortex has been described, in studies on waking cognitive neuroscience, to be related to self-referential cognition and to the monitoring of performance. Activation of these structures within REM sleep might represent a role for REM sleep in the internal monitoring of aspects of the self, especially those having emotional significance given the activation of other related limbic and paralimbic structures.33 Brain Imaging and Other Characteristic Features of REM Sleep Rapid eye movements constitute a prominent feature of REM sleep. Cerebral mechanisms underpinning the generation of spontaneous ocular movements differ between REM sleep and wakefulness in humans. Regional cerebral blood flow changes in the lateral geniculate bodies and in the striate cortex are significantly more correlated to ocular movement density during REM sleep than during wakefulness,35 a pattern later confirmed using fMRI.36 This pattern of activity is reminiscent of ponto-geniculo-occipital (PGO) waves, prominent phasic bioelectrical potentials associated with eye movements, which occur in isolation or in bursts just before and during REM sleep and are most easily recorded in cats and rats in the mesopontine tegmentum, the lateral geniculate bodies, and the occipital cortex.37 Another important feature in REM sleep is the instability in autonomic regulation and especially in cardiovascular regulation. During wake, the right insula is involved in cardiovascular regulation38 but during REM sleep, the variability in heart rate is related to the activity in the right amygdaloid complex.39 The functional connectivity between the amygdala and the insular cortex, two brain areas involved in cardiovascular regulation, differ significantly in REM sleep as compared to wake.39 These results suggest a functional reorganization of central cardiovascular regulation during REM sleep. Experience-Dependent Modifications of Regional Brain Function during NREM and REM Sleep Waking experience substantially influences regional brain activity during subsequent sleep. For instance, the blood flow of the hippocampus and parahippocampal gyrus during NREM sleep is increased in subjects who were navigating in a virtual town during the previous waking period, as compared to naive participants.40 The level of hippocampal activity expressed during SWS positively correlates with the improvement of performance in route
retrieval on the next day, suggesting that hippocampal activity during NREM sleep is related to offline processing of spatial memory.40 Similarly, several brain areas activated during the execution of a serial reaction time task during wake (brainstem, thalamus, and occipital, parietal and premotor areas) are significantly more active during REM sleep in subjects previously trained on the task in comparison to nontrained subjects.41 This enhancement of regional brain activity during posttraining REM sleep is observed only when the material to learn is presented in a structured manner as compared to random presentation.42 It is then suggested to be associated with significant changes in brain functional connectivity.43 Collectively, these results support the hypothesis that the memory of a motor sequence is further processed during REM sleep in humans (Fig. 18-4). (For more information on memory processing in relation to sleep, see Chapter 29.) BRAIN IMAGING AND NEURAL CORRELATES OF SLEEP–WAKE CYCLE REGULATION The timing of sleep and wake episodes is thought to be regulated by the interaction between the homeostatic sleep pressure and an intrinsic circadian oscillation.44 One study compared regional relative brain glucose metabolism between morning and evening wakefulness in healthy humans in order to define the mechanisms that maintain wakefulness across the day, in relation to the increasing sleep drive that accumulates over the wake period (see Chapter 37 for more information of sleep and wake process). Brain scans, using 18F-FDG PET, were conducted during quiet wakefulness in the morning and in the evening in 13 healthy adults (10 women, 3 men; mean age, 37 years). As expected, subjective ratings of alertness were lower in the evening than in morning. Conversely, relative regional glucose metabolism was significantly higher in the evening than in the morning in a large cluster of midline and brainstem structures. More specifically, changes were localized in the pontine and midbrain reticular formation, midbrain raphe, locus coeruleus, and posterior hypothalamus. Note that evening wakefulness is associated with increased relative metabolism in brainstem and hypothalamic arousal systems and decreased relative metabolism in posterior cortical regions. These patterns might reflect input from the circadian timing system(s) to promote wakefulness, or they might reflect the effects of increasing homeostatic sleep drive (see Section 5 of this volume). The activity of suprachiasmatic nucleus, the master circadian clock, is influenced by external temporal markers (zeitgebers), the most important of which is light. In addition to vision, light profoundly affects human physiology and modulates sleep–wake cycles, body temperature, endocrine functions, alertness, and performance.44 Animal and human studies demonstrated that a nonvisual photoreception system mediates these effects, which include the synchronization of the circadian system, suppression of melatonin, regulation of sleep, and improvements in alertness and cognition.45-49 This photoreception system recruits the retinal photoreceptors (rods and cones) and intrinsically photosensitive retinal ganglion cells expressing melanopsin.50,51 These retinal ganglion cells project to numerous
CHAPTER 18 • What Brain Imaging Reveals about Sleep Generation and Maintenance 207 –16 mm
0 mm
SRT Rest
A Trained REMS
W
B Nontrained REMS
W
C Interaction ([REMs vs. W] x [Trained vs. nontrained])
D
E
Conjunction SRT Rest Interaction ([REMs vs. W] x [Trained vs. nontrained])
16 mm
40 mm
56 mm
64 mm 8 7 6 5 4 3 2 1 0 8 7 6 5 4 3 2 1 0 8 7 6 5 4 3 2 1 0 3 2.5 2 1.5 1 0.5 0 3 2.5 2 1.5 1 0.5 0
Figure 18-4 Influence of previous waking experience, here a procedural motor sequence learning, on the distribution of regional brain activity during subsequent REM sleep. Statistical parametric maps of different contrasts are displayed at six different brain levels (from 16 mm below to 64 mm above the bicommissural plane), superimposed on the average (co-registered and normalized) MRI image of the sleeping subjects. All maps were thresholded at P < .001 (uncorrected), except for A, which was thresholded at voxel-level–corrected (P < .05). A, Brain regions activated during performance of a serial reaction time (SRT) task during wakefulness (SRT–rest). B, Brain regions activated during REM sleep (REM sleep–wakefulness) in subjects previously trained to the SRT task. C, Brain regions activated during REM sleep (REM sleep–wakefulness) in nontrained subjects. D, Brain regions activated more in trained subjects than in nontrained subjects during REM sleep; that is, the intersection of the condition (REM sleep versus wakefulness) by group (trained versus nontrained). E, Brain regions that were both recruited during the execution of motor tasks and more activated in trained than in nontrained subjects scanned during REM sleep; that is, the conjunction of (SRT–rest) with the condition [REM sleep versus wakefulness] by group [trained versus nontrained]. (Adapted from Maquet P, Laureys S, Peigneux P, et al. Experience-dependent changes in cerebral activation during human REM sleep. Nat Neurosci 2000;3:831-836.)
nuclei of the brainstem, hypothalamus, thalamus, and cortical structures; such an anatomic connectivity suggests that the nonvisual system can influence many brain functions. However, light has been shown to enhance cortical and subcortical responses induced by various cognitive challenges. Polychromatic bright white light (>7000 lux) was first shown to enhance responses to attention tasks in subcortical (hypothalamus and thalamus) and cortical areas during the night.52 Similar results were observed during daytime.53 These early experiments did not make it possible to specify the relative contribution of the different retinal photoreceptors involved. Monochromatic blue
(470 nm) light was then shown to enhance brain responses to a working memory task in areas such as the thalamus and association cortices; it prevented the decline otherwise observed with green (550 nm) light exposure.54 These results supported the potential involvement of melanopsin in eliciting these nonvisual modifications in brain responses. However, no definite claims could be made concerning the contribution of different photoreceptor classes. Subsequently, the relative contribution of S-cones, melanopsinexpressing ganglion cells, and M-cones to nonvisual brain responses to light was assessed using short duration violet (430 nm), blue (473 nm), and green (527 nm) monochromatic light exposures.55 Because light exposures were short
208 PART I / Section 4 • Physiology in Sleep
lasting, this protocol allowed the detection of subcortical brain structures involved in early nonvisual responses to light, such as the thalamus and the brainstem. Collectively, these findings show that light, and especially blue light, can not only influence the timing of sleep−wake cycles but can also profoundly and swiftly influence regional brain function. This is more likely occurring through a modulation of the activity in subcortical structures promoting alertness (e.g., anterior hypothalamus, mesopontine tegmentum, thalamus) (Fig. 18-5).45-49
Adjusted CBF (arbitrary units)
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BRAIN IMAGING AND NEURAL CORRELATES OF HUMAN SLEEP DEPRIVATION Sleep generation and maintenance are strongly affected by the homeostatic sleep drive. Understanding the neural correlates, therefore, of sleep deprivation, which increases the homeostatic sleep drive, provides additional clues from functional neuroimaging about the mechanisms of sleep generation and sleep maintenance. Wu and colleagues56 assessed regional cerebral metabolism using the 18F-FDG PET method in healthy subjects
1.1 1.05 1 0.95 0.9 0.85
before and after 32 hours of sleep deprivation. They noted prominent decreases in metabolism in the thalamus, basal ganglia, temporal lobes, and cerebellum and increases in visual cortex. Whole-brain absolute metabolic rate was not different. Thomas and coworkers57,58 described the effects of 24 hours, 48 hours, and 72 hours of sleep deprivation on waking regional cerebral metabolism assessed via 18F-FDG PET, as well as alertness and cognitive performance. Sleep deprivation was associated with global declines in absolute cerebral metabolism. Regionally, these declines were most notable in frontoparietal cortex and in the thalamus. This is consistent with studies showing that the effects of sleep deprivation on SWS are greatest in frontal EEG leads. Alertness and cognitive performance on a sleep deprivation–sensitive serial addition and subtraction test declined in association with the sleep-deprivation–associated regional deactivations. Paus and colleagues59-61 have demonstrated that blood flow in the thalamus and pontomesencephalic tegmentum as assessed by H215O PET positively correlates with arousals in sleep,59 with performance on vigilance tasks60 and with loss of consciousness associated with anesthesia.61 In
Z = + 40 mm Z = 0 mm
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A
1.02
B
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Figure 18-5 Effects on regional brain activity of exposure to bright white light during the night, as assessed with positron emission tomography. Regional cerebral blood flow (rCBF) was measured in subjects attending to auditory stimuli in near darkness following light exposures (>8000 lux) of different durations (0.5, 17, 16.5, and 0 min) during the biological night. A, Parietal and occipital areas where the regional brain blood flow is significantly increased in proportion to the duration of the previous exposure to light. Left panels, Functional data displayed at P < .05 (voxel level), superimposed on the mean normalized MRI scan. Right panels, Plots of the adjusted regional cerebral blood flow in these areas. The duration of the light exposure preceding each scan is indicated by the yellow boxes in the insert above the activity estimates. B, Suprachiasmatic area where the blood flow is significantly decreased in proportion to the duration of the previous exposure to light. Functional data are displayed at P < .001 (uncorrected), superimposed on a parasagittal view of the mean normalized MRI scan (x coordinate, 2 mm). Inset, Enlargement of the hypothalamic area. Lower panel, Corresponding adjusted blood flow for the four scans of the blocks. (Adapted from Perrin F, Peigneux P, Fuchs S, et al. Nonvisual responses to light exposure in the human brain during the circadian night. Curr Biol 2004;14:1842-1846.)
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some instances this arousal network also included the basal forebrain and anterior cingulate cortex.60 These findings regarding sleep deprivation support the role for sleep in restoring brain function in thalamocortical networks associated with higher-order cognition. One study62 assessed changes in regional brain function during sleep recovery following sleep deprivation in order to define the specific neural correlates of the sleep recovery process. Homeostatic sleep need was modulated in a within-subjects design via sleep deprivation. In four young adult healthy male subjects (mean age, 24.9 years ± 1.2 years), NREM sleep was assessed using 18F-FDG PET after a normal night of sleep and again after 36 hours of sleep deprivation. Both absolute and relative regional cerebral glucose metabolic data were obtained and analyzed. In relation to baseline NREM sleep, subjects’ recovery NREM sleep was associated with increased SWA, global reductions in whole-brain metabolism, and relative reductions in glucose metabolism in broad regions of frontal, parietal, and temporal cortex. The results demonstrate that the homeostatic recovery function of sleep is associated with global reductions in whole-brain metabolism during NREM as well as greater relative reductions in broad regions of frontal, parietal, and temporal cortex. These results show that the homeostatic function of sleep in humans involves a reduction of glucose metabolism throughout the cortex. Neurobiological models of sleep homeostasis, therefore, need to account for the inverse relationship between SWA and cerebral glucose utilization and may suggest that the increased SWA associated with recovery from sleep deprivation is a marker of an increased need for cerebral metabolic restoration.
FUNCTIONAL NEUROIMAGING IN SLEEP DISORDERS Functional neuroimaging studies in patients with sleep disorders provide additional clues to the role of various brain structures in generating and maintaining sleep. If the previously stated hypotheses regarding the role of various brain structures in these processes are correct, then these brain structures should function abnormally in some manner in patients who do not sleep well. Insomnia, for example, is a disorder in which patients have difficulty falling asleep or staying asleep or who have nonrestorative sleep along with daytime dysfunction. A review of the functional neuroimaging findings in this disorder provides additional clues, because new data are emerging on a regular basis about the neural mechanisms of sleep generation and maintenance in humans. Insomnia and Brainstem and Hypothalamic Arousal Networks Human sleep neuroimaging studies in insomnia subjects support the involvement of basic arousal networks in disturbances in NREM sleep (Video 18-1). Nofzinger and colleagues63 investigated the neurobiological basis of poor sleep in insomnia. Insomnia patients and healthy subjects completed regional cerebral glucose metabolic assessments during both waking and NREM sleep using 18F-FDG PET. Healthy subjects reported better sleep quality than
did insomnia subjects. The two groups did not differ on any measure of visually scored or automated measure of sleep. Grouping by state-interaction analysis confirmed that insomnia subjects showed a smaller decrease than did healthy subjects in relative glucose metabolism from waking to NREM sleep in the brainstem reticular core and in the hypothalamus. This study supports the concept that persistent activity in this basic arousal network may be responsible for the impaired objective and subjective sleep in insomnia patients (Figs. 18-6 and 18-7). In terms of interventions, the action of sedative–hypnotics may be primarily on these basic arousal systems. For
ARAS
ARAS
Mesial temporal cortex Hypothalamus
Hypothalamus
ARAS Thalamus
Mesial temporal cortex
Cingulate
Insular cortex
Figure 18-6 Brain structures that do not show decreased metabolic rate from waking to sleep in insomniacs. All regions shown reach statistical significance at the P < .05, corrected, level of significance in relation to healthy sleeper control subjects. ARAS, Ascending reticular activating system. (From Nofzinger EA, Buysse DJ, Germain A, et al. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry 2004; 161:2126-2131.)
Pontine brainstem
ACC, medial Thalamus prefrontal cortex
Diffuse thalamocortical network
Figure 18-7 Brain structures where metabolism during NREM sleep correlates with wakefulness after sleep onset in insomnia patients. ACC, anterior cingulate cortex. (From Nofzinger EA, Nissen C, Germain A, et al. Regional cerebral metabolic correlates of WASO during NREM sleep in insomnia. J Clin Sleep Med 2006;2(3):316-322.)
210 PART I / Section 4 • Physiology in Sleep
example, Kajimura’s group64 assessed regional cerebral blood flow, as a correlate of neuronal activity, during NREM sleep in response to triazolam, a short-acting benzodiazepine sedative–hypnotic. They found that blood flow in the basal forebrain was lower during NREM sleep following administration of triazolam than following administration of placebo. One study aimed to determine if eszopiclone, a nonbenzodiazepine cyclopyrrolone, reversed the pattern of brainstem, hypothalamus, and basal forebrain abnormalities found in insomnia patients.65 In this study, eight subjects (four women and four men; mean age, 35 years ± 13 years) completed 2 weeks of open-label eszopiclone treatment, 3 mg at bedtime. Pre- and posttreatment assessments included sleep diary, 3 nights of polysomnography, and waking and NREM sleep 18F-FDG PET scans. From preto posttreatment, insomnia patients showed improvements in all subjective measures of sleep, sleep quality, mood, and next-morning alertness. The Pittsburgh Sleep Quality Index total was 11.9 ± 2.5 pretreatment and 7.5 ± 2.3 posttreatment; paired t(7) = 3.86, P = .006. Brain-imaging analyses showed that the reduction in relative metabolism in an arousal network from waking to NREM sleep was greater following eszopiclone treatment than before. Specific regions included the pontine reticular formation and ascended into the midbrain, subthalamic nucleus, culmen of the cerebellum, and thalamus. Related neocortical areas showing this interaction included the orbitofrontal cortex, superior temporal lobe, right paracentral lobule of the posterior medial frontal lobe, right precuneus, dorsal cingulate gyrus, and portions of the frontal lobe. Comparisons involving only sleep, but not wake, revealed similar regions of posttreatment reductions in relative metabolism. These results demonstrate that eszopiclone reverses a pattern of central nervous system hyperarousal in insomnia patients. This effect is most pronounced during NREM sleep, at a time when the concentration of eszopiclone in the brain, when given before sleep, should be highest. The inhibitory actions of eszopiclone, and likely similar nonbenzodiazepine sedative–hypnotics and potentially the benzodiazepine sedative–hypnotics, then, that are likely responsible for the sedating properties of these medications appear to be largely on an arousal neural network within sleep that includes the pontine and midbrain reticular activating system. Such studies further corroborate the essential role of these structures in generating and maintaining sleep in humans (Fig. 18-8). Insomnia, Disorders of Emotion, and Limbic and Paralimbic Arousal Networks Importantly, the basic biology of arousal can be modified by neural systems that regulate emotional and goal-directed behavior. These systems may play an important role in modulating or perpetuating the increased arousal of insomnia patients. Demonstration of this provides significant support for an essential role for these systems in generating and maintaining sleep. This is especially true given the significant epidemiologic and neurobiological overlaps between insomnia and mental disorders. The results of preclinical neuroimaging studies of healthy humans and depressed humans support the importance of two neural systems in emotional behavior. A more
Pontine reticular activating system
Pontine, midbrain reticular activating system, thalamus
Figure 18-8 Brain structures that show a greater decline in metabolism from waking to NREM sleep in insomnia patients following 2 weeks of medication management with eszopiclone. (From Nofzinger EA, Buysse D, Moul D, et al. Eszopiclone reverses brain hyperarousal in insomnia: evidence from 18F-FDG PET. Sleep 2008;31:A232.)
ventrally located system, with important contributions from the amygdala, has been shown to be fundamental to the initial experience of emotions and to the automatic generation of emotional responses. The function of this system is a reactive one in response to emotional stimuli. Other structures related to this system include the anterior insula, ventral striatum, and ventral regions of the anterior cingulate cortex and ventral prefrontal cortex. A more dorsally located system, with important contributions from the dorsolateral prefrontal cortex, has been shown to be fundamental to the conscious, planned regulation of emotional behavior in light of future behavior. The function of this system is one of planning behavior in response to emotional stimuli. Other structures related to this system include the hippocampus and the dorsal regions of the anterior cingulate cortex. A primary structure in the ventral system is the amygdala. It has been shown to participate in the sensory component of emotional behavior and in the initial organization of a reactive emotional response. In humans, the amygdala shows increased activation in response to a variety of emotional stimuli including fearful faces, sad faces, threatening words, and fearful vocalizations. A reactive motor role for the amygdala includes the recruitment and coordinating of cortical arousal and vigilant attention for optimizing sensory and perceptual processing of stimuli associated with underdetermined contingencies. Recent work shows that the amygdala is anatomically connected with and functionally modulates effects on the brainstem centers involved in arousal and sleep regulation. Similarly, other components of the ventral emotional system such as the ventral striatum, the subgenual anterior cingulate cortex, and the ventromedial prefrontal cortex are known to have anatomic and functional relationships with brainstem centers that are thought to play a role in behavioral state regulation in addition to the primary roles they each play in cortical arousal. Human sleep neuroimaging studies support the role for components of the ventral emotional system in pathological sleep associated with both depression and insomnia. Nofzinger and colleagues66 used 18F-FDG PET to define
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regional cerebral correlates of arousal in NREM sleep in 9 healthy and 12 depressed patients. They assessed EEG power in the beta high-frequency spectrum as a measure of cortical arousal. They then correlated beta power with metabolism in NREM sleep. They found that beta power negatively correlated with sleep quality. Further, beta power positively correlated with ventromedial prefrontal cortex metabolism in a group of depressed subjects and a group of healthy subjects. They concluded that elevated function in the ventromedial prefrontal cortex, an area associated with obsessive behavior and anatomically linked with brainstem and hypothalamic arousal centers, may contribute to dysfunctional arousal. Nofzinger and coworkers63 also investigated the neurobiological basis of poor sleep in insomnia. Insomnia patients and healthy subjects completed regional cerebral glucose metabolic assessments during waking and during NREM sleep using 18F-FDG PET. A group by state interaction analysis confirmed that insomnia subjects showed a smaller decrease than did healthy subjects in relative metabolism from waking to NREM sleep in the insular cortex, amygdala, hippocampus, anterior cingulate, and medial prefrontal cortices. This study supports the notion that persistent overactivity in a limbic or paralimbic level of the arousal system contributes to the nonrestorative sleep in insomnia patients. Insomnia, Disorders of Emotion, and Neocortical Arousal Networks Beyond the subcortical brainstem and the hypothalamic and limbic and paralimbic neural systems, the prefrontal cortex might play a role in insomnia in several respects. As noted, there are significant epidemiologic links between insomnia and disorders of emotion. The dorsolateral prefrontal cortex is a primary structure in the dorsal emotional neural system. This structure has been shown to play an important role in executive function, including selective attention, planning, and effortful regulation of affective states. The dorsolateral prefrontal cortex maintains the representation of goals and the means to achieve them. It sends bias signals to other areas of the brain to facilitate the expression of task-appropriate responses in the face of competition with other responses. Davidson has shown the importance of left-lateralized prefrontal cortex regions in approach-related appetitive goals and the right in behavioral inhibition and vigilant attention. The dorsolateral prefrontal cortex not only is responsible for recruiting or inhibiting limbic regions as appropriate to performing tasks67 but also appears to be modulated by early limbic processing. A related component of the dorsal emotional system is the dorsal anterior cingulate cortex. This region has been associated with conflict-monitoring (e.g., it is particularly active during conditions when one must arbitrate quickly between two likely responses). Given its role in the executive aspects of emotional behavior, an abnormal increase in vigilant functions of the prefrontal cortex could lead to insomnia, whereas deficient executive behavior could be a consequence of inadequate sleep resulting from insomnia. Nofzinger’s group68 investigated regional cerebral glucose metabolism in insomnia patients and healthy sub-
jects during both waking and NREM sleep using 18F-FDG PET. Insomnia subjects scored worse on measures of daytime concentration and fatigue consistent with prefrontal cortex impairment. Insomnia patients showed increased global cerebral glucose metabolism during sleep and wake, suggesting an increased vigilant or attentive function of the neocortex consistent with hyperarousal. A group by state interaction analysis confirmed that insomnia subjects showed a smaller decrease than did healthy subjects in relative metabolism from waking to NREM sleep in the thalamus, the anterior cingulate, and medial prefrontal cortices, suggesting a persistence of thalamocortical arousal even within sleep in insomnia patients. While awake, in relation to healthy subjects, insomnia subjects showed relative hypometabolism in a broad region of the frontal cortex bilaterally; left hemispheric superior temporal, parietal, and occipital cortices; and the thalamus. Their daytime fatigue might reflect decreased activity in prefrontal cortex that results from inefficient sleep. Several interventions may alter activity in the prefrontal cortex in a beneficial manner for insomnia patients. For example, Lou and colleagues69 assessed regional brain function associated with Yoga Nidra, a meditative state in which there is a loss of conscious control and an increased awareness of sensory experience. In their study, they found reduced blood flow during meditation in an attentional network that included the dorsolateral prefrontal cortex and anterior cingulate cortex, as well as increased blood flow in posterior sensory and associative cortex associated with visual imagery. Cognitive approaches to the treatment of insomnia may have similar mechanisms of action in prefrontal areas. Serotoninergically active antidepressants also increase brain function (blood flow or metabolism) in dorsal paralimbic and dorsolateral prefrontal cortex. Increasing activity in prefrontal cortex might reverse prefrontal deficits in insomnia patients, leading to improved daytime cognitive function. Alternatively, further increase of an already metabolically overactive prefrontal cortex might increase attentive and vigilant functions, thereby producing further insomnia, a not uncommon side effect of selective serotonin reuptake inhibitor (SSRI) therapy in depressed or insomnia patients. One study has documented prefrontal hypoactivation in insomnia as predicted from the background review previously mentioned. This study investigated functional brain activation differences as a possible result of chronic insomnia, and the reversibility of these differences after nonmedicated sleep therapy. Twenty-one insomniac subjects and 12 carefully matched controls underwent fMRI scanning during the performance of a category and a letter-fluency task. Insomniac subjects were randomly assigned to either a 6-week period of nonpharmacologic sleep therapy or a wait-list period, after which fMRI scanning was repeated using parallel tasks. Task-related brain activation and number of generated words were considered as outcome measures. Compared to controls, insomnia patients showed hypoactivation of the medial and inferior prefrontal cortical areas (Brodmann areas 9, 44-45), which recovered after sleep therapy but not after a wait-list period. These studies support the hypothesis that insomnia interferes in a reversible fashion with
212 PART I / Section 4 • Physiology in Sleep
activation of the prefrontal cortical system during daytime task performance. REM Sleep in Depression Given that REM sleep activates limbic and anterior paralimbic cortex in healthy subjects, the increased REM sleep in depressed patients may reflect a greater re-activation of these structures in REM sleep. Nofzinger and coworkers68 tested this hypothesis in 24 depressed patients and 14 healthy subjects. They underwent EEG sleep studies and regional cerebral glucose metabolism assessments during both waking and REM sleep using 18F-FDG PET. Depressed patients showed greater REM sleep percentage. Consistent with the hypothesis that depressed patients would show increased activation in limbic and anterior limbic structures from waking to REM, depressed patients showed greater increases in relative metabolism from waking to REM sleep than healthy subjects in the midbrain reticular formation, including the pretectal area, and in a larger region of anterior paralimbic cortex. Additionally, depressed patients showed greater increases in relative metabolism from waking to REM sleep than healthy subjects in a broadly distributed region of predominantly left hemispheric dorsolateral prefrontal, parietal, and temporal cortex. This area included the frontal and parietal eye fields. Increased activation of the brainstem reticular formation from waking to REM sleep in depressed patients is consistent with the model of an altered balance in brainstem monoaminergic (norepinephrine and serotonin) systems and brainstem acetylcholine neuronal systems in depressed patients. A second important finding in this study was the increased activation of limbic and anterior paralimbic (hippocampus, basal forebrain/ventral pallidum, anterior cingulate, and medial prefrontal) cortex from waking to REM sleep in the depressed patients. The highest density of cholinergic axons is in core limbic structures such as the hippocampus and amygdala. Limbic and anterior paralimbic cortices also have high densities of inhibitory 5-hydroxytryptamine1A (5-HT1A) postsynaptic receptors in relation to other areas of cortex. Behaviorally, increased activation of limbic and paralimbic cortex in depressed patients may reflect a susceptibility of depressed patients to experience stimuli in a more affectively intense, negative context, given the increased activation of these structures in response to negatively valenced stimuli or increased affective states. A third major finding in this study is the relatively greater activation of executive cortex from waking to REM sleep in depressed patients. This may reflect a change in modulation of cortical function from monoaminergic during waking to cholinergic in REM sleep, coupled with a monoaminergic or cholinergic imbalance in depressed patients. Behaviorally, this might also reflect a greater involvement of executive function during REM sleep in depressed patients, perhaps in response to the increased affective state produced by the abnormal re-activation of limbic and paralimbic cortex during REM sleep in depressed patients. Fatal Familial Insomnia Perani and colleagues70 assessed cerebral metabolism in four patients with fatal familial insomnia, a prion disease
with a mutation at codon 178 of the prion protein gene. Thalamic hypometabolism was found in all cases, and more widespread nonspecific cortical hypometabolism was noted in some. Perani and colleagues suggest that the thalamic dysfunction is consistent with the neuropathologic findings in the disorder and is a hallmark of the disease. Kloppel’s group71 reported the results of a [123I] β-CIT SPECT study in two cases of fatal familial insomnia. They showed a 57% and 73% reduced availability of serotonin transporters in a thalamus-hypothalamus region in the two patients in relation to age-expected control values. Although the interpretation is not entirely clear, they suggest that this might reflect altered serotoninergic function in regions of the brain thought to be important in sleep–wake regulation in this patient group.
SUMMARY The application of functional neuroimaging methods to the study of sleep in health and disease in human subjects has provided unique insights into the neural mechanisms of sleep generation and maintenance. In many instances, these studies provide secondary support for the neural mechanisms of sleep generation and maintenance that have been discovered in preclinical research. They also provide unique insights into the involvement and interaction of broad neural networks at subcortical and cortical levels in a defined and regular manner to produce the final experience of sleep in humans. Brain imaging studies are contributing to the understanding of how wake and sleep networks can behave pathologically to produce various sleep disorders and where treatments can reverse these abnormalities. Acknowledgements The research data reported in this paper were collected with the help of grant from by the Belgian Fonds National de la Recherche Scientifique (FNRS), Fondation Médicale Reine Elisabeth (FMRE), Research Fund of the University of Liège, “Interuniversity Attraction Poles Programme— Belgian State—Belgian Science Policy,” and the United States National Institutes of Health (grants MH24652, AG00972, AG20677, RR00056, RR024153, MH30915). ❖ Clinical Pearl Neural systems related to sleep–wake regulation and the function of sleep overlap extensively with neural systems involved in essential aspects of waking cognitive and emotional behavior. Disruptions in sleep in patients with sleep disorders, therefore, can be associated with alterations in these neural systems, and, in turn, altered sleep leads to fundamental changes in these neural systems that impair waking behavior.
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214 PART I / Section 4 • Physiology in Sleep 53. Vandewalle G, Balteau E, Phillips C, et al. Daytime light exposure dynamically enhances brain responses. Curr Biol 2006;16:16161621. 54. Vandewalle G, Gais S, Schabus M, et al. Wavelength-dependent modulation of brain responses to a working memory task by daytime light exposure. Cereb Cortex 2007;17:2788-2795. 55. Vandewalle G, Schmidt C, Albouy G, et al. Brain responses to violet, blue, and green monochromatic light exposures in humans: prominent role of blue light and the brainstem. PloS One 2007; 2:e1247 56. Wu R, Bao J, Zhang C, et al. Comparison of sleep condition and sleep-related psychological activity after cognitive-behavior and pharmacological therapy for chronic insomnia. Psychother Psychosom 2006;75:220-228. 57. Thomas M, Sing H, Belenky G, et al. Neural basis of alertness and cognitive performance impairments during sleepiness. I. Effects of 24 h of sleep deprivation on waking human regional brain activity. J Sleep Res 2000;9:335-352. 58. Thomas ML, Sing HC, Belenky G, et al. Neural basis of alertness and cognitive performance impairments during sleepiness II. Effects of 48 and 72 h of sleep deprivation on waking human regional brain activity. Thalamus and Related Systems 2003;2: 199-229. 59. Paus T, Jech R, Thompson CJ, et al. Transcranial magnetic stimulation during positron emission tomography: a new method for studying connectivity of the human cerebral cortex. J Neurosci 1997; 17:3178-3184. 60. Paus T, Koski L, Caramanos Z, et al. Regional differences in the effects of task difficulty and motor output on blood flow response in the human anterior cingulate cortex: a review of 107 PET activation studies. Neuroreport 1998;9:R37-R47. 61. Paus T. Functional anatomy of arousal and attention systems in the human brain. Prog Brain Res 2000;126:65-77.
62. Johnson J, Nissen C, Germain A, et al. Modulation of sleep homeostasis via sleep deprivation leads to reductions in glucose metabolism in the cerebral cortex during recovery sleep in humans: a repeated measures PET FDG study. Sleep 2006;29:A150. 63. Nofzinger EA, Buysse DJ, Germain A, et al. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry 2004;161:2126-2131. 64. Kajimura N, Nishikawa M, Uchiyama M, et al. Deactivation by benzodiazepine of the basal forebrain and amygdala in normal humans during sleep: a placebo-controlled 15H2 PET study. Am J Psychiatry 2004;161:748-751. 65. Nofzinger EA, Buysse D, Moul D, et al. Eszopiclone reverses brain hyperarousal in insomnia: evidence from 18F-FDG PET. Sleep 2008;31:A232. 66. Nofzinger EA, Price JC, Meltzer CC, et al. Towards a neurobiology of dysfunctional arousal in depression: the relationship between beta EEG power and regional cerebral glucose metabolism during NREM sleep. Psychiatry Res 2000;98:71-91. 67. Davidson RJ, Kabat-Zinn J, Schumacher J, et al. Alterations in brain and immune function produced by mindfulness meditation. Psychosom Med 2003;65:564-570. 68. Nofzinger EA, Buysse DJ, Miewald JM, et al. Human regional cerebral glucose metabolism during non–rapid eye movement sleep in relation to waking. Brain 2002;125:1105-1115. 69. Lou HC, Kjaer TW, Friberg L, et al. A 15O-H2O PET study of meditation and the resting state of normal consciousness. Hum Brain Map 1999;7:98-105. 70. Perani D, Cortelli P, Lucignani G, et al. 18F-FDG PET in fatal familial insomnia: the functional effects of thalamic lesions. Neurology 1993;43:2565-2569. 71. Kloppel S, Pirker W, Brucke T, et al. Beta-CIT SPECT demonstrates reduced availability of serotonin transporters in patients with fatal familial insomnia. J Neural Transmitters 2002;109:1105-1110.
Cardiovascular Physiology: Central and Autonomic Regulation Richard L. Verrier and Ronald M. Harper Abstract Because of the close neurohumoral coupling between central structures and cardiorespiratory function, there is a dynamic fluctuation in heart rhythm, arterial blood pressure, coronary artery blood flow, and ventilation. Non–rapid eye movement (NREM) sleep is associated with relative autonomic stability and functional coordination between respiration, pumping action of the heart, and maintenance of arterial blood pressure. During rapid eye movement (REM) sleep, surges in cardiac-bound sympathetic and parasympathetic activity provoke accelerations and pauses in heart rhythm. These occur in association with alterations in ponto-geniculo-occipital (PGO)
During a typical night’s sleep, a broad spectrum of autonomic patterns unfolds that provides both respite and stress to the cardiovascular system. These effects are the consequences of carefully orchestrated changes in central nervous system (CNS) physiology as the brain periodically reexcites during rapid eye movement (REM) sleep from the relative tranquility of non–rapid eye movement (NREM) sleep. The main goal of this chapter is to provide insights into the central and peripheral nervous system mechanisms that regulate cardiovascular function during sleep. Particular attention is focused on cardiac electrical stability and coronary artery blood flow because these factors can trigger life-threatening cardiac arrhythmias and myocardial infarction in individuals with heart disease. Attention is also directed toward the central mechanisms underlying the high sympathetic tone found in conditions associated with sleep disordered breathing, including obstructive sleep apnea (OSA) and heart failure, and with cardiovascular function in infants, particularly because perturbations in the regulation of this system during the nocturnal period may be an important factor in the sudden infant death syndrome (SIDS). The importance of these issues to public health is underscored by the annual toll of nocturnal, sleep-related cardiac events, which account for an estimated 20% of myocardial infarctions (or 250,000) and 15% of sudden cardiac deaths (or 48,750) in the United States.1 Thus, there is an important need to increase awareness of the importance of sleep physiology and pathophysiology among cardiologists.2 For detailed report and discussion of clinical findings, see Chapters 117 and 118.
SLEEP-STATE CONTROL OF CARDIOVASCULAR FUNCTION Non-REM sleep, the initial stage, is characterized by a period of relative autonomic stability, with vagal nerve dominance and heightened baroreceptor gain. During NREM sleep, a near sinusoidal modulation of
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activity and theta rhythm that are signs of phasic central nervous system activation in REM. Whereas perturbations in autonomic nervous system activity are well tolerated in normal individuals, those with heart disease may be at risk during REM sleep. The stress on the system has the potential for triggering life-threatening arrhythmias and myocardial infarction. During NREM sleep in the severely compromised heart, there is a potential for hypotension, which can in turn impair blood flow through stenotic coronary vessels. In both states, the coexistence of coronary disease and apnea is associated with heightened risk because of the challenge of dual control of the respiratory and cardiovascular systems.
heart rate variation occurs due to a coupling with respiratory activity and cardiorespiratory centers in the brain and results in what is termed normal respiratory sinus arrhythmia (Fig. 19-1). During inspiration, heart rate accelerates briefly to accommodate increased venous return, resulting in increased cardiac output, whereas during expiration, a progressive slowing in rate ensues. This normal sinus variability in heart rate, particularly during NREM sleep, is generally indicative of cardiac health, whereas the absence of intrinsic variability has been associated with cardiac pathology and advancing age.3 The reflexive cardiovascular changes during breathing manifested as cyclical heart rate variation also have a converse relationship, as transient elevation of arterial blood pressure results in a slowing, cessation, or diminution of breathing efforts. This effect is enhanced during sleep,4 when even small reductions in arterial blood pressure increase respiratory rates.5,6 These breathing pauses and increased rates apparently serve as compensatory mechanisms to normalize arterial blood pressure. Absence of these normal breathing pauses and diminished breathing variation, as well as reductions in respirationinduced heart rate variation, are characteristic of infants who later succumb to SIDS7 and may hint at a failure of compensatory mechanisms underlying the syndrome. Reduced heart rate variability is also typical of infants afflicted with congenital central hypoventilation syndrome, a condition in which the drive to breathe is lost during sleep.8 Obstructive sleep apnea in children is accompanied by exaggerated heart rate variation.9 Thus, the common denominator of cardiac risk associated with depressed heart rate variability appears to be loss of normal vagal nerve function. Sympathetic nerve activity appears to be relatively stable during NREM sleep, and its cardiovascular input is reduced by more than half from wakefulness to stage 4 of NREM sleep.10 In general, the autonomic stability of NREM sleep, with hypotension, bradycardia, and reductions in cardiac output and systemic vascular resistance, provide a 215
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216 PART I / Section 4 • Physiology in Sleep
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Figure 19-1 The x-axis represents successive heartbeats and the intervals between heartbeats from a healthy 4-month-old infant during wakefulness (AW), quiet sleep (QS), and rapid eye movement (REM) sleep. The y-axis represents time (in milliseconds [MS]) between those heartbeats. Note rapid modulation of intervals during quiet sleep contributed by respiratory variation. Note also lower frequency modulation during REM sleep, and epochs of sustained rapid rate during wakefulness.
relatively salutary neurohumoral background during which the heart has an opportunity for metabolic restoration.11 The bradycardias appear to be caused mainly by an increase in vagal nerve activity, whereas the hypotension is primarily attributable to a reduction in sympathetic vasomotor tone.12 During transitions from NREM to REM sleep, bursts of vagal nerve activity may result in pauses in heart rhythm and frank asystole.13 REM sleep is initiated at 90-minute intervals and, in subserving brain neurochemical functions and behavioral adaptations, can disrupt cardiorespiratory homeostasis.14 The brain’s increased excitability during REM sleep can result in major surges in cardiac sympathetic nerve activity to the coronary vessels. Baroreceptor gain is reduced. Heart rate fluctuates strikingly, with marked episodes of tachycardia and bradycardia.15,16 Cardiac efferent vagus nerve tone is generally suppressed during REM sleep,11 and breathing patterns are highly irregular and can lead to oxygen reduction, particularly in patients with pulmonary or cardiac disease.14 The neurons activating the principal diaphragmatic respiratory muscles normally escape the generalized inhibition,17 although accessory and upper airway muscles diminish activity.18 This loss of activity is especially marked in infant thoracic and abdominal muscles during REM sleep.19 During sleep apnea, there may be cessation of central respiratory activity or peripheral obstruction several hundred times each night, with the potential for dire consequences for cardiorespiratory activity.
Mamillary bodies
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Figure 19-2 A, Midline view demonstrating injury in pontine raphé, cerebellum, and hypothalamus of heart failure patients, as detected by T2 relaxometry procedures. Pontine raphé (arrow), fibers of the fornix, hypothalamus, and cerebellum show injury. B, Mammillary body volume loss in obstructive sleep apnea (OSA). Left: Cartoon of mammillary bodies. Center: Control mammillary bodies of a control subject. Right: Mammillary bodies in OSA patient. (Data from Woo MA, Kumar R, Macey PM, et al. Brain injury in autonomic, emotional, and cognitive regulatory areas in patients with heart failure. J Cardiac Fail 2009;15(3):214-223, and from Kumar R, Birrer BVX, Macey PM, et al. Reduced mammillary body volume in patients with obstructive sleep apnea. Neurosci Lett 2008;438:330-334. Drawing by Acerland International.)
CARDIORESPIRATORY INTERACTIONS Central Mechanisms The integration of cardiorespiratory function during sleep is achieved at several levels in the neuraxis. Several pontine and suprapontine, as well as cerebellar, mechanisms have the capability of altering cardiorespiratory patterns during both sleep and wakefulness. The importance of the pontine structures in REM sleep activation has been documented by positron emission tomography imaging studies of REM sleep dreaming, which demonstrate preferential activation of the limbic and paralimbic regions of the forebrain in REM sleep compared with waking or with NREM sleep.20-22 The midline raphé of the pons contains serotonergic neurons that play significant roles in vascular control23; the neurons are damaged in heart failure (Fig. 19-2), likely as a consequence of impaired perfusion and hypoxia accompanying impaired breathing during sleep in the condition.24 The orbital frontal cortex, portions of the hippocampal formation, and hypothalamic structures are frequently included among forebrain structures participating in cardiorespiratory patterning as well as affective behavior. The central nucleus of the amygdala is strategically positioned to regulate cardiac and respiratory functions of affective behavior, because it projects extensively to the parabrachial pons and the nucleus of the solitary tract, the dorsal motor nucleus, and the periaqueductal gray region, all areas exerting significant influences on
CHAPTER 19 • Cardiovascular Physiology: Central and Autonomic Regulation 217
cardiac action. Portions of the amygdala, hippocampal formation, and frontal and insular cortices all participate in mediating the transient arterial blood pressure elevation elicited by cold pressor challenges or Valsalva maneuvers, as indicated by functional magnetic resonance.25 The inspiratory and expiratory loading that accompanies impaired breathing during sleep likely recruits these central nervous system structures. The hippocampal formation and recipients of its output fibers in the fornix, the mammillary bodies, are of particular interest, because these structures are severely injured in both OSA and heart failure patients (Fig. 19-2B).24,26-28 In addition to its role in blood pressure regulation, the hippocampus, and particularly the mammillary bodies, serves significant roles in recent (antereograde) memory.29 Other conditions with comparable injury and memory impairment, such as Korsakoff syndrome accompanying chronic alcoholism, are associated with thiamine deficiency, a consequence of fluid regulation or malnutrition.30 The sympathetic activation in OSA, leading to profuse sweating during sleep, and the usual interventional therapy of diuresis of heart failure patients predispose patients to loss of thiamine. The insular cortex deserves special attention over other cortical areas that express regulatory action on cardiovascular control during sleep and waking states. Both animal and human studies show that the area modulates both sympathetic and parasympathetic action, with sympathetic outflow principally controlled by the right insula and parasympathetic action by the left31 (although both sides apparently interact).32 Of interest for the sleep field are the marked deficits found in the insula in conditions with sleep-disordered breathing and high sympathetic tone— namely, heart failure and OSA.33-36 Heart failure patients exhibit severe insular gray matter loss, preferentially on the right side (Fig. 19-3A),37 and impaired functional magnetic resonance signal responses to cold pressor challenges and to Valsalva maneuvers in addition to an inability to mount appropriate heart rate responses.38,39 Patients with OSA also show aberrant heart rate and insular responses to cold pressor challenges and Valsalva maneuvers with both amplitude and timing of the neural responses affected in the breathing task.40,41 Lateralized insular responses are also relevant to epilepsy, because a propensity exists for some types of seizure discharge to occur during sleep states. Seizure discharge can exert profound influences on arterial blood pressure and heart rate,42 and a unilateral seizure focus could trigger unique autonomic responses. The influence of cortical structures on subcortical sites carries significant import for cardiorespiratory control. Of all neural structures that can exert control over cardiovascular and respiratory activity in both sleep and waking states, the cerebellum is particularly significant. Although not classically considered to be a component of either breathing or cardiac control, a role for the cerebellum has been known for over half a century.43 A portion of this role is mediated through vestibular/cerebellar mechanisms in regulating blood pressure.44 Vestibular mechanisms modify arterial blood pressure responses to rapid postural changes, a process familiar to hypotensive individuals who suffer syncope on rising rapidly from the horizontal position. Lesions of the cerebellar fastigial nucleus can result in ineffective compensatory responses
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Figure 19-3 Areas of gray matter loss (arrows) within the insula (i) of heart failure patients (n = 9) (A), and in the hippocampal region (ii) and cerebellum (iii) of obstructive sleep apnea (OSA) patients (n = 21) (B). Gray matter loss was calculated from structural magnetic resonance imaging scans relative to controls. The 0 to 5 scale represents t values; all light areas are significant (P < .05). (A, From Woo MA, Macey PM, Fonarow GC, et al. Regional brain gray matter loss in heart failure. J Appl Physiol 2003;95:677-684; B, from Macey PM, Henderson LA, Macey KE, et al. Brain morphology associated with obstructive sleep apnea. Am J Resp Crit Care Med 2002;166:1382-1387.)
to hypotension,45 with ensuing death. Cerebellar damage, with significant gray matter loss in the cerebellar cortex and deep nuclei, occurs in heart failure cases37 (see Fig. 19-3B) and in OSA46 and likely contributes to aberrant state-related cardiovascular control in these syndromes. The contributions of abnormal cerebellar development or cerebellar insults to cardiorespiratory disturbances have long been known.47-49 Cardiorespiratory Homeostasis An important consideration in preserving circulatory homeostasis during sleep is the coordination of control over two systems: the respiratory, essential for oxygen exchange, and the cardiovascular, for blood transport. The difficult balancing act of regulating two motor systems, one that supplies somatic musculature (i.e., diaphragmatic, intercostal, abdominal, and upper airway musculature) and the other involving regulation of autonomic pathways to the heart and vasculature, is a formidable task during sleep. This challenge is particularly daunting in individuals who have diseased respiratory or cardiovascular systems, particularly in the form of apnea or heart failure, or in infants, whose developing control systems may become compromised. Activity of the respiratory neurons varies greatly between sleep states, as does the regularity of heart rhythm. Tachycardia, polypnea, sweating, and dramatic elevations in arterial blood pressure secondary to intense autonomic activity occur primarily during REM sleep. Maintenance of perfusion of vital organs through app ropriate arterial blood pressure control is essential for
218 PART I / Section 4 • Physiology in Sleep
cardiorespiratory homeostasis. Respiratory mechanisms are recruited to support cardiovascular action by assisting venous return and by reflexively altering cardiac rate. Rapid eye movement sleep induces a near paralysis of accessory respiratory muscles and diminishes descending forebrain influences on brainstem control regions.50,51 Those reorganizations of control during REM sleep have the potential to interfere substantially with compensatory breathing mechanisms that assist arterial blood pressure management and to remove protective forebrain influences on hypotension or hypertension. The significant interaction between breathing and arterial blood pressure is evident in normalization of blood pressure by continuous positive airway pressure in patients with apnea-induced hypertension.52 The control of arterial blood pressure during sleep is of particular interest to those examining potential mechanisms of failure in SIDS. Several reports indicate that the final sequence in SIDS may be the result of failure in cardiac rhythm.53 Specifically, bradycardia and hypotension, rather than an initial breathing cessation, characterize the final event.54,55 There may be antecedent tachycardia for up to 3 days. The terminal events in SIDS are similar to the two stages of shock, namely, an initial sympathoexcitation followed by a sudden, centrally triggered sympathoinhibition and bradycardia, leading to a life-threatening fall in arterial blood pressure. Some monitored SIDS cases show a near total loss of arterial blood pressure within a minute of onset of the fatal event. Apparently, the inadequate compensatory mechanisms displayed prior to the fatal event by infants at risk for SIDS fail to provide sufficient support. Because SIDS deaths occur largely during sleep, some interaction of state and compensatory mechanisms is suspected. The prone sleeping position contributes to an enhanced risk for SIDS, which possibly derives from the vestibular and cerebellar contributions to arterial blood pressure control44 described earlier. Because vestibular mechanisms assist mediation of arterial blood pressure to postural changes, static stimuli, such as those from the prone (as opposed to the supine) position, can directly modify cardiovascular responses to blood pressure challenges.56-59 Sleep effects on vestibular systems must be considered in examination of arterial blood pressure control mechanisms.
SLEEP STATE–DEPENDENT CHANGES IN HEART RHYTHM Recent evidence indicates that the pronounced changes in heart rate occurring during REM sleep and transitions between sleep states are attributable to distinct mechanisms associated with specific brain sites rather than representing a continuum of autonomic change. Heart Rate Surges Several investigators have reported REM-induced increases in heart rate in experimental animals.12,15,60-63 Accelerations consisting of an abrupt, although transitory, 35% to 37% increases in rate that are concentrated during phasic REM were observed in canines (Fig. 19-4). These marked heart rate surges are accompanied by a rise in mean arterial blood pressure and are followed by a rate deceleration that
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Figure 19-4 Effects of non–rapid eye movement (NREM) sleep (slow-wave sleep), rapid eye movement (REM) sleep, and quiet wakefulness on heart rate, phasic and mean arterial blood pressure, phasic and mean left circumflex coronary flow, electroencephalogram (EEG), and electrooculogram (EOG) in the dog. Sleep spindles are evident during NREM sleep, eye movements during REM sleep, and gross eye movements on awakening. Surges in heart rate and coronary flow occur during REM sleep. (From Kirby DA, Verrier RL. Differential effects of sleep stage on coronary hemodynamic function. Am J Physiol 1989;256: H1378-H1383.)
is apparently baroreceptor mediated. Because the sequence is completely abolished by interruption of sympathetic neural input to the heart,60-62 the acceleration does not appear to be dependent on withdrawal of parasympathetic nerve activity.15,62 Rapid eye movement sleep state–dependent heart rate surges have also been observed in felines. The rate accelerations are linked to CNS activation as reflected in a concomitant increase in hippocampal theta frequency, PGO activity, and eye movements.63 In cats, the appearance of theta waves is characteristic of arousal, orienting activity, alertness, and REM sleep.63-67 The surges are abolished by cardioselective beta-adrenergic blockade with atenolol, suggesting, as in canines, that the peripheral effect is attributable to bursting of cardiac sympathetic efferent fiber activity, which directly affects heart rate. The main difference in rate responses between the two species is that in dogs, the rate acceleration is accompanied within seconds by a baroreflex-mediated deceleration. The precise basis for these differences in the pattern of heart rate responses is unclear, but a plausible explanation is that the canine studies were performed in beagles, a strain that is
CHAPTER 19 • Cardiovascular Physiology: Central and Autonomic Regulation 219
bred for intense physical activity, which is a factor known to augment baroreceptor responsiveness. Heart Rhythm Pauses A complementary finding to centrally mediated heart rate surges is the observation in cats of an abrupt deceleration in heart rhythm that occurs predominantly during tonic REM sleep and is not associated with any preceding or subsequent change in heart rate or arterial blood pressure (Fig. 19-5).68 The involvement of the vagus nerve appears to be directly initiated by central influences, as there is no antecedent or subsequent change in resting heart rate or arterial blood pressure. The primary involvement of CNS activation is demonstrated by the consistent, antecedent, abrupt cessation of PGO activity and the concomitant interruption of hippocampal theta rhythm. In normal human volunteers, Taylor and colleagues69 observed heart rate decelerations during REM sleep that preceded eye movement bursts by 3 seconds; they suggested that the phenomenon reflects an orienting response at the onset of dreaming. How these changes in CNS activity lead to the tonic REM sleep-induced increase in vagus nerve tone to suppress sinus node activity remains unknown. Notwithstanding extensive studies of the physiologic and anatomic bases for PGO activity, little is known about its conductivity and functional relationship to heart rhythm control during sleep. The most likely basis for the abrupt deceleration in heart rate during tonic REM sleep is a change in the centrally induced pattern of autonomic activity to the heart. This could be the result of a decrease in sympathetic nerve activity or of an enhancement of vagus nerve tone, or both in combination. In felines, cardioselective beta1-adrenergic
blockade with atenolol did not affect the incidence or magnitude of decelerations, but muscarinic blockade with glycopyrrolate completely abolished the phenomenon. These observations suggest that the tonic REM sleep-induced decelerations are primarily mediated by cardiac vagus nerve efferent fiber activity. It is well known that enhanced vagal activity can abruptly and markedly affect the sinus node firing rate.70 Because beta-adrenergic blockade exerted no effect on the frequency or magnitude of decelerations, it does not appear that withdrawal of cardiac sympathetic tone is an important factor in the observed rate changes. Respiratory interplay is not an essential component of the deceleration, as the phenomenon often occurred in the absence of a temporal association with inspiratory effort. This primary heart rate pause phenomenon appears to be distinct from baroreceptor-mediated reductions in heart rate that almost invariably follow accelerations in rate and elevation of arterial blood pressure (Fig. 19-6).12 This second group of heart rhythm pauses was observed in canines and occurs mainly during the transition from slow-wave sleep to desynchronized sleep and more frequently during phasic than tonic REM sleep. They persisted for 1 to 8 seconds and were followed by dramatic increases in coronary blood flow averaging 30% and ranging up to 84%, which were independent of metabolic activity of the heart as reflected in the heart rate–blood pressure product. An intense burst of vagus nerve activity appears to produce the phenomenon, because the pauses
Postasystole CBF surge during interruption of SWS by EEG desynchronization Slow-wave sleep
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Figure 19-5 Representative polygraphic recording of a primary heart rate deceleration during tonic rapid eye movement (REM) sleep. During this deceleration, heart rate decreased from 150 to 105 BPM, or 30%. The deceleration occurred during a period devoid of ponto-geniculo-occipital (PGO) spikes in the lateral geniculate nucleus (LGN) or theta rhythm in the hippocampal (CA 1) leads. The abrupt decreases in amplitude of hippocampal theta waves (CA 1), PGO waves (LGN), and respiratory rate (diaphragm, DIA) are typical of transitions from phasic to tonic REM. ECG, electrocardiogram; EMG, electromyogram. (From Verrier RL, Lau RT, Wallooppillai U, et al. Primary vagally mediated decelerations in heart rate during tonic rapid eye movement sleep in cats. Am J Physiol 1998;43:R1136-R1141.)
EEG desynchronization
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Figure 19-6 Coronary blood flow (CBF) surge during deep non-rapid eye movement (NREM) sleep interrupted by electroencephalographic (EEG) desynchronization. This response pattern is common and appears to represent a brief, low-grade arousal. The 4.2-second pause in heart rhythm was followed by a brief increase of 46% in average peak CBF and a decrease of 49% in the heart rate–systolic blood pressure product. ECG, electrocardiogram; EEG, electroencephalogram; EMG, electromyogram; EOG, electrooculogram; LGN, lateral geniculate nucleus field potential recordings; SWS, slow wave sleep. (From Dickerson LW, Huang AH, Nearing BD, et al. Primary coronary vasodilation associated with pauses in heart rhythm during sleep. Am J Physiol 1993;264:R186-R196.)
220 PART I / Section 4 • Physiology in Sleep
developed against a background of marked respiratory sinus arrhythmia with varying degrees of heart block (with nonconducted P waves) and with low heart rate. Moreover, they could be emulated by electrical stimulation of the vagus nerve. Guilleminault and colleagues71 documented similar pauses in healthy young adults.
CORONARY ARTERY BLOOD FLOW REGULATION DURING SLEEP Striking changes in coronary blood flow occur during REM and sleep-state transitions.13,60-62,72 Vatner and coworkers72 studied the effects of the sleep–wake cycle on coronary artery function in baboons. During the nocturnal period, when the animals were judged to be asleep by behavioral indicators, coronary blood flow increased sporadically by as much as 100%. The periodic oscillations in blood flow were not associated with alterations in heart rate or arterial blood pressure and occurred while the animals remained motionless with eyes closed. Because the baboons were not instrumented for electroencephalographic recordings, no information was obtained regarding sleep stage, nor was the mechanism for the coronary blood flow surge defined. Concomitant with the heart rate surges of REM sleep observed in canines60-62 as described earlier were remarkable, episodic surges in coronary blood flow with corresponding decreases in coronary vascular resistance. These phenomena occurred predominantly during periods of REM sleep marked by intense phasic activity as defined by the frequency of eye movements.62 There were no significant changes in mean arterial blood pressure. Heart rate was elevated during the coronary flow surges, suggesting an increase in cardiac metabolic activity as the basis for the coronary vasodilation. In fact, the close coupling between the heart rate–blood pressure product, an index of metabolic demand, and the magnitude of the flow surges indicates that the surges do not constitute a state of myocardial hyperperfusion. These surges in coronary blood flow appear to result from enhanced adrenergic discharge, because they were abolished by bilateral stellectomy, and not from nonspecific effects of somatic activity or respiratory fluctuations. During severe coronary artery stenosis (with baseline flow reduced by 60%), phasic decreases in coronary arterial blood flow, rather than increases, were observed during REM sleep coincident with these heart rate surges (Fig. 19-7).61 An increase in adrenergic discharge could lead to a coronary blood flow decrement by at least two possible mechanisms. The first is by stimulation of alpha-adrenergic receptors on the coronary vascular smooth muscle. Such an effect, however, could be only transitory, as alphaadrenergic stimulation results in brief (10 to 15 seconds) coronary constriction even during sympathetic nerve stimulation in anesthetized animals73 or during intense arousal associated with aversive behavioral conditioning.74 The second possible mechanism is mechanical: a decrease in diastolic coronary perfusion time caused by the surges in heart rate. In support of this explanation, we found a strong correlation (r2 = 0.96) between the magnitude of the increase in heart rate and the decrease in coronary blood flow.61 The link between REM-induced changes in heart
Slow-wave sleep
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Figure 19-7 Effects of sleep stage on heart rate, mean and phasic arterial blood pressure, and mean and phasic left circumflex coronary artery blood flow in a typical dog during coronary artery stenosis. Note phasic decreases in coronary flow occurring during heart rate surges while the dog is in rapid eye movement (REM) sleep. EEG, electroencephalogram; EOG, electrooculogram. During REM sleep, the EEG reveals a characteristic lower amplitude, higher frequency pattern than in slowwave sleep. The EOG tracing indicates the presence of eye movements during REM but not slow-wave sleep. (Reprinted from Kirby DA, Verrier RL. Differential effects of sleep stage on coronary hemodynamic function during stenosis. Physiol Behav 1989;45:1017-1020, with permission.)
rate and the occurrence of myocardial ischemia in patients with advanced coronary artery disease is consistent with clinical experience.75
IMPACT OF SLEEP ON ARRHYTHMOGENESIS Central Nervous System Sites Influencing Cardiac Electrical Stability Extensive investigation of CNS-induced cardiac arrhythmias has provided evidence that triggering of arrhythmias by the CNS is not only the consequence of intense activation of the autonomic nervous system, but also is a function of the specific neural pattern elicited. Regulation of cardiac neural activity is highly integrated and is achieved by circuitry at multiple levels (Fig. 19-8).76 Higher brain centers operate through elaborate pathways within the hypothalamus and medullary cardiovascular regulatory sites. Baroreceptor mechanisms have long been recognized as integral to autonomic control of the cardiovascular system, as evidenced by heart rate variability and baroreceptor sensitivity testing of both cardiac patients and normal subjects. The intrinsic cardiac nerves and fat pads provide local neural coordination independent of higher brain centers. Newly recognized is the phenomenon of electrical remodeling attributable to nerve growth and degeneration. At the
CHAPTER 19 • Cardiovascular Physiology: Central and Autonomic Regulation 221
Cerebral cortex
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Figure 19-8 Synthesis of new and present views on levels of integration important in neural control of cardiac electrical activity during sleep. More traditional concepts focused on afferent tracts (dashed lines) arising from myocardial nerve (N) terminals and reflex receptors (e.g., baroreceptors) that are integrated centrally within hypothalamic and medullary cardiostimulatory and cardioinhibitory brain centers and on central modulation of sympathetic and parasympathetic outflow (solid lines) with little intermediary processing at the level of the spinal cord and within cervical and thoracic ganglia. More recent views incorporate additional levels of intricate processing within the extraspinal cervical and thoracic ganglia and within the cardiac ganglionic plexus, where recently described interneurons are envisioned to provide new levels of noncentral integration. Release of neurotransmitters from postganglionic sympathetic neurons is believed to enhance excitation in the sinoatrial node and myocardial cells through norepinephrine binding to beta1-receptors, which enhances adenyl cyclase (AC) activity through intermediary stimulatory G-proteins (Gs). Increased parasympathectomy outflow enhances postganglionic release and binding of acetylcholine to muscarinic (M2) receptors, and through coupled inhibitory G-proteins (Gi), inhibits cyclic AMP production (cAMP). The latter alters electrogenesis and pacemaking activity by affecting the activity of specific membrane Na, K, and Ca channels. New levels of integration are shown superimposed on previous views and are emphasized here to highlight new possibilities for intervention. (Reprinted from Lathrop DA, Spooner PM. On the neural connection. J Cardiovasc Electrophysiol 2001;12:841-844.)
level of the myocardial cell, autonomic receptors influence G proteins to control ionic channels, pumps, and exchangers. The influence of the vagus nerve on ventricular electrical properties is contingent on the level of sympathetic tone, a phenomenon referred to as accentuated antagonism. The underlying mechanism is release of acetylcholine by vagus nerve activation, which presynaptically inhibits norepinephrine release from sympathetic nerve endings and antagonizes second messenger formation at the cardiac receptor level.77 Thus, the balance in cardiac input from either limb of the autonomic nervous system and their interactions must be considered. Several intermediary mechanisms may alter the capacity of CNS activity to trigger atrial and ventricular arrhythmias. These mechanisms include direct effects of neurotransmitters on the myocardium and its specialized conducting system and changes in myocardial perfusion due to alterations in coronary vasomotor tone, enhanced platelet aggregability, or both. The net influence on the heart thus depends on a complex interplay between the specific neural pattern elicited and the underlying cardiac pathology. Over 90 years ago, Levy78 demonstrated that ventricular tachyarrhythmias can be elicited in normal animals by stimulating specific areas in the brain. This finding was subsequently confirmed in several species. Hockman and colleagues,79 using stereotactic techniques, demonstrated that cerebral stimulation and hypothalamic activation evoked a spectrum of ventricular arrhythmias. Stimulation of the posterior hypothalamus causes a 10-fold increase in the incidence of ventricular fibrillation elicited by experimental occlusion of the coronary artery.80 This enhanced vulnerability was linked to increased sympathetic nerve activity, because beta-adrenergic receptor blockade, but not vagotomy, prevented it. These findings are consistent with clinical reports that cerebrovascular disease (particularly intracranial hemorrhage) can elicit significant cardiac repolarization abnormalities and life-threatening arrhythmias.81,82 Cryogenic blockade of the thalamic gating mechanism or its output from the frontal cortex to the brainstem83 and of the amygdala84 delayed or prevented the occurrence of ventricular fibrillation during stress in pigs. Ventricular arrhythmias also ensue immediately on cessation of diencephalic or hypothalamic stimulation, but these require intact vagi and stellate ganglia.85,86 The likely electrophysiologic basis for such post-CNS stimulation arrhythmias is the loss of rate-overdrive suppression of ectopic activity. This phenomenon occurs when the vagus nerve regains its activity after cessation of centrally induced adrenergic stimulation. Accordingly, the enhanced automaticity induced by adrenergic stimulation of ventricular pacemakers is exposed when vagus nerve tone is restored and slows the sinus rate.86 Although these arrhythmias may be dramatic in appearance (including ventricular tachycardia), they rarely degenerate into ventricular fibrillation.87 This proarrhythmic effect of dual autonomic activation has been erroneously interpreted as profibrillatory. The antiarrhythmic influence of beta-adrenergic receptor blockade may result in part from blockade of central beta-adrenergic receptors. Parker and coworkers88 determined that intracerebroventricular administration of subsystemic doses of l-propranolol (but not d-propranolol)
222 PART I / Section 4 • Physiology in Sleep
significantly reduced the incidence of ventricular fibrillation during combined left anterior descending coronary artery occlusion and behavioral stress in the pig. Surprisingly, intravenous administration of even a relatively high dose of l-propranolol was ineffective. The latter result may relate in part to a species dependence because, unlike canines, pigs do not exhibit suppression of ischemiainduced arrhythmias in response to beta-blockade.89 It was proposed that the centrally mediated protective effect of beta-blockade is the result of a decrease in sympathetic nerve activity and in plasma norepinephrine concentration.88,90,91 Importantly, whereas central actions of betaadrenergic receptor blockers may play an important role in reducing susceptibility to ventricular fibrillation during acute myocardial ischemia, they are unlikely to constitute the sole mechanism, as beta-blockers prevent the profibrillatory effect of direct stimulation of peripheral sympathetic structures such as the stellate ganglia.92 It is noteworthy that the three beta-blockers that have long-term effects on mortality of cardiac patients (propranolol, metoprolol, and carvedilol) are all lipophilic93 and therefore cross the blood–brain barrier readily and affect sleep structure, with significant perturbations of sleep continuity.94 Autonomic Factors in Arrhythmogenesis during Sleep Non-REM sleep is generally salutary with respect to ventricular arrhythmogenesis, as indicated both by extensive studies of neurocardiac interactions and by clinical experience. Activation of the vagus nerve reduces heart rate, increases cardiac electrical stability, and reduces ratepressure product, an indicator of cardiac metabolic activity, to improve the supply-demand relationship in stenotic coronary artery segments. However, in the setting of severe coronary disease or acute myocardial infarction, hypotension during NREM can lead to myocardial ischemia because of inadequate coronary perfusion pressure and thereby provoke arrhythmias and myocardial infarction.11,95 The abrupt increases in vagus nerve tone that can occur during periods of REM or sleep-state transitions can result in significant pauses in heart rhythm, bradyarrhythmias, and, potentially, triggered activity, a mechanism of the lethal cardiac arrhythmia torsades de pointes. Patients with the long QT syndrome who have the type 3 phenotype are more prone to experience torsades de pointes at night rather than during stress or exercise.56 Tonic control of the vagus nerves over the caliber of the epicardial coronary vessels96 could be an important factor in dynamic regulation of coronary resistance as a function of the sleep– wake cycle. An important question is whether tonic vagus nerve activity exerts a protective or a deleterious influence on myocardial perfusion and arrhythmogenesis in individuals with atherosclerotic disease. In these patients, nocturnal surges in vagus nerve activity could precipitate myocardial ischemia and arrhythmias as a result of coronary vasoconstriction rather than dilation in atherosclerotic segments, in patients with impaired release of endothelium-derived relaxing factor.97 Because of the attendant surges in sympathetic nerve activity and in heart rate, REM sleep has the potential for triggering ventricular arrhythmias.98,99 The striking variability of heart rate and breathing pattern can have a sig-
nificant impact on cardiovascular functioning, as is evident in the development of ischemia and arrhythmias in patients whose myocardium is compromised. Indeed, the only clinical studies in which sleep staging has been employed have identified REM as the state in which arrhythmias occurred.11,100,101 The increase in sympathetic nerve activity that arises at the onset of REM sleep10 provides a potent stimulus for ventricular tachyarrhythmias because of the arrhythmogenic influence of neurally released catecholamines. Sympathetic nerve activation by stimulation of central78-80,85,86 or peripheral adrenergic structures,92,102 infusion of catecholamines,103 or imposition of behavioral stress104 can increase cardiac vulnerability in the normal and ischemic heart. These profibrillatory influences are substantially blunted by beta-adrenergic receptor blockade.104 A wide variety of supraventricular arrhythmias can also be induced by autonomic activation.87 Enhanced sympathetic nerve activity increases cardiac vulnerability in the normal and in the ischemic heart by complex mechanisms. The major indirect effects include an impaired oxygen supply–demand ratio resulting from increased cardiac metabolic activity and coronary vasoconstriction, particularly in vessels with injured endothelium and in the context of altered preload and afterload. The direct profibrillatory effects on cardiac electrophysiologic function are attributable to derangements in impulse formation or conduction, or both.87 Increased levels of catecholamines activate beta-adrenergic receptors, which in turn alter adenylate cyclase activity and intracellular calcium flux. These actions are probably mediated by the cyclic nucleotide and protein kinase regulatory cascade, which can alter spatial heterogeneity of calcium transients and consequently increase dispersion of repolarization. The net influence is an increase in susceptibility to ventricular fibrillation.74,105 Conversely, reduction of cardiac sympathetic drive by stellectomy has proved to be antifibrillatory. Notwithstanding the evidence that autonomic factors have the potential for significantly altering susceptibility to arrhythmias, the observation that the heart rate surges of REM sleep are conducive to myocardial ischemia, and the epidemiologic data in humans on the extent of sleepinduced cardiac events,1 there is a paucity of information regarding the effects of myocardial infarction on the cardiovascular system during sleep. Ventricular ectopic activity, but not ventricular fibrillation, has been documented during NREM sleep in pigs after myocardial infarction.106 This pattern may be attributable to slowing of heart rate and increased vagus nerve activity during NREM sleep, conditions that can inhibit the normal overdrive suppression of ventricular rhythms by sinoatrial node pacemaker activity and result in firing of latent ventricular pacemakers and triggered activity. Snisarenko107 found significant elevations in heart rate in both the acute (4 to 10 days) and subacute (3 to 12 months) periods following myocardial infarction in a feline model. In the acute period, these effects were accompanied by increased wakefulness, decreased heart rate variability, and severely disordered sleep. In the intervening weeks, sleep quality recovered fully until, in the subacute period, beta-blockade with propranolol led to renewed, pronounced disturbances in sleep structure, with increased wakefulness, reduction in REM
CHAPTER 19 • Cardiovascular Physiology: Central and Autonomic Regulation 223
sleep, and prolongation of stages 1 and 2 of NREM sleep. He attributed these results to reflex activation of adrenergic, noradrenergic, and dopaminergic nerves in several brain structures after coronary artery ligation.108
SUMMARY Sleep states exert a major impact on cardiorespiratory function. This is a direct consequence of the significant variations in brain states that occur in the normal cycling between NREM and REM sleep. Dynamic fluctuations in CNS variables influence heart rhythm, arterial blood pressure, coronary artery blood flow, and ventilation. Whereas REM-induced surges in sympathetic and parasympathetic nerve activity with accompanying significant surges and pauses in heart rhythm are well tolerated in normal people, patients with heart disease may be at heightened risk for life-threatening arrhythmias and myocardial ischemia and infarction.75,99 During NREM sleep, in the severely compromised heart, a potential for hypotension exists that can impair blood flow through stenotic coronary vessels to trigger myocardial ischemia or infarction.11 Damage to central brain areas that regulate autonomic activity and coordinate upper airway and diaphragmatic action can lead to enhanced sympathetic outflow, increasing risk in heart failure and contributing to hypertension in OSA. Coordination of cardiorespiratory control is especially pivotal in infancy, when developmental immaturity can compromise function and pose special risks. Throughout sleep, the coexistence of coronary disease and apnea is associated with heightened risk of cardiovascular events109 resulting from the challenge of dual control of the respiratory and cardiovascular systems.
❖ Clinical Pearl REM sleep is characterized by surges in sympathetic and vagus nerve activity, which are well tolerated in normal individuals but which may result in cardiac arrhythmias, myocardial ischemia, and myocardial infarction in those with heart disease. During NREM sleep, systemic blood pressure may fall, potentially reducing flow through stenotic coronary vessels, which may precipitate cardiac ischemia or infarction. In essence, sleep constitutes an autonomic stress test for the heart, and nighttime monitoring of cardiorespiratory function is of considerable diagnostic value.110
Acknowledgments This work was supported by National Institutes of Health grant MH13923 from the National Institute of Mental Health, and HD22695, HL22418, and HL60296 from the National Institute of Child Health and Human Development and the National Heart, Lung, and Blood Institute, Bethesda, Maryland. Additional support was provided by the Mind-Body Network of the John D. and Catherine T. MacArthur Foundation. The authors thank Sandra S. Verrier for her editorial contributions.
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52. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995; 96:1897-1904. 53. Schwartz PJ, Stramba-Badiale M, Segantini A, Austoni P, et al. Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med 1998;338:1709-1714. 54. Meny RG, Carroll JL, Carbone MT, Kelly DH. Cardiorespiratory recordings from infants dying suddenly and unexpectedly at home. Pediatrics 1994;93:43-49. 55. Harper RM, Bandler R. Finding the failure mechanism in the sudden infant death syndrome. Nat Med 1998;4:157-158. 56. Sahni R, Schulze KF, Kashyap S, Ohira-Kist K, et al. Body position, sleep states, and cardiorespiratory activity in developing low birth weight infants. Early Hum Dev 1999;54:197-206. 57. Sahni R, Schulze KF, Kashyap S, Ohira-Kist K, et al. Postural differences in cardiac dynamics during quiet and active sleep in low birthweight infants. Acta Paediatr 1999;88:1396-1401. 58. Galland BC, Taylor BJ, Bolton DP, Sayers RM. Vasoconstriction following spontaneous sighs and head-up tilts in infants sleeping prone and supine. Early Hum Dev 2000;58:119-132. 59. Galland BC, Hayman RM, Taylor BJ, Bolton DP, et al. Factors affecting heart rate variability and heart rate responses to tilting in infants aged 1 and 3 months. Pediatr Res 2000;48:360-368. 60. Kirby DA, Verrier RL. Differential effects of sleep stage on coronary hemodynamic function. Am J Physiol 1989;256:H1378H1383. 61. Kirby DA, Verrier RL. Differential effects of sleep stage on coronary hemodynamic function during stenosis. Physiol Behav 1989;45:1017-1020. 62. Dickerson LW, Huang AH, Thurnher MM, Nearing BD, et al. Relationship between coronary hemodynamic changes and the phasic events of rapid eye movement sleep. Sleep 1993;16:550-557. 63. Rowe K, Moreno R, Lau RT, Wallooppillai U, et al. Heart rate surges during REM sleep are associated with theta rhythm and PGO activity in the cat. Am J Physiol 1999;277:R843-R849. 64. Sakai K, Sano K, Iwahara S. Eye movements and hippocampal theta activity in cats. Electroencephalogr Clin Neurophysiol 1973;34: 547-549. 65. Kemp IR, Kaada BR. The relation of hippocampal theta activity to arousal, attentive behaviour and somato-motor movements in unrestrained cats. Brain Res 1975;95:323-342. 66. Lerma J, Garcia-Austt E. Hippocampal theta rhythm during paradoxical sleep: Effects of afferent stimuli and phase relationships with phasic events. Electroencephalogr Clin Neurophysiol 1985; 60:46-54. 67. Sei H, Morita Y. Acceleration of EEG theta wave precedes the phasic surge of arterial pressure during REM sleep in the rat. Neuroreport 1996;7:3059-3062. 68. Verrier RL, Lau RT, Wallooppillai U, Quattrochi J, et al. Primary vagally mediated decelerations in heart rate during tonic rapid eye movement sleep in cats. Am J Physiol 1998;43:R1136-R1141. 69. Taylor WB, Moldofsky H, Furedy JJ. Heart rate deceleration in REM sleep: An orienting reaction interpretation. Psychophysiology 1985;22:110-115. 70. Pappano AJ. Modulation of the heartbeat by the vagus nerve. In: Zipes DP, Jalife J, editors. Cardiac electrophysiology: from cell to bedside. Philadelphia: Saunders; 1995, p. 411-422. 71. Guilleminault C, Pool P, Motta J, Gillis AM. Sinus arrest during REM sleep in young adults. N Engl J Med 1984;311: 1006-1010. 72. Vatner SF, Franklin D, Higgins CB, Patrick T, et al. Coronary dynamics in unrestrained conscious baboons. Am J Physiol 1971; 221:1396-1401. 73. Feigl EO. Coronary physiology. Physiol Rev 1983;63:1-205. 74. Billman GE, Randall DC. Mechanisms mediating the coronary vascular response to behavioral stress in the dog. Circ Res 1981;48: 214-223. 75. Nowlin JB, Troyer WG Jr, Collins WS, Silverman G, et al. The association of nocturnal angina pectoris with dreaming. Ann Intern Med 1965;63:1040-1046. 76. Lathrop DA, Spooner PM. On the neural connection. J Cardiovasc Electrophysiol 2001;12:841-844. 77. Verrier RL, Antzelevitch C. Autonomic aspects of arrhythmogenesis: the enduring and the new. Curr Opin Cardiol 2004;19:2-11. 78. Levy AG. The exciting causes of ventricular fibrillation in animals under chloroform anesthesia. Heart 1912;4:319-378.
CHAPTER 19 • Cardiovascular Physiology: Central and Autonomic Regulation 225 79. Hockman CH, Mauck HP, Hoff EC. ECG changes resulting from cerebral stimulation: II. A spectrum of ventricular arrhythmias of sympathetic origin. Am Heart J 1966;71:695-700. 80. Verrier RL, Calvert A, Lown B. Effect of posterior hypothalamic stimulation on the ventricular fibrillation threshold. Am J Physiol 1975;228:923-927. 81. Cropp GJ, Manning GW. Electrocardiographic changes simulating myocardial ischemia and infarction associated with spontaneous intracranial hemorrhage. Circulation 1960;22:25-38. 82. Hugenholtz PG. Electrocardiographic abnormalities in cerebral disorders: report of six cases and review of the literature. Am Heart J 1962;63:451-461. 83. Skinner JE, Reed JC. Blockade of frontocortical-brain stem pathway prevents ventricular fibrillation of ischemic heart. Am J Physiol 1981;240:H156-H163. 84. Carpeggiani C, Landisman C, Montaron M-F, Skinner JE. Cryoblockade in limbic brain (amygdala) prevents or delays ventricular fibrillation after coronary artery occlusion in psychologically stressed pigs. Circ Res 1992;70:600-606. 85. Korteweg GCJ, Boeles JTF, Ten Cate J. Influence of stimulation of some subcortical areas on electrocardiogram. J Neurophysiol 1957;20:100-107. 86. Manning JW de V, Cotten M. Mechanism of cardiac arrhythmias induced by diencephalic stimulation. Am J Physiol 1962;203:11201124. 87. Janse MJ, Wit AL. Electrophysiological mechanisms of ventricular arrhythmias resulting from myocardial ischemia and infarction. Physiol Rev 1989;69:1049-1169. 88. Parker GW, Michael LH, Hartley CJ, Skinner JE, et al. Central beta-adrenergic mechanisms may modulate ischemic ventricular fibrillation in pigs. Circ Res 1990;66:259-270. 89. Benfey BG, Elfellah MS, Ogilvie RI, Varma DR. Antiarrhythmic effects of prazosin and propranolol during coronary artery occlusion and reperfusion in dogs and pigs. Br J Pharmacol 1984;82:717-725. 90. Lewis PJ, Haeusler G. Reduction in sympathetic nervous activity as a mechanism for the hypotensive action of propranolol. Nature 1975;256:440. 91. Privitera PJ, Webb JG, Walle T. Effect of centrally administered propranolol on plasma renin activity, plasma norepinephrine, and arterial pressure. Eur J Pharmacol 1979;54:51-60. 92. Schwartz PJ, Vanoli E, Zaza A, Zuanetti G. The effect of antiarrhythmic drugs on life-threatening arrhythmias induced by the interaction between acute myocardial ischemia and sympathetic hyperactivity. Am Heart J 1985;109:937-948. 93. Hjalmarson A, Olsson G. Myocardial infarction: effects of betablockade. Circulation 1991;84(Suppl 6):VI-101-107.
94. Kostis JB, Rosen RC. Central nervous system effects of betaadrenergic blocking drugs: the role of ancillary properties. Circulation 1987;75:204-212. 95. Broughton R, Baron R. Sleep patterns in the intensive care unit and on the ward after acute myocardial infarction. Electroencephalogr Clin Neurophysiol 1978;45:348-360. 96. Kovach JA, Gottdiener JS, Verrier RL. Vagal modulation of epicardial coronary artery size in dogs. A two-dimensional intravascular ultrasound study. Circulation 1995;92:2291-2298. 97. Ludmer PL, Selwyn AP, Shook TL, Wayne RR, et al. Paradoxical vasoconstriction induced by acetylcholine in atherosclerotic arteries. N Engl J Med 1986;315:1046-1051. 98. Lown B, Verrier RL. Neural activity and ventricular fibrillation. N Engl J Med 1976;294:1165-1170. 99. Andrews TC, Fenton T, Toyosaki N, Glasser SP, et al. Subsets of ambulatory myocardial ischemia based on heart rate activity: circadian distribution and response to anti-ischemic medication. Circulation 1993;88:92-100. 100. Smith R, Johnson L, Rothfeld D, Zir L, et al. Sleep and cardiac arrhythmias. Arch Intern Med 1972;130:751-753. 101. Rosenblatt G, Hartman E, Zwilling GR. Cardiac irritability during sleep and dreaming. J Psychosom 1973;17:129-134. 102. Verrier RL, Thompson PL, Lown B. Ventricular vulnerability during sympathetic stimulation: role of heart rate and blood pressure. Cardiovasc Res 1974;8:602-610. 103. Han J, Moe GK. Nonuniform recovery of excitability in ventricular muscle. Circ Res 1964;14:44-60. 104. Kovach JA, Nearing BD, Verrier RL. An angerlike behavioral state potentiates myocardial ischemia-induced T-wave alternans in canines. J Am Coll Cardiol 2001;37:1719-1725. 105. Levy MN. Role of calcium in arrhythmogenesis. Circulation 1989;80(6 Suppl):IV23-IV30. 106. Skinner JE, Mohr DN, Kellaway P. Sleep-stage regulation of ventricular arrhythmias in the unanesthetized pig. Circ Res 1975;37:342-349. 107. Snisarenko AA. Cardiac rhythm in cats during physiological sleep in experimental myocardial infarction and beta-adrenergic receptor blockade. Cor Vasa 1986;38:306-314. 108. Sole MJ, Hussain MN, Lixfeld W. Activation of brain catecholaminergic neurons by cardiac vagal afferents during acute myocardial ischemia in the rat. Circ Res 1980;47:166-172. 109. Shah NA, Yaggi HK, Concato J, Mohsenin V. Obstructive sleep apnea as a risk factor for coronary events or cardiovascular death. Sleep Breath 2010;14:131-136. 110. Verrier RL, Josephson ME. Impact of sleep on arrhythmogenesis. Circ Arrhythmia Electrophysiol 2009;2:450-459.
Cardiovascular Physiology: Autonomic Control in Health and in Sleep Disorders Paola A. Lanfranchi and Virend K. Somers Abstract Autonomic control of circulation is pivotal in ensuring an adequate cardiac output to the vital organs through continuous and rapid adjustments of heart rate (HR), arterial blood
Autonomic circulatory control operates via parasympathetic neurons to the heart and sympathetic neuronal efferents to the heart, blood vessels, kidneys and adrenal medulla. Parasympathetic stimulation of the heart, through the activation of cardiac muscarinic receptors, results in bradycardia, whereas sympathetic stimulation of the heart, through activation of beta1 adrenoreceptors, results in tachycardia and increased contractility. Sympathetic activation in the vascular bed induces both vasoconstriction, by stimulating alpha1 adrenoreceptors, and vasodilation by stimulating beta2 adrenoreceptors. Several reflexes, including the arterial baroreflex, cardiopulmonary reflexes, and chemoreflexes are also important in the rapid adjustments of circulation that occur in association with postural changes, hypoxia, temperature changes, and perhaps sleep. Heart rate (HR) and blood pressure (BP) have a 24-hour rhythm characterized by a significant reduction during nighttime hours, secondary to changes in activity and posture, as well as sleep and circadian influences. This physiological pattern can be altered by sleep loss and sleep disorders, with important implications for cardiovascular health. Autonomic neural output to the cardiovascular system is also sleep-stage–dependent, with a global reduction in sympathetic drive to the heart and vessels, and a shift toward cardiac parasympathetic dominance with deepening stages of non-REM sleep. On the other hand, REM sleep is dominated by remarkable fluctuations between parasympathetic and sympathetic activity, leading to sudden changes in HR and BP. Finally, significant autonomic changes accompany electrocortical arousal from sleep as well as periodic leg movements during sleep. Heart rate changes seemingly precede cortical activation and motor activity. The critical role of the autonomic nervous system in maintaining homeostasis during sleep is demonstrated by disorders that are associated with autonomic dysregulation, such as obstructive sleep apnea (see Chapter 119). Obstructive sleep apnea is associated with increases in sympathetic neural activity both during sleep and wakefulness, and may be mediated through heightened chemoreflex sensitivity. Sympathetic drive may play a role in the higher prevalence of cardiovascular disease in these patients.
INTRODUCTION The cardiovascular autonomic nervous system seeks to maintain homeostasis through precise control of numerous 226
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20
pressure (BP), and redistribution of blood flow. In the longer term, neural circulatory control appears to be coupled with the circadian rhythm, the sleep−wake cycle, and ultradian rhythms, including rapid eye movement (REM) and non−rapid eye movement (NREM) sleep processes.
hemodynamic variables, including heart rate, arterial blood pressure, and peripheral blood flow, on a beat-by-beat basis. The cardiovascular autonomic nervous system appears to be intimately linked to sleep and circadian physiology, as demonstrated by the disrupted autonomic control that accompanies sleep loss and sleep apnea. Sleep disruption may lead to altered neural circulatory control. On the other hand, whether primary alterations in autonomic function may translate into sleep disturbances is not known. This chapter is introduced by a general overview of autonomic cardiovascular regulation and of its central and peripheral controllers, followed by a description of the methods used to explore cardiovascular neural control during sleep in humans and their advantages and limitations. We then seek to outline some of the current knowledge of neural circulatory control during normal sleep and how it may change as a consequence of sleep deprivation, sleep apnea, and autonomic dysfunction such as may occur in diabetes.
THE CARDIOVASCULAR AUTONOMIC NERVOUS SYSTEM: DEFINITION AND FUNCTIONS The cardiovascular autonomic nervous system is a highly integrated network that controls visceral functions, which on a short timescale (seconds to hours), adjusts the circulation in keeping with behavior, the environment, and emotions. Its primary role is to ensure an adequate cardiac output to the vital organs through continuous and rapid adjustments of HR, arterial BP, and redistribution of blood flow. In the longer term, this neural circulatory regulation appears to be coupled with the circadian rhythm, the sleep–wake cycle, and some ultradian rhythms, including rapid eye movement (REM) and non–rapid eye movement (NREM) sleep processes, as well as hormones implicated in long-term BP regulation. Neural control of circulation operates via parasympathetic neurons to the heart and sympathetic neuronal efferents to the heart, blood vessels, kidneys, and adrenal medulla. Parasympathetic stimulation of the cardiovascular system is mediated primarily through the vagus nerve by means of the activation of muscarinic receptors and results in bradycardia. Sympathetic stimulation of the heart acts through activation of beta1 adrenoreceptors at the sinoatrial node (the cardiac pacemaker) and in the myocardium (the cardiac muscle) and results in tachycardia
CHAPTER 20 • Cardiovascular Physiology: Autonomic Control in Health and in Sleep Disorders 227
and increased contractility. Sympathetic activation in the vascular bed induces vasoconstriction by stimulating alpha1 adrenoreceptors (in the skin and splanchnic districts) and vasodilation by stimulating beta2 adrenoreceptors (in the heart and skeletal muscles). Parasympathetic and sympathetic efferent activity to the heart may also modulate cardiac electrophysiological properties that can be relevant to the genesis of several types of arrhythmias, particularly in the presence of a proarrhythmic substrate. Central organization of the autonomic nervous system and its relationship with sleep modulating mechanisms are detailed in Chapter 19. Briefly, autonomic impulses to the vasculature and heart originate from the vasomotor center in the brainstem, located bilaterally in the reticular substance of the medulla and pons. The vasomotor center is in turn modulated by higher nervous system regions in the pons, mesencephalon, and diencephalon, including the hypothalamus and many portions of the cerebral cortex. Several cardiovascular reflexes are also important in the rapid adjustments of blood pressure occurring in association with postural changes, hypoxia, exercise, and moderate temperature changes, and may also be implicated in cardiovascular changes observed during sleep. These include the arterial baroreflex, cardiopulmonary reflexes, and chemoreflexes. The renin-angiotensin-aldosterone system, vasopressin, and other vasoactive mechanisms may also contribute to cardiovascular regulation during sleep. More information on the interaction between cardiovascular disorders and sleep can be found in Section 14 of this book. Arterial Baroreflex The arterial baroreflex is an important regulator of BP in the short term.1 The baroreceptors are sensory receptors in the aortic arch and carotid sinuses that relay in the medullary regions of the brain. Changes in arterial baroreceptor afferent discharge trigger reflex adjustments that buffer or oppose the changes in BP. For instance, increasing increments in BP stretch the receptors, resulting in heightened afferent traffic to the brainstem neuronal network. This inhibits efferent sympathetic outflow to cardiac and vascular smooth muscle and increases parasympathetic cardiac tone, resulting in slowing of HR, reduction in contractility, and increased peripheral vasodilation with subsequent decrease in BP. A decrease in BP has opposite effects, and elicits reflex tachycardia, increased contractility and peripheral vasoconstriction with subsequent increase in BP. Cardiopulmonary Reflexes These reflexes are triggered by the stimulation of lowpressure receptors located in the atria, ventricles, and pulmonary arteries. Cardiopulmonary receptors are volume receptors that serve to mitigate changes in BP in response to changes in blood volume. The firing pattern of these receptors parallels the pressure changes within the cardiac chambers or vessels and helps to regulate blood volume. Cardiopulmonary reflex activation results in peripheral vasodilation, reduction in sympathetic outflow to the kidney, and activation of the posterior pituitary gland to inhibit the release of antidiuretic hormone, resulting in increased urine excretion.
Arterial and cardiopulmonary reflexes are implicated in BP regulation during postural changes. Assumption of the upright position produces a caudal shift in blood volume and acutely reduces stroke volume and BP. The circulatory adjustment to this orthostatic stress is rapid and is characterized by a reflexive increase in HR and peripheral vascular resistance, followed by enhanced secretion of antidiuretic hormone and renin-angiotensin. Recumbency, as occurs during sleep, produces an increased volume load in the cardiac chambers and elicits the opposite effects. The Chemoreflexes The chemoreflexes mediate the ventilatory response to hypoxia and hypercapnia, and they also exert important cardiovascular effects.2 The peripheral arterial chemoreceptors, the most important of which are located in the carotid bodies, respond primarily to changes in the partial pressure of oxygen. Hypoxemic stimulation elicits an increase in respiratory muscle output, inducing hyperventilation, and an increase in sympathetic outflow to peripheral blood vessels, resulting in vasoconstriction. Hyperventilation in turn activates pulmonary stretch receptors, which buffer the increases in sympathetic and vagal outflow, thereby maintaining homeostasis under normal conditions. During apnea, when hyperventilation is absent or prevented, vasoconstriction is potentiated and occurs simultaneously with activation of cardiac vagal drive resulting in bradycardia, collectively termed the “diving reflex,” a protective mechanism which helps preserve blood flow to the heart and brain while limiting cardiac oxygen demand.3,4 The central chemoreceptors are located in the brainstem and respond to changes in pH mediated primarily by carbon dioxide tension. Stimulation of central chemoreceptors by hypercapnia also elicits sympathetic and respiratory activation, but without the cardiovagal effects seen with hypoxia.2
MEASURES TO EXPLORE AUTONOMIC CHANGES DURING SLEEP AND THEIR PHYSIOLOGICAL SIGNIFICANCE Heart Rate, Arterial Blood Pressure, and Their Variability RR interval, the time elapsed between two successive R-waves of the QRS signal on the electrocardiogram (and its reciprocal, the HR) is a function of intrinsic properties of the sinus node as well as autonomic influences. Blood pressure is a function of vascular resistance (an expression of arterial constriction or dilation) and cardiac output (the blood volume being pumped by the heart in 1 minute), which is a function of HR, cardiac contractility, and diastolic blood volume, all components controlled in part by the autonomic nervous system. Autonomic cardiovascular regulation can be investigated through the quantification of average HR and BP as assessed in steady conditions (wakefulness and sleep, for instance) or in their responses to endogenous or exogenous challenges (e.g., changes in posture, response to respiratory changes, and arousal from sleep).
228 PART I / Section 4 • Physiology in Sleep
RRI (msec)
ECG
(Fig. 20-1 and Table 20-1).9 The HF components of RR variability primarily reflect the respiration-driven modulation of sinus rhythm, evident as sinus arrhythmia, and have been used as an index of tonic vagal drive. Nonneural mechanical mechanisms, linked to respiratory fluctuations in cardiac transmural pressure, atrial stretch, and venous return, are also determinants of HF power, and may become especially important after cardiac denervation such as heart transplantation.10 The LF rhythm, which appears to have a widespread neural genesis,11 reflects in part the sympathetic modulation of the heart12 as well as the baroreflex responsiveness to the beat-to-beat variations in arterial BP,13 but can also be modulated by LF or irregular breathing patterns. Importantly, LF oscillations in respiration confound the interpretation of the LF component of cardiovascular variability in helping to understand the autonomic characteristics of cardiovascular control. Therefore, in any assessment of the relative contributions of the LF and HF components to any particular physiologic state or disease condition, it is crucial to ensure that the respiratory pattern is limited to the HF component. The LF to HF ratio is used to provide an index of the sympathovagal balance on the sinus node,14 as long as measurements are obtained in strictly controlled conditions. Finally, the VLF has been hypothesized to reflect thermoregulation and the renin-angiotensin system.15 Regarding BP variability, LF components in systolic BP variability are considered an index of efferent sympathetic vascular modulation, whereas the HF components reflect mechanical
1000 900 800 700 600 500 1
83
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PSD (msec2/Hz)
Both HR and BP exhibit spontaneous fluctuations that can be described by the standard deviation around the mean, or by their rhythmic and nonrhythmic characteristics. When described by the standard deviation over 24-hour ambulatory recordings, high variability of the RR interval is a recognized index of the ability of the cardiovascular system to cope with environmental challenges.5 On the contrary, heightened BP variability is found to accompany aging and hypertension.6 Among the various cyclic components that characterize 24-hour HR and BP variability, those occurring from daytime wakefulness to nighttime sleep have received the attention of most investigators. Specifically, HR and BP physiologically decrease during night hours.7 This pattern is evident in ambulatory subjects, and even in recumbent subjects maintaining the sleep–wake cycle.8 The contribution of circadian versus noncircadian factors and how these may be modified in sleep disorders will be discussed hereafter. RR intervals and BP also manifest short-term oscillations in a frequency range between 0 and 0.5 Hz, which appear to be under the influence of intrinsic autonomic rhythms and of respiratory inputs. Spectral analysis of RR intervals and BP variability provides an estimate on how power (i.e., variance) of the signal is distributed as a function of frequency. Indeed, RR intervals and BP variability appear to be organized in three major components, the high-frequency (HF) (greater than 0.15 Hz) respiratory band, the low-frequency (LF) band (around 0.1 Hz) and the very–low-frequency (VLF) band (0.003-0.039 Hz)
2500 1875 1250 625 0
PSD (mHg2/Hz)
ARTERIAL BLOOD PRESSURE
SP1 (mm Hg)
0.00 0.10 0.20 0.30 0.40 0.50 Hz 1000 200 170 140 110 80 50 1
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500 250 0
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0.00 0.10 0.20 0.30 0.40 0.50 Hz
RESPIRATION
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PSD (UA2/Hz)
RS1 (UA)
1,000,000 250 100 –50 –200 –350 –500 1
B
750,000 500,000 250,000 0
Beat #
A
750
C
0.00 0.10 0.20 0.30 0.40 0.50 Hz
Figure 20-1 ECG, beat-to-beat blood pressure and respiration recordings (A), temporal series of RR intervals, BP Beat # and respiration (B), and power spectra of RR, BP and respiration variability (C) in a single healthy subject. (RRI, RR interval; SP1, systolic pressure; RS1, respiration; PSD, power spectrum density; UA, arbitrary unit.)
CHAPTER 20 • Cardiovascular Physiology: Autonomic Control in Health and in Sleep Disorders 229
Table 20-1 Spectral Components of RR Variability in the Short Term (∼5 minutes) DESCRIPTION ANALYSIS OF SHORT-TERM RECORDINGS (5 MIN)
VARIABLE
UNITS
Total power
msec2
The variance of RR intervals over the temporal series analyzed
Approximately ≤0.4 Hz
VLF
msec2
Power in the very–low-frequency range
≤0.04 Hz
LF
msec2
Power in the low-frequency range
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%
LF power in normalized units LF/(Total power—VLF) × 100
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%
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LF/HF
FREQUENCY RANGE
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Ratio LF [msec2]/ HF [msec2]
effects of respiration on blood pressure changes.12 Measurements of HF, LF, and VLF are usually made in absolute values (msec2), but LF and HF are often presented in normalized units (NU), which represent the relative value of each power component in proportion to the total power minus the VLF components (see Table 20-1). Normalization allows minimizing the effect of changes in total power on LF and HF components. Traditional spectral analysis techniques include fast Fourier Transform algorithms and autoregressive modeling, which in most instances provide comparable results.16 These techniques require stationarity of the signal being processed, and therefore cannot be applied to processes in which there is significant transient activity (e.g., sleep onset, arousals, sleep stages transition, and awakening). In addition, such methods have to be used with caution in association with respiratory or motor events (e.g., periodic limb movement, bruxism). More advanced algorithms of signal processing can be used to overcome this limitation and permit the assessment of dynamic changes in autonomic cardiovascular control during transient events (e.g., sleep onset, arousal, bruxism, etc.)17 and help define the temporal relationship between dynamic changes occurring in different systems, such as electroencephalogram (EEG) and electrocardiogram (ECG).18,19 The most commonly used algorithms include short-time Fourier Transform, Wigner-Ville distribution, Time Varying Autoregressive models, and Wavelets and Wavelet Packets.17 Finally, in addition to the periodic oscillatory behavior observed in RR intervals and arterial BP, a less specific variability occurs with nonperiodic behavior, which can be described by methods based on nonlinear system theory (“chaos theory and fractal analysis”).20 The physiological basis for this nonharmonic beat-to-beat behavior, which extends over a wide time range (seconds to hours), is still unsettled, although it has been proposed that it is under higher central modulation.21 The application of this type of analysis to sleep cardiovascular physiology is still limited.
in blood pressure.22 Two techniques have been mainly used in sleep research to assess spontaneous baroreflex modulation of heart rate: the sequence technique and the spectral analysis tecnique. The first identifies sequences of consecutive beats in which progressive increases in systolic BP are followed by a progressive lengthening in RR (or vice versa). The slope of the regression line between RR intervals and systolic BP within these sequences is taken as the magnitude of the reflex gain. The second is based on crossspectral analysis of short segments of SBP and RR and relies on the assumption that a certain frequency band of RR variability, between 0.04 and 0.35 Hz, is modulated by the baroreflex. Baroreflex sensitivity is expressed by the gain of the transfer function relating changes in blood pressure to coherent changes in RR or muscle sympathetic nerve activity (MSNA). Preejection Period The preejection period (PEP) is the time elapsed between the electrical depolarization of the left ventricle (QRS on the ECG) and the beginning of ventricular ejection and represents the time the left ventricle contracts with the cardiac valves closed. The PEP is influenced by sympathetic activity acting via beta1 adrenoreceptors and shortens under stimulation. The PEP can be derived noninvasively from impedance cardiography, which converts changes in thoracic impedance (as measured by electrodes on the chest and neck) to changes in volume over time and allows tracking of volumetric changes such as those occurring during the cardiac cycle. This method has been applied, although not intensively, to assess cardiac sympathetic influences in steady state conditions during sleep.23,24 The application to transient sympathetic responses is unfortunately limited because errors can occur in interpretation in the presence of BP increases, which can induce a lengthening of the PEP (instead of the expected shortening) due to the longer time required to overcome the external pressure.
Baroreflex Sensitivity The arterial baroreflex is important in buffering short term changes in BP. The gain of the arterial baroreflex, or baroreflex sensitivity, is measured by the degree of change in heart rate or sympathetic traffic for a given unit change
Microneurographic Recording of Sympathetic Nerve Activity Microneurography provides direct information on sympathetic vasomotor and sudomotor activity to muscle and skin. Muscle sympathetic nerve activity (MSNA), usually
230 PART I / Section 4 • Physiology in Sleep
measured at the peroneal nerve, induces vasoconstriction, and is modulated by the baroreflex.25 MSNA also increases in response to hypoxic and hypercapnic chemoreceptor stimulation.2 Skin sympathetic nerve activity reflects thermoregulatory output related to sudomotor and vasomotor activity and is affected by emotional stimuli but not by the baroreflex. Although microneurography provides a direct measure of peripheral sympathetic drive, it is invasive and technically demanding for both operator and patient. In addition, the information provided is limited to regional sympathetic neural activity. Given the heterogeneity of systemspecific innervations, MSNA and skin sympathetic nerve activity assessments may not necessarily reflect global sympathetic tone.
simpler approach to provide an estimate of the cumulative catecholamine secretion over time and has been used widely in the clinical and sleep research settings. Urinary catecholamine excretion is strictly dependant on renal function. Therefore, a correction of excreted catecholamine for indices of renal function (urinary creatinine) is recommended.
Peripheral Arterial Tone and Pulse Transit Time Peripheral arterial tone (PAT), as measured from the finger, provides an indirect index of sympathetic vasoconstrictory mechanisms directed to the peripheral vascular bed. It is based on measurement of the pulsatile volume changes in the vascular bed at the fingertip, which decreases secondary to sympathetically mediated alpha-adrenergic vasoconstriction. Hence, a decrease in the signal may correspond to increased sympathetic drive, although other factors may be involved. PAT is noninvasive and can be monitored continuously during sleep. PAT has been proposed as a measure of the autonomic changes occurring with arousal in adults and children,26,27 and in combination with actigraphy and oxymetry has been used in the diagnosis of sleep apnea.28 Pulse transit time (PTT) refers to the time it takes a pulse wave to travel between two arterial sites.29 In practice, in a noninvasive estimate of PTT, the R-wave in the ECG is generally used to indicate the starting point of the measure and the peripheral waveform (assessed by photoplethysmography at the finger) to indicate the end of the measure. PTT is sensitive to moment-to-moment sympathetic neural activity and shortens when BP increases and lengthens when BP falls. Importantly, PTT encompasses several physiological components that are difficult to control for, and intersubject comparison is not recommended. Only intraindividual relative PTT changes from a baseline condition (over several readings) are recommended. Like PAT, PTT can also be monitored continuously and has been used in the assessment of sympathetic responses to arousals26,27 and respiratory events, especially in children.30
SLEEP RELATED CARDIOVASCULAR AUTONOMIC CHANGES Day–Night Changes in Neural Circulatory Control Heart rate and BP physiologically decrease during nighttime as compared to daytime in ambulant subjects as well as in subjects kept in the supine position for 24 hours.8 Specifically, the normal 24-hour BP pattern consists of a systolic blood pressure reduction of greater than or equal to 10% during sleep compared to daytime, a reduction which is commonly referred to as “dipping.” Posture and activity strongly influence HR and BP during the day,32 whereas posture and sleep affect HR and BP at night.8 However, the nocturnal sleep-related cardiovascular dipping is evident even in subjects who maintain the supine position for 24 hours,8 which underscores the importance of sleep in inducing decreases in nighttime HR and BP. Studies investigating the autonomic changes associated with the sleep–wake cycle noted that indices of parasympathetic function, such as RR interval and HF components of RR variability, begin to change as early as 2 hours before sleep onset23 whereas indices of cardiac and peripheral sympathetic activity such as LF to HF ratio, preejection period, MSNA, and catecholamines start to decrease only after sleep onset and continue to decrease with the deepening of sleep.23,25,31 Morning awakening induces a stepwise activation of the sympathoadrenal system, with increased HR, BP, and plasma catecholamines, with further increases occurring with postural change and physical activity.33 Studies conducting 24 hours of sleep deprivation in supine conditions showed that the nocturnal fall of HR and cardiovagal indices is still present, whereas the fall in nocturnal BP and PEP prolongation (i.e., decreased sympathetic activity) are blunted.23,34 Therefore, it may be that HR and parasympathetic mechanisms are largely under circadian influences and might be implicated in mechanisms preparatory to sleep, whereas sympathetic drive to the heart and vessels is mainly linked to the sleep–wake cycle.
Systemic Catecholamines Measurement of plasma catecholamines (epinephrine and norepinephrine) provides an estimate of global sympathetic activity. However, blood norepinephrine reflects only a small percentage (8%-10%) of neurotransmitter release during sympathetic activation. Moreover, the relatively rapid clearance of catecholamine from the blood stream may limit the ability to detect transient changes in sympathetic activity. Consequently, only frequent sampling through sleep may detect changes related to the sleep–wake cycle and sleep stages.31 The measure of urinary excretion of catecholamine and their metabolites is a
Physiologic Responses to NREM and REM Sleep In healthy subjects, autonomic cardiovascular regulation varies considerably with sleep stage and different autonomic patterns dominate in NREM versus REM sleep. As NREM sleep progresses from stage 1 to stage 4, RR intervals, respiratory mediated HF components of RR variability, and PEP increase whereas BP, LF components in systolic BP variability, and MSNA significantly decrease, compared to wakefulness. These changes suggest an increase in cardiovagal drive and a reduction in cardiac and peripheral sympathetic activity8,35,36 (Fig. 20-2). Baroreflex
CHAPTER 20 • Cardiovascular Physiology: Autonomic Control in Health and in Sleep Disorders 231
AWAKE
STAGE 4 SNA 125
SNA BP
BP
125
0 0
REM
SNA 125
K
125 0 STAGE 3
BP (mm Hg)
SNA BP
BP (mm Hg)
STAGE 2
0 T 10 sec
SNA 125 0
Figure 20-2 Recordings of sympathetic nerve activity (SNA), and mean blood pressure (BP) in a single subject while awake and while in stages 2, 3, 4 and REM sleep. SNA and BP gradually decrease with the deepening of NREM sleep. Heart rate, BP and BP variability increase during REM sleep, together with a profound increase in the frequency and amplitude in SNA. Reprinted from Somers VK, Dyken ME, Mark AL, et al. Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med 1993;328:303-307. (K, K complexes; T, muscle twitches.)
sensitivity appears also to be increased during NREM sleep compared to wakefulness37; however, the response is variable. Namely, compared with wakefulness, baroreflex gain is heightened in response to BP increments rather than decrements during NREM sleep. This mechanism probably serves to ensure the maintenance of stable low BP and HR during NREM sleep. In contrast, REM sleep is a state of autonomic instability, dominated by remarkable fluctuations between parasympathetic and sympathetic influences, which produce sudden and abrupt changes in heart rate and blood pressure.38 The average HR and BP are higher during REM compared to NREM sleep, as is sympathetic neural vasomotor drive.25 The cardiovascular excitation of REM sleep is also reflected by a significant increase of the low frequency components, and a shift of the LF to HF ratio toward sympathetic predominance.8 RR Variability and EEG Coupling Studies assessing the overnight relationship between RR variability and EEG profiles showed the dynamic of RR variability is closely related to the dynamic of EEG reflecting the depth of sleep. The presence of an ultradian 80- to 120-minute rhythm in the normalized LF, with high levels during REM sleep and low levels during slow-wave sleep (SWS) was recently described.39 These oscillations were strikingly coupled in a “mirror-image” to the overnight oscillations in delta wave activity, which reflect sleep deepening and lightening. Similarly, it was reported that normalized HF components of RR variability were coherent with all EEG spectral bands, with a maximum gain (ratio HF amplitude/EEG amplitude was higher) for delta activity and minimum (i.e., the same ratio was lower) with
beta activity.40 The two oscillations were coupled with a phase shift of several minutes, with cardiac changes preceding the EEG changes. Although the mechanisms underlying this coupling is not known, it has been hypothesized that there might be a central generator synchronizing the oscillatory process in autonomic and sleep functions, where cardiovascular function may anticipate sleep-stage changes.39 Autonomic Responses Associated with Arousal from Sleep and from Periodic Leg Movements Arousals Electrocortical arousal from sleep (i.e., EEG desynchronization with appearance of low-voltage, high-frequency EEG) either spontaneous, provoked by an exogenous stimuli, or in the context of sleep-disordered breathing, is associated with sympathetic neural surges, leading to transient increases in HR, BP, and MSNA.41-43 The typical cardiac response is biphasic with tachycardia lasting 4 to 5 seconds followed by bradycardia, with HR increasing prior to cortical arousals. Using Time-Variant analysis it appears that the surge in sympathoexcitation as represented by LF components of RR variability and BP variability remains substantially elevated above baseline long after the HR, BP, and MSNA return to baseline values.18 This can be particularly relevant in conditions characterized by frequent arousals across the night, conceivably leading to a sustained sympathetic influence on the cardiovascular system. Auditory stimuli during sleep may result in autonomic and respiratory modifications even in the absence of overt EEG activation (“autonomic arousal”), or in association with an EEG pattern different from conventional arousal, such as K-complexes or bursts of delta waves not followed by EEG desynchronization (“subcortical arousal”).42,43 These observations imply that there is a range of partial arousal responses implicating autonomic responses with EEG manifestations different from classical arousals and even without any EEG response. The different EEG patterns and the associated cardiac response indicate a hierarchical spectrum of increasing strength from the weaker high-amplitude delta burst to a stronger low-voltage alpha rhythm43 (Fig. 20-3). Periodic Leg Movements during Sleep Periodic leg movements (PLMs) are described as a repetitive rhythmic extension of the big toe and dorsiflexion of the ankle, with occasional flexion at the knee and hip. Periodic leg movements can occur during wakefulness (PLMW) as well as during sleep (PLMS). Periodic leg movements during sleep recur frequently in several sleep disorders (such as restless leg syndrome, narcolepsy, REM sleep behavior disorder, and sleep apnea) and in patients with congestive heart failure44 but are also a frequent finding in healthy, asymptomatic subjects especially with advancing age.45 In the context of sleep apnea, PLMS may coexist with (and are often difficult to distinguish from) respiratory-related leg movements, which are part of the arousal response at the end of airway obstruction (in obstructive sleep apnea) or at the peak of ventilation (in central sleep apnea). Approximately 30% of PLMS
232 PART I / Section 4 • Physiology in Sleep HEART RATE PATTERN
F2-C1 C3-T2
16
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0 MA
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–2 –4 10b 9b 8b 7b 6b 5b 4b 3b 2b 1b 1a 2a 3a 4a 5a 6a 7a 8a 9a 10a 11a 12a 13a 14a 15a 16a 17a 18a 19a 20a
ECG
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2
P2-O2 EOG
∆HR beats/min
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EMG
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18
Figure 20-3 Heart rate response in association with different patterns of EEG activation with arousal during sleep (arrow). Reprinted (modified) from Sforza E, Jouny C, Ibanez V. Cardiac activation during arousal in humans: further evidence for hierarchy in the arousal response. Clin Neurophysiol 2000;111:1611-1619. PAT, phases of transitory activation; MA, microarousal; D, delta bursts; K, K-complexes bursts.
are associated with cortical arousal, whereas more than 60% are associated with K-complexes or bursts of delta waves.46 What causes PLMS is still unknown. However, studies of cardiovascular changes associated with PLMS and their temporal relationship with EEG events are providing new insights into the physiological mechanisms of PLMS. A stereotyped autonomic response accompanies PLMS, consisting of a rapid rise in HR and arterial BP46,47 followed by a significant and rapid bradycardia and a return of BP to baseline values (Fig. 20-4). Such cardiovascular changes are present whether or not the PLMS are associated with arousals; however, the magnitude of the cardiovascular response is greater when PLMS are associated with cortical arousals. In addition, the amplitude of cardiovascular responses of PLM is greater during sleep than that associated with spontaneous or simulated PLM while awake.47 These observations suggest that the intensity of cardiovascular response observed with PLMS is related to the degree of central brain activation (brainstem to cortical activation) that accompanies PLMS and much less to the somatomotor response (i.e., not a classical sensory motor reflex). Studies assessing the temporal relationship between the leg motor event and autonomic and cortical activation consistently reported that changes in HR and EEG activity precede by several seconds the leg movement.46,48 Specifically, HR and EEG delta waves rise first, followed by motor activity and eventually progressive activation, of faster EEG frequencies (i.e., in the alpha, beta, and sigma frequencies). A recent study assessing the dynamic time course of RR variability changes and EEG changes in association with PLMS confirmed the LF components of RR variability to be the first physiological change to occur, followed by EEG changes in delta frequencies, and thereafter the leg movement with or without faster EEG frequencies.19 These data corroborate an original hypothesis suggesting the presence of an integrative hierarchy of the arousal response primarily involving the autonomic
responses with sympathoexcitation, then progressing towards EEG synchronization (represented by bursts of delta waves) and finally EEG desynchronization (arousal) and eventually awakening.46 In this view, leg movements are part of the same periodic activation process that is responsible for cardiovascular and EEG changes during sleep.48 The clinical significance of PLMS has been a subject of debate. Recent findings linked the presence of PLMS to poorer cardiovascular health and outcome. A recent study in a large cohort of subjects with congestive heart failure revealed PLMS to be a strong independent predictor of cardiac mortality, after correction for several confounders.49 The mechanisms underlying this association are unknown. Enhanced central sympathetic outflow or the cardiovascular consequences of repetitive BP surges during sleep could be implicated in this association.
IMPACT OF AGING ON NEURAL CIRCULATORY RESPONSE TO NORMAL SLEEP Aging leads to profound morphologic and functional alterations in the cardiovascular system and its autonomic control.50 Among these changes, basal central sympathetic drive appears enhanced (increase in resting plasma catecholamine, MSNA and LF components of RR variability) but the HR responsiveness to sympathetic stimuli is attenuated, at least in part because of a loss of cardiac receptor sensitivity to catecholamines. The increased central sympathetic drive in older subjects is reflected during sleep by a reduction of RR variability and relatively lower parasympathetic influences, which appear linked to the loss of slow-wave sleep.51 The cardiac response to EEG arousals and PLMS is also modified by age. Specifically, the HR increments are attenuated and bradycardia is less profound in older as compared to younger subjects.52,53 The attenuated tachycardia can be part of the general age-related attenuation in the
CHAPTER 20 • Cardiovascular Physiology: Autonomic Control in Health and in Sleep Disorders 233
EEG LL RL EKG
A
BP
EEG = Electroencephalogram LL = Left leg electromyogram RL = Right leg electromyogram EKG = Electrocardiogram BP = Beat-to-beat blood pressure
B Figure 20-4 EKG, beat-to-beat blood pressure and polysomnographic recording in a compact window (A), and wider temporal window (B) in a subject with restless leg syndrome. Significant HR and BP increases accompany periodic leg movements. Reprinted (modified) from Pennestri MH, Montplaisir J, Colombo R, et al. Nocturnal blood pressure changes in patients with restless legs syndrome. Neurology 2007;68:1213-1218.
cardiac response to sympathetic stimuli, whereas impairment in baroreflex mechanisms, encountered in older individuals, could be a factor implicated in the blunted bradycardia.
EFFECTS OF DISORDERED SLEEP AND PRIMARY AUTONOMIC DYSFUNCTION ON DAY–NIGHT AUTONOMIC CHANGES Effects of Sleep Loss and Sleep Disorders on Nighttime BP As mentioned previously, HR and BP physiologically decrease during nighttime as compared to daytime, a reduction commonly referred to as “dipping.” The persistence of high nighttime systolic BP and lack of systolic BP dipping are clinically important and have been linked to precursors of atherosclerosis, including inflammation and endothelial dysfunction.54 Lack of systolic dipping,55 and more recently, also lack of HR dipping,56 have been associated with increased cardiovascular mortality, after correction of several confounding variables, including daytime values. Sleep loss and sleep disturbances have been invoked as some of the potential factors underlying these abnormalities. Controlled studies show that during partial sleep deprivation/restriction (allowing 4 hours sleep) nighttime BP and catecholamine levels remain high while nighttime nocturnal wakefulness is maintained, and then decrease normally in association with subsequent sleep.57,58 In the same studies, the morning surge in BP and catecholamine appear more pronounced after sleep deprivation than in control conditions, particularly in hypertensive subjects.57,58 A study in male workers showed that, relative to a normal working day allowing 8 hours of sleep, working overtime and sleeping 4 hours induced higher daytime BP on the
following day, accompanied by higher LF components of heart rate variability and increased urinary excretion of norepinephrine.59 Hence, it appears that sleep loss: 1) is associated with persistence of high sympathetic activity and attenuates physiological nocturnal BP dipping, as long as nocturnal wakefulness is maintained; 2) may enhance sympathetic activation during morning awakening; and 3) induces sustained sympathetic activation with increased BP during the following day. In different cohorts of normotensive and hypertensive subjects without sleep disorders, absence of BP dipping was associated with indices of poor and fragmented sleep, including longer wake-time after sleep onset and higher arousal frequency.60,61 An attenuation of nocturnal SBP dipping has also been noted in normotensive subjects with primary insomnia.61a In these subjects, however, higher night-time SBP and blunted dipping occurred in the absence of conventionally defined criteria of poor sleep, but instead was associated with increased EEG activity in the beta frequencies, a common feature in insomniacs,61b which stems from a hyperactivation of the central nervous system during their sleep. Increased nighttime BP has been reported in subjects with moderate to severe obstructive sleep apnea,62 with the degree of BP alteration being proportional to the severity of sleep apnea. Loss of Diurnal Variation in Autonomic Function in Diabetes Mellitus: What Comes First? Cardiovascular autonomic neuropathy is a serious complication of diabetes mellitus, and results from damage of autonomic fibers involved in HR and BP control, in the presence of impaired glucose metabolism.63 In subjects with insulin-independent diabetes (or type 2 diabetes) the 24-hour periodicity of HR and RR variability is lost, with attenuated sympathetic mechanisms in the
234 PART I / Section 4 • Physiology in Sleep
daytime and blunted parasympathetic function during the night.64 In subjects with different degrees of glucose abnormalities without overt diabetes, RR variability and its spectral components appear similar to controls in the daytime, but are significantly altered during sleep, with strikingly higher normalized LF and lower HF, proportional to the degree of insulin resistance.65 Insulin resistance (a state where there is a reduced biologic effect of insulin) and sympathetic overactivity are known to be linked and possibly potentiate each other, with insulin increasing sympathetic activity and neuroadrenergic mechanisms acting to increase plasma glucose availability and to reduce peripheral insulin sensitivity. These data suggest that a primary alteration in the autonomic nervous system may occur during sleep in these subjects before overt diabetes is evident and is linked to the level of insulin resistance. However, one study also observed that selectively altered nighttime autonomic function was also present in nondiabetic offspring of type 2 diabetic parents, whether or not they had insulin resistance,66 suggesting that nighttime impaired parasympathetic mechanisms, likely of genetic origin, may precede metabolic abnormalities. Type 2 diabetes is a complex disease that derives from the interaction of environmental factors on a background of a genetic susceptibility. Chronic sleep debt, either due to sleep restriction or sleep apnea, has been shown to be one factor that can alter glucose handling67 and increases the likelihood of developing type 2 diabetes.68 Little is known about the relationship and interactions between these sleep disturbances and early autonomic dysfunction in subjects with differing severities of glucose abnormalities and their healthy offspring.
SYMPATHETIC ACTIVATION IN OBSTRUCTIVE SLEEP APNEA The sympathetic nervous system appears to play a key role in the cardiac pathophysiology of sleep apnea (see also Chapter 119 in this volume). Even when patients with obstructive sleep apnea are awake and breathing normally and in the absence of any overt cardiovascular disease such as hypertension or heart failure, they have evidence for impaired sympathetic cardiovascular regulation. Specifically, they have high levels of muscle sympathetic nerve activity, increased catecholamines, faster heart rates, and attenuated heart rate variability.69 Furthermore, even though they are normotensive, they have excessive blood pressure variability.70 During sleep, because of activation of the peripheral and central chemoreflexes by hypoxia and hypercapnia, sympathetic activity increases even further. In the setting of apnea, the inhibitory effect of the thoracic afferents is absent, thus resulting in further potentiation of sympathetic activation. The consequent vasoconstriction results in surges in blood pressure as noted earlier. Sympathetic activity abruptly ceases at onset of breathing due to the inhibitory effect of the thoracic afferents (Fig. 20-5).71 This may explain how chronic intermittent hypoxia in normals causes hypertension.72 In a minority of patients with obstructive sleep apnea, the diving reflex, noted earlier, is activated. Therefore these patients may have marked bradyarrhythmias in association with the obstructive apnea even though they do not have any intrinsic conduction system abnormality.4 The bradycardia is secondary to cardiac vagal activation due to the combination of hypoxia and apnea.
EOG EEG
EMG EKG SNA RESP OSA
OSA
OSA
BP (mm Hg)
200 100 0 20 sec Figure 20-5 Sympathetic nerve activity (SNA) and blood pressure (BP) recordings in association with obstructive sleep apnea (OSA). SNA increases progressively during the apnea because the activation of the peripheral and central chemoreflexes by hypoxia and hypercapnia. The consequent vasoconstriction results in marked surges in BP, which reaches the peak during the hyperventilation. SNA abruptly ceases at onset of breathing due to the inhibitory effect of the thoracic afferents. The arrows indicate increases in muscle tone (i.e., EMG) toward the end of the apneaic phases in relation to arousals from REM sleep. Reprinted from Somers et al.71 with permission of the publisher.
CHAPTER 20 • Cardiovascular Physiology: Autonomic Control in Health and in Sleep Disorders 235
SUMMARY The autonomic nervous system is intimately linked to central neural state changes. This is especially true for physiologic sleep and sleep disorders. It is clear that although the different stages of physiologic sleep result in structured changes in neural circulatory control, disturbed sleep, such as is seen in patients with obstructive sleep apnea, with PLMS, or in sleep deprivation, acts to disrupt the sleep-related physiologic variations in autonomic regulation of heart rate and blood pressure. Our knowledge of this general area is limited by the tools available for comprehensive and direct assessment of the autonomic nervous system in humans. Although microneurography provides a direct measurement of sympathetic neural activity to the peripheral blood vessels, this measurement itself has limitations. The other options available are primarily those that monitor blood and urine levels of catecholamines. Measurements such as heart rate and blood pressure variability, while providing some insight, provide only indirect information on autonomic cardiovascular control, and are limited due to problems with regard to acquisition of data, confounding effects of medications and abnormal breathing patterns, and inconsistencies with regard to interpretation. Rigorous methods in line with the standard recommendations9 are mandatory. Therefore, although this chapter seeks to address some of the current knowledge in the area of neural circulatory control during normal and disordered sleep, the available data are limited in part because of methodological shortcomings and also because of the obvious difficulties inherent in nighttime studies of sleep physiology in humans. ❖ Clinical Pearl The autonomic nervous system is the mediator of central–cardiovascular interactions occurring during sleep and its normal function appears to be important in preserving health. Despite the recognized methodological limitations (technically demanding and cautious interpretation of outcome of interest as described in Table 20-1), broadening sleep polygraphic monitoring to include heart rate and blood pressure recordings may contribute to a better understanding of the physiology and pathology of sleeprelated cardiovascular autonomic modulation. These considerations suggest an important potential avenue for innovation in the management of medical disorders that may, in part, be sleep related (e.g., hypertension, diabetes, periodic limb movement, sleep disordered breathing).
REFERENCES 1. Sleight P, Ekberg DL. Human baroreflexes in health and disease. Oxford: Clarendon; 1992. 2. Somers VK, Mark AL, Abboud FM. Sympathetic activation by hypoxia and hypercapnia—implications for sleep apnea. Clin Exp Hypertens A 1988;10(Suppl. 1):413-422. 3. Daly MD, Angell-James JE, Elsner R. Role of carotid-body chemoreceptors and their reflex interactions in bradycardia and cardiac arrest. Lancet 1979;1:764-767. 4. Somers VK, Dyken ME, Mark AL, et al. Parasympathetic hyperresponsiveness and bradyarrhythmias during apnoea in hypertension. Clin Auton Res 1992;2:171-176.
5. Lombardi F, Parati G. An update on: cardiovascular and respiratory changes during sleep in normal and hypertensive subjects. Cardiovasc Res 2000;45:200-211. 6. Mancia G. Autonomic modulation of the cardiovascular system during sleep. N Engl J Med 1993;328:347-349. 7. Millar-Craig MW, Bishop CN, Raftery EB. Circadian variation of blood-pressure. Lancet 1978;1:795-797. 8. van de Borne P, Nguyen H, Biston P, et al. Effects of wake and sleep stages on the 24-h autonomic control of blood pressure and heart rate in recumbent men. Am J Physiol 1994;266:H548-H554. 9. Heart rate variability: standards of measurement, physiological interpretation and clinical use. Task Force of the European Society of Cardiology and the North American Society of Pacing and Electrophysiology. Circulation 1996;93:1043-1065. 10. Bernardi L, Salvucci F, Suardi R, et al. Evidence for an intrinsic mechanism regulating heart rate variability in the transplanted and the intact heart during submaximal dynamic exercise? Cardiovasc Res 1990;24:969-981. 11. Montano N, Porta A, Malliani A. Evidence for central organization of cardiovascular rhythms. Ann N Y Acad Sci 2001;940:299-306. 12. Pagani M, Lombardi F, Guzzetti S, et al. Power spectral analysis of heart rate and arterial pressure variabilities as a marker of sympathovagal interaction in man and conscious dog. Circ Res 1986;59: 178-193. 13. Sleight P, La Rovere MT, Mortara A, et al. Physiology and pathophysiology of heart rate and blood pressure variability in humans: is power spectral analysis largely an index of baroreflex gain? Clin Sci Lond 1995;88:103-109. 14. Malliani A, Pagani M, Lombardi F, et al. Cardiovascular neural regulation explored in the frequency domain. Circulation 1991;84: 482-492. 15. Akselrod S, Gordon D, Ubel FA, et al. Power spectrum analysis of heart rate fluctuation: a quantitative probe of beat-to-beat cardiovascular control. Science 1981;213:220-222. 16. Parati G, Saul JP, Di Rienzo M, et al. Spectral analysis of blood pressure and heart rate variability in evaluating cardiovascular regulation. A critical appraisal. Hypertension 1995;25:1276-1286. 17. Cerutti S, Bianchi AM, Mainardi LT. Advanced spectral methods for detecting dynamic behaviour. Auton Neurosci 2001;90:3-12. 18. Blasi A, Jo J, Valladares E, et al. Cardiovascular variability after arousal from sleep: time-varying spectral analysis. J Appl Physiol 2003;95:1394-1404. 19. Guggisberg AG, Hess CW, Mathis J. The significance of the sympathetic nervous system in the pathophysiology of periodic leg movements in sleep. Sleep 2007;30:755-766. 20. Lombardi F. Chaos theory, heart rate variability, and arrhythmic mortality. Circulation 2000;101:8-10. 21. Togo F, Yamamoto Y. Decreased fractal component of human heart rate variability during non-REM sleep. Am J Physiol Heart Circ Physiol 2001;280:H17-H21. 22. Persson PB, DiRienzo M, Castiglioni P, et al. Time versus frequency domain techniques for assessing baroreflex sensitivity. J Hypertens 2001;19:1699-1705. 23. Burgess HJ, Trinder J, Kim Y, et al. Sleep and circadian influences on cardiac autonomic nervous system activity. Am J Physiol 1997;273:H1761-H1768. 24. Burgess HJ, Trinder J, Kim Y. Cardiac autonomic nervous system activity during presleep wakefulness and stage 2 NREM sleep. J Sleep Res 1999;8:113-122. 25. Somers VK, Dyken ME, Mark AL, et al. Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med 1993;328: 303-307. 26. Pillar G, Bar A, Shlitner A, et al. Autonomic arousal index: an automated detection based on peripheral arterial tonometry. Sleep 2002;25:543-549. 27. O’Brien LM, Gozal D. Potential usefulness of noninvasive autonomic monitoring in recognition of arousals in normal healthy children. J Clin Sleep Med 2007;3:41-47. 28. Pittman SD, MacDonald MM, Fogel RB, et al. Assessment of automated scoring of polysomnographic recordings in a population with suspected sleep-disordered breathing. Sleep 2004;27:1394-1403. 29. Foo JY, Lim CS. Pulse transit time as an indirect marker for variations in cardiovascular related reactivity. Technol Health Care 2006;14:97-108. 30. Foo JY. Pulse transit time in paediatric respiratory sleep studies. Med Eng Phys 2007;29:17-25.
236 PART I / Section 4 • Physiology in Sleep 31. Dodt C, Breckling U, Derad I, et al. Plasma epinephrine and norepinephrine concentrations of healthy humans associated with nighttime sleep and morning arousal. Hypertension 1997;30:71-76. 32. Kario K, Schwartz JE, Pickering TG. Ambulatory physical activity as a determinant of diurnal blood pressure variation. Hypertension 1999;34:685-691. 33. Linsell CR, Lightman SL, Mullen PE, et al. Circadian rhythms of epinephrine and norepinephrine in man. J Clin Endocrinol Metab 1985;60:1210-1215. 34. Kerkhof GA, Van Dongen HP, Bobbert AC. Absence of endogenous circadian rhythmicity in blood pressure? Am J Hypertens 1998; 11:373-377. 35. Somers VK, Dyken ME, Mark AL, et al. Sympathetic-nerve activity during sleep in normal subjects. N Engl J Med 1993;328:303-307. 36. Bonnet MH, Arand DL. Heart rate variability: sleep stage, time of night, and arousal influences. Electroencephalogr Clin Neurophysiol 1997;102:390-396. 37. Legramante JM, Marciani MG, Placidi F, et al. Sleep-related changes in baroreflex sensitivity and cardiovascular autonomic modulation. J Hypertens 2003;21:1555-1561. 38. Guilleminault C, Pool P, Motta J, et al. Sinus arrest during REM sleep in young adults. N Engl J Med 1984;311:1006-1010. 39. Brandenberger G, Ehrhart J, Piquard F, et al. Inverse coupling between ultradian oscillations in delta wave activity and heart rate variability during sleep. Clin Neurophysiol 2001;112:992-996. 40. Jurysta F, van de Borne P, Migeotte PF, et al. A study of the dynamic interactions between sleep EEG and heart rate variability in healthy young men. Clin Neurophysiol 2003;114:2146-2155. 41. Davies RJ, Belt PJ, Roberts SJ, et al. Arterial blood pressure responses to graded transient arousal from sleep in normal humans. J Appl Physiol 1993;74:1123-1130. 42. Morgan BJ, Crabtree DC, Puleo DS, et al. Neurocirculatory consequences of abrupt change in sleep state in humans. J Appl Physiol 1996;80:1627-1636. 43. Sforza E, Jouny C, Ibanez V. Cardiac activation during arousal in humans: further evidence for hierarchy in the arousal response. Clin Neurophysiol 2000;111:1611-1619. 44. Javaheri S. Sleep disorders in systolic heart failure: a prospective study of 100 male patients. The final report. Int J Cardiol 2006; 106:21-28. 45. Pennestri MH, Whittom S, Adam B, et al. PLMS and PLMW in healthy subjects as a function of age: prevalence and interval distribution. Sleep 2006;29:1183-1187. 46. Sforza E, Nicolas A, Lavigne G, et al. EEG and cardiac activation during periodic leg movements in sleep: support for a hierarchy of arousal responses. Neurology 1999;52:786-791. 47. Pennestri MH, Montplaisir J, Colombo R, et al. Nocturnal blood pressure changes in patients with restless legs syndrome. Neurology 2007;68:1213-1218. 48. Ferrillo F, Beelke M, Canovaro P, et al. Changes in cerebral and autonomic activity heralding periodic limb movements in sleep. Sleep Med 2004;5:407-412. 49. Yumino D, Wang H, Floras JF, et al. Association between periodic limb movements in sleep and increased mortality risk in patients with heart failure. Circulation 2008;118:796. 50. Lakatta EG. Cardiovascular regulatory mechanisms in advanced age. Physiol Rev 1993;73:413-467. 51. Crasset V, Mezzetti S, Antoine M, et al. Effects of aging and cardiac denervation on heart rate variability during sleep. Circulation 2001;103:84-88. 52. Goff EA, O’Driscoll DM, Simonds AK, et al. The cardiovascular response to arousal from sleep decreases with age in healthy adults. Sleep 2008;31:1009-1017.
53. Gosselin N, Lanfranchi P, Michaud M, et al. Age and gender effects on heart rate activation associated with periodic leg movements in patients with restless legs syndrome. Clin Neurophysiol 2003; 114:2188-2195. 54. von Kanel R, Jain S, Mills PJ, et al. Relation of nocturnal blood pressure dipping to cellular adhesion, inflammation and hemostasis. J Hypertens 2004;22:2087-2093. 55. Fagard RH, Celis H, Thijs L, et al. Daytime and nighttime blood pressure as predictors of death and cause-specific cardiovascular events in hypertension. Hypertension 2008;51:55-61. 56. Ben-Dov IZ, Kark JD, Ben-Ishay D, et al. Blunted heart rate dip during sleep and all-cause mortality. Arch Intern Med 2007;167: 2116-2121. 57. Lusardi P, Mugellini A, Preti P, et al. Effects of a restricted sleep regimen on ambulatory blood pressure monitoring in normotensive subjects. Am J Hypertens 1996;9:503-505. 58. Lusardi P, Zoppi A, Preti P, et al. Effects of insufficient sleep on blood pressure in hypertensive patients: a 24-h study. Am J Hypertens 1999;12:63-68. 59. Tochikubo O, Ikeda A, Miyajima E, et al. Effects of insufficient sleep on blood pressure monitored by a new multibiomedical recorder. Hypertension 1996;27:1318-1324. 60. Loredo JS, Nelesen R, Ancoli-Israel S, Dimsdale JE. Sleep quality and blood pressure dipping in normal adults. Sleep 2004;27: 1097-1103. 61. Pedulla M, Silvestri R, Lasco A, et al. Sleep structure in essential hypertensive patients: differences between dippers and non-dippers. Blood Press 1995;4:232-237. 61a. Lanfranchi PA, Pennestri MH, Fradette L, et al. Nighttime blood pressure in normotensive subjects with chronic insomnia: implications for cardiovascular risk. Sleep 2009;32:760-766. 61b. Perlis ML, Merica H, Smith MT, et al. EEG activity and insomnia. Sleep Med Rev 2001;5:363-374. 62. Pankow W, Nabe B, Lies A, et al. Influence of sleep apnea on 24-hour blood pressure. Chest 1997;112:1253-1258. 63. Vinik AI, Ziegler D. Diabetic cardiovascular autonomic neuropathy. Circulation 2007;115:387-397. 64. Bernardi L, Ricordi L, Lazzari P, et al. Impaired circadian modulation of sympathovagal activity in diabetes. A possible explanation for altered temporal onset of cardiovascular disease. Circulation 1992; 86:1443-1452. 65. Perciaccante A, Fiorentini A, Paris A, et al. Circadian rhythm of the autonomic nervous system in insulin resistant subjects with normoglycemia, impaired fasting glycemia, impaired glucose tolerance, type 2 diabetes mellitus. BMC Cardiovasc Disord 2006;6:19. 66. Fiorentini A, Perciaccante A, Paris A, et al. Circadian rhythm of autonomic activity in non diabetic offsprings of type 2 diabetic patients. Cardiovasc Diabetol 2005;4:15. 67. Spiegel K, Leproult R, Van CE. Impact of sleep debt on metabolic and endocrine function. Lancet 1999;354:1435-1439. 68. Zizi F, Jean-Louis G, Brown CD, et al. Sleep duration and the risk of diabetes mellitus: epidemiologic evidence and pathophysiologic insights. Curr Diab Rep 2010;10(1):43-47. 69. Narkiewicz K, Somers VK. Sympathetic nerve activity in obstructive sleep apnoea. Acta Physiol Scand 2003;177:385-390. 70. Narkiewicz K, Somers VK. Cardiovascular variability characteristics in obstructive sleep apnea. Auton Neurosci 2001;90:89-94. 71. Somers VK, Dyken ME, Clary MP, et al. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995;96:1897-1904. 72. Gilmartin GS, Lynch M, Tamisier R, Weiss JW. Chronic intermittent hypoxia in humans during 28 nights results in blood pressure elevation and increased muscle sympathetic nerve activity. Am J Physiol Heart Circ Physiol 2010 Jun 25. (Epub ahead of print)
Respiratory Physiology: Central Neural Control of Respiratory Neurons and Motoneurons during Sleep Richard L. Horner Abstract Any anatomical or physiological abnormality that compromises the respiratory system in wakefulness can predispose a person to significant breathing disorders during sleep. Such abnormalities include an anatomically small upper airspace that increases the reliance on the pharyngeal muscles to maintain adequate airflow and to prevent obstructive sleep apnea. Patients with restrictive lung diseases or neuromuscular weakness rely, to varying degrees, on the activation of nondiaphragmatic respiratory muscles to help maintain adequate ventilation in wakefulness, but this compensation can be reduced or absent in sleep, leading to severe hypoventilation. These and other examples highlight that sleep is a state of vulnerability for the respiratory system, and that loss of a “wakefulness stimulus” that is sufficient to sustain adequate breathing in wakefulness is central to the pathogenesis of a variety of respiratory disorders during sleep. This simple concept has been an enduring principle in respiratory medicine because, ultimately, it is the root mechanism to under-
RESPIRATORY NEUROBIOLOGY: BASIC OVERVIEW Medullary Respiratory Neurons and Motoneurons There are bilateral columns of neurons in the medulla with activity patterns that vary in phase with some component of the respiratory cycle. The dorsal respiratory group (DRG) is located in the dorsomedial medulla, specifically in the ventrolateral nucleus of the solitary tract, and contains predominantly inspiratory neurons (Fig. 21-1).1,2 The DRG and the other subnuclei of the solitary tract are also the primary projection sites for vagal afferents from the lung, and afferents from the carotid and aortic chemoreceptors and baroreceptors, that exert important reflex influences on breathing. These projections indicate that the nuclei of the solitary tract, including the DRG, are key sites of integration of sensory information from the lung, as well as information regarding the prevailing levels of arterial Pco2, Po2, pH, and systemic blood pressure. The ventral respiratory group (VRG) extends from the facial nucleus to the first cervical segment of the spinal cord and contains both inspiratory and expiratory neurons (see Fig. 21-1).1,2 The nucleus ambiguus also consists of a rostrally to caudally extending column neurons expressing respiratory-related activity, with subregions regions containing motoneurons that innervate the muscles of the larynx and pharynx that are not considered part of the VRG.3 In addition to the nucleus ambiguus, rostrally to caudally the VRG is comprised of Bötzinger complex (expiratory) neurons, pre-Bötzinger complex (inspiratory) neurons, rostral retroambigualis
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stand sleep effects on breathing. To this end there have been significant recent developments in identifying the neurochemical substrates underlying this wakefulness stimulus, central to which is an understanding of the neurobiology of sleep, its impact on central respiratory neurons and motoneurons, and the important role of tonic excitatory (nonrespiratory) drives in contributing to the overall level of excitability in the respiratory system. Moreover, like the realization that sleep onset is not simply the passive withdrawal of wakefulness, breathing during sleep is not simply due to the passive withdrawal of the “wakefulness stimulus.” For example, non–rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep are fundamentally different neurobiological states, which have distinct effects on the control of respiratory neurons and motoneurons. Accordingly, NREM and REM sleep pose different problems to breathing during sleep in different individuals with different pathologies, and understanding these mechanisms is necessary for physiological understanding of the spectrum of sleep-related breathing disorders and their appropriate clinical management.
(predominantly inspiratory) neurons and caudal retroambigualis (predominantly expiratory) neurons (see Fig. 21-1).1,2 The VRG and DRG contain both bulbospinal respiratory premotoneurons (i.e., neurons that project to spinal motoneurons, which in turn innervate the respective respiratory pump and abdominal muscles of breathing), and propriobulbar neurons (i.e., neurons that project to, and influence the activity of, other medullary respiratory neurons but themselves do not project to motoneurons) (see Fig. 21-1).1,2 The hypoglossal, trigeminal, and facial motor nuclei also innervate muscles important to pharyngeal motor control and the maintenance of upper airway patency (see Fig. 21-1).4 It is important to stress, however, that the expression of respiratory-related activity is not restricted to neurons of the DRG, VRG, and cranial motoneurons innervating the pharyngeal and laryngeal muscles. For example, neurons expressing respiratoryrelated activity in the pons (i.e., the pontine respiratory group; PRG in Fig. 21-1) are thought to play an important role in shaping the activity of medullary respiratory neurons during breathing.3 Pre-Bötzinger Complex Pre-Bötzinger complex neurons have pacemaker-like properties that are thought important to the generation of the basic respiratory rhythm and the expression of rhythmic neuronal activity elsewhere in the respiratory network (see Fig. 21-1).5,6 Respiratory rhythm-generating preBötzinger complex neurons coexpress mu-opioid and neurokinin-1 receptors (i.e., the receptors for Substance P) that slow and increase respiratory rate respectively.6 The presence of mu-opioid receptors on pre-Bötzinger complex 237
238 PART I / Section 4 • Physiology in Sleep Tensor palatini
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Figure 21-1 Ventral view of the brainstem (cerebellum removed) showing the main aggregates of respiratory neurons in the dorsal respiratory group (DRG) and ventral respiratory group (VRG). In the latter, the location of the expiratory (E) and inspiratory (I) neurons in the Bötzinger complex (BC), preBötzinger complex (PBC), rostral retroambigualis (R-RA), and caudal retroambigualis (C-RA) are shown. The location of cervical inspiratory neurons (CIN) and respiratory-related neurons in the lateral reticular formation (RF) projecting to the hypoglossal motor nucleus (XII) are also shown. The projections of inspiratory and expiratory neurons are depicted as solid and dashed lines, respectively, while excitatory and inhibitory synaptic connections are depicted by arrowhead and square symbols, respectively. Inspiratory and expiratory motor pools in the spinal cord are depicted by closed and open circles, respectively. The electromyographic activities of various inspiratoryrelated (e.g., tongue, diaphragm, and external intercostal) and expiratory (e.g., internal intercostal and abdominal) muscles are shown. Note that the level of respiratory-related and tonic activities varies for different muscles, with some muscles such as the tensor palatini expressing mainly tonic activity. The onset of muscle activity with respect to the diaphragm is shown by the dashed line. The rootlets of cranial nerves V, VII, IX, X, XI, XII, and the cervical (C) and thoracic (T) segments of the spinal cord are also shown, as are the motor nuclei of cranial nerves XII, VII and V. The locations of the pontine respiratory group (PRG) and the nucleus ambiguus (NA) are shown, although their projections are not included for clarity.
neurons may explain a component of the clinically important phenomenon of respiratory rate depression with opioid drugs.7 The development of uncoordinated (ataxic) diaphragm breathing after lesions of neurokinin-1 expressing pre-Bötzinger complex neurons in animal studies, with this abnormal breathing first appearing in sleep,8 suggest
that pre-Bötzinger complex neurons may contribute to normal breathing in vivo. Loss of pre-Bötzinger complex neurons, for example, with aging, may predispose a person to abnormal breathing and central apneas in sleep.6 Neuronal Connections The anatomical connections between the neurons that comprise the essential respiratory network (i.e., respiratory propriobulbar, premotoneurons, and motoneurons), and the membrane properties of these cells, are ultimately responsible for the two key components of overall respiratory activity, that is, the generation of respiratory rhythm and the shaping of the central respiratory drive potentials that activate respiratory motoneurons (pattern generation). An analysis of the mechanisms involved in the generation of the basic respiratory rhythm is outside the scope of this chapter, and the interested reader is referred to excellent summaries of the concepts underlying pacemaker models (where respiratory rhythm is intrinsic to some cells, and these cells then drive others in the respiratory network), network models (where respiratory rhythm is dependent upon the inhibitory and excitatory synaptic connections between neurons, and the tonic excitation derived from both the respiratory chemoreceptors and the reticular formation), and hybrid models.1,3,6 With respect to the tonic drive to the respiratory system arising from the respiratory chemoreceptors, this would include both the peripheral and central chemoreceptors, the latter including neurons at the ventral medullary surface such as the retrotrapezoid nucleus, as well as inputs from CO2-activated sleep state–dependent neurons of the aminergic arousal system (e.g., serotonin and noradrenergic neurons, see the following section of this chapter).9 There are further aspects of the organization of the central respiratory network that are particularly relevant to understanding the effects of sleep on respiratory neurons and motoneurons and these concepts are discussed briefly later. During inspiration the central respiratory drive potential is transmitted to phrenic and intercostal motoneurons via monosynaptic connections from inspiratory premotor neurons of the DRG and VRG (see Fig. 21-1).1 Bötzinger complex expiratory neurons have widespread inhibitory connections throughout the brainstem and spinal cord, and these neurons inhibit inspiratory premotoneurons and motoneurons during expiration (see Fig. 21-1). Caudal retroambigualis neurons also increase the excitability of spinal expiratory motoneurons in expiration (see Fig. 21-1), although this excitation does not necessarily reach the threshold to manifest as expiratory muscle activity. Of physiological and clinical relevance, these fundamental aspects of the neural control of spinal respiratory motoneuron activity appear to be different than the mechanisms controlling the activity of pharyngeal motoneurons. For example, animal studies show that the source of inspiratory drive to hypoglossal motoneurons is different from the source of drive to phrenic motoneurons, being predominantly from the reticular formation lateral to the hypoglossal motor nucleus (lateral tegmental field) for the former, and from bulbospinal VRG and DRG neurons for the latter (see Fig. 21-1).1 Importantly, the reticular
CHAPTER 21 • Respiratory Physiology: Central Neural Control of Respiratory Neurons and Motoneurons during Sleep 239
formation provides a significant source of tonic drive to the respiratory system, with this drive being particularly affected in sleep.3 Further differences in the functional control of pharyngeal and diaphragm muscles is shown by the observation that, unlike phrenic motoneurons, hypoglossal motoneurons are not actively inhibited in expiration.1 Accordingly, the activity of the genioglossus muscle in expiration is simply a manifestation of the prevailing tonic inputs. The practical implication of this circuitry is that the overall activation of hypoglossal motoneurons during breathing is comprised of an inspiratory drive adding to a continuous tonic drive that persists in expiration when the inspiratory activation is withdrawn. Moreover, this tonic drive to the pharyngeal muscles, which contributes to baseline airway size and stiffness, is most prominent in wakefulness but withdrawn in sleep, so leading to an upper airspace that is more vulnerable to collapse. A more detailed analysis of the neural mechanisms controlling the activity of respiratory neurons and motoneurons follows a brief overview of the brain mechanisms modulating the states of wakeful-
ness, non–rapid eye movement (NREM) sleep and REM sleep.
SLEEP NEUROBIOLOGY: BASIC OVERVIEW Although a more detailed discussion of arousal and sleep state regulation is provided in Section 2 of this volume, some details are particularly pertinent to the control of respiratory neurons and motoneurons in sleep. Accordingly, a brief overview of the neurobiology of sleep and wakefulness-generating systems is presented hereafter. Wakefulness Figure 21-2 shows some of the main neuronal groups contributing to the ascending arousal system from the brainstem that promotes wakefulness. This ascending arousal system includes the cholinergic laterodorsal and pedunculopontine tegmental nuclei that promote cortical activation via excitatory thalamocortical projections.10 The ascending arousal system also incorporates the aminergic
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Tongue Diaphragm External intercostal Internal intercostal Abdominal Figure 21-2 Saggital section of the brain showing the main wake and sleep-generating neural systems. In wakefulness, acetylcholine (ACh); orexin (OX); histamine (His); dopamine (DA); 5-hydroxytryptamine (5-HT); and noradrenaline (NA) containing neurons contribute to brain arousal (arrowheads). This ascending arousal system is inhibited in sleep by gamma-aminobutyric acid (GABA)containing neurons from ventrolateral preoptic (VLPO) neurons (inhibitory projections shown by dashed lines). By their anatomical projections to the pons, medulla and spinal cord, these wake- and sleep-promoting neuronal systems are also positioned to influence respiratory neurons and motoneurons (see Fig. 21-1). However, whether the influences of the different arousal-related neurons is excitatory or inhibitory will depend on the receptor subtypes activated (this uncertainty is shown by solid squares). Overall, these changes in neuronal activities across sleep–wake states, and their impact on respiratory neurons and motoneurons, mediate the stereotypical changes in the tonic and respiratory components of activity for different respiratory muscles, and their different susceptibilities to motor suppression in sleep. RF depicts the reticular formation. (Adapted from Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437:1257-1263.)
240 PART I / Section 4 • Physiology in Sleep
arousal system that originates from brainstem neuronal groups principally containing serotonin (dorsal raphé nuclei), noradrenaline (locus coeruleus), histamine (tuberomammillary nucleus), and dopamine (ventral periaqueductal grey). Orexin neurons from the perifornical region of the hypothalamus and cholinergic neurons from the basal forebrain also contribute to this ascending arousal system.10 Overall, multiple neuronal systems contribute to cortical arousal and wakefulness. These neuronal systems are also positioned to influence respiratory neurons and motoneurons via their anatomical projections to the pons, medulla, and spinal cord (see Fig. 21-2). NREM Sleep Sleep is actively generated by neurons in the ventrolateral preoptic area, anterior hypothalamus, and basal forebrain (see Fig. 21-2).10 These neurons become active in NREM sleep, an effect influenced by the thermal stimulus that accompanies the circadian-mediated decline in body temperature at normal bedtime.11 This circadian-mediated decline in body temperature is mediated by a change in the set-point of hypothalamic temperature-regulating neurons, which initially leads to a relative “warm stimulus” as body temperature is at first higher than the new set-point, that is, before heat loss occurs. This warm stimulus activates NREM sleep-active hypothalamic neurons and so promotes sleep onset. This effect of internal body temperature on sleep is distinct from the influences of ambient environmental temperature on sleep regulation. Activation of ventrolateral preoptic neurons leads to a direct suppression of cortical arousal, this via ascending inhibitory cortical projections. Ventrolateral preoptic neurons also promote sleep by descending inhibition of the aforementioned brainstem arousal neurons via release of gamma-aminobutyric acid (GABA) and galanin.11,12 This effect of GABA explains the sedative-hypnotic effects of barbiturates, benzodiazepines, and imidazopyridine compounds that enhance GABA-mediated neuronal inhibition via interactions with binding sites on the GABAA receptor.13 GABAA receptors are also strongly implicated in respiratory control and are present throughout the respiratory network,14 excessive stimulation of which can promote respiratory depression.15 In summary, sleep onset is triggered by increased GABAergic neuronal activity, and this is accompanied by a massed and coordinated withdrawal of activity of brainstem arousal neurons comprising serotonergic, noradrenergic, histaminergic and cholinergic neurons. Given the widespread projections of these sleep state–dependent neuronal groups, these changes in neuronal activity in sleep are also positioned to influence respiratory neurons and motoneurons (see Fig. 21-2).16 REM Sleep Decreased serotonergic and noradrenergic activity preceding and during REM sleep withdraws inhibition of the laterodorsal and pedunculopontine tegmental nuclei.10,12 This effect leads to increased acetylcholine release into the pontine reticular formation to trigger REM sleep.17,18 Exogenous application of cholinergic agonists or acetylcholinesterase inhibitors (to increase endogenous acetylcholine) into the pontine reticular for-
mation is used to mimic this process experimentally in animal studies, that is, the “carbachol model of REM sleep.”17,18 A significant component of the motor suppression of REM sleep is mediated by descending pathways involving activation of medullary reticular formation relay neurons19 that are inhibitory to spinal motoneurons via release of glycine.20 Despite the strong experimental support for the interaction of pontine monoaminergic and cholinergic neurons as being primarily responsible for the initiation and maintenance of REM sleep, recent evidence has implicated a glutamatergic-GABAergic mechanism.21,22 One of the key differences between the aminergic-cholinergic and the glutamatergic-GABAergic hypotheses of REM sleep generation is that the motor atonia is produced by different pathways, that is, the latter framework does not require a relay in the medullary reticular formation.22 Rather, in the glutamatergic-GABAergic mechanism of REM sleep induction, the REM sleep-active pontine neurons are thought to lead to suppression of spinal motoneuron activity via long glutamatergic projections to the ventral horn of the spinal cord, which then activate local glycinergic interneurons to inhibit motor activity.22 Such a mechanism is likely involved in the strong inhibition of spinal intercostal motoneurons in REM sleep, but whether collaterals from these specific long descending glutamatergic projections also synapse onto glycinergic inhibitory interneurons in the hypoglossal motor pool is not established.16 In summary, a number of neural systems show changes in activity across sleep–wake states and project to respiratory neurons and motoneurons. Given that motoneurons are the final common output pathway for the influence of the central nervous system on motor activity, this chapter will initially focus on the control of respiratory motoneurons across sleep–wake states before addressing the control of the central respiratory neurons that ultimately drive breathing via those motoneurons.
CONTROL OF RESPIRATORY MOTONEURONS A characteristic and defining feature of mammalian motor activity is that postural muscle tone is highest in wakefulness, decreased in NREM sleep, and minimal in REM sleep, with the hypotonia of REM sleep punctuated by occasional muscle twitches that are associated with vigorous eye movements and phasic REM sleep events.20 Whether respiratory muscle activity is affected in the same way as postural muscle activity across sleep–wake states is somewhat complicated by the interaction of the primary influence of sleep state (e.g., producing suppression of muscle tone) and any subsequent respiratory response (e.g., to compensate for any hypoventilation). On balance, however, the overall stereotyped pattern of suppression of postural muscle activity across sleep–wake states also typically occurs in respiratory muscles, with the degree of sleep state–dependent modulation being most readily apparent in those muscles that combine respiratory and nonrespiratory (e.g., postural and behavioral) functions such as the intercostal and pharyngeal muscles.23 In these respiratory muscles, decreases in activity typically occur immediately
CHAPTER 21 • Respiratory Physiology: Central Neural Control of Respiratory Neurons and Motoneurons during Sleep 241
at sleep onset23 indicating a primary suppressant effect of sleep neural mechanisms on the activity of respiratory motoneurons, that is, before any compensatory increase in activity takes place in response to altered blood gases, mechanical loads, or sleep-disordered breathing. In contrast to those respiratory muscles with both respiratory and nonrespiratory functions, the diaphragm has an almost sole respiratory function and undergoes lesser suppression of activity in NREM sleep and is largely spared the motor inhibition of REM sleep (see Fig. 21-2).24 Chapters 22 and 23 provide more detail regarding clinical aspects of the control of breathing and upper airway function during sleep, whereas in this chapter the fundamental mechanisms underlying these effects of sleep on the respiratory system are presented.
Tonic
DETERMINANTS OF RESPIRATORY MOTONEURON ACTIVITY Tonic and Respiratory-Related Inputs to Respiratory Motoneurons The changes in muscle tone across sleep–wake states ultimately result from the impact of sleep neural mechanisms on the electrical properties and membrane potential of individual motoneurons located in the respective motor pools in the central nervous system. In turn, the excitability of individual motoneurons changes across sleep–wake states because of varying degrees of excitatory and inhibitory inputs to those motoneurons from sleep–wake related regions in the brain, and from neurons activated during specific behaviors such as purposeful motor acts in
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Presynaptic modulation Sum of inputs at motoneuron
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Respiratory-related Tonic Electromyographic activity
Muscle
Electromyographic activity
A
Respiratory drive potentials
B
} Respiratory
Tonic membrane potential
C
} Respiratory
} Tonic
Apnea
Threshold for neural activity D
E
} Respiratory
} “Respiratory”
Figure 21-3 Schema to show how converging tonic (e.g., postural, nonrespiratory) and respiratory inputs to a motoneuron summate to produce the tonic and respiratory components of electromyographic activity. These premotor tonic and respiratory inputs can be excitatory or inhibitory, but in this figure they are shown as excitatory for simplicity. Panels A to E further show how changes in the tonic and respiratory components of respiratory muscle activity can result from independent changes in either tonic drives affecting tonic membrane potential (A, B, C, and E, e.g., as may occur upon transitions from wakefulness to NREM and REM sleep), or the magnitude of the respiratory drive potential (B vs. D, e.g., as may occur in NREM and REM sleep compared to wakefulness). Changes in respiratory drive potential at the motoneuron can result from decreases in the input from respiratory neurons, presynaptic modulation of that input and/or changes in input resistance of the motoneuron membrane (see text for further details). In the examples shown in A to E, respiratory drive is indicated as three depolarizing potentials, each associated with the generation of motoneuron action potentials when the membrane potential exceeds threshold (dashed line). Panel E also shows that timevarying alterations in membrane potential, e.g., as occurs in REM sleep, can produce respiratory muscle activation unrelated to the prevailing respiratory input (see E, lower red line). Therefore, from peripheral measurements of diaphragm activity or airflow there appears to be five “breaths,” although there are only three respiratory drive potentials generated by the central respiratory oscillator.
242 PART I / Section 4 • Physiology in Sleep
wakefulness.16 At each individual motoneuron, therefore, the relative strengths and balance between time-varying excitatory and inhibitory inputs ultimately determines net motor output, with neural activity being generated when the membrane potential rises above threshold for the production of action potentials (Fig. 21-3). In addition to the excitatory and inhibitory nonrespiratory inputs to a motoneuron that alter membrane potential across sleep–wake states, a respiratory motoneuron also receives additional inputs (excitatory and inhibitory) that alter membrane excitability and neural activity in phase with the inspiratory or expiratory phases of the respiratory cycle. Simply put, a respiratory motoneuron resembles a postural motoneuron in its control except that it receives an additional rhythmic drive related to respiration, that is, the central respiratory drive potential. Figure 21-3 highlights that the electromyographic activity recorded in a given respiratory muscle is critically dependent on the overall sum of the respiratory and nonrespiratory (i.e., tonic) inputs to the motoneurons innervating that muscle. Appreciating the importance of both the tonic- and respiratory-related inputs to a motoneuron in determining overall motor output is critical to any interpretation of the changes in respiratory muscle activity observed across sleep–wake states. Indeed, periods of hypoventilation, apparent central apnea, and even the sporadic respiratory muscle activations that occur during REM sleep can all result from independent effects of sleep neural processes on the tonic and respiratory-related inputs to a respiratory motoneuron (see Fig. 21-3A to E). For example, the apparent absence of activity recorded in a respiratory muscle cannot be taken as evidence that the controlling circuitry is inactive, that is, an apparent apnea may not be truly due to a “central” cessation of respiratory drive. Indeed, a simple withdrawal of tonic drive in sleep may be sufficient to take a population of motoneurons close to, or below, the threshold for the generation of motor activity, such that any excitatory respiratory inputs to the motoneurons are subthreshold for the generation of action potentials, and so are not revealed as respiratory muscle activity (see Fig. 21-3C). In summary, nonrespiratory tonic drives exert important influences on the resting membrane potential of respiratory motoneurons, and so significantly modulate the excitability of motoneurons in response to the incoming central respiratory drive potential. This significant effect of nonrespiratory tonic drives on the activity of respiratory motoneurons has clear physiological relevance because when identified experimentally, the tonic drive to respiratory motoneurons is typically reduced from wakefulness to NREM sleep, and this will importantly contribute to sleep-related reductions in respiratory muscle activity and consequent hypoventilation (see Fig. 21-3A to B).25,26 Tonic drive to respiratory motoneurons can also be further reduced in REM sleep, although time-varying fluctuations in this tonic drive can produce transient increases or decreases in respiratory muscle activity and contribute to changes in lung ventilation in REM sleep by a mechanism independent of effects on the respiratory-related inputs (see Fig. 21-3E). Indeed, the presence of endogenous excitatory inputs to respiratory motoneurons in REM sleep (i.e., unrelated to breathing and akin to the mecha-
nisms producing phasic muscle twitches in limb muscles), can produce sporadic activation of respiratory muscle and contribute to the expression of rapid and irregular breathing in REM sleep (see Fig. 21-3E), even in the presence of low CO2 levels that are otherwise sufficient to produce central apnea in NREM sleep.25,26 Electrical Properties of Motoneurons The electrical properties of the motoneuron membrane also significantly affect the responses of that motoneuron to a given synaptic input. For example, reduced motoneuron responses to an incoming respiratory drive potential could be due to the aforementioned effects of reduced tonic drives and consequent membrane hyperpolarization (see Fig. 21-3), but also due to the electrical resistance of the motoneuron membrane itself. The input resistance of a membrane is defined as its voltage response to a given synaptic current, with a decrease in input resistance resulting in less membrane depolarization for a given synaptic drive, that is, a decrease in cell excitability (see Fig. 21-3). This electrical property of excitable membranes has clear physiological relevance because there is a large (~44%) decrease in input resistance of motoneurons in REM sleep compared to NREM sleep and wakefulness.20 In addition, there are transient fluctuations in input resistance that occur throughout REM sleep episodes, such as the decreased input resistance of somatic motoneurons that occurs in temporal association with the phasic events of REM sleep. Such an effect likely contributes to the periods of marked suppression of inspiratory upper airway muscle activity in humans during phasic REM sleep compared to tonic REM sleep.27 In summary, an increase in motoneuron input resistance in REM sleep, especially in association with eye movements, can contribute to decreased motor outflow to the pharyngeal and respiratory pump muscles, and so to periods of increased upper airway resistance and hypoventilation. Moreover, such decreases in respiratory motoneuron activity can occur despite the persistence of a continuing, and even heightened, activity of the central respiratory neurons that innervate those motoneurons in REM sleep (Fig. 21-4, and see later section, Control of Respiratory Neurons).3,26 This observation highlights that a powerful inhibition or disfacilitation (i.e., withdrawal of excitation) must be taking place at respiratory motoneurons to explain the periods of reduced motor output despite continuing, and even heightened, inputs from respiratory neurons in REM sleep (see Fig. 21-4).3,28 Presynaptic Modulation The control of respiratory motoneuron activity by changes in sleep state–dependent neuromodulators or inputs from respiratory neurons often emphasizes the postsynaptic effects of released neurotransmitters (discussed previously). However, such postsynaptic effects do not fully account for the control of motoneuron activity as presynaptic modulation of the prevailing inputs is also important in motor control (see Fig. 21-3). For example, inhibitory inputs arriving at a nerve terminal prior to the subsequent arrival of a descending excitatory drive can lead to marked reductions in the release of excitatory neurotransmitters, so leading to the suppression of moto-
CHAPTER 21 • Respiratory Physiology: Central Neural Control of Respiratory Neurons and Motoneurons during Sleep 243
Phasic REM sleep neurons Variable inhibition and/or disfacilitation in REM sleep
Heightened respiratory neuronal activity in REM sleep
Respiratory motoneuron
Hypopnea Respiratory muscle Hyperpnea Figure 21-4 Schema, modified from Orem, 1980, to show how respiratory motoneurons receive competing excitatory (arrowheads) and inhibitory (squares) drives in REM sleep, the balance of which leads to time-varying increases and decreases in respiratory rate and amplitude that manifests as hyperpnea and hypopnea. Additional factors that contribute to this variable lung ventilation in REM sleep are the similar competing excitatory and inhibitory influences at (1) pharyngeal motoneurons in REM sleep that lead to time-varying alterations in upper airway size and resistance, and (2) chest wall and abdominal muscles20 that modulate resting lung volume and compliance of the chest wall. (Modified from Orem J. Neuronal mechanisms of respiration in REM sleep. Sleep 1980;3:251-267.)
neuron activity. Such presynaptic modulation of neuronal activity is thought to be significant for information processing in neurons innervated by several converging pathways, as is the case for the organization of respiratory motoneurons (see Fig. 21-3). Accordingly, under specific behaviors some inputs can be selectively suppressed while others are left unaffected. This presynaptic modulation of specific inputs allows for selective control of motoneuron excitability, an effect that could not be achieved by a generalized postsynaptic modulation that affects the whole cell. This differential control has particular relevance to the control of motoneurons with dual respiratory and nonrespiratory functions, for example, hypoglossal motoneurons innervating the genioglossus muscle of the tongue. In hypoglossal motoneurons the presynaptic inhibition of the incoming central respiratory drive potentials allows for the switching of motor output appropriate for other behaviors such as swallowing, sucking, or speech without the interference of respiration.29 Tonic and Respiratory-Related Activity in Respiratory Muscle Some respiratory muscles exhibit more respiratory-related activity than others, whereas other muscles are more tonically active and exhibit little respiratory-related activity (see Figs. 21-1 and 21-2). For example, the genioglossus muscle of the tongue shows both tonic and respiratoryrelated activity, with the decreased activity of this muscle during sleep being strongly linked to the pathogenesis of obstructive sleep apnea.30 Similarly, the different intercostal muscles show varying degrees of respiratory-related and
tonic activities related to both the respiratory and postural functions of these muscles, with the expression of this respiratory-related versus tonic activity varying with anatomical location in the chest wall and ongoing behaviors.24,31 Suppression of intercostal muscle activity in REM sleep is thought to increase the compliance of the chest wall and contribute to decreased functional residual capacity, effects that can contribute to hypoventilation especially in infants because of the already highly compliant chest wall.24 In contrast to these muscles with respiratory-related activity, the tensor palatini muscle of the soft palate displays mostly tonic activity, with this tonic activity being progressively decreased from wakefulness to NREM and REM sleep. The tonic activity in the tensor palatini is thought to enhance stiffness in the segment of the upper airway at the level of the soft palate, a consistent site of airway closure in obstructive sleep apnea.4 Accordingly, decreases in tonic tensor palatini muscle activity from wakefulness to sleep (see Fig. 21-2) contribute to increased upper airway resistance and the predisposition to airway occlusion in sleep, with this effect of sleep predominantly affecting breathing by an effect on the tonic (nonrespiratory) inputs to these motoneurons that receive little or no respiratory input at rest. Ultimately, whether some muscles exhibit respiratory-related activity at rest depends on both the “strength” of the input from respiratory neurons compared to the tonic drives (see Fig. 21-5 and later section, Control of Respiratory Neurons),3 and also the degree of suppression of the respiratory activity by vagal afferents related to lung volume.4
NEUROMODULATION OF RESPIRATORY MOTONEURONS ACROSS SLEEP–WAKE STATES Studies addressing the neurochemical basis for the modulation of respiratory motor activity across natural sleep– wake states, in vivo, have largely been confined to the hypoglossal and trigeminal motor nuclei.16,17,20,32 This focus on pharyngeal motoneurons is clinically relevant to understanding the pathogenesis of obstructive sleep apnea, with airway obstructions occurring behind the tongue both at the level of the soft palate and below.4 In contrast to this focus on pharyngeal motoneurons, there is a lack of similar studies investigating the control of intercostal and phrenic motoneurons in naturally sleeping animals. Nevertheless, studies of spinal motoneurons have provided important information regarding the control of postural motoneurons across sleep–wake states.20 Given that intercostal motoneurons perform both postural and respiratory functions, the mechanisms identified at primary postural motoneurons likely have close similarities to the mechanisms controlling the nonrespiratory (postural) component of intercostal motor activity. A focus on the control of motoneurons innervating the muscles of the respiratory pump is also relevant to this chapter because significant hypoventilation can occur in sleep, especially REM sleep, in patients with restrictive lung diseases (e.g., kyphoscoliosis and obesity hypoventilation) and neuromuscular weakness (e.g., postpolio, muscular dystrophy, amyotrophic lateral sclerosis and partial diaphragm paralysis).33 The following sections summarize the major findings from animal studies
244 PART I / Section 4 • Physiology in Sleep Discharge of respiratory neuron Airflow (inspiration ↓) η2 = 0.90
η2 = 0.75
η2 = 0.54
η2 = 0.44
η2 = 0.15 1 sec Nonrespiratory Input
Figure 21-5 Five different medullary respiratory neurons recorded in intact cats in NREM sleep. These neurons vary in the strength of their relationship to breathing, an effect that is quantified by the η2 statistic with values ranging from 0 (weak relationship) to 1.0 (strong relationship). High η2 cells are considered to be more strongly influenced by respiratory inputs than nonrespiratory inputs, and vice versa for low η2 cells. (Modified from Orem J, Kubin L. Respiratory physiology: central neural control. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 3nd ed. Philadelphia: Saunders; 2000. pp. 205-220.)
Respiratory Input
Nonrespiratory Input
Respiratory Input
Respiratory Neuron
High η2 activity
addressing the sleep state–dependent modulation of respiratory motor activity. These data derive, in large part, from studies at the hypoglossal motor nucleus, a model motor pool with dual respiratory and nonrespiratory functions.16 Excitatory Influences across Sleep–Wake States The concept of a tonic drive activating respiratory muscle in wakefulness but not in sleep (i.e., the wakefulness stimulus for breathing) has been an important and enduring notion in respiratory medicine,3,24 not least because it is useful in modeling sleep effects on breathing and understanding the pathogenesis of sleep-related breathing disorders. Neurons of the aminergic arousal system provide an important source of tonic drive to the respiratory system (see Fig. 21-2).3,16,17 Serotonin and noradrenaline-containing neurons have been of particular attention experimentally because these neurons send excitatory projections to respiratory motoneurons, and these neurons show their highest activity in wakefulness, reduced activity in NREM
Low η2 activity
sleep and minimal activity in REM sleep, that is, a pattern that may contribute to reduced respiratory muscle activity in sleep via withdrawal of excitation.3,16,17 Animal studies show that an endogenous noradrenergic drive to the hypoglossal motor nucleus contributes to both the respiratory and tonic components of genioglossus muscle activation in wakefulness, and the residual expression of respiratory-related activity that persists in NREM sleep as the tonic drive is withdrawn.34 Moreover, this noradrenergic contribution to genioglossus muscle tone was minimal in REM sleep, so explaining, at least in part, the periods of genioglossus muscle hypotonia during REM sleep.34,35 The identification of an endogenous excitatory noradrenergic drive that contributes to genioglossus muscle activation in wakefulness, but with this drive being withdrawn in sleep, is particularly significant because since the first clinical description of obstructive sleep apnea, this was the first identification of a neural drive contributing to the sleep state–dependent activity of a muscle that is central to this disorder. The location of the central noradrenergic neurons that may provide this drive to hypo-
CHAPTER 21 • Respiratory Physiology: Central Neural Control of Respiratory Neurons and Motoneurons during Sleep 245
glossal and other respiratory motoneurons is reviewed elsewhere.16 Given the widespread projections of brainstem aminergic neurons, they are also positioned to provide an endogenous input to other respiratory neurons and motoneurons, and so influence respiratory pump muscle activity and ventilation across sleep–wake states.36,37 Recent data also implicate a role for endogenous glutamatergic inputs in the tonic excitatory drive that increases pharyngeal muscle activity in wakefulness, the withdrawal of which contributes to reduced activity in sleep.16,38,39 In contrast to these functionally active tonic inputs, endogenous levels of serotonin at the hypoglossal motor nucleus contribute less to the changes in genioglossus muscle activity in sleeping animals.16 It remains to be determined if this minimal influence of endogenous serotonin on genioglossus muscle activity also applies to humans. If so, it may explain (at least in part) the lack of clinically significant effects on pharyngeal muscle activity and obstructive sleep apnea severity with administration of selective serotonin reuptake inhibitors in humans.16,40,41 Local application of serotonergic, noradrenergic and glutamatergic agonists to the hypoglossal or trigeminal motor nuclei produces robust motor activation in wakefulness and NREM sleep.16,39 These observations provide “proof of principle” to the notion that it may be possible to develop pharmacological strategies to increase respiratory muscle activity in sleep, for example, as a potential treatment for obstructive sleep apnea. Importantly, however, a major component of the motor activation observed in response to these agonists in NREM sleep is overcome in REM sleep.16,39 There is an important practical implication of this differential modulation of pharyngeal motor responses to otherwise potent excitatory neuromodulators between NREM and REM sleep. For example, even if it is possible to effectively target pharyngeal motoneurons with directed pharmacological manipulations, (e.g., as a potential treatment for obstructive sleep apnea) then different strategies may be required to produce sustained pharyngeal muscle activation throughout both the NREM and REM sleep stages, as the neurobiology of motor control is fundamentally different between these two states.16 Inhibitory Influences across Sleep–Wake States Glycine and GABA are the main inhibitory neurotransmitters in the central nervous system. Glycine and GABAA receptor stimulation at the hypoglossal motor nucleus in vivo produces the expected depression of genioglossus muscle activity, whereas antagonism of these receptors increases genioglossus activity across all sleep–wake states.16 The augmentation of respiratory-related motor activity with application of antagonists for these inhibitory neurotransmitters fits with the notion of a tonic inhibitory tone that constrains the rhythmic activation of respiratory neurons and motoneurons via gain modulation.42 The inhibitory effects of GABA at respiratory neurons14 and motoneurons16 is also clinically relevant given the widespread use of sedative hypnotic drugs in modern society. For example, benzodiazepine and imidazopyridine drugs are commonly prescribed as sedative hypnotics (e.g., lorazepam and zolpidem, respectively),
and both these classes of sedatives promote sleep by enhancing GABA-mediated neuronal inhibition via interactions with binding sites on GABAA receptors.13 However, the presence of lorazepam and zolpidem at the hypoglossal motor nucleus also leads to inhibition of genioglossus muscle activity.16 This inhibitory effect of sedative hypnotics at respiratory motor nuclei may underlie a component of the respiratory depression observed clinically with excessive GABAA receptor stimulation, and the predisposition of some individuals to obstructive sleep apnea with sedative hypnotics.15 Large inhibitory glycinergic potentials appear to play an important role in the inhibition of spinal motoneuron activity in REM sleep,20 and this likely explains the inhibition of intercostal respiratory muscle activity in this sleep state.24 However, glycine and GABAA receptor antagonism at the hypoglossal and trigeminal motoneuron pools fails to reverse the profound tonic suppression of genioglossus or masseter muscle activity in REM sleep, although in both cases this antagonism increases the amount or magnitude of the phasic motor activations observed during REM sleep.16,32 Nevertheless, these increases in motor activity during REM sleep with glycine and GABAA receptor antagonism does implicate a functional role for inhibitory neurotransmission in the control hypoglossal and trigeminal motor activity in REM sleep,16 although this may not be as profound as the inhibition demonstrated at spinal motoneurons.20 The degree of suppression observed in a variety of respiratory pump muscles in REM sleep appears strongly correlated with the muscle spindle density of these different muscles.31 The diaphragm has few, if any, spindles and little inhibition in REM sleep, whereas different intercostal muscles (especially the external inspiratory intercostals) have significant numbers of muscle spindles and profound suppression of activity in REM sleep, with the degree of suppression varying with muscle spindle density.24,31 Of clinical relevance, acute diaphragm paralysis leads to increased reliance on the intercostal and accessory muscle to maintain effective lung ventilation, but this compensation is lost in REM sleep as the motoneurons innervating these muscles with dual respiratory and postural functions are inhibited.43 Interestingly, however, patients with chronic bilateral diaphragm paralysis are able to recruit nondiaphragmatic inspiratory muscle activity during REM sleep, and so lessen any attendant hypoventilation. This compensation suggests that the central nervous system of these patients is able to functionally reorganize the drives controlling the accessory respiratory muscles such that activity is less suppressed by REM sleep mechanisms in the long term.44,45 In summary, current information from sleeping animals indicate that reduced excitation, largely via withdrawal of endogenous noradrenergic and glutamatergic inputs, is principally responsible for reductions in pharyngeal muscle tone from wakefulness to NREM and REM sleep.16,17,39 In comparison, an endogenous serotonergic drive plays a lesser role.16 Increased inhibitory neurotransmission via glycine and GABA also contributes to suppression of pharyngeal motor activity in REM sleep, but the contribution of this mechanism appears much less than expected16,17,39 from studies at spinal motoneurons.46
246 PART I / Section 4 • Physiology in Sleep
CONTROL OF RESPIRATORY NEURONS Respiratory Neurons Vary in the Strength of Their Relationship to Breathing Pioneering studies by Orem and colleagues in sleeping animals led to the fundamental concepts that still best explain the neural basis for sleep effects on breathing, including the nature of the wakefulness stimulus and the rapid, irregular breathing pattern of REM sleep.3 Crucial to these advances was the development of a statistical method to quantify the strength and consistency of the respiratory-related activity of a neuron with respect to its overall discharge. The strength of this relationship was quantified by the “eta-squared statistic” (η2), with η2 values ranging from 0 (i.e., weak relationship) to 1.0 (strong relationship),3 and with different brainstem respiratory neurons varying in the strength of their relationship to the breathing cycle (see Fig. 21-5). The interpretation and physiological meaning of the η2 value for a particular respiratory neuron is best explained in the following quote where cells with high η2 values were considered to be “quintessentially respiratory…., protected from non-respiratory distortions, perhaps because of rigid sequences of excitatory and inhibitory postsynaptic potentials that preclude activity that is not strictly respiratory.”3 In contrast, the activity of “low η2-valued cells is the apparent result of mixtures of inputs that have respiratory and non-respiratory forms.”3 Figure 21-5 further illustrates this concept that the degree of respiratory-related activity of a given respiratory neuron (i.e., its η2 value) depends on the balance of the respiratory and nonrespiratory inputs to that neuron, an important concept given that respiratory neurons with different η2 values are differentially affected by sleep–wake state. Respiratory Neuron Activity in NREM Sleep The concept that the degree of respiratory-related activity exhibited by a particular respiratory neuron depends on the balance of its nonrespiratory and respiratory inputs assumes greater physiological and clinical relevance with the key observation that neurons with high η2 activity (which are presumably tightly coupled to, and controlled by, the respiratory oscillator) are least affected by the transition from wakefulness to NREM sleep, whereas low η2 neurons (which are less influenced by the respiratory oscillator, but strongly influenced by nonrespiratory tonic drives) are most affected by the change from wakefulness to NREM sleep, such that their activity can even cease during sleep (Fig. 21-6).3 Importantly, respiratory neurons with low η2 values that become inactive in sleep are not ceasing their activity because these neurons are losing their respiratory input. Indeed, reexcitation of these silent respiratory neurons during sleep (by iontophoretic application of the excitatory amino acid glutamate) restores their activity, and reveals the ongoing respiratory-related activity that was previously subthreshold.3,47 The major principle here, best articulated by Orem, is that the magnitude of the “effect of sleep on a respiratory neuron is proportional to the amount of non-respiratory activity in the activity of that neuron,” such that the “wakefulness stimulus to breathing is non-respiratory in form and affects some
High η2 unit (small action potentials) Low η2 unit (large action potentials) Awake Airflow (inspiration ↓) Drowsy
NREM
A
1 sec
Awake Airflow (inspiration ↑) NREM
REM
B Figure 21-6 A, The activity of high η2 medullary respiratory neurons is little affected by NREM sleep, whereas the activity of low η2 cells is significantly suppressed in NREM sleep. This differential effect of NREM sleep on these different classes of respiratory neurons is thought to be due to the particular sensitivity of the tonic nonrespiratory inputs to changes in sleepwake state, which is the basis of the “wakefulness stimulus” for breathing. B, Example showing increased and advanced activity of a late inspiratory neuron in REM sleep.
respiratory neurons more than others.”3 This principle, which highlights the importance of tonic drives in the expression of both tonic and respiratory neuronal activities, was also illustrated in Figure 21-3 for respiratory motoneurons where the same fundamental concepts apply. Respiratory Neuron Activity in REM Sleep REM sleep is characterized by overall depression of the ventilatory responses to hypercapnia and hypoxia,24 and also by periods of profound suppression of motor activity in respiratory muscles (e.g., intercostal and pharyngeal)16,17 and nonrespiratory (postural) muscles.20 Transient periods of respiratory rate slowing also occur in REM sleep, that may be mediated by the increased release of acetylcholine into the pontine reticular formation as part of the REM sleep process.18 It would be incorrect, however, to consider REM sleep as a state of overall depression of central respiratory neurons because, as for most cells in the central nervous system, the activity of brainstem respiratory neurons is typically greater in REM sleep than in NREM sleep. For example, late inspiratory neurons have increased and advanced activity in REM sleep, that is, cells that discharge in the latter part of inspiration in NREM
CHAPTER 21 • Respiratory Physiology: Central Neural Control of Respiratory Neurons and Motoneurons during Sleep 247
sleep can be active throughout inspiration in REM sleep (see Fig. 21-6).3 Nevertheless, there is considerable variation around the mean level of discharge of respiratory neurons in REM sleep associated with tonic and phasic events.3 For example, increased ponto-geniculo-occiptal wave activity, a defining feature of phasic REM sleep events, is associated with increased activity of medullary respiratory neurons. This latter observation has been taken to suggest that the activity of respiratory neurons in REM sleep is strongly influenced by processes peculiar to the neurobiology of REM sleep rather than intrinsic to the respiratory network.3 This concept of nonrespiratory inputs having significant influences on the activity of neurons and motoneurons in the respiratory network has similarities to the major influence of tonic drives that were discussed in the context of the wakefulness stimulus to breathing. Together, these concepts serve to highlight that the activity levels of central respiratory neurons and motoneurons is due to the interaction of their respiratory and nonrespiratory inputs, with the latter having major influences on overall respiratory activity and being particularly sensitive to changes in sleep–wake state. As discussed previously for respiratory motoneurons, this fundamental effect of REM sleep in activating central respiratory neurons can lead to periods of increased respiratory rate and respiratory muscle activity unrelated to homeostatic feedback regulation and to prevailing blood gas tensions.3,25,26 This increased activity of central respiratory neurons in REM sleep would most likely produce periods of increased respiratory rate and higher respiratory muscle activity at times when the normally timevarying inhibition of respiratory motoneurons is briefly weakened or withdrawn (see Figs. 21-3 and 21-4). That REM sleep can lead to periods of heightened diaphragm activity unrelated to prevailing blood gas tensions has particular relevance to the clinical observation that hypocapnic central apneas most commonly occur in NREM sleep, but can be absent in REM sleep when breathing is characteristically erratic.48,49 Figure 21-4 illustrates how this balance of excitatory and inhibitory influences at respiratory motoneurons can underlie the highly variable respiratory activity in REM sleep, including periods of respiratory depression despite activation of central respiratory neurons. Neuromodulation of Respiratory Neurons across Sleep–Wake States Unlike the studies performed at respiratory motor pools,16,17 there have been no studies addressing the neurochemicals that may mediate the control of respiratory neurons in vivo as a function of sleep–wake states. Nevertheless, it is a reasonable working hypothesis that the neuronal groups involved in the modulation of respiratory motoneurons across sleep–wake states also likely affect respiratory neurons. Accordingly, influences from brainstem reticular formation neurons (likely glutamatergic) are positioned to provide a source of tonic drive to respiratory neurons, with this influence altering from wakefulness to NREM and REM sleep.3,16,17,39 Neurons of the brainstem reticular formation system generally show decreased activity in NREM sleep compared to wakefulness, with increased activity in
REM sleep,3,19 that is, a pattern similar to the changes in respiratory neuron activity. Electrical stimulation of the midbrain reticular formation can convert the activity of several respiratory muscles or motor nerves from a sleeplike pattern to one more like wakefulness.3 Indeed, it has been postulated that one important source of the tonic (nonrespiratory) input to medullary respiratory neurons when awake (i.e., the wakefulness stimulus) arises from the reticular formation.3 The source(s) of the drive(s) activating central respiratory neurons in REM sleep, however, has not been determined. Neurons of the aminergic arousal system (serotonergic, histaminergic, and noradrenergic), and other sleep state– dependent neuronal groups, are also positioned to provide a source of tonic (nonrespiratory) drive to respiratory neurons across sleep–wake states. However, whether these tonic drives would be excitatory or inhibitory to respiratory neurons depends on the receptor subtypes activated, and the pre- or postsynaptic location of these receptors (see Figs. 21-2 and 21-3 for reference). This lack of knowledge of the sleep state-dependent neuromodulation of respiratory neurons needs to be addressed by further research, which may also identify specific pharmacological approaches that may be appropriate to preserve respiratory neuron activity in sleep and so minimize respiratory depression. The various brain structures that exert behavioral control of the respiratory system should also be considered as a source of the wakefulness stimulus for breathing3 but it is not known if this collection of inputs shares the same neurochemicals as the aforementioned inputs from the reticular formation and sleep state–dependent neuronal systems.
❖ Clinical Pearl The withdrawal of the wakefulness stimulus to breathing at the transition from wakefulness to sleep is the principal mechanism that precipitates the major clinical sleep-related breathing disorders. Current evidence identifies neurons of the aminergic arousal system and reticular formation as providing the key components of this wakefulness stimulus. Withdrawal of this tonic excitatory drive to the muscles of the upper airway is thought to underlie the normal sleeprelated increase in upper airway resistance, and the hypoventilation, flow-limitation, and obstructive sleep apnea observed in susceptible individuals (e.g., those with already anatomically narrow upper airways). Patients with restrictive lung diseases and neuromuscular weakness rely, to varying degrees, on the activation of nondiaphragmatic respiratory muscles to help maintain adequate ventilation in wakefulness, but this compensation can be reduced or absent in sleep, leading to severe hypoventilation as the essential tonic excitatory drive that is present in wakefulness is withdrawn. REM sleep mechanisms can also lead to inhibition of respiratory motoneurons, so explaining the typically worse severity of abnormal breathing events in REM sleep compared to NREM sleep.
248 PART I / Section 4 • Physiology in Sleep
Acknowledgments RLH holds a Tier 1 Canada Research Chair in Sleep and Respiratory Neurobiology. The author’s research is supported by grants from the Canadian Institutes of Health Research and Ontario Thoracic Society. The author also acknowledges development grants from the Canada Foundation for Innovation and the Ontario Research and Development Challenge Fund. REFERENCES 1. Duffin J. Functional organization of respiratory neurones: a brief review of current questions and speculations. Exp Physiol 2004; 89:517-529. 2. Rekling JC, Feldman JL. PreBotzinger complex and pacemaker neurons: hypothesized site and kernel for respiratory rhythm generation. Annu Rev Physiol 1998;60:385-405. 3. Orem J, Kubin L. Respiratory physiology: central neural control. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 3rd ed. Philadelphia: Saunders; 2000. p. 205-220. 4. Horner RL. Motor control of the pharyngeal musculature and implications for the pathogenesis of obstructive sleep apnea. Sleep 1996;19:827-853. 5. Smith JC, Ellenberger HH, Ballanyi K, et al. Pre-Botzinger complex: a brainstem region that may generate respiratory rhythm in mammals. Science 1991;254:726-729. 6. Feldman JL, Del Negro CA. Looking for inspiration: new perspectives on respiratory rhythm. Nat Rev Neurosci 2006;7: 232-241. 7. McCrimmon DR, Alheid GF. On the opiate trail of respiratory depression. Am J Physiol Regul Integr Comp Physiol 2003;285: R1274-R1275. 8. McKay LC, Janczewski WA, Feldman JL. Sleep-disordered breathing after targeted ablation of preBotzinger complex neurons. Nat Neurosci 2005;8:1142-1144. 9. Mitchell GS. Back to the future: carbon dioxide chemoreceptors in the mammalian brain. Nat Neurosci 2004;7:1288-1290. 10. Jones BE. Basic mechanisms of sleep-wake states. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 3rd ed. Philadelphia: Saunders; 2000. p. 134-154. 11. McGinty D, Szymusiak R. The sleep-wake switch: a neuronal alarm clock. Nat Med 2000;6:510-511. 12. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437:1257-1263. 13. Mendelson WB. Hypnotics: basic mechanisms and pharmacology. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 3rd ed. Philadelphia: Saunders; 2000. p. 407-413. 14. McCrimmon DR, Mitchell GS, Dekin MS. Glutamate, GABA, and serotonin in ventilatory control. In: Dempsey JA, Pack AI, editors. Regulation of breathing. New York: Dekker; 1995. p. 151-218. 15. Robinson RW, Zwillich CW. Medications, sleep and breathing. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 3rd ed. Philadelphia: Saunders; 2000. p. 797-812. 16. Horner RL. Neuromodulation of hypoglossal motoneurons during sleep. Respir Physiol Neurobiol 2008;164:179-196. 17. Kubin L, Davies RO, Pack L. Control of upper airway motoneurons during REM sleep. News Physiol Sci 1998;13:637-656. 18. Lydic R, Baghdoyan HA. Sleep, anesthesiology, and the neurobiology of arousal state control. Anesthesiology 2005;103:12681295. 19. Siegel JM. Brainstem mechanisms generating REM sleep. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 3rd ed. Philadelphia: Saunders; 2000. p. 112-133. 20. Chase MH, Morales FR. Control of motoneurons during sleep. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 3rd ed. Philadelphia: Saunders; 2000. p. 155-168.
21. Luppi PH, Gervasoni D, Verret L, et al. Paradoxical (REM) sleep genesis: the switch from an aminergic-cholinergic to a GABAergic-glutamatergic hypothesis. J Physiol Paris 2006;100: 271-283. 22. Fuller PM, Saper CB, Lu J. The pontine REM switch: past and present. J Physiol 2007;584:735-741. 23. Worsnop C, Kay A, Pierce R, et al. Activity of respiratory pump and upper airway muscles during sleep onset. J Appl Physiol 1998;85: 908-920. 24. Phillipson EA, Bowes G. Control of breathing during sleep. In: Cherniack NS, Widdicombe JG, editors. Handbook of physiology, sect 3, the respiratory system, vol II, Control of breathing, part 2. Bethesda, Md: American Physiological Society; 1986. p. 649-689. 25. Horner RL, Kozar LF, Kimoff RJ, et al. Effects of sleep on the tonic drive to respiratory muscle and the threshold for rhythm generation in the dog. J Physiol 1994;474:525-537. 26. Orem J, Lovering AT, Dunin-Barkowski W, et al. Endogenous excitatory drive to the respiratory system in rapid eye movement sleep in cats. J Physiol 2000;527:365-376. 27. Wiegand L, Zwillich CW, Wiegand D, et al. Changes in upper airway muscle activation and ventilation during phasic REM sleep in normal men. J Appl Physiol 1991;71:488-497. 28. Orem J. Central respiratory activity in rapid eye movement sleep: augmenting and late inspiratory cells. Sleep 1994;17:665673. 29. Bellingham MC, Berger AJ. Presynaptic depression of excitatory synaptic inputs to rat hypoglossal motoneurons by muscarinic M2 receptors. J Neurophysiol 1996;76:3758-3770. 30. Remmers JE, deGroot WJ, Sauerland EK, et al. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 1978;44: 931-938. 31. Duron B, Marlot D. Intercostal and diaphragmatic electrical activity during wakefulness and sleep in normal unrestrained adult cats. Sleep 1980;3:269-280. 32. Brooks PL, Peever JH. Glycinergic and GABAA-mediated inhibition of somatic motoneurons does not mediate REM sleep motor atonia. J Neurosci 2008;28:3535-3545. 33. Goldstein RS. Hypoventilation: neuromuscular and chest wall disorders. Clin Chest Med 1992;13:507-521. 34. Chan E, Steenland HW, Liu H, et al. Endogenous excitatory drive modulating respiratory muscle activity across sleep-wake states. Am J Respir Crit Care Med 2006;174:1264-1273. 35. Fenik VB, Davies RO, Kubin L. REM sleep-like atonia of hypoglossal (XII) motoneurons is caused by loss of noradrenergic and serotonergic inputs. Am J Respir Crit Care Med 2005;172:13221330. 36. Fenik V, Marchenko V, Janssen P, et al. A5 cells are silenced when REM sleep-like signs are elicited by pontine carbachol. J Appl Physiol 2002;93:1448-1456. 37. Li A, Nattie E. Catecholamine neurones in rats modulate sleep, breathing, central chemoreception and breathing variability. J Physiol 2006;570:385-396. 38. Steenland HW, Liu H, Horner RL. Endogenous glutamatergic control of rhythmically active mammalian respiratory motoneurons in vivo. J Neurosci 2008;28:6826-6835. 39. Burgess C, Lai D, Siegel J, et al. An endogenous glutamatergic drive onto somatic motoneurons contributes to the stereotypical pattern of muscle tone across the sleep-wake cycle. J Neurosci 2008:28: 4649-4660. 40. Smith IE, Quinnell TG. Pharmacotherapies for obstructive sleep apnoea: where are we now? Drugs 2004;64:1385-1399. 41. Veasey SC. Pharmacotherapies for obstructive sleep apnea: how close are we? Curr Opin Pulm Med 2001;7:399-403. 42. Zuperku EJ, McCrimmon DR. Gain modulation of respiratory neurons. Respir Physiol Neurobiol 2002;131:121-133. 43. Stradling JR, Kozar LF, Dark J, et al. Effect of acute diaphragm paralysis on ventilation in awake and sleeping dogs. Am Rev Respir Dis 1987;136:633-637. 44. Bennett JR, Dunroy HM, Corfield DR, et al. Respiratory muscle activity during REM sleep in patients with diaphragm paralysis. Neurol 2004;62:134-137. 45. Arnulf I, Similowski T, Salachas F, et al. Sleep disorders and diaphragmatic function in patients with amyotrophic lateral sclerosis. Am J Respir Crit Care Med 2000;161:849-856.
CHAPTER 21 • Respiratory Physiology: Central Neural Control of Respiratory Neurons and Motoneurons during Sleep 249
46. Chase MH, Morales FR. The control of motoneurons during sleep. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 2nd ed. Philadelphia: Saunders; 1994. p. 163-175. 47. Foutz AS, Boudinot E, Morin-Surun MP, et al. Excitability of “silent” respiratory neurons during sleep-waking states: an iontophoretic study in undrugged chronic cats. Brain Res 1987;404:10-20.
48. Yumino D, Bradley TD. Central sleep apnea and Cheyne-Stokes respiration. Pro Am Thorac Soc 2008;5:226-236. 49. Xi L, Smith CA, Saupe KW, et al. Effects of rapid-eye-movement sleep on the apneic threshold in dogs. J Appl Physiol 1993;75: 1129-1139. 50. Orem J. Neuronal mechanisms of respiration in REM sleep. Sleep 1980;3:251-267.
Respiratory Physiology: Understanding the Control of Ventilation Neil J. Douglas Abstract During sleep, the relative regularity of breathing in resting wakefulness is replaced by marked respiratory variability due to changes in the drive to both the respiratory pump muscles and the upper airway dilating muscles. Breathing during wakefulness is controlled by several factors including voluntary and behavioral elements; chemical factors, including low oxygen levels; high carbon dioxide (CO2) levels and acidosis; and mechanical signals from the lung and chest wall (see Chapter 21 for more information). During sleep, there is loss of voluntary control and a decrease in the usual ventilatory responses to both low oxygen (hypoxemic) and high carbon dioxide (hypercapnic) levels. Both the hypoxemic and hypercapnic responses are most depressed in rapid eye movement (REM) sleep.
INTRODUCTION Many respiratory problems during sleep are related to sleep-induced changes in the control of ventilation. Much is known about the control of breathing during wakefulness, but less about how breathing is controlled in sleeping normal subjects or in patients with sleep disorders. The major goal of the respiratory control system is homeostasis, to keep blood gases tensions in a tight range to allow the body to maintain normal metabolic functions. Unlike the heart, the respiratory muscles do not have a built-in pacemaker. These muscles receive impulses from a region in the medulla that has been called the respiratory center, respiratory oscillator, respiratory signal generator, and respiratory pacemaker. For breathing to change as physiological conditions change, the respiratory center receives and responds to three general types of information: chemical information (from chemoreceptors responding to Pao2, Paco2, and pH), mechanical information (from receptors in the lung and chest wall), and behavioral information (from higher cortical centers) to allow breathing to be altered during speech, swallowing, and other activities. The aspects of awake control that may have impact on control of breathing during sleep are reviewed later. Chemical Information The carotid body senses Pao2 (arterial concentration of O2) which sends impulses to the medulla via the ninth cranial nerve. Ventilation usually increases only when Pao2 is less than 60 mm Hg. When Pao2 drops acutely below 30 to 40 mm Hg, the medulla (see Chapter 21 for more information of the brainstem network associated to the control of breathing) may be depressed by the hypoxemia; thus, ventilation may decrease. Carbon dioxide is sensed in both the carotid body and a region of the medulla called the central chemoreceptor. As Paco2 (arterial concentration of CO2) increases, there is a brisk linear increase in ventilation. Drugs that depress central nervous system 250
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These blunted ventilatory responses during sleep are clinically important. They permit the marked hypoxemia that occurs during REM sleep in patients with lung or chest wall disease and may also be important in the pathogenesis of upper airway obstruction during sleep. Sleep alters both breathing pattern and respiratory responses to many external stimuli. These changes allow the development of sleep-related hypoxemia in patients with respiratory disease and may contribute to the pathogenesis of apneas in patients with the sleep apnea syndrome. This chapter reviews the control of ventilation in adults during sleep and its relevance to these clinical problems (see Section 13 of this volume).
function (e.g., some benzodiazepines, opioids) may profoundly depress chemical drives to breathe in normal altitude (see Chapter 24 for the paradoxical effects of benzodiazepines on respiration during sleep in high altitude). Mechanical Information In the presence of lung diseases or changes in the load of the respiratory system, receptors in the lung and chest wall send impulses to the medulla. Those in the lung are the best understood: The receptors respond to irritation, inflation (stretch), deflation, and congestion of blood vessels. The information from these sensors travels centrally via the vagus nerve. The major result of stimulating these sensors is to shorten inspiration and reduce tidal volume to cause a rapid, shallow breathing pattern. Information from Higher Central Nervous System Centers The respiratory system is used for many nonbreathing functions (e.g., singing, laughing, crying, and speaking) that are directed by higher brain centers. The efferent pathways involved in these activities may actually bypass the respiratory center in the medulla; thus, these nonrespiratory activities can override the metabolic homeostatic function of the respiratory control system. It appears that just as abnormal chemistry may increase the drive to breathe, there is a respiratory drive linked to wakefulness. As one sleeps, arouses, and dreams, there may be dramatic changes in the information from higher central nervous system (CNS) centers.
PHYSIOLOGY OF VENTILATORY CONTROL DURING SLEEP This chapter largely focuses on the effects of sleep on the various mechanisms controlling breathing in adult humans.
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Hypoxic Ventilatory Response during Sleep Adult Human Beings The ventilatory response to hypoxia falls during sleep in healthy adults (Fig. 22-1).1-4 The hypoxic ventilatory response was lower during non–rapid eye movement (NREM) sleep than during wakefulness in the studies in which the subjects were exclusively or mostly men1,2 but the responses were similar in wakefulness and NREM sleep in the studies in which women predominated.3-5 It is not clear why there is such a difference between the genders in the effect of sleep on the hypoxic ventilatory response and whether hormonal factors might be important. Comparison of the results in men and women (Fig. 22-2) shows that the major gender difference is in the levels of ventilatory response during wakefulness, which is much higher in men than in women,4 whereas the responses in NREM sleep were not different between the genders. During NREM sleep both the ventilatory responses to
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hypocapnic hypoxia and the posthypoxic ventilatory decline were similar between the genders.6 It was also found that the posthypoxic ventilatory decline in NREM sleep was not associated with a decline in respiratory frequency nor with any change in airway mechanics.7 The hypoxic ventilatory response during rapid eye movement (REM) sleep is lower than in NREM sleep in both men and women.1-4 The hypoxic ventilatory response during REM sleep was remarkably similar in all three directly comparable studies:1,2,4 about 0.4 L/min/percentage Sao2 (see Fig. 22-2). Adult Animals The isocapnic hypoxic ventilatory response has been found to be unchanged8 or decreased9 during sleep in dogs with tracheostomies and decreased during sleep in goats.10 Hypercapnic Ventilatory Response during Sleep Adult Human Beings The hypercapnic ventilatory response is depressed during sleep in adult human beings (Fig. 22-3). Studies performed in either electroencephalogram-documented11-14 or presumed15-17 NREM sleep showed that the slope of the ventilation-CO2 response line falls during NREM sleep, compared with wakefulness. Two large studies12,13 suggested that the decrease in response from wakefulness to NREM sleep is approximately 50%. Although Bülow12 reported lower responses in stages 3 and 4 sleep than in stage 2 sleep, later researchers13,18 found no such difference. In fact, Bülow did not apply statistics, and his data indicate considerable overlap (see Figs. 21, 26, and 27 in reference 12). Indeed, no separation is evident until high
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Figure 22-3 Mean relationship between expired ventilation and increasing end-tidal PCO2 in 12 subjects, 6 male and 6 female, indicating the mean + SE resting ventilation-CO2 setpoint during wakefulness. (From Douglas NJ. Control of ventilation during sleep. Clin Chest Med 1985;6:563. [Redrawn from Douglas NJ, White DP, Weil JV, et al. Hypercapnic ventilatory response in sleeping adults. Am Rev Respir Dis 1982;126: 758-762.])
252 PART I / Section 4 • Physiology in Sleep
CO2 levels are reached when the number of data points is small. NREM sleep does not significantly change the position of the ventilation-CO2 response line, as assessed by the rebreathing technique with extrapolation of the CO2 response line to the intercept at zero ventilation.13,18 However, as the slope of the response line decreases during NREM sleep, the CO2 increment between the awake resting ventilatory set-point and the ventilatory response line is increased significantly during NREM sleep (see Fig. 22-3).12,13 Berthon-Jones and Sullivan18 found that healthy women did not change the hypercapnic ventilatory response from wakefulness to NREM sleep, a result consistent with the finding by Davis and colleagues19 of higher ventilatory responses during sleep in women than in men. In contrast, neither Douglas and colleagues13 nor Gothe and colleagues20 identified any difference between the genders in any stage. Three groups have measured the hypercapnic ventilatory response during REM sleep in adults. Douglas and colleagues13 found that in 10 of 12 subjects, the hypercapnic response was lowest in REM sleep, compared with either wakefulness or NREM sleep. The mean hypercapnic ventilatory response during REM sleep was 28% of the level during wakefulness (see Fig. 22-3). These authors were unable to accurately define the position of the hypercapnic ventilatory response line because some responses during REM sleep had negative slopes. Berthon-Jones and Sullivan18 and White21 found a tendency for the lowest responses to occur during REM sleep. Adult Animals As in adult human beings, the hypercapnic ventilatory response is lower in NREM sleep than in wakefulness in dogs22,23 and cats,24 with a further drop in response from NREM to REM sleep.22-25 Sullivan and colleagues23 found that the hypercapnic ventilatory response was lower in phasic than in tonic REM sleep in dogs. Ventilatory Response to Chemical Stimuli: Conclusions In summary, there appear to be genuine gender and species differences in the effect of sleep on the hypoxic ventilatory response. Although there are no major species differences in the effect of sleep on the hypercapnic ventilatory response, there may be gender differences. In human adults without disordered breathing, both ventilatory responses are reduced during sleep and are at their lowest during REM sleep.
ADDED RESISTANCE AND AIRWAY OCCLUSION DURING SLEEP Adult Human Beings Sleep modifies the ventilatory response to added inspiratory resistance.26-29 All studies agree that NREM sleep blunts the respiratory timing response to added resistance,26-30 with some reporting a net effect on ventilation as well.27,29,30 In adults with asthma, the ventilatory response to induced bronchoconstriction is not modified by sleep.31 Issa and Sullivan32 reported that, in response to airway occlusion, there was a progressive increase in respiratory
effort during NREM sleep and rapid, shallow breathing during REM sleep. Animals In both dogs33,34 and cats,24 ventilatory compensation for added loads is maintained during NREM sleep at the level found in wakefulness. However, when the respiratory system is further stressed by combining resistive loading with hypercapnia, the ventilatory and airway occlusion responses to loading are found to be impaired during both NREM and REM sleep.24 In summary, it is not yet clear precisely what effect increased airflow resistance has on ventilation during sleep, particularly during REM sleep, in adults.
AROUSAL RESPONSES Isocapnic Hypoxia In normal subjects, isocapnic hypoxia is a poor stimulus to trigger arousal from sleep (Fig. 22-4), with many subjects remaining asleep with Sao2 as low as 70%1,2,5 and no difference between NREM and REM sleep in arousal threshold. Conversely, the arousal sensitivity to hypoxia is decreased in REM sleep in patients having obstructive sleep apnea with asphyxial hypoxia,35 in dogs with isocapnic hypoxia,8,9 and in cats with hypocapnic hypoxia.36 Carotid body denervation reduces arousal sensitivity in dogs7 but does not alter the arousal threshold in cats.36 Hypercapnia Hypercapnia also produces arousal from sleep at variable levels3,11,13 but awakens most subjects before the end-tidal CO2 has risen by 15 mm Hg above the level in wakefulness.3,11-13 Berthon-Jones and Sullivan16 reported arousal thresholds up to 6 mm Hg higher in slow-wave sleep than in either stage 2 or REM sleep in male but not in female subjects, whereas Douglas and associates13 found no gender or sleep stage-related differences. Hypoxia increases the sensitivity to CO2 arousal.35 Added Resistance Human beings tend to arouse from sleep following either the addition of an inspiratory resistance28 or the occlusion of inspiration.37 Added inspiratory resistance was found to produce a similar percentage increase in arousal frequency in stages 2 and 3/4 and REM sleep.26 However, the arousal frequency during control sleep periods was lowest in stages 3/4 sleep and remained significantly lower during slowwave sleep than in REM sleep after the addition of inspiratory resistance (Fig. 22-5).24,25 Arousal from REM sleep after airway occlusion32,38 is far more rapid than arousal from NREM sleep (Fig. 22-6; nearly 3 times quicker in REM), whereas patients with obstructive apneas have longer apneas during REM sleep. Upper airway receptors would be exposed to respiratory pressure changes in normal people with airway occlusion but in patients with sleep apnea receptors above the level of occlusion would not experience pressure swings. However, it is unclear why these upper airway receptors should be more effective in REM sleep than in NREM sleep in normal subjects.
CHAPTER 22 • Respiratory Physiology: Understanding the Control of Ventilation 253
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Arousal response to experimental chemostimulation was found to occur at a similar level of ventilation regardless of stimulus.16 The final common pathway for arousal from sleep after hypoxia, hypercapnia, or increased resistance may actually be the level of ventilatory effort.39 This is compatible with the observation that patients with the “upper airway resistance syndrome” tend to awaken at relatively reproducible levels of intrathoracic pressure and that this arousal occurs without the development of either significant hypoxemia or significant hypercapnia. Arousal responses are affected by previous sleep history. For example, sleep fragmentation in normal subjects sig-
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Figure 22-5 Timing of arousal after application of inspiratory resistance of 4, 7, or 10 cm H2O/L/sec in stages 2 and 3/4 and REM sleep. Those occasions in which arousal occurred within 2 min of addition of resistance are indicated by red circles, and those in which arousal did not occur within 2 min by blue circles. (From Gugger M, Molloy J, Gould GA, et al. Ventilatory and arousal responses to added inspiratory resistance during sleep. Am Rev Respir Dis 1989;140:1301-1307.)
nificantly reduced the frequency of arousal in response to inspiratory resistive loading in stage 2 sleep and in early REM sleep periods with increasing arousability from REM later in the night.40 There was no effect of sleep fragmentation on the arousal response to resistive loading in stages 3 and 4 sleep. Bronchial Irritation Sleep suppresses the cough response to inhaled irritants in human beings,41 dogs,42 and cats,43 with cough occurring only after arousal. Similarly, in patients with chronic bronchitis and emphysema, cough is suppressed during sleep.44
254 PART I / Section 4 • Physiology in Sleep
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There is no difference between NREM and REM sleep in the arousal response to inhaled citric acid in human beings,41 but in dogs, the arousal responses both to instilled water and to inhaled citric acid are markedly depressed during REM sleep.45 Ventilatory Response to Arousal The converse of considering which elements of respiration cause arousal is examining the effect of arousal on ventilation. Awakening from sleep, whatever the arousing response, leads to an increase in ventilation46,47 just as sleep onset is associated with a decrease in ventilation. In normal subjects, the magnitude of the cardiorespiratory response to arousal from sleep is independent of the level of CO2 suggesting that it results from reflex activation and not because of a homeostatic response.48 The cardiorespiratory response to arousal declines with age.49
CONTROL OF BREATHING RHYTHM DURING SLEEP Spontaneously occurring breathing irregularities during sleep are reviewed in several chapters of Section 13 of this volume, but a few points are relevant to this chapter. Human Beings Bülow12 found that the healthy subjects who had the most irregular breathing during NREM sleep had the greatest CO2 tolerance between the awake ventilation-CO2 setpoint and their CO2 response line. This CO2 control laxity at sleep onset may be important in the pathogenesis of breathing irregularities, which are common at this time.12,50 The induction of experimental hypocapnia, either alone or in conjunction with hypoxia, can induce irregular breathing in normal subjects during NREM sleep51 with frequent central apneas around and below the apnea threshold. The apnea threshold is higher in premenopausal women than in men or postmenopausal women.52 Hypocapnia may also induce occlusive apneas, especially when an inspiratory resistance is added.53 After airway occlusion in NREM sleep, ventilatory overshoot may occur, especially in those
with high hypercapnic ventilatory responses,14 and this could contribute to respiratory instability during sleep. Subjects with high hypoxic ventilatory responses have a greater variability in ventilation during sleep.54 During REM sleep, irregular breathing is the norm in adults, and neither isocapnic hypoxia nor hypercapnia regularize this pattern.1,13 Animals Spontaneous irregular breathing is uncommon in NREM sleep in mature animals. In REM sleep, irregular breathing is universal and is not regularized by hypoxia,8 hyperoxia,42 hypercapnia,23 metabolic alkalosis,42 carotid body resection,55 or vagotomy,56,57 and indeed respiratory irregularity may increase after vagotomy.57
UPPER AIRWAY–OPENING MUSCLES DURING SLEEP In cats, the activity of upper airway opening muscles decreases during NREM sleep, with a further marked reduction during REM sleep.56 During wakefulness, the activity of these muscles parallels that of the diaphragm during respiratory stimulation with either hypoxia or hypercapnia.58,59 Both genioglossal60 and palatal muscle60,61 tone decrease during sleep in normal human beings (see Chapters 21 and 23 for more information). Decreases in genioglossal and palatal muscle activity occur immediately at alpha-theta transition in parallel with changes in diaphragm muscle tone62 and affect inspiratory more than tonic or expiratory motor units in the genioglossus.63 These decreases are greater in older subjects.64 This appears to be due to increased activation of these muscles in wakefulness, probably due to anatomical narrowing of the upper airway, and the subsequent loss of the wakefulness drive to these muscles, rather than to a selective decrease in an effect of age on the responsiveness to negative pressure during sleep.65 This is compatible with the increased collapsibility of the upper airway during sleep with age.66 Genioglossal activity is relatively insensitive to hypoxia, hypercapnia or applied resistance during NREM sleep in adults,67 although both chemoreceptor and negative pressure receptor inputs to the genioglossus are still present in NREM sleep.68 Recent studies have shown that intermittent hypoxia in normal subjects is associated with increased ventilation, decreased upper airways resistance, and increased phasic genioglossal EMG that persisted up to 20 minutes into the recovery period.69,70 Neither genioglossus nor tensor palatini activity increased in response to applied resistance during NREM sleep in men or women.71 FACTORS INFLUENCING RESPIRATORY CONTROL DURING SLEEP Mechanisms that are likely to contribute to decreased ventilatory responses during sleep include the following: Decreased Basal Metabolic Rate Basal metabolic rate falls during sleep, with no major difference in the levels in the different sleep stages.72,73 Both
CHAPTER 22 • Respiratory Physiology: Understanding the Control of Ventilation 255
ventilation and ventilatory responses are reduced when metabolic rate falls,74 although the physiological sensornetwork related mechanism for this is unclear. The decreased basal metabolic rate during sleep is probably a factor in the decreased chemosensitivity during sleep but cannot explain the further reduction in ventilatory response from NREM to REM sleep. Cerebral Blood Flow–Metabolism Relationship Brain blood flow increases during sleep.75-78 The 4% to 25% increase in brain blood flow in slow-wave sleep compared with wakefulness is explicable on the basis of the mild hypercapnia that results from hypoventilation.77 Brain blood flow increases markedly during REM sleep, the rise being as large as 80% in one study.76 In goats, Santiago and colleagues77 found a 26% increase in brain blood flow during REM sleep and found this to be greater than could be explained by the increase in CO2. They also found that brain metabolism in REM sleep was similar to that in wakefulness. This increase in the brain blood flow brain– metabolism ratio would depress central chemoreceptor activity during REM sleep and might be a factor in reducing ventilatory responses during REM sleep. However, in human beings, Madsen and colleagues79 reported that changes in cerebral blood flow paralleled changes in cerebral oxygen metabolism during both slow-wave and REM sleep (see also Chapter 18). Neurological Changes during Sleep Cortical activity influences breathing, with mental concentration increasing both ventilation80 and ventilatory responses.12 It seems probable that the hypoventilation and decreased responses to chemical and mechanical stimuli in NREM sleep partially reflect the loss of the “wakefulness” drive to ventilation.81 During REM sleep, sensory and motor functions are impaired. There are both presynaptic and postsynaptic inhibitions of afferent neurons82 that result in raised arousal thresholds to external stimuli83 and postsynaptic inhibition of motoneurons84 that produces the postural hypotonia typical of REM sleep.85 This combination of decreased sensory and motor function probably contributes to the marked impairment of ventilatory responses during REM sleep. It has been suggested that the irregular breathing and impaired ventilatory responses during REM sleep result from alteration of the control of ventilation by behavioral factors.81 However, evidence suggests that chemical stimuli are the most important ones during REM sleep in humans.86 Furthermore, at least in cats,58 there seems to be a positive correlation between the activity of some medullary respiratory neurons during REM sleep with pontine-generated discharges termed ponto-geniculo-occipital (PGO) waves. PGO waves are one of the basic electrophysiological phenomena of REM sleep, and thus the dysrhythmic nature of breathing in REM sleep may relate directly to the dysrhythmic nature of REM sleep itself. This is supported by the observation that tidal volume is closely related to the density of eye movements during REM sleep in human beings.87
Neuromechanical Factors Chest-Abdominal Movement It has been suggested that decreased ventilatory responses in REM sleep result from hypotonia of the intercostal muscles. Although there is no doubt that chest movement and the intercostal electromyogram (EMG) are decreased during REM sleep as compared with NREM sleep, the studies that have included measurements during wakefulness show that chest movement contributes a similar proportion to tidal volume in REM sleep as in wakefulness.88-90 Clearly, further EMG studies are required, as are studies on the contribution of the chest to ventilation during the different components of REM sleep.91 Reduced Functional Residual Capacity Functional residual capacity is decreased during REM sleep.92 Although this might contribute to the hypoxia in REM sleep, it is unlikely to contribute to the decreased ventilatory responses because volume reduction usually increases these responses.93 Increased Airflow Resistance Airflow resistance increases during sleep. The increase is maximal in NREM sleep in human beings,94,95 although in cats, resistance seems to be highest during REM sleep.59 This increased resistance is due to hypotonia of the upper airway opening muscles during sleep. Some of the diminution in ventilatory responses between wakefulness and NREM sleep may be due to changes in upper airway resistance because the occlusion pressure response to hypercapnia is well maintained during NREM sleep.21 The study96 that looked at the threshold CO2 level for respiratory muscle activation in intubated subjects in whom upper airways resistance was thus kept constant suggested that there are sleep-stage–related differences in the neuromuscular response to CO2. The CO2 level at which respiratory muscle augmentation occurred rose significantly from wakefulness to NREM sleep. The occlusion pressure response to hypercapnia is markedly reduced during REM sleep21 which indicates diminution of neuromuscular function. In summary, the main cause for the decrease in ventilatory responses during NREM sleep is the loss of the wakefulness drive to breathe coupled with the decrease in metabolic rate and increase in airflow resistance. The further reduction during REM sleep is likely to result from altered CNS function during REM sleep.
CLINICAL SEQUELAE OF ABNORMAL VENTILATORY RESPONSES The impaired ventilatory responses permit the development of hypoventilation during sleep and of sleep-related hypoxemia in patients with hypoxic chronic bronchitis and emphysema97-99 and other respiratory diseases that cause hypoxia.100,101 In all of these conditions, the hypoxia is most marked in REM sleep, when the ventilatory responses are at their lowest. The remarkable insensitivity to external stimuli during sleep allows patients with all of these conditions to develop
256 PART I / Section 4 • Physiology in Sleep
clinically significant hypoxia and hypercapnia before arousal occurs. Instability of the control of breathing during sleep may contribute to the development of the obstructive sleep apnea-hypopnea syndrome in some patients.102 Paradoxically, enhanced ventilatory responses may be present in some patients, which may destabilize ventilation and lead to periodic breathing.103 This may be an important factor in the development of Cheyne-Stokes respiration in left ventricular heart failure.104 In heart failure, central apnea during sleep may be initiated by an acute increase in ventilation and reduction in Paco2 following a spontaneous arousal.105 When Paco2 falls below the threshold level required to stimulate breathing, the drive to respiratory muscles and airflow cease, and central apnea result. Apnea persists until Paco2 rises above the threshold required to stimulate ventilation. Prolonged circulation time appears not to play a key role in initiating central apneas, and indeed cardiac transplantation with normalisation of cardiac function does not always prevent Cheyne-Stokes respiration.105 The major influence of circulation time appears to be on the lengths of the hyperpneic phase and of the total periodic breathing cycle.106 Once triggered, the pattern of alternating hyperventilation and apnea is sustained by the combination of increased respiratory chemoreceptor drive, pulmonary congestion, arousals, and apnea-induced hypoxia, which cause oscillations in Paco2 above and below the apneic threshold. Inhalation of a CO2-enriched gas to raise Paco2 abolishes Cheyne-Stokes respiration in heart failure.107 The clinical effectiveness of continuous positive airway pressure therapy in this situation is debated.108,109 For more details on sleep disorders breathing, Section 13 of this volume can be consulted.
❖ Clinical Pearl Decreased ventilatory responses to hypoxia, hypercapnia, and inspiratory resistance during sleep, particularly in REM sleep, permit REM hypoxemia in patients with chronic obstructive pulmonary disease, chest wall disease, and neuromuscular abnormalities that affect the respiratory muscles. Decreased ventilatory responses may also contribute to the development of hypoventilation syndromes and the sleep apnea/hypopnea syndrome.
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60. Mezzanote WS, Tangel DJ, White DP. Influence of sleep onset on upper airway muscle activity in apnea patients versus normal controls. Am J Respir Crit Care Med 1996;153:1880-1887. 61. Tangel DJ, Mezzanote WS, White DP. Influence of sleep on tensor palatini EMG and upper airways resistance in normal man. J Appl Physiol 1991;70:2574-2581. 62. Worsnop C, Kay A, Pierce R, et al. Activity of respiratory pump and upper airway muscles during sleep onset. J Appl Physiol 1998;85:908-920. 63. Wilkinson V, Malhotra A, Nicholas CL, et al. Discharge patterns of human genioglossus motor units during sleep onset. Sleep 2008;31:525-533. 64. Worsnop C, Kay A, Kim Y, et al. Effect of age on sleep onset-related changes in respiratory pump and upper airway muscle function. J Appl Physiol 2000;88:1831-1839. 65. Fogel RB, White DP, Pierce RJ, et al. Control of upper airway muscle activity in younger versus older men during sleep onset. J Physiol 2003;553:533-544. 66. Eikermann M, Jordan AS, Chamberlin NL, et al. The influence of aging on pharyngeal collapsibility during sleep. Chest 2007;131: 1702-1709. 67. Stanchina ML, Malhotra A, Fogel RB, et al. Genioglossus muscle responsiveness to chemical and mechanical stimuli during nonrapid eye movement sleep. Am J Respir Crit Care Med 2002; 165:945-949. 68. Lo YL, Jordan AS, Malhotra A, et al. Genioglossal muscle response to CO2 stimulation during NREM sleep. Sleep 2006;29:470477. 69. Pierchala LA, Mohammed AS, Grullon K, et al. Ventilatory longterm facilitation in non-snoring subjects during NREM sleep. Respir Physiol Neurobiol 2008;160:259-266. 70. Chowdhuri S, Pierchala L, Aboubakr SE, et al. Long-term facilitation of genioglossus activity is present in normal humans during NREM sleep. Respir Physiol Neurobiol 2008;160:65-75. 71. Pillar G, Malhotra A, Fogel R, et al. Airway mechanics and ventilation in response to resistive loading during sleep: influence of gender. Am J Respir Crit Care Med 2000;162:1627-1632. 72. Brebbia DR, Altshuler KZ. Oxygen consumption rate and electroencephalographic stage of sleep. Science 1965;150:16211623. 73. White DP, Weil JV, Zwillich CK. Metabolic rate and breathing during sleep. J Appl Physiol 1985;59:384-391. 74. Zwillich C, Sahn S, Weil J. Effects of hyper-metabolism on ventilation and chemosensitivity. J Clin Invest 1977;60:900-906. 75. Mangold R, Sokoloff K, Conner E, et al. The effects of sleep and lack of sleep on the cerebral circulation and metabolism of normal young men. J Clin Invest 1955;34:1092-1100. 76. Reivich M, Isaacs G, Evarts E, et al. The effect of slow wave sleep and REM sleep on regional cerebral blood flow in cats. J Neurochem 1968;15:301-306. 77. Santiago TV, Guerra E, Neubauer JA, et al. Correlation between ventilation and brain blood flow during sleep. J Clin Invest 1984; 73:497-506. 78. Townsend RE, Prinz PN, Obrist WD. Human cerebral blood flow during sleep and waking. J Appl Physiol 1973;35:620-625. 79. Madsen PL, Schmidt JF, Wildschiodtz G, et al. Cerebral O2 metabolism and cerebral blood flow in humans during deep and rapid-eye movement sleep. J Appl Physiol 1991;70:2597-2601. 80. Asmussen E. Regulation of respiration: “The black box.” Acta Physiol Scand 1977;99:85-90. 81. Phillipson EA. Control of breathing during sleep. Am Rev Respir Dis 1978;118:909-939. 82. Pompeiano O. Mechanisms of sensorimotor integration during sleep. Prog Physiol Psychol 1973;3:1-179. 83. Steriade M, Hobson JA. Neuronal activity during the sleep-waking cycle. Prog Neurobiol 1976;6:155-376. 84. Nakamura Y, Goldberg LJ, Chandler SH, et al. Intra-cellular analysis of trigeminal motor neuron activity during sleep in the cat. Science 1978;199:204-207. 85. Pompeiano O. The control of posture and movements during REM sleep: neurophysiological and neurochemical mechanisms. Acta Astronautica 1975;2:225-239. 86. Meza S, Giannouli E, Younes M. Control of breathing during sleep assessed by proportional assist ventilation. J Appl Physiol 1998;84:3-12.
258 PART I / Section 4 • Physiology in Sleep 87. Gould GA, Gugger M, Molloy J, et al. Breathing pattern and eye movement density during REM sleep in man. Am Rev Respir Dis 1988;138:874-877. 88. Mortola JP, Anch AM. Chest configuration in supine man: wakefulness and sleep. Respir Physiol 1978;35:201-213. 89. Stradling JR, Chadwick GA, Frew AJ. Changes in ventilation and its components in normal subjects during sleep. Thorax 1985; 40:364-370. 90. Tabachnik E, Muller NL, Bryan AC, et al. Changes in ventilation and chest wall mechanics during sleep in normal adults. J Appl Physiol 1981;51:557-564. 91. Millman RP, Knight H, Chung DC, et al. Changes in compartmental ventilation in association with eye movements during REM sleep. J Appl Physiol 1988;65:1196-1202. 92. Hudgel DW, Devadatta P. Decrease in functional residual capacity during sleep in normal humans. J Appl Physiol 1984;57:13191322. 93. Cherniack NS, Stanley NN, Tuteur PG, et al. Effect of lung volume changes on respiratory drive during hypoxia and hypercapnia. J Appl Physiol 1973;35:635-641. 94. Hudgel DW, Martin RJ, Johnson B, et al. Mechanics of the respiratory system and breathing pattern during sleep in normal humans. J Appl Physiol 1984;56:133-137. 95. Lopes JM, Tabachnik E, Muller NL, et al. Total airway resistance and respiratory muscle activity during sleep. J Appl Physiol 1983;54:773-777. 96. Ingrassia TS 3rd, Nelson SB, Harris CD, et al. Influence of sleep state on carbon dioxide responsiveness: a study of the unloaded respiratory pump in man. Am Rev Respir Dis 1991;144:11251129. 97. Douglas NJ, Calverley PMA, Leggett RJE, et al. Transient hypoxaemia during sleep in chronic bronchitis and emphysema. Lancet 1979;1:1-4. 98. Fleetham JA, Mezon B, West P, et al. Chemical control of ventilation and sleep arterial oxygen desaturation in patients with COPD. Am Rev Respir Dis 1980;122:583-589.
99. Koo KW, Sax DS, Snider GL. Arterial blood gases and pH during sleep in chronic obstructive pulmonary disease. Am J Med 1975;58:663-670. 100. Mezon BL, West P, Israels J, et al. Sleep breathing abnormalities in kyphoscoliosis. Am Rev Respir Dis 1980;122:617-621. 101. Muller NL, Francis PW, Gurwitz D, et al. Mechanism of hemoglobin desaturation during rapid-eye-movement sleep in normal subjects and in patients with cystic fibrosis. Am Rev Respir Dis 1980;121:463-469. 102. Younes M, Ostrowski M, Thompson W, et al. Chemical control stability in patients with obstructive sleep apnea. Am J Respir Crit Care Med 2001;163:1181-1190 103. Cherniack NS. Apnea and periodic breathing during sleep. N Engl J Med 1999;341:985-987. 104. Javaheri S. A mechanism of central sleep apnea in patients with heart failure. N Engl J Med 1999;341:949-954. 105. Mansfield DR, Solin P, Roebuck T, et al. The effect of successful heart transplant treatment of heart failure on central sleep apnea. Chest 2003;124:1675-1681. 106. Bradley TD, Floras JS. Sleep apnea and heart failure: Part II. Central sleep apnea. Circulation 2003;107:1822-1826. 107. Lorenzi-Filho G, Rankin F, Bies I, et al. Effects of inhaled carbon dioxide and oxygen on Cheyne-Stokes respiration in patients with heart failure. Am J Respir Crit Care Med 1999;159: 1490-1498. 108. Arzt M, Floras JS, Logan AG, et al. Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation 2007;115: 3173-3180. 109. Kasai T, Usui Y, Yoshioka T, JASV Investigators. Effect of flowtriggered adaptive servo-ventilation compared with continuous positive airway pressure in patients with chronic heart failure with coexisting obstructive sleep apnea and Cheyne-Stokes respiration. Circ Heart Fail 2010;3:140-148.
Normal Physiology of the Upper and Lower Airways Raphael C. Heinzer and Frédéric Sériès Abstract The respiratory system can be divided into compartments made up of the upper and lower airways. The mechanics of both compartments are strongly influenced by sleep. Lung volume, rib cage muscle activity and minute ventilation tend to decrease during sleep, as does the activity of upper airway stabilizing muscles. The upper airway also plays a critical role in determining ventilation and breathing pattern during sleep.
Chapters 21 and 22 described the basis of the physiology of respiratory function during wake and sleep. In this chapter we focus on the physiologic determinants of respiration used to estimate the breathing function in normal persons. The ultimate goal is to allow readers who are not familiar with the field of respiratory medicine to benefit from the more subtle concepts that will help them to better understand sleep-disordered breathing. The aim of breathing is to provide oxygen to the different body parts and to eliminate carbon dioxide resulting from cell metabolism. This is achieved through continuous gas exchange between inspired and exhaled air and the blood in the pulmonary circulation. Once blood coming from the right heart has been loaded with oxygen, it reaches the left heart, which sends it to every part of the body through the arterial system. The different organs then take up oxygen from the arterial blood and remove carbon dioxide. Blood loaded with carbon dioxide travels through the venous system to reach the pulmonary circulation, where carbon dioxide passively diffuses through the alveolocapillary membrane into the airway, where it is exhaled. Survival depends upon the integrity of this physiologic process, and death can occur if this system stops for more than a few minutes. Therefore, maintenance of normal arterial blood gases involves several physiologic systems (control of breathing, thoracopulmonary mechanics, circulatory characteristics, blood-transport characteristics) that are intimately linked to one another. This chapter focus only on the mechanical properties of the chest and upper and lower airway, which are the main determinants of ventilation during sleep (Box 23-1).
ANATOMY AND PHYSIOLOGY The upper airway, which includes nasal cavities, pharynx, and larynx, serves to moisten and warm the air and conduct it to the trachea and lungs. Upper airway muscles are also involved in phonation and swallowing. A very subtle regulation of the cord vocal tension also allows humans to speak and sing during exhalation. It is hypothesized that the evolution of speech in humans, which requires substantial mobility of the pharynx, led to a loss of the rigid support
Chapter
23
Its patency is influenced not only by pharyngeal and orofacial muscle activity but also by thoracopulmonary mechanics. Sleep thus has a strong impact on upper airway aperture and mechanical properties. Even though obesity and pharyngeal anatomy play an important role in the development of sleepinduced disordered breathing, sleep plays a key role in determining upper airway instability and therefore in determining the pathophysiology of this disorder.
of the upper airway, which makes it more collapsible than in most mammals. Breathing is possible through either the nose or the mouth, but nasal breathing is the physiologic breathing route. The lower airway includes the trachea and the lungs (bronchi and alveoli). Thin blood vessels, the capillaries lining the alveoli, allow gas exchange between inspired air and blood. The rib cage provides protection for the lungs and also allows them to change volume from a minimum of about 1.5 L to a maximum of 6 to 8 L, depending on the height and sex of the person.1 The ribs articulate with the transverse processes of the thoracic vertebrae and have flexible anterior cartilaginous connections with the sternum. The lungs are covered by thin visceral pleura. The inner aspects of each hemithorax are lined with parietal pleura. The virtual space between the visceral and parietal pleura contains a few milliliters of lubricating fluid, which allows them to slide against each other easily during ventilation. Due to its proximity to the pleural tissue, the esophageal pressure varies in parallel with the changes in pleural pressure and is often used to quantify respiratory efforts. Respiratory Muscles The diaphragm is the main muscle of respiration. It is a dome-shaped muscle that separates the thoracic and abdominal cavities. The diaphragm is innervated by the phrenic nerves. During inspiration, the neural outflow coming from the central respiratory centers leads to diaphragm contraction; the shortening of the diaphragm muscles fibers flattens the diaphragm, making it lose its dome shape and thus increasing intrathoracic volume. Intercostal muscles can also increase the intrathoracic volume by elevating ribs and increasing the anteroposterior diameter of the thorax (Fig. 23-1). Accessory breathing muscles such as the scalene or sternocleidomastoid are not active during normal breathing, but they can be recruited during an effort or in the presence of thoracopulmonary disorders. Elastic Forces and Lung Volumes An isolated lung (not surrounded by the thoracic cage) will tend to contract until it eventually collapses owing to the 259
260 PART I / Section 4 • Physiology in Sleep
MUSCLES OF INSPIRATION
Maximal inspiration
MUSCLES OF EXPIRATION
IC
IRV
Sternocleidomastoid Scalenes Internal intercostals
External intercostals
Sternum: Expiration Inspiration
Diaphragm
Internal oblique Transversus abdominis
VC TV
TLC
End expiration FRC
External oblique
End inspiration
ERV
Maximal expiration
RV Diaphragm: Expiration Inspiration
Rectus abdominis
Figure 23-1 Representation of inspiratory and expiratory muscles from abdomen to neck. The main inspiratory muscles include the diaphragm and external intercostal muscles. Accessory inspiratory muscles include the scalene and sternocleidomastoid muscles. Expiration is usually a passive process. However internal intercostals and abdominal muscles are recruited during forced expiration. (Reproduced from Netter FH. Atlas of human anatomy. Philadelphia: Elsevier Saunders; 2006.)
Box 23-1 Some Definitions Used in Respiratory Mechanics Chest or Lung Compliance Change in volume per change in pressure: ΔV/ΔP Minute Ventilation Tidal volume times respiratory rate: VT × RR Laminar Flow Change in pressure per resistance: ΔP/R Turbulent Flow Pressure drop along the airway is proportional to flow and its square values: ΔP ∝ aV + bV2 (V is air flow, and a and b are constants)
large amount of elastic fibers inside the lung tissue. The lung is thus submitted to a constant recoil force. In contrast, the isolated thoracic cage tends to expand to a volume about 1 L more than its natural in vivo resting position. In a relaxed subject with an open airway and no airflow, the inward elastic recoil of the lungs will be balanced by the outward resting force coming from the thoracic cage. Lung compliance or distensibility is defined as the change in lung volume per unit change in transmural pressure gradient: Compliance = ∆V ∆P where V is volume and P is pressure. The lung volume, in the natural resting end-expiratory position, is its functional residual capacity (FRC). Total lung capacity (TLC) is reached when the thoracic cage and lungs are fully expanded (maximal inspiratory effort).
Figure 23-2 Schematic illustration of the static lung volumes determined by a spirometer in which airflow velocity does not play a role. Lung capacity is estimated by the sum of two or more lung-volume subdivisions. ERV, expiratory reserve volume; FRC, functional residual capacity; IC, inspiratory capacity; IRV, inspiratory reserve volume; RV, residual volume; TLC, total lung capacity; VC, vital capacity; VT; , tidal volume. Reproduced with permission from AARC Clinical Practice Guideline Static Lung Volumes: 2001 Revision and Update. Respir Care 2001;46:531–539.
Residual volume (RV) represents the volume remaining in the lungs at the end of a forced expiration. Vital capacity (VC) is the maximum amount of air that can be expelled after the lungs have been fully inflated. Tidal volume (Vt) is the volume of air inspired or expired during each quiet breathing cycle (Fig. 23-2). The typical Vt value is 500 mL, but it can dramatically increase during exercise. Only about two thirds of inspired air participates in oxygen and carbon dioxide exchange because the volume corresponding to upper airway, trachea, and bronchi do not contri bute to gas exchanges; this area is the dead space (Vds) of the respiratory tract.1 Breathing Cycle and Minute Ventilation Air always flows from an area of higher pressure to one of lower pressure. The pressure inside the pleural space is generated by the forces developed during inspiration and expiration and is proportional to the amount of respiratory effort. The pleural pressure represents the driving pressure. During inspiration, the diaphragm and intercostal muscles contract and the pressure inside the thorax decreases below the atmospheric pressure (negative transpulmonary pressure gradient). This gradient is responsible for air movement from the nose (atmosphere) to the tracheobronchial tree down to the alveoli. During expiration, the inspiratory muscles relax, making resting expiration a passive phenomenon. However, during active expiration (volitional or during exercise), the contraction of abdominal and external intercostal muscles enhances the changes in intrathoracic pressure. This causes an abrupt increase in pleural pressure to a less-negative value. This rise in pleural pressure causes the alveolar pressure to rise by the same amount, thus resulting in a positive pressure gradient from the alveoli to the mouth, which is responsible for exhalation. Lung and chest volume decrease as air flows out, causing lung recoil pressure to fall until a new equilibrium is reached at FRC. Respiratory rate, or breathing frequency, represents the number of breaths per minute. Average respiratory rate in a healthy adult at rest is about 12 (range, 10 to 18) per
CHAPTER 23 • Normal Physiology of the Upper and Lower Airways 261
E) can be calculated with the minute. Minute ventilation ( V following equation: E = VT × RR V where RR is the respiratory rate. During quiet breathing, a typical value is 6 L/min but the volume can rise to 180 L/ min during exercise. Resistance Different profiles of airflow may be observed inside the airways depending on airway anatomy (division of tracheobronchial tree) and mechanical properties (caliber, shape, collapsibility) of the airway structures and on the amount of driving pressure. With a constant laminar flow regimen, the resistance is directly proportional to the pressure gradient along the tube: Flow = ∆P R where ΔP is the pressure difference and R is the resistance. Airflow is described as turbulent when the pressure drop along the airway is proportional to flow and its square values: ∆P ∝ aV + bV 2 where ΔP is the pressure difference and V is the air flow. Airflow along airways is complex and usually consists of a mixture of laminar and turbulent flow. In normal lungs, respiratory resistance depends mainly on airways diameter. The velocity of airflow and airways diameter decreases in successive airways generation from a maximum in the trachea to almost zero in the smallest bronchioles. A third flow regimen is represented by flow limitation, where flow plateaus once the driving pressure has reached a given level. In this regimen, the flow value depends on the difference between intraluminal and extraluminal pressure as well as on the compliance of the concerned airway. Flow limitation can occur during expiration when the pressure generated by expiratory forces increases intraluminal pressure and induces an external compression of the airway walls at the same time. This pattern of flow is, however, more prone to occur during inspiration at the level of the upper airway. Upper airway resistance depends on nasal and pharyngeal anatomy, position of the vocal cords, and lung volume (see later).
EFFECTS OF OBESITY AND BODY POSTURE ON LUNG VOLUMES In an awake normal and healthy subject, there is a reduction in FRC and TLC in the supine position in comparison to upright body position.2 This reduction is thought to be due to an increase in intrathoracic blood volume or to the gravitational effect of abdominal contents pushing the relaxed diaphragm into a more rostral position.3 This change in diaphragm position reduces the diaphragm’s ability to contract, as suggested by a decreased maximal inspiratory pressure in the supine posture with respect to the upright and sitting positions.4 Moreover, this restrictive defect in lung volume increases the work of breathing and deteriorates gas exchange by decreasing the ventilation-perfusion ratio in the dependent parts of the lungs. Decreased lung volume can also increase upper airway resistance by reducing the
caudal traction of the mediastinum and trachea on the pharyngeal walls, making them more collapsible during inspiration (discussed further later).5-8 In obese subjects, a restrictive defect in lung volume is also observed when they are sitting. There is a further small decrease of about 70 to 80 mL from about 2.4 L (for an average-sized man) in FRC and TLC when obese subjects lay supine.2 Considering the effects of abdominal volume on lung function in sitting obese subjects, one would expect a greater reduction in lung volume when they adopt the supine position compared to lean persons. However, a lesser decline in FRC and TLC in obese subjects in the supine position is reported.2,3,9 One possible explanation is that in sitting obese subjects, the diaphragm is already shifted in a more rostral position and it cannot move much farther in the supine position. Two experimental studies also suggest that there may be a protective or adaptive mechanism against large changes in endexpiratory lung volume during wakefulness10 and sleep.11 Maximal minute ventilation, expiratory reserve volume, forced vital capacity (FVC), and, to a lesser extent, forced expiratory volume in 1 second (FEV1) are also affected by obesity.12 The estimated reduction of FVC is 17.4 mL/kg weight gain for men and 10.6 mL/kg weight gain for women.13 Men show more impairment of FVC with weight gain than women, possibly because of differential patterns of fat deposition: waist circumference is negatively associated with FVC and FEV1. On average, a 1-cm increase in waist circumference was associated with a 13-mL reduction in FVC.14 All these changes observed from upright to supine positions and in obese persons may contribute to the exacerbation of respiratory disturbances in the presence of sleep-disordered breathing as described in Section 13 of this volume.
EFFECTS OF SLEEP ON LUNG VOLUME There is a modest but significant decrease in FRC occurring during sleep in most healthy subjects. FRC decreases by about 200 mL in stage 2 non–rapid eye movement (NREM) sleep and by 300 mL during slow-wave sleep and REM sleep when measured with a helium dilution technique in comparison to normal value awake (~2.4 L for an average-sized man).15 When plethysmongraphy is used to measure differences in lung volume, a 440 to 500 mL decrease in lung volume was reported in NREM sleep (stages 2 to 3 and 4), with a similar decrease in REM sleep.16 Possible mechanisms of the decrease in FRC during sleep are diaphragm hypotonia inducing rostral displacement of the diaphragm, alteration of the respiratory timing from central generator of breathing, decrease in lung compliance, decrease in thoracic compliance, and central pooling of blood (see Chapters 21 and 22). A reduction in tidal volume by about 6% to 15% has been reported during NREM sleep (stages 2 to 4), with a further decrease during REM sleep (about 25% lower than during wake).17,18 Minute ventilation is significantly lower during all NREM sleep stages compared to wake and further decreases during REM sleep, especially during phasic REM (about 84% of the level during wake) (Fig. 23-3).17-20 This is due to a faster and shallower breathing
262 PART I / Section 4 • Physiology in Sleep 8
· VE (l/min)
+X
+X
7
+
6 0.6
VT (l)
+X
+
0.4
+
16 f (b/min)
+
+
+
3/4
REM
14
Awake
2
Sleep stage Figure 23-3 Effects of sleep on ventilation and lung volumes. Minute ventilation ( V E), tidal volume (VT) and breathing frequency (f) during wakefulness and different sleep stages are illustrated. V is reduced during NREM sleep, with a further reduction in REM sleep. +, P < .05 vs. awake; X: P < .05 vs. REM sleep. (Reproduced with permission from Douglas NJ, White DP, Pickett CK, et al. Respiration during sleep in normal man. Thorax 1982;37[11]:840-844.)
pattern in all sleep stages with a lower tidal volume, especially during REM sleep. This is, however, controversial because another study showed no significant change in Vt between wakefulness and any sleep stage and suggested that the decrease in minute ventilation (8% in NREM and 4% in REM sleep) is due to a decrease in respiratory rate.21 Most studies agree, however, that during NREM sleep there is an increase in the rib cage’s contribution to Vt associated with an approximately 34% increase in the activity of intercostal muscles.20-22 There is thus an apparent contradiction between the increase in electromyogram (EMG) activity of thoracic muscles and a decrease in minute ventilation. A possible explanation is that even though muscle activity increases, the actual negative thoracic pressure decreases because of a decrease in the efficiency of muscle contraction during NREM sleep.23 During REM sleep the relative contribution of the rib cage and abdomen is not significantly different compared to wakefulness.20 Age and sex do not seem to significantly alter sleep-related changes in lung volume.
EFFECTS OF SLEEP ON BREATHING PATTERN AND BLOOD GASES During NREM sleep, the decrease in minute ventilation induces a drop in Pao2 of 3 to 9 mm Hg and an increase in Paco2 and Paco2 levels ranging from 2 to 4 mm Hg.24,25 During stable NREM sleep, the breathing pattern is usually regular. However, periodic breathing with waxing and waning ventilation is commonly observed at sleep onset (unstable NREM sleep).26,27 Complete cessation of breathing for more than 10 seconds with respiratory effort (obstructive sleep apnea) or without respiratory effort (central sleep apnea) can even occur at this time in healthy persons. In these circumstances, this transient periodic breathing seems to be due to an unstable ventilatory feedback loop (loop gain). A low arousal threshold during this stage can also induce instability in the sleep–wake cycle and contribute to unstable breathing. Because of the higher CO2 set point during sleep, arousals are associated with a sudden increase in ventilation, which will then decrease CO2 level. If the CO2 level is below the apnea threshold (CO2 level below which the central respiratory drive is abolished) when sleep resumes, an apnea can occur and breathing will resume only when the CO2 level again reaches the sleep set point. The magnitude and the breathing fluctuation depend on several factors such as chemoreceptor sensitivity (controller gain), lung-to-chemoreceptor circulation delay, and the efficiency of the respiratory system in inducing changes in CO2 level (plant gain) (see also Chapter 22).28 During REM sleep, ventilation is notably variable both in amplitude and frequency. This heterogeneity seems to be directly related to the intensity of phasic activity as indicated by bursts of eye movements. Specifically, phasic REM activity, characterized by a high density of rapid eye movements and muscle twitches, seems to have an inhibitory influence on ventilation.18 Overall alveolar ventilation tends to fall by about 20% compared to wakefulness, mainly because of a fall in tidal volume.20 Upper Airway Among the above-reviewed mechanical determinants of ventilation, the upper airway plays a unique role because its mechanical properties are dramatically affected by sleep. The airway can be divided into intrathoracic and extrathoracic components. These include the upper part of the trachea, the larynx, and the different pharyngeal (nasopharynx, velopharynx, orophrarynx, hypopharynx) segments. The upper airway corresponds to the pharyngeal and laryngeal structures. The airway should remain open throughout the respiratory cycle. The intrathoracic, tracheal, and laryngeal airway structures are supported by cartilaginous structures that prevent them from collapsing during tidal breathing in normal persons. Pharyngeal airways do not have such rigid support and are prone to close when there is an imbalance between the forces that tend to dilate or close them. From a mechanical point of view, the upper airway behaves as a Starling resistor, where the pharyngeal airway represents the collapsible segment and is situated between two noncollapsible structures (larynx and nasopharynx).
CHAPTER 23 • Normal Physiology of the Upper and Lower Airways 263
Muscular P Vi max (ml.s–1)
500
Vi
Driving P
Intraluminal P
400 300 200 100 0 –10 –8
A
–6
–4
–2
0
2
Driving pressure (cm H2O)
Tissular P
Nasal airway
Pharynx
Larynx
Figure 23-4 Schematic representation of the upper airway (UA) and of the forces applied to the pharyngeal airway. The muscular pressure (P) represents the dilating force coming from the tonic and phasic activity of UA dilator muscles. The intraluminal pressure and the tissue pressure both tend to occlude the UA. P, pressure; Vi, inspiratory flow.
Vi max (ml.s–1)
500 400
c a
300 200 100 0 0
B The flow pattern depends on the forces applied inside and outside the collapsible segment. The transmural pressure gradient is the net pressure difference between all these opposite forces. The collapsing forces are represented by the negative inspiratory transmural pressure gradient and the pressure applied by upper airway tissue (Fig. 23-4). The contraction of upper airway stabilizing muscles (upper airway dilators) is the main dilating force, the other being represented by tracheal traction (see Fig. 23-4). Therefore, the amount and timing of the neuromuscular activation process of upper airway stabilizing muscles and the mechanical properties of upper airway tissues play a pivotal role in determining upper airway stability. According to the Starling resistance model,29 inspiratory flow increases with rising inspiratory efforts (driving pressure) up to a maximal value and then plateaus independently of respiratory efforts (Fig. 23-5A). These features of the flow–pressure relationship characterize a flow limitation regimen. The steepness of the initial rise in flow depends on the resistance upstream and downstream to the collapsing site. The pressure at which flow begins to plateau depends on upper airway mechanical properties. The critical pressure (Pcrit) represents the pressure at which the dilating forces cannot overcome the collapsing ones, leading to upper airway closure. The changes in maximal inspiratory flow with modifying upstream pressure can be used to determine Pcrit and resistance upstream to the collapsing site. There is a linear positive relationship between these variables (see Figure 23-5B). The slope of the relationship corresponds to the reciprocal of upstream resistance, and the pressure at which flow is zero represents Pcrit. In a given subject, an increase in the propensity for the upper airway to occlude translates the flow–pressure relationship to the right without changes in slope (i.e., slope a to slope b), making the Pcrit value more positive. In the situation of a decrease in upstream resistance, the steepness of the slope will rise (greater changes in flow
b 1/R upstream
Pcrit
1
2
3
4
5 6
Pmask (cm H2O)
Figure 23-5 A, A representative example of the relationship between the respiratory flow over the driving pressure during a flow-limited breath. The instantaneous flow value reaches a maximum value and then plateaus despite the continuous decrease in driving pressure. B, Typical relationship between flow and upstream pressure during a series of flow-limited breaths. An increase in the instability of the upper airway (UA) will be accompanied by a right shift of the flow/pressure curve (slope b). A decrease in upstream resistance will increase the slope of the flow/pressure curve (slope c). Vi max, maximal inspiratory flow; 1/R upstream, reciprocal of upstream resistance; Pcrit, critical pressure; Pmask, mask pressure.
with changing upstream pressure), but the Pcrit value will remain unchanged (i.e., slope a to slope c). Collapsing Forces The negative intrathoracic pressure generated by diaphragmatic contraction is transmitted to the whole airway from the alveoli to the nose to create inspiratory flow. At the pharyngeal level, the difference between intraluminal and peritissue pressures (transmural pressure) represents a suction force that tends to dynamically close the upper airway. According to the Bernoulli principle, the pressure along the walls of a tube drops with the increase in its velocity, making the intraluminal pressure decrease (become more negative) with increasing inspiratory flow. Changes in flow from a laminar to a turbulent pattern increase air velocity near airway walls that will further reduce intraluminal pressure. The weight of upper airway tissue significantly influences upper airway stability. In animals, upper airway critical pressure increases proportionally to the weight applied to the hyoid arch.30 This could account for the fact that positive pressure needs to be applied to open upper airway in anesthetized paralyzed patients with sleep apnea,31 who
264 PART I / Section 4 • Physiology in Sleep
are known to have large amount of muscular and adipose tissue surrounding the upper airway.32 On the other hand, negative pressure applied around the neck significantly unloads the upper airway,33 and resection of upper airway tissue improves Pcrit in sleep apnea patients.34 Dilating Forces Contraction of inspiratory muscles (diaphragm, intercostals, accessory muscles) leads to lung inflation. The downward movement of the diaphragm produces a longitudinal traction of the bronchi and of the trachea. This traction is transmitted to the upper airway and contributes to unloading the upper airway.35 From a dynamic point of view, tracheal traction improves upper airway stability by unfolding upper airway soft tissue and by decreasing extraluminal airway pressure.36,37 Numerous upper airway stabilizing muscles (such as the genioglossus, levator palatini, tensor palatini, geniohyoid, musculus uvulae, palatopharyngeus) contribute to the maintenance of upper airway patency (Fig. 23-6). Activation of masseter and pterygoid muscles may also contribute to stabilizing the upper airway by their influence on the position of the mouth and the mandible.38 The activation profile of the upper airway muscles is characterized by their tonic activity, the respiratory-related and afferent reflex–mediated phasic activities.39 This last factor is an important determinant of activity of the upper airway muscles, the negative pressure developed inside the upper airway having a positive feedback on muscle activity through activation of tensoreceptor and mechanoreceptor pathways.40 Tonic activity contributes to the maintenance of the upper airway aperture, its obligatory fall during sleep leading to a reduction in upper airway volume.41,42 Inspira-
MUSCLES OF PHARYNX: LATERAL VIEW Pharyngobasilar fascia Tensor veli palatini muscle Levator veli palatini muscle Lateral pterygoid plate Pterygoid hamulus Buccinator muscle (cut) Pterygomandibular raphe Buccinator crest of mandible Oblique line of mandible
Digastric muscle (anterior belly) Mylohyoid muscle Hyoid bone Stylohyoid muscle (cut) Thyroid cartilage Median cricothyroid ligament Cricothyroid muscle Cricoid cartilage Trachea
Digastric muscle (posterior belly) (cut) Styloid process Superior pharyngeal constrictor muscle Styloglossus muscle Stylohyoid ligament Stylopharyngeus muscle Middle pharyngeal constrictor muscle Hyoglossus muscle Greater horn of hyoid bone Superior horn of thyroid cartilage Thyrohyoid membrane Inferior pharyngeal constrictor muscle Tendinous arch Zone of sparse muscle fibers Cricopharyngeus muscle (part of inferior pharyngeal constrictor) Esophagus
Figure 23-6 Representation of upper airway (UA) muscles. (Reproduced from Netter FH. Atlas of human anatomy. Philadelphia: Elsevier Saunders; 2006.)
tory phasic activity has an automatic component that is linked with the central respiratory activity through projections of premotor inspiratory neurons to the hypoglossal motor nucleus (see Chapter 21 for more information).43 Neuromodulators (serotonin, norepinephrine, glutamate, thyrotropin releasing hormone, substance P) play a key and complex role in the activity of upper airway muscles.44,45,46,47 In lean animals, resting tonic and phasic activities of the genioglossus muscles mainly depend on endogenous norepinephrine rather than serotonin drive on hypoglossal motor nucleus48,49 but these neuromodulators have similar stimulating effects.48 However, the influence of the serotonin drive on upper airway stabilizing muscle activity may be enhanced if upper airway patency is compromised, as demonstrated by the detrimental effects of serotonin antagonists (ritanserine) on upper airway caliber and stability, and on the occurrence on breathing abnormalities in animal models of obstructive sleep apnea.50,51 Such changes in the balance of the norepinephrine–serotonin drive could result from facilitating hypoglossal nerve activities induced by intermittent hypoxia52 or from the relative vulnerability of norepinephrine and serotonin neurons to intermittent severe hypoxia.53,54 Stimulation of peripheral chemoreceptors by intermittent hypoxia can lead to a prolonged rise in minute ventilation (long-term facilitation)55,56 and a decrease in upper airway resistance (see also Chapter 22).57,58 These ventilatory and upper airway facilitation effects are thought to be mediated by the serotonin-driven changes in activity of the phrenic and hypoglossal nerves52,59 through plasticity. In humans, posthypoxia upper airway facilitation is observed during sleep in subjects who have flow-limited breaths (snorers and apneic subjects)58,60 but is not observed during wake61,62,63 unless periodic desaturation is associated with hypercapnia.64 Apart from the influence of the amount of phasic activation of upper airway muscles, the dynamic profile of this phasic activity plays a key role in the maintenance of upper airway patency. Phasic activation of upper airway muscles precedes and reaches its peak value earlier than that of respiratory muscles.65,66 Phasic activity and the preactivation delay increase with increasing central respiratory activity65,67 and with decreasing upper airway pressure.68 This activation pattern decreases upper airway resistance and prevents upper airway inspiratory collapse. The occurrence of upper airway obstruction in normal subjects during wake, when this pre-activation of upper airway stabilizing muscles is lost (i.e., diaphragmatic pacing, phrenic nerve stimulation, iron lung ventilation),69 further supports the importance of the upper airway muscles’ pre-activation pattern in maintaining upper airway patency. The link that exists between ventilatory and upper airway stability (see later) could result from the common activation process of respiratory and upper airway stabilizing muscles originating from the central pattern generator that would be responsible for the fine tuning in the amplitude and activation pattern of these different muscle groups. Another phasic component comes from the reflex activation of upper airway muscles linked with the decrease in upper airway pressure during inspiration.68 Upper airway mechanoreptor afferents contribute to modulation of the different components of upper airway muscle activity as
CHAPTER 23 • Normal Physiology of the Upper and Lower Airways 265
suggested by the effects of local anesthesia on tonic and phasic activities70 and on genioglossus reflex–mediated negative pressure response.71,72 Therefore, modulating any of these components of the upper airway muscle activation profile can have an influence on upper airway patency73,74 and stability.75,76,77,78
EFFECTS OF SLEEP ON UPPER AIRWAY MUSCLE ACTIVITY The loss of wakefulness stimulus contributes to the sleepinduced decrease in upper airway muscles’ activity.79 Tonic and phasic upper airway activities are significantly altered during sleep.80,81,82 The impact of sleep on the activation profile of upper airway muscles differs among the different muscles. The tensor palatini has a tonic activity, but the genioglossus, palatoglossus, and levator palatini demonstrate phasic activities. These activity levels are higher during wake, but only tensor palatini activity consistently falls at sleep onset.81 The decrease in tensor palatini activity correlates with the sleep-induced rise in upper airway resistance, and there is a compensatory rise in genioglossus activity.83 The tensor palatini and genioglossus muscles strongly differ in their response to negative airway pressure both during wake and sleep,84 no correlation being found between tensor palatini activity and driving pressure. Even if tensor palatini and genioglossus activities are governed by different efferent motor fibers (trigeminal motor nucleus versus hypoglossal motor nucleus), both activities depend on central neuromodulator drive.85,86 The preferential decrease in upper airway muscle tonic activity observed during sleep87 may relate to decrease in central excitatory drive to upper airway motor nuclei coming from the loss of the wake corticomotor stimulating drive and from a decrease in the stimulating effects of neuromodulators.48,49,88,89 Sleep may also compromise upper airway stability by altering the pattern of pre-activation of upper airway muscles.90 The loss of such pre-activation is associated with the rise in upper airway resistance and upper airway closure. The reappearance of EEG alpha activity restores the normal pre-activation pattern with a parallel drop in upper airway resistance and ventilatory resumption. The neuromuscular activation process of upper airway and respiratory muscles are closely linked. Tidal inspiration has a facilitating effect (increase in amplitude and latency of motor response) on diaphragm bulbospinal activity that is enhanced during sleep. This can be attributed to the loss of a wake-related tonic depolarization of phrenic motor neurons with secondary unmasking of the role of the bulbospinal command on the corticomotor excitability of the diaphragm. It is not known how sleep interacts with the facilitating effect of inspiration on upper airway muscle excitability.91 On the other hand, there is evidence that breathing instability during sleep may promote upper airway closure. Obstructive breathing disorders are mainly observed during stages 1 and 2 and REM, where ventilation is physiologically unstable, and rarely during slow-wave sleep, where breathing amplitude and frequency are particularly regular.92 Breathing remains unstable (periodic) following
resumption of upper airway obstruction with tracheostomy in patients with obstructive sleep apnea.93 In normal sleeping subjects, the induction of periodic breathing can lead to partial upper airway obstruction.94 Ventilatory stimulation with CO2 decreases the occurrence of obstructed breaths in sleep apnea patients.95 In patients with moderate increase in upper airway collapsibility, the frequency of obstructive sleep-disordered breathing correlates with the amount of breathing instability.96
FACTORS INFLUENCING STABILIZING AND COLLAPSING FORCES For a given amount of upper airway neuromuscular outflow, the net mechanical effect of the neuromuscular activation process depends on the mechanical effectiveness of the contraction of upper airway stabilizing muscles.97 Such function depends on factors such as the shape and dimensions of the upper airway. In fact, the amount of phasic activity required to maintain a given upper airway cross-sectional area increases when the upper airway axis goes from a transversal to an anteroposterior orientation.98,99 Lung volumes influence upper airway dimension as demonstrated by the decrease in pharyngeal crosssectional area and the increase in upper airway resistance and collapsibility when lung volume decreases from total lung capacity to residual volume.100-102 Upper airway dimension also varies throughout the respiratory cycle, being maximal at the beginning of expiration and minimal at end expiration.103 Vascular tone also interacts with upper airway collapsibility through its effect on upper airway dimension; the decrease in vascular tone or increase in vascular content decreases upper airway caliber but not upper airway collapsibility.104 These physiologic situations can interact with upper airway patency and favor the obstruction of the upper airway if upper airway stability is already compromised (i.e., highly compliant upper airway). The mechanical conditions that prevail during muscle contraction also determine the force they can develop. The suctioning effect of negative intraluminal pressure can result in a lengthening of upper airway muscles during inspiration (eccentric contraction)105 that interferes with their ability to dilate the upper airway and leads to upper airway muscle fatigue and structural damage.106-108 The characteristics of the soft tissues surrounding the upper airway muscles also influence the ability of these muscles to improve upper airway patency, the increase in tissue stiffness altering the transmission of the dilating force to the upper airway structure.109 In the future, electrical stimulation of the hypoglossal nerve may be used to improve upper airway patency.110 CONCLUSION Numerous factors are involved in the regulation of normal breathing, including a predominant role of different muscles such as respiratory and upper airway muscles as well as the mechanical conditions that determine the effectiveness of their contraction. Sleep can interfere with several determinants of normal ventilation such as ventilatory control, skeletal muscle activity, and lung volumes.
266 PART I / Section 4 • Physiology in Sleep
Therefore, because of the influence of thoracopulmonary mechanics on upper airway patency and the close link between respiratory and upper airway muscles, sleep also has a strong impact on upper airway aperture and mechanical properties. A perfect understanding of sleep-related changes in respiratory physiology is key to improving our knowledge of sleep-disordered breathing because these principles are involved in all nocturnal breathing disturbances: hypoventilation, periodic breathing, central apnea, and upper airway closure. ❖ Clinical Pearl Numerous factors contribute to ventilation and mechanical properties of the thoracopulmonary system. As sleep interacts with several of these factors, it has an impact on ventilation and gas exchanges through its effect on airway resistance, thoracopulmonary compliance, and lung volumes. Because of its effect on upper airway muscle control and chest mechanics, sleep has a strong influence on upper airway stability. Persons with compromised upper airway anatomy can thus develop obstructive sleep-induced disordered breathing, especially during the transition between wake and sleep.
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16. Ballard RD, Irvin CG, Martin RJ, et al. Influence of sleep on lung volume in asthmatic patients and normal subjects. J Appl Physiol 1990;68(5):2034-2041. 17. Skatrud JB, Dempsey JA. Airway resistance and respiratory muscle function in snorers during NREM sleep. J Appl Physiol 1985; 59(2):328-335. 18. Gould GA, Gugger M, Molloy J, et al. Breathing pattern and eye movement density during REM sleep in humans. Am Rev Respir Dis 1988;138(4):874-877. 19. Douglas NJ, White DP, Pickett CK, et al. Respiration during sleep in normal man. Thorax 1982;37(11):840-844. 20. Stradling JR, Chadwick GA, Frew AJ. Changes in ventilation and its components in normal subjects during sleep. Thorax 1985; 40(5):364-370. 21. Tabachnik E, Muller NL, Bryan AC, et al. Changes in ventilation and chest wall mechanics during sleep in normal adolescents. J Appl Physiol 1981;51(3):557-564. 22. Mortola JP, Anch AM. Chest wall configuration in supine man: wakefulness and sleep. Respir Physiol 1978;35(2):201-213. 23. Lopes JM, Tabachnik E, Muller NL, et al. Total airway resistance and respiratory muscle activity during sleep. J Appl Physiol 1983;54(3):773-777. 24. Naifeh KH, Kamiya J. The nature of respiratory changes associated with sleep onset. Sleep 1981;4(1):49-59. 25. Trinder J, Whitworth F, Kay A, et al. Respiratory instability during sleep onset. J Appl Physiol 1992;73(6):2462-2469. 26. Thomson S, Morrell MJ, Cordingley JJ, et al. Ventilation is unstable during drowsiness before sleep onset. J Appl Physiol 2005;99(5):2036-2044. 27. Cherniack NS. Respiratory dysrhythmias during sleep. N Engl J Med 1981;305(6):325-330. 28. Khoo MC. Determinants of ventilatory instability and variability. Respir Physiol 2000;122(2-3):167-182. 29. Ayappa I, Rapoport DM. The upper airway in sleep: physiology of the pharynx. Sleep Med Rev 2003;7(1):9-33. 30. Koenig JS, Thach B. Effects of mass loading on the upper airway. J Appl Physiol 1988;64:2294-2299. 31. Isono S, Remmers J, Tanaka A. Anatomy of pharynx in patients with obstrictive sleep apnea and in normal subjects. J Appl Physiol 1997;82:1319-1326. 32. Stauffer JL, Buick MK, Bixler EO, et al. Morphology of the uvula in obstructive sleep apnea. Am Rev Respir Dis 1989;140:724-728. 33. Wolin AD, Strohl KP, Acree BN, et al. Responses to negative pressure surrounding the neck in anesthetized animals. J Appl Physiol 1990;68:154-160. 34. Schwartz AR, Schubert N, Rothman W, et al. Effect of uvulopalatopharyngoplasty on upper airway collapsibility in obstructive sleep apnea. Am Rev Respir Dis 1982;145:527-532. 35. Van de Graaff WB. Thoracic traction on the trachea: mechanisms and magnitude. J Appl Physiol 1991;70:1328-1336. 36. Thut DC, Schwartz AR, Roach D, et al. Tracheal and neck position influence upper airway airflow dynamics by altering airway length. J Appl Physiol 1993;75:2084-2090. 37. Kairaitis K, Byth K, Parikh R, et al. Tracheal traction effects on upper airway patency in rabbits: the role of tissue pressure. Sleep 2007;30:179-186. 38. Hollowell DE, Suratt PM. Activation of masseter muscles with inspiratory resistance loading. J Appl Physiol 1989;67:270-275. 39. Horner RL, Innes JA, Morrell MJ, et al. The effect of sleep on reflex genioglossus muscle activation by stimuli of negative airway pressure in humans. J Physiol 1994;476:141-151. 40. Pillar G, Fogel RB, Malhotra A, et al. Genioglossal inspiratory activation: central respiratory vs mechanoreceptive influences. Respir Physiol 2001;127:23-38. 41. Fogel RB, Trinder J, White DP, et al. The effect of sleep onset on upper airway muscle activity in patients with sleep apnoea versus controls. J Physiol 2005;564:549-562. 42. Strohl KP, Fouke JM. Dilating forces on the upper airway of anesthetized dogs. J Appl Physiol 1985;58:452-458. 43. Peever JH, Shen L, Duffin J. Respiratory pre-motor control of hypoglossal motoneurons in the rat. Neuroscience 2002;110: 711-722. 44. Horner RL. Respiratory motor activity: influence of neuromodulators and implications for sleep disordred breathing. Can J Physiol Pharmacol 2007;85:155-165.
CHAPTER 23 • Normal Physiology of the Upper and Lower Airways 267 45. Sood S, Liu X, Liu H, et al. 5-HT at hypoglossal motor nucleus and respiratory control of genioglossus muscle in anesthetized rats. Respir Physiol Neurobiol. 2003;138:205-221. 46. Jelev A, Sood S, Liu H, et al. Microdialysis perfusion of 5-HT into hypoglossal motor nucleus differentially modulates genioglossus activity across natural sleep-wake states in rats. J Physiol 2001; 532:467-481. 47. Reckling JC. Synaptic control of motoneuronal excitability. Physiol Rev 2000;80:767-852. 48. Sood S, Morrison JL, Liu H, Horner RL. Role of endogenous serotonin in modulating genioglossus muscle activity in awake and sleeping rats. Am J Respir Crit Care Med 2005;172:13381347. 49. Sood S, Raddatz E, Liu X, et al. Inhibition of serotonergic medullary raphe obscurus neurons suppresses genioglossus and diaphragm activities in anesthetized but not conscious rats. J Appl Physiol 2006;100:1807-1821. 50. Veasey SC, Panckeri KA, Hoffman EA, et al. The effects of serotonin antagonists in an animal model of sleep-disordered breathing. Am J Respir Crit Care Med 1996;153:776-786. 51. Nakano H, Magalung UJ, Lee SD, et al. Serotonergic modulation of ventilation and upper airway stability in obese Zucker rats. Am J Respir Crit Care Med 2001;163:1191-1197. 52. Richmonds CR, Hudgel DW. Hypoglossal and phrenic motoneuron responses to serotonergic active agents in rats. Respir Physiol 1996;106:153-160. 53. Zhan G, Serano F, Fenik P, et al. NADPH oxidase mediates hypersomnolence and brain oxidative injury in a murine model of sleep apnea. Am J Respir Crit Care Med 2005;172:921-929. 54. Veasey SC, Zhan G, Fenik P, et al. Long-term intermittent hypoxia: reduced excitatory hypoglossal nerve output. Am J Respir Crit Care Med 2004;170:665-672. 55. Millhorn DE, Eldridge FL, Waldrop TG, et al. Prolonged stimulation of respiration by endogenous central serotonin. Respir Physiol 1980;42:171-188. 56. Bach KB, Mitchell GS. Hypoxia-induced long-term facilitation of respiratory activity is serotonin dependent. Respir Physiol 1996;104:251-260. 57. Shkoukani M, Babcock MA, Badr MS. Effect of episodic hypoxia on upper airway mechanics in humans during NREM sleep. J Appl Physiol 2002;92:2565-2570. 58. Babcock M, Shkoukani M, Aboubakr SE. Determinants of longterm facilitation in humans during NREM sleep. J Appl Physiol 2003;94:53-59. 59. Bocchiaro CM, Feldman JL. Synaptic activity-independent persistent plasticity in endogenously active mammalian motoneurons. Proc Natl Acad Sci 2004;10:4292-4295. 60. Aboubakr SE, Taylor A, Ford R, et al. Long-term facilitation in obstructive sleep apnea patients during NREM sleep. J Appl Physiol 2001;91:2751-2757. 61. McEvoy RD, Popovic RM, Saunders NA. Effects of sustained and repetitive isocapnic hypoxia on ventilation and genioglossal and diaphragmatic EMGs. J Appl Physiol 1996;81:866-875. 62. Jordan AS, Catcheside PG, O’Donoghue FJ, McEvoy RD. Long-term facilitation of ventilation is not present during wakefulness in healthy men or women. J Appl Physiol 2002;93:21292136. 63. Khodadadeh B, Badr MS, Mateika JH. The ventilatory response to carbon dioxide and sustained hypoxia is enhanced after episodic hypoxia in OSA patients. Respir Physiol Neurobiol 2006;150: 122-134. 64. Harris DP, Balasubramaniam A, Badr MS, Mateika JH. Longterm facilitation of ventilation and genioglossus muscle activity is evident in the presence of elevated levels of carbon dioxide in awake humans. Am J Physiol Regul Integr Comp Physiol 2006;291: R1111-R1119. 65. Strohl KP, Hensley MJ, Hallett M, et al. Activation of upper airway muscles before onset of inspiration in normal humans. J Appl Physiol 1980;49:638-642. 66. Van Lunteren E, Van de Graaff WB, Parker DM, et al. Nasal and laryngeal reflex responses to negative upper airway pressure. J Appl Physiol 1984;56:746-752. 67. Parisi RA, Neubauer JA, Frank MM, et al. Correlation between genioglossal and diaphragmatic responses to hypercapnia during sleep. Am Rev Respir Dis 1987;135:378-382.
68. Van Der Touw T, O’Neill N, Brancatisano A, et al. Respiratoryrelated activity of soft palate muscles: augmentation by negative upper airway pressure. J Appl Physiol 1994;76:424-432. 69. Hyland RH, Hutcheon MA, Perl A, et al. Upper airway occlusion induced by diaphragm pacing for primary alveolar hypoventilation: implications for the pathogenesis of obstructive sleep apnea. Am Rev Respir Dis 1981;124:180-185. 70. Fogel RB, Malhotra A, Shea SA, et al. Reduced genioglossal activity with upper airway anesthesia in awake patients with OSA. J Appl Physiol 2000;88:1346-1354. 71. Horner RL, Innes JA, Holden HB, et al. Afferent pathways for pharyngeal dilator reflex to negative pressure in man. J Physiol 1991;436:31-44. 72. Berry RB, McNellis MI, Kouchi K, et al. Upper airway anesthesia reduces phasic genioglossus activity during sleep apnea. Am J Respir Crit Care Med 1997;156:127-132. 73. Hudgel DW, Chapman KR, Faulks C, et al. Changes in inspiratory muscle electrical activity and upper airway resistance during periodic breathing induced by hypoxia during sleep. Am Rev Respir Dis 1987;135:899-906. 74. Oliven A, Odeh M, Gavriely N. Effect of salicylate on upper airway dilating muscles in anesthetized dogs. Am Rev Respir Dis 1989;139:170-175. 75. Sériès F, Marc I. Influence of genioglossus tonic activity on upper airway dynamics assessed by phrenic nerve stimulation. J Appl Physiol 2002;92:418-423. 76. Oliven A, Odeh M, Gavriely N. Effect of hypercapnia on upper airway resistance and collapsibility in anesthetized dogs. Respir Physiol 1989;75(1):29-38. 77. Schwartz AR, Thut DC, Russ B, et al. Effect of electrical stimulation of the hypoglossal nerve on airflow mechanics in the isolated upper airway. Am Rev Respir Dis 1993;147:1144-1150. 78. Philip-Joët F, Marc I, Sériès F, et al. Effects of genioglossus response to continuous negative airway pressure on upper airway collapsibility. J Appl Physiol 1996;80:1466-1474. 79. Lo YL, Jordan AS, Malhotra A, et al. The influence of wakefulness on pharyngeal airway muscle activity. Thorax 2007;62:799805. 80. Shea SA, Edwards JK, White DP. Effects of sleep-wake transitions and rapid eye movement sleep on pharyngeal muscle response to negative pressure in humans. J Physiol 1999;520:897-908. 81. Wheatley JR, Tangel DJ, Mezzanotte WS, et al. Influence of sleep on response to negative airway pressure of tensor palatini muscle and retropalatal airway. J Appl Phsyiol 1993;75:21172124. 82. Horner RL, Innes JA, Morrell MJ, et al. The effect of sleep on reflex genioglossus muscle activation by stimuli of negative airway pressure in humans. J Physiol (London) 1994;476:141-151. 83. Tangel DJ, Mezzanotte WS, White DP, et al. Influence of sleep on tensor palatini EMG and upper airway resistance in normal men. J Appl Physiol 1991;70(6):2574-2581. 84. Malhotra A, Pillar G, Fogel RB, et al. Genioglossal but not palatal muscle activity relates closely to pharyngeal pressure. Am J Respir Crit Care Med 2000;162:1058-1062. 85. Nakamura M, Yasuda K, Hasumi-Nakayama Y, et al. Colocalization of serotonin and substance P in the postnatal rat trigeminal motor nucleus and its surroundings. Int J Dev Neurosci 2006;24(1): 61-64. 86. Kubin L, Tojima H, Davies RO, et al. Serotonergic excitatory drive to hypoglossal motoneurons in the decerebrate cat. Neurosci Lett 1992;139:243-248. 87. Tangel DJ, Mezzanotte WS, Sandberg EJ, et al. Influences of NREM sleep on the activity of tonic vs. inspiratory phasic muscles in normal men. J Appl Physiol 1992;73(3):1058-1066. 88. Kujirai T, Caramia MD, Rothwell JC, et al. Corticocortical inhibition in human motor cortex. J Physiol 1993;471:501-519. 89. Chan E, Steenland HW, Liu H, et al. Endogenous excitatory drive modulating respiratory muscle activity across sleep-wake states. Am J Respir Crit Care Med 2006;174:1264-1273. 90. Hudgel DW, Harasick T. Fluctuations in timing of upper airway and chest wall inspiratory muscle activity in obstructive sleep apnea. J Appl Physiol 1990;69:443-450. 91. Sériès F, Wang W, Mélot C, Similowski T. Concomitant responses of upper airway stabilizing muscles to transcranial magnetic stimulation in normal humans. Exp Physiol 2008;93:496-502.
268 PART I / Section 4 • Physiology in Sleep 92. Cherniack NS. Respiratory dysrythmia during sleep. N Engl J Med 1981;305:325-330. 93. Onal E, Lopata M. Periodic breathing and the pathophysiology of occlusive sleep apneas. Am Rev Respir Dis 1982;126:676-680. 94. Onal E, Burrows DL, Hart RH. Induction of periodic breathing during sleep causes upper airway obstruction in humans. J Appl Physiol 1986;61:1438-1443. 95. Hudgel DW, Hendricks C, Dadley A. Alteration in obstructive apnea pattern induced by changes in oxygen and carbon dioxide inspired concentrations. Am Rev Respir Dis 1988;138:16-19. 96. Wellman A, Jordan AS, Malhotra A, et al. Ventilatory control and airway anatomy in obstructive sleep apnea. Am J Respir Crit Care Med 2004;170:1225-1232. 97. Remmers JE, deGroot WJ, Sauerland EK, et al. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 1978;44:931938. 98. Leiter JC. Upper airway shape. Is it important in the pathogenesis of obstructive sleep apnea. Am J Respir Crit Care Med 1996;153: 894-898. 99. Rodenstein DO, Dooms G, Thomas Y, et al. Pharyngeal shape and dimensions in healthy subjects, snorers, and patients with obstructive sleep apnea. Thorax 1990;45:722-727. 100. Burger CD, Stanson AW, Daniels BK, et al. Fast-CT evaluation of the effect of lung volume on upper airway size and function in normal men. Am Rev Respir Dis 1992;146:335-339. 101. Sériès F, Cormier Y, Desmeules M, La Forge J. Influence of passive changes in lung volumes on upper airway resistance in normal subjects. J Appl Physiol 1990;68:2159-2164.
102. Sériès F, Marc I. Effects of lung volume on upper airway collapsibility in normal awake subjects. J Appl Physiol 1993;75: 1222-1225. 103. Schwab RJ, Gefter WB, Hoffman EA, et al. Dynamic upper airway imaging during awake respiration in normal subjects and patients with sleep disordered breathing. Am Rev Respir Dis 1993;148: 1385-1400. 104. Wasicko MJ, Hutt DA, Parisi RA, et al. The role of vascular tone in the control of upper airway collapsibility. Am Rev Respir Dis 1990;141:1569-1577. 105. Brennick MJ, Parisi RA, England SJ, et al. Influence of preload and afterload on genioglossus muscle length in awake goats. Am J Respir Crit Care Med 1997;155:2010-2017. 106. Petrof BJ, Pack AI, Kelly AM, et al. Pharyngeal myopathy of loaded upper airway in dogs with sleep apnea. J Appl Physiol 1994; 76:1746-1752. 107. Newham DJ, McPhail G, Mills KR, et al. Ultrastructural changes after concentric and eccentric contractions of human muscle. J Neurol Sci 1983;61:109-122. 108. Friberg D, Ansved T, Borg K, et al. Histological indications of a progressive snorers disease in an upper airway muscle. Am J Respir Crit Care Med 1998;157:586-593. 109. Sériès F, Côté C, St. Pierre S. Dysfunctional mechanical coupling of upper airway tissues in sleep apnea syndrome. Am J Respir Crit Care Med 1999;159:1551-1555. 110. Kezirian EJ, Boudewyns A, Eisele DW, et al. Electrical stimulation of the hypoglossal nerve in the treatment of obstructive sleep apnea. Sleep Med Rev 2010 Jan 27. (Epub ahead of print)
Respiratory Physiology: Sleep at High Altitudes John V. Weil Abstract Sleep disturbance is a common cause of discomfort among the constellation of symptoms after ascent to high altitude. Subjectively, the sensation is that of a restless or sleepless night. Individuals commonly experience awakening from sleep with a feeling of suffocation, taking a deep breath, feeling much improved, and falling back to sleep. Objective observations show associated periodic breathing and frequent awakenings but relatively little change in total sleep time. Sleep stages are generally shifted from deeper toward lighter sleep stages. Periodic breathing at altitude seems to reflect the respiratory dilemma of acute altitude ascent in which the stimulatory effects of hypoxia are opposed by the inhibitory action of hypocapnic alkalosis. The outcome is respiratory oscillation. Hypocapnic alkalosis induces apnea, which in turn lessens alkalotic inhibition and augments hypoxic stimulation. This triggers hyperpnea, which lessens respiratory stimulation by decreasing hypoxia and increasing alkalosis, leading to recurrent apnea. The occurrence of altitude related apnea with lessening of ventilatory stimuli is enhanced during sleep.
PHYSIOLOGIC ADJUSTMENT TO HIGH ALTITUDE Primary among the changes in physical environment that attend the ascent to altitude is a decrease in barometric pressure such that although the fractional concentration of O2 is similar to that at sea level, O2 tension—the product of fractional concentration and barometric pressure—is reduced (Fig. 24-1). This decreased O2 tension of ambient air presents a threat to arterial and tissue oxygenation and elicits a series of responses that may act to minimize tissue hypoxia. These consist of early increases in ventilation and cardiac output, and, during more prolonged exposure, rises in circulating red cell concentration and adaptive changes in peripheral tissue, including increased spatial density of capillaries and mitochondria. Reading Chapters 21 and 22 may help one to further understand the physiological changes associated with sleep and breathing in high altitude. Increased Ventilation Probably the earliest, best studied, and one of the most important of these responses is increased ventilation, which acts to minimize the extent of alveolar hypoxia and arterial hypoxemia in the face of a decrease in ambient O2 tension. The magnitude of the ventilatory response increases with increasing altitude, but it also varies considerably among individuals at a fixed altitude. This variability in part reflects intrinsic, interindividual differences in the strength of the basal (preascent) ventilatory response to hypoxia.1 In addition, ventilation progressively increases over several days after ascent to high altitude. This gradual increase occurs despite the fact that the increasing ventila-
Chapter
24
On balance, the poor subjective quality of sleep seems to reflect the fragmentation of sleep by frequent arousals linked to the marked changes in respiratory pattern of periodic breathing. Arousals commonly occur at the transition from the end of apnea to the onset of hyperpnea. Subsequent acclimatization to altitude is associated with lessening of periodic breathing and better-quality sleep. The most common treatment is prophylactic administration of acetazolamide, an inhibitor of carbonic anhydrase, which likely works by reducing alkalotic ventilatory inhibition. The results of recent studies suggest that benzodiazepines and other sleep-promoting agents may improve sleep quality without apparent adverse effects. In this chapter, relevant features of acute physiologic adjustment to high altitude are briefly summarized; then the characteristics of the sleep disturbance at high altitude, its pathogenesis, and therapeutic interventions are reviewed. Although much of the focus is on sleep after acute ascent to high altitude, alterations in sleep during long-term altitude exposure are also briefly mentioned. Information in this chapter may also be relevant to the pathophysiology of central sleep apnea at low altitude (see Section 13).
tion is lessening hypoxia, which is the presumed stimulus to breathing, and increasing hypocapnic alkalosis, which is a ventilatory inhibitor. This is the phenomenon of ventilatory acclimatization to high altitude, which is manifested as a progressive decrease in arterial Pco2 (Paco2) with increasing ventilation over several days. Although the mechanism of acclimatization is debated, studies in humans and animals suggest that increased hypoxic sensitivity of the carotid body may be a major contributor.2 In any case, it is during the early phase of altitude adjustment, shortly after ascent, that sleep disturbances appear to be most marked; they tend to improve during the period of acclimatization. Sleep Disturbances The earliest systematic study of sleep at altitude was a report in 1970 of studies of subjects working in Antarctica, where a combination of geographic elevation and terrestrial spin produces decreased barometric pressure ranging from 485 to 525 mm Hg, equivalent to an altitude of 4500 to 5000 meters. The men stationed there experienced a sleep disturbance termed polar red-eye, and electroencephalographic studies showed major disruption of sleep with a marked decrease in slow-wave sleep (stages 3 and 4).3 Although these changes were ascribed to hypobaric hypoxia, the effects of isolation and disturbances of light– dark cycle that are typical in persons living at the South Pole clouded their interpretation. As research at low altitude began to elucidate the close links between breathing and sleep and showed that sleep disruption was often closely linked to changes in respiratory rhythm, such as occurs in sleep apnea, studies were performed at high altitude with simultaneous monitoring 269
270 PART I / Section 4 • Physiology in Sleep
of sleep state and respiratory pattern. Breathing and sleep interactions were studied in normal subjects at sea level and during a stay of several days on the summit of Pike’s Peak (4300 meters).4 On the initial night after ascent, most subjects exhibited periodic breathing that was present
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during roughly half the time asleep but varied among subjects from 0% to 93%. Sleep was characterized by significant decreases in stages 3 and 4, with an increased number of arousals (Fig. 24-2). In most but not all subjects who initially showed periodic breathing, this tended to decrease over subsequent nights, with a decreased number of arousals. Although there was a trend toward more wakefulness, the duration of sleep (total sleep time) was not significantly reduced compared with that at sea level. Although most of these subjects complained of poorquality sleep, this could not be related to abbreviated sleep, which, as mentioned, was of normal duration. Rather, it seemed associated with an increased number of awakenings. Many of these were synchronous to the transition from termination of apnea to onset of hyperpnea and thus were similar in some respects to the arousal seen in sleep apnea syndromes at low altitude. Although this suggests that periodic breathing, frequent awakenings, and poor-quality sleep are mechanistically interrelated, there must be some reservation about this because increased awakenings in one subject occurred in the absence of periodic breathing and because oxygen administration abolishes periodic breathing but not the increased frequency of awakenings.4-7 It appears, however, that most of the sleep fragmentation at altitude is related to the increased frequency of arousals that are temporally linked to apneas.8
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Figure 24-2 All-night sleep plots for a single subject during a night at sea level (upper plot) and the first night at altitude (lower plot). Time in hours is plotted on the horizontal axis. Lights out occurred at the small vertical arrow in each plot. Sleep stage is shown on the vertical axis: A, awake; R, REM sleep; D, stage 1 sleep; 2, stage 2 sleep; 3/4, stages 3 and 4 sleep combined. Sleep at high altitude was associated with increased fragmentation by frequent awakenings and a reduction in stage 3/4 sleep. (Reprinted from Reite M, Jackson D, Cahoon RL, et al. Sleep physiology at high altitude. Electroencephalogr Clin Neurophysiol 1975;38: 463-471.)
CHAPTER 24 • Respiratory Physiology: Sleep at High Altitudes 271
Poor subjective quality of sleep might also reflect altitude-associated changes in sleep stage distribution. Most studies find that sleep at high altitude is characterized by an increase in light sleep (stage 1) with a decrease in stage 2 sleep, and a relative paucity of deeper stages (3 and 4) of non–rapid eye movement (NREM) sleep. Total sleep time is usually unchanged, but there is a significant increase in time spent awake, and there is shortening of sleep epochs, which are fragmented by frequent arousals.4,5,7,9 There seems to be no consistent change in the amount of rapid eye movement (REM) sleep, which is variably found to be either unchanged,4,7 increased, or decreased6,10 at altitude. The disparity between subjective evaluation of sleep quality and the objective findings of normal sleep duration most likely reflects the importance of sleep continuity in the apparent subjective quality of sleep and suggests that sleep fragmentation despite normal cumulative duration produces the impression of sleeplessness.4,8,11,12 As mentioned earlier, total sleep time is remarkably preserved or even increased4,8,11,12 in the face of the disruptive effect of periodic breathing. Perhaps this paradox is explained by the frequent but largely unstudied observation that ascent to altitude induces sleepiness, which is consistent, prompt, and often profound. Although this may be due to hypoxia, a study in normal subjects at low altitude showed marked sleepiness induced by brief voluntary hyperventilation, pointing to a potential role of hypocapnia.13 Regardless of its cause, the hypnotic effect of altitude could contribute to the maintenance of total sleep duration. Hypocapnia may also suppress REM sleep; a study in sleeping cats at simulated altitude and during mechanical hyperventilation showed decreases in REM sleep that were reversed by CO2 administration.14 In summary, on the first few nights following ascent to altitude, sleep is typically of near normal duration with increases in sleep stages 1 and 2 and decreases in stages 3 and 4. Periodic breathing is present in a substantial proportion of sleep with frequent arousals and disruption of sleep continuity.
PERIODIC BREATHING In the mid-19th century, Cheyne and Stokes described the crescendo–decrescendo breathing pattern in cardiac patients that now bears their names.15 That periodic breathing is frequent during sleep in normal individuals at high altitude was observed shortly thereafter by Tyndall in 1857, by Egli-Sinclair and Mosso in 1893 and 1894, and by Douglas and colleagues16 in 1913, and it continues to be a consistent finding in current studies of sleep after ascent to high altitude.4,9,17-20 The respiratory dysrhythmia of sleep at altitude is one of machinery-like periodicity (Fig. 24-3) similar to that seen at low altitude in patients with heart failure (see Chapter 122) or with central nervous system (CNS) disorders. The temporal pattern of periodic breathing and its linkage to sleep stages show some night-to-night variation and considerable intersubject differences,4,6,10,19,21-25 yet on balance, periodicity is usually evident early in sleep and during light stages. Periodic breathing at altitude may also occur in wakefulness, especially during periods of drowsiness.26-28 The pattern, as mentioned, is similar to that of
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Figure 24-3 Breathing pattern and arterial oxygen saturation (SaO2) in a normal subject during sleep at high altitude (4300 meters). Such a pattern is seen throughout much of sleep in most individuals after ascent. There is characteristic, monotonously repetitive, machinery-like periodic alternation of apnea and repetitive clusters of hyperpneic breaths. (From Weil JV, Kryger MH, Scoggin CH. Sleep and breathing at high altitude. In: Guilleminault C, Dement WC, editors. Sleep apnea syndromes. New York: Alan R Liss; 1978. p. 119-136.)
patients with central apnea at low altitude, but with shorter cycle length ranging from 12 to 34 seconds, which progressively shortens with increasing altitude29-31 and differs from the longer cycles of 40 to 90 seconds in patients with heart failure.32 The shorter cycle length at altitude is thought attributable to increased peripheral chemoreceptor sensitivity.33 The most obvious aspect of this periodicity is the oscillation of tidal volume, and with a less obvious change in breathing frequency. However, there are subtle, but parallel, variations in frequency that produce a reinforcing effect on ventilatory oscillation.29 Like periodic breathing at sea level, periodicity at altitude is often initiated by movement or a deeper breath with a transient increase in hypocapnia. Periodicity at altitude is also most prevalent in light, stage 1 or 2 sleep. Although deeper stages of NREM sleep are relatively rare after acute ascent, the propensity to periodic breathing seems much reduced at these times. The most striking influence of sleep stage on periodic breathing is the observation in most,4,7,25 but not all,5,6 studies that REM sleep promptly and consistently terminates periodicity and restores regular breathing However, periodicity seems to persist in REM sleep at altitudes greater than 4300 meters.8 To our knowledge, no data are yet available on the long term risks of high-altitude sleep on health for either occasional or regular high-altitude sleepers. During sleep, ventilation and oxygenation fall below waking values, and the relative sleep induced decreases are similar at altitude and at sea level.34 However, the important difference is that at altitude, basal (awake) oxygenation and Pco2 are lower and thus closer to critical ventilatory thresholds (Fig. 24-4). Oxygen tensions fall closer to the descending limb of the dissociation curve, where values are associated with desaturation and are nearer the threshold for stimulation of ventilation. Similarly, CO2 tensions fall to values nearer the “dog-leg,” below which CO2 may lose its ventilatory stimulus potential, and they closely approach the Pco2 apneic threshold below which breathing ceases during sleep.35 As a result, small variations in gas tensions have much greater effects on ventilation at altitude with greater stimulation by hypoxia and increased inhibition by hypocapnia.
Vent-response curve
Vent-response curve
272 PART I / Section 4 • Physiology in Sleep
Altitude S Sea level W
S
W
W Sea level
S
Altitude
W
W Awake
Altitude
High
Low PO2
Sea level
S
S
Low
Sleep High
PCO2
Figure 24-4 A schematic illustration of the relationship of blood gases to ventilatory responses during wakefulness and sleep at sea level and high altitude. At altitude, during wakefulness (W), arterial oxygen tensions (PO2) move lower toward the steeper portion of the hypoxic ventilatory response curve, an effect that is augmented during sleep (S). Hyperventilation causes arterial PCO2 tensions during wakefulness and sleep to decrease and move closer to the “dog-leg” of the CO2 response curve, where the ventilatory response to PCO2 is greatly reduced. The result is that during sleep at high altitude, small changes in the partial pressure of either oxygen (PO2) or carbon dioxide (PCO2) produce much greater changes in ventilation than at low altitude. This sets the stage for respiratory instability.
Respiratory pauses in sleep at altitude are mainly of central origin, unassociated with snoring or other noises suggestive of obstruction and accompanied by decreased rib cage and abdominal activity.5,7,17,19,36 There is no evident association with the usual risk factors for obstruction, such as obesity. However, at low altitude, many apneas are “mixed” with both central and obstructive features.37,38 This is most likely a reflection of the phasic “respiratory” nature of many upper airway muscles such that loss of drive reduces activation of both classic inspiratory muscles and those responsible for maintenance of upper airway patency. The hypoxia of altitude may act to decrease airway obstruction. A study of subjects with known obstructive sleep apnea at low altitude showed that at a simulated altitude of 2750 meters obstructive events were entirely replaced by central apneas.39 This likely reflects an increase in ventilatory drive in hypoxia which may augment the activity of muscles of the upper airway.40 On the other hand, sleep studies of subjects living at moderate altitude (above 2400 meters) that were conducted at a lower altitude (1370 meters) in comparison to the altitude of residence, show that at lower altitude, the respiratory disturbance index (RDI) was reduced. This is largely due to a decrease in central events compared to studies at the higher altitude of residence. There was no change in frequency of obstructive apneas, although the latter were more prolonged at a low altitude.41 This finding points to the importance of performing diagnostic sleep studies at the altitude of residence, that is, the places where the subjects are living on a regular basis. As mentioned, sleep disturbances and periodic breathing seem to be most pronounced during the first few nights after ascent to moderate altitude, with a tendency toward more regular breathing on subsequent nights. However, most studies find substantial interindividual differences in the extent and persistence of periodic breathing and several studies describe the prolonged persistence of periodic breathing over 10 days to 5 weeks at altitudes greater than
4500 meters.19,36,42,43 This might reflect incomplete acclimatization at very high altitudes. Mechanisms In the early 1900s, ingenious experiments done at low altitude explored the physiologic mechanisms of periodic breathing and highlighted the importance of both hypoxia and hypocapnia.44 The authors were aware that during wakefulness, breathing was characterized by intrinsic momentum, a “flywheel” effect that caused breathing to continue despite brief hypocapnia. The study revealed also that respiratory periodicity could be readily induced in normal subjects by intense, sustained voluntary hyperventilation with room air, which produced apnea followed by Cheyne-Stokes respiration. When hyperventilation was produced with an O2-enriched gas, apnea was induced without periodic breathing. Such findings indicate the importance of hypoxia in the induction of breathing periodicity. Furthermore, they also support the specific role of phasic hypoxia through the application of dead space containing the CO2 absorber soda lime, which produced rebreathing-induced hypoxia without the usual attendant hypercapnia. When the resulting progressive hyperpnea produced an increase in tidal volume sufficient to bring in “fresh air” replete with O2, the resolution of hypoxia produced apnea followed by recurrent rebreathinginduced hypoxia and perpetuation of the cycle. These findings pointed to the combined roles of hypocapnia, which initiates apnea, and hypoxia, which stimulates hyperpnea, in the genesis of periodic breathing. Similar principles apply at high altitude, as suggested by findings that the administration of O2 or CO2 abolishes periodic breathing.4,17,22,36 Roles of Hypoxia and Hypocapnia Interpretation of the specific roles of O2 and CO2 is complicated, firstly because O2 administration improves oxygenation but also reduces ventilation and increases Paco2
CHAPTER 24 • Respiratory Physiology: Sleep at High Altitudes 273
with lessening of alkalosis. Secondly, the administration of CO2 corrects respiratory alkalosis but also increases ventilation and improves oxygenation. Despite this difficulty, considerable evidence suggests that although hypoxia may be contributory, hypocapnic alkalosis may have a particularly important role. Respiratory alkalosis is typical in patients with classic Cheyne-Stokes respiration at low altitude45 and occurs in normal subjects in whom apneas during sleep have been noted to occur after transient episodes of decreased end-tidal Pco2 and presumed increase in blood pH.26 The critical role of hypocapnia in periodic breathing in sleep at altitude became clearly evident when periodic breathing in NREM sleep at simulated altitude (barometric pressure of 455 mmHg equivalent to an altitude of 4300 meters) was abolished by a selective increase in Paco2.17 This was achieved through the administration of low levels of CO2 with added nitrogen to prevent the increase in oxygen saturation (Sao2) that would be anticipated as a result of the stimulation of ventilation by a rising Paco2. In one subject, during NREM sleep, the appearance of periodic breathing during the induction of hypoxia was temporally related closely to the fall in end-tidal CO2 rather to the decrease in Po2. Similarly, this study showed that breathing was regular in NREM sleep in hypoxia when CO2 was added to maintain isocapnia. However, when CO2 administration was terminated, periodic breathing occurred when the end-tidal CO2 fell, although the extent of hypoxia remained constant. The Apneic Threshold An experimental study showed that apneas could be consistently produced at low altitude in NREM sleep through the induction of hypocapnia by passive positive-pressure hyperventilation against a background of either hypoxia or hyperoxia.46 Apnea tended to occur when the end-tidal CO2 was lowered 1 to 3 mm Hg below levels observed during wakefulness (the apneic threshold). Thus, hypoxia alone seems insufficient to produce periodic breathing, for which a fall in Pco2, below an apneic threshold, seems important (Fig. 24-5). Just as apneas at low altitude frequently follow sighs or breaths of increased tidal volume with a drop in Pco2,26 breaths of increased tidal volume with decreased end-tidal Pco2 often trigger periodic breathing at altitude.17,36 It thus appears that the events leading to periodic breathing at altitude begin with hypoxia, which stimulates hyperventilation, and the resulting hypocapnic alkalosis induces apnea, as illustrated in Figure 24-6. Apnea, in turn leads to enhanced ventilatory stimulation by increasing hypoxemia and lessening hypocapnic alkalosis, which promotes subsequent hyperpnea and arousal. The ensuing increase in ventilation lessens hypoxia and restores hypocapnic alkalosis, promoting the recurrence of apnea. Indeed, another study suggested that a stable and slightly elevated Pco2 is necessary for stable rhythmic breathing during low-altitude sleep.26 Role of Decreased PCO2 versus Increased pH in the Generation of Apnea It is clear that apneas at altitude are reversed by the administration of CO2, but this also reverses alkalosis. Observations described later show the resolution of periodic
Periodic breathing
Regular breathing O2 administration
100
Normoxia
90 SaO2 (%)
80
CO2 administration
70 Hypoxia
60
35
40
45
PaCO2 mm Hg Figure 24-5 Relationship of respiratory pattern to arterial partial pressure of CO2 (PaCO2) and oxygen saturation (SaO2). This figure is a schematic representation of data of Berssenbrugge et al.17 and demonstrates that reduction in PCO2 is a critical determinant of periodic breathing in normal human subjects during hypoxia. Even a small increase in PCO2 after administration of either O2 or CO2 restores normal breathing. This effect seems largely independent of changes in SaO2. (From Weil JV. Sleep at high altitude. Clin Chest Med 1985;6:615-621.)
Altitude ascent hypoxia
Sleep
Hyperventilation Hypocapnic alkalosis Ventilatory inhibition
Apnea
↑PCO2 /↓ PO2 Ventilatory stimulation
↓PCO2 /↑ PO2
Hyperventilation arousal
Figure 24-6 Schematic summary of mechanisms responsible for periodic breathing during sleep at altitude. Altitude-induced hypoxia stimulates increased ventilation. The resulting hypocapnic alkalosis together with the effects of sleep promotes apnea. During altitude-related apnea, increasing hypoxemia and lessening of hypocapnic alkalosis stimulate resumption of ventilation and arousal. This augments oxygenation and lessens hypocapnic alkalosis, permitting recurrence of apnea.
breathing during acclimatization and its prevention by the use of inhibitors of carbonic anhydrase. In both instances, hypocapnia is, if anything, accentuated whereas alkalosis is reduced, which suggests a dominant role for decreased pH in the genesis of apnea.
274 PART I / Section 4 • Physiology in Sleep
Chemosensory Mechanisms Ventilatory oscillation in response to the rapidly changing arterial blood gases in periodic breathing points to an important role for the fast-responding carotid body in the genesis of this respiratory periodicity. Studies in sleeping dogs with denervation or isolated perfusion of the carotid body show that carotid body chemoreception is necessary for induction of periodic breathing after a ventilatory overshoot induced by mechanical ventilation. The findings showed that carotid body silencing by hypocapnia likely contributes to acute posthyperventilation apnea.35 The importance of hypocapnia and alkalosis in the genesis of periodic breathing suggests, in turn, a role for the strength of the ventilatory response to the hypoxia of high altitude, which is the primary cause of hyperventilation and hypocapnia after ascent. Theoretical considerations suggest that increased controller gain contributes to respiratory instability and periodicity.33,47-49 These models emphasize the role of the curvilinear peripheral chemoreceptor response to hypoxia (for which the slope [gain] increases in hypoxia) and the steepening of the ventilatory response to hypercapnia by hypoxia. In a study of healthy subjects after acute ascent to high altitude, it was found that the extent of periodic breathing was greatest in subjects with the highest ventilatory responses to both hypoxia and hypercapnia measured before and after ascent.34 Several subsequent studies have reaffirmed the association of high hypoxic ventilatory responses and periodic breathing in sleep at a high altitude17,19,21,22,36,42 (Fig. 24-7), although some have found no relationship.31,50 A steeper slope of ventilatory response to hypercapnia might imply a greater inhibitory action of hypocapnia. Two studies
RELATION BETWEEN PERIODIC BREATHING AND HYPOXIC VENTILATORY RESPONSE 100
Percent PB
80 r = 0.86 P < .05
60
40
20
0 0
1
2
3
HVR (L/min/kg) Figure 24-7 Positive correlation of prevalence of periodic breathing (PB) in sleep at 6542 meters and hypoxic ventilatory response (HVR). (From Goldenberg F, Richalet JP, Onnen I, et al. Sleep apneas and high altitude newcomers. Int J Sports Med 1992;13:S34-S36.)
suggest an association of periodicity with increased hypercapnic ventilatory response,19,34 but this is less consistent than the correlation with hypoxic response. Finally, recent studies in rats with isolated CNS and peripheral perfusion indicate that central hypocapnia induces increased peripheral chemoreceptor hypoxic sensitivity—a possible contributor to periodicity in hypocapnic states.51 Hypocapnia also alters the control of cerebral blood flow. Studies of sleep at high altitude report an association of the extent of periodic breathing with impairment of the cerebral blood flow responses to changes in Pco2. The normal central vasodilation with hypercapnia and vasoconstriction with hypocapnia tend to preserve CNS acid-base homeostasis in the face of changes in arterial Pco2 and loss of this regulation may contribute to respiratory instability at high altitude and in patients with heart failure.52 Role of Sleep A series of studies demonstrated that the withdrawal of classic stimuli to breathing by the administration of O2, induction of metabolic alkalosis, or blockade of vagal afferents led to little change in respiratory rhythm during wakefulness but to profound pauses and slowing of breathing in sleep.53 This echoes the suggestion of other investigators related to the fact that wakefulness acts in some fashion to sustain respiratory rhythm even in the absence of ventilatory stimuli, but that during sleep the maintenance of respiratory rhythm becomes critically dependent on such stimulation.28,44 Hyperventilation thus seems to be an excellent way to induce a respiratory pause in sleep because it simultaneously induces hyperoxia and withdrawal of hydrogen ion–CO2 stimulation. Indeed, posthyperventilation apnea, which is variable in occurrence in wakefulness54 but consistently found in sleep, is likely an example of such a relationship.46 Influence of Altitude Acclimatization The extent of periodic breathing shows a progressive decline over successive nights at moderate altitude, less than 4500 meters,34 which suggests that the process of ventilatory acclimatization to altitude may act in some fashion to decrease the tendency toward periodic breathing. This is in some respects paradoxical, because the increased hypoxic ventilatory response and decreased Pco2 and persistent alkalosis seen with acclimatization would be expected to increase periodic breathing. It may be that acclimatization acts to lessen the inhibitory effects of respiratory alkalosis on ventilation or produces local correction of alkalosis at some chemosensitive site and thus reduces the absolute value of Paco2 required to produce an apnea (apneic threshold). However, increasing altitude appears to increase the persistence of periodic breathing and sleep disruption. At an altitude of 3776 meters, increases in arousals and awake time were found to persist for 5 days,55 and at a simulated altitude of 5050 meters, periodic breathing and increased frequency of arousals were found to persist for 4 weeks.43 Consequences of Periodic Breathing Fragmentation of sleep by frequent awakenings is an important probable byproduct of periodic breathing, which is, in turn, a contributor to the subjective sense of
CHAPTER 24 • Respiratory Physiology: Sleep at High Altitudes 275
poor-quality sleep. As mentioned, arousals often occur in close synchrony to apnea termination—so close that it is unclear whether arousal stimulates resumption of breathing or the resumption of breathing causes arousal. It also is unclear whether these arousals are triggered by chemosensory responses to apnea-induced asphyxia, by mechanical stimuli, or by central command signals associated with the abrupt resumption of breathing. Observations at low altitude suggest that apnea-associated arousals correlate poorly with chemical variables but have a consistent relationship to mechanical stimuli, suggesting linkage to the resumption of ventilatory effort rather than to blood chemistry.56 Regardless of the precise cause of arousal, it seems likely that the awakening or lightening of sleep stage contributes to periodicity by reversing the respiratory depressant influence of sleep and enhancing the postapneic hyperpnea. Although periodic breathing likely contributes to the generation of arousals, as mentioned, a clear dissociation is seen with O2 administration, which abolishes periodic breathing but fails to prevent arousals.4 Factors responsible for this residual excess remain unknown. The net influence of periodic breathing on average ventilation in sleep at altitude is incompletely understood. Although it has been suggested that the respiratory pauses may exaggerate nocturnal hypoxemia,57 most studies show little effect on average ventilation. Indeed, when a difference is found, there appears to be better ventilation and oxygenation during periodic than during regular breathing, with a lesser incidence of symptoms of altitude adaptation that are linked to relative hypoventilation.7,8,19,21 The association of periodic breathing with better ventilation may reflect the association of periodicity with increased chemosensitivity, which raises the level of overall ventilation. It may also be that periodic breathing is mechanically and energetically efficient. The high tidal volumes of the hyperpneic phase enhance relative alveolar versus dead space ventilation, and apneas conserve respiratory muscle work. Modeling suggests that optimal oxygenation, at least “pressure cost,” is produced by clusters of two to four large breaths separated by apneas.29,58 Such a pattern might be especially efficient at altitude, where decreased air density reduces the respiratory pressure cost. However, it has been suggested that the potential benefits of periodicity may be most evident at low to moderate altitudes, whereas at elevations greater than 3500 meters, associated sleep fragmentation overrides any benefits of periodicity.59 Relationship of Sleep Disturbance and Periodic Breathing to Altitude Syndromes Rapid altitude ascent is often associated with two wellrecognized syndromes of acute altitude maladaptation: acute mountain sickness (AMS; manifested by loss of appetite, nausea, vomiting, decreased mental acuity, insomnia, and, in rare cases, coma) and high-altitude pulmonary edema (HAPE). Although these are most common in the early postascent period when sleep disturbance and respiratory periodicity are also most pronounced, most studies find that periodic breathing in sleep is not correlated with the development or severity of these syndromes. Indeed, in subjects with pronounced altitude syndromes, periodic breathing tends to be replaced by an irregular, nonperiodic pattern (Fig. 24-8).5,21 However, in one study, periodic
1 min Figure 24-8 Impedance plethysmograms show irregular, nonperiodic, breathing during sleep at 2850 meters in four subjects susceptible to high-altitude pulmonary edema. (From Fujimoto K, Matsuzawa Y, Hirai K, et al. Irregular nocturnal breathing patterns at high altitude in subjects susceptible to high-altitude pulmonary edema [HAPE]: a preliminary study. Aviat Space Environ Med 1989; 60:786-791.)
breathing was found to be more frequent in those with HAPE than in those with AMS or in control subjects.60 This might be a result of stimulation of intrapulmonary afferents and ventilation–perfusion imbalance related to pulmonary edema with consequent exaggerated hypoxemia and hypocapnia. As mentioned, periodic breathing is linked to increased hypoxic ventilatory response, which may improve oxygenation and reduce the likelihood or severity of these maladaptive syndromes. It may be that AMS is more associated with hypoxemia rather than periodic breathing during sleep as suggested by a study in trekkers that found a trend toward an association of sleep hypoxemia with the severity of AMS.61 However the role of sleep was questioned by a study of high-altitude expedition members, which found that headache (a common feature of AMS) occurred only 26% of the time during sleep or on awakening.62 The well-known decline in daytime intellectual function at altitude most likely reflects in part the CNS effects of hypoxemia compounded by the cerebral vasoconstrictor effects of hypocapnia and sleep fragmentation.63 Living High, Training Low This strategy, commonly used by athletes as an adjunctive conditioning measure, typically entails sleeping at moderate simulated altitudes of 2500 to 3000 meters, usually in a normobaric hypoxic room or tent, with daytime training at altitudes below 1250 meters. These conditions may differ from those at true altitude because these closed normobaric rooms or tents tend to retain some expired CO2 which may reduce periodic breathing. Most studies of sleep under such conditions have been done on the first night of exposure. Nocturnal oxygen saturations are moderately reduced, by about 6%, to a level of 89% to 90% accompanied by increases in periodic breathing, respiratory disturbance indices and arousals.64-67 Typically these studies find large interindividual variation in the extent of these changes. One study tested the idea that this variation might reflect differences in the strength of the hypoxic ventilatory response among subjects, but found no correlation of preascent measures of the response to findings in sleep at simulated altitude.66
276 PART I / Section 4 • Physiology in Sleep
Sleep architecture shows variable changes that include decreased slow-wave64 and REM sleep,66 whereas others find no changes.67 As mentioned, most studies are of a single night’s exposure, and so they shed no light on the extent and influence of acclimatization. However, two studies of successive night’s of simulated altitude exposure found an increase in oxygenation likely due to acclimatization,68,69 and one study showed persistence of an increase in RDI and arousal on both the 15th and 18th nights of exposure.69 The extent to which these changes influence daytime function is not entirely clear. Studies report variable impairment of function, sleepiness, and fatigue,64,67,68 but no apparent symptoms of AMS.68
TREATMENT The treatment and prophylaxis of sleep abnormalities at high altitude is similar to those used to control the daytime syndrome of AMS. Staged, gradual ascent to altitude is an effective way to prevent or blunt sleep-related symptoms, but this may be inconvenient. Pharmacologic approaches include carbonic anhydrase inhibitors, hypnotic agents, stimulators of peripheral chemosensitivity, and progestational agents. Noninvasive positive pressure ventilation has also been evaluated as a possible treatment.69a Carbonic Anhydrase Inhibitors Acetazolamide is the most common and best studied agent used for amelioration of sleep disturbance at altitude; it has the advantage of also reducing symptoms of AMS.70-73 This class of agents produces marked reductions in periodic breathing in sleep with higher and less oscillatory Sao2 (Fig. 24-9).22,74 In two studies of sleep at altitude, acetazolamide markedly improved both the mean level and the stability of arterial oxygenation during sleep and reduced the proportion of sleep time during which periodic breathing occurred by roughly 50%.20,25 However, the linkage of decreased periodic breathing to improved average oxygen-
ation is variable. Awakenings that occur more frequently in sleep at high altitude are reduced and subjective and objective sleep quality is improved with augmentation of stage 2 sleep and decreased wakefulness.20,25 Mechanisms responsible for the beneficial effects of acetazolamide are the topic of continuing investigation and debate.75 However, the primary action of these agents is likely the blockade of enzymatic hydration of CO2 to carbonic acid in a wide array of sites including kidney, peripheral chemoreceptors, red blood cells and brain.76 Blockade of carbonic anhydrase could also promote the accumulation of CO2 in tissue, which might be responsible for the increase in cerebral blood flow induced by the intravenous administration of acetazolamide77 and could stimulate central chemoreceptors. However, these central effects are minimal or absent with the relatively low doses used for symptom reduction at altitude,78,79 and selective agents with action limited to the kidney seem as effective as acetazolamide in reducing periodic breathing.73 Thus, the main mechanism of action is most likely the renal tubular effect with induction of systemic metabolic acidosis (Fig. 24-10). Reduction in respiratory periodicity with these agents may be in part the result of lessening of hypoxemia secondary to stimulation of ventilation by acidosis, but carbonic anhydrase inhibitors have a similar utility in eliminating central apneas at low altitude,80,81 where hypoxemia is not a likely factor. Studies in animals indicate that acetazolamide blunts peripheral chemoreceptor sensitivity possibly due to inhibition of the linkage of changes in Pco2 to oscillation of intracellular pH76 or to other actions independent of carbonic anhydrase inhibition.75 This reduction in the fast-response peripheral chemoreceptor activity combined with increased activity of slow responding central chemoreceptor drive related to systemic metabolic acidosis may explain the reduction in periodic
Hypoxia
80
Acetazolamide
Hyperventilation
Kidney
SaO2 (%)
70 60
Hypocapnia
50 Alkalosis
X
Bicarbonate diuresis
X 0
1
2
3
4
5
6
Hours of sleep Figure 24-9 Average arterial oxygen saturation (SaO2) in a sleeping subject at altitude (5360 meters) without (blue area) and with (yellow area) acetazolamide. Treatment raised and stabilized arterial oxygen saturation. (From Sutton JR, Houston CS, Mansell AL, et al. Effect of acetazolamide on hypoxemia during sleep at high altitude. N Engl J Med 1979;301: 1329-1331.)
Apnea Figure 24-10 Schematic representation of potential mechanisms by which carbonic anhydrase inhibitors (e.g., acetazolamide) decrease periodic breathing during sleep at high altitude. These agents promote a bicarbonate diuresis, which lessens alkalosis and reduces apnea but augments hyperventilation and hypocapnia. This suggests that alkalosis may be more important than hypocapnia in the genesis of periodic breathing.
CHAPTER 24 • Respiratory Physiology: Sleep at High Altitudes 277
breathing.76 In sleeping dogs with mechanically induced ventilatory overshoot, acidosis lowers the apneic Pco2 threshold relative to basal levels and thus increases the drop in Pco2 required to induce apnea (the CO2 reserve), an action that may contribute to the reduction of periodic breathing with acetazolamide.35,82 Administration of acetazolamide raises ventilation with improved oxygenation and greater hypocapnia during wakefulness and sleep at altitude,70,71 suggesting an effect on ventilatory control. Although hypoxic and hypercapnic ventilatory responses are shifted upward (higher ventilation at all points), the steepness of the relationship is unchanged, indicating no potentiation of ventilatory sensitivity.25,74,83-85 Overall, the findings suggest that these agents act primarily on the kidney to produce a metabolic acidosis, which drives ventilation without any clear effect on peripheral or central chemoreceptor sensitivity. Benzodiazepines Benzodiazepine medications can substantially reduce hypoxic ventilatory responses86 and were once thought to be hazardous in patients with respiratory disorders of sleep. However, recent evidence suggests that in low doses they are relatively safe in such situations and seem to produce no increase in sleep-disordered breathing in older87 or in nonselected patients with apnea.88 In sleeping patients with chronic obstructive pulmonary disease, there is no clear increase in apnea or hypopnea or worsening of hypoxemia,89,90 and little or no adverse effect is seen in patients with obstructive apnea.91 In patients with heart failure, temazepam decreased arousals and improved daytime alertness with no change in the extent of periodic breathing or oxygenation in sleep.92 Three studies suggest the safety and potential utility of these agents in the sleep disturbance of high altitude.5,93,94 Shortened latency, decreased arousals, increased sleep efficiency, increased REM sleep, and subjectively better sleep were evident with low-dose temazepam is subjects sleeping above 4000 meters.94 Benzodiazepines may also slightly reduce periodicity, augment slow-wave sleep, and reduce wakefulness during acclimatization but not in early nights after ascent.5 In a single-blinded, randomized protocol in subjects at 5300 meters, temazepam (10 mg) consistently improved subjective sleep quality, with quicker onset, fewer awakenings, and less awareness of periodic breathing than placebo. Subjects felt more rested the following day. Compared to placebo, mean Sao2 in sleep was unchanged and oscillations in Sao2 were reduced.93 Other Agents Zolpidem and zalepon have been found to be well tolerated at altitude. A study of these agents at a simulated altitude of 4000 meters, and another in trekkers at 3613 meters showed that compared to placebo, both agents increased sleep efficiency and decreased wakefulness and that zolpidem increased slow wave sleep. Neither drug had an effect on nocturnal respiratory pattern or oxygen saturation and neither decreased daytime cognitive or physical performance.95,96 Almitrine, which stimulates the carotid body and augments hypoxic ventilatory responses, augments arterial oxygenation during sleep but increases respiratory period-
icity.42 These effects would be expected to decrease the continuity and subjective quality of sleep, but this has not been directly studied. Theophylline, which had been shown to reduce symptoms of acute mountain sickness, improves sleep acutely after ascent to moderate altitude (3454 meters) with marked reductions in sleep disordered breathing, desaturation index and arousals to an extent comparable to findings with acetazolamide.97 It has been suggested that this agent might be useful in subjects in whom acetazolamide is contraindicated due to sulfonamide hypersensitivity. However, 70% of subjects experienced palpitations with theophylline raising the possibility of arrhythmic risk. Progestational agents such as medroxyprogesterone acetate substantially reduce periodic breathing with little change in oxygenation in sojourners,25 but they have greater effects on oxygenation in long-term residents with chronic mountain sickness.18 Whether other agents that are used to treat HAPE (such as calcium channel blockers and glucocorticoids) affect breathing, oxygenation, and symptoms related to sleep remains unknown.
SLEEP AT HIGH ALTITUDE AFTER LONG-TERM ADAPTATION Little is known about sleep and breathing in normal longterm residents of high altitude, although some data can be found in the literature.98 In Leadville, Colorado, with an altitude of 3100 meters, normal subjects have sleep duration and distribution of stages comparable to those in subjects at lower altitude, and similar findings were reported in healthy natives in the Andes at 4330 meters,99 but in neither study were direct comparisons were made. Although little or no prolonged sleep apnea was noted in such subjects, the majority did have various kinds of respiratory dysrhythmia, typically an undulant oscillation in depth of breathing without true apnea but with swings in Sao2 (Fig. 24-11). Because these subjects were middle-aged men, in whom respiratory dysrhythmias are known to be common during sleep at low altitude, it is unclear to what extent the breathing in sleep at chronic
Breathing pattern
SaO2 (%)
90 80 70
88% 78%
Figure 24-11 Breathing pattern and arterial oxygenation in a subject with chronic mountain polycythemia during sleep at his native altitude of 3100 meters. The breathing pattern consists of an undulating depth of breathing with oscillation of arterial oxygen saturation (SaO2). (From Kryger M, Glas R, Jackson D, et al. Impaired oxygenation during sleep in excessive polycythemia of high altitude: improvement with respiratory stimulation. Sleep 1978;1:3-17.)
278 PART I / Section 4 • Physiology in Sleep
high altitude truly differs from that at sea level. It is possible that arterial desaturation induced by high altitude shifts Sao2 during sleep to the steeper portion of the dissociation curve and thereby amplifies the influence of ventilatory dysrhythmia on Sao2. Ventilatory and Sao2 oscillations similar to those observed by Kryger and colleagues98 have also been described at high altitude by Lahiri and colleagues36 in Sherpas native to high altitude but not in Sherpas native to low altitude. The potential contribution of ethnic and/ or genetic differences is suggested by a study comparing Tibetan and Chinese Han residents of 4000 meters. Sleep was studied in a hypobaric chamber at simulated altitudes of 2261 and 5000 meters. At the higher altitude, Tibetans had more periodic breathing, higher Sao2, and better sleep structure than did the Han subjects.100 Although decreased hypoxic ventilatory response during wakefulness has been observed in natives of Leadville101 and in Sherpas native to high altitude,102 it is unclear whether this contributes to respiratory dysrhythmia and hypoxemia in highlanders during sleep at altitude. However, improvement in hypoxemia during wakefulness and sleep in long-term residents at high altitude with use of the ventilatory stimulant medroxyprogesterone acetate suggests that decreased ventilatory drive may have a permissive role.98,103 Similar findings are reported for acetazolamide which over a three week’s treatment in residents in the Andes at 4300 m increased oxygen saturation and markedly reduced the apnea-hypopnea index during sleep.104 Natives and long-term residents of high altitude exhibit chronic mountain sickness or Monge’s disease, a syndrome of excessive polycythemia with headache, dizziness, breathlessness, and sleep disturbance. The pathophysiology of the syndrome is debated, but likely is induced by increased hypoxemia reflecting the combined effects of altitude, decreased ventilatory drive and lung dysfunction. Compared to normal subjects, individuals with chronic mountain sickness exhibit exaggerated hypoxemia during sleep without an increase in RDI.104-106 These subjects also exhibit greater daytime hypoxemia and thus the role of sleep-associated desaturation remains uncertain.
CONCLUSIONS The sensation of disrupted sleep after ascent to high altitude is associated with frequent awakenings, which in part probably reflect sleep fragmentation by respiratory dysrhythmia typically consisting of monotonously repetitive periodic breathing. This periodicity is produced by ventilatory inhibition by hypocapnic alkalosis alternating with stimulation by hypoxia, which terminates apnea and initiates hyperpnea with consequent hypocapnia, leading to perpetuation of periodicity. Sleep disruption and periodic breathing decrease with time at moderate altitude and are also considerably reduced by pretreatment with acetazolamide, which reduces alkalosis. In long-term residents of high altitude, less-distinctive, undulating respiratory dysrhythmias are described, with unstable and decreased arterial oxygenation. The most common treatment is prophylactic administration of acetazolamide, an inhibitor of carbonic anhy-
drase, which likely works by reducing alkalotic ventilatory inhibition. Recent studies suggest that benzodiazepines and other hypnotic agents may improve sleep quality without apparent adverse effects.107 ❖ Clinical Pearl Sleep at altitude is disturbed by the opposing influences of hypoxic stimulation and alkalotic inhibition which lead to periodic breathing and frequent associated arousals. Effective treatments include correction of alkalosis with acetazolamide or blunting of hypoxic stimulation with some benzodiazepines.
REFERENCES 1. Moore LG, Harrison GL, McCullough RE, et al. Low acute hypoxic ventilatory response and hypoxic depression in acute altitude sickness. J Appl Physiol 1986;60:1407-1412. 2. Bisgard GE. Carotid body mechanisms in acclimatization to hypoxia. Respir Physiol 2000;121:237-246. 3. Joern AT, Shurley JT, Brooks RE, et al. Short-term changes in sleep patterns on arrival at the South Polar Plateau. Arch Intern Med 1970;125:649-654. 4. Reite M, Jackson D, Cahoon RL, et al. Sleep physiology at high altitude. Electroencephalogr Clin Neurophysiol 1975;38: 463-471. 5. Goldenberg F, Richalet JP, Onnen I, et al. Sleep apneas and high altitude newcomers. Int J Sports Med 1992;13:S34-S36. 6. Mizuno K, Asano K, Okudaira N. Sleep and respiration under acute hypobaric hypoxia. Jpn J Physiol 1993;43:161-175. 7. Normand H, Barragan M, Benoit O, et al. Periodic breathing and O2 saturation in relation to sleep stages at high altitude. Aviat Space Environ Med 1990;61:229-235. 8. Wickramasinghe H, Anholm JD. Sleep and breathing at high altitude. Sleep Breath 1999;3:89-102. 9. Miller JC, Horvath SM. Sleep at altitude. Aviat Space Environ Med 1977;48:615-620. 10. Anholm JD, Powles AC, Downey RD, et al. Operation Everest II: arterial oxygen saturation and sleep at extreme simulated altitude. Am Rev Respir Dis 1992;145:817-826. 11. Bonnet MH. Performance and sleepiness as a function of frequency and placement of sleep disruption. Psychophysiology 1986;23: 263-271. 12. Netzer NC, Strohl KP. Sleep and breathing in recreational climbers at an altitude of 4200 and 6400 meters: observational study of sleep and patterning of respiration during sleep in a group of recreational climbers. Sleep Breath 1999;3:75-82. 13. Ohi M, Chin K, Hirai M, et al. Oxygen desaturation following voluntary hyperventilation in normal subjects. Am J Respir Crit Care Med 1994;149:731-738. 14. Lovering AT, Fraigne JJ, Dunin-Barkowski WL, et al. Hypocapnia decreases the amount of rapid eye movement sleep in cats. Sleep 2003;26:961-967. 15. Ward M. Periodic respiration. A short historical note. Ann R Coll Surg Engl 1973;52:330-334. 16. Douglas C, Haldane J, Henderson Y, et al. Physiological observations made of Pike’s Peak, Colorado, with special reference to adaptation to low barometric pressures. Philosophical Trans R Soc Lond 1913;203:185-381. 17. Berssenbrugge A, Dempsey J, Iber C, et al. Mechanisms of hypoxiainduced periodic breathing during sleep in humans. J Physiol 1983;343:507-526. 18. Kryger M, McCullough RE, Collins D, et al. Treatment of excessive polycythemia of high altitude with respiratory stimulant drugs. Am Rev Respir Dis 1978;117:455-464. 19. Masuyama S, Kohchiyama S, Shinozaki T, et al. Periodic breathing at high altitude and ventilatory responses to O2 and CO2. Jpn J Physiol 1989;39:523-535. 20. Sutton JR, Houston CS, Mansell AL, et al. Effect of acetazolamide on hypoxemia during sleep at high altitude. N Engl J Med 1979; 301:1329-1331.
CHAPTER 24 • Respiratory Physiology: Sleep at High Altitudes 279 21. Fujimoto K, Matsuzawa Y, Hirai K, et al. Irregular nocturnal breathing patterns high altitude in subjects susceptible to highaltitude pulmonary edema (HAPE): a preliminary study. Aviat Space Environ Med 1989;60:786-791. 22. Lahiri S, Barnard P. Role of arterial chemoreflex in breathing during sleep at high altitude. Prog Clin Biol Res 1983;136:75-85. 23. Lahiri S, Data PG. Chemosensitivity and regulation of ventilation during sleep at high altitudes. Intern J Sports Med 1992;13: S31-S33. 24. Normand H, Vargas E, Bordachar J, et al. Sleep apneas in high altitude residents (3,800 m). Intern J Sports Med 1992;13: S40-S42. 25. Weil JV, Kryger MH, Scoggin CH. Sleep and breathing at high altitude. In: Guilleminault C, Dement WC, editors. Sleep apnea syndromes. New York: Alan R Liss; 1978. p. 119-136. 26. Bulow K. Respiration and wakefulness in man. Acta Physiol Scand Suppl 1963;59:1-110. 27. Douglas C, Haldane J. The causes of periodic or Cheyne-Stokes breathing. J Physiol 1909;38:401-419. 28. Douglas CG, Haldane JS. The regulation of normal breathing. J Physiol 1909;38:420-440. 29. Brusil PJ, Waggener TB, Kronauer RE, et al. Methods for identifying respiratory oscillations disclose altitude effects. J Appl Physiol 1980;48:545-556. 30. Waggener TB, Brusil PJ, Kronauer RE, et al. Strength and cycle time of high-altitude ventilatory patterns in unacclimatized humans. J Appl Physiol 1984;56:576-581. 31. West JB, Peters R Jr, Aksnes G, et al. Nocturnal periodic breathing at altitudes of 6,300 and 8,050 m. J Appl Physiol 1986;61: 280-287. 32. Naughton M, Benard D, Tam A, et al. Role of hyperventilation in the pathogenesis of central sleep apneas in patients with congestive heart failure [see comments]. Am Rev Respir Dis 1993;148:330-338. 33. Topor ZL, Vasilakos K, Younes M, et al. Model based analysis of sleep disordered breathing in congestive heart failure. Respir Physiol Neurobiol 2007;155:82-92. 34. White DP, Gleeson K, Pickett CK, et al. Weil JV. Altitude acclimatization: influence on periodic breathing and chemoresponsiveness during sleep. J Appl Physiol 1987;63:401-412. 35. Smith CA, Nakayama H, Dempsey JA. The essential role of carotid body chemoreceptors in sleep apnea. Can J Physiol Pharmacol 2003;81:774-779. 36. Lahiri S, Maret K, Sherpa MG. Dependence of high altitude sleep apnea on ventilatory sensitivity to hypoxia. Respir Physiol 1983; 52:281-301. 37. Badr MS, Toiber F, Skatrud JB, et al. Pharyngeal narrowing/ occlusion during central sleep apnea. J Appl Physiol 1995;78: 1806-1815. 38. Fletcher EC. Recurrence of sleep apnea syndrome following tracheostomy. A shift from obstructive to central apnea. Chest 1989;95:205-209. 39. Burgess KR, Cooper J, Rice A, et al. Effect of simulated altitude during sleep on moderate-severity OSA. Respirology 2006;11:6269. 40. Warner G, Skatrud JB, Dempsey JA. Effect of hypoxia-induced periodic breathing on upper airway obstruction during sleep. J Appl Physiol 1987;62:2201-2211. 41. Patz D, Spoon M, Corbin R, et al. The effect of altitude descent on obstructive sleep apnea. Chest 2006;130:1744-1750. 42. Hackett PH, Roach RC, Harrison GL, et al. Respiratory stimulants and sleep periodic breathing at high altitude. Almitrine versus acetazolamide. Am Rev Respir Dis 1987;135:896-898. 43. Salvaggio A, Insalaco G, Marrone O, et al. Effects of high-altitude periodic breathing on sleep and arterial oxyhaemoglobin saturation. Eur Respir J 1998;12:408-413. 44. Douglas CG, Haldane JS, Henderson Y, et al. The physiological effects of low atmospheric pressures as observed on Pike’s Peak, Colorado. J Physiol 1912;LXXXV:65-67. 45. Gotoh F, Meyer JS, Takagi Y. Cerebral venous and arterial blood gases during Cheyne-Stokes respiration. Am J Med 1969;47: 534-545. 46. Skatrud JB, Dempsey JA. Interaction of sleep state and chemical stimuli in sustaining rhythmic ventilation. J Appl Physiol 1983; 55:813-822. 47. Cherniack N, Gothe B, Strohl K. Mechanisms for recurrent apneas at altitude. In: West JB, Lahiri S, editors. High altitude
and man. Bethesda, Md: American Physiological Society; 1984. p. 129-140. 48. Khoo MC, Anholm JD, Ko SW, et al. Dynamics of periodic breathing and arousal during sleep at extreme altitude. Respir Physiol 1996;103:33-43. 49. Khoo MC, Kronauer RE, Strohl KP, et al. Factors inducing periodic breathing in humans: a general model. J Appl Physiol 1982; 53:644-659. 50. Powles AC, Sutton JR, Gray GW, et al. Sleep hypoxemia at altitude: its relationship to acute mountain sickness and ventilatory responsiveness to hypoxia and hypercapnia. In: Folinsbee LJ, editor. Environmental stress: individual human adaptations. New York: Academic Press; 1978. p. 373-381. 51. Day TA, Wilson RJ. Brainstem PCO2 modulates phrenic responses to specific carotid body hypoxia in an in situ dual perfused rat preparation. J Physiol 2007;578:843-857. 52. Ainslie PN, Burgess K, Subedi P, et al. Alterations in cerebral dynamics at high altitude following partial acclimatization in humans: wakefulness and sleep. J Appl Physiol 2007;102:658-664. 53. Sullivan C, Kosar L, Murphy E, et al. Primary role of respiratory afferents in sustaining breathing rhythm. J Appl Physiol 1978; 45:11-17. 54. Tawadrous FD, Eldridge FL. Posthyperventilation breathing patterns after active hyperventilation in man. J Appl Physiol 1974; 37:353-356. 55. Mizuno K, Asano K, Inoue Y, et al. Consecutive monitoring of sleep disturbance for four nights at the top of Mt Fuji (3776 m). Psychiatry Clin Neurosci 2005;59:223-225. 56. Berry RB, Gleeson K. Respiratory arousal from sleep: mechanisms and significance. Sleep 1997;20:654-675. 57. Milledge JS. The ventilatory response to hypoxia: how much is good for a mountaineer? Postgrad Med J 1987;63:169-172. 58. Ghazanshahi SD, Khoo MC. Optimal ventilatory patterns in periodic breathing. Ann Biomed Eng 1993;21:517-530. 59. Kupper T, Schoffl V, Netzer N. Cheyne Stokes breathing at high altitude: a helpful response or a troublemaker? Sleep Breath 2008;12:123-127. 60. Eichenberger U, Weiss E, Riemann D, et al. Nocturnal periodic breathing and the development of acute high altitude illness. Am J Respir Crit Care Med 1996;154:1748-1754. 61. Burgess KR, Johnson P, Edwards N, et al. Acute mountain sickness is associated with sleep desaturation at high altitude. Respirology 2004;9:485-492. 62. Silber E, Sonnenberg P, Collier DJ, et al. Clinical features of headache at altitude: a prospective study. Neurology 2003;60:1167-1171. 63. Bonnet MH. [Sleep fragmentation as the cause of daytime sleepiness and reduced performance]. Wien Med Wochenschr 1996;146: 332-334. 64. Hoshikawa M, Uchida S, Sugo T, et al. Changes in sleep quality of athletes under normobaric hypoxia equivalent to 2,000-m altitude: a polysomnographic study. J Appl Physiol 2007;103:2005-2011. 65. Kinsman TA, Hahn AG, Gore CJ, et al. Respiratory events and periodic breathing in cyclists sleeping at 2,650-m simulated altitude. J Appl Physiol 2002;92:2114-2118. 66. Kinsman TA, Townsend NE, Gore CJ, et al. Sleep disturbance at simulated altitude indicated by stratified respiratory disturbance index but not hypoxic ventilatory response. Eur J Appl Physiol 2005;94:569-575. 67. Pedlar C, Whyte G, Emegbo S, et al. Acute sleep responses in a normobaric hypoxic tent. Med Sci Sports Exerc 2005;37:10751079. 68. Brugniaux JV, Schmitt L, Robach P, et al. Living high-training low: tolerance and acclimatization in elite endurance athletes. Eur J Appl Physiol 2006;96:66-77. 69. Kinsman TA, Gore CJ, Hahn AG, et al. Sleep in athletes undertaking protocols of exposure to nocturnal simulated altitude at 2650 m. J Sci Med Sport 2005;8:222-232. 69a. Johnson PL, Popa DA, Prisk GK, et al. Non-invasive positive pressure ventilation during sleep at 3800 m: relationship to acute mountain sickness and sleeping oxyhaemoglobin saturation. Respirology 2010;15(2):277-282. 70. Cain SM, Dunn JD. Low doses of acetazolamide to aid accommodation of men to altitude. J Appl Physiol 1966;21:1195-2000. 71. Forwand SA, Landowne M, Follansbee JN, et al. Effect of acetazolamide on acute mountain sickness. N Engl J Med 1968;279: 839-845.
280 PART I / Section 4 • Physiology in Sleep 72. Hackett PH, Rennie D. The incidence, importance, and prophylaxis of acute mountain sickness. Lancet 1976;2:1149-1155. 73. Swenson ER. Carbonic anhydrase inhibitors and ventilation: a complex interplay of stimulation and suppression. Eur Respir J 1998;12:1242-1247. 74. Sutton JR, Gray GW, Houston CS, et al. Effects of duration at altitude and acetazolamide on ventilation and oxygenation during sleep. Sleep 1980;3:455-464. 75. Swenson ER, Teppema LJ. Prevention of acute mountain sickness by acetazolamide: as yet an unfinished story. J Appl Physiol 2007;102:1305-1307. 76. Leaf DE, Goldfarb DS. Mechanisms of action of acetazolamide in the prophylaxis and treatment of acute mountain sickness. J Appl Physiol 2007;102:1313-1322. 77. Hauge A, Nicolaysen G, Thoresen M. Acute effects of acetazolamide on cerebral blood flow in man. Acta Physiol Scand 1983; 117:233-239. 78. Huang SY, McCullough RE, McCullough RG, et al. Usual clinical dose of acetazolamide does not alter cerebral blood. Respir Physiol 1988;72:315-326. 79. Teppema LJ, Balanos GM, Steinback CD, et al. Effects of acetazolamide on ventilatory, cerebrovascular, and pulmonary vascular responses to hypoxia. Am J Respir Crit Care Med 2007;175:277-281. 80. DeBacker WA, Verbraecken J, Willemen M, et al. Central apnea index decreases after prolonged treatment with acetazolamide. Am J Respir Crit Care Med 1995;151:87-91. 81. White DP, Zwillich CW, Pickett CK, et al. Central sleep apnea. Improvement with acetazolamide therapy. Arch Intern Med 1982;142:1816-1819. 82. Nakayama H, Smith CA, Rodman JR, et al. Effect of ventilatory drive on carbon dioxide sensitivity below eupnea during sleep. Am J Respir Crit Care Med 2002;165:1251-1260. 83. Bashir Y, Kann M, Stradling JR. The effect of acetazolamide on hypercapnic and eucapnic/poikilocapnic hypoxic ventilatory responses in normal subjects. Pulm Pharmacol 1990;3:151-154. 84. Swenson ER, Leatham KL, Roach RC, et al. Renal carbonic anhydrase inhibition reduces high altitude sleep periodic breathing. Respir Physiol 1991;86:333-343. 85. Swenson ER, Hughes JM. Effects of acute and chronic acetazolamide on resting ventilation and ventilatory responses in men. J Appl Physiol 1993;74:230-237. 86. Lakshminarayan S, Sahn SA, Hudson LD, et al. Effect of diazepam on ventilatory responses. Clin Pharmacol Ther 1976;20:178-183. 87. Camacho ME, Morin CM. The effect of temazepam of respiraton in elderly insomniacs with mild sleep apnea. Sleep 1995;18:644-645. 88. Hoijer U, Hedner J, Ejnell H, et al. Nitrazepam in patients with sleep apnoea: a double-blind placebo-controlled study. Eur Resp J 1994;7:2011-2015. 89. Gentil B, Tehindrazanarivelo A, Lienhart A, et al. Respiratory effects of midazolam in patients with obstructive sleep apnea syndromes. Ann Fran Anes Reanim 1994;13:275-279.
90. Steens RD, Pouliot Z, Millar TW, et al. Effects of zolidem and triazolam on sleep and respiration in mild to moderate chronic obstructive pulmonary disease. Sleep 1993;16:318-326. 91. Berry RB, Kouchi K, Bower J, et al. Triazolam in patients with obstructive apnea. Am J Resp Crit Care Med 1995;151:450-454. 92. Biberdorf DJ, Steens R, Miller TW, et al. Benzodiazepines in congestive heart failure: effects of temazepam on arousability and Cheyne-Stokes respiration. Sleep 1993;16:529-538. 93. Dubowitz G. Effect of temazepam on oxygen saturation and sleep quality at high altitude: randomised placebo controlled crossover trial. BMJ 1998;316:587-589. 94. Nicholson AN, Smith PA, Stone BM, et al. Altitude insomnia: studies during an expedition to the Himalayas. Sleep 1988;11: 354-361. 95. Beaumont M, Batejat D, Coste O, et al. Effects of zolpidem and zaleplon on sleep, respiratory patterns and performance at a simulated altitude of 4,000 m. Neuropsychobiology 2004;49: 154-162. 96. Beaumont M, Batejat D, Pierard C, et al. Zaleplon and zolpidem objectively alleviate sleep disturbances in mountaineers at a 3,613 meter altitude. Sleep 2007;30:1527-1533. 97. Fischer R, Lang SM, Leitl M, et al. Theophylline and acetazolamide reduce sleep-disordered breathing at high altitude. Eur Respir J 2004;23:47-52. 98. Kryger M, Glas R, Jackson D, et al. Impaired oxygenation during sleep in excessive polycythemia of high altitude: improvement with respiratory stimulation. Sleep 1978;1:3-17. 99. Coote JH, Stone BM, Tsang G. Sleep of Andean high altitude natives. Eur J Appl Physiol Occup Physiol 1992;64:178-181. 100. Plywaczewski R, Wu TY, Wang XQ, et al. Sleep structure and periodic breathing in Tibetans and Han at simulated altitude of 5000 m. Respir Physiol Neurobiol 2003;136:187-197. 101. Weil JV, Byrne-Quinn E, Sodal IE, et al. Acquired attenuation of chemoreceptor function in chronically hypoxic man at high altitude. J Clin Invest 1971;50:186-195. 102. Hackett PH, Reeves JT, Reeves CD, et al. Control of breathing in Sherpas at low and high altitude. J Appl Physiol 1980;49: 374-379. 103. Kryger M, Weil J, Grover R. Chronic mountain polycythemia: a disorder of the regulation of breathing during sleep? Chest 1978;73:303-304. 104. Richalet JP, Rivera-Ch M, Maignan M, et al. Acetazolamide for Monge’s disease: efficiency and tolerance of 6-month treatment. Am J Respir Crit Care Med 2008;177:1370-1376. 105. Reeves JT, Weil JV. Chronic mountain sickness. A view from the crow’s nest. Adv Exp Med Biol 2001;502:419-437. 106. Spicuzza L, Casiraghi N, Gamboa A, et al. Sleep-related hypoxaemia and excessive erythrocytosis in Andean high-altitude natives. Eur Respir J 2004;23:41-46. 107. Luks AM. Which medications are safe and effective for improving sleep at high altitude? High Alt Med Biol 2008;9:195-198.
Sleep and Host Defense James M. Krueger and Jeannine A. Majde Abstract Sleepiness, like fever, is commonly experienced at the onset of an infection or other cause of systemic inflammation. Changes in sleep in response to microbes appear to be one facet of the acute phase response. Typically, soon after infectious challenge, animals exhibit excess time spent in non– rapid eye movement sleep and decreased total rapid eye movement sleep. The exact time course of sleep responses depends upon the infectious agent used, the route of administration, and the time of day the infectious challenge is given. There is a common perception that sleep loss can render one vulnerable to infection. Many studies have combined sleep deprivation with measurement of one or more parameters of the immune response. A few studies have combined sleep deprivation with infectious challenge. After mild sleep depriva-
INTRODUCTION Most individuals have experienced the intense desire to sleep that may occur at the onset of more severe infections. Further, many have received the advice from loving parents and grandparents to get plenty of rest to prevent, or help recover from, infectious diseases. These experiences suggest a connection between sleep and host defense systems. Indeed, Hippocrates, Aristotle, and many of our predecessors acknowledged such a relationship. But only within the past 15 years have modern science and medicine systematically investigated whether sleep has anything to do with host defense systems. This chapter is organized around four main sections related to this issue. They are: 1) the acute phase response and host defense; 2) sleep changes after infectious challenge; 3) sleep loss effects on immune function; 4) sleep and immunity share common regulatory molecules; and finally, in the Clinical Pearl section: sleep and recuperation. The available evidence, thus far, is consistent with a role for sleep in maintaining resistance to infections. THE ACUTE PHASE RESPONSE AND HOST DEFENSE A major theme of this chapter is that excess sleep as a host defense is part of the acute phase response (APR) to inflammatory challenge and shares numerous immunoregulatory molecules with other APRs. Related concepts and terminology are found in the following section. Enhanced sleep in response to infections occurs in the context of dozens of other responses, collectively termed the APR. Recent advances in innate immunity research provide a framework for understanding many of the shared mechanisms underlying the APR in general and sleep regulation specifically. The APR is a critical innate immune
Chapter
25
tion, several immune system parameters (such as natural killer cell activity) change, and resistance to a viral challenge is decreased in individuals that spontaneously sleep less. After prolonged (2 to 3 weeks) sleep deprivation, rats become septicemic. Studies have not yet been done to determine the effects of sleep deprivation on recuperation from an infection. Small amounts of sleep loss may promote host defenses, whereas prolonged sleep loss is devastating. The molecular mechanisms responsible for the changes in sleep associated with infection appear to be an amplification of a physiological sleep regulatory biochemical cascade. This chain of events includes well-known immune response modifiers such as interleukin-1, tumor necrosis factor-α, prostaglandins, nitric oxide, and adenosine. All these substances are normal constituents of the brain and are involved in physiological sleep regulation.
response1 that follows any inflammatory challenge, such as an infection or traumatic injury. Local inflammatory challenges, for example, minor cuts or bruises, may activate a low-level APR that is not perceived by the victim. But when the challenge is severe enough, it activates a fullblown systemic APR within 24 hours and the patient feels sick. In the case of infections, the function of the APR is to wall off and destroy invading microorganisms, to remove tissue debris, and to alert the host to the invasion so that systemic protective responses are mobilized. The systemic inflammatory response activates the brain, liver, and bone marrow to react in a stereotypic manner. The APR has both behavioral (fever, excess sleep, anorexia, etc.) and biochemical markers (C-reactive protein, serum amyloid A, mannose binding protein, etc.). Increased secretion of a broad array of endocrine hormones, including the stress hormones, also occurs. This complex of responses leads to host protective behaviors (such as social withdrawal that avoids predation),2 physiological responses (such as fever, which can thermally inhibit growth of some microorganisms),3 and immune responses (such as mobilization of leukocytes and natural killer (NK) cells.)1 Hormonal changes (such as prolactin regulation of antimicrobial nitric oxide levels)4 and biochemical changes (such as potentiation of microbial phagocytosis)5 also contribute to host defense. The APR is the first line of defense against infections and the trigger for acquired immunity mediated by specific antibodies and cytotoxic T lymphocytes needed to clear the infection.6 A major class of protein mediators, the cytokines, initiates the APR.7 Cytokines are generally associated with immune cells, but they are made by all cells. Over 100 of these intercellular signaling molecules have been identified, and the complexity of their interactions rivals that of the nervous system. Cytokines induce themselves and other cytokines, and they form biochemical cascades 281
282 PART I / Section 4 • Physiology in Sleep
SLEEP CHANGES AFTER INFECTIOUS CHALLENGE Viral Challenge Viral diseases that cause central nervous system lesions and/or systemic inflammation can affect sleep.13 In von Economo’s seminal paper14 he related the location of brain lesions in encephalitis lethargica to changes in sleep patterns.* This work led to the concept that sleep was an active process, not simply the withdrawal of sensory stimuli, and to the idea that there was some degree of localization of neural networks regulating sleep. Despite the importance of this work, many years passed before the direct effects of viral infections on sleep were experimentally determined. During the early stages of human immunodeficiency virus (HIV) infections, before AIDS onset, patients have excess stage 4 NREM sleep during the latter half of the night.16 Another central nervous system viral disease, rabies, is also associated with disrupted sleep.17 In *Although von Economo’s encephalitis (or encephalitis lethargica) is commonly thought to have been caused by the 1918 influenza virus, recent analyses reveal that the disease preceded the 1918 pandemic and is probably an autoimmune complication of streptococcal infections affecting the basal ganglia.15
THE LOCAL SLEEP HOMEOSTAT Microbes, LPS, MPs, dsRNA, sleep loss, temperature, feeding, stress
Cell electrical and metabolic activity Extracellular ATP P2 receptors Sleep regulatory substances IL1β, TNFα, other cytokines
NFκB
Adenosine
NOS
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COX-2 Inhibitors GHRH (e.g., IL4, IL10, IL13, CRH, Hours sTNFR, sIL1R, IL1RA, TGF, Gene transcription glucocorticoids) and translation
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characterized by much redundancy. Cytokines are classified into two major groups, type I cytokines that promote inflammation (proinflammatory) and type II cytokines that suppress it (antiinflammatory).8 Three proinflammatory cytokines, specifically interleukin (IL)-1β, tumor necrosis factor-α (TNF-α), and IL-6, appear to be primary triggers of the APR, including the situation when excess NREM sleep occurs.7,9 The class II cytokines such as interferon (IFN)-α, IFN-β, IL-4, and IL-10 downregulate the APR and may also modulate the sleep response; for example, IL-4 and IL-10 inhibit spontaneous NREM sleep (Fig. 25-1). Cytokines can act in an autocrine, juxtacrine, paracrine, or endocrine manner to activate numerous APRs via such effectors as nitric oxide, adenosine, and prostaglandins.7,9,10 A major breakthrough in our understanding of the APR is the recognition that all known microorganisms have one or more biologically stable and chemically unique structural components, or they produce one during replication.11 These components are termed pathogen-associated molecular patterns, or PAMPs. These PAMPs are recognized by a specialized group of membrane-bound or intracellular receptors (pathogen recognition receptors, or PRRs)6 that include the Toll-like receptors (TLRs) and the nucleotide-binding domain and leucine-rich repeat domain receptors (NLRs) (more commonly designated as nucleotide-binding oligomerization domain, or Nod, proteins.)12 The PRR binding of microbial PAMPs induces cytokines, and these cytokines in turn upregulate PRRs and cytokines in neighboring tissues, resulting in amplification of the response. Thus in infectious illness, microorganisms induce cytokines, then cytokines activate the APR and thereby facilitate host defense via dozens of protective mediators and activated immune cells.1,7 Enhanced non– rapid eye movement (NREM) sleep appears to be one outcome of this cytokine cascade in infectious illness.
Figure 25-1 Local sleep homeostat. IL-1β and TNF-α are part of the brain cytokine network that includes several other endogenous somnogenic substances and sleep inhibitory substances. Cell electrical and metabolic activity, induced by multiple stimuli including inflammatory signals, is associated with ATP release. ATP via purine P2 receptors causes the release of IL-1β and TNF-α from glia. They, in turn, activate NFκB. Redundant pathways as well as negative feedback signals involving additional cytokine and hormones provide stability to the sleep regulatory system as well as alternative mechanisms by which a variety of sleep promoting, or sleep inhibitory, stimuli may affect sleep. Our current knowledge of the biochemical events involved in sleep regulation is much more complicated than that shown here. For example, multiple additional cytokines (e.g., acidic fibroblast growth factor) enhance sleep.10 TNFR, soluble TNF receptor; anti-TNF, anti-TNF antibody; NGF, nerve growth factor; NFκB, nuclear factor κB; IL1RA, IL1 receptor antagonist; sILIR, soluble IL1 receptor; anti-IL1, anti-IL1 antibody; CRH, corticotropin releasing hormone; PG, prostaglandin; COX-2, cyclooxygenase-2; TGF, transforming growth factor; NOS, nitric oxide synthase; A1R, adenosine A1 receptor; GHRH, growth hormone releasing hormone; (→) indicates stimulation; (—) indicates inhibition.
such diseases, it is difficult to distinguish whether the effects of the viral infection on sleep are direct or whether they result from virus-induced brain lesions.13 Influenza virus localizes to the respiratory tract during the early stage of disease and has been used in several sleep investigations. Smith and colleagues18 at the British Common Cold Unit reported that low doses of influenza in humans induce excess behavioral sleep and cognitive dysfunction; these symptoms appear after low viral doses that fail to induce the better known characteristics of the APR, such as a fever. However, polysomnography was not used in this study. More recently, animal studies of influenza viral infections clearly show that sleep is profoundly affected by
CHAPTER 25 • Sleep and Host Defense 283
% Of time in NREMS
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Figure 25-2 Influenza virus challenge induces prolonged increases in NREM sleep (top panel) and decreases in REM sleep (bottom panel) in mice. Data are from reference 19. Filled triangles represent data collected after viral inoculation. Open triangles represent the averaged baseline data collected over a 3-day period just prior to viral inoculation. Horizontal dark bars show lights-off periods for each experimental day.
infectious challenge. The sleep changes in influenzainfected mice,19 illustrated in Figure 25-2, are similar to those seen in bacterial infections (described hereafter). In a rabbit model, intravenous injections of influenza virus are also associated with large increases in NREM sleep, although the virus fails to replicate in this species.13 The influenza-infected mouse is more applicable to humans because mouse-adapted strains of this virus can be inoculated via the respiratory tract and can fully replicate in the lungs, causing a severe APR. Mice challenged intranasally with influenza virus display profound increases in NREM sleep lasting 3 or more days, while rapid eye movement (REM) sleep is inhibited7,13 (see Fig. 25-2). The macrophage appears to the critical immune cell type driving increased NREM sleep, whereas NK cells, neutrophils, and T lymphocytes do not play a significant role.20 Different strains of mice respond differentially to viral challenge21 indicating a strong genetic component affecting the sleep response to influenza virus. Genetic regulation of the inflammatory response to influenza in mice and humans has been reviewed.22 One generic viral PAMP that induces excess sleep and other APRs is virus-associated double-stranded (ds) RNA. All viruses examined to date produce virus-associated dsRNA, which is generally derived from the annealing of
viral replication products rather than from the virus itself.23 Virus-associated dsRNA is recognized by the PRR TLR3, as well as intracellular helicases, and dsRNA induces numerous cytokines such as IL-1, IL-6, TNFα, and IFN.23 Virus-associated dsRNA can be extracted from lungs of infected mice24 and is capable of inducing an APR in rabbits similar to that of live virus. Similarly, rabbits given short double-stranded (but not single-stranded) oligomers that correspond to a portion of influenza gene segment 3 also exhibit large increases in NREM sleep.7 Synthetic dsRNA (polyriboinosinic : polyribocytidylic acid, or poly I : C) induces an APR virtually identical to that of influenza virus when inoculated into the lungs of mice primed with IFN-α. Poly I : C administered to rabbits also induces an influenza-like APR, but the corresponding single strands of poly I and poly C are inert. In rabbits, poly I : C can substitute for virus in the induction of hyporesponsive state to viral challenge. These observations7,23 suggest that virus-associated dsRNA is sufficient to initiate the APRs seen in influenza-infected mice. Mice deficient in TLR3 demonstrate attenuation of influenza APRs.23a Rabbits challenged with viable virus or poly I : C have increased plasma antiviral activity that occurs concomitantly with the changes in sleep. The antiviral activity is attributed to IFN-α and other cytokines. Injection of IFN-α into rabbits also induces sleep responses similar to those induced by virus, poly I : C, or the double-stranded viral oligomers.25 High doses of IFN-α also stimulate NREM sleep in other species,26 but lower doses that simulate levels of IFN-α seen during an infection inhibit both NREM and REM sleep in humans.27 Interferons have long been thought to play a major role in viral (and poly I : C) symptoms.23 A tool now widely used by researchers to better understand the role of a specific cytokine or hormone in host defense is the so-called knockout (KO) mouse.7 These mice have a single gene deletion, and comparing their responses with wild-type mice provides valuable insights into contributions of a single gene product, such as type I IFN, to the APR. Mice genetically deficient for the receptor that binds both IFN-α and IFN-β (the type I receptor) still respond to poly I : C challenge with excess sleep and a hypothermic response similar to that seen in infected wild-type mice. However, the APR occurs earlier in influenza-infected IFN-receptor KO mice,28 suggesting that type I IFNs may modulate the APR by regulating proinflammatory cytokine production. Influenza-infected IFN-receptor KO mice are less ill in the later phase of the infection and appear to recover sooner.28 Our current hypothesis is that cytokines (other than IFNs) that are known to be somnogenic are likely to mediate the excess sleep response to influenza virus. For example, influenza virus challenge of mice deficient in both the 55-kD and 75-kD TNF receptors reduces EEG delta power, a measure of sleep intensity, whereas in wild-type controls delta power increases.29 Duration of NREM sleep and REM sleep changed to the same extent in both strains after viral challenge. Another mediator that plays a role in both sleep and host defense4 is nitric oxide synthesized by multiple nitric oxide synthetases (NOSs).30 Mice deficient in either neuronal NOS or inducible NOS have attenuated NREM sleep
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responses to influenza challenge compared to infected wild-type controls.30 Mice and rats with natural mutations of the growth hormone releasing hormone (GHRH) receptor express a dwarf phenotype and altered spontaneous NREM sleep.31 The GHRH receptor is a candidate gene for regulation of NREM sleep increases in response to influenza virus,13 and its expression is upregulated in the hypothalamus by IL-1β. If dwarf mice with nonfunctional GHRH receptors (called lit/lit mice) are infected with influenza virus, then they fail to show the increase in NREM sleep or EEG delta power seen in heterozygous controls.32 Instead, infected lit/lit mice manifest a pathological state with EEG slow waves, enhanced muscle tone and increased mortality.32 Such results indicate that single genes can substantially modify sleep responses to infectious challenge and suggest that the sleep responses forming part of the APR at least correlate with survival. Influenza virus has been a popular model for acute phase studies because it has been assumed that the virus does not invade the brain or lead to the complications associated with neurovirulent viruses. Recent studies in our laboratory, however, demonstrate that the strain of influenza most commonly employed in acute phase studies rapidly invades the olfactory bulb of the mouse brain following intranasal inoculation.33 The virus activates microglia in the outer layer of the bulb and induces significant IL-1β and TNF-α upregulation at the same time (15 hours postinfection) that the APR (hypothermia, in this case) begins.33 These studies suggest that cytokines made in the olfactory bulb could impact the APR to influenza virus. Bacterial Challenge Sleep responses are also observed after bacterial challenge. Indeed, results obtained after challenging rabbits with the gram-positive bacteria Staphylococcus aureus were the first to suggest that NREM sleep responses formed part of the APR.34 In those experiments rabbits were given S. aureus intravenously to induce septicemia; within a few hours of the inoculation large excesses in NREM sleep were observed. Associated with the increase in NREM sleep were increases in amplitude of EEG slow waves. EEG slow wave ( 1 2 to 4 Hz) amplitudes are thought to be indicative of the intensity of NREM sleep. This initial phase of increased duration and intensity of NREM sleep lasted about 20 hours; it was followed by a more prolonged phase of decreased duration of NREM sleep and decreased EEG slow wave amplitudes.34 During both phases of the NREM sleep changes, REM sleep was inhibited and animals were febrile. Other changes characteristic of the APR, for example, fibrinogenemia and neutrophilia, occurred concurrently with the changes in sleep.34 In subsequent studies in which gram-negative bacteria and other routes of administration were used, a similar general pattern of biphasic NREM sleep responses and REM sleep inhibition was observed.7,13 However, the timing of sleep responses depends upon both the bacterial species and the route of administration. For example, after intravenous administration of Escherichia coli, NREM sleep responses are rapid in onset, but the excess NREM sleep phase lasts only 4 to 6 hours. The subsequent phase of reduced NREM sleep and reduced amplitude of EEG slow waves is sustained for
relatively long periods. In contrast, if the gram-negative bacterium Pasteurella multocida is given intranasally, a different time course of sleep responses is observed. In this case, the increased NREM sleep responses occur after a longer latency and the magnitude of the increases in NREM sleep is less than the effects of this pathogen given by other routes of administration. P. multocida is a natural respiratory pathogen in rabbits. The intestinal lumen of mammals contains large amounts of bacteria, some of which leak into the intestinal lymphatics under normal conditions. Changes in intestinal permeability by inflammatory challenges increase the release of bacterial products into the lymphatics. Local lymph node macrophages phagocytose and digest these bacterial products,9,35 releasing somnogenic PAMPs as described later. This mechanism is viewed as operating at a low basal rate under normal conditions and is amplified greatly during systemic inflammation. It is also likely to be involved in sleep responses induced by sleep deprivation and excess food intake (discussed hereafter). Reduction of bacterial populations in the intestine is associated with a reduction of sleep.36 A specific muramyl peptide derived from bacterial cell wall peptidoglycans was isolated from the brain and urine of sleep-deprived subjects.37 This muramyl peptide was the first bacterial PAMP to be associated with sleep regulation.37 Peptidoglycan components are recognized by certain NLRs7 and appear to play a major role in the pathogenesis of inflammatory mucosal diseases.7 The sleep promoting activity of muramyl peptides is dependent upon their chemical structure.38 Many muramyl peptides are also immune adjuvants and pyrogenic, although the structural requirements for these biological activities are distinct from those required for sleep-promoting activity.7,38 Another bacterial cell wall product that is involved in sleep responses that are induced by gram-negative bacteria is the lipopolysaccharide component of cell wall endotoxin. Lipopolysaccharide is the dominant PAMP associated with endotoxin, it binds to TLR4,7 and has been intensively studied with respect to sleep effects in both animal models10 and humans.39 Lipopolysaccharide and its toxic moiety, lipid A, are somnogenic in animals and man.7,38 Modification of the lipid A structure alters somnogenic activity (e.g., conversion of diphosphoryl lipid A to monophosphoryl lipid A) and reduces its somnogenicity. Humans inoculated with lipopolysaccharide and followed for 12 hours manifest sleep changes, fever, cytokine expression, and hormonal changes39 somewhat similar to those seen in animals, though EEG changes are distinct from those seen in rabbits or rats and NREM sleep increases require a higher dose of lipopolysaccharide than does REM sleep reduction. Other microbes, for example, fungal organisms such as Candida albicans or protozoans such as Trypanosoma brucei brucei express their own PAMPs, bind to specific TLRs, and also have the capacity to induce sleep responses.40 Some of these microbe-induced sleep responses are quite interesting. Trypanosomiasis in rabbits is associated with recurrent bouts of enhanced NREM sleep occurring about every 7 days. Trypanosomes undergo antigenic variations in the host; the proliferating new antigenic variants stimulate the host immune response, and such periods are
accompanied by excess NREM sleep.40 Like bacteria and viruses, fungi and protozoans have the capacity to enhance cytokine production by the host. In summary, infectious challenge is associated with profound changes in sleep. As mentioned in the overview of the APR, PRRs such as the TLR and NLR receptor families detect the various somnogenic PAMPs described previously and provide an overarching theory that explains why diverse microbial factors activate stereotypic host defense responses such as fever, anorexia, and excess sleep.7 These microbe-induced sleep responses are now considered part of the APR, and, like the other components of this response, sleep may be adaptive.
SLEEP LOSS EFFECTS ON IMMUNE FUNCTION Answering the question of whether sleep loss affects immune function is difficult. For example, what measurement should one use to assess immune function? The important question is whether sleep loss renders the animal more vulnerable to infectious challenge, tumor formation, or systemic inflammatory diseases. (We already know that sleep loss renders one more vulnerable to accidental injury.) Unfortunately, only a very few studies have directly measured host outcomes; instead the approach most often used is to pick one or more parameters associated with the immune system, for example, NK cell activity or plasma cytokine levels, and determine whether they change after sleep deprivation. Often such results leave the reader uninformed as to whether the outcome is adverse or beneficial for the host. In addition, it is very difficult in sleep deprivation studies to isolate sleep loss, per se, as the independent variable. Sleep deprivation can be associated with stress, increased locomotor activity, changes in feeding patterns, hormonal changes, and changes in body temperature. Each of these variables is known to affect immune function. Despite these limitations, a picture is emerging that suggests that sleep loss does indeed influence the immune system. Paradoxically, short-term sleep deprivation may enhance host defenses, whereas long-term sleep loss is detrimental in animals and humans. Animal studies in which short-term sleep deprivation is used are consistent with most human studies. Toth and colleagues challenged rabbits with E. coli before or after 4 hours of sleep deprivation. They concluded that sleep deprivation failed to exacerbate the E. coli-induced clinical illness.41 In rats partially deprived of sleep for several days and challenged with a subdermal allogeneic carcinoma, host defenses were improved by sleep deprivation because rats deprived of sleep had smaller tumors than those in control animals.42 In contrast, in mice deprived of sleep for 7 hours that were immunized against influenza virus and then rechallenged with influenza virus just prior to sleep deprivation, the sleep-deprived, immunized mice (but not the immunized control mice) failed to clear the virus from their lungs.43 These results strongly suggest that sleep loss is detrimental to host defenses. However, in a similar study,44 sleep loss failed to alter preexisting mucosal and humoral immunity in either young or senescent mice. The variation in the effects of sleep deprivation on mouse influenza outcomes is likely due to the variation in the sleep
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deprivation protocols, endpoints analyzed, and influenza models employed.7 The effects of long-term sleep deprivation on host defenses of experimental animals are more striking. If rats obtain only about 20% of their normal sleep, after a period of 2 to 3 weeks they die.45 Yoked control rats, which manage to keep about 80% of their normal sleep during the deprivation period, survive. The experimental rats, but not the yoked controls, develop septicemia.45 Bacteria cultured from the blood were primarily facultative anaerobes indigenous to the host and environment. These results clearly suggest that innate host defenses are compromised by long-term sleep loss. In another model of sleep deprivation in which rats are placed on a small pedestal in a pool of water, similar results were obtained.46 After 72 hours of REM sleep loss, they could culture bacteria from mesenteric lymph nodes. These results suggest that sleep loss likely amplifies the normally-occurring process of gut permeability to bacteria and bacterial products. As discussed later, food intake affects gut permeability to bacteria and bacterial products47 and also affects sleep. An independent literature clearly indicates that sleep loss is associated with changes in parameters normally associated with the immune response. Cytokines, such as IFN, IL-1β, and TNF-α, are well known for their roles as immune response modifiers as discussed previously. These substances are affected by sleep deprivation.31 More than 30 years ago, Palmblad and colleagues48 showed that after sleep deprivation, the ability of human lymphocytes to produce antiviral activity is enhanced. More recently, many laboratories have obtained similar results. For example, sleep deprivation enhances TNF-α production in streptococcal-stimulated white blood cells. Other stressors, unlike sleep deprivation, fail to prime for systemic production of TNF-α, whereas sleep loss increases the ability of lipopolysaccharide-stimulated monocytes to produce TNF-α.38 The ability of cultures of whole blood to produce IL-1β and IFN γ in response to lipopolysaccharide is maximal at the time of sleep onset.31 In humans or animals, sleep deprivation leads to enhanced nocturnal plasma levels of IL-1–like activity.31 There are several reports that show in normal people that plasma levels of cytokines are related to the sleep– wake cycle. Such relationships were first described in humans showing that plasma IL-1 activity was related to the onset of slow wave sleep.49 Plasma levels of TNF vary in phase with EEG slow-wave amplitudes.50 There is also a temporal relationship between sleep and IL-1β activity.51 Several clinical conditions associated with sleepiness, such as sleep apnea, chronic fatigue syndrome, chronic insomnia, preeclampsia, postdialysis fatigue, psychoses, rheumatoid arthritis, and AIDS are associated with enhanced plasma levels of TNF and other cytokines.31 Only those sleep apnea patients showing elevated TNF activity experience fatigue.52 Other facets of the immune response are also linked to sleep. Over 25 years ago, altered antigen uptake after sleep deprivation was reported.53 Studies carried out in the 1970s also showed a decrease in lymphocyte DNA synthesis after 48 hours of sleep deprivation and a decrease in phagocytosis after 72 hours of sleep deprivation.48,54 Sleep deprivation also induces changes in mitogen responses.7 Circulating
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immune complexes fall during sleep and rise again just before getting out of bed and in mice sleep deprivation reduces IgG catabolism, resulting in elevated IgG levels.7 In contrast, one study failed to show an effect of sleep deprivation on spleen cell counts, lymphocyte proliferation or plaque-forming cell responses to antigens in rats.55 In an extensive elegant study of humans deprived of sleep for 64 hours, there was also a failure to show an effect of sleep deprivation on proliferative responses to mitogens.56 However, they did show a depression of CD4, CD16, CD56 and CD57 lymphocytes after one night of sleep loss, although the number of CD56 and CD57 lymphocytes increased after two nights of sleep loss. Another group57 also showed that a night of sustained wakefulness reduced counts of all lymphocyte subsets measured. Finally, 8 hours of sleep deprivation suppressed the secondary antibody response to sheep red blood cells in rats.58 Changes in NK cell activity in conjunction with sleep and sleep loss have been measured by several laboratories.7 In several studies, NK cell activity decreased after sleep deprivation. In contrast, increased NK cell activity after sleep deprivation is reported in other studies. In normal men and women, NK cell activity may decrease with sleep.59 However, insomnia is associated with a reduction of NK cell activity.60 It is likely that circulating NK cell activity, as well as NK cell activity in a variety of tissue compartments, is sensitive to sleep though the exact tissue distribution of NK cell activity is likely dependent upon the specific experimental conditions. Three clinical studies have examined the effects of sleep deprivation on functional immunity by following antibody responses in human subjects to viral vaccines. Acute sleep deprivation for one whole night following immunization with hepatitis A vaccine at 9:00 am (0900h) results in an antibody response at 4 weeks that is about half that seen in subjects that slept regularly from 11:00 pm (2300h) to 7:00 am (0700h) on the night following vaccination.61 Sleeping subjects show increases in growth hormone, prolactin, and dopamine, but decreases in thyrotropin, norepinephrine, and epinephrine in comparison to sleep-deprived subjects.61 Another vaccination study was conducted in subjects restricted to 4 hours of sleep for 4 nights and then immunized with influenza vaccine.62 Sleep deprivation continued for 2 more nights after the vaccination. Then subjects were allowed to sleep for 12 hours over 7 days to recover.62 Antibody determinations at 10 days following vaccination reveal that sleep-deprived subjects express influenza antibodies at less than half the level seen in controls.62 However, by 3 weeks following immunization, antibody titers are similar in both groups.62 Analysis of the antibody response to influenza vaccine in moderate to severe obstructive sleep apnea revealed no differences in immune responsiveness.63 No analyses of resistance to infection, cellular immunity, cytokine expression or other immune parameters were conducted in these studies. Susceptibility to infection has been used as an end point in two human studies. Shift workers are considered chronically sleep deprived, and a large study of shift workers revealed an increased incidence of infections in those who experienced the most shift changes64; however, sleep time was not quantified in these individuals, and many other
variables (including circadian rhythm disruption and stress) confound the interpretation of these results. Recently a study was conducted in subjects in whom self reports of sleep duration and sleep efficiency were acquired daily for two weeks prior to controlled challenge with a “cold” virus.65 Individuals with less than 7 hours of sleep per night or those with sleep efficiency below 92% were more likely to develop colds.65 This study was carefully conducted in a substantial number of subjects, but with this method of sleep quantification neither the duration of spontaneous sleep deprivation prior to the study, nor its cause (e.g., stress), is known. In summary, analysis of sleep deprivation effects on immune function is confounded by stress and other coincident physiological responses in animals. Concurrent physiological changes (other than stress) also complicate sleep deprivation studies in humans.7 Sleep deprivation protocols are not standardized in animal or human studies, making comparison of results difficult. Despite the problems with available data, collectively the extensive literature on sleep deprivation and immune changes suggests that short-term deprivation potentiates immune function whereas long-term deprivation leads to functional immune suppression.
SLEEP AND IMMUNITY SHARE COMMON REGULATORY MOLECULES Substantial evidence now suggests that IL-1β and TNF-α are involved in physiological sleep regulation and levels change in sleep associated with pathology.31 Sleep deprivation is associated with enhanced sleepiness, sleep rebound, sensitivity to kindling and pain stimuli, cognitive and memory impairments, performance impairments, depression and fatigue. Administration of exogenous IL-1β or TNF-α induces all of these sleep loss-induced symptoms.10,31 Further, chronic sleep loss-associated pathologies such as metabolic syndrome, chronic inflammation, and cardiovascular disease are also associated with changes in IL-1β and TNF-α activity10,31 or in some cases blocked if these cytokines are inhibited.66-68 Clinically available inhibitors of either IL-1β67 (e.g., the IL-1–receptor antagonist, anakinra) or TNF-α68 (e.g. the TNF-α soluble receptor, etanercept) reduce spontaneous sleep in experimental animals and alleviate fatigue and excess sleepiness in humans with pathologies such as sleep apnea and rheumatoid arthritis. The IL1-receptor antagonist and TNF soluble receptor are normal gene products found in blood and brain and their levels are altered by sleep.10 In addition to being immunocyte products whose production is amplified by viral and bacterial products, both IL-1β and TNF-α are also found in normal brain.10,31 Both IL-1β mRNA and TNF-α mRNA have diurnal rhythms in the brain with the highest values being associated with periods of maximum sleep. TNF-α protein levels also have a sleep-associated diurnal rhythm in several brain areas and IL-1β cerebrospinal fluid levels vary with the sleep–wake cycle.69 Cortical expression of TNF-α in layers II through IV is enhanced by afferent activity,70 and this may be part of the process that is responsible for local use-dependent sleep.10
Administration of either IL-1β or TNF-α (and IL-1α and TNF-β, as well) promotes NREM sleep.10,31 The excessive NREM sleep occurring after either IL-1β or TNF-α injection appears to be physiological in the sense that sleep remains episodic, sleep-cycle length remains normal and sleep is readily reversible if animals are disturbed. Further, IL-1β or TNF-α enhance NREM sleep intensity, as measured by the amplitude of EEG delta waves. The effects of IL-1 on sleep depend upon dose and the time of day it is given. IL-1 and TNF inhibit the binding of the BMAL/CLOCK complex in the suprachiasmatic nucleus71; this action may be responsible for the differential effects of these cytokines at different times of the day. Finally, knockout strains of mice that lack either the type I IL- receptor or the 55 kD TNF receptor sleep less than strain controls.10,31 Sleep deprivation, excessive food intake and acute mild increases in ambient temperature are effective somnogens. The somnogenic actions of each of these manipulations are associated with enhanced production of either IL-1 or TNF. After sleep deprivation, brain levels of IL-1β mRNA increase.10,31 The NREM sleep rebound that would normally occur after sleep deprivation is greatly attenuated if either IL-1 or TNF is blocked using antibodies or soluble receptors. In humans and rabbits, IL-1 plasma levels increase during sleep deprivation. The actions of excessive feeding on NREM sleep and liver and brain production of IL-1 represent physiological change yet they likely involve the actions of bacterial cell wall products. Gut permeability to bacteria and bacterial products is influenced by dietary factors47 and the gramnegative bacteria cell wall product, endotoxin, is a normal constituent of portal blood.72 Endotoxin stimulates IL-1 production in liver and elsewhere. Other bacterial cell wall products, for example, muramyl peptides, also have the capacity to stimulate IL-1 and TNF production38 and cross the intestinal wall into lymph. NREM sleep responses induced by muramyl dipeptide are attenuated if animals are pretreated with either blockers of IL-1 or TNF.10,31,38 As mentioned previously, prolonged sleep deprivation results in bacteremia. It thus seems likely that the interaction of those bacteria with liver macrophages results in the amplification of the physiological processes that are also associated with excessive food intake. IL-1 and TNF act within a cascade of events (see Fig. 25-1). For example, both IL-1 and TNF stimulate nuclear factor kappa B (NFκB) production. NFκB is a DNA-binding protein involved in transcription. Other somnogenic cytokines, such as acidic fibroblast growth factor, epidermal growth factor, and nerve growth factor also stimulate NFκB production. NFκB promotes IL-1 and TNF production and thus forms a positive feedback loop (see Fig. 25-1). Activation of NFκB also promotes IL-2, IL-6, IL-8, IL-15 and IL-18 production; all of these cytokines promote sleep in rats.10,31,38 Sleep deprivation is associated with the activation of NFκB in the cerebral cortex, basal forebrain cholinergic neurons, and the lateral hypothalamus.10,31,38 Growth hormone–releasing hormone (GHRH) is likely involved in IL-1 promotion of NREM sleep. There is an independent literature implicating GHRH in sleep regulation.31 Administration of GHRH promotes NREM sleep and inhibition of GHRH inhibits spontaneous NREM
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sleep. Finally, as mentioned previously, the GHRH receptor seems necessary for an effective response to viral challenge.32 The mechanisms by which sleep regulatory substances (SRSs) are regulated and induce sleep are beginning to be understood. TNF and IL-1 neuronal expressions are enhanced in response to afferent activity. For instance, excessive stimulation of rat facial whiskers for 2 hours enhances IL-1 and TNF immunoreactivity in cortical layers II through IV of the somatosensory cortical columns receiving the enhanced afferent input.70 What is it about neuronal activity or wakefulness that causes the enhanced SRS activity? Neuronal activity manifests as presynaptic and postsynaptic events that act in both the short and long term. Neuronal activity in presynaptic neurons results in the release of transmitters and ATP.73 In turn, some of that ATP is converted to adenosine and some ATP acts on purine P2X7 receptors on glia to release TNF and IL-1.10 In immunocytes, ATP performs a similar cytokine releasing action.74 The extracellular adenosine derived from ATP interacts with neurons via the adenosine A1 receptor (A1AR); this action results in hyperpolarization via K+ channels. The ATP-released TNF activates NFκB in postsynaptic and presynaptic neurons.10 NFκB enhances the A1AR, thereby rendering the cell more sensitive to adenosine. NFκB also enhances production of production a subunit of the AMPA receptor gluR1 mRNA. AMPA receptors make the postsynaptic neuron more sensitive to glutamate.10,75 The time courses of enhanced receptor or ligand mRNA are much slower than the direct actions of adenosine or TNF; the subsequent production of protein offers a way for the brain to keep track of prior neuronal network activity and translate that activity into a greater sleep propensity. The various time courses of action of the neurotransmitters (msec), the conversions of ATP to adenosine and its actions (sec) and the actions of ATP-induced release of cytokines and their subsequent actions on gene transcription and translation (min-hours) provide a mechanism for activity-dependent oscillations of neuronal assembly sleep.75 There is a growing literature linking the somnogenic cytokines to more classical sleep mechanisms. IL-1β and TNF-α interact with a variety of neurotransmitter systems. The list includes glutamate, serotonin, acetylcholine, gamma amino butyric acid, histamine, and dopamine.10,31 Little is known about the specificity of these interactions for sleep, although there are some promising investigations. For example, the depletion of brain serotonin blocks muramyl dipeptide–induced NREM sleep responses and attenuates IL-1–induced sleep responses.76 In another report, the same group directly measured medial preoptic serotonin metabolism after IL-1β treatment and concluded that serotonergic activation could play a role in mediating the effects of IL-1 on sleep.77 Within the hypothalamus, IL-1β activates sleep-active neurons and inhibits wakeactive neurons.78 TNF-α promotes sleep if microinjected into the anterior hypothalamus while injection of a soluble TNF receptor into this area reduces sleep.79 TNF-α is also somnogenic if injected into the locus coeruleus.79 This latter observation likely relates to TNF-α interactions with α2 adrenergic receptive mechanisms and norepinephrine release.80 Interestingly, TNF-α or IL-1β, if applied
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locally onto the surface of the cerebral cortex unilaterally, enhances EEG delta activity on the side to which it is applied but not the contralateral side.81,82 Conversely, application of the TNF soluble receptor unilaterally onto the cortex of sleep-deprived rats attenuates sleep lossinduced EEG delta activity on the side injected, but not on the opposite side. These latter data suggest that TNF-α acts locally within the cortex (in addition to its somnogenic actions in the hypothalamus) to enhance EEG synchronization and possibly sleep intensity. In fact, application of TNF-α directly to the cortex enhances the probability of individual cortical columns entering into a sleeplike state.70 In summary, sleep control mechanisms and the immune system share regulatory molecules.83 The best characterized are IL-1β and TNF-α. These substances are involved in physiological NREM sleep regulation and are key players in the development of the acute phase response induced by infectious agents. During the initial response to infectious challenge these proinflammatory cytokines are upregulated and thereby amplify physiological sleep mechanisms leading to the acute phase sleep response.
❖ Clinical Pearl Although physicians have always prescribed bed rest to aid in recuperation from infections and other maladies, as yet there is no direct evidence that sleep aids in recuperation. Such studies are difficult to perform as the recovery from an infection, for instance, will be influenced by the baseline severity of the infection (i.e., differences in exposure or innate resistance that determine the replication level and dissemination of the invading microbe) as well as by what the patient does during the infection. Physicians will continue to prescribe bed rest and often this is just what the patient wishes to do. It seems likely that such advice is beneficial, as enhanced sleep is clearly part of the adaptive APR. The only evidence of which we are aware that is relevant to this issue is consistent with the concept that sleep aids in recuperation. After infectious challenge, animals that have robust NREM sleep responses have a higher probability of survival than animals that fail to exhibit NREM sleep responses.84 Although this evidence is strictly correlative in nature, it behooves those of us interested in sleep and sleep disorders to investigate this a little further. Perhaps our grandmothers’ folk wisdom pertaining to the preventative and curative attributes of sleep is correct.
Acknowledgments This work was suggested, in part, by grants from the National Institutes of Health, NS-25378, NS-27250, NS-31453, and HD 36520. REFERENCES 1. Kapetanovic R, Cavaillon JM. Early events in innate immunity in the recognition of microbial pathogens. Expert Opin Biol Therapy 2007;7:907-918.
2. Hart BL. Biological basis of the behavior of sick animals. Neurosci Biobehav Rev 1988;12:123-137. 3. Mackowiak PA. Direct effects of hyperthermia on pathogenic microorganisms: teleologic implications with regard to fever. Rev Infect Dis 1981;3:508-520. 4. Meli R, Raso GM, Bentivoglio C, et al. Recombinant human prolactin induces protection against Salmonella typhimurium infection in the mouse: role of nitric oxide. Immunopharmacol 1996; 34:1-7. 5. van Vliet SJ, Dunnen JD, Gringhuis SI, et al. Innate signaling and regulation of dendritic cell immunity. Curr Opin Immunol 2007;19:435-440. 6. Germain RN. An innately interesting decade of research in immunology. Nat Med 2004;10:1307-1320. 7. Majde JA, Krueger JM. Links between the innate immune system and sleep. J Allergy Clin Immunol 2005;116:1188-1198. 8. Gadina M, Hilton D, Johnston JA, et al. Signaling by type I and II cytokine receptors: ten years after. Curr Opin Immunol 2001;13: 363-373. 9. Opp MR. Cytokines and sleep. Sleep Med Rev 2005;9:355364. 10. Krueger JM. The role of cytokines in sleep regulation. Cur Pharm Design 2008;14:3408-3416. 11. Akira S, Uematsu S, Takeuchi O. Pathogen recognition and innate immunity. Cell 2006;124:783-801. 12. Kaparakis M, Philpott DJ, Ferrero RL. Mammalian NLR proteins; discriminating foe from friend. Immunol Cell Biol 2007;85: 495-502. 13. Toth LA. Microbial modulation of sleep. In: Lydic R, Baghdoyan H, editors. Handbook of behavioral state control: cellular and molecular mechanisms. Boca Raton, Fla: CRC Press; 1999. p. 641-657. 14. Von Economo C. Sleep as a problem of localization. J Nerv Ment Dis 1930;71:249-259. 15. Kristensson K. Avian influenza and the brain—comments on the occasion of resurrection of the Spanish flu virus. Brain Res Bull 2006;68:406-413. 16. Norman SE, Chediak AD, Freeman C, et al. Sleep disturbances in men with asymptomatic human immunodeficiency (HIV) infection. Sleep 1992;15:150-155. 17. Gourmelon P, Biet D, Clarencon D, et al. Sleep alterations in experimental street rabies virus infection occur in the absence of major EEG abnormalities. Brain Res 1991;554:159-165. 18. Smith A. Sleep, colds, and performance. In: Broughton RJ, Ogilvie RD, editors. Sleep, arousal and performance. Boston: Birkhauser; 1992. p. 233-242. 19. Fang J, Sanborn CK, Renegar KB, et al. Influenza viral infections enhance sleep in mice. Proc Soc Exp Med Biol 1995;210:242252. 20. Toth LA, Hughes LF. Macrophage participation in influenza-induced sleep enhancement in C57BL/6J mice. Brain Behav Immun 2004;18:375-389. 21. Toth LA, Verhulst SJ. Strain differences in sleep patterns of healthy and influenza-infected inbred mice. Behav Genet 2003; 33:325-336. 22. Trammell RA, Toth LA. Genetic susceptibility and resistance to influenza infection and disease in humans and mice. Expert Rev Mol Diagn 2008;8:515-529. 23. Majde JA. Viral double-stranded RNA, cytokines and the flu. J Interferon Cytokine Res 2000;20:259-272. 23a. Majde JA, Kapas L, Bohnet SG, et al. Attenuation of the influenza virus sickness behavior in mice deficient in Toll-like receptor 3. Brain Behav Immun 2010;24:306-315. 24. Majde JA, Brown RK, Jones MW, et al. Detection of toxic viralassociated double-stranded RNA (dsRNA) in influenza-infected lung. Microb Pathol 1991;10:105-115. 25. Kimura M, Majde JA, Toth LA, et al. Somnogenic effects of rabbit and human recombinant interferons in rabbits. Am J Physiol 1994;267:R53-R61. 26. DeSarro GB, Masuda Y, Ascioti C, et al. Behavioral and ECoG spectrum changes induced by intracerebral infusion of interferons and interleukin-2 in rats are antagonized by naloxone. Neuropharmacology 1990;29:167-179. 27. Späth-Schwalbe E, Lange T, Perras P, et al. Interferon-α acutely impairs sleep in healthy humans. Cytokine 2000;12:518-521.
28. Traynor TR, Majde JA, Bohnet SG, et al. Interferon type I receptordeficient mice have altered disease symptoms in response to influenza virus. Brain Behav Immun 2007;21:311-322. 29. Kapas L, Bohnet SG, Traynor TR, et al. Spontaneous and influenza virus-induced sleep are altered in TNFa double-receptor deficient mice. J Appl Physiol 2008;105:1185-1198. 30. Chen L, Duricka D, Nelson S, et al. Influenza virus-induced sleep responses in mice with targeted disruptions in neuronal or inducible nitric oxide synthases. J Appl Physiol 2004;97:17-28. 31. Obal F Jr, Krueger JM. Biochemical regulation of sleep. Frontiers Biosci 2003;8:520-550. 32. Alt JA, Obal F Jr, Traynor TR, et al. Alterations in EEG activity and sleep after influenza viral infection in GHRH receptor-deficient mice. J Appl Physiol 2003;95:460-468. 33. Majde JA, Bohnet SG, Ellis GA, et al. Detection of mouse-adapted human influenza virus in the olfactory bulb of mice within hours after intranasal infection. J Neurovirol 2007;13:399-409. 34. Toth LA, Krueger JM. Alterations in sleep during Staphylococcus aureus infection in rabbits. Infect Immun 1988;56:1785-1791. 35. Johannsen L, Wecke J, Obál F Jr, et al. Macrophages produce somnogenic and pyrogenic muramyl peptides during digestion of staphylococci. Am J Physiol 1991;260:R126-R133. 36. Brown R, Price RJ, King MG, et al. Are antibiotic effects on sleep behavior in the rat due to modulation of gut bacteria? Physiol Behav 1990;48:561-565. 37. Krueger JM, Karnovsky ML, Martin SA, et al. Peptidoglycans as promoters of slow-wave sleep. II. Somnogenic and pyrogenic activities of some naturally occurring muramyl peptides; correlations with mass spectrometric structure determination. J Biol Chem 1984;259:12659-12662. 38. Pabst MJ, Beranova S, Krueger JM. A review of the effects of muramyl peptides on macrophages, monokines and sleep. Neuro Immuno Modulation 1999;6:261-283. 39. Mullington J, Korth C, Hermann DM, et al. Dose-dependent effects of endotoxin on human sleep. Am J Physiol Regul Integr Compar Physiol 2000;278:R947-R955. 40. Toth LA, Tolley EA, Broady R, et al. Sleep during experimental trypanosomiasis in rabbits. Proc Soc Exp Biol Med 1994;205: 174-181. 41. Toth LA, Opp MR, Mao L. Somnogenic effects of sleep deprivation and Escherichia coli inoculation in rabbits. J Sleep Res 1995;4:30-40. 42. Bergmann BM, Rechtschaffen A, Gilliland MA, et al. Effect of extended sleep deprivation on tumor growth in rats. Am J Physiol 1996;271:R1460-R1464. 43. Brown R, Pang G, Husband AJ, et al. Suppression of immunity to influenza virus infection in the respiratory tract following sleep disturbance. Reg Immunol 1989;2:321-325. 44. Renegar KB, Floyd RA, Krueger JM. Effects of short-term sleep deprivation on murine immunity to influenza virus in young adult and senescent mice. Sleep 1998;21:241-248. 45. Everson CA, Toth LA. Systemic bacterial invasion induced by sleep deprivation. Am J Physiol 2000;278:R905-R916. 46. Landis C, Pollack S, Helton WS. Microbial translocation and NK cell cytotoxicity in female rats sleep deprived on small platforms. Sleep Res 1997;26:619. 47. Deitch EA. Bacterial translocation: the influence of dietary variables. Gut 1994;35:S23-S27. 48. Palmblad J, Cantell K, Strander H, et al. Stressor exposure and immunological response in man: interferon producing capacity and phagocytosis. Psychosom Res 1976;20:193-199. 49. Moldofsky H, Lue FA, Eisen J, et al. The relationship of interleukin-1 and immune functions to sleep in humans. Psychosom Med 1986;48:309-318. 50. Darko DF, Miller JC, Gallen C, et al. Sleep electroencephalogram delta frequency amplitude, night plasma levels of tumor necrosis factor α and human immunodeficiency virus infection. Proc Natl Acad Sci USA 1995;92:12080-12086. 51. Covelli V, D’Andrea L, Savastano S, et al. Interleukin-1 beta plasma secretion during diurnal spontaneous and induced sleeping in healthy volunteers. Acta Neurol (Napoli) 1994;16:79-86. 52. Mills P, Kim JH, Bardwell W, et al. Predictors of fatigue in obstructive sleep apnea. Sleep Breath 2008;12:397-399. 53. Casey FB, Eisenberg J, Peterson D, et al. Altered antigen uptake and distribution due to exposure to extreme environmental temperatures or sleep deprivation. Reticuloendothelial Soc J 1974;15:87-90.
CHAPTER 25 • Sleep and Host Defense 289 54. Palmblad J, Petrini B, Wasserman J, et al. Lymphocyte and granulocyte reactions during sleep deprivation. Psychosom Med 1979; 41:273-278. 55. Benca RM, Kushida CA, Everson CA, et al. Sleep deprivation in the rat: VII. Immune function. Sleep 1989;12:47-52. 56. Dinges DF, Douglas SD, Zaugg L, et al. Leukocytosis and natural killer cell function parallel neurobehavioral fatigue induced by 64 hours of sleep deprivation. J Clin Invest 1994;93:19301939. 57. Born J, Lange T, Hansen K, et al. Effects of sleep and circadian rhythm on human circulating immune cells. J Immunol 1997; 158:4454-4464. 58. Brown R, Price RJ, King MG, et al. Interleukin-1β and muramyl dipeptide can prevent decreased antibody response associated with sleep deprivation. Brain Behav Immun 1989;3:320-330. 59. Moldofsky H, Lue FA, Davidson J, et al. Comparison of sleepwake circadian immune functions in women vs men. Sleep Res 1989;18:431. 60. Irwin M, Smith TL, Gillin JC. Electroencephalographic sleep and natural killer activity in depressed patients and control subjects. Pschosom Med 1992;54:10-21. 61. Lange T, Perras B, Fehm HL, et al. Sleep enhances the human antibody response to hepatitis A vaccination. Psychosom Med 2003;65:831-835. 62. Spiegel K, Sheridan JF, Van Cauter E. Effect of sleep deprivation on response to immunization. JAMA 2002;288:1471-1472. 63. Dopp JM, Wiegert NA, Moran JJ, et al. Humoral immune responses to influenza vaccination in patients with obstructive sleep apnea. Pharmacotherapy 2007;27:1483-1489. 64. Mohren DC, Jansen NW, Kant IJ, et al. Prevalence of common infections among employees in different work schedules. J Occup Environ Med 2002;44:1003-1011. 65. Cohen S, Doyle WJ, Alper CM, et al. Sleep habits and susceptibility to the common cold. Arch Intern Med 2009;169:62-67. 66. Omdal R, Gunnarsson R. The effect of interleukin-1 blockade on fatigue in rheumatoid arthritis—a pilot study. Rheumatol Int 2005;25:481-484. 67. Franklin CM. Clinical experience with soluble TNF p75 receptor in rheumatoid arthritis. Semin Arthrit Rheum 1999;29:171-181. 68. Larsen CM, Faulenbach M, Vaag A, et al. Interleukin-1-receptor antagonist in type 2 diabetes mellitus. N Engl J Med 2007;356: 1517-1526. 69. Lue FA, Bail M, Jephthah-Ochola J, et al. Sleep and cerebrospinal fluid interleukin-1-like activity in the cat. Int J Neurosci 1988; 42:179-183. 70. Churchill L, Rector DM, Yasuda K, et al. Tumor necrosis factor alpha: activity dependent expression and promotion of cortical column sleep in rats. Neurosci 2008;156:71-80. 71. Cavadini G, Petrzilka S, Kohler P, et al. TNF-alpha suppresses the expression of clock genes by interfering with E-box-mediated transcription. Proc Natl Acad Sci USA 2007;104:12843-12848. 72. Jacob AI, Goldberg PK, Bloom N, et al. Endotoxin and bacteria in portal blood. Gastroenterology 1977;72:1268-1270. 73. Burnstock G. Physology and pathophysiology of purinergic neurotransmission. Physiol Rev 2007;87:659-797. 74. Ferrari D, Pizzirani C, Adinolfi E, et al. The P2X7 receptor: a key player in IL-1 processing and release. J Immunol 2006;176: 3877-3883. 75. Krueger JM, Rector DM, Roy S, et al. Sleep as a fundamental property of neuronal assemblies. Nature Rev Neurosci 2008;9:910-919. 76. Imeri L, Bianchi S, Mancia M. Muramyl dipeptide and IL1 effects on sleep and brain temperature following inhibition of serotonin synthesis. Am J Physiol 1997; 273:R1663-R1668. 77. Gemma C, Imeri L, Grazia De Simoni M, et al. Interleukin-1 induces changes in sleep, brain temperature, and serotonergic metabolism. Am J Physiol 1997;272:R601-R606. 78. Alam N, McGinty D, Bashir T, et al. Interleukin-1 beta modulates state-dependent discharge activity of preoptic area and basal forebrain neurons: Role in sleep regulation. Eur J Neurosci 2004;20: 207-216. 79. Kubota T, Li N, Guan Z, et al. Intrapreoptic microinjection of TNFα enhances non-REM sleep in rats. Brain Res 2002;932:37-44. 80. Elenkov IJ, Kovacs K, Duda E, et al. Presynaptic inhibitory effect of TNFα on the release of noradrenaline in isolated median eminence. J Neuroimmunol 1992;41:117-120.
290 PART I / Section 4 • Physiology in Sleep 81. Yoshida H, Peterfi Z, Garcia-Garcia F, et al. State-specific asymmetries in EEG slow wave activity induced by local application of TNF alpha. Brain Res 2004;1009:129-136. 82. Yasuda T, Yoshida H, Garcia-Garcia F, et al. Interleukin-1β has a role in cerebral cortical state-dependent electroencephalographic slowwave activity. Sleep 2005;28:177-184.
83. Thomas KS, Motivala S, Olmstead R, Irwin MR. Sleep depth and fatigue: role of cellular inflammatory activation. Brain Behav Immun 2010 (in press). 84. Toth LA, Tolley EA, Krueger JM. Sleep as a prognostic indicator during infectious disease in rabbits. Proc Soc Exp Biol Med 1993;203:179-192.
Endocrine Physiology in Relation to Sleep and Sleep Disturbances Eve Van Cauter and Esra Tasali Abstract Sleep exerts important modulatory effects on most components of the endocrine system. Pathways mediating the impact of sleep on peripheral endocrine function and metabolism include the activity of the hypothalamic releasing and inhibiting factors on pituitary hormone release and the autonomous nervous system control of endocrine organs. Modulatory effects of sleep on endocrine release are not limited to the hormones of the hypothalamic-pituitary axes; these effects are also observed for the hormones controlling carbohydrate metabolism, appetite regulation, and water and electrolyte balance. Sleep loss is associated with disturbances of hormone
MODULATION OF ENDOCRINE FUNCTION BY SLEEP–WAKE HOMEOSTASIS AND CIRCADIAN RHYTHMICITY In healthy adults, reproducible changes of essentially all hormonal and metabolic variables occur during sleep and around wake–sleep and sleep–wake transitions. These daily events reflect the interaction of central circadian rhythmicity and sleep–wake homeostasis. Thus, the dual control of sleep timing and quality by circadian processes (i.e., Process C) and sleep–wake homeostasis (i.e., Process S) is readily reflected in the modulatory effects exerted by sleep on endocrine and metabolic function. Pathways by which central circadian rhythmicity and sleep-wake homeostasis affect peripheral endocrine function and metabolism include the modulation of the activity of the hypothalamic releasing and inhibiting factors and the autonomous nervous system control of endocrine organs. Findings from genome-wide association studies also support a role of circulating melatonin levels on specific endocrine targets, including the pancreatic beta cells.1-3 The relative contributions of circadian timing compared with homeostatic control in the regulation of the temporal organization of hormone release vary from one endocrine axis to another. Similarly, modulatory effects of the transitions between wake and sleep (and vice versa) and between non–rapid eye movement (NREM) and rapid eye movement (REM) stages also vary from one hormone to another. Circadian oscillations can be generated in many peripheral organs, including tissues that release endocrine signals such as adipocytes and pancreatic beta cells.4 These “local” oscillators appear to be under the control of the central pacemaker in the suprachiasmatic nuclei either directly via neural and endocrine signals, or indirectly via its control of behavioral rhythms such as the sleep–wake cycle and the rhythm of feeding. The possible involvement of these peripheral oscillators on the temporal organization of endocrine release and metabolic function during waking and sleeping remains to be investigated.
Chapter
26
secretion and metabolism, which may have clinical relevance, particularly as voluntary partial sleep curtailment has become a highly prevalent behavior in modern society. Reduced sleep quality also adversely affects endocrine release and metabolism. Evidence suggests that part of the constellation of hormonal and metabolic alterations that characterize normal aging may reflect the deterioration of sleep quality. Major metabolic diseases such as obesity, type 2 diabetes, and polycystic ovary syndrome are all associated with sleep disturbances, which may promote the development or exacerbate the severity of the condition. Strategies to reverse decrements in sleep quality may have beneficial effects on endocrine and metabolic function.
To differentiate between effects of circadian rhythmicity and those subserving sleep–wake homeostasis, researchers have used experimental strategies that take advantage of the fact that the central circadian pacemaker takes several days to adjust to a large sudden shift of sleep–wake and light–dark cycles (such as occur in jet lag and shift work). Such strategies allow for the effects of circadian modulation to be observed in the absence of sleep and for the effects of sleep to be observed at an abnormal circadian time. Figure 26-1 illustrates mean profiles of hormonal concentrations, glucose levels, and insulin-secretion rates (ISR) observed in healthy subjects who were studied before and during an abrupt 12-hour delay of the sleep–wake and dark–light cycles. To eliminate the effects of feeding, fasting, and postural changes, the subjects remained recumbent throughout the study, and the normal meal schedule was replaced by intravenous glucose infusion at a constant rate.5 As shown in Figure 26-1, this drastic manipulation of sleep had only modest effects on the wave shape of the cortisol profile, in sharp contrast with the immediate shift of the growth hormone (GH) and prolactin (PRL) rhythms that followed the shift of the sleep–wake cycle. The temporal organization of thyroid-stimulating hormone (TSH) secretion appears to be influenced equally by circadian and sleep-dependent processes. Indeed, the evening elevation of TSH levels occurs well before sleep onset and has been shown to reflect circadian phase. During sleep, an inhibitory process prevents TSH concentrations from rising further. Consequently, in the absence of sleep, the nocturnal TSH elevation is markedly amplified. Both sleep and time of day clearly modulated glucose levels and ISR. Nocturnal elevations of glucose and ISR occurred even when the subjects were sleep deprived, and recovery sleep at an abnormal circadian time was also associated with elevated glucose and ISR. This pattern of changes in glucose levels and ISR reflected changes in glucose use because, when glucose is infused exogenously, endogenous glucose production is largely inhibited. 291
292 PART I / Section 4 • Physiology in Sleep
Plasma GH (µg/L)
20 15 10 5 0
Plasma cortisol (µg/dL)
18 22 02 06 10 14 18 22 02 06 10 14 18 22 20 15 10 5 0
Plasma TSH (µU/mL)
4
Plasma PRL (% of mean)
250
Plasma glucose (% of mean)
18 22 02 06 10 14 18 22 02 06 10 14 18 22
130
3 2 1 18 22 02 06 10 14 18 22 02 06 10 14 18 22
200 150 100 50 18 22 02 06 10 14 18 22 02 06 10 14 18 22 120 110 100 90 80 18 22 02 06 10 14 18 22 02 06 10 14 18 22
ISR (% of mean)
160 140 120 100 80 60 18 22 02 06 10 14 18 22 02 06 10 14 18 22 Clock time Period of nocturnal sleep Period of nocturnal sleep deprivation Period of daytime recovery sleep
Figure 26-1 From top to bottom: Mean 24-hour profiles of plasma growth hormone (GH), cortisol, thyrotropin (TSH), prolactin (PRL), glucose, and insulin secretion rates (ISR) in a group of eight healthy young men (20 to 27 years old) studied during a 53-hour period including 8 hours of nocturnal sleep, 28 hours of sleep deprivation, and 8 hours of daytime sleep. The vertical bars on the tracings represent the standard error of the mean (SEM) at each time point. The blue bars represent the sleep periods. The red bars represent the period of nocturnal sleep deprivation. The orange bars represent the period of daytime sleep. Caloric intake was exclusively under the form of a constant glucose infusion. Shifted sleep was associated with an immediate shift of GH and PRL release. In contrast, the secretory profiles of cortisol and TSH remained synchronized to circadian time. Both sleep-dependent and circadian inputs can be recognized in the profiles of glucose and ISR. (Adapted from Van Cauter E, Spiegel K. Circadian and sleep control of endocrine secretions. In: Turek FW, Zee PC, editors. Neurobiology of sleep and circadian rhythms. New York: Marcel Dekker; 1999; and Van Cauter E, Blackman JD, Roland D, et al. Modulation of glucose regulation and insulin secretion by sleep and circadian rhythmicity. J Clin Invest 1991;88:934-942.)
First we will review the interactions between sleep and endocrine release in the hypothalamic-pituitary axes and the roles of sleep in carbohydrate metabolism, appetite regulation, and hormone control of body-fluid balance. Table 26-1 provides basic information about the hormones that will be discussed in this chapter. We then summarize the growing body of evidence linking decrements of sleep duration or quality that occur with sleep restriction, in sleep disorders, or as a result of normal aging, and disturbances of endocrine and metabolic function. Lastly, we review recent evidence linking disorders of sleep–wake regulation and metabolic and endocrine diseases, including obesity, type 2 diabetes, and polycystic ovary syndrome (PCOS). For a review of sleep abnormalities in other endocrine diseases, the reader is referred to Chapter 125.
THE GROWTH HORMONE AXIS Pituitary release of GH is stimulated by hypothalamic GH-releasing hormone (GHRH) and inhibited by somatostatin. In addition, the acylated form of ghrelin, a peptide produced predominantly by the stomach, binds to the growth hormone secretagogue (GHS) receptor and is a potent endogenous stimulus of GH secretion.6 There is a combined and probably synergic role of GHRH stimulation, elevated nocturnal ghrelin levels, and decreased somatostatinergic tone in the control of GH secretion during sleep. Although sleep clearly involves major stimulatory effects on GH secretion, the hormones of the somatotropic axis, including GHRH, ghrelin, and GH, in turn appear to be involved in sleep regulation.7 In healthy adult subjects, the 24-hour profile of plasma GH levels consists of stable low levels abruptly interrupted by bursts of secretion. The most reproducible GH pulse occurs shortly after sleep onset.8 In men, the sleep-onset GH pulse is generally the largest, and often the only, secretory pulse observed over the 24-hour span. In women, daytime GH pulses are more frequent, and the sleep-associated pulse, although still present in the vast majority of individual profiles, does not account for the majority of the
CHAPTER 26 • Endocrine Physiology in Relation to Sleep and Sleep Disturbances 293
Table 26-1 Origin and Main Action of Hormones HORMONE
MAIN SECRETING ORGAN
MAIN ACTION IN ADULTS
Growth hormone (GH)
Pituitary gland
Anabolic hormone that regulates body composition
Prolactin (PRL)
Pituitary gland
Stimulates lactation in women; pleiotropic actions
Adrenocorticotropic hormone (ACTH)
Pituitary gland
Stimulates release of cortisol from adrenal cortex
Cortisol
Adrenal cortex
Stress hormone, antiinsulin effects
Thyroid-stimulating hormone (TSH)
Pituitary gland
Stimulates the release of thyroid hormones from the thyroid gland
Luteinizing hormone (LH)
Pituitary gland
Stimulates ovarian and testicular function
Follicle-stimulating hormone (FSH)
Pituitary gland
Stimulates ovarian and testicular function
Testosterone
Gonads
Stimulates spermatogenesis
Estradiol
Ovaries
Stimulates follicular growth
Insulin
Pancreas
Regulates blood glucose levels
Melatonin
Pineal gland
Hormone of the dark that transmits information about the light–dark cycle
Leptin
Adipose tissue
Satiety hormone regulating energy balance
Ghrelin
Stomach
Hunger hormone regulating energy balance
24-hour secretory output. Sleep onset elicits a pulse in GH secretion whether sleep is advanced, delayed, or interrupted and reinitiated. The mean GH profile shown in Figure 26-1 illustrates the maintenance of the relationship between sleep onset and GH release in subjects who underwent a 12-hour delay shift of the sleep–wake cycle. There is a consistent relationship between the appearance of delta waves in the EEG and elevated GH concentrations and maximal GH release occurs within minutes of the onset of slow-wave sleep (SWS).8,9 In healthy young men, there is a quantitative correlation between the amount of GH secreted during the sleep-onset pulse and the duration of the slow-wave episode.10 Pharmacologic stimulation of SWS with oral administration of low doses of gammahydroxybutyrate (GHB), a drug used for the treatment of narcolepsy, as well as with ritanserin, a selective 5-hydroxytryptamine (5-HT2) receptor antagonist, results in increases in GH secretion.11,12 Sedative hypnotics that are ligands of the GABAA receptor such as benzodiazepines and imidazopyridines, do not increase nocturnal GH release, consistent with their lack of stimulation of slow-wave activity.13 The mechanisms that underlie the relationship between early sleep and GH release are unclear. The significance of this relationship is that anabolic processes in the body are synchronized to a state when behavioral rest occurs and when cerebral glucose use is at its lowest point.14 There is good evidence to indicate that stimulation of nocturnal GH release and stimulation of SWS reflect, to a large extent, synchronous activity of at least two populations of hypothalamic GHRH neurons.14 Sleep-onset GH secretion appears to be primarily regulated by GHRH stimulation occurring during a period of decreased somatostatin inhibition of somatotropic activity. Indeed, in humans, GH secretion during early sleep may be nearly totally suppressed by administration of a GHRH antagonist.15 The late evening and nocturnal hours coincide with the trough of a diurnal variation in hypothalamic somatostatin tone16 that is likely to facilitate nocturnal GH release. It is also possible that ghrelin plays a role in causing increased GH
secretion during sleep because the normal 24-hour ghrelin profile shows a marked nocturnal increase peaking in the early part of the night.17,18 The upper panel of Figure 26-1 shows that the secretion of GH is increased during sleep independently of the circadian time when sleep occurs and that sleep deprivation results in greatly diminished release of this hormone. However, a slight increase may be observed during nocturnal sleep deprivation, indicating the existence of a weak circadian component that could reflect, as discussed earlier, lower somatostatin inhibition. Following a night of total sleep deprivation, GH release is increased during the daytime such that the total 24-hour secretion is not significantly affected.19 Again, the mechanisms underlying this compensatory daytime secretion are unknown, but they could involve decreased somatostatinergic tone or elevated ghrelin levels. Marked rises in GH secretion before the onset of sleep have been reported by several investigators.20-22 Presleep GH pulses may reflect the presence of a sleep debt, as they occur consistently after recurrent experimental sleep restriction.23 The short-term negative feedback inhibition exerted by GH on its own secretion may also explain observations of an absent GH pulse during the first slow wave period, when a secretory pulse occurred before sleep onset. Awakenings interrupting sleep have an inhibitory effect on GH release.24,25 Thus, sleep fragmentation generally decreases nocturnal GH secretion.
THE CORTICOTROPIC AXIS Activity of the corticotropic axis—a neuroendocrine system associated with the stress response and behavioral activation—may be measured peripherally via plasma levels of the pituitary adrenocorticotropic hormone (ACTH) and of cortisol, the adrenal hormone directly controlled by ACTH stimulation. The plasma levels of these hormones decline from an early morning maximum throughout the daytime and are near the lower limit of most assays in the
294 PART I / Section 4 • Physiology in Sleep
late evening and early part of the sleep period. Thus, sleep is normally initiated when corticotropic activity is quiescent. Reactivation of ACTH and cortisol secretion occurs abruptly a few hours before the usual waking time. The mean cortisol profile shown in Figure 26-1 illustrates the remarkable persistence of this diurnal variation when sleep is manipulated. Indeed, the overall waveshape of the profile is not markedly affected by the absence of sleep or by sleep at an unusual time of day. Thus, the 24-hour periodicity of corticotropic activity is primarily controlled by circadian rhythmicity. Nevertheless, modulatory effects of sleep or wake have been clearly demonstrated. Indeed, a number of studies have indicated that sleep onset is reliably associated with a short-term inhibition of cortisol secretion,5,26 although this effect may not be detectable when sleep is initiated at the time of the daily maximum of corticotropic activity, that is, in the morning.27 Under normal conditions, because cortisol secretion is already quiescent in the late evening, this inhibitory effect of sleep, which is temporally associated with the occurrence of slow-wave sleep,28-30 results in a prolongation of the quiescent period. Therefore, under conditions of sleep deprivation, the nadir of cortisol secretion is less pronounced and occurs earlier than under normal conditions of nocturnal sleep. Conversely, awakening at the end of the sleep period is consistently followed by a pulse of cortisol secretion.5,25,31 During sleep deprivation, the rapid effects of sleep onset and sleep offset on corticotropic activity are obviously absent, and, as may be seen in the profiles shown in Figure 26-1, the nadir of cortisol levels is higher than during nocturnal sleep (because of the absence of the inhibitory effects of the first hours of sleep), and the morning maximum is lower (because of the absence of the stimulating effects of morning awakening). Overall, the amplitude of the rhythm is reduced by approximately 15% during sleep deprivation as compared to normal conditions. In addition to the immediate modulatory effects of sleep–wake transitions on cortisol levels, nocturnal sleep deprivation, even partial deprivation, results in an elevation of cortisol levels on the following evening.32 Sleep loss thus appears to delay the normal return to evening quiescence of the corticotropic axis. This endocrine alteration is remarkably similar to that occurring in normal aging, where increases in evening cortisol levels of similar magnitude are consistently observed. This interpretation is consistent with findings in normal subjects submitted to recurrent partial sleep restriction, as discussed later.
THE THYROID AXIS Daytime levels of plasma TSH are low and relatively stable and are followed by a rapid elevation starting in the early evening and culminating in a nocturnal maximum occurring around the beginning of the sleep period.30,33 The later part of sleep is associated with a progressive decline in TSH levels, and daytime values resume shortly after morning awakening. The first 24 hours of the study illustrated in Figure 26-1 are typical of the diurnal TSH rhythm. Because the nocturnal rise of TSH occurs well before the time of sleep onset, it probably reflects a circadian effect. However, a marked effect of sleep on TSH
secretion may be seen during sleep deprivation (clearly seen in Fig. 26-1), when nocturnal TSH secretion is increased by as much as 200% over the levels observed during nocturnal sleep. Thus, sleep exerts an inhibitory influence on TSH secretions, and sleep deprivation relieves this inhibition.30,34 Interestingly, when sleep occurs during daytime hours, TSH secretion is not suppressed significantly below normal daytime levels. Thus, the inhibitory effect of sleep on TSH secretion appears to be operative when the nighttime elevation has taken place, indicating once again the interaction of the effects of circadian time and the effects of sleep. When the depth of sleep at the habitual time is increased by prior sleep deprivation, the nocturnal TSH rise is more markedly inhibited, suggesting that SWS is probably the primary determinant of the sleep-associated fall.30 Awakenings interrupting nocturnal sleep appear to relieve the inhibition of TSH and are consistently associated with a short-term TSH elevation. Circadian and sleep-related variations in thyroid hormones have been difficult to demonstrate, probably because these hormones are bound to serum proteins and thus their peripheral concentrations are affected by diurnal variations in hemodilution caused by postural changes. However, under conditions of sleep deprivation, the increased amplitude of the TSH rhythm may result in a detectable increase in plasma triiodothyronine (T3) levels, paralleling the nocturnal TSH rise.35 If sleep deprivation is continued for a second night, then the nocturnal rise of TSH is markedly diminished as compared with that occurring during the first night.35,36 It is likely that following the first night of sleep deprivation, the elevated thyroid hormone levels, which persist during the daytime period because of the prolonged half-life of these hormones, limit the subsequent TSH rise at the beginning of the next nighttime period. Data from a study of 64 hours of sleep deprivation suggest that prolonged sleep loss may be associated with an upregulation of the thyroid axis, with lower levels of TSH and higher levels of thyroid hormones.37 As discussed in the section on chronic sleep restriction, this was indeed the case in a study of the endocrine and metabolic effects of a sleep debt resulting from bedtime curtailment to 4 hours per night for 6 nights.38,39 The inhibitory effects of sleep on TSH secretion are time dependent, and that may cause, under specific circumstances, elevations of plasma TSH levels that reflect the misalignment of sleep and central circadian timing. In a study examining the course of adaptation to an abrupt 8-hour advance of the sleep–dark period in healthy young men,40 TSH levels increased progressively because daytime sleep failed to inhibit TSH and nighttime wakefulness was associated with large circadian-dependent TSH elevations. As a result, mean TSH levels following awakening from the second shifted sleep period were more than twofold higher than during the same time interval following normal nocturnal sleep. This overall elevation of TSH levels was paralleled by a small increase in T3 concentrations.40 This study demonstrated that the subjective discomfort and fatigue often referred to as “jet-lag syndrome” are associated not only with a desynchronization of bodily rhythms but also with a prolonged elevation of a hormone concentration in the peripheral circulation.
CHAPTER 26 • Endocrine Physiology in Relation to Sleep and Sleep Disturbances 295
PROLACTIN SECRETION Under normal conditions, PRL levels undergo a major nocturnal elevation starting shortly after sleep onset and culminating around midsleep. Decreased dopaminergic inhibition of PRL during sleep is likely to be the primary mechanism underlying this nocturnal PRL elevation. In adults of both sexes, the nocturnal maximum corresponds to an average increase of more than 200% above the minimum level.35 Morning awakenings and awakenings interrupting sleep are consistently associated with a rapid inhibition of PRL secretion.35 Studies of the PRL profile during daytime naps or after shifts of the sleep period have consistently demonstrated that sleep onset, irrespective of the time of day, has a stimulatory effect on PRL release. This is well illustrated by the profiles shown in Figure 26-1, in which elevated PRL levels occur both during nocturnal sleep and during daytime recovery sleep, whereas the nocturnal period of sleep deprivation was not associated with an increase in PRL concentrations. However, the sleep-related rise of
PRL may still be present, although with a reduced amplitude, when sleep does not occur at the normal nocturnal time. Maximal stimulation is observed only when sleep and circadian effects are superimposed.41-43 A close temporal association between increased prolactin secretion and slow wave activity is apparent.44 However, in contrast to the quantitative correlation between amount of slow wave activity and amount of GH release that has been evidenced in men, no such “dose-response” relationship has been demonstrated for prolactin. Awakenings interrupting sleep inhibit nocturnal PRL release.44 Benzodiazepine and imidazopyridine hypnotics taken at bedtime may cause an increase in the nocturnal PRL rise, resulting in concentrations near the pathological range for part of the night.45,46 This is illustrated for triazolam and zolpidem in Figure 26-2. Neither triazolam nor zolpidem has any effect on the 24-hour profiles of cortisol, melatonin, or GH. A recent report showed that chronic treatment of insomnia with the melatonin receptor agonist ramelteon also increases prolactin release in women, but not in men.47
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Figure 26-2 Effects of commonly used hypnotics on the 24-hour profile of plasma prolactin (PRL) in healthy young subjects. Data are mean plus standard error of the mean. Samples were collected at 15- to 20-minute intervals. Sleep was polygraphically recorded. Top, effects of bedtime administration of triazolam (0.5 mg). Bottom, effects of bedtime administration of zolpidem (10 mg). Both benzodiazepine and nonbenzodiazepine hypnotics cause transient hyperprolactinemia during the early part of sleep. Time in bed is denoted by the blue bars. Arrows denote time of drug administration. (Data from Copinschi G, Van Onderbergen A, L’HermiteBalériaux M, et al. Effects of the short-acting benzodiazepine triazolam taken at bedtime on circadian and sleep-related hormonal profiles in normal men. Sleep 1990;13:232-244; Copinschi G, Akseki E, Moreno-Reyes R, et al. Effects of bedtime administration of zolpidem on circadian and sleep-related hormonal profiles in normal women. Sleep 1995;18:417-424; and Van Cauter E, Spiegel K. Circadian and sleep control of endocrine secretions. In: Turek FW, Zee PC, editors. Neurobiology of sleep and circadian rhythms. New York: Marcel Dekker; 1999.)
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There is evidence from animal studies that PRL is involved in the humoral regulation of REM sleep.48 The primary effect is a stimulation of REM sleep, which appears to be dependent on time of day. Recent findings indicate that prolactin deficient mice have decreased REM sleep.49
THE GONADAL AXIS The relationship between the 24-hour patterns of gonadotropin release and gonadal steroid levels varies according to the stage of maturation, and it is gender dependent in young adulthood (for review see Van Cauter et al.35). Prior to puberty, luteinizing hormone (LH) and folliclestimulating hormone are secreted in a pulsatile pattern, and an augmentation of pulsatile activity is associated with sleep onset in a majority of both girls and boys. The increased amplitude of gonadotropin release during sleep is one of the hallmarks of puberty. Both sleep and circadian rhythmicity contribute to the nocturnal elevation of gonadotropin pulses in pubertal children. As the pubescent child enters adulthood, the daytime pulse amplitude increases as well, eliminating or diminishing the diurnal rhythm. In pubertal girls, a diurnal variation of circulating estradiol levels, with higher concentrations during the daytime instead of the nighttime, becomes apparent. It has been suggested that the lack of parallelism between gonadotropin and estradiol levels reflects an approximate 10-hour delay between gonadotropin stimulation and the subsequent ovarian response. In pubertal boys, a nocturnal rise of testosterone coincides with the elevation of gonadotropins. In adult men, the day–night variation of plasma LH levels is dampened or even undetectable. During the sleep period, LH pulses appear to be temporally related to the REM–NREM cycle.50 Despite the low amplitude of the nocturnal increase in gonadotropin release, a marked diurnal rhythm in circulating testosterone levels is present, with minimal levels in the late evening, a robust rise following sleep onset and maximal levels in the early morning.51,52 Thus, the robust circadian rhythm of plasma testosterone may be partially controlled by factors other than LH. The nocturnal rise of testosterone appears temporally linked to the latency of the first REM episode,53 as plasma levels continue to rise until the first REM episode occurs. A robust rise of testosterone may also be observed during daytime sleep, suggesting that sleep, irrespective of time of day, stimulates gonadal hormone release.54 Experimental sleep fragmentation in young men resulted in attenuation of the nocturnal rise of testosterone, particularly in subjects who did not achieve REM sleep.55 Androgen concentrations in young adults decline significantly during periods of total sleep deprivation and recover promptly once the sleep is restored.54,56 In contrast, pharmacological suppression of testosterone in healthy men appears to have no effect on the total amount and overall architecture of nighttime sleep.57 In women, the 24-hour variation in plasma LH is markedly modulated by the menstrual cycle.58,59 In the early follicular phase, LH pulses are large and infrequent, and a marked slowing of the frequency of secretory pulses occurs during sleep, suggestive of inhibitory effect of sleep on pulsatile gonadotropin-releasing hormone
(GnRH) release. Awakenings interrupting sleep are usually associated with a pulse of LH concentration.60 In the midfollicular phase, pulse amplitude is decreased, pulse frequency is increased, and the frequency modulation of LH pulsatility by sleep is less apparent. Pulse amplitude increases again by the late-follicular phase. In the early luteal phase, the pulse amplitude is markedly increased, the pulse frequency is decreased, and nocturnal slowing of pulsatility is again evident. In the mid- and late-luteal phase, pulse amplitude and frequency are decreased, and there is no modulation by sleep. In older men, the amplitude of LH pulses is decreased but the frequency is increased and no significant diurnal pattern can be detected.61-63 The circadian variation of testosterone persists, although markedly dampened.63 The sleep-related rise is still apparent in older men, but its amplitude is lower and the relationship to REM latency is no longer apparent.64 It is likely that decreased sleep quality as occurs in aging as well as in sleep disorders (e.g., obstructive sleep apnea) plays a role in the dampening of the sleep-related testosterone rise. In postmenopausal women, gonadotropin levels are elevated, but they show no consistent circadian pattern.65 A number of studies66-68 have indicated that estrogen replacement therapy has modest beneficial effects on subjective and objective sleep quality, particularly in the presence of environmental disturbance69 or sleep-disordered breathing.66,67,70
GLUCOSE REGULATION The consolidation of human sleep in a single 7- to 9-hour period implies that an extended period of fast must be maintained overnight. Despite the prolonged fasting condition, glucose levels remain stable or fall only minimally across the night. In contrast, if subjects are awake and fasting in a recumbent position, in the absence of any physical activity, glucose levels fall by an average of 0.5 to 1.0 mmol/L (± 10 to 20 mg/dL) over a 12-hour period.71 Thus, a number of mechanisms that operate during nocturnal sleep must intervene to maintain stable glucose levels during the overnight fast. The lower panels of Figure 26-1 show profiles of blood glucose and ISR obtained in normal subjects who were studied under conditions of constant glucose infusion,76 a condition that results in a marked inhibition of endogenous glucose production. Thus, when subjects receive a constant glucose infusion, changes in plasma glucose levels reflect mainly changes in glucose use. A marked decrease in glucose tolerance (reflected in higher plasma glucose levels) is apparent during nighttime as well as daytime sleep. A smaller elevation of glucose and insulin also occurs during nocturnal sleep deprivation, indicating an effect of circadian-dependent mechanisms. During nocturnal sleep, the overall increase in plasma glucose ranged from 20% to 30%, despite the maintenance of rigorously constant rates of caloric intake. Maximal levels occur around the middle of the sleep period. During the later part of the night (i.e., at the time of the so-called dawn phenomenon), glucose tolerance begins to improve, and glucose levels progressively decrease toward morning values. The mechanisms underlying these robust variations
CHAPTER 26 • Endocrine Physiology in Relation to Sleep and Sleep Disturbances 297
SLEEP AND APPETITE REGULATION Sleep plays an important role in energy balance. In rodents, food shortage or starvation results in decreased sleep77 and, conversely, total sleep deprivation leads to marked hyperphagia.78 The identification of hypothalamic excitatory neuropeptides, referred to as hypocretins or orexins, that have potent wake-promoting effects and stimulate food intake, has provided a molecular basis for the interactions between the regulation of feeding and sleeping.79,80 Orexincontaining neurons in the lateral hypothalamus project directly to the locus coeruleus and other brainstem and hypothalamic arousal areas, where they interact with the leptin-responsive neuronal network involved in balancing food intake and energy expenditure. Orexin-containing neurons are active during waking and quiescent during sleep. Orexin activity is inhibited by leptin, a satiety hormone, and stimulated by ghrelin, an appetite promoting hormone. Leptin, a hormone released by the adipocytes, provides information about energy status to regulatory centers in the hypothalamus.81 Circulating leptin concentrations in humans show a rapid decline or increase in response to acute caloric shortage or surplus, respectively. These changes in leptin levels have been associated with reciprocal changes in hunger. The 24-hour leptin profile shows a
9 Leptin (ng/ml) ↓ – appetite
in set-point of glucose regulation across nocturnal sleep are different in early sleep and late sleep. Under conditions of constant glucose infusion, the decrease in glucose tolerance during the first half of the sleep period is reflected in a robust increase in plasma glucose, which is followed by a more than 50% increase in insulin secretion. It is estimated that about two thirds of the fall in glucose use during sleep is due to a decrease in brain glucose metabolism72 related to the predominance of slow wave stages, which are associated with a 30% to 40% reduction in cerebral glucose metabolism as compared to the waking state.73 (See Chapter 18.) The last third of the fall would then reflect decreased peripheral use. Diminished muscle tone during sleep and rapid antiinsulin-like effects of the sleep-onset GH pulse are both likely to contribute to decreased peripheral glucose uptake. The nocturnal elevation of melatonin levels could contribute to the nocturnal decrease in glucose tolerance because of an inhibitory effect of melatonin on insulin release from beta cells.2,74 During the later part of the sleep period, glucose levels and insulin secretion decrease to return to presleep values, and this decrease appears to be partially due to the increase in wake and REM stages.75 Indeed, glucose use during the REM and wake stages is higher than during NREM stages.73 In addition, several other factors may also contribute to the decline of glucose levels during late sleep. These include the hypoglycemic activity of previously secreted insulin during early sleep, the increased insulinindependent glucose disposal due to transient mild hyperglycemia, and the quiescence of GH secretion and thus the rapid attenuation of the short-term inhibitory effects of this hormone on tissue glucose uptake. Finally, the later part of the night appears to be associated with increased insulin sensitivity, reflecting a delayed effect of low cortisol levels during the evening and early part of the night.76
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Clock time Figure 26-3 Typical 24-hour profiles of plasma leptin (top) (an appetite-suppressing hormone) and ghrelin (bottom) (a hungerpromoting hormone) from a healthy lean young man. Time in bed is denoted by the blue bars. The vertical lines denote the time of presentation of identical high-carbohydrate meals. (Unpublished data.)
marked nocturnal rise, which is partly dependent on meal intake.82 The upper panel of Figure 26-3 shows a typical 24-hour profile of plasma leptin levels in a normal man. The nocturnal elevation of leptin has been thought to suppress the hunger during the overnight fast. Although daytime food intake plays a major role in the nocturnal rise of leptin, a study using continuous enteral nutrition to eliminate the impact of meal intake showed the persistence of a sleep-related leptin elevation, though the amplitude was lower than during normal feeding conditions.83 Prolonged total sleep deprivation results in a decrease in the amplitude of the leptin diurnal variation.84 Ghrelin is also involved in regulating energy balance6 and stimulating appetite.85 Daytime profiles of plasma ghrelin levels are primarily regulated by the schedule of food intake: Levels rise sharply before each designated meal time and fall to trough levels within 1 to 2 hours after eating. A study examining spontaneous meal initiation in the absence of time- and food-related cues provided good evidence for a role for ghrelin in meal initiation.86 The 24-hour profile of ghrelin levels shows a marked nocturnal rise, which is only modestly dampened when subjects are sleep deprived.17 The nocturnal ghrelin rise partly represents the rebound of ghrelin following the dinner meal. Despite the persistence of the fasting condition, ghrelin levels do not continue to increase across the entire sleep period and instead decrease during the later part of the night. The lower panel of Figure 26-3 illustrates a
298 PART I / Section 4 • Physiology in Sleep
representative 24-hour profile of ghrelin from a normal subject who ingested three carbohydrate-rich meals.
WATER AND ELECTROLYTE BALANCE DURING SLEEP Water and salt homeostasis is under the combined control of vasopressin, a hormone released by the posterior pituitary, the renin-angiotensin-aldosterone system, and the atrial natriuretic peptide. Urine flow and electrolyte excretion are higher during the day than during the night, and this variation partly reflects circadian modulation. In addition to this 24-hour rhythm, urine flow and osmolarity oscillate with the REM–NREM cycle. REM sleep is associated with decreasing urine flow and increasing osmolarity. Vasopressin release is pulsatile but without apparent relationship to sleep stages.87 Levels of atrial natriuretic peptide are relatively stable and do not show fluctuations related to the sleep–wake or REM–NREM cycles.88 Whether the levels of plasma atrial natriuretic peptide exhibit a circadian variation is still a matter of controversy.88 A close relationship between the beginning of REM episodes and decreased activity has been consistently observed for plasma renin activity.87,89-91 Figure 26-4 illustrates the 24-hour rhythm of plasma renin activity in a subject studied during a normal sleep–wake cycle and in a subject studied following a shift of the sleep period. A
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Figure 26-4 The 24-hour profiles of plasma renin activity sampled at 10-minute intervals in a healthy subject. A, Nocturnal sleep from 23:00 to 07:00. B, Daytime sleep from 07:00 to 15:00 after a night of total sleep deprivation. The temporal distribution of stages wake (W); REM; 1, 2, 3, and 4 are shown above the hormonal values. The oscillations of plasma renin activity are synchronized to the REM–NREM cycle during sleep. (From Brandenberger G, Follenius M, Goichot B, et al. Twentyfour hour profiles of plasma renin activity in relation to the sleep-wake cycle. J Hypertens 1994;12:277-283.)
remarkable synchronization between decreased plasma renin activity and REM stages is apparent during both sleep periods.92 This relationship was confirmed in studies with selective REM-sleep deprivation in healthy subjects.93 Increases in plasma renin activity parallel increases in slow-wave EEG activity.94 In conditions of abnormal sleep architecture (e.g., narcolepsy, sleeping sickness), the temporal pattern of plasma renin activity faithfully reflects the disturbances of the REM–NREM cycle.87 A well-documented study95 has delineated the mechanisms responsible for oscillations of plasma renin activity during sleep. The initial event is a reduction in sympathetic tone, followed by a decrease in mean arterial blood pressure and an increase in slow-wave activity. The rise in plasma renin activity becomes evident a few minutes after the increase in slow-wave activity. During REM sleep, sympathetic activity increases, whereas renin and slow-wave activity decrease and blood pressure becomes highly variable. The increased release of renin during sleep is associated with elevated levels of plasma aldosterone.96 Acute total sleep deprivation dampens the nighttime elevation of plasma aldosterone and increases natriuresis.97
CHRONIC SLEEP RESTRICTION: IMPACT ON ENDOCRINE AND METABOLIC FUNCTION Voluntary sleep curtailment has become a very common behavior in modern society. Data from the 2008 “Sleep in America” poll indicate that although working adults report a sleep need of an average of 7 hours and 18 minutes to function at best, 44% of them sleep fewer than 7 hours and 16% sleep fewer than 6 hours on a typical weeknight.98 Sleep times in European countries appear to follow a similar trend.99 The cumulative sleep loss per workweek of a substantial portion of the adult population may correspond to as much as one full night of sleep deprivation. Several laboratory studies involving extension of the bedtime period for prolonged periods of time have provided evidence that the “recommended 8-hour night” does not meet the sleep need of healthy young adults, who may carry a substantial sleep debt even in the absence of obvious efforts at sleep curtailment.100-102 Although the impact of various durations of acute total sleep deprivation on endocrine function and glucose metabolism has been documented in multiple studies, the much more common condition of partial chronic sleep restriction has not received nearly as much attention. The following subsections review, respectively, the laboratory and epidemiologic evidence supporting an adverse impact of recurrent partial sleep restriction on hormones, glucose metabolism, and body weight regulation. Laboratory Studies Figure 26-5 summarizes the hormonal and metabolic findings of the first “sleep debt study”39 which examined the impact of 6 days of sleep restriction to 4 hours per night as compared to 6 days of sleep extension to 12 hours per night in a group of healthy young men.23,38,39 The findings suggest that sleep restriction has adverse effects on multiple endocrine axes as well as on glucose metabolism.
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Figure 26-5 The 24-hour profiles of plasma GH, plasma cortisol, plasma TSH, plasma glucose, serum insulin and plasma leptin levels in 11 healthy young men who were studied after 1 week of bedtime restriction to 4 hours per night (left panels) and 1 week of bedtime extension to 12 hours per night (right panels). The blue bars represent the bedtime period. On the cortisol profiles, the blue areas show the increase in evening cortisol levels and the arrows indicate the timing of the nadir. On the glucose and insulin profiles, the blue area shows the response to the morning meal. On the leptin profiles, the arrows indicate the timing of the nocturnal acrophase. (From Spiegel K, Leproult R, Van Cauter E. Impact of a sleep debt on metabolic and endocrine function. Lancet 1999;354:1435-1439; Spiegel K, Leproult R, Colecchia E, et al. Adaptation of the 24-hour growth hormone profile to a state of sleep debt. Am J Physiol 2000;279:R874-R883; and Spiegel K, Leproult R, L’Hermite-Balériaux M, et al. Leptin levels are dependent on sleep duration: relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin. J Clin Endocrinol Metab 2004;89:5762-5771.)
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The sleep-onset GH pulse was observed in all individual profiles for both sleep conditions. However, after partial sleep restriction, all subjects exhibited a GH pulse prior to sleep onset. There was a negative correlation between presleep GH secretion and sleep-onset GH release. This profile of GH release is quite different from that observed during acute total sleep deprivation (see Fig. 26-1, top panels), where minimal GH secretion occurs during nocturnal wakefulness and GH secretion rebounds during daytime recovery sleep. When compared to the fully rested condition, the state of sleep debt was associated with alterations of the 24-hour profile of cortisol, including a shorter quiescent period and elevated levels in the evening (see Fig. 26-5, second panel shaded areas). This alteration was similar to that observed after acute total or partial sleep deprivation32 and may reflect decreased efficacy of the negative feedback regulation of the hypothalamic-pituitary-adrenal axis.39 Restriction and extension of sleep duration were also associated with clear changes in thyrotropic function. The nocturnal elevation of plasma TSH was dampened and thyroid hormone levels were higher in the sleep debt state.39 Previous studies have demonstrated that total sleep deprivation is initially associated with a marked increase in TSH secretion (see Fig. 26-1), which becomes smaller when sleep deprivation continues, presumably because of negative feedback effects from slowly rising levels of thyroid hormones. Similar mechanisms are likely to underlie the alterations in thyrotropic function after recurrent partial sleep restriction. Bedtime curtailment results in a higher glucose response to breakfast despite similar insulin secretion (see Fig. 26-5, lower panels). The difference in peak postbreakfast glucose levels between the sleep debt and fully rested conditions (i.e., ± 15 mg/dL) is consistent with a state of impaired glucose tolerance. Intravenous glucose tolerance testing confirms this deterioration in glucose tolerance.39 Reduced glucose tolerance is the combined consequence of a decrease in glucose effectiveness, a measure of noninsulin dependent glucose use, and a reduction in the acute insulin response to glucose despite a trend for decreased insulin sensitivity. The product of insulin sensitivity and acute insulin response to glucose, that is, the disposition index, a validated marker of diabetes risk,103 was decreased by nearly 40% in the state of sleep debt, reaching levels typical of populations at an elevated risk of diabetes.104,105 These findings were confirmed in a subsequent randomized crossover study comparing two 10-hour nights versus two 4-hour nights.106 Mean levels of the satiety hormone leptin were reduced by 20% to 30% under sleep restriction as compared to extension (see Fig. 26-5, lowest panels).38 This effect size of sleep restriction is comparable to that occurring after three days of dietary restriction by approximately 900 kcal per day under normal sleep conditions.107 Further, there is a clear dose-response relationship between sleep duration and characteristics of the leptin profile38 (Fig. 26-6, upper panels). Indeed, mean leptin levels gradually increase from 4 hours to 8 hours and to 12-hour bedtime condition. Importantly, these differences in leptin profiles occur despite identical amounts of caloric intake, similar seden-
tary conditions, and stable weight. A reduction of peak leptin levels has also been reported in volunteers studied after 7 days of 4-hour bedtimes.108 In a randomized crossover study of two nights of 4 hours in bed versus two nights of 10 hours in bed, daytime profiles of leptin and of the hunger hormone ghrelin were measured, and the subjects completed validated scales for hunger and appetite for various food categories (Fig. 26-6, lower panel).109 Overall leptin levels were decreased by an average of 18% and ghrelin levels were increased by 28%, and the ghrelin : leptin ratio increased by more than 70%. Hunger showed a 23% increase, and appetite for nutrients with high carbohydrate content was increased by more than 30% when sleep was restricted. If this increase in hunger were to translate into a commensurate increase in food intake, weight gain would be expected. A recent laboratory study of overweight middle-aged adults who were submitted to 2 weeks of 1.5 hour of sleep extension or restriction in a randomized crossover design indeed showed an increase in food intake from snacks during sleep restriction.110 However, the participants gained weight under both sleep conditions and differences in leptin or ghrelin levels were not detected. Two epidemiologic studies have confirmed and extended these findings with observations of reduced leptin levels, after controlling for body mass index (BMI) or adiposity, in habitual short sleepers.111,112 Higher ghrelin levels were also associated with short sleep.111 A subsequent smaller study involving only postmenopausal women did not confirm the link between sleep duration, leptin, and ghrelin levels,113 but very few participants had short sleep durations. Epidemiologic Studies Over the past ten years, a large number of studies have examined associations between sleep duration and the prevalence and incidence of type 2 diabetes and obesity. Nearly all these studies explored existing data sets that included self reported sleep duration and none of them determined whether short sleep was the result of bedtime curtailment or was due to the presence of a sleep disorder or other co-morbidities. Four cross-sectional studies found a significant association between short sleep and the risk of diabetes.114-117 In four of six prospective studies, short sleep at baseline was found to predict a higher incidence of diabetes.118-123 The follow-up period ranged from 10 to 18 years. By the end of 2008, more than 40 cross-sectional epidemiological studies have provided evidence for an association between short sleep and higher BMI. One metaanalysis found that the pooled odds ratio (OR) linking short sleep to obesity was 1.89 in children and 1.55 in adults.124 Another meta-analysis reported an OR of 1.58 in children with short sleep duration and an OR of 1.92 in children with the shortest sleep duration.125 A systematic review concluded that short sleep duration appears independently associated with weight gain, particularly in younger age groups.126 A cross-sectional analysis that uniquely assessed sleep duration by wrist actigraphy in more than 6,000 men and women, ages 67 to 99 years, and showed that, compared to sleeping 7 to 8 hours per night,
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Figure 26-6 Upper panel, mean (± SEM) 24-hour leptin profiles obtained after 6 days of 4 hours, 8 hours, and 12 hours in bed in 9 healthy lean men studied at bed rest who ate 3 identical carbohydrate-rich meals. At the end of these bedtime conditions, the subjects slept an average of 3 hours 48 minutes in the 4-hour in bed condition, 6 hours 52 minutes in the 8-hour in bed condition, and 8 hours 52 minutes in the 12-hour in bed condition. Note that all the characteristics of the 24-hour leptin profile (overall mean, nocturnal maximum, amplitude) gradually increased from the 4-hour to the 12-hour bedtime condition. The blue bars represent the sleep periods. (From Spiegel K, Leproult R, L’Hermite-Balériaux M, et al. Leptin levels are dependent on sleep duration: relationships with sympathovagal balance, carbohydrate regulation, cortisol, and thyrotropin. J Clin Endocrinol Metab 2004;89:5762-5771). Lower panel, mean (± SEM) daytime profiles of plasma leptin and ghrelin observed in healthy subjects after 2 days with 4-hour bedtimes or 2 days with 10-hour bedtime. Caloric intake was exclusively under the form of a constant glucose infusion. (From Spiegel K, Tasali E, Penev P, Van Cauter E. Sleep curtailment results in decreased leptin levels, elevated ghrelin levels and increased hunger and appetite. Annals Int Med 2004;141(11):846-850.)
sleeping fewer than 5 hours was associated with a BMI that was, on average, 2.5 kg/m2 greater in men and 1.8 kg/m2 in women, after adjusting for multiple potential confounders.127 Finally, 9 of 10 longitudinal studies on sleep duration and obesity risk in children and adults, found that shorter sleep durations are associated with an increased risk for overweight and obesity a few years later.128,129 This body of epidemiologic evidence supports the hypothesis that sleep curtailment may be a nontraditional lifestyle factor contributing to the epidemic of obesity.130
REDUCED SLEEP QUALITY AND SLEEP DISORDERS: IMPACT ON ENDOCRINE AND METABOLIC FUNCTION Experimental Reduction of Sleep Quality Early studies have been consistent in showing that experimentally-induced full awakenings interrupting nocturnal sleep consistently trigger pulses of cortisol secretion.25,131,132 Furthermore, in an analysis of cortisol profiles during
daytime sleep, it was observed that 92% of spontaneous awakenings interrupting sleep were associated with a cortisol pulse.132 Aging and sleep disorders are associated with reduced sleep quality, including lower amounts of SWS without systematic decrease in sleep duration. The initiation of SWS is associated with a decrease in cerebral glucose use, stimulation of GH secretion, inhibition of cortisol release, decreased sympathetic nervous activity and increased vagal tone. (See Chapter 20 for autonomic measures.) All these correlates of SWS affect total body glucose regulation, suggesting that low amounts of SWS may be associated with reduced glucose tolerance. A study tested this hypothesis by selectively suppressing SWS (using acoustic stimuli) in healthy young adults and examining the impact on the response to intravenous glucose injection.133 The amount of SWS was reduced by nearly 90%, similar to what occurs over the course of four decades of aging. Such low levels of SWS are also typical of moderate to severe obstructive sleep apnea (OSA). Importantly, this intervention did not reduce total sleep duration. Slow-wave activity was markedly reduced
302 PART I / Section 4 • Physiology in Sleep SLOW-WAVE ACTIVITY (µv2)
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Figure 26-7 Left panel, mean (± SEM) profiles of slow-wave activity (µV2) for the first four NREM–REM sleep cycles (NREM1, NREM2, NREM3, and NREM4) during baseline and in each experimental night of slow-wave activity suppression (Night 1, Night 2, Night 3). Slow-wave activity was markedly and similarly reduced in each experimental night compared to baseline, and the largest reductions were achieved during the first two NREM cycles. Right panel, mean (± SEM) insulin sensitivity, acute insulin response to glucose, disposition index, and glucose tolerance at baseline and after 3 nights of slow-wave sleep (SWS) suppression. (From Tasali E, Leproult R, Ehrmann D and Van Cauter E. Slow wave sleep and the risk of type 2 diabetes in humans. Proc Natl Acad Sci USA 2008;105(3):1044-1049).
in each experimental night compared to baseline (Fig. 26-7, left panels). After 3 nights of SWS suppression, insulin sensitivity was decreased by ∼25% (Fig. 26-7, right panels), reaching the level reported in older adults and in populations at high risk for diabetes.134 This decrease in insulin sensitivity was not compensated for by an increase in insulin release, because acute insulin response to glucose remained virtually unchanged. Consequently, diabetes risk, as assessed by the disposition index was lower and glucose tolerance was reduced, reaching the range typical of impaired glucose tolerance. These laboratory findings demonstrate that reduced sleep quality, without change in sleep duration, may adversely affect glucose regulation. In this study where SWS was suppressed while carefully avoiding full awakenings, cortisol levels were not affected
at any time of the day or night.133 An increase in daytime sympathovagal balance, as assessed by spectral analysis of heart rate variability, was identified as one of the possible mechanisms mediating the adverse impact of SWS suppression on glucose metabolism. Studies in Population and Clinic-Based Samples A number of cross-sectional as well as prospective epidemiologic studies (reviewed in detail in references 104 and 128) have provided evidence for an association between self-reported poor sleep quality, and the prevalence or incidence of diabetes, after controlling for age, BMI, and various other confounders. Of note, in 6 of 7 prospective studies that examined self-reported problems (such as difficulty initiating or maintaining sleep, use of sleeping pills,
CHAPTER 26 • Endocrine Physiology in Relation to Sleep and Sleep Disturbances 303
dence for a possible dysregulation of energy balance in this patient population.141
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Figure 26-8 Mean 24-hour profiles of plasma cortisol in young people with insomnia with low total sleep time (blue squares) as compared to young people with insomnia with high total sleep time (orange circles). The blue bar indicates the sleeprecording period. The error bars indicate standard error of the mean (SEM). (From Vgontzas A, Bixler EO, Lin HM, et al. Chronic insomnia is associated with neurohumoral activation of the hypothalamo-pituitary-adrenal axis: clinical implications. J Clin Endocrinol Metab 2001;86:3787-3794).
or insomnia complaint), poor sleep quality was associated with an increased risk of diabetes.119,120,123,135-138 Two clinic-based studies have examined the relationship between sleep duration and quality and glycemic control in type 2 diabetes. The first study administered the Pittsburgh Sleep Quality questionnaire to 161 African-American diabetic patients.115 Higher perceived sleep debt or lower sleep quality were associated with poorer glycemic control after controlling for age, sex, BMI, insulin use, and the presence of complications.115 Importantly, the magnitude of these effects of sleep duration or quality was comparable to that of commonly used oral antidiabetic medications. The second study used actigraphy in 47 diabetic patients and 23 nondiabetic controls under freeliving conditions.170 After adjusting for age, gender, and schooling, measures of sleep fragmentation were significantly higher in the patients with diabetes, and glycemic control correlated inversely with sleep efficiency. Insomnia There have been remarkably few studies of hormonal and metabolic variables in subjects with physician-diagnosed insomnia. A well-documented study139 in patients with insomnia revealed that those with decreased total sleep time have higher cortisol levels across the night (Fig. 26-8). It is unclear whether this relative hypercortisolism is the result of sleep fragmentation and the associated sleep loss, or, alternatively, whether hyperactivity of the corticotropic axis is causing hyperarousal and insomnia. Recent views on chronic insomnia propose that it is a disorder of hyperarousal during both the night and the daytime, with associated hyperactivity of the hypothalamic-pituitary-adrenal axis.140 A recent study involving 14 patients with insomnia found decreased nocturnal ghrelin levels, providing evi-
OSA There is a growing body of evidence linking OSA to abnormalities of glucose metabolism, including insulin resistance and glucose intolerance. For a summary of the present state of knowledge, refer to Chapter 114 of this volume as well as to recent reviews.142,143 Obstructive sleep apnea is also associated with disturbances in the control of weight and appetite regulation. Indeed, patients with OSA appear more predisposed to weight gain than similarly obese subjects without OSA.144 Consistent with the upregulation of ghrelin observed following sleep restriction in healthy subjects,109,111,145 patients with OSA—who usually have decreased total sleep time— have higher ghrelin levels. Elevated leptin levels, after controlling for BMI, are also consistently observed in OSA.144 This hyperleptinemia in OSA is in contrast with the lower leptin levels that occur following sleep restriction in normal lean subjects38,108,109 and in chronic short sleepers without OSA independently of BMI and adiposity.111,112 Hyperleptinemia in OSA is thought to reflect leptin resistance.144 Successful treatment of OSA by continuous positive air pressure (CPAP) should lead to a reduction in leptin resistance, a decrease in ghrelin levels, and thus weight loss. Only two studies have measured ghrelin levels after CPAP treatment and both reported a decrease in ghrelin levels.146,147 However, the findings on the effect of CPAP on body weight and visceral adiposity are mixed. Weight loss has been reported in one study after 6 months of CPAP,148 whereas another study found no weight loss after one year of CPAP use.149 Six months of CPAP therapy added to a weight reduction program have not resulted in greater weight loss.150 If weight loss is important, loss of visceral fat is by far more relevant from a metabolic point of view. Again, the studies are scarce and provide conflicting results.151-153 AGE-RELATED SLEEP ALTERATIONS: IMPLICATIONS FOR ENDOCRINE FUNCTION Normal aging is associated with pronounced age-related alterations in sleep quality, which consist primarily of a marked reduction of SWS (stages 3 and 4), a reduction in REM stages, and an increase in the number and duration of awakenings interrupting sleep (see Chapter 3). There is increasing evidence that these alterations in sleep quality may result in neuroendocrine disturbances, suggesting that some of the hormonal hallmarks of aging may partly reflect the deterioration of sleep quality.154 GH Axis There are mutual interactions between somatotropic activity and sleep that are evident both in youth and older age. Sex and age differences are illustrated in the upper panels of Figure 26-9. In normal young men, there is a “dose-response” relationship between slow-wave sleep/ slow-wave activity (SWS/SWA) and GH secretion, and
304 PART I / Section 4 • Physiology in Sleep MEN Growth hormone (µg/L)
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that in older adults, levels of insulin-like growth factor (IGF-1), the hormone secreted by the liver in response to stimulation by GH, are correlated with the amounts of SWS,159 is consistent with this finding. The relative GH deficiency of elderly adults is associated with increased fat tissue and visceral obesity, reduced muscle mass and strength, and reduced exercise capacity. The persistence of a consistent relationship between SWS and GH secretion in older men suggests that drugs that reliably stimulate SWS in older adults may represent a novel strategy for GH replacement therapy.
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Figure 26-9 Upper panels, mean 24-hour profiles of plasma growth hormone in healthy young (18-33 years old) and older (51 to 72 years old) men (left) and women (right). Young women were studied in the follicular phase of the menstrual cycle. Older women were postmenopausal and not on hormone replacement therapy. The blue bars represent the sleep periods. Lower panels, mean 24-hour profiles of plasma prolactin in the same subjects. (From Van Cauter E, Plat L and Copinschi G. Interrelations between sleep and the somatotropic axis. Sleep 1998;21:533-566; Latta F, Leproult R, Tasali E, et al. Sex differences in nocturnal growth hormone and prolactin secretion in healthy older adults: relationship with sleep EEG variables. Sleep 2005;28:1519-1524; and Caufriez A, Leproult R, L’Hermite-Balériaux M, et al. A potential role for endogenous progesterone in modulation of growth hormone, prolactin and thyrotropin secretion during normal menstrual cycle. Clin Endocrinol 2009;71:535-542).
the sleep-onset GH pulse is often the largest pulse observed over the 24-hour span. In normal young women, daytime GH pulses are more frequent and the sleep-onset pulse, while generally present, is smaller.155,156 The GH profiles shown in Figure 26-9 illustrate gender differences in healthy older adults. In both gender groups, a significant amount of GH secretion occurs in the late evening, before habitual bedtime, at a time when GH secretion is usually quiescent in young adults.157 Such presleep GH pulses may appear in young subjects when studied in a state of sleep debt.23 In older men, but not women, the quantitative relationship between SWS/delta activity and sleep-onset GH release persists. In contrast, in older women, presleep GH release inhibits both the amount of GH secreted during sleep and sleep consolidation as evidenced by negative correlations between presleep GH secretion and sleep maintenance.157 The impact of aging on the amount of SWS and on GH release occurs with a similar chronology characterized by major decrements from early adulthood to midlife (Fig. 26-10).158 Reduced amounts of SWS were found to be a significant predictor of reduced GH secretion in middle life and late life, independently of age. The observation
Prolactin Secretion In both men and women, the majority of the daily release of prolactin occurs during sleep, irrespective of age. The lower panels of Figure 26-9 illustrate typical profiles in healthy nonobese young and older men and women. The sex difference is apparent both during daytime and nighttime in young adulthood but in older age only nighttime levels are affected. A nearly 50% dampening of the nocturnal PRL elevation is evident in elderly men and women.160 This age-related endocrine alteration may partly reflects the increased number of awakenings (which inhibit PRL release) and decreased amounts of REM stages (which stimulate PRL release).157 Besides its role in the control of lactation and parental behavior, prolactin has multiple actions, including on metabolism and immunoregulation. Age-related alterations in sleep architecture and their clear impact on nocturnal prolactin release could thus impact healthy aging. Pituitary-Adrenal Axis There are highly consistent, sex-specific alterations in the diurnal pattern of basal cortisol secretion across the lifetime.161 Figure 26-11 shows 24-hour profiles typical of younger and older men and women. In young adulthood, overall cortisol levels are lower in women than in men because the female response to the early morning circadian signal is slower and of lesser magnitude and the return to quiescence is more rapid. In men, the nocturnal quiescent period is shorter and the early morning elevation is higher and more prolonged. During aging, there appears to be a progressive decline in the endogenous inhibition of nocturnal cortisol secretion in both men and women, as reflected by a delay of the onset of the quiescent period and higher nocturnal cortisol levels. In contrast to the rapid decline of SWS and GH secretion from young adulthood to midlife, the impact of age on REM sleep, sleep fragmentation, and evening cortisol levels does not become apparent until later in life. As illustrated in Figure 26-10, REM sleep, wake after sleep onset, and evening cortisol levels follow the same chronology of aging, that is, no alteration until midlife, and then a steady rise from midlife to old age.158 There is a significant negative relationship between the loss of REM sleep in old age and the inability to achieve or maintain the quiescence of the corticotropic axis. Both animal and human studies have indicated that deleterious effects of hypothalamic-pituitary-adrenal hyperactivity are more pronounced at the time of the trough of the rhythm than at the time of the peak. Therefore, modest elevations in evening cortisol levels could facilitate the development of central and
CHAPTER 26 • Endocrine Physiology in Relation to Sleep and Sleep Disturbances 305
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Figure 26-10 Mean (SEM) amounts of wake after sleep onset (top panel), slow-wave sleep (stages III and IV, middle left panel), REM sleep (middle right panel), growth hormone (GH) secretion during sleep (lower left panel) and nadir of plasma cortisol concentrations (lower right panel) by age group in 149 healthy nonobese men. Sleep stages are expressed as a percentage of the sleep period, defined as the time interval between sleep onset and final morning awakening. (From Van Cauter E, Leproult R, Plat L. Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men. JAMA 2000;284:861-868.)
peripheral disturbances associated with glucocorticoid excess, such as memory deficits and insulin resistance, and further promote sleep fragmentation. Pituitary-Gonadal Axis A progressive decline in testosterone levels occurs with aging in normal men. Starting at 30 to 40 years of age, testosterone concentrations decrease by 1% to 2% per year. In elderly men, the diurnal variation of testosterone is still detectable, but the nocturnal rise is markedly damp-
ened.51 One study indicated that the considerable interindividual variability of testosterone levels in healthy elderly men might be partly related to differences in sleep quality.162 Indeed, both total and free (i.e., biologically active) morning testosterone levels were significantly correlated with total sleep time achieved during a night of laboratory polysomnography. A difference in total sleep time between 4.5 and 7.5 hours translated into a clinically meaningful difference in total testosterone levels, as concentrations around 200 to 300 ng/dL are considered to be
306 PART I / Section 4 • Physiology in Sleep 24-HOUR CORTISOL PROFILES 450 Plasma cortisol (nmol/L)
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Figure 26-11 Mean 24-hour cortisol profiles in men (left panel) and women (right panel) 50 years of age and older (n = 25 and n = 22, respectively; green lines) as compared to 20- to 29-year-old subjects (n = 29 and n = 20, respectively; red lines). The shaded area at each time point represents the SEM. (From Van Cauter E, Leproult R, Kupfer DJ. Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab 1996;81:2468-2473.)
borderline-low for older men, and concentrations around 500 to 700 ng/dL represent midnormal values typical of healthy young adults. A similar robust correlation was found with the usual amount of nighttime sleep monitored by actigraphy at home.162 Thus, it is important to inquire about poor or insufficient sleep in the interpretation and management of low testosterone levels in older men.
SLEEP DISTURBANCES IN METABOLIC AND ENDOCRINE DISORDERS Obesity Obesity is a major risk factor for OSA.163 Complaints of daytime sleepiness may be present in obese subjects even in the absence of OSA.164-167 In obese subjects without OSA, there may be disturbances in sleep architecture, including lighter and more fragmented sleep as compared to nonobese controls.165 Severely obese patients without OSA may have significantly shorter sleep latencies than lean age-matched controls.164 Excessive daytime sleepiness has been found in 35% of obese subjects (BMI 40 ± 6 kg/ m2) without OSA compared to 2.7% in age-matched nonobese controls.167 It has been proposed that excessive daytime sleepiness and fatigue (i.e., tiredness without increased sleep propensity) in obese individuals without OSA could be due to a disruption of sleep homeostasis caused by elevated levels of proinflammatory cytokines released by visceral fat (interleukin-6 and tumor necrosis factor-α).168 In a cohort of 1300 middle-aged men and women who had one night of laboratory polysomnography, 47% of obese subjects reported subjective sleep disturbances (insomnia, sleep difficulty, excessive daytime sleepiness) as compared to 26% of nonobese individuals. Thus, the association between short sleep and high BMI evidenced in multiple epidemiologic studies may partly reflect the high prevalence of sleep disturbances and emotional stress.169
Type 2 Diabetes As mentioned previously, there is evidence indicating that type 2 diabetes is associated with poor sleep quality, both by self report and based on actigraphy.115,170 There is also emerging evidence for a high prevalence of OSA in diabetics.171-175 It has been suggested that the presence and severity of OSA may have clinically significant adverse effects on glycemic control. There is also evidence that CPAP treatment of OSA in diabetic patients may have beneficial effects on glycemic control. Out of 6 studies that assessed glycemic control in a total number of nearly 150 diabetic patients with OSA, 5 were positive.176-180 Notably, the negative study reported an average nightly therapeutic CPAP use of only 3.6 hours.181 Polycystic Ovary Syndrome Polycystic ovary syndrome, the most common endocrine disorder of premenopausal women, is characterized by hyperandrogenism, obesity, insulin resistance, and an elevated risk of type 2 diabetes. Insulin resistance is often referred to as a hallmark of PCOS. Obstructive sleep apnea is present in at least 50% women with PCOS.182-187 Insulin resistance and reduced glucose tolerance in women with PCOS are largely due to the presence of OSA.185 Both the prevalence of impaired glucose tolerance and the degree of insulin resistance increase in direct proportion to the severity of OSA (Fig. 26-12). Women with PCOS who have preserved normal glucose tolerance are not more insulin resistant than non-PCOS control women. Thus, PCOS appears to be comprised of two subphenotypes: PCOS with OSA and PCOS without OSA. Polycystic ovary syndrome with OSA is clearly associated with a higher risk of diabetes.185 Thus, assessment of OSA in PCOS is highly recommended because the correction of OSA may greatly improve the prognosis. Unfortunately, most clinicians who treat PCOS today are not yet aware of the high risk of OSA in patients with PCOS, and that obesity is not a prerequisite.188,189
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CHAPTER 26 • Endocrine Physiology in Relation to Sleep and Sleep Disturbances 307
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Figure 26-12 Prevalence of impaired glucose tolerance (IGT), top and degree of insulin resistance, bottom as assessed by the HOMA index, in control women without OSA, women with PCOS without OSA, and women with PCOS women with mild (5
❖ Clinical Pearl Sleep exerts marked modulatory effects on most components of the endocrine system and has an important impact on glucose regulation. There is rapidly accumulating evidence from both laboratory and epidemiologic studies indicating that sleep loss and poor sleep quality are associated with hormonal disturbances and an increased risk of obesity and diabetes. Sleep disorders may also exacerbate the severity of an existing condition. Findings suggest that part of the constellation of hormonal and metabolic alterations that characterize normal aging may reflect the deterioration of sleep quality. Strategies to improve sleep quality may have beneficial effects on endocrine and metabolic function.
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146. Harsch IA, Konturek PC, Koebnick C, et al. Leptin and ghrelin levels in patients with obstructive sleep apnoea: effect of CPAP treatment. Eur Respir J 2003;22:251-257. 147. Takahashi K, Chin K, Akamizu T, et al. Acylated ghrelin level in patients with OSA before and after nasal CPAP treatment. Respirology 2008;13:810-816. 148. Loube DI, Loube AA, Erman MK. Continuous positive airway pressure treatment results in weight less in obese and overweight patients with obstructive sleep apnea. J Am Diet Assoc 1997;97: 896-897. 149. Redenius R, Murphy C, O’Neill E, et al. Does CPAP lead to change in BMI? J Clin Sleep Med 2008;4:205-209. 150. Kajaste S, Brander PE, Telakivi T, et al. A cognitive-behavioral weight reduction program in the treatment of obstructive sleep apnea syndrome with or without initial nasal CPAP: a randomized study. Sleep Med 2004;5:125-131. 151. Chin K, Shimizu K, Nakamura T, et al. Changes in intra-abdominal visceral fat and serum leptin levels in patients with obstructive sleep apnea syndrome following nasal continuous positive airway pressure therapy. Circulation 1999;100:706-712. 152. Trenell MI, Ward JA, Yee BJ, et al. Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome. Diabetes Obes Metab 2007;9:679-687. 153. Vgontzas AN, Zoumakis E, Bixler EO, et al. Selective effects of CPAP on sleep apnoea-associated manifestations. Eur J Clin Invest 2008;38:585-595. 154. Van Cauter E, Leproult R. Sleep and diabesity in older adults. In: Pandi-Perumal SR, Monti JM, Monjan AA, editors. Principles and practice of geriatric sleep medicine. Cambridge, UK: Cambridge University Press; 2009. p. 101-121. 155. Copinschi G, Van Cauter E. Effects of ageing on modulation of hormonal secretions by sleep and circadian rhythmicity. Hormone Res 1995;43:20-24. 156. Van Cauter E. Hormones and sleep. In: Kales A, editor. The pharmacology of sleep. Berlin: Springer Verlag; 1995. p. 279-306. 157. Latta F, Leproult R, Tasali E, et al. Sex differences in nocturnal growth hormone and prolactin secretion in healthy older adults: relationships with sleep EEG variables. Sleep 2005;28:15191524. 158. Van Cauter E, Leproult R, Plat L. Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men. JAMA 2000;284:861-868. 159. Prinz P, Moe K, Dulberg E, et al. Higher plasma IGF-1 levels are associated with increased delta sleep in healthy older men. J Gerontol 1995;50A:M222-M226. 160. van Coevorden A, Mockel J, Laurent E, et al. Neuroendocrine rhythms and sleep in aging men. Am J Physiol 1991;260:E651E661. 161. Van Cauter E, Leproult R, Kupfer DJ. Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab 1996;81:2468-2473. 162. Penev PD. Association between sleep and morning testosterone levels in older men. Sleep 2007;30:427-432. 163. Young T, Peppard PE, Taheri S. Excess weight and sleep-disordered breathing. J Appl Physiol 2005;99:1592-1599. 164. Vgontzas AN, Bixler EO, Tan TL, et al. Obesity without sleep apnea is associated with daytime sleepiness. Arch Intern Med 1998;158:1333-1337. 165. Vgontzas AN, Tan TL, Bixler EO, et al. Sleep apnea and sleep disruption in obese patients. Arch Internal Med 1994;154:17051711. 166. Resta O, Foschino Barbaro MP, Bonfitto P, et al. Low sleep quality and daytime sleepiness in obese patients without obstructive sleep apnoea syndrome. J Intern Med 2003;253:536-543. 167. Resta O, Foschino-Barbaro MP, Legari G, et al. Sleep-related breathing disorders, loud snoring and excessive daytime sleepiness in obese subjects. Int J Obes Relat Metab Disord 2001;25: 669-675. 168. Vgontzas AN, Bixler EO, Chrousos GP. Obesity-related sleepiness and fatigue: the role of the stress system and cytokines. Ann N Y Acad Sci 2006;1083:329-344. 169. Vgontzas AN, Lin HM, Papaliaga M, et al. Short sleep duration and obesity: the role of emotional stress and sleep disturbances. Int J Obes 2008;32:801-809.
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170. Trento M, Broglio F, Riganti F, et al. Sleep abnormalities in type 2 diabetes may be associated with glycemic control. Acta Diabetol 2008;45:225-229. 171. Einhorn D, Stewart DA, Erman MK, et al. Prevalence of sleep apnea in a population of adults with type 2 diabetes mellitus. Endocr Pract 2007;13:355-362. 172. West SD, Nicoll DJ, Stradling JR. Prevalence of obstructive sleep apnoea in men with type 2 diabetes. Thorax 2006;61:945-950. 173. Resnick HE, Redline S, Shahar E, et al. Diabetes and sleep disturbances: findings from the Sleep Heart Health Study. Diabetes Care 2003;26:702-709. 174. Katsumata K, Okada T, Miyao M, et al. High incidence of sleep apnea syndrome in a male diabetic population. Diabetes Res Clin Pract 1991;13:45-51. 175. Elmasry A, Lindberg E, Berne C, et al. Sleep-disordered breathing and glucose metabolism in hypertensive men: a population-based study. J Intern Med 2001;249:153-161. 176. Dawson A, Abel SL, Loving RT, et al. CPAP therapy of obstructive sleep apnea in type 2 diabetics improves glycemic control during sleep. J Clin Sleep Med 2008;4:538-542. 177. Hassaballa HA, Tulaimat A, Herdegen JJ, et al. The effect of continuous positive airway pressure on glucose control in diabetic patients with severe obstructive sleep apnea. Sleep Breath 2005; 9:176-180. 178. Babu AR, Herdegen J, Fogelfeld L, et al. Type 2 diabetes, glycemic control, and continuous positive airway pressure in obstructive sleep apnea. Arch Intern Med 2005;165:447-452. 179. Harsch IA, Schahin SP, Bruckner K, et al. The effect of continuous positive airway pressure treatment on insulin sensitivity in patients with obstructive sleep apnoea syndrome and type 2 diabetes. Respiration 2004;71:252-259.
180. Brooks B, Cistulli PA, Borkman M, et al. Obstructive sleep apnea in obese noninsulin-dependent diabetic patients: effects of continuous positive airway pressure treatment on insulin responsiveness. J Clin Endocrinol Metab 1994;79:1681-1685. 181. West SD, Nicoll DJ, Wallace TM, et al. Effect of CPAP on insulin resistance and HbA1c in men with obstructive sleep apnoea and type 2 diabetes. Thorax 2007;62:969-974. 182. Vgontzas AN, Legro R, Bixler EO, et al. Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: role of insulin resistance. J Clin Endocrinol Metab 2001;86:517-520. 183. Gopal M, Duntley S, Uhles M, et al. The role of obesity in the increased prevalence of obstructive sleep apnea syndrome in patients with polycystic ovarian syndrome. Sleep Med 2002;3:401-404. 184. Fogel RB, Malhotra A, Pillar G, et al. Increased prevalence of obstructive sleep apnea syndrome in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 2001;86:1175-1180. 185. Tasali E, Van Cauter E, Ehrmann D. Polycystic ovary syndrome and obstructive sleep apnea. Sleep Med Clin 2008;3:37-46. 186. Tasali E, Van Cauter E, Ehrmann DA. Relationships between sleep disordered breathing and glucose metabolism in polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:36-42. 187. Tasali E, Van Cauter E, Hoffman L, et al. Impact of obstructive sleep apnea on insulin resistance and glucose tolerance in women with polycystic ovary syndrome. J Clin Endocrinol Metab 2008; 93:3878-3884. 188. Subramanian S, Desai A, Joshipura M, et al. Practice patterns of screening for sleep apnea in physicians treating PCOS patients. Sleep Breath 2007;11:233-237. 189. Yang HP, Kang JH, Su HY, et al. Apnea-hypopnea index in nonobese women with polycystic ovary syndrome. Int J Gynaecol Obstet 2009;105:226-229.
Gastrointestinal Physiology in Relation to Sleep William C. Orr ABSTRACT The gastrointestinal system is regulated by both the autonomic nervous system and the enteric nervous system (ENS), a complex network of neurons located within the entire luminal gastrointestinal tract. Esophageal peristalsis is largely regulated by the ENS and, to a much lesser extent, by vagal input. There is a diminution in peristaltic amplitude and a substantial decrease in the swallowing rate and concomitant prolongation of esophageal acid clearance during sleep. Transient lower esophageal sphincter relaxations have been shown to be decreased during sleep. The basic myoelectric activity of the stomach is regulated by a gastric pacemaker located in brainstem that emits a basic electrical rhythm of approximately three cycles per minute and forms the basis for the production of gastric contractile activity. There is also periodic electrical spike activity associated with gastric contractions. This basic electrical cycle can be measured noninvasively with appropriately placed elec-
INTRODUCTION A description of the normal physiology of any organ system rarely includes the normal alterations of that system during sleep. It would seem inappropriate that nearly one third of the functioning time of an organ system would be ignored in describing its functioning. Profound alterations have been documented during sleep in describing normal physiology, yet these changes do not become part of the litany in describing normal physiology. Sleep-related, or circadian changes, have been most commonly addressed in describing blood pressure and the definition of hypertension, but this has not been accomplished with either the description of or clinical application of sleep-related changes in gastrointestinal (GI) physiology. This can be largely attributed to the inaccessibility of the luminal GI tract to easy measurement. Monitoring any of the basic functions of the GI system requires invading an orifice, which is an unpleasant experience and one that would generally be assumed to be disruptive of normal sleep. The functioning of the luminal GI tract (to which this review is confined) reflects the final common pathway of a complex interaction of the central nervous system (CNS) with both the autonomic nervous system (ANS) and the ENS. The latter is a complex neuronal network that is woven throughout the subserosal layers of the luminal GI tract. The ENS provides an autonomous source of GI motor activity. The movement through the GI tract is controlled and regulated by the ENS and the ANS, and the interaction of these two influences ultimately determines that appropriate movement, at an appropriate rate, occurs throughout the passage from mouth to anus. Alterations in GI functioning during sleep appear to be quite different depending on the particular organ studied and its function within the GI system. For example, spon312
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trodes on the surface of the abdomen. This basic pacemaker activity has been shown to be altered during non-REM sleep (e.g., decrease activity). There is, in normal individuals, a peak in acid secretion occurring at approximately midnight, whereas patients with duodenal ulcer disease have increased acid secretion throughout the circadian cycle unrelated to sleep stage. Intestinal motility is largely composed of the cyclic (every 90 min) occurrence of a sequence of contractions, the migrating motor complex (MMC), which is regulated almost completely by the ENS. This activity is not correlated with rapid eye movement sleep. With sleep, the MMC cycle becomes shorter. During sleep, the colon is relatively quiescent. The high amplitude peristaltic contractions are associated with defecation. Anal rectal functioning, on the other hand, has an endogenous oscillation that is most evident during sleep, resulting in primarily retrograde propagation. This likely serves a protective function against the involuntary loss of rectal contents during sleep.
taneous esophageal function is markedly reduced during sleep because there is no need for this organ to function except in the event of food being transmitted from the upper esophageal area. This rarely occurs without volitional swallowing, which is diminished significantly during sleep. On the other hand, rectal motor activity persists during sleep, which appears to be a mechanism necessary to preserve continence during sleep. The ultimate description of GI functioning and its complex physiology requires that autonomic and central control be separated from the intrinsic control generated by the ENS. Because sleep essentially represents a relative state of reversible isolation from cortical influences, the study of GI motor functioning during sleep allows an assessment of autonomous activity without higher cortical influence. Thus, the study of GI motility during sleep allows the separation of CNS and ENS processes and a more clear understanding of what has been referred to as the brain-gut axis. More information on the interaction between gastrointestinal disorders and sleep is described by this author in Chapter 127 of this volume.
HISTORICAL ASPECTS Interest in GI physiology during sleep preceded the development of sophisticated techniques for monitoring GI function by at least 100 years. For example, Friedenwald,1 in 1906, described the secretory function of the stomach during sleep and reported that it was not appreciably altered. In 1924, Johnson and Washeim2 reported a decrease in the volume of gastric juice secreted during sleep, and, in addition, they reported an increase in the acidity of the gastric juice. Henning and Norpoth3 measured acidity hourly during sleep, and they reported that sleep was associated with a cessation of acid secretion and,
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conversely, patients with gastric ulcers did appear to maintain continuous acid secretion. These results were confirmed nearly 20 years later.4 In 1915, Luckhardt5 described the inhibition of gastric motility during periods of sleep, which, from his description, sounded like rapid eye movement (REM) sleep. His observations were made in dogs and were described in association with “sonorous respiration” (snoring?), irregular breathing, movements of the forelimbs and hindlimbs, and occasional “abortive yelps.” Luckhardt stated, “I assumed that the dog was experiencing during sleep a form of cerebral excitation akin to or identical with the dreaming state in man.” A few years later, in 1922, Wada6 reported an extensive study of hunger and its relation to gastric and somatic activity by use of simultaneous records of gastric contractions and body movements during sleep. Gastric contractions were reported that were often associated with body movements and reports of dreaming. The techniques used in these studies were obviously somewhat crude, but it is clear that interest in GI function during sleep was not a development of the more modern era of sleep investigation.
GASTRIC FUNCTION DURING WAKE AND SLEEP Acid Secretion Gastric acid secretion has been shown to exhibit a clear circadian rhythm, which was initially described by Sandweiss and colleagues.7 It remained, however, for Moore and Englert to provide a definitive description of the circadian oscillation of gastric acid secretion in normal subjects.8 These investigators described a peak in acid secretion occurring generally between 10:00 pm and 2:00 am while confirming already established data that indicated that basal acid secretion in the waking state is minimal in the absence of meal stimulation. Similar results have been described in patients who have duodenal ulcer (DU) disease with levels of acid secretion markedly enhanced throughout the circadian cycle.9,10 It is clear from these results that there is an endogenous circadian rhythm of unstimulated basal acid secretion, but it is not clear that this is specifically altered in any way by sleep. Initial interest in the role of sleep in gastric acid production was stimulated by the work of the eminent University of Chicago surgeon Dr. Lester Dragstedt.11 An interest in the pathogenesis of DU disease and the possible role of nocturnal gastric acid secretion in this process was further stimulated by the studies of Levin and colleagues.9,12 They analyzed hourly samples of acid secretion in both normal subjects and patients with DU disease, and they identified nearly continuous acid secretion throughout the night in normal volunteers. They described a considerable degree of night-to-night and subject-to-subject variation. In contrast to the normal subjects, there were increases in both volume and acid concentration during sleep in patients with DU disease as suggested earlier for premier study. Although emphasizing night-to-night variation, they found that the patients with DU disease who tended to be high secreters were consistently high, and those who were
low secreters were consistently low. These studies paved the way for more extensive investigations into the role of nocturnal acid secretion in the pathogenesis of DU disease. This study is at variance with the study by Sandweiss and colleagues,7 which did not find a substantial difference in nocturnal acid secretion between normal subjects and patients with DU. These discrepant results may be due to varying degrees of ulcer activity in the patients studied. As previously noted, perhaps the most influential work in nocturnal gastric acid secretion has been done by Dragstedt.11 Using hourly collections of overnight acid secretion in normal subjects and in patients with DU disease, he reported that the nocturnal acid secretion in patients with DU disease is 3 to 20 times greater than that in his normal subjects. He reported that this greater secretion was abolished by vagotomy, which invariably produced prompt ulcer healing. These data were interpreted to be strong evidence in favor of a “nervous” origin for DU disease. The decade of the 1950s ushered in the “golden age” of sleep investigation. The realization that sleep is not a unitary, passive state of consciousness focused considerable interest on its unique physiology. The first study to describe gastric acid secretion during conditions of polysomnographic (PSG) monitoring was reported in 1960 by Reichsman and colleagues.13 Using relatively crude determinations of stages of sleep, they found no correlation between gastric acid secretion and sleep stages in normal subjects. A subsequent study by Armstrong and colleagues14 reported the rather startling finding of a hypersecretion of acid during REM sleep in patients with DU disease. Both of these studies suffered from a major methodological flaw in that they used drugs to induce sleep. Another problem in these studies was the relatively small data sample per subject, in most cases only a single night. Earlier studies documented the considerable night-to-night variability in acid secretion. Thus, studying a patient or a normal volunteer for a single night with a nasogastric tube would undoubtedly result in numerous awakenings and generally poor sleep, with correspondingly more variable acid secretion. Stacher and colleagues15 studied gastric acid secretion in a group of normal volunteers during PSG-monitored natural sleep. They reported no significant differences in acid secretion during the non–rapid eye movement (NREM) stages of sleep; however, they reported that REM sleep was associated with an inhibition of acid secretion. This study, although avoiding the use of drugs to induce sleep, used a rather cumbersome technique for determining acid output. It was measured by an intragastric titration from a telemetric pH capsule and involved numerous disruptions in the patients’ sleep. Thus, although it was natural sleep, it was at best fragmented sleep. The variability of these results and the various methodological problems of previous studies prompted a concurrent study of both normal subjects and patients with DU disease. Orr and colleagues16 studied five normal volunteers and five patients with DU disease, and each subject was studied for 5 consecutive nights in the sleep laboratory. The study involved continuous aspiration of gastric contents divided into 20-minute aliquots for gastric analysis as well as complete PSG monitoring for the determination of sleep stages. In addition, serum gastrin levels were
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assessed at 20-minute intervals throughout the study. The results did not reveal any significant correlation between the sleep stage (REM vs. NREM) and acid concentration or total acid secretion. Furthermore, there was no relationship between any of these variables and serum gastrin levels. These data did show, however, that the patients with DU failed to inhibit acid secretion during the first 2 hours of sleep, which was consistent with the previously reported studies by Levin and colleagues,12 which suggested that acid secretion is poorly inhibited during sleep in patients with DU disease. In conclusion, the data would support the presence of a clear-cut circadian rhythm in basal acid secretion, with a peak occurring in the early part of the normal sleep interval. However, there are no definitive data at the present time that would suggest a major effect of sleep stages on this process. If one conclusion can be drawn from the various studies that have been done assessing gastric acid secretion during sleep, it would be that acid secretion is extremely variable from night to night and from person to person, and for this reason definitive conclusions require numerous replications across and within a large number of subjects and patients. The extremely demanding logistics of sleep studies, as well as the obvious aversive aspects of probe placement via the nasal passages or anal canal make the acquisition of such data exceedingly difficult.
GASTRIC MOTOR FUNCTION DURING SLEEP The motor function of the stomach serves to empty solids and liquids into the duodenum at an appropriate rate and pH. The stomach is functionally divided into two sections: the fundus of the stomach functions primarily to control liquid emptying into the duodenum, whereas the antrum controls emptying of solids.17 Because liquids and solids are handled differently by the stomach, the regulation of gastric emptying is correspondingly complicated, involving intrinsic regulation of motor activity as well as specific alterations associated with the ingestion of liquids and solids. Thus, although gastric emptying itself can be regarded as the final common pathway reflecting the motor activity of the stomach, one must keep in mind that the processes of liquid and solid emptying are regulated by quite different mechanisms. There have been many reports of gastric motility during sleep, with sometimes contradictory results. Inhibition of gastric motility during sleep was documented in a study by Scantlebury and colleagues,18 in which they implicated the “dream mechanism” as a part of this inhibitory process. A cortical inhibitory mechanism acting through the splanchnic nerve is the postulated mechanism of this inhibition. Nearly 30 years later, using somewhat more sophisticated measurement techniques, Bloom and colleagues19 found that gastric motility was enhanced during sleep, compared with waking. Baust and Rohrwasser20 studied gastric motility during PSG-monitored sleep, and they also described a marked enhancement in gastric motility during sleep, but their findings were restricted to REM sleep. Only a year later, a decrease in gastric motility during REM sleep was reported.21 No consistent findings concerning alterations
by sleep stage were noted in a study in unanesthetized and unrestrained cats.22 Hall and colleagues23 reported data on gastric emptying during sleep. This study required the patient to sleep with a nasogastric tube through which 750 ml of 10% glucose was administered. After 30 minutes, the gastric contents were aspirated, and the residual volume was determined. Aspiration was followed by a washout meal of 150 ml of saline. This process was done during the presleep waking interval, during NREM and REM sleep, and during postsleep waking. These data suggested a more rapid gastric emptying during REM sleep and a slower emptying during the postsleep–waking state. The emptying of a hypertonic solution is controlled by vagally mediated osmoreceptors in the duodenum. These data, therefore, would suggest a possible anticholinergic action during REM sleep and a cholinergic process during the postsleep–waking state. These data represent only an approximation of the alterations in gastric emptying during sleep because these measurement techniques are relatively crude, and gastric emptying is a complex process. Dubois and colleagues24 have described a technique that permits the simultaneous assessment of acid secretion, water secretion, and the fractional rate of emptying. These techniques have been applied to the assessment of gastric functioning during sleep; the results indicate that in normal subjects, acid secretion, water secretion, and the fractional rate of emptying all showed significant decrements during sleep.25 There did not appear to be any differences between REM and NREM sleep, but all of these measures demonstrated a significant difference between presleep waking and REM sleep. Data obtained by use of radionuclide emptying assessments suggest that this difference may be a circadian, rather than a sleep-dependent, effect. Studies by Goo and colleagues26 have shown a marked delay in gastric emptying of solids in the evening, compared with the morning. Gastric motor functioning is characterized by an endogenous electrical cycle generated by the gastric smooth muscle. The electrical rhythm is generated by a pacemaker located in the proximal portion of the greater curvature of the stomach.27 The electrical cycle occurs at a frequency of approximately three per minute and represents the precursor to contractile activity of the stomach, which allows movement of gastric contents to the antrum and subsequent emptying into the duodenum. The gastric electrical rhythm can be measured by surface electrodes placed in the periumbilical area. The identification of this basic motor function of the stomach requires highly sophisticated measurement, digital filtering, and spectral analysis to describe the parameters of this oscillation.28 The noninvasive measurement of the gastric electrical rhythm is called electrogastrography (EGG). The progressive sophistication of the measurement and analytic techniques has allowed a reliable noninvasive technique to measure an important function of the GI system. The sophisticated analysis of gastric electrical activity has documented three fundamental characteristics of this electrical rhythm that determine its normal activity. First, the power in the frequency band is approximately three per minute. This is essentially a method of quantifying the extent to which the wave approximates a sinusoidal rhythm,
CHAPTER 27 • Gastrointestinal Physiology in Relation to Sleep 315
SWALLOWING AND ESOPHAGEAL FUNCTION Interest in esophageal function during sleep was stimulated by 24-hour esophageal pH studies, which documented the important role of nocturnal gastroesophageal reflux (GER) in the pathogenesis of reflux esophagitis.32 Gastroesophageal reflux may occur in normal people even while upright and awake (Fig. 27-1). This occurrence was identified primarily postprandially in normal subjects and was associated with multiple episodes of reflux that were relatively rapidly (in less than 5 min) neutralized. Studies by these investigators and others have documented that in normal individuals, sleep is relatively free of episodes of GER.32-36 The utilization of 24-hour pH studies to describe GER during the circadian cycle has focused on the description of subject reports of recumbence and the extent to which that positional report can adequately rep-
NORMAL POSTPRANDIAL REFLUX (in normal volunteer) 8 6 pH
and the power reflects the peak-to-peak amplitude of the cycle. Second, more sophisticated techniques devised by Chen and colleagues29 have allowed a minute-by-minute characterization of the cycle. This has permitted other parameters to describe the normal function of the gastric electrical rhythm. For example, 1-minute segments can be analyzed for 15 to 20 minutes and the percentage of 1-minute segments in which the peak amplitude is located at the dominant frequency can be calculated. Normal is approximately 70% or greater. Third, this technique of 1-minute segmental analysis, termed the running spectrum, also allows determination of the instability coefficient, which describes the variability of the center frequency of the cycle. A larger coefficient means greater instability of the endogenous oscillation. Generally, it has been thought that the gastric electrical rhythm is a product of the endogenous functioning of the gastric electrical pacemaker and that it is generally without influence from the CNS. However, sleep studies have challenged this traditional belief. Initially, studies showed a significant decline in the power in the three-per-minute cycle during NREM sleep.30 There is a significant recovery of this toward the waking state during REM sleep. Further preliminary data from our laboratory have used running spectral analysis to describe a profound instability in the functioning of the basic electrical cycle during NREM sleep.31 These two studies clearly suggest that NREM sleep is associated with a marked alteration or destabilization of the basic gastric electrical rhythm. It might be concluded from these results that higher cortical input or a degree of CNS arousal must be present in order to stabilize and promote normal gastric functioning and consequently normal gastric emptying. It would seem clear from the results described that definitive statements concerning the alteration of gastric motor function and gastric emptying during sleep or specific sleep stages cannot be made. Difference in methodology used could explain such discrepancies. It would have to be concluded that gastric motor function appears to be diminished during sleep, but it is not clear whether this is specifically the result of altered gastric emptying attributable to sleep, per se, or whether this is simply a natural circadian rhythm independent of sleep.
4 2
Meal 0 16:00
Heartburn 17:00
18:00
19:00
Time (PM) Figure 27-1 Pattern of gastroesophageal reflux in the waking state. Reflux is noted when the esophageal pH falls below 4.0. Episodes are generally short postprandial events.
Mean percent total time pH <4
* 12.8
14 12 10
*P < .0001 n = 64
* 8.5
8
* 4.3
6 4 2 0 Upright
Supine-awake
Supine-asleep
Figure 27-2 Esophageal acid contact in the upright, recumbent awake, and recumbent during the sleeping interval noted during 24-hour pH recording. (Adapted from Dickman R, Shapiro M, Malagon IB, Powers J, Fass R. Assessment of 24-h oesophageal pH monitoring should be divided to awake and asleep rather than upright and supine time periods. Neurogastroenterol Motil 2007;19:709-715.)
resent the sleeping interval. In a study of normal subjects and patients with gastroesophageal reflux disease (GERD) it was shown that recumbent waking is distinctly different from recumbency noted during the sleeping interval in that the latter is associated with overall less acid contact (Fig. 27-2).37 However, when reflux does occur during sleep, it is associated with a marked prolongation in the acid clearance time (Fig. 27-3). Data from these studies suggest that the prolongation in acid clearance during sleep is due to several factors. First, and perhaps most important, there is a delay in the conscious response to acid in the esophagus during sleep, and studies have documented that an arousal response almost invariably precedes the initiation of swallowing.33,34 In fact, a relatively predictable and inverse relationship has been described between the acid clearance time and the amount of time the individual spends awake during the acid clearance interval. That is, if an individual responds with an awakening and subsequent swallowing when acid is infused in the distal esophagus during sleep, clearance is substantially faster than if an individual has a prolonged latency to the initial arousal response.34,35 Another important aspect of complete neutralization of the acidic distal
316 PART I / Section 4 • Physiology in Sleep SLEEP REFLUX SUPINE SLEEP CONDITION
UES PRESSURE 100
8
80 mm Hg
pH
6 4 2
60 40 20
0
0 0:40
1:00
1:20
1:40
Figure 27-3 Pattern of gastroesophageal reflux during sleep. Reflux is noted when the esophageal pH falls below 4.0. Reflux events during sleep are characterized by prolonged acid clearance (return to pH above 4.0.)
esophagus is salivary flow. It has been demonstrated that saliva is essential to the neutralization of the acidic esophagus.38 This finding is important because it has been shown that salivary flow stops completely with the onset of sleep, which would therefore substantially retard the acid neutralization.39 It is well known that swallowing initiates the acid clearance process, and, in general, swallowing is considered a volitional act. Thus, one would expect that it would be substantially depressed during altered states of consciousness, such as sleep. Studies have clearly confirmed this supposition by showing a significant diminution in swallowing frequency during sleep.40,41 Although the state of sleep certainly depresses the frequency of swallows, it appears that swallowing is usually associated with a brief arousal response.34,36 Studies on normal volunteers suggest that even though the swallowing frequency is substantially diminished during sleep, peristalsis appears to be completely normal.34 This includes primary peristalsis, which is initiated by a swallow, and secondary peristalsis, which is not preceded by a swallow. However, in a study of cats42 it was noted that, although swallowing frequencies diminished during sleep as noted in human beings, peristaltic amplitudes are hypotonic during REM sleep. Thus, it can be concluded that alterations in esophageal acid clearance during sleep would be primarily the result of two factors: decreased swallowing frequency and absence of salivary flow. A study has addressed the issue of esophageal function during sleep and has clearly shown that esophageal motor activity is sleep stage dependent.43 This study showed that the frequency of primary contractions in the esophagus (peristaltic contractions preceded by a swallow) diminish progressively from stage 1 to stage 4 sleep. Of interest is the fact that secondary peristaltic contractions (spontaneous contractions) showed a similar decline from waking to stage 4 sleep but showed a significant recovery during REM sleep. Similarly, a more recent study describing upper esophageal sphincter (UES) functioning during PSG-monitored sleep showed a progressive decline during NREM sleep with a modest bump up during REM sleep (Fig. 27-4).44 This suggests that skeletal muscle tone (the UES is primarily the cricopharyngeus muscle), as well as spontaneous, or secondary, esophageal peristaltic contrac-
W
Stage 2
SWS
REM
Figure 27-4 Upper esophageal sphincter (UES) pressure noted during sleep stages. REM, rapid eye movement; SWS, slow-wave sleep; W, awake. (Adapted from Bajaj JS, Bajaj S, Dua KS, et al. Influence of sleep stages on esophago-upper esophageal sphincter contractile reflex and secondary esophageal peristalsis. Gastroenterology 2006;130:17-25.)
GER DURING SLEEP 100 % Reflux events
0:20
80 60 40 20 0 WASO
Stage 1
Stage 2
SWS
REM
Figure 27-5 Gastroesophageal reflux (GER) noted during sleep stages. REM, rapid eye movement; SWS, slow-wave sleep; WASO, wake after sleep onset. (Adapted from Penzel T, Becker HR, Brandenburg U, et al. Arousal in patients with gastrooesophageal reflux and sleep apnoea. Eur Respir J 1999;14: 1266-1270.)
tions are perhaps more influenced by the endogenous level of CNS arousal. As has been described in previous studies, this study identified long periods of nocturnal esophageal motor quiescence with apparently random bursts of contractions.45,46 Secondary peristaltic contractions during sleep were noted to be of diminished amplitude and shorter duration when compared with primary contractions. In addition, primary peristaltic contractions appeared to be of higher amplitude during sleep than during waking. This supports the notion that primary and secondary contractions may be controlled by different mechanisms and that waking CNS influences may inhibit primary peristaltic contractions. These results await confirmation by other studies. It would appear from these data that studying esophageal function during sleep allows a clearer understanding of central, peripheral, and enteric nervous system mechanisms controlling esophageal function. Gastroesophageal reflux has been shown to occur during sleep, primarily during NREM stage 2 (Fig. 27-5).47,48 The actual mechanism of GER during sleep has been addressed in an elegant study which utilized a specially designed monitoring device.36 The lower esophageal sphincter (LES) pressure was continuously monitored during sleep. In addition, a pH probe was placed in the distal esophagus
CHAPTER 27 • Gastrointestinal Physiology in Relation to Sleep 317
to identify episodes of GER. They determined that the majority of episodes of reflux occurred in association with a spontaneous decline in the lower esophageal sphincter pressure to close to the intragastric pressure. This pressure decline creates a common cavity between the stomach and the esophagus, and because there is a 5-mm Hg pressure gradient between the stomach and the midesophagus, this would create a situation particularly conducive to the reflux of gastric contents into the esophagus. As also noted in other studies, the majority of these episodes were associated with a brief arousal response, although they were identified in some cases without movement.47,48 Other reflux events were noted to occur when the LES pressure was clearly above the intragastric baseline, thereby creating a pressure barrier to reflux. Under these circumstances, reflux occurs mechanically, by the creation of intraabdominal pressure that is sufficient to overcome the pressure barrier in the LES. Thus, reflux could occur under these circumstances during transient arousals from sleep associated with positional change, coughing, or swallowing. The UES serves as an additional protective barrier to prevent the aspiration of noxious material into the lungs. The upper esophageal sphincter is tonically contracted, and a pressure of between 40 and 80 mm Hg usually exists within this sphincter. Swallowing induces a reflex relaxation to allow the positioning of food and liquids in the upper esophagus, where the normal peristaltic mechanism transports these materials into the stomach. The tonic contraction of the upper esophageal sphincter therefore prevents the ingestion of material into the esophagus with a previous volitional swallow. A study has documented relatively little change in the functioning of the upper esophageal sphincter during sleep, including REM sleep.49 Only a modest decline in the resting pressure was noted. This observation is somewhat surprising because the cricopharyngeal muscle is a skeletal muscle, and if this finding can be verified, it would be one of the few skeletal muscles in the body that does not show a substantial inhibition during REM sleep. In fact, in the more recent study noted earlier, this skeletal muscle shows significant decline in basal pressure in the upper sphincter, and an increase, rather than decrease during REM sleep (see Fig. 27-3).44 Obviously, persisting tone in the upper esophageal sphincter during REM sleep is advantageous because it protects the lungs from the aspiration of gastric contents. For more information on the GER related to sleep disorder breathing, see Chapter 127.
INTESTINAL MOTILITY DURING SLEEP The primary functions of the small and large intestine are transport and absorption. These functions are intimately related in that, for example, rapid transit through the colon results in poor absorption and loose, watery stools, whereas slow transit results in increased water absorption, slow transit of fecal material to the rectum, and the clinical consequence of infrequent defecation and complaints of constipation. Alterations in the motor function of the lower bowel are evident from clinical phenomena, such as the occurrence of nocturnal diarrhea in diabetics and noc-
turnal fecal incontinence, which is commonly noted in patients with ileoanal anastomosis.50 The accessibility of the motility of the GI tract to monitoring decreases with distance from the oral cavity. The earliest attempts at measurement were purely observational. Cannon,51 for example, fluoroscopically observed the progress of food through the intestines of the cat. Similar observational techniques were employed by subsequent investigators to describe the differences in intestinal motility during waking and sleep.52,53 These individuals exteriorized a small section of dog intestine and determined via visual observation that motility was relatively unaffected by sleep. In 1926, a similar fluoroscopic observation of exteriorized human intestine was made.54 In agreement with the animal studies, these observations reported no change in intestinal motility during sleep. Prolonged monitoring of the large and small bowel by use of a variety of sophisticated techniques, including telemetry, implanted microelectrodes, and suction electrodes, has allowed a more comprehensive description of intestinal motor activity. On the basis of these studies, tonic activity in the stomach and small bowel has been described as a basic electrical rhythm and as more phasic phenomena, such as the migrating motor complex (MMC), which is a wave of intestinal contraction beginning in the stomach and proceeding through the colon. The MMC consists of a dependent pattern of interdigestive motor phenomena. Subsequent to food ingestion there is an interval of motor quiescence termed phase I. This is followed by a period of somewhat random contractions throughout the small bowel and this is called phase II. Phase III describes a coordinated peristaltic burst of contractile activity that proceeds distally throughout the small bowel. Food ingestion establishes a pattern of vigorous contraction throughout the distal stomach and small bowel. If no food enters the stomach, the MMC cycle has a period of about 90 minutes.55 In a recent study55 the activity of the MMC subsequent to a meal was assessed during waking and during subsequent sleep. In addition, they assessed the behavior of a variety of regulatory peptides. They concluded that postprandial intestinal motor activity was substantially altered by sleep, primarily a reduction in the fed pattern of intestinal motility. Because there was little appreciable alteration in peptide levels, the authors concluded that the alteration in small bowel motility was most likely neurally mediated. The authors noted that responses were similar to those described after vagotomy in the waking state. This suggests that reduced levels of arousal result in diminished vagal modulation of the ENS. Jejunal motor activity has been described in 20 normal subjects during sleeping and waking states; no differences in the incidence of migrating motor complexes activity were found.56 Another study reported that sleep prolonged the interval between motor complexes in the small intestine.57 A subsequent study by the same group revealed a sleep-related diminution in the number of contractions of a specific type in the jejunum.58 These changes were also seen in patients with DU and vagotomies as well as in normal subjects, which suggests that this phenomenon is independent of vagal control and unaffected by duodenal disease. The issue of the alteration of the MMC during
318 PART I / Section 4 • Physiology in Sleep
sleep has been addressed, and results showed a statistically significant relationship between REM sleep and the onset of MMCs originating in the duodenum.59 A study has described an obvious circadian rhythm in the propagation of the MMC, with the slowest velocities occurring during sleep.60 This finding appears to be the effect of a circadian rhythm rather than a true modulation by sleep. These results have been confirmed by a study which also noted that the esophageal involvement in the MMC was decreased during sleep, with a corresponding tendency for MMCs to originate in the jejunum at night.61 The relationship between the MMC cycle and REM sleep has been described. It was found that during sleep, there was a significant reduction in the MMC cycle length as well as the duration of phase II of the MMC.62 The MMCs were distributed equally between REM and NREM sleep with no obvious alteration in the parameters of the MMC by sleep stage. These data give evidence of alteration in periodic activity in the gut during sleep, but they are also consistent with the notion that the two cycles (i.e., MMCs and REM sleep) are independent. The same group of investigators have examined how the presence or absence of food in the GI tract alters small bowel motility during sleep.63 A late evening meal restored phase II activity of the MMC, which is normally absent during sleep. These MMC changes during the sleeping interval have been substantially confirmed by subsequent ambulatory studies but without the benefit of PSG.64,65 With the development of more sophisticated electronic measuring and recording techniques, more accurate measures of intestinal motility have been possible in both animals and humans. Unfortunately, these studies have produced results that conflict with those noted earlier from direct observation. Decreases in small intestinal motility during sleep were reported in two separate studies conducted 20 years apart.66,67 Specific duodenal recordings in humans have been conflicting, showing no change in one instance and a decrease in duodenal motility during sleep in another.19,66 A different approach to duodenal recording was employed to record duodenal electromyographic (EMG) activity during various stages of sleep. This story showed an inhibition of duodenal EMG activity during REM sleep and an increase in activity with changes from one sleep phase to another.68 In a subsequent study, a decrease in duodenal EMG activity during sleep was described by the same group.69 They also noted an activity rhythm of 80 to 120 minutes per cycle that was impervious to the changes associated with the sleep–wake cycle.
SLEEP, ABDOMINAL PAIN, AND IRRITABLE BOWEL SYNDROME Sleep, intestinal motility, and symptoms of abdominal pain have been studied in patients with irritable bowel syndrome (IBS). Striking differences between sleeping and waking small bowel motor activity have been described.70 The marked increase in contractility seen in the daytime is notably absent during sleep. In a related study, it was noted that propulsive clusters of small bowel motility were somewhat enhanced in the daytime in patients with IBS, and this distinguished them from controls.71 Patients often
had pain associated with these propulsive contractions, but there was no difference in small bowel activity between patients with IBS and controls during sleep. Interestingly, an increase in REM sleep has been described in patients with IBS.72 This has been proposed as evidence of a CNS abnormality in patients with this complex, enigmatic disorder. The relationship of pain to motor abnormalities of the luminal GI tract has had varying results and it has proven difficult to link, for example abdominal pain to any specific intestinal motor disorder. The issue of abdominal pain in IBS is more thoroughly discussed in Chapter 127.
EFFECT OF INTESTINAL MOTILITY ON SLEEP Although this chapter has concentrated on the effects of sleep on GI motility, there have been some fascinating studies addressing the issue of how intestinal motility may affect sleep. A practical and provocative thought concerning this issue relates to the familiar experience of postprandial somnolence. There is some question about whether it actually exists. These thoughts raise the issue of whether there may be changes in the GI system with food ingestion that could produce a hypnotic effect. Along these lines, an intriguing observation was made by Alverez73 in 1920. He noted that distention of a jejunal balloon caused his human subject to drop off to sleep. The hypnotic effects of afferent intestinal stimulation have also been documented in animal studies. Perhaps the most notable work was a study which induced cortical synchronization in cats by both mechanical and electrical stimulation of the small bowel.74 These results were interpreted to be the effect of rapidly adapting phasic afferent fibers from the small intestine carried to the CNS via the splanchnic nerve. These data strongly suggest the existence of a hypnogenic effect of luminal distention. In a subsequent study, these same investigators reported an increase in the duration of slow-wave sleep and an increase in the number of episodes of paradoxical sleep in cats subjected to low-level intestinal stimulation.75 The authors also acknowledged the possible hypnogenic role of intestinal hormones such as cholecystokinin, and they cited a study76 in which administration of intestinal hormones produced a pronounced increase in paradoxical sleep episodes. The final common pathway of the afferent stimulation from the intestinal tract would presumably result in an increase in sleepiness subsequent to either luminal distention or hormonal secretion postprandially. In a fascinating study concerning neuronal processing during sleep,77 it was shown that neurons in the visual cortex, which usually respond to visual stimulation in the waking state, are activated during sleep by electrical stimulation of the stomach and small bowel. In an attempt to document the presence of postprandial sleepiness objectively, a study was undertaken to measure sleep onset latency both with and without a prior meal.78 Statistically, the results of this test did not support the presence of documentable postprandial sleepiness in 16 normal volunteers. However, it was obvious from these results that there was a small group of individuals in whom there was clearly a substantial decrease in the sleep onset latency after ingestion of a meal. This phenomenon seems
CHAPTER 27 • Gastrointestinal Physiology in Relation to Sleep 319
to be affected by many variables including the volume of the meal, the meal constituents, and the circadian cycle of the individual. In a follow-up study,79 this same group tested the hypothesis that afferent stimulation from the gastric antrum would enhance postprandial sleepiness. This was tested by comparing an equal volume distention of the stomach with water to an equal caloric solid meal and liquid meal. Sleep onset latency was determined subsequent to each of these conditions. Because antral stimulation results from the digestion of a solid meal, sleep onset latency should be shorter subsequent to the consumption of the solid meal. This was confirmed in this study in that the sleep onset latency after the solid meal was significantly shorter than the equal volume water condition. These results are compatible with the animal studies cited earlier and lend further support to the notion that contraction of the lumen of the GI tract produces afferent stimulation, which induces drowsiness.
COLONIC AND ANORECTAL FUNCTION DURING SLEEP The colon has two main functions: transport and absorption. These are critically determined by the motor activity of the colon, which determines the rate of transport and, therefore, indirectly, the rate of absorption from the colonic lumen. Thus, alterations in colonic motility will have significant consequences in terms of transit through the colon and water absorption and ultimately clinical consequences such as constipation and diarrhea. In the early 1940s a study described a decrease in colonic function during sleep.80 These results have been confirmed by two other studies that included measurements of the transverse, descending, and sigmoid colon.81,82 In one of these studies,82 a clear inhibition of colonic motility index is evident during sleep in the transverse, descending, and sigmoid colon segments, with a marked increase in activity on awakening. Certainly, this explains the common urge to defecate on awakening in the morning. Neither of these studies attempted to document sleep with standard PSG. However, in a subsequent study,83 colonic activity from cecum to rectum was monitored continuously for 32 hours, and sleep was monitored via PSG. This study again noted a rather marked decrease in colonic motor activity during sleep, but it also described an interesting abolition in propagating waves during slow-wave sleep. During REM sleep, the frequency of propagating events rose substantially. Other studies do not provide evidence for any significant change in colonic motility or variability in the rectosigmoid colon during sleep.84,85 However, a study of colonic myoelectrical activity in the human being suggested a decrease in spike activity during sleep.86 Again, this study does not determine whether the results are accounted for on the basis of true physiological sleep or simply reflect a circadian variation in colonic activity independent of sleep. Collectively, these studies would suggest an inhibition of colonic contractile and myoelectric activity during sleep, and other studies have documented the fact that there is diminished colonic tone during sleep.87 Resumption of the waking state, and consequently increased CNS arousal, would suggest two different effects on colonic motility.
First, it appears that spontaneous awakening does induce high-amplitude peristaltic contractions as described by Narducci and noted earlier, and this appears to be somewhat different than colonic motor activity induced by a sudden awakening from sleep. In one study, sudden awakenings from sleep induced a pattern of segmental colonic contractions,88 rather than the propagating high-amplitude peristaltic contractions noted in a previous study.82 These data are of considerable interest in that they demonstrate not only the influence of higher cortical functions on colonic motility but also the fact that the state of consciousness can affect the colon in rather subtle ways in terms of the induction of different patterns of colonic motility. The striated muscle of the anal canal was evaluated during sleep in a 1953 study that included EEG documentation of sleep.89 These investigators described a marked reduction in EMG activity during sleep. They concluded that this muscle is under voluntary control. In another study,90 anal canal pressure was measured continuously during sleep, but without PSG monitoring. The results indicated a decrease in the minute-to-minute variation and the amplitude of spontaneous decreases in anal canal pressure during sleep. These results have been largely confirmed in a study involving the ambulatory monitoring of anorectal activity that noted a decrease in anal canal resting pressure during sleep, as well as alterations in rectal motor complexes (RMC) that were noted to be similar in waking and sleep in the midrectum.91 However, in the distal rectum, this motor pattern was found to be more prevalent during sleep. They also noted that during sleep, the anal canal resting pressure exceeded that of the rectal pressure, which would seem to be important in maintaining rectal continence during sleep. The structures of the rectum and anal canal are vital in maintaining normal bowel continence and ensuring normal defecation. In general, normal defecation is associated with sensory responses to rectal distention and appropriate motor responses of the muscles of the anal canal. These responses would include a contraction of the external anal sphincter and a transient decrease in the internal anal sphincter pressure associated with rectal distention. It is thought that the high resting basal pressure in the internal anal sphincter of the anal canal, as well as the response of the external anal sphincter to rectal distention, is critical in maintaining continence. For assessment of the effect of sleep on these anorectal sensorimotor responses, 10 normal volunteers were studied during sleep with an anorectal probe in place.92 This probe permits the transient distention of the rectum via a rectal balloon while the responses of the internal and external anal sphincters can be simultaneously monitored. This study documented a marked decrease—and, in most subjects, an abolition—of the external anal sphincter response to rectal distention. The internal anal sphincter response remained unaltered. In addition, there was no evidence of an arousal response with up to 50 mL of rectal distention during sleep. The normal threshold of response in the waking state is approximately 10 to 15 mL. These results confirm that the external anal sphincter response to rectal distention is most likely a learned response, whereas the internal anal sphincter response is clearly a reflex response
320 PART I / Section 4 • Physiology in Sleep
to rectal distention because it persists during sleep. It also raises certain clinical questions with regard to the phenomenon of nocturnal diarrhea and the maintenance of fecal continence during sleep. In an ambulatory study of anorectal functioning, it was demonstrated that external anal sphincter contractions occurred periodically during sleep, and these periodic bursts of activity were followed by motor quiescence.93 These spontaneous contractions were associated with a rise in the anal canal pressure, but internal anal sphincter contractions were shown to occur independently of external anal sphincter activity. The sampling reflex, which is a spontaneous relaxation of the internal anal sphincter, occurred frequently in the waking state but was markedly reduced during sleep. An important study has shed light on intrinsic analrectal functioning, which is altered during sleep.94 These investigators confirmed the presence of an endogenous oscillation in rectal motor activity, and they have specifically noted that these bursts of cyclic rectal motor activity occupied approximately 44% of the overall recording time at night. They described the incidence of this motor activity to be nearly twofold greater at night than during the daytime. Of particular importance is the finding that the majority of contractions were propagated in a retrograde direction. Other studies have shown that rectal motor activity is not altered by REM sleep.90 Two other studies have shown that anal canal pressure is decreased during sleep.95,96 However, of particular interest is the fact that even though there was a diminution in anal canal pressure during sleep, anal canal pressure was always greater than rectal pressure even in the presence of cyclic rectal motor activity.95 These studies collectively shed important light on the mechanisms of rectal continence during sleep. There appear to be at least two mechanisms that prevent the passive escape of rectal contents during sleep. First, rectal motor activity increases substantially during sleep, but the propagation is retrograde rather than anterograde. Furthermore, these physiologic studies have shown that, even under the circumstances of periodic rectal contractions, the anal canal pressure is consistently above that of the rectum. Both of these mechanisms would tend to protect against rectal leakage during sleep, and alterations in these mechanisms would explain loss of rectal continence during sleep in individuals with diabetes or who have undergone ileal-anal anastomosis.
CONCLUSIONS There are marked alterations in the GI system during sleep, and these have numerous consequences in terms of normal digestive processes as well as digestive disease (reviewed in Chapter 127). Our understanding of the modulation of GI function by sleep has increased. In the future, research will focus on the direct effects on the GI physiology of orexins A and B and other neuropeptides that play a role in arousal and sleep as well as on appetite, regulation of feeding, and energy homeostasis.97 Clearly, the past 50 years have shown a marked increase in interest in sleep and GI physiology, and this will undoubtedly continue as the importance of sleep physiology and pathophysiology is further revealed.
❖ Clinical Pearl Suppression of nocturnal acid secretion is an important element of healing duodenal ulcers and remains a mainstay in the treatment of GERD. This in turn can reduce the pulmonary complications of GERD.
REFERENCES 1. Friedenwald J. On the influence of rest, exercise and sleep on gastric digestion. Am J Med 1906;1:249-255. 2. Johnson RL, Washeim H. Studies in gastric secretion. Am J Physiol 1924;70:247-253. 3. Henning N, Norpoth L. Die Magensekretion waehrend des Schlafes. Dtsch Arch Klin Med 1932;172:558-562. 4. Banche M. La secrezione gastric notturna durante il sonno. Minerva Med 1950;1:428-434. 5. Luckhardt AB. Contributions to the physiology of the empty stomach. Am J Physiol 1915;39:330-333. 6. Wada T. Experimental study of hunger in its relation to activity. Arch Psychol 1922;8:1-65. 7. Sandweiss DJ, Friedman HF, Sugarman MH, et al. Nocturnal gastric secretion. Gastroenterology 1946;1:38-54. 8. Moore JG, Englert E. Circadian rhythm of gastric acid secretion in man. Nature 1970;226:1261-1262. 9. Levin E, Kirsner JB, Palmer WL, et al. A comparison of the nocturnal gastric secretion in patients with duodenal ulcer and in normal individuals. Gastroenterology 1948;10:952-964. 10. Feldman M, Richardson CT. Total 24-hour gastric acid secretion in patients with duodenal ulcer: comparison with normal subjects and effects of cimetidine and parietal cell vagotomy. Gastroenterology 1986;90:540-544. 11. Dragstedt LR. A concept of the etiology of gastric and duodenal ulcers. Gastroenterology 1956;30:208-220. 12. Levin E, Kirsner JB, Palmer WL, et al. The variability and periodicity of the nocturnal gastric secretion in normal individuals. Gastroenterology 1948;10:939-951. 13. Reichsman F, Cohen J, Colwill J, et al. Natural and histamineinduced gastric secretion during waking and sleeping states. Psychosom Med 1960;1:14-24. 14. Armstrong RH, Burnap D, Jacobson A, et al. Dreams and acid secretions in duodenal ulcer patients. New Physician 1965;33:241-243. 15. Stacher G, Presslich B, Starker H. Gastric acid secretion and sleep stages during natural night sleep. Gastroenterology 1975;68:14491455. 16. Orr WC, Hall WH, Stahl ML, et al. Sleep patterns and gastric acid secretion in duodenal ulcer disease. Arch Intern Med 1976;136: 655-660. 17. Dubois A, Castell DO. Abnormal gastric emptying response to pentagastrin in duodenal ulcer disease. Dig Dis Sci 1981;26:292-296. 18. Scantlebury RE, Frick HL, Patterson TL. The effect of normal and hypnotically induced dreams on the gastric hunger movements of man. J Appl Physiol 1942;26:682-691. 19. Bloom PB, Ross DL, Stunkard AJ, et al. Gastric and duodenal motility, food intake and hunger measured in man during a 24-hour period. Dig Dis Sci 1970;15:719-725. 20. Baust W, Rohrwasser W. Das Verhalten von pH und Motilitat des Megens in naturlichen Schlaf des Menschen. Pflugers Arch 1969;305:229-240. 21. Yaryura-Tobias HA, Hutcheson JS, White L. Relationship between stages of sleep and gastric motility. Behav Neuropsychiatry 1970;2:22-24. 22. Fujitani Y, Hosogai M. Circadian rhythm of electrical activity and motility of the stomach in cats and their relation to sleep-wakefulness states. Tohoku J Exp Med 1983;141:275-285. 23. Hall WH, Orr WC, Stahl ML. Gastric function during sleep. In: Brooks FP, Evers PW, editors. Nerves and the gut. Thorofare, NJ: Slack; 1977. p. 495-502. 24. Dubois A, Van Eerdewegh P, Gardner JD. Gastric emptying and secretion in Zollinger-Ellison syndrome. J Clin Invest 1977;59: 255-263. 25. Orr WC, Dubois A, Stahl ML, et al. Gastric function during sleep (Abstract). Sleep Res 1978;7:72.
CHAPTER 27 • Gastrointestinal Physiology in Relation to Sleep 321
26. Goo RH, Moore JG, Greenburg E, et al. Circadian variation in gastric emptying of meals in humans. Gastroenterology 1987;93: 515-518. 27. Chen JZ, McCallum RW, Familoni BO. Validity of the cutaneous electrogastrogram. In: Chen JZ, McCallum RW, editors. Electrogastrography: principles and applications. New York: Raven Press; 1994. p. 103-125. 28. Chen JZ, McCallum RW, Smout AJPM, et al. Acquisition and analysis of electrogastrographic data. In: Chen JZ, McCallum RW, editors. Electrogastrography: principles and applications. New York: Raven Press; 1994. p. 3-30. 29. Chen JZ, McCallum RW, Lin Z. Comparison of three running spectral analysis methods. In: Chen JZ, McCallum RW, editors. Electrogastrography: principles and applications. New York: Raven Press; 1994. p. 75-99. 30. Orr WC, Crowell MD, Lin B, et al. Sleep and gastric function in irritable bowel syndrome: derailing the brain-gut axis. Gut 1997;41:390-393. 31. Elsenbruch S, Harnish MJ, Orr WC, et al. Disruption of normal gastric myoelectric functioning by sleep. Sleep 1999;22:453-458. 32. Johnson LF, DeMeester TR. Twenty-four-hour pH monitoring of the distal esophagus: a quantitative measure of gastroesophageal reflux. Am J Gastroenterol 1974;62:325-332. 33. DeMeester TR, Johnson LF, Joseph CJ, et al. Patterns of gastroesophageal reflux in health and disease. Ann Surg 1976;184: 459-470. 34. Orr WC, Johnson LF, Robinson MG. The effect of sleep on swallowing, esophageal peristalsis, and acid clearance. Gastroenterology 1984;86:814-819. 35. Orr WC, Robinson MG, Johnson LF. Acid clearing during sleep in patients with esophagitis and controls. Dig Dis Sci 1981;26:423. 36. Dent J, Dodds WJ, Friedman RH, et al. Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects. J Clin Invest 1980;65:256-257. 37. Dickman R, Shapiro M, Malagon IB, et al. Assessment of 24-h oesophageal pH monitoring should be divided to awake and asleep rather than upright and supine time periods. Neurogastroenterol Motil 2007;19:709-715. 38. Helm JF, Dodds WJ, Hogan WJ, et al. Acid neutralizing capacity of human saliva. Gastroenterology 1982;83:69-74. 39. Schneyer LH, Pigman W, Hanahan L, et al. Rate of flow of human parotid, sublingual, and submaxillary secretions during sleep. J Dent Res 1956;35:109-114. 40. Lear CSC, Flanagan JB Jr, Moorees CFA. The frequency of deglutition in man. Arch Oral Biol 1965;10:83-96. 41. Lichter J, Muir RC. The pattern of swallowing during sleep. Electroencephalogr Clin Neurophysiol 1975;38:427-432. 42. Anderson CA, Dick TE, Orem J. Swallowing in sleep and wakefulness in adult cats. Sleep 1995;18:325-329. 43. Castiglione F, Emde C, Armstrong D, et al. Nocturnal oesophageal motor activity is dependent on sleep stage. Gut 1993;34:16531659. 44. Bajaj JS, Bajaj S, Dua KS, et al. Influence of sleep stages on esophagoupper esophageal sphincter contractile reflex and secondary esophageal peristalsis. Gastroenterology 2006:130:17-25. 45. Armstrong D, Emde C, Bumm R, et al. Twenty-four-hour pattern of esophageal motility in asymptomatic volunteers. Dig Dis Sci 1990;35:1190-1197. 46. Smout AJPM, Breedijk M, van der Zouw C, et al. Physiological gastroesophageal reflux and esophageal motor activity studied with a new system for 24-hour recording and automated analysis. Dig Dis Sci 1989;34:372-378. 47 Freidin N, Fisher MJ, Taylor W, et al. Sleep and nocturnal acid reflux in normal subjects and patients with reflux oesophagitis. Gut 1991;32:1275-1279. 48. Penzel T, Becker HR, Brandenburg U, et al. Arousal in patients with gastro-oesophageal reflux and sleep apnoea. Eur Respir J 1999; 14:1266-1270. 49. Kahrilas PJ, Dodds WJ, Dent J, et al. Effect of sleep, spontaneous gastroesophageal reflux, and a meal on upper esophageal sphincter pressure in normal human volunteers. Gastroenterology 1987;92: 466-467. 50. Metcalf AM, Dozois RR, Kelly KA, et al. Ileal J pouch-anal anastomosis: clinical outcome. Ann Surg 1985;202:735-739. 51. Cannon WB. The movements of the intestine studied by means of the roentgen rays. Am J Physiol 1902;6:275-276.
52. Barcroft J, Robinson CS. A study of some factors influencing intestinal movements. Am J Physiol 1929;67:211-220. 53. Douglas DM, Mann FG. An experimental study of the rhythmic contractions in the small intestine of the dog. Am J Dig Dis 1977;6:318-322. 54. Hines LE, Mead HCA. Peristalsis in a loop of small intestine. Arch Intern Med 1926;38:536-543. 55. Soffer EE, Adrian TE, Launspach J, et al. Meal-induced secretion of gastrointestinal regulatory peptides is not affected by sleep. Neurogastroenterol Motil 1997;9:7-12. 56. Archer L, Benson MJ, Green WJ, et al. Radiotelemetric measurement of normal human small bowel motor activity during prolonged fasting. J Physiol 1979;296:53P. 57. Thompson DG, Wingate DL. Characterisation of interdigestive and digestive motor activity in the normal human jejunum (Abstract). Gut 1979;20:A943. 58. Ritchie HD, Thompson DG, Wingate DL. Diurnal variation in human jejunal fasting motor activity. In: Proceedings of the American Physiological Society. March 1980; p. 54-55. 59. Finch P, Ingram D, Henstridge J, et al. The relationship of sleep stage to the migrating gastrointestinal complex of man. In: Christensen J, editor. Gastrointestinal motility. New York: Raven Press; 1980. p. 261-265. 60. Kumar D, Wingate D, Ruckebusch Y. Circadian variation in the propagation velocity of the migrating motor complex. Gastroenterology 1986;91:926-930. 61. Kellow JE, Borody TJ, Phillips SF, et al. Human interdigestive motility: variations in patterns from esophagus to colon. Gastroenterology 1986;91:386-395. 62. Kumar D, Idzikowski C, Wingate DL, et al. Relationship between enteric migrating motor complex and the sleep cycle. Am J Physiol Gastrointest Liver Physiol 1990;259(6):G983-G990. 63. Kumar D, Soffer EE, Wingate DL, et al. Modulation of the duration of human postprandial motor activity by sleep. Am J Physiol 1989;256(5):G851-G855. 64. Wilson P, Perdikis G, Hinder RA, et al. Prolonged ambulatory antroduodenal manometry in humans. Am J Gastroenterol 1994; 89:1489-1495. 65. Wilmer A, Andrioli A, Coremans G, et al. Ambulatory small intestinal manometry. Detailed comparison of duodenal and jejunal motor activity in healthy man. Dig Dis Sci 1997;42:1618-1627. 66. Helm JD, Kramer P, MacDonald RM, et al. Changes in motility of the human small intestine during sleep. Gastroenterology 1948; 10:135-137. 67. Sadler HH, Orten AU. The complementary relationship between the emotional state and the function of the ileum in a human subject. Am J Psychiatry 1968;124:1377-1381. 68. Spire JP, Tassinari CA. Duodenal EMG activity during sleep. Electroencephalogr Clin Neurophysiol 1971;31:179-183. 69. Tassinari CA, Coccagna G, Mantovani M, et al. Duodenal EMG activity during sleep in man. In: Jovanovic UJ, editor. The nature of sleep. Stuttgart, Germany: Gustav Fischer Verlag; 1973. 70. Kellow JE, Gill RC, Wingate DL. Prolonged ambulant recordings of small bowel motility demonstrate abnormalities in the irritable bowel syndrome. Gastroenterology 1990;98:1208-1218. 71. Kellow JE, Phillips SF. Altered small bowel motility in irritable bowel syndrome is correlated with symptoms. Gastroenterology 1987;92:1885-1893. 72. Kumar D, Thompson PD, Wingate DL, et al. Abnormal REM sleep in the irritable bowel syndrome. Gastroenterology 1992; 103:12-17. 73. Alverez WC. Physiologic studies on the motor activities of the stomach and bowel in man. Am J Physiol 1920;88:658-660. 74. Kukorelli T, Juhasz G. Sleep induced by intestinal stimulation in cats. Physiol Behav 1976;19:355-358. 75. Juhasz G, Kukorelli T. Modifications of visceral evoked potentials during sleep in cats. Act Nerv Super (Praha) 1977;19:212-214. 76. Rubenstein EH, Sonnenschein RR. Sleep cycles and feeding behavior in the cat: role of gastrointestinal hormones. Acta Cient Venez 1971;22:125-128. 77. Pigarev IN. Neurons of visual cortex respond to visceral stimulation during slow wave sleep. Neuroscience 1994;62:1237-1243. 78. Stahl ML, Orr WC, Bollinger C. Postprandial sleepiness: objective documentation via polysomnography. Sleep 1983;6:29-35. 79. Orr WC, Shadid G, Harnish MJ, et al. Meal composition and its effect on postprandial sleepiness. Physiol Behav 1997;62:709-712.
322 PART I / Section 4 • Physiology in Sleep 80. Adler HF, Atkinson AJ, Ivy AC. A study of the motility of the human colon: an explanation of dyssynergia of the colon, or of the unstable colon. Am J Dig Dis 1941;8:197-202. 81. Rosenblum MJ, Cummins AJ. The effect of sleep and of Amytal on the motor activity of the human sigmoid colon. Gastroenterology 1954;27:445-450. 82. Narducci F, Bassotti G, Gaburri M, et al. Twenty four hour manometric recording of colonic motor activity in healthy man. Gut 1987;28:17-25. 83. Furukawa V, Cook IJ, Panagopoulos V, et al. Relationship between sleep patterns and human colonic motor patterns. Gasteroenerology 1994;107:1372-1381. 84. Kerlin P, Zinsmeister A, Phillips S. Motor responses to food of the ileum, proximal colon, and distal colon of healthy humans. Gastroenterology 1983;84:762-770. 85. Posey EL, Bargen JA. Observations of normal and abnormal human intestinal motor function. Am J Med Sci 1951;221:10-20. 86. Frexinos J, Bueno L, Fioramonti J. Diurnal changes in myoelectric spiking activity of the human colon. Gastroenterology 1985;88: 1104-1110. 87. Steadman CJ, Phillips SF, Camilleri M, et al. Variation of muscle tone in the human colon. Gastroenterology 1991;101:373-381. 88. Bassotti G, Bucaneve G, Betti C, et al. Sudden awakening from sleep: effects on proximal and distal colonic contractile activity in humans. Eur J Gastroenterol Hepatol 1990;2:475-478.
89. Floyd WF, Walls EW. Electromyography of the sphincter and externus in man. J Physiol 1953;122:599-609. 90. Orkin BA, Hanson RB, Kelly KA, et al. Human anal motility while fasting, after feeding, and during sleep. Gastroenterology 1991;100: 1016-1023. 91. Ronholt C, Rasmussen O, Christiansen J. Ambulatory manometric recording of anorectal activity. Dis Colon Rectum 1999;12: 1551-1559. 92. Whitehead WE, Orr WC, Engel BT, et al. External anal sphincter response to rectal distention: learned response or reflex. Psychophysiology 1981;19:57-62. 93. Kumar D, Waldron D, Williams NS, et al. Prolonged anorectal manometry and external anal sphincter electromyography in ambulant human subjects. Dig Dis Sci 1990;35:641-648. 94. Rao SS, Welcher K. Periodic rectal motor activity: the intrinsic colonic gatekeeper? Am J Gastroenterol 1996;91:890-897. 95. Ferrara A, Pemberton JH, Levin KE, et al. Relationship between anal canal tone and rectal motor activity. Dis Colon Rectum 1993; 36:337-342. 96. Enck P, Eggers E, Koletzko S, et al. Spontaneous variation of anal “resting” pressure in healthy humans. Am J Physiol 1991;261: G823-G826. 97. Baccari BC. Orexins and gastrointestinal functions. Curr Protein Pept Sci 2010;11:148-155.
Body Temperature, Sleep, and Hibernation Kurt Kräuchi and Tom de Boer Abstract The human sleep–wake cycle is usually tightly coupled to the circadian time course of core body temperature. The circadian regulation of heat loss in the evening, via distal skin regions, is intimately associated with sleepiness and the ease to fall asleep, whereas the homeostatic increase in sleep pressure does not influence the thermoregulatory system. The rise in heat loss and reduction in heat production during lying down and relaxing behavior before sleep is hypothesized to be part of the role of sleep as a mechanism for energy conservation and may be a remnant of our evolutionary past. After sleep initiation, non–rapid eye movement (NREM) sleep to rapid eye movement (REM) sleep cycle fluctuations seem to have minor thermoregulatory functions, especially in humans. From experimental data obtained in humans and rodents, it can be concluded that warming can increase sleep propensity, sleep consolidation, and the duration of SWS (slow-wave sleep). In contrast, the effects of cooling on sleep are not yet sufficiently studied. More systematic investigations applying
INTRODUCTION The objective of this chapter is to cover the physiology of the relationship between the thermoregulatory system and the sleep regulatory system. Both are driven, independently, by two interacting physiological principles, homeostasis and circadian regulation. The chapter is divided in 3 main sections: 1) a brief introduction into the circadian regulation of core body temperature (CBT); 2) the interaction of sleep and thermoregulatory mechanisms; 3) hibernation, a special condition displayed by a limited amount of mammalian species. Animals increase survival by residing in a safe sleeping site, and have used sleep to maximize energy savings by reducing body and brain energy consumption and to conduct a variety of recuperative processes.1,2 Knowledge about thermophysiology and its relation to sleep leads to the hope that temperature related interventions can alleviate sleep disturbances and be helpful to cure certain aspects of sleep and alertness problems in the general population. A vast amount of knowledge is found in the literature on the variability in rest–sleep states and on thermophysiology across the animal kingdom.1,2 In order to limit the scope of this chapter, only findings from humans, rats, ground squirrels, and hamsters have been reviewed. CIRCADIAN REGULATION OF CORE BODY TEMPERATURE Fifty years ago, Aschoff3 showed that the human body consists of two thermophysiological compartments, the heat producing, homeothermic core, and the heat-loss regulating, poikilothermic shell. The size of the latter is largely dependent on environmental temperature. In a
Chapter
28
different temperature levels, particularly in the range where thermoregulation is achieved solely by vasomotor responses (the thermoneutral zone), are needed to develop applicable thermal therapeutic strategies for sleep disturbances. From anatomical and neurophysiological studies it has become clear that the preoptic-anterior-hypothalamus (POAH) is the main integrator of sleep and thermoregulatory information. It receives input from brain areas involved in circadian and sleep–wake regulation, and skin and brain areas recording body and environmental temperature. The POAH integrates this information and influences vigilance states and body temperature in response to that input. The torpid state, particularly of those animals that display daily torpor, may be a valuable model to investigate the relationship between thermoregulation and sleep. During daily torpor, the animals seem to apply similar physiological processes as occur in humans during normal entrance into sleep, but in a more extreme way, providing an excellent opportunity to investigate these processes in detail.
warm environment the shell is small, in a cool environment large, and thus acts as a buffer to protect the core from dangerous cooling. All peripheral tissues such as fat, skin, and in particular skeletal muscles of the legs and arms can contribute substantially to the size of the shell, provided that peripheral blood flow is low. Therefore, rates of blood flow through muscles and skin are the main determinants of shell size variability and hence of peripheral insulation. The distal skin regions, in particular fingers and toes, are our main thermoeffectors to lose body heat as they possess the physical and physiological properties to best serve the function of heat loss. They have ideal surface shapes (round, small radius) for good heat transfer to the environment—the surface-to-volume coefficient increases from proximal to distal skin sites. Therefore, the distal skin temperatures provide a good measure of the shell size. CBT comprises the temperature of the brain and the abdominal cavity, including inner organs (e.g., liver, heart, kidney).3 In most placental mammals CBT is regulated around 37° C, whereas the brain is the main target for homeothermy allowing control of all behavioral and physiological processes over a broad environmental temperature range. A detailed description of the thermoregulatory system can be found elsewhere.4 CBT is regulated between thermoeffector thresholds, which are subject to circadian oscillations.5 Circadian rhythms in mammals are generated by the self-sustaining central pacemaker localized in the suprachiasmatic nuclei (SCN) of the hypothalamus and are usually entrained to the 24-hour solar day mainly by the synchronizer light.6 A rostral projection from the SCN to the preoptic-anteriorhypothalamus (POAH) conveys the circadian signal to the thermoregulatory system.6 The regulation of CBT results from the concerted action of the homeostatic and circadian 323
324 PART I / Section 4 • Physiology in Sleep
processes. In humans, the daily decline of CBT in the evening results from a regulated decline in the thermoregulatory thresholds of heat production and heat loss; the inverse happens in the morning. When heat production surpasses heat loss, body heat content increases, and vice versa. Approximately 70% to 90% of body heat content is located in the body core, depending on environmental temperature; therefore, changes in CBT reflect to a great extent changes in body heat content. Heat production and heat loss are modified by activities such as muscular exertion and fluid and food intake that are not randomly distributed over the circadian cycle. These behaviors induce so-called masking effects, and differentially modify the endogenous rhythm of CBT.7 In order to disentangle circadian from masking effects of an overt diurnal pattern, the constant routine (CR) protocol has been developed in humans.8 With this protocol it was shown that the time course of heat production precedes heat loss, and CBT varies as an intermediate resultant.8 Heat production and heat loss are not only separated in time but also in space in the body.3 Under resting conditions, about 70% of heat production depends on the metabolic activity of inner organs, whereas body heat loss is initiated via heat redistribution from the core to the shell through blood flow to the distal skin regions.3 Thermoregulatory distal skin blood flow is regulated by the autonomic nervous system via constriction or dilatation of arteriovenous anastomoses. These are shunts between arterioles and venules, exclusively found in distal skin regions (e.g., toes, fingers).3 When they are open, warm blood flows rapidly and directly from arterioles to the dermal venous plexus enabling an efficient heat exchange from the core to the distal skin. The exact neural process by which this regulation is achieved is still a matter of debate9; however, sympathetic nerve activity seems to be crucial for peripheral vasoconstriction. The endogenous time course of distal skin temperatures (hands and feet), measured during a CR, exhibits an inverse circadian rhythm in comparison with CBT, whereas the former is phase advanced by about 100 minutes8 (i.e., in the evening distal skin temperatures rise before CBT declines). The amplitude of distal skin temperatures rhythm is about three times larger than those of CBT.8,10 In contrast, temperatures of proximal skin regions (e.g., thigh, infraclavicular region, stomach, forehead) follow a parallel change to CBT and the amplitudes are of similar magnitude.8,10 This inverse relation between distal and proximal temperature rhythms reflects the differences in thermophysiological regulatory mechanisms as described above.3 The distal minus proximal skin temperature gradient (DPG) provides therefore a selective measure of distal skin blood flow, and hence body heat loss via the extremities.3 Nocturnal secretion of the pineal hormone melatonin, which is under control of the SCN, plays a crucial role in the endogenous downregulation of CBT in the evening.11 Administration of melatonin in the afternoon, when endogenous melatonin levels are low, provokes exactly the same thermophysiological effects as observed naturally in the evening.11 Whether melatonin induces distal vasodilatation in humans by acting directly on blood vessels receptors or indirectly via modulation of sympathetic nerve activity, or both remains to be determined.11 In addition,
both subjective ratings of sleepiness and level of activity in the electroencephalographic (EEG) theta and alpha range as an objective outcome of sleepiness–wake state, are increased.11 Moreover, it is noteworthy that the rise in melatonin secretion in the evening belongs to a wellorchestrated circadian physiological regulation controlled by the SCN, which in turn downregulates CBT, increases sleepiness, and promotes sleep.
RELATIONSHIP BETWEEN THE SLEEP REGULATORY AND THE THERMOREGULATORY SYSTEM The most evident explanation whether and why the sleep regulatory and thermoregulatory systems are interrelated is a teleological one: sleep is for energy conservation.2,12,13 All species sleep or rest when their energy expenditure is low. Rest or quiet wakefulness, is a prerequisite for sleep in all species.1,12,13 These observations represent the starting point of all energetic explanations why we sleep. Human sleep evolved from ancestral sleep and it is quite possible that earlier forms of sleep were linked to energy conservation in ancestors with a smaller body size. There are two mechanisms that enable sleep to conserve energy. One is that sleep reduces energy expenditure indirectly by reducing activity. This mechanism would also be active when animals only exhibit quiet wakefulness. Alternatively sleep induces an additional decline in energy expenditure below that accomplished by quiet wakefulness by a change in physiology. Human sleep is only accompanied by a modest decline in energy expenditure below the level of quiet waking.13-15 However, energy conservation may be particularly important in small animals and infants.2,13,16 Their high surface-to-body-mass ratio is ideal to dissipate heat and renders energy conservation achieved by sleep highly adaptive.13 When body size increases and sensory-motor systems mature in the course of infant development, a parallel decrease in sleep time occurs.2,16 In the following subsections, two lines of evidence will be presented to clarify the relationship between sleep and thermoregulatory systems: 1) at baseline thermal comfort condition; and 2) following various conditions such as circadian, temperature, sleep pressure changes. Furthermore, recent research has provided new insights into the relationship between thermoregulation and sleep on the basis of neuroanatomical studies showing significant interaction of the two systems. Co-variation of Sleep and Thermophysiological Variables Baseline Conditions In order to compare the sleep and thermoregulatory systems it is crucial to separate circadian from masking components of an overt diurnal pattern. This is much easier to accomplish in humans than in animals. In spite of this advantage, the most neglected factor in human research is the so-called lying down effect. A change from standing to supine body position induces redistribution of heat from the core to the periphery, thereby increasing skin temperatures, decreasing CBT, and in parallel increasing sleepiness.17 This effect lasts about 1 to 2 hours,17 and significantly confounds the endogenous time course of CBT in a
classical sleep recording protocol where lying down occurs about 0.5 hours before lights off. The temporal relationship between thermophysiological variables, heart rate, subjective ratings of sleepiness and salivary melatonin secretion under CR conditions before habitual bedtime and for the following sleep episode is summarized in Figure 28-1. The only thing that changed during this protocol was that the low intensity lights were switched off with the implicit permission to fall asleep. Before lights off the previously described endogenous pattern of CBT down regulation is visible. In the evening, heart rate (an indirect measure of intrasubject variation of heat production) declined first, followed by heat loss, and finally by a decrease in CBT. Subjective ratings of sleepiness increased in parallel with distal proximal gradient (DPG) and salivary melatonin levels. The proximal skin temperature exhibited a similar pattern as CBT. Immediately after lights off, and before sleep stage 2, distal and proximal skin temperature increased and heart rate declined.18 In addition, an increase in sweating rate is often observed, depending on CBT.19 The typical increase in distal skin temperature, as shown in Figure 28-1, is caused by heat redistribution from the core to the shell. Similar findings at sleep onset have been described in the lower leg.20 However, CBT exhibited only a slight but significant increase in the rate of change after lights off,3,21 leading to approximately 0.3° C lower CBT values during sleep compared to quiet wakefulness.22 In contrast to the fast changes in skin temperature, the decline in CBT is slow, which can be explained by the reduced cardiac output during sleep initiation impeding a faster heat loss during the sleep episode, under thermoneutral conditions.18 The magnitude of the decrease in CBT is negatively correlated with environmental temperature.23 A DPG of 0° C indicates that during sleep, the thermoregulatory shell has disappeared, therefore resembling a state similar to that of the human body in awake state in a warm environment (e.g., 35° C).3 Heat redistribution from the core to the shell is completed within approximately 1 hour after lights off. Such a completely relaxed one-compartment body is prone to a fast cooling when sleep occurs in a cool environment. In normal sleep environment, CBT is protected during sleep because humans and animals try to occupy a sleep berth in a comfortable thermal environment.13 When sleep is initiated outside the natural temporal niche by taking an afternoon nap, similar thermophysiological changes occur right after lights off and before the initiation of sleep stage 2.24 There are subjects, mostly women, exhibiting a proneness to cold hands and feet and, therefore, to a large shell.25,26 These subjects show a significant co-morbidity for prolonged sleep stage 2 onset latency (SOL2).25,26 In fact, it has been shown that subjects with sleep onset insomnia respond to a mild heating with reduced thermoregulatory heat loss from their fingers.27 After a sleep episode, transition to waking is accompanied by an inverse thermophysiological pattern.24 This period is named sleep inertia; after awakening it takes a certain time interval to recover all physiological and cognitive functions.24 During that time, a similar but inverse time course in distal vasoconstriction is observed.24 It is noteworthy and of clinical relevance that similar thermophysiological effects as seen during sleep initiation can be
CHAPTER 28 • Body Temperature, Sleep, and Hibernation 325
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–4
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Hours after lights off Figure 28-1 Time course of heart rate core body temperature (CBT), and its rate of change, salivary melatonin, sleepiness, distal and proximal skin temperatures, and the distal-proximal skin temperature gradient (DPG) in a baseline 7.5-hour constant routine followed by a 7.5-hour sleep period, yellow area. (Adapted from Kräuchi K, Cajochen C, Werth E, Wirz-Justice A. Functional link between distal vasodilation and sleeponset latency? Am J Physiol Regul Integr Comp Physiol 2000;278(3):R741-R748.) Continuously measured data are plotted in 30-minute bins. Mean values of N = 18 male subjects (± SEM). Subjective ratings of sleepiness: KSS, Karolinska sleepiness scale; MEL, melatonin; bpm, beats/min. Note: Distal and proximal skin temperatures exhibit inverse time course before lights off, but were nearly indistinguishable about 1 hour thereafter. Heart rate reflects the study protocol rhythm of one hourly food and water intake before lights off and declined sharply thereafter. Mean sleep onset latency: 12 minutes ± 4 minutes.
observed after administration of benzodiazepines28 and with certain relaxation techniques like yoga, autosuggestion of warmth, autogenic training, and meditation without falling asleep.3,28-30 These techniques induce a withdrawal in muscular and cutaneous sympathetic nerve activity, which leads to increased distal skin temperature and to a
37.1 37.0 36.9 36.8 36.7
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36.6 80 60 40 20 0 125
Slow-wave activity
reduction in heart rate, energy expenditure, and CBT.28,29 Therefore, distal vasodilatation followed by a drop in CBT appears to be a thermophysiological event, which is primarily related to relaxation occurring before sleep onset.31 Studies carried out with humans to describe changes in thermophysiological variables show that changes in CBT, proximal and distal skin temperature related to the NREM– REM sleep cycle are very small.32,33 Heart rate is clearly increased shortly before and during REM sleep, relative to NREM sleep, which is, however, reflected only in a minor increase in energy expenditure during REM sleep.15 Extensive studies on thermophysiological alterations regarding the NREM–REM sleep cycle, concluded that changes in brain heat production are practically not relevant for changes in brain temperature.34 To our knowledge, only one human study recorded brain temperature together with sleep-EEG data, but no significant systematic changes regarding the NREM–REM sleep cycle were found.35 One of the advantages of animal research is the parallel recording of body and brain temperature. In many small mammals (rabbit, rat, Djungarian hamster) NREM sleep is associated with a decrease in brain temperature, whereas REM sleep and waking are associated with an increase in brain temperature (Fig. 28-2).36,37 In an elegant study performed with rats it was shown that heat is redistributed across the body when vigilance states change.38 At the initiation of NREM sleep, the brain and intraperitoneal temperature decreased whereas the tail skin temperature increased. The opposite occurred at the transition from NREM sleep to awake. At transitions from NREM sleep to REM sleep, brain temperature rose slightly, whereas intraperitoneal and tail temperatures did not change. These data are in accordance with those obtained in humans. Heat is redistributed from the core to the shell at the onset of sleep. Humans thermoregulate by vasodilatation and vasoconstriction of blood vessels within the skin of extremities; in rats similar changes are observed in the tail. The main difference lies in the timing of the redistribution of heat relative to the onset of sleep and waking. In humans changes are visible several hours before sleep onset; in the rat the same changes occur at the immediate onset of sleep. This difference is probably related to the smaller body size and to the ultradian sleep– wake pattern in the rat that renders a time-lag of several hours to be nonfunctional. Applying a CR in rodents is not possible. However, on the basis of the relationship between brain temperature and vigilance states, it was possible to subtract the influence of vigilance state changes on brain temperature, rendering a mathematical CR.39 This study concluded that, in the rat, approximately 90% of the variance in brain temperature is caused by changes in vigilance. A recent study confirmed that vigilance state–related changes in brain temperature are independent of the functioning of the circadian clock because they remained intact after removing the SCN.40 Taken together, there are robust thermoregulatory effects induced by lying down and the relaxing sleep behavior, however, the NREM–REM sleep cycle seems to have minor thermoregulatory function in humans. The thermoregulatory mechanisms, which are active during the wake– sleep transition, redistribute heat from the core to the shell
Brain temperature
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100 75 50 25 0 0
10
20
30
40
Time (min) Figure 28-2 A 40-minute record of brain temperature measured at the parietal cortex, integrated EMG activity from the neck muscles, and EEG slow-wave activity (SWA, mean EEG power density between 0.75 Hz and 4.0 Hz), of a Djungarian hamster (Phodopus sungorus). Blue = waking, Red = NREM sleep, Green = REM sleep. Values are plotted for 8-second epochs. Note the decrease of brain temperature at the entrance into NREM sleep and the increase during REM sleep and waking.
and induce a decline in heart rate, energy expenditure,14,15 and CBT. Relaxing behavior before sleep belongs inseparably to sleep; therefore, these data are not in contradiction with the energy conservation hypothesis of sleep. The accompanying thermoregulatory effects in humans may be a remnant of their evolutionary past. Changed Circadian Conditions It has been observed that subjects living under normal conditions choose their bedtime (lights off) at the maximal rate of decrease in their CBT rhythm.41 However, when subjects are living on self-selected sleep–wake schedules in a time-free environment, bedtime is phase delayed close to the CBT minimum, which is an indication that the sleep– wake cycle and the circadian rhythm of CBT are separate but usually entrained (synchronized) oscillatory systems.42 Unfortunately, neither direct nor indirect measurements of heat loss and heat production were carried out in parallel in these studies. Therefore it is possible that CBT is not the crucial variable for sleep induction, but rather one of its determinants, that is, heat loss. Because heat loss seems to be closely linked to sleep initiation, it may be speculated that the circadian rhythm of heat loss is phase delayed under free-run conditions. The duration of sleep episodes was maximal when initiated at the time when CBT reaches its maximum and, at the opposite, minimal sleep lengths occurred when sleep was initiated during the rising phase of the CBT rhythm.16 There is also a reproducible and robust circadian rhythm in sleep onset latency to sleep stage 2 (SOL2), which is
closely related to the circadian CBT rhythm and thermoregulatory effects as described previously.43 In forced desynchrony studies (i.e., living on a scheduled 28-hour day including a 9.33- to 18.66-hour sleep–wake cycle) it was shown that SOL2 is longest at the circadian phase where CBT reaches its maximum, that is, 1.5 hours before CBT starts to decline and melatonin secretion rises.44 At this circadian phase, named the “wake-maintenance zone,”45 inner heat conduction is lowest as indicated by largest difference between CBT and distal skin temperature, as well by largest negative DPG values. Thereafter, SOL2 declines rapidly and is minimal around the time when CBT reaches its circadian trough, when inner heat conduction is largest (distal skin temperature is highest and the difference between CBT and distal skin temperature is lowest). However, it remains to be determined whether thermal interventions, like lower leg warming, at the wakemaintenance zone are successful to reduce SOL2, as melatonin administration was shown to do.46 Under most experimental conditions, REM sleep propensity exhibits a strong circadian pattern with a peak approximately 1 to 2 hours after CBT has reached its circadian minimum.44 The circadian rhythm of REM sleep propensity is closely phase locked with the circadian rhythm of CBT with a phase lag of 1 to 2 hours. Taken together, self-selected sleep timing, SOL2, REM sleep latency, REM sleep propensity, and sleep duration are closely associated with CBT. In spite of the fact that these variables are not fully in phase with CBT, which precludes a direct link to CBT, it is quite possible that one of the determinants of CBT (e.g., heat production, heat loss) is directly interrelated. It still remains to be established whether these rhythms are independently governed by the SCN or causally linked directly to measured thermophysiological outcomes. These correlative findings lead to the question of how sleep is affected by thermoregulatory challenges. Intervention Studies in Humans Effects of thermal interventions (heating or cooling) on sleep are not easy to investigate. Thermal intervention, either applied passively or actively by physical exercise, induces significant changes in skin temperatures and CBT.14,16,47,48 Not only is the intensity of a thermal intervention crucial, but also the skin region selected and the time of application. During sleep only passive thermal loads can be applied. It has been shown that sleep reduces the thresholds and gains of the autonomic temperature defense mechanisms and expands the interthreshold zone (the temperature range for activation of metabolic heat production or evaporative heat loss).16,48,49 These threshold changes are modest in slow-wave sleep (SWS), but much stronger in REM sleep.16,48 As a consequence, CBT and skin temperatures are more sensitive to changes in environmental temperature. Maximal total sleep time (TST) is found in the thermoneutral zone (the range of ambient temperature at which temperature regulation is achieved solely by vasomotor responses), whereas REM sleep is more vulnerable to thermal interventions than is SWS.16,48 Too powerful of thermal interventions induce arousals and awakenings, which in turn can change thermoregulatory effects, for example,
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elevating CBT.48 When a thermal load is given repeatedly, the thermoregulatory system can adapt and the effects on sleep are changed; for example, the arousing effects are reduced. Aborigines in the Central Australian desert and nomadic Lapps in Arctic Finland were experiencing comparable degrees of cold exposure during the night and both showed lower thermoregulatory thresholds for shivering before modern technology arrived.50,51 As a consequence, CBT was more reduced during sleep and undisturbed sleep occurred at a lower environmental temperature. Many modalities of thermal interventions on sleep are understudied. In addition, the impact of thermal interventions on the sleep of normal and sleep-disturbed subjects may differ. Changing Temperatures It has been shown that ambient temperature, especially in combination with high humidity, is of importance for both quantity and quality of sleep.48 When sleep occurs in warm environmental temperature (between 31° C and 38° C) duration of wakefulness increases and, at the opposite the duration of REM sleep and NREM sleep decreases.14,16,47,48 Also cold exposure (21° C) induced more awakenings, less time in sleep stage 2 and less TST; however, without affecting duration of other sleep stages, marked thermoregulatory effects were induced under such manipulations.14 The decrease in CBT observed during the night episode was larger at 21° C compared to a thermoneutral 29° C condition. During REM sleep, forehead temperature and oxygen consumption increased and feet temperature decreased in comparison to SWS with cold exposure. Therefore, cold-exposed humans may not exhibit a complete inhibition of thermoregulation during REM sleep as it has been observed in small mammals. When during sleep the ambient temperature is gradually decreased, an earlier CBT nadir and an advanced peak for REM sleep propensity was obtained.52 It was also shown that duration of sleep stage 4 is increased when the normal nocturnal decrease of CBT is augmented by a constant and mild reduction in ambient temperature, in spite of decreased sleep efficiency.52 Similarly, after a reduction in ambient temperature by 2° C during sleep, it was observed that the increase in SWS occurred with the rise in slowwave activity (SWA; EEG power density between ~1 to 4 Hz) without any change in sleep efficiency and reduced amount of REM sleep.53 The thermal manipulation reduced not only leg skin temperature but also CBT and heart rate. Taken together, the augmentation of heat loss leading to reduced CBT during sleep seems to be the crucial variable for increased SWS. In humans, body heat content and hence CBT can also be effectively manipulated by body immersion in warm or cold baths. For instance, due to rapid conductive heat loss in a cold bath, CBT falls faster compared with that observed in air at the same temperature. Rewarming of the cool shell after cool bathing leads to a characteristic after-drop in CBT.54 Several studies showed effects of positive heat load on sleep;14,47,48 however, no study examined effects on sleep after a cold bath. In general, passive body heating (40° to 43° C for 30 to 90 minutes; CBT increase: 1.4° to 2.6° C) has a positive effect on many aspects of sleep in healthy young adults and in older and
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sleep-disturbed subjects. It was found that warm bathing in the evening shortened sleep onset latency, enhanced SWS duration, and sometimes reduced REM sleep duration. The increase in SWS, however, is not dependent on a reduction in REM sleep. Bathing performed in the morning or early afternoon had no effect on sleep architecture.14,47 In principle, actual levels of CBT at sleep onset or the decline in CBT afterward could be related to the amount of SWS after warm bathing.14,47 Additionally, a phase delay of the CBT nadir during the night sleep episode has been described after evening hot bathing, which correlates with increased SWS.55 All these CBT characteristics could be intercorrelated (i.e., directly after a positive heat load the velocity of CBT decline is larger, the CBT level is elevated before sleep onset and the overt CBT nadir during sleep may be delayed). However, the phase shifting effects of passive heat loads in humans have not been studied systematically. Variables other than CBT, for instance skin temperature, may play a role. The available findings are inconsistent due to the diversity in study designs and methodology and the low statistical power of many studies. In one study, hot full-body bathing and hot foot bathing were applied 35 minutes before lights off.56 Only during full-body bathing did CBT increase (by about 1° C); however, both conditions increased mean skin temperatures and reduced sleep onset latency and movement during sleep. These findings indicate that elevated skin temperature is crucial for a rapid onset of sleep and not changes in CBT. Older sleepdisturbed subjects respond to hot foot bathing with slightly reduced sleep onset latency (SOL) to sleep stage 1 and significantly decreased wakefulness in the second NREM sleep period.57 In these older subjects, not only DPG but also CBT was elevated after hot foot bathing during the first hour of sleep. Of clinical relevance is the data describing that the use of electric heat blankets throughout the night reduced REMS duration and TST,58 suggesting that the heat load exerted through the blanket is a too-strong thermal intervention that disturbs sleep rather than supports sleep. In a series of experiments, the effects of tiny changes in skin temperatures of only 0.4° to 2° C within the thermal comfort zone, without significantly altering CBT, were investigated on several sleep parameters.59 It was demonstrated that intermittent elevation in skin temperature during the sleep episode suppresses nocturnal awakenings and triggers shifts to deeper sleep in young and older healthy subjects and in insomniac patients.59 Whole-night studies are needed to confirm that the sleep-depth enhancing effect of mild skin warming can indeed be sustained. Nevertheless, these findings support the importance of skin temperatures, primarily proximal skin temperatures (including the trunk) but also more distal skin regions, such as legs and arms, for these effects. Other studies revealed that subtle skin temperature warming was associated with a faster onset of sleep in young and older subjects and in older insomniac and narcoleptic patients.59-61 At present stage, it cannot be concluded which thermophysiological correlate represents the causal factor to increase SWS and reduce SOL. Nevertheless heat load before sleep seems to increase the propensity of SWS.
Intense exercise is a manipulation that can also raise CBT by 2° C or more. Subsequently, CBT declines as a result of the thermoregulatory heat loss drive via increased vasodilatation and sweating. A number of reproducible exercise-induced changes on sleep have been identified after exercise in the evening: shortened SOL, increased TST and SWS, longer REM sleep onset latency and less REM sleep.62,63 Exercise exhibits negative effects on sleep when performed close to the start of sleep— the optimal temporal positioning of physical activity is thought to be between 4 and 8 hours before bedtime.63 Chronic exercise studies have not provided much stringent evidence of a sleep promoting effect. Conversely, with reduced exercise load in trained athletes, SWS and REM sleep onset latency were reduced, and REM sleep duration and SOL were increased.64 Taken together, after intense exercise, sleep appears to commence faster and is deeper. In conclusion, warm distal skin temperatures either induced by endogenous circadian heat loss regulation in the evening, homeostatic downregulation of CBT after passive and active heat load, or selective skin warming predisposes a rapid onset of sleep. More sophisticated studies with respect to skin regions are necessary to show which areas (e.g., shoulder, stomach, legs, hands, or feet) should be warmed to exhibit the strongest effects on sleep initiation and sleep architecture. The increase in skin temperatures could be the causal factor for the acceleration of sleep onset and the increase of SWS. Further studies must investigate the optimal time-interval between thermal intervention and bedtime and which physiological mechanisms are involved in the observed effects. It is possible that thermal afferents provide a signal for the sleep-inducing brain regions in the hypothalamus.28,65 Changing Sleep Pressure The studies of sleep deprivation effects on the thermoregulatory system cannot be understood without considering the circadian time at which the deprivation is occurring. All thermophysiological variables undergo significant circadian changes. Additionally, the effects of an experimental overnight sleep deprivation on the thermoregulatory system have to be controlled for changes in body position, locomotor activity, food intake, and light intensity. Using the CR-protocol, it was shown that a 40-hour total sleep deprivation does not change CBT, distal and proximal skin temperatures, heart rate, and energy expenditure in spite of the huge increase in sleepiness.8,10 A comparison with a sleep-pressure–reducing protocol, including regularly scheduled naps, provided evidence that changes in sleep pressure do not influence the thermoregulatory system.10 Additionally, the nocturnal 8-hour sleep episodes before and after the two protocols revealed that CBT and distal and proximal skin temperatures also did not differ even though a large difference in SWA was observed.10 Taken together, the circadian modulation of sleepiness is primarily related to the circadian regulation of distal vasodilatation and hence to heat loss and circadian CBT reduction, whereas the homeostatic regulated increase of sleep pressure does not influence the thermoregulatory system,18 as earlier suggested.66 To be more conclusive, longer sleep deprivations may need to be performed to test whether the
thermoregulatory system remains independent of sleep pressure. Intervention Studies in Rodents Changing Temperature The main interventions applied in rodents are manipulation of ambient temperature and manipulation of brain temperature. In the rat a general decrease in the daily percentage of REM sleep was seen when ambient temperature decreased,38,67 indicating that REM sleep is very sensitive to changes in temperature and is incompatible with low ambient temperature. Djungarian hamsters enter REM sleep easier when brain temperature is relatively low,68 but probably also in this species REM sleep will disappear first when ambient temperature is lowered. In this context, low ambient temperatures are applied as a tool to investigate REM sleep regulatory mechanisms.69,70 In general the impression exists that increasing ambient temperature increases sleep pressure. When ambient temperature was increased to 33° to 35° C for 3 hours, which resulted in a brain temperature of approximately 40° C, subsequent NREM sleep displayed more slow waves compared to sleep-matched controls.71 The amount of REM sleep did not change compared to controls, and brain temperature was significantly decreased in the first 5 hours of recovery. Under these conditions animals slept less during the heating compared to baseline, indicating that ambient temperatures that are too high override sleep demand. In two separate experiments where ambient temperature was increased to 30° to 32° C for 24 hours, cortical brain temperature was significantly increased by 0.3° to 1.0° C, but hypothalamic temperature did not change.72,73 This treatment resulted in one case in increased NREM sleep, and in both experiments it resulted in an increase in SWA in NREM sleep in the dark period. These data indicate that changes in sleep can be induced by increasing ambient temperature without changing hypothalamic temperature. Another approach is heating the POAH and increasing hypothalamic brain temperature locally, without changing ambient temperature. This approach resulted in increased SWA and NREM sleep during 1 hour of warming (1.0° C above baseline) in cats.74 One hour of cooling (2.0° C below baseline) did not elicit a response. The data suggest that an acute increase in ambient or brain temperature (0.3° to 1.0° C) can increase NREM sleep and possibly can increase the occurrence of SWA in the NREM sleep EEG. Changing Sleep Pressure During sleep deprivation, brain temperature is higher compared to baseline, and subsequent recovery is characterized by a decrease in brain temperature below baseline and an increase in NREM sleep and SWA in NREM sleep.37,73,75,76 This result was interpreted as a heat load incurred during the sleep deprivation which is subsequently recovered by increasing NREM sleep and SWA.66 One of the clear results obtained from these experiments is a negative correlation between the amount of NREM sleep and the level of brain temperature.68,75 There is, however, no significant correlation between SWA in NREM sleep and brain temperature,68,75 ruling out the
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possibility that the depth of sleep determines brain temperature directly. Moreover, in Djungarian hamsters, which are well adapted to a short winter photoperiod when brain temperature is 1° C below summer photoperiod brain temperature, recovery sleep after sleep deprivation is accompanied by an increase in brain temperature.68 This is in contrast with the long photoperiod where sleep deprivation is followed by a decrease in brain temperature.37,68 A correlation between SWA and brain temperature, combining these data, supported the notion that brain temperature after sleep deprivation is set to the same temperature in both conditions,68 suggesting that there may be an optimal temperature for high-amplitude slow waves in NREM sleep during recovery. Two experiments that used rats and raised ambient temperature to 32° C during a sleep deprivation of 2.5 hours73 or 3 hours76 did not result in similar outcomes. Short lasting increases in SWA and NREM sleep were observed after 2.5 hours of sleep deprivation,73 but not after 3 hours of sleep deprivation.76 In contrast, a short-lasting increase in REM sleep was observed after the 3-hour sleep deprivation,76 but not after the 2.5-hour sleep deprivation.73 It can be questioned whether consistent results can be obtained in the rat with these short sleep deprivation durations. Probably a more systematic approach, scanning different ambient temperatures with longer sleep deprivations, is needed to resolve these differences. Brain Temperature, EEG, and Thermosensitive Neurons The EEG is influenced by changes in brain temperature as well. From analysis of the EEG of the Djungarian hamster during spontaneous entrance into the hypothermic state torpor (see section on hibernation), and from experiments where either rats, cats, or humans were cooled, it was found that the amplitude and frequency of the EEG changes when brain temperature decreases. The amplitude becomes smaller, and prominent frequencies in the EEG slow down with decreasing temperature.77 This relation between EEG frequency and brain temperature was shown to follow a Q10 of approximately 2.5,78 which means that the frequency became 2.5 times slower when brain temperature decreased by 10° C. Under influence of euthermic changes this effect is relatively small, but it can be significant even for frequencies below 5 Hz.77 Frequencies like the theta rhythm (6 to 9 Hz) in rodents77,79 and frequencies above 10 Hz77 are significantly influenced by these daily changes in brain temperature. Measuring the electrical activity of neurons in the POAH revealed the activity of two distinct types of neurons that either increase or decrease firing rate when brain temperature increases. The latter are called “cold sensitive” neurons, whereas the first group are called “warm sensitive” neurons. A biochemical process (i.e., neuronal firing) that slows down when temperature is increased is quite unique; therefore, cold sensitive neurons, when observed, can be considered genuine. In contrast, a biochemical process that speeds up when temperature is increased is quite normal and has been theoretically explained at the end of the 19th century.77 Many processes, ranging from the firing rate of SCN neurons80 and the frequency of prominent EEG waves77 to muscle
330 PART I / Section 4 • Physiology in Sleep
contraction,81 double or triple when temperature is increased by 10° C (2 < Q10 < 3). To identify warm sensitive neurons, two definitions are applied in the literature. The first determines that an increase in firing rate needs to be more than double when temperature is increased by 10° C (Q10 > 2).82 The second says that the increase in firing rate needs to be more than 0.8 impulses/sec/1° C warming.83 Both are insufficient. The definition of a Q10 above 2 ignores the fact that most biochemical processes have a Q10 somewhere between 2 and 3. Therefore, Q10 of at least 3 needs to be reached before one can be relatively sure that the change in firing rate can be distinguished from the passive biochemical response of the temperature insensitive neurons. With the second definition, fast firing neurons have a relatively large chance to be included even when they follow the passive biochemical Q10 rule of doubling firing rate when temperature is increased by 10° C. Nevertheless, there are genuine warm sensitive neurons in the POAH84 and other brain areas, like the diagonal band.85 The firing rate of warm and cold sensitive neurons in the POAH is known to be vigilance-state–dependent. Most warm sensitive neurons increase their activity at the onset of NREM sleep. On the other hand, most cold sensitive neurons are more active during waking.84,85 Those results emphasize the importance of polysomnographic recordings to be able to disentangle the vigilancestate–related changes in firing rate from temperature related changes.86 Noradrenergic afferents from sleep– wake regulatory centers like the locus coeruleus and the lateral tegmental system are also involved in the change in firing rate observed in the POAH.87 The changes in firing rate of the ensemble of neurons are thought to shape the sleep–wake response to thermoregulatory demands encountered by the animal.
HIBERNATION The hypothermic state observed during the hibernation season may be a valuable model to investigate the relationship between thermoregulation and sleep and may generate relevant data to the understanding of human physiology. Most hibernating mammals are small and weigh between 10 grams and 1000 grams.88 During the hibernation season these animals spend a considerable amount of time in a torpid state with body temperature below euthermic temperatures (i.e., below 30° to 32° C). This sustained hypothermic state is entered voluntarily and can be terminated by the animal. Body temperature can drop by more than 35° C,89 and the metabolic rate is only a fraction of that during normothermia.90 In hibernators the torpid state can last for several days or weeks. A group of smaller mammals with body weights between 5 grams and 50 grams displays daily torpor in which body temperature is dropped for a couple of hours during the rest phase, but returns to euthermia during the active phase.88 Both hibernation and daily torpor result in substantial energy savings91,92 and are therefore considered to be adaptive mechanisms that permit the conservation of energy during unfavorable environmental conditions. Whether circadian rhythms continue during hibernation is unclear. In hibernating ground squirrels, rest–activity
rhythms only slowly reappeared a couple of days after termination of torpor bouts, and this correlated with the number of vasopressin containing neurons in the SCN.93 Also sleep–wake distribution in hibernating ground squirrels did not show a circadian modulation.94 In contrast, responses to, for instance, sleep deprivation, temperature changes, and other homeostatic regulatory processes, are still functioning.95-99 Under certain circumstances a small circadian modulation of body temperature can be observed during hibernation;100 however, we may conclude that the contribution of the circadian clock is reduced whereas homeostatic regulation seems to be virtually identical to its regulation outside the hibernation season. Thermoregulation and Metabolic Rate Reduction The mechanism by which the animals reach the reduction in metabolic rate is still controversial. The traditional view was that metabolic rate falls as body temperature decreased at torpor entry. The Q10 of metabolic rate between euthermia and torpor is often close to 2, which is typical for biochemical processes;77 therefore, the reduction in metabolic rate seems to be explained solely by the temperature effect on biochemical processes in the body.101,102 However, Q10 values above 3 for metabolic rate have been observed during torpor entry and during torpor at relatively high temperatures. It was proposed that an additional physiological inhibition must be involved in the reduction of metabolic rate.103,104 Metabolic rate is down regulated before torpor entry, and the decrease in body temperature is the consequence and not the cause of the metabolic rate reduction.105-107 As an alternative hypothesis it was proposed that metabolic rate is a function of the difference between ambient temperature and body temperature, similar as during euthermia.105 As this difference is generally very small during torpor, metabolic rate is equally reduced. Inhibition of metabolic rate during torpor may be caused by reduced pH, which slows down metabolic processes.108 In hibernating ground squirrels the respiratory quotient (RQ) drops during entrance into torpor and rises during subsequent arousal, suggesting CO2 storage, which may result in decreased pH. In contrast, in Djungarian hamsters, which display daily torpor, RQ increases during entrance into torpor and decreases before emergence from torpor. Changes in enzyme activity are other candidates for metabolic rate reduction. Mitochondrial respiration is reduced by 50% during torpor in hibernating ground squirrels, compared with euthermic individuals. The previous data support the notion that the mechanism of metabolic rate reduction differs between hibernators and animals that use daily torpor.108 The reduction in metabolic rate in animals who display daily torpor is largely determined by the decrease in body temperature, whereas hibernators seem to apply some kind of extra reduction in metabolic rate. For some essential, but unknown reason, deep torpor in hibernators is interrupted on a regular basis by short (<24 hours) euthermic periods.109,110 Above 0° C body temperature, torpor bout length correlates negatively with ambient temperature,111 and metabolic rate depends on ambient temperature and, therefore, body temperature. The timing of the euthermic period (also called arousal)
correlates with the ambient temperature and the metabolic rate of the animal during the preceding hibernation bout. More recent experiments indicate that the arousal is probably not induced by a process accumulating in the course of a multiday torpor bout, but that there exists a separate arousal process of which the onset is more susceptible at higher body or ambient temperatures.112 Although the mechanism of the arousal is not known, it appears to be totally endogenous in its origin. The question of the reason for the arousal is important. The function of hibernation is energy conservation, and energy expenditure during the hibernation season is reduced to less than 15% of what the animals would have expended if they remained euthermic throughout the winter season.90 However, there is still room for improvement, because the energetic costs of the periodic arousals constitute 64% to 90% of the total energy expenditure during the hibernation season.90,113,114 It has been proposed that arousals are required to eliminate metabolic waste products, to replenish blood glucose levels, or to restore cellular electrolyte balance. All these hypothesis have not survived critical experimental testing.115 Based on EEG observations it was proposed that animals terminate torpor and return to euthermia to restore a sleep debt.116,117 Non-REM sleep was deepest at the beginning of a euthermic period and most of the euthermic period was spent in sleep. The putative restorative function of NREM sleep was thought to be incompatible with torpor. Torpor and Sleep Animals in torpor appear to be sleeping. They remain in their nest in a sleeplike posture with elevated arousal thresholds. Based on several behavioral and physiological findings it is generally accepted that torpor has evolved as an extension of sleep. Analysis of the EEG when animals enter torpor shows that rodents are mainly in NREM sleep and that REM sleep is reduced or not present.118,119 Recordings of neuronal activity in the hypothalamus of hibernators with brain temperatures between 10° and 20° C indicate that these animals keep alternating between long NREM sleep bouts and short waking bouts.120 Below 10° C it is not possible to determine vigilance states with electrophysiological methods.120 These findings supported the hypothesis that NREM sleep is an adaptive behavior for energy conservation, which function is strengthened during torpor.12,92,121 However, when the animals subsequently emerge from torpor they immediately enter deep NREM sleep irrespective of whether the animals emerge from deep hibernation116,117 or daily torpor.119 This observation suggested that during deep torpor the function of sleep cannot be fulfilled completely, and animals have to return to euthermia to recover from a sleep deprivation incurred during the hypothermic state. In the Djungarian hamster, the hypothesis was confirmed by combining daily torpor with sleep deprivation experiments.95 In contrast, similar experiments in hibernating ground squirrels resulted in rejection of the sleep deprivation hypothesis.97,98 There appear to be fundamental differences between animals who display daily torpor and hibernating animals that display multiple-day torpor bouts. The mechanism of metabolic rate reduction seems to differ.108 Another fun-
CHAPTER 28 • Body Temperature, Sleep, and Hibernation 331
damental difference between the two groups of animals is the effect of torpor on subsequent sleep. In hibernating animals who display deep torpor, such as ground squirrels or hamsters, regulation of temperature and sleep seems to be reduced to a level that currently cannot be measured reliably. In contrast, animals who display daily torpor appear to make use of the same processes, although applied in an extreme way, which reduces body temperature at the onset of sleep in humans. This latter similarity may provide an opportunity to investigate the relationship between sleep and body temperature with much larger variability.
❖ Clinical Pearl Humans with cold hands and feet are predisposed for difficulties initiating sleep. Better knowledge about sleep thermophysiology may help to develop evidence-based thermal interventions to alleviate sleep disturbances and to manage certain aspects of sleep and alertness problems in the general population. Therefore, to assess dysfunctional thermoregulation, clinicians can use objective skin temperature measurements in conjunction with patient self reports about thermal discomfort (e.g., sensation of cold hands and feet) to diagnose, monitor, and advise patients on their sleep disturbances or thermal discomfort–related complaints.
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332 PART I / Section 4 • Physiology in Sleep 15. Fontvieille AM, Rising R, Spraul M, et al. Relationship between sleep stages and metabolic rate in humans. Am J Physiol 1994; 267:E732-E737. 16. Bach V, Telliez F, Libert JP. The interaction between sleep and thermoregulation in adults an neonates. Sleep Med Rev 2002; 6:481-492. 17. Kräuchi K, Cajochen C, Wirz-Justice A. A relationship between heat loss and sleepiness: effects of postural change and melatonin administration. J Appl Physiol 1997;83:134-139. 18. Kräuchi K. The human sleep-wake cycle reconsidered from a thermoregulatory point of view. Physiol Behav 2007;90: 236-245. 19. Geschickter EH, Andrews PA, Bullard RW. Nocturnal body temperature regulation in man: a rationale for sweating in sleep. J Appl Physiol 1966;630:623-630. 20. Sindrup JH, Kastrup J, Jorgensen B, et al. Nocturnal variations in subcutaneous blood flow rate in lower leg of normal human subjects. Am J Physiol 1991;260:H480-H485. 21. Kräuchi K, Cajochen C, Werth E, et al. Functional link between distal vasodilation and sleep-onset latency? Am J Physiol Regul Integr Comp Physiol 2000;278:R741-R748. 22. Barrett J, Lack L, Morris M. The sleep-evoked decrease of body temperature. Sleep 1993;16:93-99. 23. Muzet A, Libert J-P, Candas V. Ambient temperature and human sleep. Experientia 1984;40:425-429. 24. Kräuchi K, Cajochen C, Wirz-Justice A. Waking up properly: is there a role of thermoregulation in sleep inertia? J Sleep Res 2004;13:121-127. 25. Kräuchi K, Fontana P, Gasio P, et al. Cold extremities and difficulties initiating sleep: evidence of co-morbidity from a random sample of a Swiss urban population. J Sleep Res 2008;17:420-426. 26. Vollenweider S, Wirz-Justice A, Flammer J, et al. Chronobiological characterization of women with primary vasospastic syndrome: body heat loss capacity in relation to sleep initiation and phase of entrainment. Am J Physiol Regul Integr Comp Physiol 2008; 294:R630-R638. 27. van den Heuvel C, Ferguson S, Dawson D. Attenuated thermoregulatory response to mild thermal challenge in subjects with sleeponset insomnia. Sleep 2006;29:1174-1180. 28. Gilbert SS, Van den Heuvel CJ, Ferguson SA, et al. Thermoregulation as a sleep signalling system. Sleep Med Rev 2004;8:81-93. 29. Recordati G. A thermodynamic model of the sympathetic and parasympathetic nervous systems. Auton Neurosci 2003;103:1-12. 30. Sarang PS, Telles S. Oxygen consumption and respiration during and after yoga relaxation techniques. Appl Psychophysiol Biofeedback 2006;31:143-153. 31. Kräuchi K, Cajochen C, Werth E, et al. Warm feet promote the rapid onset of sleep. Nature 1999;401(6748):36-37. 32. Dijk DJ, Czeisler CA. Body temperature is elevated during the rebound of slow-wave sleep following 40-h of sleep deprivation on a constant routine. J Sleep Res 1993;2:117-120. 33. Cajochen C, Kräuchi K, Wirz-Justice A. Dynamics of skin and core body temperature and heart rate in human sleep after a single administration of melatonin. J Sleep Res 1996;5(Suppl. 1):26. 34. Parmeggiani PL. REM sleep related increase in brain temperature: a physiologic problem. Arch Ital Biol 2007;145:13-21. 35. Landolt HP, Moser S, Wieser HG, et al. Intracranial temperature across 24-hour sleep-wake cycles in humans. Neuro Report 1995; 6:913-917. 36. Kawamura H, Sawyer CH. Elevation in brain temperature during paradoxical sleep. Science 1965;150:912-913. 37. Deboer T, Franken P, Tobler I. Sleep and cortical temperature in the Djungarian hamster under baseline conditions and after sleep deprivation. J Comp Physiol A 1994;174:145-155. 38. Alföldi P, Rubicsek G, Cserni G, et al. Brain and core temperatures and peripheral vasomotion during sleep and wakefulness at various ambient temperatures in the rat. Pflügers Arch 1990;417:336-341. 39. Franken P, Tobler I, Borbely AA. Sleep and waking have a major effect on the 24-hr rhythm of cortical temperature in the rat. J Biol Rhythms 1992;7:341-352. 40. Baker FC, Angara C, Szymusiak R, et al. Persistence of sleep-temperature coupling after suprachiasmatic nuclei lesions in rats. Am J Physiol Regul Integr Comp Physiol 2005;289: R827-R838.
41. Campbell SS, Broughton RJ. Rapid decline in body temperature before sleep: fluffing the physiological pillow? Chronobiol Int 1994;11:126-131. 42. Zulley J. Distribution of REM sleep in entrained 24 hour and freerunning sleep–wake cycles. Sleep 1980;2:377-389. 43. Lack LC, Gradisar M, Van Someren EJW, et al. The relationship between insomnia and body temperatures. Sleep Med Rev 2008; 12:307-317. 44. Dijk DJ, Czeisler CA. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci 1995;15:3526-3538. 45. Lavie P. Melatonin: role in gating nocturnal rise in sleep propensity. J Biol Rhythms 1997;12:657-665. 46. Rajaratnam SMW, Middleton B, Stone BM, et al. Melatonin advances the circadian timing of EEG sleep and directly facilitates sleep without altering its duration in extended sleep opportunities in humans. J Physiol 2004;561:339-351. 47. Liao W-C. Effects of passive body heating on body temperature and sleep regulation in the elderly: a systematic review. Int J Nursing Stud 2002;39:803-810. 48. Buguet A. Sleep under extreme environments: effects of heat and cold exposure, altitude, hyperbaric pressure and microgravity in space. J Neurological Sci 2007;262:145-152. 49. Heller HC, Edgar DM, Grahn DA, et al. Sleep, thermoregulation, and circadian rhythms. In: Fregly MJ, editor. Handbook of Physiology, sect 4: environmental physiology. New York: Oxford University Press; 1996. p. 1361-1374. 50. Hammel HT, Elsner RW, Le Messurier DH, et al. Thermal and metabolic responses of the Australian aborigine exposed to moderate cold in summer. J Appl Physiol 1959;14:605-615. 51. Lange Andersen K, Loyning Y, Nelms JD, et al. Metabolic and thermal response to a moderate cold exposure in nomadic Laps. J Physiol (London) 1960;15:649-653. 52. Dewasmes G, Signoret P, Nicolas A, et al. Advances of human core temperature minimum and maximal paradoxical sleep propensity by ambient thermal transients. Neurosci Lett 1996;215: 25-28. 53. Togo F, Aizawa S, Arai J, et al. Influence on human sleep patterns of lowering and delaying the minimum core body temperature by slow changes in the thermal environment. Sleep 2007;30: 797-802. 54. Marino F, Booth J. Whole body cooling by immersion in water at moderate temperatures. J Sci Med Sport 1998;1:73-82. 55. Dorsey CM, Teicher MH, Cohen-Zion M, et al. Core body temperature and sleep of older female insomniacs before and after passive body heating. Sleep 1999;22:891-898. 56. Sung E-J, Tochihara Y. Effects of bathing and hot footbath on sleep in winter. J Physiolog Anthropol 2000;19:21-27. 57. Liao WC, Chiu MJ, Landis CA. A warm footbath before bedtime and sleep in older Taiwanese with sleep disturbance. Res Nurs Health 2008;31:514-528. 58. Okamoto-Mizuno K, Tsuzuki K, Ohshiro Y, et al. Effects of an electric blanket on sleep stages and body temperature in young men. Ergonomics 2005;48:749-757. 59. Raymann RJ, Swaab DF, Van Someren EJ. Skin deep: enhanced sleep depth by cutaneous temperature manipulation. Brain 2008; 131:500-513. 60. Fronczek R, Overeem S, Lammers GJ, et al. Altered skin-temperature regulation in narcolepsy relates to sleep propensity. Sleep 2006;29:1444-1449. 61. Raymann RJ, Swaab DF, Van Someren EJ. Skin temperature and sleep-onset latency: changes with age and insomnia. Physiol Behav 2007;90:257-266. 62. Driver HS, Taylor SR. Exercise and sleep. Sleep Med Rev 2000;4:387-402. 63. Atkinson G, Fullick S, Grindey C, et al. Exercise, energy balance and the shift worker Sports Med 2008;38:671-685. 64. Hague JFE, Gilbert SS, Burgess HJ, et al. A sedentary day: effects on subsequent sleep and body temperatures in trained athletes. Physiol Behav 2002;6869:1-7. 65. Van Someren EJW. Mechanisms and functions of coupling between sleep and temperature rhythms. Prog Brain Res 2006;153: 309-324.
CHAPTER 28 • Body Temperature, Sleep, and Hibernation 333 66. McGinty D, Szymusiak R. Keeping cool: a hypothesis about the mechanisms and functions of slow-wave sleep. Trends Neurosci 1990;13:480-487. 67. Valatx JL, Roussel B, Cure M. Sleep and cerebral temperature in rat during chronic heat exposure. Brain Res 1973;55:107122. 68. Deboer T, Tobler I. Shortening of the photoperiod affects sleep distribution, EEG and cortical temperature in the Djungarian hamster. J Comp Physiol A 1996;179:483-492. 69. Amici R, Cerri M, Ocampo-Garces A, et al. Cold exposure and sleep in the rat: REM sleep homeostasis and body size. Sleep 2008;31: 708-715. 70. Amici R, Zamboni G, Perez E, et al. Pattern of desynchronized sleep during deprivation and recovery induced in the rat by changes in ambient temperature. J Sleep Res 1994;3:250-256. 71. Morairty SR, Szymusiak R, Thomson D, et al. Selective increases in non-rapid eye movement sleep following whole body heating in rats. Brain Res 1993;617:10-16. 72. Gao BO, Franken P, Tobler I, et al. Effect of elevated ambient temperature on sleep, EEG spectra, and brain temperature in the rat. Am J Physiol 1995;268:R1365-R1373. 73. Obal F Jr, Alfoldi P, Rubicsek G. Promotion of sleep by heat in young rats. Pflügers Arch 1995;430:729-738. 74. McGinty D, Szymusiak R, Thomson D. Preoptic/anterior hypothalamic warming increases EEG delta frequency activity within nonrapid eye movement sleep. Brain Res 1994;667:273-277. 75. Franken P, Dijk DJ, Tobler I, et al. Sleep deprivation in rats: effects on EEG power spectra, vigilance states, and cortical temperature. Am J Physiol 1991;261:R198-R208. 76. Tobler I, Franken P, Gao B, et al. Sleep deprivation in the rat at different ambient temperatures: effect on sleep, EEG spectra and brain temperature. Arch Ital Biol 1994;132:39-52. 77. Deboer T. Brain temperature dependent changes in the electroencephalogram power spectrum of humans and animals. J Sleep Res 1998;7:254-262. 78. Deboer T, Tobler I. Temperature dependence of EEG frequencies during natural hypothermia. Brain Res 1995;670:153-156. 79. Deboer T. Electroencephalogram theta frequency changes in parallel with euthermic brain temperature. Brain Res 2002;930: 212-215. 80. Miller JD, Cao VH, Heller HC. Thermal effects on neuronal activity in suprachiasmatic nuclei of hibernators and nonhibernators. Am J Physiol 1994;266:R1259-R1266. 81. Daniel EE, Boddy G, Bong A, et al. A new model of pacing in the mouse intestine. Am J Physiol Gastrointest Liver Physiol 2004;286:G253-G262. 82. Eisenman JS, Edinger HM, Barker JL, et al. Neuronal thermosensitivity. Science 1971;172:1360-1362. 83. Boulant JA. Cellular mechanisms of neuronal thermosensitivity. J Therm Biol 1999;24:333-338. 84. Alam N, Szymusiak R, McGinty D. Local preoptic/anterior hypothalamic warming alters spontaneous and evoked neuronal activity in the magno-cellular basal forebrain. Brain Res 1995;696: 221-230. 85. Alam MN, McGinty D, Szymusiak R. Thermosensitive neurons of the diagonal band in rats: relation to wakefulness and non-rapid eye movement sleep. Brain Res 1997;752:81-89. 86. Berner NJ, Heller HC. Does the preoptic anterior hypothalamus receive thermoafferent information? Am J Physiol 1998;274: R9-R18. 87. Kumar VM, Vetrivelan R, Mallick HN. Noradrenergic afferents and receptors in the medial preoptic area: neuroanatomical and neurochemical links between the regulation of sleep and body temperature. Neurochem Int 2007;50:783-790. 88. Geiser F, Ruf, T. Hibernation versus daily torpor in mammals and birds: physiological variables and classification of torpor patterns. Physiol Zool 1995;68:935-966. 89. Barnes BM. Freeze avoidance in a mammal: body temperatures below 0 degree C in an Arctic hibernator. Science 1989;244: 1593-1595. 90. Wang LCH. Time pattern and metabolic rates of natural torpor in the Richardson’s ground squirrel. Can J Zool 1978;57:149-155. 91. Berger RJ. Comparative aspects of energy metabolism, body temperature and sleep. Acta Physiol Scand 1988;133:21-27.
92. Heller HC. Sleep and hypometabolism. Can J Zool 1988;66: 61-69. 93. Hut RA, Van der Zee EA, Jansen K, et al. Gradual reappearance of post-hibernation circadian rhythmicity correlates with numbers of vasopressin-containing neurons in the suprachiasmatic nuclei of European ground squirrels. J Comp Physiol 2002; 172:59-70. 94. Larkin JE, Franken P, Heller HC. Loss of circadian organization of sleep and wakefulness during hibernation. Am J Physiol Regul Integr Comp Physiol 2002;282:R1086-R1095. 95. Deboer T, Tobler I. Slow waves in the sleep electroencephalogram after daily torpor are homeostatically regulated. Neuroreport 2000;11:881-885. 96. Deboer T, Tobler I. Sleep regulation in the Djungarian hamster: comparison of the dynamics leading to the slow-wave activity increase after sleep deprivation and daily torpor. Sleep 2003;26: 567-572. 97. Strijkstra AM, Daan S. Dissimilarity of slow-wave activity enhancement by torpor and sleep deprivation in a hibernator. Am J Physiol 1998;275:R1110-R1117. 98. Larkin JE, Heller CH. The disappearing slow wave activity of hibernators. Sleep Res Online 1998;1:96-101. 99. Lyman CP, Willis JC, Malan A, et al. Hibernation and torpor in mammals and birds. New York: Academic; 1982. 100. Ruby NF, Dark J, Burns DE, et al. The suprachiasmatic nucleus is essential for circadian body temperature rhythms in hibernating ground squirrels. J Neurosci 2002;22:357-364. 101. Guppy M, Withers P. Metabolic depression in animals: physiological perspectives and biochemical generalizations. Biol Rev Camb Philos Soc 1999;74:1-40. 102. Snapp BD, Heller CH. Suppression of metabolism during hibernation in ground squirrels (Citellus lateralis). Physiol Zool 1981; 54:297-307. 103. Geiser F. Reduction of metabolism during hibernation and daily torpor in mammals and birds: temperature effect or physiological inhibition? J Comp Physiol B 1988;158:25-37. 104. Storey KB, Storey JM. Metabolic rate depression and biochemical adaptation in anaerobiosis, hibernation and estivation. Q Rev Biol 1990;65:145-174. 105. Heldmaier G, Ruf T. Body temperature and metabolic rate during natural hypothermia in endotherms. J Comp Physiol B 1992; 162:696-706. 106. Heldmaier G, Steiger R, Ruf T. Suppression of metabolic rate in hibernation. In: Carey C, Florant GL, Wunder BA, Horwitz B, editors. Life in the cold. Boulder, Colo: Westview; 1993. 107. Nicol S, Andersen NA, Mesch U. Metabolic rate and ventilatory pattern in the echidna during hibernation and arousal. In: Augee ML, editor. Platypus and echidnas. Sydney: Royal Zool Soc NSW; 1992. 108. Geiser F. Metabolic rate and body temperature reduction during hibernation and daily torpor. Annu Rev Physiol 2004; 66:239-274. 109. French AR. Allometries of the durations of torpid and euthermic intervals during mammalian hibernation: a test of the theory of metabolic control of the timing of changes in body temperature. J Comp Physiol B 1985;156:13-19. 110. Barnes BM, Kretzmann M, Licht P, et al. The influence of hibernation on testis growth and spermatogenesis in the golden-mantled ground squirrel, Spermophilus lateralis. Biol Reprod 1986;35: 1289-1297. 111. Geiser F, Kenagy GJ. Torpor duration in relation to temperature and metabolism in hibernating ground squirrels. Physiol Zool 1988;61:442-449. 112. Strijkstra AM, Hut RA, Daan S. Does the timing mechanism of periodic euthermia in deep hibernation depend on its homeostatic need? In: Lovegrove BG, McKechnie AE, editors. Hypometabolism in animals: torpor, hibernation and cryobiology. Pietermaritzburg: University of KwaZuluNatal; 2008. p. 157-162. 113. Kayser C. L’hibernation des mammiferes. Annee Biol 1953;29: 109-150. 114. Daan S. Activity during natural hibernation in three species of vespertilionid bats. Neth J Zool 1973;23:1-71. 115. Willis JC. The mystery of the periodic arousal. In: Lyman CP, Willis JC, Malan A, Wang LCH, editors. Hibernation and torpor
334 PART I / Section 4 • Physiology in Sleep in mammals and birds. New York: Academic Press; 1982. p. 92-103. 116. Daan S, Barnes BM, Strijkstra AM. Warming up for sleep? Ground squirrels sleep during arousals from hibernation. Neurosci Lett 1991;128:265-268. 117. Trachsel L, Edgar DM, Heller HC. Are ground squirrels sleep deprived during hibernation? Am J Physiol 1991;260:R1123R1129. 118. Walker JM, Garber A, Berger RJ, et al. Sleep and estivation (shallow torpor): continuous processes of energy conservation. Science 1979;204:1098-1100.
119. Deboer T, Tobler I. Sleep EEG after daily torpor in the Djungarian hamster: similarity to the effect of sleep deprivation. Neurosci Lett 1994;166:35-38. 120. Krilowicz BL, Glotzbach SF, Heller HC. Neuronal activity during sleep and complete bouts of hibernation. Am J Physiol 1988;255: R1008-R1019. 121. Obal F Jr, Rubicsek G, Alfoldi P, et al. Changes in the brain and core temperatures in relation to the various arousal states in rats in the light and dark periods of the day. Pflügers Arch 1985; 404:73-79.
Memory Processing in Relation to Sleep Philippe Peigneux and Carlyle Smith Abstract Although each of us empirically recognizes the utmost importance of sleep for the quality of our everyday life, its functions have long remained shrouded in mystery. Beyond its putative physiologic functions, there is now growing evidence that sleep plays a prominent role in brain plasticity and in memoryconsolidation processes. According to this proposal, memory traces formed during a learning episode are not immediately stored in their definitive form. Rather, they are initially kept in a labile, fragile state, during which they can be easily disrupted. Over time and especially during sleep, they subsequently undergo a series of transformations during which they will be consolidated and fully integrated into long-term memory. In this chapter, we present experimental data that provide support for the hypothesis that sleep exerts a promoting effect on plastic processes of memory consolidation. Some studies have assessed the effects of posttraining sleep deprivation on memory consolidation and on the reorganization of the neural substrates of long-term memories. Others have
In 1867, Hervey de Saint Denys, fascinated by his dreams since the age of 14, published Les Rêves et les Moyens de les Diriger.1 In his book, he reported a series of ingenious experiments showing that experienced events are incorporated into our dreams, in which they can be combined to create original associations between “memory images” of the past. Hence, he strongly opposed the idea that sleep may be a sudden drop in a state of cognitive “non-being” in which our resting brain is disconnected. On the contrary, he claimed that “a sleep without dreams cannot exist, just as a wake state without mentation does not exist.” Besides dreaming activity, however, addressed in Section 7 of this book, we know that the sleeping brain houses a wide set of cognitive processes, including the ongoing treatment of elaborated external stimuli, the revival of experiences, and last, but not least, the consolidation of new information in memory. Interestingly, recognition that persistence of mental activity in the sleeper may be an integral part of the physiologic processes that subtend memory consolidation arose only in the last quarter of the 20th century. The hypothesis had to wait till now to receive widespread acknowledgement, as illustrated by the fact that for the first time a chapter devoted to sleep in relation to memory has been introduced in this fifth edition of Principles and Practices in Sleep Medicine. This chapter introduces the issues surrounding the role that sleep may play in memory consolidation, focusing on human data. Reviews about relationships between sleep and memory in animals are addressed can be found elsewhere.2-4 We will here outline key findings and milestones in probing the sleep-for-memory hypothesis, as well as ongoing debates and thoughtful questions that remain.
Chapter
29
investigated the effects of learning on posttraining sleep and reexpression of behavior-specific neural patterns during posttraining sleep, and still others have probed the effects of within-sleep stimulation on sleep patterns and overnight memories. Besides-demonstrating a role of sleep in memory consolidation processes, these studies have also indicated that sleep stages are functionally different, in that they may subserve distinct memory processes. Available evidence reveals complex interactions between sleep and memory systems, in agreement with the fact that memory is a complex construct of specialized memory subdomains, and that sleep is composed of distinct stages characterized by specific physiologic mechanisms. Despite advances that have refined our understanding of the relationships between sleep and cognitive processes, the underlying mechanisms still remain to be fully elucidated. Further steps are now required to understand how sleep disorders and pathologies accompanied by sleep disturbances affect cognitive functions, and especially learning and memory consolidation in humans, eventually leading to remedial interventions.
Before approaching the subject, however, we will briefly introduce the concepts of memory consolidation and memory systems in humans. Previous chapters have shown that sleep is a multidimensional state of vigilance, composed of rapid eye movement (REM) and non-REM (NREM) episodes that present distinctive features and rely on specific neuroanatomic substrates.4 From both cognitive and neurophysiologic perspectives, memory is not a unitary phenomenon. Rather, memory should be seen as a generic concept for information storage, encompassing a series of specific subdomains.5 Consequently, the interaction between multidimensional states of sleep and distinctive memory systems makes it logical that not all sleep manipulations will have the same impact on performance, depending on the various parameters embedded in the memory task.2,6,7 We will examine the growing number of behavioral studies that have enlightened our understanding of the role played by sleep episodes in memory consolidation. The rapid evolution of neurophysiologic techniques and analytical approaches allows scrutiny of the complex relations between cognitive processes and their underlying neural substrates. Part of this chapter will focus on the neurophysiologic mechanisms acting in sleep to support, or at least favor, memory consolidation processes. Molecular biology of memory consolidation is beyond the scope of this chapter and is reviewed elsewhere.4 The relationship between consolidation of learning and sleep is a crucial issue because memory is at the root of most of our daily behaviors, such as simple skill acquisition (e.g., typewriting), sophisticated operational procedures (e.g., using computer-based systems), and keeping track of personal events and relationships. 335
336 PART I / Section 4 • Physiology in Sleep
MEMORY SYSTEMS AND MEMORY CONSOLIDATION We are able to learn, store, and remember various types of information in different ways and for variable periods of time, from conscious acquisition strategies to incidental detection of environmental events. Cerebral damage can selectively alter some of these processes while leaving others undisturbed. These simple observations have led to the proposal that memory is not a unitary phenomenon but rather a complex construct of more or less specialized memory subdomains.5 First, a seminal distinction that dates back to William James is made between short- and long-term memory stores. The former is dedicated to the temporary storage of volatile information for up to seconds, whereas the latter, the main focus in this chapter, houses potentially lasting information that is deemed consolidated and less susceptible to disruption. Long-term memories in humans may further belong to multiple systems, primarily delineated between declarative and nondeclarative memories (Fig. 29-1). Distinguishing features of declarative memory are that information is easily accessible to verbal description and that encoding or retrieval is usually carried out explicitly— that is, the subject is aware that the stored information exists and is being accessed. Declarative memory is further composed of semantic and episodic memory components. Semantic memory is the receptacle for our general knowledge about the world, regardless of the spatiotemporal context of knowledge acquisition (e.g., we know that Paris is the capital of France, and that fuel is combustible, but we are probably unable to recollect how and when we learned these facts). Episodic memory, on the other hand, refers to the system that stores events and information along with their contextual location in time and space (e.g., I can vividly remember having visited the British Museum with my cousin on a rainy day in the fall of 1993).
Declarative memory
Emotion
Episodic memory
Semantic memory
Personally experienced events, spatial and temporal memory features
Facts and concepts about the world, general knowledge
Nondeclarative memory
Skills and habits
Priming
Conditioning
“How to” knowledge, perceptual, motor and cognitive abilities
Processing facilitation after prior exposure
Elementary associative memory
Figure 29-1 Schematic organization of long-term memory systems.
Distinctive features of nondeclarative memories are that they are not easily accessible to verbal description and can be acquired and reexpressed implicitly. Thus, our behavioral performance can be affected by the new memory even if we are not consciously aware that new information has been encoded or is being retrieved. Memory abilities aggregated under the nondeclarative label also gather different forms: skills, habits, priming, and conditioning. Although grouped under the nondeclarative label, these various processes are subtended by distinct neuroanatomic substrates in both humans and animals, further suggesting their relative independence.5 Besides the transverse division between long-term memory subsystems proposed by these influential models, there is a dynamic longitudinal process. Newly acquired information is not immediately stored at the time of learning in its final form, if such a stable state exists. Rather, memories undergo a series of transformations over hours, days, or even years, during which time they are gradually incorporated into preexisting sets of mnemonic representations,8-10 or are subjected to forgetting.11 This is the concept of memory consolidation, which can be defined as the time-dependent process that converts labile memory traces into more permanent or enhanced forms.12 These transformations are made possible by our brain plasticity—that is, the capacity of the brain to modify its structure and function over time, within certain boundaries.13 Eventually, time-dependent processes of consolidation and the ensuing robust memory trace will enduringly adjust the behavioral responses to the recent environmental changes, thereby enlarging the organism’s behavioral repertoire.14 Scientific evidence suggests that sleep and the associated processes of brain plasticity4 are major players in timedependent processes of memory consolidation, acting as key constituents in the chain of transformations that help integrate information for the long term. Furthermore, these studies suggest that distinct sleep stages may have distinct memory-related functions, which has been interpreted in two different but nonexclusive ways. According to the dual-process hypotheses, REM and NREM sleep act differently on memory traces depending on the memory system or process to which they belong. For example, it has been proposed that slow-wave sleep (SWS)—the deepest stage of NREM sleep—facilitates consolidation of declarative and spatial memories, whereas REM sleep facilitates consolidation of nondeclarative memories.15,16 Another interpretation is that particular sequences of sleep states reflect the succession of brain processing events supporting memory consolidation.17 An example is the proposal that REM sleep actively consolidates or integrates complex associative information, whereas NREM sleep passively prevents retroactive interference of recently acquired complex associative information.18 In this view, SWS and REM sleep play complementary roles and have to act serially to consolidate the new memory trace, in a double-step process.19,20 Both approaches assume that it is sleep on the first posttraining night that is important for memory consolidation. Nonetheless, it would be premature to claim that only sleep may achieve the necessary conditions to consolidate novel memories in the nervous system, as both sleeplike cognitive and neural processes of
memory consolidation have also been observed during wakefulness.21-23
METHODS FOR STUDYING THE ROLE OF SLEEP FOR MEMORY CONSOLIDATION Three experimental approaches have been used to test the hypothesis that sleep exerts a favorable or promoting effect on memory consolidation. These approaches focus on (1) the effects of posttraining sleep deprivation on memory consolidation and on the reorganization of the neural substrates of long-term memories, (2) the effects of learning on posttraining sleep and reexpression of behavior-specific neural patterns during posttraining sleep, or (3) the effects of within-sleep stimulation on sleep patterns and overnight memories. Posttraining Sleep Deprivation The first and probably most ancient line of investigation has probed the putatively detrimental effect of sleep deprivation on the night after learning, based on the assumption that memory performance over the long term will be better if participants are allowed to sleep after learning rather than being deprived of sleep. In classic procedures, subjects learn new material. Afterward, some participants are allowed to sleep normally whereas others either do not sleep at all (total sleep deprivation), are awakened at the onset of occurrences of the sleep stage under study (selective sleep deprivation), are kept awake during the period of the night in which the sleep stage is predominant (partial sleep deprivation), or have a shortened sleep duration (sleep restriction). Finally, prenight and postnight memory measures are compared between sleeping and sleepdeprived subgroups, either the next day or several days later. Jenkins and Dalenbach24 used this approach about 85 years ago and found that the forgetting curve for newly learned verbal material described by the German psychologist Ebinghaus was significantly dampened by the presence of an intermediate period of sleep. Nonetheless, they did not attribute this effect to a specific role of sleep per se in memory processing but merely to the protective role that sleep may have against “interference, inhibition, or obliteration of the old by the new.”24 However, this hypothesis of a purely passive role for sleep in memory processes has been challenged by studies of selective sleep deprivation that attribute a specific role to REM sleep in memory storage and consolidation, in both human and animal species.25 Also, it was demonstrated that memory over an interval with relatively high amounts of stage 4 sleep (i.e., in the first half of the night) was superior to memory over an interval with relatively high amounts of REM sleep (i.e., in the second half of the night).26 This seemingly apparent contradiction was resolved later, with the demonstration that recall of paired-associate lists was significantly better after sleep than wakefulness in the first part of the night only, whereas consolidation of mirrortracing skills specifically benefited from sleep in the second part of the night.15 Results showed that memories belonging to the declarative and nondeclarative systems do not benefit from the same sleep components. Other experimental manipulations inferred a specific role for stage 2
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sleep in the second part of the night for the consolidation of motor memories.27,28 Hence, sleep deprivation studies have suggested that each stage of human sleep (REM sleep, SWS, stage 2 sleep) might be involved in a distinctive way in learning and memory consolidation processes.6,7 In the recent past, neuroimaging investigations have complemented these findings using functional magnetic resonance imaging (fMRI). As in behavioral paradigms, subjects are trained to the task and then either deprived of sleep or allowed to sleep on the following night. A few days later, cerebral activity is recorded during memory retrieval and the two posttraining sleep conditions are compared. One or two additional nights of regular sleep are usually allowed after the posttraining night before testing in the scanner, to avoid different arousal states that may confound neural activity associated with memory retrieval between sleeping and sleep-deprived subjects. These neuroimaging studies have yielded two important contributions. First, they have demonstrated that sleep deprivation during the posttraining night eventually impedes the reorganization and optimization of the cerebral activity, subtending delayed retrieval of consolidated memories during wakefulness.29-32 Second, they have shown that sleepdependent changes in memory-related brain activity patterns may be present even when similarity in behavioral performance between posttraining sleep conditions suggests an absence of sleep-related effect on memory.30,32 The latter results further indicate that long-term memory performance can be achieved using different cerebral strategies initiated as a function of the status of sleep during the posttraining night. Posttraining Sleep Modifications The second line of investigation stemmed from the reasoning that if newly acquired information underwent an ongoing process of consolidation during sleep, then this should be reflected in neural and physiologic features of posttraining sleep. Using electroencephalographic (EEG) recording techniques, numerous animal studies have reported changes in, or memory-related associations with, a series of postlearning sleep parameters, including sleep stage duration or proportion relative to total sleep time, density of rapid eye movements, power increase in selected EEG frequency ranges, changes in density and duration of phasic events (e.g., spindles, ponto-geniculo-occipital waves), and reexpression of learning-specific neural patterns (for reviews, see references 3, 4, 6, 33, 34). Likewise, in humans, numerous EEG studies have evidenced that both the architecture of sleep and distinctive features of sleep stages can be affected by prior learning experience. For example, postlearning sleep modifications have been shown when looking at absolute or proportional (i.e., relative to total sleep time) increases in the duration of REM sleep,6,20,35-37 stage 2 sleep38 and SWS20 episodes. Other studies have reported increased density of rapid eye movements39,40 and stage 2 spindle activity in the sigma frequency band,41-50 as well as increases in REM sleep theta power.51 Many found statistical correlations between quantitative parameters of sleep and overnight performance improvements20,37,41-44,48-50 or levels of performance at the end of learning,45 suggesting a close link between changes in sleep physiology and memory consolidation. In support
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of the double-step hypothesis described earlier, other studies evidenced relationships between performance changes and the organization of NREM/REM sleep cycles.19,52 Hence, these investigations, mostly based on noninvasive electrophysiologic techniques, have consistently demonstrated that physiology of sleep is influenced by prior learning during the day. Additionally, waking experience was shown to influence the content of hypnagogic hallucinations53 and of dreams collected on awakening from sleep stages54,55 on the postexposure night, although delayed incorporations of up to weeks have also been reported often.55 Noninvasive neuroimaging studies, especially using positron emission tomography (PET) measurements, with their better spatial resolution and whole brain coverage, have been used to look more precisely at the neural correlates of postlearning modifications during sleep. They have shown that neural activity occurring during waking task practice in learning-dedicated cerebral structures can be reexpressed or continued during both REM56,57 and NREM58 stages of sleep, as well as during posttraining wakefulness.21 These data were in close agreement with intracerebral recording studies in animals, which demonstrated neuronal reactivation during sleep.59,60 The animal data suggested reactivation of coherent memory traces in key cerebral structures during sleep that was deemed to contribute to or reflect the result of the memory consolidation process. However, these seminal animal studies did not experimentally establish the behavioral relevance of reactivations in neuronal ensembles, as they never sought to show a relationship with subsequent behavioral modifications. A significant contribution of human neuroimaging data was to show that experience-dependent reactivations of local—that is, hippocampal—activity during SWS are correlated to overnight gains in memory performance after spatial navigation.58 On the other hand, levels of implicit procedural learning achieved before sleep correlated with the amplitude of reactivation in cortical areas during REM sleep,57 at which time connectivity patterns between learning-related areas were additionally reinforced.61 Taken together, human reactivation studies have suggested the neuronal replay of previous experience during sleep, and that posttraining sleep activity in brain areas involved during the learning episode represents a neural signature of memory-related cognitive processes. Another (but not exclusive) hypothesis is that learning in the awake state induces local synaptic changes that themselves induce local changes in slow-wave activity (SWA), the main marker of sleep homeostasis, and that these changes are ultimately beneficial to imprint novel memories.62 In support of this view, high-density electrophysiologic recordings have demonstrated local increases in SWA in learning-related areas during posttraining NREM sleep, correlating with overnight performance improvements.63 Within-Sleep Stimulations Finally, a third approach to demonstrate memory processing during sleep has been to provide specific stimulations during sleep with the aim of investigating whether meaningful stimuli could be recognized or new associations formed, or whether presleep learning can be modified by nonawakening stimulations. Evidence for such phenomena
would indicate that active plastic processes are taking place during sleep. In line with animal studies,33 preliminary data have indicated the possibility of heart rate conditioning in man during NREM sleep,64 suggesting plasticity during sleep. On the other hand, no learning effect was found for lists of paired-associate words presented during either REM or stage 2 sleep and tested immediately afterward.65 Although these results suggest a limitation in learning capacity during sleep, there is consistent evidence that sleeping subjects remain able to detect and discriminate external sensory events as indexed by event-related auditory potentials (ERPs).66,67 Likewise, nociceptive stimulations during sleep persistently elicit evoked responses.68 ERP and fMRI data also indicated higher sensitivity to external stimuli during tonic than phasic periods of REM sleep.69,70 Higherlevel processing of externally presented events was also found during sleep, as auditory ERPs are elicited after hearing one’s own name both while sleeping and awake.71 Nonetheless, brain responsiveness during sleep is not independent of prior waking experience. Learning semantic associations72 or discriminating auditory patterns67 during wakefulness leads to changes in evoked response potentials during sleep,72 even up to 2 days later.67 These results support the idea that external events can be processed during certain periods of sleep, and that stimulus significance affects this processing. Further demonstrating an active role for sleep in memory consolidation processes, several studies have established that stimulations in the posttraining sleep period may enhance performance as compared with a standard, unmodified posttraining night.73-77 Presentation of nonawakening auditory stimulations during REM sleep after Morse code learning73 or re-presentation during REM sleep of sounds heard in background while learning a complex logic task74 increased overnight memory. This effect was present only when auditory stimulations were displayed in coincidence with the bursts of rapid eye movements that reflect phasic ponto-geniculo-occipital (PGO) activity in man. Likewise, presentation during SWS of odors that were used as contextual cues during the learning episode triggered hippocampal responses and improved overnight retention of declarative memories.77 Transcranial direct-current stimulation that modulates excitability in cortical areas improved declarative memory when applied during SWS,76 especially when application of oscillating potentials at about 0.75 Hz induced slow oscillationlike potential fields that mimic the slow oscillations of deep NREM sleep.75 Finally, artificially maintaining high levels of cortisol feedback and cholinergic tone during SWS impairs hippocampus-dependent declarative memory formation,78-80 suggesting that the natural shift in central nervous system cholinergic tone from high levels during acquisition-related wakefulness periods to minimal levels during SWS optimizes declarative memory consolidation.81 On the other hand, preventing natural increases in cortisol during REM sleep periods appears to enhance amygdala-dependent emotional memory.80 These studies have demonstrated beneficial (or detrimental) effects of various stimulations and manipulations in the posttraining sleep periods on overnight gains in performance, and therefore have provided interesting evidences that sleep
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does not play a merely passive role in memory processing by protecting novel memories from interference. Rather, they support the hypothesis that sleep acts in a complex manner in providing optimal conditions for the consolidation of novel memories in the nervous system.
mPFC sites when initial encoding was followed by a night of sleep than by sleep deprivation, suggesting that sleep leads to long-lasting changes in the representation of memories at the neuroanatomic level.31 These results may be consistent with the hypothesis that sleep exerts an effect on the gradual semanticization of the learned material.
SLEEP AND DECLARATIVE MEMORY As discussed, long-term declarative memory comprises semantic and episodic memory components. Experimental data indicate that the role of sleep in consolidating these two memory components may be dissociated to a certain extent, and that emotional variables play a modulatory role in episodic memory consolidation. These aspects will be covered in the following section.
Episodic Memory The effect of sleep on episodic memory has been extensively studied using a series of declarative memory paradigms encompassing learning of verbal material such as lists of words or paired-associate words15,31,41,42,50,51,75,76,78,79,84-89 and sentences or prose passages,90 and explicit encoding of landscapes,83 objects’ locations,77 faces,91 visuospatial memory,16,48 and navigation in virtual30,32,58,92 or natural93 environments. Among these, most studies using partial behavioral15,16,31,85 or pharmacologic79 sleep deprivation have consistently found that SWS, or at least the first half of the night of sleep (which is rich in SWS), is beneficial for the consolidation of novel declarative memories. Consolidation of declarative learning was also linked to increased spindle activity during posttraining stage 2 sleep,41,42,48-50 as well as to the alteration of SWS94 and spindles95 in schizophrenia. Spindles are strong candidates to subtend memory consolidation processes during sleep because they are thought to support neural plasticity.96 As well, declarative learning abilities have been linked with increased spindle activity during stage 2 sleep44,97 and periodic arousal fluctuations during non-REM sleep98 in healthy subjects. On the other hand, declarative memory deficits are associated with decreased sleep spindle activity in patients with Alzheimer’s disease,99 and NREM sleep duration and number of cycles in patients with chronic nonrestorative sleep.100 However, others reported that overnight performance gains on declarative verbal memory depend primarily on preserved organization of sleep cycles—that is, sleep continuity—rather than on the integrity of a specific sleep stage per se.19 These studies may stand in contrast with much older ones that showed impairment in recall of sentences and short stories101 or lists of words102 after selective REM sleep deprivation. Also, a more recent study found that REM sleep deprivation specifically impaired recall of spatial and temporal features of memories, as well as the subject’s confidence in his own remembering,89 these parameters being considered as genuine components of episodic memory, as opposed to general recall, which may partially rely on semantic, decontextualized memories.2 Accordingly, it has been reported that consolidation during sleep enhances explicit recollection in recognition memory103 and strengthens the original temporal sequence structure for lists of triplet words.104
Semantic Memory Few studies have looked at the role of sleep for consolidation of semantic information, although ERP studies have demonstrated that semantic processing of externally presented stimuli is possible during REM and stage 2 sleep, but not during SWS.66,71,72 Also, it has been shown that the semantic priming (i.e., the facilitatory processing effect resulting from prior presentation of semantically related material) qualitatively differs upon awakening from stage 2 and REM sleep.82 Despite evidence for residual semantic processing, attempts to create novel semantic associations using direct auditory stimulation during sleep have been unsuccessful.65 Other evidence for a role of sleep in processing newly acquired semantic memories are not fully conclusive because the tasks that have been used comprise other cognitive components that may obscure the interpretation.2 For example, improvement in a French immersion course over 6 weeks was correlated with REM sleep increases,36 but learning a novel language is a task that involves episodic memory processes as well as the creation of novel semantic associations. Likewise, learning Morse code, which was found to be associated with increases in REM sleep parameters,37 may be viewed as a specific form of cognitive procedural learning of novel associations. Also, it is believed that transfer of novel information from hippocampus-dependent episodic memory stores to neocortical, semantic, decontextualized memory representations is a gradual process that may take years to complete.8 Therefore, protocols in which initial encoding, posttraining sleep periods and retrieval are temporally close are probably not best suited to segregate the semantic component of memory from other constituents. A few neuroimaging studies have investigated the cerebral correlates of declarative memory retrieval after extended periods of time (up to 6 months) using pairedassociate list of words31 or pictures of landscapes.83 Although these experiments were not specifically designed to probe whether the memorized material was semanticized at the time of retesting, neuroimaging results clearly indicated a transfer from activity in hippocampal locations, observed early after learning, toward activity in medial prefrontal cortical (mPFC) sites recorded 6 months later during memory retrieval.31,83 Furthermore, total sleep deprivation on the postlearning night hindered this gradual process of consolidation. Six months after learning verbal material, memory retrieval more strongly activated the
Emotion in Episodic Memory The role of emotional variables in sleep-dependent processes has been a focus of recent interest.80,90,105-108 Emotion can be seen as an important contextual cue in retention of episodic memories, although it is not necessarily processed explicitly. Nonetheless, emotional material was found to be better recalled after REM than after NREM sleep90 and to be altered after sleep deprivation,105 although more for the emotional content than the context of the
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information.108 However, others have found emotional memories to be better preserved, or at least less disrupted, than neutral memories after total sleep deprivation.80,106 These latter results suggest that consolidation of emotional memories also occurs efficiently during awake periods, an effect that may be explained by the important ecologic value of rapidly acquiring emotional stimulus– response associations. Similarly, it was found that sleep deprivation does not alter behavioral performance in an ecologically valid virtual navigation task.30,32 Importantly, a lack of behavioral effect does not guarantee that sleep was without any consequence on memory consolidation processes, as, in the case of both navigation and emotional memories, underlying patterns of brain activity at retrieval were effectively altered by sleep deprivation on the posttraining night.30,32,106
SLEEP AND NONDECLARATIVE MEMORIES As mentioned, memory abilities aggregated under the nondeclarative label may be relatively independent from both cognitive and neuroanatomic standpoints.5 Skills and habits that refer to the gradual acquisition of novel perceptual, motor, and cognitive abilities through repeated practice (e.g., discriminating figures, playing piano, riding a bicycle, detecting environmental regularities) have been the most widely investigated in relation to sleep. In this respect, numerous studies have found that posttraining sleep boosts acquisition levels on nonverbal motor,35,46,109-115 perceptual,20,54,116-124 and perceptual– motor15,27,29,43,45,56,57,61,63,125-129 procedural learning tasks. Additionally, a few studies have found that sleep particularly enhances procedural memory performance in brain-damaged individuals,130,131 but not in patients suffering from degenerative Parkinson’s disease,132 suggesting the importance of sleep in motor rehabilitation programs. Next, we further describe the role of sleep in (1) perceptual, (2) motor, and (3) perceptual–motor learning, and (4) priming. Sleep and Perceptual Learning One of the most consistent findings in the literature is the prominent role of sleep in the development of visual discrimination abilities. Most studies have used the texture discrimination task initially proposed by Karni and Sagi,133 where learning is retinotopic (i.e., specific to the trained visual quadrant).20,116,120-124 It was initially found that selective REM sleep deprivation, but not SWS deprivation, abolished overnight performance improvement during visual perceptual learning, whereas no or only feeble improvements occurred over episodes of wakefulness.133 However, another study using the same task found that improvement in visual discrimination skills was mostly disrupted by early sleep deprivation (i.e., rich in SWS), and even more so by total sleep deprivation.116 This apparent contradiction was partially resolved with the finding that overnight improvement was a direct function of both the amount of SWS in the first quarter of the night and the amount of REM sleep in the late quarter of the night,20 suggesting that SWS prompts memory formation, which is possibly, but not necessarily, consolidated during REM
sleep. There is further evidence of the complementary roles of sleep stages in the offline (i.e., occurring outside of actual practice) processes of consolidation for visual perceptual learning. Indeed, others have found that repeated practice on a task within the same day does not lead to any improvement and can even result in performance deterioration for the trained visual quadrant, unless there is an intervening sleep episode.123 But most importantly, they demonstrated that the duration of the sleep episode and its constituent phases is crucial in this process, as 30-minute daytime naps merely discontinued performance deterioration over repeated sessions,123 60-minute naps reverted performance to its original level,123 and 90-minute naps yielded improvement in discrimination performance.122 The main differences were more time spent in NREM sleep in the 60-minute nap than in the 30-minute nap, and the occurrence of REM sleep in the 90-minute nap. Other studies confirm the importance of posttraining sleep in the consolidation of coarse visual discrimination119 as well as the effect of visual adaptation paradigms on subsequent sleep parameters,54 thus demonstrating the importance of both REM and NREM sleep stages for consolidation of procedural abilities in the visual system. However, sleep-dependent improvements cannot yet be fully generalized across modalities, as contradictory results have been reported in the auditory domain. Whereas some authors have reported a beneficial influence of sleep on acquisition of auditory discrimination skills118,134 and perceptual generalization of phonologic categories,117 others have found that the same amount of time spent in the awake state is sufficient to allow the development of auditory identification abilities.135,136 With respect to more sophisticated auditory discrimination abilities, however, it has been shown that integration of newly learned spoken word forms, which must be discriminated from similarsounding entries during auditory word recognition, requires an incubation-like period containing sleep.137 Sleep and Motor Learning Using a simple sequential thumb-to-fingers opposition task, Karni and coworkers investigated the time-dependent evolution of motor learning.10 They showed that skilled performance on this task is acquired across an initial, within-session, fast learning phase, followed by a slow phase of consolidation and optimization that can extend for several weeks of repeated practice. Using the same task or a keyboard-presses variant, others subsequently found that posttraining sleep significantly enhanced performance in the absence of further practice, as compared with the same amount of time elapsed awake.46,109,111,112 However, contrary to the observations made using perceptual visual discrimination tasks described in the prior section, it cannot be claimed here that posttraining time spent awake prevents the formation of long-term motor memories, as performance merely stabilizes at the level achieved at the end of learning and does not deteriorate but rather modestly improves over repeated practice sessions. Still, a transitory boost in performance that is observed 5 to 30 minutes after the end of learning138 disappears if tested without an intermediate sleep period more than 4 hours later.46,138 Interestingly, performance improvement over the 5- to
30-minute boost predicts performance levels after a night of sleep.138 This precocious posttraining period appears important for the initial stabilization of motor memories,21 as learning an interfering sequence of movements during 30 minutes to 2 hours after training disrupts delayed, sleep-dependent consolidation of the original material,109,114 unless a nap is allowed.114 This role of sleep for motor memory consolidation extends beyond a genuine motor component, as training-related changes in sleep architecture are observed after practice of a sequence of finger movements but not after random key-presses,110 as well as after acquiring new and complex motor patterns such as trampolining35,115 but not after the familiar and well-learned motor activities of soccer or dancing.115 These latter results are in line with the demonstration that sleep provides maximal benefit for motor-skill procedures that proved to be most difficult during learning.113 Motor learning–related changes in posttraining sleep parameters were mostly observed during stage 2 sleep,46,110,111 although others have reported links with REM sleep115,139 or sleepcycle organization.35 Further studies are needed to delineate precisely the role and benefit of sleep on motor learning. Sleep and Perceptual–Motor Learning The motor learning tasks just described have definite features. They are self-initiated, and acquisition is initially carried out in an explicit, almost declarative manner, as the motor sequence of movements to be generated is already known and can even be verbalized. In this respect, motor procedural learning reflects the optimization of predefined motor forms possibly created with the con tribution of episodic memory processes. In contrast, perceptual–motor procedural learning entails a motor performance triggered by external stimulations, but the organization of the material to be learned is not necessarily obvious to the subject, although it affects its performance. This type of task potentially allows us to distinguish the role of sleep for consolidation of unconsciously as opposed to consciously formed memories. We will cover this aspect after reviewing perceptual–motor studies. It was initially found that performance improvement on the pursuit rotor task was blocked by total sleep deprivation and by sleep deprivation of the second part of the night, but not by selective REM sleep deprivation.27 Task improvement was also associated with increased sleep spindle activity,45,51 suggesting that consolidation of motor adaptive memories is mostly dependent on stage 2 sleep. Functional MRI additionally showed that posttraining total sleep deprivation hampered both performance improvement and the reorganization of brain activity on a visuomotor pursuit task with hidden regularities in the target’s trajectory.29 However, mirror-tracing skills were reported to improve more during the late part of the night,15 and to be associated with REM sleep increases in well-performing individuals,51 suggesting that this latter task is rather REM sleep dependent. Still, performance improvement on mirror tracing was also found to occur after naps dominated by stage 2 sleep125 and to correlate with stage 2 sleep spindle activity.43 This apparent discrepancy between sleep stages and task associations in the
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perceptual–motor learning domain might be explained by differences in initial skill levels of participants. Indeed, an association was reported between performance improvement on the pursuit rotor task and stage 2 spindle activity in highly skilled subjects, whereas a similar relationship was established with REM density in less skilled subjects,128 in line with the proposal that motor skills tasks involving REM and stage 2 sleep might depend on two separate, but overlapping, neural systems.28 This interpretation may be consistent with neuroimaging data that have established a relationship between posttraining REM sleep activity and the consolidation of higher-order perceptual–motor cognitive skills. Indeed, subcortical and neocortical areas already activated during practice on a probabilistic sequence-learning task140 (i.e., a paradigm of implicit sequence learning) were reactivated during posttraining REM sleep in subjects previously trained to the task.56,57,61 It was further demonstrated that these reactivations were not merely activity dependent but occurred specifically because a rules-based sequence was implicitly learned during prior practice,57 supporting the hypothesis that REM sleep is deeply involved in the reprocessing and optimization of the high-order information contained in the material to be learned, as opposed to its motor component alone. Moreover, it was found in a 40-hour constant routine protocol in which subjects were allowed 75 minutes of sleep every 150 minutes that sequence learning improved after naps, and most especially after naps that followed the circadian peak of REM sleep and in which REM sleep was present.141 Nonetheless, further studies using sequence-learning tasks have raised several issues, and some of these remain to be solved. It has been claimed that sleep is beneficial for sequence learning only when acquisition of the sequential regularities practiced during the task was explicit, with time alone being sufficient for the consolidation of implicitly acquired sequences.23,142 These results appear to contradict the findings of REM-sleep dependency for high-order probabilistic sequence learning, in which learning was undoubtedly implicit.57,140,141 However, one overlooked difference between these studies and those claiming a sleep dependency exclusively for explicit sequential material is that the latter have used deterministic, repeated sequences, whereas the probabilistic sequences used in the former studies are much more ambiguous. It is therefore possible that sleep (and especially REM sleep) mostly supports the consolidation of implicitly acquired complex relationships. This interpretation may be in line with the proposal that different aspects of a procedural memory are processed separately during consolidation, such as the movement sequence in itself (e.g., a repeated, deterministic sequence) improves over daytime wakefulness periods independently of sleep, whereas its goal (e.g., the complex, abstract rules for item succession in a probabilistic sequence) improves after a night of sleep.129 How and whether offline processes of memory consolidation do actually benefit from posttraining sleep may also be a function of the circadian moment of the day when the material is acquired,127 as well as the nature of the complex interactions between declarative and procedural memory systems.22 The complexity of these interactions is further illustrated by the demonstration that learning-related
342 PART I / Section 4 • Physiology in Sleep
cerebral responses in cerebral structures linked to procedural (i.e., striatum) and declarative (i.e., hippocampus) memory systems are both linearly related to an overnight gain in performance in an implicit oculomotor sequencelearning task.143 Sleep and Priming Perceptual priming refers to the facilitation or bias in the processing of a stimulus as a function of a recent encounter with that stimulus.144 The few studies that have investigated a role for sleep in consolidating the memory representations subtending priming16,145,146 or priming-like147,148 effects have yielded discrepant results. Although studies have found that intervening deprivation of sleep, and especially REM sleep, alters priming effects in word-stem completion16 as well as in face processing,145 and enhances reactivity for emotional pictures,147 another study (using better controlled tachistoscopic identification of drawings) failed to disclose sleep-dependent effects.146 A variant of priming is the “mere exposure effect,” obtained when incidental exposure to initially novel stimuli (e.g., nonsense words, line drawings, ideograms, faces, novel three-dimensional objects) increases the likelihood that they will be favored over nonpresented items later on during a preference judgment.144 Using this task to investigate the effects of time, postexposure sleep, and cerebral lateralization, it was found that although detrimental in both hemispheres, total sleep deprivation did not affect performances to the same extent, suggesting interhemispheric differences in sleep-dependent processes of memory consolidation.148 Indeed, sleep deprivation abolished all memory effects only in the right hemisphere.148 Interhemispheric differences in wake- and sleep-dependent memory consolidation processes should therefore be investigated in more detail in the future.
SLEEP-DEPENDENT MECHANISMS OF BRAIN PLASTICITY AND MEMORY CONSOLIDATION In this section, we provide a rapid overview of specific mechanisms viewed as particularly important to support sleep-stage–related processes of brain plasticity and memory consolidation: PGO waves, hippocampal rhythms, and sleep spindles. PGO Waves Ponto-geniculo-occipital waves are prominent phasic bioelectrical potentials, closely related to rapid eye movements, occurring in isolation or in bursts during the transition from NREM to REM sleep or during REM sleep itself. PGO waves are a fundamental process of REM sleep in animals, playing a significant role in central nervous system maturation.34 Intracerebral recordings in epileptic patients,149 and noninvasive PET,150 fMRI,151 and magnetoencephalography152 scanning in healthy volunteers, indicate that the rapid eye movements observed during REM sleep are generated by mechanisms similar or identical to PGO waves in animals. Most importantly, animal data have suggested that PGO activity during REM sleep is associated with learning and memory consolidation,34 suggesting that activation of this generator during
REM sleep may represent one of the natural physiologic processes of memory, possibly through the synchronization of fast oscillations that would convey experiencedependent information in thalamocortical and intracortical circuits.153 Despite evidence from animal studies, a direct demonstration of the association between PGO activity and memory consolidation during REM sleep in humans has yet to be done. Nonetheless, the hypothesis is supported by studies showing an increase in the density of rapid eye movements during REM sleep after procedural learning40,154 and intensive learning periods,39 or a correlation between retention levels after learning Morse code and the frequency of rapid eye movements during posttraining REM sleep.37 Also, presenting sounds in the background while learning a complex logic task in the awake state enhanced next-morning performance when the same sounds were presented again during REM sleep. Most interestingly, however, enhancement was found only when sounds were coincident with the bursts of posttraining rapid eye movements that reflect PGO activity,74 further suggesting the association of REM sleep with memory consolidation processes. Also, it has been proposed that during human phasic REM sleep, propagation of PGO activity in the parahippocampal or hippocampal area is linked with verbal learning performance and mnemonic retention values.155 Hippocampal Rhythms The theta rhythm (i.e., regular sinusoidal oscillations in the frequency range of 4 to 7 Hz recorded in the hippocampal EEG) is a prominent signature of REM sleep in mammals, including humans.156 Theta represents the online state of the hippocampus, believed to be critical for temporal coding or decoding of active neuronal ensembles and the modification of synaptic weights.156 Additionally, population synchrony of pyramidal cells is maximal during quiet wakefulness and SWS associated with sharp waves (i.e., sharp waves of SWS are the consequence of synchronous discharge of bursting CA3 pyramidal neurons) and fast ripples (140 to 200 Hz). Sharp waves and ripples during SWS constitute good candidates to induce neuronal plasticity.157 Thus, the alternation between both REM sleep/active-awake theta activity and SWS/quiet-wakefulness sharp waves and ripples could contribute to brain plasticity. According to the two-stage model of memory formation,157 neocortical information activates the entorhinal input, which will cause synaptic changes to occur in the hippocampal CA3 system during learning associated with active waking and REM sleep theta rhythmic activity in the hippocampus. In the subsequent nontheta state (i.e., SWS, but possibly also quiet wakefulness), previously activated neurons are reactivated during sharp wave bursts, and the memory representation transiently stored in the CA3 region can be transferred to neocortical targets for the long term. Accordingly, human brain imaging studies have demonstrated after spatial navigation in a virtual town the experience-dependent reactivation of hippocampal activity during SWS, but not during REM sleep.58 Similarly, an odor-cued activation in hippocampus-related memory areas was observed during SWS,77 eventually leading to
overnight performance improvement. These studies also found long-term transfer of hippocampal memories toward neocortical stores,31,83 an effect disturbed by sleep deprivation on the posttraining night.31 In parallel, neuroimaging data have suggested the offline persistence of memory-related cerebral activity during active wakefulness and its dynamic evolution in the hippocampus.21 Although this model is well supported by the these data and may account for the offline processing of declarative material, the fact that reactivations have been observed during both posttraining REM sleep56,57 and wakefulness21 after procedural, nonhippocampal learning suggests that other routes for consolidation exist, which should likewise be investigated. Sleep Spindles and Slow Waves Traditionally, the sleep spindle has been defined as the presence of rhythmic 12- to 14-Hz activity lasting a minimum of 0.5 seconds and displaying an increasing, then decreasing, amplitude envelope. This definition has expanded to 12 to 16 Hz and includes both slow (11.5- to 14-Hz) and fast (14- to 16-Hz) spindles, which may reflect two separate spindle generators with different brain topographies.158,159 Although spindles occur most frequently in stage 2, they also appear to a lesser extent in delta sleep (stages 3 and 4). A negative reciprocal relationship between SWA and spindle occurrence seems to exist in NREM sleep.158 Spindle mechanisms have been studied in the cat.160,161 They are considered to result from intrinsic properties and from the connectivity patterns of the thalamic neurons. Spindle generation seems an ideal mechanism for neural plasticity.96 Therefore, spindles may play an important role in the processes of memory consolidation during sleep. Accordingly, several studies have reported links between the consolidation of verbal declarative memory and increases in spindle density during the nocturnal and diurnal sleep that follows learning.41,42,44,49 Verbal memory association with spindle density increased in the left frontocentral scalp location at night, whereas memory for faces did not elicit this effect.49 Similarly, postlearning increases are observed during daytime napping in low-frequency spectral power (11.25 to 13.75 Hz), particularly in the left frontal scalp region. Additionally, these increases are positively correlated with learning performance in the difficult word-association task, but not in the easy word-association task or control condition.42 Similarly for procedural memory, posttraining stage 2 sleep deprivation impaired memory for a perceptual–motor task,27 and the amount of stage 2 correlated with learning progress on the fingertapping task.109,111 Also, intensive training on perceptual– motor learning tasks results in marked increases in number and density of spindles during subsequent stage 2 sleep47 as well as an increase in average spindle duration.51 Posttraining increases in slow sigma power (12 to 14 Hz) have been observed in frontal and occipital regions with no changes in high-frequency sigma.51 Napping studies using the same task provided similar results: subjects who regularly napped showed positive correlations between postnap performance and stage 2 spindle density.162 In this case, low-frequency spindles (12 to 14 Hz) were correlated with performance at frontal sites, whereas high-frequency
CHAPTER 29 • Memory Processing in Relation to Sleep 343
spindle activity (14 to 16 Hz) was correlated with performance at central and parietal sites. Moreover, subjects who did not nap on a regular basis did not benefit from an experimental nap in the study design.162 In another study using a longer (60- to 90-minute) nap after motor performance for the finger-tapping task, it was found that those subjects with the most significant increases in motor performance also had the largest increases in stage 2 sleep, with a significant correlation between spindle density and postnap performance that was confined to the learning hemisphere.46 Finally, a marked increase in stage 2 spindle densities was observed after acquisition of the finger-tapping task, but not after a control motor task, indicating that the changes were not the result of general motor activity.110 That spindles have been related to consolidation for both declarative and nondeclarative memories indicates their prominent role in sleep-dependent memory processes. Still, it should be noticed that although stage 2 has been the predominant stage of sleep involved, closer examination showed that REM sleep appeared to be more important for some participants after perceptual–motor learning.128 To explain this, it has been proposed that there are two independent neural systems for sleep-dependent memory consolidation, one involved with stage 2 sleep, the other with REM sleep. In this respect, subjects who report the perceptual–motor task as being a novel experience show an increase in density of rapid eye movements during postacquisition REM sleep, but no changes in stage 2 sleep parameters. On the other hand, those individuals who find the task to be similar to others they have already experienced in their lives (as shown by reasonably good performance on the first few trials of the task) will show an increase in spindle density during stage 2 sleep but no changes in REM sleep. These latter subjects are considered to be refining an existing motor program rather than learning a new one.28 In addition, spindle oscillations are grouped and regulated by slow waves163 that are thought to be important for memory consolidation, as discussed earlier. Indeed, experience-dependent regional increases in delta activity have been shown during NREM sleep,63 suggesting local homeostatic mechanisms for memory consolidation.62 Furthermore, coherence was found to increase after learning in the depolarizing phase of the slow oscillations below the 1-Hz frequency.163 On the other hand, transcranial direct current stimulation that may contribute to modulation of cortical excitability was found to improve the overnight retention of declarative memories when applied during NREM sleep at a slow rhythm whose frequency (less than 1 Hz) approximates these slow oscillations,75 further suggesting a facilitatory role of slow oscillatory EEG activity in neuronal plasticity and the ongoing transformations and consolidation of memory traces.
Conclusions Although their results are at times elusive, studies supporting the proposal that sleep is an integral component in the offline processes that subtend memory consolidation have now substantially flourished. Still, when compared with other domains of cognition, the field remains
344 PART I / Section 4 • Physiology in Sleep
underdeveloped. There is an urgent need for replication and validation of studies to confirm or disprove a series of hypotheses regarding which memories can benefit from sleep, and in which circumstances this can occur. Furthermore, the mechanisms that support these processes remain to be fully elucidated and understood. Most important, we need to understand how sleep disorders and the numerous pathologies accompanied by sleep disturbances affect cognitive processes, especially learning and memory, and to understand the extent to which sleep manipulation helps or speeds up resolution of these pathologies. This is an exciting area of research for sleep specialists, neuroscientists, and cognitive psychologists, who should join forces to help patients suffering from sleep-related afflictions.
❖ Clinical Pearls In the long term, patients with inadequate REM sleep may be expected to experience more difficulty learning novel cognitive procedures than same-age individuals with healthy sleep. Patients exhibiting little or impaired slow-wave sleep may be impaired in declarative learning (e.g., memorizing large amounts of factual material). Those with specific stage 2 sleep disturbances can be expected to have trouble refining and performing reasonably simple motor skill tasks. Patients with poor sleep quality or pathologies affecting all sleep stages can be expected to have deteriorated long-term performance with all types of memory. Sleep is only a part of memory consolidation processes, however, so these deficits may manifest in a subtle manner and may, to a certain extent, be compensated for by alternative consolidation strategies. In-depth clinical investigation of memory problems should always be done by a trained neuropsychologist.
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113. Kuriyama K, Stickgold R, Walker MP. Sleep-dependent learning and motor-skill complexity. Learn Mem 2004;11:705-713. 114. Korman M, Doyon J, Doljansky J, Carrier J, et al. Daytime sleep condenses the time course of motor memory consolidation. Nat Neurosci 2007;10:1206-1213. 115. Buchegger J, Fritsch R, Meier-Koll A, Riehle H. Does trampolining and anaerobic physical fitness affect sleep? Percept Mot Skills 1991;73:243-252. 116. Gais S, Plihal W, Wagner U, Born J. Early sleep triggers memory for early visual discrimination skills. Nature Neurosci 2000;3: 1335-1339. 117. Fenn KM, Nusbaum HC, Margoliash D. Consolidation during sleep of perceptual learning of spoken language. Nature 2003;425: 614-616. 118. Gaab N, Paetzold M, Becker M, Walker MP, et al. The influence of sleep on auditory learning: a behavioral study. Neuroreport 2004;15:731-734. 119. Matarazzo L, Franko E, Maquet P, Vogels R. Offline processing of memories induced by perceptual visual learning during subsequent wakefulness and sleep: a behavioral study. J Vis 2008;8: 71-79. 120. Gais S, Rasch B, Wagner U, Born J. Visual-procedural memory consolidation during sleep blocked by glutamatergic receptor antagonists. J Neurosci 2008;28:5513-5518. 121. Walker MP, Stickgold R, Jolesz FA, Yoo S-S. The functional anatomy of sleep-dependent visual skill learning. Cereb Cortex 2005;15:1666-1675. 122. Mednick S, Nakayama K, Stickgold R. Sleep-dependent learning: a nap is as good as a night. Nat Neurosci 2003;6:697-698. 123. Mednick SC, Nakayama K, Cantero JL, Atienza M, et al. The restorative effect of naps on perceptual deterioration. Nat Neurosci 2002;5:677-681. 124. Karni A, Tanne D, Rubenstein S, Askenasy JJM, et al. Dependence on REM sleep of overnight improvement of a perceptual skill. Science 1994;265:679-682. 125. Backhaus J, Junghanns K. Daytime naps improve procedural motor memory. Sleep Med 2006;7:508-512. 126. Smith C, MacNeill C. Memory for motor task is impaired by stage 2 sleep loss. J Sleep Res 1992;21:139. 127. Cohen DA, Robertson EM. Motor sequence consolidation: constrained by critical time windows or competing components. Exp Brain Res 2007;177:440-446. 128. Peters KR, Smith V, Smith CT. Changes in sleep architecture following motor learning depend on initial skill level. J Cogn Neurosci 2007;19:817-829. 129. Cohen DA, Pascual-Leone A, Press DZ, Robertson EM. Off-line learning of motor skill memory: a double dissociation of goal and movement. PNAS USA 2005;102:18237-18241. 130. Gomez Beldarrain M, Astorgano AG, Gonzalez AB, GarciaMonco JC. Sleep improves sequential motor learning and performance in patients with prefrontal lobe lesions. Clin Neurol Neurosurg 2008;110:245-252. 131. Siengsukon CF, Boyd LA. Sleep enhances implicit motor skill learning in individuals poststroke. Top Stroke Rehabil 2008;15: 1-12. 132. Marinelli L, Crupi D, Di Rocco A, Bove M, et al. Learning and consolidation of visuo-motor adaptation in Parkinson’s disease. Parkinsonism Relat Disord 2009;15:6-11. 133. Karni A, Sagi D. Where practice makes perfect in texture discrimination: evidence for primary visual cortex plasticity. PNAS USA 1991;88:4966-4970. 134. Atienza M, Cantero JL, Stickgold R. Posttraining sleep enhances automaticity in perceptual discrimination. J Cogn Neurosci 2004; 16:53-64. 135. Gottselig JM, Hofer-Tinguely G, Borbely AA, Regel SJ, et al. Sleep and rest facilitate auditory learning. Neuroscience 2004;127: 557-561. 136. Roth DA, Kishon-Rabin L, Hildesheimer M, Karni A, et al. A latent consolidation phase in auditory identification learning: time in the awake state is sufficient. Learn Mem 2005;12:159164. 137. Dumay N, Gaskell MG. Sleep-associated changes in the mental representation of spoken words. Psychol Sci 2007;18:35-39. 138. Hotermans C, Peigneux P, Maertens de Noordhout A, Moonen G, et al. Early boost and slow consolidation in motor skill learning. Learn Mem 2006;13:580-583.
139. Fischer S, Hallschmid M, Elsner AL, Born J. Sleep forms memory for finger skills. PNAS USA 2002;99:11987-11991. 140. Peigneux P, Maquet P, Meulemans T, Born J. Striatum forever despite sequence learning variability: a random effect analysis of PET data. Hum Brain Mapp 2000;10:179-194. 141. Cajochen C, Knoblauch V, Wirz-Justice A, Krauchi K, et al. Circadian modulation of sequence learning under high and low sleep pressure conditions. Behav Brain Res 2004;151:167-176. 142. Spencer RM, Sunm M, Ivry RB. Sleep-dependent consolidation of contextual learning. Curr Biol 2006;16:1001-1005. 143. Albouy G, Sterpenich V, Balteau E, Vandewalle G, et al. Both the hippocampus and striatum are involved in consolidation of motor sequence memory. Neuron 2008;58:261-272. 144. Butler LT, Berry DC. Understanding the relationship between repetition priming and mere exposure. Br J Psychol 2004;95: 467-487. 145. Wagner U, Hallschmid M, Verleger R, Born J. Signs of REM sleep dependent enhancement of implicit face memory: a repetition priming study. Biol Psychol 2003;62:197-210. 146. Rauchs G, Lebreton K, Bertran F, Pelevin A, et al. Effects of partial sleep deprivation on within-format and cross-format priming. Sleep 2006;29:58-68. 147. Wagner U, Fischer S, Born J. Changes in emotional responses to aversive pictures across periods rich in slow-wave sleep versus rapid eye movement sleep. Psychosom Med 2002;64:627-634. 148. Peigneux P, Schmitz R, Willems S. Cerebral asymmetries in sleepdependent processes of memory consolidation. Learn Mem 2007; 14:400-406. 149. Salzarulo P, Lairy GC, Bancaud J, Munari C. Direct depth recording of the striate cortex during REM sleep in man: are there PGO potentials? EEG Clin Neurophysiol 1975;38:199-202. 150. Peigneux P, Laureys S, Fuchs S, Delbeuck X, et al. Generation of rapid eye movements during paradoxical sleep in humans. Neuroimage 2001;14:701-708. 151. Wehrle R, Czisch M, Kaufmann C, Wetter TC, et al. Rapid eye movement-related brain activation in human sleep: a functional
CHAPTER 29 • Memory Processing in Relation to Sleep 347 magnetic resonance imaging study. Neuroreport 2005;16:853857. 152. Ioannides AA, Corsi-Cabrera M, Fenwick PB, del Rio Portilla Y, et al. MEG tomography of human cortex and brainstem activity in waking and REM sleep saccades. Cereb Cortex 2004;14:56-72. 153. Amzica F, Steriade M. Progressive cortical synchronization of ponto-geniculo-occipital potentials during rapid eye movement. Neuroscience 1996;72:309-314. 154. Smith C. Changes in density of REM sleep following acquisition of cognitive procedural tasks in humans. Actas Fisiol 2001;7:27. 155. Bodizs R, Bekesy M, Szucs A, Barsi P, et al. Sleep-dependent hippocampal slow activity correlates with waking memory performance in humans. Neurobiol Learn Mem 2002;78:441-457. 156. Buzsaki G. Theta oscillations in the hippocampus. Neuron 2002;33:325-340. 157. Buzsaki G, Carpi D, Csicsvari J, Dragoi G, et al. Maintenance and modification of firing rates and sequences in the hippocampus: does sleep play a role. In: Maquet P, Smith C, Stickgold R, editors. Sleep and brain plasticity. Oxford, UK: Oxford University Press; 2003. p. 247-269. 158. De Gennaro L, Ferrara M. Sleep spindles: an overview. Sleep Med Rev 2003;7:423-440. 159. Schabus M, Dang-Vu TT, Albouy G, Balteau E, et al. Hemodynamic cerebral correlates of sleep spindles during human non-rapid eye movement sleep. PNAS USA 2007;104:13164-13169. 160. Amzica F, Steriade M. Integration of low-frequency sleep oscillations in corticothalamic networks. Acta Neurobiol Exp 2000;60: 229-245. 161. Steriade M. Corticothalamic resonance, states of vigilance and mentation. Neuroscience 2000;101:243-276. 162. Milner CE, Fogel SM, Cote KA. Habitual napping moderates motor performance improvements following a short daytime nap. Biol Psychol 2006;73:141-146. 163. Molle M, Marshall L, Gais S, Born J. Learning increases human electroencephalographic coherence during subsequent slow sleep oscillations. Proc Natl Acad Sci U S A 2004;101:13963-13968.
Sensory and Motor Processing during Sleep and Wakefulness John H. Peever and Barry J. Sessle Abstract The loss of consciousness upon entrance into sleep is accompanied by a reduction in both sensory and motor processing. For example, sleep triggers loss of muscle tone and motor reflexes and it acts to reduce sensory perception (e.g., of auditory stimuli) that promotes and, in fact, enables maintenance of sleep processes themselves. Sensory and motor processes and their integration are also differentially affected during different sleep states. For example, respiratory reflexes, such as the ventilatory response to hypercapnia, are reduced during non–rapid eye movement (NREM) sleep, whereas they are virtually abolished during rapid eye movement (REM) sleep. Such observations suggest that sensory processes and their accompanying motor output responses are not simply affected by global sleep phenomenon, but that discrete NREM and REM sleep mechanisms modulate and control these processes in a sleep-state–dependent manner. Changes in sensory processing during sleep also affect the somatosensory pathways that transduce and relay nociceptive signals both to and within the central nervous system (CNS).
Sleep has a profound impact on the mechanisms by which the CNS transduces and expresses sensory and motor commands. Transmission of sensory information to the CNS is markedly attenuated during sleep, which enables sleep continuity; however, there are circumstances whereby some sensory inputs such as pain may influence sleep patterns. Sleep mechanisms not only modulate the pathways that relay sensory commands to the nervous system, but also affect the manner in which regulatory brain centers such as the thalamocortical circuits relay afferent inflow to appropriate sensory and motor control centers, including somatic motoneurons. The neurocircuits that generate sleep–wake states also affect the fundamental integration and expression of sensorimotor processes. This chapter is divided in three parts: pathways and mechanisms of sensory processes, especially those related to pain; the integration of sensory and motor processes; and finally, respiratory reflexes. Each part considers these functions during sleep and wakefulness because our main objective is to provide an overview of how changes in sensory and motor processes and their integration during sleep contribute to both normal and abnormal physiology. We also discuss the mechanisms by which sleep influences the central processing of nociceptive information and how pain itself may affect sleep. Although all sensory and motor systems are affected by sleep, we primarily focus on how sleep impacts the sensorimotor processes of spinal reflexes and the respiratory responses to chemical (e.g., CO2) and mechanical stimuli (e.g., airway pressure). We focus on these physiological systems because it is important for the clinician to realize that sleep-related changes in sensorymotor processing and their integration have a direct impact on human health and disease and can underlie common and serious sleep disorders. (see Chapter 124 for fibromyalgia; Chapter 126 for pain; Section 13 for sleep-disor348
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30
Not only are these sensory mechanisms affected by sleep, but sleep is also affected by nociceptive processes. Interactions between pain and sleep are involved in sleep disturbances in patients suffering from chronic pain such as those afflicted with cancer or fibromyalgia. Clarification of sleep-pain interactions could be used to develop new or improved strategies for enhancing sleep quality in chronic pain patients. Importantly, abnormal sensory and motor functions during different sleep states underlie and contribute to common sleep disorders and disturbances. For example, reduced chemical control of breathing during sleep plays a pivotal role in congenital central hypoventilation syndrome—a sleeprelated respiratory disorder that is characterized by severe and often life-threatening hypoventilation during sleep, and pathological motor control during REM sleep underlies REM sleep behavior disorder. Abnormal motor control and sensory processes also play a central role in sleep disorders such as periodic limb movement disorder (PLMD), narcolepsy/ cataplexy, and obstructive sleep apnea (OSA).
dered breathing; and, for movement disorders during sleep [e.g., PLMD and bruxism] see Chapters 90 and 99).
MODULATION OF SENSORY PROCESSES DURING SLEEP AND WAKEFULNESS Sensory Pathways and Mechanisms The body’s peripheral tissues (e.g., skin, mucosa, muscles, and joints) are supplied by small-, medium-, and largediameter primary afferent nerve fibers. The medium- and large-diameter afferents are myelinated and comprise Aβ and Aδ afferents, most of which terminate in the tissues as sense organs (receptors) detecting tactile or proprioceptive stimuli applied to the tissues. However, some of the Aδ afferents, along with unmyelinated C-fiber afferents, terminate in the tissues as free nerve endings, many of which act as nociceptors—that is, they are the sense organs that respond to noxious stimulation of the peripheral tissues; other Aδ or C-fiber afferent terminals function as thermoreceptors responding to warming or cooling stimuli. The activation of nociceptors may result in the elicitation of action potentials in the Aδ or C-fiber afferents, and these action potentials are conducted along the afferents into the CNS and thereby provide the brain with sensory-discriminative information about the location, quality, intensity, and duration of the noxious stimulus.1-4 In some cases, a prolonged increase in excitability of the nociceptors may occur after tissue injury or inflammation, to the stage where they become more responsive to noxious stimulation or even start responding to stimuli that normally are innocuous. Thus, this process of “peripheral sensitization” may contribute to the hyperalgesia (increased sensitivity to a stimulus that is normally painful) and
CHAPTER 30 • Sensory and Motor Processing during Sleep and Wakefulness 349
allodynia (pain resulting from a stimulus that does not normally provoke pain) that occur in certain pain conditions. Numerous chemical mediators are involved in peripheral sensitization of nociceptive endings as well as in their activation by noxious stimuli, including several that also have actions in the CNS (e.g., glutamate, serotonin [5-HT], noradrenaline).5-7 The primary afferents in spinal nerves supplying skin, viscera, and musculoskeletal tissues of the limbs, trunk, and neck project to the spinal cord and synapse on secondorder neurons that are predominantly located in the spinal dorsal horn and the dorsal column nuclei.3,4 The afferents innervating orofacial tissues project mainly to the trigeminal brainstem sensory nuclear complex (V-BSNC). This structure is subdivided into the main or principal sensory nucleus and the spinal tract nucleus, which from rostral to caudal comprises three subnuclei known as oralis, interpolaris, and caudalis.2,8,9 The subnucleus caudalis has many anatomical and physiological features that are analogous to those of the spinal dorsal horn.8 Another brainstem region receiving primary afferent inputs is the solitary tract nucleus (NTS); it contains second-order neurons on which respiratory and alimentary tract afferents, taste afferents, and cardiovascular and chemoreceptor and baroreceptor afferents synapse, and plays an important role in autonomic (e.g., respiratory, cardiovascular) functions, taste, and reflexes evoked from the respiratory and alimentary tracts (e.g., cough, swallow). The spinal Aδ and Aβ primary afferents conducting actions potentials evoked by tactile or proprioceptive stimuli terminate principally in the spinal dorsal horn and dorsal column nuclei, where they may activate second-order nonnociceptive neurons (e.g., low-threshold mechanoreceptive [LTM] neurons). Analogous trigeminal afferents terminate at all levels of the V-BSNC. The Aδand C-fiber primary afferents carrying thermoreceptive or nociceptive information predominantly terminate in the spinal dorsal horn (Fig. 30-1) and subnucleus caudalis (Fig. 30-2). The main excitatory neurotransmitters or neuromodulators released from the central terminals of the nociceptive afferents are glutamate and substance P.4,8 In addition to LTM and thermoreceptive neurons, there are nociceptive neurons that are of two main types: nociceptive-specific (NS) neurons that are excited only by noxious stimuli (e.g., pinch, heat) applied to a localized receptive field in peripheral tissues (e.g., skin), and wide dynamic range (WDR) neurons that are excited by nonnoxious (e.g., tactile) stimuli as well as by noxious stimuli. Nociceptive afferent inputs relayed to many neurons in the spinal dorsal horn and subnucleus caudalis appear to derive exclusively from superficial (e.g., cutaneous) tissues and endow these neurons with coding properties, suggesting that they are critical neural elements for the detection and discrimination of superficial pain. However, nociceptive information from deep tissues (e.g., muscle, joint, viscera) is predominantly processed by subsets of these cutaneous nociceptive spinal dorsal horn or caudalis neurons that receive extensive convergent afferent inputs from these tissues. These convergence patterns appear to underlie the CNS mechanisms contributing to deep pain, and may also explain the poor localization, spread, and referral of pain that are typical of pain conditions involving
TRANSMISSION
MODULATION Cortex
A
H
Thalamus PAG
RVM Spinothalamic tract
Midbrain
Medulla
Spinal cord
Figure 30-1 Major nociceptive pathways from spinal tissues. A schematic of the ascending and descending pathways that transmit and modulate nociceptive signals from spinally innervated tissues. Nociceptive afferents synapse onto spinothalamic neurons in the spinal dorsal horn, which in turn relay afferent signals to the thalamus and then to the cortex (e.g., anterior and posterior cingulate cortex). Ascending spinothalamic neuronal inputs are also modulated by descending pathways located in higher brain centers such as the cortex, amygdala (A) and hypothalamus (H). Such descending pathways convergence in the periaqueductal gray (PAG) and then in the rostral ventral medulla (RVM) before synapsing onto spinothalamic neurons. (From Price DD. Psychological mechanisms of pain and analgesia. Seattle: IASP Press; 1999, p. 250-271.)
deep tissues. Some of the convergent afferent inputs also may be “unmasked” in pathophysiological situations and become more effective in exciting the nociceptive neurons. Neuroplastic changes can be manifested in caudalis and spinal dorsal horn (and thalamocortical) nociceptive neurons as a result of nociceptive afferent inputs evoked by injury or inflammation.4,8 This neuroplasticity results from the release from the nociceptive afferent terminals of neurochemicals, such as glutamate, that act via N-methyld-aspartate receptor mechanisms to induce a cascade of intracellular events in the nociceptive neurons. These events can result in an increase in neuronal excitability, reflecting what has been termed a “central sensitization” of the nociceptive neurons. The neuroplastic alterations in the nociceptive neuronal properties, and in the reflex neuromuscular changes and other behavioral activities that may be induced by injury or inflammation, represent mechanisms that along with peripheral sensitization (discussed previously) can explain the allodynia and hyperalgesia as well as pain spread and referral that characterize several pain conditions. Some neurons in the spinal dorsal horn, dorsal column nuclei, solitary tract nucleus, and the V-BSNC give rise to axons that ramify within that structure and serve to modulate the activity of other neurons. Nevertheless, many neurons in these various structures project to other spinal cord or brainstem regions including the reticular formation, raphe nuclei, and spinal ventral horn or cranial nerve motor nuclei. Such connections provide the central circuitry underlying autonomic and muscle reflex responses to peripheral stimuli or provide sensory inputs to neurons in some of these structures that contribute to descending modulatory systems (discussed hereafter). In view of the
350 PART I / Section 4 • Physiology in Sleep
cate a role for them in defining the spatiotemporal features of peripheral stimuli, and thus in the sensory-discriminative dimension of pain. In contrast, the spatiotemporal coding properties of most nociceptive neurons in the medial thalamic nuclei and posterior nuclear group and their connections to areas such as the anterior cingulate cortex are more suggestive of a role in the motivational or affective dimensions of pain. These features are generally consistent with brain imaging findings in humans that noxious stimuli activate several cortical regions, including the somatosensory cortex and the anterior cingulate cortex.13,14
Cerebral cortex
Sensory inputs • Facial skin • Oral mucosa • Tooth • Cranial vessels • Muscle • TMJ
Thalamus
Main sensory
Motor nuclei RF
Brainstem
Oralis
Interpolaris
Trigeminal ganglion Caudalis
Spinal cord
Figure 30-2 Major somatosensory pathway from the face and mouth. Trigeminal primary afferents project via the trigeminal ganglion to second-order neurons in the trigeminal brainstem sensory nuclear complex. These neurons may project to neurons in higher levels of the brain (e.g., thalamus) or in brainstem regions such as cranial motor pools or the reticular formation (RF). Not shown are the projections of some cervical nerves and cranial nerve VII, X, and XII afferents to the trigeminal complex and the projection of many VII, IX, and X afferents to the solitary tract nucleus. TMJ, temporomandibular joint. (From Sessle BJ. Acute and chronic craniofacial pain: brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates. Crit Rev Oral Biol Med 2000;11: 57-91.)
role that the raphe and reticular formation areas play in wakefulness and sleep, projections to these areas also may provide neural substrates by which noxious stimulation may influence sleep and consciousness.10 Many neurons in the spinal dorsal horn, dorsal column nuclei, NTS, and V-BSNC also (or instead) project to the contralateral thalamus (see Figs. 30-1 and 30-2), either directly or via multisynaptic paths. The main regions of the thalamus that receive and relay this sensory information are the ventrobasal complex (or ventroposterior nucleus in the primate) as well as the medial thalamus and the posterior nuclear group.3,11,12 These thalamic regions contain LTM and thermoreceptive neurons that project to the overlying somatosensory cerebral cortex, where their relayed signals are processed by similar neurons to provide for the detection and localization of tactile and nonnoxious thermal stimuli. In addition, NS and WDR neurons occur in these thalamic regions and most have spatiotemporal coding properties and connections to NS and WDR neurons in the overlying somatosensory cortex that indi-
Modulation of Sensory Processes Including Those Related to Pain In addition to its role in transferring to the cortex neural signals used for sensory, affective, and motivational functions, the thalamus is also the site of modulatory influences involved in the state of consciousness. The thalamocortical transfer of sensory information is subject to modulation or “gating” as a result of facilitatory and inhibitory processes exerted by local neural circuits or inputs to the thalamus and cortex from other CNS regions such as the reticular formation.15-17 These gating process is especially apparent during changes in behavioral state and consciousness such as during NREM sleep, a period characterized by a marked attenuation during NREM sleep so that sleep continuity is not disrupted. Nonetheless, modification of somatosensory transmission can also occur at spinal and brainstem levels, and may also be operational in varying degrees during different behavioral states and indeed may contribute to specific features of these states, for example, the hypotonia of REM sleep. These modulatory mechanisms may involve neural circuits within the spinal dorsal horn, V-BSNC, and NTS and adjacent regions as well as inputs from primary afferents and descending inputs from reticular formation, raphe nuclei locus coeruleus (LC), and cerebral cortex, to name a few. Various neurochemicals are used by these circuits and inputs, for example, gamma-aminobutyric acid (GABA), noradrenaline, 5-HT, and opioids. In the case of nociceptive transmission, the variety of inputs and interconnections in spinal dorsal horn and subnucleus caudalis noted earlier provide the basis for considerable interaction between the various afferent inputs derived from peripheral tissues (e.g., so-called segmental or afferent inhibition) or from intrinsic brain regions (e.g., descending inhibition). Examples include the interneuronal system within the substantia gelatinosa of the spinal dorsal horn and subnucleus caudalis, and the descending inputs to these structures from the periaqueductal gray/ raphe nuclei, reticular formation, cerebral cortex and several other brain centers (see Fig. 30-1). Several neurochemicals, including GABA, 5-HT, noradrenaline, dopamine, hypocretin, cholecystokinin, prolactin, melatonin, and opioids (e.g., enkephalins), provide a neurochemical substrate by which many of the afferent and descending inputs can exert their modulatory actions on nociceptive transmission; it is notable that many of these neurochemicals and descending influences also are involved in sleep mechanisms.15,16 Inhibitory influences exerted by many of these inputs on nociceptive neurons have been implicated as intrinsic mechanisms contributing to the analgesic
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effects of several procedures used to control pain, including deep brain stimulation, acupuncture, and opiate-related (e.g., morphine) and 5-HT agonist (e.g., amitriptyline) drugs. Some, instead, have a role in facilitating nociceptive transmission, for example, in the central sensitization process noted earlier.4,8 Processing Related to Pain during Sleep and Wakefulness As noted previously, sensory transmission through the spinal cord and brainstem, as well as thalamus and cerebral cortex, may be modulated during sleep and thereby may contribute, for example, to the decreased responsiveness to external stimuli during NREM sleep to favor sleep continuity. The modulatory influences on nociceptive neurons of behavioral factors, including state of alertness, attention, and distraction, are just some examples where the higher brain centers involved in these states give rise to descending influences operating at these levels and thereby contribute to the influence of these behavioral factors on pain. Unfortunately, although much has been learned independently about pain and sleep, there has been only limited investigation of how sleep affects pain and vice versa (see Chapter 126). There is evidence that sensory processing, including that related to pain, is reduced in sleep states compared to wakefulness, but the underlying processes are still unclear. Nonetheless, with the advent of studies in chronic (awake and sleeping) animal preparations as well as more conventional anesthetized preparations, as well as some correlated studies in humans, it has been shown that somatosensory transmission through several ascending pathways originating in the spinal dorsal horn is tonically diminished during REM sleep; nonetheless, the gating process is quite complex during REM sleep because modulation of somatosensory transmission may be different between phasic and tonic REM sleep.18 There is also evidence of complex gating during NREM sleep, including findings that sensory transmission through some ascending tracts may be attenuated in some stages of NREM sleep and that this is reflected in reduced thalamic and cortical activity in these stages.16-20 Recent studies also suggest that the modulation of spinal sensory transmission during REM sleep appears to involve presynaptic inhibition as well as postsynaptic inhibitory mechanisms, thus supporting earlier findings that presynaptic regulatory processes are important in REM sleep and contribute to the reduction in motor activity during this sleep phase (discussed hereafter). There is evidence that the presynaptic inhibitory processes in the spinal cord utilize GABA, and the postsynaptic inhibition utilizes glycine. Several other neurochemicals released from neurons in higher brain centers have also been implicated in the sleepdependent modulation of spinal cord neurons or their thalamic targets; these include 5-HT, noradrenaline, acetylcholine, and hypocretin.16,18-20 A complex gating mechanism has also been documented in the rostral components of the V-BSNC that is state dependent, for example, the activity of many rostral V-BSNC neurons and their responses to sensory inputs, including those evoked by noxious (tooth pulp) stimuli, may be presynaptically and postsynaptically inhibited during REM sleep through respectively GABA and gly-
cine-based modulatory processes.16,18-20 However, comparable investigations have not been made in more caudal V-BSNC nociceptive (e.g., caudalis) neurons, which as noted previously have many features analogous to those of spinal dorsal horn nociceptive neurons and play crucial roles in trigeminal nociceptive transmission; thus, if and how sleep stages affect their properties is an important field requiring future study. It should also be noted that the state-dependent processes on spinal and V-BSNC nociceptive transmission that have been revealed have only been studied in acute sleep models, and it is unclear what neural modulatory processes are involved in the more clinically challenging sleep–pain interactions that may occur in chronic pain conditions (discussed later). Furthermore, if nociceptive afferents inputs do reach cortical levels and result in the conscious feeling of pain, then sleep may be disrupted to alert the individual of the noxious event. Clinical Correlates When healthy subjects are sleeping in conditions favoring good sleep quality (e.g., a quiet, comfortable environment), low-intensity stimuli may have little or no effect on sleep quality, whereas a loud noise or a sudden pain attack during sleep can produce awakening that might trigger anxiety or concern that impedes subsequent sleep21 (see Chapter 126). Nonetheless, there are several other factors in addition to pain that can influence sleep quality (e.g., past experiences, psychological variables, anxiety, mood, life style, health status, and any concomitant pain–sleep interactions). In the case of pain patients, they may experience long delays in falling asleep, as well as sleep-stage shifts, frequent sleep arousals, and undesirable body movements; furthermore, some analgesic drugs (e.g., opioids) may affect sleep patterns (see Chapter 126). Although the majority of patients with chronic pain report that pain occurred before or at the onset of poor sleep, suggesting that pain may have a direct effect on sleep quality, studies using experimental noxious stimuli have revealed only minor sleep disturbance in healthy subjects.22,23 However, these studies have elicited acute pain, and it remains unclear the mechanisms by which chronic pain may negatively influence sleep quality. Nonetheless, as noted earlier, chronic pain can be associated with neuroplastic changes in spinal dorsal horn, V-BSNC, and thalamocortical relays, so there is potential for these or other pain-related changes to have effects on sleep; however, how these changes influence the brainstem and thalamocortical circuits involved in sleep is largely unknown.16 The reverse situation, that poor sleep might be a significant cause of pain, is also unclear. There are reports that experimental sleep deprivation or fragmentation can lead to pain, and that restoration of sleep quality (continuity and duration) can reduce this pain in humans. Likewise in animals, sleep limitation leads to a reduction in nociceptive threshold during wakefulness that is reversed once sleep is restored. However, some studies suggest that other factors (e.g., fatigue, mood changes, cognitive impairment) may be involved24 and thereby raise doubts whether poor sleep is indeed a dominant or a pathognomonic cause of pain. Thus, at present, there is a need to further investigate the relationship between chronic pain and poor sleep quality.
352 PART I / Section 4 • Physiology in Sleep
MODULATION OF SENSORIMOTOR PROCESSES DURING SLEEP AND WAKEFULNESS Sleep mechanisms markedly affect sensorimotor functions. Sleep not only suppresses basal muscle tone, but it also attenuates, and in some cases even abolishes motor reflexes (see Chapter 31). Sensory and motor processes and their integration are also differentially affected by prevailing behavioral states. For example, during wakefulness, chemical and mechanical stimulation of laryngeal tissues evokes coughing; however, during sleep the same stimulus only elicits a brief expiration. Such observations not only suggest that sensorimotor processes are suppressed by sleep, but that sleep mechanisms themselves control the integration and expression of sensorimotor processes. Sensorimotor Pathways and Mechanisms The afferent inputs that access the spinal cord, brainstem, thalamus, and cerebral cortex are involved not only in perceptual processes but also are involved in sensorimotor integration and control.1,9,25,26 The neuromuscular system is reflexively influenced by receptors that signal pain, touch, joint position, muscle stretch, or tension. In the case of muscles of the trunk, neck, and limbs, afferents from spinally innervated tissues enter the dorsal root and project into the spinal cord where they can excite or inhibit α-motoneurons that innervate skeletal muscles. The α-motoneurons that innervate craniofacial muscles (e.g., jaw, soft palate, laryngeal and tongue) reside in motoneuron pools in the brainstem, most notably the trigeminal, facial, ambiguus, and hypoglossal nuclei. One source of afferent input that reflexively influences α-motoneurons is derived from the muscle spindle, a stretch-sensitive receptor signaling muscle length. The group Ia primary afferents innervating muscle spindles monosynaptically excite α-motoneurons to produce contraction of the stretched muscle. This monosynaptic circuitry is the neural substrate for the H-reflex and jaw-closing reflex. Muscle spindle afferents are a fundamental motor control mechanism in limb, neck, and trunk muscles; however, because there are insignificant numbers of muscle afferents in most craniofacial muscles (e.g., anterior digastric, facial, pharyngolaryngeal muscles), other receptor systems, for example, receptors in tooth-supporting tissues and in the pharyngeal and laryngeal mucosa, play a significant role in the control of these muscles.1,9,25 Some afferent inputs trigger either excitatory or inhibitory reflexes via affecting the activity of interneurons, which are located in the spinal dorsal horn, V-BSNC, NTS, or within motor pools themselves. Both interneurons and motoneurons are also modulated by the descending neural systems that regulate somatosensory transmission such as the reticular formation, limbic system, lateral hypothalamus, basal ganglia, LC, red nucleus, cerebellum, and sensorimotor cerebral cortex.25,26 Some of these systems are also involved in the initiation of movements (e.g., the primary motor cortex), others in the control and guidance of movements and their integration with other sensorimotor functions (e.g., basal ganglia; spinal or brainstem pattern generators for locomotion, chewing, swallowing) and yet others in the regulation of sleep–wake
states themselves (e.g., periaqueductal gray, lateral pontine tegmentum and lateral hypothalamus).27 Processing of Somatic Reflexes during Sleep and Wakefulness Sleep influences the processing of sensory-motor responses such as the withdrawal reflex, jaw-closing reflex, jawopening reflex, and other H-reflexes. Because changes in somatic reflex responses are linked to movement disorders, such as PLMD and restless leg syndrome (RLS),28 it is important to consider how such reflexes are normally affected by sleep and to identify mechanisms by which these reflexes are modulated during sleep. We will also discuss how H-reflexes are affected during periods of cataplexy because such changes provide valuable insight into understanding how brain function is affected by narcolepsy. The withdrawal reflex (also known as the flexion reflex) is a polysynaptic multisegmental spinal reflex that triggers withdrawal (flexion) of the stimulated limb. It functions to remove the affected limb from potentially noxious stimuli that could cause tissue damage. The withdrawal reflex is composed of two excitatory responses. The first component (termed RII) is considered a tactile response and is characterized by muscle activation (e.g., biceps femoris muscle) that occurs 40 to 60 msec after nerve stimulation (e.g., sural nerve). The second component (termed RIII) occurs 85 to 120 msec after stimulation and is considered a nociceptive polysynaptic reflex.29 The first and second components probably represent the respective activation of A-beta and A-delta cutaneous afferent fibers. Because there is a robust correlation between the RIII threshold and subjective pain thresholds, we will primarily examine sleep effects on this component of the reflex. Sleep has a marked impact on the expression of the withdrawal reflex in humans. Compared to wakefulness there is a significant increase in the stimulus intensity required to activate the reflex during both NREM and REM sleep.30 The polysynaptic jaw-opening reflex (a reflex analogous to the withdrawal reflex) is also suppressed during NREM sleep in monkeys; reduced trigeminal motoneuron excitability is one factor that may cause suppression of this reflex during NREM sleep.10,31 Although stimulus thresholds are elevated during sleep, the withdrawal reflex, like other somatic reflexes, is most reliably activated and most stable during NREM sleep. There is also an increase in the latency to the RIII component during both NREM and REM sleep,30 suggesting that sleep reduces nociceptive reflex excitability and acts to filter sensory inputs in order to preserve sleep continuity. However, there is an increase in both the magnitude and duration of the RIII reflex during REM sleep. This is paradoxical because monosynaptic reflexes are maximally suppressed during this state32 and somatic motoneurons are hyperpolarized during REM sleep in cats.33 The mechanism(s) underlying RIII reflex facilitation during REM sleep is unknown. Unlike the RIII nociceptive component, the RII tactile reflex is absent during sleep.30 This observation is physiologically important because it suggests that sleep differentially affects the individual components of the sensory pathways that mediate this two-part reflex, which implies
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2 Figure 30-3 Magnitude of the H-reflex during sleep and wakefulness.The H-reflex of the calf muscle is triggered by electrical stimulation of the tibial nerve in a 22-year-old man during wakefulness, NREM sleep, and REM sleep. Compared to wakefulness (Wake), the H-reflex is depressed in NREM sleep and abolished in REM sleep. Numbers 1 and 2 are separate examples of reflex responses during different sleep–wake states. (From Shimizu A, Yamada, Y Yamamoto J, et al. Pathways of descending influence on H reflex during sleep. Electroenceph Clin Neurophysiol 1966;20:337-347.)
that sleep mechanisms do not impact all physiological systems equally. This concept is of clinical relevance because it suggests that sleep suppresses tactile responses (i.e., RII), which if activated by body repositioning for example, could cause unwanted arousal; whereas, nociceptive reflexes (i.e., RIII) and their motor component remain active during sleep. Preservation of this protective reflex would therefore ensure that painful stimuli elicit appropriate motor responses and if necessary arousal from sleep. Sleep also has powerful effects on the expression of monosynaptic reflexes such as the masseteric jaw-closing reflex and the classic H-reflex. There is a progressive reduction in the magnitude of the H-reflex amplitude during stages 1 to 4 of NREM sleep and a near complete loss of the reflex during REM sleep in humans (Fig. 30-3).32 Animal studies also show that the stimulus intensity needed to trigger the masseteric reflex is increased in sleep and that reflex responses are reduced during NREM sleep, minimal during tonic REM sleep, and maximally suppressed during periods of active REM sleep (i.e., during rapid eye movements). Because trigeminal motoneurons, which ultimately mediate the masseteric reflex, are inhibited by GABA and glycine during both NREM and REM sleep,31 such inhibitory mechanisms may act to shunt the excitatory afferent inputs onto motoneurons during sleep. However, there is evidence that presynaptic inhibition of Ia afferents onto spinal motoneurons may also function to suppress monosynaptic spinal reflexes during REM sleep.34 Therefore, descending inhibitory inputs acting on both motoneurons and Ia afferents contribute to reduce monosynaptic reflexes during sleep. Clinical Correlates Sleep Bruxism Sleep bruxism, classified as a sleep-related movement disorder, is characterized by tooth grinding and jaw clenching that can lead to destruction of teeth or dental restorations and cause jaw and head pain (see Chapter 99).35,36 It occurs in 8%-10% of the adult population and is characterized by
rhythmic episodes of involuntary jaw muscle activity primarily during NREM sleep and less frequently in REM sleep. It is characterized by phasic contractions of jaw muscles, with three or more muscle bursts, although it can also manifest as tonic jaw muscle activity lasting 2 seconds or more or a mixture of the phasic and tonic activities. Because rhythmic jaw activity also occurs in most healthy subjects during sleep, sleep bruxism may represent an extreme manifestation of this normal pattern. Although the etiology and pathophysiology of sleep bruxism is not fully understood, abnormal sensorimotor processing within the CNS level rather than an abnormal processing of peripheral sensory feedback (e.g., from the teeth) underlies the genesis of sleep bruxism.10 Brainstem structures (e.g., reticular formation, LC, raphe nuclei ) that influence sleep–wake control and sensorimotor processes also influence the mechanisms underlying sleep bruxism, and involve many of the same neurochemicals (e.g., 5-HT, GABA, acetylcholine, dopamine). In addition, the rhythmic movements appear secondary to CNS events related to “arousals,” with increases in autonomic (cardiac and respiratory) and brain activity reflecting reactivation of the reticular formation arousal system preceding the movements.35 The activity of noradrenergic cells in the LC may also contribute to the pathogenesis of sleep bruxism (see Chapter 99). Descending cortical pathways, producing rhythmic masticatory movements during wakefulness, may also be involved in bruxism. Recent findings comparing corticallyinduced jaw movements in the awake versus sleep state indicate that cortical influences are suppressed during NREM sleep.10 These findings suggest that corticobulbar excitatory influences are deactivated during sleep to preserve sleep continuity, and provide indirect support for the importance of brainstem structures in the genesis of sleep bruxism. PLMD and RLS Restless leg syndrome is a common neurologic disorder that results from pathological sensory and motor processing (see Chapter 90). It is characterized by unpleasant, uncomfortable, or painful sensations in the limbs, most often the legs, which lessen or disappear following limb movement.36 Symptoms of RLS worsen during the night and can cause sleep disturbances that underlie the excessive daytime sleepiness and somnolence that typify RLS. Most RLS patients also experience periodic limb movements (PLMs) that occur mainly during NREM sleep. Periodic limb movements are characterized by brief (0.5 to 5 seconds), repetitive limb movements, mainly in the legs, that occur every 5 to 90 seconds. Common physiological mechanisms probably underlie both RLS and PLMs because 80% of RLS patients also experience PLMs and both RLS and PLMs are treated with dopaminergic drugs28 (see Chapter 90). Abnormal sensorimotor processing contributes to both RLS and PLMs. For example, there is marked hyperexcitability of both monosynaptic and polysynaptic reflexes in RLS and PLMs patients.28 The threshold required to activate the withdrawal reflex is lower and the response magnitude is larger during sleep in RLS and PLMs patients than in healthy controls.28 There are also changes in the
354 PART I / Section 4 • Physiology in Sleep 1.6 1.4 Discharge rate (Hz)
response attributes of the soleus H-reflex in RLS and PLMs patients, specifically there is an increased late facilitation and a decreased late inhibition of the reflex response.37 Reduced inhibition of either spinal motoneurons or presynaptic mechanisms may underlie the facilitation of motor responses and could explain why RLS and PLMs patients experience hyperexcitability of spinal reflexes. Brain imaging studies show changes in thalamic, cerebellar, and pontine activity in RLS and PLMs patients,38 suggesting that these regions may affect spinal reflex activity and hence contribute to RLS and PLMs.
1.2 1 0.8 0.6 0.4 0.2 0 AW
Narcolepsy Cataplexy is characterized by a sudden loss of skeletal muscle tone (i.e., atonia) despite maintenance of consciousness, and it is a pathognomonic symptom of narcolepsy. It is generally triggered by strong positive emotions (see Chapter 85). Because motor atonia is a defining feature of both cataplexy and REM sleep, similar neurocircuits may mediate both motor phenomena. In human and canine narcolepsy, the atonia of cataplexy can last from several seconds to several minutes. In both dogs and humans the monosynaptic H-reflex is either absent or minimal during cataplectic attacks.39 This observation demonstrates that the “wakefulness drive,” which has been proposed to cause loss of muscle tone in sleep,40 does not mediate motor suppression during cataplexy because wakefulness is preserved during this state. Loss of excitatory noradrenergic drives onto motoneurons may mediate the loss of muscle tone and the H-reflex during cataplexy because noradrenergic cells in the LC project to motoneurons, and they cease firing during cataplectic attacks in narcoleptic dogs (Fig. 30-4).41 Furthermore, because LC neurons reduce their discharge activity in NREM sleep and virtually stop firing during REM sleep,41 loss of noradrenergic drives onto motoneurons may also explain why motor reflexes and muscle tone are reduced in NREM and REM sleep.42
RESPIRATORY REFLEXES DURING SLEEP AND WAKEFULNESS Sleep not only affects the processing of spinal and craniofacial sensorimotor activities, but it also changes how the respiratory system responds to both mechanical and chemical stimuli (see Chapters 21 and 22). We focus on sensorymotor integration in upper airway and craniofacial muscles because sleep-dependent changes in these reflexes can cause respiratory instability during sleep. Airway reflexes, including coughing, swallowing, laryngeal closure, apnea, and the negative-pressure reflex, function to protect the airway from inhalation of inappropriate substances and to preserve airway patency during vulnerable periods such as during anesthesia and sleep. There are a multitude of afferent nerve endings in the upper alimentary and airway mucosa and muscles that detect changes in muscle tone, pressure, airflow, temperature, and chemical status (e.g., acidic fluids) that respond to and thus trigger appropriate respiratory reflexes. Hereafter we summarize how some airway reflexes are affected by sleep, and then discuss the potential mechanisms underlying state-dependent regulation of such reflexes.
CAT
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Figure 30-4 Discharge activity of putative noradrenergic cells in the locus coeruleus of narcoleptic dogs during wakefulness, sleep, and cataplexy. The discharge rate of cells in the locus coeruleus is tightly correlated with behavioral state. Cell activity is maximal during active and quiet wakefulness (AW and QW, respectively), reduced during NREM sleep, and minimal or absent when motor hypotonia/atonia is present, that is, during REM sleep and cataplexy (CAT). (From Wu M-F, Gulyani SA, Yau E, et al. Locus coeruleus neurons: cessation of activity during cataplexy. Neurosci 1999;91:1389-1399.)
Airway Negative-Pressure Reflex One of the most clinically relevant reflexes is the airway response to negative pressure. The airway negativepressure reflex is characterized by increased upper airway muscle tone in response to the negative suction pressures generated by diaphragmatic contraction. During normal breathing the reflex is inactive because airway pressure is below the stimulus threshold required to trigger it; however, during sleep, particularly REM sleep, reductions in airway muscle tone cause airway narrowing and increased resistance, which increases negative pressure, and this triggers the pressure reflex. The primary function of the negative-pressure response is to increase upper airway muscle tone when airway pressures threaten to occlude the airspace. This reflex response plays an important role in obstructive sleep apnea (OSA) (see Clinical Correlates section hereafter and Section 13). The negative-pressure reflex is typified by short-latency activation of a variety of craniofacial and pharyngeal muscles (e.g., tensor palatini and genioglossus) when airway pressure drops below a variable threshold. Studies using resistive loading, which approximates the effects of sleep on airway pressure, show that the negativepressure reflex is reduced in sleep and indeed is often absent except in the presence of hypercapnia or hypoxia.43 Studies in both animals and humans show that the magnitude of pharyngeal dilator activation is reduced during NREM sleep and further reduced during REM sleep (Fig. 30-5).44 The mechanisms mediating the airway negative-pressure reflex are not fully understood. Changes in pressure are probably detected by mechanoreceptors located within both airway mucosa and airway muscles themselves; whether both mechanisms operate at all levels of the airway is unknown. Trigeminal nerve afferents play a particularly
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Figure 30-5 The airway negative-pressure reflex is suppressed during sleeping. A typical example of the airway negative-pressure reflex in a human subject during wakefulness and sleep. Top traces represent integrated and raw EMG activity recorded from the genioglossus muscle and the bottom trace represents changes in airway pressure. During waking negative airway pressure (–25 cm H2O) triggers a short latency activation of genioglossus muscle tone; however, during NREM sleep the reflex magnitude is suppressed and there is a significant increase in response latency. (From Horner RL, Innes JA, Morrell MJ, et al. The effect of sleep on reflex genioglossus muscle activation by stimuli of negative airway pressure in humans. J Physiol 1994;476:141-151.)
important role in detecting upper airway pressure changes because trigeminal afferents not only respond to pressure changes, but also the pressure reflex is diminished when regions of the airspace innervated by trigeminal afferents are locally anesthetized.45 Reductions in the negative-pressure reflex during sleep could, at least in part, be mediated by changes in the excitability of trigeminal pathways. Neuronal activity in the rostral V-BSNC is reduced during REM sleep18; because some of these neurons relay their excitatory signals to the respiratory centers and motoneurons that trigger reflex expression, reductions in their activity could function to reduce reflex responses in sleep, particularly during REM sleep. Changes in airway pressure are also detected by mechanoreceptors supplied by the superior laryngeal nerve; such afferent signals are relayed to the NTS before reaching respiratory centers. Because excitatory (e.g., serotonergic raphe neurons, hypocretin cells) and inhibitory (GABAergic in the ventrolateral preoptic nucleus) components of the sleep-generating circuitry also project to and synapse onto NTS neurons, then reduced excitation and increased inhibition of NTS neurons could act to reduce the negative-pressure reflex during sleep.27 In addition, GABAergic and glycinergic inhibition of upper airway motoneurons during NREM and REM sleep31 may function to shunt the excitatory signals arising from pressure afferents; this effect would also limit the expression of the negative-pressure reflex during sleep.
Laryngeal and Bronchopulmonary Reflexes Chemoreceptors in the nose, mouth, pharynx, larynx, and lower airways (e.g., trachea) detect various chemical stimuli that elicit protective upper airway reflexes. Stimulation of the larynx with acidic liquids or mechanical forces causes the laryngeal reflex, which during wakefulness in adults triggers swallowing or coughing. However, during NREM and REM sleep the laryngeal reflex is not simply suppressed (and the stimulus threshold increased), it is transformed into a fundamentally different motor response. Compared to the waking reflex, which triggers coughing, laryngeal stimulation during sleep often initiates apnea and bradycardia (Fig. 30-6).46 Activation of bronchopulmonary receptors also elicits different respiratory motor responses during waking and sleep. Mechanical activation of the bronchopulmonary receptors that detect changes in airflow and/or lung stretch triggers the cough reflex during wakefulness, but elicits reflexive apnea during both NREM and REM sleep.47 Such an observation implies that sleep circuits inhibit the expression of these reflex responses or that activation of wake-generating circuits are required to trigger these reflexes. The mechanisms responsible for reversing laryngeal and bronchopulmonary reflexes during sleep have not been determined. However, this type of response reversal has been previously identified and studied in other motor pathways. During wakefulness, auditory stimuli (e.g., sudden loud noises) or skeletal muscle stimulation (e.g.,
356 PART I / Section 4 • Physiology in Sleep
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NREM (B)
1 0 100
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Figure 30-6 Laryngeal stimulation triggers the cough reflex during wakefulness but not during sleep. Examples demonstrating how laryngeal stimulation effects respiratory activity during wakefulness (A) and sleep (B) in a dog. The top trace represents airflow (V), inspiration is upwards and expiration is downwards, the trace below this is EEG and below that is heart rate (ECG); the bottom trace indicates when and how much water was injected into the larynx. Injection of 0.2 ml of water into the laryngeal region of the trachea caused immediate expiration followed by the cough reflex (A). Injecion of the same volume of water during NREM sleep only produced a brief expiration; it did not trigger the cough reflex (B). (From Sullivan CE, Murphy E, Kozar LF, et al. Waking and ventilatory responses to laryngeal stimulation in sleeping dogs. J Appl Physiol 1978;45:681-689.)
muscle stretch) cause reflexive activation of somatic motoneurons and subsequent facilitation of skeletal muscle tone; however, during REM sleep identical stimuli, albeit at greater intensities, cause the opposite effect—that is, motoneuron inhibition and reduced muscle tone. This type of state-dependent response reversal is mediated, at least in part, by the pontomescencephalic reticular formation (PMRF) that participates in sleep–wake regulation.48 Stimulation of the PMRF causes excitatory postsynaptic potentials (i.e., excitation) in trigeminal motoneurons when the jaw-closing masseteric reflex is evoked during waking, but PMRF stimulation during REM sleep triggers inhibitory postsynaptic potentials (i.e., inhibition) in motoneurons and reduced masseteric reflex output.48 The PMRF may therefore function to gate sensory-motor reflexes during different sleep–wake states; during wakefulness it allows sensory stimuli to produce appropriate motor facilitation such as coughing, however, during sleep when motor activation could elicit inappropriate arousals, such stimuli trigger motor inhibition (e.g., apnea). Whether this type of response reversal underlies state-dependent changes in laryngeal and bronchopulmonary reflexes is unknown. Processing of Chemoreflexes during Sleep and Wakefulness During wakefulness, respiratory control mechanisms are acutely sensitive to changes in blood and tissue CO2 levels, with subtle increases in CO2 levels causing potent increases in ventilation. However, sleep has profound effects on the respiratory sensitivity to CO2, which influences the control of breathing during sleep. During sleep, ventilation decreases even though CO2 levels increase. The decrease in ventilation is paradoxical because increased CO2 levels trigger potent increases in ventilation during waking. These changes are of physiological importance because during waking a 1 mm Hg increase in the partial pressure of CO2 (Pco2) causes a 20%-30% increase in ventilation; however, during sleep CO2 levels can increase by 2 to 6 mmHg without affecting breathing. Therefore, during sleep there is a change in the relationship between ventila-
tion and the mechanisms that detect CO2 levels; this change reflects the fact that sleep dramatically affects the processing of respiratory chemoreflexes. The hypercapnic ventilatory response undergoes two important changes during sleep. First, the Pco2 threshold that normally triggers increased ventilation during wakefulness is significantly increased during sleep. This sleeprelated change indicates that higher CO2 levels are required to increase ventilation during sleep and this could partially explain why ventilation decreases below waking levels during NREM sleep. Second, compared to waking there is a significant reduction in the sensitivity of the ventilatory response to CO2 during sleep. For example, there is a 25%-75% decrease in the hypercapnic ventilatory response during NREM sleep compared to waking. REM sleep also has a profound impact on the ventilatory sensitivity to CO2. Compared to NREM sleep, there is a further reduction in the hypercapnic ventilatory response during REM sleep. In fact, CO2 sensitivity is often suppressed to such a degree that high levels of CO2 have negligible affects on breathing during REM sleep. In dogs even high levels of CO2 have minimal effects on breathing, and despite potent CO2 stimulation, the irregular breathing patterns (e.g., rapid fluctuations in tidal volume and breathing frequency) that predominate during REM sleep still persist.49 This is a notable observation because such levels of CO2 would normally cause breathing to become deep and regular during waking and NREM sleep. The persistence of irregular breathing during REM sleep indicates that REM phenomena override the sensory control of breathing. CO2 sensitivity is different during tonic (i.e., no eye movements) versus phasic (i.e., eye movements) REM sleep. Compared to either waking or NREM sleep, the ventilatory response to CO2 is potently suppressed during periods of phasic REM sleep. In contrast, the CO2 response during tonic REM sleep is no different than during NREM sleep; however, CO2 sensitivity remains below waking levels during this state.50 This observation is important because it underscores the fact that CO2 sensitivity is differentially affected by NREM and REM sleep and that it
CHAPTER 30 • Sensory and Motor Processing during Sleep and Wakefulness 357
also subject to intrastate variability. Such findings suggest that behavioral states have a marked impact on the sensory mechanisms by which the CNS detects and responds to changes in CO2. Sleep also affects the manner by which different respiratory muscles respond to CO2. In both humans and animals, hypercapnia causes marked increases in both diaphragmatic and upper airway (e.g., the genioglossus muscle) muscle activity; however, compared to waking there is a marked reduction in levels of muscle activity during both NREM and REM sleep. Although hypercapnia increases diaphragmatic muscle tone during NREM and REM sleep, the sensitivity of genioglossus upper airway muscle tone is severely blunted during REM sleep.51 Therefore, although hypercapnia can trigger increased diaphragm activity in REM sleep, it has comparatively minimal effects on recruiting upper airway muscles whose activation is required for keeping the airspace open and for overcoming OSA (see Clinical Correlates section hereafter). Sleep-dependent suppression of respiratory muscle function could limit the expression of the hypercapnic ventilatory response. Although respiratory muscle tone is reduced in NREM sleep, it is unlikely that this change explains reduced CO2 sensitivity because hypercapnic exposure during this state increases ventilation and respiratory muscle tone (e.g., diaphragm and genioglossus) to within waking levels. However, during REM sleep upper airway muscle tone is minimal and virtually unresponsive to hypercapnia; these effects could mask the ventilatory response to CO2. Bypassing the upper airway via chronic tracheotomy can prevent the stereotypical loss of the ventilatory responses to CO2 during REM sleep in cats,52 which suggests that loss of upper airway muscle tone is, at least in part, responsible for the suppression of CO2 sensitivity during REM sleep. However, it is unlikely that REM sleep muscle atonia fully accounts for suppression of the hypercapnic ventilatory response because CO2 responses are minimal or absent during phasic REM sleep when skeletal muscles are transiently activated and CO2 responses are present during tonic REM sleep when skeletal muscle tone is lowest.50
140
There are two known mechanisms by which the nervous system detects changes in CO2 levels. First, sensory cells (glomus cells) in the carotid body chemoreceptors respond to changes in arterial Pco2 (and O2). It is unknown how this sensing mechanism contributes to sleep-related changes in CO2 sensitivity; however, because glomus cells relay their afferent signals to the brain via the NTS, it is possible that sleep mechanisms impacting the activity of NTS neurons could affect CO2 sensitivity. Second, there are also intrinsic CO2 sensing mechanisms located within the brain itself. These CO2 sensors, termed central chemoreceptors, consist of neurons that respond to local tissue changes in CO2, which in turn trigger ventilation. The primary areas that detect changes in CO2 are the NTS, LC, raphe nuclei, and retrotrapezoid nucleus (RTN).53 Hypocretin/orexin neurons in the lateral hypothalamus, which form part of the neurocircuitry underlying arousal, also respond to and detect changes in CO2. Focal acidification (i.e., increased CO2) of hypocretin neurons causes them to depolarize and increase their firing frequency.54 Genetic deletion of hypocretin neurons reduces the ventilatory response to CO2 in awake mice and promotes respiratory instability during NREM and REM sleep,55 suggesting that hypocretin neurons act as central CO2 sensors that function to maintain normal respiratory reflexes during both sleep and waking. Animal research demonstrates that some CO2 sensors are able to detect changes in CO2 only during waking whereas others are able to detect CO2 changes only during sleep. For example, local increases in CO2 within the retrotrapezoid nucleus activates breathing only during waking, the same stimulus has no effect on breathing during sleep (Fig. 30-7).53 Although CO2 stimulation of the NTS triggers increased ventilation during both waking and sleep, the response is significantly larger during waking than sleep. Therefore, the RTN and NTS could serve as the primary CO2 sensors during wakefulness; loss of their CO2 sensitivity during sleep may explain why the hypercapnic ventilatory response is suppressed during sleep. Although CO2 sensitivity is reduced in sleep it is not abolished, therefore, other CO2 sensors must continue to monitor
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Figure 30-7 Some CO2 sensors only function during wakefulness while others only function during sleep. Graphs A and B represent changes in ventilation triggered by activation of CO2 sensors in the retrotrapezoid nucleus RTN (A) or raphe nucleus (B) during wakefulness (green line) and sleep (red line) in behaving rats. To activate CO2 sensors, 25% CO2 (in saline) was perfused directly into either the RTN or raphe nuclei; this CO2 concentration has physiologically relevant effects on CO2 sensors. Activation of CO2 sensors in the RTN only increases ventilation during waking, it has no effect during sleep (see A). Conversely, activation of CO2 sensors in the raphe nucleus only increases ventilation during sleep, ventilation is unaffected during wake (see B). (From Nattie EE. Central chemosensitivity, sleep, and wakefulness. Respir Physiol 2001;129:257-268.)
358 PART I / Section 4 • Physiology in Sleep
tissue CO2 levels during sleep. The serotonergic raphe nucleus is one potential candidate because local increases in CO2 levels in this brain region increase breathing only during sleep, it does not affect breathing during wakefulness (see Fig. 30-7).53 The raphe nucleus may therefore be the primary CO2 sensor during sleep. This concept is supported by the fact that mice lacking functional serotonin neurons have abnormal arousal responses to CO2 stimulation during sleep. The neurocircuits that regulate sleep may also influence the ability of CO2 sensors to transmit their excitatory drives to respiratory centers, thus limiting the expression of the hypercapnic ventilatory response during sleep. For example, because monoaminergic (e.g., noradrenergic in the LC; see Fig. 30-4) and hypocretin neurons reduce their discharge activity during sleep and because these neurons also project to CO2 sensors (e.g., RTN) then reduced excitatory drive from these sites would limit the ability of CO2 sensors to relay their afferent signals to respiratory motor pools and to the respiratory centers that trigger the CO2 response. Conversely, increased inhibitory drives from the GABAergic neurons in the ventrolateral and median preoptic nuclei that regulate NREM sleep could function to suppress CO2 sensitivity during this state because such inhibitory regions also project to CO2 sensors and respiratory centers. Therefore, both reduced excitation and increased inhibition during sleep may curtail CO2 sensing mechanisms such that the hypercapnic ventilatory response is reduced in sleep.
lematic because sleep reduces the sensitivity of the mechanoreflexes and chemoreflexes needed to overcome apnea. Therefore, apnea continues until the accompanying asphyxia produces arousal from sleep. This viscous cycle occurs repeatedly throughout the night and it underlies the sleep fragmentation, excessive daytime sleepiness and related comorbidities (e.g., hypertension) that typify OSA.
Clinical Correlates Although breathing continues without respite during wakefulness, it becomes fragile during sleep, and in about 2%-5% of the adult population, it is punctuated by transient apneas, which can manifest clinically as sleepdisordered breathing (see Section 13). Obstructive sleep apnea is the most common and serious respiratory-related sleep disorder. Its prevalence is growing, given its link with obesity and the current obesity epidemic. A defining feature of OSA is that it occurs exclusively during sleep— patients with OSA breathe normally while awake but not while asleep. Changes in both chemical and mechanical processing during sleep account for the drastic changes in respiratory control that contribute to OSA. Reduced upper airway muscle tone during sleep, particularly REM sleep, is the primary cause of OSA; it causes either airway narrowing or complete airway obstruction, both of which lead to hypoventilation and subsequent asphyxia. Under waking conditions, these respiratory stimuli (i.e., airway narrowing and asphyxia) trigger upper airway muscle tone, which reopens the airspace by activating both the negative-pressure reflex and the hypercapnic ventilatory responses. However, because these reflexes are suppressed during sleep, they are only partially activated; therefore, airway muscle tone does not cause airway reopening. Accordingly, the airway remains occluded and asphyxia worsens until it finally triggers awaking from sleep. Although wakefulness reinstates and reactivates the respiratory reflexes that increase muscle tone and thus causes airway reopening, it also causes hyperventilation, which in turn leads to hypocapnia. Hypocapnia then reflexively triggers a brief apnea, but this occurs during reentrance into sleep; this is prob-
REFERENCES
❖ Clinical Pearl Determining how sleep controls sensory and motor processes is of notable importance to sleep medicine because some sleep disorders result from disturbances in sensory or motor control. There is evidence that nociceptive transmission in the CNS is affected by sleep and that acute pain causes some sleep disturbance, but the extent and mechanisms by which chronic pain influences sleep, and vice versa, are largely unexplored. Clinicians need to be mindful that there is no simple relationship between chronic pain and sleep quality. Abnormalities in motor control during sleep underlie most of the major sleep disorders, including OSA, narcolepsy and cataplexy, RLS and PLMD, and sleep bruxism. Identifying the underlying mechanisms of motor regulation during sleep is, therefore, a prerequisite for developing more rational treatments for such sleep disorders.
1. Sessle BJ. Mechanisms of oral somatosensory and motor functions and their clinical correlates. J Oral Rehabil 2006;33(4):243-261. 2. Sessle BJ. Sensation from the orofacial region. In: Squire L, editor. New encyclopedia of neuroscience. Oxford, UK: Elsevier; 2009. 3. Willis WD. Spinal cord nociceptive pathways. In: Flor H, Kalso E, Dostrovsky JO, editors. Proceedings of the 11th World Congress on Pain, Progress in Pain Research and Management. Seattle: IASP Press; 2006. p. 269-284. 4. Woolf CJ, Salter MW. Plasticity and pain: role of the dorsal horn. In: McMahon SB, Koltzenburg M, editors. Textbook of pain. 5th ed. London: Elsevier Churchill Livingstone; 2006. p. 91-105. 5. Julius D. The molecular biology of thermosensation. In: Dostrovsky JO, Carr DB, Koltzenburg M, editors. Proceedings of the 10th World Congress on Pain, Progress in Pain Research and Management. Seattle: IASP Press; 2003. p. 345-354. 6. Dray A. Future pharmacologic management of neuropathic pain. J Orofac Pain 2004;18(4):381-385. 7. Lam DK, Sessle BJ, Cairns BE, Hu JW. Neural mechanisms of temporomandibular joint and masticatory muscle pain: a possible role for peripheral glutamate receptor mechanisms. Pain Res Manag 2005;10:145-152. 8. Sessle BJ. Acute and chronic craniofacial pain: brainstem mechanisms of nociceptive transmission and neuroplasticity, and their clinical correlates. Crit Rev Oral Biol Med 2000;11:57-91. 9. Dubner R, Sessle BJ, Storey AT. The neural basis of oral and facial function. New York: Plenum Press; 1978. 10. Lavigne GJ, Huynh N, Kato T, Okura K, et al. Genesis of sleep bruxism: motor and autonomic-cardiac interactions. Arch Oral Biol 2007;52:381-384. 11. Dostrovsky JO, Craig AD. Ascending projection systems. In: McMahon SB, Koltzenburg M, editors. Textbook of pain. 5th ed. London: Elsevier; 2006. p. 187-203. 12. Craig AD. Mechanisms of thalamic pain. In: Henry JL, Panju AA, Yashpal K, editors. Central post-stroke pain. Seattle: IASP Press; 2007. p. 81-100. 13. Bushnell MC. Brain imaging of pain: a thirty-year perspective. In: Merskey H, Loeser JD, Dubner R, editors. The paths of pain 19752005. Seattle: IASP Press; 2005. p. 285-297.
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14. Davis KD. Recent advances in imaging pain. In: Flor H, Kalso E, Dostrovsky JO, editors. Proceedings of the 11th World Congress on Pain. Seattle: IASP Press; 2006. p. 387-396. 15. Fuller PM, Saper CB, Lu J. The pontine REM switch: past and present. J Physiol 2007;584(Pt 3):735-741. 16. Rye DB, Freeman AAH. Pain and its interaction with thalamocortical excitability states. In: Lavigne G, Sessle B, Choinière M, Soja PJ, editors. Sleep and pain. Seattle: IASP Press; 2007. p. 77-98. 17. Massimini M, Ferrarelli F, Huber R, Esser SK, et al. Breakdown of cortical effective connectivity during sleep. Science 2005;309: 2228-2232. 18. Soja PJ. Modulation of prethalamic sensory inflow during sleep versus wakefulness. In: Lavigne G, Sessle BJ, Choinière M, Soja PJ, editors. Sleep and pain. Seattle: IASP Press; 2007. p. 45-76. 19. Kakigi R, Wang X, Inui K, Qiu Y. Modulation of pain-related cortical activity by sleep and attention. In: Lavigne G, Sessle BJ, Choinière M, Soja PJ, editors. Sleep and pain. Seattle: IASP Press; 2007. p. 175-187. 20. Nofzinger EA, Derbyshire SWG. Pain imaging in relation to sleep. In: Lavigne G, Sessle B, Choinière M, Soja PJ, editors. Sleep and pain. Seattle: IASP Press; 2007. p. 153-174. 21. Lavigne G, Khoury S, Laverdure-Dupont D, Denis R, et al. Tools and methodological issues in the investigation of sleep and pain interactions. In: Lavigne G, Sessle BJ, Choinière M, Soja PJ, editors. Sleep and pain. Seattle: IASP Press; 2007. p. 235-263. 22. Lavigne G, Zucconi M, Castronovo C, Manzini C, et al. Sleep arousal response to experimental thermal stimulation during sleep in human subjects free of pain and sleep problems. Pain 2000;84: 283-290. 23. Bentley A. Pain perception during sleep and circadian influences: the experimental evidence. In: Lavigne G, Sessle BJ, Choinière M, Soja PJ, editors. Sleep and pain. Seattle: IASP Press; 2007. p. 123-136. 24. Kundermann B, Lautenbacher S. Effects of impaired sleep quality and sleep deprivation on diurnal pain perception. In: Lavigne G, Sessle BJ, Choinière M, Soja PJ, editors. Sleep and pain. Seattle: IASP Press; 2007. p. 137-152. 25. Sessle BJ. Orofacial motor control. In: Squire L, editor. New encyclopedia of neuroscience. Oxford, UK: Elsevier; 2009. 26. Wiesendanger M. Motor system organization. In: Adelman G, Smith BH, editors. Encyclopedia of neuroscience. 3rd ed. New York: Elsevier; 2004. 27. Peever JH, McGinty D. Why do we sleep? In: Lavigne G, Choinière M, Sessle B, Soja P, editors. Sleep and pain. Seattle: IASP Press; 2007. p. 1-8. 28. Bara-Jimenez W, Aksu M, Graham B, Sato S, et al. Periodic limb movements in sleep: state-dependent excitability of the spinal flexor reflex. Neurology 2000;54:1609-1616. 29. Sandrini G, Serrao M, Rossi P, Romaniello A, et al. The lower limb flexion reflex in humans. Prog Neurobiol 2005;77:353-395. 30. Sandrini G, Milanov I, Rossi B, Murri L, et al. Effects of sleep on spinal nociceptive reflexes in humans. Sleep 2001;24:13-17. 31. Brooks PL, Peever JH. Glycinergic and GABA(A)-mediated inhibition of somatic motoneurons does not mediate rapid eye movement sleep motor atonia. J Neurosci 2008;28:3535-3545. 32. Hodes R, Dement WC. Depression of electrically induced reflexes (“H-Reflexes”) in man during low voltage EEG “sleep.” Electroencephalogr Clin Neurophysiol 1964;17:617-629. 33. Nakamura Y, Goldberg LJ, Chandler SH, Chase MH. Intracellular analysis of trigeminal motoneuron activity during sleep in the cat. Science 1978;199:204-207. 34. Morrison AR, Pompeiano O. Depolarization of central terminals of group Ia muscle afferent fibres during desynchronized sleep. Nature 1966;210:201-202. 35. Lavigne GJ, Khoury S, Abe S, Yamaguchi T, et al. Bruxism physiology and pathology: an overview for clinicians. J Oral Rehabil 2008; 35:476-494.
36. Lavigne GJ, Montplaisir JY. Restless legs syndrome and sleep bruxism: prevalence and association among Canadians. Sleep 1994;17:739-743. 37. Rijsman RM, Stam CJ, de Weerd AW. Abnormal H-reflexes in periodic limb movement disorder; impact on understanding the pathophysiology of the disorder. Clin Neurophysiol 2005;116: 204-210. 38. Unrath A, Muller HP, Ludolph AC, Riecker A, et al. Cerebral white matter alterations in idiopathic restless legs syndrome, as measured by diffusion tensor imaging. Mov Disord 2008;23:1250-1255. 39. Guilleminault C, Wilson RA, Dement WC. A study on cataplexy. Arch Neurol 1974;31:255-261. 40. Phillipson EA, Bowes G. Control of breathing during sleep. In: Cherniack NS, Widdicombe JG, editors. Handbook of physiology: the respiratory system. Bethesda, Md: American Physiological Society; 1986. p. 649-689. 41. Wu MF, Gulyani SA, Yau E, Mignot E, et al. Locus coeruleus neurons: cessation of activity during cataplexy. Neuroscience 1999; 91:1389-1399. 42. Schwarz PB, Yee N, Mir S, Peever JH. Noradrenaline triggers muscle tone by amplifying glutamate-driven excitation of somatic motoneurones in anaesthetized rats. J Physiol 2008;586(Pt 23): 5787-5802. 43. Aronson RM, Onal E, Carley DW, Lopata M. Upper airway and respiratory muscle responses to continuous negative airway pressure. J Appl Physiol 1989;66:1373-1382. 44. Issa FG, Edwards P, Szeto E, Lauff D, et al. Genioglossus and breathing responses to airway occlusion: effect of sleep and route of occlusion. J Appl Physiol 1988;64:543-549. 45. Horner RL, Innes JA, Holden HB, Guz A. Afferent pathway(s) for pharyngeal dilator reflex to negative pressure in man: a study using upper airway anaesthesia. J Physiol 1991;436:31-44. 46. Sullivan CE, Murphy E, Kozar LF, Phillipson EA. Waking and ventilatory responses to laryngeal stimulation in sleeping dogs. J Appl Physiol 1978;45:681-689. 47. Sullivan CE, Kozar LF, Murphy E, Phillipson EA. Arousal, ventilatory, and airway responses to bronchopulmonary stimulation in sleeping dogs. J Appl Physiol 1979;47:17-25. 48. Chandler SH, Nakamura Y, Chase MH. Intracellular analysis of synaptic potentials induced in trigeminal jaw-closer motoneurons by pontomesencephalic reticular stimulation during sleep and wakefulness. J Neurophysiol 1980;44:372-382. 49. Phillipson EA, Kozar LF, Rebuck AS, Murphy E. Ventilatory and waking responses to CO2 in sleeping dogs. Am Rev Respir Dis 1977;115:251-259. 50. Sullivan CE, Murphy E, Kozar LF, Phillipson EA. Ventilatory responses to CO2 and lung inflation in tonic versus phasic REM sleep. J Appl Physiol 1979;47:1305-1310. 51. Parisi RA, Neubauer JA, Frank MM, Edelman NH, et al. Correlation between genioglossal and diaphragmatic responses to hypercapnia during sleep. Am Rev Respir Dis 1987;135:378-382. 52. Fraigne JJ, Dunin-Barkowski WL, Orem JM. Effect of hypercapnia on sleep and breathing in unanesthetized cats. Sleep 2008;31: 1025-1033. 53. Nattie EE, Li A. Central chemoreception is a complex system function that involves multiple brain stem sites. J Appl Physiol 2009; 106:1464-1466. 54. Williams RH, Jensen LT, Verkhratsky A, Fugger L, et al. Control of hypothalamic orexin neurons by acid and CO2. Proc Natl Acad Sci U S A 2007;104:10685-10690. 55. Nakamura A, Zhang W, Yanagisawa M, Fukuda Y, et al. Vigilance state-dependent attenuation of hypercapnic chemoreflex and exaggerated sleep apnea in orexin knockout mice. J Appl Physiol 2007; 102:241-248.
Chronobiology
Section
Fred W. Turek 31 Introduction: Master
Circadian Clock and Master Circadian Rhythm 32 Circadian Rhythm in Mammals: Formal Properties and Environmental Influences 33 Anatomy of the Mammalian Circadian System 34 Physiology of the Mammalian Circadian System
35 The Human Circadian
Timing System and Sleep–Wake Regulation 36 Melatonin and the Regulation of Sleep and Circadian Rhythms 37 Sleep Homeostasis and Models of Sleep Regulation 38 Circadian Rhythms in Sleepiness, Alertness, and Performance
39 Animal Models for
Disorders of Circadian Functions: Whole Organism 40 Animal Models for Disorders of Chronobiology: Cell and Tissue 41 Circadian Disorders of the Sleep–Wake Cycle
Introduction: Master Circadian Clock and Master Circadian Rhythm Fred W. Turek
One of the distinguishing characteristics of sleep in animals as diverse as insects, fish, and mammals is that the timing of sleep and wake for the vast majority of species is rigidly confined to certain times of the day or night. As detailed in a number of chapters in this section, the master biological clock regulating the timing of sleep and wake in mammals also regulates most, if not all, 24-hour (i.e., circadian) behavioral, physiologic, and biochemical rhythms. This master circadian clock is located in the bilaterally paired suprachiasmatic nucleus (SCN) in the anterior hypothalamus (Chapters 32 to 34). Although it has been discovered that many tissues and organs can generate circadian rhythms in vitro, and therefore independent of the SCN (Chapters 39 and 40), the SCN remains at the top of the hierarchy of the mammalian circadian clock system. Similarly, one could argue that the sleep–wake cycle represents the master circadian rhythm; the SCN’s control of this rhythm in turn controls the timing and expression of a multitude of downstream rhythms. Although the expression of many 24-hour rhythms may be primarily under the control of the circadian clock in the SCN, many rhythms largely depend on whether the organism is asleep or awake, regardless of the circadian clock time.1 Undoubtedly, the expression of most rhythms at the behavioral, physiologic, and biochemical levels are regulated by the integration of inputs from the circadian clock and the sleep–wake state of the animal. Indeed, it can be argued that the entire temporal organization of an organism represents some combined effect of circadian clock outputs and the sleep–wake state of the organism. Thus, the circadian and sleep control centers have evolved together to ensure that the timing of internal events relative to one another and to the external environment are coordinated in such a fashion to maximize the survival of the species. 360
5
Chapter
31
Of particular note of the downstream rhythms regulated by the circadian clock is the feeding rhythm. A number of studies have demonstrated that the timing of food intake can regulate the expression of circadian clock genes in many peripheral tissues,2 which in turn control the 24-hour rhythm in the expression of many clock-controlled genes, perhaps up to 10% of all genes expressed in a given tissue.3 The many interactions among the systems regulating circadian, sleep, and energy balance, from molecular to behavioral rhythms, have led to much interest in the importance of these linkages to obesity, diabetes, and cardiometabolic disorders.2 The need to rest, and the need to adjust to the daily changes in the physical environment due to celestial mechanics, certainly represented two Darwinian pressures that guided the evolution of living organisms since the beginning of time. (At an earlier time in the history of Earth, the solar day is thought to have been 18 hours; with the change to the current 24-hour day occurring over millions of years, there was plenty of time for clock genes to be altered so the molecular circadian cycle stayed in synchrony with the solar day.) As detailed in the rest of this chapter, the early linkage for the need to rest, and to rest at a specific phase of the daily external environment, might have resulted in the circadian clock and sleep–wake cycle evolving together and being integrated with each other at many different levels of organization.
INTEGRATION OF THE CIRCADIAN CLOCK AND SLEEP–WAKE SYSTEMS The first three chapters in this section deal primarily with the circadian clock system, with a focus on the formal properties and rules that govern the generation of
CHAPTER 31 • Introduction: Master Circadian Clock and Master Circadian Rhythm 361
circadian rhythms (Chapter 32), the anatomy of the neural clock system in mammals (Chapter 33) and the physiology of the mammalian circadian clock system (Chapter 34). Chapters that review the molecular and genetic bases for the actual circadian clock core machinery, which has been highly conserved at least from insects to mammals, are included in Section 3. Chapters 35 and 37 involve discussions from different vantage points about how the circadian clock system is highly integrated with the sleep–wake regulatory system. Chapter 36 focuses on the still mysterious pineal gland hormone, melatonin, and its role as perhaps a bridge between the circadian and sleep systems. Although the synthesis and release of melatonin is under tight regulatory control via circadian neural signals from the SCN, melatonin itself can act as a chronobiotic and influence the timing of SCN-controlled rhythms, and it also appears to be a hypnotic that can directly influence the drive to sleep. The complex nature of the interaction between the clock and sleep regulatory systems require more of an overview, and this is provided later. Chapter 38 focuses on how the circadian clock and sleep loss—together and independently—regulate neurobehavioral performance. The disruption of circadian rhythms in humans during rapid travel across time zones and during shift work has been linked to a variety of mental and physical abnormalities for many years (see Section 9, Occupational Sleep Medicine), but only in the last few years have animal models begun to emerge that are elucidating the extent of the importance of internal circadian synchronization for the health and well-being of the organism as a whole as well as for the molecular events that are disrupted at the level of cells and tissues (Chapters 39 and 40). The final chapter in this Section (Chapter 41) reviews how the clock system underlies disorders related to the timing of the sleep–wake cycle that can lead to a disruption of the timing of internal rhythms with one another, as well as the timing of the sleep–wake cycle and other rhythms with the external environment. In the now classic two-process model of Borbély and colleagues in Chapter 35, the timing of sleep and wake is a function of a homeostatic process that defines sleep need as depending on the previous amount of sleep and wake (Process S), and the circadian clock (Process C) that modulates the timing and propensity of sleep. However, as noted by Czeisler and colleagues in Chapter 35, the interactions between the circadian pacemaker and sleep homeostat should not be underestimated, and there is great difficulty in separating these two processes functionally. In addition, recent findings in genetics and anatomy (see Section 3 of this volume and Chapter 33) also tend to blur the distinction between the homeostatic and circadian inputs in the regulation of the sleep–wake cycle. In the two-process model, the electroencephalographic (EEG) slow-wave activity (SWA) in non–rapid eye movement (NREM) sleep serves as an indicator of sleep homeostasis either under baseline or after sleep deprivation. There is substantial evidence to indicate that sleep homeostasis, as defined by the SWA during NREM sleep, is independent mechanistically from the circadian clock, but it is not known how the two processes actually contribute to the overall sleep need of the organism or what role
the circadian clock might play in other homeostatically regulated sleep–wake events, such as total sleep time or NREM or REM sleep time under baseline or sleepdeprivation conditions. Indeed, the finding that different alleles in the canonical circadian clock gene, per, in humans is associated with different SWS emphasizes how closely linked the circadian clock and the homeostatic process are in regulating sleep (see Section 3).
REGULATING SLEEP AMOUNT: A HOMEOSTATIC AND A CIRCADIAN INPUT Many sleep and wake traits are under homeostatic control. That is, the longer one is awake or deprived of specific sleep stages (e.g., REM sleep deprivation), the greater will be the drive to recover the lost sleep or sleep stage. However, this might only be true following short periods of sleep deprivation, because during continuous chronic partial sleep deprivations in rodents, there is a loss of the homeostatic recovery sleep increase, as the sleep–wake system appears to change from a homeostatic to an allostatic response system.4 In addition, the different phases of normal sleep and wake are under circadian control; the clock is doing more than saying wake up or go to sleep at specific times of day. An unanswered question is: What actually regulates the amount of sleep? Or put another way: What are the relative contributions of the homeostatic and circadian process to the actual amount of time a given animal is awake and interacting with the external world, or asleep and avoiding the external world? Studies in laboratory, zoo, and wild animals reveal that sleep times are unrelated to taxonomic classification, and as noted by Siegel,5 “the range of sleep times of different primates extensively overlaps that of rodents, which overlaps that of carnivores, and so on across many orders of mammals.” The total sleep time is correlated in a global sense to body size; for example, the opossum sleeps 18 hours, the ferret sleeps 14.4 hours, the cat sleeps 12.5 hours, the dog sleeps 10.1 hours, the human sleeps 8 hours, and the elephant sleeps 3 hours.5 Whereas on a global level body size (and associated metabolic rate) is inversely related to total sleep time, there appear to be other factors regulating sleep time as indicated by the fact that the smaller mouse sleeps about the same amount as the larger rat.6-9 Indeed, there is considerable variability in sleep time among strains of mice; strains of mice that are of similar size and of the same species can show total sleep time differences up to as much as 2.5 hours.8 In the evolution of life on Earth, there has been great pressure for organisms to adapt their lifestyle to the external world and to coordinate the internal temporal environment so as to maximize the chances of survival and to pass on their genetic material to the next generation. Total sleep time could be expected to be part of the survival strategy to ensure that animals are engaged as well as disengaged with the external environment at the appropriate times of day and night. Similarly, as noted earlier, the sleep–wake cycle can be considered as the master circadian rhythm, becaus the expression of so many behavioral and physiologic rhythms are tied to the sleep–wake or activity– rest cycle. Thus, the total amount of sleep and wake might
362 PART I / Section 5 • Chronobiology
have evolved in individual species, in part, to create an internal temporal framework, in conjunction with the circadian clock, to maximize survival and reproduction fitness. The fact that the circadian clock is a major determiner of the pressure to sleep or the ability to stay awake has mechanistic indications on various neural, genetic, and molecular levels, as well as potentially important therapeutic implications for treating sleep–wake disorders.10,11 The finding in humans, rodents, and flies that the circadian clock is regulating not only the timing of sleep and wake but also the propensity to sleep and wake renders the circadian clock system a potential target for interventions that could promote sleep and wakefulness that go beyond interventions in use today.10-13
❖ Clinical Pearl The circadian clock may be sending an alerting signal at some times of the day as well as a sleep signal at other times of the day. Thus, a disruption of these signals could lead to daytime sleepiness or nighttime insomnia, or both. Alteration of the circadian clock at the molecular or systems level could lead to sleep disorders that go beyond just the abnormal timing of sleep relative to our social and work environment, and the clock itself could represent a useful target for altering sleep and wake characteristics via pharmacologic and nonpharmacologic interventions.
REFERENCES 1. Leproult R, Spiegel K, Van Cauter E. Endocrine Physiology. In: Kryger MH, editor. Atlas of Clinical Sleep Medicine. Philadelphia: Elsevier; 2010. p. 56-60. 2. Laposky AD, Bass J, Kohsaka A, Turek FW. Sleep and circadian rhythms: key components in the regulation of energy metabolism. FEBS Lett 2008;582:142-151. 3. Panda S, Antoch MP, Miller BH, Su AI, et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 2002;109(3):307-320. 4. Kim Y, Laposky AD, Bergmann BM, Turek FW. Repeated sleep restriction in rats leads to homeostatic and allostatic responses during recovery sleep. Proc Natl Acad Sci U S A 2007;104(25):10697-10702. 5. Siegel JM. Why we sleep. Sci Am 2003;289(5):92-97. 6. Dugovic C, Solberg LC, Redei E, Van Reeth O, et al. Sleep in the Wistar-Kyoto rat, a putative genetic animal model for depression. Neuroreport 2000;11(3):627-631. 7. Everson CA, Bergmann BM, Rechtschaffen A. Sleep deprivation in the rat. III. Total sleep deprivation. Sleep 1989;12(1):13-21. 8. Franken P, Malafosse A, Tafti M. Genetic determinants of sleep regulation in inbred mice. Sleep 1999;22(2):155-169. 9. Koehl M, Battle SE, Turek FW. Sleep in female mice: a strain comparison across the estrous cycle. Sleep 2003;26(3):267-272. 10. Naylor E, Bergmann BM, Krauski K, Zee PC, et al. The circadian Clock mutation alters sleep homeostatsis in the mouse. J Neurosci 2000;20(21):8138-8143. 11. Wisor JP, O’Hara BF, Terao A, Selby CP, et al. A role for cryptochromes in sleep regulation. BMC Neurosci 2002;3(1):20. 12. Hendricks JC. Sleeping flies don’t lie: the use of Drosophila melanogaster to study sleep and circadian rhythms. J Appl Physiol 2003; 94(4):1660-1672. 13. Maywood ES, Fraenkel E, McAllister CJ, Wood N, et al. Disruption of peripheral circadian timekeeping in a mouse model of Huntington’s disease and its restoration by temporally scheduled feeding. J Neurosci 2010;30:10199-10204.
Circadian Rhythms in Mammals: Formal Properties and Environmental Influences Ralph E. Mistlberger and Benjamin Rusak Abstract Circadian rhythms are approximately 24-hour cycles of behavior and physiology that are generated by endogenous biological clocks (pacemakers or oscillators). Circadian rhythms persist (free-run) with near–24-hour periods (cycle lengths) in time-free environments, but normally they are synchronized to the 24-hour day by environmental stimuli (zeitgebers, or time cues). Synchrony is achieved by a process of entrainment, which involves daily stimulus-induced phase shifts that correct for the difference between the intrinsic period of the pacemaker and the period of the environmental cycle. Light is the dominant zeitgeber for most species and can induce phase shifts that vary in magnitude and direction depending on the circadian phase of exposure. Circadian rhythms in some species can also be shifted and entrained by stimuli other than light, such as scheduled feeding, exercise, social interactions, and temperature variations (nonphotic stimuli). Entrainment to feeding schedules is
THE NATURE OF CIRCADIAN RHYTHMS A salient characteristic of sleep in humans is its daily rhythmicity. A similar 24-hour rhythmicity characterizes most aspects of the behavior, physiology, and biochemistry of living organisms. Historically, daily rhythms were interpreted as innate or acquired responses to environmental stimuli, such as light, temperature, and humidity, that vary markedly with time of day. However, as early as 1729, it was reported that the daily rhythm of leaf movements of the heliotrope Mimosa does not depend on continued exposure to the day–night cycle; that is, the rhythm persisted (free-ran) in constant dark (DD). Many studies have since confirmed that daily rhythms in a great variety of species, including humans, free-run, often indefinitely and with impressive precision, despite housing in controlled environments that lack variations in lighting, temperature, food access, or other stimuli (Fig. 32-1).1 Persistence of daily rhythms for many cycles in the absence of environmental time cues suggests that organisms possess one or more endogenous clocklike timekeeping mechanisms. If these mechanisms were biochemical processes within organisms, they might reasonably be expected to show dependence of rate (frequency, the reciprocal of which is cycle duration or period, represented by the Greek letter τ) on tissue temperature, because chemical processes are almost universally temperature-dependent. Yet, for these mechanisms to time behavior and physiology accurately, they must be capable of cycling at a constant rate, despite variations in tissue temperature caused by changes in metabolism (for homeothermic species) or environmental conditions (for heterothermic species). The
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mediated by a circadian pacemaker that is separate from the pacemaker mediating synchrony to light–dark cycles. Interactions between photic and nonphotic zeitgebers are complex; light and exercise, for example, depending on their relative timing and magnitude, may be synergistic or mutually inhibitory in producing phase shifts. Stable entrainment in natural environments therefore likely reflects integration of multiple zeitgebers by multiple formally distinct pacemakers and oscillators. Overt rhythms in behavior and physiology might emerge only weeks or months postnatally, but the circadian pacemaker responsible for entrainment to light cycles in adulthood is also entrained prenatally by maternal cues. Over the life span, circadian rhythms exhibit changes in period, amplitude, and responsiveness to zeitgebers. Some of these changes can lead to altered circadian organization in older people, which can contribute to disruptions in physiologic mechanisms, including those regulating sleep.
evidence accumulated in the 1950s that daily rhythms in most organisms show an impressive stability of period across a range of temperatures fueled a debate over whether daily rhythms were truly endogenously generated or whether they reflected a response of the organism to some unknown, periodic environmental “factor X” associated with Earth’s rotation on its axis (e.g., electromagnetic fields2). Although the mechanism by which daily rhythms maintain a stable period at different temperatures remains to be fully elucidated, the physiologic plausibility of such a mechanism is no longer in doubt.3 The evidence is now overwhelming that daily rhythms are generated by endogenously rhythmic internal clocks. The most compelling behavioral evidence in support of the endogenous clock concept is the observation that daily rhythms in constant conditions typically express stable τs that deviate from the 24-hour periodicity of the solar day and thus would rapidly slide out of phase with any geophysical correlate of planetary rotation. This circadian (Latin, “approximately a day”) periodicity exhibits individual differences around a species-typical mean, usually within the range of 23 to 25 hours. Consequently, individual animals housed separately under identical environmental conditions gradually drift out of synchrony with local time and with each other. Moreover, shorter (than 24 hours) or longer (than 24 hours) circadian τs (reflecting faster or slower running circadian clocks, respectively) can be promoted by selective breeding or induced by gene mutations (see Chapter 12). A variety of drugs, hormones, environmental manipulations, and processes associated with aging can also modulate clock periodicity (discussed further later). All of these observations are consistent 363
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Figure 32-1 Circadian rhythms free-running in the absence of a fixed light–dark cycle, plotted in conventional actogram format to facilitate comparisons across species. A, The circadian rhythm of polygraphically recorded wake time in a C57 mouse in constant dark. Each line represents 48 consecutive hours, and consecutive days are aligned vertically (thus the data are double-plotted, i.e., the right half of the chart is a duplicate of the left half, but is moved up one line). Data were averaged in 6-minute time bins, and a black bar was assigned to those bins during which wake time accounted for more than 50% of the 6 minutes. This plotting format reveals at a glance that there is a bout of continuous waking lasting 2 to 3 hours in each circadian cycle, and this bout occurs a bit earlier each 24-hour day; that is, the circadian cycle is less than 24 hours. The format also illustrates the polyphasic nature of sleep in the mouse. B, The circadian rhythm of polygraphically recorded wake time in a Sprague-Dawley rat in constant dim light (1.5 lux). Behavioral state was scored in 30-second epochs that were collapsed into 30-minute time bins for plotting (circles denote time bins with wake occupying more than 50% of the 30 minutes). Over time in constant light, circadian rhythms in rats gradually dampen. C, Circadian rhythm of sleep time of a human in temporal isolation for 45 days. Solid bars indicate sleep. Instabilities of sleep onset across days might illustrate a volitional factor that can override the circadian clock. Occasional missed sleep episodes can then shift the circadian clock by exposure to light or to nonphotic cues (e.g., being awake or eating) during the subjective night. (A, Modified from Welsh DK, Engel EM, Richardson GS, et al. Precision of circadian wake and activity onset timing in the mouse. J Comp Physiol [A] 1986;158:827-834; B, modified from Eastman C, Rechtschaffen A. Circadian temperature and wake rhythms of rats exposed to prolonged continuous illumination. Physiol Behav 1983; 31:417-427; C, modified from Czeisler CA, Weitzman ED, Moore-Ede MC, et al. Human sleep: its duration and organization depend on its circadian phase. Science 1980; 210:1264-1267.)
with the hypothesis that there is a genetically specified internal circadian clock that drives daily rhythms in behavior and physiology. Indeed, circadian rhythms are known to persist in constant conditions on space shuttles in orbit, completely removed from any hypothetical terrestrial factor X.4 Over the past few decades, circadian clocks have been localized in the brains and other tissues of several species, and genes and proteins that comprise the gears of these clocks have now been identified in cyanobacteria, a fungus, insects, fish, and mammals (for references, see Chapter 12). Thus, the focus of research in this area is no longer on whether circadian rhythms are generated by internal clocks but, rather, what the components and processes of these clocks are, how they control behavior and physiology, how they are synchronized to the environment, and what impact they have on a variety of medical conditions. In addition, a major current focus is on understanding how our internal clocks might be manipulated to treat problems related to circadian timing, such as the disturbances of sleep, arousal, and other physiologic processes associated with shift work, rapid transmeridian jet travel, blindness, and other conditions. An understanding of the functional properties of circadian clocks is essential to set the framework for the cellular and molecular analyses that address these impor-
tant questions. This chapter reviews the basic functional properties of circadian clocks, and subsequent chapters review the neurobiological and molecular genetic analyses of these clocks.
PARAMETERS AND MEASUREMENT OF CIRCADIAN RHYTHMS Overt circadian rhythms have phase and amplitude dimensions (Fig. 32-2). Phase (conventionally represented by the Greek letter f) refers to any point within a cycle. An observable phase (e.g., daily wakeup time) can be used as the hand of a clock to track its motion. The elapsed time between successive occurrences of a particular phase represents τ. The f and τ of an observed circadian rhythm reflect parameters of the underlying circadian clock, namely, its current position and its rate of cycling, respectively. Amplitude refers to the range of values that an overt circadian rhythm can assume through the course of its cycle. One measure of amplitude is the difference between the peak value and the mean value of a purely sinusoidal rhythm (the acrophase of a fitted cosine wave; see Fig. 32-2). However, the amplitude of an overt rhythm cannot be taken to represent a parameter of the underlying clock, because many factors downstream from the clock can
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affect the level and range of particular observable behavioral or physiologic variables. The experimental analysis of circadian rhythms has relied heavily on a few organisms that exhibit precise and easily measured circadian rhythms (e.g., wheel running, body temperature, plasma melatonin) or that provide advanced molecular genetic resources. Behavioral and physiologic data are typically acquired by sensors whose outputs are monitored continuously by computers. Data stored in digital format are amenable to time-series analyses (e.g., linear regression, spectral analysis) using a variety of established techniques to measure f and τ and to curvefitting procedures (e.g., cosinor analysis, see Fig. 32-2) to measure f and amplitude.5-7 Despite the broad range of species studied and variables monitored, the formal properties of circadian rhythms are remarkably general, a feature consistent with an ancient origin for circadian clocks. In this chapter, we refer primarily to the literature from studies of mammalian circadian rhythms.
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Figure 32-2 A, Circadian rhythm of core body temperature recorded from a rat by telemetry. The data are single-plotted (each line is 24 hours, with 5-minute bins plotted left to right and consecutive days aligned vertically). Heavy bars indicate time bins when temperature was greater than the daily mean. The interval with lights off (12 hours) is denoted by the shading. B, Average waveform constructed from the data in A. The thin line represents the raw data and the heavy line represents a running average. A cosine function was fit to the smoothed data, and the arrow denotes the peak (acrophase) of the function. Note that the waveform of the temperature rhythm in light–dark has a prominent square wave component, which is evident particularly during the nocturnal segment; thus, a cosine function is not an optimal fit, because the acrophase occurs about 6 hours before the true peak in the raw data. (Mistlberger, unpublished data). C, Nomenclature and commonly used abbreviations for parameters of circadian rhythms and zeitgebers. For definitions, see text.
ADAPTIVE SIGNIFICANCE OF CIRCADIAN RHYTHMS Circadian clocks are thought to have several important functions that enhance reproductive fitness in natural environments. A primary function is to promote consolidated periods of activity (active engagement with the environment) and rest (withdrawal from environmental engagement), and to restrict these to appropriate phases of the solar day, resulting in nocturnal (night-active), diurnal (day-active) or crepuscular (dawn- and dusk-active) chronotypes that are consistent with the sensory and other adaptations of a given species. A fundamental advantage of using an internal clock to regulate rest–activity cycles is that physiologic changes can be mobilized in anticipation of the transitions between day and night that herald the dramatic ecologic differences between these daily phases. This allows an anticipatory, rather than reactive, regulation of physiology, thus ensuring that the organism is fully prepared for activity or rest at the correct time. Humans and other diurnal species thus exhibit a gradual increase in body temperature, plasma cortisol, and sympathetic autonomic tone beginning several hours before habitual wake onset, thereby facilitating a rapid switch from sleep to alert waking8 (see Chapter 35). Similar preparatory processes occur in reverse to facilitate sleep onset (e.g., body temperature declines, melatonin secretion begins). In at least some species, the circadian clock has been exploited not only as a device for driving daily rhythms (i.e., a pacemaker function) but also as a true clock that can be continuously consulted to provide a sense of time. Evidence for this function is available from studies showing that some animals can discriminate time of day without external cueing and thereby learn to associate the time and place of food availability.9,10 Some species use this time sense to navigate using celestial cues as a compass, which requires continuous adjustment of the angle of movement relative to the sun’s apparent position in the sky.11 The circadian clock is also used by many species to measure day length for the purposes of regulating seasonal reproduction, hibernation, and other functions for which anticipation is critical.12
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ENVIRONMENTAL INFLUENCES Photic Entrainment Effects of Light on Circadian Phase To achieve the adaptive functions of pacemaker and continuously consulted clock, it is imperative that the circadian clock maintain an appropriate phase relation to local environmental time. This challenge is complicated by seasonal variations in day length; outside the equatorial zones, the hours of dawn and dusk shift systematically each day as Earth rotates on its axis and tilts slowly toward and away from the sun. The circadian clock therefore has two tasks: it must generate a cycle that approximates the period of the day–night cycle, and it must track a particular phase of the day–night cycle, so that diurnal animals become active near dawn and nocturnal animals become active near dusk.13 The process by which this optimal synchronization occurs is called entrainment, defined as phase and period control of one oscillating process by another. In the case of the daily sleep–wake cycle and other circadian rhythms, entrainment to local environmental time is mediated by the actions of periodic environmental stimuli (zeitgebers, German for “time-givers”) on the circadian clock. As might be expected, light is a virtually universal zeitgeber for the circadian rhythms displayed by most organisms, from cyanobacteria to mammals. The mechanism by which light entrains circadian rhythms has been investigated by assessing the effects of discrete applications of light on circadian rhythms free-running in DD.14 Brief light pulses cause phase shifts of free-running rhythms whose magnitude and direction depend on when within the circadian cycle the light pulse is presented (Fig. 32-3A and B). This phase dependence of light effects is illustrated graphically by plotting the size and direction of the phase shift against the circadian phase of light presentation, producing a phase-response curve (PRC) for light (see Fig. 32-3C). The PRC for brief light pulses is universal in its general shape. Light exposure at the beginning of the subjective night (when nocturnal species are normally active and diurnal species are asleep), induces a phase-delay shift, whereby the onset of the next subjective day (rest phase in nocturnal species, active phase in diurnal species) is reset to a later time, and the circadian cycle resumes its free-run from this new phase. Light exposure toward the end of the subjective night induces a shift in the opposite direction, a phase advance, whereby the next subjective day begins earlier than usual. During most of the subjective day, light pulses have relatively little effect, defining a dead zone on the PRC. The shape of the PRC for light pulses suggests that entrainment can be accomplished by a phase-delaying action of light at dusk and a phase-advancing action at dawn, producing a net daily shift equal to the difference between τ of the circadian pacemaker and the period (T) of the light–dark cycle (24 hours in natural environments). Consistent with this hypothesis, known as the discrete (or nonparametric) model of entrainment,13 organisms can be entrained to photoperiods consisting of only two brief light pulses in each 24-hour cycle, simulating dawn and dusk (see Fig. 32-3F). Stable entrainment under such skeleton photoperiods has been documented in several species and appears to be similar in most respects to entrainment
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Figure 32-3 Phase shifting and entrainment by light. A, Circadian rhythm of wheel running recorded from a hamster in constant dark. On the day indicated by the arrow, the hamster was exposed to light for 30 minutes (open circle). The pulse was timed to occur at circadian time 20, which is 8 circadian hours (where 1 circadian hour = τ/24) after the daily onset of wheel running (denoted circadian time 12, by convention, and estimated by fitting a regression line to the activity onsets for 7 to 10 days before the day of light exposure). On the day after the light pulse, activity occurs earlier than predicted by extrapolation from the preceding free-run. After several days of transient advancing cycles, a stable phase-advance shift of several hours is revealed. Transients are by definition the cycles before the full shift is completed. B, In this experiment, the light pulse (arrow) was presented at circadian time 14. This induced a small phase-delay shift of about 1 hour, which was complete within one circadian cycle. Phase resetting without transients is typical of light-induced delay shifts. C, A full phase-response curve depicting the relation between the circadian time of light exposure and the magnitude and direction of the resulting phase shift. Delay shifts occur to light early in the subjective night (approximately circadian time 10 to 15) and advance shifts to light late in the subjective night (circadian time 15 to 24 hr). D, An 8-hour phase advance of the light–dark cycle, illustrating gradual re-entrainment by a series of approximately 1-hour phase advances each day (due to differential exposure of the delay and advance portions of the circadian pacemaker’s phase-response curve to light). Note inhibition of activity by light during the later portion of the hamster’s active period, during the first few days after the light–dark shift. E, A 6-hour phase delay of the light–dark cycle, illustrating gradual reentrainment by delay shifts. Note inhibition of running early in the hamster’s active period. F, Stable entrainment to a skeleton photoperiod in a hamster exposed to two daily 30-minute pulses of light (denoted by the vertical bars), simulating dawn and dusk and defining a 14-hour day (diurnal rest period) and 10-hour night (nocturnal active period). The hamster’s activity rhythm began to phase delay when the morning light pulse was omitted, and a stable phase was restored when a full 14:10 photoperiod was implemented. (C, Modified from Takahashi JS, DeCoursey PJ, Bauman L, et al. Spectral sensitivity of a novel photoreceptive system mediating entrainment of mammalian circadian rhythms. Nature 1984;308:186-188; D, modified from Mistlberger RE, Nadeau J. Ethanol and circadian rhythms in the Syrian hamster: effects on entrained phase, reentrainment rate and period. Pharm Biochem Behav 1992;43:159-165; E and F are from Mistlberger, unpublished data).
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under a full photoperiod. In fact, studies of nocturnal rodents in seminatural environments indicate that selfselected brief exposures to light at dawn or dusk (or both) might account fully for entrainment in these species.15 The τ of a circadian pacemaker and its circadian rhythm of sensitivity to light (summarized quantitatively in the PRC) determine several important properties of entrainment. One property is the limited range of entrainment. The circadian clock can entrain to light–dark cycles only if there is a relatively close match between τ and T of the light–dark cycle. For stable entrainment to occur, the difference between τ and T generally cannot exceed the maximum daily phase shift that can be induced by exposure to available light. Thus, entrainment of humans to the solar day on Mars (24.6 hours) is feasible (assuming a τ of 24.2 hours, this requires a 24 min delay each day), whereas stable entrainment to the 18-hour duty cycle on an American submarine crew should be virtually impossible (a 6-hour advance being required each circadian cycle16). A second property of entrainment that is determined by τ, T, and PRC shape is the phase relation between rhythm and zeitgeber during stable entrainment (see Fig. 32-2C). The phase relation, or phase difference (abbreviated Ψ), is the difference in minutes (or radial degrees, if expressed as a phase angle) between a definable circadian rhythm phase (e.g., wake onset) and a definable zeitgeber phase (e.g., sunrise, in which case the phase relation can be abbreviated ΨLD). Stable entrainment will occur at whatever ΨLD results in the photic stimulation that generates a net phase shift that precisely compensates for the difference between τ and T. If τ is less than 24 hours, then a net phase delay is required each circadian cycle. A larger net delay will occur when evening light stimulates more of the phase-delay portion of the PRC and when morning light stimulates less of the phase-advance portion. This occurs if the PRC (i.e., the circadian clock) is shifted slightly to the left (i.e., earlier) relative to environmental time. Thus, a bird with a short circadian τ assumes a more positive ΨLD, resulting in an earlier onset of activity at dawn. By contrast, if τ longer than 24 hours, a net daily advance is required, stable entrainment will occur at a more negative ΨLD, and wakeup time will occur later relative to dawn. The shape of the PRC of course also plays a role. The case can be made that ΨLD is the ultimate target of natural selection for the value of τ and the shape of the PRC, a premise summarized indirectly in the aphorism that the early bird gets the worm. Individual differences in τ might also account for the early-bird and night-owl phenotypes that we recognize among humans. In fact, an extreme form of the early-bird phenotype (advanced sleep-phase syndrome) has been traced to a molecular change that affects the periodicity of the human circadian clock,17 and the strongly delayed phenotype of teenagers has been attributed to lengthening of τ during puberty.18 Differences in ΨLD can also occur as a result of small differences in PRC shape or in the strength of the zeitgeber (e.g., the duration, intensity, or wavelength of light exposure each day). A third important property of entrainment determined by τ and the PRC is the response of circadian rhythms to acute displacements of the light–dark cycle. If the light– dark cycle is advanced by 6 to 9 hours, simulating a rapid trip east from North America to Europe, the circadian
clock re-entrains gradually, by small phase shifts (transient cycles) over several days. The size and direction of these shifts is determined by τ; the intensity, wavelength, and precise timing of light; and the shape of the PRC (specifically, the area under the delay and advance portions and the phase at which resetting crosses over from delays to advances). Syrian hamsters have a species-typical τ very close to 24 hours and a relatively large advance-to-delay ratio of their PRC (see Fig. 32-3C). Not surprisingly, they re-entrain to an advance of the light–dark cycle by daily phase advances of about 1 hour (see Fig. 32-3D) and to a delay of light–dark cycle by a series of about 1-hour daily delays. By contrast, Norway rats typically express a τ longer than 24 hours (e.g., see Fig. 32-1B) and re-entrain to an 8-hour light–dark advance by phase delaying 16 hours. The average endogenous τ in humans is slightly longer than 24 hours, which likely contributes in most people to more rapid re-entrainment after flying west (requiring a delay) than east (requiring an advance), and explains why humans might phase delay for many cycles to achieve a large phase advance.19 Effects of Light on Circadian Period Daily light-induced phase shifts may be critical for adjusting circadian rhythms to large displacements of the light– dark cycle, as, for example, following shift-work rotations or transmeridian jet travel or migration, but quantitative models suggest that phase resetting alone might not be sufficient to explain the precision of observed circadian rhythms during steady-state entrainment.20 Stable, highprecision entrainment might also require modulation of intrinsic pacemaker τ. Plasticity of pacemaker τ has been demonstrated in both light pulse and T-cycle entrainment studies. Light pulses early in the subjective night induce phase-delay shifts and tend to lengthen τ in DD, whereas pulses late in the subjective night induce phase-advance shifts and tend to shorten τ.20 In natural environments, light exposure early in the subjective night would occur when τ is less than 24 hours, and lengthening of τ in response to light would tend to move τ closer to 24 hours. Similarly, light exposure late in the subjective night would occur when τ is longer than 24 hours, and shortening of τ would move it closer to 24 hours. Evidence that such τ matching occurs is provided by T-cycle experiments, which show that τ in DD tends to be longer following entrainment to T longer than 24 hours and tends to be shorter following entrainment to T shorter than 24 hours.21,22 These aftereffects on τ can persist for many weeks, and they are likely the basis for the observation that the upper and lower limits of entrainment to T cycles can be extended if the T cycles are gradually lengthened or shortened, respectively. Experimental analysis of entrainment mechanisms has relied heavily on a few nocturnal rodent species that have remarkably precise wheel-running rhythms, permitting easy measurement of even small changes in phase. Although relatively little work has been done on diurnal mammals, the available light-pulse PRCs and τ-response curves appear to be qualitatively similar to those for nocturnal rodents.20,23,24 Thus, the mechanism of discrete entrainment by daily phase and τ adjustments induced by light exposure at dawn and dusk appears to be available to diurnal species, including humans.25
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The photic environments of diurnal and nocturnal animals differ to the extent that diurnal animals are exposed to light throughout the daytime. Whether this additional midday light contributes to entrainment is uncertain. When light is on continuously (LL), simulating the high arctic summer, τ varies systematically with light intensity.26 In nocturnal rodents, LL slows the circadian clock (i.e., τ is lengthened), shortens the daily active phase, and reduces total daily activity (see Fig. 32-5D). In diurnal animals, LL generally has the opposite effects, although there are more exceptions across species (and diurnal primates, in particular, tend not to conform). These empirical generalizations are collectively known as the circadian rule26 and suggest that light could facilitate entrainment by continuous modulation of τ. This forms the basis for a continuous or parametric model of entrainment.20,26 A continuous effect of light on τ could explain the observation that animals can entrain to constant illumination with a 24-hour sinusoidal variation in intensity. Entrainment under such conditions could be accomplished by accelerating or slowing the angular motion of the pacemaker throughout the day, with the net result of a 24-hour τ and stable ΨLD. In less-extreme photoperiods, light might still overlap large portions of the delay and advance zones of the PRC, and this is also sufficient to modulate τ, as indicated by aftereffects of photoperiod on τ in DD (the longer the light period in light–dark, the longer the τ in DD in nocturnal rodents and, less consistently, the shorter the τ in diurnal animals). A continuous action of light on τ might seem to be particularly relevant to diurnal animals, given their additional exposure to light in the morning and evening hours relative to nocturnal animals. However, the aftereffect of photoperiod on τ is also evident in DD following entrainment to skeleton photoperiods in which the interval between evening and morning light pulses is altered to simulate longer or shorter day lengths. Thus, day length, defined by sunrise and sunset, is sufficient to modify τ, and light exposure between these two points might not be necessary. Field studies of a semifossorial diurnal rodent, the European ground squirrel, reveal that they emerge from lighttight burrows several hours after sunrise and return to the burrow several hours before sunset.27 The light–dark cycle is therefore self-selected, which should result in a systematic drift toward dawn or dusk, consistent with an endogenous non–24-hour τ. Instead, they exhibit a precise 24-hour activity rhythm that reflects time of year, with the active phase expanding and contracting with day length across the year, always avoiding dawn and dusk. If the ground squirrel’s rhythm is truly entrained, then its circadian pacemaker must be responsive to light during the day. Although the middle of the day is considered a dead zone, based on studies of brief light pulses in nocturnal species, this feature may be absent from the PRC of some diurnal species, as has been proposed for humans.28 Effects of Light on Circadian Amplitude It is also possible that extended daily light exposure in diurnal animals affects the amplitude of the circadian clock. A widely used model of the circadian clock treats it as a limit-cycle oscillator that has phase and amplitude dimensions and a preferred trajectory of oscillation between
two or more state variables.29,30 When the phase of the oscillation is shifted acutely, the amplitude of oscillation may also transiently change before the preferred trajectory (the limit cycle) is re-established. A continuous or very strong zeitgeber (e.g., critically timed bright light) may drive the state parameters to a low amplitude trajectory, or even a point of singularity characterized by zero amplitude. When the amplitude of oscillation is small, a resetting stimulus of given intensity can elicit larger phase shifts. Such effects might underlie potentiated responses to phase-shifting stimuli in Syrian hamsters after exposure to 2 days of LL.31,32 If the long photoperiod of summer at high latitudes does affect the amplitude of the circadian clock, then this might also affect the ΨLD at which entrainment stabilizes. Such effects remain to be demonstrated empirically. Dual Oscillator Models Another influential heuristic model of the circadian clock postulates that the master, light-entrainable circadian pacemaker consists of two coupled oscillators, each with a full or partial PRC to light13 (in mammals, this clock is located in the hypothalamic suprachiasmatic nucleus [SCN]; see Chapters 33 and 34). When entrained to a natural photoperiod, the two oscillators are assumed to be coupled with a phase relation such that one is affected primarily by morning light and the other is affected primarily by evening light. This dual-oscillator model accounts successfully for many features of circadian rhythms observed under skeleton and non–24-hour light– dark cycles and in response to light–dark shifts and light pulses. Although the model was developed to explain photic entrainment and photoperiodic timing of annual rhythms, it was inspired by the observation that animals exposed to constant lighting conditions for several weeks often exhibit splitting of their circadian rhythms (including those of activity, temperature, and hormone levels) into two components. In nocturnal hamsters, these features emerge after exposure to bright LL for many days. The two split components often free-run with different τs for at least a few cycles before coupling stably in an antiphase relation (Fig. 32-4A). The components rapidly revert to normal coupling under standard photoperiods, but they can be maintained in the split state by certain exotic photoperiods.33 A two-oscillator organization appears to generalize to at least some diurnal organisms, as perhaps the best examples of prolonged splitting are seen in diurnal tree shrews maintained in DD.34 The two-oscillator formalism continues to stimulate debate and experiment in search of its cellular and molecular basis35,36 (see Chapter 34). Although anatomic bases for two-oscillator models have been identified in left–right, dorsomedial–ventrolateral and rostral–caudal compartments of the SCN, many of the properties of a two-oscillator system can be simulated by a multiple oscillator network model.37 Nonphotic Entrainment Masking and Entrainment An important distinction in chronobiology is that between masking and entraining effects of environmental stimuli. Light can entrain circadian rhythms in virtually every
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Figure 32-4 A, Wheel running activity of a Syrian hamster in constant light. The rhythm splits into two components that free-run with different periods for about 10 days and then couple in antiphase. Note that the period of the free-running rhythm shortens after the split, suggesting that τ in the coupled state depends on the phase relation between two underlying oscillators. B, Wheelrunning rhythm of a rat entrained to a 12 : 12 light–dark cycle during ad lib feeding, restricted feeding (open vertical bars) and food deprivation. Running is primarily nocturnal during ad lib feeding. A prominent bout of running anticipates a 3-hour daily mealtime, and it remains coupled to mealtime when feeding intervals are extended from 24 to 26 hours. Activity persists at the predicted mealtime when food is withheld for 3 days (note heavy bouts of daytime running, and rapid reversion to nocturnal activity when food is restored). C, Free-running rhythm of a rat in constant light does not entrain to a restricted 3-hour daily mealtime (open vertical bars) despite anticipatory activity. These data suggest that there are separate pacemakers driving freerunning (light-entrainable) circadian rhythms and food-anticipatory rhythms. D, Free-running activity rhythm of a hamster in constant light entrains to a restricted daily feeding and drinking opportunity (open vertical bars). (A, From Pickard GE, Turek FW. The suprachiasmatic nuclei: two circadian clocks? Brain Res 1983;268:201-210; B, from Mistlberger RE, Marchant EG. Computational and entrainment models of circadian food-anticipatory activity: evidence from non–24-hour feeding schedules. Behav Neurosci 1995;109:790-798; C, from Mistlberger, unpublished data; D, from Mistlberger RE. Effects of scheduled food and water access on circadian rhythms of hamsters in constant light, dark, and light : dark. Physiol Behav 1993;53:509-516.)
species that has been studied carefully. In many species, light also has direct effects on the expression of behavior and physiology.26,38 In nocturnal rodents, light at night inhibits locomotor activity and promotes sleep. Light in this case constitutes a negative masking stimulus, because it suppresses a behavior at a circadian phase when that behavior is usually present, thereby masking the true phase of the circadian clock. An example of partial negative masking is illustrated in Figure 32-3D and E; activity early or late in the hamster’s subjective night is strongly suppressed by light exposure following a delay or advance, respectively, of the light–dark cycle. In diurnal animals, light usually stimulates activity; at night this would constitute a positive masking effect. Another well-known masking effect of light is acute suppression of nocturnal pineal melatonin secretion,39 a rapid response that is evident in nocturnal and diurnal animals. These direct effects of environmental stimuli on physiology and behavior contribute to the waveform of daily rhythms in natural environments. They can also present interpretive difficulties in evaluating whether a periodic environmental stimulus functions as a true zeitgeber (i.e., affects the pacemaker rather than only overt behavior). A periodic signal can entrain a behavioral or physiologic rhythm, in which case it is functioning as a zeitgeber, or it can directly impose a rhythm without affecting an underlying oscillator, in which case it is functioning as a masking stimulus. As the examples related to light exposure illustrate, the same stimulus can act as either a zeitgeber or a masking agent depending on circumstances. The criteria
for distinguishing masking from entrainment are based on the properties of oscillator entrainment discussed in relation to photic cycles: • An entrained rhythm should persist (free-run) in the absence of the periodic stimulus, just as photically entrained rhythms persist in constant lighting conditions, and the initial phase of the free-run should reflect the apparent phase of the rhythm during entrainment. • An entrained rhythm should follow an environmental cycle over only a limited range of environmental periods. • The phase relation between an entrained rhythm and an environmental cycle should vary depending on the values of τ and T. • This phase relation should be re-established if the environmental cycle is abruptly shifted. If the rhythm is a direct response to the environmental cycle, shifting will be immediate. If, instead, it reflects entrainment of an underlying oscillator, several transient cycles may be evident before the prior phase relation is re-established. Many effects of nonphotic stimuli on rhythms have been described,40 but few have been rigorously demonstrated to function as zeitgebers. The following sections review the evidence for the nonphotic cues that meet these criteria and can therefore be said to entrain circadian rhythms. Scheduled Feeding Rats provided with food for only a few hours at the same time each day show changes in locomotor activity, body temperature, and other physiologic variables that antici-
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pate the daily mealtime.41,42 These anticipatory responses begin to emerge within several days of scheduled feeding, and they appear to be generated independently of photically entrained rhythms. If the meal is provided in the middle of the light period, rats exhibit two main bouts of activity each day: an intense bout before mealtime and at least some activity persisting during the usual nocturnal active period (see Fig. 32-4B). If the light–dark cycle is replaced by LL or DD, photically entrained rest–activity rhythms free-run and premeal activity remains coupled to mealtime (see Fig. 32-4C). It is common, then, to observe two circadian activity components in food-restricted rats in constant lighting, one free-running with a period slightly different from 24 hours, and a second, food-anticipatory component with a period of exactly 24 hours. Several models have been proposed to account for the emergence of food-anticipatory activity rhythms.41 Most findings, however, are explained parsimoniously by the hypothesis that anticipatory activity is generated by foodentrained circadian oscillators that are separate from the light-entrained pacemaker41,42: • Anticipatory responses occur only when the period of the food-availability cycle is within a broad circadian range of about 22 to 33 hours. • The phase relation between onset of anticipatory activity and mealtime becomes increasingly positive as the period of the feeding cycle is lengthened, and it becomes less positive as it is shortened. • Phase shifting the feeding time is usually followed by gradual rather than immediate shifts of the activity peak to resynchronize to the mealtime. • When the period of the food-availability cycle is abruptly shortened or lengthened from 24 hours to 22 hours or 30 hours, the meal-synchronized rhythm can dissociate from feeding time and free-run for many cycles. • When food is made freely available, the control exerted by these oscillators over behavior diminishes, resulting in a loss of overt activity related to the former mealtime. However, when the rat is subsequently deprived of food for several days, activity reappears at the circadian phase previously associated with feeding time. Taken together, these observations provide strong evidence that a self-sustained oscillator is involved in generating meal-anticipatory activity and indicate that its influence on behavior is gated by the animal’s motivational state. Other studies show that rats can use food-entrainable oscillators to discriminate time of day, which might enable them to anticipate multiple feeding times and link these with multiple feeding places.10 Dissociation of foodanticipatory rhythms from light–dark-entrained rhythms suggests separate food- and light-entrainable circadian clocks, and lesion studies have confirmed that the master light-entrainable circadian pacemaker (the SCN) is not necessary for food-entrained rhythms. Although foodanticipatory behavioral rhythms have been described in numerous species, only in rats, hamsters, and mice have the appropriate studies been done to confirm mediation by a separate food-entrained clock.43-45 The broad physiologic significance of such foodentrained rhythms may be related to the discovery that most, if not all, peripheral organs and tissues express genes with a circadian rhythm that is entrained preferentially by
feeding cycles rather than light–dark cycles.46,47 When animals are forced or enticed to eat outside of their usual active phase, these peripheral oscillators shift to remain synchronized to mealtime, but the SCN remains coupled to the light–dark cycle. This finding suggests that one route by which the SCN might normally coordinate peripheral oscillators and rhythms is by controlling the daily rhythm of food intake. Although it has been sought in peripheral organs and in the brain, there is still no convincing evidence implicating any known structure as the physiologic substrate for the food-entrainable clock. The dorsomedial region of the hypothalamus, for example, has been suggested as the site of the food-entrainable pacemaker for behavioral anticipation, but there is strong evidence that this is not the case.48,49 The stimuli associated with food acquisition and ingestion that provide the timing signals necessary to entrain circadian oscillators are also not well characterized, and they might extend to rewarding stimuli other than food.50,51,52 The use of separate pacemakers to mediate food and light entrainment in rats confers flexibility on the circadian organization of their behavior and permits anticipation of a stable window of food availability at any time of day, without necessarily altering the phase of photically entrained activity rhythms. Occasionally, feeding schedules do entrain or markedly shift the entire circadian system in rats,53 and in some species this may be the rule rather than the exception (see Fig. 32-4E).54-57 In these cases, it is not clear which stimuli associated with scheduled feeding serve as the zeitgeber for the light-entrainable circadian clock in the SCN. For example, the SCN clock may be entrained indirectly as a result of its coupling relations with food-entrained oscillators located elsewhere. Alternatively, the SCN may be entrained by stimuli from specific ingested nutrients, metabolic hormones associated with their ingestion, or nonspecific stimuli, such as the arousal associated with anticipatory activity or the thermogenic consequences of digestion. Temperature Free-running rhythms in a variety of heterothermic species can be entrained by 24-hour cycles of ambient temperature.58 However, responses of homeothermic animals to temperature cycles are more variable. In some species, temperature cycles failed to entrain various circadian rhythms,59 whereas in other species, including squirrel monkeys,60 pig-tailed macaques,61 rats, and a marsupial mouse,62 temperature cycles have clear entrainment effects in at least some individuals. The mechanism by which temperature entrains circadian rhythms in mammals is unclear. The SCN circadian pacemaker, studied in vitro, can be phase shifted by temperature pulses (step changes from 34° to 37°C), possibly by a direct effect on clock gene transcription or translation.63 In homeothermic species in vivo, however, entrainment to temperature pulses would seem unlikely to involve a direct effect on circadian oscillators in the brain, assuming that brain temperature is well defended homeostatically. However, some mammals can regularly sustain very low body temperatures, and in these cases significant changes in pacemaker temperature may alter τ or phase,
Activity and Arousal States In an early description of the circadian rule, Aschoff noted that the relation between light intensity and τ might be mediated by changes in arousal states, because bright LL both lengthens τ and suppresses activity in nocturnal rodents.26 A later study provided some support for the idea that metabolic rate, arousal, or some correlate of these affected the circadian pacemaker, in that the free-running τ of activity rhythms (measured as general locomotor activity using photocell interruptions) was longer in hamsters with access to running wheels.65 More-recent studies indicate that this effect is weak in hamsters66 but is robust in rats67 and mice68: τ shortens when wheels are available and lengthens when wheels are locked. Evidently, some correlate of spontaneous, clock-regulated wheel-running activity provides a feedback signal that can alter the rate at which the circadian pacemaker cycles. The effects of behavior on functional properties of the circadian pacemaker were not widely recognized until the late 1980s, when a series of studies demonstrated unequivocally that acutely stimulated locomotor activity and arousal can reliably induce large phase shifts in hamsters (Fig. 32-5A and B) and, if repeated on a daily basis, can entrain free-running rhythms in hamsters, rats, and mice. The earliest of these studies showed that hamsters could be phase-shifted or entrained simply by changing their litter or cages69 or by the opportunity for a 30-minute daily bout of foraging activity in an open field, despite little or no eating at that time.70 More-robust phase shifts were reliably obtained by confining hamsters in DD to novel running wheels for 2 to 3 hours. Hamsters that ran continuously while in the wheel exhibited phase shifts of 2 to 3 hours or more.71 As with phase-shifting light stimuli, the magnitude and direction of the phase shifts evoked by activity depend on when the stimulus is scheduled. The shape of the associated PRC, however, is markedly different; running stimulated during the midsubjective day (the dead zone for photic stimuli) induces large phase-advance shifts, whereas running during the mid-to-late subjective night (the advance zone for photic stimuli) induces small phase delays (see Fig. 32-5C). These findings indicate that the circadian clock in mammals has distinct circadian rhythms of sensitivity to photic and nonphotic stimuli. A variety of stimuli (e.g., cold, hunger, dark, drugs) have been shown to induce phase shifts in hamsters by stimulating activity.72-75 Shifts of this type can also be induced independently of activity under some conditions, indicating that exercise is not always necessary and that arousal may be sufficient.76-80 A variety of drugs have also been shown to induce phase advances during the subjective day that are either not associated with increased activity or are
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CHAPTER 32 • Circadian Rhythms in Mammals: Formal Properties and Environmental Influences 371
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Figure 32-5 Phase-shifting effects of 3-hour bouts of arousal stimulated by confinement to a novel running wheel during the middle of the subjective day (rest period) in Syrian hamsters. Arrowheads denote the beginning and ending of confinement to novel running wheel. A, A 150-minute phase advance induced by running on the third day of constant dark. B, A 350-minute phase advance induced by running on the third day of constant light. Lights were turned off during running and left off for the next 3 days. C, Phase response curve to 3-hour bouts of wheel running. D, An 8-hour phase shift of light–dark, combined with 3 hours of stimulated running at the onset of darkness on the first night of the advanced light–dark cycle. The hamster re-entrains to light–dark within 1 cycle (compare this with Figure 32-3D, same hamster without stimulated running). E, Phase delay of nocturnal activity in a hamster entrained to light–dark and subjected to novelty-induced running each day. F, Inversion of the circadian activity rhythm in a hamster entrained to a skeleton photoperiod (two 30-minute light pulses) and subjected to novelty induced running. Such inversions are prevented by full photoperiods. (A and B, From Mistlberger RE, Antle MC, Webb IC, et al. Circadian clock resetting by arousal: the role of stress and activity, Am J Physiol 2003;285:R917-R925; C, modified from Mrosovsky N, Salmon PA, Menaker M, et al. Nonphotic phase-shifting in hamster clock mutants. J Biol Rhythms 1992;7:41-49; D, modified from Mistlberger RE, Nadeau J. Ethanol and circadian rhythms in the Syrian hamster: effects on entrained phase, re-entrainment rate and period. Pharm Biochem Behav 1992;43:159-165; E, from Sinclair SV, Mistlberger RE. Activity reorganizes circadian phase of Syrian hamsters under full and skeleton photoperiods. Behav Brain Res 1997;87:127-137.)
not blocked by procedures that prevent activity. These drugs might directly activate pathways (e.g., serotonin, neuropeptide Y) that mediate the effects of activity and arousal on the circadian clock.81,82 The adaptive significance of the phase-shifting effects of activity in hamsters is unclear, but it might represent a mechanism for modulating circadian activity patterns in response to biologically important events related, for example, to social or sexual interactions (for a review, see reference 83). The potential practical applications of this phenomenon are, however, notable. For example, a single 3-hour bout of appropriately scheduled wheel activity in hamsters can greatly accelerate re-entrainment to a shifted light–dark cycle84 (compare Fig. 32-3D with Fig. 32-5D), and repeated daily bouts can alter the phase of entrainment to an light–dark cycle.85,86 Scheduled activity can shift cir-
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cadian rhythms in humans,87 and may thus represent a useful tool for manipulating the circadian system to remedy acute disorders associated with travel across time zones or with shift work or disorders of entrainment such as are commonly experienced by the blind.88 Social Cues Interactions among members of the same species are known to phase shift, entrain, or modify τ of free-running rhythms in several species.83 Interpreting these effects can be problematic, because social interactions can exert strong masking effects on behavior and can also determine the pattern of light exposure and food intake, thereby complicating attributions of causality. Examples of mutual coordination of co-housed hamsters have been reported,89 and large phase-advance shifts can occur in socially subordinate or dominant hamsters co-housed for 3 hours during the midrest period in the dominant hamster’s cage.77 In most cases, however, social effects on circadian timing appear to be weak, and typically the circadian rhythms of rats, mice, and hamsters housed individually in adjacent cages, or in pairs within the same cage, do not become mutually synchronized despite auditory, olfactory, and visual contact.90 Blind humans might also display freerunning sleep-wake and other rhythms despite exposure to the social cues of a 24-hour society.83,88 In cases where social stimuli do shift circadian timing, the mechanisms are not known, but effects on arousal states are probably a necessary, if not sufficient, component of this mechanism. Interactions between Photic and Nonphotic Zeitgebers The significant effects of spontaneous activity on freerunning τ in rats and mice, and of stimulated activity on phase in free-running hamsters, suggest that the steadystate, entrained phase of circadian rhythms might reflect integration of photic and nonphotic stimuli. A number of studies have examined whether activity stimulated each day at a particular phase of the light–dark cycle can alter entrainment to light–dark cycles. The results of some of these studies suggest that photic and nonphotic inputs combine linearly, in accordance with their respective PRCs. For example, activity or arousal induced in the middle of the light period by triazolam injections, wheel confinement, social or sexual stimuli, or restricted feeding can advance the phase of nocturnal activity onset,54,85 whereas activity induced late in the subjective night can delay the phase of activity onset.85,86 Other results indicate that under some circumstances, photic and nonphotic stimuli can combine nonlinearly and produce phase changes that are not predictable from photic and nonphotic PRCs. Two studies have shown that activity induced in the middle of the light period can in some cases significantly delay, rather than advance, nocturnal activity onset.86,91 This apparent delay might reflect splitting of the activity rhythm into two components, one that delays with respect to dark onset and another that advances and aligns with the midday wheel-running session.33,86,91 Other studies have examined the interactive effects of single pulses of photic and nonphotic stimuli in combination.81,82 The results again suggest complex, nonlinear
interactions, including mutual inhibition (phase shifts to activity blocked by a subsequent light pulse, or the reverse) and synergy (greatly accelerated re-entrainment to a light– dark cycle shift by a single bout of running stimulated at the beginning of the new dark period84; see Fig 32-5D). The analysis of the rules of interaction between photic and nonphotic zeitgebers is still at an early stage but should benefit from progress made on the molecular basis of circadian clock resetting.
CIRCADIAN RHYTHMS ACROSS THE LIFESPAN Assessment of biological rhythmicity across the mammalian lifespan presents many methodologic and interpretive challenges. Nevertheless, a valid cross-species generalization is that circadian rhythms in behavioral, physiologic, or neural functions are first evident prenatally, stabilize and entrain to light–dark cycles within the first few weeks (e.g., in rodents) or months (e.g., in humans) postnatally, and might exhibit changes in phase, period, amplitude, and response to zeitgebers in old age, with considerable variability within and among species. In rodents, behavioral rhythmicity is not apparent before the second week after birth.92,93 Extrapolation of the phase at which behavioral and physiologic rhythms emerge back to prenatal life indicates, however, that the circadian pacemaker is functioning at or before birth in rats, hamsters, and mice. 2-Deoxyglucose autoradiography has been used to confirm that the circadian pacemaker located in the SCN expresses a daily rhythm of glucose metabolism as early as day 19 of gestation, which is 2 to 3 days before birth and before significant synaptogenesis in the SCN.94 Although the fetal pacemaker lacks most input and output pathways, its metabolic rhythm is synchronized to the dam by a mechanism that involves pacemaker sensitivity to endogenous dopamine and maternal melatonin. After birth, the pacemaker becomes sensitive to photic stimuli during days 2 to 6, at which time it loses sensitivity to dopamine.95 Maternal coordination of the fetus in utero ensures that when the pacemaker becomes coupled to effector systems for behavior and physiology after birth, the emerging rhythms in these functions are appropriately phased with respect to the day–night cycle and to rhythms of the dam. Studies of the human fetus in utero have revealed daily variations in fetal motility, heart rate, and other variables by 20 to 22 weeks of gestation.96 Although these rhythms may be driven directly by maternal factors, evidence for circadian periodicities of various functions in premature infants suggests that humans can generate rhythms endogenously as early as 30 weeks of gestation.97 Neonates tracked over the first year of life exhibit a gradual emergence of circadian rhythmicity that initially appears to free-run but that generally becomes synchronized to the day–night cycle within 2 to 3 months. The conditions under which infants are maintained (e.g., on-demand versus scheduled feeding) can greatly influence the temporal organization of sleep–wake states (reviewed in reference 96). The extent to which maturation of masking and entrainment processes contributes to the appearance of synchronized rhythms early in life is unknown.
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Poor sleep is a primary concern of the aged, and deterioration of circadian organization may be a significant contributing factor. The most widely observed change in circadian rhythmicity with age is a decrease in the amplitude of a variety of rhythms, including activity, temperature, and sleep–wake under entrained and free-running conditions.98 However, a reduced rhythm amplitude is difficult to interpret and could reflect changes in intrinsic properties of the pacemaker (e.g., coupling among a population of cellular oscillators) or changes upstream or downstream from the molecular machinery of the circadian clock. Changes upstream from the pacemaker might include reductions in transmission of, or sensitivity to, photic or nonphotic stimuli. There is evidence that phase shifts to light at low intensities are reduced in aged rodents, but that responses to saturating intensities are greatly enhanced, at least at the transition point between delays and advances on the photic PRC.99 These effects are consistent with a reduced sensitivity to light at the receptor level and reduced amplitude of oscillation at the pacemaker level. Phase-shift responses to nonphotic stimuli (e.g., triazolam injections, dark pulses) have also been reported to be reduced in aged rodents in some studies99 but not others,100 and they may to some extent be secondary to a reduced running response to the stimulus in old animals. Daily rhythms of sleep in aged humans are commonly viewed as fragmented, with less sleep at night and more napping during the day.101 A reduced amplitude of circadian rhythms has been reported in entrained and freerunning humans in many but not all studies.98,101 Failure to observe differences between young and old subjects in some samples might reflect individual differences and illustrate limitations of cross-sectional studies, because these of necessity include only survivors in the advanced-age groups, whose circadian mechanisms might differ from those of others in the cohort. In addition, the unknown histories of light exposure and entrainment of subjects in these studies might contribute significantly to observed differences. Another commonly observed effect of aging in rodents and humans is an advanced ΨLD.98,101 This would be consistent with a shortening of τ, which has been consistently observed in studies employing extended longitudinal designs,102 although not in studies employing cross-sectional designs.103,104 Detection of τ changes may depend on the use of sufficiently aged subjects (many studies have used middle-aged subjects), on the duration of recording (after-effects of previous photoperiods might obscure agerelated changes), and on the recording method. In rats and mice, for example, wheel-running activity shortens τ, and its intensity is significantly attenuated with age. Changes of τ intrinsic to an aging pacemaker might thus be obscured by changes secondary to a reduction of feedback signals from behavior, arousal, hormones, or other factors. It has been suggested that loss of temporal order may be a contributing cause, rather than merely a consequence, of aging.105 In aged rodents, loss of circadian rhythmicity predicts impending death,106 and extended exposure to lighting schedules at the limits to entrainment can reduce life span in some invertebrate species.107 Mutant hamsters with τs that do not permit stable entrainment to 24-hour cycles develop vascular and renal diseases and die at an
early age, but these conditions do not emerge if they are entrained to compatible cycle lengths.108 Although loss of rhythmicity due to experimental ablation of the SCN circadian pacemaker is not fatal to laboratory rodents, effects on mean and maximal lifespan have not been studied carefully. The empirical database does not allow strong conclusions about causal relations between altered circadian organization and the normal aging process, but abnormal circadian organization appears to promote early disease onset in some conditions (see also Chapters 39 and 40).
CONCLUSION This overview of the properties of circadian regulation of behavior and physiology highlights the complexity of the underlying circadian system. The circadian system in mammals is sensitive to light and nonphotic cues, and manipulations of these have revealed a multiplicity of circadian clocks and complex interactions among inputs to these clocks. Black-box models of the circadian system based on a vast descriptive literature have provided a framework for analyses at the neurobiological and molecular level, and progress at these levels has been remarkable since the turn of the century. This work is reviewed in detail in Chapters 33 and 34.
❖ Clinical Pearl If generation or entrainment of circadian rhythm is disrupted by aging, blindness or other conditions, this interruption can be expected to directly affect the consolidation or timing of sleep, producing such symptoms as sleep fragmentation, sleep-onset insomnia, early morning arousals, and daytime sleepiness. Lifestyles associated with abnormal exposure to zeitgebers, such as with shiftwork and transmeridian jet travel, are also associated with disrupted sleep due to the natural delays and impediments in resynchronizing circadian clocks to shifted behavioral and environmental cycles.
REFERENCES 1. Aschoff J, editor. Handbook of behavioral neurobiology: biological rhythms, vol. 4. New York: Plenum; 1981. 2. Brown FA. Response to pervasive geophysical factors and the biological clock problem. Cold Spring Harbor Symp Quant Biol 1960;25:57-72. 3. Dunlap JC, Loros JJ, Colot HV, Mehra A, et al. A circadian clock in Neurospora: how genes and proteins cooperate to produce a sustained, entrainable, and compensated biological oscillator with a period of about a day. Cold Spring Harbor Symp Quant Biol. 2007;72:57-68. 4. Sulzman FM, Ellman D, Fuller CA, Moone-Ede MC, et al. Neurospora circadian rhythms in space: a reexamination of the endogenous-exogenous question. Science 1984;225:232-234. 5. Enright JT. Data analysis. In: Aschoff J, editor. Handbook of behavioral neurobiology: biological rhythms, vol. 4. New York: Plenum; 1981. p. 21-40. 6. Van Cauter E, Huyberechts S. Problems in the statistical analysis of biological time series: the cosinor test and the periodogram. J Interdisc Cycle Res 1973;4:41-57. 7. Refinetti, R. Laboratory instrumentation and computing: comparison of six methods for the determination of the period of circadian rhythms. Physiol Behav 1993;54:869-875.
374 PART I / Section 5 • Chronobiology 8. Moore-Ede MC, Sulzman F. Internal temporal order. In: Aschoff J, editor. Handbook of behavioral neurobiology: biological rhythms, vol. 4. New York: Plenum; 1981. p. 215-241. 9. Biebach, H Falk, JR Krebs. The effect of constant light and phase shifts on a learned time-place association in garden warblers (Sylvia borin): hourglass or circadian clock. J Biol Rhythms 1991; 6:353-365. 10. Mistlberger RE, de Groot MH, Bossert J, Marchant EG. Discrimination of circadian phase in intact and SCN ablated rats. Brain Res 1996;739:12-18. 11. Zhu H, Sauman I, Yuan Q, Casselman A, et al. Cryptochromes define a novel circadian clock mechanism in monarch butterflies that may underlie sun compass navigation. PLoS Biol 2008;6(1):e4. 12. Goldman BD. Mammalian photoperiodic system: formal properties and neuroendocrine mechanisms of photoperiodic time measurement. J Biol Rhythms 2001;16:283-301. 13. Pittendrigh CS, Daan S. A functional analysis of circadian pacemakers in nocturnal rodents. IV. Entrainment: pacemaker as clock. J Comp Physiol [A] 1976;106:291-331. 14. DeCoursey PJ. Daily light sensitivity rhythm in a rodent. Science 1960;131:33-35. 15. DeCoursey PJ. Circadian photoentrainment: parameters of phase delaying. J Biol Rhythms 1986;1:171-186. 16. Kelly TL, Neri DF, Grill JT, Ryman D, et al. Nonentrained circadian rhythms of melatonin in submariners scheduled to an 18-hour day. J Biol Rhythms 1999;14:190-196. 17. Toh KL, Jones CR, He Y, Edie EJ, et al. An hPer2 phosphorylation site mutation in familial advanced sleep phase syndrome. Science 2001;291:1040-1043. 18. Crowley SJ, Acebo C, Carskadon MA. Sleep, circadian rhythms, and delayed phase in adolescence. Sleep Med 2007;8:602-612. 19. Aschoff J, Wever R. The circadian system of man. In: Aschoff J, editor. Handbook of behavioral neurobiology: biological rhythms, vol. 4. New York: Plenum; 1981. p. 311-331. 20. Beersma DG, Daan S, Hut RA. Accuracy of circadian entrainment under fluctuating light conditions: contributions of phase and period responses. J Biol Rhythms 1999;14:320-329. 21. Pittendrigh CS, Daan S. A functional analysis of circadian pacemakers in nocturnal rodents. I. The stability and lability of spontaneous frequency. J Comp Physiol [A] 1976;106:223-252. 22. Scheer FA, Wright KP Jr, Kronauer RE, Czeisler CA. Plasticity of the intrinsic period of the human circadian timing system. PLoS One 2007;2(1):e721. 23. Mahoney M, Bult A, Smale L. Phase response curve and lightinduced fos expression in the suprachiasmatic nucleus and adjacent hypothalamus of Arvicanthis niloticus. J Biol Rhythms 2001;16: 149-162. 24. Sharma VK, Daan S. Circadian phase and period respones to light stimuli in two nocturnal rodents. Chronobiol Internat 2002;19: 659-670. 25. Czeisler, CA. The effect of light on the human circadian pacemaker. Ciba Found Symp 1995;183:254-290. 26. Aschoff J. Exogenous and endogenous components in circadian rhythms. Cold Spring Harbor Symp Quant Biol 1960;25:1126. 27. Hut RA, van Oort BE, Daan S. Natural entrainment without dawn and dusk: the case of the European ground squirrel (Spermophilus citellus). J Biol Rhythms 1999;14:290-299. 28. Jewett ME, Rimmer DW, Duffy JF, Klerman EB, et al. Human circadian pacemaker is sensitive to light throughout subjective day without evidence of transient. Am J Physiol 1997;273:R1800R1809. 29. Lakin-Thomas PL. A beginner’s guide to limit cycles, their uses and abuses. Biol Rhythm Res 1995;26:216-232. 30. Johnson CH, Elliott J, Foster R. Fundamental properties of circadian rhythms. In: Dunlap JC, Loros J, DeCoursey PJ, editors. Chronobiology: biological timekeeping. Sunderland, Mass: Sinauer; 2004. p. 67-106. 31. Mistlberger RE, Belcourt J, Antle MC. Circadian clock resetting by sleep deprivation without exercise: dark pulses revisited. J Biol Rhythm 2002;17:227-237. 32. Knoch M, Gobes S, Pavlovska I, et al. Brief exposure to constant light promotes strong (Type 0) circadian phase resetting responses to nonphotic stimuli in Syrian hamsters. Eur J Neurosci, 2004;19: 2779-2790.
33. Gorman MR, Elliott JA. Entrainment of 2 subjective nights by daily light : dark : light : dark cycles in 3 rodent species. J Biol Rhythms 2003;18:502-512. 34. Meijer JH, Daan S, Overkamp GJ, Hermann PM. The twooscillator circadian system of tree shrews (Tupaia belangeri) and its response to light and dark pulses. J Biol Rhythms 1990;5:1-16. 35. de la Iglesia HO, Meyer J, Carpino A Jr, Schwartz WJ. Antiphase oscillation of the left and right suprachiasmatic nuclei. Science 2000;290:799-801. 36. Daan S, Albrecht U, van der Horst GT, Illnerová H, et al. Assembling a clock for all seasons: are there M and E oscillators in the genes. J Biol Rhythms 2001;16:105-116. 37. Beersma DG, van Bunnik BA, Hut RA, Daan S. Emergence of circadian and photoperiodic system level properties from interactions among pacemaker cells. J Biol Rhythms 2008;23:362-373. 38. Mrosovsky N. Masking: history, definitions, and measurement. Chronobiol Int 1999;16:415-429. 39. Klein D, Weller J. Rapid light-induced decrease in pineal serotonin N-acetyltransferase activity. Science 1972;177:532-533. 40. Rusak B. Vertebrate behavioral rhythms. In: Aschoff J, editor. Handbook of behavioral neurobiology: biological rhythms, vol. 4. New York: Plenum; 1981. p. 183-213. 41. Mistlberger R. Circadian food anticipatory activity: formal models and physiological mechanisms. Neurosci Biobehav Rev 1994;18: 1-25. 42. Stephan FK. The “other” circadian system: food as a zeitgeber. J Biol Rhythms 2002;17:284-292. 43. Stephan FK, Swann JM, Sisk CL. Entrainment of circadian rhythms by feeding schedules in rats with suprachiasmatic lesions Behav Neural Biol 1979;25:545-554. 44. Abe H, Rusak B. Anticipatory activity and entrainment of circadian rhythms in Syrian hamsters exposed to restricted palatable diets. Am J Physiol 1992;263:R116-R124. 45. Marchant EG, Mistlberger RE. Anticipation and entrainment to feeding time in intact and SCN-ablated C57Bl/6j mice. Brain Res 1997;765:273-282. 46. Schibler U, Ripperger J, Brown SA. Peripheral circadian oscillators in mammals: time and food. J Biol Rhythms 2003;18:250-260. 47. Green CB, Takahashi JS, Bass J. The meter of metabolism. Cell 2008;134:728-742. 48. Landry GJ, Yamakawa GR, Webb IC, Mear MJ, et al. The dorsomedial hypothalamic nucleus is not necessary for the expression of circadian food-anticipatory activity in rats. J Biol Rhythms 2007;22(6):479-483. 49. Mistlberger RE, Yamazaki S, Pendergast JS, Landry GJ, et al. Comment on “differential rescue of light- and food-entrainable circadian rhythms.” Science 2008;322(5902):675; author reply 675. 50. Mistlberger R, Houpt T, Moore-Ede M. Food-anticipatory rhythms under 24h schedules of limited access to single macronutrients. J Biol Rhythms 1990;5:35-46. 51. Mistlberger RE. Anticipatory activity rhythms under daily schedules of water access in the rat. J Biol Rhythms 1992;7:149-160. 52. Rosenwasser AM, Schulkin J, Adler NT. Anticipatory appetitive behavior of adrenalectomized rats under circadian salt-access schedules. Anim Learn Behav 1988;16:324-329. 53. Stephan FK. The role of period and phase in interactions between feeding- and light-entrainable circadian rhythms. Physiol Behav 1986;36:151-158. 54. Mistlberger RE. Effects of scheduled food and water access on circadian rhythms of hamsters in constant light, dark, and light : dark. Physiol Behav 1993;53:509-516. 55. Kennedy GA, Coleman GJ, Armstrong SM. Restricted feeding entrains circadian wheel-running activity rhythms of the kowari. Am J Physiol 1991;261:R819-R827. 56. Abe H, Kida M, Tsuji K, Landry GJ, et al. Feeding cycles entrain circadian rhythms of locomotor activity in CS mice but not in C57BL/6J mice. Physiol Behav 1989;45:397-401. 57. Castillo MR, Hochstetler KJ, Tavernier RJ Jr, Greene DM, et al. Entrainment of the master circadian clock by scheduled feeding. Am J Physiol Regul Integr Comp Physiol 2004;287:R551-R555. 58. Sweeney B, Hastings J. Effects of temperature upon diurnal rhythms Cold Spring Harbor Symp Quantum Biol 1960;25:87-104. 59. Stewart MC, Reeder WG. Temperature and light synchronization experiments with circadian activity in two color forms of the rock pocket mouse. Physiol Zool 1968;41:149-156.
CHAPTER 32 • Circadian Rhythms in Mammals: Formal Properties and Environmental Influences 375 60. Aschoff J, Tokura H; Circadian activity rhythms in squirrel monkeys: entrainment by temperature cycles. J Biol Rhythms 1986;1:91-100. 61. Tokura H, Aschoff J. Effects of temperature on the circadian rhythm of pig-tailed macaques, Macaca nemestrina. Am J Physiol 1983;245:R800-R804. 62. Francis A, Coleman G. Ambient temperature cycles entrain the free-running circadian rhythms of the stripe-faced dunnart. J Comp Physiol 1990;167:357-362. 63. Ruby NF, Burns DE, Heller HC. Circadian rhythms in the suprachiasmatic nucleus are temperature-compensated and phase-shifted by heat pulses in vitro. J Neurosci 1999;19:8630-8636. 64. Lee TM, Holmes WG, Zucker I. Temperature dependence of circadian rhythms in golden-mantled ground squirrels. J Biol Rhythms 1990;5:25-34. 65. Aschoff J, Figala J, Poppel E. Circadian rhythms of locomotor activity in the golden hamster measured with two different techniques. J Comp Physiol Psychol 1973;85:20-28. 66. Mrosovsky N. Further experiments on the relationship between the period of circadian rhythms and locomotor activity levels in hamsters. Physiol Behav 1999;66:797-801. 67. Yamada N, Shimoda K, Ohi K, Takahaski S, et al. Free-access to a running wheel shortens the period of free-running rhythm in blinded rats. Physiol Behav 1988;42:87-91. 68. Edgar DK, Martin CE, Dement WC. Activity feedback to the mammalian circadian pacemaker: influence on observed measures of rhythm period length. J Biol Rhythms 1991;6:185-199. 69. Mrosovsky N. Phase-response curves for social entrainment. J Comp Physiol [A] 1988;162:35-46. 70. Rusak B, Mistlberger RE, Losier B, Jones CH, et al. Daily hoarding opportunity entrains the pacemaker for hamster activity rhythms J Comp Physio. [A] 1988;64:165-171. 71. Reebs SG, Mrosovsky N. Effects of induced wheel running on the circadian activity rhythms of Syrian hamsters: entrainment and phase-response curve. J Biol Rhythms 1989;4:39-48. 72. Van Reeth O, Turek F. Stimulated activity mediates phase shifts in the hamster circadian clock induced by dark pulses or benzodiazepines. Nature. 1989;339:49-51. 73. Marchant E, Mistlberger R. Morphine phase shifts circadian rhythms in mice: role of behavioral activation. Neuroreport 1996; 7:209-212. 74. Mistlberger RE, Marchant EG, Sinclair SV. Nonphotic phase shifting and the motivation to run: cold exposure re-examined. J Biol Rhythms 1996;11:208-215. 75. Mistlberger RE, Webb IC, Simon MM, Tse D, Su C. Effects of food deprivation on locomotor activity, plasma glucose and circadian clock resetting in Syrian hamsters. J Biol Rhythms 2006;21(1): 33-44. 76. Antle MC, Mistlberger RE. Circadian clock resetting by sleep deprivation without exercise in the Syrian hamster. J Neurosci 2000;20:9326-9332. 77. Mistlberger RE, Antle MC, Webb IC, Jones M, et al. Circadian clock resetting by arousal: the role of stress and activity. Am J Physiol 2003;285:R917-R925. 78. Binkley S, Mosher K. Direct and circadian control of sparrow behaviour by light and dark. Physiol Behav 1985;35:785-798. 79. Zatz M, Mullen D, Moskal JR. Photoendocrine transduction in cultured chick pineal cells: effects of light, dark, and potassium on the melatonin rhythm. Brain Res 1988;438:199-215. 80. Rosenwasser AM. Neurobiology of the mammalian circadian system: oscillators, pacemakers, and pathways. In: Fluharty SJ, Grill HJ, editors. Progress in psychobiology and physiological psychology, vol. 18. San Diego: Elsevier Academic Press; 2003. p. 1-38. 81. Challet E, Pevet P. Interactions between photic and nonphotic stimuli to synchronize the master circadian clock in mammals. Front Biosci 2003;8:S246-S257. 82. Yannielli P, Harrington ME. Let there be “more” light: enhancement of light actions on the circadian system through non-photic pathways. Prog Neurobiol 2004;74:59-76. 83. Mistlberger RE, Skene DJ. Social influences on circadian rhythms in man and animal. Biol Rev 2004;79:533-556.
84. Mrosovsky N, Salmon P. A behavioural method for accelerating re-entrainment of rhythms to new light–dark cycles. Nature 1987; 330:372-373. 85. Mistlberger RE. Scheduled daily exercise or feeding alters the phase of photic entrainment in Syrian hamsters. Physiol Behav 1991;50:1257-1260. 86. Sinclair S, Mistlberger R. Activity reorganizes circadian phase of Syrian hamsters under full and skeleton photoperiods. Behav Brain Res 1997;87:127-137. 87. Buxton OM, Lee CW, L’Hermite-Baleriaux M, Turek FW, et al. Exercise elicits phase shifts and acute alterations of melatonin that vary with circadian phase. Am J Physiol 2003;284:R714-R724. 88. Klerman EB, Rimmer DW, Dijk DJ, Knonauer RE, et al. Nonphotic entrainment of the human circadian pacemaker. Am J Physiol 1998;274:R991-R996. 89. Paul MJ, Schwartz WJ. On the chronobiology of cohabitation. Cold Spring Harbor Symp Quant Biol 2007;72:615-621. 90. Refinetti R, Nelson DE, Menaker M. Social stimuli fail to act as entraining agents of circadian rhythms in the golden hamster. J Comp Physiol 1992;170:181-187. 91. Mrosovsky N, Janik D. Behavioral decoupling of circadian rhythms. J Biol Rhythms 1993;8:57-65. 92. Reppert SM. Circadian rhythms: basic aspects and pediatric implications. In: Styne DM, editor. Current concepts in pediatric endocrinology. London: Elsevier Science Publishers; 1987. p. 91-125. 93. Reppert SM. Interaction between the circadian clocks of mother and fetus. Ciba Found Symp 1995;183;198-211. 94. Moore RY, Shibata S, Bernstein ME. Developmental anatomy of the circadian system. In: Reppert SM, editor. Development of circadian rhythmicity and photoperiodism in mammals. Ithaca, NY: Perinatology Press; 1989. p. 1-23. 95. Weaver DR, Reppert SM. Definition of the developmental transition from dopaminergic to photic regulation of c-fos gene expression in the rat suprachiasmatic nucleus. Mol Brain Res 1995;33: 136-148. 96. Reppert SM, Rivkees SA. Development of human circadian rhythms: implications for health and disease. In: Reppert SM, editor. Development of circadian rhythms and photoperiodism in mammals. Ithaca, NY: Perinatalogy Press; 1989. p. 245-259. 97. Mirmiran M, Lunshof S. Perinatal development of human circadian rhythms. In: Buijs RM, Kalsbeek A, Romijn HJ, et al, editors. Progress in brain research, vol. 111. London: Elsevier Science BV, 1996. p. 217-225. 98. Monk TH. Aging human circadian rhythms: conventional wisdom may not always be right. J Biol Rhythms 2005;20:366-374. 99. Turek FW, Penev P, Zhang Y, Van Reeth O, et al. Alterations in the circadian system in advanced age. Circadian clocks and their adjustment. Ciba Found Symp 1995;183:212-234. 100. Duncan MJ, Deveraux AW. Age-related changes in circadian responses to dark pulses. Am J Physiol 2000;279:R586-R590. 101. Miles LE, Dement WC. Sleep and aging. Sleep 1980;3:119-220. 102. Pittendrigh C, Daan S. Circadian oscillations in rodents: a systematic increase in their frequency with age. Science 1974;186:548550. 103. Valentinuzzi VS, Scarbrough K, Takahashi JS, Turek FW. Effects of aging on the circadian rhythm of wheel-running activity in C57BL/6 mice. Am J Physiol 1997;273:R1957-R1964. 104. Czeisler CA, Duffy JF, Shanahan TL, Brown EN, et al. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 1999;284:2177-2181. 105. Gibson EM, Williams WP 3rd, Kriegsfeld LJ. Aging in the circadian system: considerations for health, disease prevention and longevity Exp Gerontol 2009;44(1-2):51-56. 106. Wax TM, Goodrick CL. Nearness to death and wheel running behavior in mice Exp Gerontol 1978;13:233-236. 107. Pittendrigh C, Minis D. Circadian systems: longevity as a function of circadian resonance in Drosophila melanogaster. Proc Natl Acad Sci U S A 1972;69:1537-1539. 108. Martino TA, Oudit GY, Herzenberg AM, Tata N, et al. Circadian rhythm disorganization produces profound cardiovascular and renaldisease in hamsters. Am J Physiol Regul Integr Comp Physiol 2008;294:R1675-R1683.
Anatomy of the Mammalian Circadian System Joshua J. Gooley and Clifford B. Saper Abstract Circadian rhythms in mammals, including sleep–wake cycles, are endogenously driven by the suprachiasmatic nucleus (SCN) in the anterior hypothalamus. The SCN consists of ventrolateral (SCNvl) and dorsomedial (SCNdm) components based on differences in chemoarchitecture, peptide phenotype, and afferent–efferent projection pattern, and this organizational scheme is conserved across mammalian species. The SCN is functionally subdivided to generate a coordinated circadian rhythm of neuronal activity in the SCN, to integrate photic and nonphotic time cues to reset the circadian phase of SCN neurons, and to transmit circadian output signals to effector systems to temporally coordinate genetic, physiologic, and behavioral rhythms with daily changes in the environment. The near–24-hour rhythm of neuronal activity in the SCN is normally entrained to the 24-hour light–dark cycle defined by Earth’s rotation. Photic information reaches the SCN directly via the retinohypothalamic tract (RHT) and indirectly through other retinorecipient structures including the intergeniculate leaflet (IGL) in the thalamic lateral geniculate nucleus (LGN). Visual photoreceptors (rods and cones) and intrinsically photosensitive melanopsin-containing retinal ganglion cells contribute to photic circadian entrainment, and RHT axons likely signal light information to the SCN by releasing glutamate and pituitary adenylate cyclase–activating polypeptide (PACAP). The SCN also receives dense input from neuropeptide Y (NPY)and gamma-aminobutyric acid (GABA)–containing neurons in the IGL and serotoninergic input from the median raphe nucleus (MRN). The IGL and MRN are not essential for circadian entrainment or rhythmicity, but they appear to play a modulatory role in regulating light-induced circadian phase shifts and transmitting nonphotic information to the circadian clock.
INTRINSIC ORGANIZATION OF THE SUPRACHIASMATIC NUCLEUS The intrinsic organization of the suprachiasmatic nucleus (SCN) must allow it to generate a coordinated circadian rhythm of neuronal activity in the SCN and to integrate photic and nonphotic time cues to reset the circadian phase of SCN neurons. The SCN must also be organized to transmit circadian output signals to effector systems, to temporally coordinate genetic, physiologic, and behavioral rhythms with daily changes in the environment (i.e., the light–dark cycle and food availability), thus maximizing survival. In the following section we examine the intrinsic organization of the SCN and how this organizational scheme fulfills the aforementioned roles of the SCN. We begin with a basic histologic description of the SCN, including the neurotransmitter content and distribution, followed by an analysis of the functional role of these neurotransmitters in coordinating the circadian rhythm of neuronal activity within the SCN. In addition to classical neuronal synaptic transmission, other modes of intercel376
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Despite the widespread role of the SCN in regulating behavioral, physiologic, and genetic rhythms, SCN output is largely confined to the hypothalamus. The primary neuronal pathway underlying the circadian regulation of sleep–wake cycles involves a dense SCN efferent projection to the adjacent subparaventricular zone (SPZ), followed by a secondary projection to the dorsomedial hypothalamic nucleus (DMH), which projects to other brain regions critical for regulating sleep and wakefulness. The SCN also projects directly and indirectly to the paraventricular hypothalamic nucleus (PVH) to regulate corticosteroid secretion and synthesis of the hormone melatonin. Although SCN neuronal connectivity is required for maintenance of endocrine rhythms, diffusible SCN signals are sufficient to generate weak circadian cycles of rest and activity. In mammals, the master circadian pacemaker in the SCN determines the period and phase of behavioral rhythms including sleep–wake cycles, and disruption of the circadian system is associated with deficits in sleep–wake behavior and cognitive performance. Identifying the neuronal pathways and neurotransmitters that regulate entrainment and generation of circadian rhythms is important for developing therapies (e.g., pharmacologic or light therapy) to improve the quality of sleep–wake cycles and performance, especially in persons with circadian rhythm sleep disorders. In this chapter, we describe the intrinsic organization, inputs, and outputs of the circadian clock in the SCN. We focus on the functional anatomy of the circadian system in rodents, particularly rats, and primates including humans, with emphasis on the neuronal circuitry underlying the circadian control of sleep–wake and rest–activity cycles and how SCN afferent–efferent projections and neurotransmitters regulate behavioral output.
lular communication are thought to participate in synchronizing individual cellular oscillators and modulating the effects of light on SCN neuronal activity.1 Cytoarchitecture In Nissl-stained sections of rodent and monkey brains, the SCN is a conspicuous structure easily identified by its tightly compacted small-diameter neurons; it is located immediately dorsal to the optic chiasm and lateral to the third ventricle (Fig. 33-1A). In humans, homologous neurons may be identified by immunohistochemical stains for their neurotransmitters, but the cell group is much less salient in Nissl-stained sections. In rats, the SCN measures less than 1 mm in the rostrocaudal axis and approximately 350 µm in diameter at the midlevel. Medially, the SCN is separated from the ependymal cells of the third ventricle by the periventricular nucleus, and ventrally the SCN indents the dorsal border of the optic chiasm. SCN neurons are among the smallest of the brain, and in rats each of the bilaterally paired SCNs contains approximately 8000 to
CHAPTER 33 • Anatomy of the Mammalian Circadian System 377
3V
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Figure 33-1 The suprachiasmatic nucleus (SCN) is composed of ventrolateral (SCNvl) and dorsomedial (SCNdm) subdivisions. A, In Nissl-stained coronal sections in rats, the SCN can be identified by its tightly compacted small-diameter neurons located immediately dorsal to the optic chiasm and lateral to the third ventricle. B, VIP-immunoreactive (ir) perikarya are found in the SCNvl. C, AVP-ir cell bodies are found in the SCNdm. 3V, third ventricle; AVP, arginine vasopressin; OC, optic chiasm; VIP, vasoactive intestinal polypeptide. Scale bars equal 200 µm.
10,000 neurons.2 Based on neuronal morphology, ultrastructure, neurotransmitter phenotype, and afferent–efferent projections, the SCN can be divided into dorsomedial (SCNdm) and ventrolateral (SCNvl) components, commonly referred to as the shell and core, respectively. The neurons in the SCNdm are smaller and more tightly compacted than those located in the SCNvl, and Golgi stains of SCN neurons show that the dendritic arbors of SCNvl neurons are more extensive than those of SCNdm neurons. Ultrastructural analysis of the SCN has revealed that SCNvl neurons have more organelles, rough endoplasmic reticulum, and nuclear invaginations, whereas soma–soma appositions are most commonly observed between neurons within the SCNdm.2 Neurotransmitters Synthesized in the Suprachiasmatic Nucleus The SCNdm and SCNvl subdivisions can be easily distinguished by their neurotransmitter content. In rats, many SCNvl neurons contain vasoactive intestinal polypeptide (VIP; see Fig. 33-1B), peptide histidine isoleucine (PHI), gastrin-releasing peptide (GRP), or neurotensin (NT). VIP and PHI arise from the same precursor polypeptide and are therefore coexpressed in SCNvl neurons. The distribution of GRP-containing neurons largely overlaps that of VIP and PHI, but GRP-immunoreactive (ir) neurons are also located more laterally. The SCNdm is best defined by a population of arginine vasopressin (AVP)containing neurons (see Fig. 33-1C). Angiotensin II–containing cells are also found throughout the SCNdm subdivision, and enkephalin (ENK)-ir neurons are located in more lateral regions of the SCNdm. Relatively few somatostatin (SOM)-ir neurons and substance P (SP)-ir neurons are found in the SCNdm of rats, and they are typically found at the border of the SCNdm and SCNvl. The inhibitory neurotransmitter GABA is heavily expressed throughout both SCN subdivisions, and it is contained in most, if not all, SCN neurons (Video 33-1).3 As in rodents, the monkey SCN region that receives the heaviest retinohypothalamic input is characterized by VIP immunoreactivity.4 These VIP neurons are surrounded by an area of AVP-ir cells, suggesting that the SCNvl and SCNdm subdivisions are conserved in primates. Monkey SCN neurons in both subdivisions also express the syn-
thetic enzyme glutamic acid decarboxylase (GAD), indicating that these neurons are GABAergic. In addition, NT-ir neurons are scattered throughout the monkey SCN, with a distribution much broader than that observed in rodents. Consistent with other species, Nissl stains of the human hypothalamus reveal the SCN as a compact group of small-diameter cells dorsal to the optic chiasm and lateral to the third ventricle. Although the boundaries of the human SCN are sometimes difficult to discern in Nisslstained material,5 the human SCN can be readily identified and subdivided based on VIP and AVP immunoreactivity.4 Similar to rodents, VIP-ir cells compose most of the ventral and central part of the SCN, whereas AVP-ir neurons surround the VIP cells in the caudal SCN. Preproenkephalin messenger RNA (mRNA) is expressed in the dorsal SCN,6 partially overlapping the distribution of AVP-ir neurons, and scattered SOM-containing neurons are found in the medial SCN.7 In humans, an extensive population of NT-ir cells is found throughout the SCN, representing the largest known population of SCN neurons.8 Also, neuropeptide Y (NPY)-ir neurons are found throughout the SCN, with the greatest density found in the central part of the nucleus, where they overlap with the distribution of VIP-ir cells. Because NPY-containing cells are absent in the rodent SCN, but a heavy afferent projection arises from NPY-ir neurons in the intergeniculate leaflet (IGL) of the lateral geniculate nucleus (LGN), it has been proposed that the NPY-ir cells in human SCN function similarly to the geniculohypothalamic tract (GHT) neurons in rodents. It is currently unclear whether there is an IGL homologue in the human brain, but a population of NPY-ir neurons has been identified in the pregeniculate nucleus bordering the LGN.9 It has yet to be determined whether the dense NPY-ir terminal plexus in the human SCN originates solely from NPY-ir perikarya within the boundaries of the nucleus or if there is an additional source of input from NPY-containing neurons in the pregeniculate nucleus. In summary, the SCN can be subdivided into ventrolateral (core) and dorsomedial (shell) components based on neurotransmitter phenotype, and this organizational scheme is conserved across mammalian species. The relative distribution and projections (discussed later) of SCN neurons expressing VIP, AVP, and gamma-aminobutyric
378 PART I / Section 5 • Chronobiology
acid (GABA) are conserved in rodents and primates, and the bulk of retinal input is to the SCNvl. There are notable species-specific differences, however, in the abundance and distribution of some SCN neurotransmitters. For example, the relative number of neurons in the human SCN that express NT or NPY far exceeds the number observed in other species. Therefore, the human SCN is likely functionally homologous to the SCN of other mammals, but the relative contributions and combinations of SCN neurotransmitters that regulate circadian rhythms might vary across species. Inter- and Intra-suprachiasmatic Nucleus Connectivity Early studies of the SCN’s anatomy using the Golgi method suggested that SCN neurons are highly interconnected.2 Subsequent studies using immunohistochemistry for SCN neurotransmitters, electron microscopy, and neuronal tracing confirm these results. Axonal terminals immunoreactive for AVP, angiotensin II, and ENK are primarily found in the SCNdm; SOM- and SP-containing fibers are predominantly found in the SCNvl; and VIPand GRP-ir terminal boutons extend throughout both SCN subdivisions. Electron microscope studies of the SCN have shown that VIP-ir perikarya receive synaptic input from AVP- and SOM-ir axon terminals, AVP-ir cell bodies make synaptic contact with VIP- and SOM-ir axons, and VIP-ir, GRP-ir, SOM-ir, and AVP-ir neurons form synapses with cells containing the same peptide.10,11 A caveat of these studies, however, is that the source of the terminals could not be determined. Consistent with Golgi-stained material, some peptide-ir fibers from the SCN also cross the midline, and injection of retrograde tracer into one SCN results in retrogradely labeled neurons in the contralateral SCN, showing that the bilaterally paired SCN are interconnected. Tracing studies in rats using the transneuronal retrograde tracer pseudorabies virus (PRV; Bartha strain) showed that commissural connections primarily exist from SCNdm to SCNdm and SCNvl to SCNvl, and the flow of information in each SCN is predominantly unidirectional from the SCNvl to the SCNdm.12 Likewise, unilateral intra-SCN injection of anterograde tracer into the dorsomedial or ventrolateral SCN of hamsters reveals a prominent projection from the SCNvl to the SCNdm and not vice versa.13
FUNCTIONAL ROLE OF NEUROTRANSMITTERS WITHIN THE SUPRACHIASMATIC NUCLEUS To coordinate the ensemble of circadian gene expression and electrical activity in the SCN, neurons of the circadian clock must communicate extensively with each other. The dense network of SCN neuron interconnectivity likely plays an important role in establishing stable phase relationships between SCN neurons. Upon exposure to light during the subjective night, retinorecipient neurons in the SCNvl appear to be chiefly responsible for resetting the circadian phase of neurons in the SCNdm. The mechanism by which SCN neurons phase shift or synchronize the circadian rhythm of other SCN neurons, however, is poorly understood.
Vasoactive Intestinal Polypeptide VIP-ir perikarya are found extensively throughout the SCNvl, overlapping with the heaviest region of RHT terminals. Retinal axons form synapses with VIP-ir neurons in the SCNvl, and light induces c-Fos (a transcription factor commonly used as a marker for cellular activity) in VIP-containing neurons during the subjective night. VIP-ir neurons project heavily to both subdivisions within the SCN, consistent with the distribution of VPAC2 receptor (which binds both VIP and PACAP with equal affinity).14 VIP-containing SCN neurons also send efferent projections beyond the borders of the SCN; these projections are discussed later. VIP mRNA is expressed rhythmically in a light–dark cycle, but not in constant darkness, suggesting that VIP levels are predominantly regulated by light. Similar to the effects of VIP on SCN electrical activity in vitro, microinjection of VIP into the SCN region in vivo shifts the circadian rhythm of wheel-running activity similar to the way light does.15 VIP knockout mice exhibit normal diurnal locomotor rhythms in a light–dark cycle, but they show a reduction in the circadian amplitude of wheel-running activity in constant darkness.16 As in VIP-deficient mice, VPAC2-receptor knockout mice can synchronize their behavior to the light–dark cycle (probably due to the masking effects of light on behavior) but have profoundly weakened locomotor activity rhythms in constant darkness.17 Recent studies suggest that the loss of behavioral rhythmicity in VPAC2-receptor–deficient mice is due to dampened circadian rhythms of clock gene expression in individual SCN neurons, as well as from a loss of synchrony between SCN neurons.18 These data are consistent with a model in which light regulates VIP expression in SCNvl neurons, and these neurons reset or synchronize the phase of other SCNvl and SCNdm neurons by VIP signaling through the VPAC2 receptor. Redundant or compensatory pathways appear to contribute to the maintenance of SCN rhythms, however, because a lowamplitude rest–activity rhythm is still evident in many VIP-receptor and VPAC2-receptor–deficient mice. Gastrin-Releasing Peptide The distribution of GRP-expressing neurons largely overlaps the region of VIP immunoreactivity in the SCNvl, and many neurons contain both neurotransmitters. As expected, RHT terminals form synapses with GRP-ir neurons in the SCNvl, and light induces c-Fos in GRP-containing cells during the subjective night. Similar to VIP, GRP content exhibits a diurnal rhythm in a light–dark cycle, but not in constant darkness, suggesting that GRP levels are regulated by light. GRP receptor is predominantly found in the SCNdm, but low levels of GRP receptor expression are also found in the SCNvl. Consistent with the effects of GRP on SCN neuronal activity in vitro, microinjection of GRP into the SCN induces small phase shifts of locomotor activity, with phase-response properties similar to lightinduced shifts of the rest–activity rhythm.15 Also similar to the effects of light, GRP induces expression of the clock genes mPer1 and mPer2 in the dorsal SCN.19 GRPdeficient mice show normal rest–activity rhythms in constant darkness, however, indicating that GRP signaling is not required for the expression of behavioral circadian
rhythms. Therefore, light regulates GRP expression in the SCNvl, and GRP signaling plays a limited or redundant role in shifting the circadian phase of SCNdm neurons. Vasopressin AVP and AVP V1a receptor mRNA are primarily found in the SCNdm, suggesting that AVP signaling within the SCN is largely restricted to the dorsomedial subdivision.20 In addition to intra-SCN local projections, AVP-ir fibers from the SCN project to other hypothalamic areas including the medial preoptic area (MPOA), SPZ, DMH, and PVH, and to the paraventricular thalamic nucleus. Despite the abundance of AVP and AVP V1a receptor mRNAs in the SCNdm, AVP signaling appears to play a limited or redundant role in the regulation of circadian rhythms. AVP shows a circadian rhythm of gene expression in constant darkness,21 but AVP-deficient Brattleboro rats show normal behavioral circadian rhythms,22,23 indicating that AVP is not required for generating SCN rhythm or for output of rest–activity cycles. Furthermore, injection of AVP or V1 receptor antagonists into the SCN region does not alter the phase or period of locomotor activity,24 and AVP does not shift SCN electrical activity in SCN slices. Gamma-Aminobutyric Acid Most, if not all, neurons in both SCN subdivisions contain GABA, suggesting that the output of SCN neurons is principally inhibitory. GABA is found in approximately half of all presynaptic axons in the SCN,25 and GABA- or GAD-ir axons form synapses with all types of neurons studied in the SCN.11 GABAergic terminals in the SCN derive from SCN afferent projections and from GABAcontaining neurons intrinsic to the circadian clock. Histologic and functional studies indicate that GABA acts on both ionotropic GABAA receptors and metabotropic GABAB receptors in the SCN. In situ hybridization and immunocytochemical studies have shown that several GABAA receptor subunits and the GABAB1 receptor subunit are found in the SCN. Given that the functional properties of GABA receptors depend upon the subunit’s composition, and GABAA receptor subunits in the SCN are differentially distributed,26 the effects of GABA on SCN neuronal activity may also be regionally specific. In cell cultures, GABAA or GABAB receptor agonists inhibit the firing rate of individual SCN neurons, but only GABAA receptor agonists induce circadian phase–dependent shifts of neuronal activity.27 Thus, GABA induces phase shifts of neuronal firing in vitro by activating the GABAA receptor subtype. In dissociated cell culture, SCN neurons normally display independent and asynchronous circadian rhythms of neuronal firing, but daily administration of GABA synchronizes SCN neuronal electrical rhythms.27 Thus, GABAergic signaling might play a role in coordinating the circadian phase of individual SCN cellular oscillators, but this has not been tested in vivo. Similar to results in cell culture, GABAA receptor agonists inhibit neuronal and metabolic activity of SCN neurons in hypothalamic brain slices,28,29 and the GABAB receptor agonist baclofen inhibits optic nerve–stimulated field potentials.30 Consistent with in vitro data, lightinduced phase shifts of locomotor activity are blocked by both GABAA and GABAB receptor agonists.31,32 A relatively
CHAPTER 33 • Anatomy of the Mammalian Circadian System 379
small population of SCN neurons, located predominantly in the SCNdm, exhibits excitatory responses to GABA.33 Collectively, these results suggest that GABAergic signaling within the SCN plays a complex role in the regulation of circadian rhythms. Based on in vitro data, GABA might reset and coordinate the circadian rhythm of SCN electrical activity via GABAA receptor, and GABAA and GABAB receptors may be important for modulating RHT input to the SCN. As is discussed later, GABAergic SCN afferent projections, especially from the IGL, might also be important in nonphotic resetting of circadian phase. In addition, SCN efferent projection neurons are GABAergic, suggesting that GABA may be the principal neurotransmitter of the circadian timing system.
ROLE OF CALCIUM-BINDING PROTEINS IN THE SUPRACHIASMATIC NUCLEUS The circadian pacemaker exhibits a circadian rhythm in spontaneous firing in which SCN neurons are more active during subjective day compared to subjective night. SCN neurons exhibit spontaneous oscillations in membrane potential that are thought to be regulated by L-type voltage-sensitive calcium channels, voltage-gated sodium channels, and calcium-dependent potassium channels.34,35 The amplitude of L-type Ca2+ currents in SCN neurons is highest during the daytime, corresponding to an increase in intracellular Ca2+ concentration. In vivo, the diurnal entry of Ca2+ likely regulates light-induced and circadian phase–dependent changes in gene expression, including phosphorylation-dependent induction of the transcription factor cAMP (cyclic adenosine monophosphate) response element–binding protein (CREB), and the subsequent induction of the immediate-early gene c-fos in the SCN. Intracellular Ca2+ homeostasis is likely regulated by the Ca2+-binding proteins calbindin-D28K (CB) and calretinin (CAL), which are found in the SCN. Similar to other Ca2+binding proteins, CB and CAL might function as cytosolic Ca2+ buffers to limit the availability of intracellular Ca2+, thereby regulating Ca2+-mediated signaling across the circadian cycle. In hamsters, RHT axons form synapses on CB-ir neurons, and light induces c-Fos in these cells.36 SCN lesion and transplantation studies suggest that the CB-ir subregion in hamsters may be important for the expression of locomotor activity rhythms.37 Consistent with these findings, targeted disruption of the CB gene in mice reduces the amplitude of circadian behavior.38 CB-ir and CAL-ir neurons have also been described in the SCN of monkeys and humans, suggesting that Ca2+-binding proteins play an important role in the regulation of circadian behavior across species.7,39 SUPRACHIASMATIC NUCLEUS INPUTS The endogenous circadian rhythm of neuronal activity in the intact SCN is close to, but not exactly, 24 hours. Therefore, the circadian clock must be reset daily by extrinsic time cues to entrain the circadian rhythm of electrical activity in the SCN to the imposed solar day length.
380 PART I / Section 5 • Chronobiology
INPUT
Hypothalamus Limbic system
PVT
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DMH
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IGL PAG
Septum BSTL
A Retina
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Brain
RCA
Figure 33-2 Afferent and efferent projections of the suprachiasmatic nucleus (SCN). A, SCN afferent projections terminate differentially in the SCNvl and SCNdm. Neurotransmitters contained in these projections are shown next to the arrows. B, SCN efferent projections are primarily confined to the hypothalamus. 5-HT, 5-hydroxytryptamine (serotonin); BSTL, bed nucleus of the stria terminalis; DMH, dorsomedial hypothalamic nucleus; GABA, gamma-aminobutyric acid; Glu, glutamate; IGL, intergeniculate leaflet; MPOA, medial preoptic area; MRN, median raphe nucleus; NPY, neuropeptide Y; OPT, olivary pretectal nucleus; PACAP, pituitary adenylate cyclase–activating polypeptide; PAG, periaqueductal gray matter; PVH, paraventricular hypothalamic nucleus; PVT, paraventricular thalamic nucleus; RCA, retrochiasmatic area; SCNdm, dorsomedial suprachiasmatic nucleus (shell); SCNvl, ventrolateral suprachiasmatic nucleus (core); SPZ, subparaventricular zone.
VLPO
RHT
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OUTPUT
PVH
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Retina The retinohypothalamic tract (RHT) is the densest input to the SCN and was first identified in 1972 by autoradiographic tracing methods.41,42 In contrast to most other retinofugal projections, retinal efferents to the SCN are bilateral, with a slight to moderate contralateral predominance in most species (Fig. 33-3A). When retrograde tracers are injected into the SCN, a homogeneous population of small-diameter retinal ganglion cells (RGCs; about 13 µm diameter in the rat) that morphologically resemble type III (rat) or gamma (cat) RGCs is labeled in each retina, representing approximately 0.1% to 3% of all RGCs.43,44 Although the RHT sends its densest projection to the SCNvl, smaller numbers of RHT axons reach the SCNdm, SPZ, anterior hypothalamic area (AHA), retrochiasmatic area (RCA), MPOA, ventrolateral preoptic
SCN
PTA
IGL
B To coordinate behavioral, physiologic, and genetic circadian rhythms appropriately with diurnal changes in the environment, such as changes in the light–dark cycle or food availability, the circadian timing system processes photic and nonphotic inputs. The SCN is functionally divided such that the SCNvl receives dense input from the retina, IGL, and the midbrain raphe nuclei, and the SCNdm primarily receives projections from other hypothalamic areas, basal forebrain, limbic cortex, septal area, and brainstem (Fig. 33-2A).40
vSPZ
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Optic chiasm
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SCNvl Glu
A
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Output Sleep–wake state
Circadian regulation of sleep & locomotor activity
Circadian rhythms
Pupillary light reflex
Photic and nonphotic regulation of SCN
Figure 33-3 Retinal input to the circadian timing system from melanopsin-containing retinal ganglion cells. A, Following intraocular injection of cholera toxin B subunit into the left eye, anterogradely labeled axons project bilaterally to the SCN of rats, as shown in a horizontal section through the optic chiasm. B, Melanopsin-containing retinal ganglion cells project to brain areas involved in processing nonvisual information, including the SCN and IGL. The branched solid arrow to the SCN and PTA indicates collateralized projections, and the branched dashed arrow to the SCN and IGL indicates proposed axon collaterals. Long dashed arrows indicate physiologic and behavioral outputs of the targeted retinorecipient brain areas. Direct projections between brain areas are shown, but indirect projections are not shown for reasons of clarity. IGL, intergeniculate leaflet; Opn4+ RGCs, melanopsin-positive retinal ganglion cells; ON, optic nerve; OT, optic tract; PTA, pretectal area; RHT, retinohypothalamic tract; SCN, suprachiasmatic nucleus; VLPO, ventrolateral preoptic nucleus; vSPZ, ventral subparaventricular zone. (B from Gooley JJ, Lu J, Fischer D, et al. A broad role for melanospin in nonvisual photoreception. J Neurosci 2003;23:7093-7106. Copyright 2003 by the Society for Neuroscience.)
nucleus (VLPO), and lateral hypothalamic area (LHA), especially in the region bordering the supraoptic nucleus.45 In contrast to most species, the retinohypothalamic projection in monkeys has been described as predominantly ipsilateral.46 Similar to the rodent retina, the monkey retina projects most strongly to the ventral SCN, and scattered terminals are found throughout the dorsal SCN and extend into other hypothalamic areas including the AHA, espe-
cially dorsal to the SCN (equivalent to the SPZ defined in rodents), and the RCA.4 Although an intact RHT is required for photic circadian entrainment in mammals, light resetting does not require the presence of classical visual photopigments (rhodopsin and cone opsins).47 In the absence of rod and cone function, the invertebrate-like opsin melanopsin (Opn4) is sufficient to mediate circadian responses to light. Melanopsin is found primarily in the retinal ganglion cell (RGC) layer of mammals,48 and both anterograde and retrograde tracing strategies have been used to demonstrate that many melanopsin-containing RGCs project heavily to the SCN.49,50 Melanopsin-containing RGCs are intrinsically photosensitive and depolarize in response to light,51,52 and recent studies suggest that there may be multiple subclasses of melanopsin-expressing RGCs.53,54 Similar to the spectral sensitivity of the melanopsin cells,51,52 phase shifting and melatonin suppression are most sensitive to short-wavelength blue light,55-59 indicating that melanopsin plays an important role in circadian photoreception in mammals. Consistent with these observations, Opn4 null mice show attenuated phase shifts of the rest–activity rhythm in response to bright light.60,61 Nevertheless these animals still synchronize to a light–dark cycle, indicating there are redundant phototransduction pathways that mediate photic circadian entrainment. As bipolar cells in the eye form synapses with the dendrites and soma of melanopsincontaining neurons,62 melanopsin-containing RGCs likely receive indirect photic input from rods and cones as well. Recent studies indicate that both classical visual photoreceptors and melanopsin-containing RGCs participate in light entrainment in normally sighted persons, but the relative contribution of these photoreceptor classes has yet to be determined.63-65 Photic circadian entrainment is only abolished in animals without rod, cone, and melanopsin function or in mice in which the melanopsin-containining RGCs are genetically ablated.66-69 Thus, classical visual photopigments and melanopsin play a complementary role in photic circadian entrainment, and the melanopsincontaining RGCs function as a necessary conduit for light information to reach the circadian clock in the SCN. In addition to the SCN, melanopsin-expressing RGCs project to other brain areas that are involved in nonvisual photoreception including the VLPO, SPZ, olivary pretectal nucleus (OPT), and IGL (see Fig. 33-3B).70,71 Some melanopsin-expressing RGCs send bifurcating axons to both the SCN and OPT,70 and a subset of RGCs projects to both the SCN and IGL.72 Each of these retinorecipient brain areas is interconnected with the SCN, suggesting that photic input from melanopsin-containing RGCs can modulate circadian rhythms via multiple routes. The projection to the sleep-promoting VLPO provides a direct substrate for the regulation of sleep–wake state,73 and the projection to the SPZ might supplement circadian output from the SCN that determines the phase of the sleep–wake cycle (discussed later). Several lines of evidence suggest that photic information is conveyed to the SCN via the release of excitatory amino acids such as glutamate from RHT terminals. Most lightresponsive SCN neurons exhibit excitatory responses, and at the electron microscope level, RHT terminals predominantly form asymmetrical Gray’s type-1 synapses on SCN
CHAPTER 33 • Anatomy of the Mammalian Circadian System 381
neurons, presumed to be excitatory.74 Glutamate and N-acetylaspartylglutamate (NAAG), which is metabolized to its constituent amino acids glutamate and aspartate, have been localized to RHT terminals in the SCN.75,76 In a brain slice preparation, optic nerve stimulation induces the release of glutamate and aspartate in the SCN, but not GABA.77 Glutamate mimics the effects of optic nerve stimulation on the circadian rhythm of SCN neuronal activity in vitro,78 and microinjection of N-methyl-d-aspartate (NMDA) into the SCN region in vivo mimics the phaseshifting effects of light on rest–activity rhythms.79 Similar to the effects of light, NMDA injected into the SCN region during the subjective night induces expression of c-fos in the SCN and acutely suppresses the synthesis of melatonin in the pineal gland.80,81 Consistent with pharmacologic studies implicating various glutamate receptor subtypes on SCN neuronal activity, receptor subunits from the NMDA-, a-amino-3hydroxyl-5-methyl-4-isoxazole-propionic acid (AMPA)–, and kainate-preferring classes of ionotropic glutamate receptors are found in the SCN, in addition to subunits from metabotropic glutamate receptors.82 Most glutamate receptor subunits appear to be concentrated in the SCNvl, but the abundance and regional distribution of each glutamate receptor subunit varies. Because the physiologic properties of glutamate receptors depend on the subunit’s composition, the effects of glutamate on SCN neurons can differ with respect to the region-specific expression of glutamate receptor subunits. RGCs that give rise to the RHT also express PACAP, and these PACAP-containing RGCs coexpress melanopsin.50 At the electron microscope level, PACAP is seen to co-localize with glutamate at RHT terminals, suggesting that both glutamate and PACAP transmit photic information to the circadian clock.83 In vitro and in vivo studies indicate that the phase-shifting effects of PACAP are concentration dependent: High concentrations of PACAP induce phase advances during the subjective day similar to the effects of dark pulses or NPY, and low concentrations of PACAP yield phase shifts similar to those induced by light.84 Also, PACAP binds the PAC1 receptor and VPAC2 receptor with equal affinity, both of which are expressed in the SCN. Thus, determining the endogenous role of PACAP signaling in the SCNvl has presented a significant challenge. Mice deficient in the PAC1 receptor appear to entrain normally to a light–dark cycle, indicating that PAC1 signaling is not required for photic circadian entrainment.85 However, circadian phase–dependent deficits in light resetting are observed in PAC1−/− mice, suggesting that PACAP plays a partially redundant role in transmitting photic information to the SCN. Intergeniculate Leaflet In rodents, the IGL is a thin cellular layer sandwiched between the dorsal and ventral subdivisions of the LGN of the thalamus. Caudally, the IGL sweeps ventromedially at the lateral border of the medial geniculate nucleus, where it becomes contiguous with the zona incerta. In contrast to the dorsal and ventral LGN, which receive a predominantly contralateral projection from the eye, the IGL receives a dense bilateral projection from melanopsincontaining RGCs,86 with a slight to moderate contralateral
382 PART I / Section 5 • Chronobiology
predominance in most species. IGL neurons also receive dense afferents from the ipsilateral and contralateral IGL and RCA and smaller projections from the SCN, locus coeruleus, midbrain raphe, and brainstem cholinergic nuclei.87 The IGL projects heavily to the SCNvl via the geniculohypothalamic tract (GHT) and also sends efferents to hypothalamic areas adjacent to the SCN, including the SPZ and RCA. In addition, the IGL sends axons to the DMH, midline thalamus, pretectum, periaqueductal gray (PAG), superior colliculus, and the lateral and dorsal terminal nuclei of the accessory optic system.88 Most, if not all IGL neurons (about 2000 on each side of the brain in rats) contain the inhibitory neurotrans mitter GABA,3 and the IGL is characterized by large populations of NPY- and ENK-containing neurons.87,89 NPY-containing neurons in the IGL project heavily to the SCNvl subdivision, and GABA has been shown to colocalize with NPY in GHT terminals in the SCN,3 indicating that these transmitters may be coreleased. NPY-ir terminals form synapses on VIP-containing neurons in the SCNvl, which also receive afferents from the retina. In rats, ENK-containing IGL neurons project to the contralateral IGL and not the SCN, but in hamsters enkephalinergic IGL neurons project to both the contralateral IGL and the SCN.89 As in the SCN, light-responsive neurons in the IGL are thought to encode changes in irradiance and show sustained responses to light, and some RGCs that project to the SCN send bifurcating axons to the IGL.72 Unlike the dorsal LGN, which functions as a thalamic relay in imageformation processes, the IGL has a well-defined role in the regulation of circadian rhythms. Lesions of the IGL have been reported to result in a broad array of circadian phenotypes, including a slower rate of re-entrainment following a shift in the photoperiod, a block in the lengthening of circadian period by constant light, elimination of NPYtype phase responses induced by novel wheel-induced locomotion, and a block in the ability of wheel running access to synchronize circadian rhythms.90 Thus, the IGL transmits both photic and nonphotic information to the circadian clock. IGL-lesioned animals are clearly able to entrain to light–dark cycles, however, indicating that the IGL plays a modulatory, rather than principal, role in regulating photic circadian entrainment and rhythm generation. The effects of NPY and photic stimuli on the circadian pacemaker appear to be mutually inhibitory. Consistent with the effects of NPY on SCN electrical activity in hypothalamic slices, microinjection of NPY into the SCN region induces phase advances in locomotor activity during the subjective day,90,91 and NPY-induced phase shifts are attenuated by glutamate or light.92,93 Conversely, glutamate-induced phase shifts in SCN electrical activity or light-induced phase advances in locomotor activity can be inhibited by NPY.94 In vitro pharmacologic studies indicate that NPY inhibits neuronal discharge and NMDAinduced phase shifts via the Y5 receptor,95 whereas NPY-induced phase shifts are mediated by the Y2 receptor.96 Consistent with in vitro data, NPY attenuates lightinduced phase shifts of rest–activity via Y1 or Y5 receptors, or both,97 and NPY-induced phase shifts of locomotor activity appear to be mediated by the Y2 receptor.98 Y1and Y5-receptor mRNAs are highly expressed in the rat
SCN, but surprisingly the Y2 receptor has yet to be detected, suggesting that it may be located on presynaptic terminals. Midbrain Raphe Nuclei The SCN receives a dense serotoninergic input from neurons in the median raphe nucleus (MRN) and relatively sparse input from neurons in the dorsal raphe nucleus (DRN).99 Serotonin (5-HT)-ir axonal terminals in the SCNvl overlap extensively with the terminal fields of the RHT and GHT and form synapses with VIP-ir neurons. In contrast to the MRN, the DRN projects to the IGL and to the SPZ immediately dorsal to the SCN, with few fibers to the SCN itself. Similar to NPY, the effects of 5-HT and photic stimuli on the circadian pacemaker appear to be mutually inhibitory. Phase shifts induced by light, optic nerve stimulation, or glutamate are attenuated by administration of 5-HT during the subjective night, and 5-HT–induced phase advances during the subjective day are inhibited by glutamate agonists or optic chiasm stimulation.100 The midbrain raphe nuclei are not required for photic circadian entrainment or for maintaining circadian rhythmicity, but 5-HT clearly modulates photic and nonphotic input to the circadian clock. Lesions of the midbrain raphe nuclei have been reported to phase advance the locomotor activity onset, lengthen the activity phase, induce deficits in rhythmicity in constant light, and reduce the amplitude or clarity of circadian rhythms.101 Several 5-HT receptor subtypes have been described in the SCN of hamsters, mice, or rats,101,102 but current functional evidence is strongest for 5-HT1B and 5-HT7 receptors in regulating circadian rhythms. In vitro and in vivo evidence suggest the 5-HT1B receptor mediates inhibitory effects of 5-HT on light-induced phase shifts and melatonin suppression.103-105 In addition, electron microscopic studies have shown that 5-HT1B receptor immunoreactivity is predominantly found in presynaptic terminals of RHT and nonoptic axons, whereas the dendrites and cell bodies of SCN neurons contained relatively little 5-HT1B immunoreaction product.106 In vitro pharmacologic studies indicate the 5-HT7 receptor mediates 5-HT–induced phase advances in SCN neuronal firing during the subjective day and the inhibitory effects of 5-HT on SCN spontaneous discharge.107,108 Consistent with these findings, 5-HT7 agonists induce phase advances in hamster behavioral circadian rhythms during the subjective day109,110 and inhibit light-induced phase shifts and c-Fos in the SCN.101,111 The 5-HT7 receptor has been localized to GABA-ir, VIP-ir, and AVP-ir dendrites in the SCN as postsynaptic receptors and also to presynaptic axonal terminals.106 In summary, the retinal projection to the SCNvl mediates photic circadian entrainment in mammals, and RHT axons are thought to transmit light information to the SCN via the release of glutamate and PACAP. Classical visual photoreceptors (rods and cones) or melanopsincontaining RGCs at the origin of the RHT are sufficient for photic circadian entrainment, but the absence of both types of photoreceptors abolishes entrainment to light– dark cycles. The SCNvl also receives dense input from NPY- and GABA-containing neurons in the IGL and
serotoninergic input from the MRN. Light appears to have mutually antagonistic effects to NPY or 5-HT on SCN electrical activity and circadian phase shifting, but the IGL and MRN are not essential for circadian entrainment or rhythmicity. Thus, the IGL and MRN are thought to play a modulatory role in regulating light-induced circadian phase shifts and transmitting nonphotic information to the SCN.
SUPRACHIASMATIC NUCLEUS OUTPUTS The SCN plays a principal role in the circadian regulation of sleep–wake cycles and the diurnal release of endocrine factors, such as melatonin and corticosteroids, that influence behavioral state. In this section we discuss SCN efferent pathways, with particular emphasis on neuronal circuits regulating the circadian control of sleep. Considering the important role that the SCN plays in regulating circadian physiology and behavior, hormones, and reproduction status, the number and density of SCN efferent pathways are surprisingly limited (see Fig. 33-2B).112,113 The SCN projects rostrally to limbic structures, including the lateral septum and bed nucleus of the stria terminalis (BSTL), and to the MPOA and VLPO. The SCN sends dorsal projections to the midline thalamus, including the PVT and paratenial thalamic nuclei, and dorsocaudally to the SPZ, PVH, and DMH. A caudal projection from the SCN terminates in the RCA, and some fibers branch toward the supraoptic nucleus and the LHA. The SCN also sends a minor projection laterally to the IGL and small posterior projections to the OPT and central gray matter. Based on retrograde tracing studies in rats, the SCNdm projects more strongly to the MPOA, DMH, and BSTL, whereas the SCNvl projects more strongly to the lateral septum and tuberal hypothalamus.113,114 The projections of the SCNdm and SCNvl partially overlap, however, and both SCN subdivisions project strongly to the SPZ and midline thalamus. Local SCN projections have been mapped in primates by performing immunohistochemisty for VIP.4,8 In monkeys, as in rats, VIP-ir axons project rostrally into the MPOA and dorsally into the SPZ and AHA ventral to the PVH. Some VIP-ir terminals from the SCN are also observed in the PVH, LHA, and PVT. A dense VIPcontaining projection extends caudally into the RCA, and some fibers continue into the capsule of the VMH, DMH, and dorsal hypothalamic area. In humans, VIP-containing SCN neurons project most heavily into the region just dorsal to the SCN and extending to the area just ventral to the PVH, corresponding to the SPZ in rodents. Similar to that in monkeys, the SCN in humans also sends a dense VIP-ir projection caudally into the RCA. Sleep–Wake Rhythm The densest output from the SCN is to the SPZ, which is located immediately dorsal to the SCN and extends dorsocaudally ventral to the PVH.112 The projection to the SPZ has been demonstrated by conventional neuronal tracing techniques and by immunohistochemistry for SCN peptides such as AVP and VIP, which send axons dorsocaudally into the SPZ. Tracing studies have shown that the
CHAPTER 33 • Anatomy of the Mammalian Circadian System 383
SCNvl projects more strongly to the lateral SPZ, whereas the SCNdm projects more densely to the medial SPZ.114 Consistent with these results, AVP-ir axonal terminals are found medially in the SPZ, whereas VIP-ir terminals are found more laterally. The SPZ innervates similar targets as the SCN but in much greater density, suggesting that the SPZ functions as an amplifier of circadian output from the SCN. Cellspecific lesions of the SPZ eliminate circadian rhythms of sleep, locomotor activity, and core body temperature, suggesting that the SPZ is part of the primary neuronal pathway mediating the output of SCN-generated circadian rhythms.115 Lesions in the ventral part of the SPZ abolish the circadian rhythms of sleep and locomotor activity while having lesser effects on body temperature rhythms, whereas lesions in the dorsal SPZ reduce the body temperature rhythm while having minimal effects on rhythms of wake– sleep or locomotor activity. The ventral SPZ, in turn, sends a strong projection caudally to the DMH. Cellspecific lesions of the DMH eliminate the circadian rhythms of sleep–wake, locomotor activity, feeding, and plasma corticosteroids but not body temperature or plasma melatonin.116 Hence, the major neuronal pathway mediating the SCN-generated circadian rhythm of sleep is through a first-order projection to the SPZ, followed by a second-order projection to the DMH. As would be expected, the DMH projects to brain areas involved in regulating sleep and wakefulness including a primarily GABAergic projection to the VLPO, a sleepactive area in the anterior hypothalamus. The SCN and SPZ also send minor projections directly to the VLPO, but the projection originating from the DMH is one of the largest inputs to the VLPO.117 The VLPO, which contains the inhibitory neurotransmitters GABA and galanin, is thought to promote sleep via its projections to the ascending arousal systems.118,119 The DMH also sends a primarily glutamatergic projection to the lateral hypothalamus, which contains wake-promoting neurons, including the wake-active orexin-expressing neurons.116 Thus, the DMH receives circadian input directly from the SCN and indirectly via the SPZ and projects to the VLPO and LHA, which are critical in the regulation of sleep–wake, defining a putative pathway for the circadian regulation of sleep and wakefulness (Fig. 33-4). The relay of SCN circadian signals in the SPZ and then the DMH might allow modification of circadian rhythms by other inputs such as food availability, external temperature, or social cues. Consistent with this hypothesis, cell-specific lesions of the DMH block food entrainment of sleep–wake, locomotor activity, and body temperature rhythms.120 Furthermore, in mice with targeted disruption of the clock gene Bmal1, restoration of Bmal1 expression in DMH neurons is sufficient to drive entrainment to restricted daytime feeding.121 These findings indicate that the DMH plays a critical role in integrating both photic and nonphotic information in order to establish a pattern of sleep–wake behavior that is most adaptive for survival. Circadian Regulation of Endocrine Rhythms Melatonin Rhythm Melatonin is a light-regulated and circadian rhythm–regulated hormone that is thought to promote sleep in humans
384 PART I / Section 5 • Chronobiology
Corticosteroid release
PVH DMH vSPZ
LHA (orexin)
SCN GABA
Glu TRH
GABA, HA NE, 5-HT Arousal system (TMN, LC, DRN)
VLPO GABA galanin
Figure 33-4 Circadian regulation of sleep–wake. The neuronal pathway that regulates circadian sleep–wake cycles (SCN→vSPZ→DMH, indicated in light yellow) directly interacts with arousal- and sleep-promoting brain regions (indicated in light orange), providing a putative pathway for the circadian regulation of sleep–wake. Solid arrows indicate prominent neuronal projections, and dashed arrows indicate relatively small projections. Neurotransmitters contained in these projections are shown next to the arrows. DMH, dorsomedial hypothalamic nucleus; DRN, dorsal raphe nucleus; GABA, gamma-aminobutyric acid; Glu, glutamate; HA, histamine; 5-HT, 5-hydroxytryptamine (serotonin); LC, locus coeruleus; LHA, lateral hypothalamic area; NE, norepinephrine; PVH, paraventricular hypothalamic nucleus; SCN, suprachiasmatic nucleus; TMN, tuberomammillary nucleus; TRH, thyrotropin-releasing hormone; VLPO, ventrolateral preoptic nucleus; vSPZ, ventral subparaventricular zone.
and regulates photoperiod-dependent effects on reproduction status in some mammals. The SCN is required for the circadian synthesis and release of melatonin in the pineal gland, which is regulated via a circuitous pathway.122 A subset of SCN neurons projects directly to dorsal parvocellular neurons in the autonomic subdivision of the PVH. These PVH neurons send an excitatory projection to the sympathetic preganglionic neurons in the intermediolateral cell column (IML) in the upper thoracic spinal cord. The IML sends a cholinergic projection to the superior cervical ganglion (SCG), and the SCG postganglionic sympathetic neurons send a noradrenergic projection to the pineal gland. The release of noradrenalin activates alpha- and beta-adrenergic receptors in the pineal gland that stimulate the production of melatonin by controlling the enzyme serotonin N-acetyltransferase. The SCN is most active during the subjective day and inhibits tonic activity of PVH neurons, likely via GABAergic signaling, thereby resulting in a lower firing rate in the remainder of the pathway and promoting inhibition of melatonin synthesis. Thus, melatonin is produced during the subjective night, when SCN activity is low, and this is a common feature of both diurnal and nocturnal animals. Exposure to light during the subjective night activates SCN neurons via the retinohypothalamic tract, resulting in the inhibition of melatonin synthesis through the aforementioned pathway. Melatonin can also provide direct feedback to the circadian system via melatonin receptors (MT1 and MT2)
located in the SCN. Melatonin acutely inhibits SCN electrical activity, and this response is mediated by the MT1 receptor.123 In vivo, the locomotor activity rhythm of rats can be entrained by periodic administration of melatonin as long as the SCN remains intact,124 suggesting that melatonin-receptor signaling in the SCN is required for melatonin-induced entrainment. Melatonin-induced phase shifts persist in MT1- or MT2-receptor knockout mice, however, suggesting that melatonin receptor subtypes might play a redundant role in this response.123,125 Daily administration of melatonin can entrain the circadian system of blind persons who show deficits in circadian photoreception, indicating that melatonin elicits phase shifts of the human circadian clock.126,127 Corticosteroid Rhythm Early lesion studies of the SCN showed loss of the circadian rhythm of adrenal corticosterone, the major glucocorticoid in rodents.128 The circadian rhythm of corticosteroids rises sharply before the waking period, presumably to promote a general state of readiness in anticipation of the myriad stressors associated with the active phase. SCN neurons project directly and indirectly to the DMH, which is critical for expression of the corticosteroid rhythm, and the DMH sends efferents to the PVH. By analogy with the circadian timing system controlling the sleep rhythm, it is likely that the ventral SPZ is also an obligate relay for corticosteroid rhythms, but this hypothesis remains to be tested. The SCN also sends a direct projection to the PVH, and some anterogradely labeled fibers from the SCN closely appose corticotropin-releasing hormone (CRH)-containing neurons in the parvocellular division of the PVH. This is a relatively weak projection, however, and in animals with DMH lesions it is not capable of maintaining corticosteroid rhythms.116 The CRH-containing neurons in the PVH project to the median eminence, where CRH is released into the portal circulation and activates the release of adrenocorticotropic hormone (ACTH) from the anterior pituitary gland. The SCN-driven release of ACTH into the blood results in the rhythmic induction of corticosteroid secretion from the adrenal gland. Diffusible Suprachiasmatic Nucleus Output Signals In SCN-lesioned hosts, transplantation of fetal SCN grafts into the third ventricle restores a low-amplitude circadian rest–activity rhythm with the period of the donor animal. However, photic entrainment, reproductive responses to photoperiod, estrous cycles, and corticosteroid and melatonin rhythms are not restored by SCN transplants. Polymer-encapsulated SCN transplants that prevent neuronal communication between host and donor tissue reinstate low levels of locomotor activity rhythms in SCN-lesioned hosts, suggesting that a diffusible factor can partially reconstitute the rest–activity cycle.129 The distance of SCN transplants from the normal site of the SCN is an important factor for the recovery of the locomotor rhythm, indicating that a diffusible factor acts locally in a paracrine fashion. Candidate diffusible mediators have been identified in the SCN that might regulate the output of circadian
behavioral rhythms, including sleep–wake cycles. Transforming growth factor (TGF)-α is a secreted factor that is expressed rhythmically in the SCN with higher expression levels corresponding with the inactive phase in nocturnal animals (subjective day). Infusion of TGF-α into the third ventricle reversibly inhibits the circadian expression of wheel-running, sleep–wake, and body temperature rhythms, but it does not affect the underlying phase of the circadian clock.130 Recent data indicate that TGF-α is expressed mainly by astrocytes in the SCN, suggesting that a novel neural–glial interaction in the SCN may be involved in secreting TGF-α.131 TGF-α functions through the epidermal growth factor (EGF) receptor, which has been described in the peri-SCN region and medial hypothalamus in rodents and monkeys. In future studies, it will be important to determine whether endogenous TGF-α signaling plays a critical role in shaping circadian behavior. Similar to TGF-α, cardiotrophin-like cytokine (CLC) exhibits a circadian rhythm of expression in the SCN that peaks during the subjective day. CLC receptors are found along the third ventricle, and infusion of CLC into the third ventricle acutely inhibits locomotor activity without affecting the timing of the circadian clock.132 In addition, blockade of CLC receptors with neutralizing antibodies results in increased behavioral activity during the subjective day, suggesting that CLC might function as an SCN output factor that regulates circadian expression of rest–activity. Prokineticin 2 (PK2) is another secreted protein that functions as a putative output molecule of the circadian pacemaker.133 PK2 is a clock-controlled gene that is rhythmically expressed in the SCN, with higher expression levels observed during the subjective day. Intracerebroventricular injection of PK2 inhibits locomotor activity during the subjective night in rats (the active phase), and PK2 null mice show attenuated circadian rhythms of sleep–wake, body temperature, and glucocorticoids.134 Consistent with a role for PK2 as an SCN output factor, PK2 receptor has been described in many SCN output regions including the PVH, DMH, PVT, paratenial nucleus, lateral septum, and the SCN itself,133 and PK2-receptor knockout mice show reduced circadian expression of rest–activity and body temperature rhythms.135
SYNCHRONIZATION OF CENTRAL AND PERIPHERAL OSCILLATORS In addition to the master circadian clock in the SCN, circadian expression of clock genes has been demonstrated in nearly all tissues studied, as well as in many sites in the brain.136 It is therefore surprising that under baseline conditions, when the SCN is ablated the other circadian oscillators rapidly fall out of synchrony, and the animal is unable to mount effective circadian rhythms. Hence, under most conditions, it seems clear that the SCN must normally entrain these subordinate oscillators to ensure coordinated changes in physiology that are appropriately timed to the rest–activity cycle. As with the SCN, extraSCN clocks show rhythmic clock gene expression and widespread rhythmic transcription of clock-controlled genes.137-139 Circadian rhythms of gene expression in extraSCN tissues can persist in vitro for several days, indicating
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that the SCN is not required for short-term maintenance of rhythmicity.139 Under normal conditions in vivo, however, the SCN determines the phase and synchrony of clock gene expression in peripheral clocks, and SCNlesioned animals show a loss of synchronous circadian gene expression in peripheral tissues.140,141 Thus, the SCN is normally hierarchically dominant in determining circadian phase and maintaining long-term rhythmicity in peripheral clocks. The phase of peripheral oscillators, however, can become uncoupled from the SCN pacemaker. In animals that are exposed to circadian cycles of restricted food availability, circadian gene expression in tissues such as the liver, kidney, and heart entrain to the feeding cycle rather than to the phase of SCN activity or the light–dark cycle.142,143 The role of circadian clocks in peripheral tissues and the mechanism(s) by which rhythmic SCN output or nonphotic zeitgebers synchronize peripheral oscillators is currently an area of intense interest.
CONCLUSION The SCN regulates the circadian sleep–wake rhythm via a primary projection to the SPZ, followed by a secondary projection to the DMH. The DMH, in turn, projects to brain areas critical for promoting sleep or wakefulness, defining a putative pathway for the circadian regulation of sleep–wake cycles. A direct projection from the SCN to the PVH mediates rhythmic control of melatonin secretion from the pineal gland, and an indirect projection from the SCN to the PVH via the DMH is critical for the circadian release of corticosteroids. Although SCN neuronal projections are required for photic entrainment and circadian control of endocrine rhythms, SCN-diffusible factors are sufficient to support a weak circadian rest–activity rhythm and, likely, sleep–wake cycles. Although candidate diffusible mediators of circadian phase have been recently identified, the pathways underlying nonneuronal SCN regulation of behavioral rhythms have yet to be determined, as are the SCN efferent pathways regulating the phase of circadian rhythms in peripheral tissues.
❖ Clinical Pearl The suprachiasmatic nucleus provides a 24-hour genetic clock, which allows daily scheduling of wake– sleep, feeding, corticosteroid secretion, and other bodily functions during a normal light–dark cycle. This cycle can be modified by light exposure or by administeration of melatonin, which resets the suprachismatic clock, but new evidence suggests that feeding schedules and social interactions can reset the daily activity cycle by acting on circuits that are downstream of the clock. Thus, in patients with difficulty adjusting to shift work, jet lag, or other disruptions of their schedules, in addition to adjusting light exposure and taking melatonin, it is possible to adjust to a new schedule more quickly if the meal times, social interactions, and sleep–activity schedule of the new environment are adopted as soon as possible.
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388 PART I / Section 5 • Chronobiology 93. Biello SM, Golombek DA, Harrington ME. Neuropeptide Y and glutamate block each other’s phase shifts in the suprachiasmatic nucleus in vitro. Neuroscience 1997;77(4):1049-1057. 94. Weber ET, Rea MA. Neuropeptide Y blocks light-induced phase advances but not delays of the circadian activity rhythm in hamsters. Neurosci Lett 1997;231(3):159-162. 95. Gribkoff VK, Pieschl RL, Wisialowski TA, Van den Pol AN, et al. Phase shifting of circadian rhythms and depression of neuronal activity in the rat suprachiasmatic nucleus by neuropeptide Y: mediation by different receptor subtypes. J Neurosci 1998;18(8):30143022. 96. Golombek DA, Biello SM, Rendon RA, Harrington ME. Neuropeptide Y phase shifts the circadian clock in vitro via a Y2 receptor. Neuroreport 1996;7(7):1315-1319. 97. Lall GS, Biello SM. Attenuation of circadian light induced phase advances and delays by neuropeptide Y and a neuropeptide Y Y1/ Y5 receptor agonist. Neuroscience 2003;119(2):611-618. 98. Huhman KL, Gillespie CF, Marvel CL, Albers HE. Neuropeptide Y phase shifts circadian rhythms in vivo via a Y2 receptor. Neuroreport 1996;7(7):1249-1252. 99. Moga MM, Moore RY. Organization of neural inputs to the suprachiasmatic nucleus in the rat. J Comp Neurol 1997;389(3): 508-534. 100. Prosser RA. Glutamate blocks serotonergic phase advances of the mammalian circadian pacemaker through AMPA and NMDA receptors. J Neurosci 2001;21(19):7815-7822. 101. Morin LP. Serotonin and the regulation of mammalian circadian rhythmicity. Ann Med 1999;31(1):12-33. 102. Roca AL, Weaver DR, Reppert SM. Serotonin receptor gene expression in the rat suprachiasmatic nuclei. Brain Res 1993;608(1):159-165. 103. Pickard GE, Weber ET, Scott PA, Riberdy AF, et al. 5HT1B receptor agonists inhibit light-induced phase shifts of behavioral circadian rhythms and expression of the immediate-early gene c-fos in the suprachiasmatic nucleus. J Neurosci 1996;16(24):82088220. 104. Pickard GE, Smith BN, Belenky M, Rea MA, et al. 5-HT1B receptor-mediated presynaptic inhibition of retinal input to the suprachiasmatic nucleus. J Neurosci 1999;19(10):4034-4045. 105. Rea MA, Pickard GE. A 5-HT1B receptor agonist inhibits lightinduced suppression of pineal melatonin production. Brain Res 2000;858(2):424-428. 106. Belenky MA, Pickard GE. Subcellular distribution of 5-HT1B and 5-HT7 receptors in the mouse suprachiasmatic nucleus. J Comp Neurol 2001;432(3):371-388. 107. Prosser RA. Serotonin phase-shifts the mouse suprachiasmatic circadian clock in vitro. Brain Res 2003;966(1):110-115. 108. Shibata S, Tsuneyoshi A, Hamada T, Tominaga K, et al. Phaseresetting effect of 8-OH-DPAT, a serotonin1A receptor agonist, on the circadian rhythm of firing rate in the rat suprachiasmatic nuclei in vitro. Brain Res 1992;582(2):353-356. 109. Bobrzynska KJ, Godfrey MH, Mrosovsky N. Serotonergic stimulation and nonphotic phase-shifting in hamsters. Physiol Behav 1996;59(2):221-230. 110. Mintz EM, Gillespie CF, Marvel CL, Huhman KL, et al. Serotonergic regulation of circadian rhythms in Syrian hamsters. Neuroscience 1997;79(2):563-569. 111. Glass JD, Selim M, Rea MA. Modulation of light-induced c-Fos expression in the suprachiasmatic nuclei by 5-HT1A receptor agonists. Brain Res 1994;638(1-2):235-242. 112. Watts AG, Swanson LW, Sanchez-Watts G. Efferent projections of the suprachiasmatic nucleus: I. Studies using anterograde transport of Phaseolus vulgaris leucoagglutinin in the rat. J Comp Neurol 1987;258(2):204-229. 113. Watts AG, Swanson LW. Efferent projections of the suprachiasmatic nucleus: II. Studies using retrograde transport of fluorescent dyes and simultaneous peptide immunohistochemistry in the rat. J Comp Neurol 1987;258(2):230-252. 114. Leak RK, Moore RY. Topographic organization of suprachiasmatic nucleus projection neurons. J Comp Neurol 2001;433(3):312334. 115. Lu J, Zhang YH, Chou TC, Gaus SE, et al. Contrasting effects of ibotenate lesions of the paraventricular nucleus and subparaventricular zone on sleep–wake cycle and temperature regulation. J Neurosci 2001;21(13):4864-4874.
116. Chou TC, Scammell TE, Gooley JJ, Gaus SE, et al. Critical role of dorsomedial hypothalamic nucleus in a wide range of behavioral circadian rhythms. J Neurosci 2003;19;23(33):10691-10702. 117. Chou TC, Bjorkum AA, Gaus SE, Lu J, et al. Afferents to the ventrolateral preoptic nucleus. J Neurosci 2002;22(3):977-990. 118. Sherin JE, Shiromani PJ, McCarley RW, Saper CB. Activation of ventrolateral preoptic neurons during sleep. Science 1996;271(5246): 216-219. 119. Sherin JE, Elmquist JK, Torrealba F, Saper CB. Innervation of histaminergic tuberomammillary neurons by GABAergic and galaninergic neurons in the ventrolateral preoptic nucleus of the rat. J Neurosci 1998;18(12):4705-4721. 120. Gooley JJ, Schomer A, Saper CB. The dorsomedial hypothalamic nucleus is critical for the expression of food-entrainable circadian rhythms. Nat Neurosci 2006;9(3):398-407. 121. Fuller PM, Lu J, Saper CB. Differential rescue of light- and food-entrainable circadian rhythms. Science 2008;320(5879):10741077. 122. Teclemariam-Mesbah R, Ter Horst GJ, Postema F, Wortel J, et al. Anatomical demonstration of the suprachiasmatic nucleus-pineal pathway. J Comp Neurol 1999;406(2):171-182. 123. Liu C, Weaver DR, Jin X, Shearman LP, et al. Molecular dissection of two distinct actions of melatonin on the suprachiasmatic circadian clock. Neuron 1997;19(1):91-102. 124. Cassone VM, Chesworth MJ, Armstrong SM. Entrainment of rat circadian rhythms by daily injection of melatonin depends upon the hypothalamic suprachiasmatic nuclei. Physiol Behav 1986;36(6): 1111-1121. 125. Jin X, von Gall C, Pieschl RL, Gribkoff VK, et al. Targeted disruption of the mouse Mel(1b) melatonin receptor. Mol Cell Biol 2003;23(3):1054-1060. 126. Lockley SW, Skene DJ, James K, Thapan K, et al. Melatonin administration can entrain the free-running circadian system of blind subjects. J Endocrinol 2000;164(1):R1-R6. 127. Sack RL, Brandes RW, Kendall AR, Lewy AJ. Entrainment of freerunning circadian rhythms by melatonin in blind people. N Engl J Med 2000;343(15):1070-1077. 128. Moore RY, Eichler VB. Loss of a circadian adrenal corticosterone rhythm following suprachiasmatic lesions in the rat. Brain Res 1972;42(1):201-206. 129. Silver R, LeSauter J, Tresco PA, Lehman MN. A diffusible coupling signal from the transplanted suprachiasmatic nucleus controlling circadian locomotor rhythms. Nature 1996;382(6594): 810-813. 130. Kramer A, Yang FC, Snodgrass P, Li X, et al. Regulation of daily locomotor activity and sleep by hypothalamic EGF receptor signaling. Science 2001;294(5551):2511-2515. 131. Li X, Sankrithi N, Davis FC. Transforming growth factor-alpha is expressed in astrocytes of the suprachiasmatic nucleus in hamster: role of glial cells in circadian clocks. Neuroreport 2002;13(16): 2143-2147. 132. Kraves S, Weitz CJ. A role for cardiotrophin-like cytokine in the circadian control of mammalian locomotor activity. Nat Neurosci 2006;9(2):212-219. 133. Cheng MY, Bullock CM, Li C, Lee AG, et al. Prokineticin 2 transmits the behavioural circadian rhythm of the suprachiasmatic nucleus. Nature 2002;417(6887):405-410. 134. Li JD, Hu WP, Boehmer L, Cheng MY, et al. Attenuated circadian rhythms in mice lacking the prokineticin 2 gene. J Neurosci 2006; 26(45):11615-11623. 135. Prosser HM, Bradley A, Chesham JE, Ebling FJ, et al. Prokineticin receptor 2 (Prokr2) is essential for the regulation of circadian behavior by the suprachiasmatic nuclei. Proc Natl Acad Sci U S A 2007;104(2):648-653. 136. Schibler U, Sassone-Corsi P. A web of circadian pacemakers. Cell 2002;111(7):919-922. 137. Panda S, Antoch MP, Miller BH, Su AI, et al. Coordinated transcription of key pathways in the mouse by the circadian clock. Cell 2002;109(3):307-320. 138. Storch KF, Lipan O, Leykin I, Viswanathan N, et al. Extensive and divergent circadian gene expression in liver and heart. Nature 2002;417(6884):78-83. 139. Yamazaki S, Numano R, Abe M, Hida A, et al. Resetting central and peripheral circadian oscillators in transgenic rats. Science 2000;288(5466):682-685.
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CHAPTER 33 • Anatomy of the Mammalian Circadian System 389 142. Damiola F, Le Minh N, Preitner N, Kornmann B, et al. Restricted feeding uncouples circadian oscillators in peripheral tissues from the central pacemaker in the suprachiasmatic nucleus. Genes Dev 2000;14(23):2950-2961. 143. Stokkan KA, Yamazaki S, Tei H, Sakaki Y, et al. Entrainment of the circadian clock in the liver by feeding. Science 2001; 291(5503):490-493.
Physiology of the Mammalian Circadian System Alan M. Rosenwasser and Fred W. Turek Abstract The bilaterally paired suprachiasmatic nuclei (SCN) of the anterior hypothalamus were first identified in the early 1970s as critical for the normal expression of circadian rhythms, and they have long been considered to be the master circadian pacemaker in mammals. Only in the past decade, however, has the molecular basis of circadian rhythm generation been revealed to involve transcription-translation feedback loops(s) comprising a number of “clock genes” and their protein products. Similarly, although it has been known for many years that the circadian clock synchronizes (“entrains”) to environmental light–dark cycles through direct retinal projections to the SCN, only in the past few years have the functional retinal photoreceptors been identified as a unique subset of melanopsin-containing, directly photosensitive retinal ganglion cells. Just as the cellular and molecular mysteries of the circadian pacemaker and its synchronization are being unraveled, new findings have also revealed that the organization of the circadian timing system at the organismal level is much more complex and interesting than previously thought. The circadian system is now seen as hierarchically organized
A great deal of new information has been obtained in just the past few years about the mammalian circadian timing system at the molecular, cellular, neural systems, and behavioral levels. These advances have led to improved understanding of the neuroanatomy, neurochemistry, and molecular neurobiology of the circadian pacemaker, how this pacemaker is synchronized (entrained) to the external environment—primarily by the 24-hour light–dark cycle (see Chapter 33)—and how it regulates a variety of peripheral oscillating systems. This chapter reviews recent findings on the structure and function of the mammalian circadian timing system, with an emphasis on the newly emerging multioscillatory nature of this system, how the master circadian clock in the hypothalamus receives inputs from the internal and external environment, and how the clock regulates the wide diversity of biochemical, molecular, cellular, physiologic, and behavioral rhythms.
THE SUPRACHIASMATIC NUCLEUS: MASTER CIRCADIAN PACEMAKER The exciting realization that molecular circadian clocks exist in many tissues and organs throughout the brain and body has revolutionized our understanding of how the overall mammalian circadian timing system is organized. Nevertheless, there is still substantial evidence from a variety of different types of experiments that the hypothalamic suprachiasmatic nucleus (SCN) is the site of a “master” circadian pacemaker, responsible for regulating—directly or indirectly—most, if not all circadian rhythms in mammals.1-3 Over the years, a variety of studies involving SCN lesions, in vivo and in vitro recordings of SCN neural activity, functional metabolic mapping, fetal 390
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and widely distributed, such that the master clock in the SCN synchronizes multiple “downstream” circadian oscillators distributed throughout the brain and body. Indeed, most, if not all, tissues and organs of the body appear to contain the core molecular circadian clock machinery, such that the molecular clock in the SCN entrains similar molecular clocks throughout the body to ensure overall internal temporal organization. Thus, there are two revolutionary developments in the circadian clock field: (1) the elucidation of the core molecular clock machinery, and (2) the demonstration that most, if not all, tissues can express the 24-hour molecular clock. These developments have opened up an entirely new area of biomedical research on the importance of internal timing for health and disease. With hundreds and even thousands of genes exhibiting rhythmic expression in any given organ system, under the control of both central (i.e., SCN) and local (i.e., within the tissues) self-sustained circadian oscillations, the circadian clock system clearly plays a central role in regulating cellular function in many ways. Thus the balance between health and disease may be highly dependent on the proper synchrony within and between central and peripheral oscillating systems.
tissue transplantation, and molecular rhythm analysis have revealed that the SCN is not only capable of sustained rhythmic activity, both in vitro and in vivo, but also is responsible for maintaining coherent circadian rhythmicity in central and peripheral tissues, as well as in a wide range of physiological and behavioral processes.4,5 Although early mathematical models raised the possibility that the circadian pacemaker could be constructed from an ensemble of coupled, high-frequency (i.e., noncircadian) oscillatory units, it is now clear that the generation of circadian signals by the SCN is fundamentally a cellular process. Studies using a variety of in vitro models, including long-term SCN cell culture,6 simultaneous recording of multiple single units using multielectrode plates,7,8 and optical monitoring of calcium flux9 or gene expression10 in individual SCN neurons, have now provided compelling evidence that circadian oscillation is indeed a cell-autonomous process, expressed in many, and possibly all, individual SCN neurons. Nevertheless, this multitude of cellular circadian oscillators normally interacts to produce coherent circadian patterns of behavior.11 Although the mechanisms underlying intra-SCN oscillator coupling have not been identified completely, early studies using tetrodotoxin revealed that individual neuronal oscillators in the SCN apparently remain synchronized even in the absence of sodium-dependent action potentials, both in vivo and in vitro.12,13 Thus, it has been suggested that gap junctions, glial coupling, calcium-dependent action potentials, or local diffusible signals may be responsible for maintaining interoscillator synchrony. (For reviews, see Shirakawa et al.14 and Miche and Colwell.15) Further, despite the evidence that action potentials are dispensable for the coupling of cellular oscillators, recent studies have
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revived the idea that intra-SCN synaptic signaling plays an essential role in this process.16,17 Although early studies demonstrated that protein synthesis was involved in the generation of circadian signals,18,19 analysis of the fundamental circadian oscillatory mechanism has more recently been extended to the molecular genetic level. The discovery of the first mammalian circadian clock gene, Clock,20,21 was followed quickly by the identification of a number of other “core” clock genes, many of which showed clear homology to previously or later discovered circadian clock genes in the fruit fly.22 At present, putative mammalian clock genes include three Per genes (Per1, Per2, Per3), Tim, Clock, Bmal, CK1e, and two plant cryptochrome gene homologs (Cry1 and Cry2), all of which are expressed in SCN neurons.23 These genes and their protein products interact to form interlocking negative and positive autoregulatory transcription–translation feedback loops that define the molecular core of the circadian oscillator.24 These basic molecular feedback loops are modulated by posttranslational biochemical processes, leading eventually to the display of remarkably precise 24-hour rhythms in metabolic, physiologic, and behavioral processes.22-24 The core negative feedback loop of the molecular clock involves PER and CRY protein heterodimers that negatively regulate the transcriptional activity of CLOCK and BMAL heterodimers via direct protein-protein interactions (Fig. 34-1). In turn, inhibition of CLOCK/BMAL activity results in reduced Per and Cry gene transcription, leading eventually to disinhibition of CLOCK/BMAL activity. This negative feedback loop results in rhythmic transcription of specific clock genes in the in vivo25,26 and in vitro SCN,10,27,28 and, as discussed later, in many non-SCN tissues as well. In addition, molecular outputs from the core oscillator result in rhythmic expression of a large number of clock-controlled genes (i.e., genes that are controlled by, but not part of, the core circadian oscillator loop), which in turn serve as the basis for rhythmic outputs to myriad other cellular processes.22,23 Ultimately, these molecular processes are reflected in circadian behavioral rhythmicity, as amply documented by analysis of altered circadian pacemaker function in mice carrying a mutation of the Clock gene29 or null or loss-of-function mutations of Per and Cry genes,30-32 as well as in tau-mutant hamsters carrying a mutation of the CK1e gene.33 Interestingly, mutation or deletion of circadian clock genes has also been shown recently to affect sleep–wake homeostasis, as well as several forms of affective behavior, suggesting possible molecular links between the circadian, sleep-regulatory, and motivational systems of the brain.34,35
Figure 34-1 Essential elements of the core molecular loop underlying circadian timing at the cellular level in mammals. The transcription factors CLOCK (Clk) and BMAL1 (B) form a protein heterodimer that promotes the transcription of several rhythmically transcribed clock genes, including the Per (“period”) genes Per1, Per2, and Per3, and the Cry (cryptochrome) genes Cry1 and Cry2. In addition, CLOCK and BMAL1 also drive transcription of a large number of “clock-controlled genes” (CCGs), that convey the circadian timing signal to a wide variety of cellular processes. The protein products of the Per and Cry genes dimerize in several different combinations, including both PER-CRY (as shown here) and PER-PER pairings. After nuclear translocation, PER and CRY inhibit the transcriptional effects of CLOCK-BMAL1 through direct protein-protein interactions, and thus exert negative autoregulation of their own transcription. This negative feedback results in circadian expression of Per and Cry transcripts. This basic transcriptiontranslation negative feedback loop is modulated by several post-translational processes. For example, casein kinase 1 epsilon (CK1ε) acts to regulate the nuclear translocation of the PER-CRY dimer, and also functions to phosphorylate the Per protein, thereby tagging it for subsequent degradation by ubiquitin. Through these actions, CK1ε plays a critical role in regulating the period of the molecular clock. At the behavioral level, this model predicts (1) the shortening of free-running period seen in tau-mutant hamsters carrying a mutation of the CK1ε gene, (2) the lengthening of free-running period seen in Clockmutant mice, and (3) the loss of coherent free-running rhythms seen in Clock mice and in Per- and Cry-knockout mice. It should be noted that the molecular clockworks also includes a positive feedback loop, omitted from this diagram, that regulates the availability of BMAL1, and that appears to increase the overall stability of the clock.
Functional Neuroanatomy of the Suprachiasmatic Nucleus Traditionally, the SCN has been characterized as comprising distinct ventrolateral and dorsomedial subdivisions.36 Recently, however, this scheme has been reconceptualized to include SCN “core” and “shell” subnuclei, a concept that may better accommodate species differences in the anatomic distribution of neuropeptides, afferent terminal fields, and gene expression patterns in the SCN37,38 (Fig. 34-2). Although SCN neurons express a large number of neuropeptides, core and shell subnuclei have been most
commonly identified by the concentration of arginine vasopressin–positive neurons in the SCN shell, and by vasoactive intestinal peptide (VIP)–positive and gastrinreleasing peptide (GRP)–positive neurons in the SCN core. Beyond this basic organization, however, clear species differences have been noted, even among nocturnal rodents. For example, the hamster SCN core contains a very distinct and compact cluster of photoresponsive calbindin-positive cells, which is absent in the rat.37 In light
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Figure 34-2 Core and shell organization of the suprachiasmatic nucleus (SCN). The vast majority of SCN neurons release the inhibitory amino acid transmitter gamma-aminobutyric acid (GABA). In the SCN core (yellow), GABA is commonly colocalized with one or more neuropeptides, including vasoactive intestinal polypeptide (VIP) and gastrin-releasing peptide (GRP), whereas neurons of the SCN shell (orange) frequently contain GABA colocalized with arginine vasopressin (VP). SCN core neurons project to other core neurons, to SCN shell neurons, and to extra-SCN targets, most prominently in the diencephalon and basal forebrain; SCN shell neurons project to other shell neurons, and to extra-SCN targets, but not to SCN core neurons. This anatomic organization implies that the flow of information within the SCN is generally from core to shell. Consistent with this suggestion, the three best-characterized SCN afferent systems, originating in the retina, the intergeniculate leaflet of the thalamus (IGL), and the mesencephalic raphe nuclei, converge in the SCN core. Retinal afferents contain the excitatory amino acid transmitter glutamate (GLU) as well as the neuropeptides substance P (SP) and pituitary adenyl cyclase–activating peptide (PACAP); raphe afferents contain 5-hydroxytryptamine (5-HT; serotonin); and IGL afferents contain neuropeptide Y (NPY) and GABA. Beyond these core afferents, several less wellcharacterized afferent systems converge in the SCN shell, including acetylcholine (ACh)-containing projections from the basal forebrain (BF) and pons, medullary norepinephrine (NE)containing projections, and histamine (HA)-containing projections from the posterior hypothalamus (Post hyp). A number of other anatomically identified but functionally uncharacterized SCN afferent systems have been omitted from this figure, and are not discussed in the chapter.
of this and other species differences as well as other complexities in SCN organization, it has been argued that the popular distinction between SCN core and shell may be such an extreme oversimplification as to impede understanding of the functional organization of this critical structure.2 Although the specific functions of chemically defined SCN cell populations are not fully known, a reasonable heuristic is that VIP and GRP neurons the SCN core serve to collate information relevant to pacemaker entrainment,
whereas the vasopressinergic neurons of the SCN shell are primarily responsible for the self-sustaining generation of the circadian timing signal. These suggestions are consistent with findings that (1) major SCN efferent systems converge in the core subnucleus36,37; (2) spontaneous circadian rhythmicity in neuronal activity, neuropeptide release, and cfos and Per gene expression is seen more reliably in the SCN shell than in the core39-41; and (3) administration of SCN core peptides such as vasoactive intestinal peptide and gastrin-releasing peptide can mimic both light-induced phase shifting and Per gene expression in the SCN, in vivo and in vitro.42-44 On the other hand, the view that SCN core and shell functions reflect circadian entrainment and circadian pacemaking functions, respectively, is probably too simplistic because (1) light-evoked responses are seen in SCN shell as well as in core neurons; (2) several arousal-related SCN afferents of limbic origin target the SCN shell36-38; and (3) in vitro studies have revealed independent circadian rhythmicity in secretion of both SCN core and SCN shell peptides, which may free-run with different periods in the same tissue, implicating separate core and shell oscillators.45 Light Input to the Pacemaker: The Retinohypothalamic Tract Numerous studies have established that a specialized retinal projection system, referred to as the retinohypothalamic tract (RHT), is both necessary and sufficient for photic entrainment of the circadian pacemaker.46 The RHT originates from a distinct subset of retinal ganglion cells separate from those giving rise to the primary visual pathways,47 and terminates mainly in the SCN, as well as more sparsely in the anterolateral hypothalamus, subparaventricular zone, and supraoptic region.48-49 In addition, RHT axon collaterals also project to the thalamic intergeniculate leaflet (IGL; Fig. 34-3), which, as discussed later, is an important component of the circadian system. Although nonretinal photoreception plays a major role in circadian entrainment in nonmammalian vertebrates,50 mammalian photoreception appears to be based entirely on retinal mechanisms. Remarkably, retinally degenerate strains of mice, in which nearly all classic photoreceptors (i.e., rods and cones) are lost by early adulthood, exhibit normal circadian responses to light.51 More recently, similar findings have been reported in genetically engineered mice with a total developmental absence of both rods and cones, demonstrating conclusively that circadian light entrainment can be mediated by a novel, nonrod, noncone photoreceptor system.52 Recent studies indicate that the protein melanopsin, found specifically within the small subset of retinal ganglion cells giving rise to the RHT, serves as a circadian photoreceptor molecule in a novel population of photosensitive RHT retinal ganglion cells.53,54 Surprisingly, however, although melanopsincontaining ganglion cells are sufficient for circadian entrainment, studies with melanopsin knock-out mice reveal that this photopigment is not necessary for entrainment.55,56 Indeed, entrainment is only fully abolished when both classical and melanopsin-based photoreception is eliminated,57 revealing a degree of functional redundancy in how the SCN receives entrainment information from the photic environment.
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Figure 34-3 Overview of functional neuroanatomic pathways in the mammalian circadian system. Major suprachiasmatic nucleus (SCN) afferent systems originating in the retina and raphe nuclei also target the intergeniculate leaflet of the thalamus (IGL), which in turn projects to the SCN. Retinal projections to the SCN and IGL mediate photic input to the circadian system, raphe projections to the SCN and IGL mediate the effects of certain nonphotic, behavioral state–related signals, and IGL-SCN projections are involved in mediation of both photic and nonphotic signaling to the SCN pacemaker. As described in the text, photic and nonphotic pathways generally interact via both preand postsynaptic mechanisms to produce mutually antagonistic effects on the circadian pacemaker. Thus, photic signals evoke circadian phase shifting during subjective night and antagonize nonphotic phase shifting during subjective day, whereas signals related to arousal and wakefulness evoke phase shifting during subjective day and antagonize photic phase shifting during subjective night. These antagonistic interactions are mediated in part at the level of the SCN, but the scheme presented here suggests that the IGL is also a probable locus for interaction between photic and nonphotic signals—a hypothesis that is largely unexplored. SCN outputs appear to include both neural efferents as well as secreted paracrine signals. GABA, gammaaminobutyric acid; GLU, glutamate; 5-HT, 5-hydroxytryptamine (serotonin); NPY, neuropeptide Y; PACAP, pituitary adenyl cyclase–activating peptide; PK, prokineticin; SP, substance P; VIP, vasoactive intestinal polypeptide.
Retinohypothalamic tract terminals release an excitatory amino acid neurotransmitter, glutamate, in response to photic stimulation. Extensive evidence from in vivo and in vitro studies indicates that glutamate acts through both N-methyl-d-aspartate (NMDA) and non-NMDA receptors and a variety of intra cellular signaling molecules (e.g., Ca2+, nitric oxide, calmodulin/calmodulin kinase, protein kinase C, protein kinase G, cyclic adenosine monophosphate–responsive element-binding protein [CREB], and others),58 and immediate early-response genes including c-fos,59 leading to increased expression of Per1 and, after a delay, Per2.60,61 The protein products of these genes represent state variables of the molecular oscillator, such that alterations in their transcription levels, when superimposed on the ongoing circadian transcription cycle, correspond functionally to phase shifts of the oscillator (Fig. 34-4). In addition to glutamate, RHT terminals also release two identified peptide cotransmitters, substance P (SP) and pituitary adenyl cyclase-activating peptide (PACAP). SP appears to play an important role in RHT transmission
because selective SP antagonists block light-induced phase shifting and early-response gene expression in vivo,62-64 as well as glutamate receptor-mediated phase shifting in vitro.65 By itself, SP can mimic at least one component of the photic phase–response curve (phase delays during early subjective night) both in vivo and in vitro.66 Supporting its putative role of a modulatory cotransmitter, the phaseshifting effects of SP appear to depend on SP-evoked glutamate release, and they can be blocked by the NMDA antagonist, MK-801.65 In contrast, PACAP administration has been reported either to antagonize or mimic the effects of glutamate on circadian phase shifting and Per gene expression in vitro, depending on dose and on circadian phase of administration.67-69 Specifically, when administered at relatively high doses, PACAP blocks the effects of glutamate during subjective night and evokes phase advances during subjective day, but when administered at much lower doses, PACAP actually mimics or potentiates the effects of glutamate on the SCN pacemaker. Other Functional Inputs to the Circadian Clock An additional major SCN afferent system arises from the IGL, a distinct retinorecipient region of the lateral geniculate complex, intercalated between the dorsal and ventral lateral geniculate nucleus.70-72 The projection from the IGL to the SCN is referred to as the geniculohypothalamic tract (GHT), and GHT neurons release both neuropeptide Y and gamma-aminobutyric acid (see Fig. 34-3). Retinal signals are conveyed to the IGL in part by axon collaterals of RHT neurons,73 and GHT and RHT terminal fields are largely coextensive within the SCN core. Thus, it is not surprising that early functional studies emphasized the possible role of the IGL/GHT system in providing a secondary, indirect pathway for photic entrainment of the circadian pacemaker.71,72 Although the IGL is clearly not necessary for photic entrainment, lesions of the IGL/GHT do produce subtle modifications in the ability of light signals to effect phase and period control of the circadian clock.72 In addition to its role as a secondary source of photic signaling to the circadian clock, the IGL also plays a preeminent role in the nonphotic regulation of the circadian system by arousal-related stimuli. Thus, IGL lesions abolish the phase-shifting effects of noveltyinduced wheel running74,75 and benzodiazepine administration in hamsters,76-78 as well as the period-shortening effect of running-wheel access in rats79 and the entrainment effect of scheduled daily treadmill activity in mice.80 Another major SCN afferent system converging on the SCN core originates from the serotonergic midbrain raphe, especially the median raphe nucleus.81,82 In addition, ascending serotonergic projections originating in the dorsal raphe nucleus innervate the IGL, providing a second potential route for serotonergic regulation of the SCN circadian pacemaker (see Fig. 34-3). Extensive evidence has implicated serotonergic projections to the SCN (and IGL) in two distinct functions: (1) modulation of photic effects on the circadian pacemaker during the subjective night,83 and (2) mediation of nonphotic effects on the pacemaker during subjective day.84 Thus, serotonin depletion potentiates photic phase shifting and impairs the response to nonphotic phase-shifting stimuli.85,86 Conversely,
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Circadian phase Figure 34-4 A simple qualitative-molecular model for circadian phase shifting by photic and nonphotic signals, and for their mutually antagonistic interaction. In this “phase-only” model, amplitude is fixed and the underlying state variable (here, Per1 transcript level) can oscillate only within predetermined upper and lower bounds, such that the Per1 level represents the phase of the molecular oscillator. During the subjective night, Per1 levels are relatively low (solid line), and light pulses (or corresponding neurotransmitters or intracellular messengers) induce an abrupt increase in transcript level (arrow). Early in the night, when Per1 levels are normally decreasing, this increase in transcription essentially forces the oscillator to repeat part of its normal trajectory, and is thus equivalent to resetting the oscillator to an earlier phase, resulting in a permanent phase delay (dashed line). In contrast, late in the night, Per1 levels are normally increasing, such that a light-induced increase in transcription forces the oscillator to omit part of its normal trajectory, equivalent to resetting the oscillator to a later phase, and resulting in a permanent phase advance. Opposite to light pulses, arousal-related signals (or corresponding neurotransmitters or intracellular messengers) induce abrupt decreases in Per1 transcription, resulting in phase delays during early subjective day and phase advances during late subjective day. Thus, the model predicts that photic and nonphotic phase– response curves (PRCs) should have essentially identical shapes, but should be phase-displaced by 180 degrees (12 circadian hours) along the horizontal axis; these predictions are at least roughly consistent with experimental observations.69 Further, this model accounts for the general insensitivity of the circadian pacemaker to photic phase shifting during midsubjective day and to nonphotic phase shifting during midsubjective night: Because the underlying state variable can vary only within a predetermined range, stimuli that increase Per1 transcription are ineffective when transcript levels are already maximal, and stimuli that decrease Per1 transcription are ineffective when transcript levels are already minimal. Nevertheless, despite these periods of insensitivity, nonphotic signals would remain capable of counteracting light-evoked increases in transcription, and photic signals would remain capable of counteracting arousal-evoked decreases in transcription. Finally, the exact waveform and phasing of the photic and nonphotic PRCs would obviously depend on the exact waveform and phasing of the underlying spontaneous transcription cycle, here presented arbitrarily as two interlocking circular arcs centered over midsubjective day and midsubjective night. GABA, gammaaminobutyric acid; GLU, glutamate; 5-HT, 5-hydroxytryptamine (serotonin); NPY, neuropeptide Y; PACAP, pituitary adenyl cyclase–activating peptide; SP, substance P.
electrical stimulation of the serotonergic raphe and systemic or intra-SCN administration of serotonergic agonists inhibits photic phase shifting during subjective night and evokes nonphotic phase shifting during subjective day.87-90 Although in vivo experiments using direct intracerebral administration of the serotonin 5-HT1A/7 receptor agonist 8-OH-DPAT [8-hydroxy-2-(di-N-propylamino) tetralin] administration have identified several potential loci in the circadian system for serotonergic phase shifting, including the SCN, the IGL, and the median and dorsal raphe nuclei.89,90 The ability of direct serotonin application to the in vitro SCN to evoke circadian phase shifts indicates that stimulation of intra-SCN serotonin receptors is sufficient to phase shift the pacemaker.91 In addition, whereas light during the middle of the subjective day is normally thought to have no effects on the circadian clock, light at this time can block the phase-shifting effects of a serotonin agonist.92 These latter results indicate that serotonergic (nonphotic) and photic (glutamatergic) inputs to the SCN are reciprocally inhibitory. Because the phase-shifting effects evoked by serotonergic stimulation closely resemble those seen with other nonphotic phase-shifting stimuli, including novelty-induced activity, sleep deprivation, and benzodiazepine and neuropeptide Y administration,1,85 several studies have directly examined the potential role of serotonergic afferents to the SCN and IGL in mediating the effects of behavioral state on the circadian pacemaker. Thus, arousal, wakefulness, and motor activity are all associated with increased forebrain serotonin release,93-95 and serotonin content in the rat SCN is correlated positively with spontaneous activity level and negatively with free-running period.96 Indeed, state-dependent variations in serotonin release appear to mediate (1) phase-shifting by activity or sleep deprivation,94 (2) the effects of activity level on freerunning period,95 (3) entrainment by scheduled daily treadmill activity80 and restricted daily running wheel access,97and (4) activity-dependent inhibition of photic phase shifting.98 Several other chemically identified pathways provide afferent inputs to the circadian system, including noradrenergic projections from the locus coeruleus, cholinergic projections from the basal forebrain and pontine tegmentum, and histaminergic projections from the posterior hypothalamus.1 In addition, noradrenergic and cholinergic projections both innervate the IGL, providing an alternate pathway by which these transmitter systems could alter SCN circadian pacemaker function. Unlike the retinal, geniculate, and raphe projections described previously, which form generally overlapping terminal fields in the SCN core, these afferents target preferentially the SCN shell (see Fig. 34-2).37,38 Although SCN shell afferents are less studied than the SCN core afferents, sufficient data exist to suggest that these SCN shell afferents also contribute to circadian pacemaker regulation.1
MULTIPLE-OSCILLATOR NATURE OF THE CIRCADIAN SYSTEM The evidence reviewed previously (and in other chapters in this volume) amply demonstrates the critical role of the SCN in circadian regulation, and justifies the use of the
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term “pacemaker” to describe its function. Nevertheless, the circadian system is now known to comprise a multiplicity of circadian oscillators that are distributed throughout the brain and body. As reviewed previously,99,100 many behavioral and physiological studies conducted in the premolecular era revealed that circadian systems may exhibit several different types of complex dissociations among multiple rhythmic subcomponents. For example, two or more discrete daily activity epochs may emerge from the single, normally consolidated activity period, a phenomenon known as splitting.101,102 Such phenomena at the behavioral and endocrine level strongly imply the existence of an underlying multioscillatory neurobiologic circadian system. Nevertheless, interest in these complex phenomena was deprioritized for several years, coincident with the ongoing maturation of molecular analyses of the pacemaker mechanism, which focused largely on the SCN (or similar pacemaker-like structures in nonmammalian animals). It is probably fitting, then, that these same molecular approaches, and especially the finding that mammalian clock genes are expressed not only in the SCN but also in other brain regions103,104 and in many peripheral tissues as well,105-107 have spurred renewed interest in the identification and functions of multiple circadian oscillators and how they are organized into an anatomically distributed circadian timing system. Within the SCN pacemaker, the observation that individual SCN neurons can express cell-autonomous rhyth-
micity in both molecular and physiological processes6-10 demonstrates that the pacemaker is itself composed of numerous, potentially autonomous but normally coupled, cellular circadian oscillators. Further, the appearance of circadian desynchrony at the behavioral level may reflect robustly persisting but uncoupled rhythmicity at the neuronal level108 (Fig. 34-5). SCN cellular oscillators may also form functionally-specific multicellular assemblies. For example, spontaneous or forced splitting of circadian activity rhythms into two distinct daily bouts is associated with splitting of SCN neurons into distinct neuronal populations with firing rhythms peaking in antiphase.109-110 These two functionally distinct neuronal populations are likely to be associated with Pittendigh’s “morning” and “evening” oscillators. In addition, the clock genes Per1 and Per2 exhibit a significant degree of functional specialization within the SCN,111,112 and according to one hypothesis, Per1 and Per2 represent state variables of morning and evening oscillators, respectively.113,114 An important ongoing challenge for circadian biologists is to continue the integration of modern insights into the molecular nature of the circadian clock with the earlier and equally important era of the field when many of the formal properties and basic principles underlying circadian organization were initially defined.115,116 Outside the SCN, recent evidence suggests that several non-SCN neural and neuroendocrine tissues are capable of expressing autonomous (although generally damped)
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Figure 34-5 Relationship between rhythmicity at the behavioral (A, D), tissue (B, E), and cellular (C, F) levels. These experiments used Per1:GFP transgenic mice in which green flourescent protein (GFP) serves as a real-time optical reporter of Per1 gene expression, measured by flourescent emissions and expressed in arbitrary units (AU) of intensity. When maintained in long-term constant light (LL), some animals sustain persisting, coherent rhythmicity at the behavioral level (e.g., A). When SCN tissue is cultured from such animals, robust gene expression rhythms are seen at both the whole-SCN (B) and individual neuronal (C) levels. In contrast, animals that become arrhythmic at the behavioral level (e.g., D) also fail to express coherent rhythmicity at the tissue level (E). Nevertheless, individual SCN reurons in such cultures contiue to show robust gene expression rhythms, but fail to show the normal intercellular synchrony as seen in rhythmic animals (F). Thus, maintenance of normal coupling relationships among potentially autonomous cellular oscillators is essential for the display of coherent rhythmicity at the behavioral and physiological levels. (From Ohta H, Yamazaki S, McMahon DG. Constant light desynchronizes mammalian clock neurons. Nature Neurosci 2005;8:267-269.)
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circadian oscillations.104 The first demonstration of autonomous, self-sustained circadian rhythmicity in non-SCN mammalian neural tissue was the finding that cultured hamster retinae display persisting circadian rhythmicity in melatonin secretion.117 More recently, real-time optical monitoring of Per gene (or protein) expression has been employed to demonstrate autonomous tissue-level and cellular-level rhythmicity in non-SCN neural tissue, including the retina,118 as well as in a wide variety of nonneural tissues collected from Per-luciferase or Per-GFP transgenic reporter mice.103-107 Within the central nervous system, such studies have revealed self-sustaining gene expression rhythms in the SCN, neuroendocrine tissues (pineal, pituitary), diencephalic nuclei (e.g., hypothalamic arcuate and paraventricular nuclei, thalamic paraventricular nucleus), and olfactory bulbs. Indeed, an impressive series of experiments have revealed that the olfactory bulb contains a self-sustained circadian clock, that is normally entrained by the SCN, and that regulates circadian rhythmicity in the functional sensitivity of the olfactory system.119
Although the relationships between these extra-SCN neural oscillators and the SCN pacemaker have not been fully elucidated, it appears that at least certain types of behavioral rhythm splitting may involve dissociations between intra-SCN and extra-SCN central clocks.120 Similar techniques have also been used to reveal rhythmic Per expression in a wide variety of peripheral cells and tissues, including the liver, lung, kidney, skin, skeletal muscle, and heart.105-107 Though the initial studies found these peripheral rhythms to be highly damped and dependent on periodic input from the SCN for their continuous expression, the use of a real-time reporter of PER2 protein levels107 revealed that circadian oscillations in cultured peripheral tissues can in fact persist for many cycles (Fig. 34-6). In addition, analysis of multiple peripheral tissues harvested from individual SCN-lesioned animals showed that normal phase relationships among peripheral clocks are lost after SCN lesions,107 indicating that the SCN normally synchronizes rather than drives these peripheral rhythms (see Fig. 34-6). Indeed, even when damping of
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Figure 34-6 Superimposed plots of bioluminescent data from pituitary and lung tissues from individual animals that were intact and maintained on a light–dark cycle (LD controls) or in constant darkness (DD controls), as well as from suprachiasmatic nucleus (SCN)-lesioned animals. The tissue was maintained in vitro and made use of a Period2:Luciferase fusion protein as a real-time reporter of circadian dynamics. The first three cycles in culture are represented; each animal’s record is a different shade. Although tissues collected from individual animals on an LD cycle, and relative to activity onset in DD control animals, were in phase with one another, phase desynchronization is evident in individual records of the SCN-lesioned animals for both tissues. (From Yoo SH, Yamazaki S, Lowrey PL, et al. PERIOD2:LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc Natl Acad Sci U S A 2004;101:5339-5346.)
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rhythmicity is seen at the multicellular or tissue levels, this may reflect uncoupling among individual self-sustaining oscillators, rather than a loss of rhythmicity, at the cellular level.108,121,122 Self-sustaining peripheral oscillators may also dissociate from the SCN pacemaker even in intact animals when exposed to certain environmental conditions, such as after light–dark cycle phase shifts (i.e., simulated jet lag)123 or during restricted feeding schedules, which entrain peripheral but not SCN Per gene oscillations.124 These observations indicate that the SCN pacemaker normally serves to entrain both central and peripheral secondary oscillations generated by a broadly distributed population of autonomous cellular oscillators, but that under certain conditions, these downstream oscillators are capable of adaptive (and possible maladaptive) disengagement from SCN control (Fig. 34-7). With the provocative title “Circadian lessons from peripheral clocks: Is the time of the mammalian pacemaker up?,” Brandstaetter suggested that the elucidation of peripheral circadian clocks might require “… the hypothalamic SCN of a rodent … to resign from its major function.”125 Nevertheless, to paraphrase the American humorist, Mark Twain, we maintain that it is premature to announce the passing of the SCN pacemaker. For years prior to the identification of peripheral molecular clocks, the circadian research community speculated that the circadian pacemaker may regulate downstream “slave oscillators.” Although it is now clear that many cells, tissues, and organs can produce autonomous circadian rhythms (using similar molecular clock machinery as expressed in SCN cells) in the absence of the SCN, this does not mean these downstream oscillators are normally independent of the SCN. Indeed, what is emerging in the field is the hypothesis that the SCN is still—as we write in late 2010—the “master oscillator” or pacemaker, regulating all (or nearly all) circadian rhythms, whether directly or indirectly. Rhythms are regulated directly when circadian information in the form of neural or neuroendocrine signals from the SCN directly imposes circadian timing on the neural and physiologic systems regulating a particular functional output. However, “indirect” control is also important, as, for example, when the SCN’s direct control of behavioral rhythms (e.g., feeding, sleep–wake state) alters an organism’s metabolic, endocrine, or physiologic processes, which in turn control (entrain) other rhythms. In animals, a broad network of direct and indirect controls ensures that the SCN and other central and peripheral oscillators maintain specific phase relationships, resulting in the overall temporal coordination of the system. After all, it is only humans (and perhaps their live-in domestic pets) that routinely override their biologic clocks with respect to the control of behavioral rhythms such as the sleep–wake cycle or the feeding cycle. Only humans sleep or eat at inappropriate times with respect to the adaptively appropriate environmental time. Whether direct or indirect, the SCN in mammals still appears to control the expression of all circadian rhythms, and in 2010 it is not time (yet) for the SCN pacemaker to give up its preeminent and central role in the circadian timing system. Nevertheless, it is clearly true that our enriched appreciation of the multioscillatory and physiologically diffuse nature of the mammalian circadian system has opened up
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Figure 34-7 The multioscillatory circadian timing system includes a large number of autonomously rhythmic circadian clock cells distributed within both central and peripheral tissues. Molecular feedback loops drive circadian rhythms in gene expression and other cellular processes within individual clock cells (see Fig. 34-1); these molecular loops are based on similar, but not necessarily identical genes and proteins in different tissues. The circadian pacemaker resides in the SCN and is entrained by light–dark cycles and other environmental stimuli. Cellular oscillators within SCN neurons are characterized by relatively strong intercellular coupling, which maintains phase synchrony among individual cells and underlies robustly self-sustaining rhythmicity at the tissue level. Nevertheless, under certain conditions (e.g., constant light), these coupling relationships may be sufficiently weakened such that coherent rhythmicity is lost at the tissue (and behavioral) levels (see Fig. 34-5). Cellular oscillators also underlie tissue-level rhythmicity in genomic and physiologic processes in other neural tissues as well as in many peripheral tissues and organs. In general, cellular oscillators outside the SCN appear to be less strongly coupled relative to those within the SCN, and thus depend on rhythmic inputs from the SCN to maintain phase synchrony. In the absence of such input from the central SCN pacemaker, a loss of phase synchrony at the cellular level may be reflected in dampening of rhythmicity at the tissue level (see Fig. 34-6). Together, SCN and non-SCN central neural oscillators result in rhythmic behavior (such as food intake and motor activity), autonomic nervous system (ANS) function and hypothalamicpituitary-adrenal (HPA) axis hormone secretion. These behavioral and physiological rhythms in turn can give rise to other rhythmic signals (e.g., glucose availability, corticosterone levels, and body temperature) that serve to maintain phase synchrony among peripheral oscillators, probably in a tissuespecific manner. In turn, the activity of peripheral oscillators may give rise to rhythmic signals (e.g., peripheral hormones, autonomic afferents, and metabolic signals) that contribute to the synchronization of the SCN pacemaker and other central oscillators.
398 PART I / Section 5 • Chronobiology
new approaches for understanding the temporal organization of mammalian physiology and behavior. Furthermore, this new picture has raised important questions about the potential adverse health effects that may be associated with a loss of normal synchronization between and among central and peripheral oscillations.5 For example, circadian disruption has been linked to sleep disorders, obesity and diabetes, heart disease, psychiatric disorders, and cancer. (See Chapter 39 for full discussion of the adverse health effects of disrupting the overall circadian temporal organization.) Indeed, the Per2 gene appears to play an important role in suppression of mammalian tumorigenesis, and may partially mediate the increased cancer risk seen in human shift-workers and in mice subjected to experimental circadian disruption.126,127 Given that approximately 5%-10% of the entire genome is expressed rhythmically in any given tissue or organ,128,129 many other mechanisms linking circadian synchrony and desynchrony to health and disease will undoubtedly emerge in the next few years.130 Although circadian dysregulation may be uncommon in natural animal populations, it certainly occurs quite often in humans who can override their circadian clock and exert substantial volitional control over their sleep–wake cycles. Under such circumstances, abnormal phase relationships are expressed between sleep–wake behaviors (and other rhythmic processes tightly linked to sleep or wake states) and the circadian clock (and rhythmic processes tightly linked to it). Although the internal desynchronies that occur with jet lag and shift work may be the most dramatic, they are not the only examples of such dyschrony. Indeed, social constraints, work schedules, and the use of artificial lighting may result in the widespread occurrence of “social jet lag” even in people living under relatively stable entrained conditions.131 Regardless of work or travel schedules, humans in our modern, around-the-clock society are certainly becoming less strictly diurnal, opposing millions of years of evolutionary selection.
SUMMARY AND CONCLUSIONS The primary pacemaker for the mammalian circadian system is contained in the SCN, and the mechanisms underlying the pacemaker function of this structure are being elucidated rapidly at the molecular, cellular, and physiological levels. The SCN contains a large number of normally coupled, but potentially autonomous cellular oscillators that generate a circadian time base through the expression of a complex molecular feedback loop. The activity of the core molecular loop results in the circadian expression of a large number of clock-controlled genes, which in turn regulate coordinated circadian rhythms in the metabolism, electrical activity, and neurotransmitter and neuropeptide release of SCN neurons. These processes result in the transmission of circadian timing signals to both passive targets and to inherently rhythmic downstream oscillators throughout the brain and periphery. The core molecular loop is entrained by a number of convergent SCN afferent pathways. Photic signals are transmitted from a specialized set of photoreceptive retinal ganglion cells by a dedicated neural pathway (the RHT) to the SCN, and activity in this pathway results in the release of glutamate as well as multiple peptidergic co-transmit-
ters. Other major SCN afferents arise from the IGL and raphe nuclei, which form terminal fields that largely overlap the RHT terminal field in the SCN core. These afferents serve to regulate photic signaling in the SCN during the subjective night and to mediate the phase-shifting effects of nonphotic stimuli, including behavioral activity and arousal, during the subjective day. Two revolutionary developments in the circadian clock field—(1) the elucidation of the core molecular clock machinery, and (2) the demonstration that most, if not all, tissues/organs can themselves generate the 24-hour molecular clock—have opened up an entirely new area of biomedical research on the importance of internal circadian timing for health and disease. Thus, it can be argued that we are at the beginning of a new era in understanding human health and disease. With hundreds and even thousands of genes oscillating in most, if not all tissues and organs, under the control of both central and local selfsustained circadian oscillations, normal health and wellbeing undoubtedly depend on the maintenance of proper internal synchronization. Furthermore, internal synchronization (or desynchronization) can occur on two levels, between separate oscillating systems (i.e., among tissuelevel clocks within the organism) and within each selfsustained system (i.e., among cellular clocks within individual tissues), and the balance between health and disease is likely to be highly dependent on proper synchrony at both levels. ❖ Clinical Pearl Most, if not all mammalian organs, tissues, and cells contain the core molecular circadian clock machinery, and can produce circadian rhythms in vitro. This greatly heightens the theoretical importance of internal synchronization for normal physiologic function. Abnormal circadian timing between and within tissue and organ systems could be just as important as the overproduction or underproduction of key cellular mediators to overall health. Internal temporal dysfunction may thus be at the root of many physical and mental diseases. Although jet lag and shift work have been the primary ways in which circadian dyschrony were thought to occur, it is probable that circadian dyschrony at the cellular, tissue, and behavioral levels may turn out to play much more widespread roles in human medical and psychiatric pathologies.
Acknowledgments Preparation of this review was supported in part by NIH grant P01-AG011412. REFERENCES 1. Rosenwasser AM. Neurobiology of the mammalian circadian system: oscillators, pacemakers, and pathways. Prog Psychobiol Physiol Psychol 2003;18:1-38. 2. Morin LP, Allen CN. The circadian visual system, 2005. Brain Res Rev 2006;51:1-60. 3. Vansteensel MJ, Michel S, Meijer JH. Organization of cell and tissue circadian pacemakers: a comparison among species. Brain Res Rev 2008;58:18-47.
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The Human Circadian Timing System and Sleep–Wake Regulation Charles A. Czeisler and Orfeu M. Buxton Abstract The circadian pacemaker (or biological clock) confers endogenous rhythmicity with a period just slightly greater than 24 hours, persists independent of periodic changes in the external environment, and has timing or phase relative to the time of day that is genetically determined and can be modified or reset by environmental inputs. Under appropriate conditions, melatonin, body temperature, and many other physiologic processes can be used to assess circadian phase or biological
The circadian pacemaker (or biological clock) is phylogenetically ubiquitous, found in species from prokaryotes to humans. Circadian pacemakers have several defining characteristics: endogenous rhythmicity that persists independent of periodic changes in the external environment, a near-24-hour period (circadian from Latin circa meaning “about” and dies meaning “day”), and the capacity for environmental input to modify or reset timing or phase of the rhythm.1-3 We provide an overview of the human circadian timing system, including the pacemaker with its inputs and outputs, and describe how this pacemaker interacts with sleep–wake regulatory processes to influence physiologic variables including hormone levels, autonomic nervous system activity, neurobehavioral performance, and the propensity for and timing and internal structure of sleep. We also consider the influence of episodic and daily recurring behaviors, including sleep itself, on these physiologic variables relative to that of the endogenous circadian pacemaker.
IDENTIFYING THE MAMMALIAN CIRCADIAN PACEMAKER In mammals, the suprachiasmatic nucleus (SCN) in the anterior hypothalamus is the central neural pacemaker of the circadian timing system. On the basis of careful patient histories characterized by disruptions of sleep–wake timing (e.g., insomnia, reversal of the sleep–wake schedule), Fulton and Bailey4 postulated in 1929 a region in the anterior hypothalamus that appeared to regulate not the occurrence of sleep but its timing within the 24-hour day. It was not until in 1972 that the SCN was identified as the site of the mammalian circadian pacemaker,5,6 and further research has conclusively established the SCN as a principal source of endogenous rhythmicity in mammals.7 Physiologic studies show that multiple distributed circadian oscillators drive daily rhythms in peripheral systems.8 Molecular research confirms the presence of peripheral clocks that use the same molecular machinery as the central circadian pacemaker in the SCN. Pacemakers like the SCN convey internal synchrony to these distributed oscillators. 402
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clock time. Although environmental light–dark schedules are the primary circadian synchronizer, other nonphotic stimuli such as exercise can shift circadian phase. The circadian pacemaker interacts with sleep–wake regulatory processes to influence many physiologic variables: hormone levels, autonomic nervous system activity, neurobehavioral performance, and the propensity for and timing and internal structure of sleep. Environmental, social, behavioral, and genetic factors; pharmacologic agents; and age influence most elements of this system.
INFLUENCE OF SLEEP AND CIRCADIAN RHYTHMS ON HUMAN PHYSIOLOGY The discovery of the SCN’s role as a central circadian pacemaker set the stage for understanding how it drives the prominent daily fluctuations in a wide array of physiologic functions in human subjects synchronized to the 24-hour day and on a normal sleep–wake schedule, (Fig. 35-1, left column of panels).9-17 Core body temperature is lowest and melatonin levels (not shown) are highest11,16,18 during night sleep. Cortisol is low at habitual sleep onset but high at habitual morning wake time. The temporal profile of each of these parameters when these endogenous circadian rhythms are entrained or synchronized to the 24-hour day exhibits a characteristic fingerprint that results from a combination of drives from the timing of the sleep– wake state to the endogenous circadian pacemaker and responses evoked by other factors such as posture, mood, exercise, and environmental lighting.16,19 To characterize the circadian pacemaker–driven component of a diurnal temporal profile from the effects of sleep–wake state, behavior, posture, and periodic and environmental stimuli, the constant-routine protocol originally proposed by Mills and colleagues20 has been refined and extended.21 In the constant routine, subjects typically undergo continuous enforced wakefulness throughout day and night in a constant posture at a constant minimal activity and in constant, relatively dim, ambient illumination.22 Under such conditions, the temporal profiles of many physiologic variables are significantly altered, and we can separate the component of these rhythms that is driven by the endogenous circadian pacemaker from those that reflect changes in the sleep–wake state, posture, or periodic external environment.21 Given the influence of posture23 and the minimal influence of sleep24 on the endogenous circadian melatonin rhythm, we have sometimes used a constant posture protocol in which subjects are maintained in a constant semirecumbent posture in constant dim light but are allowed to sleep at night so that melatonin circadian phase can be assessed. Body temperature declines during sleep19,25-27 as illustrated by the profile of core body temperature recorded
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Figure 35-1 Comparison of temporal profiles of an array of physiologic and behavioral variables from subjects studied under baseline conditions while maintaining a regular schedule of nocturnal sleep (yellow shaded area) and daytime wake at their habitual times (left column of panels) compared with profiles from subjects under constant-routine conditions while maintaining a schedule of continuous wake in a constant semirecumbent posture (right column of panels). The vertical dashed line indicates habitual wakeup time during the week before the study, when subjects were required to maintain a regular sleep– wake schedule. All data are from normal young men, 18 to 30 years old, studied under similar conditions. For a given variable, data in the left panel are from the same subjects as data in the right panel; however, not all variables were monitored in the same subjects. Activity data were measured with a wrist actigraph (Vitalog Monitoring Inc., Redwood City, CA) worn on the nondominant wrist. PTH, parathyroid hormone; TSH, thyroid-stimulating hormone. (TSH data reproduced with permission from Allan JS, Czeisler CA. Persistence of the circadian thyrotropin rhythm under constant conditions and after lightinduced shifts of circadian phase. J Clin Endocrinol Metab 1994;79:508-512, © The Endocrine Society. Prolactin data reproduced with permission from Waldstreicher J, Duffy JF, Brown EN, Rogacz S, Allan JS, Czeisler CA. Gender differences in the temporal organization of prolactin (PRL) secretion: evidence for a sleep-independent circadian rhythm of circulating PRL levels—a Clinical Research Center study. J Clin Endocrinol Metab 1996;81:1483-1487, © The Endocrine Society. PTH data reproduced with permission from El Hajj Fuleihan G, Klerman EB, Brown EN, Choe Y, Brown EM, Czeisler CA. Parathyroid hormone circadian rhythm is truly endogenous. J Clin Endocrinol Metab 1997;82:281-286, © The Endocrine Society.)
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during a normal sleep–wake schedule and on a constant routine (see Fig. 35-1, right column of panels). It is apparent that the sleep episode itself (including associated changes in posture, light intensity, and activity level) generates a drop in body temperature relative to wake.8,19,27-31 This sleep episode–induced drop in temperature combines
with the circadian-driven decline in body temperature (which exhibits a nadir during the latter half of the habitual nocturnal sleep episode) to yield a larger apparent amplitude than that of the endogenous circadian component alone (as measured on constant routine). Urine volume is another variable that exhibits a robust oscillation under constant-routine conditions but is also influenced by sleep–wake state.11,32 Rhythmicity in some variables appears nearly independent of sleep–wake state. The temporal pattern of the hormone melatonin is relatively unchanged whether a subject is asleep or awake all night on a constant routine,33 although significant age-dependent effects of sleep and sleep deprivation on melatonin amplitude have been quantified.24 Posture is reported to influence circulating melatonin concentrations somewhat.23 The temporal profile of cortisol is also relatively unchanged whether a person sleeps on a habitual schedule or remains awake all night, although cortisol levels are elevated on the following afternoon and evening.34 Plasma cortisol concentrations can be suppressed if sleep onset occurs at the crest of the cortisol rhythm rather than at the nadir.35 Several other hormones are sensitive to sleep–wake state. Sleep opposes the circadian rhythm regulating thyroid-stimulating hormone (TSH), inhibiting TSH release during the peak of the endogenous circadian TSH rhythm, which otherwise occurs in the middle of the night.12,15,36-38 Under entrained conditions, nocturnal TSH is blunted by the timing of sleep such that TSH levels are highest just before sleep onset and continue to be suppressed during the remainder of the sleep episode. This inhibitory effect
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of sleep on TSH secretion has been closely associated with slow-wave sleep39 and with relative delta power in the sleep electroencephalogram (EEG).40 Growth hormone, prolactin, and parathyroid hormone levels all show a prominent sleep-dependent increase.37,41 For growth hormone, a major sleep-related secretory episode is associated with slow-wave sleep42 and with relative delta power of the sleep EEG,43 though such associations for prolactin are controversial.44-46 Interestingly, growth hormone levels blunted by acute sleep deprivation are elevated by recovery sleep such that the average 24-hour levels are conserved,47 and following sleep restriction for 1 week, they are significantly elevated by the combination of a presleep and circadianrelated secretory episode and typical but prolonged sleeprelated response.47 Leptin levels exhibit circadian rhythmicity, although the typical day–night pattern is reflected in the interaction of circadian rhythmicity with energy intake and expenditure17 and sleep duration.48 Ghrelin levels exhibit a day–night variation related to energy intake related to the presence of sleep49 and to sleep duration.50 Ultradian variations in the release of renin from the kidney—a key factor in blood pressure control—are closely linked to the timing of the rapid eye movement (REM) and non-REM (NREM) sleep cycle,51,52 an association evident even among patients with disturbed sleep, whose plasma renin profiles reflect pathologic changes in sleep structure. Increased relative delta power in the sleep EEG is associated with increased levels of plasma renin activity, whereas decreased slow-wave activity is associated with a decrease.53 In 1979, Aschoff pointed to some evidence for an endogenously rhythmic component even among sleep-dependent hormones, particularly with respect to the magnitude of the response evoked by sleep.54 Using the constantroutine protocol, it has been shown that in the absence of sleep, prolactin and parathyroid hormone also have an endogenous circadian component that is lowest a few hours after habitual wakeup time.13,14,37 A study involving repeated injections of growth hormone–releasing hormone (GHRH) across the day demonstrated elevated peak growth hormone (GH) responses in the evening, suggesting that diurnal variation in GH secretion reflects, in part, circadian rhythmicity in the response to GNRH.55 Effects of the interaction between sleep-dependent and circadian factors on these hormones can be important when the sleep–wake schedule is not synchronized with the circadian pacemaker. With shift workers who must acutely remain awake on the first night shift, for example, one would expect a substantial increase in TSH release over secretion under normal sleep–wake conditions during entrainment (see Fig. 35-1). On the other hand, these workers would be deprived of their normally higher levels of growth hormone, prolactin, and parathyroid hormone during the waking night. Such alterations of the profiles of a variety of hormones have been documented in laboratory studies of night-shift workers.56 In a laboratory simulation of circadian misalignment with the imposed sleep–wake and eating schedule induced by night shift work and transmeridian travel, subjects exhibited increased leptin and increased glucose (despite increased insulin) and misalignment of the endogenous circadian rhythm of cortisol
secretion with respect to the inverted sleep–wake schedule, along with the expected reduction in sleep efficiency.57 The circadian pacemaker significantly influences a variety of neurobehavioral and cognitive functions.58-64 Under the conditions of the constant routine, subjects display a circadian variation in short-term memory, cognitive performance, and alertness that is tightly coupled to the timing of the body temperature rhythm (Fig. 35-2).65 During a constant routine, these cognitive functions tend to be at their nadir shortly after habitual wakeup time due to an interaction between sleep loss and the circadian rhythms of performance.
EFFECTS OF LIGHT ON HUMAN CIRCADIAN RHYTHMS The light–dark cycle is the primary environmental signal that synchronizes circadian systems in a wide array of species, including humans.1,11,19,22,32,33,66-68 Nonvisual, or non–image-forming retinal photoreception provides input to the circadian system, the pupillary light reflex, and other systems. Direct retinal input travels via the retinohypothalamic tract, a monosynaptic pathway by which information about the environmental light–dark cycle reaches the SCN.69-74 Postmortem studies reveal that the human brain contains the same key structural elements—the SCN and retinohypothalamic tract—as that of other mammals.71,75,76 Neuropathologic studies associate damage to these structures with abnormalities in the timing of the sleep–wake cycle and other circadian rhythms.77-79 More recent research in rodents and humans shows that the three-cone system and rods, the visual photoreceptors, are not required for transmitting light signals to the circadian system.72-74,80-84 Retinal ganglion cells were thought only to pass on information from the rods and cones, but a distinct set of ganglion cells in the inner retinal layer that project to the SCN70 are intrinsically photosensitive. Only the ganglion cells that project from retina to SCN selectively contain the vitamin A–based photopigment melanopsin.72,85 Animal studies determining the action spectrum show that blue-green light (about 450 to 500 nm), which matches the sensitivity peak of melanopsin, is the most potent in shifting circadian phase in animals83,86 and for melatonin suppression in humans,80,81,84 consistent with data on phase-shifting responses in humans.84,87 Within this specific set of intrinsically photosensitive retinal ganglion cells, melanopsin is the active photopigment. Rods and cones that synapse onto melanopsin-containing ganglion cells also participate, creating redundancy in circadian photoreception.88,89 A neural output pathway of the SCN passes through the intermediolateral cell column of the upper thoracic spinal cord, to the superior cervical ganglion which provides sympathetic input into the pineal gland.90 The absence of melatonin in patients who have cervical spinal cord injury is due to disruptions of this neural pathway to the pineal gland91 and is associated with decreased sleep efficiency.92 Photic Suppression of Melatonin Secretion The neural pathway from the SCN to the pineal provides for the regulation of the pineal output of melatonin by the
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Figure 35-3 Melatonin-suppression test in a healthy sighted subject (upper panel) and a blind participant (lower panel). In each, plasma melatonin (upper green traces) and temperature (lower red traces) were measured repeatedly during a constant routine (hatched bar) and subsequent episode(s) of sleep (solid blue bars). The light intensity was ~10 to 15 lux during the constant routines, less than ~0.02 lux during the sleep episodes, and ~10,000 lux during 90 to 100 minutes of exposure to bright light (open columns) 22 to 23 hours after the initial fitted temperature minimum (encircled Xs). In both participants plasma melatonin concentrations decreased markedly in response to bright light and increased after the return to dim light. (Reproduced with permission from Czeisler CA, Shanahan TL, Klerman EB, Martens H, et al. Suppression of melatonin secretion in some blind patients by exposure to bright light. N Engl J Med 1995;332:6-11.)
Relative clock hour Figure 35-2 Daily patterns of short-term memory, cognitive performance, subjective alertness (mm), and core body temperature (°C) averaged across 18 subjects during a 36-hour constant routine. Data collection times are normalized with respect to each subject’s regular wakeup time (assigned a reference value of 8:00 am and indicated by the downward arrow). The extent to which memory and performance scores deviated from the subject’s 24-hour mean is averaged across subjects. Data are expressed as percentages by which these absolute deviations differed from the subjects’ overall 24-hour mean score (assigned a reference value of zero). Each point is the centered mean (SEM) of all determinations made across a 2hour interval for performance, alertness, and temperature and across a 4-hour interval for short-term memory. (Reproduced with permission from Johnson MP, Duffy JF, Dijk D-J, Ronda JM, et al. Short-term memory, alertness and performance: a reappraisal of their relationship to body temperature. J Sleep Res 1992;1:24-29.)
SCN,90,93 including inhibition of melatonin release by retinal light exposure via a retinolypothalamic pathway,94 which can be used as an assay for the functional input of light into the circadian system.95,96 Preservation of light-induced melatonin suppression in otherwise totally blind people, suffering from severe damage to the outer retina,96 led to the discovery that a distinct visual system mediates photic entrainment.97,98 The nocturnal increase in melatonin is illustrated in Figure 35-3 (upper panel) for a normally sighted subject on a constant routine.96 During a second peak of melatonin on the next night, a bright light stimulus induced an acute suppression of melatonin levels, which returned to elevated nighttime levels after light exposure was terminated. In the lower panel, bright light still suppresses melatonin even in a totally blind subject with no conscious light
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perception and a negative electroretinogram. The loss of conscious light perception does not necessarily indicate the loss of photic input to the circadian timing system,96 although this was not the case in all such blind individuals. Two distinct visual systems exist: one for visual perception and a separate non-image forming visual system for synchronization of the circadian pacemaker in the SCN, alerting input to the sleep switch in the ventrolateral preoptic area (VLPO), suppression of melatonin secretion, and mediation of the pupillary light reflex.70-89,96-98 Human Phase-Response Curves to Light In circadian biology, the phase-response curve (PRC) is used to characterize the synchronizing effects of light on a circadian pacemaker.1,22,99,100 To construct a photic PRC, discrete light stimuli are applied systematically over the entire circadian cycle, and the magnitudes of light-induced phase shifts are plotted as a function of circadian phase at which the organism is exposed to the stimuli. In human experiments, the constant routine has been used to estimate both the initial circadian phase of the pacemaker before stimulus and the final circadian phase after stimulus. The difference between the initial and final circadian phases represents the light-induced phase shift. All circadian systems exhibit a characteristic photic PRC, in which the largest light-induced phase shifts are generated in the subjective night of the circadian cycle. Phase delays are generated to light stimuli in the late subjective day and early subjective night, and phase advances are generated in the late subjective night and early subjective day.1 Figure 35-4 illustrates the PRC to a single pulse of light in humans. In humans, phase delays were observed in response to single, 6.7-hour bright light pulses applied before the minimum of the core body temperature cycle, on average about 2.3 hours before habitual wakeup time. Phase advances were observed when such light pulses were applied after the core body temperature nadir. The resultant human PRC to single light pulses101 exhibits the classic
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pattern of light PRCs in many organisms,1,100 including phase advances and delays. The response to light during the subjective day of a three-pulse PRC reveals that the human circadian pacemaker responds to light throughout the subjective day,102 a characteristic of the human PRC that is similar to that reported for other species,1,100 and suggests that appropriate light intensities can shift the phase of the human pacemaker in morning and late afternoon or evening as well as at night. This has important clinical implications, such as use of phototherapy to reset circadian phase in delayed or advanced sleep phase disorder. Photic Resetting of the Pineal Melatonin Rhythm Because circadian rhythms are expressed in many physiologic and neurobehavioral variables, the phase of the pacemaker may be estimated by using any of these variables as a marker. In humans, the core body temperature rhythm is often a preferred marker of circadian phase, because it can accurately represent the underlying pacemaker’s characteristics under certain conditions. However, melatonin can be an even more precise circadian marker,11,33,103,104 which is less heavily influenced by sleep and posture.23,105 In humans studied during a constant routine, melatonin reflects the phase of the underlying pacemaker following light-induced phase shifts better (less variability) than the endogenous component of the core body temperature rhythm.105 Both rhythms shift equivalently whether to an earlier or a later hour.11,104 Such studies demonstrate that the endogenous circadian melatonin rhythm can be reset to any desired phase within 2 to 3 days by light exposure.104 Furthermore, photic stimuli designed to suppress the amplitude of the endogenous circadian temperature cycle also suppress the amplitude of the endogenous circadian melatonin rhythm.104 The use of the melatonin rhythm as a circadian marker has additional practical advantages: melatonin in human saliva correlates well with that in plasma, and it allows the evaluation of circadian phase in patients with suspected circadian rhythm disorders or research subjects relatively noninvasively.106 Human Dose-Response Curve to Circadian Phase-Resetting Effects of Light In addition to dependence on wavelength, the degree of light-induced phase shift also depends upon light stimulus intensity and consecutive days of exposure. Three consecutive daily pulses of light can generate a larger phase shift than a single light pulse. This intensity relationship also applies to brightness or illuminance level of light to which the retina is exposed. Following a 6.5-hour, single bright light stimulus of different intensities at a circadian phase known to generate a phase delay, an increase in resetting response is seen at 50 lux, with maximum slope at 100 lux and maximum shifts by about 550 lux. The light intensity versus resetting response relationship is clearly nonlinear (Fig. 35-5)107 and can be predicted with a mathematical model.108,109 The observation that ordinary room lighting of ~100 lux with only 1% of the intensity induces 50% of the resetting response to a 10,000 lux stimulus has important implications. We are exposed to bright light for a relatively short
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Illuminance (lux) Figure 35-5 Illuminance-response curve of the phase-shifting effect of light on the human circadian pacemaker. Shifts in phase of the melatonin rhythm following the 6.5-hour light pulses, as assessed 1 day after the photic stimulus, are fit with a four-parameter logistic model, using a nonlinear least-squares analysis, that predicts an inflection point of the curve (i.e., sensitivity of the system) at ~120 lux; phase shifts saturate at ~550 lux. Data from individual participants represented by closed boxes, model by solid line, and 95% confidence intervals by dashed lines. (Adapted with permission from Zeitzer JM, Dijk D-J, Kronauer RE, Brown EN, et al. Sensitivity of the human circadian pacemaker to nocturnal light: melatonin phase resetting and suppression. J Physiol (Lond) 2000;526:695-702.)
time each day,110-112 but in modern industrialized societies we are exposed to ordinary indoor room light for many hours, a predominance of exposure that may have a greater impact on our circadian system than a few minutes of exposure to bright light. Figure 35-6 illustrates the influence of the circadian pacemaker and the sleep–wake state on physiologic variables and the influence of light input via the eye to the circadian pacemaker. The feedback loop from the sleep– wake state to the eye represents the effects of exposure to the environmental light cycle, because the sleeping state in humans is usually associated with eyelid closure and selfselected exposure to darkness, achieved by drawing window shades and switching off artificial light sources, whereas the waking state in humans is usually associated with opening of the eyelids and exposing the retina to light via self-selected use of artificial light or exposure to outdoor light during waking hours. Under a strict sleep–wake and light exposure schedule, the pacemaker’s timing is consistent from day to day. However, whenever sleep is initiated late or terminated early, or a waking episode occurs within a sleep episode, the associated light exposure can reset the pacemaker. This association between waking and light exposure and the fact that low light intensity has a significant resetting effect on the pacemaker has practical relevance for routine sleep–wake scheduling and for understanding the influence of sleep disruption, which is often associated with light exposure, on circadian phase.
Figure 35-6 Schema illustrating influence of the circadian pacemaker (circle with oscillator symbol) and sleep–wake state (octagon) on several physiologic variables. Under normal conditions, the circadian pacemaker and sleep–wake state each influence these variables; relative contribution and nature of interaction (i.e., synergistic or oppositional) of each depends upon the variable observed. Also illustrated are the influences of environmental illumination on the human circadian clock via the eye and of the sleep–wake state in determining timing of this illumination via behavioral action (i.e., switching off artificial indoor room lights, drawing bedroom window shades at bedtime, eyelid closure during sleep, and eyelid opening during waking).
NONPHOTIC CIRCADIAN PHASE RESETTING AND REENTRAINMENT Nonphotic input to the human circadian system is less well characterized than photic input. Results of early studies, which focused on social cues such as gong sounds or regularly scheduled performance tests, meals, and bedtimes,113 were confounded by limitations of phase measures used and self-selected lighting conditions. Exposure of healthy young men to nocturnal exercise of 1 to 3 hours’ duration resulted in phase delays in nocturnal melatonin the following day114,115 that appeared more consistent after a 3-hour moderate-intensity session than after a 1-hour high-intensity session.116 Early evening 1-hour high-intensity exercise (at approximately 6:30 pm) elicited phase advances significantly different from the phase delays in response to morning, afternoon, and nocturnal exercise and in noexercise subjects (Fig. 35-7). In a study of the facilitation of re-entrainment to a delay-shifted sleep–wake episode in extremely dim light (to control for ambient light during exercise), exercise during the biological night produced phase delays compared with no exercise.115 Thus, appropriately timed nonphotic stimuli such as exercise or other forms of arousal can facilitate adaptation to acute changes in light–dark cycle. That appropriately timed exposure to exercise also results in phase advances is demonstrated by partial entrainment to a 23.5-hour light–dark and sleep–wake schedule in healthy volunteers exercising at moderate intensity twice daily (midday and late afternoon) over 2 weeks.117 Subjects exercising daily in late afternoon exhibited partial entrainment, advancing on average 10 minutes per day more than nonexercising controls, consistent with phase-advancing effects of late afternoon or early evening exercise on the human circadian clock. Given the slightly
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Timing of exercise (after melatonin onset, hours) Figure 35-7 Phase-response curves in response to exercise at different circadian times of day. Phase delays were observed in response to nocturnal exercise, phase advances were observed in response to exercise during late afternoon or early evening. Closed circles indicate phase shifts in response to high-intensity, 1-hour nocturnal exercise and daytime exercise. Upward165 and downward triangles166 (top panel) and diamonds (bottom panel) indicate phase shifts in response to low-intensity, 3-hour exercise sessions. The line indicates a significant relationship between phase shifts and circadian time of exercise (r2 = 0.28, P = .0003; slope significantly different from zero). Dashed curves indicate 95% confidence intervals of slope of line. (Reproduced with permission from Buxton OM, Lee CW, L’Hermite-Balériaux M, Turek FW, Van Cauter E. Exercise elicits phase shifts and acute alterations of melatonin levels that vary with circadian phase. Am J Physiol 2003;284(3):R714-R724. © 2003 American Physiological Society.)
greater than 24-hour endogenous circadian period of humans and the net daily phase advance required for stable entrainment, evening exercise, particularly repeated daily exposure, could result in daily phase advances leading to nonphotic entrainment of the human circadian system if the timing and intensity of the exercise were optimized.
INVESTIGATING CIRCADIAN AND SLEEP–WAKE DEPENDENT MODULATION The Kleitman Protocol Separation from 24-Hour Environmental and Behavioral Cues Nathaniel Kleitman was the first investigator to study human circadian rhythms in the absence of periodic
24-hour cues in the external environment (Fig. 35-8).61 Core body temperature records from one of his two subjects in Mammoth Cave, Kentucky, in 1938, who underwent a 28-hour imposed sleep–wake schedule, were compared with laboratory data collected at the University of Chicago from the same subject living on a 24-hour routine61 (shown in Fig. 35-9). On a 24-hour schedule, there were seven cycles of the body temperature rhythm, as one would expect over the course of a 1-week recording. The week with an imposed 28-hour schedule also has 7 cycles of body temperature rhythm, but only 6 sleep–wake cycles (see Fig. 35-9, upper panel). Despite the confounding effect of sleep itself on core body temperature, this experimental protocol still separated the influence of timing of the sleep–wake schedule from that of the circadian pacemaker—at least in this subject.
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Figure 35-8 Professor Nathaniel Kleitman (left) attends to experimental equipment while fellow research subject Bruce Richardson lies in bed deep within Mammoth Cave in Kentucky where, for the first time, human subjects were studied while shielded from periodic environmental changes on Earth’s surface. The two pioneers lived on an imposed 28-hour sleep– wake schedule in these quarters from June 4 to July 6, 1938, in an effort to approximate uniform environmental and behavioral conditions, free from the influence of Earth’s 24-hour day. In a 60-foot wide chamber free from any external environmental sounds, the temperature remained at 54 ºF (±1º), humidity approached complete vapor saturation, and darkness was absolute when the artificial light used during waking hours was shut off. The Mammoth Cave Hotel provided daily meals, which were consumed upon awakening and after the 7th and 13th hour of each 19-hour waking day. (Photo courtesy of National Park Service, Mammoth Cave National Park, Mammoth, Kentucky; description adapted from Kleitman N: Sleep and wakefulness. Chicago: University of Chicago Press; 1963. p. 178-179).
This imposed desynchrony between sleep–wake schedule and output of the circadian pacemaker driving the temperature rhythm occurs when the non–24-hour sleep– wake schedule is outside the range of entrainment or range of capture of the circadian system. This protocol, termed the forced-desynchrony protocol, is useful in evaluating the influence of the circadian pacemaker on many physiologic variables, because it allows separation of the confounding effect of the sleep–wake schedule from the output of the endogenous circadian pacemaker.31,61,68 Figure 35-10 illustrates a raster plot of a forced-desynchrony experiment incorporating core body temperature and wake data for a subject living on a 28-hour day in a laboratory shielded from external time cues.118 The waking episodes in this protocol are 18 hours, 40 minutes, followed by sleep episodes of 9 hours, 20 minutes. Core body temperature exhibited a period of 24.3 hours in this subject and was therefore desynchronized from both the 24-hour day and the timing of the imposed 28-hour sleep–wake schedule. Separating Circadian Modulation and Sleep–Wake Modulation The constant-routine protocol does not permit complete and unconfounded separation of the circadian and homeostatic influences on neurobehavioral and physiologic vari-
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Figure 35-9 Weekly body temperature rhythms of a subject under two different routines of sleep and wake. Top, Data from subject K on a 28-hour daily routine of 19 hours’ wake and 9 hours’ sleep during Prof. Kleitman’s historic forced-desynchrony protocol (see Fig. 35-8). Data based on last 3 weeks in Mammoth Cave. Bottom, Laboratory data recorded at the University of Chicago from subject K on his customary daily 24-hour routine of 17 hours’ wake and 7 hours’ sleep. Shaded areas indicate time in bed attempting to sleep. Data are from the 5 weeks after the 24-hour routine of living. Each weekly record shows seven body-temperature waves, within minima in shaded areas on the customary 24-hour routine but not on the artificial 28-hour sleep–wake schedule. This subject’s endogenous circadian temperature cycle maintained a near-24-hour oscillation, despite the scheduled 28-hour length of his sleep–wake cycle. Temperature data from subject R (not shown) appeared to adapt to the non–24-hour routine, something not observed in more-recent forced-desynchrony studies. Interindividual differences in the strength of endogenous versus evoked components of the body temperature rhythm might account for what appeared to be circadian adaptation during forced desynchrony in subject R of Kleitman’s pioneering experiment. (Figure and parts of legend adapted with permission from Kleitman N. Sleep and wakefulness. Chicago: University of Chicago Press; 1963. © 1963 by the University of Chicago.)
ables. However, in the Kleitman forced-desynchrony protocol, sleep and wake are distributed much more evenly over the entire circadian cycle during the course of the experiment. It is thus possible to average data over either successive circadian cycles or successive sleep–wake episodes to separate these components. Averaging isolates the circadian profile of the variable of interest by removing the contribution of the confounding sleep–wake contribution in the averaging process. Conversely, the temporal contribution of the sleep–wake profile can be isolated from the confounding circadian influence. This averaging process is similar to that of cortical evoked potential recordings that effectively subtract background noise not temporally related to the evoked response. Neurobehavioral Functions To understand and predict the time course of neurobehavioral function, we must recognize the influence of the sleep–wake state on what is termed a sleep homeostat31 driving neurobehavioral functions, as is apparent when we examine these variables during a longer course of sleep deprivation when more than one circadian cycle has elapsed.58,65 The cyclic influence of the circadian
410 PART I / Section 5 • Chronobiology W
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pacemaker on alertness and performance is superimposed on an overall decline in function during the experiment, as described in models incorporating both homeostatic and circadian influences in the regulation of sleep and wake.119,120 The rate of this performance decline increases sharply under conditions of chronic sleep restriction. In a 20-hour forced-desynchrony protocol, the temporal profiles of cognitive performance and subjective sleepiness as a function of both circadian phase and time in the scheduled day122 (Fig. 35-11) suggest that the overall magnitudes of circadian and wake-dependent drives are similar during a typical waking day. From the timing of circadian and sleep-dependent profiles, we can qualitatively reconstruct their separate contributions to maintenance of alertness and performance over a normal waking day (see Fig. 35-11). In the first half of the day following wake time, there is little homeostatic sleep drive because it was discharged by the prior sleep episode, so both alertness and cognitive performance are high. In the latter half of the waking episode, when homeostatic sleep drive would oth-
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Figure 35-10 Double plot of a 28-hour forced-desynchrony protocol. Successive days are plotted next to and beneath each other. Scheduled sleep episodes are indicated by open narrow bars, polysomnographically determined wake within each sleep episode is indicated by red tick marks below the narrow open bars, and intervals during which core body temperature was below mean are indicated by the blue area. Intrinsic temperature cycle of 24.3 hours from this subject’s data was estimated by nonparametric spectral analysis of core body temperature data during the forced-desynchrony part of the protocol. The broken line indicates the phase of circadian temperature rhythm minimum, as estimated by this analysis. The encircled X indicates the minimum of endogenous circadian rhythm of core body temperature unmasked by the 40-hour constant-routine protocol (narrow open bars). (Reproduced with permission from Dijk D-J, Czeisler CA. Paradoxical timing of the circadian rhythm of sleep propensity serves to consolidate sleep and wakefulness in humans. Neurosci Lett 1994;166:63-68.)
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Figure 35-11 Double plots of the main effects of the circadian phase relative to the minimum of core body temperature CBTmin (left panels) and duration of scheduled wake (right panels: w = wake; s = sleep) on neurobehavioral measures. Plotted points show deviation from mean values during forced desynchrony and standard errors of the mean (SEMs). For all panels, values plotted lower in the panel represent impairment of that measure. Addition Task (ADD) (A), Digit Symbol Substitution Task (DSST) (B), and Probed Recall Memory (PRM) (C) scores were derived from total correct responses. Psychomotor Vigilance Task (PVT) results represent median reaction time (D) and total lapses (E, reaction times >500 msec). Karolinska Sleepiness Scale (KSS) scores (F) represent responses on this 1 through 9 Likert-type scale in which higher scores represent greater sleepiness. (Reproduced with permission from Wyatt JK, Ritz-De Cecco A, Czeisler CA, Dijk DJ. Circadian temperature and melatonin rhythms, sleep, and neurobehavioral function in humans living on a 20-h day. Am J Physiol 1999;277:R1152-R1163.)
erwise cause alertness and cognitive performance to decline, the circadian drive rises and opposes that decline, thereby sustaining a high, stable level of alertness throughout the normal waking day. Remarkably, neurobehavioral performance, as measured by reaction time, can be preserved during this circadian wake maintenance zone even under conditions of chronic sleep restriction.121 Sleep and Wake Similar dynamics apply for reconstructing the respective circadian and homeostatic contributions to sleep and wake. The raster plot of the forced-desynchrony experiment (Fig. 35-10) shows that almost all wake within a scheduled sleep episode occurs when the subject’s sleep episode is not in phase with the body temperature nadir,118
CHAPTER 35 • The Human Circadian Timing System and Sleep–Wake Regulation 411 Corresponding time of day during entrainment 18 6 18 6 18 Wakefulness (% of recording time [RT])
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Figure 35-13 Wake during scheduled sleep episodes (expressed as percentage of recording time) as a function of circadian temperature phase. Sleep episodes were assigned to 12 30-degree bins based on circadian phase at lights out. (Adapted with permission from Dijk D-J, Czeisler CA. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci 1995;15:3526-3538.)
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Figure 35-12 Variations in occurrence and internal organization of sleep with circadian temperature cycle phase (94 days of data from four subjects). B indicates bed rests in which REM sleep episodes occurred within 10 min after bed rest onset are indicated by green areas; those in which REM sleep episodes occurred within 30 min after bedrest onset are indicated by peach areas. (Reproduced with permission from Czeisler CA, Zimmerman JC, Ronda JM, Moore-Ede MC, et al. Timing of REM sleep is coupled to the circadian rhythm of body temperature in man. Sleep 1980;2:329-346.)
an observation first quantified by Kleitman from his Mammoth Cave data.61 Averaging polysomnographically recorded sleep data from free-running subjects on a selfselected cycle and in an environment free of time cues yields the data in Figure 35-12, showing the temporal profiles of sleep parameters as a function of circadian
phase.123 The circadian contribution to REM sleep timing is robust and exhibits a maximum centered just after the core body temperature nadir. Figure 35-13 depicts sleep-dependent changes in the propensity for wake as a function of the circadian phase at which a sleep episode is initiated.31 Under entrained conditions, a consolidated bout of sleep is maintained with minimal wake during the scheduled sleep episode by initiating the sleep episode at the end of the wake maintenance zone. However, when sleep is initiated in the early morning hours (as in a shift worker after the first night shift), a high percentage of time is spent in wake during the latter half of this intended sleep episode. During entrained conditions, homeostatic drive for sleep is greatest after an extended bout of wake at sleep onset and facilitates sleep in the first half of the night. In the latter half of the sleep episode, as the homeostatic drive declines, the circadian drive for sleep becomes greatest, thus maintaining elevated sleep drive through the end of the sleep episode. These two components interact to facilitate consolidated sleep throughout the night.31,118 The three-dimensional representation in Figure 35-14 combines the temporal profiles of circadian and sleepdependent drives to illustrate their respective contributions in maintaining wake.31,118 A maximum in sleepiness quantified by slow rolling eye movements occurs at the endogenous circadian temperature nadir, which corresponds to occurring just before the habitual wake time. The sleep-dependent contribution exhibits an increasing profile over the wake episode, with the greatest propensity to slow eye movements after 14 hours of wakefulness. When this increasing homeostatic sleep pressure combines with an adverse circadian phase, the drive for sleep is so
412 PART I / Section 5 • Chronobiology
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Figure 35-14 Quasi three-dimensional plot of slow rolling eye movements (SREMs) within scheduled wake episodes relative to circadian phase and time elapsed since start of wake episode. Data were assigned to twelve 30-degree circadian-phase bins and six 112-minute time-since-start-of-wake-episode bins. Each point represents SREMs expressed as percentage of recording time in a bin. (Adapted with permission from Cajochen C, Wyatt JK, Bonikowska M, et al: Non-linear interaction between circadian and homeostatic modulation of slow eye movements during wakefulness in humans. J Sleep Res 2000;9:58.)
Neurobehavioral • Sleep–wake propensity • Alertness • Vigilance • Cognitive Performance
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Figure 35-15 Schema illustrating combined influence of circadian clock and sleep–wake state on neurobehavioral variables (sleep–wake propensity, alertness, vigilance, and cognitive performance). Sleep–wake state influence is illustrated via an intermediary of the sleep homeostat (SH in blue diamond).
great that slow eye movements and lapses of attention often intrude involuntarily during wake. The performance impairment is an order of magnitude more severe when extended wakefulness coincides with an adverse circadian phase under conditions of chronic sleep restriction.121 The circadian and sleep–wake modulation of sleep–wake propensity and neurobehavioral function are illustrated schematically in Figure 35-15. Experimental evidence indicates that a simple additive model cannot account for variations in alertness and cognitive performance data.58,63,65,124 In fact, there is relatively little circadian variation in various waking neurobehavioral measures in the first few hours of wake when averaged across all circadian phases, and the circadian contribution increases as a function of number of hours awake, suggesting that homeostatic and circadian drives are not independent and further suggesting a nonadditive interaction between homeostatic and circadian systems that drive alertness and cognitive performance.125 Furthermore, the buildup of the homeo-
static drive in response to acute sleep deprivation is distinct from the response to chronic sleep loss.121 Internal Sleep Structure REM sleep propensity varies with circadian phase.19,31,123,126 Studies with nap opportunities evenly distributed throughout day and night every 1.5 to 3 hours first established the REM sleep propensity rhythm in a protocol that did not involve concomitant variations in prior wake length.19,123,127,128 REM sleep latency, the rate of REM sleep accumulation, REM sleep episode duration, and REM sleep propensity were then shown to vary with phase of the endogenous circadian temperature cycle in freerunning subjects whose self-selected rest-activity cycle spontaneously desynchronized from the timing of the endogenous circadian temperature cycle (see Fig. 35-12).19,123,129 The peak of the endogenous circadian rhythm in REM sleep propensity in these subjects was just after the nadir of the endogenous component of the circadian temperature cycle, coincident with the circadian peak of sleepiness and sleep propensity (see Figs. 35-11 to 35-14).19,123,129 During such spontaneous desynchrony, free-running subjects who chose to go to bed near the peak of the REM sleep propensity rhythm usually exhibited sleep-onset REM sleep episodes,19,123,129 an otherwise rare phenomenon normally diagnostic of narcolepsy. Under these conditions, the density of REMs per minute of REM sleep exhibits a sleep-dependent variation apparently dissociated from the REM sleep propensity rhythm itself.130 These findings on the timing of the circadian REM sleep propensity rhythm have since been confirmed and extended with polysomnography data from subjects studied in the forced-desynchrony protocol.31,118 Because sleep episodes in the forced-desynchrony protocol always begin after a fixed duration of enforced wake, the results were less subject to the confounding effects of systematic variations in prior wake durations characteristic of spontaneous desynchrony. Furthermore, because subjects were scheduled to remain in bed for a fixed interval on the forceddesynchrony protocol, results were not confounded by self-selected termination of the sleep episode, although circadian variations in sleep efficiency prevent complete elimination of this confounding factor. Nonetheless, under such conditions, the twofold circadian variation in REM sleep propensity again peaked just after the nadir in the endogenous circadian component of body temperature rhythm, within each fifth of the scheduled sleep episode, notwithstanding the average sleep-dependent increase in REM sleep propensity.31 A sleep-dependent increase in REM sleep propensity independent of circadian phase was also quantified. A significant nonadditive interaction between circadian phase and time since the start of the sleep episode was found from the REM sleep data collected during forced desynchrony.31 With the forced-desynchrony protocol, significant and substantial circadian and sleep-dependent variations in NREM sleep propensity were also observed, whereas the robust sleep-dependent decline in slow-wave activity was associated with only a small but statistically significant variation of slow-wave activity as a function of circadian phase.31 Similar circadian variations in internal sleep structure are documented in a blind patient whose circadian
CHAPTER 35 • The Human Circadian Timing System and Sleep–Wake Regulation 413
Potential Feedback Pathways As is typical of physiologic regulatory systems, feedback pathways play a significant role in this system. The neurobehavioral variables influenced by the circadian pacemaker and the sleep homeostat can influence the sleep–wake state via the influence of wake and sleep propensity on determination of sleep and wake times. For example, a sleep episode is more likely to be initiated following a rise in sleep propensity to a high level during an extended waking episode, and a sleep episode is more likely to be terminated following a decline in sleep propensity to a low level over the course of a sleep episode. This influence on behavior, in turn, influences the level of the sleep homeostat and, because of associated changes in light exposure and activity, it can affect the phase or amplitude (or both) of the circadian pacemaker. There may be another important feedback pathway in this system. Studies demonstrating that melatonin receptors can be found on cells within the human SCN draw attention to a potential feedback pathway from the pineal gland to the SCN via circulating melatonin. Several physiologic studies suggest that exogenous melatonin has a phase-resetting effect on the human circadian pacemaker, and both a PRC and dose-dependent phase shifting have been reported. The first such study that has thoroughly controlled for retinal light exposure has revealed that the resetting responses to melatonin are even greater than previously reported.133 There is also great interest in the potential efficacy of melatonin as a hypnotic because the sleep-promoting effects of exogenous melatonin depend on circadian phase, as established in young adults on a forced-desynchrony protocol.134 Examination of the temporal profile of endogenous melatonin secretion during the forced-desynchrony protocol shows a daily circadian increase in melatonin levels coincident with a decrease in wake (Fig. 35-16).132 This melatonin rise might open a gate that allows sleep to occur.135 These data suggest feedback from the pineal gland to both the circadian pacemaker and neurobehavioral variables involved in regulating the sleep–wake state. Other physiologic systems might also affect sleep-regulating mechanisms, such as an effect of growth hormone136,137 on sleep.
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pacemaker was not synchronized to the 24-hour day, despite his decades-long maintenance of a regular sleep– wake schedule.131 Such blind patients, in essence, live in society on the biological equivalent of a forced-desynchrony protocol, because the 24-hour day is outside the range of entrainment of the circadian pacemaker in such patients. Quantitative analysis of the sleep EEG reveals circadian variations in EEG activity during NREM and REM sleep,132 with low-frequency sleep spindle activity in NREM sleep paralleling the endogenous circadian melatonin rhythm. Overall, these data indicate that the timing and internal structure of sleep are profoundly dependent on an interaction between robust circadian and homeostatic regulatory factors, with circadian factors predominant in the regulation of REM sleep and with sleep-dependent factors predominant in the regulation of slow-wave sleep.
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Circadian phase (degrees) 0 degrees = melatonin maximum Figure 35-16 Phase relationships between endogenous circadian rhythms of wakefulness and plasma melatonin were assessed during a forced-desynchrony protocol. Data were plotted against the circadian phase of the plasma melatonin rhythm (0 degrees on the lower abscissa scale corresponds to fitted melatonin maximum). To compare with entrained conditions, the upper abscissa scale indicates the approximate clock time corresponding to circadian melatonin rhythm during the first day of the forced-desynchrony protocol (i.e., immediately on release from entrainment). Plasma melatonin data are expressed as z-scores to correct for interindividual differences in mean values. Wake is expressed as a percentage of recording time (RT). Data are double plotted (i.e., all data plotted left of the dashed vertical line are repeated to the right of the vertical line). (Adapted from Dijk D-J, Shanahan TL, Duffy JF, et al. Variation of electroencephalographic activity during non–rapid eye movement and rapid eye movement sleep with phase of circadian melatonin rhythm in humans. J Physiol [Lond] 1997;505[3]: 851-858.)
Intrinsic Period of the Human Circadian Pacemaker Early human studies were performed in the absence of environmental synchronizers but were confounded by selfselected exposure to ordinary room light, which led to the erroneous conclusion that the average period of the human circadian pacemaker was 25 hours.66-68 Subjects were permitted to illuminate their living quarters while awake and switch off lighting while asleep, because these experiments were predicated on the incorrect belief that ordinary room light had no resetting effect on the human circadian system.138,139 Thus, results of these studies were systematically compromised by this retinal light exposure.66-68,140 Recognition of this confounding effect led to the use of Kleitman’s forced-desynchrony protocol to assess the
414 PART I / Section 5 • Chronobiology
intrinsic period of the human circadian pacemaker.66-68,141,142 Using simulations based on Kronauer’s mathematical model of the effect of light on the circadian system, under conditions of self-selected room lighting, the observed period of the circadian temperature rhythm would appear to be 25 hours even when an actual circadian input period of 24.1 to 24.2 hours was employed.140 Subsequent studies using the forced-desynchrony protocol have controlled the intensity of background illumination and timing of exposure to the light–dark cycle.66-68 With this forced-desynchrony protocol in subjects living in dim light (about 10-15 lux) on either a 28-hour or a 20-hour schedule, the average intrinsic period of the circadian pacemaker is estimated to be much closer to 24 hours, with an average period of about 24.2142 rather than 25 hours (Fig. 35-17). This holds true for all of the circadian markers tested—core body temperature, melatonin, and cortisol—and is consistent with results of other studies under a variety of protocols.143-146 Entrainment studies have functionally confirmed the intrinsic circadian period in humans to be near 24 hours, because a weak stimulus (candlelight during the scheduled day and sleep in darkness during the scheduled night) can entrain most people to a light-dark cycle with an imposed period of 24.0 hours but not an imposed period of 23.5 or 24.6 hours.147
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AGING AND CIRCADIAN SLEEP– WAKE REGULATION Aging also has a pervasive influence on many aspects of the circadian and sleep–wake regulating system.148-155 The prevalence of disrupted sleep complaints is much greater in older than in young people. In fact, 57% of people in the United States older than 65 years complain of at least one chronic sleep problem, 43% complain of difficulty initiating or maintaining sleep, and 19% complain of awakening too early in the morning.156 Key to examining this question is the extent to which the circadian pacemaker or the sleep homeostat is involved in these agerelated changes. In experiments using a constant-routine protocol, the minima of core body temperature tended to occur at a later clock time in young subjects than in healthy elderly subjects, and core body temperature rhythm tended to exhibit higher amplitude in young than in healthy elderly subjects (Fig. 35-18).150,157 However, in forced-desynchrony experiments with healthy young and elderly subjects, the circadian period did not differ between these groups.142,158 Although circadian period might still differ in older people with compromised health or with sleep disorders, a change in period is not a necessary consequence of aging. A forceddesynchrony study confirmed an earlier constant-routine study showing that older subjects have their circadian phase set to an earlier hour and exhibit a lower amplitude of the body temperature rhythm. More important, other results from this study suggest that young subjects can sleep over a much wider range of circadian phases than
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0 23.8 23.9 24.0 24.1 24.2 24.3 24.4 24.5 24.6 Intrinsic circadian period (hr) Figure 35-17 Histogram of intrinsic circadian period (τ) estimates derived from young and older subjects. Green bars indicate intrinsic circadian period estimates of older participants; pink bars indicate young participants. Each participant’s estimated intrinsic circadian period is reported as the average of estimated periods from his or her core body temperature, melatonin, and cortisol rhythms. (Reproduced with permission from Czeisler CA, Duffy JF, Shanahan TL, Brown EN, et al. Stability, precision, and near–24-hour period of the human circadian pacemaker. Science 1999;284:2177-2781.)
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CHAPTER 35 • The Human Circadian Timing System and Sleep–Wake Regulation 415
older people, who also wake up at an earlier internal circadian phase,157,159 which might also explain why their circadian system is shifted to an earlier hour. If older people wake up spontaneously at an earlier circadian phase, they will be exposed to light at an earlier hour, which will, in turn, reset their pacemaker to an earlier hour and essentially exacerbate this problem.157 Remarkably, older participants are much less vulnerable to the adverse effect of sleep loss and misalignment of circadian phase on neurobehavioral performance.160
INFLUENCE OF SOCIAL FACTORS The independent self-selection of sleep and wake times in humans is another important factor in the sleep-regulation system. Although circadian and homeostatic drives for sleep influence the choice of sleep and wake times via a feedback pathway, social factors often override that influence. In contrast, animal behavior exhibits activity and sleep predictable enough to be used as markers of the time of day. Humans, especially since the advent of alarm clocks and artificial lighting, can and do override the signals from the circadian and sleep–wake regulating system and freely decide to stay awake because of job or school requirements or recreational and social events. Thus, modern humans may be more sleep deprived than their ancestors.161 The long-term consequences of this relatively recent trend in industrialized society are unknown. Yet the modern consolidated sleep episode is significantly different from that under more naturalistic conditions in which sleep episode duration was determined by longer length of darkness in the natural winter environment.161,162 The most conspicuous example of this selfselection is rotating shift work, when people choose to work in direct opposition to the modulation of circadian and homeostatic regulatory systems, resetting in internal temporal dissociation, fragmented sleep, and impaired wake. Therefore, in any realistic model of the human circadian and sleep–wake regulatory system, such environmental and societal influences must be recognized. CONCLUSION We can assemble an overall system schema and incorporate the feedback pathway of neurobehavioral variables on sleep–wake state and the putative feedback pathways from melatonin and other physiologic variables onto the circadian pacemaker and neurobehavioral function (Fig. 35-19). This schema incorporates the global influence of environmental, social, behavioral, genetic, pharmacologic, and age as factors influencing all elements of this system, together with the decrements in neurobehavioral performance and alertness that immediately follow the sleep-to-wake transition, a phenomenon called sleep inertia. The time course of sleep inertia has been shown to persist for as long as several hours after a long sleep episode.163,164 Though the final schema incorporates much of what is known about the role of the circadian pacemaker in regulating sleep, it is not intended to completely represent all factors involved in the regulation of sleep, which is beyond the scope of this chapter. Nevertheless, its strength is its use in understanding the interplay between circadian and homeostatic drives
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Figure 35-19 Overall schema illustrating potential influence of the circadian clock on neurobehavioral and physiological variables and of physiological variables (e.g., melatonin, body temperature) on neurobehavioral variables or circadian clock (dashed arrows), feedback influence of variables on sleep–wake state (solid arrow), influence of sleep–wake state on variables through sleep homeostat (SH) and sleep inertia (SI) (solid arrows). Global influence of environment, behavior, age, social factors, genetics, and drugs on virtually all elements contributing to sleep–wake regulation are also represented.
and perhaps as a framework for initiating future scientific inquiry. The complexity of interactions of the circadian pacemaker and the sleep homeostat in regulating cycle should not be underestimated, and it is important to understand the difficulty in functionally separating these two processes. Under ordinary circumstances, when persons sleep at night in darkness and are awake in daylight, we cannot distinguish the relative contributions of the sleep homeostat from that of the circadian pacemaker to a given recurrent daily characteristic, symptom, or disorder of sleep or wake (e.g., narcolepsy, delayed sleep phase syndrome). A pathologic event, such as a nocturnal seizure, that occurs the same time each night may be driven by the circadian pacemaker, the sleep homeostat, a specific sleep stage, or some combination of these processes. It is currently possible, though difficult, to experimentally dissociate these factors for research purposes (e.g., using the forceddesynchrony protocol in humans or suprachiasmatic lesions in animals). Clinically feasible techniques, such as measurement of dim-light salivary melatonin onset, can provide useful information about circadian phase.106 However, a routine complete clinical assessment of whether a disorder is circadian or homeostat-dependent awaits the results of continued basic and clinical research. Acknowledgments The research conducted in the Division of Sleep Medicine has been supported by grants NIA-1-RO1-AG06072, NIA-PO1-AG09975 and NIA-1-U01-12642 from the National Institute on Aging; grant NIMH-1-RO1MH45130 from the National Institute of Mental Health; grant RO1-HL52992 from the National Heart Lung and
416 PART I / Section 5 • Chronobiology
Blood Institute; grants NAG9-524 and NAG5-3952 from the National Aeronautics and Space Administration; the National Aeronautics and Space Administration through the NASA Cooperative Agreement NCC 9-58 with the National Space Biomedical Research Institute; and Grant numbers 1 UL1 RR025758-01 and M01-02635, Harvard Clinical and Translational Science Center from the National Center for Research Resources and by the Brigham and Women’s Hospital.
❖ Clinical Pearl Disruption of the circadian timing system by shift work, travel across time zones, and the activities of our round-the-clock society has an adverse effect on many physiologic variables including hormones, glucose, metabolism, autonomic nervous system activity, neurobehavioral performance, and the propensity for and timing and internal structure of sleep. This disruption can result in patient complaints of insomnia or excessive daytime sleepiness and can impair overall health.
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151. Touitou Y, Bogdan A, Haus E, Touitou C. Modifications of circadian and circannual rhythms with aging. Exp Gerontol 1997;32: 603-614. 152. Myers BL, Badia P. Changes in circadian rhythms and sleep quality with aging: mechanisms and interventions. Neurosci Biobehav Rev 1995;19:553-571. 153. Bliwise DL. Sleep in normal aging and dementia. Sleep 1993; 16:40-81. 154. Monk TH, Buysse DJ, Reynolds CF III, Kupfer DJ, et al. Subjective alertness rhythms in elderly people. J Biol Rhythms 1996;11: 268-276. 155. Monk TH, Buysse DJ, Reynolds CF III, Kupfer DJ, et al. Circadian temperature rhythms of older people. Exp Gerontol 1995;30: 455-474. 156. Foley DJ, Monjan AA, Brown SL, Simonsick EM, et al. Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep 1995;18:425-432. 157. Duffy JF, Dijk DJ, Klerman EB, Czeisler CA. Later endogenous circadian temperature nadir relative to an earlier wake time in older people. Am J Physiol 1998;275:R1478-R1487. 158. Duffy JF, Czeisler CA. Age-related change in the relationship between circadian period, circadian phase, and diurnal preference in humans. Neurosci Lett 2002;318:117-120. 159. Dijk DJ, Duffy JF, Riel E, Shanahan TL, et al. Ageing and the circadian and homeostatic regulation of human sleep during forced desynchrony of rest, melatonin and temperature rhythms. J Physiol (Lond) 1999;516.2:611-627. 160. Duffy JF, Wilson HJ, Wang W, Czeisler CA. Healthy older adults better tolerate sleep deprivation than young adults. J Am Geriatr Soc 2009;57:1245-1251. 161. Wehr TA, Moul DE, Barbato G, Giesen HA, et al. Conservation of photoperiod-responsive mechanisms in humans. Am J Physiol 1993;265:R846-R857. 162. Wehr TA, Giesen HA, Moul DE, Turner EH, et al. Suppression of men’s responses to seasonal changes in day length by modern artificial lighting. Am J Physiol 1995;269:R173R178. 163. Achermann P, Werth E, Dijk DJ, Borbély AA. Time course of sleep inertia after nighttime and daytime sleep episodes. Arch Ital Biol 1995;134:109-119. 164. Jewett ME, Wyatt JK, Ritz-De Cecco A, Khalsa SB, et al. Time course of sleep inertia dissipation in human performance and alertness. J Sleep Res 1999;8:1-8. 165. Van Reeth O, Sturis J, Byrne MM, Blackman JD, et al. Nocturnal exercise phase delays circadian rhythms of melatonin and thyrotropin secretion in normal men. Am J Physiol 1994;266: E964-E974. 166. Buxton OM, Frank SA, L’Hermite-Balériaux M, Leproult R, et al. Roles of intensity and duration of nocturnal exercise in causing phase delays of human circadian rhythms. Am J Physiol 1997;273: E536-E542.
Melatonin and the Regulation of Sleep and Circadian Rhythms Béatrice Guardiola-Lemaître and Maria Antonia Quera-Salva Abstract Biological functions are organized according to time-dependent cycles (circadian; i.e., 24 hours, and seasonal, i.e., a year). Such regulation is universal in living species including humans and mammals, and is determined by the alternation of day and night. In humans, circadian rhythms concern rest– activity, wake–sleep cycle, metabolic homeostasis, cardiovascular functions, and immunomodulation. Similarly, many hormones also influence circadian rhythms that are related to biological functions. Among these hormones, melatonin plays a key role as a resynchronizing agent on circadian rhythms, including rest–activity, when internal or external parameters have disrupted their circadian rhythmicity. Melatonin is secreted only during the night in all species whether
All biological processes are organized according to timedependent cycles, the most basic ones being the 24-hour cycle (the circadian rhythm)1,2 and seasonal cycles (the circannual rhythm).3 Such temporal regulation is universal in living species including humans, because for a billion years Earth’s rotation around its own axis, which determines the day–night alternation, has lasted about 24 hours. Healthy subjects exhibit a circadian rhythm of secretion of many hormones, including melatonin, cortisol, and adrenocorticotropic hormone (ACTH), with additionally a circannual rhythm for testosterone in men and monthly cycles for reproductive hormones in women.4 There is also a circadian rhythm for body temperature, blood pressure, heart rate, and urinary excretion of electrolytes.5,6 As a result, there is harmonious synchronization in the functioning of cells, allowing the different physiologic functions to adapt to the needs of the organism with respect to the rest–activity cycle. Most documented rhythms are described for hypothalamic, hypophysial, gonadal, and adrenocortical functions. This is of interest because it is now well established that the hypothalamic pathways can integrate all the sensory information from the internal and external environment and fine-tune the integrated information with the intricate balance between the needs and demands of various physiologic systems, including brain function, the cardiovascular system, glucose and lipid metabolism, the gastrointestinal system, reproduction, and immunology.7 After a million years of evolution, the central clock located in the suprachiasmatic nucleus (SCN) has acquired autonomous functioning, with an endogenous period slightly longer than 24 hours,8 which persists even in the absence of temporal signals. However, in normal conditions, the circadian master clock is closely synchronized to the 24-hour environmental cycle, thanks to synchronizers, of which the external light–dark cycle is the dominant one.9 Light thus is the major zeitgeber for the SCN. Photic stimuli are transmitted to the SCN through the retinohypothalamic and the retinogeniculohypothalamic pathways. 420
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36
their activities are diurnal or nocturnal. For this reason melatonin cannot be considered a sleeping hormone. Melatonin acts at the level of the suprachiasmatic nucleus—the main clock of the organism, which generates nocturnal melatonin secretion and expresses melatonin receptors. Melatonin secretion is characterized by a peak, which occurs in the middle of the night, and the length of its secretion is directly dependent on time of exposure to the light and dark periods. Variations of melatonin secretion and phase position are correlated with altered or disrupted circadian rhythms. Conversely, when administered at the light-to-dark transition or with appropriate timing, melatonin resets the suprachiasmatic nucleus. This resynchronizing activity on circadian rest–activity cycles contributes to the improvement of certain sleep disorders related to circadian rhythm.
The SCN circadian pacemaker function is regulated by the neurohormone melatonin, which is secreted in the pineal gland. Photic information is transmitted from the eye to the SCN, from the SCN to the paraventricular nucleus (PVN) of the hypothalamus, then to the pineal gland through a multisynaptic pathway. Melatonin is secreted at night and suppressed by light during the day. Thus melatonin secretion modulates the function of the circadian clock by signaling day–night information to the endogenous pacemaker. Because melatonin receptors are expressed in most organs, glands, and tissues, melatonin regulates the circadian pattern of secretion of hormones, including cortisol, the rest–activity cycle, and core body temperature (Fig. 36-1).10 In addition, melatonin secretion is modulated by seasonal variations in the respective duration of day and night, with duration and amplitude of nocturnal melatonin peak increasing with the lengthening of the dark period in autumn. Thus, melatonin adapts biological functions to preparing for hibernation in hibernating species and to reproductive seasonal cycles. Disruption of the physiologic circadian rhythmicity induced by endogenous or by environmental factors, which deregulate the master clock function, results in altered melatonin secretion patterns often associated with pathologic disorders, including altered rest–activity cycle and wake–sleep disorders. When administered at the appropriate time, melatonin by its re-entraining effect on the SCN can improve parameters of the wake–sleep cycle in certain circadian rhythm sleep disorders.
MELATONIN: SYNTHESIS, RECEPTORS, AND CIRCADIAN SECRETION PATTERN Biosynthesis The neurohormone melatonin is secreted by the pineal gland. Melatonin derives from serotonin, which is first
CHAPTER 36 • Melatonin and the Regulation of Sleep and Circadian Rhythms 421 Summer
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Figure 36-1 Melatonin, suprachiasmatic nucleus (SCN), and the autonomic nervous system.
Circadian rhythms
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The clock is localized in the suprachiasmatic nucleus. The clock controls nocturnal melatonin secretion. Melatonin distributes photoperiodic day/night and circadian message. Melatonin synchronizes circadian and seasonal function. Figure 36-3 Melatonin: A circadian and seasonal regulator of the suprachiasmatic nucleus.
Tryptophan TPOH β-AR AC
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Figure 36-2 Synthesis and synthesis regulation pathways of melatonin.
N-acetylated, then O-methylated to lead to N-acetyl-5methoxytryptamine or melatonin, which is directly released into the general circulation.11 This synthesis occurs only during the night in all species, regardless of diurnal or nocturnal activity.12-15 Norepinephrine released during the night stimulates the beta-adrenergic receptors present on the pinealocytes and hence the synthesis of the enzyme N-acetyltransferase, which is synthesized and activated only during the night, and finally drives the rhythmicity of melatonin secretion (Fig. 36-2).16-18 Melatonin levels in the pineal gland are low during the day, begin to increase shortly after onset of darkness, reach peak levels at mid darkness, and then decrease late in the night to reach daytime levels shortly before light onset.
Melatonin secretion is inhibited by light. This action is mediated via a photoreceptor system in melanopsin-containing, light-sensitive retinal ganglion cells.19 The activity of the pineal gland is very sensitive to the circadian and seasonal variations in length of the photoperiod, namely, the respective duration of light and dark exposure. In hibernating animals, melatonin regulates seasonality parameters. Exogenous administration of melatonin can also control the rest–activity rhythm entrainments through melatonin receptors located in the SCN (Fig. 36-3). Melatonin Receptors Melatonin transmits photoperiodic information to the SCN and also to many tissues or organs in the body through specific melatonin receptors expressed both in the whole central nervous system (including SCN) and in virtually all cells of the organism. Three receptors have been cloned. The signaling pathways of melatonin receptors depend on cell type. MT1 and MT2 receptors are G protein–coupled receptors with seven transmembrane domains (Fig. 36-4). MT1 and MT2 receptors are coupled to cyclic adenosine monophosphate (cAMP) and calcium, whereas only MT2 receptors are coupled to cyclic guanosine monophosphate (cGMP) (Fig. 36-5). In mammals, more than 100 structures containing melatonin receptors have been identified in the central nervous system, thus reflecting the important role played by melatonin at the cellular level on brain structures. MT1 and MT2 receptors are also present in peripheral tissues including the retina, adrenal glands, liver, arteries, heart, kidneys, gastrointestinal tract, macrophages, adipocytes, and blood platelets.20-22 The sensitivity of these receptors occurs at the dark-to-light transition and coincides with onset of melatonin secretion, thus explaining why exogenous melatonin is only active when administered at the proper time—transition from day to night, whatever the species
422 PART I / Section 5 • Chronobiology MT1–MT2–Mel1c melatonin receptors
HN
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At least 3 amino-acids are implicated in the ligand binding and/or functioning (arrows). Binding to the G protein A: alanine, C: cysteine, H: histidine, I: isoleucine, N: asparagine, R: arginine, S: serine, V: valine, Y: tyrosine
Figure 36-4 Melatonin receptors MT1, MT2, MT1C.
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Figure 36-5 Melatonin receptors MT1 and MT2: modulation of genetic transcription.
(diurnal or nocturnal)—because melatonin-induced sensitization is present only during the night period.23,24 cAMP is a core component of the circadian pacemaker, suggesting that daily activation of cAMP signaling driven by transcriptional oscillators sustains the progression of transcriptional rhythm and could participate in synchronization.25 The third binding site of melatonin, MT3, has been characterized as a melatonin-sensitive form of the quinine oxidoreductase 2 (QR2, EC 1.6.99.2). MT3 (QR2) binding sites are widely distributed in mammals.26,27 The role of
the MT3 binding site is not fully understood. In view of the relationship of QR2 with the redox status of cells, it might participate in the antioxidant activity of melatonin.28 Finally, melatonin has been shown to bind to a nuclear receptor identical to nuclear orphan receptors, called RZR/ROR.29,30 Melatonin Secretion The area under the curve of plasma or saliva melatonin, or urinary 6-sulfatoxymelatonin (its main metabolite), is used to assess the melatonin secretion pattern. Both timing and duration of melatonin secretion are critical features with regard to physiologic functions. In order to reliably assess physiologic or pathologic variations of melatonin, serial serum or saliva samples over the whole period of night and day are required. Melatonin secretion is characterized by a peak that occurs in the middle of the night, as shown by serial serum or saliva determinations over 24-hour periods. The presence of two peaks of secretion has also been reported at times31,32 and is related to possible dual oscillator control of melatonin synthesis. In healthy persons the timing, amplitude, and even discrete profile of melatonin secretion are highly reproducible from day to day.33 No consistent gender differences have been found. There are seasonal variations in human melatonin secretion, with an earlier phase in summer.34 Melatonin secretion level and duration increases in autumn and winter in northern latitudes in response to the shortening of the photoperiod.35 This allows the organism to adapt metabolic processes to the cold period by regulating thermogenesis36 and to adapt to hibernation with its prolonged sleep in hibernating animals.37 Melatonin secretion declines during development and with aging.38-40
PHYSIOLOGIC ROLE OF MELATONIN IN THE REST–ACTIVITY CYCLE: CONSEQUENCES FOR SLEEP There is a close parallel between the circadian rhythms of rest–activity alternation and of melatonin secretion in normal diurnal animals and humans. Conversely, in nocturnal animals, onset of melatonin secretion coincides with locomotor activity. For this reason, a direct role of melatonin on sleep is not credible. There is no demonstrated causal relationship between onset and duration of melatonin secretion in normal conditions of sleep. In fact, melatonin does not affect the sleep pattern in rats with normal circadian rhythms. A possible sedative effect is excluded in rats in view of the lack of activity of melatonin in the spontaneous motor activity test, because melatonin does not decrease locomotor activity at doses up to 16 mg/kg (including those that re-entrain rest–activity cycles), and it does not induce behavioral changes at doses up to 32 mg/ kg. These data are in agreement with other data obtained in mice in a free exploration test, where no sedative effect was observed with melatonin (up to 30 mg/kg). Furthermore, melatonin does not potentiate barbitural sleep.41 Normal human subjects living in usual conditions (active period in the day and rest in the night) have characteristic
CHAPTER 36 • Melatonin and the Regulation of Sleep and Circadian Rhythms 423
patterns of sleep-onset latency, sleep duration and efficiency (ratio of total sleep time to total sleep period), slow-wave sleep (SWS), and rapid eye movement (REM) sleep. Thus, objective measurements of sleep by means of polysomnography recording, together with subjective assessment of sleep quality, allow researchers to evaluate sleep–wake cycle disturbances in pathologic conditions by comparison with mean values recorded in healthy subjects.42 In addition, serial measurements of physiologic parameters (body temperature, heart rate, blood pressure) and circulating levels of hormones allow researchers to determine the normal circadian rhythm typically observed in healthy subjects, thus providing biomarkers of normal circadian rhythm, the ones most clearly dependent on circadian rhythm being body temperature and cortisol secretion. Core body temperature exhibits a clear circadian rhythm, with the highest value in the evening and the lowest in the middle of the night. Conversely, maximal secretion of cortisol takes place in the morning, with a progressive decline over the day to reach its lowest level in the evening, after falling asleep.10 Exogenous melatonin administration has a phase-shifting effect in the SCN’s neuronal activity, the chronobiotic effect. This effect varies according to the time melatonin is administered.43 In diurnal species, daily administration of exogenous melatonin in the evening, before endogenous melatonin secretion, advances the phase of the circadian rhythms, thus resulting in earlier falling asleep and waking. Animal models of circadian rhythm disruption have been developed in order to reproduce the disorders observed in humans and analyze their mechanisms. In the murine models, various parameters have been assessed such as behavior, melatonin secretion, biomarkers, functionality of the hypothalamus, and clock genes. Concerning rest–activity disorders, several animal models have been set up, such as free-running conditions as a model of time-zone change syndrome, negative phase angle as a model of delayed sleep phase syndrome, and light-hour phase advance shift as a model of shift-work sleep disorders. In such conditions, wake–sleep cycles can be analyzed with computers using actimeters or transmitters recording locomotor activity and body temperature. In these different animal models, melatonin (0.1-3 mg/kg) was able to resynchronize disrupted rest–activity cycles.44,45 Similarly, administration of exogenous melatonin in healthy volunteers in the evening or at bedtime at small doses (0.310 mg) induces drowsiness and shorter sleep latency.33 Through its receptors in most organs and cells, melatonin modulates the circadian patterns of thyroid, growth, and hypophysogonadal hormones,46 as well as regulation of carbohydrate and lipid metabolism, vasoconstriction and relaxation of cerebral and coronary arteries, urine output, and immune and antioxidant responses and processes. Therefore, it is not surprising that melatonin secretion has been found to be altered in a number of pathologic conditions associated with the desynchronization of circadian rhythms. Alterations in the usual rest–activity rhythm from exogenous, environmental causes (such as night work or long transmeridian flights) or endogenous misalignment of the circadian clock with the light–dark cycle result in sleep
disorders, collectively defined as circadian rhythm sleep disorders (CRSDs).42,47-49 In all of these CRSDs, melatonin secretion is altered, as shown by determination of the dimlight melatonin onset.50 In view of the chronobiotic resynchronizing properties of melatonin, timed exogenous melatonin administration has been tried to improve sleep disorders associated with disturbed biological rhythms,47,51 and melatonin receptor agonists have been designed for this purpose.49 Exogenous melatonin administration has direct and circadian effects on sleep, without concomitant changes in sleep duration.52 Distal heat loss, via increased skin temperature, seems to be intimately coupled with sleep induction. Exogenous melatonin administration during the day, when melatonin is essentially absent, mimics the endogenous thermophysiologic processes occurring in the evening and induces sleepiness. Thus the sleep-facilitating effect of melatonin may be related to a hypothermic response mediated by peripheral vasodilation.53 The effects of administration of exogenous melatonin on sleep and endogenous melatonin secretion time54,55 were first studied in healthy volunteers and in patients with insomnia. Overall, administration of exogenous melatonin to healthy volunteers in the evening or at bedtime at small doses (0.3-10 mg) induces drowsiness and decreases sleep latency.56 In insomnia, no study showed a significant effect in nonelderly adults at doses of between 0.3 and 5 mg,57 but a single study demonstrated subjective improvement in sleep quality at a dose of 75 mg.58
CIRCADIAN RHYTHM SLEEP DISORDERS OF EXOGENOUS CAUSES ASSOCIATED WITH ALTERED MELATONIN SECRETION PATTERN Disruption of the physiologic circadian rhythm due to changes in environmental conditions (e.g., shift work, sleep debt, exposure to light during the night, or transmeridian flights) results in clinical symptoms in parallel with alteration of melatonin secretion. Shift Work and Shift Work Sleep Disorder Shift working (or night work)—that is, working in the dark period normally devoted to sleep—is a major cause of desynchronization of biological rhythms and has multiple adverse clinical consequences including behavioral changes, sleep disorders, safety problems at work, altered hormonal and metabolic regulation, and susceptibility to hormonedependant cancers.59-62 Impairment of Attention Disturbances of attention have important implications in occupational medicine62,63 inasmuch as night work is becoming increasingly prevalent.64 Nowadays, nearly 20% of workers in industrialized countries are shift workers— that is, persons who work at night on regular or rotating schedules65—and 5% to 10% of them suffer from shiftwork sleep disorder (SWSD),66 defined as excessive sleepiness during nocturnal working hours with insomnia in the daytime sleep period. Loss of alertness during working
424 PART I / Section 5 • Chronobiology
hours, mainly in the early morning, has important safety issues in drivers, especially in long-haul truck drivers,67 and in night nurses or physicians on duty in emergency departments, who are prone to professional errors.59,68 Tolerance to longer or irregular night work varies among individuals69-71 according to their spontaneous flexibility to changes in biological rhythms,62,63,72 which itself can depend on genetic determinants.73,74 Various combinations of timed bright light, scheduled dark, and melatonin have been proposed to reset circadian rhythms and improve sleep quality in night-shift workers,75-77 with encouraging results.50 However, exposing people to light therapy at night can have unwanted effects by chronically inhibiting melatonin secretion, and administration of exogenous melatonin to night or shift workers has not been of proven benefit in real-life conditions, most probably due to nonoptimal timing and duration of the treatment. Increased Incidence of Hormone-Dependent Cancer The Nurses’ Health Study (NHS), involving a cohort of 78,562 nurses, showed a significantly increased incidence of breast cancer among those who worked on a rotating night shift schedule for 30 years or more.78 An increased risk of breast cancer has also been observed in women exposed to light during the night, either at home79 or at work, including nurses, airline flight attendants, and radio operators.80-83 This increased incidence in breast cancer appears to be related to the altered circadian regulation of melatonin that results from exposure to light during night hours. Indeed, melatonin has immunomodulatory and antioncogenic properties84 and has been shown to suppress growth of murine mammary tumors.85 A lower urinary excretion of 6-sulfatoxymelatonin was found in nurses working the night shift compared with those working the day shift. The plasma level of melatonin is decreased in night workers, and nurses who exhibited the lowest levels of melatonin were especially at risk for developing breast cancer.86 Metabolic Dysregulation Spiegel and colleagues87 evaluated the impact of sleep duration on the circadian profiles of plasma leptin, cortisol, thyroid-stimulating hormone (TSH), glucose, and insulin concentrations and on the sympathovagal balance. Sleep restriction (4 hours of sleep) resulted in a decreased nocturnal peak of leptin and TSH, concomitant with an elevated sympathovagal balance and an evening increase in cortisol level, together with higher plasma glucose levels during the first 90 minutes following breakfast despite a slight increase in plasma insulin, as compared with conditions of normal (8 hours) or extended (12 hours) sleep time. The same group reported that sleep restriction is associated with decreased leptin and increased ghrelin levels, concomitant with enhanced hunger and appetite.88 Thus, alterations in the neuroendocrine mechanisms involved in food regulation in sleep-deprived subjects concur to enhance appetite and favor the development of obesity, and epidemiologic studies have found an association between shift work and overweight.89-92 Moreover, sleep deprivation and shift work result in insulin resistance93-96 and thus favor the development of the metabolic syndrome and type 2 diabetes.97,98 Sleep restriction in
young healthy subjects to 4 hours per night for 5 consecutive nights resulted in symptoms of early-stage diabetes.99 Experimental sleep restriction has been associated with an increase in risk factors for cardiovascular disease such as high levels of C-reactive protein.100 Interestingly, a genetic variant near MTNR1B has been associated with increased fasting plasma glucose levels and risk for type 2 diabetes, representing a possible link between circadian rhythm and glucose homeostasis.101 Hypertension Neurohormonal dysregulation induced by sleep disorders alters the circadian rhythm of blood pressure and favors the development of hypertension.102 In a large longitudinal population study, self-reported short sleep duration (5 hours per night or less) was associated with a two-fold increase in the risk of incident hypertension.103 Hypertensive patients who lack the physiologic nocturnal decrease in blood pressure (nondippers) have a blunted nocturnal surge in melatonin secretion, and nocturnal administration of controlled-release melatonin significantly reduced systolic and diastolic blood pressure in such patients.104 In patients with moderately severe essential hypertension, repeated daily melatonin intake at bedtime significantly reduced systolic and diastolic nocturnal blood pressure and increased the day–night amplitude of the rhythms in systolic and diastolic pressures.105 However, in these patients it is essential to exclude sleep apnea syndrome. Transmeridian Flights and Jet Lag Disorder The rapid passage across multiple time zones in longdistance transmeridian air travel results in desynchronization of the internal circadian rhythm from the day–night status at the destination. The sudden disruption of the rest–activity cycle leads to a set of symptoms including insomnia, premature awakening, diurnal sleepiness, and loss of efficiency known as the jet lag disorder. Intensity of the disorder varies according to duration and intensity of flight, number of time zones crossed (usually seven or more) and individual tolerance.106 Eastward flights, which provoke a marked phase advance, are the most distressing.107 Besides unpleasant consequences for air flight passengers, jet lag is also problematic for airplane crew, with the risk of altered vigilance and reactivity. Various protocols involving timed bright-light exposure or melatonin administration, or both, have been tried in order to prevent or alleviate jet lag symptoms. Ideally, this timing should be adapted to the peculiar circadian phase of each person.108 Protocols have been specifically designed to phase advance the circadian rhythm of travelers planning eastward flights crossing nine or more time zones, including a 1-hour earlier wakeup time and bedtime every day for the 3 consecutive days preceding the flight, with 30 minutes of bright light on awakening and melatonin in the afternoon. In a randomized study, melatonin (either 0.3 or 3 mg) induced a significantly larger phase advance than did placebo (2.6 versus 1.7 hours).107 A comparative analysis of nine randomized trials has shown that melatonin taken close to the target bedtime at
CHAPTER 36 • Melatonin and the Regulation of Sleep and Circadian Rhythms 425
the destination (10 pm to midnight) decreased jet lag from flights using five or more time zones, the benefit being greater for eastward flights. Slow-release melatonin was less effective, suggesting that a higher peak concentration is more efficient.109
CIRCADIAN RHYTHM SLEEP DISORDERS OF ENDOGENOUS ORIGIN Circadian rhythm sleep disorders characterized by complaints of insomnia or daily sleepiness primarily result from alterations in the internal circadian timing system or misalignment between the normal timing of sleep and the 24-hour social and physical environment. The two main types of primary circadian rhythm sleep disorders include the advanced sleep phase syndrome (ASPS) and the delayed sleep phase syndrome (DSPS).42,110-112 Advanced Sleep Phase Syndrome In ASPS, most evening activity is preempted by an obligatory early bedtime with waking up at 3 am or earlier. This pattern is often observed among older people.113 It parallels the advanced rhythm of body core temperature and melatonin secretion peak114 resulting from endogenous alteration of the biological clock.115,116 Reduced photoreception can also occur in the disorder. In murine models of ASPS, administration of melatonin (1-3 mg/kg) or analogues restored or improved damped rhythm of body core temperature and locomotor activity.117 Melatonin 0.3 to 5 mg had no demonstrable effects in nonelderly adults. However, sleep quality was restored in 12 very old subjects (mean age, 76 years) with chronic insomnia and abnormally low 6-sulfatoxymelatonin peak excretion during the night thanks to daily administration of controlled-release melatonin.116 Delayed Sleep Phase Syndrome Delayed sheep phase syndrome (DSPS) is defined by abnormally late sleep and wake time with difficulty arising in time to fulfill morning obligations. The relative contribution of endogenous and exogenous factors underlying this phenomenon have not been fully delineated. This pattern is often observed in younger people with few rigidly scheduled work or social commitments (e.g., students or the unemployed); it is also common in night people (owls). Nowadays, a number of young people upset their circadian rhythms by sitting in front of a computer screen until late in the evening, thereby inhibiting secretion of endogenous melatonin and thus delaying the sleep– wake cycle. In cases of DSPS due to primary circadian sleep–wake dysregulation, melatonin peak secretion is spontaneously delayed. In a randomized, placebo-controlled study in eight such patients, exogenous melatonin (5 mg daily) given 5 hours before the patient’s normal bedtime induced onset of sleep 90 minutes earlier than with placebo.118 In another study, melatonin (5 mg) given in accordance with times of endogenous melatonin secretion advanced the sleeping time by a mean of 115 minutes and the waking time by 106 minutes.119 In a double blind, cross-over, placebo-controlled study of 25 patients with phase delay,
melatonin given 5 hours before the start of endogenous melatonin secretion advanced melatonin secretion by 90 minutes but advanced sleep onset by only 38 minutes.120 In a double-blind study in 40 children aged 6 to 12 years presenting with sleep-onset insomnia for at least 1 year, melatonin (5 mg) administered at 6 pm for 4 weeks advanced the time of sleep onset by a mean of 75 minutes and advanced the start of secretion of endogenous melatonin by 41 minutes; the treatment was well tolerated and was discontinued without problem.121 In another placebocontrolled study, melatonin (0.3 or 3 mg) given 1.5 to 6.5 hours before dim-light melatonin onset advanced the circadian phase of endogenous melatonin and sleep onset, an earlier time of administration being more effective.122 Melatonin-synchronizing effects were tested in children with severe neurodevelopmental diseases with and without epilepsy, who often suffer from disorganized circadian rhythms and DSPS. In a double-blind, placebo-controlled, cross-over trial in 51 children aged 2 to 18 years with neurodevelopmental disabilities, slow-release melatonin (5 mg) improved sleep latency and total sleep time, thus reducing stress in the family.123 Melatonin has also been used in children with attention-deficit/hyperactivity disorder (ADHD) with sleep-onset insomnia. In a randomized, double-blind, placebo-controlled trial in 105 of such children, melatonin advanced circadian sleep–wake rhythms and endogenous melatonin secretion, with enhanced total time asleep.124 However, determining the optimal parameters for scheduling and dosing melatonin will require more studies. Blindness Blind persons who are totally deprived of light perception have desynchronization of their biological rhythm to free running. Daily administration of melatonin in the evening is efficient to restore a normal rest–activity cycle.125 The effectiveness of melatonin therapy depends upon its time of administration relative to the timing of the patient’s circadian clock.126 Aging Aging is associated with alterations of sleep–wake timing, body core temperature, heart rate, blood pressure, and hormone secretion and higher incidence of type 2 diabetes or cancer. Many potential causes may be involved, including primary sleep disorder, depression, medical illness, or medications. However, age-related alteration of the biological clock and of circadian regulations appear to be the major causes of rest–activity dysregulation associated with insomnia in elderly subjects.113 Two randomized multicenter trials studied large (more than 300) numbers of insomnia patients aged 55 years and older using prolonged-release melatonin formulations. A 2-mg tablet taken 2 hours before bedtime showed significant improvement in sleep quality and morning alertness, shortened sleep latency, and absence of withdrawal effect at drug discontinuation.127-129 Some studies found a possible relationship between agerelated sleep disturbance and decreased melatonin secretion,40,130 and other studies found a similar reduction in
426 PART I / Section 5 • Chronobiology
melatonin secretion in poor and good sleepers.131 However, in a study on insomnia patients aged 55 years and older, those with lower excretion of melatonin had a higher response to melatonin replacement therapy.132
CENTRAL NERVOUS SYSTEM DISORDERS ASSOCIATED WITH ALTERATION OF MELATONIN SECRETION PATTERNS Pinealectomy Pinealectomy performed for pinealomas (which account for 3% to 8% of brain tumors in children) is followed by dramatically reduced or abolished melatonin secretion.133-135 In some cases, melatonin replacement therapy improves insomnia or hypersomnia.135 We recently observed six young adults who, following resection and radiotherapy of the pineal region for secreting germinomas, presented with insomnia136; one of them developed bipolar disorder and psychosis 2 years later together with severely disturbed sleep–wake rhythms. Replacement therapy with slow-release melatonin (2 mg daily over 1 to 2 months) at 9 pm was followed by an improvement in sleep quality and reduction of fatigue, a normalization of sleep–wake cycles, and an improvement of educational performance in all of those patients. The patient with psychosis was able to progressively stop antidepressants, antipsychotics, and anxiolytics 2 months after the beginning of slow-release melatonin treatment. This case may be considered in humans as a model of the essential role of melatonin secretion in regulating sleep. Alzheimer’s Disease Circadian rhythm disturbances have also been observed in patients with Alzheimer’s disease. Rest–activity rhythm disturbances manifest as fragmentation of the rhythm, weak coupling with zeitgebers, and high levels of activity during the night. Melatonin secretion rhythm is impaired by both age and cognitive impairment, with reduced nocturnal melatonin levels.137 These rest–activity disturbances can be improved by increasing environmental lighting and daytime activity.138 Mood Disorders It has long been observed that abnormalities in circadian rhythms are associated with mood disorders such as major depressive disorder, bipolar disorder, and seasonal affective disorder. Melatonin has been proposed as a combined marker for the susceptibility to develop affective disorders.139 Subtyping of affective disorders with respect to various markers (psychomotor symptoms, monoamine oxidase, cortisol, and melatonin plasma levels) allowed researchers to identify patients with latent bipolar disorder140 and thus may be of help for patient profiling. Other Pathologic Conditions In acute intermittent porphyria, patients with epileptic seizures exhibit a significantly lower melatonin urinary excretion compared with their relatives without epilepsy.141
In patients suffering from migraine, melatonin secretion is altered and relief of migraine following administration of melatonin has been reported.142 There is increasing evidence that headache disorders are connected with melatonin secretion and pineal function. Indeed, some headaches have a clear-cut seasonal and circadian pattern, such as cluster and hypnic headaches. Melatonin levels have been found to be decreased in both migraine and cluster headache.143 In the Smith-Magenis syndrome, a rare genetic disease resulting from a deletion on chromosome 17, clinical features include mild dysmorphism, short stature, various malformations, and mental retardation, which are associated with major behavioral disturbances and severe sleep disorder. In these children, the circadian rhythm of melatonin secretion is inversed, melatonin being abnormally secreted during the day. This represents the first biological model of behavioral and sleep disorder in a genetic disease.144 Treatment with b-blockers to reduce melatonin synthesis and nocturnal melatonin replacement have been shown to improve sleep and daytime behavior in these patients. Improvement of sleep or of daytime vigilance following administration of exogenous melatonin has been reported in conditions as varied as schizophrenia,145 insomnia following brain injury146 fibromyalgia,147 and periodic lower limb movement disorder,148 and insomnia associated with asthma149 or Parkinson’s disease.150-153
CONCLUSION The crucial importance of the temporal regulation of body functions was only recently recognized. Since the pioneer works on chronobiology in the 1970s, considerable progress has been made in the knowledge of central and peripheral clocks that govern circadian rhythmicity. The SCN is the master clock that governs circadian rhythms of biological processes. Melatonin is a key player in the regulation of the SCN in re-entraining its rhythmicity. The molecular substrate of the complex clock gene system has been identified. Simultaneously, clinical observation discovered the deleterious consequences of disruption of circadian rhythms, provoked by environmental conditions such as shift work, jet lag, or stress, of endogenous origin. Disrupted biological rhythms are associated with circadian rhythm sleep disorders, mood disorders, hypertension, obesity, type 2 diabetes, and cancer, all pathologic conditions of importance in terms of public health. The strong association between disruption of circadian rhythms and these pathologic manifestations led to the concept that restoring harmonious rhythmicity should improve the health of affected subjects. This applies particularly to circadian rhythm sleep disorders in which timed melatonin administration is of therapeutic interest, such as jet lag and DSPS. Nevertheless, large randomized, controlled clinical trials are still required to assess safety and efficacy of administration of exogenous melatonin (or agonists) in patients with sleep disorders related to disruption of the circadian wake–rest cycle.
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❖ Clinical Pearl Besides its role in resynchronizing the circadian system, melatonin may improve sleep in schizophrenia, traumatic brain injury, fibromyalgia, and Parkinson’s disease.
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122. Mundey K, Benloucif S, Harsanyi K, et al. Phase-dependant treatment of delayed sleep phase syndrome with melatonin. Sleep 2005;28(10):1271-1278. 123. Wasdell M, Jan J, Bomben M, et al. A randomized, placebocontrolled trial of controlled release melatonin treatment of delayed sleep phase syndrome and impaired sleep maintenance in children with neurodevelopmental disabilities. J Pineal Res 2008;44(1): 57-64. 124. van der Heijden BC, Smits M, van Someren EJ, et al. Effect of melatonin on sleep, behavior, and cognition in ADHD and chronic sleep-onset insomnia. J Am Acad Child Adolesc Psychiatry 2007; 46(2):233-241. 125. Skene DJ, Arendt J. Circadian rhythm sleep disorders in the blind and their treatment with melatonin. Sleep Med 2007;8(6):651-655. 126. Lewy AJ, Emens J, Lefler B, et al. Melatonin entrains free-running blind people according to a physiological dose-response curve. Chronobiol Int 2005;22(6):1093-1106. 127. Wade A, Ford I, Crawford G, et al. Efficacy of prolonged release melatonin in insomnia patients aged 55-80 years: quality of sleep and next-day alertness outcomes. Curr Med Res Opin 2007; 23(10):2597-2605. 128. Lemoine P, Nir T, Laudon M, Zisapel N. Prolonged-release melatonin improves sleep quality and morning altertness in insomnia patients aged 55 years and older and has no withdrawal effects. J Sleep Res 2007;16(4):372-380. 129. Wade A, Downie S. Prolonged-release melatonin for the treatment of insomnia in patients over 55 years. Expert Opin Investig Drugs 2008;10:1567-1572. 130. Haimov I, Laudon M, Zisapel N, et al. Sleep disorders and melatonin rhythms in elderly people. BMJ 1994;309(6948):167. 131. Lushington K, Dawson D, Kennaway DJ, Lack L. The relationship between 6-sulphatoxymelatonin and polysomnographic sleep in good sleeping controls and wake maintenance insomniacs, aged 55-80 years. J Sleep Res 1999;8:57-64. 132. Leger D, Laudon M, Zisapel N. Nocturnal 6-sulfatoxymelatonin excretion in insomnia and its relation to the response to melatonin replacement therapy. Am J Med 2004;116(2):91-95. 133. Vorkapic P, Waldhauser F, Bruckner R, et al. Serum melatonin levels: a new neurodiagnostic tool in pineal region tumors? Neurosurgery 1987;21(6):817-824. 134. Etzioni A, Luboshitzky R, Tiosano D, et al. Melatonin replacement corrects sleep disturbances in a child with pineal tumor. Neurology 1996;46(1):261-263. 135. Kocher L, Brun J, Borson-Chazot F, et al. Increased REM sleep associated with melatonin deficiency after pinealectomy: a case study. Chronobiol Int 2006;23(4):889-901. 136. Quera-Salva MA, Bensmail D, Hartley S, et al. Circadian rhythms in young adults following pinealectomy. Sleep 2008;31:0157. 137. Ferrari EA, Arcaini A, Gornati R, et al. Pineal and pituitaryadrenocortical function in physiological aging and in senile dementia. Exp Gerontol 2000;35(9-10):1239-1250. 138. van Someren EJ, Hagebeuk EE, Lijzenga C, et al. Circadian rest– activity rhythm disturbances in Alzheimer’s disease. Biol Psychiatry 1996;40(4):259-270. 139. Wahlund B. Melatonin in psychiatric disorders—subtyping affective disorder. Biol Signals Recept 1999;8(1-2):120-125. 140. Wahlund B, Grahn H, Saaf J, Wetterberg L. Affective disorder subtyped by psychomotor symptoms, monoamine oxidase, melatonin and cortisol: identification of patients with latent bipolar disorder. Eur Arch Psychiatry Clin Neurosci 1998;248(5):215-224. 141. Bylesjo I, Forsgren L, Wetterberg L. Melatonin and epileptic seizures in patients with acute intermittent porphyria. Epileptic Disord 2000;2(4):203-208. 142. Vogler B, Rapoport AM, Tepper SJ, et al. Role of melatonin in the pathophysiology of migraine: implications for treatment. CNS Drugs 2006;20(5):343-350. 143. Peres MF, Masruha MR, Zukerman E, et al. Potential therapeutic use of melatonin in migraine and other headache disorders. Expert Opin Investig Drugs 2006;15(4):367-375. 144. De Leersnyder H, de Blois MC, Bresson JL, et al. [Inversion of the circadian melatonin rhythm in Smith-Magenis syndrome]. Rev Neurol (Paris) 2003;159(11 Suppl.):6S21-6S26. 145. Shamir E, Rotenberg V, Laudon M, et al. First-night effect of melatonin treatment in patients with chronic schizophrenia. J Clin Psychopharmacol 2000;20(6):691-694.
430 PART I / Section 5 • Chronobiology 146. Kemp S, Biswas R, Neumann V, et al. The value of melatonin for sleep disorders occuring post-head injury: a pilot RCT. Brain Inj 2004;18(9):911-919. 147. Citera G, Arias M, Maldonado-Cocco J, et al. The effect of melatonin in patients with fibromyalgia: a pilot study. Clin Rheumatol 2000;19(1):9-13. 148. Kunz D, Bes F. Exogenous melatonin in peridic limb movement disorder: an open clinical trial and a physothesis. Sleep 2001;24(2): 183-187. 149. Campos F, da Silva-Junior F, de Bruin V, de Bruin P. Melatonin improves sleep in asthma: a randomized, double-blind, placebocontrolled study. Am J Respir Crit Care Med 2004;170(9):947-951.
150. Dowling G, Mastick J, Colling E, et al. Melatonin for sleep disturbances in Parkinson’s disease. Sleep Med 2005;6(5):459-466. 151. Medeiros C, Carvalhedo de Bruin P, et al. Effect of exogenous melatonin on sleep and motor dysfunction in Parkinson’s disease. A randomized, double blind, placebo-controlled study. J Neurol 2007;254(4):459-464. 152. Adi N, Mash DC, Ali Y, et al. Melatonin MT1 and MT2 receptor expression in Parkinson’s disease. Med Sci Monit 2010;16:BR61-7. 153. Aurora RN, Zak RS, Maganti RK, et al. Standards of Practice Committee; American Academy of Sleep Medicine. Best practice guide for the treatment of REM sleep behavior disorder (RBD). J Clin Sleep Med 2010;6:85-95.
Sleep Homeostasis and Models of Sleep Regulation Peter Achermann and Alexander A. Borbély Abstract Sleep homeostasis denotes a basic principle of sleep regulation. A sleep deficit elicits a compensatory increase in the intensity and duration of sleep, and excessive sleep reduces sleep propensity. It is as though sleep pressure is maintained within a range delimited by an upper and lower threshold. Sleep homeostasis is represented in the two-process model of sleep regulation by Process S, which increases during waking and declines during sleep. The timing and propensity of sleep are modulated also by a circadian process. Electroencephalographic (EEG) slow-wave activity (SWA) serves as an indicator of sleep homeostasis in non–rapid eye movement (NREM) sleep. The level of SWA, a correlate of sleep intensity, is determined by the duration of prior sleep and waking. Power in the range of sleep spindles exhibits in part an inverse relationship to SWA. In the waking EEG, theta activity shows a rising trend
Chapter
37
with the progression of wakefulness and might represent a marker of Process S. However, in contrast to SWA, theta activity undergoes a marked circadian modulation. Advanced versions of the two-process model were applied to simulate the SWA pattern in a variety of experimental schedules. Other models of sleep regulation have been proposed that are based on changes at the neuronal level or on formal mathematical considerations. Evidence has been accumulating for the existence of a local, use-dependent facet of sleep regulation. In humans and animals a selective unihemispheric regional cortical activation during waking gives rise to a predominant local increase of sleep intensity in the previously activated cortical region as reflected by SWA. The synaptic homeostasis theory has been advanced to account for these effects and their functional significance in the framework of brain plasticity.
Three distinct processes underlie sleep regulation. A homeostatic process, whose level is a function of prior sleep and waking, plays a major role in sleep regulation. Sleep is also modulated by a circadian process, a clocklike mechanism that is independent of prior sleep and waking. An ultradian process occurs within sleep and is represented by the alternation of the two basic sleep states: non–rapid eye movement (NREM) sleep and rapid eye movement (REM) sleep. One of the main topics of this chapter is sleep homeostasis. Homeostasis has been defined as “the coordinated physiological processes, which maintain most of the steady states in the organism.”1 The term sleep homeostasis2 refers to the aspect of sleep regulation dependent on sleep–wake, as homeostatic mechanisms counteract deviations from an average reference level of sleep. These mechanisms augment sleep propensity when sleep is curtailed or absent, and they reduce sleep propensity in response to excess sleep. The interest in the modeling approach to sleep regulation has increased since the turn of the century. Models help delineate the processes involved in the regulation of sleep and thereby offer a conceptual framework for the analysis of existing and new data.3 Reviews of modeling circadian oscillators are provided by Roenneberg and colleagues4 and Beersma.5
waves of the electroencephalogram (EEG). One of the most important functional EEG parameters is referred to as slow-wave activity (SWA). It is equivalent to delta activity and encompasses components of the EEG signal in the frequency range of approximately 0.5 to 4.5 Hz as obtained by spectral analysis.6 In addition to delta waves, a low-frequency component with a mean peak value of 0.7 to 0.8 Hz is present in the EEG power spectrum of NREM sleep.7,8 The typical decline in delta activity from the first to the second NREM sleep episode is not present at frequencies below 2 Hz.7 This could indicate that the low-frequency component reflects a separate process that differs from the one represented by delta activity. Alternatively, the results could be due to a frequency shift in the course of sleep.9 The changes of the low-frequency component in response to naps did not differ from those of SWA.10 Increased sleep pressure resulted in a redistribution of waves between 0.5 and 2 Hz: The number of waves per minute was reduced below 0.9 Hz while they were increased above 1.2 Hz; EEG power was increased only above 1 Hz.11 Periodicities at even lower frequencies include the recurrence of sleep spindles at 4-second intervals,7,12 the tendency of slow waves to recur at 20- to 30-second intervals,7 and a cortical infraslow oscillation (0.02 to 0.2 Hz).13
HOMEOSTATIC REGULATION OF SLEEP Electroencephalographic Slow-Wave Activity: A Physiologic Indicator of NREM Sleep Homeostasis Slow-Wave Sleep and Slow-Wave Activity NREM sleep is not a homogeneous substate of sleep but can be subdivided according to the predominance of slow
Slow Waves and Sleep Intensity It was recognized as early as 1937 that sleep intensity is reflected by the predominance of slow waves in the sleep EEG.14 Subsequent studies confirmed that the responsiveness to stimuli decreases as EEG slow waves become more predominant.15 Under physiologic conditions, this EEG parameter can be regarded therefore as an indicator of sleep depth or sleep intensity (for sleep intensity in animals, see Chapter 9). 431
432 PART I / Section 5 • Chronobiology
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Figure 37-1 Left, Changes of relative spectral power density over the first four NREM-REM sleep cycles of a baseline night (N = 8). In each frequency bin the data are expressed relative to the value in the fourth cycle (100%; horizontal line). Right, Effect of sleep deprivation (40.5 hours waking) on spectra of the sleep EEG. In each bin, the values of the first two recovery nights are plotted relative to the baseline night (100%). The upper and lower horizontal bars below the abscissa indicate for the left part significant differences between cycle 1 and 2, and between cycle 2 and 3, respectively, and for the right part between recovery 1 and baseline, and between recovery 2 and baseline, respectively. EEG, electroencephalogram; NREM, non– rapid eye movement; REM, rapid eye movement. (Modified from Borbély AA, Baumann F, Brandeis D, et al. Sleep deprivation: effect on sleep stages and EEG power density in man. Electroencephalogr Clin Neurophysiol 1981;51:483-493.)
Global Time Course of Slow-Wave Activity during Sleep Slow-wave sleep (SWS, the high-intensity part of NREM sleep) appeared to be a good candidate for a physiologic marker of sleep homeostasis. The predominance of SWS in the early part of the sleep episode was documented in several early studies.15-17 All-night spectral analysis of the sleep EEG made it possible to quantify SWA and to delineate its time course during sleep.6 Its mean value per cycle plotted for consecutive NREM–REM sleep cycles showed a monotonic decline over the first three cycles. Figure 37-1 (left) shows the changes of mean EEG power density over four cycles for the frequency range between 0.25 and 20 Hz. The values of each bin are expressed relative to the reference level of cycle 4 (100%). Note that although the largest changes occur in the low delta range, they encompass frequencies up to the theta band. Nap Studies The analysis of daytime naps is useful for assessing the level of SWA after various durations of waking. Naps taken later in the day contained more SWS than naps taken earlier in the day. In a detailed study of daytime naps scheduled at 2-hour intervals throughout the day, direct evidence for a monotonic rise of SWA over the course of the day was obtained.10,18-20 If naps reverse the rising trend
0 1 2 3 4 5 6 7 8 9 1011121314 Hours after lights off
Figure 37-2 Time course of slow-wave activity (power in the 0.75- to 4.5-Hz band; lower curves) and activity in the spindle frequency range (13.25- to 15.0-Hz; upper curves) recorded under baseline conditions and after sleep deprivation (36 hours of wakefulness). NREM sleep episodes were subdivided into 20 equal intervals and REM sleep episodes were divided into 5 intervals. Mean values per interval were calculated before averaging across subjects (N = 8 except for cycle 8 of recovery sleep, where N = 6) and were expressed relative to the mean level in baseline NREM sleep (100%). The mean timing of REM sleep episodes is delimited by vertical lines and horizontal bars above the abscissa. EEG, electroencephalogram; NREM, non– rapid eye movement; REM, rapid eye movement. (Reanalysis of the data from Dijk DJ, Brunner DP, Borbély AA. Time course of EEG power density during long sleep in humans. Am J Physiol 1990;258:R650–R651, by D. Aeschbach.)
of slow-wave propensity, a reduction of SWA in the subsequent nighttime sleep can be expected. This prediction was borne out by the results of several experiments (see reference 21 for literature references). Furthermore, when the duration of nighttime sleep was shortened, SWA in a subsequent morning nap was enhanced.22,23 Effect of Sleep Deprivation It has repeatedly been shown that partial or total sleep deprivation gives rise to increased SWS in the recovery night (see reference24 for a review of the older literature). Webb and Agnew17 presented compelling evidence that SWS increases as a function of prior waking. The quantitative assessment of SWA using all-night spectral analysis revealed that a night without sleep (i.e., 40.5 hours of wakefulness) resulted in an enhancement of this EEG parameter during recovery sleep.6 Figure 37-1 (right) illustrates the changes of power density in the two recovery nights relative to the baseline level (100%). In the first recovery night, the largest increase was present in the low delta range, the part of the spectrum undergoing the largest changes in the course of baseline sleep (see Fig. 37-1, left). Figure 37-2 depicts the global trend as well as the ultradian dynamics of SWA over successive NREM–REM sleep cycles. The prolongation of the waking period causes a prominent rise of SWA during recovery sleep. A declining trend over three to four cycles is evident in both records. Note that the peaks are at a steady and low level during the last four cycles of recovery sleep.
CHAPTER 37 • Sleep Homeostasis and Models of Sleep Regulation 433
The enhancement of SWA by sleep deprivation was confirmed in several studies25,26 (for references before 1992, see reference 27; for animals, see Chapter 9). The extent of the increase was shown to be a function of the duration of prior waking.20,28 Intranight Rebound after Selective Slow-Wave Deprivation The propensity of SWA does not necessarily dissipate during sleep but may persist at an elevated level if SWS is prevented. Thus suppression of slow waves by acoustic stimuli during the first 3 hours of sleep resulted in a prominent rise of SWA after the stimuli were discontinued.29 In another study, daytime sleep episodes with and without SWS deprivation were compared.30 The experimental suppression of SWS during an interval corresponding to 90% of the undisturbed episode resulted in an increased accumulation of SWS and an extension of sleep duration. Topographic studies revealed regional differences in the effectiveness of and response to selective SWS deprivation.31 Taken together, the results indicate that slow waves are not merely an epiphenomenon of sleep but reflect major sleep-regulating mechanisms. Ultradian Dynamics of Slow-Wave Activity and Spindle-Frequency Activity Buildup of Slow Wave Activity within NREM Sleep Episodes Not only are the mean level and the peak of SWA determined by the duration of prior waking and sleep but also the rise rate within single NREM sleep episodes.32-34 It is evident from Figure 37-2 that the rise rate of SWA decreases over the first three episodes both under baseline conditions and during recovery from sleep deprivation. In addition, the effect of prolonged waking manifests itself in a steeper buildup of SWA within NREM sleep episodes.25,26,34 A decrease in the slope of single slow waves was associated with a reduction of sleep pressure during sleep in humans and animals,35,36 a change that could be simulated in a model by reducing synaptic strength.37 However, amplitude and slope of slow waves were highly correlated in the 0.5 to 2 Hz range.11 Slow-Wave Activity and Spindle-Frequency Activity The term spindle-frequency activity (SFA) is used to denote the power in the frequency range of sleep spindles (12 to 15 Hz). There is a close correspondence between this measure and measures based on the occurrence of sleep spindles.25 The time courses of SWA and SFA differ in several respects. The global decline of SWA does not occur in the spindle frequency range. Within NREM sleep episodes, SFA shows a bimodal pattern with an initial and a terminal peak. This gives rise to a U-shaped curve within the episode and a partly inverse relationship to SWA (see Fig. 37-2).25,38-43 Regulation of REM Sleep The principles underlying REM sleep regulation seem to be more complex than those for NREM sleep regulation. This was evident in a selective REM sleep–deprivation experiment,44 where two salient observations were made
that were difficult to reconcile. On the one hand, REM sleep deprivation necessitated a dramatic rise in the frequency of interventions during the night to prevent this sleep state. On the other hand, there was a modest rise in the number of interventions across the three consecutive deprivation nights, and the 40% REM sleep rebound in the first recovery night by no means compensated for the amount of REM sleep lost. Two hypotheses were advanced. In the first, it is assumed that the homeostatic drive is strong, which is reflected by the dramatic rise in interventions during the deprivation nights. Waking may in part substitute for REM sleep, thereby accounting for the moderate night-to-night increase in interventions and the small REM sleep rebound. According to the second hypothesis, the homeostatic drive for REM sleep is weak and the rising trend in the number of interventions is attributed to circadian factors as well as to a sleep-dependent disinhibition of REM sleep propensity. This hypothesis could explain the limited savings from one night to the other as well as the modest rebound. A novel facet of REM sleep regulation was revealed in a selective REM sleep–deprivation study.45 Muscle atonia, the hallmark of REM sleep, was shown to occur also in NREM sleep. Its distribution exhibited features suggesting an association with REM sleep regulation. Thus atonia in NREM sleep showed a bimodal pattern after sleep onset, a declining trend when sleep began in the morning, and an initial enhancement after selective REM sleep deprivation. The results suggested the possibility that the NREM sleep state characterized by atonia might contribute to the compensation of a REM sleep deficit. Also a follow-up study supports the notion that NREM sleep with atonia can be used as a marker of the homeostatic and circadian REM sleep regulation.46 NREM versus REM Sleep Homeostasis Effect of NREM Sleep Pressure on REM Sleep Homeostasis During recovery from total sleep deprivation, SWS and EEG SWA exhibit an immediate rebound, whereas the increase in REM sleep is delayed to subsequent nights or is not present at all. Selective REM sleep deprivation augments REM sleep pressure, which is manifested by the increasing number of interventions required to prevent REM sleep episodes (for the older literature, see references in reference 24). However, the occurrence of a REM sleep rebound during recovery sleep is smaller than expected on the basis of the deficit.44,47 This suggests that REM sleep is not as finely regulated as SWS. However, this notion is contradicted by partial sleep-deprivation studies. A REM sleep deprivation in the first 5 hours of sleep induced a REM sleep rebound in the subsequent 2.25 hours.48 A curtailment of sleep duration during two or four nights, which induced a substantial REM sleep deficit, was followed by a REM sleep rebound in the two recovery nights.49,50 In these experiments, the REM sleep rebound occurred at a time when slow wave pressure was either low at the end of sleep48 or was much less increased than REM sleep pressure.49,50 These results also suggest that REM sleep is indeed regulated but that the manifestation of REM sleep homeostasis is hampered by an elevated slow wave pressure.
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Figure 37-3 A, Relationship between homeostatic markers of the sleep EEG and waking EEG. Increase (%) of SWA (0.75 to 4.5 Hz) in the first NREM sleep episode from baseline to recovery sleep is plotted as a function of the rise rate (%/hr) of theta power (5.0 to 8.0 Hz) in waking. The linear regression line fitted through seven data points is indicated (r = 0.851, r2 = 0.724, P = .015). Subject #10 was excluded from the regression. B, Association between rise of SWA in sleep and theta activity in waking illustrated for two subjects. Mean SWA per NREM sleep episode is plotted at the beginning of each episode and expressed relative to the baseline value of the first NREM sleep episode (100%). Exponential functions were fitted through the data points (solid curves). The regression line represents theta power in waking (interrupted line). C, Topographic distribution of the rise rate of theta power (top) during waking and of the increase of SWA (bottom) in the first NREM sleep episode from baseline to recovery sleep. Maps are based on 27 EEG derivations (average reference; extended 10-20 system). Values are plotted on a color scale at the corresponding position on the planar projection of the hemispheric scalp model. Values between electrodes were linearly interpolated. EEG, electroencephalogram; NREM, non–rapid eye movement; REM, rapid eye movement; SWA, slow-wave activity. (Adapted from Finelli, LA, Baumann H, Borbély AA, Achermann P. Dual electroencephalogram markers of human sleep homeostasis: correlation between theta activity in waking and slow-wave activity in sleep. Neuroscience 2000;101:523-529).
Effect of REM Sleep Pressure on the NREM Sleep EEG In accordance with the notion of a mutual inhibitory interaction of the factors controlling SWA and REM sleep,24 not only is REM sleep is inhibited by slow-wave pressure but SWA is also inhibited by REM sleep pressure. Thus, selective REM sleep deprivation led to a significant reduction in the low-frequency activity of the NREM sleep EEG,48 an observation that was also made in an animal experiment.51 The rise in REM sleep pressure induced by repeated partial sleep deprivation suppressed the typical low-delta peak in the NREM sleep spectrum.49,50 However, this effect was not seen after selective REM sleep deprivation.44 Homeostatic Marker in the Waking Electroencephalogram It had been shown in early studies that power in the theta band (theta activity) and alpha activity of the waking EEG is associated with sleepiness52,53 and that total53 or partial
sleep deprivation50 enhanced the power in these frequency bands. A saturating exponential function with a time constant of 18.18 hours was reported to fit the rise of theta activity in the waking EEG.54 Spectral analysis showed that the largest changes occurred in the theta band (see reference 55 for review).56 These undergo a circadian modulation in addition to the changes related to wake time.56-60 During prolonged wakefulness, subjective sleepiness correlated positively with theta activity with a focus in frontal derivations and negatively with alpha activity at all derivations.61 A forced desynchrony study with a scheduled waking episode of 28 hours showed a monotonic rise of delta and beta activity in the frontocentral derivation.60 An analysis of persons subjected to sleep deprivation revealed that the rise rate of theta activity in the waking EEG is correlated with the increase of SWA in the first NREM sleep episode of recovery sleep (Fig. 37-3A and B).56 Moreover, both effects were largest in frontal areas (see Fig. 37-3C). In summary, theta activity in waking and SWA in sleep may be markers of a common homeostatic sleep process.
CHAPTER 37 • Sleep Homeostasis and Models of Sleep Regulation 435
Independence and Interactions of Homeostatic and Circadian Processes There is evidence that homeostatic and circadian facets of sleep regulation can be independently manipulated and therefore may be controlled by separate mechanisms. Thus, throughout a 72-hour sleep-deprivation period, the subjective alertness ratings continued to show a prominent circadian rhythm.62 Conversely, in a study in which the phase of the circadian process (as indexed by body tem-
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perature and plasma melatonin) was shifted by bright light in the morning, the time course of SWA remained unaffected.63 A powerful experimental paradigm is the forced desynchrony schedule in which the homeostatic and circadian facet of sleep can be separately analyzed.64 In this longterm protocol, the imposed sleep-waking cycle (e.g., 20 hours or 28 hours) lies outside the range of entrainment of the circadian pacemaker. When this schedule is maintained for 3 weeks, sleep occurs at different circadian phases. The contributions of the homeostatic and circadian components can be estimated by folding the data of the variable investigated either at the period of the imposed sleep-waking cycle or at the period of circadian rhythm. Various claims of the two-process model were supported by the results obtained in this paradigm.64 As shown in Figure 37-4, the variation of SWA is accounted for mainly by homeostatic (i.e., sleep–wake dependent) factors, whereas the percentage of REM sleep, NREM sleep, SFA (sigma activity), and sleep consolidation are determined by both homeostatic and circadian factors. Furthermore, a previously postulated sleep-related disinhibition of REM sleep24 was confirmed. Differences in homeostatic markers were observed between morning-type and evening-type persons.65-67 It is important to consider the different light exposure between extreme morning-type and evening-type persons in the interpretation of the findings.68 The role of the metrics used and whether homeostatic and circadian processes exhibit a linear or a nonlinear interaction are still under discussion.69 In the rat, sleep deprivation was shown to affect the discharge rate of
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Figure 37-4 Circadian and sleep-dependent or homeostatic factors in sleep regulation. The main effects of circadian phase and sleep homeostasis on sleep were analyzed by aligning the data relative to the circadian component of the body temperature cycle (left panels) or the beginning of the sleep opportunity (right panels). Slow-wave activity shows weak circadian and strong sleep-dependent modulation; sigma (sleep spindle) activity shows strong circadian and sleep-dependent modulation. NREM sleep percentage shows equal circadian and sleepdependent component. REM sleep percentage shows marked circadian maximum just after the temperature nadir and sleepdependent increase (disinhibition). Wakefulness in scheduled sleep episodes shows that the circadian drive for wakefulness is maximal 7 to 9 hours before temperature nadir, which is 1 to 3 hours before habitual bedtime; there is a strong wakedependent increase. Sleep latency shows strong circadian modulation; the longest sleep latencies occur 7 to 9 hours before the body temperature nadir, and the shortest sleep latencies occur at the body temperature nadir. NREM, non–rapid eye movement; REM, rapid eye movement; TST, total sleep time. (Modified from Dijk DJ, Czeisler CA. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves and sleep spindle activity in humans. J Neurosci 1995;15:3526-3538; and Dijk DJ, Czeisler CA. Paradoxical timing of the circadian rhythm of sleep propensity serves to consolidate sleep and wakefulness in humans. Neurosci Lett 1994;166:63-68. This figure corresponds to Figure 34-4 of Dijk DJ, Franken P. Interaction of sleep homeostasis and circadian rhythmicity: dependent or independent systems? In: Kryger MH, Roth T, Dement WC. Principles and practice of sleep medicine. 4th ed. Philadelphia: Elsevier Saunders; 2005:418-434.)
436 PART I / Section 5 • Chronobiology Table 37-1 Two-Process Model and Related Models DESIGNATION
ASSUMPTION
DESCRIPTION AND COMMENT
Two-process model24,73,76,77
Sleep propensity is determined by a homeostatic Process S and circadian Process C. The interaction of S and C determines the timing of sleep and waking.
Time course of S derived from EEG slow-wave activity; phase position and shape (skewed sine wave) of C derived from sleep duration data obtained at various times of the 24-hr cycle.
Model of ultradian variation of slow-wave activity78-80
Derived from the two-process model. The level of S determines the buildup rate and the saturation level of slow-wave activity within NREM sleep episodes.
In contrast to the original two-process model, the change of S, not the level of S, corresponds to slow-wave activity; i.e., the decline of S is proportional to the amount of slow-wave activity. A REM sleep oscillator triggers the decline of slow-wave activity prior to REM sleep.
Three-process model of sleepiness– alertness regulation87-89,143
Sleepiness and alertness are simulated by the combined action of a homeostatic process, a circadian process, and sleep inertia (Process W). Extension to include performance, sleep latency, and sleep length. Adaptation of homeostatic process to account for performance prediction in sleep-restriction protocols.
Parameters derived from rated sleepiness during sleep–wake manipulations. Alertness normogram for sleep-related safety risks.
Interactive mathematical models of alertness and cognitive throughput90
Alertness and cognitive throughput are determined by a nonlinear interaction of a homeostatic (H) and a circadian (C) process. Sleep inertia is also included. H shows a sigmoidal decline during waking and a saturating exponential increase during sleep at a rate determined by the circadian phase.
Parameters derived from sleep-inertia studies, sleep-deprivation studies initiated across all circadian phases, and 28-hr forced desynchrony studies.
NREM, non–rapid eye movement; REM, rapid eye movement.
neurons in the SCN.70 However, it has not been shown that the effect is restricted to the SCN and does not occur outside this structure.
sleep. The following synopsis is restricted to major models that include a mathematical description. Their main features are summarized in Tables 37-1 to 37-3.
MODELS OF SLEEP REGULATION Models help delineate the processes involved in the regulation of sleep and thereby offer a conceptual framework for the analysis of existing and new data. In addition, they inspire new experiments to test the predictions of the models. Models may address processes at different levels (from the microscopic [cellular] level to the macroscopic [systemic] level) and at different time scales (from the range of milliseconds or seconds up to hours or days). Being aware of the power and limitations of models is important for selecting the most appropriate one for the question to be addressed. Process-oriented models such as the twoprocess model can deal with the dynamics of sleep regulation at the systemic level and account for responses on a time scale of minutes to hours. In contrast, neuronal models are appropriate for explaining specific features of the sleep EEG such as the generation of slow waves or sleep spindles. The term model has been loosely applied to hypothetical descriptions of events, features, and processes related to
Two-Process Model and Related Models The two-process model and related models are summarized in Table 37-1. Further models inspired by the twoprocess model addressing performance simulations were discussed in a special issue of Aviation, Space, and Environmental Medicine71 and elsewhere.3,27,55,72,73 The relationship between SWS and the duration of prior waking has been documented by Webb and Agnew17 and placed into a theoretical framework by Feinberg.74 The two-process model, originally proposed to account for sleep regulation in the rat,2,75 postulates that a homeostatic process (Process S) rises during waking and declines during sleep, and it interacts with a circadian process (Process C) that is independent of sleep and waking. The time course of the homeostatic variable S was derived from EEG SWA (Fig. 37-5A). Various aspects of human sleep regulation were addressed in a qualitative version of the two-process model.24 An elaborated, quantitative version of the model was established in which Process S varied between an upper and a lower threshold that are both modulated by a single circadian process.76,77 This model was able to account for such diverse phenomena as recovery from sleep depri-
CHAPTER 37 • Sleep Homeostasis and Models of Sleep Regulation 437
Table 37-2 Models Based on Detailed Neuronal Architecture Describing (Sleep) EEG Phenomena and Their Underlying Mechanisms DESIGNATION
ASSUMPTION
DESCRIPTION/COMMENT
Model of sleep and wakefulness in the thalamocortical system37,112,144
Large-scale computer model (65,400 neurons; 4,860,450 connections) encompassing portions of two visual areas and associated thalamic and reticular thalamic nuclei. Primary thalamocortical circuits include a morphological three-layered primary visual cortical area, reticular nucleus, and dorsal thalamus and secondary visual area (with its associated thalamic sectors)
Waking mode: model exhibits irregular spontaneous firing and selective responses to visual stimuli Sleep mode: neuromodulatory changes lead to slow oscillations Simulation of TMS effects in modified model encompassing three-layered motor cortex Modeling the effects of synaptic strength on slow waves
Model of thalamocortical slow-wave sleep oscillations and transitions to activated states145
Four-layered one-dimensional thalamocortical network (225 neurons) consisting of cortical pyramidal cells, interneurons and thalamocortical and thalamic reticular neurons
Model captures many essential features of NREM sleep and activated states in the thalamocortical system and transitions between the states
Cellular and network mechanisms of slow oscillatory activity (<1 Hz) and wave propagations in a cortical network model146
One-dimensional strip of cortical neurons (1024 pyramidal cells and 256 interneurons) equidistantly distributed and interconnected by biologically plausible synaptic dynamics
Biophysical network model of slow oscillations. Reproduces single neuron behavior and collective network firing patterns in control conditions as well as under pharmacologic manipulations
Neuronal basis of the slow (<1 Hz) oscillation in NRT neurons113,147
Biophysically realistic model of a single NRT neuron Single-compartment Hodgkin and Huxley type of model including various voltage and intracellular ion-gated currents
Reliable simulation of main features of slow oscillations including membrane potential inflections at transitions from up to down states, slow depolarization during down state, presence of rhythmic LTCP burst sequences at switch from down to up state, and decelerating tonic firing during the up state
LTCP, low-threshold Ca2+ potentials; NREM, non–rapid eye movement; NRT, nucleus reticularis thalami; TMS, transcranial magnetic stimulation.
vation, circadian phase dependence of sleep duration, sleep during shift work, sleep fragmentation during continuous bed rest, and internal desynchronization in the absence of time cues.77 In a later version of the model (proposed by Beersma and colleagues18 and Dijk and colleagues29 and formalized by Achermann and Borbély78,79) it is the change of S, and not its level, that is proportional to the momentary amount of SWA. The elaborated model addressed not only the global changes of SWA as represented by Process S but also the changes within NREM sleep episodes. In general, a close fit was obtained between the simulated and empirical SWA data and their time course (see Fig. 37-5D). In particular, the occurrence of late SWA peaks during extended sleep could be simulated (see Fig. 37-5C). The simulations demonstrated that the model accounts in quantitative terms for empirical data and predicts the changes induced by the prolongation of waking or sleep. This version of the model was used to simulate the dynamics of SWA in an experimental protocol with an early evening nap21 and the effect of changes in REM sleep latency on the time course of SWA.80 The model was recently applied to simulate sleep in narcoleptic patients.81 Zavada and coworkers82 used this model’s approach to investigate regional aspects of sleep homeostasis.
Finally, the data analysis showed that not only the timing of sleep but also the changes in daytime vigilance are governed by the interaction of Processes S and C, as simulated by Daan and colleagues.77 The rising homeostatic sleep pressure during waking seems to be compensated by the declining circadian sleep propensity.77,83-85 Conversely, during sleep the rising circadian sleep propensity might serve to counteract the declining homeostatic sleep pressure, thereby ensuring the maintenance of sleep.86 Based on a similar concept, the changes of subjective sleepiness and alertness ratings were simulated by a combined action of a homeostatic Process (S), a circadian Process (C), and a process representing sleep inertia (W) (three-process model; see Table 37-1).87,88 The model has been expanded89 to account for discrepancies observed in experiments of chronic sleep restriction. Jewett and Kronauer (see Table 37-1)90 proposed interactive mathematical models of subjective alertness and cognitive throughput in humans. A homeostatic component (H) falls in a sigmoidal manner during waking and rises in a saturating exponential manner during sleep. The rise of H during sleep is determined by the circadian phase. H interacts with a circadian component (C),91 accounting for the effect of light on the circadian pacemaker. The amplitude of C depends on the level of H.
438 PART I / Section 5 • Chronobiology Table 37-3 Intermediate-Level Network Models Capturing Essential Features of Sleep–Wake Dynamics and EEG Phenomena DESIGNATION
ASSUMPTION
DESCRIPTION/COMMENT
Quartet neural system of sleep and wakefulness115
Neural system consisting of sleepactive preoptic or anterior hypothalamic neurons (N-R group); wake-active hypothalamic and brain stem neurons (WA group); brainstem neurons (REM group); and basal forebrain, hypothalamic, and brainstem neurons (W-R group) WA neurons have mutual inhibitory couplings with REM and N-R neurons. W-R neurons have mutual excitatory couplings with WA and REM neurons. REM neurons receive unidirectional inhibition from N-R neurons. N-R neurons are activated by sleeppromoting substances
Model reproduced sleep and wakefulness patterns of rats Human sleep-wakefulness rhythms were simulated by adapting a few model parameters
Quantitative model of sleep–wake dynamics based on physiology of the brainstem ascending arousal system114
Quantitative, physiology-based model of ascending arousal system using continuum neuronal population modeling Model includes VLPO (where circadian and homeostatic drives enter the system), monoaminergic and cholinergic nuclei of the ascending arousal system, and corresponding interconnections
Simulation of human sleep–wake cycle with physiologically reasonable voltages and firing rates Mutual inhibition between wakepromoting monoaminergic group and sleep-promoting VLPO causes flip-flop behavior
Mathematical model of network dynamics governing mouse sleep–wake behavior 116,148
Sleep–wake network composed of coupled relaxation oscillation equations Network includes wake-, sleep-, and REM sleep–promoting populations
Simulation of dynamics underlying state transitions and predictions of mechanisms of transitions Incorporation of orexin signaling
The K-complex and slow oscillation in terms of a mean-field cortical model117
Mean-field macrocolumn model of the cerebral cortex Incorporation of Hebbian-type learning rule
Interpretation of K-complex as momentary excursion of cortex from stable low-firing state to unstable high-firing state Hypothesis that slow oscillation can be considered as periodic oscillation between two metastable solutions of the mean-field model
Contribution of lamina 5 neuronal and network dynamics to lowfrequency EEG phenomena149
Principal intrinsic properties of neocortical cells in layer 5 and their network behavior in simplified simulation
Emergence of several important EEG phenomena such as alpha rhythms, slow-wave sleep oscillations, and some form of cortical seizure Prediction of ability of layer 5 cells to produce resonance-like neuronal recruitment known as augmenting response
Network model for activitydependent sleep regulation118
Local sleep states evolve through integration of local activity inputs, loose couplings with neighboring cortical columns, and global regulation (e.g., by the circadian input)
Sleep is considered as emerging from the local sleep states of functional units (cortical columns)
NREM, non–rapid eye movement; REM, rapid eye movement, VLPO, ventrolateral preoptic area.
In addition, a sleep inertia component (W) is included. In contrast to the two- and three-process models, a nonlinear interaction is assumed. Whether the interaction is linear or nonlinear is still unresolved.92,93 A statistical approach to test for nonlinear interactions was proposed69 and is based on a comparison of model predictions and empirical data.
Experiments with chronic sleep restriction demonstrated that the homeostatic sleep drive is not associated with neurobehavioral performance.94 The latter showed a cumulative impairment with a considerable degree of individual variability. To account for the slow recovery of neurobehavioral functions after sleep deprivation, the possibility of a second homeostatic process with a very long
CHAPTER 37 • Sleep Homeostasis and Models of Sleep Regulation 439
SWA (%)
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Figure 37-5 Two-process model of sleep regulation. A, Simulations of the homeostatic Process S according to different experimental conditions. The blue line indicates baseline condition with an 8-hour sleep episode; the red line indicates sleep deprivation (40 hours of wakefulness) and recovery sleep; the dashed line indicates the effect of a 2-hour daytime nap at 18:00 hr. B, Sleep regulation in the mouse. Time course of slow-wave activity (SWA) and simulation with the optimized time constants for the increase (Ti) and decrease (Td) and initial value (IV) of Process S for C57BL/6J mice (n = 8). Curves and shaded areas connect 1-hour mean values (± SEM) for 24-hour baseline, 6-hour sleep deprivation and 18-hour recovery. The close fit between the simulation of Process S (pink areas) and time course of empirical SWA (solid line) indicates that the model can predict SWA from the temporal organization of sleep. Diamonds indicate differences between simulation and data (P < .05; two-tailed paired t-test). For the comparison between SWA and S, SWA was transformed according to a linear regression. Inset: Mean values of Ti, Td and IV (SEM) and the mean r-value of the fit between SWA and S. C, Empirical SWA (top), sleep stages (center), and simulation of slow-wave activity (SWA) and Process S (bottom) of an individual extended baseline sleep episode starting at 00:00 hr (prior waking: 17 hours). Empirical and simulated SWA were standardized with respect to the mean value of the first 7 hours of sleep. Values are plotted for 1-minute intervals. D, Mean empirical (blue line) and simulated SWA (pink line) (n = 8) of an extended baseline experiment (analysis of first 8 hours). Significant differences are indicated by open circles (paired t-test; P < .05). Bars on top and the interrupted vertical lines indicate REM sleep episodes (mean values). REM, rapid eye movement. (B modified from Huber R, Deboer T, Tobler I. Effects of sleep deprivation on sleep and sleep EEG in three mouse strains: empirical data and simulations. Brain Res 2000;857:8-19. C and D modified from Achermann P, Dijk DJ, Brunner DP, Borbély AA. A model of human sleep homeostasis based on EEG slow-wave activity: quantitative comparison of data and simulations. Brain Res Bull 1993;31:97-113).
time constant was considered.95 McCauley and colleagues96 expanded the two-process model to a broader class of models that have a dynamic repertoire capturing waking neurobehavioral functions across a wide range of wake– sleep schedules. Models of sleep, fatigue, and performance based in large part on the two-process model are presented in a special issue of Aviation, Space, and Environmental Medicine.71 Kronauer and colleagues have added a nonphotic component to their light-based model of the human circadian pacemaker.97 The nonphotic input was a square waveform
of the sleep–wake cycle. With this extension, the authors account for changes in the circadian pacemaker in response to variations of the sleep–wake schedule. However, they are careful to point out that the effects reported in the literature are not necessarily due to sleep per se, but possibly to other factors related to the timing of the sleep– wake cycle (e.g., motor activity, posture, food intake). Most of these models are generally based on average data limiting prediction of individual performance. Current models of performance can address individual differences only if individuals were characterized in advance. Two
440 PART I / Section 5 • Chronobiology
approaches to predict individual performance in sleepdeprivation experiments have been proposed.98,99 Both approaches are based on the two-process model and on a continuous parameter update as soon as new empirical data are available. Although the qualitative version of the two-process model had originated from animal data,2,75 the quantitative version of the model was elaborated on the basis of findings from human studies. In the meantime, quantitative simulations of NREM sleep homeostasis were also performed in rats100-103 and mice (see Fig. 37-5B).104,105 SWA of consecutive 4-second epochs in a 24-hour baseline, a 6-hour sleep deprivation, and an 18-hour recovery period104 served as the database for the simulation in mice. As in the original human version of the model, Process S was assumed to decrease exponentially in NREM sleep and to increase according to a saturating exponential function in waking. Unlike in the human model, an increase of S was assumed to occur also in REM sleep. After optimizing the initial value of S (IV) as well as its time constants (increase Ti; decrease Td), a close fit was obtained between the hourly mean values of SWA in NREM sleep and the prediction of Process S (see Fig. 37-5B) (see also Chapter 9). Modeling REM Sleep Whereas many models have focused on NREM sleep homeostasis, on the interaction of NREM and REM sleep, and on the circadian oscillator, REM sleep regulation has been largely ignored. This is due to the complex and not yet clearly understood principles underlying REM sleep regulation (see earlier). The NREM–REM sleep cycle has been accounted for by the limit cycle reciprocal interaction model on the basis of interacting neuronal systems (for a recent version and for the activation-synthesis model see reference 106). Attempts were made to integrate various concepts into a combined model.107,108 Saper and coworkers proposed in their flip-flop model a mode of interaction between different neurotransmitter systems that accounts for the sharp state transitions between waking and sleep109 as well as between NREM and REM sleep.110,111 Mathematical models incorporating these ideas are discussed later (see Table 37-3). Neurophysiologic Models To investigate the possible role of different oscillations such as slow oscillations or sleep spindles, computational models of neuronal networks were developed to simulate cellular activity in different sleep states. Such models, in addition, contribute to the better understanding of basic neuronal mechanisms. Neuronal models may be subdivided into neurophysiologic models (see Table 37-2) based on detailed neuronal architecture (e.g., neurons, synapse) and intermediate-level models that capture essential features (see Table 37-3) or mean field models (approximation of activity of a large ensemble of neurons as a field with a wide influence; see Table 37-3). A main challenge is to relate mechanisms of EEG generation to the underlying neuronal structures of the neocortex. Subcortical structures may be essential for generating certain EEG patterns (e.g., sleep spindles) but are only indirectly measured at the level of the scalp as part of a network phenomenon.
The neuronal models summarized in Table 37-2 encompass various degrees of complexity ranging from large scale networks112 to a single neuron.113 They all address the generation of slow oscillations (slower than 1 Hz) characterized by slow membrane potential fluctuations of cortical neurons, with depolarizing (up state) and hyperpolarizing (down state) components alternating with a frequency slower than 1 Hz. In addition, Hill and Tononi112 simulate effects of neuromodulators or changes in synaptic strength.37 The intermediate level models summarized in Table 37-3 describe the sleep–wake dynamics,114-116 EEG phenomena such as slow oscillations and K-complexes,117 and sleep as an emergent property of interacting cortical columns.118 The model of sleep–wake dynamics114 was guided by the work of Saper and colleagues.109,119 Mutual inhibition between sleep-promoting and wake-promoting neuronal populations resulted in flip-flop–like behavior.
CONCLUSIONS AND PERSPECTIVES Ever since the first EEG recording by Hans Berger with a Siemens galvanometer, technical advances were instrumental for progress in sleep research. This has been evident in regard to the issues addressed in this chapter. The increasing ease of recording the sleep EEG from multiple derivations, combined with access to computer programs to analyze and visualize the data, have made it possible to explore the sleep process on a regional level. Differences became readily apparent between frontal and occipital derivations120,121 and between the left and right hemispheres.122 Frontal derivations have been shown to exhibit the largest response to changes in sleep pressure in terms of both SWA during sleep and theta activity during waking.123-125 The topographic analysis of the EEG revealed that the frontal predominance of low-frequency activity is a common feature of NREM sleep, REM sleep, and waking and therefore represents a state-independent trait.124 Regional differences pose a challenge to modeling, because differences in the characteristics of the homeostatic process (e.g., time constants, level of asymptote) can reflect different regulatory features of specific neuronal ensembles. The report of unihemispheric deep sleep in the dolphin126,127 constituted not only evidence for a regional segregation of the sleep process but also raised the question of its functional significance. Hypotheses have been advanced implying that regional increases in neuronal activity and metabolic demand during wakefulness might result in selective changes in EEG synchronization of these neuronal populations during NREM sleep.118,128,129 Benington and Heller128 proposed that adenosine, which is released upon increased metabolic demand via facilitated transport by neurons and glia cells throughout the central nervous system, promotes slow EEG potentials. Thus a use-dependent local mechanism would underlie the sleep deprivation–induced changes in the sleep EEG. The theory of a local, use-dependent increase of sleep intensity was tested by investigating whether a local activation of a particular brain region during wakefulness affects the EEG recorded from the same site during sleep. The first positive result consisted of an the increase in lowfrequency activity over the contralateral somatosensory cortex in the first hour of sleep following a vibratory stimu-
CHAPTER 37 • Sleep Homeostasis and Models of Sleep Regulation 441
lus to the contralateral hand.130 This regional use-dependent effect was subsequently confirmed and extended.131 Analogous findings were obtained in the rat and human where unilateral sensory or optic stimuli, respectively, during waking caused an interhemispheric shift in lowfrequency power in the NREM sleep EEG.132,133 Conversely, in a human study the selective understimulation of the cortical arm projection area during waking achieved by unilateral arm immobilization induced a reduction of power over the corresponding cortical region during subsequent sleep.134 The notion of sleep homeostasis, originally derived from the sleep–wake–dependent changes of the EEG slow waves, was recently expanded to the synaptic level. Tononi and Cirelli135,136 proposed a synaptic homeostasis hypothesis postulating that synaptic strength is maintained over time by alternating phases of predominant potentiation during waking with phases of predominant depression during sleep. NREM sleep and the typical slow waves would subserve synaptic downscaling and thereby safeguard energy, space, and cellular supplies. The synaptic homeostasis hypothesis has the merit of relating the changes at the level of the EEG to well-known mechanisms at the synaptic level and thereby allowing specific predictions that can be simulated37 and also tested by electrophysiologic and neurochemical techniques in both humans and animals.137-140 Krueger and collaborators141 also underline the local aspect of sleep. Starting from an early theoretical paper,129 they view sleep as an emergent property of cortical columns and propose a nonlinear mathematical model to account for the interactions between columns.118 The term “model” was applied by Saper and colleagues109 to the flip-flop switch, a mode of interaction between different neurotransmitter systems that accounts for the sharp state transitions between waking and sleep. However, the processes were not characterized in mathematical terms. In conclusion, models have proved useful for delineating regulating processes underlying such a complex and littleunderstood phenomenon as sleep, and they thereby offer a conceptual framework for analyzing existing and new data. The major models have already inspired a considerable number of experiments. Ideally, the specification of model parameters should be based on physiologic data obtained for the entire sleep episode. Once the parameter estimation is satisfactory for a specific empirical data set, predictions can be made for different experimental protocols. A new empirical data set can then be used to validate the model and, if necessary, to adjust the model parameters. Such an iterative approach has been taken in the attempt to validate an extended version of the two-process model79 and also in the continuous refinement of the circadian pacemaker model accounting for the changes induced by light.91,142 Future challenges of the modeling approach to sleep include the simulation of changes at the level of individuals as well as accounting for the regional differences of sleep-related variables. Acknowledgments This work was supported by the Swiss National Science Foundation and the Zurich Center for Integrative Human Physiology.
❖ Clinical Pearl The common experience that a good night’s sleep dissipates fatigue and tiredness and regenerates energy points to a specific restorative function of sleep that cannot be achieved by merely resting. Sleep homeostasis denotes a basic principle of sleep regulation that can lead to a better understanding of sleep pathologies. Deficient sleep homeostasis might account for the altered sleep architecture in depression, and the transient normalization of sleep propensity can explain the antidepressant effect of sleep deprivation. The elucidation of sleep homeostasis at the cellular and molecular levels is likely to open new avenues for the pharmacologic therapy of sleep disorders.
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Circadian Rhythms in Sleepiness, Alertness, and Performance Namni Goel, Hans P.A. Van Dongen, and David F. Dinges Abstract The biological clock in the suprachiasmatic nuclei (SCN) of the anterior hypothalamus regulates human behavior as it changes across the 24-hour day. Consequently, circadian rhythms can be detected in almost all variables describing sleepiness and neurobehavioral performance, which explains why individuals are less alert in the early morning or late at night, even with prior sleep. A variety of factors (e.g., posture, background noise) can mask the circadian rhythm profile of neurobehavioral functioning; thus, it is important to study the circadian rhythmicity of such functions under strictly controlled laboratory conditions. In addition, many masking
CIRCADIAN RHYTHMS Subjective Measures of Sleepiness and Alertness Both wakefulness and sleep are modulated by an endogenous circadian regulating system, the biological clock, located in the SCN of the anterior hypothalamus. Beyond simply driving sleep onset and offset, the SCN also modulates hour-to-hour waking behavior, as reflected in sleepiness and cognitive performance, generating circadian rhythmicity in virtually every neurobehavioral variable. Before discussing circadian rhythmicity in waking functions, it is important to define terms relating to waking function. In this chapter, neurobehavioral functions include sleepiness, behavioral alertness, and performance. Sleepiness refers to subjective reports of the desire to sleep or of efforts to resist sleep. Behavioral alertness refers to the degree to which an organism can quickly and reliably use selective and sustained attention. Performance refers to cognitive functions ranging in complexity from psychomotor vigilance and working memory to logical reasoning and decision making. The interaction of the circadian and sleep–wake systems in regulating sleepiness and performance is described in the second part of this chapter. Sleep propensity1,2 is not covered in this chapter, because our focus is on effortful waking cognitive performance and its associated subjective states. Many different subjective measures of sleepiness and alertness can assess circadian rhythmicity in neurobehavioral variables, as long as the scale requests ratings on the immediate state of the subject. These include visual analogue scales (VAS)3; Likert-type rating scales such as the Stanford Sleepiness Scale (SSS)4 and the Karolinska Sleepiness Scale (KSS)5; and adjective checklists such as the Activation-Deactivation Adjective Check List (AD-ACL)6 and Profile of Mood States (POMS).7 Despite structural differences among these scales, all self-reports of sleepiness tend to be highly intercorrelated and because they are relative psychometrics, they are subject to a number of sources of variance. For example, as shown in Figure 38-1, the effects of cognitive performance on subjective alertness
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influences (e.g., sensory stimulation, body movement) are an integral part of the system regulating waking neurobehavioral functions. Even after controlling for such masking influences, however, measurements of the endogenous circadian rhythmicity in sleepiness and cognitive performance still reflect the interaction of the biological clock with sleep homeostatic drive. Moreover, other significant factors, such as individual differences in circadian rhythms and the genetics underlying such differences, also affect neurobehavioral performance. Accurate prediction of cognitive performance deficits, alertness, and sleepiness across the circadian cycle is best achieved via an understanding of all of these interactions with the biological clock.
are evident only when sleep loss has commenced and this effect is modulated by circadian variation. Objective Measures of Cognitive Performance Many studies of circadian rhythms rely on objective performance measures to track the temporal dynamics of endogenous circadian rhythmicity. Classic examples of such measures include search-and-detection tasks8 and simple and choice reaction time tasks,9 sorting,10 logical reasoning,11 memory access,12 and real-world tasks such as meter reading accuracy13 and school performance.14 Typically, response speed and accuracy to a series of repetitive stimuli are analyzed, although the sensitivity of the performance metric used to track circadian variation will depend heavily on whether the task is work-paced versus subjectpaced, on speed versus accuracy tradeoffs in performance metrics,15 on the rate and number of responses acquired during the task, on whether the task metrics reflect performance variability or mean performance, and on the overall technical precision of the measurement. Even short-duration, work-paced tasks that precisely measure variability in performance can be used to demonstrate circadian variation.16 Earlier studies have concluded that different tasks17,18 and different task outcomes19,20 may yield distinct peak phases of circadian rhythmicity, suggesting that many distinct circadian rhythms using different clock mechanisms exist.21,22 This hypothesis, however, has not been substantiated to a reasonable degree of scientific certainty. Under strictly controlled laboratory conditions, most intertask differences in circadian variation disappear.23,24 As illustrated in Figure 38-2, under controlled sleep deprivation conditions, the circadian rhythms of neurobehavioral performance variables co-vary with each other and with subjective sleepiness. Importantly, these rhythms mimic the circadian profile of core body temperature, one conventional marker of the biological clock.25,26 Under entrained conditions, higher and lower core body temperature values typically correspond to good and poor performance, respectively.24,27,28 445
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Time of day (hr) Figure 38-1 Average subjective alertness ratings (visual analogue scale [VAS]) in 24 healthy adults during 64 hr of wakefulness, after 8 hr of sleep (dark blue bar) from 11:30 pm until 7:30 am. In this experiment, subjects were tested on a 35-min performance and mood neurobehavioral battery every 2 hr when awake. Alertness ratings are shown for two conditions: (1) ratings made just before each 35-min performance test bout (open circles); and (2) ratings made directly after each 35-min performance test bout (closed circles). No graphic or statistical differences between prebout and postbout alertness ratings were evident during the 16-hr baseline day, or during the first 16 hr of wakefulness in the sleep deprivation period. However, for most of the time from 2 am on the first night awake until 10 pm after 62 hr awake, postbout alertness ratings were statistically significantly lower (P ≤ .05) than prebout ratings (times involving statistically significant differences are shown with boxes containing asterisks at the top of the graph). Only near the circadian peak in body temperature (i.e., from 8 pm until 10 pm) did these prebout versus postbout differences disappear during sleep deprivation. Such data highlight the masking effect of activity-based factors on subjective ratings of alertness, and the circadian rhythm therein, especially when a heightened pressure for sleep exists.
Masking and Other Influences Subjective measures of sleepiness and alertness are vulnerable to numerous confounding influences that can “mask” their circadian rhythmicity. Masking refers to the evoked effects of noncircadian factors on measurements of circadian rhythmicity. The context in which such measurements are taken (i.e., the environmental and experimental conditions) is a major source of masking effects. Masking can alter or obscure a circadian rhythm, or it can create the appearance of a circadian rhythm. Masking factors specifically affecting sleepiness and alertness include: demand characteristics of the experiment,29 distractions by environmental stimuli and noise,30 boredom and motivational factors,31-33 stress,34 food intake,35,36 posture and activity,37,38 ambient temperature,32 lighting conditions,39,40
and stimulant drug intake (e.g., caffeine, modafinil, amphetamine).41-43 Physical, mental, and social activities can represent masking factors that interact with endogenous circadian rhythms in neurobehavioral functions. This is illustrated in Figure 38-1: The effects of performing cognitive tests on subjective estimates of alertness are apparent at certain circadian phases during sleep deprivation. Subjects report feeling less alert after they are challenged to perform. Thus, prior activity can influence subjective estimates and can interact with circadian effects if not properly controlled when measuring the rhythmicity of subjective states. Sleep and sleep loss can also be considered masking factors when measuring circadian rhythmicity in certain neurobehavioral variables. Therefore, virtually all neurobehavioral measures reflect to varying degrees a combination of endogenous circadian rhythmicity, sleep homeostatic drive, and a number of other (masking) effects interacting to produce the behavioral result. Direct Effects on the Biological Clock Many stimuli also affect the biological clock itself by phase-shifting other circadian rhythms such as melatonin and body temperature, and therefore can affect circadian rhythmicity of neurobehavioral measures. Such stimuli— which have varying effects on the body depending upon their magnitude and the time of administration—include light, exercise, exogenous melatonin, triazolam administration, food intake, social cues, and auditory stimuli (reviewed in Goel44,45). As such, it is important to also minimize or control potential zeitgebers (i.e., time givers) in laboratory studies designed to measure neurobehavioral performance. The Midafternoon Dip Some individuals display a short-term afternoon dip in the circadian profiles of neurobehavioral variables and core body temperature, which is called the midafternoon, siesta, postlunch, or postprandial dip. This dip has been observed in field studies (e.g., see Bjerner et al.13) and in controlled laboratory experiments (e.g., see Monk et al.46) independent of food intake, although it has not been found consistently.47,48 Field studies of human performance support the existence of a midafternoon dip,49 but such data cannot be considered definitive because of the uncontrolled influence of differential amounts of activity by individuals over time (i.e., exposure). The most compelling evidence for the existence of a midafternoon dip derives from studies on sleep propensity50,51 and from the natural timing of daytime naps.52 Nevertheless, because of the inconsistent observation of the midafternoon dip in performance and sleepiness, the phenomenon remains poorly understood, and its relationship to the biological clock remains unclear. The Practice Effect and Other Artifacts The well-known practice effect that occurs when cognitive tasks are performed repeatedly can limit (mask) the ability to detect circadian rhythmicity in these tasks. This is illustrated in Figure 38-3, which shows performance on a stan-
CHAPTER 38 • Circadian Rhythms in Sleepiness, Alertness, and Performance 447
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Figure 38-2 Circadian co-variation of changes in subjective sleepiness as assessed by (reversed) visual analogue scale (VAS); in cognitive performance as assessed by the digit symbol substitution task (DSST); in 10% fastest reaction times (RT) in msec as assessed by the psychomotor vigilance task (PVT); and in core body temperature (CBT) as assessed by a rectal probe. Data shown are the mean values from five subjects who remained awake in dim light, in bed, in a constant routine protocol, for 36 hr consecutively (a distance-weighted least-squares function was fitted to each variable). The circadian trough is evident in each variable (marked by vertical broken lines). A phase difference is also apparent, such that all three neurobehavioral variables had their average minimum between 3.0 hr and 4.5 hr after the time of the body temperature minimum. This phase delay in neurobehavioral functions relative to CBT has been observed in many protocols, but remains unexplained. Although body temperature reflects predominantly the endogenous circadian clock, neurobehavioral functions are also affected by the homeostatic pressure for sleep, which escalates with time awake and which may contribute to the phase delay through interaction with the circadian clock. Although this explanation is not universally supported by the available data, it is necessary to correct the common misconception that alertness and performance are worst at CBT minimum. Neurobehavioral functions usually show a circadian decline at night as is observed in CBT, but they continue their decline after CBT begins to rise, making the subsequent 2-hr to 6-hr period (i.e., clock time approximately 6 am to 10 am) a zone of maximum vulnerability to loss of alertness and to performance failure.
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dard serial addition-subtraction task improving across three consecutive days. The practice effect can be difficult to distinguish from the circadian rhythm of performance. This problem might possibly be circumvented by testing subjects in different orders across times of day—the practice effect is then balanced out by averaging over subjects. This approach assumes that the practice effect and the circadian performance rhythm are additive and have the same relationship in every subject. Because this assumption has remained untested, it is unclear whether practice effects on cognitive tests can be averaged out reliably. Thus, a better method for addressing this problem may be to train subjects to asymptotic performance levels before attempting to assess circadian rhythmicity in cognitive performance.
Practice effects are not the only masking factors that may hide, accentuate, or otherwise distort circadian rhythmicity in task performance. Many of the same variables that mask circadian rhythmicity in subjective estimates of sleepiness and alertness can also mask circadian variation in performance. The effects of masking vary from distortions of the range of circadian variation to changes in the shape of the circadian curve; even concealment of the circadian rhythm is possible (as shown in Fig. 38-3, in which sleep prevents measurement of nocturnal performance and the practice effect obscures circadian variation in diurnal performance). Thus, it is difficult to extract meaningful information about the amplitude (i.e., magnitude) and the phase (i.e., timing) of the circadian rhythm in performance measures without understanding the masking effects that influence these variables. Not only is performance often affected by learning, aptitude, and other masking factors (e.g., lighting, background noise, demand characteristics, as listed previously), but it is also affected by subjects changing their performance strategy on a task.53 Thus, it can be difficult to distinguish the circadian rhythm in task performance from that of simultaneous changes in performance strategy, unless a task prevents the subject from adopting alternative performance strategies. The same difficulty applies to compensatory effort (that is, increased effort to keep up performance), the effects of which are particularly notable if subjects are informed about their results during a performance task (i.e., performance feedback). What this means relative to measuring circadian variation in performance is that the task selected for measurement can determine the extent to which circadian variation can be observed. Thus, a performance task that is not influenced by learning, response strategy, or compensatory effort will be much more likely to reveal the
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Time of day (hr) Figure 38-3 Practice effect in average cognitive throughput performance for 29 healthy adult subjects tested every 2 hr from 7:30 am until 11:30 pm each day, during a 3-day period in which they were allowed up to 8 hr of sleep per night (blue bars). The performance task was the serial addition/subtraction test, which is part of the Walter Reed performance assessment battery.54a In this task, subjects were presented with a rapid sequence of two single digits (0 to 9) followed by an operator (plus or minus), and they were instructed to enter only the least-significant single digit of the algebraic sum, unless the result was negative, in which case 10 was to be added to the answer first. Note the substantial learning curve (i.e., practice effect) across days, resulting in a doubling of the mean correct responses within 25 trials. This effect dominates the performance profile, obscuring circadian changes within days. Practice effects “contaminate” nearly all tasks involving cognitive operations.
extent of endogenous circadian modulation of behavior than a task vulnerable to these masking factors. The Psychomotor Vigilance Test (PVT) is an example of the former, whereas the serial addition-subtraction task is an example of the latter. The fundamental point is that cognitive performance is like any other measurement domain: the assay used to assess circadian variation must be sensitive to that variation more than to other common sources of variance-especially when measuring human behavior. Electroencephalographic and Ocular Measures The circadian rhythm in cognitive performance reflects functional changes in the brain. Evoked potentials or event-related potentials (ERPs)—the brain potentials associated with reaction to a stimulus—have been used to measure alertness. Event-related potential measurements must be taken consecutively and frequently (i.e., many stimuli must be presented) to average out the background electroencephalogram (EEG). Therefore, ERPs are usually recorded during repetitive search-and-detection and reaction time tasks. Diurnal changes in the amplitude and the location of ERP waves have been interpreted as reflecting circadian variations in alertness.54b,55 Hemispheric differences have been detected,56 suggesting separate circadian
rhythms for the left and right hemispheres. Interpretation of ERP data is difficult due to masking from a variety of sources (e.g., see Geisler and Polich57). Circadian variations in alertness have also been associated with changes in the background EEG during wakefulness. The amount of theta and alpha activity (i.e., EEG activity in the frequency bands from 4 to 8 Hz and from 8 to 12 Hz, respectively) in the resting EEG with eyes remaining either open or closed (to avoid artifacts from blinking) have been related to alertness level.58-60 However, difficulties in the recording and analysis of waking EEG61,62 have limited its interpretability. Furthermore, significant effects in the EEG occur primarily when alertness is much lower than what is normally encountered at the trough of circadian variation—such as when subjects are sleep deprived.63 The EEG has also been used to measure the latency to fall asleep (as a measure of sleep propensity) at various times of day. These sleep latency tests include the Multiple Sleep Latency Test (MSLT)1 and the Maintenance of Wakefulness Test (MWT)49 as well as variants of these paradigms. Slow eyelid closures, slow rolling eye movements (SEMs), and a number of other ocular variables relate to sleepiness.5,64-68 Pupil diameter relates to autonomic tone (i.e., pupils dilate with greater sympathetic dominance), and autonomic tone co-varies with sleep pressure.69 Pupillometry may therefore also yield estimates of sleepiness, but only if environmental light and other confounding influences on pupil diameter are strictly controlled. The various ocular measures of sleepiness have been investigated primarily under conditions of considerable sleep loss, when the observed effects are more substantial than those found across the circadian cycle. Whether ocular measures can be used reliably for detecting circadian fluctuations in sleepiness remains to be determined. Interindividual Variability in Circadian Rhythms Subjects show interindividual differences in the free-running circadian period (tau; τ).70 Subjects also demonstrate interindividual differences in circadian amplitude26,71 and circadian phase25,26,71 that appear to be due mostly to genetic influences.71 There are several standardized methods for assessing interindividual differences in circadian rhythms. One recently developed and accurate method using molecular techniques can determine individual differences in τ, amplitude and phase-resetting, which relate to diurnal phase preference, using cultured human fibroblasts from skin biopsies or blood samples.72-74 Standard physiological estimates of circadian phase include the dim light melatonin onset (DLMO)75 and core body temperature minimum.25,26 The aforementioned methods are important for characterizing interindividual variation in circadian rhythmicity. Morningness-Eveningness Morningness-eveningness (i.e., the tendency to be an early “lark” or a late “owl”) is perhaps the most frequently measured interindividual variation in circadian rhythmicity. Morning- and evening-type individuals differ endogenously in the circadian phase of their biological clocks.25,26 Self-report measures, such as the Horne-Östberg Morn-
CHAPTER 38 • Circadian Rhythms in Sleepiness, Alertness, and Performance 449
ingness-Eveningness Questionnaire (MEQ)76 and its variants (e.g., see Smith et al.77), and more recently developed scales such as the Munich Chronotype Questionnaire,78,79 which differentiates timing of activities on workdays versus free days, are the most commonly used measures of circadian phase preference because of their convenience and cost effectiveness. Age affects morningness-eveningness as shown in laboratory studies80 and more naturalistic population-based settings (reviewed in Roenneberg et al.79 and Foster and Roenneberg et al.81). In addition, gender has been reported to influence morningness and eveningness with women showing a greater skew toward morningness than men.79,82,83 This difference in circadian phase preference is an enduring trait, with a significant genetic basis.84-86 As such, chronotype is a phenotypic aspect of circadian rhythmicity in humans.87 The genetic basis of morningness-eveningness in the general population has been investigated by targeting several core circadian genes which have yielded mixed results.88 For example, the 3111C allele of the CLOCK gene 5′-UTR region has been associated with eveningness and delayed sleep timing in some studies89,90 but not others.91-93 Similarly, the variable number tandem repeat (VNTR) polymorphism in PERIOD3 (PER3), another core clock gene, has been linked to diurnal preference, but not uniformly.94-99 In addition, the 111G polymorphism in the 5′-untranslated region of PERIOD2 (PER2) has been associated with morning preference,100 as has the T2434C polymorphism of PERIOD1 (PER1).101 Because morningness-eveningness represents a continuum, it is likely this trait is polygenic (influenced by several genes), with each gene contributing to the determination of circadian phase preference. Thus, further studies investigating other clock genes, as well as replication of the PER and CLOCK findings, are needed to establish precisely the molecular genetic components of behavioral circadian phase preference.
CIRCADIAN RHYTHMICITY VERSUS SLEEP AND WAKE Sleep Deprivation Considerable research has been devoted to unmasking circadian rhythms, that is, eliminating sources of extraneous variance to expose the endogenous circadian rhythms of variables of interest, including alertness and cognitive performance. The constant routine procedure102 is generally regarded as the gold standard for measuring circadian rhythmicity. By keeping subjects awake with a fixed posture in a constant laboratory environment for at least 24 hours, circadian rhythms in a variety of physiologic and neurobehavioral variables can be recorded without biases (see Fig. 38-2). Indeed, the circadian rhythm of body temperature is believed to be free of masking effects when derived under a constant routine. When neurobehavioral variables are considered, the elimination of sleep (i.e., sleep deprivation) and the stimuli used to sustain wakefulness can constitute masking factors. In constant routine experiments, these untoward masking effects are evident in subjective measures of sleepiness and alertness.25,103 Figure 38-2 shows the somewhat reduced values for subjective alertness as well as cognitive and psy-
chomotor performance after 30 hours awake in a constant routine, compared with the values of these variables 24 hours earlier (i.e., at the same circadian phase but without sleep deprivation). A progressive change associated with the time spent awake is typically superimposed on the circadian rhythm of neurobehavioral variables (e.g., see Åkerstedt et al.104 and Van Dongen and Dinges105). When total sleep deprivation is continued for several days (whether in a constant routine procedure or an experimental design involving ambulation), the detrimental effects on alertness and performance increase, and although the circadian process can nonetheless be exposed,106 it is overlaid on a continuing (nearly linear) change reflecting increasing homeostatic pressure for sleep (e.g., see Bohlin and Kjellberg107). This is illustrated in Figure 38-4 for PVT performance lapses. It is noteworthy that decreased alertness during the circadian trough is associated with increased intraindividual variability in performance. This is evidenced by intermittent lapsing,108 which has been hypothesized to reflect wake state instability. The wake state instability hypothesis posits that sleep-initiating mechanisms may interfere with wakefulness, making sustained performance unstable and dependent on compensatory mechanisms.109 Sleep–Wake Regulation The apparent superposition of circadian modulation of alertness and performance on monotonic changes during sleep deprivation has prompted efforts to mathematically model the regulatory processes involved in sleep-wake regulation. The two-process model of sleep regulation has been applied to the temporal profiles of sleep110,111 and wakefulness.112 The model consists of a homeostatic process (Process S) and a circadian process (Process C), which combine to determine the timing of sleep onset and offset. The homeostatic process represents the drive for sleep that increases during wakefulness (as can be observed when wakefulness is maintained beyond habitual bedtime into the night and subsequent day) and decreases during sleep (which represents recuperation obtained from sleep). When the “homeostat” increases above a certain threshold, sleep is triggered; when it decreases below a different threshold, wakefulness is invoked. The circadian process represents daily oscillatory modulation of these threshold levels. It has been suggested that the circadian system actively promotes wakefulness more than sleep,113 although this hypothesis is not universally accepted. The circadian drive for wakefulness may be experienced as spontaneously enhanced alertness in the early evening even after a night without sleep (see Fig. 38-2). The homeostatic and circadian processes are thought to interact to determine waking neurobehavioral functions as expressed in alertness and performance.114 This is clearly seen in prolonged sleep deprivation experiments (see Figs. 38-1, 38-2, and 38-4). Thus, alertness and performance, sleep, and sleeplessness are not only masking factors, but also dynamic biologic variables that interact with the circadian system. Forced Desynchrony The forced desynchrony protocol,115,116 conducted in temporally and environmentally isolated conditions, is an
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experimental procedure particularly suitable for studying the interaction of the circadian and homeostatic processes.23,48,117 In this protocol, a subject’s imposed timing of sleep and waking deviates considerably from the normal 24-hour day (e.g., 20- or 28-hour days), such that the subject’s biological clock is unable to synchronize to this schedule. The subject experiences two distinct influences simultaneously: the schedule of predetermined sleep and waking times representing the homeostatic system, and the rhythm of the subject’s unsynchronized (i.e., free-running) circadian system. Neurobehavioral variables can be
recorded during the subject’s waking periods of this schedule. By folding the data over either the free-running circadian rhythm or the imposed sleep–wake cycle, the other component can be balanced out. Thus, the separate effects of the circadian rhythm and wake duration (i.e., homeostatic drive for sleep) on neurobehavioral variables can be assessed. Not surprisingly, forced desynchrony studies have found that both the circadian and homeostatic processes influence sleepiness and performance. The interaction of the two systems is oppositional during natural diurnal wake periods (from approximately 7 am until 11 pm), such that a relatively stable level of alertness and performance can be maintained throughout the day.48,116 This may explain why in many studies of alertness and performance, very little temporal variation is observed during the waking portion of a normal day (see Fig. 38-4). The interaction of the homeostatic and circadian processes is believed to be nonlinear (i.e., nonadditive).48,118 Therefore, the separation of circadian and homeostatic influences on neurobehavioral variables presents a conceptual and mathematical problem, and it is difficult, if not impossible, to quantify the relative importance of the two influences on neurobehavioral functions. Moreover, their relative contributions may vary across different experimental conditions23,48 and among subjects (e.g., see Lenné et al.119). Ultradian Days The importance of taking into account sleep when studying alertness and performance has led to the design of paradigms with very short, (i.e., ultradian) artificial days. Such paradigms seek to redistribute the opportunities for sleep and wakefulness across the natural 24-hour day in order to sample waking behavior across the circadian cycle without significantly curtailing the total amount of sleep allowed. Studies have been performed with a “90-minute day” schedule,120 which alternately permits subjects to sleep for 30 minutes and forces them to stay awake for 60 minutes, and with a “7/13-minute sleep–waking” schedule,2 which alternately allows subjects to sleep for 7 minutes and forces them to stay awake for 13 minutes. With respect to objective measures, studies with very short days have primarily focused on sleep propensity rather than alertness and performance. However, subjective sleepiness scores have been recorded in both the 90-minute day schedule120 and the 7/13-minute sleep–waking schedule.121 After 24 hours of 7/13-minute sleep–waking cycles, the level of subjective sleepiness is elevated with respect to the initial level 24 hours earlier; this is not the case in the 90-minute day schedule. Thus, at least with respect to subjective sleepiness, sleep obtained across 24 hours of the 7/13minute sleep–waking schedule may not have the same recovery potential as natural nighttime sleep. Cognitive performance was assessed in one experiment using the 7/13-minute sleep–waking schedule.122 A clear circadian rhythm emerged for response time on a choice reaction time task. Furthermore, a movement time component showed a circadian rhythm as well, but also an overall gradual increase over time. This may reflect a growing homeostatic pressure for sleep across the ultra-
CHAPTER 38 • Circadian Rhythms in Sleepiness, Alertness, and Performance 451
dian days. This study shows that even in paradigms with very short artificial days it is difficult to separate the circadian and homeostatic influences on neurobehavioral functions. Sleep inertia is another problem that interferes with the assessment of alertness and performance.123 Sleep inertia is the cognitive performance impairment, feeling of disorientation, grogginess, and tendency to fall back asleep experienced immediately after awakening.124,125 It may affect alertness and performance on every artificial day of a study with ultradian days. There are some indications that circadian and homeostatic influences interact with sleep inertia, varying its impact across artificial days126 and complicating estimation of its effect. Genetics of Individual Differences in Circadian Rhythms Interindividual differences in morningness-eveningness (chronotype) are believed to manifest into extreme cases classified as primary circadian rhythm sleep disorders (CRSDs), with altered phase relationships of the biological clock to the light–dark cycle, including alterations in sleep timing.127,128 Thus, extreme eveningness is thought to result in CRSD, delayed sleep phase type (usually referred to as a disorder and abbreviated as DSPD128) whereas extreme morningness can manifest as CRSD, advanced sleep phase type (usually referred to as a disorder and abbreviated as ASPD128).127 The extent to which these phase-displacement disorders reflect differences in endogenous circadian period, amplitude, coupling, entrainment, or other aspects of clock neurobiology has received recent attention. The genetic basis of DSPD and ASPD related to phenotypic chronotype has been investigated in recent years, and both demonstrate links to core clock genes.88 DSPD, the most common circadian rhythm sleep disorder in the general population, is characterized by an inability to fall asleep at the desired and “normal” time of day; the average onset of sleep in DSPD occurs in the early morning (3 am to 6 am), and the average wake up time occurs in the late morning to early afternoon (11 am to 2 pm).128 DSPD also may be characterized by a longer than normal tau (25.38 hours).129 The VNTR polymorphism in PER3 is associated with DSPD in large sample studies,94,95,97 and the 3111C allele of the CLOCK gene 5′-UTR region also has been related to DSPD.89 In addition, a specific haplotype of PER3, which includes the polymorphism G647, is associated positively with DSPD,97 whereas the N408 allele of casein kinase I epsilon (CK1ε) protects against DSPD.130 ASPD is a rare disorder characterized by 3- to 4-hour advanced sleep onsets and wake times relative to desired, normal times.128,131 It may be characterized by a shorter than normal tau (23.3 hours).132 In one study, ASPD was shown to be associated with a mutation in PER2,133 although a later study failed to replicate this finding.134 Another study has implicated mutations in casein kinase I delta (CK1δ) in ASPD.135 Future studies on additional core clock genes are needed to determine other mutations which may underlie this disorder. Morningness-eveningness and differences in circadian phase preference are reflected in the diurnal course of neurobehavioral variables (as reviewed in Kerkhof136 and
Van Dongen137)—some people perform consistently better in the morning, whereas others are more alert and perform better in the evening. How genetic variants underlying morningness-eveningness and disorders of chronotype affect performance and alertness under normal and sleepdeprived conditions remains a new field of investigation. Two recent studies have shown that the longer, 5-repeat allele of the VNTR polymorphism in PER3, a clock gene linked to diurnal preference and DSPD, may be associated with higher sleep propensity both at baseline and after total sleep deprivation (TSD), and worse cognitive performance following TSD.98,99 We examined this association in a chronic, partial sleep-deprivation (PSD) protocol.138 When participants were asleep at the circadian phase that appears to be important for PER3’s regulation of performance responses to TSD. We found that the PER3 VNTR polymorphism was not associated with individual differences in neurobehavioral responses, although it was related to one marker of sleep homeostatic response to PSD. The PER3 genotypes were comparable at baseline and showed equivalent interindividual vulnerability to PSD, indicating that PER3 does not contribute to the neurobehavioral effects of chronic sleep loss.138 Notably, the role of other clock gene polymorphisms in response to TSD and PSD remains unknown. Collectively, six core clock genes (PER1, PER2, PER3, CLOCK, CK1δ, and CK1ε) have thus far been associated with interindividual differences in diurnal preference or its extreme variants. This is a relatively new, active area of research with promising implications for objectively detecting differential vulnerability to circadian disorders and lifestyles that adversely affect alertness, performance, and sleep homeostasis.
CONCLUSION The circadian drive for wakefulness, the homeostatic drive for sleep, the sleep inertia effect, and various endogenous and exogenous “masking” factors simultaneously affect neurobehavioral functioning, as shown schematically in Figure 38-5. In addition, interindividual differences and the genetics underlying such differences affect neurobehavioral variables. When alertness and performance are considered, masking factors cannot be regarded as mere undesirable influences that should be ignored or controlled. Rather, they are an integral part of the regulation of neurobehavioral functions and the interaction of the subject with his or her environment. Manipulation of endogenous and exogenous stimuli may affect the circadian and homeostatic systems through mechanisms that cannot yet be accurately quantified. Understanding circadian rhythmicity in neurobehavioral functions is important when either the sleep–wake rhythm is displaced, as is the case during night-shift work,139 or when the circadian rhythm is displaced, as is the case after transmeridian flights.140 In such situations, the interaction of the circadian and homeostatic influences decreases alertness and performance. This problem is compounded when sleep is lost on a chronic basis. Eventually, performance deficits and sleepiness reach considerable levels,141,142 inducing opportunities for accidents.143,144
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Sleep inertia
Endogenous stimuli
❖ Clinical Pearl Homeostatic drive for sleep
Waking neurobehavioral function
Exogenous stimuli
Clinicians should recognize that 24-hour profiles of sleepiness and performance combine the effects of endogenous circadian rhythmicity, homeostatic regulation of sleep, sleep inertia, and a variety of endogenous and exogenous stimuli or “masking” influences. Individual differences in circadian rhythms and their underlying genetic basis also play a role. Distinguishing these factors is important for proper diagnosis and treatment of sleep disorders involving excessive daytime sleepiness or circadian rhythm sleep disorders.
Circadian drive for wakefulness Figure 38-5 Schematic representation of the (speculative) oppositional interplay of circadian and homeostatic drives in the regulation of alertness, performance, and related neurobehavioral functions. This representation was inspired by a number of theoretical conceptualizations by other authors, but it does not necessarily reflect their original intentions. Included are the two-process model of sleep regulation110,111 and the opponent-process model of sleep–wake regulation113; the threeprocess model of the endogenous neurobiological regulation of subjective sleepiness114,145; and results of a study on the effects of postural, environmental, cognitive, and social stimulation (masking) on neurobehavioral functions at different circadian phases during sleep deprivation146. The schematic is necessarily simplified (e.g., the nonlinear interaction between the circadian and homeostatic drives118 and the systematic interindividual differences in these two processes64,147,148 are not represented here). As illustrated in the upper part of the figure, wakefulness typically begins with rapidly dissipating sleep inertia, which suppresses neurobehavioral functioning for a brief period after awakening. The homeostatic drive for sleep accumulates throughout wakefulness, and progressively downregulates neurobehavioral performance and alertness (while increasing subjective sleepiness). Unlike the circadian system, which is limited by its amplitude, the homeostatic drive for sleep can accumulate far beyond the levels typically encountered in a 24-hr day (illustrated by the increasing density of downward arrows). In opposition to these influences on performance and alertness is the endogenous circadian rhythmicity of the biological clock. Through its promotion of wakefulness, the circadian system modulates the enhancement of performance and alertness. The improvement in waking neurobehavioral functions by the circadian drive is an oscillatory output that periodically involves robust opposition to the homeostatic drive, alternated with periods of withdrawal of the circadian drive for wakefulness. Critical modulators of neurobehavioral functions other than the sleep and circadian drives are subsumed in the schematic under the broad categories of endogenous and exogenous stimulation. Although common in the real world, these factors are considered masking factors in most laboratory experiments. They can include endogenous (e.g., anxiety) or exogenous (e.g., environmental light) wake-promoting processes that oppose the homeostatic drive for sleep. Alternatively, they can include endogenous (e.g., narcolepsy) or exogenous (e.g., rhythmic motion) sleep-promoting processes that oppose the circadian drive for wakefulness either directly, or indirectly by exposing the sleep drive.1,149 The neurobiologic underpinnings of these exogenous and endogenous processes are undoubtedly diverse, and few of their interactions with the circadian and homeostatic systems have been studied systematically (e.g., see Sharafkhaneh and Hirshkowitz150).
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Animal Models for Disorders of Circadian Functions: Whole Organism Alec J. Davidson and Fred W. Turek Abstract Although nearly all species adhere to a strictly programmed day–night behavior pattern, humans have developed lifestyles that circumvent the environmental 24-hour cycle. Shift work, jet lag from frequent international travel, and extreme lifestyles appear to increase the likelihood and severity of a variety of diseases. This link has been studied in animal models, and the results have provided compelling, but still
One of the most prominent features of life is that plants and animals change their behavior on a regular and consistent basis every 24 hours to match changes in the physical environment that are imposed directly or indirectly by the rotation of the earth. In addition to the easily observed changes in behaviors such as leaf movement, feeding, and sleep and wake, essentially all cellular and physiologic processes within a given organism are also expressing changes over a 24-hour period that repeat themselves like clockwork from day to day. Indeed, as detailed in Chapters 31 to 34, there is an internal clock located in the suprachiasmatic nuclei (SCN) of the hypothalamus of mammals that synchronizes the animal to the 24-hour solar day, primarily through environmental inputs from the changes in the light–dark (LD) cycle. In turn, the SCN appears to directly or indirectly synchronize hundreds of internal 24-hour rhythmic changes in behavior and in physiologic and cellular functions to both the external environment (external synchronization) and the internal environment (internal synchronization). One exception to the almost universal feature of regular 24-hour changes in the natural life of an organism is the human. Among the myriad of environmental and lifestyle changes brought about by modern technology is the 24-hour society: our new ability, due to artificial light, to engage in activities at night that in the evolutionary past were limited to the daytime. Of particular interest is shift work, brought about by both technology and economic forces, which thrusts a significant proportion of workers (by some estimates, 15% or more in the United States)1 into highly nontraditional patterns of activity and rest. The sleep–wake cycle of the shift worker represents a significant break from the world in which we evolved, where light and dark alternated reliably. The internal clock system, present in perhaps all living organisms, developed as an adaptation to this predictable day–night geophysical pattern. The biological consequences and causes of living at odds with the normal day–night cycle are just beginning to be appreciated. Shift work, loosely defined to include static night shifts, flex shifts, extended shifts, rotating shifts, and frequent international travel by airline flight crews, has been linked with increased risk of colorectal,2 breast,3 lymphatic,4 and prostate5,6 cancers, as well as gastric ulcers,7,8 obesity,9 diabetes,10,11 stroke,11 coronary 456
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limited, evidence that the effects of circadian disruption are observable in laboratory-model systems. The relationship between altered behavior patterns may occur after disruption of organization of the circadian clock system at the single cell, organ, or systems level. This chapter focuses on what is known about the adverse effects of disrupting the circadian clock system of the entire organism based on studies using alterations of genetics, physiology, and the circadian environment.
heart disease, atherosclerosis, and heart attack.11-14 The mechanisms for these correlations between shift-work exposure and disease are unknown. Although shift work and jet lag have commonly been the focus of study about the adverse effects of disassociating biological time from real time, technology (television, computers, internet) now allows us to routinely be awake or asleep at any hour, thus spreading the health concerns associated with shift work well beyond that limited population. This drastic change in lifestyle for millions of humans, when coupled with a recent remarkable discovery about the circadian system in animals, makes it particularly important that we develop more (and better) animal models for disorders of circadian function. This recent discovery is that the molecular circadian clock machinery is present not only in the cells of the central circadian clock in the SCN but also in the cells of many other areas of the brain, as well as in most peripheral tissues (e.g., lung, heart, liver, pancreas, muscle).15,16 Furthermore, these cell- and tissuespecific molecular circadian clocks appear to be regulating the 24-hour rhythmic expression of at least 10% of the genes in any given tissue, indicating that circadian dysregulation at the whole-animal level, as well as in specific tissues and organs, could alter the normal synchrony of many components of living systems. Disrupting circadian rhythms could have profound implications for health and disease. This chapter focuses on what is known about the adverse effects associated with disrupting the circadian clock system of the entire organism based on studies using genetic and environmental animal models, and Chapter 40 reviews the evidence for circadian disruption at the cellular, tissue, and organ levels.
DESTROYING THE MASTER CIRCADIAN CLOCK IN THE SCN: EFFECTS ON HEALTH AND WELL-BEING It has made circadian researchers uneasy that although we claim that normal circadian temporal organization is important for the health and survival of the organism, when we ablate the central SCN clock that regulates all 24-hour behavioral and physiologic rhythms, nothing appears to happen to the overall health of the organism.
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We remove the heart, lung, or liver and the animal dies, but remove the clock and nothing happens. SCN lesions are an obvious approach to studying the effects of the loss of internal timing on health and longevity, but a search of the literature finds not a single published report describing a health consequence of SCN ablation in the laboratory. This suggests that either the experiments were not performed or, equally likely, no effects were observed when the studies were attempted (and then the researchers did not publish the negative results). It might be concluded that such negative findings after destruction of the SCN (in rodents, at least) indicate that the SCN itself is not critical for the life or health of the organism, but caution is warranted in interpreting such laboratory-based SCNlesion studies. Possibly, the use of safe, sanitized, and unchallenging environmental conditions for studies of rodents has prevented the observation of adverse health consequences in SCN-lesioned animals. For example, although a laboratory rodent whose SCN has been lesioned does not die, a wild animal without a clock with which to synchronize to the 24-hour changes in the physical environment (temperature, predators, food availability) might be adversely affected. Data to support this hypothesis are surprisingly limited, but we might intuitively expect that a normally nocturnal rodent in a field in the middle of the day would soon fall prey to a soaring hawk. This rodent, out of synchrony with the external environment, would not compete well with other members of its species, which evolved to be active at night. The lack of strong experimental evidence, however, most likely simply represents an absence of data. Fortunately, one opportunistic cat, meddling with a field study on SCN-lesioned diurnal antelope ground squirrels, lent support for the intuitive expectation of external synchrony.17 These ground squirrels had lesions aimed at the SCN (and verified to be arrhythmic by monitoring daily running-wheel behavior prior to release) and were housed in a large outdoor enclosure along with unlesioned control animals. Behavioral monitoring revealed significantly more nighttime activity among the lesioned squirrels than in the controls. A feral cat entered the enclosure and killed 60% of the lesioned squirrels but only 29% of the controls. This unplanned event revealed a protective role for the biological clock in the “semi wild,” a finding that would be difficult to repeat under normal laboratory-animal housing conditions. In a larger follow-up study, DeCoursey and colleagues released lesioned and control eastern chipmunks with radio collars into the wild and followed the population of free-living animals for 18 months.18 Although these normally day-active chipmunks, lesioned or not, never ventured out at night, those with SCN lesions were more active during the day in their dens. Perhaps because of this restlessness, weasels were more successful in preying on the lesioned animals and killed a significantly higher proportion of them than those in the control group. So, although having no clock may carry few penalties in a nonchallenging environment, such as a cage containing no predators or infectious disease agents, and in which food and water are provided ad libitum, two key field studies exposed at least one protective role for the clock, in that it organizes behavior into a safer temporal niche.
IMPORTANCE OF “RESONANCE” OF THE TIMING OF THE INTERNAL CIRCADIAN CLOCK WITH THAT OF THE ENTRAINING LD CYCLE The free-running (i.e., not entrained) period of most plants and animals maintained under constant environmental conditions (e.g., constant darkness and temperature) is almost always close to 24 hours (hence the term circadian, or about a day), and it is rarely less than 23 hours or greater than 25 hours. This has led to the general hypothesis that organisms survive best under LD conditions when the natural free-running circadian period (tau) of the organism is close to that of the external LD cycle (T). Early studies in plants indicated this to be the case,19-21 and pioneering studies by Pittendrigh22 and Aschoff23 and their colleagues in flies support the hypothesis of the importance of T and tau being in close proximity to one another. Fruit flies, housed from the first day of adult life in symmetrical photoperiods (i.e., equal portions of light and dark) of 21 to 28 hours, were found to survive best with days that were 24 hours long, and they fared much worse when the cycles were 21 or 27 hours long.22 Studies in blowflies showed similar results: at a given time, 100% of flies exposed to LD cycles of 24 to 27 hours were still alive, whereas only 90% of flies exposed to a 23- or 28-hour day were still alive, and for flies exposed to a 22- or 20-hour day, the survival rates were only 85% and 70%, respectively.23 A slightly different question was addressed with genetic manipulation: Is there something specific about 24 hours? Carl H. Johnson’s group24 used an elegant approach to answer this question, and in the process managed to directly demonstrate the adaptive advantage not only of having a clock but also of having the right clock for the environment. Populations of cyanobacteria with altered or normal clocks were co-cultured to directly compete for survival in a variety of light cycles that were resonant with the circadian clocks in both strains, just one strain in the dish, or dissonant with both strains. The study showed that in rhythmic environments, the bacteria with normal clocks outcompeted strains with disrupted clocks. This advantage disappeared in nonrhythmic environments. When strains with different internal periods competed against one another, the photoperiod determined the winner. Resonance between the internal clock and the rhythmic environment led to dominance in the dish. The authors concluded that accurate clocks confer a selective advantage and therefore must serve important physiologic function in cyanobacteria. The only mammalian example showing a benefit of resonance between internal and external timing was only recently published. Earlier, it was shown that the tau mutant hamster, bearing a spontaneous genetic mutation that shortened the period of the circadian oscillation, had a reduced life span relative to wild-type controls25 (but see also reference 26, where opposite results were reported). Martino and colleagues have now shown that severe renal and heart disease is present in aged heterozygous tau mutant hamsters exposed to a T of 24 hours,27 but that housing the animals in a 22-hour light cycle, matched to their endogenous period, prevented the renal and cardiac
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HEALTH AND LONGEVITY IN ANIMAL MODELS OF SHIFT-WORK CONDITIONS Adverse mental and physical effects, including common age-related chronic diseases such as cardiovascular disease, diabetes, and gastrointestinal disorders, have been well documented in shift workers and lend the strongest support for the hypothesis that chronic circadian disruption has adverse health effects.28-30 The basic principle is that circadian clocks in various organs and systems organize physiologic activity in the time domain, which maximizes the efficiency with which we interact with our environment. A biologically unpredictable temporal environment, such as shift work, disables the circadian system, and may indeed increase the likelihood of pathology. One example of this process is the rhythmic synthesis and release of enzymes that metabolize ingested amino acids, which are the building blocks of proteins. Tryptophan-2,3-dioxygenase, l-serine dehydratase, and lactate dehydrogenase are all rhythmic in rodent liver (see reference 31 for review) and rise in anticipation of mealtime. Failure to release these enzymes before an unexpected meal make digestion and protein metabolism more difficult, and their inappropriately timed release (i.e., not at mealtime) not only wastes valuable metabolic resources but may be harmful. Although early studies reported a deleterious effect of chronic light-shifts on longevity in BALB/c mice,32 a more comprehensive study using CD2F1 female mice did not confirm these results.33 However, two more recent studies performed in the rodent equivalents of at-risk populations revealed significant and schedule-specific effects of chronic light-shifts on longevity. First, Penev and colleagues placed cardiomyopathic or control Syrian hamsters on a light schedule in which the light and dark periods were inverted once per week,34 and they observed a striking (average, 11%) reduction in life span in the shifted hamsters relative to the control group (Fig. 39-1). Second, Davidson and colleagues observed that a significant proportion of 2-year-old rats failed to survive a single 6-hour advance of the light cycle.35 In a follow-up study (but the first of the two to be published), they placed 27- to 30-month-old mice on one of two schedules: weekly 6-hour phase advances or weekly 6-hour phase delays, and they compared longevity between these two groups and a
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phenotypes. Ablation of the SCN at a young age also prevented the development of the pathologic cardiorenal phenotype, indicating that no clock is preferable to an incorrect clock. Taken together, the data from cyanobacteria, plants, flies, and hamsters suggest that having no clock is not a weakness in nonrhythmic or nonchallenging environments, which was first predicted by the apparent lack of profound health effects of SCN lesions. However, clocks do confer selective advantage and health benefits if they are properly matched to the environment, when compared with organisms and populations that are ill matched to their environments. Thus, one might speculate that a constantly changing 24-hour LD environment would be highly disruptive to health and longevity for normally rhythmic organisms.
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Figure 39-1 Chronic jet lag accelerates death in cardiomyopathic hamsters. A, Actograms of cardiomyopathic Syrian hamsters maintained on a constant light–dark schedule (left) and a variable light–dark schedule with weekly 12-hour shifts (right). Hours of each day are plotted from left to right; successive days are plotted beneath one another. Height of each raster is proportional to the animal’s wheel-running activity. Black and white bars above each panel indicate duration of periods of darkness and light, respectively. B, Plots of Kaplan-Meier conditional probability of survival to a given age in control (blue circles) and experimental (orange circles) groups of cardiomyopathic hamsters. A significant deterioration in survival time of the animals exposed to weekly reversal of light–dark cycle throughout their life span (orange circles) was detected using a log-rank test (P < .05). (Adapted from Penev PD, Kolker DE, Zee PC, et al. Chronic circadian desynchronization decreases the survival of animals with cardiomyopathic heart disease. Am J Physiol 1998;275:H2334-2337.)
third (control) group housed in a stationary 12 : 12 light– dark cycle.36 After just 8 weeks of shifting, they observed 47% survival in animals whose light cycle was advanced each week, 68% in those experiencing delays of the light cycle, and 83% in unshifted aged mice (Fig. 39-2A). More frequent shifts—an advance or delay every 4 days—exacerbated the mortality in advanced mice, but did not eliminate the difference between advanced mice and delayed mice, suggesting that differences in the rate of re-entrainment between advances and delays may not be the reason for the difference in mortality.
CHAPTER 39 • Animal Models for Disorders of Circadian Functions: Whole Organism 459
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Figure 39-2 Chronic jet lag accelerates death and exacerbates colitis in mice. A, Upper: survival of aged mice undergoing weekly phase shifts of the light cycle. The 27- to 30-month-old mice were housed in either a stationary 12 : 12 light–dark (LD) cycle, a schedule of weekly 6-hour phase advances, or a schedule of weekly 6-hour phase delays. On day 56, survival was 47% in advancers, 68% in delayers, and 83% in unshifted aged mice (group sizes are n = 30 for controls and advancers, and n = 28 for delayers). Lower: survival curves for mice shifted every 4 days. We found that advancers still died at a faster rate (P < .05 on day 32; group sizes: 13 advancers, 12 delayers). B, Body weight change during dextran sodium sulfate (DSS) challenge and recovery period. The progression of weight loss (% change from day 0, means ± SE) during a 7-day inflammatory challenge (DSS was added to water supply from days 1 to 7) and a 3-day recovery period (animals received pure drinking water) is presented. Before this 10-day protocol, mice were maintained on either a stable LD schedule or a 12-hour phase-shifting schedule every 5 days for 3 months. Body weight was maintained in the phase-shifted and nonshifted control groups on pure drinking water throughout the 10-day period. The effects of the DSS challenge were more pronounced in the phase-shifted group as demonstrated by an earlier onset and significantly increased loss of body weight compared with the nonshifted group. Two animals in the DSS nonshifted group and five animals in the DSS-treated shifted group (indicated by*) died during the recovery period and were not included in the repeated-measures ANOVA analysis of body weight. *P < .05, phase-shifted (DSS) versus nonshifted (DSS). P < .05, phase-shifted (DSS) versus phase-shifted H2O control. P < .05, nonshifted (DSS) versus nonshifted H2O control. (A adapted with permission from Davidson AJ, Sellix MT, Daniel J, et al. Chronic jet-lag increases mortality in aged mice. Curr Biol 2006;16:R914-R916. B adapted from Preuss F, Tang Y, Laposky AD, et al. Adverse effects of chronic circadian desynchronization in animals in a “challenging” environment. Am J Physiol Regul Integr Comp Physiol 2008; 295:R2034-R2040.)
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Although these few studies indicate that constant shifting of the clock decreases longevity in rodents, there are limited data to support the hypothesis that constant phase shifting of the circadian clock system is detrimental for specific disease states, or that circadian disorganization is a risk factor for specific organ diseases based on animal models that attempt to mimic the constant phase shifting or resetting of the circadian clock associated with shift work. This lack of evidence for the importance of maintaining a constant internal circadian temporal organization in animals has raised the possibility that the adverse health consequences of human shift work may not result from internal circadian disruption per se, but instead could result from other factors such as chronic sleep loss or the social consequences associated with working and sleeping out of synchrony with the societal norm. An alternative hypothesis is that circadian perturbation has minimal effects in healthy animals but may provoke the onset or exacerbate the severity of conditions to which the organ-
ism is predisposed as a result of either environmental or genetic factors. This alternative hypothesis was recently supported in studies of mice exposed to a LD cycle (12L : 12D) that was reversed every 5 days for 3 months. Although such treatment had no effect on body weight or intestinal histopathology in C57BL/6J (B6) mice compared with nonshifted mice, chronic shifting of the LD cycle resulted in greater weight loss and intestinal histopathology in animals challenged by chemically induced inflammation (colitis), compared with nonshifted challenged animals (see Fig. 39-2B). Taken together, these data indicate that circadian disruption may represent an important predisposing factor that could provoke the onset or worsening of various disease states, and they argue the need for more animal models that involve disrupting circadian organization under challenging environmental conditions. The use of such models could lead to deeper insights into the mechanisms whereby chronic circadian disorganizations can lead to an induction or a worsening of chronic systemic diseases. Such models could also lead to a better understanding of the importance of normal circadian organization for maintaining health, particularly for age-related diseases, because aging has been associated with detriments in circadian organization in advanced age.35,37,38 Studies in mice also indicate that loss or disruption of circadian timing can accelerate cancer progression.39,40 Most notably, it was found that subcutaneous Glasgow
460 PART I / Section 5 • Chronobiology
osteosarcoma tumors grow faster in mice housed in chronic shift-work conditions: an 8-hour advance shift every 2 days.41 Although this is an extreme jet lag or shift-work schedule, the results are consistent with others we have discussed, in that an existing illness is accelerated when internal timing is constantly disrupted by the lighting environment. There is much work to be done to develop a better understanding of how schedule shifts modulate disease processes. Further work with animal models can play a key role in developing a better understanding of the specific risks and their relative magnitudes, as well as in elucidating the mechanistic relationships that underlie these risks, and in the development of strategies to reduce those risks. For example, with rare diseases, it is difficult for epidemiologic studies to determine independent odds ratios for specific types of shift work and for specific subject groups. In contrast, animal models could be used to target specific disease processes and to address how variables such as sex, age, and history affect outcomes, as well as the relative damage incurred by different types of environmental manipulations. Such models could be used to compare advance and delay shifts,36 to vary the shift size or shift frequency, and to vary the intensity or wavelength of the entraining light stimulus. Such models can also be used to test countermeasures such as exercise, scheduled meals,42 and pharmaceuticals. These studies may provide the basis for evidence-based scheduling of shift work and early identification of individuals who are ill suited to this lifestyle.
GENETIC MODELS FOR EXAMINING THE EFFECTS OF DISRUPTED RHYTHMS AND DISEASE As will be discussed in more detail in Chapter 40, the discovery that the core molecular clock machinery is in many central and peripheral tissues and that the clock can regulate in individual tissues the 24-hour timing of at least 10% of the genes, has raised the possibility that in addition to the circadian system’s being important for the overall temporal regulation of the organism, it may play an important role in regulating many cellular pathways and networks across diverse tissues and organ systems. Mouse models that have genetic alterations in core components of the circadian clock have been generated in recent years, and in most cases a disrupted circadian phenotype has been associated with abnormal noncircadian health phenotypes. For example, the Clock mutant mouse, which has a shortened circadian wheel-running rhythm, exhibits hyperphagia and obesity, and it develops some of the pathologies associated with the metabolic syndrome including hyperleptinemia, hyperlipidemia, hepatic steatosis, hyperglycemia, and hypoinsulinemia.43 The Bmal1 knockout mouse, which is completely arrhythmic in both behavior and other physiologic functions under constant lighting conditions, appears to exhibit numerous indications of early aging, including shortened life span, sarcopenia, cataracts, reduced subcutaneous fat, and organ shrinkage.44 The Per2 knockout mouse is more susceptible to DNA damage from irradiation, thereby increasing cancer risk.45 As already mentioned, the tau mutant hamster shows adverse cardiorenal phenotypes under some LD conditions.
In addition to a possible role in disrupting rhythmic processes at the cellular and tissue level, genetic alterations in clock genes could also be affecting molecular and cellular processes through pleiotropic noncircadian effects, as most clock genes appear to be components of a number of cellular processes. For example, the role of Per2 in response to DNA damage may be entirely independent of its role in the clock mechanism. Even if this is the case, however, alterations to the molecular clock, which may happen in chronic phase shifting conditions, will probably lead to at least a temporary dysfunction of all the systems in which a particular clock gene is involved. Another example of a possible pleiotropic effect is the finding that many sleep–wake characteristics, not just the timing of sleep, are disrupted in mice harboring mutations or deletions of clock genes, including a decrease in sleep time.46 Chronic partial sleep loss has been associated with both mental and physical health disturbances, and it may lead to some of the pathophysiologic consequences associated with shift work and other circadian-disruptive environments.47,48 Indeed, separating out the adverse effects of chronic circadian disruption and chronic sleep loss is an area of research in which animal models could be very insightful.49
CONCLUSIONS Our understanding of how disorders of circadian function can lead to mental and physical health problems is
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Figure 39-3 For every normal physiologic process, there is a continuum from normal function to pathologic function. Many factors determine where each individual is on that continuum. Loss of normal circadian timing, arising either from genetic causes (e.g., Clock mutation) or from environmental or behavioral (chronic jet lag) causes, appears to tip the scale toward pathology for many physiologic processes. Therefore, the presence of multiple risk factors in either category, combined with age, may lead to profound consequences for longevity and fitness.
CHAPTER 39 • Animal Models for Disorders of Circadian Functions: Whole Organism 461
only beginning to emerge. There is a tremendous void to be filled by work in animal models, in which subject characteristics, environmental factors, including schedule parameters, and additional risk factors for specific pathologies can be strictly controlled—for example, advanced-age genetics or exposure to toxins and pathogens (Fig. 39-3).
❖ Clinical Pearl The clinician should be aware of behavioral and environmental factors such as shift work, atypical sleep– wake and activity routines, or frequent jet lag in their patients. These lifestyles probably heighten other risks to patient health.48
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18. DeCoursey PJ, Walker JK, Smith SA. A circadian pacemaker in freeliving chipmunks: essential for survival? J Comp Physiol [A] 2000;186:169-180. 19. Ketellapper HJ. Interaction of endogenous and environmental periods in plant growth. Plant Physiol 1960;35:238-241. 20. Went FW. The periodic aspect of photoperiodism and photoperiodicity. In: Withrow RB, editor. Photoperiodism and related phenomena in plants and animals. Proceedings of the Conference on Photoperiodism, October 29-November 2, 1957. Washington, DC: American Association for the Advancement of Science; 1959. p. 551. 21. Highkin HR, Hanson JB. Possible Interaction between light-dark cycles and endogenous daily rhythms on the growth of tomato plants. Plant Physiol 1954;29:301-302. 22. Pittendrigh CS, Minis DH. Circadian systems: longevity as a function of circadian resonance in Drosophila melanogaster. Proc Natl Acad Sci U S A 1972;69:1537-1539. 23. von Saint Paul U, Aschoff J. Longevity among blowflies Phormia terraenova R.D. kept in non-24-hour light-dark cycles. J Comp Physiol 1978;127:191-195. 24. Woelfle MA, Ouyang Y, Phanvijhitsiri K, Johnson CH. The adaptive value of circadian clocks: an experimental assessment in cyanobacteria. Curr Biol 2004;14:1481-1486. 25. Hurd MW, Ralph MR. The significance of circadian organization for longevity in the golden hamster. J Biol Rhythms 1998;13: 430-436. 26. Oklejewicz M, Daan S. Enhanced longevity in tau mutant Syrian hamsters, Mesocricetus auratus. J Biol Rhythms 2002;17:210-216. 27. Martino TA, Oudit GY, Herzenberg AM, et al. Circadian rhythm disorganization produces profound cardiovascular and renal disease in hamsters. Am J Physiol Regul Integr Comp Physiol 2008;294: R1675-R1683. 28. Knutsson A. Health disorders of shift workers. Occup Med (Lond) 2003;53:103-108. 29. Haus E, Smolensky M. Biological clocks and shift work: circadian dysregulation and potential long-term effects. Cancer Causes Control 2006;17:489-500. 30. Costa G. Shift work and occupational medicine: an overview. Occup Med (Lond) 2003;53:83-88. 31. Davidson AJ, Cantenon-cervantes O, Stephan FK. Daily oscillations in liver function: diurnal versus circadian rhythmicity. Liver International 2004;24:179-186. 32. Halberg F, Nelson W, Cadotte L. Living routine shifts simulated on mice by weekly or twice-weekly manipulation of light-dark cycle. In: Proc XII Int Soc Chronobiol 1977, p. 133-138. 33. Nelson W, Halberg F. Schedule-shifts, circadian rhythms and lifespan of freely-feeding and meal-fed mice. Physiol Behav 1986;38: 781-788. 34. Penev PD, Kolker DE, Zee PC, Turek FW. Chronic circadian desynchronization decreases the survival of animals with cardiomyopathic heart disease. Am J Physiol 1998;275:H2334-H2337. 35. Davidson AJ, Yamazaki S, Arble DM, et al. Resetting of central and peripheral circadian oscillators in aged rats. Neurobiol Aging 2008;29:471-477. 36. Davidson AJ, Sellix MT, Daniel J, et al. Chronic jet-lag increases mortality in aged mice. Curr Biol 2006;16:R914-R916. 37. Gibson EM, Williams WP, 3rd Kriegsfeld LJ. Aging in the circadian system: considerations for health, disease prevention and longevity. Exp Gerontol 2009;44:51-56. 38. Turek FW, Scarbrough K, Penev PD, et al. Aging of the mammalian circadian system. In: Takahashi JS, Turek FW, Moore RY, editors. Handbook of behavioral neurobiology, circadian clocks. vol. 12. New York: Kluwer Academic/Plenum; 2001. 39. van den Heiligenberg S, Depres-Brummer P, Barbason H, et al. The tumor promoting effect of constant light exposure on diethylnitrosamine-induced hepatocarcinogenesis in rats. Life Sci 1999;64:2523- 2534. 40. Filipski E, King VM, Li X, et al. Disruption of circadian coordination accelerates malignant growth in mice. Pathol Biol (Paris) 2003;51: 216-219. 41. Filipski E, Delaunay F, King VM, et al. Effects of chronic jet lag on tumor progression in mice. Cancer Res 2004;64:7879-7885. 42. Filipski E, Innominato PF, Wu M, et al. Effects of light and food schedules on liver and tumor molecular clocks in mice. J Natl Cancer Inst 2005;97:507-517.
462 PART I / Section 5 • Chronobiology 43. Turek FW, Joshu C, Kohsaka A, et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 2005;308:1043- 1045. 44. Kondratov RV, Kondratova AA, Gorbacheva VY, et al. Early aging and age-related pathologies in mice deficient in BMAL1, the core component of the circadian clock. Genes Dev 2006;20:1868-1873. 45. Fu L, Pelicano H, Liu J, et al. The circadian gene Period2 plays an important role in tumor suppression and DNA damage response in vivo. Cell 2002;111:41-50. 46. Naylor E, Bergmann BM, Krauski K, et al. The circadian clock mutation alters sleep homeostasis in the mouse. J Neurosci 2000;20:8138-8143.
47. Spiegel K, Knutson K, Leproult R, et al. Sleep loss: a novel risk factor for insulin resistance and Type 2 diabetes. J Appl Physiol 2005;99: 2008-2019. 48. Burgueño A, Gemma C, Gianotti TF, Sookoian S, Pirola CJ. Increased levels of resistin in rotating shift workers: a potential mediator of cardiovascular risk associated with circadian misalignment. Atherosclerosis 2010;210:625-629. 49. Scheer FA, Hilton MF, Mantzoros CS, Shea SA. Adverse metabolic and cardiovascular consequences of circadian misalignment. Proc Natl Acad Sci U S A 2009;106(11):4453-4458.
Animal Models for Disorders of Chronobiology: Cell and Tissue Kathryn Moynihan Ramsey and Joseph T. Bass Abstract The circadian clock network is a key integrator of behavior and metabolism that orchestrates the temporal organization of many physiologic processes in synchrony with the 24-hour rotation of Earth. In mammals, the clock is present not only within master pacemaker neurons of the hypothalamus but also within peripheral tissues, where it controls diverse processes including glucose and lipid homeostasis. At the molecu-
The sun rises and sets each day, we wake up, we eat, we go to sleep, and the whole cycle repeats itself day in and day out. Much of our physiology, including our sleep– wake patterns, locomotor activity, body temperature, and metabolism, is under the control of our internal circadian clocks. However, circadian rhythms are such an innate part of our daily behavior that we rarely pause to speculate why they even exist. The term circadian is derived from the Latin phrase circa diem, “about a day,” and our endogenous clocks maintain an approximately 24-hour rhythmicity to match Earth’s rotation around its axis. Circadian rhythms are not merely passive reflections of the environmental light–dark cycle, but rather depend upon an underlying internal endogenous clock. Our internal molecular clocks are reset or entrained on a daily basis by zeitgebers (environmental cues such as light or food) that provide information about the external time and allow us to stay in synch with the environment (Fig. 40-1). This allows organisms to anticipate, rather than simply react to, daily changes in the external environment and to synchronize behavioral and physiologic processes to optimize energy use, reproduction, and survival. For example, organisms are primed to optimize anabolic events such as gluconeogenesis in liver during the fasting/rest period to maintain glucose homeostasis in the organism and avert hypoglycemia during sleep. Studies have also demonstrated that chronic reversal of the external light–dark cycles leads to a significant reduction in survival time of cardiomyopathic hampsters,1 further emphasizing the importance of the internal circadian clock in physiology and general health. The objectives of this chapter are to gain an understanding of the normal physiologic processes that are governed by the intricate system of internal circadian clocks, to understand the consequences of disruption of the circadian system on the metabolic health of an organism, and to appreciate the reciprocal consequences of altered metabolic status of the organism on the circadian system. Thus, the overall goal of the chapter is to gain an appreciation of the complex feedback relationships between circadian clocks and metabolism and to highlight the implications of these findings for our understanding of sleep-related pathologies.
Chapter
40
lar level, the circadian clock is composed of a series of interlocking transcriptional feedback loops, and genetic and epigenetic perturbation of the clock system have been linked to the development of obesity and diabetes. Conversely, a high-fat diet has been shown to disrupt circadian rhythms of feeding, activity, and sleep. This chapter reviews the relationship between circadian and metabolic systems and the implications for cardiovascular disease, obesity, and diabetes.
CLOCK REGULATION OF PHYSIOLOGY AND SLEEP It has long been recognized that many aspects of human physiology vary depending upon the time of day. For example, heart attacks, strokes, pulmonary edema, and hypertensive crises all peak at certain times during the day.2,3 Given the invention of artificial light, the advancements and ease of jet travel, and the rampant increase in Internet and television use, people routinely extend their awake time into the night and become desynchronized from their environmental (light) cues. Indeed, in parallel with the significant decrease in sleep time in the United States over the past several decades has been a concurrent increase in prevalence of obesity.4 Numerous cross-sectional and prospective clinical studies have further revealed that reduced sleep duration and quality predicts the development of obesity and type 2 diabetes after various confounding factors were taken into account.5 Finally, diseases related to sleep, such as sleep apnea syndrome, are common in persons with the metabolic syndrome, and treating the sleep apnea has been found to improve energy balance and metabolism.5 Association studies have revealed that shift and night workers also have an elevated risk for the development of obesity and metabolic syndrome.6,7 Repeated jet lag exposure in experimental model organisms results in accelerated cardiomyopathy and premature mortality.1,8 Clinical studies have also revealed that even short-duration sleep restriction (4 hours of sleep for 6 consecutive nights) in otherwise healthy subjects results in impaired glucose tolerance and reduced insulin responsiveness.9 Humans with night-eating syndrome may also be further predisposed to the metabolic syndrome.10 In addition to these examples of chronic misalignment between the cycles of sleep/ fasting and wake/feeding, genetic polymorphisms within Clock and Bmal1 have also been shown to be associated with metabolic phenotypes, including obesity, hypertension, and type 2 diabetes.11-13 Collectively, these data suggest that both the time of day and the amount and time of sleep–wake cycles are critical to maintain metabolic homeostasis and the overall health of the organism. 463
464 PART I / Section 5 • Chronobiology External cues/ zeitgebers
Clock oscillators
Clock output –
PERs CRYs
Feeding
Light Brain (SCN) clock
+ BMAL1 CLOCK
Sleep–wake cycle
Pers, Crys
E-box Rev-erbs, Rors, Nampt
– +
Food
Peripheral clocks
NAMPT
Hormones Metabolic pathways
SIRT1
Bmal1
↑
NAD+
RORE REV-ERBs
Figure 40-1 Clocks coordinate feeding and metabolism with environmental cues. Light is the predominant zeitgeber of the master pacemaker in the suprachiasmatic nucleus (SCN), but food also serves as a zeitgeber to both brain and peripheral clocks. The master clock in the SCN coordinates peripheral clocks through both endocrine signals and autonomic innervation. Outputs of brain and peripheral clocks affect behavioral and metabolic responses, including feeding patterns, the sleep– wake cycle, hormone secretion, and metabolic homeostasis.
Many metabolic processes display rhythmicity across the light–dark cycle. In particular, circadian control of glucose metabolism has been well documented.14 For example, oral glucose tolerance is impaired in the evening compared to morning hours, an effect that is believed to be due to a combination of both decreased insulin secretion and altered insulin sensitivity in the evening.15 The dawn phenomenon is also a well-described phenomenon whereby glucose levels peak before the onset of the active period.16,17 Destruction of the master circadian pacemaker within the hypothalamic suprachiasmatic nucleus (SCN) abolishes the diurnal variation in glucose metabolism in rats.18 Disruption of the normal cycles of glucose tolerance and insulin secretion is a hallmark of type 2 diabetes patients,19,20 and diabetic rats display loss of daily rhythmicity of corticosterone secretion and locomotor activity.21,22 Persons with type 1 diabetes mellitus are required to adjust their daily insulin injections depending on the time of day, as insulin sensitivity and glucose tolerance fluctuate throughout the day.20 Whether circadian control of glucose metabolism can be attributable entirely to neural centers or instead may involve peripheral tissue clock function is still unknown. Thus, while it is well established that the circadian clock plays a critical role in maintaining normal rhythmicity of physiologic processes, much less understood are the molecular mechanisms underlying these phenomena.
THE CORE MOLECULAR CLOCK NETWORK The first mammalian circadian gene to be identified was Clock, or circadian locomotor output cycles kaput, discovered in a large-scale unbiased chemical mutagenesis screen for circadian variants in mice in the 1990s.23-25 Since then, rapid advances in the field have identified that the core
RORS
Figure 40-2 Core clock machinery. The mammalian circadian clock machinery consists of a network of interlocking transcription and translation feedback loops. The positive limb of the clock consists of the CLOCK and BMAL1 transcription factors, which heterodimerize and activate transcription of downstream target genes, including Period, Cryptochrome, Ror, and Rev-erb, which contain E-box enhancer sequences in their promoters. Following translation, PER and CRY multimerize, translocate back to the nucleus, and inhibit the action of CLOCK/BMAL1. Additional metabolic feedback loops including REV-ERB and NAMPT/SIRT1 are shown.
molecular clock network is composed of an autoregulatory transcription and translation feedback loop that generates 24-hour rhythms of gene expression (Fig. 40-2).26 The positive limb of the clock consists of CLOCK and BMAL1 (brain and muscle ARNT-like), members of the basic helix-loop-helix period-ARNT-single-minded (bHLHPAS) transcription factor family. CLOCK and BMAL1 heterodimerize and activate transcription of downstream target genes, including the period (Per1, Per2, and Per3) and cryptochrome (Cry1 and Cry2) genes, which contain E-box enhancer elements in their promoters. Following translation and posttranslational modifications, the PER and CRY proteins heterodimerize and translocate back to the nucleus, where they inhibit the transcriptional activity of CLOCK/BMAL1, thereby constituting the negative limb of the clock. This entire cycle takes approximately 24 hours to complete before cycling anew. Additional regulatory loops are further superimposed upon this core loop to provide flexibility and adaptability in regulating the circadian clock.27,28 For example, CLOCK/BMAL1 also activates the transcription of the retinoic acid–related orphan nuclear receptors Rev-erbα and Rorα, which inhibit and activate, respectively, transcription of Bmal1 itself.29 Genetic mouse models have revealed key roles for each of the core clock genes in the generation and maintenance of circadian rhythmicity. Mice with a dominant-negative mutation in the Clock gene have an initial lengthening of their free-running period before becoming arrhythmic in constant darkness,24 whereas Bmal1 knockout mice display a complete loss of rhythmicity in constant darkness.30 Per1/ Per2 and Cry1/Cry2 double-knockout mice also display arrhythmicity that is much more pronounced than in the
CHAPTER 40 • Animal Models for Disorders of Chronobiology: Cell and Tissue 465 CENTRAL NERVOUS SYSTEM CLOCK OUTPUTS
Sleep/ wakefulness
Feeding/ energy expenditure
PERIPHERAL CLOCK OUTPUTS
Gluconeogenesis
Insulin secretion
Glucose clearance
Fat accumulation
Figure 40-3 Role of central pacemaker and peripheral clocks. The master circadian clock resides within the suprachiasmatic nucleus (SCN) of the brain, and the core clock machinery exists in extra-SCN regions of the brain and most, if not all, peripheral tissues. The master pacemaker clock synchronizes and coordinates the peripheral clocks, which have been found to play key roles in the metabolic homeostasis.
single mutants, demonstrating compensation within the negative limb of the clock.31-33 Identification of the molecular components of the core clock complex was key to further understanding how the clock network controls both behavior and physiology in the whole organism. It was initially believed that the master pacemaker in the SCN was the sole clock-regulating rhythms throughout the body. However, pioneering work led by Schibler and others demonstrated that the molecular clock mechanism operates in a cell autonomous fashion in nonneuronal mammalian cells and in most, if not all, peripheral tissues and extra-SCN regions of the brain in addition to the SCN.34-36 The master pacemaker clock in the SCN, which receives light input from the eyes via the retinohypothalamic tract, synchronizes the peripheral clocks, whose phase is approximately 4 hours delayed compared to the SCN (Fig. 40-3, Video 40-1). Although the function of most of the peripheral clocks remains to be determined, these findings have revolutionized our understanding of how the clock and metabolic networks overlap to regulate physiologic processes in the whole organism. A major question that has arisen from such studies is how extra-SCN and peripheral tissue clocks are integrated to maintain metabolic constancy across the sleep-wake cycle. Similarly, the effect of peripheral clock disruption on neural energy sensing remains an important and relatively unexplored topic of investigation.
MOLECULAR GENE EXPRESSION PATTERNS GOVERNED BY THE CLOCK The core circadian clock components are well defined, but the targets that in turn regulate the rhythmicity of downstream metabolic processes are much less clear. One example of a known clock target is D-element binding protein (Dbp), a transcription factor that binds to the insulinresponse element of key metabolic genes involved in gluconeogenesis and lipogenesis.37 Because oscillation of CLOCK/BMAL1 activity in liver induces 100-fold changes in expression of Dbp, it is easy to imagine how this would translate to rhythmic regulation of metabolic processes such as gluconeogenesis. Microarray analyses have further revealed a plethora of information regarding the vast number of genes that are under control of the clock in the brain and within peripheral tissues. An estimated 3% to 20% of the entire transcriptome displays 24-hour oscillation of gene expression within liver, heart, fat, and SCN, and many of these genes are key rate-limiting enzymes and transcription factors involved in metabolic processes including lipid metabolism, gluconeogenesis, and oxidative phosphorylation.38,39 There is very little overlap of cycling gene transcripts among the different tissues—only 37 genes showed similar patterns of gene expression between heart and liver, suggesting that tissue-specific rhythmic gene expression allows each cell or tissue to function optimally at appropriate times in the light–dark cycle. For example, during the fasting/sleep period, expression of genes involved in glucose production, glycogen breakdown, and fatty acid oxidation are elevated in order to help the organism maintain glucose homeostasis in the fasted state. During the feeding/wake period, there is a peak in expression of the appropriate gastrointestinal tract enzymes that are required for optimal absorption and digestion of nutrients.40 Thus, the circadian patterns of metabolic gene expression may facilitate the switch between the daily cycles of fasting and feeding. NUTRIENT SENSORS AT THE INTERSECTION OF CLOCK AND METABOLIC PATHWAYS A critical question that has emerged from these studies concerns the nature of the molecular link between the circadian and metabolic pathways. Is there a molecular sensor that is common to both pathways that can act to synchronize the external nutritional status of the organism with the core circadian network in order to optimize fuel harvesting and use with the daily cycles of fasting and feeding? Two families of proteins act as nutrient sensors at the intersection of the circadian and metabolic pathways. Nuclear Hormone Receptors A large number of the nuclear hormone receptor proteins (transcription factors activated by the binding of dietary lipids and fat-soluble hormones) oscillate in peripheral tissues, including liver, skeletal muscle, and adipose tissue.41 Several of these oscillating nuclear hormone receptors,
466 PART I / Section 5 • Chronobiology
including Rev-erbα, Rorα, and Pparα, not only affect downstream metabolic genes but also constitute part of a complex feedback loop within the clock network because they are both directly regulated by and directly regulate the core clock genes themselves. For example, REV-ERBα regulates hepatic gluconeogenesis, adipocyte differentiation, and lipid metabolism in addition to its role as a repressor of Bmal1 transcription.29,42-45 RORα and PPARα, both positive regulators of Bmal1 transcription, are involved in lipogenesis and lipid and glucose metabolism.46-49 It is likely that the circadian rhythmicity of the nuclear hormone receptors contributes to the daily oscillation in glucose and lipid metabolism. Because the nuclear hormone receptor family is regulated by both the clock and hormonal signals, and in turn affects downstream metabolic pathways as well as the core clock itself, this family of proteins has a unique role at the intersection of circadian and metabolic pathways. NAD Biosynthesis and Sirtuins Nicotinamide adenine dinucleotide (NAD) biosynthesis and the NAD-dependent deacetylase SIRT1 have also emerged at the intersection of the circadian and metabolic pathways. Early studies indicated that the cellular redox status of the cell, represented by the NAD cofactors NAD(H) and NADP(H), regulates the transcriptional activity of CLOCK and its homologue NPAS2.50 The reduced forms of these cofactors increase, and the oxidized forms decrease, the ability of CLOCK/BMAL1 to bind DNA. Recent studies have further linked the biosynthesis of NAD itself with the core molecular clock.51,52 CLOCK/ BMAL1 directly increases expression of the gene encoding the rate-limiting enzyme in NAD biosynthesis, nicotinamide phosphoribosyltransferase (NAMPT), in peripheral tissues including liver and white adipose tissue. Both Nampt RNA and NAD levels are reduced in livers from Clock and Bmal1mutant mice and increased in liver from mice lacking both Cry1 and Cry2, suggesting that Nampt, and therefore NAD production, is a direct downstream target of CLOCK/BMAL1. NAD is critical for cellular redox reactions, and it also serves as a substrate for the NAD-dependent and nutrient-responsive deacetylase SIRT1, which in turn negatively regulates the core molecular clock machinery by physically interacting with and inhibiting CLOCK/BMAL1 (see Fig. 40-2).51,53 Similar to the nuclear hormone receptor family of proteins, the existence of this pathway linked to the clock is particularly intriguing because NAMPT and SIRT1 are both regulated not only by the clock but also by the nutritional status of the organism. For example, Nampt is upregulated in response to decreased glucose levels in skeletal muscle in a manner dependent on adenosine monophosphate–activated protein kinase (AMPK),54,55 and fasting or caloric restriction elevates SIRT1 levels in multiple tissues.56-59 NAD and SIRT1 regulate a host of downstream metabolic processes, including glucose-stimulated insulin secretion, adipocyte differentiation, and gluconeogenesis,60 in addition to regulation of the core clock machinery. Thus, a unifying hypothesis is that the NAMPT-SIRT1-CLOCK/BMAL1 pathway is a metabolic feedback loop that coordinates daily cycles of feeding, fuel use, sleep, and activity.
DISRUPTION OF THE CLOCK IN MICE LEADS TO CHANGES IN METABOLISM The development and use of genetic model organisms has proved to be a tremendously powerful tool to further understand not only the behavioral but also the physiologic consequences of clock gene disruption on the overall health of the organism. Mice with genetic mutations in the core clock genes further support a role for the circadian network in the regulation and maintenance of glucose homeostasis. In addition to the expected circadian defects in locomotor activity and sleep, mice with a dominant negative mutation in the core Clock gene also display attenuated diurnal feeding patterns and phenotypes reminiscent of the metabolic syndrome, including obesity, hepatic steatosis, hyperlipidemia, hyperglycemia, and hypoinsulinemia.61 Bmal1 global knockout mice similarly have metabolic defects, including decreased gluconeogenesis, loss of the normal diurnal oscillations of glucose and triglycerides, and improved whole body insulin sensitivity.62 BMAL1 also plays an important role in the regulation of adipocyte differentiation and lipogenesis.63 Per2 mutant mice have altered bone density and glucocorticoid rhythms.64,65 Mice lacking both Cry1 and Cry2 display altered patterns of circulating growth hormone and sexually dimorphic metabolic genes in liver,66 and transgenic mice overexpressing mutant CRY1 develop symptoms of the metabolic syndrome, including polydipsia, polyuria, and hyperglycemia.67 A question that arises from these studies concerns whether the metabolic phenotypes result from the disruption of the core clock mechanism itself or whether they are secondary to altered feeding patterns present in these mice. However, evidence suggests that the metabolic phenotypes are indeed a result of the core clock machinery, because mice with selective ablation of Bmal1 in the liver still displayed fasting hypoglycemia and altered glucose clearance despite having normal locomotor activity and feeding patterns.68,69 Further studies with tissue-specific manipulations of the core clock components will shed light on the role of individual tissue oscillators and on the molecular mechanisms underlying the metabolic disease phenotypes observed in circadian mutant mice. CHANGES IN METABOLISM LEAD TO BEHAVIORAL AND MOLECULAR DISRUPTION OF THE CLOCK The aforementioned studies demonstrate that disruptions in the circadian system lead to profound metabolic disturbance, but several studies have also revealed that the reciprocal relationship is also true: Alterations in metabolism disrupt circadian rhythms, as well as the sleep–wake cycle. Studies have demonstrated that feeding mice a high-fat diet leads to rapid changes in the period of locomotor activity, their diurnal feeding patterns, and the abundance and rhythmicity of canonical clock genes, nuclear hormone receptors that regulate the clock, and clock-controlled genes involved in fuel use in hypothalamus and peripheral tissues.70 Mice fed a high-fat diet displayed elevated sleep time (due to increased NREM time), but they had decreased
CHAPTER 40 • Animal Models for Disorders of Chronobiology: Cell and Tissue 467
“Vicious cycle hypothesis”
bolic networks will shed new light on the treatment of diseases associated with sleep or metabolic dysfunction, such as type 2 diabetes.75 ❖ Clinical Pearl
Sleep and circadian disruption
CARDIOMETABOLIC PHENOTYPES 1) Neurobehavioral ↑ Feeding during normal rest period 2) Clinical ↑ Visceral adiposity, triglycerides, free fatty acids, leptin, glucose 3) Molecular ∆ Metabolic gene transcription (liver, fat, hypothalamus, b cell)
Figure 40-4 Circadian and metabolic pathways reciprocally affect each other. Disruption of circadian rhythms or sleep results in an increased risk for a number of metabolic phenotypes, including obesity and type 2 diabetes. Conversely, changes in metabolism (induced either by genetics or by highfat feeding) reciprocally lead to the disruption of sleep and circadian homeostasis on both a physiologic and molecular level.
sleep consolidation.71 Food-restricted animals sleep less and also have a more fragmented sleep pattern.72,73 In addition to the diet-induced changes in circadian rhythms and sleep, genetic mouse models of obesity have demonstrated similar findings with regard to sleep–wake patterns. Leptin-deficient ob/ob mice—which are obese, have hyperphagia, and develop the metabolic syndrome— also have increased NREM sleep time, decreased sleep consolidation, and decreased locomotor activity.74 Together, these data suggest the existence of a vicious cycle whereby disruption in the central control of circadian rhythms results in reduced sleep duration and quality and increased risk of obesity and diabetes; conversely, the development of obesity or insulin resistance leads to deterioration of sleep and circadian homeostasis (Fig. 40-4).
CONCLUSIONS Enormous strides have been made in our understanding of the extensive interplay between circadian and metabolic systems since the cloning of the first mammalian clock gene more than a decade ago. The circadian and metabolic systems are in delicate balance with each other—disruption of the core clock network wreaks havoc on metabolic homeostasis, and changes in metabolism (either genetic or induced by high-fat feeding) alter the circadian network and sleep homeostasis. Key issues that remain to be resolved include the relative contribution of CNS oscillators versus peripheral oscillators in the regulation of circadian and metabolic homeostasis, as well as the physiologic roles of each of the peripheral tissue clocks. Given the concurrent increase in obesity and decrease in sleep, a more detailed understanding of the molecular pathways underlying the crosstalk between the circadian and meta-
Appreciation of the circadian control of glucose metabolism is critical for the diagnosis and treatment of metabolic disorders such as type 2 diabetes, because time of day must to be taken into account as an important variable influencing the effectiveness of drug treatment (chronopharmacology).
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44. Wijnen H, Boothroyd C, Young MW, Claridge-Chang A. Molecular genetics of timing in intrinsic circadian rhythm sleep disorders. Ann Med 2002;34(5):386-393. 45. Yin L, Wu N, Curtin JC, Qatanani M, et al. Rev-erbα, a heme sensor that coordinates metabolic and circadian pathways. Science 2007; 318(5857):1786-1789. 46. Canaple L, Rambaud J, Dkhissi-Benyahya O, Rayet B, et al. Reciprocal regulation of brain and muscle Arnt-like protein 1 and peroxisome proliferator-activated receptor alpha defines a novel positive feedback loop in the rodent liver circadian clock. Mol Endocrinol 2006; 20(8):1715-1727. 47. Desvergne B, Wahli W. Peroxisome proliferator–activated receptors: nuclear control of metabolism. Endocr Rev 1999;20(5):649688. 48. Lau P, Nixon SJ, Parton RG, Muscat GE. RORα regulates the expression of genes involved in lipid homeostasis in skeletal muscle cells: caveolin-3 and CPT-1 are direct targets of ROR. J Biol Chem 2004;279(35):36828-36840. 49. Sato TK, Panda S, Miraglia LJ, Reyes TM, et al. A functional genomics strategy reveals Rorα as a component of the mammalian circadian clock. Neuron 2004;43(4):527-537. 50. Rutter J, Reick M, Wu LC, McKnight SL. Regulation of clock and NPAS2 DNA binding by the redox state of NAD cofactors. Science 2001;293(5529):510-514. 51. Nakahata Y, Kaluzova M, Grimaldi B, Sahar S, et al. The NAD+dependent deacetylase SIRT1 modulates CLOCK-mediated chromatin remodeling and circadian control. Cell 2008;134(2):329-340. 52. Ramsey KM, Yoshino J, Brace CS, Abrassart D, et al. Circadian clock feedback cycle through NAMPT-mediated NAD+ biosynthesis. Science 2009;324(5927):651-654. 53. Asher G, Gatfield D, Stratmann M, Dibner C, et al. SIRT1 regulates circadian clock gene expression through PER2 deacetylation. Cell 2008;134(2):317-328. 54. Canto C, Gerhart-Hines Z, Feige JN, Lagouge M, et al. AMPK regulates energy expenditure by modulating NAD+ metabolism and SIRT1 activity. Nature 2009;458(7241):1056-1060. 55. Fulco M, Cen Y, Zhao P, Hoffman EP, et al. Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. Dev Cell 2008;14(5):661673. 56. Al-Regaiey KA, Masternak MM, Bonkowski M, Sun L, et al. Longlived growth hormone receptor knockout mice: interaction of reduced insulin-like growth factor i/insulin signaling and caloric restriction. Endocrinology 2005;146(2):851-860. 57. Rodgers JT, Lerin C, Haas W, Gygi SP, et al. Nutrient control of glucose homeostasis through a complex of PGC-1α and SIRT1. Nature 2005;434(7029):113-118. 58. Cohen HY, Miller C, Bitterman KJ, Wall NR, et al. Calorie restriction promotes mammalian cell survival by inducing the SIRT1 deacetylase. Science 2004;305(5682):390-392. 59. Nemoto S, Fergusson MM, Finkel T. Nutrient availability regulates SIRT1 through a forkhead-dependent pathway. Science 2004; 306(5704):2105-2108. 60. Haigis MC, Guarente LP. Mammalian sirtuins—emerging roles in physiology, aging, and calorie restriction. Genes Dev 2006; 20(21):2913-2921. 61. Turek FW, Joshu C, Kohsaka A, Lin E, et al. Obesity and metabolic syndrome in circadian Clock mutant mice. Science 2005;308(5724): 1043-1045. 62. Rudic RD, McNamara P, Curtis AM, Boston RC, et al. BMAL1 and CLOCK, two essential components of the circadian clock, are involved in glucose homeostasis. PLoS Biol 2004;2(11):e377. 63. Shimba S, Ishii N, Ohta Y, Ohno T, et al. Brain and muscle Arnt-like protein-1 (BMAL1), a component of the molecular clock, regulates adipogenesis. Proc Natl Acad Sci U S A 2005;102(34):12071-12076. 64. Fu L, Patel MS, Bradley A, Wagner EF, et al. The molecular clock mediates leptin-regulated bone formation. Cell 2005;122(5):803 -815. 65. Yang S, Liu A, Weidenhammer A, Cooksey RC, et al. The role of mPer2 clock gene in glucocorticoid and feeding rhythms. Endocrinology 2009;150(5):2153-2160. 66. Bur IM, Cohen-Solal AM, Carmignac D, Abecassis PY, et al. The circadian clock components CRY1 and CRY2 are necessary to sustain sex dimorphism in mouse liver metabolism. J Biol Chem 2009; 284(14):9066-9073.
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67. Okano S, Akashi M, Hayasaka K, Nakajma O, et al. Unusual circadian locomotor activity and pathophysiology in mutant CRY1 transgenic mice. Neurosci Lett 2009;451(3):246-251. 68. Kornmann B, Schaad O, Bujard H, Takahashi JS, et al. System-driven and oscillator-dependent circadian transcription in mice with a conditionally active liver clock. PLoS Biol 2007;5(2): e34. 69. Lamia KA, Storch KF, Weitz CJ. Physiological significance of a peripheral tissue circadian clock. Proc Natl Acad Sci U S A 2008; 105(39):15172-15177. 70. Kohsaka A, Laposky AD, Ramsey KM, Estrada O, et al. High-fat diet disrupts behavioral and molecular circadian rhythms in mice. Cell Metab 2007;6(5):414-421.
71. Jenkins JB, Omori T, Guan Z, Vgontzas AN, et al. Sleep is increased in mice with obesity induced by high-fat food. Physiol Behav 2005;87(2):255-262. 72. Borbely AA. Sleep in the rat during food deprivation and subsequent restitution of food. Brain Res 1977;124(3):457-471. 73. Danguir J, Nicolaidis S. Dependence of sleep on nutrients’ availability. Physiol Behav 1979;22(4):735-740. 74. Laposky AD, Shelton J, Bass J, Dugovic C, et al. Altered sleep regulation in leptin deficient mice. Am J Physiol Regul Integr Comp Physiol 2006;290:R894-R903. 75. Silva CM, Sato S, Margolis RN. No time to lose: workshop on circadian rhythms and metabolic disease. Genes Dev 2010;24: 1456-1464.
Circadian Disorders of the Sleep–Wake Cycle Kathryn J. Reid and Phyllis C. Zee Abstract Circadian rhythm sleep disorders (CRSD) are primarily due to alterations of the circadian time-keeping system or a misalignment between the endogenous circadian rhythm and external factors that affect the timing or duration of sleep. In this chapter, the nomenclature and diagnostic criteria for CRSDs and their subtypes are based on the criteria published in the International Classification of Sleep Disorders (ICSD-2). The most commonly encountered CRSDs are delayed sleep phase disorder (DSPD) and advanced sleep phase disorder (ASPD). CRSDs are characterized by bedtimes and wake times that are usually delayed (DSPD) or advanced (ASPD) 3 or more hours relative to desired or socially acceptable sleep and wake times. Free-running disorder occurs predominantly in blind individuals and is usually characterized by a steady daily delaying drift of the major sleep period. When the nonentrained circadian clock is out of phase with the timing of conventional sleep and wake times, individuals complain of insomnia and exces-
INTRODUCTION The sleep–wake cycle is generated by a complex interaction of endogenous circadian and sleep homeostatic (need for sleep increases as a function of prior wakefulness) processes, as well as social and environmental factors. Physiological sleepiness and alertness not only varies with prior waking duration, but also exhibits circadian variation. In humans, daily variation in physiological sleep tendency reveals a biphasic circadian rhythm of wake and sleep propensity,1,2 with a midday increase in sleep tendency occurring around 2 to 4 pm, followed by a robust decrease in sleep tendency and increase in alertness that lasts through the early to midevening hours. A primary role of the circadian clock is to promote wakefulness during the day, and thus to facilitate the consolidation of sleep during the nighttime hours.1,3-5 In humans, this interaction between circadian and homeostatic processes results in approximately 16 hours of wakefulness and 8 hours of nocturnal sleep. The timing and duration of the sleep–wake cycle depends upon the synchronization of the endogenous circadian clock with the external physical light and dark cycle and social or professional demands. Circadian rhythm sleep disorders (CRSD) arise when there is disruption of this internal timing mechanism or a misalignment between the timing of the circadian clock and the 24-hour social and physical environments. These dyssynchronous states fall into two categories: (1) the terrestrial light–dark (LD) cycle may change relative to circadian timekeeping (shift work disorder and jet lag), or (2) circadian timekeeping may change relative to the terrestrial LD cycle (delayed sleep phase disorder [DSPD], advanced sleep phase disor470
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sive daytime sleepiness. Irregular sleep–wake rhythm disorder is characterized by a lack of a well-defined circadian rhythm of sleep and waking and is most commonly seen in association with neurodegenerative disorders. Although the basic pathophysiology of these disorders is an alteration in the endogenous circadian timing system, the clinical picture is often influenced by behavioral and environmental factors. Therefore, any comprehensive treatment approach for these disorders needs to address both the circadian disturbance and the behavioral or environmental factors that affect sleep and wake times. Timed exposure to circadian synchronizing agents, such as bright light and melatonin, together with adequate attention to sleep hygiene have been shown to be effective treatment for the management of CRSD. Recent advances in our understanding of the genetic and physiological basis of some types of CRSD will lead the way to improvements in both diagnostic as well as therapeutic approaches for the clinical management of these disorders.
der [ASPD], free-running disorder (FRD) and irregular sleep–wake rhythm). The first circumstance occurs in the presence of a normal circadian timekeeping system and is generally self-limited or resolves with environmental change. The latter circumstance is believed to occur because of chronic alterations in the circadian system that result in the inability of the circadian pacemaker to achieve a conventional phase relation with the external world. This chapter will focus on the second group of disorders including DSPD, ASPD, FRD, and irregular sleep–wake rhythm, whereas shift-work sleep disorder and jet lag are covered extensively in Section 9, Chapter 71. Because circadian variation in wakefulness and sleep propensity are the most apparent of the many behavioral and physiologic outputs of the circadian pacemaker, it is not surprising that the most apparent circadian rhythm disorders involve the sleep–wake cycle.6 Disruptions in the timing of sleep and wakefulness are often associated with symptoms of insomnia or excessive sleepiness that cause patients to seek medical attention. Thus, in clinical practice, CRSDs are often underrecognized, yet they should be considered in the differential diagnosis of any patient presenting with symptoms of insomnia or hypersomnia. A multimodal treatment approach of behavioral and pharmacologic strategies aimed to improve circadian function and alignment of circadian rhythms to the 24-hour environment is often necessary to consolidate sleep and improve daytime function in patients with CRSDs. Increasingly detailed knowledge about how the circadian system responds to photic as well as to nonphotic entraining agents is increasing the number of practical therapies that can be used in clinical settings.
ENTRAINMENT OF CIRCADIAN RHYTHMS The suprachiasmatic nucleus (SCN), located in the anterior hypothalamus, is the central pacemaker responsible for the generation of circadian rhythmicity in mammals.7 Animals and humans removed from the external LD cycle and other time cues (zeitgebers) exhibit a self-sustaining cycle of sleep and wakefulness as well as many other physiologic and hormonal rhythms. The endogenous frequency of this cycle of oscillation or free-running period is largely genetically determined.8 The basic molecular mechanism by which SCN neurons generate and maintain a self-sustaining rhythm is via an autoregulatory feedback loop in which oscillating circadian gene products regulate their own expression through a complex system of transcription, translation, and posttranslational processes.9 In the mouse10 and hamster,11 genes have been identified that lengthen10 and shorten11 the free-running period. The mammalian circadian period is generally slightly longer than 24 hours in diurnal animals, and slightly shorter than 24 hours in nocturnal animals. In humans, the average circadian period has been estimated to be approximately 24.18 hours12; therefore, it must be synchronized or entrained on a regular basis to the 24-hour terrestrial day by external influences. Entrainment by Light Light is the major external time cue in mammals. Light reaches the SCN by afferent projections from the retina via the retinohypothalamic tract.7 Evidence indicates that the primary circadian photoreceptors are the melanopsincontaining retinal ganglion cells, which in turn send photic information via projections to the SCN.13,14 Although circadian rhythms can be entrained to LD cycles that are not exactly 24 hours long, entrainment is restricted to cycles with periods that are close to 24 hours long.15 The range of entrainment can vary from species to species and is dependent on the experimental conditions (e.g., intensity of light–dark cycle, whether the period of the light–dark cycle is changed gradually or rapidly), but in general, animals do not entrain readily to LD cycles that are more than a few hours shorter or longer than the period of the endogenous circadian rhythm. If the period of the LD cycle is too short or long for entrainment to occur, then the circadian rhythm will free-run with a period of the endogenous pacemaker. One of the most widely used methods to examine how the LD cycle influences the circadian system has been to expose animals and humans maintained in constant conditions to pulses of light. The effects of the light pulse on a phase reference point of a circadian rhythm (e.g., onset of melatonin, minimum of body temperature) in subsequent cycles is then determined. The direction and magnitude of the phase shifts are strongly dependent on the circadian time at which the light pulse occurs. A phase– response curve (PRC) is a plot of the magnitude and direction of the time shift induced by an environmental perturbation as a function of the circadian time at which the perturbation is given. Light pulses presented near the onset of the subjective night (part of the circadian cycle that occurs during the dark or nighttime) delay circadian
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rhythms, whereas light pulses presented in the late subjective night or early subjective day (part of the circadian cycle that occurs during the light or daytime) advance circadian rhythms. Extensive studies have demonstrated that the LD cycle can entrain circadian rhythms, and that bright light can be used to manipulate human rhythms under a variety of experimental conditions.16,17 Although bright light (intensities approximating sunlight) is a very strong and reliable entraining agent for the circadian system,17 there is evidence that lower intensities, such as those encountered in ordinary room lighting can also affect the timing of human circadian rhythms.18 The discovery that in humans, both light-induced phase shifts and melatonin suppression are most sensitive to short wavelength light of approximately 460 nm19,20 provides an exciting new avenue for the development of light therapies to treat CRSDs. Entrainment by Nonphotic Signals The roles of activity and social cues as synchronizing agents for the human circadian system have been recognized since the early 1970s. Studies by Aschoff showed that scheduled bedtimes, mealtimes, and various timed social cues were able to entrain circadian rhythms.21 More recent studies indicate that sleep and social schedules may also phase shift the circadian clock.22 In addition, physical exercise during the night can produce a phase delay in human circadian rhythms.23 These findings indicate that scheduled social and physical activity programs may also be useful strategies for the treatment of CRSDs. Melatonin Melatonin is an important modulator of circadian rhythms,24 and it alters the timing of circadian rhythms in animals25 and humans.26 The circadian rhythm of melatonin production and release is controlled by the SCN via an indirect pathway, a noradrenergic synapse from the superior cervical ganglion to the pineal gland.27 The PRC for melatonin in humans indicates that administration of exogenous melatonin to humans in the early evening advances the phase of circadian rhythms, whereas administration in the early morning delays the phase, with the strongest phase-shifting effects of exogenous melatonin occurring during the evening, just preceding the increase in endogenous melatonin levels.28,29 In addition to its phase resetting properties, evidence supports a role for melatonin in sleep modulation by increasing evening sleep propensity and reducing core body temperature.24 Melatonin has been shown to decrease the firing rate of SCN neurons,30 and it has been proposed that by its inhibition of SCN firing, the increase of melatonin in the evening creates a sleep-permissive state. The potential importance of melatonin for regulating the sleep–wake cycle has led to interest in its use for treatment of insomnia and CRSDs. Indeed, there is good evidence that melatonin may be effective for entraining circadian rhythms in blind people with free-running sleep– wake cycles31 and phase advancing circadian rhythms in people with DSPD.32 Another potential use for melatonin has been suggested from the role of the circadian system in maintaining consolidation of sleep during the early morning hours in the elderly.33
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Advanced sleep phase disorder Typical sleep phase Delayed sleep phase disorder Figure 41-1 Schematic representation of the temporal distribution of sleep and wake in patients with circadian rhythm sleep disorders. Patients with advanced sleep phase disorder typically complain of evening sleepiness and either early-morning awakening or sleep disruption. Patients with delayed sleep phase disorder complain of difficulty initiating sleep, usually before 2 am, and have difficulty awakening in the morning.
DELAYED SLEEP PHASE DISORDER, DELAYED SLEEP PHASE TYPE, DELAYED SLEEP PHASE SYNDROME Clinical Features Delayed sleep phase disorder is characterized by sleep onset and wake times that are usually delayed 3 to 6 hours relative to conventional sleep–wake times (Fig. 41-1). The typical patient finds it difficult to initiate sleep before sometime between 2 and 6 am and, when free of societal constraints, prefers wake times that are between 10 am and 1 pm. Sleep itself is reported to be normal for the person’s age.34 These symptoms are chronic, usually of at least three months’—and quite often of many years’—duration. The clinical picture may be similar to sleep-onset insomnia. Patients are unable to advance their sleep times despite repeated attempts, and may report a history of prolonged sedative-hypnotic drug use, bedtime use of alcohol, behavioral interventions, or psychotherapy.35 Patients often report feeling most alert in the late evening and score highly as night people on a morningness-eveningness scale.36 Enforced “conventional” wake times may result in chronically insufficient sleep and excessive daytime sleepiness. Sleepiness is greatest in the morning and lessens as the circadian drive for wakefulness peaks in the late afternoon. In adolescents the syndrome may be associated with daytime irritability and poor school performance,37 whereas in adulthood, the syndrome may be associated with impaired job performance and associated financial difficulty, as well as with marital problems.38 DSPD may be mistaken for depression, in which the sleep–wake cycle may also be delayed (or advanced). Several studies, generally from psychiatric clinics, have emphasized an association of DSPD with mood and personality disorders.38,39 Epidemiology DSPD has been reported as young as preadolescence and beyond sixty years of age.38 Although the actual prevalence of DSPD in the general population is not well characterized, evidence from one population based study indicates a prevalence of 0.17%.40 DSPD is reported to be more common in adolescents and young adults, with a reported prevalence of 7%,41 while in middle-aged adults, the prevalence may be one tenth of that, or 0.7%.42 In a sleep disorders clinic, 6.7%34 to 16%39 of patients seen for a primary complaint of insomnia were determined to have
DSPD. There are no known gender differences in prevalence. Pathogenesis It has been pointed out that the tendency for late sleeping is not simply a function of the circadian drive for wakefulness interacting with the sleep homeostat, but rather is analogous to eating or other behaviors that are mandated by physiology but overlaid by varying individual emotional, social, and medical states.39 Although the exact cause of DSPD is not known, there have been several mechanisms proposed including both behavioral and physiological factors. Behavioral preference may play a major role in some cases of DSPD, particularly when bed times and rise times are not enforced. In adolescence for example, the biological delay in the timing of circadian rhythms43 is likely exacerbated by late evening activities, such as doing homework, watching TV, and using the internet.44 Another factor may be the use of caffeine to combat sleepiness during normal waking hours. Staying up late and waking up late in the morning or early in the afternoon may result in an abnormal relationship between the endogenous circadian rhythm and the sleep homeostatic process that regulates sleep and wakefulness. Evidence also shows that under certain conditions (a background of dim light), ambient artificial light (as low as 100 lux) at night may be of sufficient intensity to affect circadian timing.18 Therefore, light exposure later in the evening may also perpetuate and exacerbate the phase delay. Furthermore, late wake times will delay exposure to light in the morning and may prevent active advancement of the circadian clock, allowing it to drift to a new phase relation with external clock time. However, for many individuals with DSPD, symptoms often persist despite attempts to structure sleep and wake times, resulting in severe social or professional consequences,35 suggesting that behavioral factors alone do not fully explain this disorder. There is considerable evidence that DSPD is the result of alterations in the endogenous circadian system. For example, many physiologic markers of circadian phase persist in a delayed pattern despite enforced sleep–wake times,35 and there is also evidence that some individuals with DSPD have a hypersensitivity to nighttime suppression of melatonin by bright light.45 Reduced sensitivity of the oscillator to photic entrainment (i.e., a reduction in the amplitude of the advance portion of the PRC to light) has also been hypothesized, as has a prolonged free-running period length of the circadian cycle.35,46 Furthermore, the duration and timing of environmental light and dark exposure may play a role in the expression of the DSPD phenotype. For instance, the prevalence of DSPD may be increased at extreme latitudes.47 DSPD has also been reported following minor traumatic brain injury.48 There is also evidence for a genetic basis to DSPD. In some cases the syndrome may be familial presenting with an autosomal dominant mode of inheritance.49 Further support for a genetic basis for DSPD derives from reports of polymorphisms in circadian genes such as, hPer3, arylalkylamine N-acetyltransferase gene, HLA genes, and Clock.50-53 Although it is commonly accepted that DSPD is predominantly a result of alterations of circadian timing, there
is recent evidence that alterations in the homeostatic regulation of sleep may play an important role as well.54,55 Polysomnographic recordings of sleep in individuals with DSPD have shown that sleep architecture is not disrupted after the initiation of sleep when subjects are allowed to sleep until their desired wake times.37,56 However, following 24 hours of sleep deprivation, subjects with DSPD, when compared to controls, show a decreased ability to compensate for sleep loss during the subjective day and the first hours of subjective night.54,57 Therefore, it is likely that both alterations in circadian timing and impaired sleep recovery contribute to symptoms of insomnia and excessive sleepiness in DSPD. Diagnosis The diagnosis of DSPD is usually made on the basis of the patient’s history of chronic or recurrent complaint of symptoms of insomnia due to a stable delay in the timing of the major sleep and wake period.58 The sleep disturbance is associated with impairment of social, occupational, or other areas of functioning. In addition, sleep log or actigraphy monitoring should be performed for at least 7 days to demonstrate a stable delay in the timing of the habitual sleep period. Actigraphy is a practical tool for assessing sleep–wake cycles relative to clock time, and has become more widely available clinically (Fig. 41-2A).59 A morningness-eveningness questionnaire, such as the Horne-Ostberg questionnaire36 or the Munich chronotype60 questionnaire, may be useful in confirming the patient’s circadian preference, but is not required to make the diagnosis.61,62 To make the diagnosis, medical, mental, or sleep disorders that may cause alterations in the sleep–wake cycle, insomnia, or excessive sleepiness should be excluded or adequately treated. In adolescents, social maladjustment, family dysfunction, school avoidance, and affective disorders should be considered in the differential diagnosis. Nocturnal polysomnography is not necessary to establish the diagnosis, but should be performed when another primary sleep disorder such as sleep apnea or parasomnia is suspected. When performed during conventional sleep laboratory hours, polysomnography often shows a prolonged sleep onset latency as well as prolonged rapid eye movement (REM) latency, and may sometimes, in conjunction with an antecedent sleep log be a clue to the diagnosis. The use of other physiologic markers of circadian timing such as continuous recording of body temperature,63 or dim light plasma melatonin onset (DLMO)64 may also aid in determining the phase relation of circadian and terrestrial time, although routine clinical availability remains limited. DLMO is probably the most useful marker for circadian pacemaker output.65 Individuals with DSPD usually have DLMO times that occur after 10 pm (Fig. 41-3A).64,66,67 Determination of DLMO can be made by measurements of melatonin from plasma or saliva. Commercially available salivary determination of DLMO for clinical use may be feasible in the near future. Treatment The goal of therapy is to align the timing of the circadian clock with the desired 24-hour LD cycle. Richardson6 has
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noted that treatment of DSPD is the same whether it is the result of a primary behavioral or a primary physiologic process. Adherence to good sleep hygiene principles and identification and treatment of comorbid medical and psychiatric disorders are essential components in the management of DSPD. In addition, chronotherapy, light therapy, and pharmacological agents, such as melatonin, have been shown to be useful treatments for patients with DSPD. Chronotherapy The use of chronotherapy has been successful in a small group of patients in a laboratory setting.35 Chronotherapy requires a successive delay of sleep times by 3 hours daily over a 5 to 6 day period until the desired sleep time is achieved. This shift is followed by rigid adherence to a set sleep–wake schedule and good sleep hygiene practices. However, outside the laboratory setting, the potential confounding effects of light exposure at the wrong circadian time may limit the effectiveness and practicality of this approach.6 Light As described earlier, light plays a major role in resetting the human circadian pacemaker.16,17,68 Therapy with bright light in the morning (the advance portion of the human PRC) should advance the phase of circadian rhythms in DSPD, and may be more practical than chronotherapy.69 Although a number of reports of successful application of bright light therapy in DSPD exist,70-73 large, randomized, placebo-controlled studies to determine the intensity, duration, and overall effectiveness are still needed. Rosenthal and colleagues found that 2 hours of bright light exposure (2500 lux) in the morning (7 to 9 am), together with light restriction in the evening, successfully phase advanced (by 1.4 hours) circadian rhythms of core body temperature and multiple sleep latencies in 20 patients chosen prospectively after meeting clinical criteria for DSPD.73 In contrast, a retrospective report from a referral sleep clinic found that only 7 of 20 patients with DSPD treated with bright light alone were able to entrain reliably to a desired sleep schedule. The human PRC to a single 3-hour bright light pulse suggests that a light pulse given slightly before the time of body temperature minimum will result in a maximal phase delay, whereas a pulse given slightly after the minimum will cause a maximal phase advance (each about 2 hours).68 When light pulses over three successive cycles were used, larger shifts (4 to 7 hours) can be produced. Because body temperature minimum is not routinely measured clinically, light therapy is usually timed using sleep logs to estimate the patient’s endogenous circadian phase. A light pulse of 1 to 2 hours’ duration and between 2500 and 10,000 lux is usually administered toward the end of the sleep–wake cycle. Because the portion of the PRC at which the greatest phase advance can be achieved occurs during sleeping hours, light is usually given immediately upon awakening in the morning, which results in a smaller phase advance. However, in severely delayed individuals the sleep–wake cycle may not necessarily correlate with circadian phase; therefore, early morning light could in theory be inadvertently given on the delay portion of the PRC, worsening the problem. Regenstein and Pavlova39 reported a patient
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Figure 41-2 Representative rest–activity cycles recorded with wrist-activity monitoring of patients with circadian rhythm sleep disorders. The black bars indicate activity levels recorded at the nondominant wrist. A, Delayed sleep phase disorder with sleeponset times of approximately 4 to 6 am and wake times of 10 am to 2 pm. B, Advanced sleep phase disorder with sleep onset times between 8 and 10 pm and wake time between 5 and 6 am.
who slept later after receiving light exposure at 6 am. Another factor that may limit the practicality of bright light treatment is that many individuals with DSPD may find it difficult to wake in time for administration of bright light therapy.39 Although the timing, intensity, and duration of light exposure have not been fully established in clinical practice, there is sufficient evidence to support the efficacy of bright light therapy for the treatment of DSPD. The recent practice parameters established by the American
Academy of Sleep Medicine considered light therapy as a treatment guideline for DSPD.61 Melatonin Administration of exogenous melatonin also shifts the phase of the endogenous circadian clock. It should be noted that the PRC for melatonin is nearly opposite to the PRC for light exposure: melatonin delays circadian rhythms when administered in the morning and advances them when administered in the afternoon or early evening.28,74
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Figure 41-3 Dim light melatonin profiles of an individual with delayed sleep phase disorder with a dim light melatonin onset (DLMO) at 1:30 am (A) and an individual with advanced sleep phase disorder with a DLMO at 7 pm (B). The arrows indicate the DLMO calculated as two standard deviations above the mean of baseline.
In a randomized, double-blind, placebo-controlled crossover study of eight patients with DSPD, 5 mg melatonin administered at 10 pm resulted in a phase advance in all subjects, with a mean advance of sleep onset time of 82 minutes and of wake time of 117 minutes.75 Upon stopping melatonin, all patients reverted to their previous sleep– wake cycle within 2 to 3 days. A study to determine the optimal timing and dose of melatonin to treat DSPD indicates that melatonin given about 6 hours before the DLMO resulted in the largest phase advance and that there was no significant difference in the effect of either a 0.3 mg or 3mg dose.76 The physiologic (phase shifting) dose of melatonin is approximately 0.1 to 0.5 mg or one tenth to one fiftieth of commercially available preparations.77 Side effects of melatonin at these dose ranges are minimal, although sedative effects occur at higher (80 mg) doses. Melatonin has also been used successfully in several studies in children and adolescents with a combination of delayed
sleep phase and other comorbid conditions such as attention deficit disorder and neurodevelopmental disabilities.78-80 Although several studies have demonstrated the potential effectiveness of melatonin administered in the evening,32,75,76,79,81,82 the relatively small number of clinical studies, together with the variability in dose and time of administration, have been limiting factors in the development of a standardized approach for treatment with melatonin. The practice parameters established by the American Academy of Sleep Medicine considered melatonin as a treatment guideline for DSPD.61 The combination of morning bright light and early evening melatonin may be even more efficacious. However, clinical data on combined treatment modalities are lacking in DSPD. In summary, the clinical approach to a patient with DSPD should initially include assessment of circadian sleep phase by sleep diary or actigraphy measures for a period of at least 7 days.59,61 Behavioral interventions such as a structured sleep–wake schedule, good sleep hygiene practices, and avoidance of exposure to bright light in the evening should be prescribed for all patients.61 In addition, exposure to bright light in the morning (1 to 2 hours shortly after awakening) or administration of melatonin in the evening (5 to 6 hours before habitual sleep time) can advance the timing of the sleep–wake cycle. It is important to note that melatonin has not been approved by the U.S. Food and Drug Administration for this indication.
ADVANCED SLEEP PHASE DISORDER, ADVANCED SLEEP PHASE TYPE, ADVANCED SLEEP PHASE SYNDROME Clinical Features Advanced sleep phase disorder (ASPD) is characterized by habitual and involuntary sleep and wake times that are usually more than 3 hours earlier than societal means (see Fig. 41-1). Sleep itself is normal for age. Individuals often complain of persistent and often irresistible sleepiness in the late afternoon or early evening, often preventing their participation in desired evening activities. Because their circadian drive for wakefulness begins to rise prematurely, they may complain of involuntary early morning awakening (2 to 5 am) which occurs even if sleep onset is voluntarily delayed. Because of professional or social obligations, later bedtimes can lead to chronically insufficient sleep and excessive daytime sleepiness. In general, individuals with ASPD have less difficulty adjusting to the earlier schedule than those with DSPD, because societal constraints on sleep time are less rigid than on wake time. Individuals with ASPD may gravitate to professions that are in phase with their endogenous circadian clock. Because of the early morning awakening, a diagnosis of depression may be erroneously made. Epidemiology ASPD is less frequently reported83 than DSPD, possibly because affected individuals may not perceive it to be pathologic. The actual prevalence of ASPD in the general population is unknown, but is thought to be rare.40 The prevalence in middle age adults has been estimated to be
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about 1%,42 and it increases with age. Both genders appear to be equally affected. Pathogenesis As with DSPD, the etiology of ASPD is not well understood, although several hypotheses have been proposed. An abnormal PRC to light exhibiting an increased area under the advance portion of the curve could in theory result in a persistent phase advance. ASPD may also be the result of a shortened endogenous period. Evidence of a shortened free-running period of less than 24 hours has been demonstrated in a 66-year-old woman with advanced sleep and wake times, with intact or even enhanced responsiveness to photic entrainment16 and in a single member of a familial case of ASPD.84 Several familial cases of ASPD have been reported in the literature.84-86 These families show a clear autosomal dominant mode of inheritance of ASPD. Genetic analysis of these familial cases indicates that there is heterogeneity of this disorder between and even within large families. Gene polymorphisms have been identified in the circadian clock gene hPer2 in a large family with advanced sleep phase,87 and in another family a missense mutation in CKI-delta is reported.88 Diagnosis A diagnosis of ASPD is made primarily on the basis of the clinical history. Individuals have a chronic or recurrent complaint of difficulty staying awake until the desired time in the evening and inability to remain asleep until the desired and socially acceptable time for awakening. The sleep disturbance is associated with impairment of social, occupational, or other areas of functioning.58 When allowed to choose their preferred schedule, patients will exhibit normal sleep quality and duration for age and maintain an advanced, but stable phase of entrainment to the 24-hour day. Sleep log or actigraphy monitoring for at least 7 days should be performed to confirm a stable advance in the timing of the habitual sleep period.58 The use of actigraphy, if available, is frequently helpful (see Fig. 41-2B). Other medical, mental, or sleep disorders that may cause alterations in the sleep–wake cycle, insomnia, or excessive sleepiness should be excluded or adequately treated. Major affective disorders should be carefully excluded. Polysomnography is not required for the diagnosis, but in some patients, it may be necessary to evaluate for sleep-disordered breathing, periodic limb movements, or other causes of sleep disruption. Polysomnography should ideally be performed during the patient’s normal sleep period. If it is carried out during conventional laboratory hours, then a shortened or normal sleep onset latency, early REM, and early wake time may be seen. Therefore, it is important to consider depression, narcolepsy, or other disorders in the differential diagnosis.83,89 When the diagnosis is in question, additional physiological measures of circadian timing, such as continuous ambulatory monitoring of body temperature or collection of salivary melatonin samples to determine DLMO (see Fig. 41-3B) may be clinically useful to confirm the advance in circadian phase. Patients with ASPD have been reported to have a DLMO85 and core body temperature minimum84
that is advanced several hours compared to controls. A morningness-eveningness scale, such as the Horne-Ostberg questionnaire, to gauge the patient’s best time of performance, is also useful.36,62 Treatment There are several therapeutic approaches used to treat ASPD, each with practical limitations. A chronotherapeutic approach—advancing bedtime by 3 hours every 2 days until the desired bedtime was reached—has been reported,83 although relapse occurred quickly.89 Bright light therapy during the delay portion of the PRC (early evening) is usually tried, although data on its efficacy in ASPD are limited. Bright light from 7 to 9 pm in elderly subjects with sleep maintenance complaints resulted in a phase advance and reduced awakenings.90 The practice parameters established by the American Academy of Sleep Medicine considered bright light as a treatment option for ASPD.61 Melatonin given in the early morning, usually upon awakening, could in theory result in a phase delay according to data from the PRC to melatonin.28,77 However, evidence for its effectiveness or safety in the treatment of patients with ASPD is generally lacking.62,91 The sedating effects of melatonin, which can be variable in patients, may limit its usefulness in this regard.
FREE-RUNNING DISORDER, NONENTRAINED TYPE, NON–24HOUR SLEEP–WAKE SYNDROME, HYPERNYCHTHERMAL SYNDROME Clinical Features Free-running disorder (FRD) is thought to be the result of a circadian pacemaker that has no stable phase relation to the 24-hour LD cycle. Because most individuals must maintain a regular sleep–wake schedule, the clinical picture is that of periodically recurring problems with sleep initiation, sleep maintenance, and rising, as the circadian cycle of wakefulness and sleep propensity moves in and out of synchrony with a fixed sleep period time.92 Without social constraints, sleep onset and wake times are often successively delayed each day (Fig. 41–4). This is analogous to the free-running state created when all zeitgebers are removed.93 Because the duration and quality of sleep depends upon when it occurs in relation to the circadian cycle,3 phase jumps between two physiologically permissive periods for sustained sleep can be observed.94,95 Epidemiology FRD is rare in sighted people, occurring most often in totally blind individuals.92,96-98 In one series, 50% of totally blind persons had free-running plasma melatonin rhythms;97 in another, 73% were not entrained to a 24-hour sleep–wake rhythm.99 In a large study of 1073 blind individuals, FRD was estimated to occur in 18% of those that were totally blind and 13% of those that were almost blind.100 A few cases of FRD have also been reported in sighted individuals.93,101,102
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Pathogenesis The etiology in blind people is most likely either reduced or absence of the entraining effects of light, although nonphotic time cues, such as an externally imposed 24-hour sleep–wake cycle and social activity also appear insufficient to entrain some individuals.92 The melatonin rhythm may be damped103 or nonexistent,104 or may be normal but delayed.93,96 Coexistent mental retardation, which could make it difficult to process social time cues, may contribute to the symptoms in some individuals.105 In some cases, totally blind persons without conscious perception of light nevertheless exhibit normal suppression of melatonin when exposed to very bright light, and do not appear to have sleep difficulties.99 The etiology in sighted individuals is unknown. It has been postulated that sighted individuals may have a reduced sensitivity to the phase-resetting effects of light,93 and that they may have an increased incidence of psychiatric conditions,102 such as depression or certain personality disorders, which could precipitate the development of the syndrome by changing or removing social time cues.93 Nonentrained sleep–wake cycles have developed after chronotherapy for apparent delayed sleep phase type,93,106 prompting the proposal that such therapy could prolong the free running period to the point where it becomes nonentrainable to a 24-hour LD cycle.106 However, freerunning periods that are too short (less than 23 hours) or too long (greater than 27 hours)17 for stable entrainment to a 24-hour cycle have never been demonstrated in humans. Because persons with DSPD tend to receive more light exposure in the delay (evening) portion of their PRCs than during the advance portion (early morning), progres-
sive phase delays may sometimes be observed and mistaken for a nonentrained pattern.6,93 Diagnosis The diagnosis of FRD is made primarily by a clinical history of insomnia or excessive sleepiness related to abnormal synchronization between the 24-hour LD cycle and the endogenous circadian rhythm of sleep and wake propensity.58 The pattern of sleep and wake times typically delay each day with a period longer than 24 hours. The pattern is present for at least 1 month and can be confirmed by sleep diary or actigraphy for at least 7 days (but preferably longer) to establish the progressive daily drift in the timing of sleep and wake times (see Fig. 41-4). Close analysis of the sleep–wake cycle may reveal two distinct sleep–wake cycle periods, alternation between which can be manifested by phase jumps.95 The sleep disturbance should be accompanied by impairment of social, occupational, or other areas of functioning. It is important to exclude or adequately treat other medical, mental, or sleep disorder that may cause alterations in the sleep–wake cycle, insomnia, or excessive sleepiness. If the diagnosis is in question, polysomnography may be useful to evaluate for other types of sleep disorders. Polysomnography, when performed at the appropriate circadian time, is usually normal.93 Overriding behavioral factors predisposing to irregular sleep–wake cycles (substance abuse, dementia, personality or affective disorders) should also be considered in the evaluation. Treatment Melatonin appears to be emerging as the initial treatment of choice in blind and sighted individuals with
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FRD.26,93,96,98,107-109 Administration is started when the patient’s free-running period approaches the normal or desired phase (i.e., sleep onset times between 10 and 11 pm). Doses sufficient for phase shifting (0.1 to 0.5 mg) are then given between 8 and 9 pm, or near the expected time of DLMO.93,98 Initiating evening dosing when the freerunning period is not in the “normal” phase could result in an inappropriate delay or advance of circadian phase and prolong the time to entrainment. Bright light entrainment is an option in sighted individuals or in blind individuals who exhibit intact photic suppression of melatonin.110 Vitamin B12 has been anecdotally reported to be effective in treating nonentrained type,111,112 although the mechanism is unknown. Benzodiazepines have not been systematically studied, although several anecdotal reports of their possible effectiveness exist.111,112 Entrainment by nonphotic stimuli (e.g., structured social cues) alone have not been successful. The practice parameters established by the American Academy of Sleep Medicine considered bright light and melatonin administration as options for the treatment of FRD, and in blind individuals they recommended melatonin administration as a treatment guideline.61
IRREGULAR SLEEP–WAKE RHYTHM, IRREGULAR SLEEP–WAKE TYPE, IRREGULAR SLEEP–WAKE DISORDER Clinical Features Irregular sleep–wake rhythm (ISWR) is characterized by the absence of a well-defined circadian sleep–wake cycle.
There is typically no major sleep period. Rather, patients present with 3 or more sleep episodes of varying length during a 24-hour period. Diagnosis of this disorder requires a complaint of insomnia or excessive sleepiness associated with multiple irregular sleep bouts or naps during a 24-hour period.58 Despite irregular and fragmented sleep periods, the total sleep time per 24-hour period is usually normal for age. Epidemiology The prevalence of the ISWR in the general population is unknown but estimated to be rare.113 There is no evidence of gender differences. ISWR is most commonly seen in association with age-related comorbid neurological disorders such as dementia and Alzheimer’s disease.62 It is also seen in brain injury and children with mental retardation. Pathogenesis ISWR is thought to result from dysfunction of the central processes responsible for the generation of circadian rhythms114,115 or reduced exposure to bright light and regular social schedules. In institutionalized elderly and those with dementia, these factors are thought to contribute to the development and maintenance of irregular sleep–wake patterns.116,117 Even when controlling for the level of dementia, lower daytime light levels have been associated with an increase in nighttime awakenings.118 Evidence suggests that both dysfunction of circadian regulation and reduced exposure to environmental signals are likely involved in the etiology of irregular or arrhythmic sleep–wake patterns.
Diagnosis In addition to a clinical history, continuous monitoring of sleep and wake activity with actigraphy and a sleep log for a minimum of 2 weeks are useful diagnostic tools. Actigraphic recordings show disturbed or low-amplitude circadian rhythm with loss of the normal diurnal sleep–wake pattern with at least three distinct sleep periods per 24 hours (Fig. 41-5). This disturbed sleep–wake pattern should be associated with a chronic complaint of insomnia (usually sleep maintenance) and excessive daytime sleepiness. ISWR should be distinguished from poor sleep hygiene and voluntary maintenance of irregular sleep schedules as seen with shift work.58 Treatment Clinical management aims to improve the amplitude of circadian rhythms and their alignment with the external environment. Increasing exposure to synchronizing agents, such as bright light119-121 and structured social and physical activities122 has been used to consolidate sleep–wake cycles. Mixed-modality therapies combining bright light exposure, physical activity, and other behavioral elements are indicated in the treatment of ISWR as outlined in the parameters established by the American Academy of Sleep Medicine.61 Randomized, controlled studies using mixed modality therapies have shown increases in the robustness of the rest–activity rhythm and reductions in nighttime awakening following treatments that increase light levels, increase light in combination with evening melatonin administration, implement measures to keep nursing home residents out of bed during the day, implement structured physical activity, institute a bedtime routine, and reduce nighttime noise and light in residents’ rooms.123-126 Another study using a combination of bright light, chronotherapy, vitamin B12 and hypnotics was successful in 45% of patients with irregular sleep cycles.113 Evening melatonin administration has been used successfully to improve disturbed sleep–wake patterns in children and adults with mental retardation.127-129 In this population melatonin is recommended as a treatment option in the practice parameters established by the American Academy of Sleep Medicine.61 Despite the potential use of both behavioral and pharmacological interventions, treatment may be difficult and outcomes variable.
CONCLUSION Disorders of the sleep–wake cycle attributed to the disruption of the circadian timing system are characterized by an abnormal temporal distribution of the major sleep period within the 24-hour day. Although there is evidence that many of these disorders are the result of alterations in the circadian clock, more studies are needed to confirm this theory. The impact of these disorders is probably larger than estimated in terms of numbers, misdiagnoses, and health consequences. Most sleep clinics do not yet provide specific diagnostic tools to assess circadian rhythm profiles. Furthermore, many of the proposed therapies, including light, are often considered experimental by the health insurance industry. Application of our expanding knowledge of basic human circadian and sleep physiology to clinical practice remains an important challenge.
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❖ Clinical Pearl Circadian rhythm sleep disorders should be considered in the differential diagnosis of patients presenting with symptoms of insomnia or excessive sleepiness. Furthermore, circadian rhythm sleep disorders, such as delayed sleep phase disorder, may be comorbid with other types of sleep disorders, making the diagnosis and treatment even more challenging. For effective management of circadian rhythm sleep disorders, one must obtain as accurate a measure of circadian timing as possible. Sleep onset time (determined by sleep diary or actigraphy) can be useful to determine circadian phase (dim light melatonin onset occurs approximately 2 hours before sleep onset) in the clinical setting. Behavioral interventions such as sleep hygiene, particularly enforcement of stable sleep and wake times, exposure to light at the correct time of the day and avoidance of exposure at the wrong time of the day is the basic approach for all patients. Melatonin may be useful for the treatment of delayed sleep phase disorder and free-running disorder. However, melatonin has not been approved by the U.S. Food and Drug Administration for the treatment of circadian rhythm sleep disorders, and adverse vascular and endocrine effects need to be taken into account, particularly in patients who are at increased risk.
Acknowledgments We acknowledge the contribution of the late Steven K. Baker to the original version of this chapter. Support for this manuscript was provided by RO1HL69988. REFERENCES 1. Dijk DJ, Czeisler CA. Paradoxical timing of the circadian rhythm of sleep propensity serves to consolidate sleep and wakefulness in humans. Neurosci Lett 1994;166:63-68. 2. Borbely AA. A two process model of sleep regulation. Hum Neurobiol 1982;1:195-204. 3. Czeisler CA, Weitzman E, Moore-Ede MC, Zimmerman JC, et al. Human sleep: its duration and organization depend on its circadian phase. Science 1980;210:1264-1267. 4. Wever R. The circadian system of man: results of experiments under temporal isolation. New York: Springer; 1979. 5. Zulley J, Wever R, Aschoff J. The dependence of onset and duration of sleep on the circadian rhythm of rectal temperature. Pflugers Arch 1981;391:314-318. 6. Richardson G, Malin HV. Circadian rhythm sleep disorders: pathophysiology and treatment. J Clin Neurophysiol 1996;13:17-31. 7. Klein DC, Moore RY, Reppert SM. Suprachiasmatic nucleus—the mind’s clock. New York: Oxford University Press; 1991. p. 467. 8. Reppert SM, Weaver DR. Coordination of circadian timing in mammals. Nature 2002;418:935-941. 9. Dunlap JC. Molecular bases for circadian clocks. Cell 1999; 96:271-290. 10. Vitaterna MH, King DP, Chang AM, Kornhauser JM, et al. Mutagenesis and mapping of a mouse gene, Clock, essential for circadian behavior. Science 1994;264:719-725. 11. Ralph MR, Menaker M. A mutation of the circadian system in golden hamsters. Science 1988;241:1225-1227. 12. Czeisler CA, Duffy JF, Shanahan TL, Brown EN, et al. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 1999;284:2177-2181. 13. Freedman MS, Lucas RJ, Soni B, Von Schantz M, et al. Regulation of mammalian circadian behavior by non-rod, non-cone, ocular photoreceptors. Science 1999;284:502-504.
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Pharmacology
Section
Wallace Mendelson 42 Hypnotic Medications: Mechanisms of Action and Pharmacologic Effects 43 Clinical Pharmacology of Other Drugs Used as Hypnotics 44 Wake-Promoting Medications: Basic Mechanisms and Pharmacology
45 Wake-Promoting Medications: Efficacy
6
and Adverse Effects 46 Drugs That Disturb Sleep and Wakefulness
Hypnotic Medications: Mechanisms of Action and Pharmacologic Effects Wallace Mendelson Abstract Most currently available hypnotics induce sleep by acting at various moieties of the GABAA–benzodiazepine receptor complex. It is one receptor of the family of ligand-gated receptors, composed of several glycoprotein subunits, each of which appears in multiple isoforms. Microinjection studies indicate that major neuroanatomic sites of action of hypnotics from a variety of pharmacologic classes include the preoptic and other areas of the hypothalamus. Among the latter are areas
INTRODUCTION Currently, the clinically-used sedative/hypnotics in the United States include five benzodiazepines (Valium-like compounds) available in both proprietary and generic forms, three nonbenzodiazepine gamma-aminobutyric acid (GABA) agonists (zolpidem, zaleplon, and eszopiclone), and a melatonin receptor agonist (ramelteon) available as prescription agents (Table 42-1). This is a large market, involving approximately 49 million prescriptions in 2006, a growth of 53% over the previous 5 years.1 Sales in 2006 were approximately $3.7 billion. During the same year, roughly the same number of prescriptions was written for nonhypnotics prescribed for the purpose of aiding sleep; the largest among these was the antidepressant trazodone. Although these are large numbers, one could make a case that in the population at large, prescription hypnotics are taken relatively infrequently by insomniacs. In a survey of over 7000 enrollees in five large health maintenance organizations,2 patients with insomnia were divided up into those with only sleep complaints (Level 1) and those who believed that their sleep difficulties had an adverse effect on their daytime functioning (Level 2). The percentage of Level 1 insomniacs taking prescription and nonprescription hypnotics was 5.5% and 11.2%; comparable values for Level 2 insomniacs were 11.6% and 21.4%, respectively. Many patients, of course, receive other classes of prescription drugs given for purposes of helping sleep. One study of primary care patients in a
Chapter
42
centered around the function of other neurotransmitters but which receive significant GABAergic input. Connections between the preoptic area and the forebrain and brainstem, and the integrative nature of the anterior hypothalamus, help explain the mechanism by which sleep—and drugs that affect sleep—interact with a variety of physiologic systems. A number of hypnotic agents with novel mechanisms of action are currently under development and are likely to be available clinically in the next few years.
health maintenance organization indicated that 13% of insomniacs who were not considered to have affective disorder were receiving antidepressant medications.3 Many persons also self-medicate with alcohol; a telephone survey of approximately 1000 representative adults in the general population found that 10% had done so in the past year.4 A survey in the Detroit area reported that during the past year, 13% had used alcohol to aid sleep, whereas 18% used medication (either prescription or over-the-counter), and 5% had used both.5 Thus, alcohol use to help sleep is common even though it exposes the patient to the risk of ethanol dependence, and it is also relatively ineffective. Although orally administered ethanol has some sleepinducing properties, it often promotes sleep disturbance as the night progresses.6
MECHANISM OF ACTION GABAA Agonists: Benzodiazepines and the Newer Nonbenzodiazepines When the benzodiazepines first gained prominence in the 1960s, most theories of how they might act were inherited from previous studies of ethanol and barbiturates, and involved possible alterations in membrane phospholipid integrity and energy metabolism. With the discovery of the benzodiazepine receptor (now generally referred to as the GABAA–benzodiazepine receptor complex) in the late 1970s, attention was focused on the possibility that the pharmacologic effects of these compounds result from 483
484 PART I / Section 6 • Pharmacology Table 42-1 Pharmacokinetic Properties and Dosages of Some Hypnotic Drugs Used in the Treatment of Insomnia HALF-LIFE (HR)
ONSET OF ACTION (MIN)a
PHARMACOLOGICALLY ACTIVE METABOLITES
DOSE (MG)
Quazepam (Doral)
48-120
30
N-desalkyl (flurazepam)
7.5-15
Flurazepam (Dalmane)
48-120
15-45
N-desalkyl (flurazepam)
15-30
Triazolam (Halcion)
2-6
2-30
None
0.125-0.25
Estazolam (ProSom)
8-24
Intermediate
None
1-2
Temazepamc (Restoril)
8-20
45-50
None
15-30
Benzodiazepine Hypnotics
b
Loprazolamd (Dormonoct)
4.6-11.4
—
None
1-2
Flunitrazepamd (Rohypnol)
10.7-20.3
Rapid
N-desmethyl (flunitrazepam)
0.5-1
Lormetazepamd (Loramet)
7.9-11.4
—
None
1-2
Nitrazepamd (Alodorm)
25-35
Intermediate
None
5-10
1.5-2.4
Rapid
None
Nonbenzodiazepine Hypnotics Zolpidem (Ambien)
5-10 (age >65 yrs) 10-20 (age <65 yrs)
Zopicloned (Imovane)
5-6
Intermediate
None
3.75 (age >65 yrs) 7.5 (age <65 yrs)
Zaleplon (Sonata)
1
Rapid
None
Eszopiclone (Lunesta)
6
Intermediate
None
5-10 2-3 (age <65 yrs); 1-2 (age >65 yrs)
Ramelteon
1-2.6e
Intermediate
M-II
8
Clonazepam (Klonopin)
30-40
—
4-Amino derivative
0.5-3g
Diazepam (Valium)
30-100
Rapid
N-desmethyl
2-10g
Chlordiazepoxide (Librium)
24-28
Intermediate
N-desmethyl (chlordiazepoxide, demoxepam, oxazepam)
10-25g
Quetiapine (Seroquel)
5
—
Quetiapine sulfoxide
200g
Trazodone (Desyrel)
6-7
—
m-CPPh
50-100g
Nonhypnotics Sometimes Used to Aid Sleepf
Derived from Smith CM, Reynard AM. Essentials of pharmacology. Philadelphia: Saunders; 1995. p. 228, and other sources. b Citations for kinetic information of benzodiazepines are found in Maczaj.72 c Originally formulated as a hard capsule in the United States, concerns with kinetics and efficacy led to reformulation of the preparation to a soft gelatin capsule with comparable characteristics of other marketed benzodiazepines of its class.73,74 d Not available in the United States. e Active metabolite has half-life of 2-5 hrs. f Drugs that do not have U.S. Food and Drug Administration (FDA) indications for aiding sleep. g Because there is not an FDA indication for sleep, there is no FDA recommended dose for this purpose. Doses stated here are approximations of those often used in clinical practice. h m-CPP, m-chlorophenylpiperazine. a
their saturable, stereospecific binding to a specific recognition site.7,8 The receptor complex is part of a group of ligand-gated ion channel complexes that also includes the glycine, serotonin-3, neuronal nicotinic acetylcholine, and other receptors.9 It is functionally comprised of three moieties, a benzodiazepine recognition site, a GABAA recognition site, and a chloride ionophore. Molecular cloning studies indicate that structurally it is comprised of at least five different glycoprotein subunits (Fig. 42-1). The actual binding site for benzodiazepines appears to be located at the junction of the alpha and gamma subunits. Each of the subunits may have multiple isoforms.10 There appear to be as many as six alpha, three beta, and three gamma
isoforms. Studies using “knock-in” technology in mice indicate that the alpha-1 subunit may mediate both sedation and memory effects of agonists.11 This suggests that it will be unlikely to develop a hypnotic that acts at this site and that will have sleep-promoting, but not amnesic, properties. Two particular combinations of isoforms that are often noted are the Type-I (alpha 1, beta 2, gamma 2) and Type-II (alpha 3, beta 2, gamma 2) configurations. The former, the most common type representing roughly 40% of GABAA receptors, is found in most areas of the brain and localized in interneurons of the hippocampus and cortex. The latter, perhaps half as common, is found domi-
CHAPTER 42 • Hypnotic Medications: Mechanisms of Action and Pharmacologic Effects 485
Benzodiazepines γ2 β Barbiturates
GABA Alphaxalone
α
β α
Propofol Etomidate Halothane Enflurane
Figure 42-1 Schematic representation of the GABAA–benzodiazepine receptor complex, and possible sites of action of sleep-inducing drugs. (From Rudolph U, Mohler H: Analysis of GABA-A receptor function and dissection of the pharmacology of benzodiazepines and general anesthetics through mouse genetics. Annu Rev Pharmacol Toxicol 2004;44:475-498, with permission.)
nantly in spinal cord motoneurons and hippocampal pyramidal neurons. Most traditional benzodiazepine hypnotics bind to both types. Some of the newer nonbenzodiazepine agents, including zolpidem and zaleplon, bind with relatively greater specificity to the Type-I receptor. Whether this selective binding translates into more specific pharmacologic properties continues to be studied. The end result of a benzodiazepine agonist binding to its specific site is that as an outcome of a complex interaction with the GABA recognition site, the flow of negatively charged chloride ions into the neuron is enhanced, which changes the postsynaptic membrane potential and alters input resistance such that the postsynaptic neuron is less likely to achieve an action potential. This inhibitory mechanism is a very potent one in the central nervous system (CNS), because the GABAA receptor is the most widespread receptor mechanism in inhibitory synapses, comprising up to 30 percent of all synapses in the CNS. One of the intriguing features of this view is that it provides a beginning for understanding a long-standing puzzle—how hypnotic medications of many different pharmacologic classes may have relatively similar effects on the process of inducing sleep. As mentioned previously, the newer nonbenzodiazepine agents such as zolpidem and zaleplon bind to a subclass of benzodiazepine recognition sites, ethanol has profound effects on chloride channel function,6 and barbiturates bind to a distinct site.12 Barbiturates, for instance, may cause chloride channels to open for prolonged periods,13 whereas benzodiazepines may increase the frequency of opening.14 Similarly, the active metabolite of chloral hydrate9 and the anesthetic propofol15 modulate GABAA-receptor function. Several lines of evidence have also suggested that the hypnotic effects of benzodiazepines may involve presynaptic effects mediated by alterations in potential-dependent calcium channel activity.16 The calcium channel blocker nifedipine, for instance, can block the sleep-inducing effects of microinjections of triazolam into the medial preoptic area. Currently, at least two hypnotics under development address the function of auxiliary
alpha-2 delta subunits of voltage-gated calcium ion channels (Table 42-2). The original characterization of the receptor complex indicated that it mediates the anxiolytic, muscle relaxant and anticonvulsant effects of benzodiazepines.7,8 That it also mediates the sleep-inducing effects was demonstrated in a series of studies showing, for instance, that some beta-carboline compounds that act as receptor inverse agonists induce increased wakefulness, and at low doses they block sleep induction by benzodiazepines.16 The binding of benzodiazepines is stereospecific, such that an enantiomeric form (the B10 compounds) have opposite effects, one induces sleep whereas the other promotes wakefulness.6,16 Neuroanatomic Considerations In contrast to the growing understanding of the interaction of benzodiazepine agonists at a molecular level, the anatomic sites at which they act to induce sleep has been more poorly understood. The most parsimonious view would be that hypnotics act at loci thought to be important in sleep regulation on the basis of lesion or stimulation studies (a general review of the neuroanatomy of sleep is found in Chapter 7). Using that approach, Mendelson17 microinjected triazolam into a number of such sites. One of the most striking findings was how in many areas injections produced no effect on sleep (e.g., the locus coeruleus, the gigantocellular tegmental fields, the basomedial nucleus of the amygdala, and the ventrolateral preoptic area), or actually enhanced wakefulness (the dorsal raphe nuclei). In contrast, injections into the medial preoptic area (MPA) of the anterior hypothalamus consistently enhanced sleep, an anatomically very specific effect insofar as injections into nearby structures (the lateral preoptic area, the horizontal limb of the diagonal band of Broca) had no effect. The basal forebrain and anterior hypothalamus have long been thought to have an important role in sleep regulation. The MPA is a complex structure that receives afferents from many areas in the forebrain and brainstem. Among these are projections from various areas of the hypothalamus, as well as serotonergic fibers from the dorsal raphe nuclei and noradrenergic projections.18 Cell bodies and fibers of different parts cross react in immunohistochemical studies with a number of neuromodulators such as Substance P and Neuropeptide Y.19 Push-pull cannula studies have reported release of catecholamines, GABA, and glutamate.20 GABA is uniformly distributed throughout the hypothalamus, and its synthetic enzyme is found in high concentrations in the preoptic area.21 GABAA–benzodiazepine receptors appear in significant concentrations here,22 suggesting that benzodiazepines might inhibit neuronal activity. The preoptic area also contains cells that are responsive to temperature, osmolarity, glucose, and steroids,23 and it receives afferents from various sensory systems.18 The basal forebrain contains neurons that increase firing during NREM (non–rapid eye movement) sleep compared to waking (“sleep-active neurons”), although higher concentrations are found in the lateral preoptic area and diagonal band of Broca’s area.24 There are also neurons that selectively increase or decrease firing rates during REM (rapid eye movement) sleep and NREM sleep.25 Thus the preoptic area in general, and the MPA in
486 PART I / Section 6 • Pharmacology Table 42-2 Hypnotics under Development as of Mid-2010* DRUG NAME
COMPANY
PHARMACOLOGIC ACTION
INDICATION
DEVELOPMENTAL PHASE
Intermezzo
Purdue
GABAA receptor agonist: sublingual zolpidem
Middle of the night insomnia
Phase III
Zaleplon formulation
Somnus
GABAA receptor agonist: delayed release zaleplon
Sleep maintenance
Phase II
Zaleplon formulation
Intec
GABAA receptor agonist: sustained release zaleplon
Insomnia
Phase II
Silenor
Somaxon
Potent antagonist at H1 and H2 receptors, α1 adrenoceptors, and all subtypes of muscarnic acetylcholine receptors May weakly inhibit the reuptake of norepinephrine and serotonin Binds to both 5-HT1A and 5-HT2C receptors
Sleep maintenance, insomnia
Approved 2010
Pimavansrin, ACP-103
Acadia
5-HT2A receptor inverse agonist, dopamine D2/D3 receptor partial agonists, acetylcholine M1 receptor agonist
Sleep disorders, Parkinson’s disease psychosis, schizophrenia co-therapy
Phase II
HY10275
Eli Lilly
5-HT2A and histmine H1 receptor antagonist
Depression, ADHD, insomnia
Phase III
ORG 50081
Organon
5-HT2 antagonist, H1 antagonist, α2 adrenoceptor antagonist
Sleep disorders, hot flushes
Phase III
ITI007
Intracellular
5-HT2A receptor antagonist
Sleep maintenance
Phase II
TIK-301, LY156735
Tikvah Pharmaceuticals
Melatonin agonist, 5-HT2B/5HY2C antagonist
Sleep disorders
Phase II
VEC-162
Vanda Pharmaceuticals
Melatonin receptor agonist
Circadian rhythm sleep disorder, insomnia
Phase III
PD-6735
Phase 2 Discovery
Melatonin receptor agonist
Circadian rhythm sleep disorder, insomnia
Phase II
Almorexant, ACT-078573
Actelion
Orexin OX1 and OX2 receptor antagonist
Sleep disorders
Phase III
MK 4305
Merck
Dual orexin antagonist
Insomnia
Phase III
MK 6906
Merck
Dual orexin antagonist
Insomnia
Phase II
HAND 1586
Eisai
Orexin antagonist
Insomnia
Phase I
PD-200,390
Pfizer
Voltage-gated calciumchannel α2Δ subunit modulator
Sleep disorders
Phase II
* Adapted from data provided by Shawn Thomas and J>R> Becker. Neurotransmitters net, Quincy, IL. Adapted from Garrison M: New development for age-old problems. Sleep Rev 2008:9:34-37. ADHD, attention-deficit/hyperactivity disorder; GABA, gamma-aminobutyric acid; 5-HT, 5-hydroxytryptamine (serotonin).
particular, appear to have a role in coordinating various systems involved in reproductive and homeostatic functions.26 Given the bidirectional interactions of sleep with cardiovascular, thermoregulatory, endocrine, and sensory systems,27 it seems likely that the preoptic area might be involved in coordinating sleep with other systems. It may be, then, that the preoptic area is among the loci at which benzodiazepine agonists act to induce sleep. Recent work has also indicated that microinjections of pentobarbital and other GABA receptor agonists into a brainstem area, the mesopontine tegmental anesthesia area, induced an anesthesia-like state, raising the possibility that it may be involved in drug-induced loss of consciousness.28
Other Neurotransmitters Subsequent studies have also indicated that microinjections of pentobarbital,29 ethanol,30 adenosine,31 and propofol32 into the MPA enhance sleep. Indeed, looking at a somewhat broader area, adenosine has been shown to accumulate extracellularly in the basal forebrain cholinergic region,33 which in turn has efferents to cortical and thalamic systems involved in arousal; it has been suggested that alteration of functioning of this cholinergic area may be the mechanism by which the propensity to sleep is enhanced by prolonged wakefulness. Similarly, it may be that possible some of the sleep-promoting effects of antihistamines and tricyclic antidepressants (many of which
CHAPTER 42 • Hypnotic Medications: Mechanisms of Action and Pharmacologic Effects 487
have significant anticholinergic properties) might be mediated by alterations of cholinergic neurons in the basal forebrain. The histaminergic system, which is centered in the tuberomammillary nucleus of the lateral hypothalamus, sends efferents to the preoptic area34 as well as the perifornicular area35,36 and the cortex, so it also seems possible that sedative effects of antihistamines and some tricyclic antidepressants might be mediated by altering the influence of the tuberomammillary nuclei on these centers. It has also been observed that microinjection of the GABA receptor antagonist gabazine into the tuberomammillary nuclei inhibits the effects of centrally administered GABAergic agents, suggesting that this area may be involved in their pharmacologic actions.37 There has been increasing interest in the hypocretin/ orexin system, which is centered in the perifornicular region of the posterior and lateral hypothalamus, as a mechanism of arousal. There also is evidence that various defects in this system are associated with the genesis of narcolepsy (see Chapter 84). Microinjection of triazolam into this area shortens sleep latency and increases total sleep time in rats, raising the possibility that such hypnotics reduce wakefulness, either by direct action at the perifornicular area or indirectly via GABAergic outputs from the preoptic area.38 In summary, the manner in which hypnotics may function to induce sleep is not fully elucidated, but a number of findings suggest that the basal forebrain and anterior hypothalamus will be among the crucial areas to consider.
CLINICAL EFFECTS Moving from the neuroanatomic to the clinical level, less is understood about the mechanism by which hypnotics act. One approach raises the possibility that, among their actions, hypnotics alter the perception of sleep and wakefulness.39 This notion grew out of the classical observation by Rechtschaffen40 that poor sleepers, when experimentally awakened early in stage 2 sleep, tend to report that they had been awake, while good sleepers tend to report that they had been asleep. Later studies by Mendelson41,42 replicated this observation and demonstrated that after administration of triazolam, flurazepam, or zolpidem insomniacs were more likely to report that they believed they had been asleep compared to when they were given placebo. In contrast, when flurazepam or zolpidem were given to normal subjects, this effect was not evident.43 One interpretation of these data is that hypnotics such as triazolam and zolpidem may correct a misperception of sleep in some insomniacs, such that their experience of whether they are awake or asleep becomes more like that of good sleepers. Other Sleep-Inducing Agents Most over-the-counter hypnotics are first-generation antihistamines including diphenhydramine and doxylamine. Although they possess to varying degrees other properties including anticholinergic effects, their common quality is inhibition of the histamine-1 receptor. (Later generations of antihistamines are more hydrophilic, and in principle enter the CNS less readily, thus producing less sedation.) Tolerance to daytime sleepiness appears to develop rapidly, in about 4 days.44 As discussed earlier, antihistamines may
produce drowsiness by inhibiting the histaminergic pathways centered in the tuberomammillary nucleus of the posterior hypothalamus, which enhance wakefulness. It should also be noted that some tricyclic antidepressants, notably doxepin, which at the time of this writing is under development as a possible hypnotic, have significant antihistaminic (H1 and H2) properties (although also having a number of other effects, including antagonism at alpha1 adrenoreceptors and muscarinic cholinergic receptors, and binding to serotonin 2a and 2c receptor subtypes). Although there is debate about the effectiveness and range of side effects of melatonin as a hypnotic,45 there is now a potent agonist of melatonin subtypes I and II receptors available (ramelteon), and others in development (agomelatine, TIK-301, VEC-162). It has been hypothesized that melatonin and agonists might act to affect circadian systems via effects on melatonin receptors in the suprachiasmatic nucleus, but the ways in which it might alter sleep have not been well understood. It has been suggested that binding of agonists to the melatonin type I receptor decreases the waking signal from the suprachiasmatic nucleus. One possibility is that sleep-promoting effects of agonists at melatonin receptors are at least in part GABAergic. Melatonin administration is known to raise GABA concentrations in the rat hypothalamus, as well as 3H-diazepam binding in the forebrain.46 Similarly, decreases in motor activity produced by melatonin in the hamster are prevented by the benzodiazepine receptor blocker flumazenil.47 The author’s laboratory has reported that microinjections of melatonin into the medial preoptic area of the rat hypothalamus enhance sleep, suggesting that its site of action may be similar to that of benzodiazepines, barbiturates, adenosine, and ethanol, as described previously.48 Although the topic of anesthetics is beyond the scope of this chapter, we will briefly mention the intravenous agent propofol, which has made it much more practicable to induce anesthesia for prolonged periods in, for instance, intensive care unit settings. Neurochemically, its mechanism of action has not been fully elucidated, though it is known to interact with the GABAA–benzodiazepine receptor complex, with resultant decreases in acetylcholine release from the frontal cortex and hippocampus, and to also increase functional activity of dopamine and serotonin in the cortex. Interestingly, microinjection of propofol into the medial preoptic area of rats induces sleep, and this effect is blocked by the benzodiazepine receptor blocker flumazenil.49
PHARMACOKINETICS Benzodiazepines With the possible exception of temazepam, the benzodiazepines used as hypnotics are rapidly and completely absorbed, with most achieving peak plasma levels in 1.0 to 1.5 hours. Some, notably flurazepam, are detectable primarily only in the form of their active metabolites, and many display kinetics that reflect enterohepatic circulation. Generally oral administration is more reliable and complete than intramuscular injection. Although there is significant protein binding, there are few or no cases in which displacement of other protein-bound drugs is
488 PART I / Section 6 • Pharmacology
Plasma Concentration
Slow Elimination
Rapid Elimination
1
2
3
Days
Figure 42-2 A hypnotic with a relatively long elimination half life (e.g., greater than 24 hours) will accumulate during nightly use, in contrast to an agent with relatively short elimination half-life (e.g., 6 hours). (From Nicholson AN: Hypnotics: clinical pharmacology and therapeutics. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 2nd ed. Philadelphia: Saunders; 1989. pp. 355-363, with permission.)
clinically relevant. Most are very lipophilic, and they rapidly enter the CNS, where concentrations reflect unbound drug in plasma. Whereas the older, longer-acting agents are metabolized to active compounds, the shorteracting agents such as triazolam are broken down into inactive substances (Table 42-1, Video 42-1). The elimination half-lives vary widely, from the relatively short-acting triazolam, to intermediate agents such as temazepam, to long-acting substances such as flurazepam (Table 42-2). As will be discussed in Chapter 81, accumulation of the longer elimination half-life agents when taken nightly has significant bearing on one major clinical issue—the appearance of daytime residual sedation (Fig. 42-2). Because of the lipophilicity, many are rapidly redistributed, which may play as important a role in the decline in CNS effects as metabolism. Another implication of the high lipophilicity is that the volume of distribution is often increased in the elderly (who tend to have a higher ratio of lipid to muscle), resulting in an increased half-life. Most are broken down by hepatic microsomal systems and excreted as conjugated glucuronides. There is no stimulation of the hepatic microsomal systems, and hence no enhancement of the rate of breakdown of other drugs which undergo the same metabolic processes. Their own metabolism may be inhibited by some compounds such as cimetidine and some steroids, and it may be accelerated in people who smoke. The “Z Drugs” Zolpidem was the first of the “Z drugs” (zolpidem, zaleplon, zopiclone, eszopiclone), nonbenzodiazepines that bind to various subtypes of the GABAA receptor. In general, their clinical effects are similar to those of benzodiazepines, though on the basis of animal studies it has been argued that they have a wider separation in doses producing hypnotic to nonhypnotic effects.50 Several studies have suggested that they have a lower risk of dependence and misuse than the benzodiazepines. A German prescription event study, for instance, described a rate of misuse about one third that of benzodiazepines.51 It has been speculated
that this may be due to less affinity for the alpha-2 subtype, which may be related to abuse potential. In the United States the Z drugs are considered Class IV Drug Enforcement Administration (DEA) restricted agents, the same classification as the benzodiazepines. Insomniacs have been shown in several studies to have higher general health care use and costs than noninsomniacs. One recent study has suggested that during the first 6 months after initiation of treatment of insomnia with the newer nonbenzodiazepine hypnotics, general health care costs show a relative decline compared to those of untreated insomniacs.52 The broader issue of the interaction of insomnia and its treatment with other illnesses is addressed in Chapter 75 and in a recent review.53 Zolpidem Zolpidem, an imidazopyridine compound with relative selectivity for the Type-I GABAA–benzodiazepine receptor, is rapidly absorbed; due to first-pass metabolism, it has a bioavailability of 67% after oral administration of doses up to 20 mg.54 Peak concentrations are reached after 1.6 hours. Total protein binding is approximately 92%. Absorption is slightly decreased when taken on a full stomach. It has no pharmacologically active metabolites, and is eliminated primarily by renal excretion. In the United States it is also marketed as a coated two-layer tablet, in which the inner layer has a more extended release time (Ambien CR). Zopiclone and Eszopiclone Zopiclone, which is on the market in Europe and Asia but not the United States, is a cyclopyrrolone that acts at the GABAA–benzodiazepine receptor complex, but possibly at a different binding domain or by producing different conformational changes than the benzodiazepines.55 It is rapidly absorbed, with peak plasma concentrations occurring in 0.5 to 2 hours.56 Bioavailability is about 80%, implying that the first-pass effect is relatively small. It is very lipophilic and enters rapidly into the central nervous system. Protein binding is approximately 45%. It has two major metabolites, the N-oxide, which has lower pharmacologic activity, and the inactive N-desmethyl derivative, which along with various minor metabolites are excreted primarily by the kidneys and lungs. Eszopiclone, the S-isomer of racemic zopiclone, is marketed in the United States as Lunesta. Peak concentrations are achieved in 1 hour, with an elimination half-life of approximately 6 hours. It is weakly bound to protein, and metabolized via oxidation and demethylation; its biotransformation is attributed to CYP3A4 and CYP2E1.57 Eszopiclone has been found to have effectiveness without tolerance for at least 6 months,58 and was the first drug in the United States to have no limitation on duration of administration by the FDA. Zaleplon A pyrazolopyrimidine that binds selectively to the benzodiazepine-1 receptor, zaleplon is rapidly absorbed after oral administration, with peak concentrations being reached in 1 hour, and has an elimination half-life of approximately 1 hour. Protein binding is approximately 60%. It is rapidly metabolized to inactive forms, with
CHAPTER 42 • Hypnotic Medications: Mechanisms of Action and Pharmacologic Effects 489
approximately 71% of labeled compound recovered in the urine and 17% in feces. Recommendations for administration in the United States include taking it immediately before bedtime or after the patient has gone to bed and has experienced difficulty falling asleep. In the latter case, it should be taken at least 4 hours before time of arising to avoid any possible memory difficulties. Ramelteon Ramelteon is a potent agonist at the melatonin types I and II receptors, with negligible affinity for the GABAA, dopamine, serotonin, or muscarinic cholinergic receptors. It reaches peak plasma concentrations in 0.75 to 0.94 minutes, and has an elimination half-life of 1 to 2.6 hours; an active hydroxylated metabolite (M-II) has a slightly longer halflife of 2 to 5 hours. It is metabolized in the liver, primarily with CYP1A2 and to a lesser degree CYP2C9 and CYP3A4. Its mechanism of action is not fully understood, but it has been hypothesized that binding at melatonin receptor subtypes in the suprachiasmatic nucleus attenuates its waking signal. Clinically its efficacy is primarily in decreasing sleep latency, with little effect on awakenings during the night. It has essentially no dependence-producing effects, and in the United States, it is not a DEA-restricted drug.
PHARMACOLOGIC PROPERTIES Although the hypnotic benzodiazepines are given for purposes of aiding sleep, they share a spectrum of pharmacologic properties with agents given as daytime sedatives or anxiolytics; indeed, some authors have suggested that the designation of some benzodiazepines as hypnotics is as much a marketing plan as it has been a pharmacologic decision. Among their effects are anxiolytic, myorelaxant, and anticonvulsant properties. Many, particularly the longer-acting agents, have mild respiratory depressant properties,59,60 which are much less evident in shorter-acting agents.61 There is even some limited evidence that triazolam may improve sleep-disturbed respiration in central sleep apnea,62 although whether this is related to direct respiratory effects or secondary to decreasing the number of arousals (and hence postarousal respiratory pauses) during sleep is not clear. Even for the longer-acting agents, however, respiratory depression is much milder than those of older nonbenzodiazepines such as the barbiturates. In practical terms there is no significant effect in patients with normal ventilation, although it may become evident when there is preexisting compromised respiration such as in patients with chronic obstructive pulmonary disease or persons with unrecognized sleep-disordered breathing. The newer nonbenzodiazepines appear to have very few respiratory effects. One study of clinically-used doses of zaleplon, for instance, found few effects on measures of sleep-disturbed respiration in patients with mild-to-moderate obstructive sleep apnea on continuous positive air pressure.63 In most cases, the preceding generalizations in this section apply as well to zolpidem. There is some evidence from animal studies that it possesses a greater separation of hypnotic and sedative doses. It has been reported to have no respiratory depressant properties up to doses of 10 mg and to exhibit very mild inhibition of mean inspiratory drive at 20 mg.64 Zopiclone in therapeutic doses
appears to have no significant effect on sleep-disordered breathing in patients with chronic obstructive pulmonary disease.65 In general, adverse reactions to hypnotics are relatively rare and mild; one review of 3 years’ experience in a 1000bed teaching hospital found the median rate of reported adverse events to be 0.01% (1 in 10,000) doses administered and ran as high as 0.05%.28 The rate for triazolam was 0.02%.66 Unlike older hypnotics such as the barbiturates, the hypnotic benzodiazepines are relatively benign in overdose when taken alone by a medically healthy individual. They may be very toxic, however, when taken in combination with other central nervous system depressants such as alcohol, and because a significant portion of overdoses involve a combination of drugs, it is wise to treat them as potentially toxic or even lethal agents. In practice this translates into being very conscious of the possibility that a patient seeking help for sleep disturbance may be suffering from unrecognized depressive illness, and if it is present, initiating appropriate antidepressant therapy.
EFFECTS ON SLEEP Polygraphic studies of benzodiazepines indicate that, consistent with their clinical effects, sleep latency and wake time after sleep onset are generally reduced, and total sleep time is increased. As with barbiturates and ethanol, spindle activity may be increased. REM sleep time may be reduced mildly, in contrast to the very potent REM suppression induced by barbiturates. In the early years after the introduction of benzodiazepines into the U.S. market, much was made of this observation, which was interpreted to mean that they somehow produced a more natural sleep. With hindsight, many investigators recognize that the psychological effects of REM deprivation are much less clear than originally thought, and that in the case of depressed patients, REM deprivation may even be therapeutic (see Chapter 8), so whether having only mild REM suppressant properties translates into some clinical advantage seems uncertain. The benzodiazepines are, however, in contrast to the barbiturates, potent suppressors of slow-wave sleep. The same dilemma that arises in terms of REM sleep appears once again: Because the function of slow-wave sleep has not been clearly determined, the clinical significance of pharmacologically suppressing this stage remains uncertain. The nonbenzodiazepine zolpidem shares with the benzodiazepines the very mild effects on REM sleep, but in contrast does not alter slow-wave sleep, which may even increase toward more expected values in some patients with insomnia with low baseline levels. The development of neuroimaging techniques is also beginning to give insights into how the newer nonbenzodiazepines may affect the brain. One recent positron emission tomography (PET) study indicates that following eszopiclone administration, there is a more rapid decline in metabolic activity in the midbrain and pontine reticular formation during the transition from waking to NREM sleep.67 One interpretation would be that the drug is reducing the hyperarousal often seen in insomnia. Clinical efficacy studies indicate that virtually all these agents potently improve polygraphic measures of sleep and
490 PART I / Section 6 • Pharmacology
result in better subjective ratings of sleep quality during short-term use. One of the few distinctions among the benzodiazepines is that the longer-acting agents such as flurazepam may not have as much effectiveness on sleep latency until the second night of administration. One concern that was initially raised in terms of the shortacting agents such as triazolam was the possibility that the relatively rapid metabolism might lead to sleep disturbance after several hours; later studies analyzing awakenings in the latter part of the night have generally found no evidence that this is the case.68,69 Another pharmacologic property to consider is the potential for dependence. A review of this topic by a panel from academia, industry, and the government concluded that the dependence potential of currently available hypnotics in patients without a history of substance abuse is minimal.70 Ramelteon has been found to have no dependence-producing properties in standard measures. An excellent review of abuse liability and toxicity of 19 hypnotics from the days of the barbiturates through ramelteon can be found in Griffiths and Johnson.71 A variety of other issues at a clinical level include determination of whether or not tolerance develops during long-term nightly administration, and the effectiveness of nonnightly use, which are considered in Chapter 81.
FUTURE HYPNOTICS This is a very fruitful time in the development of hypnotics.75 Among compounds under development are ones that act as antagonists to specific serotonin receptor subtypes, alpha-2-delta calcium channel blockers and orexin antagonists (Table 42-2, Video 42-1). The serotonin 2-subtype receptor has been of interest for some time in relation to the action of some antidepressants and most atypical antipsychotics; serotonin subtype 2A antagonists including eplivanserin, pimavanserin and others are under development as hypnotics, with studies emphasizing improvements in sleep continuity and minimal daytime sedation. There are also compounds which combine antagonism at serotonin 2C receptors with melatonin receptor agonism. Compounds that bind to alpha-2-delta subunits of voltage-gated calcium channels, such as the anticonvulsants pregabalin and gabapentin, increase calcium ion entry into neurons and alter GABA concentrations. Both appear to increase slow-wave sleep and decrease awakenings, and are under development as hypnotics. Orexin/hypocretins are excitatory hypothalamic neuropeptides that enhance waking, and indeed a deficit in orexin-containing neurons is related to the genesis of narcolepsy (see Chapter 84); an antagonist to orexin receptors, GW649868, is under development as a hypnotic as well. As mentioned earlier, low dose administration of the tricyclic antidepressant doxepin, which has significant antihistaminergic properties as well as antagonism at alpha1 adrenoceptors and other properties, is being developed to aid sleep. Advances in medicinal chemistry are enabling the creation of hypnotics that may come in multiple preparations varying in duration of action. There has been interest in novel modes of administration including inhalation, oral sprays and oral dissolving tablets.
❖ Clinical Pearl Most currently available hypnotics induce sleep by acting on various moieties of the GABAA–benzodiazepine receptor complex; knock-in studies of the alpha-1 subunit suggest that it is unlikely that hypnotics that act by this mechanism can be developed that will be able to have sleep-inducing, but not amnesic, properties. Hypnotics with novel mechanisms of action are likely to be available for clinical use in the next few years.
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50. Sanger DJ. The pharmacology and mechanisms of action of new generation, non-benzodiazepine hypnotic agents. CNS Drugs 2004; 18:9-15. 51. Hajak G, Muller WE, Wittchen HU, Pittrow D, et al. Abuse and dependence potential for the non-benzodiazepine hypnotics zolpidem and zopiclone: a review of case reports and epidemiological data. Addiction 2003;98:1371-1378. 52. Hawkins K, Treglia M, Healey P, Wang SS, et al. Health care costs and absence from work: an administrative claims analysis of employees with and without insomnia. Manag Care Interface, in press. 53. Mendelson WB. Impact of insomnia: wide-reaching burden and a conceptual framework for comorbidity. Int J Sleep Wakefulness 2008;1:118-123. 54. Langtry HD, Benfield P. Zolpidem: a review of its pharmacodynamic and pharmacokinetic properties and therapeutic potential. Drugs 1990;40:291-313. 55. Noble S, Langtry HD, Lamb HM. Zopiclone: an update of its pharmacology, clinical efficacy and tolerability in the treatment of insomnia. Drugs 1998;55:277-302. 56. Hindmarch I. Zopiclone monograph. Manchester, UK: ADIS Press International; 1990. p. 1-68. 57. Najib J. Eszopiclone, a nonbenzodiazepine sedative-hypnotic agent for the treatment of transient and chronic insomnia. Clin Ther 2006;28:491-516. 58. Krystal AD, Walsh JK, Laska E, Caron J, et al. Sustained efficacy of eszopiclone over six months of nightly treatment: results of a randomized, double-blind, placebo controlled study in adults with chronic insomnia. Sleep 2003;26:793-799. 59. Rudolf M, Geddes DM, Turner JA, Saunders KB. Depression of central respiratory drive by nitrazepam. Thorax 1978;33:97-100. 60. Dolly FR, Block AJ. Effect of flurazepam on sleep-disordered breathing and nocturnal oxygen desaturation in asymptomatic patients. Am J Med 1982;73:239-243. 61. Mendelson WB. Drugs which alter sleep and sleep-related respiration. In: Kuna ST, editor. Sleep and respiration in aging adults. New York: Elsevier; 1991. p. 49-54. 62. Bonnet MH, Dexter JR, Arand DL. The effect of triazolam on arousal and respiration in central sleep apnea patients. Sleep 1990;13:31-41. 63. Coyle MA, Mendelson WB, Derchak PA, James SP, et al. Ventilatory safety of zaleplon during sleep in patients with obstructive sleep apnea on continuous positive airway pressure. J Clin Sleep Med 2005; 1:97. 64. Cohn MA. Effects of zolpidem, codeine phosphate and placebo on respiration. A double-blind, crossover study in volunteers. Drug Saf 1993;9:312-319. 65. Muir JF, DeFouilloy C, Broussier PM. Incidence of zopiclone vs placebo on sleep-disordered breathing in COPD patients. Am Rev Respir Dis 1988;13:12-14. 66. Mendelson WB. Adverse reactions to sedative/hypnotics: three years’ experience. Sleep 1996;19:702-706. 67. Nofzinger EA, Buysse D, Moul D, Hall M, et al. Eszopiclone reverses brain hyperarousal in insomnia: evidence from [18F]-FDG PET. Sleep 2008;31:A232. 68. Roehrs T, Zorick F, Wittig R, Roth T. Efficacy of a reduced triazolam dose in elderly insomniacs. Neurobiol Aging 1985;6:293-296. 69. Kales A, Bixler EO, Vela-Bueno A, Soldatos CK, et al. Comparison of short and long half-life benzodiazepine hypnotics: triazolam and quazepam. Clin Pharmacol Therap 1986;49:378-386. 70. Mendelson WB, Roth T, Cassela J, Roehrs T, et al. The treatment of chronic insomnia: drug indications, chronic use and abuse liability. Summary of a 2001 New Clinical Drug Evaluation Unit meeting symposium. Sleep Med Rev 2004;8:7-17. 71. Griffiths RR, Johnson MW. Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds. J Clin Psychiatry 2005;66:31-41. 72. Maczaj M. Pharmacological treatment of insomnia. Drugs 1993;45: 44-45. 73. Roehrs T, Vogel G, Vogel F, Wittig R, et al. Dose effects of temazepam tablets on sleep. Drugs Exp Clin Res 1986;12:693-699. 74. PDR. Physicians’ Desk Reference. Montvale, NJ: Medical Economics; 1998. 75. DeMartinis NA, Winokur A. Effects of psychiatric medications on sleep and sleep disorders. CNS Neurol Disord Drug Targets 2007; 6:17-29.
Clinical Pharmacology of Other Drugs Used as Hypnotics Daniel J. Buysse Abstract Various drugs other than benzodiazepine receptor agonists are used as hypnotics. These include drugs originally developed as antidepressants, anticonvulsants, and antipsychotics; hormones and other “natural” substances; and newer drugs developed specifically to treat insomnia. Understanding of the pharmacokinetics, pharmacodynamics, sleep effects, and side effects of these drugs is essential for clinical practice. Sedating tricyclic and other antidepressant drugs show considerable heterogeneity in terms of half-lives, receptor pharmacology, and sleep effects. They act primarily through serotonin, norepinephrine, and histamine receptor effects. Evidence for their positive effects on sleep continuity comes mainly from studies of depressed patients, although doxepin is now being investigated in very low doses specifically for treatment of insomnia. Some antidepressants increase slow-wave sleep and reduce REM sleep. Melatonin and melatonin receptor agonists have a very short duration of action. Their sleep effects are probably mediated by effects on melatonin receptors in the suprachiasmatic nucleus, and their most consistent sleep effect is reduction of sleep latency. Antihistamines antagonize the effects of histamine, a wake-promoting neurotransmitter synthesized in
Benzodiazepine receptor agonists are the most widely used drugs for the treatment of insomnia. Benzodiazepine receptor agonists, one melatonin receptor agonist, one sedating tricyclic compound and a small number of older drugs with questionable agonist safety profiles (e.g., barbiturates, methyprylon) are currently approved by the Food and Drug Administration (FDA) as hypnotics. However, no class of drugs is universally efficacious for any condition, and other classes of drugs are frequently used for the treatment of insomnia. Persistent concerns about potential side effects of benzodiazepine receptor agonists, such as tolerance, dependence, and abuse, have also led clinicians to investigate other classes of drugs for insomnia treatment. Finally, the search for other drugs to treat insomnia is warranted by the complexity of neurochemical regulation of sleep–wake states and the complexity of insomnia itself, which is manifested by different symptoms and is likely to have multiple causes. Pharmacoepidemiology data indicate that prescribers often use non–benzodiazepine receptor agonist drugs to treat insomnia. Data from the National Disease and Therapeutic Index between 1986 and 1996 show that benzodiazepine hypnotic prescriptions fell by almost 50%, whereas the use of antidepressant drugs to treat insomnia increased by 146%.1 The majority of this increase was accounted for by prescription of trazodone. In fact, trazodone was the most commonly prescribed drug to treat insomnia in 1996. A variety of subsequent data demonstrate that trazodone and other antidepressants continue to be either the first or second most commonly prescribed hypnotic agents in the United States.2-4 Supported by NIH grants MH024652, AG015138, AG020677.
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43
the posterior hypothalamus with widespread cortical projections. They are widely used because of their clear effects on subjective sedation. A limited amount of evidence exists for their effects on nocturnal sleep, and like antidepressants, they can have potentially serious side effects. Valerian extracts have uncertain pharmacokinetics and mechanisms of action. They appear to affect primarily sleep latency, although some studies also show increased slow-wave sleep. Small numbers of studies suggest that sedating antipsychotic drugs, tiagabine, gabapentin, and sodium oxybate (gammahydroxybutyrate) may increase slow-wave sleep, with variable effects on sleep continuity. These drugs have a wide variety of receptor effects, and the mechanisms of their effects on human sleep are poorly understood. Few human sleep studies have been conducted with any of these agents, particularly in patients with insomnia. Current studies are investigating the effects of serotonin 5-HT2A antagonists and orexin (hypocretin) receptor agonists on sleep in insomnia. Future studies will be needed to understand the appropriate role of these drugs in the treatment of sleep disorders and specifically how they will fit into emerging treatment algorithms for insomnia.
Unlike benzodiazepine receptor agonists, other drugs used to treat insomnia do not share consistent chemical structures, receptor activities, or other pharmacologic properties. Moreover, most nonapproved hypnotic drugs have not been rigorously evaluated with regard to their sleep effects, leaving uncertainties about appropriate dose, demonstrated efficacy, and side effects. Sedating antidepressants and their effects on sleep are summarized in Tables 43-1 to 43-3. The effects of other drugs used as hypnotics are summarized in Tables 43-4 and 43-5.
A MODEL OF SLEEP–WAKE REGULATION RELEVANT TO SLEEPPROMOTING DRUGS Recent findings from the basic and clinical neuroscience of sleep–wake regulation permit specific models of sleep– wake regulation and insomnia to be advanced and tested (see also Chapter 78). The model in Figure 43-1 describes non–rapid eye movement (NREM) sleep and wakefulness in humans as the products of dynamic interactions among several neural systems.5-10 Wakefulness and arousal states are generated by the ascending activity of monoaminergic brainstem nuclei, histaminergic nuclei in the posterior hypothalamus, and cholinergic nuclei of the pontine tegmentum and basal forebrain (a to c). Activity of these arousal systems is promoted by input from orexin (hypocretin) neurons in the perifornical lateral hypothalamus (LHA) during wakefulness and inhibited by gamma-aminobutyric acid (GABA) and galaninergic neurons in the ventrolateral preoptic area (VLPO) and median preoptic area (MnPO) of the hypothalamus at the onset of sleep (c).
CHAPTER 43 • Clinical Pharmacology of Other Drugs Used as Hypnotics 493
Table 43-1 Pharmacokinetic Properties of Sedating Antidepressant Drugs*
TMAX
USUAL DOSE (MG)
METABOLISM (CYP ENZYMES)
(RANGE)
t1
2
DRUG
DRUG CLASS
ANTIDEPRESSANT
Doxepin
Tricyclic
2-8 hours
Major: 2D6, 2C19 Minor: 1A2, 3A4
20 hours (10-30)
100-300
10-150‡ 3-6§
Amitriptyline
Tricyclic
2-8 hours
Major: 2D6, 2C19 Minor: 1A2, 3A4
30 hours (5-45)
100-300
25-150
Trimipramine
Tricyclic
2-8 hours
Major: 2D6, 2C19 Minor: 1A2, 3A4
25 hours (15-40)
100-300
25-150
Trazodone
Phenylpiperazine
1-2 hours
3A4, 2D6
9 hours (3-14)
200-600
25-150
Nefazodone
Phenylpiperazine
1 hour
3A4, 2D6, 2C19
2-4 hours (6-18 for active metabolites)
150-450
50-150
Mirtazapine
Noradrenergic and specific serotonergic antidepressant
1-3 hours
3A4, 2D6, 1A2
25 hours (13-40)
15-45
HYPNOTIC†
15-30
*Sources: references 18, 20, 21, 43, 44, 67, 152. † Hypnotic doses are based on published studies and common clinical practice. No formal dose-ranging studies for this indication have been published. CYP, cytochrome P-450 (individual letters and numbers in the table represent specific CYP enzymes); t 12, elimination half-life; tmax, time to maximal concentration. ‡ Traditional formulations. § FDA-approved hypnotic dose.
Table 43-2 Receptor Pharmacology of Sedating Antidepressant Drugs* RECEPTOR EFFECTS
DRUG
NE REUPTAKE
5-HT REUPTAKE
5-HT2 RECEPTOR ANTAGONISM
ALPHA1ADRENERGIC RECEPTOR ANTAGONISM
M1 ANTAGONISM (ANTICHOLINERGIC)
H1 ANTAGONISM (ANTIHISTAMINE)
+++
Doxepin
+
0/+
+
+++
++
Amitriptyline
+
++
+
+++
+++
++
Trimipramine
0
0
+
+++
++
+++
Trazodone
0
+
++
++
0
0/+
Nefazodone
0
++
++
++
0
+
Mirtazapine
0/+
0
++
+
+
+++
OTHER EFFECTS
5-HT1A, 5-HT1C, and alpha2 antagonism Alpha2 and 5-HT1 antagonism
*Sources: references 18, 21, 43, 152, 200. H, histamine receptor; 5-HT, serotonin; M, muscarinic cholinergic receptor; NE, norepinephrine. Numbers after receptor abbreviations indicate specific receptor subtype. + Indicates strength of effect relative to other antidepressant drugs; 0 indicates no significant effect.
The LHA and VLPO/MnPO are in dynamic equilibrium with each other to ensure stable sleep–wake states (d). The timing and overall level of activity in the LHA and VLPO are tightly regulated by homeostatic sleep drive and the circadian timing system (e), which also indirectly affect output of brainstem arousal centers (f). Descending inputs from cortical-diencephalic cognitive and affective centers further modulate sleep–wake balance (g) and are in turn modulated by ascending input from arousal centers, both directly and through thalamic pathways (a, b). Finally, corticothalamic oscillations underlie the characteristic elec-
trophysiologic events of NREM sleep, sleep spindles, and delta oscillations. Findings from human functional neuroimaging studies are consistent with this model. Compared with wakefulness, NREM sleep is associated with decreased global blood flow and glucose metabolism as well as with large regional decreases in dorsolateral and medial prefrontal cortex, amygdala and cingulate cortex, thalamus, and brainstem-hypothalamic centers.11-13 The influence of the circadian timing system is suggested by diurnal variation in regional metabolism during wakefulness in humans,
494 PART I / Section 6 • Pharmacology Table 43-3 Polysomnographic Effects of Sedating Antidepressant Drugs on Sleep* DRUG
SLEEP LATENCY
SLEEP CONTINUITY†
STAGE 3/4 NREM SLEEP AMOUNT, %
REM SLEEP
OTHER ↓ Sleep apnea (minor effect) ↔ or ↑ periodic limb movements ↑ Restless legs symptoms May induce eye movements during NREM sleep
Doxepin
↓
↑
↔
↓ Amount, % of REM ↑ Phasic eye movements (REM density)
Amitriptyline
↓
↑
↔
↓ Amount, % of REM ↑ Phasic eye movements (REM density)
Trimipramine
↓
↑
↔
↔ Amount, %
Trazodone
↓
↔ to ↑
↑
↔ Amount, % (↓ to ↑ in individual studies)
Nefazodone
↔
↑
↔
↔
Mirtazapine
↓
↑
↔
↔
*Reported effects are based on preponderance of evidence from published studies (see text for details). Many effects are inconsistent between individual studies. ↑ Indicates increase from pretreatment baseline; ↓ indicates decrease from pretreatment baseline; ↔ indicates no change from pretreatment baseline. † Sleep continuity refers to the proportion of sleep relative to wakefulness after sleep onset, as reflected by measures such as sleep efficiency. Other indicators of sleep continuity, such as wakefulness after sleep onset and number of awakenings, would have opposite signs. Thus, ↑ indicates improvement in overall sleep continuity.
1 2 3 6 Cognitive-Affective System Dorsal (Cognitive) Vental (Affective) system system (g) Sleep–Wake Regulatory System Sleep–Wake State Switching System 1 (e) Homeostatic VLPO LHA 3 sleep drive “Sleep switch” “Wake stabilizer” 5 4 (d) Circadian timing system 4
Thalamus
1
(c) 2 5 6 (f)
Brainstem-Hypothalamic Arousal Systems LC, raphe, LDT/PPT, TMN
(a) (b)
Figure 43-1 Solid arrows indicate direct anatomic or physiologic pathways. Dotted arrows indicate indirect pathways. LC, locus coeruleus; LDT, laterodorsal pontine tegmentum; LHA, lateral hypothalamus perifornical area; PPT, pedunculopontine tegmentum; TMN, tuberomammillary nucleus of the posterior hypothalamus; VLPO, ventrolateral preoptic area. See text for explanation of letters and numbers.
with increased brainstem-hypothalamic activity in the morning relative to the evening.14 Finally, increasing homeostatic sleep drive with total sleep deprivation leads to large reductions in cortical, diencephalic, and brainstem structures during wakefulness and sleep.15-17 Sleep-promoting medications may affect sleep–wake regulatory systems at several levels, as indicated in Figure 43-1. Benzodiazepine receptor agonists (1) may directly affect the sleep–wake state-switching system but also have direct cortical, thalamic, and brainstem effects. Sedating antidepressant and antipsychotic medications (2), through their activity on monoaminergic systems, are most likely to affect corticolimbic systems and brainstem-hypothalamic arousal systems. The effects of antihistamines (3) are
most likely to result from antagonism of histamine receptors in the hypothalamus and cortex that receive projections from the tuberomammillary nucleus. Melatonin and melatonin receptor agonists (4), through their effects on MT1 and MT2 receptors, influence the “wake signal” from the suprachiasmatic nucleus and circadian timing system. Investigational orexin antagonists (5) are likely to inhibit the effect of orexin-hypocretin on brainstem-hypothalamic arousal centers, and 5-HT2 antagonists (6) are most likely to have corticolimbic and brainstem sites of action. Thus, it seems likely that different types of sleep-promoting drugs achieve their effects through very different actions on very different components of the sleep–wake regulatory system.
SEDATING ANTIDEPRESSANTS Overview More than two dozen drugs are FDA approved as antidepressants in the United States, but several of these are used, mainly in low doses, for the treatment of insomnia. These include the tricyclic antidepressants (TCAs) doxepin, trimipramine, and amitriptyline as well as the heterocyclic drugs trazodone and mirtazapine. Low-dose doxepin (3 mg and 6 mg) was approved by the FDA for the treatment of insomnia in March, 2010; other sedating antidepressants have not been approved for this indication. The chemical structures of sedating antidepressants are shown in Figure 43-2, and pharmacokinetic properties are summarized in Table 43-1. The complex receptor effects of sedative antidepressants are summarized in Table 43-2. The majority of data regarding the effects of antidepressant drugs on human sleep come from studies in patients with depression, with use of doses higher than those typically used for insomnia. Formal dose ranging studies have
CHAPTER 43 • Clinical Pharmacology of Other Drugs Used as Hypnotics 495
Table 43-4 Summary of Other Drugs Used to Treat Insomnia* MECHANISM OF ACTION
DRUG
DRUG TYPE
TMAX
METABOLISM
t1
Melatonin
Hormone
20-60 minutes
Conjugation; oxidation by CYP enzymes
40-60 minutes
Agonist at MT1 and MT2 receptors
Diphenhydramine
Ethanolamine antihistamine
2-2.5 hours
Hepatic demethylation, oxidation
4-8 hours
Antagonize histamine H1 receptors
Doxylamine
Ethanolamine antihistamine
2-3 hours
Majority excreted unchanged in urine; some hepatic metabolism
10 hours
Antagonize histamine H1 receptors
Valerian
Plant extract
Uncertain because of multiple constituents
Uncertain because of multiple constituents
Uncertain because of multiple constituents
Uncertain; may increase GABA formation, interact with l–amino acid transporter receptor, or act as adenosine receptor agonist
Gabapentin
Anticonvulsant (structural analogue of GABA)
3-3.5 hours
Renal excretion (unchanged)
5-9 hours
Uncertain; may affect GABA release or interact with l–amino acid transporter protein
Tiagabine
Anticonvulsant
1-1.5 hours
CYP3A4
8 hours
Inhibits GABA transporter GAT1
Choral hydrate
Two-carbon molecule
Short
Converted to trichloroethanol, which undergoes conjugation
5-10 hours (for trichloroethanol)
Barbiturate-like effect at GABAA receptors
Olanzapine
Thienobenzodiazepine 4-6 hours antipsychotic
CYP1A2, CYP2D6
20-54 hours
Antagonizes H1, alpha1-adrenergic, alpha2-adrenergic, M1, 5-HT2, D2 receptors
Quetiapine
Dibenzothiazepine antipsychotic
1-2 hours
CYP3A4
6 hours
Antagonizes H1, alpha1-adrenergic, M1, 5-HT2, D2 receptors
Gammahydroxybutyrate
Endogenous four-carbon molecule
30-45 minutes
Metabolized to GABA, succinic semialdehyde, water, and carbon dioxide
20-70 minutes
May act directly as neurotransmitter, increase brain dopamine levels
2
*Data compiled from sources indicated in the text. CYP, cytochrome P-450 system (individual letters and numbers represent CYP families); D2, dopamine type 2 receptor; GABA, gammaaminobutyric acid; H1, histamine type 1 receptor; 5-HT, 5-hydroxytryptamine (serotonin); M1, muscarinic cholinergic type 1 receptor; MT, melatonin; t 12 , elimination half-life; tmax, time to maximal concentration.
not been conducted to determine optimal hypnotic doses, except for doxepin. Sleep effects of sedating antidepressant drugs have been discussed elsewhere18,19 and are summarized in Table 43-3. Tricyclic Antidepressant Drugs Tricyclic antidepressants share a core cyclic structure and differ from one another in their specific side chains (see Fig. 43-2). TCAs are often subgrouped according to side chain structures as tertiary or secondary amines. Tertiary amine TCAs are metabolized to secondary amine TCAs. Both the parent drugs and their metabolites have
measurable blood levels and pharmacologic activity. Tertiary TCAs are generally more sedating than secondary TCAs. Pharmacokinetics Tricyclic antidepressants are absorbed moderately quickly from the gastrointestinal tract, with maximum concentrations occurring at 2 to 6 hours after the dose. They undergo extensive (30% to 90%) first-pass metabolism and are extensively protein bound (up to 95%). Consequently, bioavailability is low after oral administration.18,20,21 TCAs are lipophilic, ensuring large volumes of distribution and high
496 PART I / Section 6 • Pharmacology Table 43-5 Polysomnographic Effects of Other Drugs Used to Treat Insomnia* DRUG Melatonin
SLEEP LATENCY
SLEEP CONTINUITY†
STAGE 3/4 NREM SLEEP AMOUNT, %
REM SLEEP
↓
↔ to ↑
↔
↔
OTHER
Diphenhydramine
↓
↔ to ↑
↔ to ↑
↓
Valerian
↓
↔ to ↑
↔ to ↑
↔ to ↑
Gabapentin
↔
↔ to ↑
↑
↔
Reduced periodic limb movements
Tiagabine
↔
↑
↑
↔
Results based on single study
Chloral hydrate
↓
↑
↔
↔ to ↓
Rapid tolerance may develop
Olanzapine
↔ to ↓
↑
↑
↔ to ↓
Reports of increased periodic limb movements, sleep eating
Gammahydroxybutyrate
↔ to ↓
↑
↑
↔ to ↓
↓ Alpha NREM intrusions in fibromyalgia patients
Inconsistent effects on sleep continuity, stage 3/4 across studies
*Reported effects are based on preponderance of evidence from published studies (see reference 124 and text for details). Many effects are inconsistent between individual studies. ↑ Indicates increase from pretreatment baseline; ↓ indicates decrease from pretreatment baseline; ↑ indicates no change from pretreatment baseline. † Sleep continuity refers to the proportion of sleep relative to wakefulness after sleep onset, as reflected by measures such as sleep efficiency. Other indicators of sleep continuity, such as wakefulness after sleep onset and number of awakenings, would have opposite signs. Thus, ↑ indicates improvement in overall sleep continuity.
Amitriptyline
Doxepin O CH3
CH3
CHCH2CH2 – N
CHCH2CH2 – N
CH3
CH3
Trimipramine
Trazodone N
N
N
CH3
N – CH2CH2CH2 – N
N–
O
Cl
CH2CHCH2 – N CH3
CH3
Nefazodone
O – CH2CH2
N N
N – CH2CH2CH2 – N
N–
––
CH3CH2
Mirtazapine
O
Cl
N
N N CH3
Figure 43-2 Chemical structures of sedating antidepressant drugs.
concentrations in the brain. TCAs have half-lives of approximately 15 to 30 hours. Tricyclic antidepressants undergo extensive hepatic metabolism, including oxidative demethylation of the side chains and hydroxylation of the ring structure,18-20 followed by conjugation and renal excretion. Hepatic metabolism of TCAs primarily involves CYP2C19 and CYP2D6
as well as CYP1A2 and CYP3A4.19-21 At usual doses, metabolism of TCAs follows linear kinetics, that is, drug blood levels (and metabolism) are proportional to dose; but at higher doses, metabolic enzymes can become saturated, leading to nonlinear pharmacokinetics, that is, higher blood levels than predicted by dose alone.19 Wide interindividual variability in metabolism of TCAs is due to popu-
CHAPTER 43 • Clinical Pharmacology of Other Drugs Used as Hypnotics 497
Pharmacodynamics and Receptor Pharmacology Tricyclic antidepressants interact with a variety of neurotransmitter receptors, including serotonin, norepinephrine, acetylcholine, and histamine. Effects on sleep probably represent the combined effects of many of these actions. Amitriptyline and doxepin inhibit both serotonin and norepinephrine reuptake transporters, whereas trimipramine has minimal reuptake effects. Tertiary TCAs including amitriptyline and doxepin have relatively more pronounced effects on serotonin than on norepinephrine reuptake, whereas their secondary amine metabolites have more pronounced effects on norepinephrine reuptake.19,23 After chronic dosing, additional effects on serotonergic and noradrenergic neurotransmission are also observed: desensitization of presynaptic 5-HT1A autoreceptors; upregulation (sensitization) of postsynaptic 5-HT1A receptors; and both downregulation and antagonism of postsynaptic 5-HT2 receptors.24 At 5-HT2 receptors, antagonism of the 5-HT2C subtype is more strongly associated with increasing slow-wave sleep compared with 5-HT2A receptors.25 The net effect of TCA receptor effects is an enhancement of 5-HT effects in the central nervous system (CNS). Noradrenergic effects of TCAs include desensitization of presynaptic alpha2 autoreceptors and a compensatory downregulation of postsynaptic beta receptors,18 with a net effect of increasing noradrenergic neurotransmission. TCAs also antagonize peripheral alpha1- and alpha2-adrenergic receptors, which accounts for their cardiovascular effects. Sedating TCAs also antagonize M1 muscarinic cholinergic and H1 histamine receptors. Amitriptyline is the most anticholinergic of all antidepressants, and doxepin is a more potent antihistamine than many drugs marketed as antihistamines, including diphenhydramine. In the doses recently approved for treatment of insomnia (3 to 6 mg), doxepin is relatively selective for H1 antagonism relative to serotonergic, adrenergic, and cholinergic effects. Effects on Human Sleep Subjectively, tertiary tricyclic drugs are perceived as sedating, associated with reports of decreased sleep latency and wakefulness during the sleep period and improved sleep quality among depressed patients. Secondary TCAs such as desipramine are less sedating and may even be subjectively alerting. The polysomnographic (PSG) effects of sedating TCAs in depression have been studied extensively. Reduced sleep latency, reduced wakefulness during sleep, and increased sleep efficiency have been reported in depressed patients treated with amitriptyline,26-28 doxepin,29 and trimipramine30,31 and in primary insomnia patients treated with doxepin32,33 and trimipramine.34 By contrast, secondary TCAs such as desipramine and nortriptyline
Awake Sleep stages
lation variability in CYP2D6 polymorphisms and activity.22 Age is associated with decreased metabolic clearance by CYP3A4 and decreased renal clearance.18,20 CYP3A4 can be induced by drugs such as barbiturates and tamoxifen, leading to reduced TCA levels; CYP2D6 can be inhibited by drugs such as antipsychotic drugs, methylphenidate, fluoxetine, and paroxetine, leading to increased TCA levels.19 Grapefruit juice is a common if unsuspected inhibitor of CYP3A4.
Stage 1/REM
Stage 2
Stage 3/4
Pretreatment 22:00
00:00
A
02:00
04:00
06:00
04:00
06:00
Time
Awake Sleep stages
Stage 1\REM
Stage 2
Stage 3/4
On amitriptyline 22:00
B
00:00
02:00 Time
Figure 43-3 Effects of amitriptyline on EEG sleep in a 54-yearold depressed woman. A, Baseline sleep histogram during acute depressive episode showing prolonged sleep latency, reduced sleep efficiency, and reduced stage 3/4 sleep. B, Sleep histogram after treatment with amitriptyline for 24 days (final dose, 200 mg) and remission of symptoms. Compared with baseline, the histogram during treatment shows reduced sleep latency, improved sleep efficiency, reduced REM sleep, and prolonged REM latency.
have little or no effect on sleep onset and continuity measures in depressed patients.27,35 Doxepin and amitriptyline have consistent effects on sleep stage architecture, including reductions in rapid eye movement (REM) sleep percentage and increases in phasic REM activity and REM sleep latency.26,28,29,36,37 Trimipramine differs from most TCAs in its effects on REM sleep, which has been reported to increase, to decrease, or to remain unchanged during treatment.28,30,31,34 Doxepin, amitriptyline, and trimipramine have inconsistent effects on stage 3/4 NREM, which has been reported to increase in some studies37 but not in most others.28,30,31,33 The effects of a TCA on PSG sleep are illustrated in Figure 43-3. In early studies of insomnia patients, relatively low doses of doxepin (25 to 50 mg) and trimipramine (50 to 200 mg) were associated with improved overall subjective sleep quality and daytime well-being compared with placebo.33,34 PSG effects of doxepin include reduced wakefulness and sleep latency and increased sleep time and sleep efficiency.38 A short-term study of doxepin (1, 3, and 6 mg) in primary insomnia demonstrated reduced wakefulness after sleep onset, wake time during sleep, and (at the highest dose) sleep latency as well as increased sleep time and sleep efficiency.39,39a Sleep efficiency was increased in each third of the night and each hour of the night, but with no demonstrable effect on next-day alertness or psychomotor
498 PART I / Section 6 • Pharmacology
performance. Doxepin 3 mg and 6 mg was approved by the FDA in March, 2010 for the treatment of insomnia characterized by sleep maintenance difficulty. Trimipramine has been reported to reduce wakefulness and improved sleep efficiency without affecting sleep time or sleep latency.40 Other effects of TCAs on PSG sleep can include increases in periodic limb movements during sleep and the appearance of eye movements during NREM sleep; such effects are particularly noted with strongly serotonergic TCAs such as clomipramine. TCAs do not worsen sleep apnea and may have a small beneficial effect.36 The acute effects of TCAs on sleep in depression are maintained during 1 to 3 years of maintenance treatment.36,41 Rebound insomnia, indicated by decreased sleep time and sleep efficiency, may occur on discontinuation of sedating TCAs.42 Side Effects Anticholinergic side effects of doxepin and amitriptyline include dry mouth, increased perspiration, constipation, and urinary retention. More serious effects include precipitation of ocular crises in patients with narrow-angle glaucoma, seizures, and anticholinergic delirium, which are dose related and typically occur at blood levels above 300 ng/mL.18 Side effects related to antihistaminic properties include sedation and weight gain. Studies of very low dose doxepin (1 to 6 mg) show a low rate of side effects, with somnolence being the most common.39 Side effects related to alpha1 antagonism include orthostatic hypotension with attendant risks of lightheadedness, syncope, and falls. TCAs typically increase heart rate. They also slow cardiac electrical conduction due to type I antiarrhythmic (quinidine-like) effects, which can lead to prolongation of the QRS duration and PR and QT intervals and heart block. TCA overdose lethality is largely due to cardiovascular toxicity, which can occur at doses as low as 10 times the therapeutic antidepressant daily dose. On the other hand, TCAs have no effect on cardiac contractility, and they can suppress atrial and ventricular ectopy.18 Trazodone and Nefazodone Trazodone is a tetracyclic antidepressant drug, and nefazodone is structurally similar. Nefazodone is not recommended for the treatment of insomnia because of potential hepatotoxicity, but data relating to sleep effects are presented here for general information. Pharmacokinetics Trazodone is rapidly absorbed, with peak plasma concentrations occurring 1 to 2 hours after oral doses. Like TCAs, it is highly (85% to 95%) protein bound. Nefazodone is rapidly and completely absorbed but rapidly metabolized, resulting in low bioavailability (about 20%). Trazodone and nefazodone have short half-lives of approximately 5 to 9 hours and 2 to 4 hours, respectively. However, active metabolites of nefazodone have slightly longer half-lives.43,44 The major metabolic pathway for trazodone and nefazodone is N-dealkylation to produce m-chlorophenylpiperazine (mCPP), an active metabolite that possesses serotonergic activity.21,43 Both drugs also undergo oxidation. Trazodone and mCPP are substrates for CYP2D6, and trazodone is also metabolized to a lesser extent by
CYP3A4. Nefazodone is oxidized by CYP3A4 and CYP2C19. Drugs that inhibit CYP3A4, such as ketoconazole, inhibit trazodone and nefazodone metabolism and decrease mCPP formation.43 Nefazodone and hydroxynefazodone themselves can also inhibit the activity of CYP3A4, thereby impairing the clearance and raising the plasma level of other drugs metabolized by the same route, including alprazolam, diazepam, and triazolam.45 Nefazodone metabolism and hepatic clearance are also reduced by age and liver impairment. Pharmacodynamics and Receptor Pharmacology Trazodone is a relatively weak but specific inhibitor of the serotonin reuptake transporter with minimal affinity for norepinephrine or dopamine reuptake. Trazodone also inhibits serotonin 5-HT1A, 5-HT1C, and 5-HT2 receptors. It has essentially no affinity for M1 receptors, but it does have moderate H1 histamine receptor antagonism. Finally, trazodone is a relatively weak antagonist of alpha2-adrenergic receptors and a somewhat more potent antagonist of alpha1 receptors.21,43 Like trazodone, nefazodone is a serotonin 5-HT2 receptor antagonist and a weak inhibitor of both serotonin and norepinephrine reuptake. Unlike trazodone, nefazodone shows little affinity for serotonin 5-HT1A receptors; adrenergic alpha1, alpha2, or beta receptors; or histamine H1 receptors.43 The active metabolite mCPP inhibits serotonin reuptake and is a partial agonist at postsynaptic 5-HT2C receptors. These actions can lead to increased side effects from trazodone and nefazodone among individuals who are “poor metabolizers” through CYP2D6 or who are taking inhibitors of CYP2D6, such as fluoxetine.44 Nefazodone shows nonlinear pharmacokinetics, resulting in greater than proportional plasma levels after higher doses.43 Effects on Human Sleep Studies of trazodone effects on human sleep have been limited by small sample sizes, particularly in PSG studies, and by study designs that have typically included sleep only as a secondary endpoint. In addition, many studies specifically addressing the sleep effects of trazodone have not included double-blind, placebo-controlled, randomized study designs. No published study has examined PSG outcomes with trazodone in patients with primary insomnia.46 Sedation is a common effect of trazodone in the treatment of depression, reported by more than 40% of patients. When it is specifically assessed, subjective sleep quality is improved by trazodone in healthy controls47 and in patients with depression48-51 and alcohol dependence.52 A study of sustained-release trazodone versus sertraline showed greater improvement in sleep disturbances with trazodone.53 However, some negative studies with respect to sleep quality in depressed subjects have also been reported.54 Polysomnographic studies have not consistently reported the effects of trazodone on sleep continuity. The available evidence is inconsistent with regard to effects on sleep latency, total sleep time, and sleep efficiency; about half of the published studies show improvements in these measures.53 Trazodone improved sleep efficiency, total sleep time, and wakefulness during sleep in older controls,47 in patients with depression49,55,56 (including depressed patients
CHAPTER 43 • Clinical Pharmacology of Other Drugs Used as Hypnotics 499
concurrently treated with selective serotonin reuptake inhibitors51), and in abstinent alcohol-dependent patients.57 Some negative studies with regard to sleep continuity have also been reported in younger healthy controls,58 in which ceiling effects may have been an issue, and in some studies of depressed patients with small numbers of subjects.48,54 Unlike most TCAs, trazodone has little effect on the amount of REM sleep; a majority of studies show no significant change49,55,56,58 or a small decrease.47,54 Trazodone is also associated with increased stage 3/4 NREM sleep in a majority of studies.47-49,51,56,58 In one study, a small reduction in apnea-hypopnea index and no change in periodic limb movements were noted.49 Although no information has been published about its long-term effects on sleep, rebound insomnia has been noted on discontinuation after several weeks of use.47 Only one study has been published on the effects of trazodone in primary insomnia compared with both placebo and zolpidem.59 Compared with placebo, trazodone (50 mg) was associated with reduced subjective sleep latency, awakenings, and wake time during sleep and increased subjective sleep time, ease of falling asleep, and sleep quality. These findings appeared to persist for both study weeks, but significant differences versus placebo were noted only during the first week because of late improvements in the placebo condition. The magnitude of effects with trazodone was similar to that for zolpidem (10 mg). Nefazodone is less consistently sedating than trazodone. A series of studies in depressed patients comparing nefazodone and fluoxetine showed that both drugs improved subjective sleep disturbance, but nefazodone had a significantly greater effect.60-62 Nefazodone was associated with increased PSG sleep efficiency, decreased wakefulness during sleep, and no change in sleep latency. REM sleep was increased in two of the studies and unchanged in one, and stage 3/4 was decreased in two studies and increased in one. Thus, nefazodone appears to have somewhat less potent effects on either sleep continuity or slow-wave sleep than trazodone has. No published studies have specifically examined nefazodone in patients with primary insomnia. Side Effects Trazodone can produce side effects including orthostatic hypotension, lightheadedness, and weakness.43 Unlike TCAs, trazodone does not have anticholinergic side effects, but it can have antihistaminic effects such as weight gain. Case reports suggest a potential for ventricular tachyarrhythmias.63 A potentially serious effect of trazodone is priapism, sustained painful erections in men.64 Although it is uncommon, priapism can be serious, requiring prompt surgical treatment. The risk appears to be greatest early in the course of treatment, and it can occur even at low doses. The incidence of abnormal erections during trazodone treatment is approximately 1 per 6000 male patients treated. Fatalities have been reported with overdoses of trazodone, although most of these occurred in conjunction with other drug ingestion. Unlike zolpidem and triazolam, trazodone is not associated with subjective effects associated with abuse potential.65 Common side effects associated with nefazodone include dry mouth, somnolence, dizziness, nausea, blurred vision,
and postural hypotension.43 Nefazodone has been associated with serious hepatic toxicity, in some cases leading to fulminant hepatic failure and death.66 The reported rate of life-threatening liver failure is estimated at 1 case per 250,000 to 300,000 patient-years of exposure. This risk has led to withdrawal of nefazodone from the market in some countries. On the other hand, nefazodone has not been associated with fatal toxicity in overdose. There has been concern that mCPP, the metabolite of trazodone and nefazodone, can contribute to the development of the “serotonin syndrome” when this drug is used in combination with other serotonergic drugs, such as selective serotonin reuptake inhibitors. The serotonin syndrome includes symptoms of confusion or delirium, restlessness similar to akathisia, muscle irritability, hyperreflexia, and autonomic instability including hypotension. Mirtazapine Pharmacokinetics Mirtazapine is rapidly absorbed, undergoes extensive firstpass metabolism, and is about 85% protein bound, yielding bioavailability of about 50%.67,68 Mirtazapine has an elimination half-life of approximately 20 to 40 hours. Mirtazapine undergoes N-demethylation (producing an active metabolite) and N-oxidation, followed by conjugation and excretion. CYP2D6 and, to a lesser extent, CYP3A4 and CYP1A2 are the major enzymes involved in mirtazapine metabolism. Mirtazapine follows linear pharmacokinetics, but its metabolism is affected by both age and sex; metabolic clearance is reduced in women and in older adults as well as in those with liver disease.67 Although mirtazapine itself does not strongly inhibit or induce hepatic enzymes, mirtazapine blood levels are decreased by medications such as carbamazepine that induce CYP enzymes and increased by medications such as fluoxetine that inhibit CYP enzymes. Pharmacodynamics and Receptor Pharmacology Mirtazapine is a very weak inhibitor of noradrenergic reuptake and has no effect on serotonin reuptake.69 However, similar to TCAs, it increases serotonergic and noradrenergic neurotransmission through blockade of alpha2 autoreceptors and heteroreceptors.44 It also has prominent antagonist activity at 5-HT2, 5-HT3, H1, and alpha1-adrenergic receptors,69 which may contribute to its hypnotic effects. Effects on Human Sleep Mirtazapine is reported to be subjectively sedating in clinical studies of depression. In a PSG study in healthy adults, mirtazapine decreased sleep latency, awakenings, and stage 1 NREM sleep and increased stage 3/4.70 In a study of six depressed patients, mirtazapine had similar effects, decreasing sleep latency, increasing sleep efficiency and sleep time, and having no significant effect on REM or stage 3/4 sleep.71 Thus, although it is potentially promising, mirtazapine has not yet been adequately evaluated as a hypnotic. Side Effects In addition to causing sedation, mirtazapine is associated with increased appetite, weight gain, and dry mouth,
500 PART I / Section 6 • Pharmacology
probably related to its antihistaminic properties. Clinical observations suggest that mirtazapine may be less sedating at doses above 30 mg per day than at lower doses. This is hypothesized to be related to greater noradrenergic effects relative to antihistaminic and serotonergic effects at lower doses.68 Mirtazapine has not been associated with serious toxicity or death in overdose.
SEROTONIN RECEPTOR (5-HT2A/2C) ANTAGONISTS As discussed before, several antidepressants are antagonists of serotonin 5-HT2 receptors, which is thought to underlie some of their sedative effect. Other compounds that antagonize 5-HT2A and 5-HT2C receptors have been investigated more specifically for their sleep effects, although some of them have also been investigated as antidepressant or antianxiety drugs as well. The role of serotonin in sleep–wake regulation was a central tenet of the monoamine theory of sleep and wakefulness,72 stemming from the observation that destruction of serotonin neurons in the dorsal raphe, or depletion with reserpine, results in severe insomnia. Subsequent observations showed serotonergic raphe neurons to be most active during wakefulness, less active during NREM sleep, and virtually inactive during REM sleep.73 The large number of serotonin actions and receptor subtypes makes it difficult to propose any general function of this widespread neurotransmitter. 5-HT2A/2C receptors are G protein– coupled receptors that are widely distributed in the CNS, including the cortex, hippocampus, amygdala, thalamus, hypothalamus, and brainstem. They functionally interact with and affect the activity of GABAergic, dopaminergic, and cholinergic neurons.74 Early evidence in healthy humans showed that ritanserin, a 5-HT2A/2C antagonist, increased slow-wave sleep and delta electroencephalographic (EEG) activity in a dosedependent fashion, with inconsistent and smaller magnitude effects on subjective sleep quality and PSG sleep latency and awakenings.75-78 A comparison with ketanserin, a more selective 5-HT2A antagonist, suggested that the effects of ritanserin on 5-HT2C receptors were more likely to explain its slow-wave sleep-enhancing actions.78 Another 5-HT2 antagonist, SR 46349B, was observed to have effects similar to those of ritanserin, increasing visually scored slow-wave sleep and suppressing REM sleep.79 This agent also increased slow-wave activity and reduced spindle frequency activity on quantitative EEG measures. Ritanserin was found to have few effects on sleepiness or psychomotor function, even with daytime administration. Among poor sleepers, ritanserin had a small effect on the number of awakenings, in addition to the previously described slowwave sleep effect and improved subjective sleep quality.80,81 Acute discontinuation led to rebound insomnia. Although ritanserin was not further developed as a hypnotic medication, several new 5-HT2 antagonists are undergoing clinical trials for this indication. The first published study with APD-125 demonstrated reduced wakefulness after sleep onset and wakefulness during sleep, increased slow-wave sleep, and improved subjective sleep, but no effect on sleep latency, in patients with chronic insomnia.82
MELATONIN AND MELATONIN RECEPTOR AGONISTS Biosynthesis, Physiologic Regulation, and Specific Compounds As reviewed elsewhere in this volume, melatonin is a hormone endogenously synthesized from serotonin and produced in the pineal gland, retina, and intestinal tract. Melatonin production is acutely suppressed by light acting on the retina. The noradrenergic sympathetic nervous system, acting through the superior sympathetic ganglion, stimulates pineal melatonin production. Specifically, beta1 stimulation with alpha1 amplification leads to increased availability of N-acetyltransferase, the rate-limiting enzyme in melatonin biosynthesis.83 Hence, beta- and alpha-adrenergic antagonists may affect melatonin synthesis. A number of synthetic melatonin receptor agonists have been developed and tested in laboratory and clinical studies. These include ramelteon and agomelatine (S-20098), a serotonergic-melatonergic antidepressant.84,85 Pharmacokinetics Exogenous melatonin is rapidly absorbed, with peak levels occurring in about 20 to 30 minutes. It has a 40- to 60-minute elimination half-life.86 When it is formulated with absorption-retarding binders, systemic availability can be prolonged to mimic the normal period of nocturnal secretion.87,88 Approximately 85% of an oral dose is removed by hepatic first-pass metabolism. Metabolism includes oxidation by CYP1A2 and CYP2C19, followed by glucuronate and sulfate conjugation and renal excretion.89 Melatonin is secreted in breast milk. Ramelteon is also rapidly absorbed, with time to maximal concentration of 0.75 to 1 hour and elimination half-life of 0.8 to 2.5 hours.90 Pharmacodynamics and Receptor Effects Three subtypes of melatonin receptors have been identified; MT1 and MT2 subtypes are most prevalent in the suprachiasmatic nucleus and retina and most likely related to phase-shifting effects of melatonin. Melatonin receptors are also found in reproductive organs, immune cells, and vasculature, where they can mediate both vasoconstriction and vasodilation. Melatonin has effects in regulating retinal light sensitivity, seasonal breeding patterns, systemic immunity, and cancer cell growth. Ramelteon is a selective, high-affinity MT1 and MT2 melatonin receptor agonist. Effects on Human Sleep In humans, melatonin has been studied both as a chronobiotic (where the intended effect is to phase shift circadian rhythms) and as a hypnotic (where the intended effect is to induce or to maintain sleep). Its use as a chronobiotic is discussed elsewhere in this volume. The potential hypnotic actions of melatonin have been studied in healthy adults,91,92 adults and children with insomnia,93,94 older adults with insomnia,87 dementia patients,88,95 medically ill adults,96 and patients with affective disorders.97 These studies have used a wide range of doses from less than 1 mg to more than 80 mg and a variety of administration schedules.98,99 A dose-response effect has not been demonstrated.
CHAPTER 43 • Clinical Pharmacology of Other Drugs Used as Hypnotics 501
A number of studies have shown that melatonin is associated with reduced sleep latency and improved quality of sleep by self-report, with less consistent effects on sleep maintenance and duration.96,100-103 Studies using actigraphy and PSG outcomes in pediatric, older adult, and nursing home populations also suggest modest effects on sleep latency, with less consistent increases in total sleep time.87,88,93-95,104,105 Melatonin has been reported to decrease sleep latency and awakenings and to increase sleep time in children with neurodevelopmental disabilities and sleep or circadian rhythm disturbances.106,107 Paradoxically, melatonin may act preferentially as a hypnotic in situations of low homeostatic drive for sleep (e.g., during the daytime period of low endogenous secretion).108-110 A meta-analysis examined melatonin effects on PSG and actigraphy measures from 17 studies of predominantly healthy subjects. Melatonin was associated with a mean decrease of 4.0 minutes in sleep latency, a mean increase of 2.2% in sleep efficiency, and a mean increase in sleep duration of 12.8 minutes.111 Heterogeneity in melatonin doses and subject characteristics as well as the fact that most studies were not conducted in subjects with insomnia may have affected these findings. Ramelteon is associated with reduced sleep latency and increased sleep time, but not with consistent changes in wakefulness after sleep onset or other sleep continuity measures. In several studies, changes were more robust in PSG measures than in self-report measures. When it was administered to healthy adults in the novel sleep laboratory environment, ramelteon was associated with improved subjective sleep quality, reduced subjective and PSG sleep latency, and increased PSG sleep time but no changes in sleep continuity.112 In short-term (2 nights) administration to adult chronic insomnia patients, ramelteon was associated with reduced subjective and PSG sleep latency, increased PSG sleep time, reduced slow-wave sleep, and no effect on wakefulness after sleep onset113; a similar study in older adults yielded similar findings but with a significant effect on sleep efficiency and no effect on self-report measures. Five-week studies in adults with chronic insomnia showed a similar pattern of reduced sleep latency and increased sleep time by self-report and PSG measures, but no change in sleep efficiency.114,115 Ramelteon had no effect on sleep-disordered breathing or other measures of sleep in a group of patients with sleep apnea.116 Agomelatine, an antidepressant with both melatonin MT1/MT2 agonist and serotonin 5-HT2C antagonist properties, may also have effects on sleep and circadian rhythms. A study of agomelatine administration in evening hours to healthy elderly men showed no effects on PSG measures of sleep, but phase advances were observed in circadian rhythms of body temperature and cortisol.117 In 6-week studies of depressed patients, agomelatine was associated with improved subjective measures of sleep latency and sleep quality,118 decreased PSG wakefulness after sleep onset, and increased sleep efficiency and slow-wave sleep.119 Side Effects Melatonin has a wide therapeutic index in humans. Despite widespread use of melatonin at low doses, no obvious public health risk has yet emerged. Nonetheless, the actual risks of protracted melatonin consumption remain unknown. The most common side effect reported from
taking melatonin is headache. Acutely, increased sleepiness and fatigue might contribute to the loss of vigilance in critical work situations. Melatonin is nonaddicting. Ramelteon is generally well tolerated; the most common side effects include headache, dizziness, somnolence, fatigue, and nausea. Rebound insomnia has not been observed, and there is no evidence for abuse potential.
ANTIHISTAMINES Specific Agents Antihistamine drugs used in the treatment of insomnia are reversible antagonists of histamine H1 receptors. Antihistamines are a diverse group of drugs broadly divided clinically into two groups on the basis of their sedative potential.120 First-generation agents include doxepin (discussed earlier under antidepressants), diphenhydramine, doxylamine, chlorpheniramine, hydroxyzine, meclizine, promethazine, and cyproheptadine. Essentially all of the over-the-counter antihistamine drugs marketed for insomnia treatment include diphenhydramine, the prototype of this class, or doxylamine. In addition, most analgesichypnotic combination medications (“pm” preparations) contain diphenhydramine. Second-generation nonsedating antihistamine drugs are used primarily for treatment of seasonal, environmental, and other allergic reactions and are not used for the treatment of insomnia. Pharmacokinetics Antihistamines are well absorbed from the gastrointestinal tract and widely distributed throughout the body, including the CNS. Most first-generation antihistamines, including diphenhydramine, have 4- to 6-hour durations of action, although specific agents, such as hydroxyzine and meclizine, may last for up to 24 hours. Diphenhydramine is extensively metabolized by CYP enzymes and has an elimination half-life of 4 to 8 hours.121 Pharmacodynamics and Receptor Pharmacology Histamine is widely present throughout the CNS and the body. Three types of histamine receptors have been described, labeled H1, H2, and H3. Histamine is synthesized from histidine by the action of l-histidine decarboxylase and is metabolized by methylation and oxidative deamination.120 In most tissues, histamine is stored in mast cells, which mediate allergic responses. In the CNS, histamine serves as a neurotransmitter localized to the tuberomammillary nucleus of the posterior hypothalamus. Histaminergic neurons project widely to the brainstem and cerebral cortex and promote wakefulness.122 Histaminergic neurons fire actively during wakefulness, reinforced by excitatory input from hypocretin-containing neurons of the lateral hypothalamus, and are inhibited during sleep by the activity of GABAergic projections from the ventrolateral preoptic area.123 Histamine has a variety of effects in the periphery, including H1 receptor–mediated vasodilation, increased capillary permeability, bronchoconstriction, and contraction of the gut and H2-mediated gastric acid secretion. H3 receptors serve as presynaptic autoreceptors that mediate feedback inhibition of histamine synthesis and release.
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H1 receptor antagonists have a variety of CNS and systemic effects. Well-described CNS effects include sedation, decreased alertness, decreased reaction times, and sleepiness.124 Paradoxically, a minority of patients respond with CNS activation, including restlessness, anxiety, and increased alertness. Systemic effects of antihistamines include inhibition of immediate hypersensitivity reactions mediated by mast cell release of histamine. In addition, H1 antagonists decrease capillary permeability, thus inhibiting edema, wheal reactions, and the itch response. H1 antihistamines also have minor effects of antagonizing respiratory smooth muscle, relaxing bronchospasm, and promoting vasodilation.120 Many of the early sedating antihistamines, including diphenhydramine, have muscarinic anticholinergic effects similar to those of atropine. In addition, diphenhydramine increases serotonergic neurotransmission and antagonizes alpha-adrenergic receptors. The “nonsedating” H1 antagonists have very little CNS effect because of their inability to penetrate the blood–brain barrier, thus limiting their actions to the periphery. Effects on Human Sleep Antihistamines such as diphenhydramine and doxylamine are associated with subjective drowsiness and sleepiness, leading to their widespread use as over-the-counter hypnotic agents. However, their efficacy has not been well studied. A study of 10 healthy adults showed increased motor activity with diphenhydramine compared with placebo and no significant effect on self-reported sleep outcomes.125 Clinical trials using doses of 12.5 to 50 mg in hospitalized and outpatient samples of poor sleepers have shown subjective improvements in sleep latency, nocturnal awakenings, sleep duration, and sleep quality.126-128 A comparative trial of temazepam (15 mg) and diphenhydramine (50 mg) in older adults with insomnia showed a reduction in awakenings but not in sleep latency, total sleep time, or sleep quality with diphenhydramine.129 Approximately 50% of subjects experienced rebound symptoms with temazepam and diphenhydramine, and the rate of other side effects was similar. The largest published trial compared diphenhydramine and valerian-hops combination with placebo in a total of 184 adults.130 Diphenhydramine was associated with significantly greater change in selfreported sleep efficiency, but not in sleep latency or total sleep time, relative to placebo; a global measure of selfreport outcome, the Insomnia Severity Index, showed significantly greater reductions in the diphenhydramine group than in the placebo group. PSG-measured sleep latency, sleep efficiency, and total sleep time also showed no significant group differences. Other PSG studies have examined daytime sleepiness with sedating and nonsedating antihistamines. These studies confirm the hypnotic effect of drugs such as diphenhydramine but show no significant sedation with nonsedating drugs such as astemizole, loratadine, or cetirizine131-133 and also show tolerance to the daytime sedative effect of diphenhydramine.134 Side Effects Impairment of psychomotor performance with diphenhydramine has been well documented.124 Epidemiologic studies have also suggested cognitive impairment associ-
ated with diphenhydramine use in the elderly.135 Other side effects related to CNS activity include dizziness, fatigue, and tinnitus. Peripheral side effects can include decreased appetite, nausea, vomiting, diarrhea, and constipation as well as weight gain. A number of case reports have also documented potentially serious side effects of doxylamine, including coma, rhabdomyolysis, and resultant kidney failure.136
VALERIAN Pharmacokinetics Valerian preparations include more than 400 extracts, mainly derived from the roots of the plant species Valeriana officinalis. These extracts contain a number of chemicals with CNS activity, including sesquiterpenes, valepotriates, valerenic acid, and various other alkaloids, in unknown proportions.137 The constituents of a specific valerian preparation also depend on the actual valerian species used, the method of extraction (aqueous versus ethanolic), and the combination with other herbs or agents such as hops.138 Because of the multiple constituents of valerian preparations, their pharmacokinetics have not been well described. Doses in clinical studies have typically ranged from 400 to 900 mg per day. Pharmacodynamics and Receptor Pharmacology The exact mechanism of action of valerian preparations is also unknown. The GABA-like activity of valerian extracts is suggested by their sedative, anxiolytic, myorelaxant, and possible anticonvulsant effects.139 Valerian extracts contain a small amount of GABA, but GABA is not transported across the blood–brain barrier, and valerian extracts do not act on benzodiazepine receptors. Valerenic acid may actually inhibit brain GABA metabolism. Other potential mechanisms of action include serotonin receptor activity and adenosine receptor antagonism. Finally, some components of valerian, including valepotriates, may act as prodrugs transformed into homobaldrinal, a compound that inhibits motor activity in mice.137 Effects on Human Sleep The effects of valerian extracts on sleep in humans have been investigated in healthy young adults and middle-aged and older adults with insomnia. Duration of treatment has ranged from 1 day to 14 days, and outcome measures have included self-reports, actigraphy, and polysomnography. Subjective effects of valerian preparations include decreased sleep latency, improved sleep quality, and decreased awakenings.140,141 Effects on PSG sleep include increased stage 3/4 and reduced stage 1 NREM sleep.142,143 Although improved sleep latency and sleep efficiency have been observed in some PSG studies, sleep continuity effects of valerian are inconsistent.143-145 A systematic review of valerian preparations found no significant effects of ethanolic extracts on subjective or objective sleep measures, inconsistent effects of aqueous valerian extracts, limited and variable evidence for valepotriate preparations, and mixed but predominantly negative evidence for valerian combinations.138 Overall, this review concluded
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that research findings to date do not support the efficacy of valerian preparations for improving subjective sleep outcomes. Side Effects Side effects associated with valerian have been reported to be few and mild and include headache and weakness. Morning sleepiness is an infrequent side effect.137
GABAPENTIN AND PREGABALIN Gabapentin and pregabalin were initially developed as anticonvulsant drugs, but they have subsequently found widespread use in treatment of neuropathic and fibromyalgia pain, periodic limb movement disorder, bipolar mood disorder, and insomnia. Typical daily doses of gabapentin range from 300 to 2100 mg, taken in divided doses with larger doses in the evening hours. Gabapentin absorption is moderately rapid (2 to 3 hours to maximal absorption) and has bioavailability of 35% to 60%, with lower availability at higher doses (nonlinear pharmacokinetics). It is distributed extensively, has an elimination half-life of 5 to 9 hours, and is excreted unchanged in urine. Doses of pregabalin are typically 150 to 600 mg in divided doses. Absorption of pregabalin is rapid (1 hour to maximal absorption) and is not affected by dose (linear pharmacokinetics). Like gabapentin, it is excreted unchanged in the urine and has a half-life of 4.5 to 7 hours. Therefore, doses of both drugs may need to be adjusted in patients with reduced renal clearance.146,147 Gabapentin and pregabalin may have several mechanisms of action for their analgesic and sedative effects. Both drugs are structural analogues of GABA but do not appear to interact with GABAA or GABAB receptors or to influence GABA reuptake, although they may promote formation of GABA in the CNS.148-150 Both drugs selectively bind with high affinity to the alpha2 delta subunit of N-type voltage-gated calcium channels, which reduces the release of excitatory neurotransmitters such as glutamate and norepinephrine and is thought to be related to their analgesic effects.151 Other potential mechanisms of action include antagonism of N-methyl-d-aspartate (NMDA) receptors and interaction with the l–amino acid transporter receptor.152 Side effects associated with gabapentin and pregabalin include sedation and fatigue, dizziness, headache, and ataxia and a less common risk of leukopenia. Gabapentin and pregabalin are consistently associated with improvement on self-reported sleep measures in patients with various pain conditions (e.g., fibromyalgia, neuropathic pain, postherpetic neuralgia, postsurgical pain).147,151,153 Although these drugs are sometimes used clinically for primary insomnia or other forms of comorbid insomnia, their sleep effects have not been systematically evaluated. A small study of gabapentin administered for 16 days to healthy adults showed no change in subjective sleep quality for most subjects, trends for reduced awakenings and periodic limb movement arousal index, and a significant increase in slow-wave sleep.154 Pregabalin administered to healthy adults was likewise associated with improved subjective sleep quality; reduced sleep latency and REM sleep; and increased sleep efficiency, total sleep time, and slow-
wave sleep.155 Similar effects on self-report and PSG sleep continuity, but not on slow-wave sleep, were seen when pregabalin was added to monotherapy with other drugs in epilepsy patients.156 In patients with restless legs syndrome, gabapentin has been associated with improved sleep continuity, increased stage 3/4 sleep, and reduced periodic limb movements.157 No published studies have formally evaluated gabapentin in insomnia. An open pilot study of gabapentin in alcohol-dependent patients with comorbid insomnia showed improvements in insomnia symptoms and feelings of tiredness in the morning.52
TIAGABINE Tiagabine was initially developed as an adjuvant anticonvulsant drug. It inhibits the GABA transporter GAT1, thereby reducing GABA reuptake into presynaptic neurons and glia and increasing the inhibitory actions of GABA in the CNS.148 Tiagabine has been investigated in doses of 4 to 16 mg for the treatment of insomnia. These doses are much lower than those used in epilepsy, probably because of the induction of hepatic metabolic enzymes by concurrent antiepileptic drugs. Tiagabine is rapidly absorbed and extensively protein bound; it is metabolized by CYP3A4 and has a terminal elimination half-life of approximately 8 hours. An early study of tiagabine in healthy adults demonstrated increased slow-wave sleep and EEG activity in frequencies of 0.5 to 10 Hz as well as improved sleep efficiency.158 Subsequent studies in primary insomnia confirmed dose-dependent increases in slow-wave sleep as well as reduced stage 1 NREM and REM sleep, but with small and inconsistent effects on total sleep time and wakefulness after sleep onset and no effect on sleep efficiency. Selfreported sleep outcomes showed no consistent changes,159,160 and similar effects were observed in older adults with primary insomnia.161,162 Side effects of tiagabine include dose-dependent dizziness, nausea, somnolence, and reduced objective measures of alertness. New-onset seizures have been observed in a small number of subjects, limiting its clinical utility. GABOXADOL Gaboxadol, also known as THIP, is a direct GABAA receptor agonist with effects distinct from those of benzodiazepine receptor agonists.163 Benzodiazepine receptor agonists are active at a wide range of GABA receptor subtypes, but especially those with alpha1 subunits, which are primarily synaptic in location. Synaptic GABA receptors are activated during fast synaptic transmission, transiently hyperpolarize and inhibit postsynaptic neurons, and desensitize rapidly. Gaboxadol is a potent agonist of GABA receptors that contain alpha4, alpha6, and delta subunits, which have more restricted anatomic distribution in the thalamus, hippocampus, and cerebellum and are mainly extrasynaptic in location. Extrasynaptic GABA receptors are sensitive to low concentrations of GABA and desensitize slowly, and their activation induces sustained neuronal effects.164,165 Gaboxadol is rapidly absorbed, reaching peak concentration within 30 minutes, with a half-life of approximately 1.5 to 2 hours.164
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In experimental models using healthy subjects, gaboxadol (5 to 15 mg) reduced self-reported and PSG sleep latency and wakefulness after sleep onset and increased total sleep time and EEG delta and theta activity.166-168 Short-term studies in patients with primary insomnia show similar findings, comparable to those seen with zolpidem as an active comparator.169,170 Gaboxadol also increased slow-wave sleep. Gaboxadol is not associated with typical indicators of abuse potential in animal or human studies.164 Common side effects include headache, nausea and vomiting, somnolence, and fatigue. Gaboxadol has also been associated with dissociative reactions including hallucinations and disorientation, which have led to suspension of clinical studies in the United States.
OREXIN ANTAGONISTS Orexin (hypocretin) is a peptide neurotransmitter localized to the perifornical neurons of the lateral hypothalamus. Orexinergic neurons have widespread excitatory projections to the brainstem and posterior hypothalamic arousal centers and serve to stabilize the wake-promoting function of these centers.171,172 Orexin receptor antagonists are currently being developed as potential hypnotic compounds. A human phase I study of the hypocretin receptor antagonist ACT-078573 showed decreased alertness and increased sleepiness with daytime administration that was similar to but longer lasting than the effect observed with zolpidem.173 Daytime EEG studies also showed increased delta and theta activity as well as dose-dependent decrease in sleep latency and increase in sleep efficiency and sleep time. CHLORAL HYDRATE Chloral hydrate has been used as a hypnotic and as a sedative in children undergoing clinical procedures. Chloral hydrate is a prodrug, rapidly converted by alcohol dehydrogenase in the liver to the active compound trichloroethanol, which acts at the barbiturate recognition site on GABAA receptors. Metabolism of trichloroethanol occurs through hepatic conjugation, with a half-life of approximately 5 to 10 hours. Sleep effects include subjective and objective reduction in sleep latency and improvement in sleep continuity, with little effect on stage 3/4 sleep or REM sleep.124 Because chloral hydrate is a skin and mucus membrane irritant, it can have side effects of unpleasant taste, gastrointestinal distress, nausea, and vomiting. Other potential side effects include lightheadedness, nightmares, and ataxia. A more serious potential side effect is hepatic injury. Fatal overdoses are possible, and chronic use can result in severe withdrawal. Chloral hydrate is not recommended for treatment of insomnia in adults or children, given its low therapeutic index and the availability of safer alternative drugs. SEDATIVE ANTIPSYCHOTIC DRUGS Second-generation antipsychotic drugs have significantly higher rates of somnolence than placebo in clinical trials.174 This effect may be clinically useful in the treatment of insomnia, particularly among patients with severe depres-
sion, bipolar disorder, and psychotic disorders. Although many different antipsychotic drugs have sedative effects (see reference 175 for review), olanzapine and quetiapine are the drugs most commonly used in nonpsychotic and non-bipolar patients for this purpose. Typically, olanzapine is administered in doses of 2.5 to 20 mg and quetiapine in doses of 25 to 200 mg at bedtime. Unlike older antipsychotic drugs that antagonize primarily dopamine receptors, olanzapine has a variety of receptor effects including antagonism of serotonin 5-HT2A, muscarinic cholinergic, H1, and alpha1-adrenergic receptors as well as activity at serotonin 5-HT2C, 5-HT3, and 5-HT6 receptors.152,176,177 Olanzapine is structurally similar to benzodiazepines. Quetiapine, like olanzapine, is an antagonist of serotonin 5-HT2A, H1, and alpha1 receptors. It has somewhat more potent dopamine D2 receptor antagonism than olanzapine does, but its dopamine binding is rapidly reversible. Olanzapine is rapidly absorbed, but a significant portion of the drug is metabolized in first-pass circulation. Its peak concentration occurs at about 6 hours, and it has a terminal elimination half-life of 20 to 54 hours. It is metabolized through the activity CYP1A2 and CYP2D6. Quetiapine is also rapidly absorbed, but it reaches peak concentration in about 1.5 hours and has a terminal elimination half-life of approximately 6 hours. Quetiapine is also metabolized in the liver, primarily through CYP3A4. Both of these antipsychotic drugs have a lower incidence of extrapyramidal side effects than that of traditional antipsychotic drugs such as haloperidol. However, both can cause hypotension. In addition, olanzapine has been associated with weight gain and glucose intolerance as well as with neurocognitive impairment at higher doses. Quetiapine has been associated with prolongation of the QTc interval on electrocardiography. Both olanzapine and quetiapine are subjectively sedating. Uncontrolled and placebo-controlled treatment studies using these medications as primary or adjunctive treatments demonstrate improved subjective sleep quality and reduced sleepiness in patients with schizophrenia,178,179 unipolar depression,180,181 and bipolar depression.182 In PSG studies with small numbers of healthy control subjects, olanzapine is associated with decreased sleep latency, wakefulness, and stage 1 NREM sleep and increased sleep efficiency, stage 2, and stage 3/4 NREM sleep, with no consistent effect on REM; subjective sleep quality is also improved.183-187 Similar self-reported and PSG effects have been demonstrated in small clinical studies of patients with depression,188 mania,189 and schizophrenia.190 Quetiapine administered acutely to healthy subjects has been reported to decrease sleep latency; to increase sleep time, sleep efficiency, and subjective sleep quality; and to reduce REM sleep.191 One open-label 6-week trial of quetiapine (25 to 75 mg) in patients with primary insomnia showed improved subjective sleep measures and increased sleep time and sleep efficiency.192 Small uncontrolled and controlled studies have also examined the effects of other second-generation antipsychotics, including risperidone and clozapine, in patients with schizophrenia.175 Both drugs are associated with improved sleep continuity, and risperidone is associated with increased slow-wave sleep.
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Given their potentially significant neurologic and metabolic side effects, antipsychotic drugs are best reserved for treatment of individuals who have insomnia comorbid with major psychiatric disorders, particularly psychotic and bipolar disorders.
SODIUM OXYBATE (GAMMA-HYDROXYBUTYRATE) Sodium oxybate, the sodium salt of gamma-hydroxybutyrate (GHB), is FDA approved for the treatment of cataplexy in patients with narcolepsy and is also recommended for the treatment of excessive sleepiness.193 GHB is an endogenous short-chain fatty acid that is synthesized from GABA. GHB acts as a neuromodulator-neurotransmitter, has two specific neuronal recognition sites, and is also a ligand for GABAB receptors. It is widely distributed in the brain, including the hippocampus, nucleus accumbens, basal ganglia, cortex, and brainstem. GHB acts primarily to inhibit the release of co-localized neurotransmitters, but its net effect may be to increase or to decrease neuronal activity, depending on which other neurotransmitter (e.g., dopamine, GABA, serotonin, glutamate) is affected. Pharmacologic concentrations of GHB act primarily to decrease neuronal activity through GABAB modulation, but this brief period of inhibition may be followed by increased neuronal activity; this effect may explain the initial sedative effect of GHB when it is administered at night, followed by increased alertness the next day.194 GHB effects on the CNS include sedation and, in higher doses, coma. GHB has few effects on the cardiovascular and respiratory systems. GHB is absorbed rapidly after oral administration, particularly because it is administered as a liquid, with peak concentrations approximately 30 to 60 minutes after administration. GHB is not bound to plasma protein. It is metabolized to a limited extent to GABA. GHB is also decomposed to water and carbon dioxide and exhaled. The mean half-life is quite short, ranging from 20 to 70 minutes (mean, 53 minutes).195 GHB is subjectively sedating. In healthy subjects, GHB increases stage 3/4 sleep, decreases stage 1, and reduces REM latency.196,197 When it is administered to patients with narcolepsy, its PSG effects include reduced REM latency and awakenings and increased stage 3/4 sleep, sleep efficiency, and sleep duration.194,198 A study in fibromyalgia patients showed similar results, with reduced sleep latency and REM sleep, increased stage 3/4 sleep, and reduction in alpha EEG intrusion during NREM sleep.199 GHB has not been formally assessed for its hypnotic properties in patients with other types of insomnia. The rapid sedative effects of GHB, particularly when it is combined with alcohol, have led to abuse. Other side effects of GHB include excess salivation, increased dreaming, sleepwalking, and gastrointestinal effects such as vomiting. It is also associated with amnesia, similar to other benzodiazepine receptor agonist hypnotic agents. In overdoses, GHB can be associated with acute delirium.195 High-dose recreational users of GHB have been described to have a withdrawal symptom characterized by insomnia, tremor, and anxiety.
Acknowledgment The author wishes to acknowledge the contributions of Paula Schweitzer, PhD, and Douglas E. Moul, MD, MPH, to earlier versions of this chapter, including the chapter in Principles and Practice of Sleep Medicine, 4th edition, 2005. ❖ Clinical Pearl Antidepressants, antihistamines, and other drugs are often considered to be safer alternatives to benzodiazepine receptor agonists for treatment of insomnia. However, in most cases, their efficacy has not been well demonstrated, and they can have clinically important side effects. Understanding of the clinical pharmacology and known sleep effects of these medications is critical to their rational use in clinical practice. These drugs may be useful when benzodiazepine receptor agonists are contraindicated or ineffective or when comorbidities such as severe psychiatric illness are present.
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CHAPTER 43 • Clinical Pharmacology of Other Drugs Used as Hypnotics 509
161. Walsh JK, Randazzo AC, Frankowski S, Shannon K, et al. Doseresponse effects of tiagabine on the sleep of older adults. Sleep 2005;28:673-676. 162. Roth T, Wright KP, Walsh J. Effect of tiagabine on sleep in elderly subjects with primary insomnia: a randomized, double-blind, placebo-controlled study. Sleep 2006;29:335-341. 163. Harrison NL. Mechanisms of sleep induction by GABAA receptor agonists. J Clin Psychiatry 2007;68(Suppl 5):6-12. 164. Ebert B, Wafford KA, Deacon S. Treating insomnia: current and investigational pharmacological approaches. Pharmacol Ther 2006;112:612-629. 165. Lu J, Greco MA. Sleep circuitry and the hypnotic mechanism of GABAA drugs. J Clin Sleep Med 2006;2:S19-S26. 166. Walsh JK, Deacon S, Dijk DJ, Lundahl J. The selective extrasynaptic GABAA agonist, gaboxadol, improves traditional hypnotic efficacy measures and enhances slow wave activity in a model of transient insomnia. Sleep 2007;30:593-602. 167. Mathias S, Zihl J, Steiger A, Lancel M. Effect of repeated gaboxadol administration on night sleep and next-day performance in healthy elderly subjects. Neuropsychopharmacology 2005;30:833-841. 168. Walsh JK, Snyder E, Hall J, Randazzo AC, et al. Slow wave sleep enhancement with gaboxadol reduces daytime sleepiness during sleep restriction. Sleep 2008;31:659-672. 169. Deacon S, Staner L, Staner C, Legters A, et al. Effect of short-term treatment with gaboxadol on sleep maintenance and initiation in patients with primary insomnia. Sleep 2007;30:281-287. 170. Lundahl J, Staner L, Staner C, Loft H, et al. Short-term treatment with gaboxadol improves sleep maintenance and enhances slow wave sleep in adult patients with primary insomnia. Psychopharmacology (Berl) 2007;195:139-146. 171. Szymusiak R, McGinty D. Hypothalamic regulation of sleep and arousal. Ann N Y Acad Sci 2008;1129:275-286. 172. Nishino S. The hypocretin/orexin receptor: therapeutic prospective in sleep disorders. Expert Opin Investig Drugs 2007;16:17851797. 173. Brisbare-Roch C, Dingemanse J, Koberstein R, Hoever P, et al. Promotion of sleep by targeting the orexin system in rats, dogs and humans. Nat Med 2007;13:150-155. 174. Scherk H, Pajonk FG, Leucht S. Second-generation antipsychotic agents in the treatment of acute mania: a systematic review and meta-analysis of randomized controlled trials. Arch Gen Psychiatry 2007;64:442-455. 175. Monti JM, Monti D. Sleep in schizophrenia patients and the effects of antipsychotic drugs. Sleep Med Rev 2004;8:133-148. 176. Baldessarini RJ, Tarazi FI. Drugs and the treatment of anxiety disorders: psychosis and mania. In: Hardman JG, Limbird LE, editors. Goodman and Gilman’s the pharmacological basis of therapeutics. New York: McGraw-Hill; 2001. p. 485-520. 177. Baldessarini RJ. Drug therapy of depression and anxiety disorders. In: Brunton LL, Lazo JS, Parker KL, editors. Goodman and Gilman’s the pharmacological basis of therapeutics. New York: McGraw-Hill; 2006. p. 429-459. 178. Yamashita H, Mori K, Nagao M, Okamoto Y, et al. Influence of aging on the improvement of subjective sleep quality by atypical antipsychotic drugs in patients with schizophrenia: comparison of middle-aged and older adults. Am J Geriatr Psychiatry 2005;13: 377-384. 179. Yamashita H, Mori K, Nagao M, Okamoto Y, et al. Effects of changing from typical to atypical antipsychotic drugs on subjective sleep quality in patients with schizophrenia in a Japanese population. J Clin Psychiatry 2004;65:1525-1530. 180. Todder D, Caliskan S, Baune BT. Night locomotor activity and quality of sleep in quetiapine-treated patients with depression. J Clin Psychopharmacol 2006;26:638-642. 181. Baune BT, Caliskan S, Todder D. Effects of adjunctive antidepressant therapy with quetiapine on clinical outcome, quality of sleep
and daytime motor activity in patients with treatment-resistant depression. Hum Psychopharmacol 2007;22:1-9. 182. Vieta E, Calabrese JR, Goikolea JM, Raines S, et al. Quetiapine monotherapy in the treatment of patients with bipolar I or II depression and a rapid-cycling disease course: a randomized, double-blind, placebo-controlled study. Bipolar Disord 2007;9:413425. 183. Sharpley AL, Vassallo CM, Cowen PJ. Olanzapine increases slowwave sleep: evidence for blockade of central 5-HT2C receptors in vivo. Biol Psychiatry 2000;47:468-470. 184. Salin-Pascual RJ, Herrera-Estrella M, Galicia-Polo L, Laurrabaquio MR. Olanzapine acute administration in schizophrenic patients increases delta sleep and sleep efficiency. Biol Psychiatry 1999; 46:141-143. 185. Lindberg N, Virkkunen M, Tani P, Appelbery B, et al. Effect of a single-dose of olanzapine on sleep in healthy females and males. Int Clin Psychopharmacol 2002;17:177-184. 186. Sharpley AL, Vassallo CM, Pooley EC. Allelic variation in the 5-HT2C receptor (HT2RC) and the increase in slow wave sleep produced by olanzapine. Psychopathology 2001;153:271-272. 187. Gimenez S, Clos S, Romero S, Grasa E, et al. Effects of olanzapine, risperidone and haloperidol on sleep after a single oral morning dose in healthy volunteers. Psychopharmacology (Berl) 2007;190: 507-516. 188. Sharpley AL, Attenburrow ME, Hafizi S, Cowen PJ. Olanzapine increases slow wave sleep and sleep continuity in SSRI-resistant depressed patients. J Clin Psychiatry 2005;66:450-454. 189. Moreno RA, Hanna MM, Tavares SM, Wang YP. A doubleblind comparison of the effect of the antipsychotics haloperidol and olanzapine on sleep in mania. Braz J Med Biol Res 2007;40: 357-366. 190. Salin-Pascual RJ, Herrera-Estrella M, Galicia-Polo L, Laurrabaquio MR. Olanzapine acute administration in schizophrenic patients increases delta sleep and sleep efficiency. Biol Psychiatry 1999;46: 141-143. 191. Cohrs S, Rodenbeck A, Guan Z, Pohlmann K, et al. Sleep-promoting properties of quetiapine in healthy subjects. Psychopharmacology (Berl) 2004;174:421-429. 192. Wiegand MH, Landry F, Bruckner T, Pohl C, et al. Quetiapine in primary insomnia: a pilot study. Psychopharmacology (Berl) 2008; 196:337-338. 193. Wise MS, Arand DL, Auger RR, Brooks SN, et al. Treatment of narcolepsy and other hypersomnias of central origin. Sleep 2007; 30:1712-1727. 194. Pardi D, Black J. Gamma-hydroxybutyrate/sodium oxybate: neurobiology, and impact on sleep and wakefulness. CNS Drugs 2006;20:993-1018. 195. Meredith B, Cupp MJ, Tracy TS. γ-Hydroxybutyric acid (GHB), γ-butyrolactone (GBL), and 1,4-butanediol (BD). In: Cupp MJ, Tracy TS, editors. Forensic science: dietary supplements: toxicology and clinical pharmacology. Totowa, NJ: Humana Press; 2003. p. 173-195. 196. Lapierre O, Montplaisir J, Lamarre M, Bedard MA. The effect of gamma-hydroxybutyrate on nocturnal and diurnal sleep of normal subjects: further considerations on REM sleep-triggering mechanisms. Sleep 1990;13:24-30. 197. Van Cauter E, Plat L, Scharf MB, Leproult R, et al. Simultaneous stimulation of slow-wave sleep and growth hormone secretion by gamma-hydroxybutyrate in normal young men. J Clin Invest 1997;100:745-753. 198. Scrima L, Hartman PG, Johnson FH, Thomas EE, et al. The effects of gamma-hydroxybutyrate on the sleep of narcolepsy patients: a double-blind study. Sleep 1990;13:479-490. 199. Scharf MB, Baumann M, Berkowitz DV. The effects of sodium oxybate on clinical symptoms and sleep patterns in patients with fibromyalgia. J Rheumatol 2003;30:1070-1074.
510 PART I / Section 6 • Pharmacology
Wake-Promoting Medications: Basic Mechanisms and Pharmacology Seiji Nishino and Emmanuel Mignot Abstract Central nervous system stimulants currently used in sleep medicine include amphetamine-like compounds (l- and d-amphetamine, l- and d-methamphetamine, l- and d-methylphenidate, pemoline), mazindol, modafinil, some antidepressants with stimulant properties (e.g., bupropion), and caffeine. The effect of most of these drugs on wakefulness is primarily mediated through an inhibition of dopamine reuptake or transport and in some cases through increased dopamine release. Inhibition of adrenergic uptake also probably has some stimulant effects. Biogenic amine transporters (for dopamine, norepinephrine, and serotonin [5-HT]) are located at nerve terminals and are important in terminating transmitter action and maintaining transmitter homeostasis. In the past decade, monoamine transporters have been cloned and their molecular mechanisms have been elucidated. Genetically engineered mice lacking these molecules (knockout mice) have also become available. In parallel with these discoveries, potent and selective ligands for dopamine, norepinephrine, and 5-HT
CENTRAL NERVOUS STIMULANTS: DEFINITIONS Although it is widely used, central nervous system (CNS) stimulant is a loosely defined scientific term. In Drugs and the Brain by S. Snyder, stimulants are “drugs that have an alerting effect; they improve the mood and quicken the intellect.” In Handbook of Sleep Disorders by J.D. Parkes, CNS stimulation implies “an increase in neuronal activity due to enhanced excitability, with a change in the normal balance between excitatory and inhibitory influences. This may result from blockage of inhibition, enhancement of excitation, or both.” In A Primer of Drug Action by R.M. Julien, “psychomotor stimulants (psychostimulants)” is the term used, and psychostimulants are said to induce excitement, alertness, euphoria, a reduced sense of fatigue, and increased motor activity. Psychostimulants include dopamine uptake blockers, dopamine-releasing agents, adenosine receptor blockers, and acetylcholine receptor stimulants. In The Pharmacological Basis of Therapeutics by Goodman and Gilman, “indirect sympathomimetic amines” refers to amphetamines as the “most potent compounds with respect to stimulation of the CNS.” In this chapter, CNS stimulant is the generic term used for all wake-promoting compounds of potential use in the treatment of excessive daytime sleepiness (EDS). (See Chapters 4 and 45 for the classification of EDS disorders and the indications of CNS stimulants for patients affected with sleep disorders.) EDS is a common symptom in patients with sleep disorders and in the general population at large. CNS stimulants are generally effective on EDS independently of its underlying cause; however, they should be used cautiously because of their potential for 510
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44
transporters have been developed. The results of pharmacologic studies using these new ligands in canines and knockout mice models suggest the importance of the dopamine transporter for the mode of action of amphetamines and amphetamine-like compounds (as well as mazindol and bupropion) on wakefulness. Importantly, however, the various stimulants also have differential effects on dopamine storage (through vascular monoamine transporter inhibition) or release and in most cases also have substantial effects on other monoaminergic systems. The mode of action of modafinil, a more recent compound that rapidly became a first-line treatment of excessive daytime sleepiness in narcolepsy, is controversial, but it is increasingly suggested to primarily involve dopamine reuptake inhibition. Other mechanisms of action involved in wake promotion include adenosine receptor antagonists, such as those found in caffeine. More recently, novel classes of wake-promoting therapeutics are being developed, including glutamatergic and histaminergic modulators, and preclinical and clinical evaluation is in progress.
misuse and abuse. In this chapter, we review the neurochemical, neurophysiologic, and neuropharmacologic properties of the CNS stimulants most commonly used in sleep medicine. This is followed by a perspective on future stimulant treatments.
AMPHETAMINES AND AMPHETAMINE-LIKE COMPOUNDS Historical Perspective Amphetamine was first synthesized by Alles in 1897, but its stimulant effects were not recognized until 1929. Alles wanted to find a synthetic substitute for the recently banned ephedrine, a compound isolated from the Ephedra vulgaris plant in 1925. Amphetamine increases energy, elevates mood, prevents fatigue, increases vigilance and prevents sleep, stimulates respiration, and causes electrical and behavioral arousal from natural or drug-induced sleep. It was rapidly shown to be a safer and cheaper alternative to ephedrine as a stimulant. In World War II, amphetamine was supplied to paratroopers and commandos. British troops alone were issued 72 million tablets. In Japan, methamphetamine, initially used for munitions factory workers, flooded the civilian market at the end of the war; 5% of the Japanese population between the ages of 16 and 25 years became dependent on the drug. More than 50 “amphetamine” preparations containing amphetamine or derivatives, alone or in combination with other drugs (most notably barbiturates), were on the market after World War II. Narcolepsy was probably the first condition for which amphetamine was used clinically. It revolutionized therapy for the condition, although it was not curative.
CHAPTER 44 • Wake-Promoting Medications: Basic Mechanisms and Pharmacology 511
The piperazine derivative of amphetamine, methylphenidate, was introduced in 1959 by Yoss and Daly.1 The use of amphetamine in treatment of parkinsonism dates to 1937, when it was first used to alleviate muscle rigidity and postencephalitis parkinsonism. By 1968, its use in the treatment of this condition was largely suspended because of more effective dopaminergic agents. Until the dangers of amphetamine dependence and abuse became recognized, amphetamine was widely used in the treatment of obesity. It was also prescribed in the treatment of sedative abuse and alcoholism to offset sleepiness and lethargy. Bradley and Bowen2 were the first to report on the use of amphetamine to modify antisocial behavior in children: “when children are withdrawn or lethargic, the amphetamine tended to make them more alert, more accessible to persons and the environment.” A paradoxical calming effect was also noted in some children and aggressive adults. Most notably, a selected group of children who were “hyperactive” tended to move more quietly, to be calmer, and to be less quarrelsome after being treated with amphetamine. In 1958, methylphenidate was introduced to treat hyperactivity in children (see reference 3). These observations preceded reports on the effects of amphetamine and methylphenidate in the hyperkinetic child (children diagnosed with what is now called attention-deficit/ hyperactivity disorder [ADHD]). Although no controlled trials have investigated the use of stimulants in depression, many case series suggest effectiveness in some treatment-resistant cases. The use of stimulants with monoamine oxidase inhibitors is generally not advised but has not been reported to induce significant hypertension or hyperthermia. The combination of amphetamines with low (anticataplectic) doses of tricyclics is often prescribed in narcolepsy-cataplexy without any problem, and combining these substances in depression has been shown to be effective although not recommended because of the risk of dependence and abuse. Part of the beneficial effects of amphetamine on depression may be due to a reduction of fatigue and apathy rather than to a genuine antidepressant effect. From a historical perspective, the number of indications for amphetamine stimulants has narrowed considerably over the years to primarily include narcolepsy, ADHD, and treatment-resistant depression. The rationale for this change has been the realization of the risk of abuse and dependence with these compounds. The introduction of other effective therapies for these conditions (e.g., modafinil for narcolepsy, atomoxetine for ADHD) has also led to narrower indications, although many new formulations and isomer-specific preparations have been recently developed and are increasingly used, mostly for the treatment of ADHD. Structure-Activity Relationships and Major Chemical Entities It is helpful to the understanding of the pharmacology of stimulant drugs to distinguish potency and efficacy; these terms are too often used incorrectly in colloquial language. Efficacy refers to the therapeutic effects that can be achieved by a drug, whereas potency describes the amount of the drug needed to achieve therapeutic effects. In general, potency correlates with the affinity of the drug for
its target, whereas efficacy reflects how much maximal effect can be achieved when the targets are fully occupied. These two characteristics are uncorrelated. Phenylisopropylamine (amphetamine) has a simple chemical structure resembling endogenous catecholamines (Fig. 44-1). This scaffold forms the template for a wide variety of pharmacologically active substances. Although amphetamine possesses strong central stimulant effects, minor modifications can result in agents with a broad spectrum of effects, including nasal decongestion, anorexia, vasoconstriction, and antidepressant effects (for the monoamine oxidase inhibitor tranylcypromine), and hallucinogenic properties (MDMA [methylenedioxymethamphetamine] and MDA [methylenedioxyamphetamine]). The phenylisopropylamine molecule can be divided into three structural components: (1) an aromatic nucleus, (2) a terminal amine, and (3) an isopropyl side chain. Substitution on the aromatic nucleus generally produces less potent if not entirely inactive stimulants.4 The substitution of two or more methoxy groups plus addition of ethyl, methyl, or bromine groups on the aromatic nucleus creates hallucinogens of various potencies. Ecstasy (MDMA) is built on a methamphetamine backbone, with a dimethoxy ring extending from the aromatic group. If a similar compound is synthesized with a primary amine (without the methyl group), it creates Love (MDA). Substitution at the amine group is the most common alteration. Methamphetamine, which is characterized by an additional methyl group attached to the amine (a secondary substituted amine), is more potent than amphetamine, probably because of increased CNS penetration. An intact isopropyl side chain appears to be needed to maintain stimulant efficacy. Changing the propyl to an ethyl side chain, for example, creates phenylethylamine, an endogenous neuroamine that has mood- and energy-enhancing properties but is less potent and has a much shorter half-life than amphetamine. The pharmacologic effects of most amphetamine derivatives are isomer specific. These differential effects occur at both the pharmacokinetic level (absorption, brain penetration, metabolism, distribution volume, elimination) and the pharmacodynamic profile level (actual pharmacologic effects). d-Amphetamine, for example, is a far more potent stimulant than the l-derivative. In electroencephalographic (EEG) studies, d-amphetamine is four times more potent than l-amphetamine in inducing wakefulness.5 The relative effects of the d and l isomers of amphetamine on norepinephrine and dopamine transmission explain some of these pharmacodynamic differences (for details, see the pharmacology section for each compound). Not all effects are stereospecific, however. For example, both enantiomers are equipotent at suppressing rapid eye movement (REM) sleep in humans and rats and at producing amphetamine psychosis. Amphetamine-like compounds, such as methylphenidate, pemoline, and fencamfamin, are structurally similar to amphetamines; all compounds include a benzene core with an ethylamine group side chain (see Fig. 44-1). Both methylphenidate and pemoline were commonly used for the treatment of EDS in narcolepsy, but pemoline has been withdrawn from the market in several countries
512 PART I / Section 6 • Pharmacology
Dopamine HO HO
CH2 − CH − NH2
Norephinephrine H HO O HO CH2 − CH − NH2
Cocaine O
O
H
H O
N-CH3
H O
H
Amphetamines Amphetamine
Methamphetamine CH3
CH2 − CH − NH2
Modafinil Armodafinil R-Modafinil NH2
CH3 CH2 − CH − N − CH3 H
S
Amphetamine-like stimulants Methylphenidate
S-Modafinil NH2
O
S
O
O O
Xanthine derivative Pemoline
Caffeine CH3
CH − C NH
O − CH3 O
O
O
N N
N H
NH
H3C
N N
O
CH3
Figure 44-1 Chemical structures of amphetamine-like stimulants, cocaine, modafinil, armodafinil, and caffeine (a xanthine derivative) compared with dopamine and norepinephrine.
because of liver toxicity (Table 44-1). The most commonly used commercially available form of methylphenidate is a racemic mixture of both a d and l enantiomer. In this preparation, the d-methylphenidate mainly contributes to its clinical effects, especially after oral administration. This is due to the fact that l-methylphenidate, but not d-methylphenidate, undergoes a significant first-pass metabolism (by deesterification to l-ritalinic acid). A single isomer form of d-methylphenidate is also marketed under the brand name of Focalin. Cocaine also mediates its psychostimulant effects by blocking catecholamine reuptake (mainly dopamine), but its structure is different from that of amphetamine-like compounds (see Fig. 44-1). The fact that cocaine and some dopamine transporter inhibitors are drugs of abuse is responsible for schedule labeling of such drugs by the Food and Drug Administration. Amphetamines are highly lipid soluble molecules that are well absorbed by the gastrointestinal tract. Peak levels are achieved approximately 2 hours after oral administration, with rapid tissue distribution and brain penetration. Protein binding is highly variable, with an average volume of distribution of 5 L/kg. Both hepatic catabolism and renal excretion are involved in the inactivation of amphetamine. Amphetamine can be metabolized in the liver by either aromatic or aliphatic hydroxylation, yielding parahydroxyamphetamine or norephedrine, respectively, both of which are biologically active. The metabolism of amphetamine and amphet-
amine-like compounds is pH dependent. Amphetamine is metabolized into benzoic acid (23%), which is subsequently converted to hippuric acid or to parahydroxyamphetamine (2%). This in turn is converted to parahydroxynorephedrine (0.4%). Thirty-three percent of the oral dose is excreted unchanged in the urine. Urinary excretion of amphetamine and many amphetamine-like stimulants is greatly influenced by urinary pH. At urinary pH 5.0, the elimination half-life of amphetamine is short, about 5 hours; but at pH 7.3, it increases to 21 hours. Sodium bicarbonate will delay excretion of amphetamine and prolong its clinical effects, whereas ammonium chloride will shorten amphetamine action (and can possibly induce toxicity). Methylphenidate is almost totally and rapidly absorbed after oral administration. Methylphenidate has low protein binding (15%) and is short acting; effects last approximately 4 hours, with a half-life of 3 hours. The primary means of clearance is through the urine, in which 90% is excreted. Molecular Targets of Amphetamine Action The molecular targets mediating amphetamine-like stimulant effects are complex and vary according to the specific analogue or isomer used and the dose administered. Amphetamine increases catecholamine (dopamine and norepinephrine) release and inhibits reuptake from presynaptic terminals. This results in increase in catechol-
CHAPTER 44 • Wake-Promoting Medications: Basic Mechanisms and Pharmacology 513
Table 44-1 Commonly Used Pharmacologic Compounds for Excessive Daytime Sleepiness STIMULANT COMPOUND (SCHEDULE)
USUAL DAILY DOSES*
T1/2 (hr); SIDE EFFECTS, NOTES
Amphetamine and Amphetamine-like CNS Stimulants d-Amphetamine
sulfate (II)
5-60 mg (15 mg, 100 mg)
T1/2 16-30; Irritability, mood changes, headaches, palpitations, tremors, excessive sweating, insomnia
Methamphetamine HCl (II)
5-60 mg (15 mg, 80 mg)
T1/2 9-15; Same as d-amphetamine; may have greater central over peripheral effects than d-amphetamine†
Methylphenidate HCl (II)
10-60 mg (30 mg, 100 mg)
T1/2 3; Same as amphetamines; better therapeutic index than d-amphetamine, with less reduction of appetite or increase in blood pressure; short duration of action
Pemoline (IV)
20-115 mg (37.5 mg, 150 mg)
T1/2 11-13; Less sympathomimetic effect, milder stimulant; slower onset of action, a tendency for drug buildup; may produce liver toxicity; had been with drawn from the U.S. market
Dopamine or Norepinephrine Uptake Inhibitor Mazindol (IV)
2-6 mg (NA)
T1/2 10-13; Weaker CNS stimulant effects; anorexia, dry mouth, irritability, headaches, gastrointestinal symptoms; reported to have less potential for abuse
Other Agents for Treatment of Excessive Daytime Sleepiness Modafinil‡ (IV)
100-400 mg (NA)
T1/2 9-14; No peripheral sympathomimetic action; headaches, nausea; reported to have less potential for abuse
Armodafinil (IV)
150-250 mg
T1/2 10-15; Similar to those of modafinil
Monoamine Oxidase Inhibitor with Alerting Effect Selegiline
5-40 mg (NA)
T1/2 2; Low abuse potential; partial (10%-40%) interconversion to amphetamine
100-200 mg (NA)
T1/2 3-7; Weak stimulant effect; 100 mg of caffeine is roughly equivalent to one cup of coffee; palpitations, hypertension
Xanthine Derivative Caffeine§
*Dosages recommended by the American Sleep Disorders Association are listed in parentheses (usual starting dose and maximal dose recommended). † Methamphetamine is reported to have more central effects and may predispose more to amphetamine psychosis. The widespread misuse of methamphetamine has led to severe legal restriction on its manufacture, sale, and prescription in many countries. l-Amphetamine (dose range, 20 to 60 mg) is not available in the United States but probably has no advantage over d-amphetamine in the treatment of narcolepsy (slightly weaker stimulant). ‡ The half-life of s-enantiomer of modafinil is short at 3-4 hours, and thus the half-life of racemic modafinil mostly reflects the half-life of armodafini (r-enantiomer). § Caffeine can be bought without prescription in the form of tablets (NoDoz, 100 mg; Vivarin, 200 mg caffeine) and is used by many patients with narcolepsy before diagnosis. CNS, central nervous system; NA, not applicable.
amine concentrations in the synaptic cleft and enhances postsynaptic stimulation. The presynaptic modulations by amphetamines are mediated by specific catecholamine transporters6 (Fig. 44-2). Axelrod and colleagues first demonstrated that epinephrine can be rapidly and selectively taken up by the heart, spleen, and glandular organs, each of which has significant sympathetic innervation. It was subsequently discovered that norepinephrine-containing neurons bind and take up norepinephrine against a concentration gradient, suggesting the existence of selective norepinephrine transporters. Further experiments also found that these transporters not only can carry catecholamine back into nerve terminals but also can release catecholamines by reverse efflux. The molecules responsible, the dopamine transporter (DAT) and the norepinephrine transporter (NET), have now been cloned and characterized. The DAT and NET proteins are about 620–amino acid proteins with 12 puta-
tive membrane-spanning regions. Amphetamine derivatives are known to inhibit the uptake and to enhance the release of dopamine, norepinephrine, or both by interacting with the DAT and the NET. These transporters normally move dopamine and norepinephrine from the outside to the inside of the cell. This process is sodium dependent; sodium and chloride bind to the dopamine or norepinephrine transporter to immobilize it at the extracellular surface and to alter the conformation of the dopamine or norepinephrine binding site so that it facilitates substrate binding. Substrate binding allows movement of the carrier to the intracellular surface of the neuronal membrane, driven by sodium concentration gradients. Interestingly, in the presence of some drugs such as amphetamine, the direction of transport appears to be reversed (see Fig. 44-2). Dopamine and norepinephrine are thus moved from the inside of the cell to the outside through a mechanism called exchange diffusion, which occurs at low doses (1 to 5 mg/kg) of
514 PART I / Section 6 • Pharmacology
Tyrosine
Amphetamine
DA reuptake inhibitor
TH DOPA AADC
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DA
DA
DA
Amphetamine Amphetamine
Dopamine Vesicles containing dopamine
DOPAC
VMAT
D2
MA O
DA
Presynaptic receptor
/3
Mitochondria DAT Presynaptic
HVA
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MAO D1
–
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D5 Gs AC Gi + –
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D3
COMT
DA
D4 Go Postsynaptic Ion channels
Cellular responses
DAT Na+ Cl–
DA
B Dopamine reuptake inhibitor Amphetamine Dopamine
C Postsynaptic dopamine receptors Facilitation Inhibition
Figure 44-2 A, Schematic representations of dopaminergic terminal neurotransmission in relation to mode of action of dopamine (DA) reuptake inhibitors and amphetamine. The DA transporter (DAT) is one of the most important molecules located at the dopaminergic nerve terminals and regulates dopaminergic neurotransmission. (1) Amphetamine interacts with the DAT carrier to facilitate DA release from the cytoplasm through an exchange diffusion mechanism (see C). At higher intracellular concentrations, amphetamine also (2) disrupts vesicular storage of DA and (3) inhibits the monoamine oxidase (MAO). Both these actions increase cytoplasmic DA concentrations. (4) Amphetamine also inhibits DA uptake by virtue of its binding to and transport by the DAT. These mechanisms all lead to an increase in DA synaptic concentrations, and these are independent of the phasic activity of the neurons. Increased synaptic concentration of DA stimulates postsynaptic DA receptors (D1 type [1, 5] and D2 type [2, 3, 4] receptors). AADC, aromatic acid decarboxylase; AC, adenylyl cyclase; cAMP, cyclic adenosine monophosphate; COMT, catechol-Omethyltransferase; D1-D5, dopamine receptors 1 through 5; DA, dopamine; DAT, dopamine transporter; DOPA, 3,4-dihydroxyphenylalanine; DOPAC, dihydroxyphenylacetic acid; Gi, Go, and Gs, protein subunits; HVA, homovanillic acid; MAO, monoamine oxidase; 3-MT, methroxytyramine; TH, tyrosine hydroxylase; VMAT, vesicular monoamine transporter. B, Effects of dopamine reuptake inhibitors and amphetamines at the dopaminergic nerve terminal. Sodium and chloride bind to the DAT to immobilize it at the extracellular surface. This alters the conformation of the DA binding site on the DAT to facilitate substrate (i.e., DA) binding. DAT reuptake inhibitors bind to DAT competitively and inhibit DA-DAT bindings, resulting in increasing DA concentrations in the synaptic cleft. C, Amphetamine, in competition with extracellular DA, binds to the transporter. Substrate binding allows the movement of the carrier to the intracellular surface of the neuronal membrane, driven by the sodium and amphetamine concentration gradients, resulting in a reversal of the flow of DA uptake. Amphetamine dissociates from the transporter, making the binding site available to cytoplasmic DA. DA binding to the transporter enables the movement of the transporter to the extracellular surface of the neuronal membrane, as driven by the favorable DA concentration gradient. DA dissociates from the transporter, making the transporter available for amphetamine and thus another cycle.
amphetamine. This mechanism, rather than a simple inhibition of monoamine reuptake, is involved in the enhancement of extracellular catecholamine release by amphetamine. It explains why amphetamine in particular is more potent than expected on the basis of its relatively low binding affinity for DAT and NET.7,8 A recent in vitro experiment has shown that amphetamine transport causes an inward sodium current. As intracellular sodium ions become more available, a DAT-mediated reverse transport of dopamine occurs, producing dopamine release through the DAT transporter. At higher dose, other effects are involved. Increased serotonin (5-HT) release is also observed. Moderate to high doses of amphetamine (>5 mg/kg) also interact with the vascular monoamine transporter 2 (VMAT2; see refer-
ence 6). The vesicularization of the monoamines (dopamine, norepinephrine, serotonin, and histamine) in the CNS is dependent on VMAT2; VMAT2 regulates the size of the vesicular and cytosolic dopamine pools. Amphetamine is highly lipophilic and easily enters nerve terminals by diffusing across plasma membranes. Once inside, amphetamine depletes vesicular monoamine stores by several mechanisms. First, it binds directly, albeit with low affinity, to VMAT2, thereby inhibiting vesicular uptake. Second, amphetamine, a weak base, diffuses across the vesicular membrane in its uncharged (lipophilic) form and accumulates in the granules in its charged form (because of the lower pH of the synaptic vesicle interior). As vesicular amphetamine concentration increases, the buffering capacity of the catecholamine-containing vesicle is lost.
CHAPTER 44 • Wake-Promoting Medications: Basic Mechanisms and Pharmacology 515
The vesicular pH gradient diminishes, a loss of the free energy necessary for monoamine sequestration occurs, and vesicular monoamine uptake decreases. In addition, the collapse of the gradient purportedly results in a competition for protons between the native monoamines and amphetamine, thereby increasing uncharged vesicular neurotransmitter concentrations. All these mechanisms lead to a diffusion of the native monoamines out of the vesicles into the cytoplasm along a concentration gradient. Amphetamine can therefore be viewed as a physiologic VMAT2 antagonist that releases the vascular dopamine or norepinephrine loaded by VMAT2 into the cytoplasm. The high doses of amphetamine also inhibit monoamine oxidase activity. These mechanisms, as well as the reverse transport and the blocking of reuptake of dopamine or norepinephrine by amphetamine, lead to an increase in norepinephrine and dopamine synaptic concentrations (see reference 6), and these are independent on the phasic activity of the neurons. Various amphetamine derivatives have slightly different effects on all these systems. For example, methylphenidate also binds to the NET and DAT and enhances catecholamine release. However, it has less effect on the VMAT granular storage site than native amphetamine does. Similarly, d-amphetamine has proportionally more releasing effect on the dopamine versus the norepinephrine system compared with l-amphetamine. MDMA (Ecstasy) has more effect on 5-HT release than on catecholamine release. Of note, other antidepressant medications acting on monoaminergic systems, including dopamine, norepinephrine, and 5-HT (e.g., bupropion or mazindol, see later), tend to exert their actions by simply blocking the reuptake mechanism. Some but not all amphetamines have neurotoxic effects on monoaminergic systems. This is well established for MDMA and serotonergic systems in both humans and animals. Similarly, amphetamine derivatives with strong effects on monoamine release (typically methamphetamine and less so derivatives with simple monoamine reuptake inhibition effects, for example, methylphenidate) have neurotoxic effects on dopamine systems at high dose in animal studies, especially in the context of repeated administration mimicking binges of stimulant abuse administration. Presynaptic Modulation of the Dopaminergic System Primarily Mediates the EEG Arousal Effects How amphetamines and other stimulants increase EEG arousal has been explored by use of a canine model of the sleep disorder narcolepsy and DAT knockout mice models. Canine narcolepsy is a naturally occurring animal model of the human disorder.8 Similar to human patients, narcoleptic dogs are excessively sleepy (i.e., shorter sleep latency), have fragmented sleep patterns, and display cataplexy.8 Although amphetamine-like compounds are well known to stimulate catecholaminergic transmission, the exact mechanism by which they promote EEG arousal is still uncertain. Stimulation of either adrenergic or dopaminergic transmission or both has been suggested to play a role. In narcoleptic and control Dobermans, the effects of ligands specific for the dopamine (GBR-12909, bupropion,
and amineptine), the norepinephrine (nisoxetine and desipramine), or both the dopamine and norepinephrine (mazindol and nomifensine) transporters, as well as amphetamine and a nonamphetamine stimulant, modafinil, were studied to dissect wake-promoting mechanisms.9 The result indicated that prototypical dopamine uptake inhibitors, such as GBR-12909 and bupropion, dose dependently increased EEG arousal in narcoleptic dogs; nisoxetine and desipramine, two potent norepinephrine uptake inhibitors, had no effect on EEG arousal at doses that almost completely suppressed REM sleep and cataplexy (Fig. 44-3; see reference 9). Furthermore, the EEG arousal potency of various dopamine uptake inhibitors correlated tightly with in vitro DAT binding affinities (see Fig. 44-3), whereas a reduction in REM sleep correlated with in vitro NET binding affinities,9 suggesting that dopamine uptake inhibition is critical for the EEG arousal effects of these compounds. d-Amphetamine has a relatively low DAT binding affinity but potently (i.e., need for a low dose) promotes alertness (see Fig. 44-3). It is also generally considered more efficacious (i.e., can produce more alertness with high dose) than pure DAT reuptake inhibitors in promoting wakefulness. As described in the pharmacology section, d-amphetamine not only inhibits dopamine reuptake, it also enhances dopamine release (at lower dose by exchange diffusion and at higher dose by antagonistic action against VMAT2) and inhibits monoamine oxidation to prevent dopamine metabolism. The dopamine releasing effects of amphetamine are likely to explain the unusually high potency and efficacy of amphetamine in promoting EEG arousal. The effects of various amphetamine analogues (d-amphetamine, l-amphetamine, and l-methamphetamine) on EEG arousal and their in vivo effects on brain extracellular dopamine levels in narcoleptic dogs were compared10 to dissect wake-promoting effects of amphetamine. In vitro studies have demonstrated that the potency and selectivity for enhancing release or inhibiting uptake of dopamine and norepinephrine vary between amphetamine analogues and isomers.11 Amphetamine derivatives thus offer a unique opportunity to study the pharmacologic control of alertness in vivo. Hartmann and Cravens5 previously reported that d-amphetamine is four times more potent than l-amphetamine in inducing EEG arousal but that both enantiomers are equipotent at suppressing REM sleep in humans and rats. Enantiomer-specific effects have also been reported with methamphetamine; l-methamphetamine is much less potent as a stimulant than either d-methamphetamine or l- or d-amphetamine (see reference 11). Similarly, in canine narcolepsy, d-amphetamine is 3 times more potent than l-amphetamine and 12 times more potent than l-methamphetamine in increasing wakefulness and reducing slow-wave sleep (Fig. 44-4A).10 The results of microdialysis experiments in the same narcoleptic dogs suggest that wake-promoting effects of amphetamine derivatives correlate well with their effects on dopamine efflux (i.e., intracellular concentration, a net effect of dopamine release and dopamine uptake block). The local perfusion of d-amphetamine raised dopamine levels nine times above baseline (see Fig. 44-4B).10 lAmphetamine also increased dopamine levels by up to
516 PART I / Section 6 • Pharmacology
Percent change from baseline recording
100
50
%∆ Wake %∆ SWS %∆ REM %∆ REM/SWS
0
–50
–100 Desipramine 0.4 mg/kg
A
Nisoxetine 0.5 mg/kg
Bupropion 4.0 mg/kg
GBR-12909 1.0 mg/kg
Mazindol 0.016 mg/kg
Amineptine 4.0 mg/kg
DOSE RESPONSE EFFECT ON WAKE
DAT AFFINITY vs. WAKE –5
90
Nomifensine
In Vitro affinity to DAT Log (Ki [M])
Percent change in time spent in active wake
100
80 70 Mazindol
60 50
Modafinil Amineptine
D-Amphetamine
40 GBR-12909
30
Bupropion
20
Desipramine
10
Modafinil D-Amphetamine
Amineptine
–6 Bupropion
–7 Nomifensine Mazindol
–8
GBR-12909
Nisoxetine
y = –9.7 + 0.92x R2 = 0.61
0
–9 0.01
B
Nomifensine 0.25 mg/kg
0.1
1 Dose (mg/kg)
10
1
C
2
3
4
5
Effect on increase in EEG arousal Log (ED+40% [µmol IV])
Figure 44-3 Effects of various dopamine and norepinephrine uptake inhibitors and amphetamine-like stimulants on the EEG arousal of narcoleptic dogs and correlation between in vivo EEG arousal effects and in vitro dopamine transporter binding affinities. A and B, The effects of various compounds on daytime sleepiness were studied by 4-hour daytime polygraphic recordings (10:00 to 14:00) in narcoleptic animals (n = 4-5). Two doses were studied for each compound. All dopamine uptake inhibitors and CNS stimulants dose dependently increased EEG arousal and reduced slow-wave sleep (SWS) compared with vehicle treatment. In contrast, nisoxetine and desipramine, two potent norepinephrine uptake inhibitors, had no significant effect on EEG arousal at doses that completely suppressed cataplexy. Compounds with both adrenergic and dopaminergic effects (nomifensine, mazindol, d-amphetamine) were active on both EEG arousal and cataplexy. The effects of the two doses studied for each stimulant were used to approximate a dose-response curve; the drug dose that increased the time spent in wakefulness by 40% above baseline (vehicle session) was estimated for each compound. The order of potency of the compounds obtained was mazindol > (amphetamine) > nomifensine > GBR-12909 > amineptine > (modafinil) > bupropion. C, In vitro DAT binding was performed with [3H]-WIN 35428 onto canine caudate membranes. Affinity for the various dopamine uptake inhibitors tested varied widely between 6.5 nM and 3.3 mM. In addition, it was also found that both amphetamine and modafinil have low but significant affinity (same range as amineptine) for the DAT. A significant correlation between in vivo and in vitro effects was observed for all five dopamine uptake inhibitors and modafinil. Amphetamine, which had potent EEG arousal effects, has a relatively low DAT binding affinity, suggesting that other mechanisms, most probably monoamine releasing effects or monoamine oxidase inhibition, are also involved. In contrast, there was no significant correlation between in vivo EEG arousal effects and in vitro norepinephrine transporter binding affinities for dopamine and norepinephrine uptake inhibitors. These results suggest that presynaptic enhancement of dopamine transmission is the key pharmacologic property mediating the EEG arousal effects of most wake-promoting CNS stimulants.
CHAPTER 44 • Wake-Promoting Medications: Basic Mechanisms and Pharmacology 517
D-AMP
Cataplexy Wake REM
600 nmol/kg IV
10:00
16:00
SWS Drowsy
Wake REM Drowsy LS DS L-AMP
600 nmol/kg IV
10:00
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600 nmol/kg IV
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% Time spent in each vigilance state
1000 D-AMP L-AMP
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** **
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(**P < .01, n = 6)
0 Perfusion (100 µM) –200 –40
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CAUDATE DA LEVEL
–20
0
20 Time (min)
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100
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(*P < .05, n = 5) 50 * * *
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80
C
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20
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Figure 44-4 Effect of amphetamine (AMP) derivatives on sleep parameters during 6-hour EEG recording. A, Typical effects of amphetamine derivatives on sleep architecture in a narcoleptic dog (600 nmol/kg intravenously). Representative hypnograms with and without drug treatment are shown. Recordings lasted for 6 hours, beginning at approximately 10:00 am. Vigilance states are shown in the following order from top to bottom: cataplexy, wake, REM sleep, drowsy, light sleep (LS), and deep sleep (DS). The amount of time spent in each vigilance state (expressed as percentage of recording time) is shown on the right side of each hypnogram. d-AMP was found to be more potent than l-AMP, and l-methamphetamine (l-mAMP) was found to be the least potent, whereas all isomers equipotently reduced REM sleep. B and C, Local perfusion of amphetamine derivatives: effects on caudate dopamine (DA) and cortex norepinephrine (NE) levels. Local perfusion of d-AMP (100 µM) raised dopamine levels nine times above baseline. l-AMP also increased dopamine levels up to seven times above baseline, but this level was obtained only at the end of the 60-minute perfusion period. l-mAMP did not change dopamine levels under these conditions. In contrast, all three amphetamine isomers had equipotent enhancements on norepinephrine release. These results suggest that the potency of these derivatives on EEG arousal correlated well with measurements of dopamine efflux in the caudate of narcoleptic dogs, whereas effects on norepinephrine release may be related to REM suppressant effects.
518 PART I / Section 6 • Pharmacology
seven times, but peak dopamine release was obtained only at the end of the 60-minute perfusion period. l-methamphetamine did not change dopamine levels under these conditions. Norepinephrine was also measured in the frontal cortex during perfusion of d-amphetamine, l-amphetamine, and l-methamphetamine (see Fig. 44-4C). Although all compounds increased norepinephrine efflux, no significant difference in potency was detected among the three analogues. The fact that the potency of amphetamine derivatives on EEG arousal correlates with effects on dopamine efflux in the caudate of narcoleptic dogs further confirms that the enhancement of dopamine transmission by presynaptic modulation mediates the wake-promoting effects of amphetamine analogues. This result is also consistent with data obtained with DAT blockers (see Fig. 44-3). Considering the fact that other amphetamine-like stimulants, such as methylphenidate and pemoline, also inhibit dopamine uptake and enhance release of dopamine, presynaptic enhancement of dopamine transmission is likely to be the key pharmacologic property mediating wake promotion for all amphetamines and amphetamine-like stimulants. In contrast, there is little evidence that enhancing adrenergic transmission is wake promoting in animal studies. The role of the dopamine system in sleep regulation was further assessed by use of mice lacking the DAT gene. Consistent with a role of dopamine in the regulation of wakefulness, these animals have reduced non-REM sleep time and increased wakefulness consolidation (independently of locomotor effects).12 DAT knockout mice have also proved to be a powerful tool to help dissect the molecular mechanisms mediating the effects of nonselective monoaminergic compounds. With use of these animals, DAT was shown to be involved in mediation of locomotor activation after amphetamine and cocaine administration. Indeed, no locomotor stimulation is observed in these mice after cocaine or amphetamine administration, whereas the deletion of DAT alone does not fully eliminate cocaine reward.13 Interestingly, NET knockout mice are more sensitive to the locomotor stimulation of amphetamine, suggesting that NET may play a feedback control role on amphetamine-induced dopaminergic effects.14 With regard to sleep, the most striking finding was that DAT knockout mice were completely unresponsive to the wake-promoting effects of methamphetamine, GBR-12909 (a selective DAT blocker), and modafinil. These results further confirm the critical role of DAT in mediating the wakepromoting effects of amphetamines and modafinil12 (see Figs. 44-3 and 44-4; see also Modafinil section). Interestingly, DAT knockout animals were also found to be more sensitive to caffeine,12 suggesting functional interactions between adenosinergic and dopamine systems in the control of sleep–wake (see also caffeine section). The VMAT2 gene has been cloned, and mice lacking VMAT2 have been produced.15,16 Although homozygous VMAT2 knockout mice (VMAT2−/−) are lethal, heterozygous animals (VMAT2+/−) survive and express a 50% reduction of VMAT2 concentration. VMAT2+/− mice have a significant deficit of dopamine transmission but normal noradrenergic and serotonergic neurotransmission.15 VMAT2 heterozygous knockout mice are supersensitive to amphetamine locomotor stimulation but have attenuated
amphetamine-behavioral reward.15 Recent results in our laboratory suggest that methamphetamine and modafinil similarly promote wakefulness in both VMAT2+/− and VMAT2+/+ animals. The results contrast with the absence of any wake-promoting effects with these drugs in DAT knockout mice and further illustrate the importance of reverse efflux and dopamine reuptake inhibition through DAT (as opposed to inhibited VMAT monoamine storage) in the mode of action of stimulants. Anatomic Substrates Mediating Dopaminergic Effects on Wakefulness Anatomic studies have demonstrated two major subdivisions of the ascending dopamine projections from mesencephalic dopamine nuclei (ventral tegmental area, substantia nigra, and retrorubral [A8]): (1) the mesostriatal system originates in the substantia nigra (and partially in the ventral tegmental area) and retrorubral nucleus and terminates in the dorsal striatum (principally the caudate and putamen)17; (2) the mesolimbocortical dopamine system consists of the mesocortical and mesolimbic dopamine systems. The mesocortical system originates in the ventral tegmental area and the medial substantia nigra and terminates in the limbic cortex (medial prefrontal, anterior cingulate, and entorhinal cortices). Interestingly, dopamine reuptake is of physiologic importance for the elimination of dopamine in cortical hemispheres, limbic forebrain, and striatum but not in midbrain dopamine neurons.18 It is thus possible that amphetamine, modafinil, and dopamine uptake inhibitors have more effects on dopamine terminals of the cortical hemispheres, limbic forebrain, and striatum and that it is this effect that induces wakefulness. Local perfusion experiments of dopamine compounds in rats and canine narcolepsy have suggested that the ventral tegmental area, but not the substantia nigra, is critically involved in EEG arousal regulation.19 Dopamine terminals of the mesolimbocortical dopamine system may thus be important in mediating wakefulness after dopamine-related CNS stimulant administration. The involvement of other, less studied dopaminergic cell groups, such those located in the hypothalamus or in the ventral periaqueductal gray (recently suggested to be wake active20), is also possible and would be worth further exploration. The fact that direct dopaminergic agonists and l-dopa (dopamine precursor) drugs typically used in therapy for Parkinson’s disease are generally not strongly wake promoting in clinical practice (these compounds are mildly sedative) has been explained by the primary presynaptic effect of these compounds at low dose, an effect that may in fact reduce dopamine transmission in some projection areas.21 Indeed, dopamine agonists and antagonists typically have biphasic effects on locomotion and sleep, with dopamine agonists increasing locomotion and even producing stereotypies only at very high doses.21 A differential sensitivity of the various dopaminergic cell groups and terminals to dopamine reuptake inhibition, presynaptic versus postsynaptic dopaminergic receptor stimulation, and blockade may be responsible for the striking differential effects of dopamine reuptake blockers and agonists on motor-related symptoms versus sleep–wake.
CHAPTER 44 • Wake-Promoting Medications: Basic Mechanisms and Pharmacology 519
Indications Amphetamine and methylphenidate are primarily indicated for narcolepsy, idiopathic hypersomnia, and ADHD. Other therapeutic uses are controversial because of their abuse potential. As a result, amphetamine is classified as a schedule II substance, and methylphenidate is classified as a schedule III substance under the Controlled Substances Act of 1970. Moreover, certain states (e.g., Wisconsin) have passed even more restrictive legislation limiting the use of these substances to specific indications (see also reference 22). The use of these compounds is highly regulated and in the United States requires triplicate prescription and monthly renewal. Side Effects and Toxicology Amphetamine releases not only dopamine but also norepinephrine. Norepinephrine indirectly stimulates alpha- and beta-adrenergic receptors, a profile common to all indirectly acting sympathomimetic compounds. This results in significant cardiovascular effects. Alpha-adrenergic stimulation produces vasoconstriction, thereby increasing both systolic and diastolic blood pressure. Heart rate may slow slightly in reflex (this effect is more pronounced than indirect beta-adrenergic stimulation on heart rate at low dose), but with large doses, tachycardia and cardiac arrhythmia may occur. Cardiac output is not modulated by therapeutic doses, and cerebral blood flow is unchanged. In general, smooth muscles respond to amphetamine as they do to other sympathomimetic drugs. There is a contractile effect on the urinary bladder sphincter, an effect that has been used in treating enuresis and incontinence. Pain and difficulty in micturition may occur. Other acute side effects include mild gastrointestinal disturbance, anorexia, dryness of the mouth, tachycardia, cardiac arrhythmias, insomnia and restlessness, headaches, palpitations, dizziness, and vasomotor disturbances. Agitation, confusion, dysphoria, apprehension, and delirium may also occur. Other documented side effects include flushing, pallor, excessive sweating, and muscle pains. Tiredness and sleepiness as well as lethargy and listlessness may occur when the effects wear off, together with a mild depression of mood. For common side effects of CNS stimulant drugs in narcoleptic patients, refer to Table 44-1. Common side effects occurring during long-term treatment in narcolepsy include irritability, headache, bad temper, and profuse sweating (reported by more than one third of subjects). Other less common side effects include anorexia, gastric discomfort, nausea, talkativeness, insomnia, orofacial dyskinesia, nervousness, palpitations, muscle jerking, chorea, and tremor. Psychiatric symptoms, such as delusions and hallucinations, may also occur but are rare in narcoleptic patients who receive amphetamine. Methamphetamine (and to a lesser extent amphetamine) can be neurotoxic at high dose. This effect is mediated by a free radical increase, causing mitochondrial damage and decreasing adenosine triphosphate synthesis. In dopaminergic neurons, the neurotoxicity is mediated by formation of peroxynitrite, which can be reduced by antioxidants or l-carnitine. l-Carnitine is needed to transport long-chain fatty acids into mitochondria for fatty acid oxidation, preventing the generation of free radicals and peroxynitrite. MDMA (Ecstasy), another amphetamine derivative with a
preferential effect (and toxicity) on serotonergic neurons, appears to also decrease glutathione and vitamin E in the brain. Mice deficient in vitamin E were found to have greater susceptibility to both MDMA neurotoxicity and hepatic necrosis, a finding further supporting a free radical mechanism for amphetamine toxicity. The side effect profile of methylphenidate is similar to that of amphetamine and includes nervousness, insomnia, and anorexia as well as dose-related systemic effects, such as increased heart rate and blood pressure. Methylphenidate overdose may lead to seizures, dysrhythmias, or hyperthermia. Abuse and Misuse of Amphetamine Stimulants Abuse is repeated and willful use of a drug in a way other than prescribed or socially sanctioned. Misuse is the inappropriate use of a prescribed or nonprescribed drug, but not for “pleasure” or other nonmedicinal purposes. The misuse versus abuse definition relates to the intent behind the drug use and is therefore not always easy to apply in a medical context. Indeed, in a patient care setting, what matters most is the reinforcing property (when a prior administration causes the following administration to have more effects, especially mood-enhancing effect, a high predictor of the potential for abuse), the inability to stop either because of withdrawal effects or because of dependence or addiction (compulsive need), and the ability to do harm to self or others with the compound (toxic effects at high dose, risk of abnormal behavior). One of the best predictors of addiction, the most severe complication, is whether the drug has a street value and whether it can substitute or is subjectively liked by abusers. Methamphetamine, amphetamine, and methylphenidate all have clear street value for abusers and are addictive. Whereas reinforcement first occurs, tolerance is common during long-term administration. Appetite-suppressing effects are also often sought. Interestingly, anecdotal data suggest that these compounds are rarely problematic when they are used in patients with narcolepsy and hypocretin deficiency, a finding also supported by some animal data.23 Importantly, administration of amphetamine-like compounds in patients with narcolepsy is often negatively viewed, and the situation may be similar to that of morphine administration in patients with pain, in whom dependence is rarely a problem if there is a need to stop opiates. The mechanisms underlying abuse for amphetaminelike stimulants are complex but have been shown to primarily involve stimulation of the ventral tegmental area–dopamine systems.24 Downstream changes in adrenergic and serotonergic systems, particularly through alpha1B and 5-HT2A, may be important.25,26 Pharmacokinetic and pharmacodynamic properties as well as behavioral context are also clearly important. In terms of pharmacokinetics, it is well established that stimulants are more addictive when they are administered intravenously (or as crack for cocaine). In fact, the potential for abuse is higher when the drug is soluble and easy to inject or to smoke. Rapid absorption and brain penetration have been shown to be important through imaging studies. It is also likely that short-acting stimulants, because of the ups and downs that they produce and the resulting compulsive
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need, are more addictive than long-acting formulations, although no data are available to support this claim. Drug-Drug Interactions Drug-drug interactions with amphetamine and methylphenidate are generally pharmacodynamic-neurochemical in nature.27 A small portion of the metabolism of amphetamine and methylphenidate occurs through the cytochrome P-450 2D6, and drugs that inhibit P-450 2D6 metabolism can theoretically increase plasma levels of amphetamine. This is rarely a significant problem with therapeutic doses, however. Tricyclic drugs inhibit the metabolism of amphetamine and amphetamine-like stimulants and enhance their behavioral effects. The combination of amphetamine with tricyclics could theoretically further blood pressure increases (because of the combined effects of norepinephrine reuptake and release); but in practice, amphetamine (10 to 16 mg) and also methylphenidate (10 to 60 mg) and mazindol (2 to 12 mg) have been safely given with imipramine and clomipramine (10 to 100 mg) to treat narcolepsy-cataplexy. The dosage of amphetamine required to control narcolepsy may be reduced by a third by the simultaneous use of tricyclic drugs. Monoamine oxidase A inhibitors (e.g., nialamide, pargyline, and tranylcypromine) inhibit the removal of amphetamine by the liver and greatly potentiate the behavioral effects of amphetamine. Co-administration of monoamine oxidase inhibitors and amphetamine derivatives is generally contraindicated. In contrast to tricyclics and monoamine oxidase A inhibitors, haloperidol, reserpine, and atropine have no effect on amphetamine hydroxylation in the animal liver, although they may reduce the central effects of amphetamine.28 Chlorpromazine, trifluoperazine, perphenazine, and thioproperazine increase the halflife of amphetamine in the brain but inhibit central behavioral effects, such as stereotyped behavior in animals and euphoria in humans.28 Hypnotic drugs will prevent many behavioral effects of amphetamines, although chlordiazepoxide and diazepam increase amphetamine tissue levels.28
MODAFINIL AND ARMODAFINIL Racemic modafinil (2-[(diphenylmethyl)sulfinyl]acetamide; see Fig. 44-1) was first developed in France and has been available in Europe since 1986. Modafinil was first approved in 1998 in the United States for the treatment of narcolepsy. More recently, it has been approved for shift-work disorder and for the treatment of residual sleepiness in treated patients with the obstructive sleep apnea syndrome. Modafinil is a primary metabolite of adrafinil, a vigilance-promoting compound developed in France in the 1970s. Modafinil lacks the terminal amide hydroxy group of adrafinil (see Fig. 44-1) and is better tolerated. Pharmacokinetics Modafinil is rapidly absorbed but slowly cleared. It is approximately 60% bound to plasma proteins and has a volume distribution of 0.8 L/kg, suggesting that the coumpound is readily able to penetrate into tissues. Its half-life is 9 to 14 hours. Up to 60% of modafinil is converted into modafinil acid and modafinil sulfone, both of
which are inactive metabolites. Metabolism primarily occurs through cytochrome P-450 3A4/5, but the compound has also been reported to induce P-450 2C19 in vitro.29 Modafinil is currently available as a racemic mixture of two active isomers and as an R isomer–only preparation (armodafinil). Importantly, the R enantiomer of modafinil has a considerably longer half-life (10 to 15 hours) than the S enantiomer (3 to 4 hours).30 The dual pharmacokinetic properties of the racemic mixture may explain why modafinil is often more active when it is taken twice per day at the beginning of therapy, during the period of drug accumulation. Indications Modafinil is one of the few compounds that have been specifically developed for the treatment of narcolepsy. Early clinical trials in France and Canada have shown that 100 to 300 mg of modafinil is effective in improving daytime sleepiness in narcolepsy and hypersomnia without interfering with nocturnal sleep but has limited efficacy on cataplexy and other symptoms of abnormal REM sleep.31-33 Pharmacologic experiments in canine narcolepsy also demonstrated that modafinil has no effects on cataplexy, whereas it significantly increases time spent in wakefulness.34 A double-blind trial in 18 centers in the United States of 283 narcoleptic subjects revealed that 200 mg and 400 mg of modafinil significantly reduced EDS and improved patients’ overall clinical condition. Armodafinil was approved by the Food and Drug Administration in June 2007 for the treatment of sleepiness in association with narcolepsy, treated sleep apnea, and shift-work sleep disorder (i.e., the same indications as those of racemic modafinil).30 Armodafinil has been shown to be active for longer after administration. In patients in whom once-a-day modafinil does not cover the entire day, armodafinil may be useful. Further, lower doses of armodafinil, 150 mg and 250 mg, were used in a phase III trial, whereas earlier modafinil trials used 200 mg and 400 mg. Armodafinil is available at lower doses than modafinil, suggesting an improved safety profile. Although armodafinil may not be a revolutionary improvement in comparison to modafinil, it may have its place in the therapeutic arsenal.30 Besides approved indications for modafinil and armodafinil, several reports have suggested that modafinil is also effective for the treatment of ADHD, fatigue in multiple sclerosis, and EDS in myotonic dystrophy or Prader-Willi syndrome. Modafinil is also being used in the treatment of periodic hypersomnia, in which treatment immediately after initiation of the episode may be critical. Finally, there is significant prescription in the area of depression, most notably in the context of augmentation of more classic antidepressant effects, but as for classic stimulants, end results have been controversial. Modafinil has also been proposed as a therapy for cocaine or amphetamine addiction in small studies without clear benefits. Side Effects Modafinil is well tolerated. The most frequently reported side effects are headache and nausea.35 In addition, however, because of its dual hepatic and renal elimination profile, modafinil should be used at lower dose in hepatic and renal
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insufficiency cases and has a number of potential drug interactions. In vitro, modafinil produces a reversible inhibition of CYP2C19 in human liver microsomes. It also caused a small but concentration-dependent induction of CYP1A2, CYP2B6, and CYP3A4 activities and suppression of CYP2C9 activity in primary cultures of human hepatocytes. Clinical studies have been conducted to examine the potential for interactions with methylphenidate, dexamphetamine, warfarin, ethinylestradiol, and triazolam. The most substantive interactions observed were with ethinylestradiol and triazolam, apparently through induction of CYP3A4, primarily in the gastrointestinal system. For this reason, women of childbearing age taking low-estrogen contraception should be informed of the low possibility of an unwanted pregnancy. Interestingly, modafinil has been shown to be safe and to have additive effects on alertness when it is administered with sodium oxybate in narcolepsy. Several factors make modafinil an attractive alternative to amphetamine-like stimulants. First, animal studies suggest that the compound does not affect blood pressure as much as amphetamines do; only high doses (800 mg) have been found to be associated with higher rates of tachycardia and hypertension. This suggests that modafinil might be useful for patients with a heart condition or high blood pressure. Second, data obtained to date suggest that dependence is limited in humans with this compound,31,36 although an animal study suggested cocaine-like discriminative stimulus and reinforcing effects of modafinil in rats and monkeys. Most notably, although modafinil is almost certainly used as a convenience drug by some to fight sleepiness resulting from sleep deprivation or jetlag, it is not “liked” by the cocaine or stimulant abuser and does not have a high street value. Third, modafinil also has few effects on the neuroendocrine system. A comparison of healthy volunteers who were sleep deprived for 36 hours with those who received modafinil during sleep deprivation found no difference in cortisol, melatonin, or growth hormone levels.37 Fourth, clinical experience suggests that the alerting effects of modafinil might be qualitatively different from those observed with amphetamine.31 In general, patients feel less irritable or agitated with modafinil than with amphetamines31 and do not experience severe rebound hypersomnolence once modafinil is eliminated. This differential profile is substantiated by animal experiments. In rats and dogs, modafinil does not increase locomotion beyond the effect expected in association with increased wakefulness.34,38 Similarly, modafinil acutely decreases both REM and non-REM sleep in rats for up to 5 to 6 hours, but the effect is not followed by a rebound hypersomnolence. This profile contrasts with the intense recovery sleep seen after amphetamine-induced wakefulness.39 Considering the many advantages of modafinil over amphetamine treatment (fewer cardiovascular side effects, lower abuse potential or tolerance, and less rebound sleepiness when the drug effects are waning), modafinil has replaced amphetamine-like stimulants for the first-line treatment of EDS. Mechanism of Action The mechanism of action of modafinil or armodafinil is highly debated, although it is most likely to involve DAT
inhibition, not unlike other stimulants. There are limited numbers of studies addressing the mode of action of armodafinil, and this section therefore mostly discusses the actions of the racemic modafinil mixture. Modafinil or armodafinil has not been shown to bind to or to inhibit receptors or enzymes for most known neurotransmitters, with the exception of the DAT protein.9,40 The list includes serotonin, dopamine, norepinephrine, adenosine, galanin, melatonin, melanocortin, hypocretin-orexin, orphanin, gamma-aminobutyric acid (GABA), and glutamatergic and benzodiazepine receptors as well as transporters for GABA, norepinephrine, choline, catechol-O-methyltransferase, GABA transaminase, and tyrosine hydroxylase (see reference 30 for review). In vitro, modafinil or armodafinil binds to the DAT and inhibits dopamine reuptake.9,30,40 These binding-inhibitory effects have been shown to be associated with increased extracellular dopamine levels in the striatum of rats and dogs, suggesting functional effects. Finally, most important, modafinil effects on alertness are entirely abolished in mice without the DAT protein12 and in animals lacking D1 and D2 receptors.41 A similar abolition of wake promotion in DAT knockout mice is also observed with amphetamine and GBR-12909 (a selective DAT blocker), drugs known to work through the DAT. However, it is puzzling that modafinil, unlike other DAT inhibitors, has a low potential for abuse, a property that may simply be due to the insolubility of the compound (inability to use another formulation, for example, an intravenous formulation), the low potency (impossibility to greatly increase the dose), the slow absorption (no rapid brain effects), or the atypical binding interaction with the DAT transporter. Adrenergic effects have also been suggested to be involved in the wake promotion effects of modafinil, but these are believed to be insignificant in vivo. When it was first introduced, an involvement of alpha1 adrenergic systems was suggested as the primary mode of action of modafinil on wakefulness, based on the ability of the alpha1 antagonist prazosin to antagonize modafinil-induced increases in motor activity in mice and wakefulness in cats. However, modafinil does not bind alpha1 receptors in vivo (Ki > 10−3 M, obtained from prazosin binding in canine cortex).34 It also does not produce smooth muscle contraction in vas deferens preparations and is still wake promoting in norepinephrine-depleted animals by N(2-chloroethyl)-N-ethyl 2-bromobenzylamine (DSP-4) administration.42 Further, the hyperlocomotion produced by amphetamine, like that of modafinil, also largely depends on alpha1B receptors, a finding now explained by remodeling of the dopamine system in alpha1B knockout mice.43 Finally, previous studies in the canine model of narcolepsy have shown that alpha1 adrenergic agonists are potent anticataplectic agents44 and have significant acute hypertensive effect. Modafinil has neither anticataplectic activity nor hypertensive effects, suggesting that its alerting properties are unrelated to alpha1 adrenergic stimulation. Clinical observations provide even stronger evidence that modafinil is not a primarily adrenergic compound. Amphetamine and adrenergic reuptake blockers causes dilation of the pupils by increasing norepinephrine signaling, but modafinil has no effect on pupil size. Some studies
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have noted slight increases in heart rate or blood pressure with high doses of modafinil. However, these changes were small, and the majority of clinical studies on modafinil, including a meta-analysis of six large clinical trials of modafinil, which is the most comprehensive study on this issue, have found no changes in heart rate or blood pressure. In contrast, adrenergic reuptake blockers are well known to slightly increase blood pressure and heart rate. These clinical observations suggest that at usual clinical doses, modafinil does not increase adrenergic signaling in humans. Interestingly, Madras and colleagues45 reported by positron emission tomography imaging in the rhesus monkey that modafinil (intravenously administered) occupied striatal DAT sites (5 mg/kg, 35%; 8 mg/kg, 54%). In the thalamus, modafinil occupied NET sites (5 mg/kg, 16%; 8 mg/kg, 44%). The authors also showed that modafinil inhibited [3H]dopamine (IC50 = 6.4 µM) 5 times and 80 times more potently than [3H]norepinephrine (IC50 = 35.6 µM) and [3H]serotonin (IC50 > 500 µM) transport, respectively, through the human DAT, NET, and serotonin transporter expressed cell lines. (IC50 is the half maximal [50%] inhibitory concentration.) The data provide compelling evidence that modafinil occupies the DAT in living brain of rhesus monkeys, consistent with the DAT hypothesis, but suggest that modafinil may also act on NET, depending on drug dose, brain structure, and other physiologic conditions.
MAZINDOL Mazindol (2 to 8 mg daily) is rarely used in the United States. At these doses, mazindol produces central stimulation, a reduction in appetite, and an increase in alertness, but it has little or no effect on mood or the cardiovascular system.46 Mazindol is a weak releasing agent for dopamine that also blocks both dopamine and norepinephrine reuptake. Mazindol has a high affinity for the dopamine and norepinephrine transporters (see reference 9), yet interestingly, this compound has a low abuse potential. This compound is effective for the treatment of both EDS and cataplexy in humans47 and in canine narcolepsy, possibly because of its dual dopaminergic and noradrenergic effects.9 However, mazindol often causes significant side effects, including anorexia, gastrointestinal discomfort, insomnia, nervousness, dry mouth, nausea, constipation, urinary retention, and occasionally angioneurotic edema, vomiting, and tremor. Mazindol is a Schedule IV controlled drug. The relatively poor tolerance at higher dose may explain its lack of popularity and lower abuse potential. BUPROPION Bupropion is a dopamine reuptake inhibitor that may be useful for the treatment of EDS associated with narcolepsy (100 mg three times daily).9,48 It may be especially useful in cases associated with atypical depression.48 Bupropion is a nonscheduled compound. Convulsion is a dose-dependent risk of bupropion (0.1% at 100 to 300 mg, and 0.4% at 400 mg). Bupropion was synthesized in 1966 by a group seeking new antidepressants chemically related to tricyclic antidepressants but without any significant sympathomimetic, cholinolytic, or monoamine oxidase inhibitory
properties. Bupropion is classified as a monocyclic phenylbutylamine of the amino ketone group. It selectively blocks dopamine uptake and is 6 times more potent than imipramine and 19 times more potent than amitriptyline in blocking dopamine reuptake. The selectivity of bupropion for the DAT is not absolute. Bupropion is a weak competitive inhibitor of norepinephrine reuptake (65-fold less potent than imipramine). Very limited serotonergic effects are also observed (200-fold less potent than imipramine).
SELEGILINE (l-DEPRENYL) Selegiline is a methamphetamine derivative and a potent, irreversible, monoamine oxidase B–selective inhibitor primarily used for the treatment of Parkinson’s disease.49,50 Low doses of selegiline do not necessitate dietary restriction as usually required with other irreversible monoamine oxidase inhibitors; 10 mg of selegiline daily has no effect on the symptoms of narcolepsy, but 20 to 30 mg improves alertness and mood and reduces cataplexy, an effect comparable to that of d-amphetamine at the same dose. Selegiline may be an interesting alternative to the more classical stimulants as its potential for abuse has been reported to be very low. The fact that this compound is often considered a simple monoamine oxidase B inhibitor rather than an amphetamine precursor deserves special mention. Selegiline not only inhibits monoamine oxidase B irreversibly, it also is metabolized into amphetamine (20% to 60% in urine) and methamphetamine (9% to 30% in urine).50 In the canine model of narcolepsy, selegiline (2 mg/kg orally) was demonstrated to be an effective anticataplectic agent, but this effect was found to be mediated by its amphetamine metabolites rather than by monoamine oxidase B inhibition.51 Several trials in human narcolepsy have demonstrated a good therapeutic efficacy of selegiline on both sleepiness and cataplexy with relatively few side effects.52,53 ATOMOXETINE AND REBOXETINE These compounds are selective adrenergic reuptake inhibitors. Although atomoxetine and reboxetine (in Europe) are not stimulants, these compounds are slightly wake promoting54,55 and reduce REM sleep. The compounds can be helpful in some cases of narcolepsy and idiopathic hypersomnia. Atomoxetine was first developed as an antidepressant, failed, and is now used in therapy for ADHD.56 Atomoxetine has a short half-life and needs twice-daily administration. Reboxetine was developed as an antidepressant and was also shown to reduce mean sleep latency in narcoleptic patients on the multiple sleep latency test.55 The compounds, however, increase heart rate and blood pressure, similar to the dual serotonergic and adrenergic reuptake inhibitors venlafaxine and duloxetine. Sexual side effects are also common, but there is no risk of abuse. CAFFEINE Caffeine may be the most popular and widely consumed CNS stimulant in the world. An average cup of coffee contains 50 to 150 mg of caffeine. Tea, cola drinks, choco-
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late, and cocoa all contain significant amounts of caffeine. Caffeine can also be bought over-the-counter (NoDoz, 100 mg caffeine; Vivarin, 200 mg caffeine) and is commonly used by narcoleptic patients before diagnosis. Taken orally, caffeine is rapidly absorbed. The half-life of caffeine is 3.5 to 5 hours. The behavioral effects of caffeine include increased mental alertness, a faster and clearer flow of thought, wakefulness, and restlessness.57 Fatigue is reduced, and sleep onset is delayed. The physical effects of caffeine include palpitations, hypertension, increased gastric acid secretion, and increased urine output.57 Heavy consumption (12 cups or more a day, or 1.5 g of caffeine) causes agitation, anxiety, tremors, rapid breathing, and insomnia.57 Caffeine is a xanthine derivative. The mechanism of action of caffeine on wakefulness involves nonspecific adenosine receptor antagonism. Adenosine is an endogenous sleep-promoting substance with neuronal inhibitory effects. In animals, sleep can be induced after administration of metabolically stable adenosine analogues with adenosine A1 receptor (A1R) or A2A receptor (A2AR) agonistic properties, such as N6-l-(phenylisopropyl)-adenosine, adenosine-5′-N-ethylcarboxamide, and cyclohexyladenosine. Adenosine content is increased in the basal forebrain after sleep deprivation. Adenosine has thus been proposed to be a sleep-inducing substance accumulating in the brain during prolonged wakefulness.58 Most studies in the area of sleep and adenosinergic effects have focused on A1R-mediated effects. The rationale for this focus is that A1 receptors are widely distributed in the CNS, whereas A2A receptors are discretely localized in the striatum, nucleus accumbens, and olfactory bulb. Interestingly, sleep–wake patterns and response to sleep deprivation were recently examined in adenosine receptor A1 knockout mice and found to be generally unaltered, suggesting that the constitutional lack of adenosine A1R does not prevent homeostatic regulation of sleep. In contrast, the sleep inhibitory effects of 8-cyclopentyltheophylline (a selective A1R antagonist) were abolished in these animals, indicating A1R mediation of stimulant effects with this compound. Recent experiments using several selective A1R and A2AR agonists and A2AR knockout mice indicate that the A2AR may play an important role in sleep regulation.59 Prostaglandin D2, a somnogenic prostanoid highly concentrated in the brain, mediates its sleep-enhancing effects indirectly through an adenosine A2AR-sensitive pathway. Interestingly, the A2AR interacts strongly with dopaminergic transmission. A2AR forms a heterodimer with dopamine D2 receptors, and A2AR knockout mice have been shown to have reduced amphetamine-induced locomotor simulation and reward.60-62 Finally, Huang and associates63 reported that the wake-promoting effect of caffeine is abolished in A2AR knockout mice, whereas the effects were not altered in A1R knockout mice, suggesting a primary effect of caffeine through the A2AR, at least in this species.
FUTURE STIMULANT TREATMENTS Hypocretin-Based Therapies Hypocretin deficiency is a major cause of human narcolepsy. Intracerebroventricular injections of hypocretin are
strongly wake promoting in dogs, mice, and rats. Animal experiments using ligand-deficient narcoleptic dogs suggest that stable and centrally active hypocretin analogues (possibly nonpeptide synthetic hypocretin ligands) will need to be developed to be effective after peripheral administration.64,65 This is also substantiated by a study in mice that found normalization of sleep–wake patterns and behavioral arrest episodes (equivalent to cataplexy and REM sleep onset) in hypocretin-deficient mice knockout models supplemented by central administration of hypocretin 1.66 Hypocretin could thus be effective in the treatment of both sleepiness (i.e., fragmented sleep–wake pattern) and cataplexy. If exogenously administered hypocretin can rescue the symptoms of narcolepsy when it is administered centrally, cell transplantation–based and gene-based therapies could also be designed in the future as a viable option. To address whether hypocretin receptor function is intact after long-term hypocretin deficiency, Mishima and coworkers67 studied hypocretin receptor gene expressions of ligand-deficient narcolepsy in mice, dogs, and humans. Substantial declines (by 50% to 71%) in the expression of hypocretin receptor genes were observed in both liganddeficient humans and dogs. The result in the study of mice suggested that decline is progressive over age. Importantly, however, about 50% of baseline expression was still observed in old human subjects. Further, because narcoleptic Doberman pinschers heterozygous for the hypocretin receptor 2 mutation (with 50% receptor levels and normal levels of hypocretin) are asymptomatic, it is likely that an adequate ligand supplementation will prevent narcolepsy in hypocretin-deficient patients even if receptors are partially nonfunctional. Histaminergic H3 Antagonists Histamine has long been implicated in the control of vigilance as H1 antagonists are strongly sedative. The downstream effects of hypocretins on the histaminergic system (Hcrtr2 excitatory effects) are likely to be important in mediating the wake-promoting properties of hypocretin.68 In fact, brain histamine contents are reduced in narcoleptic dogs.69 Reduction of histamine contents is also observed in human narcolepsy and other hypersomnia of central origin.70,71 Although centrally injected histamine or histaminergic H1 agonists promote wakefulness, systemic administrations of these compounds induce various unacceptable side effects through peripheral H1 receptor stimulation. In contrast, the histaminergic H3 receptors are regarded as inhibitory autoreceptors and are enriched in the CNS. H3 antagonists enhance wakefulness in normal rats and cats72 and in narcoleptic mice models.73 Histaminergic H3 antagonists might be useful as wake-promoting compounds for the treatment of EDS or as cognitive enhancers and are under study by several pharmaceutical companies.74 Thyrotropin-Releasing Hormone Another possible area that currently gathers less pharmaceutical interest is the use of thyrotropin-releasing hormone (TRH) direct or indirect agonists. TRH itself is a small peptide that penetrates the blood–brain barrier at very high doses. Small molecules with agonistic properties and increased blood–brain barrier penetration (i.e.,
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CG3703, CG3509, or TA0910) have been developed, partially thanks to the small nature of the starting peptide.75 TRH (at the high dose of several milligrams per kilogram) and TRH agonists increase alertness and have been shown to be wake promoting and anticataplectic in the narcoleptic canine model,76,77 and TRH has excitatory effects on motoneurons. Initial studies had demonstrated that TRH enhances dopamine and norepinephrine neurotransmission, and these properties may partially contribute to the wake-promoting and anticataplectic effects of TRH. Interestingly, studies have suggested that TRH may promote wakefulness by directly interacting with the thalamocortical network; TRH itself and TRH receptor type 2 are abundant in the reticular thalamic nucleus. Local application of TRH in the thalamus abolishes spindle wave activity,78 and in the slice preparations, TRH depolarized thalamocortical and reticular-pregeniculate neurons by inhibition of leak potassium conductance.78
cretin abnormality or because of the social aspects of treating narcolepsy as a disease. The mode of action of modafinil remains controversial and probably involves dopaminergic rather than nondopaminergic effects. Whatever its mode of action is, the compound is generally found to be safer and to have a lower abuse potential than amphetamine stimulants. Its favorable side effect profile has led to an increasing use outside the narcolepsy indication, most recently in the context of shiftwork disorder and residual sleepiness in treated sleep apnea patients. This recent success exemplifies the need for development of novel wake-promoting compounds with low abuse potential. A need for treating daytime sleepiness extends well beyond the relatively rare indication of narcolepsy-cataplexy.
Glutamatergic Compounds Glutamatergic transmission is the major excitatory transmission of the mammalian brain and is increasingly believed to play a role in the generation of sleep homeostasis through changes in cortical synaptic plasticity,79 although a more general mechanism needs be involved to explain data across all species.80 Not surprisingly, therefore, compounds that are allosteric modulators of glutamatergic transmission, ampakines, are being developed as wake-promoting compounds and may have counteracting effects on sleep deprivation.81 Similarly, GluR subtype– specific compounds are likely to regulate sleep on the basis of available knockout data and pharmacologic experiments.82,83
Almost all the currently available stimulants used to treat excessive daytime sleepiness in clinical practice (amphetamines, amphetamine-like stimulants, and modafinil) act presynaptically to increase dopaminergic transmission, either by stimulating dopamine release or by blocking dopamine reuptake. These effects are believed to be critically involved in the mediation of the wake-promoting effects of these compounds. Some (e.g., amphetamines) but not all stimulants also increase adrenergic neurotransmission. Selective adrenergic uptake inhibitors have limited wake-promoting effects. Increased adrenergic neurotransmission may play a minor role in stimulant-induced wake-promoting effects. Caffeine (as an over-the-counter drug, coffee, tea, cola drinks, chocolate, and cocoa) is a nonselective adenosine receptor blocker. The potency and efficacy of caffeine are too weak to provide substantial relief in the treatment of narcolepsy. Agents stimulating the hypocretinergic and histaminergic pathways may be promising future wakepromoting compounds but are not yet available. When stimulants are used for the treatment of sleepiness, it is suggested to start with compounds that inhibit dopamine reuptake first (modafinil > methylphenidate) and then to move on to the use of dopamine-releasing agents (e.g., amphetamines) only if the other compounds are not effective enough.
CONCLUSION Amphetamine-like stimulants have been used in the treatment of narcolepsy and various other conditions for decades, yet only recently has the mode of action of these drugs on vigilance been characterized. In almost all cases, the effects on vigilance were found to be mediated through effects on the DAT. This has led to the generally widely accepted hypothesis that wake-promoting effects will be impossible to differentiate from abuse potential effects for these compounds. Importantly, however, the various medications available have differential effects and potency on the DAT and on monoamine storage and release. The various available stimulants are more or less selective for dopamine versus other amines. Even if much work remains to be done in this area, it appears more and more likely that complex properties, for example, the ability to release dopamine rather than simply to block reuptake, plus the combined effects on other monoamines (such as serotonin) may be important to explain abuse potential. Differential binding properties on the DAT itself may also be involved, together with drug potency and compound solubility. The lack of solubility of some low-potency compounds may, for example, result in an inability to administer the drug by snorting or intravenously. Finally, lower abuse potential for these compounds has long been suspected in narcolepsy-cataplexy patients, either because of the biochemical hypo-
❖ Clinical Pearls
REFERENCES 1. Yoss RE, Daly DD. Treatment of narcolepsy with ritalin. Neurology 1959;9:171-173. 2. Bradley C, Bowen M. Amphetamine (benzedrine) therapy of children’s behavior disorders. Am J Orthospychiatry 1941;11:92-103. 3. Anders TF, Ciaranello RD. Pharmacologic treatment of minimal brain dysfunction syndrome. In: Barchas JD, Berger PA, Ciaranello RD, editors. Psychopharmacology: from theory to practice. New York: Oxford University Press; 1977. p. 425-435. 4. Glennon RA. Psychoactive phaenylisopropylamines. In: Meltzer HY, editor. Psychopharmacology: the third generation of progress. New York: Raven; 1987. p. 1627. 5. Hartmann A, Cravens J. Sleep: effect of d- and l-amphetamine in man and rat. Psychopharmacology 1976;50:171-175. 6. Kuczenski R, Segal DS. Neurochemistry of amphetamine. In: Cho AK, Segel DS, editors. Psychopharmacology, toxicology and abuse. San Diego: Academic Press; 1994. p. 81-113.
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31. Bastuji H, Jouvet M. Successful treatment of idiopathic hypersomnia and narcolepsy with modafinil. Prog Neuropsychopharmacol Biol Psychiatry 1988;12:695-700. 32. Besset A, Tafti M, Villemin E, Billiard M. Effect du modafinil (300 mg) sur le sommeil, la somnolence et la vigilance du narcoleptique. Neurophysiol Clin 1993;23:47-60. 33. Boivin DB, Montplaisir J, Petit D, Lambert C, et al. Effect of modafinil on symptomatology of human narcolepsy. Clin Neuropharmacol 1993;16:46-53. 34. Shelton J, Nishino S, Vaught J, Dement WC, et al. Comparative effects of modafinil and amphetamine on daytime sleepiness and cataplexy of narcoleptic dogs. Sleep 1995;18:817-826. 35. Fry J. A new alternative in the pharmacologic management of somnolence: a phase III study of modafinil in narcolepsy. Ann Neurol 1996;40:493. 36. LaGarde D. Sustained/continuous operations subgroup of the Department of Defense human factors engineering technical group: program summary and abstracts from the 9th semiannual meeting. Pensacola, FL: Naval Aerospace Medical Research Laboratory; 1990. p. 90-91. 37. Brun J, Chamba G, Khalfallah Y, Girard P, et al. Effect of modafinil on plasma melatonin, cortisol and growth hormone rhythms, rectal temperature and performance in healthy subjects during a 36 h sleep deprivation. J Sleep Res 1998;7:105-114. 38. Edgar DM, Seidel WF, Contreras P, Vaught JL, et al. Modafinil promotes EEG wake without intensifying motor activity in the rat. Can J Physiol Pharmacol 1994;72:S1-S362. 39. Edgar DM, Seidel WF. Modafinil induces wakefulness without intensifying motor activity or subsequent rebound hypersomnolence in the rat. J Pharmacol Exp Ther 1997;283:757-769. 40. Mignot E, Nishino S, Guilleminault C, Dement WC. Modafinil binds to the dopamine uptake carrier site with low affinity. Sleep 1994;17:436-437. 41. Qu WM, Huang ZL, Xu XH, Matsumoto N, et al. Dopaminergic D1 and D2 receptors are essential for the arousal effect of modafinil. J Neurosci 2008;28:8462-8469. 42. Wisor JP, Eriksson KS. Dopaminergic-adrenergic interactions in the wake promoting mechanism of modafinil. Neuroscience 2005;132:1027-1034. 43. Tassin JP, Torrens Y, Salomon L, Lanteri C, et al. Elevated dopamine D2High receptors in alpha1b-adrenoceptor knockout supersensitive mice. Synapse 2007;61:569-572. 44. Nishino S, Fruhstorfer B, Arrigoni J, Guilleminault C, et al. Further characterization of the alpha1 receptor subtype involved in the control of cataplexy in canine narcolepsy. J Pharmacol Exp Ther 1993;264:1079-1084. 45. Madras BK, Xie Z, Lin Z, Jassen A, et al. Modafinil occupies dopamine and norepinephrine transporters in vivo and modulates the transporters and trace amine activity in vitro. J Pharmacol Exp Ther 2006;319:561-569. 46. Parkes JD, Shachter M. Mazindol in the treatment of narcolepsy. Acta Neurol Scand 1979;60:250-254. 47. Iijima S, Sugita Y, Teshima Y, Hishikawa Y. Therapeutic effects of mazindol on narcolepsy. Sleep 1986;9:265-268. 48. Rye DB, Dihenia B, Bliwise DL. Reversal of atypical depression, sleepiness, and REM-sleep propensity in narcolepsy with bupropion. Depress Anxiety 1998;7:92-95. 49. Golbe LI. Deprenyl as symptomatic therapy in Parkinson’s disease. Clin Neuropharmacol 1988;11:387-400. 50. Reynolds GP, Elsworth JD, Blau K, Sandler M, et al. Deprenyl is metabolized to methamphetamine and amphetamine in man. Br J Clin Pharmacol 1978;6:542-544. 51. Nishino S, Arrigoni J, Kanbayashi T, Dement WC, et al. Comparative effects of MAO-A and MAO-B selective inhibitors on canine cataplexy. Sleep Res 1996;25:315. 52. Hublin C, Partinen M, Heinonen EH, Puukka P, et al. Selegiline in the treatment of narcolepsy. Neurology 1994;44:2095- 2101. 53. Mayer G, Meier E, Hephata K. Selegiline hydrochloride in narcolepsy: a double-blind placebo-controlled study. Clin Neuropharmacol 1995;18:306-319. 54. Bart Sangal R, Sangal JM, Thorp K. Atomoxetine improves sleepiness and global severity of illness but not the respiratory disturbance index in mild to moderate obstructive sleep apnea with sleepiness. Sleep Med 2008;9:506-510.
526 PART I / Section 6 • Pharmacology 55. Larrosa O, de la Llave Y, Bario S, Granizo JJ, et al. Stimulant and anticataplectic effects of reboxetine in patients with narcolepsy: a pilot study. Sleep 2001;24:282-285. 56. Findling RL. Evolution of the treatment of attention-deficit/hyperactivity disorder in children: a review. Clin Ther 2008;30:942-957. 57. Rall TR. Central nervous system stimulants. In: Gilman AG, Goodman LS, Rall TW, Murad F, editors. The pharmacological basis of therapeutics, 7th ed. New York: Pergamon Press; 1985. p. 345-382. 58. Porkka-Heiskanen T, Strecker RE, Thakkar M, Bjorkum AA, et al. Adenosine: a mediator of the sleep-inducing effects of prolonged wakefulness. Science 1997;276:1265-1268. 59. Urade Y, Eguchi N, Qu WM, Sakata M, et al. Minireview: sleep regulation in adenosine A2A receptor–deficient mice. Neurology 2003;61:S94-S96. 60. Chen JF, Beilstein M, Xu YH, Turner TJ, et al. Selective attenuation of psychostimulant-induced behavioral responses in mice lacking A2A adenosine receptors. Neuroscience 2000;97:195-204. 61. Chen JF, Moratalla R, Impagnatiello F, Grandy DK, et al. The role of the D2 dopamine receptor (D2R) in A2A adenosine receptor (A2AR)– mediated behavioral and cellular responses as revealed by A2A and D2 receptor knockout mice. Proc Natl Acad Sci U S A 2001;98: 1970-1975. 62. Chen JF, Moratalla R, Yu L, Martin AB, et al. Inactivation of adenosine A2A receptors selectively attenuates amphetamine-induced behavioral sensitization. Neuropsychopharmacology 2003;28:1086-1095. 63. Huang ZL, Qu WM, Eguchi N, Chen JF, et al. Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine. Nat Neurosci 2005;8:858-859. 64. Fujiki N, Ripley B, Yoshida Y, Mignot E, et al. Effects of IV and ICV hypocretin-1 (orexin A) in hypocretin receptor-2 gene mutated narcoleptic dogs and IV hypocretin-1 replacement therapy in a hypocretin ligand deficient narcoleptic dog. Sleep 2003;6:953-959. 65. Schatzberg SJ, Barrett J, Cutter KL, Ling L, et al. Case study: effect of hypocretin replacement therapy in a 3-year-old Weimaraner with narcolepsy. J Vet Intern Med 2004;18:586-588. 66. Mieda M, Willie JT, Hara J, Sinton CM, et al. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuronablated model of narcolepsy in mice. Proc Natl Acad Sci U S A 2004;101:4649-4654. 67. Mishima K, Fujiki N, Yoshida Y, Sakurai T, et al. Hypocretin receptor expression in canine and murine narcolepsy models and in hypocretin-ligand deficient human narcolepsy. Sleep 2008;31:1119-1126. 68. Huang ZL, Qu WM, Li WD, Mochizuki T, et al. Arousal effect of orexin A depends on activation of the histaminergic system. Proc Natl Acad Sci U S A 2001;98:9965-9970.
69. Nishino S, Fujiki N, Ripley B, Sakurai E, et al. Decreased brain histamine contents in hypocretin/orexin receptor-2 mutated narcoleptic dogs. Neurosci Lett 2001;313:125-128. 70. Kanbayashi T, Kodama T, Kondo H, Satoh S, et al. CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea syndrome. Sleep 2009;32:181-187. 71. Nishino S, Sakurai E, Nevsimalova S, Yoshida Y, et al. Decreased CSF histamine in narcolepsy with and without low CSF hypocretin-1 in comparison to healthy controls. Sleep 2009;32:175-180. 72. Lin JS, Sakai K, Vanni-Mercier G, Arrang JM, et al. Involvement of histaminergic neurons in arousal mechanisms demonstrated with H3receptor ligands in the cat. Brain Res 1990;523:325-330. 73. Shiba T, Fujiki N, Wisor J, Edgar D, et al. Wake promoting effects of thioperamide, a histamine H3 antagonist in orexin/ataxin-3 narcoleptic mice. Sleep 2004;27(Suppl):A241-A242. 74. Parmentier R, Anaclet C, Guhennec C, Brousseau E, et al. The brain H3-receptor as a novel therapeutic target for vigilance and sleep-wake disorders. Biochem Pharmacol 2007;73:1157-1171. 75. Sharif NA, To ZP, Whiting RL. Analogs of thyrotropin-releasing hormone (TRH): receptor affinities in brain, spinal cords, and pituitaries of different species. Neurochem Res 1991;16:95-103. 76. Riehl J, Honda K, Kwan M, Hong H, et al. Chronic oral administration of CG-3703, a thyrotropin releasing hormone analog, increases wake and decreases cataplexy in canine narcolepsy. Neuropsychopharmacology 2000;23:34-45. 77. Nishino S, Arrigoni J, Shelton J, Kanbayashi T, et al. Effects of thyrotropin-releasing hormone and its analogs on daytime sleepiness and cataplexy in canine narcolepsy. J Neurosci 1997;17:6401-6408. 78. Broberger C, McCormick DA. Excitatory effects of thyrotropinreleasing hormone in the thalamus. J Neurosci 2005;25:1664-1673. 79. Tononi G, Cirelli C. Sleep function and synaptic homeostasis. Sleep Med Rev 2006;10:49-62. 80. Mignot E. Why we sleep: the temporal organization of recovery. PLoS Biol 2008;6:e106. 81. Porrino LJ, Daunais JB, Rogers GA, Hampson RE, et al. Facilitation of task performance and removal of the effects of sleep deprivation by an ampakine (CX717) in nonhuman primates. PLoS Biol 2005;3:e299. 82. Joo DT, Xiong Z, MacDonald JF, Jia Z, et al. Blockade of glutamate receptors and barbiturate anesthesia: increased sensitivity to pentobarbital-induced anesthesia despite reduced inhibition of AMPA receptors in GluR2 null mutant mice. Anesthesiology 1999;91: 1329-1341. 83. Steenland HW, Kim SS, Zhuo M. GluR3 subunit regulates sleep, breathing and seizure generation. Eur J Neurosci 2008;27: 1166-1173.
Wake-Promoting Medications: Efficacy and Adverse Effects Mary B. O’Malley, Shelagh K. Gleeson, and Ian D. Weir Abstract There are a variety of wake-promoting medications used to treat excessive sleepiness, ranging from over-the-counter caffeine, to Schedule II amphetamine-like compounds. Each has a potential role in the clinical treatment of excessive sleepiness due to sleep disorders. Because their pharmacologic profiles are diverse, the clinician may guide selection of the agent based on a variety of factors: time of onset, length of activity, degree of tolerance in chronic use, side effects expected, and abuse liability. Although the traditional stimulants have been prescribed most widely for disorders such as narcolepsy, modafinil, a nonsympathomimetic compound, is now consid-
Wake-promoting medications now fall into two categories: those that support wakefulness directly and are taken during the daytime, and the hypnotic, sodium oxybate, that gradually improves wakefulness over months of regular use at night. Of the daytime medications, there are three chemical classes: (1) direct-acting sympathomimetics, such as the alpha1-adrenergic agonist phenylephrine; (2) indirect-acting sympathomimetics, such as methylphenidate, amphetamine, mazindol, and pemoline; and (3) the nonstimulants that are not sympathomimetics and have different mechanisms of action, such as modafinil and caffeine. This chapter focuses on the clinical use of alerting medications.
THE HISTORY OF WAKEPROMOTING MEDICATIONS Psychostimulants have been used for centuries in tonics and other preparations to allay fatigue and treat a variety of ailments (for reviews, see Haddad1 and Angrist and Sudilovsky2). One of the oldest and most ubiquitous psychostimulants is caffeine. As early as 1672, coffee, along with leaves of sage or rosemary, was prescribed for disorders associated with sleepiness. The effect of coffee on sleepiness stems from caffeine. It has been consumed in some form for much of human history, but it was not officially discovered until 1819. The native peoples of Peru and Bolivia used cocaine, a crystalline alkaloid derived from the leaves of the coca plant, for pleasure and to increase stamina. From 1886 to 1905, cocaine was an ingredient in Coca-Cola. The medicinal use of cocaine was advocated by Freud.3 However, cocaine’s profound potential for abuse and addiction soon limited the role of this stimulant in modern medicine. In 1931, Doyle and Daniels4 described the use of ephedrine to treat the sleepiness of narcolepsy. Despite its clinically noteworthy efficacy, it was soon apparent that side effects, incomplete patient acceptance, rapid development of tolerance, and cost limited its usefulness. In 1935,
Chapter
45
ered a first-line wake-promoting agent for this disorder. Modafinil is also approved by the U.S. Food and Drug Administration (FDA) for treatment of excessive sleepiness due to shift work sleep disorder and in patients with obstructive sleep apnea whose sleepiness fails to remit despite optimal treatment with nasal continuous positive airway pressure. In addition, the rapid-acting hypnotic medication sodium oxybate has also been demonstrated to gradually improve daytime alertness in people with narcolepsy, and so has received FDA approval for the treatment of excessive sleepiness in this patient population. Understanding the underlying pharmacology of the range of alerting agents available may also clarify the qualitative aspects of wakefulness that they affect.
Prinzmetal and Bloomberg5 suggested that amphetamine sulfate would be appropriate treatment for narcolepsy because of its close relationship to ephedrine and epinephrine, its low toxicity and low cost, its prolonged action, and its lack of pronounced sympathomimetic side effects. By 1949, amphetamines, racemic B-phenylisopropylamine, in one or another of the several oral preparations as a phosphate or sulfate, had become the treatment of choice for excessive sleepiness due to narcolepsy, with a typical initial treatment of 10 mg three times daily, followed by gradual increases until sleepiness was controlled. Methylphenidate, a piperidine derivative, was introduced in the 1950s as a milder stimulant. After 1956, methylphenidate came into broad use, as suggested by Yoss and Daly.6 Pemoline, an oxazolidine compound, was later introduced as a mild central nervous system (CNS) stimulant. Mazindol, an imidazoline derivative, is another mild stimulant marketed as an appetite suppressant. Modafinil (2-iphenylmethylsulfinyl acetamide) is a racemic compound unrelated to the amphetamines or other CNS stimulants. Of all the alerting agents, modafinil has the most specific and selective wake-promoting properties, and usually has minimal side effects. Modafinil began to appear on the world market for the indication of narcolepsy and CNS hypersomnia in the early 1990s, and it is now considered a first-line agent for treatment of these conditions.7 The additional U.S. FDA–approved indications for modafinil—treatment of patients with excessive sleepiness due to shift-work sleep disorder (SWSD) and treatment of patients with obstructive sleep apnea (OSA) to augment nasal continuous positive airway pressure (CPAP)—have helped fuel discussion of the more general need for assessment and treatment of pathologic sleepiness in clinical practice. The most recent addition to the armamentarium of wake-promoting treatments is, paradoxically, a hypnotic. It is sodium oxybate (sodium salt of γ-hydroxybutyrate [GHB]). GHB, a naturally occurring inhibitory neurotransmitter that binds to GABAB and GHB receptors, 527
528 PART I / Section 6 • Pharmacology
was first used as an anesthetic and neuroprotective agent in the 1960s. In 1979, Broughton and Mamelak described improvements in nighttime sleep, daytime alertness and cataplexy symptoms in a group of 16 narcolepsy patients who took GHB at night, with sustained treatment effects over 20 months.8 Subsequent research in the 1980s and 1990s confirmed GHB as an effective anticataplectic agent that also evoked improvements in daytime alertness,9 though often patients required additional daytime use of traditional stimulant medication. GHB has been described as a “cataplexy antagonist and mild stimulant” in previous editions of this text, but has only recently been more frequently described as a wake-promoting agent.10 In 2002 sodium oxybate was granted an FDA indication for the treatment of cataplexy in narcolepsy, and an additional indication for the treatment of excessive sleepiness in narcolepsy was added in 2005.
CAFFEINE Mechanism of Action Caffeine can be extracted from plants such as coffee and tea or synthetically produced. The most popular drinks in the world—coffee, tea, and cola—contain caffeine (see Table 45-1). Caffeine is also an important CNS-active constituent of chocolate. Caffeine’s main mechanism of action on the CNS is antagonism of adenosine receptors. Adenosine-releasing neurons are found in the hypothalamus and project to cells in the cortex, basal forebrain, and to cells of the reticular activating system. It is known that endogenous adenosine levels rise with continued wakefulness and may be a fundamental part of the homeostatic sleep mechanism.11 Exogenous adenosine promotes slowwave sleep, whereas xanthines, including caffeine, block the A1 adenosine receptors, thereby inhibiting sleep onset and maintenance. Caffeine inhibits sleep in other mammals and insects through similar mechanisms.12 At high doses, caffeine stimulates the medullary vagal, vasomotor, and respiratory centers, as well as skeletal muscles, giving rise to the common side effects: gastric stimulation, diarrhea, flushing, sweating, increased heart and respiratory rates, muscle tension, and tremor. Alerting Effects Caffeine has widely recognized and used effects on alertness, mood, and cognitive performance. The usual dose in tablet form is 50 to 200 mg, and beverages contain amounts within this range as well (see Table 45-1). Caffeine shows peak blood levels 30 minutes to 1 hour after ingestion and has a half-life typically of 3 to 5 hours. In standard daily practice, 85% of Americans use caffeine, many to foster wakefulness when arising from sleep.13 This culturally accepted truism has been examined, and it is clear that caffeine effectively eliminates the cognitive fog of sleep inertia on psychomotor tasks.14 If taken before sleep, caffeine clearly postpones sleep onset, and reduces the amount of stages 3 and 4 sleep.15 Its disruptive effects on sleep are also well known: Typically, sleep efficiency declines with caffeine consumption taken within a few hours of bedtime. The sleepiness of sleep deprivation in young, healthy, non–caffeine-dependent volunteers can clearly be attenuated both subjectively and objectively using caffeine sup-
plements. In doses of 600 mg of a sustained-release preparation, caffeine reduced slow-wave activity on the electroencephalogram and improved psychomotor performance tasks after up to 36 hours of sleep deprivation.16 Similarly, two 300-mg doses of sustained-release caffeine significantly improved both vigilance and performance during 64 hours of continued wakefulness.17 In a study of U.S. Navy SEALs randomly assigned to receive 100, 200, or 300 mg caffeine or placebo after 72 hours of sleep deprivation and continuous exposure to other stressors, caffeine at 200 mg or above clearly improved tests of vigilance, alertness, and reaction time. However, it did not improve marksmanship, which is a task that requires fine motor control that tends to be worsened by caffeine.18 Compared with the potency of other alerting medications, caffeine is judged to be a moderately effective alerting agent when taken on an intermittent basis. Parkes and Dahlitz estimated that a dose of six cups of strong coffee has about the same effect as 5 mg dextroamphetamine.19 High doses of caffeine may approximate the efficacy of low doses of stimulants, or of standard doses of modafinil in maintaining alertness and performance during sleep deprivation.20 Because it is such a widely available alerting agent, caffeine stands in a unique position to help improve the safety of drivers and shift workers, if used correctly. That is, if used in sufficient doses (usually at least 200 mg), ideally in individuals who are not already moderately caffeinedependent, it may significantly improve the alertness and cognitive skills that become impaired by sleepiness. The effectiveness is greater in the sustained-release form of a 600-mg daily dose, which clearly extends the benefit of short naps for a partially sleep-deprived driver.21 Caffeine has been shown to substantially improve alertness in a simulated night shift.22 In regular practice, night shift workers do consume more caffeine than day workers, and yet they continue to be at risk of accidents both on the road and at the work place.23 Clearly, there are multiple factors, including the timing of driving home with the circadian nadir, that compromise the ability of any alerting agent to mitigate severe sleepiness. However, caffeine’s potential benefits for alertness may be lost because (1) it may not be consumed in adequate doses; (2) acute benefits are relatively short-lived, and so it must be taken at the right time; and (3) a background of caffeine dependence may reduce its overall ability to be effective. As such, caffeine is ineffective as a daily treatment for the severe sleepiness of sleep disorders such as narcolepsy and idiopathic CNS hypersomnia. Side Effects, Tolerance, and Withdrawal The most common side effect of caffeine use is disrupted nighttime sleep. Caffeine reduces slow-wave sleep and decreases total sleep time. Individual sensitivity to this varies, and usually those most sensitive to caffeine’s effects are acutely aware of it. The decline in metabolic rate with age makes caffeine an increasingly likely contributor to sleep fragmentation in the elderly. Although coffee may exacerbate several disorders such as fibrocystic breast disease, irritable bowel syndrome, peptic ulcer disease, and cardiovascular disease,24 in general, it appears that caffeine in moderation appears safe to use if side effects are not apparent. Caffeine can produce strong CNS and somatic
CHAPTER 45 • Wake-Promoting Medications: Efficacy and Adverse Effects 529
Table 45-1 Caffeine Content of Popular Ingestibles PRODUCT
SERVING SIZE
CAFFEINE CONTENT (MG)
Coffee
8 oz
110
Coffee, decaf
8 oz
5
16 oz
550
Coffees*
Starbucks Coffee, grande Starbucks Coffee, short
8 oz
250
12 oz
375
Espresso
1 oz
90
Espresso, decaf
1 oz
10
Instant coffee
8 oz
75
Caffe Latte
6 oz
90
Arizona Blue Luna Iced Coffees
8 oz
40-50
Arizona Iced Coffees
8 oz
40-50
Coffee Ice Cream
8 oz
58
Starbucks Coffee, tall
Teas* Arizona Iced Tea, Black Tea
8 oz
16
Arizona Iced Tea, Green Tea
8 oz
7.5
Arizona Iced Tea, Rx Power and Energy
8 oz
30
Brewed, imported brands
8 oz
60
Brewed, Major U.S. Brands
8 oz
40
Lipton Brisk Iced Tea
8 oz
6
Mistic Teas
8 oz
17 (avg.)
Snapple Iced Tea, all kinds
8 oz
21
Soft Drinks Josta
12 oz
58
Mountain Dew
12 oz
55.5
Surge
12 oz
52.5
Diet Coke
12 oz
46.5
Coca-Cola
12 oz
34.5
Dr. Pepper, regular or diet
12 oz
42
Sunkist Orange Soda
12 oz
42
Pepsi-Cola
12 oz
37.5
Diet Pepsi
12 oz
36
Diet RC
12 oz
54
Barqs Root Beer
12 oz
22.5
Barqs Diet Root Beer
12 oz
0
7-Up or Diet 7-Up
12 oz
0
Sprite or Diet Sprite
12 oz
0
Mug Root Beer
12 oz
0
Caffeine-Free Coke or Diet Coke
12 oz
0
Caffeine-Free Pepsi or Diet Pepsi
12 oz
0
Minute Maid Orange Soda
12 oz
0
Java Water
500 mL
125
Krank 20
500 mL
100
Caffeinated Waters and Energy Drinks
Aqua Blast
500 mL
90
Water Joe
500 mL
60-70
Aqua Java
500 mL
50-60
Red Bull
8.3 oz
80
Full Throttle
16 oz
144
Monster
16 oz
160
Wired X505
24 oz
505 Continued
530 PART I / Section 6 • Pharmacology Table 45-1 Caffeine Content of Popular Ingestibles—cont’d PRODUCT
SERVING SIZE
CAFFEINE CONTENT (MG)
Chocolate Baker’s chocolate
1 oz
26
Chocolate milk beverage
8 oz
5
Chocolate-flavored syrup
1 oz
4
Cocoa beverage
8 oz
6
Dark chocolate, semisweet
1 oz
20
Milk chocolate
1 oz
6
Medications Anacin
2 tablets
26
Aqua Ban
1 tablet
100
Cafergot
1 tablet
100
Caffedrine
2 capsules
200
Coryban-D
1 tablet
30
Darvon Compound
1 tablet
32
Dexatrim
1 tablet
200
Dristan
1 tablet
30
Excedrin, max. strength
2 tablets
130
Fiorinal
1 tablet
40
Midol
1 tablet
32
Migralam
1 tablet
100
Neo-Synephrine
1 tablet
15
NoDoz, max. strength; Vivarin
1 tablet
200
NoDoz, regular strength
1 tablet
100
Percodan
1 tablet
32
Permathene Water Off
1 tablet
100
Pre-Mens Forte
1 tablet
50
Prolamine
1 tablet
140
Triaminicin
1 tablet
30
Vanquish
1 tablet
33
*Note: The listed caffeine content is average for a standard brewed cup of coffee or tea; certain brewing methods may increase or decrease the average caffeine content per cup. From Etherton GM, Kochar MS. Coffee: facts and controversies. Arch Fam Med 1993;2:317-322.
side effects at high doses (above 4 mg/kg body weight). The most common side effects are nervousness, nausea, diarrhea, muscle twitches and cramps, and sleeplessness. Although the lethal level of caffeine is quite high—more than 10 grams for an adult, the equivalent of 100 cups of coffee—overdoses have occurred with fatal outcomes to those who submitted to the unorthodox practice of coffee enemas. Caffeine in moderate daily doses has been shown to produce a withdrawal syndrome after abrupt cessation. In one double-blinded, placebo-controlled study, an average of 235 mg/day was consumed. On discontinuation, subjects reported headache, increased sleepiness, reduced vigor, and worsened mood. These symptoms were seen by the second day after caffeine cessation (20 hours postcaffeine use).25 Although there are clearly both physical and mental changes associated with withdrawal, an expectation of symptoms may also increase the likelihood that they emerge.26
SYMPATHOMIMETIC ALERTING AGENTS Mechanism of Action As discussed in detail elsewhere, the amphetamines work by directly or indirectly increasing the activity in dopaminergic and noradrenergic CNS systems. The primary effect on alertness is mediated through increased efficacy of the dopaminergic ventral tegmental area and the noradrenergic locus coeruleus, which both project widely throughout the brain. The additional activation of other non–wake-promoting areas (e.g., striatum, nucleus accumbens) accounts for the side effects typical of the sympathomimetics, such as tics and abuse liability. Alerting Effects The clinical treatment of excessive sleepiness due to narcolepsy originated with the traditional stimulants, and the dosing guidelines have changed little since their development in the first part of the last century. The wide variety
CHAPTER 45 • Wake-Promoting Medications: Efficacy and Adverse Effects 531
Concentration (µg/L)
10
Subject 05108
8 6
Ritalin® LA Concerta ®
4 2 0
A
0
5
Concentration (µg/L)
12
B
10
15
20
25
20
25
Subject 05109
10 8 6 4 2 0 0
5
10
15
Figure 45-1 Representative concentration-time profiles of DLthreo-methylphenidate from healthy adult volunteers after administration of Ritalin LA 20 mg and Concerta 18 mg. From Markowitz JS, Straughn AB, Patrick KS, et al. Pharmacokinetics of methylphenidate after oral administration. Clin Pharmacokinet 2003;42:393-401.
of available preparations of the traditional stimulants offer a range of half-lives, and, therefore, dosing strategies to treat sleepiness (Table 45-2). Several preparations of amphetamine have been developed as oral compounds that vary in terms of the concentration of the dextro-isomer and whether a phosphate or sulfate salt is used. Some stimulants have rapid onset and short duration of effectiveness, such as immediate release formulations of methylphenidate (duration of 3 to 4 hours). Other medications have longer onset time and longer duration of action such as sustained release formulations of methylphenidate and amphetamine. Even the pharmacokinetics of different formulations of the same stimulant vary, and may impact a patient’s level of alertness throughout the day. For instance, two commercial preparations of sustained-release methylphenidate (Ritalin LA and Concerta)27 compared across several subjects exhibit similarly timed bimodal peaks in plasma levels after dosing, but significantly different blood levels between formulations (Fig. 45-1). In general, the specific pharmacokinetic profile must be considered when prescribing stimulants because it is often the most important element in shaping a patient’s wakefulness throughout the day and ability to tolerate one formulation of a medication better than others. Side Effects When used in the treatment of narcolepsy or other conditions, stimulants commonly produce side effects, including irritability, talkativeness, and sympathomimetic side effects such as sweating, particularly at higher doses. The reported frequency of side effects of stimulants in clinical practice
and in clinical trials varies from 0% to 73%; the extreme variation reflects, at least in part, differences in methods of determining side effects and the definition of a side effect. Common side effects include headaches, irritability, nervousness or tremulousness, anorexia, insomnia, gastrointestinal complaints, dyskinesias, and palpitations.6,28 Available studies show that at high doses, side effects as well as disturbed nocturnal sleep are experienced by most patients.29 Psychiatric complications with the use of sympathomimetics are dose-dependent and more likely to occur in patients with coexisting or preexisting psychiatric conditions.30,31 Psychosis and hallucinations are rare in narcoleptic patients treated with stimulants.32 There is no evidence that different agents confer a greater or lesser risk for psychotic symptoms, although the use of short-acting forms lends itself to mood swings and irritability. Cardiac and vascular complications due to prescribed sympathomimetics have been reported only rarely in people with narcolepsy. They do not appear to cause a clinically significant increases in blood pressure at commonly used doses in normotensive individuals.6,28,33 Isolated cases of severe disease such as stroke, cardiomyopathy, and ischemic vascular complications have been reported in the context of chronic use of sympathomimetics, especially at high doses. Although advanced cardiovascular disease is a reasonable contraindication to sympathomimetic therapy, there are no systematic studies indicating that well-controlled hypertension is exacerbated by moderate doses of stimulants. Dependence, Abuse, and Tolerance Amphetamines and related compounds have a high abuse potential and can produce dependence. Although most users do not become addicted, controlled use may become compulsive use, especially when the drug is readily available or when a rapid route of administration is used. A sequence of euphoria, dysphoria, paranoia, and psychosis can occur after a single exposure to a high dose or with chronic exposure to low doses. In healthy volunteers, repetitive oral administration of 5 to 10 mg of dextroamphetamine produces paranoid delusions, often with blunted effects, after a cumulative dose of 55 to 75 mg.34 Other symptoms of amphetamine abuse are motor tics, stereotypic movements, and perseveration: repetitive thoughts or organized, goal-directed, but meaningless activity35 such as repetitive cleaning, or elaborate sorting of small objects. A variety of complications can occur with intravenous, intranasal, or oral amphetamine or methamphetamine abuse. In young adults, the relative risk for stroke is estimated to be 6.5 times greater for drug abusers compared with nonabusers, with amphetamines implicated in a substantial proportion of young drug abusers with strokes.36 In people with narcolepsy, tolerance to alerting effects appears to occur with variable frequency. In one review, 10 of 100 patients had discontinued stimulants owing to failure to respond, tolerance, or side effects, and 31 others had required doubling of dosage over a 1-year period for the same control of symptoms.28 Other studies have found a similar or higher amount of tolerance evident clinically in patients using sympathomimetic agents.32,37 Tolerance
DOSE
10-40 mg
5-60 mg
Amphetamine/ dextroamphetamine XR (Adderall XR)
Dextroamphetamine SR
1.3-4 hr (food slows absorption)
10-60 mg
Methylphenidate hydrochloride ER (Ritalin ER, Concerta ER, Metadate CD)
2-4 hr
2-4 hr
200-800 mg
37.5-112.5 mg
Modafinil (Provigil)
Pemoline (Cylert)
Other Drugs
1-2 hr (food slows absorption)
10-60 mg
8 hr
Methylphenidate hydrochloride (Ritalin, Concerta)
Methylphenidate
2-3 hr
5-60 mg
Dextroamphetamine IR 7 hr
2-3 hr
5-60 mg
Amphetamine/ dextroamphetamine IR (Adderall)
Amphetamine/Dextroamphetamine
MEDICATION
ONSET TO PEAK CONCENTRATION
11-13 hr
15 hr
3.5 hr (1.3-7.7 hr)
3 hr
12 hr
12 hr
10 hr
7-34 hr (avg 10 hr)
HALF-LIFE
Table 45-2 Summary of Prescription Wake-Promoting Agents
Loss of appetite, insomnia
Headache, nausea, anxiety nervousness, insomnia, dizziness
Loss of appetite, abnormal behavior, restlessness
Weight loss, headache, insomnia, tremor, abdominal pain, anorexia, xerostomia, dysphoria, euphoria, nervous, restlessness
COMMON SIDE EFFECTS
Hepatic failure aplastic anemia, dyskinesia, Tourette’s syndrome, hallucinations, nystagmus, seizure
Drug hypersensitivity syndrome, Stevens-Johnson syndrome, toxic epidermal necrolysis due to drug hypersensitivity reaction, hypertension
Hypertension (frequent), tachyarrhythmia (frequent), thrombocytopenia, hallucinations
Cardiomyopathy, chest pain, sudden death, MI, irregular heart rate, immune hypersensitivity reaction, CVA, CNS stimulation, Tourette’s syndrome, seizure, hypertension, palpitations, psychotic disorder with prolonged use
SERIOUS SIDE EFFECTS
TCAs: hypertension
OCPs: decreased bioavailability and reduced effectiveness Other interactions: diazepam, propranolol, phenytoin, cyclosporine, carbamazepine, clomipramine
Warfarin: increased plasma concentrations and an increased risk of bleeding MAO inhibitors: hypertensive crisis Phenytoin, Phenobarbital increased serum levels
MAO inhibitors: hypertensive crisis Venlafaxine, citalopram: increased risk of serotonin syndrome Sodium bicarbonate: amphetamine toxicity by increasing absorption
IMPORTANT DRUG INTERACTIONS
Contraindicated with impaired hepatic function, associated with life-threatening hepatic failure, can decrease seizure threshold
Angioedema, hypersensitivity reaction, anaphylactoid (rare)
Caution in pts with a history of drug dependence or alcoholism Can lower convulsive threshold Contraindicated in pts taking MAOIs and pts with glaucoma, motor tics, Tourette’s syndrome
Advanced arteriosclerosis, cardiovascular disease, concomitant use of MAOIs or within 14 days of MAOI use, drug dependence, structural cardiac abnormalities, hyperthyroidism, moderate to severe hypertension Can lower seizure threshold
CONTRAINDICATIONS AND PRECAUTIONS
Black box warning for hepatic failure risk Not available in United States
Low abuse potential, Schedule IV
Black box warning: high potential for abuse
Black box warning: high potential for abuse
COMMENTS
532 PART I / Section 6 • Pharmacology
40-90 min
25-60 minutes to peak concentration Fatty food delays absorption
10-30 mg
5-10 mg
2.25-9 g in divided doses
Ritanserin
Selegiline
Sodium oxybate (gammahydroxybutyrate [GHB]) (Xyrem)
20-53 min
10 hr
40 hr
HALF-LIFE
Nausea, vomiting, enuresis, dyspepsia, abdominal pain, confusion, dizziness, somnolence, headache, incontinence
Decreased systolic arterial pressure, orthostatic hypotension, weight loss, diarrhea, indigestion headache, insomnia, xerostomia
Constipation
COMMON SIDE EFFECTS
Respiratory suppression, sleep walking, depression
Hypertensive crisis, suicidal thoughts
Prolongation of the QTc interval
SERIOUS SIDE EFFECTS
Benzodiazepines Opiates may have additive CNS and respiratory depressant effects
Meperidine, methadone, propoxyphene, tramadol: severe hypertension or hypotension, hyperpyrexia, coma, death SSRIs: increased risk of serotonin syndrome Albuterol: increased risk of tachycardia, agitation, or hypomania; TCAs: hyperpyrexia, convulsions, death Fentanyl: severe and unpredictable potentiation of opioid analgesic effects
Droperidol: increased risk of cardiotoxicity (QT prolongation, torsades de pointes, cardiac arrest)
IMPORTANT DRUG INTERACTIONS
Succinic semialdehyde dehydrogenase deficiency, concurrent treatment with sedative hypnotics, alone or combined with alcohol, has a high propensity to induce a comatose state
Meperidine, methadone, propoxyphene, tramadol, carbamazepine, oxcarbazepine, cyclobenzaprine, bupropion, mirtazapine, St. John’s wort, SSRIs, albuterol TCAs, fentanyl: contraindicated Concomitant use of dextromethorphan: can cause psychosis or unusual behavior Pheochromocytoma Caution with tyraminerich foods, increased risk of hypertensive crisis
Pts concurrently receiving class III antiarrhythmic agents or drugs known to cause hypokalemia, prolongation of QT interval arrhythmias
CONTRAINDICATIONS AND PRECAUTIONS
Can be used as drug of abuse Need to be a registered to prescribe in the United States
Black box Warning for increased the risk of suicidal thinking and behavior in children, adolescents, and young adults with major psychiatric disorders Very few data to support use for daytime sleepiness
Some improvement in daytime sleepiness in pts with narcolepsy
COMMENTS
avg, average; CNS, central nervous system; CVA, cerebrovascular accident; MAO, monoamine oxidase; MAOI, monoamine oxidase inhibitor; MI, myocardial infarction; OCP, oral contraceptive pill; pt, patient; SSRI, selective serotonin reuptake inhibitor; TCA, tricyclic antidepressant.
140 min
DOSE
MEDICATION
ONSET TO PEAK CONCENTRATION
CHAPTER 45 • Wake-Promoting Medications: Efficacy and Adverse Effects 533
534 PART I / Section 6 • Pharmacology
to stimulants appears to be more likely, or at least more evident in patients taking high doses.38,39 There is little evidence that the incidence of tolerance and side effects is less in people with narcolepsy than in others taking sympathomimetics.40 Furthermore, it does not appear that tolerance reported by some patients is an effect of inadequate nocturnal sleep rather than true tolerance, or that tolerance and other side effects are less likely to occur with methylphenidate than with dextroamphetamine.38
MODAFINIL AND ARMODAFINIL Mechanism of Action Modafinil and its R-enantiomer armodafinil is a novel medication chemically unrelated to the amphetamines or other sympathomimetic agents that is sometimes referred to as a somnolytic.41 The precise mechanism through which modafinil enhances wakefulness remains unclear. However, progress has been made in the last several years in defining its pharmacologic effects.42 A comprehensive discussion of modafinil’s mechanism of action is included elsewhere. What distinguishes modafinil from the sympathomimetic alerting medications is that modafinil appears to more selectively activate wake and sleep centers in the CNS, without significant activation of the reward/ abuse center (nucleus accumbens), motor areas (striatum), or the sympathetic nervous system. Furthermore, its alerting effects do not disrupt the evolution of normal sleep architecture once its effects have worn off or result in increasing homeostatic sleep pressure that induces rebound sleepiness. Alerting Effects Although in some individuals, 100 mg of modafinil is sufficient to sustain alertness for several hours, most patients with excessive sleepiness require doses of 200 mg per day or higher. In two large populations of narcoleptic patients on 200 to 400 mg per day, alertness measures (Maintenance of Wakefulness Test [MWT], Epworth Sleepiness Scale [ESS], Clinical Global Impression of Change) gradually increased over 9 weeks of double-blinded treatment.43,44 Clinical and subjective self-assessments of efficacy remained stable for most of those patients who enrolled in openlabel studies taking the same dose of modafinil for 3 years.44-46 Some individuals with severe sleepiness may require modafinil at 600 to 800 mg per day in divided doses (morning and noon) for effective control of their symptoms.47,48 Although these doses are significantly above the FDA-indicated guidelines, if lower doses are well tolerated but ineffective, then it is reasonable to carefully titrate up to higher doses. Modafinil is approved by the FDA for the treatment of excessive daytime sleepiness due to SWSD, and for patients with OSA who continue to have disabling sleepiness despite treatment of airway obstruction during sleep with mechanical treatments such as nasal CPAP. This expanded labeling for modafinil represents the first time that pathologic sleepiness has been more broadly defined as a symptom warranting treatment across a range of disorders. Nasal CPAP treatment has been clearly demonstrated to improve alertness in patients with OSA,49 but patients with OSA may continue to complain of daytime sleepiness. In
our experience, the most frequent cause of residual sleepiness in patients with OSA is their failure to sleep with CPAP on for a full night’s sleep on a regular basis. However, even with optimal mechanical therapy, chronic sleepiness is clearly a problem for some patients with OSA. Indeed, a recent study of patients with OSA demonstrated a clear dose-response relationship between hours of CPAP use during sleep and subjective as well as objective daytime sleepiness. However, about 20% of those study subjects with an average of 8 hours of use of CPAP per night remained excessively sleepy by self-report.50 It has been hypothesized that this residual sleepiness in OSA patients is a long-term effect of the intermittent hypoxic episodes their wake-promoting brain areas were exposed to before therapy.51 Whatever the underlying cause, it is clear that a subset of patients with OSA experience chronic residual sleepiness despite their compliance with mechanical treatments during sleep. For these patients, the adjunctive use of modafinil appears to be a reasonable and safe measure to improve their safety and quality of life. In a large, double-blinded, placebo-controlled study of patients with OSA reporting residual excessive sleepiness while on CPAP, modafinil at doses of 400 mg improved alertness by 2.6 points on the ESS above placebo-treated patients, and more than half the modafinil-treated patients reported normal ESS values (score of less than 10) by the study endpoint. Further, adjunctive modafinil treatment improved objective measures of alertness on the Multiple Sleep Latency Test (MSLT) (8.6 minutes compared with 7.4 minutes at baseline) without adversely affecting compliance with CPAP.52 Subsequent studies have also demonstrated the efficacy of modafinil in daily doses of 200 to 400 mg for improving alertness in CPAP-treated patients with OSA with residual sleepiness, and confirmed a relative absence of adverse consequences in this patient population.53,54 Another large, ill-defined population of people with chronic, problematic sleepiness is the millions of adults who keep nonstandard work hours. Although many shift workers adapt adequately to the constraints of their schedules, there are many more who suffer at least transiently from the effects of both sleep deprivation and circadian misalignment. Furthermore, it is estimated that approximately 10% of the adults working nonstandard hours have persistent complaints of excessive sleepiness or insomnia consistent with the diagnosis of SWSD.55 A recent, double-blinded, placebo-controlled study of over 200 nightshift workers demonstrated this group to be pathologically sleepy at baseline (MSLT approximately 2 minutes), with significant cognitive impairment (as measured by psychomotor vigilance task), as well as numerous mistakes, nearmisses, or accidents at work or while driving home after work. All these measures improved substantially after treatment with 200 mg modafinil taken at the beginning of their night shift. Furthermore, this treatment did not interfere with their ability to sleep during time off duty.56 On the basis of this and other evidence, the FDA approved modafinil for the treatment of excessive sleepiness due to SWSD in 2004. Together with a program of nonpharmacologic measures to protect sleep time and sleep ability in this patient population, modafinil is a potentially lifesaving treatment for these adults.
CHAPTER 45 • Wake-Promoting Medications: Efficacy and Adverse Effects 535
Side Effects and Tolerance Side effects are less frequent with modafinil than with sympathomimetics. The most common adverse event in the initial modafinil trials was a headache, which increased in frequency if the modafinil dose was high or increased too quickly.43 There have been no significant cardiovascular adverse effects from modafinil treatment in the clinical trials to date, including among patients with OSA.52 So far, it appears that only patients with a history of sensitivity to activating medications (e.g., those with mitral valve prolapse) experienced cardiovascular side effects from modafinil (e.g., palpitations, chest pain), and these symptoms reversed when the medication was discontinued. The use of modafinil has so far been reported to cause infrequent complaints of insomnia or nervousness, and these symptoms are usually transient and dose dependent. Psychotic symptoms have developed rarely, and only at high doses of modafinil.57 Cases of modafinil-induced hypersensitivity reactions, including rare cases of life-threatening allergic rashes, have also been reported. Modafinil appears to have a very low, or idiosyncratic, occurrence of tolerance. Dependence, Abuse, and Withdrawal Modafinil is a Schedule IV medication, with limited potential for abuse and dependence. In abuse liability studies conducted with seasoned substance abusers, modafinil was similar to caffeine in its rating as producing some “good effects” on a subjective rating scale, and it did not elicit any desire to procure more (i.e., “amount willing to pay” was $0).58,59 These and other studies demonstrate that modafinil’s effects are clearly different from predictably dose-dependent euphoria and the desire to have more drug that is seen with traditional stimulants like amphetamine. Moreover, modafinil has a slower onset of action, and its water-insoluble properties make it impossible to snort or inject, so it is not pharmacokinetically amenable to abuse. Postmarketing surveys and medical literature to date have identified only idiosyncratic cases of people developing addictions or cravings for modafinil. Fears that modafinil would be abused to extend the wake period by college students or others in similar situations has not been a reported widespread phenomenon. This form of abuse or overuse of wake-promoting medication is likely limited by the ultimate need to sleep—no medication is really an effective substitute for sleep—and more likely to occur with the more robustly arousing traditional stimulants. In the large clinical trials of patients taking stable doses of modafinil for sleepiness, abrupt discontinuation did not elicit specific symptoms of withdrawal; rather, patients simply returned to their initial level of sleepiness. Patients taken off modafinil will typically experience a full return of sleepiness symptoms within 2 to 3 days of cessation. There are no recovery changes to nighttime sleep because modafinil does not significantly alter nighttime sleep architecture during treatment. This lack of rebound following discontinuation is a significant advantage for patients already on modafinil requiring diagnostic polysomnography and daytime sleep testing because it significantly reduces the time needed off-medication prior to testing. Patients withdrawn from modafinil can be expected to be fully back to baseline within 5 days, whereas patients with-
drawn from chronic stimulants will need at least 3 weeks to allow normalization of sleep architecture patterns, as well as to recover from rebound hypersomnolence prior to sleep testing.
SODIUM OXYBATE Mechanism of Action Commercially available sodium oxybate, Xyrem, is the sodium salt of γ-hydroxybutyrate (GHB), a rapidly acting sedative/hypnotic medication used for the treatment of daytime sleepiness and cataplexy in narcolepsy patients. Although the precise mechanism of action is unknown, the effects may be mediated in part through interaction with GABAB and GHB receptors.60 Its highest concentration is in the dopaminergic regions such as the substantia nigra and ventral tegmental area, suggesting that endogenous GHB may also modulate the activity of dopamine neurons.61 What is interesting, and unknown, about GHB is how it reduces sleepiness—or elevates wakefulness—in patients. Each dose of sodium oxybate significantly increases delta power during sleep, and consequently dramatically enhances the density and duration of slow-wave sleep each night.62 Patients with narcolepsy beginning GHB treatment can expect to experience side effects initially, but much like antidepressant therapy, improvements in daytime functioning become robustly evident only over sustained use of weeks to months. Indeed, most patients must initially remain on any daytime wake-promoting and anticataplectic medications. It is unclear how sodium oxybate effects improvements in alertness and reduces cataplexy, but it seems reasonable to suppose the mechanism may be related to (or a consequence of) the changes to sleep it evokes each night. Alerting Effects The first report that GHB could be an effective treatment for excessive sleepiness in narcolepsy was published in 1979 by Broughton and Mamelak.8 This report and follow-up reports demonstrating GHB’s use for treatment of cataplexy in narcolepsy led to larger research protocols to confirm its effects. Two randomized, double-blind, placebo-controlled trials in patients with narcolepsy who were also being treated with traditional stimulants were the basis of FDA approval of sodium oxybate for cataplexy. Subsequent large trials demonstrated the efficacy of sodium oxybate for the treatment of sleepiness associated with narcolepsy, allowing an expanded indication for the use of this medication in narcolepsy (for review, see Wise et al.). In one placebo-controlled randomized study involving 136 narcoleptic patients with cataplexy, sodium oxybate improved subjective sleepiness in a dose-related manner by the Epworth Sleepiness Scale (ESS) but was only statistically significant at a dose of 9 grams per night.64 At this dose, the median ESS dropped from 17 to 12 with some patients falling in the normal range (ESS <10). There was also a significant reduction in the number of unintended naps or sleep attacks seen at both the 6 and 9 gram dose. In another multicenter, randomized, double-blind, placebo-controlled, parallel-arm trial study of 228 patients with narcolepsy with moderate to severe excessive daytime
536 PART I / Section 6 • Pharmacology
sleepiness (EDS) and cataplexy symptoms, sodium oxybate demonstrated a significant median increase of more than 10 minutes in the MWT, significant reduction in median ESS, and reduction in weekly unintended naps.66 In both these studies, the majority of patients remained on wakepromoting medications at stable doses during the study. In a subsequent multicenter, double-blind, placebo-controlled study of subjects with narcolepsy, sodium oxybate’s effects were measured without other wake-promoting medications (vs. placebo), in comparison to treatment with modafinil, and patients were also evaluated after given both sodium oxybate and modafinil.67 Patients treated with sodium oxybate alone (6 grams for 4 weeks and then 9 grams for the subsequent 4 weeks) were compared with patients treated with modafinil (200 to 600 mg daily). Both wake-promoting medications caused similar improvements in the patients’ alertness on the MWT compared to a placebo treatment group. The greatest improvement in the MWT was seen in a fourth group of patients taking both sodium oxybate and modafinil, suggesting an additive effect of each medication. ESS scores and weekly inadvertent naps and sleep attacks were also significantly reduced in the sodium oxybate and sodium oxybate/modafinil group but not in the modafinil group. The attempt to compare the efficacy of these two wake-promoting medications fell short in this study because modafinil-treated patients remained on doses established prior to the study, and were not further optimized to a maximally effective dose during the study. Additionally, to date there have been no studies that directly compare sodium oxybate to traditional stimulant medications. Furthermore, there have been no randomized, placebo-controlled trials for the treatment of excessive daytime sleepiness in patients other than those with narcolepsy. Side Effects Sodium oxybate is taken nightly, in divided doses on an empty stomach (no food within 3 to 4 hours of bedtime). Food will mitigate absorption of sodium oxybate, so a common source of adverse effects in patients is a variable eating schedule, which causes inconsistent effective doses of medication. The usual effective dose range is 4.5 to 9 grams per night, with half the total dose taken immediately before lying down to go to sleep and the second half 2.5 to 4 hours later. Although some patients will respond to this medication at lower doses, often patients will require the recommended dose of 6 to 9 grams per night. To minimize side effects, for some patients it may be necessary to begin at much lower doses (e.g., 1 to 2 grams per night), and increase sodium oxybate by 0.5 to 1.0 gram increments once every several nights. The most commonly reported adverse events (= 5%) in placebo-controlled trials (n = 655) associated with the use of sodium oxybate and occurring more frequently than seen in placebo-treated patients were nausea, dizziness, headache, vomiting, somnolence, and urinary incontinence. Sodium oxybate is contraindicated in patients with succinic semialdehyde dehydrogenase deficiency, due to inability of these patients to metabolize the drug. Sodium oxybate should be used with great caution in patients being treated with sedative hypnotic agents and should not be
used in combination with alcohol other CNS depressants. There is potential to impair respiratory drive when used alone or in combination with other drugs that diminish respiratory drive. Because impaired motor or cognitive function may occur when taking sodium oxybate, the elderly may be at higher risk of falls and injury. Patients should not drive or operate machinery for at least 6 hours after taking sodium oxybate. Dependence, Abuse, and Withdrawal Sodium oxybate (GHB) was available over the counter as a food supplement for many years, and it became popular with weightlifters who discovered that it accelerated muscle growth and recovery (no doubt secondary to its effect on growth hormone release during sleep). After reports of overdosing by weight lifters, increasing recreational abuse, and reported use as a “date-rape” drug, GHB supplements were banned in 1990. Popular pressure to make sodium oxybate illegal was countered by lobbying efforts on the part of narcolepsy patients who testified to the drug’s benefits when used appropriately for sleepiness and cataplexy. The end result was a unique dual-schedule mechanism such that sodium oxybate may be prescribed as a Schedule III drug through a centralized pharmacy, and abuse or diversion of sodium oxybate is prosecuted under schedule I felony charges. Sodium oxybate continues to have high street value because of its ability to induce euphoria and craving in users. There have been case reports of dependence after illicit use of sodium oxybate at frequent repeated doses in excess of the therapeutic dose range (18 to 250 grams per day). Careful monitoring of patients for dependence and abuse is necessary. The discontinuation effects of sodium oxybate have not been systematically evaluated in controlled clinical trials, but an abstinence syndrome has not been reported in clinical investigations. After cessation of treatment, patients can expect a gradual return to baseline levels of sleepiness and recurrence of cataplexy symptoms over days to weeks.68
IS ALL WAKEFULNESS THE SAME? An additional aspect of efficacy is the subjective experience of wakefulness that each medication supports. That is, sympathomimetic-induced wakefulness may not feel the same, or in fact be the same, as the wakefulness produced by caffeine, modafinil, or sodium oxybate. It has been suggested that although several neurotransmitter systems facilitate alertness through their extensive projections throughout the cortex, these systems may not be simply redundant, but rather support different aspects of wakefulness.69 In particular, the monoaminergic projections of the ascending reticular activating system may mediate a sort of “guard duty”—an externally directed vigilance or awareness of one’s surroundings—whereas the hypothalamic arousal regions (tuberomammillary nucleus and orexin systems) may perhaps support a form of internally directed vigilance—attention, motivation, insight, and planning. Normally, a healthy balance of activity from these systems should allow a person to focus on a task while being aware of the surrounding milieu. This hypothesis stems in part
CHAPTER 45 • Wake-Promoting Medications: Efficacy and Adverse Effects 537
from the observation that the excess dopamine and norepinephrine release after administration of high-dose amphetamines provokes a state of exaggerated hypervigilance, or paranoia, and executive functions, including judgment and insight, are impaired.70 In our experience, patients using modafinil or sodium oxybate often report a sense of being “simply awake,” compared with the experience of being “stimulated” on sympathomimetics. The comparison of relative efficacy on cognitive benefits may be more difficult, however, because sleepy patients frequently judge their level of wakefulness not by the degree of mental alertness present, but rather by the autonomic arousal that sympathomimetics generate. Certainly, the cognitive roles of the neurotransmitters that enhance alertness and vigor are not all clearly understood, but consideration of the varied mechanisms of alerting medications may be useful in understanding clinical outcomes.
SPECIFIC USE OF WAKE-PROMOTING MEDICATIONS In Children Side effects of sympathomimetics in children with narcolepsy have not been studied in detail; much of the available data concern the use of these agents for children with attention deficit hyperactivity disorder (ADHD). The potential side effect of greatest concern is growth retardation.71 For example, deficits in weight gain and height increase may occur after treatment of ADHD with dextroamphetamine or methylphenidate.72,73 The growth retardation effects of the sympathomimetic agents are due to drug-induced anorexia and the reduction of slow-wave sleep and attendant suppression of growth hormone release. The growth deficits may be reversed during summers off medication,73,74 and with these drug holidays, there is little or no evidence of long-term effects on growth. Obviously, the need for drug holidays to circumvent the effects on growth means that during treatment interruptions, the child may suffer disabling symptoms that hamper functioning socially and at home. Motor tics can also occur in children taking sympathomimetics,76 and these may limit dosing. Typical initial doses of these agents for treatment of ADHD in children are methylphenidate 0.3 mg/ kg; dextroamphetamine 0.15 mg/kg; followed by dose titration to achieve optimal effects. The safety of higher doses than those currently recommended for ADHD for children with narcolepsy (e.g., methylphenidate 60 mg/ day) is unknown. Neither modafinil nor sodium oxybate are currently indicated for patients under sixteen years of age. Both medications have significant potential advantages for use in children, as neither medication degrades nighttime sleep or interferes with appetite, so growth retardation may be less likely to occur compared with the sympathomimetic agents. However, phase-III studies of modafinil in children with ADHD disorder revealed an increased risk of rash, including one case reported as Stevens-Johnson syndrome.77 For this reason, modafinil should not be considered a first-line agent for treatment of sleepiness due to narcolepsy in children. Further safety and efficacy
studies are also needed for sodium oxybate in children before this medication can be recommended for this population. In Sustained Military Operations During the 1991 Persian Gulf War and during the American-led occupation of Iraq, armed forces were issued modafinil and dextroamphetamines for vigilance during sustained operations (S. Lubin, personal communication). Although there are few controlled studies, in a study of U.S. Army helicopter pilots engaged in flight simulation after prolonged periods of wakefulness, 10 mg of dextroamphetamine, compared with placebo, improved aviator simulator control on descents and turns. Performance was facilitated most noticeably after 22, 26, and 34 hours of continuous wakefulness. Alertness was sustained significantly by dextroamphetamine—there was reduced slow wave electroencephalographic activity and improved rating of vigor and fatigue. No adverse behavioral or physiologic effects were observed.78,79 Comparable results on performance have also been demonstrated with modafinil during 64 hours of sustained mental work.80 Interestingly, the recovery sleep after extended periods of modafinil treatment shows a lack of the rebound hypersomnolence characteristic of postamphetamine treatment recovery sleep.41,81 This difference suggests that modafinil exerts its alerting effects in a novel way, without invoking a rise in the homeostatic sleep drive. The Use of Wake-Promoting Agents for Sleepiness Due to Insufficient Sleep: Is There a Role? Insufficient sleep, beyond the military situation, arises in many circumstances. Common among these circumstances are jet lag and shift work. Modafinil has recently been approved for the treatment of sleepiness in SWSD. The prospective use of alerting agents to enhance the alertness and performance among resident physicians has become a focus of discussion.82,83 Some argue that such use would foster improved safety as well as learning for physicians in training. This use of alerting medications is problematic for many physicians, and active debate continues. The key points of this debate center on the relative importance of the potential benefit for safety and performance, especially when a high degree of vigilance is required, and the potential for abuse and dependency associated with these agents. The demand for alerting medications in these circumstances is likely to increase as our society continues to depend on 24-hour operations in the manufacturing, transportation, and service industries.
CHANGING OR COMBINING MEDICATIONS For most patients, abrupt replacement of one alerting agent with another should present few problems. However, for patients taking high doses of sympathomimetic medications, a gradual weaning period may be prudent. Furthermore, if the patient is switching from a traditional stimulant to modafinil, then the qualitative difference
538 PART I / Section 6 • Pharmacology
in their alerting effects—and the difference in peripheral side effects—usually necessitates a 3- to 4-week adjustment period during which the stimulant withdrawal effects dissipate, and the patient begins to experience what he or she feels like on modafinil alone. Titration toward optimum control of alertness can then be done more clearly. By combining stimulants with different durations of action it may be possible to maintain wakefulness during the day and allow for periods for napping, as well as long periods of sleep at night without producing medicationinduced insomnia. Except for studies with sodium oxybate and modafinil, there are no systematic studies of chronic treatment with more than one alerting agent at a time. Some patients report satisfactory management with combinations such as modafinil for long-lasting effects and small doses of an agent like methylphenidate on an asneeded basis. There are no known drug–drug interactions that would preclude this practice; however, in some patients, hypertension may develop or be exacerbated by the coadministration of modafinil with a prescribed or over-the-counter sympathomimetic (M. O’Malley, personal communication), so appropriate blood pressure monitoring is indicated during treatment. All of the available wake-promoting medications can be safely combined with nonsedating antidepressants used as an anticataplectic (e.g., protriptyline or fluoxetine).
RECOMMENDATIONS AND TREATMENT PLANNING Current practices in the use of alerting medications vary considerably. On the whole, patients who are medicated for excessive sleepiness are still monitored primarily by clinical assessment of their ability to remain alert during sedentary activities, with medication selection and dosing decisions adjusted accordingly. There are very few studies that directly compare the efficacy of two wake-promoting medications, though relative measures of efficacy have been developed that predict that classical stimulants may be most potent for the majority of sleepy narcoleptics.84 All prescription wake-promoting medications produce clinically significant improvements in alertness in narcolepsy, for instance, but based on the available published data, only a small proportion of very sleepy patients will achieve normal levels of alertness with medication.85 Recommendations dosing for medications are summarized in Table 45-2. Clinicians should treat individual patients based on their profile of sleepiness throughout the day and their ability to tolerate side effects. Although many authorities recommend temporary withdrawal of sympathomimetic medications or reduction of dose for 1 to 28 days if tolerance occurs (i.e., drug holidays),86,87 there are no published studies demonstrating the efficacy of drug holidays. One should also consider the effect of drug holidays on patient safety and quality of life. Another factor that probably influences clinical practice is whether an alerting medication has been placed on Schedule II by the U.S. Drug Enforcement Agency. Because of the extra paperwork required in some states to prescribe Schedule II agents, Schedule IV drugs such as modafinil
may be preferentially prescribed. Similarly, the risks of abuse or diversion may deter some clinicians from prescribing sodium oxybate. Alerting medications, however prescribed, represent only part of a comprehensive therapeutic approach to excessive somnolence. Sound sleep hygiene, attention to other substances and drugs that may disrupt the sleep– wake cycle, and periodic reassessment of symptom severity and of the need for and adequacy of treatment modalities are other important aspects of management. The physician should consider the following points in establishing the proper dose of an alerting drug and structuring a management plan. 1. Diagnosis. It is important to define as carefully as possible the factors that contribute to a patient’s excessive sleepiness. Differentiating an insidious and lifelong condition such as narcolepsy from sleepiness due to sleep related breathing disorders is essential for both the patient and the clinician. 2. Education. Clarify the goals of treatment, side effects, risks, and benefits. This process involves discussions with the patient and, perhaps, the patient’s spouse or companions. Normal alertness throughout the day may not be attainable in many patients because of the disease process, drug side effects, work schedules, and other idiosyncratic circumstances. In cases of SWSD, advocating for a work schedule change (such as a switch to daytime work hours) may be the ideal alternative to fully restore alertness. Unfortunately, many people do not have the ability to control their schedule directly and must continue to cope with their current situation. In this case, the clinician must support the patient’s need for alertness without imposing his or her judgment about the need for lifestyle changes. 3. Dosing. Begin with a low to moderate dose of a wakepromoting agent and match the drug and dosage to the patient. For most patients, aim for enough treatment to provide even alertness throughout the wake period. Modafinil or long-acting sympathomimetics provide advantages in this respect. Short-acting sympathomimetics may be useful especially for someone who needs rapid alertness on arising from sleep (e.g., in order to drive). Short-acting medications also provide opportunities for napping between doses, but also unprotected sleepiness. 4. Follow-up. Initially, pharmacologic management should be guided by regular (e.g., weekly) contact with the patient. If prescribing sympathomimetics, it is wise to measure growth (height and weight) periodically in children, and pulse and blood pressure in adults. After a patient has begun to adjust to the medication, follow up every 3 to 4 weeks, then again in 2 to 3 months. Once the dose is stable, see the patient every 6 to 12 months. Under circumstances where the patient’s safety or the safety of others depends on adequate control of excessive somnolence, laboratory confirmation of therapeutic efficacy with the MSLT or MWT is helpful. Such laboratory documentation may not be possible in certain health care settings. 5. Emphasize sleep hygiene; consider short (30-minute), prophylactic naps. The effect of sleep inertia must
CHAPTER 45 • Wake-Promoting Medications: Efficacy and Adverse Effects 539
be factored in if naps are used in the work setting. Consider the use of light therapy (or dark sunglasses on the morning ride home), melatonin, or other modalities if circadian factors impact the ability to sleep. 6. Adjust dosages based on clinical information. Narcolepsy and idiopathic hypersomnia are usually stable conditions that do not progressively worsen. For a patient who has been on a stable dose for some time (years) and now appears to require more, consider other possible causes of increased sleepiness, such as: (a) interval development of sleep apnea (a common scenario in our experience); (b) tolerance to medication; (c) change in schedule (such as a change in job shift, causing less sleep at night); (d) change in life situation (such as a new baby causing sleep disruption or a new job that requires greater vigilance, hence the patient notices his or her sleepiness interferes more often); (e) stress, anxiety, or depression; and (f) unrealistic expectations. Thus, evaluation should include a detailed history covering the aforementioned possibilities as well as a review of the patient’s sleep schedule and napping. 7. Recommend counseling and long-term support. A suddenly awake person may evoke strong feelings from family members not used to their active participation. Or, patients may become depressed or grieve the time “lost to sleep” before treatment once the degree of their prior impairment becomes clear to them. Available evidence suggests that patients tend to take less, not more, of their prescribed stimulant.88 Although the reasons for such noncompliance are undoubtedly complex and incompletely understood, it is important that the patient understand the long-term nature of his or her condition and the benefits that can be obtained with regular use of alerting medications.
CONCLUSIONS The potentially disabling symptom of sleepiness occurs in many sleep disorders. When this sleepiness does not resolve with nonpharmacologic approaches, the use of alerting medications is appropriate.89 Caffeine is widely available and is consumed by most adults in many countries. As an alerting agent, caffeine is most effective when used intermittently at doses of 200 mg or more. Severe or chronic sleepiness is best treated with one of the variety of prescription alerting medications. Treatment of excessive sleepiness associated with narcolepsy or idiopathic hypersomnia with alerting medications is almost always indicated to allow wakefulness when sustained vigilance is necessary, especially for individual and public safety. Pharmacologic treatment with modafinil is now also indicated for severe sleepiness in patients with SWSD and in patients with OSA who remain sleepy despite compliance with nasal CPAP. Sodium oxybate is cumbersome to use, but when patients are gradually titrated to effective doses, the benefits may be considerable. Because the risk for teratogenicity associated with the use of alerting agents is uncertain, these drugs in general should be avoided in pregnancy unless the benefits associated with their use are likely to outweigh the risks.
❖ Clinical Pearl The main goal of the treatment of pathologic sleepiness is to address and correct the underlying sleep disorder. When sleepiness remains an issue despite nonpharmacologic treatment (such as in patients with narcolepsy and SWSD and in some patients with OSA using CPAP), prescription alerting medications should be considered for the patient’s safety and quality of life. Modafinil is a first-line agent in patients with excessive sleepiness due to these disorders because it prompts wakefulness without many side effects or rebound hypersomnia. Sodium oxybate is often also a first-line agent in patients with narcolepsy with cataplexy. A broad array of sympathomimetic compounds are also available to treat sleepiness, but their risk of abuse, tolerance, and side effects makes them second-line agents in treating narcolepsy or for treatment of other sleep disorders “off-label.” Caffeine is a useful alerting agent only when used on an as-needed basis because of the rapid development of tolerance when taken daily.
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Drugs That Disturb Sleep and Wakefulness Paula K. Schweitzer Abstract Disturbed sleep and daytime sedation are common side effects of many medications. These side effects are the result of actions on the neural mechanisms involved in sleep–wake regulation, in particular the neurotransmitter systems involving acetylcholine, norepinephrine, serotonin, dopamine, histamine, and gamma-aminobutyric acid. Drugs may also affect homeostatic and circadian processes involved in sleep–wake regulation. Effects on neurotransmitters and neuronal systems involved in the generation of slow-wave sleep and rapid eye movement sleep can affect sleep architecture, which may
Research on the neural mechanisms involved in sleep– wake regulation suggest that sleep–wake state is controlled by a complex interaction between wakefulness-promoting and sleep-promoting nuclei in the hypothalamus and brainstem.1-3 Wake-promoting neurons include orexinergic and histaminergic nuclei in the hypothalamus, cholinergic nuclei in the brainstem, adrenergic nuclei in the locus coeruleus, serotonergic nuclei in the raphe nuclei, and dopaminergic nuclei in the midbrain ventral tegmental area. Sleep is promoted by nuclei in the basal forebrain, ventrolateral preoptic area, and anterior hypothalamus through the inhibitory neurotransmitters gamma-aminobutyric acid (GABA) and galanin. Adenosine, which has been proposed to be involved in homeostatic regulation of sleep, may promote sleep through anticholinergic activity in the basal forebrain and brainstem. Drugs can cause sedation by multiple mechanisms, either by increasing the activity of the sleep-promoting system through GABA enhancement (e.g., benzodiazepine receptor agonists, ethanol) or by inhibiting the wake-promoting system by antagonism of central histamine type 1 (H1) receptors (e.g., first-generation antihistamines, tricyclic antidepressants), alpha-adrenergic type 1 (alpha1) receptors (e.g., clonidine, certain antidepressant and antipsychotic medications), muscarinic cholinergic receptors (e.g., some antidepressants), or serotonin 5-HT2A receptors (e.g., eplivanserin, under development for insomnia). Similarly, drugs can disrupt sleep through effects on either the sleep-promoting system (e.g., inhibition of GABA by caffeine) or the wake-promoting system (e.g., stimulation of dopamine release or blockade of dopamine reuptake by amphetamines). Drugs may also affect homeostatic and circadian processes involved in sleep–wake regulation. Effects on neurotransmitters and neuronal systems involved in the generation of slow-wave sleep (SWS) and rapid eye movement (REM) sleep can affect sleep architecture. Sedating drugs may impair waking function if the sedating action occurs during waking hours, from either prolonged duration of action or administration during waking hours. Drugs that disrupt sleep can lead to impaired waking function and daytime sleepiness; drugs that promote alertness may disrupt sleep. Thus, the desired action of a drug 542
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46
affect perception of sleep quality. In addition to the receptor binding profile, properties such as lipid solubility (which determines the degree of central nervous system penetration), halflife, presence or absence of active metabolites, and interactions with other drugs may affect sleep–wake behavior. Drugs may impair daytime function directly (e.g., by sedation) or indirectly (e.g., as a result of sleep disruption). Psychotherapeutic drugs are the most common class of drugs with sleep–wake side effects. However any drug with central nervous system activity may affect sleep–wake function; side effects depend on the affected neuronal systems, time of dosing, and duration of activity.
may become an undesirable action when its effect occurs at the “wrong” time of day or night. In addition, drugs often act at multiple neural sites involved in sleep–wake regulation. Thus, the desired action of a drug may be produced by effects at specific receptor sites, and undesired actions may occur because of concomitant effects at other receptor sites. This chapter reviews drugs that are used for common medical and psychiatric conditions and that have unintended effects on sleep or wakefulness. Drugs used as hypnotics are reviewed in Chapters 42 and 43. Stimulants, including caffeine, and drugs of abuse, including alcohol and nicotine, are discussed in Chapters 44 and 45.
PSYCHOTHERAPEUTIC DRUGS Antidepressants Table 46-1 summarizes the effects of antidepressant drugs on sleep and waking behavior. Sedating antidepressants used as hypnotics are covered more fully in Chapter 43. Antidepressant drugs can improve or disturb sleep as well as affect waking function. Evaluation of the effects of these drugs on sleep and wakefulness is complicated by the fact that many individuals with depression have disturbed sleep4 as well as daytime complaints, such as fatigue, sleepiness, somatic complaints, and decreased cognitive and psychomotor functioning.5-7 In addition, polysomnographic (PSG) evidence of disturbed nocturnal sleep does not always correlate with the subjective reports of patients and is not related to the efficacy of these drugs in the treatment of depression. The first-generation antidepressants (tricyclic antidepressants and monoamine oxidase inhibitors) have multiple mechanisms of action. Some are believed to mediate the antidepressant response (e.g., through effects on serotonin, norepinephrine, and possibly dopamine); others mediate side effects such as sedation (primarily through histamine antagonism but also through alpha-adrenergic and muscarinic cholinergic antagonism), dry mouth (through cholinergic blockade), and orthostatic hypotension (through
CHAPTER 46 • Drugs That Disturb Sleep and Wakefulness 543
Table 46-1 Antidepressants: Effects on Sleep and Waking Behavior PRIMARY NEUROTRANSMITTER/ RECEPTOR ACTIVITY
SUBJECTIVE DATA (PLACEBOCORRECTED %)
Amitriptyline Doxepin Imipramine Trimipramine Clomipramine
5-HT > NE reuptake inhibition M-Ach, alpha1, H1 antagonism
Desipramine Nortriptyline Protriptyline
NE > 5-HT reuptake inhibition M-Ach, alpha1, H1 antagonism
CLASS/DRUG
PSG DATA
PERFORMANCE/MSLT DATA
Improve sleep May be sedating during the daytime, but effects may lessen with time
↑ TST ↓W ↓↓ REM ↑ PLMs
Most data on amitriptyline and imipramine Generally ↓↓ cognitive and psychomotor performance, at least with acute use in normals, but some evidence that effects lessen with time Decrements may be more likely in elderly patients Effects on depressed patients are variable No MSLT data
May disrupt sleep
↑W ↓ TST ↓↓ REM ↑ PLMs
Tricyclic antidepressants
Monoamine oxidase inhibitors
Inhibit MAO enzymes that metabolize NE, 5-HT, DA
Phenelzine, tranylcypromine
Inhibit both MAO-A and MAO-B
Insomnia Daytime sedation
Generally ↑ W, ↓ TST, ↓↓↓ REM
Limited data No MSLT data
Moclobemide
Reversible; inhibits only MAO-A
Insomnia: ∼2%-4%
No clear effects on REM
May improve cognitive function in depressed patients No MSLT data
Selegiline transdermal
Inhibits MAO-B at low doses
Insomnia at higher doses, ∼25%
No data
No data
Selective serotonin reuptake inhibitors
5-HT reuptake inhibition
Variable May worsen sleep or cause sedation Questionable differential effects among drugs
Generally ↑ W, ↓ TST, ↓ REM May ↑ PLMs
No effect or mild ↑ performance No MSLT data
Fluoxetine
5-HT reuptake inhibition
Insomnia: 10%-17% Daytime sedation: 5%-6%, up to 21%
↓ ↑ ↑ ↓ ↓ ↑ ↑
TST W S1 REM SWS SEMs PLMs
Generally no change or mild ↑ in performance ↑SL on modified MSLT
Paroxetine
5-HT reuptake inhibition
Insomnia: 7%-20% Daytime sedation: 2%-21%
↑ ↓ ↑ ↑ ↓
W TST S1 SL REM
Mixed results: mild ↑ performance, ↓ memory; ↓ in performance noted on abrupt discontinuation No MSLT data
Sertraline
5-HT reuptake inhibition
Insomnia: 9%-21% Daytime sedation: ∼7%-13%
↑ SL ↓ TST ↓ REM
No change or mild ↑ performance
Fluvoxamine
5-HT reuptake inhibition
Ratings show no sedation Clinical trials show sedation, ∼6%40%, and insomnia, ∼4%-15%
↓ ↑ ↑ ↑ ↓
No impairment in performance No change in MSLT
Citalopram
5-HT reuptake inhibition
Daytime sedation: 5%-18% Dose-dependent insomnia: 2%-11%
No change in TST, W
No impairment in performance No MSLT data
Escitalopram
5-HT reuptake inhibition
Insomnia: 1%-16% Sedation: 0%-5% Dose dependent
No data
No impairment in performance No MSLT data
TST W S1 SL REM
Continued
544 PART I / Section 6 • Pharmacology Table 46-1 Antidepressants: Effects on Sleep and Waking Behavior—cont’d
CLASS/DRUG
PRIMARY NEUROTRANSMITTER/ RECEPTOR ACTIVITY
SUBJECTIVE DATA (PLACEBOCORRECTED %)
PSG DATA
PERFORMANCE/MSLT DATA
Serotonin and norepinephrine reuptake inhibitors
Dual 5-HT and NE reuptake inhibition
Venlafaxine
Predominantly 5-HT reuptake inhibition at low doses, NE reuptake inhibition at higher doses; also weakly inhibits DA uptake
Insomnia: 3%-19% Sedation: ∼13%-31%
↓ TST ↑W ↑ PLMs ↓↓ REM
↑ Performance in normals No MSLT data
Desvenlafaxine
5-HT and NE reuptake inhibition; (major metabolite of venlafaxine)
Insomnia: 9%-15%
No data
No data
Duloxetine
5-HT and NE reuptake inhibition
Insomnia: ∼10%-18% Sedation: ∼8%-13%
↓ REM May ↑ S3 Variable effects on sleep efficiency
No data
Milnacipran (not marketed in United States)
Equipotent reuptake inhibition of both 5-HT and NE
May ↑ TST, ↓ SL
Limited data No cognitive or performance impairment
Serotonin antagonist/ reuptake inhibitors
5-HT2A antagonist/ reuptake inhibition
Trazodone
5-HT2A antagonism 5-HT reuptake, alpha1, H1 antagonism
Improves sleep Daytime sedation: 15%-49%
↑ TST ↓ SL ↓W ? ↑ SWS Minimal ↓ REM
Limited data ↓ Performance in one study on elderly No MSLT data
Nefazodone
5-HT2A antagonism 5-HT reuptake, much weaker alpha1, H1 antagonism than trazodone
Dose-dependent daytime sedation: 6%-24%
Variable May ↑ TST, ↓ W, ↑ REM
↑ Performance in one study No impairment of driving; some impairment of cognition and memory, especially with ↑ dose or duration May be “alerting” after single dose but not repeated dosing Two MSLT studies: ↑ SL
Norepinephrine and dopamine reuptake inhibitors Bupropion
Dual NE and DA uptake inhibition
Insomnia: 13%-19% Vivid dreaming Nightmares
Minimal data: may ↑ REM, ↑ sleep efficiency, ↓ SWS, ↓ PLMs
Generally no performance impairment No MSLT data
Norepinephrine and specific serotonergic antidepressant Mirtazapine
Weak NE reuptake inhibition; alpha1, alpha2, H1, 5-HT2, 5-HT3 antagonism
Improves sleep Daytime sedation: 9%-54%
↑ TST ↓ SL ↓ S1 ? ↑ SWS
↓ Performance acutely No MSLT data
Selective norepinephrine reuptake inhibitors
Selective NE reuptake inhibition
Reboxetine (not available in United States)
Selective NE reuptake inhibition
Insomnia: 11%
↓ REM Acute ↑ W
No impairment, possible improvement in psychomotor and cognitive function
Atomoxetine (marketed for treatment of ADHD)
Selective NE reuptake inhibition
Sedation in ADHD children: 7% Insomnia in ADHD adults: 8%
↑ REM latency ? ↓ W in ADHD children
CHAPTER 46 • Drugs That Disturb Sleep and Wakefulness 545
Table 46-1 Antidepressants: Effects on Sleep and Waking Behavior—cont’d PRIMARY NEUROTRANSMITTER/ RECEPTOR ACTIVITY
SUBJECTIVE DATA (PLACEBOCORRECTED %)
PSG DATA
PERFORMANCE/MSLT DATA
Maprotiline
NE uptake inhibition H1 blockade
Sedation
Minimal data
Minimal data No impairment?
Amoxapine
5-HT2 blockade NE uptake inhibition H1, alpha1 blockade
Sedation
Minimal data
Insufficient data
Mianserin (not available in United States)
5-HT2, alpha1, alpha2, H1 blockade
Sedation
↑ TST in depressed patients
Impairs performance
Agomelatine (not available in United States)
MT1 and MT2 receptor agonist and 5-HT2C antagonist
Limited data
No effect in healthy elderly
No data
Sedation
↑ SWS ↓ REM
No MSLT studies Prolongs reaction times, decreases vigilance, other cognitive impairment
CLASS/DRUG Miscellaneous
Lithium
DA, dopamine; H, histamine; 5-HT, 5-hydroxytryptamine (serotonin); M1, muscarinic cholinergic; M-Ach, muscarinic anticholinergic; MAO, monoamine oxidase; MSLT, multiple sleep latency test; MT, melatonin; NE, norepinephrine; PLMs, periodic limb movements; PSG, polysomnographic; REM, rapid eye movement; S1, stage 1; S3, stage 3; SEMs, slow eye movements; SL, sleep latency; SWS, slow-wave sleep; TST, total sleep time; W, wake.
alpha-adrenergic antagonism). Currently available antidepressants include a number of drugs that are more selective for specific receptors (e.g., selective serotonin reuptake inhibitors), which may result in fewer side effects. However, selectivity does not mean absence of activity at other receptors. Tricyclic Antidepressants Tricyclic antidepressants (TCAs) differ from one another in their relative effects in blocking serotonin versus norepinephrine reuptake as well as in the degree of antagonism of muscarinic cholinergic receptors and H1 histamine receptors.8 The more sedating TCAs tend to be more anticholinergic (amitriptyline) and more antihistaminergic (doxepin, trimipramine) but also exhibit proportionately greater inhibition of serotonin reuptake than of norepinephrine reuptake. In general, these drugs decrease sleep latency, increase total sleep time (TST), and decrease REM sleep while increasing phasic eye movements during REM.9,10 TCAs that are more adrenergic (e.g., desipramine, nortriptyline) may decrease TST and increase awakenings.11 TCAs may increase periodic limb movements and symptoms of restless legs syndrome.10 Cognitive performance and psychomotor performance are impaired with acute use in normals, but there is some evidence that these effects lessen with time.12 Low-dose doxepin has been approved as a hypnotic.12a Monoamine Oxidase Inhibitors Monoamine oxidase inhibitors (MAOIs) inhibit the action of MAO enzymes, resulting in increased concentrations of serotonin, norepinephrine, and dopamine. The classic MAOIs (e.g., isocarboxazid, phenelzine, tranylcypromine) irreversibly inhibit both MAO-A and MAO-B enzymes. Insomnia and daytime sedation are commonly reported side effects (up to 62% and 42% of patients, respectively),13
but there are no placebo-controlled studies. The most impressive PSG finding is a marked decrease in REM sleep, including almost complete abolishment of REM sleep.14 TST is also decreased. Although multiple sleep latency test (MSLT) studies are lacking, actigraphic monitoring in a small group of patients confirmed periods of decreased daytime activity coincident with reported episodes of napping, possibly associated with poor nighttime sleep. Cognitive performance and psychomotor performance do not appear to be influenced by the classic MAOIs, but data are limited.12,15 The newer MAOIs reversibly or selectively inhibit the MAO-A enzyme, resulting in fewer severe adverse effects. Drugs of this type include moclobemide (not available in the United States) and selegiline. Subjective and PSG data suggest that insomnia is more likely with higher doses.16,17 Moclobemide may enhance cognitive function in depressed outpatients.15 Selective Serotonin Reuptake Inhibitors Selective serotonin reuptake inhibitors (SSRIs) selectively and potently inhibit the reuptake of serotonin, but they also exhibit norepinephrine and dopamine reuptake inhibition, muscarinic cholinergic antagonism, inhibition of various cytochrome P-450 enzymes, and other actions. In addition, numerous serotonin receptor subtypes mediate a variety of actions. Individual SSRIs also differ in their effects on serotonin receptor subtypes as well as in their actions at other receptors, which may explain why SSRIs may be associated with both insomnia9,18 and daytime sedation.5,9,19 Polysomnographic studies of SSRIs generally indicate disruption of sleep continuity and suppression of REM sleep.11,20 Fluoxetine, which has been studied most extensively, decreases TST and increases wake time and stage 1 sleep both in normal subjects during single-night studies
546 PART I / Section 6 • Pharmacology
with doses of 20 to 60 mg21 and in depressed patients with doses of 20 to 80 mg for up to 1 year.22 Fluoxetine has been associated with prominent slow eye movements in non-REM sleep.23 SSRIs are also associated with increased frequency of periodic limb movements during sleep, restless legs syndrome,24 and REM sleep without atonia.25 Paroxetine (15 to 30 mg) decreases TST and increases awakenings in normal subjects with 1- to 2-day dosing.26 There also is evidence of increased awakenings and sleep fragmentation after 5 weeks of paroxetine treatment in depressed inpatients.27 Fluvoxamine has had similar effects on the sleep architecture of depressed patients.28 Citalopram produced the typical decrease in REM sleep but no changes in sleep latency or TST during 5 weeks of treatment in one study of depressed patients.29 SSRIs usually do not negatively affect daytime performance or cognitive functioning and may actually improve functioning in some patients, but data are limited. One placebo-controlled study reported memory impairment with paroxetine but improvement in a verbal task with sertraline.30 A single nighttime dose of fluvoxamine in healthy subjects showed increased daytime sleep latencies compared with dothiepin but no change compared with placebo in a modified MSLT study.31 Serotonin and Norepinephrine Reuptake Inhibitors Serotonin and norepinephrine reuptake inhibitors (SNRIs), which include venlafaxine, desvenlafaxine, duloxetine, and milnacipran (not available in the United States), inhibit reuptake of both norepinephrine and serotonin. In addition to treatment of both anxiety and depression, duloxetine has been approved for treatment of neuropathic pain and has been evaluated for treatment of fibromyalgia.32 Both insomnia and somnolence have been reported by patients taking these drugs.33-35 In normal subjects, 75 to 150 mg of venlafaxine produced increased wake and stage 1 sleep; in addition, in six of the eight subjects, frequent periodic limb movements (more than 25 per hour) were noted.36 In depressed inpatients treated for 1 month, venlafaxine (maximum dose, 225 mg/day) increased PSGrecorded wake after sleep onset.37 In one study of normal subjects,38 sleep efficiency was decreased with duloxetine 60 mg twice daily but increased by duloxetine 80 mg/day. In a study of depressed patients,39 duloxetine 60 to 90 mg/ day had no effect on sleep continuity by increased stage 3 sleep. REM sleep was suppressed in both studies. There are no studies that objectively evaluate daytime sleepiness and alertness. Single doses of venlafaxine improved performance and cognitive function in healthy subjects, particularly 6 to 8 hours after dosing.40 Serotonin Antagonist and Reuptake Inhibitors Trazodone and nefazodone are more fully covered in Chapter 43. Whereas both drugs block serotonin reuptake and inhibit 5-HT2 receptors, trazodone also shows histamine H1 antagonism as well as adrenergic alpha1 and alpha2 antagonism.41 Drowsiness is the most commonly reported side effect of trazodone.33 Because of its sedation, trazodone is currently more likely to be used as a hypnotic than as an antidepressant. PSG studies indicate that trazodone decreases sleep latency, may improve sleep continuity, increases SWS, but does not affect REM sleep. Nefazo-
done may increase TST but has no consistent effect on sleep latency, SWS, or REM sleep.9,42 One study in normal individuals demonstrated an increase in MSLT mean latency (i.e., decreased sleepiness) after 16 days of nefazodone treatment.43 Trazodone impairs performance in healthy individuals,44 but data on depressed individuals are inconclusive. Cognitive and performance studies of nefazodone in general show no impairment or even slight improvement in psychomotor performance and memory in middle-aged and elderly healthy subjects.45,46 Norepinephrine and Dopamine Reuptake Inhibitors Bupropion, which inhibits the uptake of dopamine and norepinephrine, is associated with insomnia in 5% to 19% of patients in clinical trials.47 In a PSG study of seven depressed patients, after 4 weeks of treatment, bupropion did not affect sleep latency or TST but did decrease REM latency and increase REM sleep percentage.46 In a study of depressed patients with periodic limb movements, sustained-release bupropion decreased periodic limb movements, possibly because of its effects on dopamine reuptake.48 Bupropion is not usually associated with cognitive or psychomotor performance impairment.44,49 Norepinephrine and Specific Serotonin Antagonists Mirtazapine, sometimes used as a hypnotic, is described more fully in Chapter 43. Mirtazapine disinhibits both serotonin and norepinephrine through blockade of alpha2 receptors.50 It is a potent antagonist of histamine H1 and 5-HT2 receptors, which probably accounts for its highly sedating activity. PSG studies indicate improvements in sleep latency and sleep continuity.51 One study suggests that restless legs syndrome symptoms develop or worsen in up to 28% of patients.52 Mirtazapine impairs driving performance and attention acutely in normals.53 Selective Norepinephrine Reuptake Inhibitors Reboxetine, not currently available in the United States, is a selective norepinephrine reuptake inhibitor. Clinical trials indicate an incidence of insomnia of approximately 10%.54 PSG studies in depressed patients showed acute increases in wake and persistent suppression of REM sleep.55 In healthy normals, reboxetine was subjectively sedating but did not impair cognitive function.56 Atomoxetine, also a selective norepinephrine reuptake inhibitor but not developed as an antidepressant, is approved for treatment of attention-deficit/hyperactivity disorder (ADHD). Clinical trials indicate somnolence in ADHD children (7% incidence) but insomnia in ADHD adults (8% incidence). A PSG study in ADHD children reported that atomoxetine increased REM latency but did not adversely affect sleep latency (unlike methylphenidate).57 Miscellaneous Antidepressants Amoxapine, a dibenzoxazepine tricyclic, and maprotiline and mianserin (not available in the United States), both tetracyclics, have sedative profiles similar to those of the TCAs, probably because of their high affinity for H1 receptors.58 Amoxapine and maprotiline are not commonly used because of other serious side effects, namely, seizures in the case of maprotiline and dopamine-blocking side effects
with amoxapine. There are no studies objectively measuring sleepiness. Minimal data suggest little cognitive impairment with maprotiline.15 In healthy individuals, mianserin impaired driving and tracking performance as well as reaction time and other psychomotor measures.12,44 Agomelatine, recently approved for treatment of depression in Europe, is a potent agonist at both melatonin MT1 and MT2 receptors as well as an antagonist at serotonergic 5-HT2C receptors. Limited non–placebo-controlled PSG data in depressed patients showed increases in sleep efficiency and SWS without effects on REM sleep compared with baseline.59 Lithium Lithium, which is used primarily in the treatment of manic-depressive illness, is subjectively associated with improved nocturnal sleep and increased daytime sleepiness, at least initially.60 Sleep disturbance is a prominent feature of mania and similar polysomnographically to that observed in major depression.61 In healthy volunteers, lithium increases SWS and decreases REM sleep62; it produces cognitive and psychomotor deficits, including prolonged reaction times, decreased vigilance, and impairment of semantic reasoning.61 Similar deficits have been shown in psychiatric patients taking lithium for periods ranging from 2 weeks to longer than 3 months,63 although it is difficult to determine whether the deficits seen in the patient population are caused by the medication or the psychiatric illness. Degree of cognitive deficit increases with age, severity of disease, and lithium concentration. Antipsychotic Drugs Table 46-2 summarizes the effects of antipsychotic drugs on sleep and waking behavior. Sedating drugs used as hypnotics (olanzapine, quetiapine) are covered more fully in Chapter 43. Antipsychotic drugs have complex pharmacologic profiles. Their antipsychotic effects are thought to be mediated primarily by antagonism of dopamine D2 receptors in the mesolimbic dopamine pathway.64 These drugs also block dopamine receptors in other neural pathways, leading to unwanted effects such as anhedonia, extrapyramidal symptoms, and hyperprolactinemia, which are commonly seen with the older or “typical” antipsychotics (e.g., chlorpromazine, haloperidol, thioridazine). These effects are decreased with the newer or “atypical” antipsychotic drugs, which in addition to blockade of dopamine receptors also antagonize serotonin receptors (especially 5-HT2A), have the ability to dissociate from D2 receptors, may have partial agonist activity at D2 receptors, or may act as partial agonists at serotonin 5-HT1A receptors.50 These drugs differ in their specificity for dopamine D2 versus D1 receptors and also differ in the degree to which they block muscarinic cholinergic, histamine, and alphaadrenergic receptors (see Table 46-2).65 Sedation is more likely in drugs with relatively more potent antagonism of histamine, alpha-adrenergic, or 5-HT2 receptors compared with antagonism of dopamine receptors.66 Patients with schizophrenia commonly have insomnia and circadian rhythm disturbances as well as cognitive impairment, complicating evaluation of the effects of antipsychotic medications. Sedation is a common side effect,
CHAPTER 46 • Drugs That Disturb Sleep and Wakefulness 547
but insomnia has also been reported. Among the older drugs, chlorpromazine and thioridazine appear to be more sedating than haloperidol. Clozapine is even more sedating than these drugs (with transient sedation reported by 54% of patients, persistent sedation by 46%, and sedation requiring drug discontinuation by 24%)66; aripiprazole is the least sedating. Whereas ziprasidone and quetiapine would be expected to be sedating given their pharmacologic profiles, they appear less sedating than other drugs, possibly because of their short half-lives. Insomnia occurs at variable rates with these drugs. Although the mechanism is not clear, options include 5-HT1A receptor agonism and restless legs symptoms secondary to dopaminergic antagonism.64 Restless legs syndrome symptoms have been reported as case reports for olanzapine, risperidone, quetiapine, and clozapine.67 There are few double-blind placebo-controlled PSG studies of antipsychotics in healthy normals and none in schizophrenia patients. Small-sample controlled studies indicate that olanzapine, quetiapine, and ziprasidone decrease sleep latency and improve sleep continuity.64,67,68 Uncontrolled studies suggest that clozapine, haloperidol, and risperidone also improve sleep.69 REM suppression is variable, whereas increased SWS is typical, except for quetiapine.64,67 There are no MSLT or other studies that objectively evaluate daytime sleepiness. Although antipsychotics cause cognitive impairment in healthy subjects,70 these drugs may have no negative effects in patient populations.71 Some of the newer drugs, in particular, appear to be more likely to improve cognitive function in patients despite significant sedation.65 Anxiolytic Drugs The primary drugs used in the treatment of anxiety disorders include antidepressants (particularly SSRIs and SNRIs), benzodiazepines, and buspirone, a 5-HT1A receptor partial agonist. Antiepileptics and atypical antipsychotics are also sometimes used. Prazosin, an antihypertensive with alpha1-adrenergic antagonism, has been used to treat nightmares in posttraumatic stress disorder.72 Antidepressants, antiepileptics, and antipsychotics are covered elsewhere in this chapter. Benzodiazepines approved for treatment of anxiety disorders (e.g., alprazolam, clonazepam, diazepam, lorazepam) have pharmacologic profiles similar to those of benzodiazepines used to treat insomnia and thus similar side effects. Given that these drugs enhance GABA at the GABAA receptor, their most common side effect is sedation.60 In nonanxious subjects, daytime administration of alprazolam and diazepam produced decreased sleep latencies as measured by MSLT on both day 1 and day 7 of treatment, with alprazolam producing greater sleepiness than diazepam on the first day of treatment.73 Performance impairment, including impairment of actual driving performance,74 is common with benzodiazepines in studies of normal subjects and patient groups for treatment periods of up to 3 weeks, particularly at higher doses. Well-controlled studies are needed to determine whether longer term use of benzodiazepine anxiolytics results in tolerance to these performance-impairing effects and whether there are differential effects between younger and older individuals.
+++ + ++ + ++
++
++ +++ + ++
+
Clozapine
Olanzapine
Quetiapine
Risperidone
Ziprasidone
+
+
Thioridazine
+
+++
+++
Haloperidol
Aripiprazole
++
D2
+
Chlorpromazine
D1
+++
+++
+
+++
+++
++
++
+
+++
5-HT2
0
0
0
+++
+++
0
++
0
++
M-ACH
++
+++
+++
++
+++
++
+++
++
+++
ALPHA1
Relative Receptor Pharmacology*
++
+
++
+++
+++
++
+
0
+
H1
+++
+
+
0
+
+++
0
0
0
5-HT1A
Insomnia: 9% Sedation: 16%
Insomnia: 17% Sedation: 30%
Insomnia: 9% Sedation: 16%
Insomnia: 18% Sedation: 29%
Insomnia: 4% Sedation: 52%
Insomnia: 24% Sedation: 12%
Insomnia: 23% Sedation: >35%
Insomnia: 25% Sedation: 23%
Sedation: 33%
SUBJECTIVE DATA
SL TST REM SWS
↓ ↑ ↓ ↑
↓ ↑ ↓ ↑
SL TST REM SWS
SL TST REM SWS
↓ SL ↑ TST ↓ REM
↓ SL ↑ TST ↑ SWS
↓ SL ↑ TST ↑ SWS
Insufficient data
Insufficient data
↓ ↑ ↓ ↑
Probable ↑ TST
PSG DATA
*Modified from Krystal A, Goforth H, Roth T. Effects of antipsychotic medications on sleep in schizophrenia. Int Clin Psychopharmacol 2008;23:150-160. D, dopamine; H, histamine; 5-HT, serotonin; M-Ach, muscarinic anticholinergic; PSG, polysomnographic; REM, rapid eye movement; SL, sleep latency; SWS, slow-wave sleep; TST, total sleep time. + Indicates binding profile relative to other drugs; 0 indicates negligible binding.
Atypical
Typical
DRUG
Table 46-2 Antipsychotic Drugs
548 PART I / Section 6 • Pharmacology
Buspirone does not have the hypnotic, anticonvulsant, and muscle relaxant properties of the benzodiazepines. The anxiolytic efficacy of buspirone is similar to that of the benzodiazepines, but its onset of action is much slower, requiring up to 3 to 4 weeks.75 Buspirone appears to act primarily as a 5-HT1A partial agonist but also has effects on D2 receptors.76 It has no affinity for the benzodiazepine receptors and does not affect GABA binding. In clinical studies of anxious patients, buspirone was comparable to placebo in the frequency of subjective reports of sedation.77 In a study of 12 patients with chronic insomnia, alertness as measured by MSLT was not impaired by buspirone 20 mg/day in divided doses during a 3-day period.78 Compared with benzodiazepine anxiolytics, buspirone appears to have few negative effects on psychomotor, cognitive, or driving performance in healthy volunteers receiving shortterm treatment or in patients treated for up to 4 weeks.78,79
ANTIEPILEPTIC DRUGS There are many antiepileptic drugs available for use, generally classified somewhat arbitrarily as “older” or “newer.”80 The older or “conventional “ drugs include benzodiazepines, carbamazepine, ethosuximide, phenobarbital, phenytoin, primidone, and valproate. Findings regarding the effects of these medications on sleep and waking are summarized in Table 46-3. Mechanisms of action include sodium channel blockade, effects on GABA (agonism, reuptake inhibition, transaminase inhibition), and glutamate blockade as well as unknown mechanisms (e.g., levetiracetam).81,82 Some of the newer drugs have a variety of mechanisms of action, which has led to their evaluation and use in other neurologic and psychiatric conditions, such as neuropathic pain, fibromyalgia, migraine, essential tremor, anxiety, schizophrenia, and bipolar disorder.83 Although developed as antiepileptic drugs, gabapentin and pregabalin are used more frequently in the treatment of neuropathic pain and fibromyalgia and, along with tiagabine, have been evaluated for insomnia. Subjectively, sedation is one of the most common adverse effects of the older antiepileptic drugs, particularly phenobarbital.82,84 Among the newer antiepileptic drugs, the incidence of reported sedation in placebo-controlled clinical trials is 5% to 15% for gabapentin, lamotrigine, levetiracetam, vigabatrin, and zonisamide and 15% to 27% for topiramate, and it is generally more prevalent during the initial treatment.85,86 The incidence of sedation with tiagabine was no different from that for placebo in placebo-controlled studies, but it was 25% in open-label, long-term studies.87 Both sedation and insomnia have been reported with felbamate. Approximately 15% to 25% of patients with neuropathic pain or fibromyalgia treated with gabapentin or pregabalin reported somnolence.88,89 Polysomnographic studies of established antiepileptic drugs in general show that these drugs produce shorter sleep latency and increase TST.82 The newer drugs show variable effects on sleep latency and sleep continuity (see Table 46-3). However, levetiracetam, gabapentin, pregabalin, and tiagabine increase SWS, whereas lamotrigine decreases SWS.90-93 Placebo-controlled studies in healthy normals indicate no decrement in MSLT latencies with levetiracetam93 and
CHAPTER 46 • Drugs That Disturb Sleep and Wakefulness 549
no increase in drowsiness on a 6-minute “awake maintenance test” with either gabapentin or topiramate, although gabapentin produced electroencephalographic slowing.94 In studies without placebo control, patients treated with phenobarbital95 or carbamazepine96 had lower mean MSLT latencies, and patients receiving carbamazepine, phenytoin, phenobarbital, or valproate demonstrated increased drowsiness on the awake maintenance test compared with healthy control subjects and untreated patients with epilepsy.85 Drug-naive patients with partial epilepsy receiving topiramate showed no change in MSLT latencies compared with healthy control subjects either at baseline or 2 months later.97 Cognitive impairment appears to be more common with phenobarbital than with other drugs, more common when multiple medications are used, and more common in children than in adults. Phenobarbital and phenytoin have most frequently been associated with significantly impaired neuropsychological function, particularly in the areas of short-term memory, concentration, and attention.95,98,99 Carbamazepine and valproate appear to be mildly impairing, whereas the newer antiepileptic drugs appear to have few negative cognitive effects, with the exception of topiramate.94,98,100,101 However, well-controlled studies are rare, and methodological problems include subject composition, choice of neuropsychological test, lack of placebo control, and sample size.100 As a number of these drugs are being increasingly used in nonepilepsy disorders,83 the need for carefully controlled studies evaluating the effects of these drugs on daytime function is increased.
ANTIPARKINSONIAN DRUGS See Chapter 87 for additional information on Parkinson’s disease and its treatment. Dopaminergic drugs used in the treatment of restless legs syndrome are further discussed in Chapter 90. Sleep complaints are extremely common in Parkinson’s disease and include insomnia, parasomnias, and daytime sleepiness.102 These complaints, which tend to worsen with disease progression, may be the result of abnormalities in sleep–wake regulation caused by the disease, accompanying symptoms such as nocturnal motor disturbance, other sleep disorders such as sleep apnea or periodic limb movements, concurrent medical or psychiatric illness, or the medications used for treatment. PSG studies of Parkinson’s patients show increased sleep fragmentation103 and decreased REM sleep and SWS102 along with increased incidence of REM behavior disorder.104 Periodic limb movements and sleep apnea are also common. MSLT studies indicate a high prevalence of excessive daytime sleepiness.105 Dopamine replacement is the primary treatment of Parkinson’s disease. Because sleep is significantly disrupted in Parkinson’s disease, it is difficult to determine whether changes in sleep and waking behavior after drug administration are due to direct effects of drug or effects of drug on disease. The principal drugs used to treat Parkinson’s disease are levodopa/carbidopa and dopamine agonists, which include ergot agonists (apomorphine, bromocriptine, cabergoline, lisuride, piribedil, and pergolide) and nonergot agonists (pramipexole, ropinirole, and rotigotine). Amantadine is
550 PART I / Section 6 • Pharmacology Table 46-3 Antiepileptic Drugs: Effects on Sleep and Waking Behavior DRUG OR CLASS
U.S. TRADE NAME
PRIMARY MECHANISM OF ACTION
SUBJECTIVE DATA*
PSG DATA
MSLT DATA
COGNITIVE/ PERFORMANCE DATA
Conventional (“older”) antiepileptic drugs Benzodiazepines
e.g., Klonopin, Valium
GABA agonism
Sedation
↓SL ↓SWS ↓REM
↓SL
Mild impairment
Carbamazepine
Tegretol
Sodium channel blockade
Sedation
? ↓SL ? ↑TST ↓REM ? ↑SWS
↓SL
Mild impairment
Ethosuximide
Zarontin
Calcium current inhibition
Sedation
↑S1
No data
No data
Phenobarbital
Phenobarbital
GABA agonism
Sedation
↓SL ↓#W ↑TST ↓REM
↓SL
Significant impairment
Phenytoin
Dilantin
Sodium channel blockade
Sedation
↓SL ↑S1 ↓SWS
No data
Moderate impairment
Primidone
Mysoline
GABA agonism
Sedation
↓SL
No data
No data
Valproic acid
Depakene
Multiple: GABA enhancement, sodium channel blockade, calcium channel inhibition
Sedation
↑TST ↓#W ↑S1
No change
Mild impairment
Newer antiepileptic drugs Felbamate
Felbatol
Glutamate blockade
Insomnia: 10% Sedation: 12%
No data
No data
No data
Fosphenytoin
Cerebyx
Sodium channel blockade
Sedation
No data
No data
No data
Gabapentin
Neurontin
Unclear, multiple Structural analogue of GABA; binds selectively to alpha2-delta subunit of voltage-gated calcium channels
Sedation: 11%-18%
↑SWS ↑REM ↑TST ↓S1 ↓#W
No data
Unclear: no to moderate impairment; better than carbamazepine
Lamotrigine
Lamictal
Sodium channel blockade
Sedation: 4%-13% Insomnia: 4%
? ↓SWS
No data
? Improved performance in epilepsy patients
Levetiracetam
Keppra
Unknown; acutely: calcium channel inhibition Chronically: synaptic vesicle SV2A binding
Sedation: 5%-7%
↑TST ↑SWS ↓REM
No difference from placebo in healthy normals
Unclear: improved performance to mild impairment
Oxcarbazepine
Trileptal
Sodium channel blockade
Sedation: 8%-24%
No data
No data
? No impairment
Pregabalin
Lyrica
Unclear, multiple Structural analogue of GABA; binds selectively to alpha2-delta subunit of voltage-gated calcium channels
Sedation: 1%-13%; 15%-21% in fibromyalgia
↓SL ↓#W ↑SWS ↓REM
No data
CHAPTER 46 • Drugs That Disturb Sleep and Wakefulness 551
Table 46-3 Antiepileptic Drugs: Effects on Sleep and Waking Behavior—cont’d PRIMARY MECHANISM OF ACTION
DRUG OR CLASS
U.S. TRADE NAME
Tiagabine
Gabitril
GABA reuptake inhibition
Topiramate
Topamax
Vigabatrin
Zonisamide
SUBJECTIVE DATA*
COGNITIVE/ PERFORMANCE DATA
PSG DATA
MSLT DATA
Sedation: 0%-5%; up to 25% in open-label studies
↑TST ↑SWS
No data
Unclear: no to mild impairment
Glutamate blockade
Sedation: 15%-27%
No data
No impairment on awake maintenance test
Mixed results: mild to moderate impairment
Sabril
GABA transaminase inhibition
Sedation: 7%-12%
No data
No change as add-on to carbamazepine
? No impairment
Zonegran
Sodium channel blockade
Sedation: 9%-13%
No data
No data
Unclear
*Placebo-adjusted incidence of sedation listed for the new antiepileptic drugs; placebo-adjusted rates are not available for the older drugs. MSLT, multiple sleep latency test; PSG, polysomnographic; REM, rapid eye movement; S1, stage 1; SL, sleep latency; SWS, slow-wave sleep; TST, total sleep time; #W, number of awakenings.
less commonly used. Adjunctive treatments include catechol-O-methyltransferase inhibitors (e.g., entacapone, tolcapone), which prolong the duration of the effect of levodopa106; anticholinergics (e.g., hyoscyamine, benztropine); and selegiline,107 an MAO-B inhibitor that preferentially oxidizes dopamine and phenylethylamine and is metabolized to methamphetamine and amphetamine. Dopamine agonists differ somewhat in their selectivity for dopamine receptor subtypes. There are five subtypes of dopamine receptors divided into two major classes, D1 (D1 and D5 subtypes) and D2 (D2, D3, D4 subtypes).108 The nonergot drugs have higher selectivity than the ergot agonists.109 Pergolide and apomorphine have both D1 and D2 agonist activity; pramipexole, ropinirole, and rotigotine are D2 selective. All three have higher specificity for the D3 receptor subtype than for the D2 subtype; however, pramipexole exhibits the highest specificity. Ergot-derived drugs also demonstrate 5-HT2A and 5-HT2B agonism. Long-term use of the ergot agonists cabergoline and pergolide has been associated with valvular heart disease, possibly associated with 5-HT2B (and perhaps 5-HT2A) agonism.109 There are some data to suggest that low doses of dopaminergic medications tend to improve sleep, whereas higher doses are likely to disrupt sleep.102,109 PSG studies have shown mixed results, including both increased and decreased REM sleep and decreased SWS. Nightmares and visual hallucinations may be increased. Improvement in parkinsonian symptoms may independently improve sleep. Although dopaminergic agonists have been associated with increases in daytime sleepiness, including sudden “sleep attacks,”110 there is controversy as to whether the sleepiness is related to the pathologic process of Parkinson’s disease or the specific drugs. Initial reports suggested that unintentional sleep episodes were related specifically to the nonergot dopamine agonists. However, subsequent data have indicated no difference in sleepiness or unintentional sleep episodes between ergot and nonergot ago-
nists.111,112 MSLT studies indicate no differences in sleepiness among various dopamine agonists including pramipexole, ropinirole, bromocriptine, or pergolide, taken alone or in combination with levodopa113,114 or compared with levodopa alone.115 Several studies suggest that higher doses of dopaminergic drugs are more likely to be associated with increased sleepiness.116,117 However, higher doses are also associated with more advanced disease. Cognitive and motor deficits are common in Parkinson’s disease. Anticholinergic drugs have been demonstrated to produce worsening of cognitive function, primarily in the areas of memory function.118 In healthy subjects, ropinirole resulted in improved fine motor activity and reaction time,119 whereas pramipexole increased subjective sedation and impaired cognitive performance,120 and pergolide impaired delayed response tasks but not memory or executive function.121 In patients with mild Parkinson’s disease, pramipexole worsened verbal fluency, whereas pergolide and l-dopa did not.122 Evaluation of the effects of these drugs on cognitive function is complicated by the frequent presence of behavioral symptoms that may affect performance. Dopaminergic medications are also used in the treatment of restless legs syndrome. Somnolence and fatigue have been reported with pramipexole and ropinirole.123 PSG data on pramipexole, ropinirole, and cabergoline generally show improvements in sleep in this population.124-126 However, these improvements are likely to be the result of treatment of symptoms rather than sedating effect of drug. In a single MSLT study in healthy normals, ropinirole decreased mean MSLT latency.127
CARDIOVASCULAR DRUGS Beta Antagonists Information on pharmacologic characteristics of beta antagonists relevant to central nervous system (CNS) sleep–wake function is given in Table 46-4. CNS side
552 PART I / Section 6 • Pharmacology Table 46-4 Beta Antagonists: Selected Pharmacologic Characteristics DRUG
LIPID SOLUBILITY*
BETA SELECTIVITY†
RELATIVE AFFINITY FOR 5-HT RECEPTORS
Acebutolol
Moderate
Beta1
Low
Atenolol
Low
Beta1
Low
Carvedilol
Low
Nonselective
High
Alpha1-adrenergic antagonism
Labetalol
Low
Beta1
Low
Alpha1-adrenergic antagonism
Metoprolol
Moderate
Beta1
Low
Nadolol
Low
Nonselective
High
Nebivolol
High
Beta1
Low
Nitric oxide–mediated vasodilating activity
Pindolol
Moderate
Nonselective
High
Intrinsic sympathomimetic activity‡
Propranolol
High
Nonselective
High
Timolol
High
Nonselective
High
Sotalol
Low
Nonselective
High
COMMENTS Intrinsic sympathomimetic activity‡
*While lipophilic compounds appear to be more disruptive of sleep than hydrophilic compounds, high beta2 and/or 5-HT receptor occupancy is probably more important in causing sleep disruption. † Nonselective beta antagonists appear to have more CNS-related side effects. They also have higher affinity for 5-HT receptors. ‡ Beta antagonists with intrinsic sympathomimetic activity act as partial agonists at beta2 receptors. 5-HT, serotonin.
effects reported with beta-blockers include tiredness, fatigue, insomnia, nightmares and vivid dreams, depression, mental confusion, and psychomotor impairment.128 While sleep disturbance appears to be more common with the more lipophilic drugs, high beta2 and/or 5-HT receptor occupancy may be more important factors in causing sleep disruption.129 Plasma concentration (degree of beta antagonism) may also be a factor.130 Drugs that are more selective for beta1 receptors have lower affinity for 5-HT receptors. On the other hand, beta antagonists decrease melatonin release through inhibition of beta1 receptors, which could affect sleep.131 Among these drugs, propranolol, which has high lipid solubility and high 5-HT affinity, is most commonly associated with disturbed sleep. Betablockers with vasodilating properties through blockade of alpha1 receptors (e.g., carvedilol, labetalol) have been associated with fatigue and somnolence.132 Nebivolol, a highly selective and lipophilic compound with endothelial nitric oxide–mediated vasodilation, appears to be less disruptive of sleep.133 One placebo-controlled study134 in normals demonstrated increased wake with propranolol, metoprolol, and pindolol but not with atenolol. However, REM sleep was decreased by all four drugs. Reviews on the effects of beta-blockers on cognitive and psychomotor performance indicate that these drugs produce few consistent neuropsychological deficits.128,129 Alpha2 Agonists Sedation is the most common side effect of both clonidine and methyldopa, occurring in 30% to 75% of patients, but the severity apparently diminishes with time.135 There are also reports of insomnia and nightmares with these drugs. In a double-blinded, placebo-controlled crossover study, hypertensive men aged 31 to 59 years who were given 0.1 to 0.3 mg of clonidine twice daily showed significantly
decreased TST compared with placebo after 3 months of use.136 Healthy subjects, however, given clonidine acutely showed increases in TST.137 No MSLT studies exist to quantify daytime sedation objectively. However, one study of a single morning dose of clonidine in young healthy subjects demonstrated microsleeps in six of eight subjects despite efforts of study personnel to keep them awake.138 Few well-controlled studies exist that evaluate the effects of these drugs on performance. Verbal memory impairment and poorer workplace performance139 have been reported in patients receiving methyldopa. Hypolipidemic Drugs Atorvastatin, lovastatin, and simvastatin have been associated with subjective reports of insomnia. However, placebo-controlled clinical trials and PSG studies of lovastatin, simvastatin, and pravastatin have in general failed to show increased sleep disturbance even with the more lipophilic compounds.140,141 However, Roth and colleagues142 reported performance decrements with lovastatin even though nocturnal sleep and daytime sleep tendency (measured by MSLT) were not affected. One PSG study in normals showed increased wake after sleep onset with lovastatin, whereas pravastatin did not differ from placebo.143 There have been case reports of short-term memory loss associated with statin use, but randomized studies using neuropsychological testing and a meta-analysis of observational studies suggest that these drugs may actually lower the odds for development of cognitive impairment.144,145 Other Cardiovascular Drugs The alpha1 antagonists (e.g., prazosin, terazosin) are sometimes associated with transient sedation. Prazosin has been used in the treatment of nightmares and sleep disturbance in combat-related post-traumatic stress disorder.72 In
placebo-controlled studies, prazosin increased TST, REM sleep, and subjective sleep quality and reduced nightmares.146,147 There are no reports of sleep disturbance or wake dysfunction with the calcium channel blockers (e.g., verapamil, nifedipine); however, these drugs decrease the effectiveness of hypnotics and potentiate the effects of stimulants, at least in studies in animals.148 Angiotensinconverting enzyme inhibitors (e.g., captopril, cilazapril) reportedly have a low incidence of central side effects. However, a dry, irritating cough is a common side effect,149 which may contribute to sleep apnea possibly related to rhinopharyngeal inflammation.150
HISTAMINE ANTAGONISTS Histamine Type 1 Receptor Antagonists The first-generation H1 antihistamines (e.g., diphenhydramine, hydroxyzine) are lipophilic and easily cross the blood–brain barrier, demonstrating H1 receptor occupancy of up to 60% or more.151,152 In addition to H1 antagonism, these drugs demonstrate muscarinic anticholinergic antagonism and may also have alpha-adrenergic and serotonergic effects. They cause decrements in alertness and performance.153,154 Because of their sedating effects, these drugs (in particular, diphenhydramine) are widely used as over-the-counter hypnotics. Subjectively, these drugs decrease sleep latency and increase sleep continuity, but PSG data are mixed. Diphenhydramine increases physiologic sleep tendency as measured by MSLT and decreases performance acutely, but tolerance may develop within 3 or 4 days,155,156 although driving may continue to be impaired.157 The second-generation H1 antihistamines (cetirizine, desloratadine, fexofenadine, levocetirizine, loratadine) are hydrophilic molecules that do not easily penetrate the CNS. Although they are much more selective than the first-generation antihistamines, H1 receptor occupancy varies from almost negligible (e.g., fexofenadine) to 30% (cetirizine).145,157 The majority of studies in normal subjects and atopic individuals generally confirm that these drugs are not sedating and do not impair performance when they are used in recommended doses.154 Whereas MSLT studies indicate that cetirizine is nonsedating,155 it has been classified as sedating by the Food and Drug Administration, and a number of studies suggest that it is more subjectively sedating and more likely to impair performance than are other second-generation H1 antagonists.158,159 Meta-analysis of 18 studies concluded that whereas second-generation antihistamines caused less performance impairment than the first-generation antihistamine diphenhydramine did, mild impairment was still present.160 There is some evidence that fexofenadine and levocetirizine may be less impairing than other second-generation drugs,152,161 although sedation may emerge with increase in dose.162 Histamine Type 2 Receptor Antagonists H2 antagonists (e.g., cimetidine, ranitidine, famotidine, and nizatidine) are unlikely to impair CNS function because these compounds do not easily cross the blood– brain barrier. However, cimetidine slows the clearance of some benzodiazepine receptor agonists, which may make
CHAPTER 46 • Drugs That Disturb Sleep and Wakefulness 553
carryover effects of hypnotics more of a problem.163 Similarly, cimetidine has been shown to increase levels of theophylline, carbamazepine, and beta-blockers, with resultant increases in the CNS effects of these drugs. Ranitidine has produced some of the same effects, although not to the extent seen with cimetidine. One crossover study comparing 1-week administration of cimetidine, famotidine, ranitidine, and placebo in normal subjects reported no differences in nocturnal sleep or daytime MSLT latencies, although cimetidine produced a slight increase in subjective estimates of sleepiness.164 H2 antagonists do not appear to affect psychomotor performance. However, both cimetidine165 and ranitidine administered in conventional doses have been associated with an increased incidence of lethargy, somnolence, and confusion in patients with renal impairment. In addition, benzodiazepine-produced impairment of psychomotor and cognitive function was prolonged with concomitant administration of cimetidine and ranitidine in healthy volunteers.166
PAIN MEDICATIONS The neurobiology of pain is complex and involves both peripheral and central mechanisms. Simplistically, activation of peripheral nociceptors (by inflammation or tissue damage) is modulated by central mechanisms that affect pain perception. Pain disrupts sleep, whereas sleep loss may increase pain sensitivity.167 Multiple neurotransmitters modulate pain processing, including substance P, endorphins (by mu opioid receptors), norepinephrine (alpha2 adrenoceptors), and serotonin (5-HT1B/D and 5-HT3 receptors).168 Drugs used in the treatment of pain include analgesics (nonsteroidal antiinflammatory drugs and opiates), antidepressants (particularly tricyclics and SNRIs), and antiepileptics.167,169 Duloxetine (an SNRI) has been approved for treatment of diabetic neuropathy. Gabapentin and pregabalin are approved for treatment of postherpetic neuralgia. In addition, pregabalin is approved for treatment of peripheral neuropathy as well as fibromyalgia. Both drugs are frequently used for neuropathic pain. These drugs are discussed in the sections on antidepressants and antiepileptics. In addition, pain and sleep are discussed more fully in Chapter 126. Opioids act at a variety of CNS receptors, including mu, kappa, delta, and nociceptin/orphanin FQ.170 All of these receptor subtypes appear to be involved in the analgesic effect of opioids, whereas the mu subtype plays a prominent role in respiratory control. Sedation is mediated by both mu and kappa receptors.168 The most common clinically used opioids are relatively selective for mu receptors. Opioid peptides (enkephalins, endorphins, dynorphins) are involved in the regulation of a number of biological activities including blood pressure, respiration, mood, pain perception, and possibly sleep.171 Somnolence is a common side effect of opioid medication.172 Degree of sedation may depend on the specific drug, dosage, and duration of use as well as on severity of the underlying disease.173 Chronic use in cancer or chronic pain patients is associated with both insomnia and daytime sleepiness and fatigue, but this may be secondary to disease or psychological function.174 Older adults appear to have increased pharmacodynamic
554 PART I / Section 6 • Pharmacology
sensitivity to opioids.175 The limited PSG data available indicate that opioids used acutely in young healthy volunteers markedly decrease SWS but have no effect on TST or wake after sleep onset.176 REM sleep may be decreased with higher doses.177 In current or former addicts, opioids also decrease TST and increase wake after sleep onset.178 Subjective quality of sleep may be improved, presumably because of improved pain control.179 Cognitive and psychomotor function are impaired, at least initially, with opioids,173,180 but there are no well-controlled studies to confirm whether these effects improve over time. Patients using opioids chronically do show cognitive impairment, but comorbid medical or psychiatric disease may be more predictive of impairment than frequency or dose of medication.181 The most serious adverse effect of opioids is respiratory depression, particularly during sleep or after surgery. Opioids act directly on the brainstem respiratory centers through mu and delta receptors and at chemoreceptors through mu receptors, resulting in a shift to the right and a change in slope of the carbon dioxide response curve.182 Opioids depress the pontine and medullary centers involved in the regulation of respiratory rhythmicity, resulting in increased respiratory pauses, irregular breathing, and decreased tidal volume.183 Respiratory depression increases with increase in opioid dose. Limited data suggest that clinically significant respiratory depression rarely occurs with standard opioid doses used acutely in healthy individuals.184,185 However, with chronic opioid use, central sleep apnea is common.186 Individuals with pulmonary disease or obstructive sleep apnea are at greater risk for sustained hypoxemia during sleep.187 Concomitant use of other sedatives including sleep aids increases the risk for potentially fatal respiratory depression. After surgery, individuals with obstructive sleep apnea receiving intravenous morphine have been shown to have pronounced oxygen desaturation, paradoxical breathing, and slow ventilation.188 Triptans, which are selective serotonin 1B/1D agonists, are currently the primary treatment of acute migraine. Somnolence is a common side effect, but its incidence varies among drugs, probably the result of differences in lipophilicity and the presence of active metabolites. Somnolence is highest with eletriptan, zolmitriptan, and rizatriptan, all of which are highly lipophilic and have active metabolites, and lowest with almotriptan, sumatriptan, and naratriptan, which have lipophilicity and no active metabolites.189 There are no PSG or MSLT data or studies evaluating cognition. Nonsteroidal antiinflammatory drugs (NSAIDs) may affect sleep because they decrease the synthesis of prostaglandin D2, suppress the normal nocturnal surge in melatonin synthesis, and attenuate the normal nocturnal decrease in body temperature.190 Prostaglandin D2 increases proportionately with increased duration of wake and may be involved in sleep initiation.191 NSAIDs inhibit cyclooxygenase (COX), blocking the synthesis of inflammatory prostaglandins. The classic NSAIDs inhibit both COX-1 (thereby accounting for their gastrointestinal toxicity) and COX-2 isoenzymes, whereas the newer NSAIDs selectively inhibit COX-2 (found primarily in the CNS, renal cortex, and vas deferens).192 Limited PSG data are mixed
and have shown both no effect193 and decreased sleep efficiency with acutely administered aspirin and ibuprofen in healthy subjects.190,194 In one placebo-controlled study of rheumatoid arthritis patients, tenoxicam (not available in the United States) improved clinical symptoms but did not affect PSG measures.195 Subjective reports suggest an improvement in sleep quality with use of NSAIDs, presumably because of a reduction in pain. Cognitive deficits are apparently rare with NSAIDs but may be a problem in older adults.196
OTHER DRUGS Corticosteroids Corticosteroids are widely believed to disrupt sleep, but the results of objective studies are inconsistent. Differences in receptor affinities between synthetic and endogenous corticosteroids, dosage, methodological issues associated with the study of patient populations, and the variety of organ systems affected by corticosteroids as well as the variety of side effects reported197 contribute to this confusion. In patient populations, corticosteroids have frequently been associated with sleep disturbance. Approximately 50% of patients treated with prednisone for optic neuritis reported sleep disturbance compared with 20% receiving placebo.198 Patients taking prednisone for oral inflammatory ulcerative disease reported a dose-related incidence of insomnia ranging from 12% to 71%.199 Parent ratings of sleep disturbance increased when steroids were added to the chemotherapy regimen of children with leukemia or other types of cancer.200 Insomnia has also been reported more frequently in patients with asthma receiving steroid medications.201 In addition, numerous anecdotal and case reports implicate systemic corticosteroid use in insomnia. Behavioral observations of 12 healthy subjects given prednisone 80 mg/day for 5 days showed decreased sleep in 25% and mild hypomania in 67%.202 Inhaled glucocorticoids do not appear to have the same negative effects, but there have been case reports of hyperactivity, insomnia, and psychosis with these drugs as well. The most consistent effect of corticosteroids on PSGrecorded sleep in normal subjects is a marked decrease in REM sleep.203 Although less consistent, there is good evidence for increased waking during the night with cortisol, dexamethasone, and prednisone. Dexamethasone, administered before bedtime, resulted in increased daytime alertness the next day as measured with MSLT.204 In a single study evaluating performance in healthy subjects, prednisone 80 mg/day given for 5 days produced increased frequency of errors of commission on a verbal memory task.205 Prednisone was associated with decreased cognitive functioning in a study of patients with systemic lupus erythematosus.206 Pseudoephedrine and Phenylpropanolamine Pseudoephedrine and phenylpropanolamine share the pharmacologic properties of ephedrine but have less potent CNS-stimulating effects. These drugs are used extensively as nasal decongestants and are available in a variety of
over-the-counter cold preparations; phenylpropanolamine is also available in over-the-counter diet aids. Although similar in chemical structure to amphetamine, phenylpropanolamine is much less lipophilic and thus has much less potent CNS effects. Phenylpropanolamine, however, has been reported to increase plasma caffeine levels,207 possibly adding to the stimulant effect of caffeine. These drugs have been reported to cause insomnia. In one study, 27% of patients given 120 mg of extended-release pseudoephedrine for 2 weeks for the treatment of allergic or vasomotor rhinitis complained of insomnia. In a PSG study, the administration of pseudoephedrine in the evening (as part of either a 60-mg four-times-daily or a sustained-release 120-mg twice-daily dosing regimen) produced increased wake time during sleep compared with the morning administration of a once-daily controlled-release formulation (240 mg).208 Further objective evaluation of dosage, timing, and duration of treatment of these drugs would be useful. Stimulants Stimulant medications (covered more fully in Chapters 44 and 45) are the primary treatment of both narcolepsy and ADHD. Their use in ADHD has increased significantly during the last 20 years. Sleep problems are common in both children and adults with ADHD.209,210 Although actigraphic, PSG, and MSLT data in children do not yield consistent findings, it appears likely that ADHD children have decreased sleep efficiency, decreased REM sleep, increased daytime sleepiness, and possibly increased prevalence of periodic limb movements in sleep.209 Limited actigraphic and PSG data in adults also indicate decreased sleep efficiency.210,211 Stimulant medication used in the treatment of ADHD includes immediate-release compounds (dextroamphetamine, methylphenidate) as well as extended-release formulations (methylphenidate [Concerta], dextroamphetamine/levoamphetamine [Adderall XR], and lisdexamphetamine [Vyvanse]). Modafinil has been studied in both children and adults but is not currently approved by the Food and Drug Administration for ADHD treatment.212 Clinical trials and subjective reports indicate increased incidence of insomnia with these drugs. Parental reports, in particular, indicate significant sleep disturbance, which may be higher with the modifiedrelease drugs. However, limited PSG and actigraphic data have yielded conflicting results. Cognitive function may improve as a result of symptom improvement rather than as a direct drug effect. Theophylline Theophylline, a respiratory stimulant and bronchodilator, is chemically related to caffeine. Peak plasma concentration is usually reached within 2 hours, but the half-life varies by preparation and is typically shorter in children (3.5 hours) and longer in adults (8 to 9 hours). Absorption is lower at night than in the morning213 and may be greatly affected by food.214 Disturbed sleep is a common complaint among patients taking theophylline. In a prospective study, patients with asthma treated with theophylline were more likely to complain of sleep maintenance difficulty (55%) than were patients treated with other asthma medications (31%)215; and in a retrospective study of treated patients with asthma,
CHAPTER 46 • Drugs That Disturb Sleep and Wakefulness 555
46% of whom complained of insomnia, only theophylline or corticosteroid therapy was associated with the complaint of insomnia.201 Most of the studies purporting that theophylline does not adversely affect sleep are limited by the lack of a placebo control or other methodological difficulties. Because theophylline improves asthma-related symptoms, there have also been reports of improved sleep continuity and decreased nocturnal awakenings associated with its use.216 Theophylline, administered for up to 3 weeks, has been shown to disturb PSG-recorded sleep in healthy subjects,217,218 patients with asthma,219 children with cystic fibrosis,220 and patients with sleep apnea221 or chronic obstructive pulmonary disease.222 Dose-dependent increase in MSLT latency and performance was noted with shortterm administration of theophylline in normals.218 In a double-blinded study, asthmatic children were more likely to exhibit behavioral or attentional problems when receiving sustained-release theophylline for 4 weeks than when taking placebo.223 However, a meta-analysis of 12 studies of theophylline did not indicate impairment in cognition or behavior.224 Furthermore, academic achievement did not differ between 72 asthmatic patients who were treated with theophylline and siblings without asthma.225
CONCLUSION Disturbed sleep, daytime sleepiness, and impaired cognitive functioning are common side effects of many medications. Negative effects may be the result of a direct action of a drug (e.g., disturbed sleep from an activating compound or carryover sedation from a long-acting hypnotic) or an indirect action (e.g., daytime sleepiness as a result of drug-induced sleep disruption). Sleep–wake regulation involves multiple neuronal systems and neurotransmitters. Drugs that increase the activity of the sleep-promoting system or decrease the activity of the wake-promoting system will be sedating, whereas drugs that act in a reciprocal fashion will be alerting. Whether these effects are considered side effects depends on when they occur. Knowledge of receptor mechanisms and pharmacokinetics can help predict which drugs will have a negative impact on sleep or wake function.
❖ Clinical Pearl Because sleep–wake regulation is complex and involves multiple neuronal sites and neurotransmitters, any drug with CNS activity has the potential to affect sleep–wake behavior. Knowledge of receptor pharmacology and pharmacokinetics is helpful in determining the likelihood of negative effects on sleep or waking function.
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149. Israili ZH, Hall WD. Cough and angioneurotic edema associated with angiotensin-converting enzyme inhibitor therapy. A review of the literature and pathophysiology. Ann Intern Med 1992;117: 234-242. 150. Cicolin A, Mangiardi L, Mutani R, et al. Angiotensin-converting enzyme inhibitors and obstructive sleep apnea. Mayo Clin Proc 2006;81:53-55. 151. Okamura N, Yanai K, Higuchi M, et al. Functional neuroimaging of cognition impaired by a classical antihistamine, d-chlorpheniramine. Br J Pharmacol 2000;129:115-123. 152 Tashiro M, Mochizuki H, Iwabuchi K, et al. Roles of histamine in regulation of arousal and cognition: functional neuroimaging of histamine H1 receptors in human brain. Life Sci 2002;72: 409-414. 153. Meltzer E. Performance effects of antihistamines. J Allergy Clin Immunol 1990;86:613-619. 154. Shamsi Z, Hindmarch I. Sedation and antihistamines: a review of inter-drug differences using proportional impairment ratios. Human Psychopharmacol 2000;15:S3-S30. 155. Schweitzer PK, Muehlbach MJ, Walsh JK. Sleepiness and performance during three-day administration of cetirizine or diphenhydramine. J Allergy Clin Immunol 1994;94:716-724. 156. Richardson GS, Roehrs RA, Rosenthal L, et al. Tolerance to daytime sedative effects of H1 antihistamines. J Clin Psychopharmacol 2002;22:511-515. 157. Tashiro M, Sakurada Y, Iwabuchi K, et al. Central effects of fexofenadine and cetirizine: measurement of psychomotor performance, subjective sleepiness, and brain histamine H1-receptor occupancy using 11C-doxepin positron emission tomography. J Clin Pharmacol 2004;44:890-900. 158. Hindmarch I. Psychometric aspects of antihistamines. Allergy 1990;50:48-54. 159. Verster JC, Volkerts ER. Antihistamines and driving ability: evidence from on-the-road driving studies during normal traffic. Ann Allergy Asthma Immunol 2004;92:294-303. 160. Bender B, Berning S, Dudden R, et al. Sedation and performance impairment of diphenhydramine and second-generation antihistamines: a meta-analysis. J Allergy Clin Immunol 2003;111:770-776. 161. Hindmarch I. CNS effects of antihistamines: is there a third generation of non-sedative drugs? Clin Exp Allergy Rev 2002;2:26-31. 162. Raemaekers J, Vermeeren A. All antihistamines cross blood-brain barrier. BMJ 2000;321:572. 163. Sanders LD, Whitehead C, Gildersleve CD, et al. Interaction of H2-receptor antagonists and benzodiazepine sedation. A doubleblind placebo-controlled investigation of the effects of cimetidine and ranitidine on recovery after intravenous midazolam. Anaesthesia 1993;48:286-292. 164. Orr WC, Duke JC, Imes NK, et al. Comparative effects of H2receptor antagonists on subjective and objective assessments of sleep. Aliment Pharmacol Ther 1994;8:203-207. 165. Schentag JJ. Cimetidine-associated mental confusion: further studies in 36 severely ill patients. Ther Drug Monit 1980;78: 791-795. 166. Sanders LD, Whitehead C, Gildersleve CD, et al. Interaction of H2-receptor antagonists and benzodiazepine sedation. Anaesthesia 1993;48:286-292. 167. Roehrs T, Roth T. Sleep and pain: interaction of two vital functions. Semin Neurol 2005;25:106-116. 168. Schug S, Garrett W, Gillespie G. Opioid and non-opioid analgesics. Best Pract Res Clin Anaesthesiol 2003;17:91-110. 169. Zin C, Nissen L, Smith M, et al. An update on the pharmacological management of post-herpetic neuralgia and painful diabetic neuropathy. CNS Drugs 2008;22:417-422. 170. Gutstein H, Akil H. Opioid analgesics. In: Hardman J, Limbird L, Gilman A, editors. Goodman and Gilman’s the pharmacological basis of therapeutics, 11th ed. New York: McGraw-Hill; 2005. p. 547-590. 171. Wilson L, Dorosz L. Possible role of the opioid peptides in sleep. Med Hypotheses 1984;14:269-280. 172. Inturrisi C. Clinical pharmacology of opioids for pain. Clin J Pain 2002;18:S3-S13. 173. Clemons M, Regnard C, Appleton T. Alertness, cognition and morphine in patients with advanced cancer. Cancer Treat Rev 1996;122:451-468. 174. Zgierska A, Brown R, Zuelsdorff M, et al. Sleep and daytime sleepiness problems among patients with chronic noncancerous
CHAPTER 46 • Drugs That Disturb Sleep and Wakefulness 559 pain receiving long-term opioid therapy: a cross-sectional study. J Opioid Manag 2007;3:317-327. 175. Nikolaus T, Zeyfang A. Pharmacological treatments for persistent non-malignant pain in older persons. Drugs Aging 2004;21:19-41. 176. Dimsdale J, Norman D, DeJardin D, Wallace M. The effects of opioids on sleep architecture. J Clin Sleep Med 2007;3:33-36. 177. Walder B, Tramer M, Blois R. The effects of two single doses of tramadol on sleep: a randomized, cross-over trial in healthy volunteers. Eur J Anaesthesiol 2001;18:36-42. 178. Cronin A, Keifer J, Davies M, et al. Postoperative sleep disturbance: influences of opioids and pain in humans. Sleep 2001;24:39-44. 179. Caldwell J, Rapoport R, Davis J, et al. Efficacy and safety of a oncedaily morphine formulation in chronic, moderate-to-severe osteoarthritis pain: results from a randomized placebo- controlled, double-blind trial and an open-label extension trial. J Pain Symptom Manage 2002;23:278-291. 180. Sjogran P. Psychomotor and cognitive functioning in cancer patients. Acta Anaesthesiol Scand 1997;41:159-161. 181. Brown R, Zuelsdorff M, Fleming M. Adverse effects and cognitive function among primary care patients taking opioids for chronic nonmalignant pain. J Opioid Manag 2006;2:137-145. 182. Robinson R, Zwillich C, Bixler E, et al. Effects of oral narcotics on sleep-disordered breathing in healthy adults. Chest 1987;91: 197-203. 183. Shook JE, Watkins W, Camporesi E. Differential roles of opioid receptors in respiration, respiratory disease, and opiate-induced respiratory depression. Am Rev Respir Dis 1990;142:895-909. 184. Robinson R, Zwillich C, Bixler E, et al. Effects of oral narcotics on sleep-disordered breathing in healthy adults. Chest 1987;91: 197-203. 185. Wang D, Teichtahl H. Opioids, sleep architecture and sleep-disordered breathing. Sleep Med Rev 2007;11:35-46. 186. Wang D, Teichtahl H, Drummer O, et al. Central sleep apnea in stable methadone maintenance treatment patients. Chest 2005; 128:1348-1356. 187. Farney R, Walker J, Cloward T, Rhondeau S. Sleep-disordered breathing associated with long-term opioid therapy. Chest 2003;123:632-639. 188. Catley D, Thornton C, Jordan C, et al. Pronounced, episodic oxygen desaturation in the postoperative period: its association with ventilatory pattern and analgesic regimen. Anesthesiology 1985;63: 20-28. 189. Dodick D, Martin V. Triptans and CNS side-effects: pharmacokinetic and metabolic mechanisms. Cephalalgia 2004;24:417-424. 190. Murphy P, Badia P, Myers B, et al. Nonsteroidal anti-inflammatory drugs affect normal sleep patterns in humans. Physiol Behav 1994;55:1063-1066. 191. Datta S, MacLean R. Neurobiological mechanisms for the regulation of mammalian sleep-wake behavior: reinterpretation of historical evidence and inclusion of contemporary cellular and molecular evidence. Neurosci Biobehav Rev 2007;31:775-824. 192. Nikolaus T, Zeyfang A. Pharmacological treatments for persistent non-malignant pain in older persons. Drugs Aging 2004;21:19-41. 193. Gengo F. Effects of ibuprofen on sleep quality as measured using polysomnography and subjective measures in healthy adults. Clin Ther 2006;28:1820-1826. 194. Horne J, Percival J, Traynor J. Aspirin and human sleep. Electroencephalogr Clin Neurophysiol 1980;49:409-413. 195. Lavie P, Hahir M, Lorder M, Scharf Y. Nonsteroidal anti-inflammatory drug therapy in rheumatoid arthritis. Lack of association between clinical improvement and effect on sleep. Arthritis Rheum 1991;34:655-659. 196. Schug S, Garrett W, Gillespie G. Opioid and non-opioid analgesics. Best Pract Res Clin Anaesthesiol 2003;17:91-110. 197. Searle JP, Compton MR. Side-effects of corticosteroid agents. Med J Aust 1986;144:139-142. 198. Chrousos GA, Kattah JC, Beck RW, et al. Side effects of glucocorticoid treatment: experience of the Optic Neuritis Treatment Trial. JAMA 1993;269:2110-2112. 199. Lozada F, Silverman S, Migliorati C. Adverse side effects associated with prednisone in the treatment of patients with oral inflammatory ulcerative diseases. J Am Dent Assoc 1984;109:269-270. 200. Harris JC, Carel CA, Rosenberg LA, et al. Intermittent high dose corticosteroid treatment in childhood cancer: behavioral and emotional consequences. J Am Acad Child Adolesc Psychiatry 1988;27: 720-725.
560 PART I / Section 6 • Pharmacology 201. Bailey WC, Richards JM, Manzella BA, et al. Characteristics and correlates of asthma in a university clinic population. Chest 1990;98:821-828. 202. Wolkowitz OM, Rubinow D, Doran AR, et al. Prednisone effects on neurochemistry and behavior: preliminary findings. Arch Gen Psychiatry 1990;47:963-968. 203. Born J, Zwick A, Roth G, et al. Differential effects of hydrocortisone, fluocortolone, and aldosterone on nocturnal sleep in humans. Acta Endocrinol (Copenh) 1987;116:129-137. 204. Rosenthal L, Folkerts M, Helmus T, et al. Administration of dexamethasone and its effects on sleep and daytime alertness. Sleep Res 1995;24:58. 205. Wolkowitz OM, Reus VI, Weingartner H, et al. Cognitive effects of corticosteroids. Am J Psychiatry 1990;147:1297-1303. 206. McLaurin E, Holliday S, Williams P, Brey R. Predictors of cognitive dysfunction in patients with systemic lupus erythematosus. Neurology 2005;64:297-303. 207. Lake CR, Rosenberg DB, Gallant S, et al. Phenylpropanolamine increases plasma caffeine levels. Clin Pharmacol Ther 1990;47: 675-685. 208. Bertrand B, Jamart J, Arendt C. Cetirizine and pseudoephedrine retard alone and in combination in the treatment of perennial allergic rhinitis: a double-blind multicentre study. Rhinology 1996:34:91-96. 209. Cohen-Zion M, Ancoli-Israel S. Sleep in children with attentiondeficit hyperactivity disorder (ADHD): a review of naturalistic and stimulant intervention studies. Sleep Med Rev 2004;8:379-402. 210. Sobanski E, Schredl M, Kettler N, Alm B. Sleep in adults with attention deficit hyperactivity disorder (ADHD) before and during treatment with methylphenidate: a controlled polysomnographic study. Sleep 2008;31:375-381. 211. Boonstra AM, Kooij JJS, Oosterlaan J, et al. Hyperactive night and day? Actigraphy studies in adult ADHD: a baseline comparison and the effect of methylphenidate. Sleep 2007;30:433-442. 212. Kumar R. Approved and investigational use of modafinil: an evidence-based review. Drugs 2008;68:1803-1839. 213. Scott PH, Tabachnik E, MacLeod S, et al. Sustained release theophylline for childhood asthma: evidence for circadian
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Psychobiology and Dreaming
Section
7
Tore Nielsen 47 Introduction: The
Changing Historical Context of Dream Research 48 The Neurobiology of Dreaming 49 Ultradian, Circadian, and Sleep-Dependent Features of Dreaming
50 Dream Content:
Quantitative Findings 51 Dream Analysis and Classification: The Reality Simulation Perspective 52 Dreams in Patients with Sleep Disorders
53 Dreams and Nightmares in Posttraumatic Stress Disorder 54 Dreaming as a MoodRegulation System 55 Why We Dream
Introduction: The Changing Historical Context of Dream Research Tore Nielsen
Dream research is undergoing a period of vitality not seen since the 1960s, when the influence of Aserinsky and Kleitman’s1 discovery on the area reached a peak (see reference 2 for review). Figure 47-1 illustrates this trend using one key index of research health: the annual number of publications on the topic. The number of publications from 1946 to 2007 is plotted on separate frequency scales for Dreams and for Sleep (minus Dreams). For Dreams, the early increase in publications peaking in the 1960s is followed by a 25-year period of stagnation, then a steady rise beginning at the turn of the 21st century. For Sleep, a steady linear growth over time since the early 1960s is unmistakable. It would be incorrect to assume that this recent growth trend in dream research reflects a resolution of methodological problems that have plagued the area for decades (see reference 3 for review). In large part, these problems remain. Rather, developments in the nature, function, and correlates of dreaming have spurred renewed activity among some researchers. The principal new developments are well represented by chapters in this section on the psychobiology of dreaming and span both basic and clinical research domains. In the realm of basic research, new results from studies assessing brain activity during sleep by positron emission tomographic imaging and recordings of cellular neuromodulation are providing insights into the nature and function of dreaming (Chapter 48). Such studies reveal possible neurophysiologic explanations for common characteristics of dream consciousness, such as increased emotionality (in limbic structures) or lack of insight (in frontal structures). In the related field of chronobiology (Chapter 49), new findings and theoretical models are starting to lay bare the underlying timing mechanisms that control
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the ebb and flow of dream processes between sleep stages (ultradian rhythm) and across the sleep–wake cycle (circadian rhythm). At a basic phenomenological level, there is a convergence of renewed interest in reality simulation as an essential characteristic of dreaming, leading to a reconsideration of how content and bizarreness measures reflect simulation processes (Chapter 51). Similarly, basic research has made considerable gains in optimizing methods for analyzing dream content and in applying these to a variety of populations (Chapter 50). This research, too, indicates that dreams accurately simulate the objects and activities of waking life and are related to general waking life dimensions but not to day-to-day events. Two dynamic areas of contemporary research hold great promise for clarifying the essential functions of dreaming. On the one hand, a large and rapidly growing body of findings supports the notion that sleep subserves various functions of memory consolidation. Dreaming’s specific role in these memory functions is only beginning to emerge, but the existing research provides a solid basis for formulating new theories of dream involvement and guiding hypothesis testing (Chapter 55). In a related vein, many studies converge in supporting the notion that dreaming serves a cross-night affect regulation function (Chapter 54). Such studies dovetail with work demonstrating a specific role for rapid eye movement (REM) sleep in the consolidation of emotional memories. In the realm of clinical research, renewed interest is indicated by several important developments. More attention is being paid to describing the characteristic alterations in dreaming that accompany sleep disorders, such as narcolepsy, insomnia, and sleep apnea (Chapter 52). Evidence now suggests that such alterations may improve diagnosis of sleep problems and provide insights into their 561
562 PART I / Section 7 • Psychobiology and Dreaming
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Figure 47-1 Annual number of research publications (2-year means) cited in the U.S. National Library of Medicine PubMed database for major MeSH topic searches Dreams and Sleep (not Dreams) (1946-2007). Ordinate scale for Sleep (in blue, right axis) is 10 times that for Dreams (green, left axis). Sharp albeit delayed rises in publications beginning in the early 1960s for both areas are attributable to the publication of Aserinsky and Kleitman (1953) and subsequent reports on the discovery of REM sleep (red data points). Unlike the profile of Sleep publications, which has increased linearly to the present day, Dreams publications declined abruptly in the early 1970s and stagnated for a quarter century (red arrow a). Since 2000, however, a renewed increase in Dreams publications is discernible (red arrow b) that may reflect wider interest in topics such as sleep-related processing of memories and emotions and the disturbance of dreaming in conditions such as posttraumatic stress disorder, REM sleep behavior disorder, and nightmare disorder.
pathophysiologic mechanisms. The changes in dreaming that occur as a function of stress and trauma, as in posttraumatic stress disorder, is a rapidly developing area (Chapter 53) and includes delineation of how dream content is modified by stress and how and why nightmares may “replay” stressful or traumatic events in nearly identical form over time. Equally important advances have occurred in research on nightmare disorder and REM sleep behavior disorder, although much of this research is discussed in chapters in the parasomnias section (see Chapters 97 and 98). To summarize, a recent resurgence of scientific interest in the study of dreaming finds its roots in key developments in basic research dealing with cognitive neuroscience, phenomenology, and content analysis as well as in
clinical studies highlighting the role of dreaming in sleep disorders, posttraumatic stress disorder, REM sleep behavior disorder, and nightmare disorder. These numerous advances may be sufficient to finally support a steady linear growth in dream research similar to that seen in other disciplines. REFERENCES 1. Aserinsky E, Kleitman N. Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science 1953;118: 273-274. 2. Nielsen TA, Germain A. Publication patterns in dream research: trends in the medical and psychological literatures. Dreaming 1998;8:47-58. 3. Stickgold R. The questions of dream research. Sleep Hypnosis 2004;3:4-7.
The Neurobiology of Dreaming Edward F. Pace-Schott Abstract Dreaming is a universal human mental state characterized by hallucinatory imagery congruent with a confabulated, temporally ordered, storylike experience. As in waking consciousness, such experiences in both rapid eye movement (REM) and non-REM (NREM) sleep are associated with activation of forebrain structures by ascending arousal systems of the brainstem, hypothalamus, and basal forebrain. Differences between forebrain activation patterns in waking and REM sleep suggest bases for their phenomenological differences. In REM compared to waking, there is relatively more activation of the brain’s limbic system and relatively less activity of cortical areas involved in higher-level cognition. REM sleep dreaming
COGNITIVE NEUROSCIENCE AND DREAMING Dreaming is a universal human experience occurring during sleep in which fictive events follow one another in an organized, storylike manner and into which are woven hallucinatory, primarily visual, images that are largely congruent with an ongoing confabulated plot. Most often, this wholly imaginary experience is uncritically accepted in the same manner as are veridical waking percepts and events. The neuroscientific significance of dreams becomes apparent by considering just two of the many remarkable aspects of this universally human mental state. The first, dreaming’s “single-mindedness and isolation,” was eloquently described by Rechtschaffen,1 and refers to the dreamer’s absorption in the dream world and plot without awareness of an alternate reality in waking excepting rare “lucidity” (the awareness that one is dreaming). From this condition of limited insight, upon awakening, one abruptly regains sufficient insight to conceptualize alternate states of mind and decide which of these one is currently experiencing. The second is the occurrence in dreams of entirely de novo imagery, plots, personages, and even motor skills (e.g., flying), emotion (e.g., religious feelings) and memory (e.g., deja vu). Therefore, dreaming is an imprecise experiential simulacrum of waking resulting from neurobiological processes that must differ from those that generate waking consciousness. Because no published functional neuroimaging study has yet awoken subjects during dreaming to link subjectively experienced features of a dream report with immediately preceding brain activity, the wealth of information on the cognitive neuroscience of waking and the neurophysiology of sleep must be related to the less experimentally accessible dream state. THE ASSOCIATION OF DREAMING WITH BEHAVIORAL STATE Early speculation that rapid eye movement (REM) sleep was the exclusive physiological substrate of dreaming2 was soon followed by awakening studies showing substantial
Chapter
48
may activate anterior and midline portions of the brain’s “default mode,” a network of structures that supports selfrelated cognition when the brain is unoccupied by external stimuli. A variety of neurochemical systems can influence dreaming, including the neuromodulators acetylcholine, dopamine, serotonin, and norepinephrine. Dream phenomena are strikingly similar to neuropsychiatric symptom complexes such as complex hallucinosis and spontaneous confabulation as well as delirium and misidentification syndromes. A descriptive model of dream generation links sleep imaging studies with known regional specialization in waking neurocognitive functions.
recall of mental experiences from non-REM (NREM) sleep.3 Nonetheless, REM reports are more frequent, longer, more bizarre, more visual, more motoric, and more emotional than are NREM reports (see review in Hobson et al.4). In an extensive review, Nielsen estimates an NREM mental-experience recall rate of 42.5% contrasting with 81.8% from REM and suggests that brain activation processes occurring outside polysomnographically scored REM (“covert REM”) may account for NREM dreaming.5 Recent Electrophysiological Findings Fast and Slow Oscillations and Dreaming REM sleep shows much more gamma frequency (30 to 80 Hz), fast brain waves (“oscillations” or “rhythms”) than does NREM sleep as measured by scalp electroencephalography (EEG),6,7 intracranial EEG (iEEG)8,9 and magnetoencephalography (MEG).6 In waking, these fast oscillations are associated with attention to stimuli and other forms of active or effortful cognition.10 During REM dreaming, fast oscillations have been hypothetically associated with cognitive and perceptual processing,11 memory processes12,13 and the temporal binding of dream imagery.14 In contrast to REM sleep, human slow-wave sleep shows very little gamma activity. It is instead associated with slower oscillations produced by recurrent interactions between the thalamus and cortex (intrinsic “corticothalamocortical” rhythms) such as sleep spindles and delta waves, and with the cortical slow (<1 Hz) oscillation that groups in time the other corticothalamocortical oscillations.15,16 The slow oscillation consists of periods of neuronal quiescence (hyperpolarized or “down” states) that alternate with shorter periods of rapid neuronal firing (depolarized or “up” states).17 Slow intrinsic oscillations may interfere with ongoing mental activity and lead to a lower frequency of dreams in NREM sleep.4 Cortical Connectivity in Sleep Declines in phase synchrony (“coherence”) of EEG rhythms between different brain regions occurring during sleep relative to waking may reflect functional 563
564 PART I / Section 7 • Psychobiology and Dreaming
disconnections that contribute to the cognitive features of dreaming. Corsi-Cabrera and colleagues have shown that, compared to waking and NREM sleep, gamma frequency oscillations in REM sleep become desynchronized between areas near the front (anterior or frontal) and those near the back (posterior) of the brain.6,7,18 These investigators suggest that loss of anteroposterior gamma coherence reflects a functional disconnection of perception-related posterior cortical areas from executive control by the frontal cortex that may contribute to the “hypofrontal” (resembling frontal-lobe dysfunction) features and bizarreness of REM sleep dreaming.6,7,12,18 During REM sleep preceding dream reports, such frontoposterior gamma decoupling was accompanied by increased gamma coherence between posterior perceptual areas, possibly enhancing perceptual vividness in REM dreams.7 Similar sleep-related declines in gamma frequency coherence between corticocortical and corticohippocampal sites have been demonstrated using iEEG.12,13 Even EEG oscillations at frequencies slower than gamma have been shown to have lower coherence between anterior and posterior recording sites in REM versus NREM sleep7,19 despite the fact that slower oscillations tend to be more globally synchronized in NREM versus REM sleep20 due to the influence of intrinsic corticothalamocortical rhythms.16 Transcranial magnetic stimulation studies demonstrate reduced functional influence between different brain regions during REM sleep.21,22 Transcallosal inhibition of motor-evoked potentials is greatly reduced immediately following REM awakenings compared to both NREM stage 2 awakenings and waking,21 and transcranial magnetic stimulation of the premotor cortex during NREM sleep fails to persist or propagate to other sites as seen in waking.22 Dreaming and Phasic Activity in Sleep In cats, a close temporal association exists between REM sleep rapid eye movements (REMs or REM saccades) and ascending potentials originating in the brainstem termed ponto-geniculo-occipital (PGO) waves.4,23 In the Activation-Synthesis (AS) hypothesis of dreaming,23 Hobson and McCarley suggest that the brainstem’s activation of the forebrain in REM allows the forebrain to synthesize dream scenarios based upon currently available information. They suggest that the PGO wave, originating in the pons and arriving at primary visual occipital cortex via the dedicated visual pathway through thalamic lateral geniculate nucleus (LGN), might be interpreted by the brain as visual information thereby leading to the visual hallucinosis of dreams. Efforts to identify human correlates of the feline PGO wave have focused on the phasic periods of REM in which clusters of REMs and other transient muscle potentials occur. Phasic REM periods are contrasted with tonic periods that are lacking in or have only isolated REMs. Conduit and colleagues24 showed that in NREM sleep stage 2, awakenings preceded by eyelid movements (ELMs) yielded a higher frequency of visual imagery reports, and they suggested both ELMs and PGOs reflect an alerting mechanism similar to the startle response. Early evidence of human PGO waves used scalp EEG recordings temporally locked to REMs (reviewed in Hobson et al.4 and Pace-Schott25). Compelling evidence for human PGO waves has recently emerged. First, using
MEG tomography, Ioannides and colleagues26 have shown that correlated phasic activity in the pons and frontal eye fields begins before a REM saccade and intensifies with increasing temporal proximity to saccade onset, suggesting a buildup of neuronal excitability that culminates in the saccade. Because such activity is greatest in the pons, they suggest that accumulating excitability is driven by the pons with correlated frontal eye field activity representing feedback from pontine activity.26 Second, in a patient with Parkinson’s disease who was implanted with depth electrodes, Lim and colleagues27 described phasic signals, with wave form and temporal characteristics very similar to the feline PGO, originating in the pedunculopontine nucleus (PPT)—a structure at the pons-midbrain (mesopontine) junction crucial for generating the feline PGO (reviewed in Hobson et al.4). Ogawa and colleagues28 provide event-related potential evidence that REMs generate perceptual experiences that could contribute to dream imagery. Brain potentials accompanying voluntary waking saccades were compared with those accompanying REM saccades. In waking, an EEG wave form known to reflect preparation for voluntary movement (“readiness potential”) was temporally locked to saccade onset, and another wave form believed to reflect visual processing of the saccade target was time-locked to saccade offset. In contrast, during REM, the wave form time-locked to saccade offset occurred in the absence of the presaccade readiness potential, suggesting that REM saccades themselves may trigger visual experiences. Using low resolution brain electromagnetic tomography, Abe and colleagues29 observed a pre–REM-saccade potential, temporally closer to saccade onset than waking readiness potentials, with current sources estimated to lie in anterior limbic regions (ventromedial, anterior cingulate, premotor, insular, temporopolar and parahippocampal cortices, basal forebrain, and uncus). Using MEG, Ioannides and colleagues26 also described REM-saccade onset linked current sources estimated to lie in the amygdala and orbitofrontal and parahippocampal cortices. The latter two groups link this presaccade limbic activity to phasically enhanced emotional processing.6,26,29 During phasic REM (versus tonic REM) sleep, increased gamma-frequency spectral power is observed across widespread scalp derivations using EEG6,11 and MEG6 as well as at specific orbitofrontal sites using iEEG.9 Gamma enhancement is accompanied by power attenuation at slower frequencies,9,11 and it is further enhanced during a 62.5 msec time window immediately preceding an actual REM saccade.6 Corsi-Cabrera and colleagues6 report that gamma coherence displays two distinct topographic changes during phasic and immediately presaccade REM relative to tonic REM. First, there is further uncoupling between frontal and parietal association areas that they suggest represents further decline in frontal control of posterior cortical perceptual-binding processes that may transiently increase cognitive distortions in dream mentation. Second, there is transient enhancement of frontolateral to midline gamma coherence that they suggest reflects phasically enhanced attentional processes subserved by midline structures. In summary, EEG and MEG studies suggest that brain activity accompanying phasic REM sleep may be related
to dream phenomena. Such phenomena include visual imagery,24,28 enhanced cognitive activity and attention,6,9,11 decoupling of executive control and perception,6,7,12,18 and enhanced emotional processing.6,26,29 Experimental Manipulation of Sleep Stage and Dreaming Takeuchi and colleagues used a sleep interruption technique to elevate the frequency of sleep onset REM periods (SOREMPs) in normal subjects.30 Dreams elicited from SOREMPs were more bizarre and had different EEG correlates than NREM dreams that occurred at similar circadian phases preceded by similar sleep–wake durations.30 For example, whereas SOREMP dreams were correlated with the amount of REM in a sleep period and with absence of alpha frequency in the EEG spectrum, NREM dreams were correlated with the presence of arousals and the persistence of alpha rhythms.30 There is now evidence that “covert REM” processes can enhance NREM dreaming. For example, partial REM deprivation (REMD) increases both REM pressure and the dreamlike quality of NREM dreams at sleep-onset,31 a time when the EEG power spectrum is very similar to that during REM sleep.32 Additionally, when Suzuki and colleagues33 experimentally constrained sleep to 20 minute naps alternating with 40 minutes of waking across 3 days, NREM-only naps yielded more dream reports at times when, in REM-containing naps, REM duration was longest (peak at 8 am). Therefore, increasing REM propensity by REMD or circadian manipulations can intensify NREM dreams.
NEURAL ACTIVATION ACROSS THE WAKE-NREM-REM CYCLE Deactivation of frontal cortices is one of the first signs of human sleep observed using EEG, MEG, and functional neuroimaging (reviewed in Pace-Schott25 and Maquet34). Positron emission tomography (PET) studies of NREM sleep show declines in brain activity relative to waking both globally34 and in many specific regions of the subcortex and cortex35,36; findings now replicated using functional magnetic resonance imaging (fMRI).37 Global and regional cerebral activity further declines with the deepening of NREM sleep34,36-38 (although, on a microscopic time frame, activity in specific regions may become transiently elevated during the depolarized “up” phase of the slow oscillation39). Following sleep onset, EEG studies show greater slow wave spectral power in frontal versus posterior scalpsites.40 Synchronization of slow-wave spectral power then spreads progressively to posterior regions,41 a trajectory also traveled by the slow (<1 Hz) oscillation.42 From these deactivated NREM conditions, in REM, there is then a prominent increase of neural activity in subcortical brain regions, including the pons and midbrain,35,43 thalamus,35,43 basal ganglia,35 limbic subcortex including the amygdala,43 hypothalamus, and ventral striatum.35 Increases are also seen in limbic-related cortices anteriorly in the rostral and subcallosal anterior cingulate,35,43 the anterior insular, more posterior (caudal) orbitofrontal and paracingulate Brodmann area (BA) 32 cortices, BA 10 in medial prefrontal cortex (mPFC),35 as
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well as more caudally in the parahippocampal gyrus and temporal pole.35 Certain visual association cortices (areas that process higher-order aspects of vision) are also active.35,44 However, multiple neuroimaging modalities show that lateral prefrontal cortices remain deactivated after the transition from NREM to REM sleep.35,43-45 When REM sleep is directly compared to waking, there is relative deactivation of the lateral prefrontal cortex.35,43,45 Maquet and colleagues45 show that regions most consistently hypoactive in REM compared to waking include middle and inferior frontal gyri as well as inferior parietal and temporoparietal junction association cortices. However, compared to waking there is greater activation of limbic and paralimbic regions.35,43,45-47 Nofzinger and colleagues46,47 have termed this area the “anterior paralimbic REM activation area” (APRA) and describe it as a “bilateral confluent paramedian zone which extends from the septal area into ventral striatum, infralimbic, prelimbic, orbitofrontal and anterior cingulate cortex”p. 192 including the hypothalamus, ventral pallidum, hippocampus, and uncus, as well as supplementary motor, pre- and subgenual anterior cingulate and insular cortices.46 Although lacking the temporal resolution of EEG and MEG, glucose metabolic 18FDG (2-deoxy-2[18F] fluorodeoxyglucose) PET studies correlating REM density with regional glucose metabolism also suggest activation of arousal, attention, and emotion networks in association with REM saccades.48 Using fMRI, Hong and colleagues49 have recently reported widespread blood oxygen level– dependent activity correlated with REMs that includes not only brainstem, thalamic, and limbic areas, but also primary and secondary sensory cortices and areas subserving oculomotor control and visuospatial attention. Recent oxygen use (H215O) PET50 and fMRI51,51a studies also correlate REMs with activation of structures corresponding to the feline PGO wave including the rostral brainstem,50,51a LGN, and occipital cortex.50,51,51a Phasic REM episodes arising from a tonic REM background show characteristic fMRI blood oxygen level–dependent changes in forebrain activity that include increased functional connectivity (the tendency to activate together) between the thalamus and a broad cortical-limbic-striatal network.52 Wehrle and colleagues52 suggest these changes represent activation, during phasic REM, of networks important to memory and emotional processing. Therefore, like EEG and MEG studies, functional neuroimaging suggests that phasic REM is associated with brain activity that might reflect intensified dream imagery, attention, and emotion.
DREAMING AND “DEFAULT MODE” NETWORKS Regions that characteristically show deactivation in response to a wide variety of goal-directed cognitive tasks have been termed the brain’s default mode.53,54 In the absence of an exteroceptive focus, these regions are believed to carry out cognitive and emotional processes relating to self-directed concerns (“self-referential cognition”).53,54 Default network regions include a posteromedial parietal region (posterior cingulate, precuneus, and retrosplenial cortices), and a lateral-inferior-parietal/superior-temporal region, the hippocampal formation (hippocampus and
566 PART I / Section 7 • Psychobiology and Dreaming
parahippocampal cortex), ventromedial prefrontal cortex (vmPFC), and dorsomedial prefrontal cortex (dmPFC).53,54 Posterior default-network regions are linked to autobiographical memory retrieval and anterior regions with selfreferential cognition.53,55 Default network activity in the vmPFC has been associated with the integration of internal stimuli reflecting bodily sensations with external, sensory stimuli54 as well as a feelings-based appraisal of whether or not such stimuli are self-related.55 Activity in the dmPFC has been associated with self-referential cognitive, behavioral, and emotional imagination (“simulation”) and its rehearsal,53,54 as well as cognitive appraisal of selfrelated stimuli.55 The dmPFC regions are also strongly activated by social cognition tasks such a those that engage abilities to infer others’ feelings, thoughts, and intentions (“theory-of-mind”).55 The default network contains two interacting subsystems, centered on the dmPFC and hippocampal formation respectively, activity in both of which correlates positively with a core network (vmPFC, posterior cingulate, retrosplenial and inferior parietal cortices) but negatively with each other.53 The hippocampal formation may access personally relevant memory whereas the dmPFC may simulate future scenarios.53 Notably, both retrospective (autobiographical) remembering and prospective simulation (imagining the future) engage much the same regions of the default network.53 Using fMRI, temporal synchrony of low frequency (0.01 to 0.1 Hz) spontaneous fluctuations of the blood oxygen level–dependent signal in waking reflects anatomical and functional connectivity among regions of the default network.56 Such synchronized fluctuations persist into attentional lapses following sleep deprivation,57 light NREM sleep58 and even stage 2 NREM sleep,59,59a but not slow-wave sleep59,59a (although default areas may transiently activate during the “up” phase of the slow oscillation39). However, reactivation of default network structures during REM, as measured by PET, is only partial.46,47 The anterior default network, vmPFC, and portions of dmPFC, as well as hippocampal and parahippocampal areas, reactivate.35,43,44,46,47 In contrast, posterior, parietal default network areas, especially the lateral inferior parietal and posterior cingulate cortex, remain deactivated.35,43,45 REM sleep dreams may, therefore, reflect default network processing with disconnection between network subsystems due to a partially deactivated core. Specifically, self-referential, emotional and social cognitive simulation, subserved by anterior default-network structures (vmPFC, dmPFC), may be isolated from hippocampally-retrieved autobiographical memory due to absence of memoryaccess facilitation by posterior default network structures (posterior cingulate and retrosplenial cortices). With limited access to episodic, autobiographical memory, REM-sleep dreaming might simulate lifelike events53 in a manner unconstrained by past realities.60
THE NEUROCHEMISTRY OF DREAMING Three major neurochemical hypotheses explain differences between dreaming and waking consciousness. The activation-synthesis and activation-input-modulation
models of Hobson and colleagues suggest that the massive increase in cholinergic (relative to noradrenergic and serotonergic) activation from the ascending reticular activating system (ARAS) during REM sleep contributes strongly to the unique nature of dream consciousness.4,23 Solms suggests that stimulation of limbic and prefrontal reward networks by dopaminergic projections from the midbrain ventral tegmental area (VTA) generates motivational impulses that initiate dreaming.61 Gottesmann suggests that dopaminergic stimulation of the cortex during REM, in the absence of waking’s inhibitory serotonergic and noradrenergic modulation, allows emergence of psychotomimetic (psychosis-like) aspects of dream consciousness.62 Acetylcholine The activation-synthesis23 and activation-input-modulation4 models suggest that forebrain activation in REM dreaming originates in ascending activation of the thalamus by mesopontine cholinergic nuclei. Much evidence exists for cholinergic enhancement of both REM and dreaming. Higher mesopontine-brainstem derived acetylcholine (ACh) concentrations during wake and REM sleep versus NREM sleep are seen in the thalamus, including the LGN.63 Cholinergic stimulation potentiates REM sleep when microinjected into the animal brainstem or when systemically administered to humans.4 Cholinesterase inhibitors can induce REM sleep with dreaming,64 and increase nightmares65 and hypnagogic hallucinations.66 Transdermal nicotine67 and its partial agonist varenicline68 intensify dreams. Nightmares induced by beta-blockers69 probably result from disinhibition of cholinergicbrainstem REM-generating mechanisms.70 Nonetheless, the most common pharmacological precipitant of waking hallucinosis is the delirium resulting from blockade of muscarinic ACh receptors.71 Moreover, extensive cholinergic deficits may cause the visual hallu cinations of Lewy body dementia.71 The apparently paradoxical association of waking hallucinosis with hypocholinergic and REM dreaming with hypercholinergic brain conditions may arise because dreaming and waking hallucinations are differently generated. Perry and Perry71 suggest that, in waking, ACh from the basal forebrain excites the GABAergic interneurons of the cortex thereby inhibiting cortical pyramidal neurons and improving the signal-to-noise ratio at their synapses. In contrast, during REM sleep, ACh from the mesopontine brainstem inhibits GABAergic interneurons of the thalamus thereby disinhibiting, as well as directly exciting, thalamocortical neurons (thalamic neurons that project to and excite the cortex) possibly, in part, via nicotinic receptors that are especially abundant in the thalamus.71 Therefore, reduced ACh in waking allows intrusion of weaker inputs, whereas increased ACh in REM sleep excites the cortex in the absence of any perceptual input—two differing conditions but both conducive to hallucinosis.71 Notably, by combining a cholinergic challenge with fMRI, Furey and colleagues72 have shown that, in waking, ACh enhances the activity of visual association cortices (in REM sleep, possibly favoring hallucination) while at the same time reducing dorsal prefrontal cortical activity (in REM sleep, possibly diminishing logic and insight).
Dopamine Because mean firing rates of dopaminergic cells in the substantia nigra pars compacta and VTA do not vary with behavioral state in the same manner as do the other aminergic nuclei, dopamine (DA) has received less study by sleep and dream researchers (reviewed in Hobson, Pace-Schott, and Stickgold4 and Hobson and Pace-Schott70). However, a key role is assigned to DA in reward-based61 and psychotomimetic62 theories of dreaming. Recent findings in rodents have begun to identify roles for DA in REM sleep. For example, enhancing REM intensity by prior REMD increases c-fos expression in the VTA,73 and DA concentrations in the mPFC and nucleus accumbens are greater during REM sleep than they are during NREM sleep.74 Because transition to a burst-firing mode releases more presynaptic DA,74 synaptic DA concentrations can vary without change in dopaminergic neurons’ mean firing rate. Dahan and colleagues75 have demonstrated just such a transition during REM sleep in DA neurons of the VTA. The REM-related increase of burst firing in the VTA may result from increased cholinergic excitation from the PPT74 that innervates76 and strongly excites77 the VTA. Although l-dopa and certain other dopaminergic agents can enhance dreaming in persons with Parkinson’s disease and other clinical conditions (reviewed in Solms,61 Pagel,69 and Hobson and Pace-Schott70), psychostimulants are not associated with dream enhancement, neuroleptics do not prevent dreaming, and there exist DA agonists that reduce, and antagonists that enhance, dreaming.70 Thus DA’s dream effects may be dependent on dosage, as well as receptor type and location. Serotonin Selective serotonin (5-HT) reuptake inhibitors and other serotonergic drugs can intensify dreaming.78 Animal studies on serotonergic hallucinogens by Aghajanian and colleagues suggest that low or fluctuating cortical 5-HT levels may induce cortical output conducive to hallucinosis.79 Serotonergic hallucinogens act presynaptically as partial 5-HT2A (serotonin-2a) receptor agonists at glutamatergic inputs to apical dendrites of layer V cortical pyramidal neurons causing an “asynchronous” release of glutamate to follow the larger action-potential mediated (“synchronous”) release.79 This late, slow release of glutamate induces prolonged excitatory postsynaptic potentials (EPSPs) that are hypothesized to underlie the cognitive-perceptual effects of the hallucinogens.79 5-HT itself does not produce such prolonged EPSPs presumably due to its inhibitory effects at 5-HT1 receptors.79 However, under conditions of decreasing 5-HT concentration, such EPSPs do emerge, and low 5-HT concentrations may generally favor asynchronous transmitter release–evoked EPSPs.79 The naturally occurring lowest levels of 5-HT occur during REM sleep, and fluctuations of 5-HT release occur during sleep stage transitions.4 Thus, these conditions may promote the natural occurrence of hallucinosis during dreaming. Notably, Nofzinger’s APRA46 includes anterior limbic cortices that contain the highest cortical concentrations of the inhibitory 5-HT1A receptor and 5-HT transporter.80 Decreased cortical 5-HT during REM sleep may allow strong cholinergic activation of these areas to enhance the cognitive and emotional dream features they support.
CHAPTER 48 • The Neurobiology of Dreaming 567
NEUROPSYCHIATRIC SYNDROMES THAT INFORM THE STUDY OF DREAMING Despite striking differences between dreaming and waking experience, the same brain subserves both of these states.35 It is therefore worthwhile to examine brain alterations that shift waking consciousness toward dreaming. Table 48-1 illustrates alterations of waking cognition that may help explain certain formal characteristics of dreaming.4 We focus here on analogies of dream plots with waking spontaneous (versus provoked) confabulation (“confabulation”) and of dream hallucinations with complex visual hallucinosis (“hallucinosis”). Confabulation Shares Neural Substrate with Dreaming Patients with confabulation recount false events, assert false beliefs, and act upon them with unshakable conviction as to their veracity.81,82 Confabulatory beliefs and memories are usually based upon real autobiographical events including those in the remote past.81,83 Confabulation results from lesions of the vmPFC, the orbitofrontal cortex, and their connections with the basal forebrain, amygdala, mediodorsal thalamic nucleus, and hypothalamus.81-83 These regions broadly overlap with Nofzinger’s APRA.46 One theory on the cognitive deficit resulting in confabulation suggests that vmPFC lesions disrupt a realitymonitoring function that preconsciously suppresses spontaneously activated memories not pertaining to present circumstances.83 Memories of past experiences are thus perceived as related to the present.83 An alternative theory posits temporal deficits to be a subset of a more general deficit in strategic retrieval and verification of memories.82 Moskovitch and colleagues84 suggest vmPFC regions subserve an early stage in memory verification—a “feeling of rightness” (FOR)—after which further evaluation of a retrieved memory takes place in dorsolateral prefrontal cortices (dlPFC). Gilboa and colleagues82 suggest impaired FOR resulting from lesions to the vmPFC and orbitofrontal cortex is crucial and sufficient for producing confabulation. The salience and strength of autobiographical memories cause self-related content to dominate the content of confabulations.82,85 Dreaming may represent a potent form of confabulation in which imaginary events are not only created and believed, but also are vividly experienced as organized, multimodal hallucinations.25,70 For example, confabulators create plausible but false explanations for inconsistencies in their stories81 closely resembling ad-hoc explanations for improbable dream occurrences.86 Hirstein81 suggests that confabulation represents an extreme example of false belief disorders such as anosognosias and misidentification syndromes. “Pathological false recognition”81 in confabulation parallels dreamers’ assigning a known identity to dream characters perceptually dissimilar to their waking counterpart,87 a phenomenon Schwartz and Maquet88 liken to Fregoli syndrome (see Table 48-1). In both confabulation81 and dreaming, altered function of the vmPFC and the orbitofrontal cortex may release from normal
Impaired working memory and attention Delusion-based logic
Bizarreness Incongruity Discontinuity Ad-hoc explanation
Dorsolateral PFC lesion Psychosis
Delirium Acute psychosis Epileptic ictus
Capgras delusion Fregoli syndrome, reduplicative paramnesia
Dorsolateral PFC lesion Psychosis Mood disorders Anxiety disorders
Amnesias: Medial temporal Diencephalic
Dorsolateral PFC PGO system Mesocortical DA system
Chemical homeostasis Visual association cortices RAS/diencephalon Limbic subcortex Prefrontal cortex
Ventral temporal cortex Fusiform face area Prefrontal cortex Limbic (e.g., amygdala)
Visual association cortices
Visual association cortices Anterior occipital Inferior temporal Feature specific (V4, MT)
Caudomedial OPFC Subcallosal cingulate Amygdala Dorsolateral PFC
Hippocampal complex Parahippocampal cortices Diencephalic pathways
Caudomedial OPFC Subcallosal cingulate Basal forebrain Chemical homeostasis
RAS/diencephalon Retino-geniculo-striate Visual association cortex Serotonergic pathways Cholinergic pathways
BRAIN SUBSTRATES OF SYMPTOMATOLOGY
D: Hobson et al. 2000 (4) Hobson 1977 (23)
D: Fosse et al. 2001 (125)
D, W: Schwartz and Maquet 2002 (88)
D, W: Solms 1997 (61)
D, W: Schwartz and Maquet 2002 (88)
W: Phan et al. 2002 (107) D: Hobson et al. 2000 (4)
W: Brown and Aggleton 2001 (113) D: Fosse et al. 2003 (60)
W: Schnider 2003 (83) W: Gilboa et al. 2006 (82) D: Hobson 2001 (58a)
W: Manford and Andermann 1998 (91) W: Collerton et al. 2005 (94) D: Hobson 2001 (58a)
W: WAKING SYMPTOM DESCRIBED D: DREAMING PHENOMENON OR SYMPTOM DESCRIBED (REFERENCE NO.)
ARAS, ascending reticular activating system; DA, dopamine system; MT, motion specific visual association area; PFC, prefrontal cortex; PGO, ponto-geniculo-occipital wave; V4, color specific visual association area.
Acute hallucinosis and disorientation
Reciprocal frequency of thought and hallucination
Temporo-occipital lesion
Visual irreminiscence Misidentification of person or place
Visual distortions: Micro/macropsia, polyopsia, achromatopsia
Visual distortions
Nonvisual dreams
Lability/reactivity, apathy/ hypoemotionality
Emotional alterations Intensification Blunting
Erroneous identification Visual hallucinosis Delusionality
Visual cortex lesions
Relative preservation of recognition memory
Recognition with episodic memory deficits
Amnesia with anterior limbic pathology Traumatic brain injury Delirium
Spontaneous confabulation Disorientation to time
Narrative form with delusionality, disorientation, lost insight, & poor self-monitoring
Peduncular hallucinosis Charles Bonnet syndrome Hallucinogen intoxication
Complex visual hallucinosis
REPRESENTATIVE SYNDROMES EXPRESSING SYMPTOMATOLOGY
Complex, realistic visual hallucinations
PHENOMENON, SYMPTOM, OR SYNDROME
WAKING SYMPTOMATOLOGY RESEMBLING DREAM FEATURE
Table 48-1 Neuropsychiatric Syndromes Which Inform the Study of Dreaming
568 PART I / Section 7 • Psychobiology and Dreaming
inhibitory, reality-monitoring, and executive constraints, innate human tendencies to create explanatory stories and fill amnestic gaps in narratives. Notably, mPFC regions have been frequently associated with normal production of narrative (reviewed in Mar89). However, prominent differences exist between dreaming and confabulation. Unlike confabulation, dreaming involves actual hallucinosis of pseudosensory elements and generates entirely novel scenes, characters, objects, and scenarios.25 For example, in one study, 25% of dream characters were novel personages.87 In another, an accurate replay of episodic memory was extremely rare in dream reports.60 Another difference is that brain areas whose destruction leads to confabulation overlap the APRA.35,43,46 Thus, hyperactivation of APRA areas in REM dreaming may alter their reality-monitoring functions in a similar manner as their damage in confabulatory83 and dream– wake confusional syndromes.61 Two observations may explain this paradox. First, abnormal activation of anterior limbic structures (e.g., by seizures) can profoundly alter consciousness.90 Second, REM sleep’s predominantly cholinergic activation, together with the absence of waking’s monoaminergic modulation, may impair reality testing in the APRA. Visual Hallucinosis in Waking and Dreaming Anatomical regions associated with dreaming and with hallucinosis also overlap. Manford and Andermann91 suggest hallucinations result when visual association cortices in the inferior occipital and temporal lobes that identify objects and scenes (the “ventral processing stream”) are released from normal restraints under three conditions: (1) loss of exogenous visual input, (2) ARAS damage that alters serotonergic and cholinergic modulation of the cortex, or (3) abnormally excitatory input.91 Conditions corresponding to each mechanisms may contribute to REM hallucinosis. First, in conditions such as Charles Bonnet syndrome, waking hallucinosis results when perceptual input to the visual association cortex is lost due to lesions of the primary visual pathway.91 In REM dreaming, there is no retinal input. Moreover, primary visual cortices are deactivated,44 perhaps decreasing their regulatory input on downstream association cortices. Second, in peduncular hallucinosis, lesions of the rostral brainstem disrupt the amount and balance of serotonergic and cholinergic input to the forebrain.91 Serotonergic raphe neurons fire at their naturally occurring minimum during REM sleep, whereas mesopontine cholinergic systems have reactivated to near-waking levels.4 Therefore, altered serotonergic-cholinergic balance during REM sleep may also favor hallucinosis. Third, irritative excitation of visual association cortices (the areas active during hallucinations in Charles Bonnet syndrome92) can produce epileptic hallucinosis.91 Ventral-stream visual association cortices are more active in REM than in either NREM or post-sleep–waking35,44 and are a hypothesized source of dream imagery.4,61 During REM, PGO waves originating in the mesopontine brainstem4,27 excite many cortical regions93 including visual association areas. Collerton and colleagues94 suggest that hallucinations result from combined sensory impairment, attentional
CHAPTER 48 • The Neurobiology of Dreaming 569
deficit, and a relatively intact scene perception that allows poorly formed “proto-objects” to resolve into erroneous percepts. In REM-sleep dreaming, ascending activation of visual association cortices may evoke hallucinatory protoobjects that, under the attentionally unstable conditions of REM, resolve into hallucinatory percepts congruent with the ongoing dream plot. Internal consistency of dream plots may then arise because the evolving dream context itself biases resolution of ambiguous percepts into plotcongruent images or directly influences which protopercepts are evoked or attended to. Dreams may thus evolve by a “boot-strapping” process whereby current images provide the context that, in turn, determines succeeding dream imagery.95 In the absence of working memory capacities that provide continuity to waking experience, the evolving dream plot can be strongly influenced by immediately prior dream experiences. In a similar manner, top-down influences from limbic cortices may bias posterior association cortices toward generating, attending to, or disambiguating imagery in a manner that is congruent with ongoing dream emotion.25
A DESCRIPTIVE MODEL OF NEURONAL NETWORKS– GENERATING DREAM PHENOMENOLOGY Behavioral states and cognitive capacities are physically instantiated in widely distributed networks with distinct epicenters of critical control in a pattern of “selectively distributed processing.”96 The following working model of neurobiological structures and networks subserving REMdream phenomenology refers to brain areas as depicted in Figure 48-1.4 These REM-active networks may also help explain NREM dreaming (see first two sections below). Ascending Arousal System Activation of the forebrain in REM sleep, as in waking, occurs through the ascending arousal systems of the brainstem,16 basal forebrain,97 and hypothalamus (areas 1 and 2 in Fig. 48-1).98 However, unlike in waking, ascending activation in REM sleep is primarily facilitated by cholinergic systems whereas aminergic neuromodulation is attenuated (reviewed in Hobson et al.4) Since mesopontine PPT and laterodorsal tegmental (LDT) cholinergic neurons project to the thalamus and basal forebrain but not the cortex,71 cortical activation in REM sleep is preceded by cholinergic activation of the diencephalon and basal forebrain. Intrinsic oscillations of NREM sleep are blocked at the thalamus by ascending activation from mesopontine cholinergic nuclei.16 Cholinergic activation excites thalamocortical neurons and inhibits the GABAergic neurons of the thalamic reticular nucleus (that inhibit thalamocortical neurons during NREM sleep) thereby disinhibiting them.16 As in waking, thalamocortical neurons then activate the cortex glutamatergically. In a second, more ventral ascending activation pathway, the LDT and PPT mesopontine nuclei project to basal forebrain nuclei that,97,99 in turn, project cholinergically to regionally specific areas of the cortex71 and produce cortical activation.97,99 In NREM sleep, phasic increases in ARAS activity due to endogenous or exogenous stimulation or autonomic
570 PART I / Section 7 • Psychobiology and Dreaming FOREBRAIN PROCESSES IN NORMAL DREAMING-INTEGRATED MODEL 4
3
• Dorsolateral prefrontal cortex • Executive functions, logic, planning • Dream: Loss of volition, logic, orientation, working memory
5
8
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• Primary motor (7) and sensory (8,10) cortices • Generation of sensory percepts and motor commands • Dream: Sensorimotor hallucinosis 9
9 5 3
6 2
• Diencephalic structures (hypothalamus, basal forebrain) • Autonomic and instinctual function, cortical arousal • Dream: Consciousness, instinctual elements 1
• Thalamic nuclei (e.g., LGN) • Relay of sensory and pseudosensory information to cortex • Dream: Transmits PGO information to cortex 7 8 10
• Anterior limbic structures (amygdala, anterior cingulate, parahippocampal cortex, hippocampus, medial orbito/frontal areas) • Emotional labeling of stimuli, goal-directed behavior, movement • Dream: Emotionality, affective salience, movement 4
2
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• Basal ganglia • Initiation of motor actions • Dream: Initiation of fictive movement
PGO
1
PGO
11
10
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• Pontine and midbrain RAS and nuclei • Ascending arousal of multiple forebrain structures • Dream: Consciousness, eye movement and motor pattern information via PGO system
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Subcortical and neocortical areas relatively activated during dreaming
Neocortical areas relatively deactivated during dreaming
Ascending activation systems
Sensory input/motor output blockade
• Inferior parietal cortex (BA 40) • Spatial integration of processed heteromodal input • Dream: Spatial organization
• Visual association cortex • Higher order integration of visual percepts and images • Dream: Visual hallucinosis
• Cerebellum • Fine tuning of movement • Dream: Fictive movement Neocortical structures preferentially contributing to circuitry active during dreaming
Figure 48-1 Forebrain processes in normal dreaming—an integration of neurophysiological, neuropsychological and neuroimaging data. Regions 1 and 2, ascending arousal systems; region 3, subcortical and cortical limbic and paralimbic structures; region 4, dorsolateral prefrontal executive association cortex; region 5, motor initiation and control centers; region 6, thalamocortical relay centers and thalamic subcortical circuitry; region 7, primary motor cortex; region 8, primary sensory cortex; region 9, inferior parietal lobe; region 10, primary visual cortex; region 11, visual association cortex; region 12, cerebellum. (From Hobson JA, PaceSchott EF, Stickgold R. Dreaming and the brain: toward a cognitive neuroscience of conscious states. Behav Brain Sci 2000;23:793842; discussion 904-1121.)
activity may transiently stimulate the same forebrain networks activated in REM sleep and waking, the subjective manifestation of which may be NREM-sleep dreaming. Thalamocortical Relay Centers and Thalamic Subcortical Circuitry During REM sleep, thalamocortical signaling may be interpreted as incoming sensory stimuli,23 and may evoke local activation of stored cognitive representations (hallucinosis of known entities) or may evoke novel representations in association cortices (as in dream bizarreness) (area 6 in Fig. 48-1). The PGO wave may be only one of many pathways for ARAS activation of the cortex via thalamic or basal forebrain intermediaries during REM sleep. For example, in the rat, the pontine p-wave in REM sleep impinges directly on limbic structures such as the amygdala, hippocampus, and entorhinal cortex, as well as the
visual cortex.100 Other pathways through the thalamus might include a nonrelay sensory route through the pulvinar nucleus directly to the visual association cortex44 or to limbic prefrontal areas via magnocellular portions of the mediodorsal nucleus. Such phasic activation of the cortex may lead to the presaccade spectral changes seen using EEG and MEG,6,26 as well as the correlation of REM density with activity of attentional structures in PET studies.48,49 During NREM sleep, intrinsic thalamocortical oscillations suppress but do not completely extinguish perception and mentation.101 NREM sleep oscillatory rhythms reflect endogenous activity of corticocortical and corticothalamocortical circuits grouped by the slow oscillation, the “up” state of which briefly returns cortical neurons to levels of high activity.16,17,39,102 Steriade102 has suggested that when this oscillatory pattern is impinged upon by phasic thala-
mocortical bursts, such as the isolated PGO waves in the NREM-REM transitional state, phasic elevation of regional activity may lead to vivid visual imagery. Notably, activation in NREM sleep of primary visual38,44 and visual association103 areas may also generate NREM-sleep imagery. Subcortical and Cortical Limbic and Paralimbic Structures In REM sleep, selective activation of limbic and paralimbic cortex and subcortex35,43,44,46,47 (area 3 in Fig. 48-1) has suggested to PET researchers roles for REM sleep in the processing of emotionally influenced memories,45,104 integration of neocortical functions with basal forebrain and hypothalamic motivational and reward mechanisms,47 or internal information processing between visual association and limbic regions.44 Such processes may underlie the emotionality4,35,104 and social nature of dreaming.25,87 Emotion, Emotional Regulation, and Dreaming It is often hypothesized that sleep and dreaming play an emotional regulatory role in healthy humans105,106 that is disrupted in mood and anxiety disorders that, in turn, can alter dreaming, as in nightmares.106 Indeed, Nofzinger’s APRA includes many of the structures implicated in the experience and expression of emotion (reviewed in Phan et al.107). Although dreams may aid in resolution of intrapersonal conflict (e.g., see Cartwright et al.105), dreaming (or accompanying sleep states) may also moderate emotional extremes by universal mammalian learning processes such as habituation (decreased autonomic reactivity with repeated exposure) and extinction (learning that conditioned feared stimuli are no longer threatening), as well as by homeostatic equilibration of stress, reward, autonomic, and neuroendocrine systems. Nielsen and Levin106 have suggested that, in normal REM sleep, activity in limbic circuits that roughly overlap Nofzinger’s APRA regulates emotion via formation of extinction memories when emotionally salient memories appear in safer contexts during dreaming. Animal108 as well as human109 studies link formation, retention, and expression of extinction learning to circuitry linking the amygdala, vmPFC, and hippocampus. Notably, a night’s sleep promotes generalization of extinction learning.110 Whereas such circuitry may be recruited by dlPFC-based cognitive processes in waking111 it may function autonomously during REM sleep (see Nielsen and Levin106). Reward systems are also activated, and positive and negative emotions may be modulated during REM sleep. VTA sources of mesolimbic and mesocortical dopamine are recruited by ascending cholinergic activation77 and, like their ventral striatal and mPFC targets, lie well within the APRA.46,47 Hypothalamic-brainstem circuits may initiate instinctively salient behavior in dreaming112 that may, in turn, recruit additional forebrain regions to enact appetitive61 or other adaptive behaviors.112 Altered Memory Processing in Dreams A cholinergically-mediated informational barrier between cortex and hippocampus in REM sleep has been proposed to underlie the paucity of episodic memories in dreams.60 However, despite inaccessibility of episodic memory,
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another aspect of declarative memory, “familiarity” or “recognition,”113 is ubiquitous in dreams. For example, 40% of dream characters may be identified on the basis of “just knowing.”87 Schwartz and Maquet88 suggest such phenomena result from the sleep-related disconnection of temporal lobe face recognition from prefrontal reality monitoring areas. Alternatively, frequent experiences of familiarity in the absence of accurate replay of episodic memories in dreams may reflect activity of recognition memory mechanisms in anterior perirhinal cortices (BA 35, BA 36), dissociated from hippocampally mediated recall. Indeed, double dissociations between recognition and remembering have been shown in human fMRI studies.113 Because perirhinal areas of the anterior medial temporal lobe are proximal to the APRA,47 altered interactions of this region with other portions of the hippocampal formation during REM sleep may produce such a dissociation. During dreaming, frontal contributions to memory retrieval may also be altered. Ventrolateral and dlPFC regions that are deactivated in REM sleep45 subserve cuespecification and search strategies, respectively.84 In contrast, caudal vmPFC, which is active in REM sleep,35,43,46,47 subserves “feeling-of-rightness”84 and the related phenomenon “feeling of knowing”114 for which more anterior PFC areas only later provide cognitive verification.84 Therefore, during REM sleep, greater activation of caudo-ventromedial than anterolateral PFC regions relative to waking may favor an indiscriminate, emotional confirmation of accuracy for any item in consciousness without the benefit of strategic volitional search or critical verification. In combination, studies of self-cognition,55 mental simulation,53 confabulation,82,83 and memory verification84,114 predict that restriction of frontal activation to vmPFC would favor a self-referential, emotionally salient state prone to producing mental simulations that evoke a powerful sense of veracity and familiarity and are uncritically believed. Social Cognition and Dreams Medial PFC regions are recruited by both emotional and social cognition.107,115 Theory-of-mind is a complex aspect of social cognition115 that is preserved in dreaming despite notable degradation of reasoning about the physical world.116,117 Brain areas most consistently activated in neuroimaging studies of theory-of-mind include mPFC (especially the paracingulate cortex, BA 32), superior temporal sulcus, and temporal poles including the amygdala.115 REM-associated activity in these areas, especially vmPFC, has been suggested to support theory-of-mind skills in dreams and to produce the ubiquity of social interactions and highly salient interpersonal emotions in dream plots.25,45,116 Motor Initiation and Control Centers Strong activation of the basal ganglia35 (area 5 in Fig. 48-1) may mediate the ubiquitous fictive motion of dreams.118 The basal ganglia are extensively connected not only with motor cortex, but also with mesopontine nuclei such as the PPT119 that contain gait circuitry and other motor pattern generators as well as REM regulatory areas (reviewed in Hobson et al.4). Activation of brainstem vestibular nuclei
572 PART I / Section 7 • Psychobiology and Dreaming
and the associated cerebellar vermis (see Braun et al.35) during REM sleep may additionally contribute vestibular sensations interpreted as flying or falling, as well as a sense of motor control. Visual Association Cortex Medial occipitotemporal cortices (area 11 in Fig. 48-1) are activated in REM sleep.35,44 These and other visual association areas may generate the visual imagery of dreams.4,61 As in waking, specific areas of the visual association cortex may process specific visual characteristics of dreaming. For example, the fusiform gyrus both mediates waking face recognition and is activated in REM sleep.35,44,47 Braun and colleagues44 suggest that REM sleep constitutes a unique cortical condition of internal information processing (between visual association and limbic cortices), functionally isolated from input (via primary visual cortex) or output (via frontal cortex) to the external world. Dream image formation may arise as ascending activation impinges on visual and multimodal association areas in occipital, temporal, and inferior parietal cortices. Inferior Parietal Lobe The supramarginal and angular gyri of the inferior parietal lobe (BA 39 and 40; area 9 in Fig. 48-1), especially in the right hemisphere, are essential for visuospatial awareness.96 These areas may generate the fictive dream space necessary for the organized hallucinatory experience of dreaming.61 Destruction of these areas is alone sufficient to produce global cessation of dreaming.61,120 Maquet et al. have found right inferior parietal cortex to be relatively activated during REM in some43 but not all45 PET studies. In REM, both the above-described visual association cortex and the vmPFC are simultaneously active.44 Therefore, in REM, self-centric reality simulation, a putative function of the vmPFC,53 and hallucinatory imagery may arise in concert. Inferior parietal multimodal association cortices may integrate different unimodal inputs and facilitate their incorporation into the emerging plot in the virtual proscenium where the dream is experienced. Dorsolateral Prefrontal Executive Association Cortex (Area 4 in Figure 48-1) Lesions of the dorsolateral prefrontal cortices (area 4 in Fig. 48-1) do not cause cessation or attenuation of dreaming, which suggests that they are nonessential for the generation of dreaming.61,120 Unlike vmPFC regions that reactivate, these dorsolateral prefrontal areas remain deactivated in REM sleep,35,43-45 possibly explaining the prominent executive deficiencies of dream mentation that include disorientation, illogic, impaired working memory, and amnesia for dreams.4 Additionally, because the prefrontal cortex regulates posterior sensory cortices,121 deactivation of the dorsolateral prefrontal cortex in REM sleep35,43,45 may promote dreaming by disconnection, release, or disinhibition of sensory association cortices (as also suggested by EEG and MEG6,7,12,18). The prefrontal cortex maintains an online representation of a goal, the means to achieve it, and the ongoing context relevant to this goal in order to “bias” the functioning of networks elsewhere in the brain toward this particular outcome.122 For example, “top-down” influence can
sensitize primary and association perceptual cortices to particular stimuli while simultaneously attenuating their sensitivity to competing stimuli.123 With diminished frontal activation during sleep, goal-directed biases in the regulation of circuits subserving working memory and attention (frontoparietal), and memory encoding and retrieval (frontotemporal) may be impaired during dreaming.4,25 Nonetheless, top-down influence in REM sleep may bias sensitivity of sensory cortices to hallucinatory percepts related to affective and social processing subserved by the vmPFC, whereas nonemotional imagery may fail to persist in the face of weakened working memory. Additionally, diminished activity in lateral frontal cortices in REM sleep45 may weaken the ability of frontal, top-down influence to modulate emotional responses to dream imagery as it does in waking emotion.111 Alteration in dreaming of specific frontal-subcortical networks may underlie dream emotional salience and executive weakness. For example, the “cognitive” fronto-striatal-thalamo-cortical circuit (linking dlPFC with dorsal striatum) may be less active than “affective” (orbitofrontal-ventral caudate) and “motivational” (anterior cingulate-nucleus accumbens) circuits.124
CONCLUSION ARAS, thalamocortical, and basal forebrain-cortical arousal systems activate the forebrain regions involved in dream construction in a manner that is chemically and anatomically different from waking. In REM sleep such activation may be more frequent and sustained and, perhaps, may proceed via different or more diverse pathways than in NREM sleep. Cortical circuits activated in REM dreaming are medial circuits linking visual association and paralimbic areas (central crescent in Fig. 48-1), but not the primary sensory and lateral frontal executive cortical regions that are active in waking.44 Therefore, dreaming is both positively and negatively emotionally salient (amygdala, ventral striatum, vmPFC), often conflictual (anterior cingulate) and social (vmPFC), while also displaying profoundly deficient working memory, orientation, and logic (lateral prefrontal and parietal deactivation). Subcortical circuits involving the limbic structures, striatum, diencephalon, and the brainstem regions are selectively activated in REM sleep. They may contribute to dreaming’s emotional (limbic subcortex), motoric (striatum, brainstem, cerebellum), instinctual (hypothalamus), and motivational (midbrain-ventral striatum) properties. ❖ Clinical Pearl The physician prescribing selective serotonin reuptake inhibitors, transdermal nicotine, varenicline, beta-blockers, dopaminergic agents, or a variety of other medications65,67-69,78 should be alert for possible dream intensification or nightmare induction. Although the percentage risks of such side effects for each particular medication are variable, patient reports are not uncommon. Other choices within the same class or a different class of medications may need to be considered if such side effects are intolerable to the patient.
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68. Lam S, Patel PN. Varenicline: a selective alpha4beta2 nicotinic acetylcholine receptor partial agonist approved for smoking cessation. Cardiol Rev 2007;15:154-161. 69. Pagel JF, Helfter P. Drug induced nightmares—an etiology based review. Hum Psychopharmacol 2003;18:59-67. 70. Hobson JA, Pace-Schott EF. Reply to Solms, Braun and Reiser. Neuropsychoanalysis 1999;1:206-224. 71. Perry EK, Perry RH. Acetylcholine and hallucinations: diseaserelated compared to drug-induced alterations in human consciousness. Brain Cogn 1995;28:240-258. 72. Furey ML, Pietrini P, Haxby JV. Cholinergic enhancement and increased selectivity of perceptual processing during working memory. Science 2000;290:2315-2319. 73. Maloney KJ, Mainville L, Jones BE. c-Fos expression in dopaminergic and GABAergic neurons of the ventral mesencephalic tegmentum after paradoxical sleep deprivation and recovery. Eur J Neurosci 2002;15:774-778. 74. Lena I, Parrot S, Deschaux O, Moffat-Joly S, et al. Variations in extracellular levels of dopamine, noradrenaline, glutamate, and aspartate across the sleep–wake cycle in the medial prefrontal cortex and nucleus accumbens of freely moving rats. J Neurosci Res 2005;81:891-899. 75. Dahan L, Astier B, Vautrelle N, Urbain N, et al. Prominent burst firing of dopaminergic neurons in the ventral tegmental area during paradoxical sleep. Neuropsychopharmacology 2007;32:1232-1241. 76. Oakman SA, Faris PL, Cozzari C, Hartman BK. Characterization of the extent of pontomesencephalic cholinergic neurons’ projections to the thalamus: comparison with projections to midbrain dopaminergic groups. Neuroscience 1999;94:529-547. 77. Kobayashi Y, Okada K. Reward prediction error computation in the pedunculopontine tegmental nucleus neurons. Ann N Y Acad Sci 2007;1104:310-323. 78. Pace-Schott EF. Serotonin and dreaming. In: Monti JM, PandiPerumal SR, Jacobs B, Nutt D, editors. Serotonin and sleep: molecular, functional and clinical aspects. Basel: Birkhauser-Verlag, 2008. 79. Aghajanian GK, Marek GJ. Serotonin and hallucinogens. Neuropsychopharmacology 1999;21:16S-23S. 80. Varnas K, Halldin C, Hall H. Autoradiographic distribution of serotonin transporters and receptor subtypes in human brain. Hum Brain Mapp 2004;22:246-260. 81. Hirstein W. Brain fiction, self deception and the riddle of confabulation. Cambridge, Mass: MIT Press, 2005. 82. Gilboa A, Alain C, Stuss DT, Melo B, et al. Mechanisms of spontaneous confabulations: a strategic retrieval account. Brain 2006; 129:1399-1414. 83. Schnider A. Spontaneous confabulation and the adaptation of thought to ongoing reality. Nature Rev 2003;4:662-671. 84. Moscovitch M, Winocur G. The frontal cortex and working with memory. In: Stuss DT, Knight RT, editors. Principles of frontal lobe function. New York: Oxford University Press; 2002. p. 392-407. 85. Ciaramelli E, Ghetti S. What are confabulators’ memories made of? A study of subjective and objective measures of recollection in confabulation. Neuropsychologia 2007;45:1489-1500. 86. Williams J, Merritt J, Rittenhouse C, Hobson JA. Bizarreness in dreams and fantasies: implications for the activation-synthesis hypothesis. Conscious Cogn 1992;1:172-185. 87. Kahn D, Stickgold R, Pace-Schott EF, Hobson JA. Dreaming and waking consciousness: a character recognition study. J Sleep Res 2000;9:317-325. 88. Schwartz S, Maquet P. Sleep imaging and the neuro-psychological assessment of dreams. Trends Cogn Sci 2002;6:23-30. 89. Mar RA. The neuropsychology of narrative: story comprehension, story production and their interrelation. Neuropsychologia 2004; 42:1414-1434. 90. Devinsky O, Morrell MJ, Vogt BA. Contributions of anterior cingulate cortex to behaviour. Brain 1995;118:279-306. 91. Manford M, Andermann F. Complex visual hallucinations. Clinical and neurobiological insights. Brain 1998;121:1819-1840. 92. Ffytche DH, Howard RJ, Brammer MJ, David A, et al. The anatomy of conscious vision: an fMRI study of visual hallucinations. Nat Neurosci 1998;1:738-742. 93. Amzica F, Steriade M. Progressive cortical synchronization of ponto-geniculo-occipital potentials during rapid eye movement sleep. Neuroscience 1996;72:309-314.
94. Collerton D, Perry E, McKeith I. Why people see things that are not there: a novel perception and attention deficit model for recurrent complex visual hallucinations. Behav Brain Sci 2005;28:737757; discussion 757-794. 95. Pace-Schott EF. Complex hallucinations in waking suggest mechanisms of dream construction, Commentary on: why people see things that are not there: a novel perception and attention deficit model for recurrent complex visual hallucinations by D. Collerton, E. Perry & I. McKeith. Behav Brain Sci 2005;28:771-772. 96. Mesulam M-M. Principles of behavioral and cognitive neurology, second edition. New York: Oxford University Press; 2000. 97. Sarter M, Bruno JP. Cortical cholinergic inputs mediating arousal, attentional processing and dreaming: differential afferent regulation of the basal forebrain by telencephalic and brainstem afferents. Neurosci 2000;95:933-952. 98. Saper CB, Scammell TE, Lu J. Hypothalamic regulation of sleep and circadian rhythms. Nature 2005;437:1257-1263. 99. Jones BE. Basic mechanisms of sleep-wake states. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 4th ed. Philadelphia: Saunders; 2005. p. 136-153. 100. Datta S, Siwek DF, Patterson EH, Cipolloni PB. Localization of pontine PGO wave generation sites and their anatomical projections in the rat. Synapse 1998;30:409-423. 101. Hobson JA, Pace-Schott EF. The cognitive neuroscience of sleep: neuronal systems, consciousness and learning. Nat Rev Neurosci 2002;3:679-693. 102. Steriade M. Neuronal basis of dreaming and mentation during slow wave (non-REM) sleep. Behav Brain Sci 2000;23:1009-1011. 103. Nofzinger EA, Buysse DJ, Miewald JM, Meltzer CC, et al. Human regional cerebral glucose metabolism during non-rapid eye movement sleep in relation to waking. Brain 2002;125:1105-1115. 104. Maquet P, Franck G. REM sleep and amygdala. Mol Psychiatry 1997;2:195-196. 105. Cartwright R, Luten A, Young M, Mercer P, et al. Role of REM sleep and dream affect in overnight mood regulation: a study of normal volunteers. Psychiatry Res 1998;81:1-8. 106. Nielsen T, Levin R. Nightmares: a new neurocognitive model. Sleep Med Rev 2007;11:295-310. 107. Phan KL, Wager T, Taylor SF, Liberzon I. Functional neuroanatomy of emotion: a meta-analysis of emotion activation studies in PET and fMRI. Neuroimage 2002;16:331-348. 108. Quirk GJ, Mueller D. Neural mechanisms of extinction learning and retrieval. Neuropsychopharmacology 2008;33:56-72. 109. Milad MR, Wright CI, Orr SP, Pitman RK, et al. Recall of fear extinction in humans activates the ventromedial prefrontal cortex and hippocampus in concert. Biol Psychiatry 2007;62:446-454.
CHAPTER 48 • The Neurobiology of Dreaming 575 110. Pace-Schott EF, Milad MR, Orr SP, Rauch SL, et al. Sleep promotes generalization of extinction of conditioned fear. Sleep 2009;32:19-26. 111. Delgado MR, Nearing KI, Ledoux JE, Phelps EA. Neural circuitry underlying the regulation of conditioned fear and its relation to extinction. Neuron 2008;59:829-838. 112. Jouvet M. The paradox of sleep: the story of dreaming. Cambridge, Mass: MIT Press, 1999. 113. Brown MW, Aggleton JP. Recognition memory: what are the roles of the perirhinal cortex and hippocampus? Nat Rev Neurosci 2001;2:51-61. 114. Schnyer DM, Nicholls L, Verfaellie M. The role of VMPC in metamemorial judgments of content retrievability. J Cogn Neurosci 2005;17:832-846. 115. Amodio DM, Frith CD. Meeting of minds: the medial frontal cortex and social cognition. Nat Rev Neurosci 2006;7:268-277. 116. Kahn D, Hobson JA. Theory of mind in dreaming: awareness of feelings and thoughts of others in dreams. Dreaming 2005;15: 48-57. 117. Pace-Schott EF. Recent findings on the neurobiology of sleep and dreaming. In: Pace-Schott EF, Solms M, Blagrove M, Harnad S, editors. Sleep and dreaming: scientific advances and reconsiderations. Cambridge, Mass: Cambridge University Press; 2003. 118. Porte HS, Hobson JA. Physical motion in dreams: one measure of three theories. J Abnorm Psychol 1996;105:329-335. 119. Rye DB. Contributions of the pedunculopontine region to normal and altered REM sleep. Sleep 1997;20:757-788. 120. Doricchi F, Violani C. Dream recall in brain-damaged patients: a contribution to the neuropsychology of dreaming through a review of the literature. In: Antrobus JS, Bertini M, editors. The neuropsychology of sleep and dreaming. Hillsdale, NJ: Lawrence Erlbaum; 1992. p. 99-143. 121. Mesulam M-M. The human frontal lobes: transcending the default mode through contingent encoding. In: Stuss DT, Knight RT, editors. Principles of frontal lobe function. New York: Oxford University Press; 2002. 122. Miller EK, Cohen JD. An integrative theory of prefrontal cortex function. Annu Rev Neurosci 2001;24:167-202. 123. Padmala S, Pessoa L. Affective learning enhances visual detection and responses in primary visual cortex. J Neurosci 2008;28: 6202-6210. 124. Saint-Cyr JA. Frontal-striatal circuit functions: context, sequence, and consequence. J Int Neuropsychol Soc 2003;9:103-127. 125. Fosse R, Stickgold R, Hobson JA. Brain-mind states: reciprocal variation in thoughts and hallucinations. Psychol Sci 2001; 12:30-36.
Ultradian, Circadian, and SleepDependent Features of Dreaming Tore Nielsen Abstract Dreaming is influenced by many of the same types of chronobiologic and sleep-dependent factors that regulate other sleep processes. These principally include the 90-minute REM–NREM ultradian rhythm, the 24-hour circadian rhythm, and the sleep-dependent increase in REM propensity. Different features of dreaming have been associated with these factors,
INTRODUCTION Previous reviews of dreaming and chronobiology1,2 concluded that strikingly little convergence had occurred between chronobiology and the study of dreaming following publication of Aserinsky and Kleitman’s work3— despite the substantial accumulations of research in both domains. This chapter focuses on new findings and formulations describing potential ultradian, circadian, and sleepdependent influences on dreaming and evidence for their interactions.4,5 The term dreaming is used in an inclusive sense equivalent to that of sleep mentation, that is, the occurrence of any subjectively experienced cognitive events during sleep. ULTRADIAN FACTORS Frequency and Length of Recalled Dreams Just as the regular alternation between rapid eye movement (REM) and non-REM (NREM) sleep is thought to be governed by a 90-minute ultradian oscillator, so to do numerous studies support the notion that the amount and intensity of dream mentation fluctuates between a high in REM sleep and a low in NREM sleep. Figure 49-1 shows that peak dream recall (~80%) occurs from REM sleep whereas the lowest level of recall is from NREM sleep (~43%). Paralleling these differences are similarly large REM–NREM differences in dream report length; REM to NREM ratios in total recalled content (TRC) vary from 2 : 1 to 5 : 1.6 Beyond such dichotomous REM–NREM differences, the oscillatory nature of dream production becomes evident when it is sampled at multiple points within REM or NREM sleep stages. Figure 49-2 (left panel) shows that the length of dream reports, as reflected in TRC, fluctuates sinusoidally as a function of time spent in NREM sleep (blue bars) and time spent in REM sleep (red bars). For NREM sleep, reports are longest from 0 to 15 minutes and from 45 to 60 minutes into stage and shortest in between; for REM sleep the opposite pattern exists.7 A similar sinusoidal fluctuation was found in a replication study (see Fig. 49-2, right panel).6 Other research supports these findings. Four separate studies8-11 showed NREM dream reports to be either more prevalent or longer when awakenings took place close to a prior REM sleep episode (5 minutes) rather than far from 576
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such as the probability of recalling dream content, the length of dream reports, and the visual intensity of the dream experience. New research clarifying interactions between ultradian, circadian, and sleep-dependent factors is beginning to provide a more complete portrait of chronobiologic influences on dream production.
one (10 minutes, 30 minutes, 12 minutes, and 15 minutes, respectively). A fifth study12 showed that NREM sleep duration preceding an awakening was negatively correlated with report length. Rosenlicht13 reported that report lengths following awakenings from REM periods of 5-minute durations were marginally shorter (P = .114) than those of 10-minute durations. However, given the close proximity of these samples (5-minute difference) on the 90-minute ultradian cycle, such a trend remains consistent with the proposed ultradian oscillator. In general, dream recall and report length findings support the possibility that dream imagery is determined by the natural variation of an imagery generator oscillating through REM and NREM sleep on a 90-minute frequency. If so, stricter dream sampling criteria that more consistently control for phase relationships between REM and NREM sampling points are needed to clearly demonstrate the relationship. On one hand, awakenings following a consistent delay for both stages (e.g., 10 minutes into the stage) may bias the size of differences between the two states. For example, using the results plotted in Figure 49-2 (left panel), awakenings conducted at 0 to 15 minutes post–stage-onset would clearly lead to a modest 2 : 1 ratio in REM : NREM word count (~200 words vs. 100 words), whereas awakenings conducted at 30 to 45 minutes post– stage-onset would lead to an enormous 20 : 1 difference (~500 words vs. 25 words). On the other hand, the common method of conducting each of several awakenings of the night progressively later into the target stage (e.g., 5 minutes into REM 1, 10 minutes into REM 2, 15 minutes into REM 3, etc.), confounds ultradian phase with circadian and sleep-dependent fluctuations (see later). More accurate assessments of the ultradian dreaming process will require experimental designs sensitive to these confounds as well as the implementation of protocols capable of separating ultradian, circadian and sleep-dependent factors, for example, forced desynchrony and ultrashort sleep–wake protocols (see later). Quality of Dream Reports Evidence also indicates that dream qualities such as vividness, intensity, and dreamlikeness oscillate with an ultradian frequency within and between REM and NREM sleep. Many studies (see reviews in Nielsen14 and Hobson et al.15) demonstrate that REM sleep reports are more
CHAPTER 49 • Ultradian, Circadian, and Sleep-Dependent Features of Dreaming 577
perceptual, hallucinatory, emotional, dramatic, physically involving, and rich with characters and visual scenes than are NREM reports, whereas the latter are more conceptual, thoughtlike, and mundane.16 However, because REM reports are also consistently longer than are NREM reports, some argue that comparing the two is valid only if this difference is statistically controlled by, for example, selecting equal-length reports, calculating proportions with a common metric, or removing report length as a co-variate. Such procedures have been criticized on methodological grounds,14,15,17 but there is nonetheless consistent evidence that qualitative REMNREM differences are maintained even after report length is controlled (see review in Nielsen14). Even with length controls, REM dream reports surpass NREM dream reports on measures of emotional intensity,18 selfreflectiveness,19 bizarreness,20,21 visual and verbal
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Figure 49-1 Percent recall of dreaming from rapid eye movement (REM) and non-REM (NREM) sleep awakenings in 50 studies from 1953 to 2007. Although fluctuations in recall can be attributed in some measure to varying definitions of dreaming from study to study, they are also consistent with the suggestion that dream formation is influenced by the natural variation of a 90-minute ultradian oscillator.
imagery,20,22,23 movement imagery,24 characters and selfinvolvement,25,26 self-representation,26 psycholinguistic structure,27 and narrative linkage.28 Clear within-stage sinusoidal variations of such qualitative measures are more difficult to demonstrate. Dream reports from “long” REM sleep episodes (9 minutes or more) are, relative to those from “short” episodes (1 minute or less), more active, distorted, dramatic, emotional, anxious, unpleasant, and vivid and contain more different scenes, more scenes with clear visualization, and more violence and hostility.16 Similar results were obtained from a small sample (N = 4) of male students each awakened 12 times—twice each from REM 2 and REM 4 for each of six REM onset time delays: 0.5, 2.5, 5.0, 10, 20, and 30 minutes. Of 12 qualities rated, emotion, anxiety, pleasantness, and clarity all showed linear increases over time; emotion, anxiety, and pleasantness showed additional trends suggesting ultradian modulation with peaks at 10 and 30 minutes.29-31 For NREM sleep, two studies suggest an ultradian oscillation opposite to that in REM sleep. In one study,32 dreamlike fantasy scale scores were lower (P < .10) for reports from 20-minute NREM (stage 4) episodes than they were for 5-minute NREM episodes matched within subjects and for time of night. In a second study,10 NREM (stage 2) reports obtained from 12-minute episodes after the end of REM sleep episodes were rated as less dreamlike than were the NREM reports obtained 5 minutes after REM sleep episodes (P < .001). Additional studies suggest that the types of memory associations that subjects produce as likely sources of their dreams oscillate with ultradian frequency. These are primarily biographical episodes (episodic memories) for NREM dream content, and a mixture of episodic and semantic memories for REM dream content.33-35 The predominance of episodic sources for NREM dreams is independent of time of night and of corrections for report length.33,35-38 In contrast to much of the preceding, variables such as plausibility and sensibleness of the dream do not vary with time-in-stage.39,40 A more exact determination of which 160 120 Median TRC
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Figure 49-2 Dream report length following awakenings from NREM and REM sleep periods of different durations in two studies. A, Mean (±SEM) report length as a function of elapsed time in stage for 88 REM and 61 NREM reports. TRC, total recall count. (From Hobson JA, Pace-Schott E, Stickgold R. Dreaming and the brain: towards a cognitive neuroscience of conscious states. Behav Brain Sci 2000;23:793-842.); B, Median (±SEM) report length as a function of elapsed time in stage for 264 REM (red line) and 247 NREM (blue line) home reports (N = 16 subjects; From Stickgold R, Malia A, Fosse R, et al. Brain-mind states: I. Longitudinal field study of sleep/wake factors influencing mentation report length. Sleep 2001;24:171-179.).
578 PART I / Section 7 • Psychobiology and Dreaming
qualitative dream features oscillate and which do not may provide clues as to the functional dynamics of dream imagery. In sum, most results from quantitative and qualitative assessments of REM and NREM dream reports support the assumption that dream production is influenced by processes with ultradian rhythmicity. The differing prevalence, length, and qualities of REM and NREM dream reports likely reflect the output of one or more imagery generation processes that are sampled at varying points along their rising and descending slopes. Oscillatory transitions between and within REM and NREM dreaming are both clearly paralleled by regular physiological oscillations, e.g., by ultradian-determined variations in REM sleep propensity. Within-stage changes include variations in EEG power, and autonomic and hormonal measures. The clearest variations occur in stage 2 sleep: autonomic activity increases for stage 2 sleep that precedes REM sleep and decreases for stage 2 sleep that precedes SWS.41 Similarly, fast EEG events such as arousals and stage 2 cyclic alternating pattern A2 and A3 phases often begin well before REM sleep.42 Even more basic regulatory systems, like pontine REM-on neurons, demonstrate a graduated oscillation that begins well before EEG-defined REM sleep onset.43 Such variations led to the speculation41 that stage 2 sleep is fundamental to the ultradian oscillatory process of sleep deepening and lightening. I have linked such changes to the gradual and imperceptible onset and offset of REM sleep processes (“covert REM processes”12,14), but they may equally well be considered ultradian variations in REM sleep propensity that reflect ultradian oscillations in the presence and intensity of dream imagery.
CIRCADIAN AND SLEEP-DEPENDENT FACTORS Purely circadian features of dream production are difficult to ascertain because their measurement is usually limited to the nocturnal portion of the sleep–wake cycle and because across-the-night changes that are identified could be due to sleep-dependent processes, circadian influences, or a combination of the two. How might sleep-dependent and circadian influences on dreaming be distinguished? As suggested in the previous section, a useful heuristic is to use the close ultradian coupling of dreaming and REM propensity to evaluate across-the-night changes in dreaming. Using a forced desynchrony protocol, sleepdependent and circadian-driven patterns of REM sleep propensity (REM%) have been isolated (Fig. 49-3).44 Figure 49-3 (panel A) shows that circadian-driven fluctuations in REM% are characterized by abrupt “switch-like”45 transitions, that is, rapid increases in the middle of the night, whereas sleep-dependent changes (panel B) are gradual and linear in nature. Applying these REM propensity patterns to dreaming, the following sections examine whether across-the-night changes in dreaming may be identified that are characterized by circadian (abrupt, switchlike) and sleep-dependent (gradual, linear) oscillations. Some changes in dream length, content, organization, and memory sources suggest circadian-style changes whereas others suggest sleep-
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Figure 49-3 Using a forced desynchrony protocol, Dijk and Czeisler44 showed that the sleep-dependent increase in REM propensity (B) parallels a gradual sleep-dependent increase in core body temperature (D) and is distinct from a circadian oscillation in REM propensity (A, double-plotted). The latter tends to vary inversely with body temperature, reaching its acrophase at about 8 am, roughly 6 hours before onset of the core body temperature plateau (C, double-plotted).
dependent changes. In the case of circadian changes, marked differences are noted between reports from the first third of the night and all later sample points (see reviews in Nielsen 20041 and Nielsen 20052). Dream Recall and Report Length Changes Across the Night Some studies reveal gradual across-the-night changes that resemble sleep-dependent effects. There is a lengthening of young adults’ dream reports sampled from early (0 to 2.5 hours) to middle (2.5 to 5 hours) to late (5 to 7.5 hours) night when awakenings are conducted at a constant 4.8 to 5 minutes into REM sleep.23,46 However, for older subjects the increase in length occurs only between middle- and late-night samples. Similarly, when mentation is sampled from the first four REM periods (awakenings all 9 minutes into each stage), a gradual increase across the night is observed for one story structure measure, the number of episodes per story (P < .001; order of means: REM 1 < REM 2 < REM 3 = REM 4) but not another, the number of statements in the event structure (P < .001; order of means: REM 1 < REM 2 = REM 3 = REM 4).47 Other findings more consistently suggest circadian switchlike changes similar to those for REM propensity and core body temperature (CBT). Our assessment of 40 subjects (135 reports)48 found that both probability of recall and mean word count were lower for REM 1 than for REM 2 through REM 5 with no difference among the latter (Fig. 49-4, A panel). Because REM awakenings were made progressively later into each REM period (5 minutes into REM 1, 10 minutes into REM 2, 15 minutes into
CHAPTER 49 • Ultradian, Circadian, and Sleep-Dependent Features of Dreaming 579
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REM 3, 20 minutes into REM 4 and REM 5); however, these findings may be confounded by an ultradian oscillation. Other studies reporting length differences for REM dreams sampled early and late in the night are limited to only two sample points per night, and no clear inference about temporal morphology can be made. For example, REM 2 reports are half the length of REM 4 reports, whether awakenings occur 10 minutes (P = .001) or 5 minutes into REM sleep (P = .07).13 Similarly, late night REM reports have higher word information counts than do early night REM reports (P < .001).18,22 Across-the-night changes for NREM dreaming parallel those for REM sleep, some displaying changes that are
gradual, others abrupt. In a study described earlier23,46 in which dreams were evaluated for early, middle, and late stage 2 awakenings, report length increased linearly across the three times for young subjects, but it was uniformly high for early and middle samples then dropped sharply in the late sample for older subjects. In contrast, awakenings from four different NREM periods per night revealed an abrupt increase in awakenings producing content from a low for NREM 1 (45%) to a plateau for NREM 2 (70%), NREM 3 (70%), and NREM 4 (74%; see Fig. 49-4, panel B).49 The ingenious application of an ultrashort sleep–wake protocol isolated a clear circadian oscillation of dreaming for NREM sleep.50 Subjects were entrained to a 20-minute nap–40-minute wake schedule over 78 hours while dream content and salivary melatonin were sampled after every awakening (Fig. 49-5A). Subjects scored dream content in response to the question How much did you dream? 0: none, 1: little, 2: a moderate amount, 3: a lot. Dreaming scores for awakenings from naps containing no REM sleep (NREM naps) varied sinusoidally over the 24-hour cycle with an acrophase at 8:00 am (see Fig. 49-5, panel B, bottom). Dreaming scores for naps containing REM sleep (REM naps) increased and decreased rather abruptly at 06:00 and 16:00 respectively (see Fig. 49-5, panel B, middle). A remarkable finding for the NREM naps was that dreaming scores paralleled the curve for REM (but not NREM) sleep propensity (Fig. 49-5, panel B, top), correlating positively at r = 0.87 (P < .0001). Why NREM dreaming would possess a sinusoidal morphology and REM dreaming a switchlike one is not clear. One possibility is that ultradian and circadian oscillations interact such that more abrupt circadian changes are enabled in REM but not NREM sleep. Another methodological concern is that the dreaming measure is not equally sensitive for the two states; the elevated plateau for REM dreaming scores may reflect a ceiling effect for the relatively crude 4-point scale used. Nonetheless, the high degree of synchrony observed between NREM dreaming and REM sleep time (r = 0.87) is consistent with the possibility that dreaming during REM and NREM sleep are influenced by the same underlying circadian oscillator. Qualities of Dream Reports Change across the Night Studies of across-the-night changes in dream qualities for the most part suggest that dreaming becomes more abruptly realistic and engaging in late relative to early sleep cycles, with dreams sampled in the first or second sleep cycles differing markedly from those in subsequent cycles. However, these qualitative changes are typically confounded by differences in report length, so the same earlier caveats about length for ultradian rhythms also apply. In the case of REM sleep, several studies converge in demonstrating abrupt early night changes consistent with a switchlike circadian influence. First, one study of 73 dreams found that REM 1 reports differed from REM 2 and REM 3 reports on several scales: REM 2 and 3 dreams had more characters, more aggression and misfortune elements, more buildings, and fewer terrain settings.51 However, for some scales, REM 1 and REM 2 reports
580 PART I / Section 7 • Psychobiology and Dreaming Day 1
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Figure 49-5 A, Experimental schedule for ultrashort sleep–wake study.50 At the end of each 20-minute nap, a dream report was obtained and rated. B, Double-plotted REM time and nap dreaming scores for subjects on the ultrashort sleep–wake protocol. Three-day means are displayed by 2-hour blocks time-locked to the onset of melatonin release (22:00). Dream scores for naps yielding REM reports (middle panel) show some circadian variation with switchlike transitions and a plateau spanning 06:00 to 16:00. Dreaming scores for NREM reports (bottom panel) clearly conform to a sinusoidal circadian oscillation with an acrophase at 08:00. The NREM dreaming score acrophase coincides with the acrophase of REM propensity (top panel, r = 0.87, P < .0001) but not of NREM propensity (not shown). A further, circasemidian component is suggested by the secondary NREM peak at 16:00. (Adapted from Suzuki H, Uchiyama M, Tagaya H, et al. Dreaming during non-rapid eye movement sleep in the absence of prior rapid eye movement sleep. Sleep 2004;27:1486-1490.)
both differed from REM 3 reports: REM 3 dreams had more sexual acts, more food elements and fewer room settings. In a second study, subject ratings on an array of variables differentiated REM 1 reports from REM 2 and REM 3 reports.16,52 Third, dreams from young adults changed more markedly from REM 1 to REM 2 (increases in 15 of 41 variables) than from REM 2 to REM 3 (6 of 41 variables) and REM 3 to REM 4 (7 of 41 variables).53
Fourth, dreams increased in dreamlike quality from REM 1 and REM 2 to all later REM periods; this included an increase in strongly emotional content (from 16.7% to 23.1%) and positive emotion (from 15.4% to 38.5%) and a decrease in neutral emotion (from 69.2% to 46.1%).54 Finally, positive correlations between time of night of REM awakenings and dream vividness (P = .01) and emotionality (P = .05) ratings have been reported,40 but such
CHAPTER 49 • Ultradian, Circadian, and Sleep-Dependent Features of Dreaming 581
correlations would be expected for either a circadian or a sleep-dependent influence. It is noteworthy that time-in-stage (ultradian) confounds exist in many of the preceding studies. Two procedures16,54 progressively increased time-in-stage before awakening for successive REM periods (5 minutes, 10 minutes, 20 minutes, etc.). A third study40 used short (5 minute) REM 1 awakenings whereas all later awakenings were either short or long (5 vs. 12 minutes). A fourth study53 targeted the end of REM episodes for awakenings, but early REM episodes are usually shorter than later ones. Altogether, however, the preceding results are surprisingly consistent with findings that are free of similar confounds. When ultradian factors were controlled by limiting awakenings to 4.8 to 5.0 minutes into each REM period,23 the number of visual nouns, action words, modifiers, and spatial relations in reports increased abruptly from the first to the second third of the night but not from the second to the third third of the night. Similarly, in a series of five studies55 that minimized ultradian confounds by limiting awakenings to 5 to 10 minutes into REM sleep, withinnight increases in left hemisphere, but not right hemisphere, processes in reports were observed. Importantly, two studies20,22 that failed to demonstrate differences between early and late night REM dreams only compared REM 2 and REM 3 dreams. As for ultradian sampling protocols that separate samples by only 5 minutes along a 90-minute curve, REM 2 and REM 3 may be too close on the 24-hour circadian curve to reveal consistent phase differences—especially if the most abrupt transition tends to take place between REM 1 and REM 2. In the case of NREM dreaming, across-the-night increases in dream quality have also been observed in studies that controlled ultradian confounds. Findings are mixed as to whether the changes are gradual or abrupt. First, dreamlike fantasy scale scores of dream reports are low in NREM 1 but then are abruptly higher in NREM 2, NREM 3, and NREM 4 (see Fig. 49-4, panel B).49 Second, NREM visual imagery scores increase linearly across the early, middle, and late thirds of the night.23 Two additional studies of only two samples per night both found increases from early-to-late night.10,20 To summarize, numerous studies demonstrate increases in dream recall or intensity across the night, although the time course of these changes is variable. Abrupt changes occur predominantly in REM sleep and are associated almost exclusively with REM 1-to-REM 2 or REM 2-toREM 3 transitions. Although it is possible that these subtly different transition points reflect different, slightly out of phase circadian processes, for example, left hemisphere and right hemisphere influences,55 it also may be that they arise from methodologic differences. Specifically, variations in the timing of lights-out relative to circadian phase may advance or delay the point at which a transition takes place. It might be that bedtimes are later than usual in most laboratory studies due to the complications of polysomnography setup and calibration; thus, most studies report earlier-than-normal transitions (i.e., REM 1 to REM 2) in dreaming. This is an easily testable possibility. As described next, some evidence suggests that delaying bedtime can, in fact, alter the circadian phase relationships of successive REM or NREM periods.
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Figure 49-6 Forced desynchrony protocol applied to dream collection. Hypothetical subject has a typical bed time of 12:00 am and typical wake time of 8:00 am. Experimental bed time is delayed by 3 hours and sleeping in is allowed. If the circadian influence on dreaming parallels that for core body temperature, then awakenings for report collection are shifted so as to occur at the nadir of the curve for report collection #1 (5:00 am) and along its rising phase for report collection #2 (~10:00 am). As predicted, dream length and vividness were increased for reports on the rising phase of the curve. (From Wamsley EJ, Hirota Y, Tucker MA, et al. Circadian and ultradian influences on dreaming: a dual rhythm model. Brain Res Bull 2007;71: 347-354.)
A forced desynchrony protocol has been used to clarify the separate roles of ultradian and circadian influences.18,22 (See Fig. 49-6 for conceptual basis of protocol.) The hypothesized circadian-driven influence on dreaming reaches its nadir near 5:00 am, its rising phase at habitual wake up time (8:00 am) and its acrophase around 12:00 pm. This rhythm is assumed to be in close phase relationship with core body temperature (CBT), whose nadir typically occurs in the early evening and whose morning rising phase correlates with decreased REM-related alpha power,56 NREM spindle density,57 and waking performance.58 On experimental nights, subjects in this protocol go to bed 3 hours later than their typical bedtime and are allowed to sleep late in the morning. This forces early night NREM dreaming to occur closer to the circadian nadir and late night NREM dreaming to occur higher on its rising slope. The first use of this protocol22 found large differences between REM and NREM dream reports on total word count, visual and verbal imagery, and bizarreness regardless of where along the hypothesized circadian curve the reports were collected. However, a circadian effect was observed that was independent of the ultradian effect: Late night dream reports of both types were longer and more visually intense than early night dream reports. For visual imagery, the circadian effect size (.23, or small) was about 30% of the ultradian effect size (.70, or large). The authors concluded that ultradian and circadian sources of cortical and subcortical activation are independent but additive in their effects on dreaming. The second study tested a more nuanced “dual rhythm” model of chronobiological interactions.18 This model
582 PART I / Section 7 • Psychobiology and Dreaming
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stipulates that some features of dream formation are, as in the previous study, due to a summation of ultradian and circadian variations in general cortical activation whereas other features are due to regional activation patterns unique to the NREM–REM ultradian rhythm. Consistent with this model, measures of dream length, dreamlike quality, dream speech, and content bizarreness proved to be additive functions of ultradian and circadian factors, that is, they were more elevated for REM than for NREM reports and for late than for early reports—without interactions between the effects. However, other features such as visual brightness, visual clarity, and emotion intensity varied only as a function of the NREM–REM factor, that is, they were more elevated for REM than for NREM reports. A third study in this series was designed to extend the dual rhythm model, but it mainly contradicted the expected results.18 NREM dreams were collected from subjects who took naps around 12:30 pm, that is, near the acrophase of the hypothesized circadian process and higher on the curve than any of the sample times in the previous study (Fig. 49-7A). These NREM nap dreams were compared with dreams collected from early and late NREM periods in the previous study. The predicted elevations in length and vividness of nap dreams relative to late morning NREM dreams were not observed. Rather, nap dreams resembled dreams from early night NREM awakenings, that is, near the nadir of the hypothesized curve (see Fig. 49-7B).4 The authors conclude that a circadian influence resembling that of CBT is inadequate to explain the findings, and they propose several circadian processes with an earlier acrophase than the CBT rhythm, for example, 8:00 am, that could account for the unexpected diminution of NREM dream vividness. They reject REM sleep propensity—the most obvious candidate—in favor of other circadian processes, such as cortisol, which follows a time course similar to that of REM propensity59 and influences memory encoding and retrieval.60,61 Cortisol has been put forward as a major influence on dreaming not only because its across-the-night increase parallels that of dream prevalence and intensity, but also because it is implicated in memory consolidation functions.5 Specifically, evidence that glucocorticoid administration interferes with episodic memory led to the proposition5 that rising levels of nocturnal endogenous cortisol similarly interfere with episodic memory consolidation during sleep. By virtue of the same mechanism, cortisol produces dreaming that lacks coherence, context, and episodic detail. Although this model accounts for the finding that episodic memory sources of dreaming are less numerous late, rather than early, in the night, it is inconsistent with other findings. For example, episodic memory performance is typically better in the morning than it is at later times,62-65 yet endogenous cortisol reaches its acrophase around 8:00 am when the worst performance levels would be expected. Further research is needed to examine whether endogenous and exogenous cortisol in fact have similar effects on memory processes and dreaming as assumed. A more parsimonious explanation for the finding of unexpectedly low dreaming scores for afternoon naps4 is that dream formation is tied to circadian oscillations of REM propensity. REM propensity reaches its acrophase
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Figure 49-7 A, Timing of three NREM report collection conditions in relation to presumed time courses of circadian-driven activation and homeostatic sleep pressure. Afternoon nap reports (~12:30 pm) were collected when circadian-driven activation was presumably much higher than during night report 1 (~5:00 am) or night report 2 (~9:30 am). However, homeostatic sleep pressure during naps was presumably also at least equal to that during night report 1. B, Word information count of NREM dream reports collected after awakenings from the three conditions. The predicted result, based on the notion that NREM dreaming is influenced by a circadian process with an acrophase paralleling that of core body temperature, was not observed. NREM dream reports were shorter, and dream imagery less vivid and bizarre, than were dreams reported at night report 2. The finding suggests rather that nap dreams were influenced by the descending phase of a circadian factor with an earlier acrophase (~8:00 am) than that of core body temperature. Both REM sleep propensity and cortisol have such morphologies and have been discussed as possible causal factors. (Adapted from Wamsley EJ, Antrobus JS. Homeostatic and circadian influences on dreaming: NREM mentation during a short daytime nap. Int J Dream Res 2008;1:27-32.)
at around 8:00 am, so its influence would be waning in parallel with the decrease in NREM dream intensity found for the afternoon naps. Evidence reviewed earlier50 indicates that NREM dreaming is remarkably strongly correlated with REM%, a primary marker of REM propensity.66 Furthermore, studies have shown that increases in REM
CHAPTER 49 • Ultradian, Circadian, and Sleep-Dependent Features of Dreaming 583
propensity by REM sleep deprivation increases the dreamlike quality of both nighttime REM dreams and sleep onset NREM dreams the following evening.67
SUMMARY Quantitative and qualitative studies reveal robust variations both within and between REM and NREM dreams that suggest ultradian influences, whereas robust acrossthe-night changes in REM and NREM dreams suggest circadian and sleep-dependent influences. Most of the latter studies, especially those concerning REM sleep, suggest that across-the-night changes are abrupt and occur early—as might be expected by analogy to the rising phase of the circadian rhythm of REM propensity at this time. However, gradual linear increases analogous to sleepdependent increases in REM% have also been observed, particularly for NREM dreams. At present, only one study has clearly demonstrated that circadian modulation of NREM dreaming and, to a lesser extent REM dreaming, is independent of sleep-dependent modulation. The literature is thus consistent with the claim that the quantity and qualities of dreaming are influenced by ultradian, circadian, and sleep-dependent factors. However, much more work is required to describe the nature of these factors and their interactions for a range of normal and abnormal populations. Several findings suggest that this work may be profitably guided by concurrently examining REM sleep propensity, which is modulated by the same three sets of factors. Particularly intriguing is evidence that NREM dreaming may be modulated by the circadian oscillation of REM sleep propensity. If REM propensity, in fact, determines variations in dream frequency and intensity in both REM and NREM sleep, then research would clearly benefit from developing better markers of REM propensity. Reduced muscle tone68 and EEG alpha (8.25 to 11.0 Hz) power69 have both been partially validated as possible markers. REM-related alpha power reductions may even be detectible during the waking state.70 Attention should also be given to the selection of dream quantity and quality measures as these vary considerably in sensitivity with different types of dream mentation. Indeed, different measures may be needed to accurately capture the oscillations of dream content in different sleep stages across the night. ❖ Clinical Pearl Atypical recall of vivid dreams may be the result of phase desynchrony between ultradian and circadian influences on dreaming.
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4. Wamsley EJ, Antrobus JS. Homeostatic and circadian influences on dreaming: NREM mentation during a short daytime nap. Int J Dream Res 2008;1:27-32. 5. Payne JD, Nadel L. Sleep, dreams, and memory consolidation: the role of the stress hormone cortisol. Learn Mem 2004;11:671-678. 6. Stickgold R, Malia A, Fosse R, et al. Brain-mind states: I. Longitudinal field study of sleep/wake factors influencing mentation report length. Sleep 2001;24:171-179. 7. Stickgold R, Pace-Schott E, Hobson JA. A new paradigm for dream research—mentation reports following spontaneous arousal from REM and NREM sleep recorded in a home setting. Conscious Cogn 1994;3:16-29. 8. Wolpert EA, Trosman H. Studies in psychophysiology of dreams I. Experimental evocation of sequential dream episodes. Arch Neurol Psychiatr 1958;79:603-606. 9. Goodenough DR, Lewis HB, Shapiro A, et al. Dream reporting following abrupt and gradual awakenings from different types of sleep. J Pers Soc Psychol 1965;2:170-179. 10. Arkin AM, Antrobus JS, Ellman SJ, et al. Sleep mentation as affected by REMP deprivation. In: Arkin AM, Antrobus JS, Ellman SJ, editors. The mind in sleep: psychology and psychophysiology. Hillsdale, NJ: Lawrence Erlbaum; 1978. p. 459-484. 11. Antrobus JS, Fein G, Jordan L, et al. Measurement and design in research on sleep reports. In: Ellman SJ, Antrobus J, editors. The mind in sleep. Psychology and psychophysiology. New York: John Wiley & Sons; 1991. p. 83-122. 12. Nielsen TA. Covert REM sleep effects on NREM mentation: further methodological considerations and supporting evidence. Behav Brain Sci 2000;23:1040-1057. 13. Rosenlicht N, Maloney T, Feinberg I. Dream report length is more dependent on arousal level than prior REM duration. Brain Res Bull 1994;34:99-101. 14. Nielsen TA. A review of mentation in REM and NREM sleep: “covert” REM sleep as a possible reconciliation of two opposing models. Behav Brain Sci 2000;23:851-866. 15. Hobson JA, Pace-Schott E, Stickgold R. Dreaming and the brain: towards a cognitive neuroscience of conscious states. Behav Brain Sci 2000;23:793-842. 16. Foulkes D. The psychology of sleep. New York: Charles Scribner’s Sons; 1966. 17. Hunt H, Ruzycki-Hunt K, Pariak D, et al. The relationship between dream bizarreness and imagination: artifact or essence? Dreaming 1993;3:179-199. 18. Wamsley EJ, Hirota Y, Tucker MA, et al. Circadian and ultradian influences on dreaming: a dual rhythm model. Brain Res Bull 2007;71:347-354. 19. Purcell S, Mullington J, Moffitt A, et al. Dream self-reflectiveness as a learned cognitive skill. Sleep 1986;9:423-437. 20. Casagrande M, Violani C, Lucidi F, et al. Variations in sleep mentation as a function of time of night. Int J Neurosci 1996; 85:19-30. 21. Porte H, Hobson JA. Bizarreness in REM and NREM reports. Sleep Res 1986;15:81. 22. Antrobus J, Kondo T, Reinsel R, et al. Dreaming in the late morning: summation of REM and diurnal cortical activation. Conscious Cogn 1995;4:275-299. 23. Waterman D, Elton M, Kenemans JL. Methodological issues affecting the collection of dreams. J Sleep Res 1993;2:8-12. 24. Porte HS, Hobson JA. Physical motion in dreams—one measure of three theories. J Abn Psychol 1996;105:329-335. 25. Strauch I, Meier B. In search of dreams. Results of experimental dream research. Albany, NY: State University of New York Press; 1996. 26. Foulkes D, Schmidt M. Temporal sequence and unit composition in dream reports from different stages of sleep. Sleep 1983;6:265-280. 27. Casagrande M, Violani C, Bertini M. A psycholinguistic method for analyzing two modalities of thought in dream reports. Dreaming 1996;6:43-55. 28. Nielsen TA, Kuiken D, Hoffmann R, et al. REM and NREM sleep mentation differences: a question of story structure? Sleep Hypn 2001;3:9-17. 29. Czaya J, Kramer M, Roth T. Changes in dream quality as a function of time into REM. Sleep Res 1973;2:122. 30. Kramer M, Roth T, Czaya J. Dream development within a REM period. In: Levin P, Koella WP, editors. Sleep 1974, Second
584 PART I / Section 7 • Psychobiology and Dreaming European Congress on Sleep Research, Rome, 1974. Basel: Karger; 1974. p. 406-408. 31. Kramer M. The selective mood regulatory function of dreaming: an update and revision. In: Moffitt A, Kramer M, Hoffman R, editors. The function of dreaming. Albany, NY: State University of New York Press; 1993. p. 139-196. 32. Tracy RL, Tracy LN. Reports of mental activity from sleep stages 2 and 4. Percept Mot Skills 1974;38:647-648. 33. Cavallero C, Cicogna P. Memory and dreaming. In: Cavallero C, Foulkes D, editors. Dreaming as cognition. New York: Harvester Wheatsheaf; 1993. p. 38-57. 34. Cicogna P, Cavallero C, Bosinelli M. Differential access to memory traces in the production of mental experience. Int J Psychophysiol 1986;4:209-216. 35. Baylor GW, Cavallero C. Memory sources associated with REM and NREM dream reports throughout the night: a new look at the data. Sleep 2001;24:165-170. 36. Cavallero C, Foulkes D, Hollifield M, et al. Memory sources of REM and NREM dreams. Sleep 1990;13:449-455. 37. Cavallero C, Cicogna P, Natale V, et al. Slow wave sleep dreaming. Sleep 1992;15:562-566. 38. Cicogna P, Cavallero C, Bosinelli M. Cognitive aspects of mental activity during sleep. Am J Psychol 1991;104:413-425. 39. Foulkes D. Dream reports from different stages of sleep. J Abnorm Soc Psych 1962;65:14-25. 40. Verdone P. Temporal reference of manifest dream content. Percept Mot Skills 1965;20:1253-1268. 41. Brandenberger G, Ehrhart J, Buchheit M. Sleep stage 2: an electroencephalographic, autonomic, and hormonal duality. Sleep 2005; 28:1535-1540. 42. Terzano MG, Parrino L, Smerieri A, et al. CAP and arousals are involved in the homeostatic and ultradian sleep processes. J Sleep Res 2005;14:359-368. 43. McCarley RW. Dreams and the biology of sleep. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 2nd ed. Philadelphia: Saunders; 1994. p. 373-383. 44. Dijk DJ, Czeisler C. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci 1995;15:3526-3538. 45. Wehr TA, Aeschbach D, Duncan WC Jr. Evidence for a biological dawn and dusk in the human circadian timing system. J Physiol 2001;535:937-951. 46. Waterman D. Rapid eye movement sleep and dreaming. Studies of age and activation. Amsterdam: University of Amsterdam; 1992. 47. Cipolli C, Bolzani R, Tuozzi G. Story-like organization of dream experience in different periods of REM sleep. J Sleep Res 1998; 7:13-19. 48. Nielsen TA, Germain A, Zadra AL, et al. Physiological correlates of dream recall vary across REM periods: eye movement density vs heart rate. Sleep Res 1997;26:249. 49. Pivik T, Foulkes D. NREM mentation: relation to personality, orientation time, and time of night. J Consult Clin Psychol 1968;32: 144-151. 50. Suzuki H, Uchiyama M, Tagaya H, et al. Dreaming during non-rapid eye movement sleep in the absence of prior rapid eye movement sleep. Sleep 2004;27:1486-1490.
51. Domhoff B, Kamiya J. Problems in dream content study with objective indicators: III. Changes in dream content throughout the night. Arch Gen Psychiatr 1964;11:529-532. 52. Foulkes D, Rechtschaffen A. Presleep determinants of dream content: Effects of two films. Percept Mot Skills 1964;19:983-1005. 53. Kramer M, McQuarrie E, Bonnet M. Dream differences as a function of REM period position. Sleep Res 1980;9:155. 54. Agargun MY, Cartwright R. REM sleep, dream variables and suicidality in depressed patients. Psychiat Res 2003;119:33-39. 55. Cohen DB. Changes in REM dream content during the night: implications for a hypothesis about changes in cerebral dominance across REM periods. Percept Mot Skills 1977;44:1267-1277. 56. Dijk DJ, Shanahan TL, Duffy JF, et al. Variation of electroencephalographic activity during non-rapid eye movement and rapid eye movement sleep with phase of circadian melatonin rhythm in humans. J Physiol 1997;505:851-858. 57. De Gennaro L, Ferrara M. Sleep spindles: an overview. Sleep Med Rev 2003;7:423-440. 58. Carrier J, Monk T. Effects of sleep and circadian rhythms on performance. In: Turek F, Zee P, editors. Regulation of sleep and circadian rhythms. New York: Marcel Dekker; 1999. 59. Uchiyama M, Ishibashi K, Enomoto T, et al. Twenty-four hour profiles of four hormones under constant routine. Psychiatry Clin Neurosci 1998;52:241-243. 60. Andreano JM, Cahill L. Glucocorticoid release and memory consolidation in men and women. Psychol Sci 2006;17:466-470. 61. Buchanan TW, Lovallo WR. Enhanced memory for emotional material following stress-level cortisol treatment in humans. Psychoneuroendocrinology 2001;26:307-317. 62. Martin B, Buffington AL, Welsh-Bohmer KA, et al. Time of day affects episodic memory in older adults. Neuropsychol Dev Cogn B Aging Neuropsychol Cogn 2008;15:146-164. 63. Intons-Peterson MJ, Rocchi P, West T, et al. Age, testing at preferred or nonpreferred times (testing optimality), and false memory. J Exp Psychol Learn Mem Cogn 1999;25:23-40. 64. May CP, Hasher L, Foong N. Implicit memory, age, and time of day: paradoxical priming effects. Psychol Sci 2005;16:96-100. 65. May CP, Hasher L, Stoltzfus ER. Optimal time of day and the magnitude of age differences in memory. Psychol Sci 1993;4: 326-330. 66. Czeisler CA, Zimmerman JC, Ronda JM, et al. Timing of REM sleep is coupled to the circadian rhythm of body temperature in man. Sleep 1980;2:329-346. 67. Nielsen TA, Stenstrom PM, Takeuchi T, et al. Partial REM sleep deprivation increases the dream-like quality of mentation from REM sleep and sleep onset. Sleep 2005;28:1083-1089. 68. Werth E, Achermann P, Borbely AA. Selective REM sleep deprivation during daytime. II. Muscle atonia in non-REM sleep. Am J Physiol Regul Integr Comp Physiol 2002;283:R527-R532. 69. Endo T, Roth C, Landolt HP, et al. Selective REM sleep deprivation in humans: effects on sleep and sleep EEG. Am J Physiol 1998;274: R1186-R1194. 70. Brunner DP, Dijk DJ, Borbely AA. Repeated partial sleep deprivation progressively changes in EEG during sleep and wakefulness. Sleep 1993;16:100-113.
Dream Content: Quantitative Findings Antonio Zadra and G. William Domhoff Abstract Considerable progress has been made in the systematic study of dream content. The most commonly used methods for collecting dream reports—laboratory awakenings, home dream logs, questionnaires, and most recent dreams collected in group settings—all have their uses and inherent advantages and disadvantages. Reliable, comprehensive, and validated instruments for the actual analysis of dream content reports have been developed, and complementary tools are now available to all researchers on the Internet. Quantitative data on dream content from laboratory and nonlaboratory settings generally converge in depicting a reliable picture about the nature of dream content in the general adult population. Few differences emerge between laboratory and home dream
Researchers and clinicians have long been fascinated by the content of dreams. Although many contemporary dream researchers suggest that dreaming is functionally significant and may subserve a biologically important function, some argue that dreams are epiphenomenal to neurophysiologic activity during rapid eye movement (REM) sleep and have no value in and of themselves even though evidence suggests they have psychological meaning. This chapter reviews methodologic issues in dream research and systematic findings on the content of people’s dreams, and it presents the implications of key findings on normative dream content. The implications for theories of dreaming are briefly considered in the final section. There is no consensus on what distinguishes dreaming from other cognitive processes, such as thinking or daydreaming, nor on what constitutes dream content. Interdisciplinary groups from the International Association for the Study of Dreams and the American Academy of Sleep Medicine concluded that “a single definition for dreaming is most likely impossible given the wide spectrum of fields engaged in the study of dreaming, and the diversity in currently applied definitions.”1 Thus, depending on one’s perspective, dreaming can be synonymous with the term “sleep mentation,” which refers to the experience of any mental activity (e.g., perceptions, bodily feelings, thoughts) during sleep, or it may be restricted to more elaborate, vivid, and story-like experiences recalled upon awakening. As highlighted by others,2 using a broadly inclusive versus more restrictive definition of dreaming has a direct and significant impact on the nature and sense of empirical data and theoretical modeling in the field. In this chapter, the term dream is conceptualized as having four interrelated meanings. First, a dream is a form of thinking during sleep that occurs when there is a certain, as yet undetermined, minimal level of brain activation in a context in which external stimuli are typically occluded and the cognitive system that keeps us aware of our surroundings is shut down. Second, a dream is something
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reports. Both data sets indicate that for the most part, dreams are a reasonable simulation of waking life characters, social interactions, activities, and settings and that dreams show systematic relationships to various dimensions of the dreamer’s waking life but not to day-to-day events. Developmental changes also occur in dream content until late adolescence, when dream content becomes surprisingly stable and consistent throughout adulthood and old age. More clinically oriented studies suggest that affect and social interactions are two key dream content variables that are most strongly related to measures of psychological well-being. Taken together, these findings have several implications for theories of dreaming and provide convincing evidence that dreams are a unique and meaningful psychological product of the mind.
people experience as a series of actual events (e.g., a sequence of perceptions, thoughts, and emotions) because the thought patterns simulate waking reality. Third, a dream is what people remember upon awakening, so it is a memory of the dreaming experience. Finally, a dream is the spoken or written report provided to investigators based on the memory of the dreaming experience. The empirical studies discussed in this chapter reveal that the events of a dream always include the dreamer as an observer or participant, and that they almost always include at least one other character besides the dreamer (either a person or an animal). In addition, the dreamer or the other characters in the dreams are invariably engaged in one or another activity (e.g., looking, walking, running) or a social interaction. Thus, the sense of participation in an event, along with characters, activities, and social interactions, is what distinguishes dreams from the more fleeting, fragmented, and thoughtlike forms of sleep mentation.
METHODS FOR COLLECTING DREAM REPORTS Researchers never study dream experiences directly. Instead, they collect and have access to descriptions of the experience, the dream report. The nature and content of the verbal or written report obtained can be influenced by a number of factors. These include the setting (e.g., home, laboratory, classroom, psychotherapy), method of awakening (e.g., spontaneous, induced), time of awakening (e.g., early, middle, or late in the sleep period), sleep stage prior to awakening (e.g., REM, non-REM [NREM] sleep), type of collection instrument (e.g., questionnaire, dream journal), reporting method (e.g., written by the subject, written by the experimenter, audio recording), instructions provided (e.g., report anything that was going through your mind before your awakening, note only your dreams), probes on reported content (no, fixed, or semistructured 585
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questions), interpersonal situation (e.g., reporting directly to an experimenter, clinician), time delay between when the dream was experienced and when it is reported, study duration, and subject characteristics (e.g., gender, personality, habitual level of dream recall). The degree to which the content of dream reports is influenced by these various factors either individually or in combination varies as a function of the collection method used. The principal sources of dream reports are the sleep laboratory, home dream journals, questionnaires, psychotherapy sessions, and classroom or other group settings where a most recent dream can be collected from everyone willing to participate. Although there is convincing evidence that working with patients’ dreams can be clinically useful,3 dream reports from the psychotherapy relationship are rarely used in systematic studies, and thus this source is not covered here. Sleep Laboratory Sleep laboratories are an excellent source of dream reports because they provide the opportunity for collecting a representative sample of a subject’s dream life, both within and across nights, under controlled conditions. Awakening subjects from several REM or NREM periods results in the collection of dream reports that may have been otherwise forgotten by the subjects upon normal awakening in the morning. Awakenings during REM, or from stage II NREM late in the sleep period, maximize the probability of recall and make it possible to collect as many as four or five dreams in a single night. On the other hand, frequent awakenings can be difficult for participants, and factors such as sleep inertia and one’s desire to return to sleep may interfere with the quality of the dream reports. However, a complimentary cued morning report of dreams recalled during the night can yield new and reliable information as to the dreams’ original contents.4 The main problem with the laboratory collection of dream reports is that it is a very costly and time-consuming process, and even though several dreams can be collected each night, it still can take many months to obtain 10 or more dreams from each of a dozen participants. Furthermore, some types of dreams, including nightmares and sexual dreams, rarely occur in the sleep laboratory, presumably due to sociocognitive factors. In addition, approximately 20% of laboratory REM dream reports reflect direct incorporations of the laboratory environment,5 even when collected over several consecutive nights.6 For our purposes, the most important outcome of detailed laboratory studies is that they provide a baseline for assessing the quality of dream reports collected by other methods. Dream Logs Prospective daily logs are used by an increasing number of dream researchers even though they require a greater investment of time and resources than do questionnaires. In fields like nightmare research, home journals are considered the gold standard for the measurement of nightmare frequency.7 Although limitations associated with longer-term retrospective assessments of dream recall and dream content are increasingly recognized, variations in home logs have received little attention.
Prospective logs can take two different forms. The first is the checklist format, in which participants indicate if there was dream recall and if so, the number and type of dreams recalled (e.g., nightmare). The second is the narrative log, in which participants are requested to provide a complete written transcript of each dream recalled. Findings from one comparison8 of these two methods of data collection suggest that narrative-log participants, having a more time-consuming task, do not take the required time to provide a complete narrative of all of their recalled dreams, as Strauch9 found with teenage boys. Instead, they may choose to focus on their more memorable, exciting or salient dreams, which would typically include bad dreams and nightmares. By comparison, people completing checklist logs would be more likely to record all of their dreams (including relatively banal or poorly recalled ones) as each entry is just as quickly completed regardless of dream type. Although writing down one’s dreams remains the most frequently used method to collect dream content, participants may also use tape recorders to dictate their reports. This approach may be particularly useful with children and younger adolescents.10 It also proved highly useful in a study of blind participants.11 Questionnaires In questionnaire studies, participants’ retrospective selfreported information concerning their dream experiences is viewed as a modest but valid way of assessing different aspects of the dream experiences themselves. Three types of information are generally collected. First, subjects can be queried about the frequency with which they experience certain kinds of dreams (e.g., everyday dreams, nightmares) over a determined period of time. There is increasing evidence, however, that data obtained with retrospective estimates differ considerably from daily prospective home logs. For instance, when compared to results from daily home logs, retrospective self-reports significantly underestimate current nightmare frequency12,13 and this rate of underestimation is not attributable to an increase in recalled dreams caused by keeping a dream log.13 Similarly, one study12 found that the magnitude of the association between trait anxiety and nightmare frequency decreased significantly when daily logs were used to measure nightmare frequency instead of retrospective self-reports. This led the authors to suggest that anxious persons do not necessarily have more nightmares, but rather that they are more likely to remember and report nightmares retrospectively. Finally, a metaanalysis14 of studies having examined the relationship between dream recall frequency and various personality dimensions found that scores on personality measures were not related to dream recall frequency per se, but rather to people’s tendency to retrospectively underestimate or overestimate their dream recall. Taken together, these findings indicate that correlates of retrospective measures of dream recall should not be assumed to be correlates of log measures of dream recall. Contrary to prospective log measures, retrospective indices of dream recall are best viewed as measures of peoples’ cognitive representations of their dream life. A second kind of information sometimes elicited via questionnaires focuses on specific dimensions of people’s
dreams or their beliefs about their general dream life. This approach assumes that there exists a valid relationship between self-reported information on the content of one’s everyday dreams and the dream experiences themselves. However, comparisons of self-report measures and logbased data indicate that this assumption may be unwarranted. For instance, one15 comparison of participants’ questionnaires and 2-week logs found no relationship between estimated frequency for the appearance of aggressive, friendly, and sexual elements and their frequency in the dream reports. Similarly, a subsequent study16 showed that when people’s level of dream recall is poor, their beliefs about the level of anxiety in their dreams is not related to the actual affective content of their everyday dreams as recorded prospectively in home logs. These findings suggest that the relation between beliefs people hold about the content of their dreams and their actual dream experiences is mediated by autobiographical memory and that these beliefs are particularly inaccurate when dream recall is low (i.e., when memories of one’s dreams are not readily available). Lastly, questionnaires are used to investigate if participants ever experienced a specific type of dream, and if so to report the most recent occurrence as best recalled. This approach allows the investigation of certain types of dreams that, due to their infrequency, are difficult to capture in laboratory settings or with home dream logs (e.g., recurrent dreams, existential dreams) or dreams that stand out in the person’s past (e.g., earliest dream recalled, most terrifying nightmare). Although useful in some research settings, the resulting dream content findings must be treated cautiously due to possible memory distortions and biases. In sum, although some dream questionnaires have good internal consistency and test-retest reliability,17 studies of their relationship to dream content and frequency findings obtained from dream journals reveal important discrepancies and raise questions as to their validity. Classroom and Other Group Settings Settings such as classrooms provide an objective and structured context for the efficient and inexpensive collection of dream reports. Anonymous participants are instructed to write down the most recent dream that they can recall on a standardized form while revealing only basic background information such as age and gender. The most recent dream method has been used with children as young as ages 10 to 11 years in different countries with surprisingly similar cross-national results.18,19 However, there is reason to believe that young children up to ages 10 to 11 years are using their waking imaginations to provide a report that fits cultural stereotypes about the nature of dreams.20 The main drawback with this method is that there is not usually time to collect any personality or cognitive measures on the people providing the reports.
ANALYZING DREAM CONTENT: INSTRUMENTS AND ISSUES Most past dream research used either rating scales at the ordinal level of measurement (“more” or “less” of a characteristic) or discrete categories at the nominal level of
CHAPTER 50 • Dream Content: Quantitative Findings 587
measurement (an element is “present” or “absent”). Rating scales are most useful for characteristics of dream reports that have degrees of intensity in waking life, such as activity level, emotionality, clarity of visual imagery, or vividness. Cohen21 reports that four dimensions of dream salience can be rated by participants in dream studies: emotionality, bizarreness, activity, and vividness. A factor analysis of the ratings of 100 REM dream reports suggests that rating scales boil down to five basic dimensions: degree of vividness and distortion, degree of hostility and anxiety, degree of initiative and striving, level of activity, and amount of sexuality.22 However, it is often difficult to establish reliability with some scales, and much of the specific information in dream reports is lost or unused with general rating scales. Of the 150 dream rating and content analysis scales reviewed by Winget and Kramer,23 the Hall and Van de Castle coding system24 is the best validated and remains the most widely used system for analyzing dream content. The Hall/Van de Castle system, which provides many of the findings presented in the rest of this chapter, rests on the nominal level of measurement and uses percentages and ratios as content indicators that can correct for the varying length of dream reports from sample to sample. The dream reports used in the original normative sample, as well as the codings for them, are available to researchers through www.dreambank.net.25 The normative findings reveal a pattern of gender differences that needs to be taken into account when doing studies of individuals. The Hall/Van de Castle coding system employs nonparametric statistics for determining P values and effect sizes, which can be obtained instantly after entering codings into the DreamSAT spreadsheet available to all researchers on www.dreamresearch.net.26 The general Hall/Van de Castle norms can be used with confidence for a variety of purposes because they have been replicated in several studies.27,28 As documented by Winger and Kramer, there exist numerous other coding systems, and many new ones have been created since their comprehensive review. However, unlike the Hall/Van de Castle system, most of these instruments have only been used by the original investigators (limiting potential for comparisons across laboratories), many use weighting systems of questionable validity, and few are based on clearly defined and objective scoring criteria that yield good interrater reliability. Moreover, as detailed elsewhere, many of these scoring systems can be duplicated by combining two or more elements of the Hall/Van de Castle system.27 Some research questions (e.g., self-reflectiveness in dreams, contextualizing images in dreams), have necessitated the creation of new instruments.29,30 The DreamThreat rating scale was developed to test an evolutionary theory of dreams that stipulates that the function of dreaming is to simulate threatening events with the intent of improving the subject’s ability to recognize and avoid diverse threats in real life.31 Although this rating scale has been criticized, it is noteworthy in that it has been used by different groups to assess various kinds of dreams and that it yields good to excellent inter-rater agreement.31-33 Taken together, findings indicate that a significant proportion of dreams contain a wide range of threats, but few of these dreams present
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realistic life-threatening events, and the dreamer rarely succeeds in escaping the threat. Finally, given the time-consuming nature of traditional scoring of dream reports, some groups have tried to develop computerized systems that can carry out such tasks both reliably and accurately. Because emotions are viewed by some dream theorists as playing a key role in structuring dream content, and given that dream affect is one of the most frequently investigated dream content variables, some of the more innovative work in this field has focused on the classification of emotions. Online search tools available to researchers at www.dreambank. net allow for rapid and accurate searches for specific words, phrases, and long word strings, and one study shows that the use of word strings for emotions yields results comparable to when standard Hall/Van de Castle codings are scored on the same dream reports.34 Another promising project is based on an algorithm that seeks to accurately categorize dream emotions both at fixed times and dynamically as the dream narrative progresses.35 Moreover, the algorithm has the potential of improving its performance as a function of training (machine learning). Although this research is still in its infancy, such innovations might allow efficient and accurate scoring of large data banks across laboratories. Problems in Studying Emotions and Bizarreness in Dreams Although both rating scales and the Hall/Van de Castle nominal coding categories have proved useful for most dimensions and elements of dream content, there are methodologic problems relating to the study of emotions and bizarreness in dreaming. Several different studies using blind coders find that negative emotions outnumber positive ones.24,36 However, very different results emerge when the dreamers themselves make a global rating of each of their dream reports on a pleasant–unpleasant dimension. Such studies regularly find that the dreamers rate the emotions in their dreams as at least equally pleasant and unpleasant, and sometimes as more pleasant.37-40 There is no ready explanation for these contrasting results with the two different methods. Dreamers also tend to attribute many more emotions to their home dreams than do blind judges when they are asked to recall the emotions that accompanied the report they have written down. However, it is an open question in need of further study as to whether or not this greater amount of emotions in self-ratings of home dream reports is the result of two extrinsic factors: the demand characteristics of such a rating task and the waking-life assumption that certain emotions would logically be present in many of the situations experienced in the dream. There is also a lack of agreement on how to assess unusual or bizarre elements in dreams, which leads to widely varying prevalence and frequent estimates. In studies that focus on clearly impossible events, the figure is 10% or less for large samples of both REM and home dreams.41,42 When sudden scene changes, uncertainties, and small distortions are included, the figure rises to between 30% and 60%.43-45 Using a rating scale based on the degree to which any dimension of the dream differs from waking experience and behavior, it was found that
75% of 500 REM reports from men and women had at least one bizarre aspect, as compared with 7% to 8% that were bizarre in three or more ways.46, p. 95-103 In addition, studies of bizarreness in dreams have been handicapped by the fact that there have been no studies comparing the nature and frequency of bizarre elements in dreams and waking thought samples from the same participants, which seems to be an essential step given the evidence that waking thought often contains unexpected and anomalous elements.47 The Importance of Adequate Sample Sizes One important variable that is all too often overlooked when investigating dream content is the sample size required to detect changes in various content variables. First, as detailed elsewhere, it is unlikely that repeatable and scientifically useful results can be obtained with dream reports much shorter than 50 words, especially when using Hall/Van de Castle content categories.27 Second, although coefficients of internal consistency for dream diaries indicate that everyday dream recall is relatively stable over time, several dream content variables appear infrequently in dream reports and show large intrasubject fluctuations.8,48 Approximately 20 dream reports from a given participant are required for correlational studies involving rare or unstable dream content variables.17 Finally, the use of an approximate randomization algorithm provides robust evidence that it takes 100 to 125 dream reports to detect significant content differences even in the more rarely observed Hall/Van de Castle indicators either between groups or in comparison to men’s and women’s normative samples, although fewer dream reports are needed with frequently occurring elements.34
QUANTITATIVE FINDINGS ON DREAM CONTENT Dream Reports from Laboratory Awakenings The best starting point for the systematic study of dream content remains the classic studies completed by dream researchers during the heyday of laboratory dream research in the 1960s and early 1970s. They show that dream content simulates everyday life to a far greater degree than had been anticipated based on the clinical cases that had been the basis for theorizing before the laboratory era of dream research.49,50 They characterize a prototypical REM dream report as a “clear, coherent, and detailed account of a realistic situation involving the dreamer and other people caught up in very ordinary activities and preoccupations, and usually talking about them”.49, p. 148 For example, of all the dream settings that were described, only 5% were exotic, in the sense of highly unusual or out of the ordinary, and less than 1% were fantastic, in the sense of unrealistic.49, p. 134 Using a conservative standard to guard against imputing any emotions to the dreamers, specific emotions were judged to be present in only 30% to 35% of the reports, with unpleasant emotions outnumbering pleasant ones by 2 to 1. Anxiety and anger were the most frequent types of emotions; erotic feelings occurred in only 8 of the 635 reports.49, p. 141 The
dreams were rated as having a low degree of bizarreness. Focusing here on the longest reports because they were more often rated as bizarre, 50% were rated as having no bizarreness, 30% as having a low degree of bizarreness, 8% as having a medium degree, and 2% as having a high degree.49, pp. 145-146 A low degree of bizarreness was also reported in a highly detailed laboratory study of that issue.42 The authors “emphasize the rarity of the bizarre in dreams” because major distortions of actual waking experiences reach a high of only 17% of all the activities and social interactions, and of 6% and 8% for all characters and physical surroundings, respectively.42, p. 367 When they carried out global ratings of each dream for overall novelty, they found that most of them contained very little novelty: Only 9% were highly improbable by waking standards; another 26% showed large but plausible differences from previous waking experiences. The issue of emotions in REM dream reports was first investigated in great depth in the sleep laboratory, where participants were quizzed in detail after each awakening about the presence of emotions and the appropriateness of the emotion to the content. Drawing on ratings by both participants and naive judges, it was concluded that about 70% of the dream reports had at least some affect.40 A study in a Swiss sleep laboratory came to very similar conclusions about the frequency and intensity of emotions in dreams.46, p. 93 Several early laboratory studies probed for any changes that might occur in dream content from REM period to REM period, uncovering very few replicable differences. Employing categories for settings, characters, activities, social interactions, and emotions, both quantitative and qualitative analyses find few or no differences from REM to REM when corrections are made for the length of report.37,51 In the most comprehensive study of this issue, there were two minor differences among 26 analyses employing Hall/Van de Castle categories for the first four REM periods, whether they were nights with single or multiple awakenings, and there were no differences with spontaneously recalled dreams that came from night or morning REM self-awakenings.52 However, there may be some degree of thematic continuity from REM to REM on a few nights.46, p. 206 REM and NREM Dream Reports Although there were indications in early laboratory studies that dreaming occurs almost exclusively in REM sleep and that there were differences in the content of REM and NREM reports, many later studies suggest that the differences in recall are not black and white, especially late in the sleep period, and that some but not all of the content differences disappear when there is a control for word length.53,54 Still, most studies conclude that dreams are more frequent and longer during REM periods and that many NREM reports seem to be thoughts, not dreams. In fact, NREM reports are more often a continuation of waking thoughts and memories, whereas there are few episodic memories in REM or home dream reports.55,56 The differences in content relate to a greater character density in REM reports, which in turn leads to the possi-
CHAPTER 50 • Dream Content: Quantitative Findings 589
bility of social interactions.41,53 Then, too, there is evidence that NREM reports late in the sleep period are more similar to REM reports than are NREM reports from the first few hours of sleep.57,58 In the most recent studies of this issue, the thoughtlike nature of NREM decreased by 56% and the hallucinatory nature increased by 62% over the course of the night, leading to the conclusion that “as the night progresses, NREM approaches the neurocognitive characteristics of REM.59, p. 302 In two separate studies it was found that the major difference between late-night REM and NREM dreams is in aggressive interactions.60 Laboratory and Home Dream Comparisons Several careful investigations reveal that there are relatively few differences between home and laboratory dream reports, even when the dreams are obtained by tape recorders in the sleep laboratory and by written reports at home.41,46 Furthermore, most of these differences disappear when the proper controls are introduced.10,61 The one exception to this generalization seems to be hostile and aggressive dream elements, which occur more frequently in the home dream reports of young adults in three different studies.41,61,62 These findings on the relatively small differences between home and laboratory dreams may be explainable in terms of the results from laboratory studies that compare what is reported from REM awakenings with what is still remembered in the morning.63,64 Such studies reveal that recency and length of report are the primary factors in later recall, which at home would lead to a representative sample of nightly dream content given the lack of content differences from REM to REM and between REM and late-night NREM. However, some of these studies also show that intensity can be a tertiary factor in morning recall, which suggests there is some selection bias toward the everyday recall of more emotionally salient content. Normative Dream Content in Home Dreams As might be expected from the results of the laboratory versus home comparisons, studies of large samples of dream content collected from young college-educated adults outside the laboratory show many similarities with the laboratory results when the same or comparable content categories are employed. Dreams mostly occur in commonplace settings, contain a large number of familiar characters, and revolve around family concerns, love interests, and activities engaged in during waking life.38,65 This point is best seen in a study of several hundred dream reports from German college men and women in which the dream content was coded for at least one instance of several simple ad hoc categories constructed to determine the degree to which the dreams involve people and activities from everyday life.66 There were four categories for familiar characters, five categories for commonplace leisure activities, and a single category for involvement in work, school, or politics. The everyday nature of most of these dreams is seen in the fact that 75% of the women’s dreams and 62% of the men’s have at least one instance of one of
590 PART I / Section 7 • Psychobiology and Dreaming
the four categories of familiar characters. Similarly, 42% of the women’s dreams and 27% of the men’s have at least one instance from one of the five leisure-time categories. The routine matters of work, school, or politics appear in 20% of the women’s dreams and 29% of the men’s dreams. Overall, only 13% of the women’s dreams and 20% of the men’s have no instance of any of the above categories. In keeping with other findings on gender differences in dream content, the men’s dreams are less likely to have familiar characters and familiar leisure time activities, and they are more likely to have instances of school, work, or politics, but the important point for purposes of this chapter is that only a minority of dreams for either gender involves unknown characters and activities that are out of the ordinary. Given the long-standing clinical and popular interest in dreams with erotic or sexual content, this dream content category has received surprisingly little attention. Questionnaire studies indicate that approximately 80% of adults answer positively to the question “Have you ever dreamed of sexual experiences?”67,68 with men reporting sexual dreams more often than women. The normative data from Hall and Van de Castle indicates that 12% of men’s dreams and 4% of women’s dreams contained sexual content, including having or attempting intercourse, petting, kissing, sexual overtures, and fantasies. However, one study of more than 3500 dream reports found no gender differences, with approximately 8% of dream reports from both men and women containing sexually related activity.69 The differences with the Hall and Van de Castle data may be partially due to sample composition (college students versus student and nonstudent adults). Alternatively, it is also possible that women actually experience more sexual dreams now than they did 40 years ago, or that they now feel more comfortable reporting such dreams due to changing social roles and attitudes, or both.
laboratory participants in frequency, length, emotions, and overall structure or to show any relationship to personality.72, p. 127 A cross-sectional replication of these results with children ages 5 to 8 years supported all of the main original findings.70 The median rate of reporting was only 20% for all age groups. The imagery in the dreams was more static than dynamic until age 7 years, and the child’s “self” character did not tend to take an active role in the dreams until age 8 years.70 As with young adult dreams, there were more characters in the girls’ dreams, and there was the same gender difference in the percentage of male and female characters. There were no failures, few negative emotions, and very few misfortunes. There were few aggressive or friendly interactions, with more friendliness in the girls’ reports.27, p. 94 The results from the longitudinal study of Swiss children ages 9 to 15 years were generally similar to those for preadolescents and adolescents in the earlier longitudinal study, and there were only relatively small changes in most categories over the 6-year period. The largest change was a decline in bizarreness for both boys and girls, as defined by degrees of deviation from waking experience and social norms; just over 60% of the dream reports had at least some degree of bizarreness at ages 9 to 11 and 11 to 13 years, but the figure fell to 41% at ages 13 to 15 years.9 In contrast to the changes in dream content from childhood to adolescence, dream content is extremely stable in terms of characters, social interactions, and most other dream elements after age 18 years according to crosssectional studies in the United States, Canada, and Switzerland that are summarized in Domhoff.27 The elderly recalled fewer dreams in one large longitudinal study,73 but separate studies suggest their dream content remained generally the same—except perhaps for aggression, where three different studies suggest a decline.74-76
Age Differences There appear to be major changes in dream content from the preschool to teen years, but there are few changes from the late teens to old age. Dream content thus seems to parallel cognitive and emotional development during childhood as well as the stability of adult personality. Much of what is known in a systematic way about children’s dreams comes from a classic longitudinal laboratory study of children between the ages of 3 and 15 years old, supplemented by a cross-sectional laboratory replication a few years later with children ages 5 to 8 years old.70 More recently, a 5-year longitudinal laboratory study of Swiss children ages 9 to 15 years old has provided additional supporting information.9,71 Detailed summaries of the methods, samples, and findings can be found elsewhere.26 The most unexpected finding in the first study was the low amount of recall from REM periods in the 3- to 5-year olds (only 27% of the REM awakenings yielded any recall that could reasonably be called a dream), and the static, bland, and underdeveloped content of the few reports that were obtained. The reports became more “dreamlike” (in terms of characters, themes, and actions) in the 5- to 7-year olds, but it was not until the children were 11 to 13 years old that their dreams began to resemble those of adult
Dream Content and Well-Being Considerable research efforts have been expended trying to establish dream content correlates of standardized personality variables, measures of psychological well-being in nonclinical samples, and indices of psychopathology in clinical populations. Taken as a whole, there is mixed evidence that psychometrically defined personality traits (e.g., neuroticism, extraversion), are related to everyday dream content.77 Robust relations, however, have been demonstrated between waking levels of well-being and specific types of dreams such as nightmares7 and recurrent dreams,78 as well as between dream content and various dimensions of waking life, including people’s general waking concerns.28,34,79 Several studies80-82 have shown that dream content is reactive to the experience of naturalistic and experimental stressors, but whether or not dreams play a role in people’s actual adaptation to stress remains an open question. In a series of longitudinal studies of REM dream reports from depressed and nondepressed adults undergoing marital separation or divorce, Cartwright and her collaborators79,83 provide suggestive evidence that dream content variables that centered around affect and the representation of the ex-spouse are associated with how well people adapt to their situation over time. Similarly, one longitudinal
study84 of normal adults found that participants’ dream content from home logs was moderately to strongly correlated to their scores on measures of psychological wellbeing both at fixed points in time and over a 6- to 10-year period, with content variables of dream affect and social interactions showing the strongest relations. Dream content in severe psychopathological conditions such as schizophrenia has been reviewed elsewhere,85 and with few exceptions, little by way of consistent findings has emerged from this literature. In addition, many studies in this field suffer from methodological problems including unclear diagnoses, inadequate controls, unknown effects of medications, few dream reports per patient, and the use of untested coding systems. Individual Case Studies Within the context of the many well-established group findings, individual case studies can be of great value for both research and possible clinical applications. The dream journals on which such studies are based have value as nonreactive measures that have not been influenced by the purposes of the investigators who later analyze them. The conclusions drawn from nonreactive archival data are considered most reliable and useful when they are based on a diversity of archives likely to have different sources of potential biases.27 Studies of several different dream journals first proved their usefulness for scientific purposes by revealing an unexpected consistency in dream content when several hundred dream reports were studied.27 This consistency begins in the late teens and continues to old age as expressed by three measures: absolute (the frequency with which an element appears remains the same year after year), relative (the incidence of one element always exceeds the incidence of another element, even though they both may increase or decrease in frequency), and developmental (there is a consistent increase or decrease from one period of time to the next). Two studies of discontinuous dream series show that the consistency revealed in continuous dream journals is not the result of practice effects.27,86 Individual dream journals also provided the basis for the most rigorous work to date on the lawfulness of dreams and their relationship to waking conceptual processes. This work by mathematical psychologist Richard Schweikert87 shows that the social networks in dreams— that is, the pattern of direct and indirect relationships among the characters—have the same properties as waking social networks in that the paths between characters are short and the clustering of characters is high. These results also hold for subnetworks, which are created by removing key characters from the overall network. Moreover, the frequency distribution of the characters and the degree distribution of characters (the frequency with which characters occur with another given character) are consistent with Zipf’s law, a power law for describing frequency distributions in which the top few entities occur very frequently and most other entities appear very rarely. Blind analyses of dream journals also have led, through the formulation of inferences that can be accepted or rejected by the dreamer and other respondents, to the conclusion that some but not all dream content is continu-
CHAPTER 50 • Dream Content: Quantitative Findings 591
ous with the dreamers’ waking conceptions, concerns, and interests.27, p. 111-133 The most direct continuities involve the main people in a dreamer’s life and the nature of the social interactions with them. There also is good continuity for many of the dreamer’s main interests and activities. However, these findings on continuity have to be qualified in two ways. First, the continuity is with general concerns, not day-to-day events. Three studies that tried to match detailed waking reports of daily concerns with dream reports, two based on REM awakenings, one based on morning recall at home, found that blind judges could not reliably match records of daily concerns or events with dream content. The content of the dreams often revolved around daily life, such as family, friends, and school, but if the actual events of the day were incorporated in any specific way, it was not understandable to independent raters.88 This finding is consistent with studies showing low levels of episodic memory in dreams.55 Secondly, the continuity usually is with both thought and behavior, but sometimes it is only with waking thought. For example, people who have highly aggressive dreams are not always aggressive people in waking life, but they usually admit to many aggressive thoughts and fantasies during the day.27 Sensory Experiences and Dreams of Blind Subjects Although the overwhelming majority of dream reports contain visual and, to a lesser extent, kinesthetic elements, the presence of other sensory modalities has also been noted in both laboratory and home dream reports.89,90 More than 50% of dream reports contain auditory experiences, and explicit references to olfactory, gustatory, and pain sensations occur in less than 1% of all dream reports. One study found that women’s dream reports were more likely to contain olfactory or gustatory sensations, whereas references to auditory and pain experiences occurred in a higher percentage of men’s dreams.90 That the more infrequent modalities of smell, taste, and pain occur at all in dreams is an important demonstration of the representational capacities of dreaming. Perhaps due to the highly visual nature of dreaming, people always have wondered if blind people dream, so some of the earliest systematic interview studies on dreams dealt with this topic, showing that people who are born blind or become blind before age 4 or 5 years old do dream even though they do not see images in their dreams,91 a finding that was then supported by laboratory studies.92,93 Nor is there much if any difference in dream content, except that there may be less aggression in their dreams.11,91 There is also much greater mention of touch, taste, and smell in blind people’s dreams.11 It is noteworthy that people who become blind after age 5 or 6 years old often have visual imagery in their dreams, which suggests that there is a window for the development of the capacity to have visual dreams that parallels what was found in longitudinal studies of children ages 3 to 7 years old.94,95 Implications for Theories of Dreaming The array of systematic results presented here suggests that a considerable amount of psychological information can be extracted from dream reports. This conclusion
592 PART I / Section 7 • Psychobiology and Dreaming
provides support for the core idea of all 20th-century dream theories, but it must be stressed that much dream content is not yet understood. The findings also suggest that a majority of dreams focus on a handful of personal concerns revolving around social interactions with family, friends, and coworkers. The greatest variability in dream content seems to concern the appearance of aggression, especially physical aggression. Despite the originality and creativity that is displayed in the cognitive production of dreams, and even given the aspects of dream content that are not understood, most dreams are more realistic and based in everyday life than is suggested by most traditional dream theories. In addition, much dream content seems more transparent than might be expected by older clinical theories that emphasize disguise or symbolism in understanding dreams. Finally, a significant minority of dreams might not be as emotionally based as theories imply, especially before the adolescent years. At the most general level, the findings based on systematic content research suggest that many dreams are the embodiment of thoughts through dramatizations of life concerns and interests. As a starting point, perhaps dreams are best understood as simulations that enact the person’s main conceptions and concerns, including emotionally salient interpersonal preoccupations. This type of conceptualization is at the heart of the continuity hypothesis, which posits a relationship between everyday dream content and general waking states and concerns. Although most of the research findings reviewed here are consistent with the continuity hypothesis, much work remains to be done to clarify which specific dimensions of waking life (e.g., particular learning tasks, daily mood, major life events, ingrained behaviors, sustained fantasies, cognitive styles) are most robustly associated to what kind of dream content and the nature of these relationships over time.55 In fact, instead of referring to the continuity, it may be more appropriate to consider multiple levels of continuity between various waking and dream parameters. The observations that dreams rarely depict episodic memories and that the nature of temporal references in dreams can take many forms (see Chapter 49) add a layer of complexity to an already difficult problem. In the end, dreaming may or may not have a function, but data convincingly show that dream content is a unique and meaningful psychological product of the human brain, and as such dreams will continue to interest and challenge clinicians and researchers alike.
❖ Clinical Pearls Examining a series of dreams often yields more meaningful information about a patient’s psychological state than focusing solely on one particularly salient dream. Changes over time in the frequency and content of repetitive dream themes, especially those involving strong affect and social interactions, are most likely to reflect a patient’s clinical progress or deterioration.
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CHAPTER 50 • Dream Content: Quantitative Findings 593 60. McNamara P, McLaren D, Durso K. Representation of the self in REM and NREM dreams. Dreaming 2007;17:113-126. 61. Weisz R, Foulkes D. Home and laboratory dreams collected under uniform sampling conditions. Psychophysiology 1970;6: 588-596. 62. Domhoff GW, Kamiya J. Problems in dream content study with objective indicators: I. A comparison of home and laboratory dream reports. Arch Gen Psychiatry 1964;11:519-524. 63. Baekland F, Lasky R. The morning recall of rapid eye movement period reports given earlier in the night. J Nerv Ment Dis 1968;147:570-579. 64. Trinder J, Kramer M. Dream recall. Am J Psychiatry 1971;128: 296-301. 65. Foulkes D. Dreaming: a cognitive-psychological analysis. Hillsdale, NJ: Erlbaum; 1985. 66. Domhoff GW, Meyer-Gomes K, Schredl M. Dreams as the expression of conceptions and concerns: a comparison of German and American college students. Imagination, Cognition & Personality 2005-2006;25:269-282. 67. Nielsen TA, Zadra AL, Simard V, Saucier S, et al. The typical dreams of Canadian university students. Dreaming 2003;13:211-235. 68. Schredl M, Ciric P, Gotz S, Wittmann L. Typical dreams: stability and gender differences. J Psychol 2004;138:485-494. 69. Zadra A. Sex dreams: what do men and women dream about? Sleep 2007;30:A376. 70. Foulkes D, Hollifield M, Sullivan B, Bradley L, et al. REM dreaming and cognitive skills at ages 5-8: a cross-sectional study. Int J Behav Dev 1990;13:447-465. 71. Strauch I, Lederbogen S. The home dreams and waking fantasies of boys and girls ages 9-15. Dreaming 1999;9:153-161. 72. Foulkes D. Children’s dreams. New York: Wiley; 1982. 73. Giambra L, Jung R, Grodsky A. Age changes in dream recall in adulthood. Dreaming 1996;6:17-31. 74. Brenneis C. Developmental aspects of aging in women: a comparative study of dreams. Arch Gen Psychiatry 1975;32:429-434. 75. Hall C, Domhoff GW. Aggression in dreams. Int J Soc Psychiatry 1963;9:259-267. 76. Zepelin H. Age differences in dreams: I. Men’s dreams and thematic apperceptive fantasy. Int J Aging Hum Development 1980;12: 171-186. 77. Blagrove M. Dreaming and personality. In: Barrett D, McNamara P, editors. The new science of dreaming. vol 2. Content, recall, and personality correlates. Westport, Conn: Praeger/Greenwood; 2007. p. 115-158. 78. Brown RJ, Donderi DC. Dream content and self-reported well-being among recurrent dreamers, past-recurrent dreamers, and nonrecurrent dreamers. J Pers Soc Psychol 1986;50:612-623. 79. Cartwright R, Agargun MY, Kirkby J, Friedman JK. Relation of dreams to waking concerns. Psychiatry Res 2006;141:261-270. 80. Duke T, Davidson J. Ordinary and recurrent dream recall of active, past and non-recurrent dreamers during and after academic stress. Dreaming 2002;12:185-197. 81. Raymond I, Nielsen TA, Lavigne G, Choiniere M. Incorporation of pain in dreams of hospitalized burn victims. Sleep 2002;25: 765-770. 82. De Koninck JM, Koulack D. Dream content and adaptation to a stressful situation. J Abnorm Psychol 1975;84:250-260. 83. Cartwright R, Baehr E, Kirkby J, Pandi-Perumal S, et al. REM sleep reduction, mood regulation and remission in untreated depression. Psychiatry Res 2003;121:159-167. 84. Pesant N, Zadra A. Dream content and psychological well-being: a longitudinal study of the continuity hypothesis. J Clin Psychol 2006;62:111-121. 85. Kramer M. Dreams and psychopathology. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. 3rd ed. Philadelphia: Saunders; 2000. p. 511-519. 86. Lortie-Lussier M, Cote L, Vachon J. The consistency and continuity hypotheses revisited through the dreams of women at two periods of their lives. Dreaming 2000;10:67-76. 87. Schweickert R. Properties of the organization of memory for people: evidence from dream reports. Psychon B Rev 2007;14:270276. 88. Roussy F, Brunette M, Mercier P, Gonthier I, et al. Daily events and dream content: unsuccessful matching attempts. Dreaming 2000;10: 77-83.
594 PART I / Section 7 • Psychobiology and Dreaming 89. Snyder F. The phenomenology of dreaming. In: Madow H, Snow L, editors. The psychodynamic implications of the physiological studies on dreams. Springfield, Ill: Charles C Thomas; 1970. p. 124-151. 90. Zadra AL, Nielsen TA, Donderi DC. Prevalence of auditory, olfactory and gustatory experiences in home dreams. Percept Mot Skills 1998;87:819-826. 91. Kirtley D. The psychology of blindness. Chicago: Nelson-Hall; 1975. 92. Berger R, Olley P, Oswald I. The EEG, eye movements, and dreams of the blind. Q J Exp Psychol 1962;14:183-186.
93. Kerr N, Foulkes D, Schmidt M. The structure of laboratory dream reports in blind and sighted subjects. J Nerv Ment Dis 1982;170: 286-294. 94. Foulkes D. Children’s dreaming. In: Cavallero C, Foulkes D, editors. Dreaming as cognition. New York: Harvester Wheatsheaf; 1993. p. 114-132. 95. Kerr N. Mental imagery, dreams, and perception. In: Cavallero C, Foulkes D, editors. Dreaming as cognition. New York: Harvester Wheatsheaf; 1993. p. 18-37.
Dream Analysis and Classification: The Reality Simulation Perspective Tore Nielsen Abstract The task of differentiating dreaming from other forms of imaginative cognition and of classifying different dream types and subtypes is largely incomplete. However, a growing interest in dreaming’s capacity for simulating waking reality experience offers a viable point of departure for furthering this unfinished task. Most types of dream content measures (e.g., prevalence, frequency, intensity, structural coherence) are predicated, directly or indirectly, on this assumption about dreaming’s capacity for simulating reality and provide converging support for the reality-simulation assumption. Even measures of dream bizarreness—which is quite common in dreams—may be understood as attempts to quantify failures
THE INCOMPLETE TASK OF DREAM CLASSIFICATION Dream psychobiologists have not traditionally regarded the classification and definition of dreaming as an empirical task; the result has been a diffuseness and artificiality of dream classifications that has had adverse effects on research.1 Yet, in this new era of cognitive and social neuroscience research, the need is increasing for an empirically based consensus on how dreaming as an object of study should be characterized. The tasks of differentiating dreaming from other forms of imaginative cognition and of differentiating types—and subtypes—of dreaming from each other are analogous to other empirically based taxonomy methods, such as the linnaean classification of basic life forms (Fig. 51-1). The features that distinguish dreaming as a unique imagery family and the features that distinguish among different dream genera within that family should be determined by systematic comparisons of samples from a variety of candidate families or genera using a sufficiently large array of defining features. The selection of which defining features to evaluate is driven by a variety of considerations, some practical and some theoretical. The classification of dreaming and dreaming subtypes shown in Figure 51-1 should be considered arbitrary for this very reason; it is based upon little available empirical work2,3 and substantial theory.4 The taxonomy of dreaming, in fact, remains incomplete. Many researchers might have abandoned attempts to classify dreaming because of methodologic obstacles, such as the seemingly infinite array of definitional attributes that could be evaluated. They might also have been hindered by the proliferation of dream theories that has distracted attention from the need for a taxonomy.
DREAMING AS REALITY SIMULATION Central to the classification task is the choice of potentially defining features to be evaluated. Of the multiplicity of
Chapter
51
of the simulation mechanism. Both simulated content and bizarreness measures may be viable approaches for completing the task of dream classification. However, a third level of analysis also related to reality simulation may prove key in this enterprise. This is simulation of the subtle, perception-like nature of waking experience, namely, the process of seeking out and picking up apparent information, as opposed to appreciation of the contents of this process. This level of subjective experience is only difficultly accessed by awake, selfreflective subjects, so its study in dream experience may require greater use of targeted probe questions and lessconventional methods such as selecting subjects for their communication abilities and training them in self-observation.
features that might be assessed, I consider here one perspective that addresses a relatively obvious and increasingly accepted aspect of dream phenomenology, namely, that the subjective nature of dreaming consists of a convincing simulation of waking reality experience. The reality simulation perspective directs attention to the evaluation of attributes that capture the essence of reality simulation as a first step in discriminating dreaming from other forms of imaginative cognition. The reality simulation capacity has been emphasized by many past and present authors as illustrated by the descriptions listed in Table 51-1. As excerpts in the table indicate, the realistic nature of dream contents has been appreciated by authors at least as early as Freud (1900). Excerpts also reveal differences in opinion as to the key features of reality simulation, such as “somatosensory invariants,” “memory schemata,” “orienting,” “conceptions,” “causally linked plots.” These differences reflect the diversity of potentially defining features of dream imagery, even within this more delimited class of reality-simulation features. The following sections review how some of the available methods for assessing dream content deal with reality simulation during dreaming. Common and emerging methods of content analysis are considered first, followed by methods that focus on apparent failures of the simulation process (bizarreness). A concluding section considers one of the limits of reality simulation, namely, the portrayal of subtle perceptual activities, as an area for future development.
CONTENT ANALYSIS METHODS AS ASSESSMENTS OF REALITY SIMULATION Many existing content analysis instruments are predicated on some version of the reality-simulation assumption, even if this is only rarely declared explicitly. These methods differ in how reality attributes are tallied or rated relative to the totality of the dream report and provide different estimates of how thoroughly a reality 595
596 PART I / Section 7 • Psychobiology and Dreaming
Imaginitive cognition
Class
Order
Klinger, 1977
Family
Genus
Species
Kuiken, 1995
ICSD-2, 2005
Sub-species
Spontaneous imagery
Instrumental imagery
Hallucination
Dreaming
Daydreaming/ fantasy
Near-death experience
Existential
Nightmares
Mundane
Transcendent
Story creation
Autobiographical recall
Imaginal problem-solving
Nontraumatic
Traumatic
Chase Paralysis
Violence Etc.
Figure 51-1 Linnaean classification of dreaming. The tasks of differentiating dreaming from other forms of imaginative cognition and of differentiating subtypes of dreaming from each other are analogous to taxonomy methods such as the classification of life forms developed by Linnaeus (first column). Features distinguishing dreaming as a unique imagery family and features distinguishing among different dream genera within that family should be determined by systematic comparisons of samples from a variety of candidate families or genera using a sufficiently large array of potentially defining features.
attribute is represented during dreaming. The most common types of measures are summarized in Table 51-2. Prevalence Many content rating systems isolate features of waking reality experience and evaluate their simple presence or absence in a dream report. The presence or absence of a self character, of pain, of sexual behavior, and so forth are common examples of isolated prevalence scales. A remarkable variety of isolated scales has been developed and assessed (Winget and Kramer16 give a compilation of scales and their psychometric properties up to 1979). More extensive batteries of rating scales include many of the prevalence type (as well as others) and are designed to assess dreaming’s realism features in a more global sense. Snyder’s system17 contains several dozen reality-based perceptual and cognitive attributes, whereas the larger, more widely used Hall/ Van de Castle system18 (see Chapter 50 for reviews) contains more than 500 attributes in 11 categories. The results of studies with both systems have been taken to support the conclusion that dreaming experience is continuous with waking life experience,12,17 that overall it reflects waking reality experience. A problematic shortcoming of prevalence measures is that the total informational content of reports is not taken into account and the relative prominence of different features is not accounted for. Frequencies Many content-rating scales, including some from the Hall and Van de Castle battery, count the number of instances of a given attribute in a dream report and thus assess the
relative prominence of features. The numbers of characters, distinct settings, or objects in a dream report are common examples of this type of measure. Frequency measures are usually reported relative to the entire dream report. Like prevalence measures, frequency counts have limited utility in comparing reports of different lengths or levels of complexity or of contrasting dream reports with different families of imaginative cognition. Intensity A common practice is to assess the intensity or predominance of content features using continuous rating scales. As applied to reality simulation, dream features might be evaluated for how vivid or true-to-life they appear or, conversely, how generally bizarre they seem. Ratings of emotional intensity in dream reports are very common instruments of this type. Intensity ratings might target global features, such as how realistic an entire dream is, or local features, such as the realism of a given character or object. They can therefore take into account the relative prominence of some features. The comparison of dream reports of different lengths can nonetheless remain problematic. Length-Corrected Measures Truly proportional measures count attributes in relation to a global measure of the total informational content in the dream report and thus resolve problems of differing report length to varying degrees. The Hall/Van de Castle system employs several proportional measures such as the percentage of aggressive actions out of all counted actions
CHAPTER 51 • Dream Analysis and Classification: The Reality Simulation Perspective 597
Table 51-1 Sample Characterizations of Dreaming as a Simulation of Waking Reality Experience REFERENCE
DESCRIPTION
Freud, 19005
Dreams are true and real mental experiences of the same kind as arise in a waking state through the agency of the senses. (p. 115)
Foulkes, 19856
Dreams are credible world analogues. (p. 37) The simulation of what life is like is so nearly perfect, the real question may be, why shouldn’t we believe that this is real? (p. 37)
Tart, 19877
In both dreaming and waking, an active, complex world simulation process is going on, basically identical in kind. … In dreaming … the kind of world, body, and self that can be simulated/experienced is vastly richer and more varied than in the waking state. (p. 155)
Hunt, 1989
8
The dream is a relatively true-to-life reconstruction of our human being-inthe-world. (p. 69) Dreaming is so much like waking that something very like clinical hallucinations can occur within it. (p. 71)
Nielsen, 19919
A primary feature of the dreaming state … is its compellingly real nature. (p. 236) Reality mimesis during the dream state … depends upon the simulation of somatosensory invariants. (p. 235)
Revonsuo, 200010
Dream experience … constitutes an organized and selective simulation of the perceptual world. (p. 882)
Hobson, 200011
[dreaming is] mental activity occurring in sleep characterized by vivid sensorimotor imagery that is experienced as waking reality despite such distinctive cognitive features as impossibility or improbability of time, place, person and actions. (p. 795)
Domhoff, 200312
Dreaming draws on memory schemata, general knowledge, and episodic memories to produce reasonable simulations of the real world … [that] express the dreamer’s “conceptions” (p. 32) The content of young children’s dreams is usually even more realistic (p. 31)
Nielsen & Stenstrom, 200513
Episodic memories … are altered in such a way that their autobiographical origins are obscured even though the subjective context within which they appear is a credible simulation of reality. (p. 1286) Dreams seem to take place in real, spatially coherent, environments with which the self interacts perceptually, for example, by orienting, seeking and assimilating sensory information, much as it does with the real world. (p. 1286)
Revonsuo, 200614
The dream world is experienced as a spatially extended and animated world, containing objects, people, and events. … The representation of the world in dreams is so amazingly realistic that it is fully justified to call it a “reality.” (p. 105)
Cicogna, 200715
If a dream is a multimodal hallucinatory simulation of the real world (Foulkes, 1985), oneiric distortions may pertain to all aspects of reality represented: images, combinations of environmental features, spatiotemporal organization, representation of self, nonself character representation, physical and logical constraints, etc. (p. 382)
Pace-Schott, 2011 (Chapter 48, this volume)
Dreams are organized into a multidimensional virtual experience temporally sequenced into a coherent plot of causally linked events. … While dreaming may be phenomenologically more or less “like waking” (Dorus, Dorus, and Rechtschaffen, 1971), it is not waking itself but a remarkable, imprecise experiential simulacrum of waking.
or the percentage of known characters out of all counted characters. Such scores permit the comparison of dreams of different length and complexity. Other researchers assess dream attributes relative to a global information measure describing the length of the dream report. Length is often assessed as a total count of information-bearing words excluding redundancies, commentary, and postawakening associations and connections. The measure is commonly referred to as word information count (WIC).19 A similar, less often used, baseline measure consists of the number of lines in the dream report. Others parse the dream report into basic conceptual units within which proportions may
be compared using a common baseline; the temporal unit (TU), by which all activities that occur simultaneously are considered a single unit,20 is one such procedure. These measures do not provide true proportions to the extent that the denominator of the ratio is not in the same metric (e.g., number of words in a report) as the numerator (number of characters). Division of intensity ratings by such correction factors is especially problematic. However, if a target attribute (e.g., visual realism) is also scored using a word count (e.g., number of words describing visual realism divided by number of words in the report19), then it may be considered a true proportion.
598 PART I / Section 7 • Psychobiology and Dreaming Table 51-2 Common Types of Measurements Used to Assess the Similarity of Dream Content to Waking Reality Attributes MEASUREMENT TYPE
BASELINE
EXAMPLES
RATER TYPE
Prevalence
Presence per dream
Pain, sex, emotion, etc.
S, J
Frequency
Number per dream
Characters
S, J
Intensity
Rating of feature per dream
Vividness, bizarreness
S, J
Structural coherence
Number of story units Number of relational categories per story unit
Number of causal linkages
J
Temporal profile
Presence or rating over time
Emotion valence
S, J
General Measures
Length-Corrected Measures (Proportion, Intensity) Word based
Number or rating per word count
Word information count (WIC), total recall count (TRC)
J
Line based
Number or rating per line of report
Emotion frequency
S, J
Unit based
Number or rating per unit count
Temporal unit (TU)
J
Category based
Number or rating per category
Number of aggressive actions per number of actions Emotion appropriate to dream
S, J
J, judge rated; S, subject rated.
Structural Coherence To date, the preceding measures have been focused largely on static components of experience that do not capture the complexity, transitions, or moment-to-moment flow so characteristic of waking reality experience. However, other types of measures have been developed that tap such features to a limited extent. One grouping of approaches concerns evaluation of the logical coherence of dream content. Some systems assess the cause, effect, enabling, and simultaneity relationships among dream components and reflect what might be referred to as the narrative complexity or story-like coherence of dream simulations. These scores are generally proportionalized relative to a basic parsing unit, such as a story episode. Narrative analyses that derive from the discourse analysis tradition21,22 purport to quantify the basic constituents of story episodes (e.g., scenes, characters, internal reactions) as well as the causal, enabling, and associational interactions among these constituents. They have been used to characterize differences between REM and NREM dreams,23 between REM dreams from different times of the night,24 and between dreams and myths.25 A shortcoming of these approaches is that they have to date been modeled on only a limited number of structures, primarily simple stories and scripts. However, waking reality experiences are composed of many such structures covering the entire range of psychological and social organization. Temporal Profiles The temporal profile is relatively rare for studies of dream content.26 The measures not only assess frequencies of an attribute in a dream report but also quantify the temporal sequencing of the attribute. One such measure is the tally of positive (P) and negative (N) affect sequences through the dream; my group reported that PN sequences are more prevalent than NP sequences.27 We have also developed a
system to assess longer sequences, a temporal profile of emotional valence in home dream reports (Table 51-3). For every line of the report, subjects evaluate the positive or negative valence of dream emotion on an 8-point scale and thereby chart out the temporal fluctuations in dream negativity. Implications for Dream Classification The preceding review illustrates that measures of the presence, frequency, intensity, proportion, or coherence of reality features capture a large part of what is simulated during dream experience. But are such measures sufficient to define and classify dreaming as a unique form of imaginative cognition? One possible reply to the affirmative is that merely the sustained presence of simulated features, regardless of their modality (e.g., visual, auditory) or content type (e.g., characters, settings), is sufficient to distinguish dreaming from other imaginal forms. Another possibility is that the presence of such features is insuf ficient, that some narrative structure is required as well. However, both possibilities are questionable on the grounds that other forms of imaginative cognition also seem to involve simulation and narrative structure (e.g., daydreaming, autobiographical memory, hallucination).
DREAM BIZARRENESS AS REALITY SIMULATION ERROR The reality simulation perspective also provides a point of departure for assessing the all-too-common portrayal of unusual, unrealistic, even phantasmagoric scenes, events, and characters in dreams. These more outré or bizarre features of dream content are typically assessed for their degree of departure from waking reality equivalents. Accordingly, dream content has been evaluated for how possible, probable, appropriate, or novel it is with respect
CHAPTER 51 • Dream Analysis and Classification: The Reality Simulation Perspective 599
Table 51-3 Example Scoring of Emotional Valence in a Home Log Dream Using a Temporal Profile Method*
35 % Incongruous or vague elements/report
31
33
30 25
23
20 14
15 10
14
15
15
16
12 8
5
S Em elf ot io ns Pl ac Ac e An tio im ns at e ob P In er j an so im ns at e o Ev bj e La nt ng s u C age og ni tio n
0
*Subjects evaluate the attribute of emotional valence on a 0-7 scale (0 = negative, 7 = positive) for each line of the dream report. The result is a clear graphical representation of the temporal fluctuations of dream negativity (rightmost column). Neg, negative; Pos, positive.
to waking experiences of the same kind. Revonsuo14 and Cicogna and coworkers15 both suggest that bizarre features of dream content are evidence for errors or disruptions in the reality simulation mechanism. Table 51-4 summarizes several of the more comprehensive methods for assessing dimensions of bizarreness in dream content. Methods of Assessment These descriptions illustrate that bizarreness is implicitly or explicitly assessed relative to waking reality standards. Thus, more thorough assessments of how reality features are accurately simulated during dreaming should contribute to a better understanding of how such features are not accurately simulated. Revonsuo and Salmivalli35 have made some progress in this regard; by counting incongruous and vague dream elements (relative to waking reality counterparts) in addition to all other dream elements, they were able to determine that bizarreness affects an average of 20% to 22% of all dream elements in a report. As shown in Figure 51-2, bizarreness is more likely to affect some types of dream elements (e.g., language, 31%; cognition, 33%) than others (self, 8%; emotions, 12%). Other research indicates that bizarreness affects about half of human characters but is much less likely to affect their intrinsic structure, such as their visual appearance or familiarity (internal bizarreness, 37.1%) than it is to affect the context within which the characters appear, such as the places they appear or the actions they perform (contextual bizarreness, 62.9%).36
Figure 51-2 Proportions of bizarre (incongruous or vague) dream elements for each of 10 types of elements in dream reports. Self attributes are rarely bizarre, whereas language and cognition elements are bizarre about a third of the time (From Revonsuo A, Salmivalli C. A content analysis of bizarre elements in dreams. Dreaming 1995;169-187.)
Despite such progress, an important shortcoming of most methods of bizarreness assessment is that the comparisons with waking reality features are made by judges who rely on their own conceptualizations of normative waking experience and have limited knowledge of subjects’ idiosyncratic experiences. Comparisons of judge- and subject-based ratings for at least one bizarreness measure (appropriateness of emotions32) demonstrate acceptable reliability, but further work with other measures is clearly required. One method for improving access to subjects’ idiosyncratic information is to encourage or train them to provide autobiographical information relevant to their dream reports.35 Another preferable method is to employ probe questions that direct the subject’s attention to specific dream attributes with a directive about how and with what they should be compared. To illustrate, one study37 employed the following item to assess potential deficits in dreamed thinking processes: Would your thinking when awake be the same as it was in the dream if the event that occurred in the dream occurred while awake? (Y, N, ?). It is important to distinguish this method from a second type in which subjects rate bizarreness relative to the context of the dream. The latter requires them to determine whether dream elements, such as characters, are bizarre relative to the ongoing context, such as the setting.36 In the study just cited, a second question was employed to assess such contextual bizarreness: Would your thinking when awake be the same as your thinking in the dream regarding the occurrence of the event itself? (Y, N, ?). Such comparisons may be difficult for naïve subjects to make and might require some degree of training to ensure adequate validity and reliability.
600 PART I / Section 7 • Psychobiology and Dreaming Table 51-4 Comprehensive Measures of Bizarreness in Dream Content* BIZARRENESS DIMENSION
DEFINITION
CATEGORIES
RATER TYPE
REFERENCE
Novelty
Six-point nominal scale for rating each of four Hall/Van de Castle categories of dream event (physical surroundings, characters, social interactions and activities, overall dream)
• Exact replication of a previous experience • Replication with minor changes • Replication with major changes • Never experienced, readily could have occurred • Never experienced, very unlikely to have occurred • Never experienced, extremely unlikely to have occurred
J
Dorus, 197128
Impossibility or improbability
Probability of occurrence of feature is less than 5% of real-life counterpart Five categories of content (plot, characters, objects, actions, thoughts or feeling states) are subclassified
• Discontinuity: rapid transition from one thought, action, image, or dream setting to an unrelated one • Incongruity: aspects of persons, places, activities do not fit together • Uncertainty: explicit vagueness or ad hoc attempts to explain bizarre events in dream
J
Hobson, 198729 Mamelak, 198930 Scarone, 200731
Feeling appropriateness
Similarity or difference between the kinds of feelings had in the dream and those expected had the dream occurred in waking life, rated on 5-point scale
• Practically identical • Pretty much the same • Similar in some ways but different in others • Pretty much different • Totally different
S, J
Foulkes, 198832
Bizarreness
Calculated as the sum of three subscales
• Discontinuities: part of a report inconsistent with other parts according to waking experience • Improbable combinations: impossible or improbable elements according to waking experience • Improbable identities: multiple, impossible or changing identities of characters or objects
J
Reinsel, 199233
Bizarreness
Four types of elements (events, characters, feelings, situations) evaluated for five subtypes of each
• Physical impossibility: metamorphosis, change of place or time, admixture of objects and characters • Physical implausibility: modification of specific features • Behavioral implausibility: adoption of uncommon behaviors • Functional implausibility: use of objects for strange functions • Incongruity of dialogue, thought and feeling relative to situation
J
Cipolli, 199334
Bizarreness
Elements of 14 categories (self, place, time, persons, animals, body parts, plants, objects, events, actions, language, cognition, emotions, sensory experiences) rated for three bizarreness types
• Incongruous element: (a) internally distorted or contextually incongruous; (b) exotic; (c) impossible; • Vague element: identity or nature is indeterminate, unknown, or obscure • Discontinuous element: sudden, unexpected appearance, disappearance, or transformation
J
Revonsuo, 199535
*Most bizarreness measures require judges to assess the extent to which dream content departs from analogous events experienced in waking reality. J, judge rated; S, subject rated.
CHAPTER 51 • Dream Analysis and Classification: The Reality Simulation Perspective 601
Implications for Dream Classification Studies of dream bizarreness add a unique dimension to the problem of defining dreaming that might prove to distinguish it from other forms of imaginative cognition. In particular, it may be the co-occurrence of simulated reality features in combination with a relatively consistent presence of anomalies in simulation that lends dreaming its idiosyncratic character. For example, the presence of bizarre attributes may be much less likely to characterize autobiographic memory recall or even daytime fantasies. On the other hand, bizarreness affects only about 22% of dream features, which suggests that it alone may be insufficient as a defining attribute.
THE PERCEPTUAL LIMITS OF REALITY SIMULATION The content and bizarreness measures considered thus far assess the more obvious successes and failures of reality simulation during dreaming, but they only remotely address the possibility that dreaming might simulate details of reality apprehension that fall beyond the introspective and reporting capacities of experimental subjects. Because subjects are not normally aware of all of the perceptual determinants of their reality experiences during wake fulness, they also might not be able to identify the determinants of their apparent reality experiences while dreaming. In this regard, some writers13-15 have begun to question how a multisensory simulation of perception is maintained both spatially and over time. This emphasis reflects an appreciation of how the apparent unity and continuity of dream subjectivity depends upon processes of spatiotemporal binding.38 Revonsuo refers to this process as “consciousness-related binding,” by which the unity of subjective percepts not linked to external stimuli—dreaming, for example—is preserved. Stenstrom and I13 have described this as a process that determines the momentto-moment stability of self-orientation or the impression that dreaming is occurring from a first-person point of view (here) and in the subjective present (now). Numerous forms of subtle perceptual activity contribute to this spatially and temporally coherent here-and-now experience of reality while awake: all actions linked to perceptual search, such as looking, listening, touching, smelling, and so forth, are of this type. Less-obvious activities are the ubiquitous orienting reaction to novel stimuli, the appreciation of gravity and other orientational information, the background awareness of posture and kinesthesia, and the sense of proprioceptive feedback.13 These perceptual activities operate largely outside of focal awareness and are typically subjugated to the central contents of consciousness—usually what is perceived to be seen, heard, felt, smelled, or tasted in the outer world. The background perceptual activities are nonetheless a constant contributor to the complex contour of subjective awareness. Although it might appear that perceptual activity is abolished during dreaming simply because there is nothing from the external world to look at, listen to, or otherwise explore, evidence suggests that some subtle perceptual activity remains. Physiologic studies point to continued activity in most perceptual systems during REM sleep:
rapid eye movements, middle ear muscle activity, fine motor activity in the extremities, phasic orienting reactions, and so on. One common hypothesis about rapid eye movements is that at least some eye movements are perception-like acts of looking at or scanning visual dream contents.39 Others suggest that phasic ponto-geniculooccipital (PGO) surges during REM sleep reflect orienting reactions to novel dream stimuli.40 Studies that administer sensory stimuli during REM sleep, such as muscle pressure or electrical impulses, appear to influence this level of subtle perceptual activity, for example, by destabilizing the normal orientation of the apparent self.41 However, for the most part, the phenomenological correlates of subtle perceptual activity remain to be investigated. The following dream sequence reported in Revonsuo14 illustrates the understated nature of this activity: I felt something under my foot; there was a stone on the floor. When I looked on the floor again after a moment, I noticed that there was a small red pill there. After a while I saw another one, but bigger. Monica said that they are medicine for the cat and that they have to be picked up. I started to help her in doing so. At this point there were lots of pills on the floor, or different colors, big and small. When I was collecting them and putting them into a metallic box, they had turned into watercolors.14, pp. 243-244 The sequence illustrates that acts of touching and looking both occur as they might in reality and, moreover, that the acts lead to the apparent acquisition of new “perceptual” information. In the first sentence, the act of touching with the foot reveals a stone on the floor; in the second, the act of looking reveals the presence of a red pill also on the floor. These sequences of perceptual action followed by information acquisition are completely consistent with the normal functioning of waking perceptual systems.42 It should also be apparent that this type of activity on the part of the dreamer is often not reported; the phrases in this sample report that describe touching and looking could have been deleted without serious loss of understanding. In fact, we may ask whether sentence 3 in the report hints at the occurrence of yet a third act of looking that was reported imprecisely (“After a while I saw”). Similarly, throughout the remainder of the dream sequence, it is very likely that incompletely reported perceptual acts accompanied the apprehension of new information (e.g., “At this point there were”). In the final sentence, the acts of “collecting” and “putting” may be seen as at least partly perceptual in nature—and these acts resulted in even more new information being discerned. Only probe questions about subtle perceptual activity that are directed at these specific junctures in the dream— and preferably administered to subjects while they are giving the report, not afterwards—could determine definitively if such activities were, in fact, represented in the background of dream experience. Targeted probe questions do, in fact, enhance the informational content of reports.37 A stark example of this is the fact that spontaneous references to the dreamed self account for less than 3% of scored dream elements,35 but probe questions reveal that self-presence occurs in almost 100% of reports.
602 PART I / Section 7 • Psychobiology and Dreaming
It should also be apparent from the preceding that subjects who possess superior skills in self-reflection and communication may be likely to provide more accurate, more detailed reports of reality simulation information of this subtler kind. There is evidence that longer home dream reports with more informational content are produced if subjects are preselected for elevated language skills and trained for 1 night in the sleep laboratory to attend to such subtle perceptual details (using short video clips, hypnagogic images, and REM dreams as practice).43 Similarly, if subjects are prompted to report bizarre dream contents, more of these contents appear in reports.35 Implications for Dream Classification Apart from the simulation of specific dream contents, such as characters, settings, and objects, the defining characteristics of dreaming may be discovered in simulating the process of apparent perception. Much less effort has gone into developing instruments for quantifying features of perceptual processes, but the use of specific targeted probes as well as the selection and training of subjects may be needed to further explore this possibility.
CONCLUSION Emerging interest in the reality simulation capacity of dreaming offers a viable point of departure for furthering the incomplete task of dream classification. A wide range of dream content measures has been developed to quantify the successful aspects of reality simulation during dreaming. Others have been produced to assess unsuccessful simulation features (bizarreness). Both types of measure have implications for how dreaming may ultimately be defined and classified. One possibility is that the relatively unbroken stream of simulations, regardless of modality (e.g., visual, auditory, kinesthetic) or content type (e.g., character, object, structural connection) gives dreaming its distinctive character. Another is that a mix of bizarreness and reality simulation distinguishes dreaming from other cognitive events. A third possibility is that the process of perceptual activity is simulated in such depth and detail during dreaming that it is indistinguishable from real perception. Although there is a shortage of measures for tapping this subtler level of reality simulation in dream content, further exploration of this possibility may well depend upon the use of specific target probes as well as the selection and training of subjects. With such developments, researchers might gain access to a heretofore unappreciated level of subjective experience that could give closure to the incomplete task of dream classification.
❖ Clinical Pearl In some sleep disorders (e.g., sleep paralysis, narcolepsy), the simulation of waking state reality experience during dreaming may become so intense that the person is convinced of the reality of events and might even come to believe that dreamed events really happened.
REFERENCES 1. Kuiken D. Dreams and self-knowledge. In: Gackenbach J, editor. Sleep and dreams: a sourcebook. New York: Garland; 1986. p. 222-247. 2. Kuiken D. Dreams and feeling realization. Dreaming 1995;5: 129-157. 3. American Academy of Sleep Medicine: ICSD-II. International classification of sleep disorders: diagnostic and coding manual. Chicago: American Academy of Sleep Medicine; 2005. 4. Klinger E. Meaning and void. Minneapolis: University of Minnesota Press; 1977. 5. Freud S. The interpretation of dreams. New York: Basic Books; 1900/1955. 6. Foulkes D. Dreaming: a cognitive-psychological analysis. Hillsdale, NJ: Lawrence Erlbaum Associates; 1985. 7. Tart CT. The world simulation process in waking and dreaming: a systems analysis of structure. J Ment Imagery 1987;145-157. 8. Hunt HT. The multiplicity of dreams: memory, imagination, and consciousness. New Haven: Yale University Press; 1989. 9. Nielsen TA. Reality dreams and their effects on spiritual belief: a revision of animism theory. In: Gackenbach J, Sheikh AA, editors. Dream images: a call to mental arms. Amityville, NY: Baywood Publishing; 1991. p. 233-264. 10. Revonsuo A. The reinterpretation of dreams: an evolutionary hypothesis of the function of dreaming. Behav Brain Sci 2000; 877-901. 11. Hobson JA, Pace-Schott E, Stickgold R. Dreaming and the brain: towards a cognitive neuroscience of conscious states. Behav Brain Sci 2000;793-842. 12. Domhoff GW. The scientific study of dreams. Neural networks, cognitive development, and content analysis. Washington, DC: American Psychological Association; 2003. 13. Nielsen TA, Stenstrom P. What are the memory sources of dreaming? Nature 2005;437(7063):1286-1289. 14. Revonsuo A. Inner presence: consciousness as a biological phenomenon. Cambridge, Mass: MIT Press; 2006. 15. Cicogna PC, Occhionero M, Natale V, Esposito MJ, et al. Bizarreness of size and shape in dream images. Conscious Cogn 2007; 381-390. 16. Winget C, Kramer M. Dimensions of dreams. Gainesville, Fla: University Presses of Florida; 1979. 17. Snyder F. The phenomenology of dreaming. In: Madow L, Snow LH, editors. The psychoanalytic implications of the psychophysiological studies on dreams. Springfield, Ill: Charles C Thomas; 1970; p. 124-151. 18. Hall C, van de Castle RI. The content analysis of dreams. New York: Appleton-Century-Crofts; 1966. 19. Smith, MR, Antrobus, JS, Gordon, E, Tucker MA, et al. Motivation and affect in REM sleep and the mentation reporting process. Conscious Cogn 2004;501-511. 20. Foulkes D, Schmidt M. Temporal sequence and unit composition in dream reports from different stages of sleep. Sleep 1983; 265-280. 21. Stein NL, Glenn CG. An analysis of story comprehension in elementary school children. In: Freedle RO, editor. New directions in discourse processing. Norwood, NJ: Ablex; 1979. p. 53-120. 22. Mandler JM, Johnson NS. Remembrance of things parsed: story structure and recall. Cogn Psychol 1977;111-131. 23. Nielsen TA, Kuiken D, Hoffmann R, Moffitt A, et al. REM and NREM sleep mentation differences: a question of story structure? Sleep Hypnosis 2001;9-17. 24. Cipolli C, Bellucci L, Mattarozzi K, Mazzetti M. Story-like organization of REM-dreams in patients with narcolepsy-cataplexy. Brain Res Bull 2008;77:206-213. 25. Kuiken DL, Nielsen TA, Thomas S, McTaggart D. Comparisons of the story structure of archetypal dreams, mundane dreams, and myths. Sleep Res 1983;196. 26. Merritt JM, Stickgold R, Pace-Schott E, Williams J, et al. Emotion profiles in the dreams of men and women. Conscious Cogn 1994;46-60. 27. Nielsen TA, Deslauriers D, Baylor G. Non-random positive and negative affect sequences in dream and waking event reports. Sleep Res 1991;163. 28. Dorus E, Dorus W, Rechtschaffen A. The incidence of novelty in dreams. Arch Gen Psychiatr 1971;364-368.
CHAPTER 51 • Dream Analysis and Classification: The Reality Simulation Perspective 603
29. Hobson JA, Hoffman SA, Helfand R, Kostner D. Dream bizarreness and the activation-synthesis hypothesis. Hum Neurobiol 1987;157-164. 30. Mamelak AN, Hobson J. Dream bizarreness as the cognitive correlate of altered neuronal behavior in REM sleep. J Cogn Neurosci 1989;201-222. 31. Scarone S, Manzone ML, Gambini O, Kantzas I, et al. The dream as a model for psychosis: an experimental approach using bizarreness as a cognitive marker, Schizoph Bull 2007;515-522. 32. Foulkes D, Sullivan B, Kerr NH, Brown L. Appropriateness of dream feelings to dreamed situations. Cogn Emot 1988;29-39. 33. Reinsel R, Antrobus J, Wollman M. Bizarreness in dreams and waking fantasy. In: Antrobus JS, Bertini M, editors. The neuropsychology of sleep and dreaming. Hillsdale, NJ: Lawrence Erlbaum Associates; 1992. p. 157-185. 34. Cipolli C, Bolzani R, Cornoldi C, De Beni R, et al. Bizarreness effect in dream recall. Sleep 1993;163-170. 35. Revonsuo A, Salmivalli C. A content analysis of bizarre elements in dreams. Dreaming 1995;169-187. 36. Revonsuo A, Tarkko K. Binding in dreams—the bizarreness of dream images and the unity of consciousness. J Consciousness Studies 2002;3-24.
37. Kahn D, Hobson JA. State-dependent thinking: a comparison of waking and dreaming thought. Conscious Cogn 2005;429-438. 38. Revonsuo A. Binding and the phenomenal unity of consciousness. Conscious Cogn 1999;173-185. 39. Herman JH, Erman M, Boys R, Peiser L, et al. Evidence for a directional correspondence between eye movements and dream imagery in REM sleep. Sleep 1984;7(1):52-63. 40. Morrison AR. Paradoxical sleep and alert wakefulness: variations on a theme. In: Chase MH, Weitzman ED, editor. Sleep disorders: basic and clinical research. New York: Spectrum Publications; 1983; p. 95-122. 41. Nielsen TA. Changes in the kinesthetic content of dreams following somatosensory stimulation of leg muscles during REM sleep. Dreaming 1993;99-113. 42. Gibson JJ. The senses considered as perceptual systems. Boston: Houghton Mifflin; 1966. 43. Solomonova E, Nielsen TA, Stenstrom P, Lara-Carrasco J, et al. Enhanced dream reports and better identification of dream memory sources following training in an introspective technique. 25th Annual Conference of the International Association for the Study of Dreams (IASD), July 8-12, 2008.
Dreams in Patients with Sleep Disorders Michael Schredl Abstract Dreaming is defined as mental activity that occurs during sleep. This chapter focuses on sleep disorders that have been studied in relation to dreaming: insomnia, sleep apnea syndrome, narcolepsy, and the restless legs syndrome. Dream recall is heightened in patients with insomnia, and their dreams reflect current stressors. Whereas breathing-related dreams in sleep apnea patients are rare, deregulation of the REM sleep system in narcolepsy also manifests in dreams,
Dreaming is defined as mental activity that occurs during sleep.1 Because dream recall and dream content have been shown to be linked to sleep physiology,2,3 the question arises as to whether the presence of a sleep disorder alters dream recall or dream content. If, for example, dream recall frequency is related to the frequency of nocturnal awakenings in healthy persons, one might expect that dream recall frequency is heightened in insomnia patients. This chapter focuses on several sleep disorders that have been studied in relation to dreaming: insomnia, sleep apnea syndrome, narcolepsy, and the restless legs syndrome. For other diagnoses, including idiopathic hypersomnia or NREM parasomnias such as sleep walking and night terrors, systematic dream content analytic studies are lacking. See Chapters 53, 97, and 98 for a discussion of nightmares4-6 and dreams in REM sleep behavior disorder7,7a and in posttraumatic stress disorder.8,9
DREAM RECALL AND SLEEP PARAMETERS IN HEALTHY PERSONS In order to interpret the dream recall findings of patients with sleep disorders, the arousal–retrieval model of dream recall10 and empirical evidence supporting it is briefly outlined. The arousal–retrieval model10 hypothesizes that two steps are necessary for recalling a dream. For the first step, a certain amount of cortical arousal is necessary in order to transfer information (in this case, the dream content) from short-term into long-term memory. A period of wakefulness must follow the dream experience for the person to recall it because these storage processes do not occur during sleep. Once the dream is stored in long-term memory, the second step of the model, retrieval of the memory, takes place. Salience11 and interference12 are factors that might affect retrieval of the information. The more salient the dream experience and the less interference that occurs during retrieval, the higher the probability that the dream will be recalled. Even the repression hypothesis13 has been integrated into the model, namely, that very intense emotions may also reduce the chance of recalling the dream. 604
Chapter
52
which are more bizarre and more negatively toned. Overall, the findings support the arousal–retrieval model of dream recall but also clearly indicate that other factors, such as cognitive impairment or microarousal, might affect the dreaming process. Content analytic findings support the continuity hypothesis of dreaming, which states that waking-life issues are reflected in dreams. The number of studies in this field is still very small, however, and further research is needed to confirm and expand the reviewed findings.
Studies in healthy persons have shown that nocturnal awakenings14,15 and low sleep quality16,17 are associated with heightened dream recall frequency, supporting the importance of the first step of the arousal–retrieval model. Findings regarding the effect of cortical activation before awakening, as measured by the electroencephalogram (EEG), on the ability to remember the dream experience are conflicting (for an overview, see reference 2). Some studies found an increase in beta activity that was related to better dream recall,18,19 but others failed to find any correlation between EEG parameters and dream recall.20,21 Because of the methodologic complexity of such studies, a conclusive statement cannot be made. Future research might use, for example, the American Academy of Sleep Medicine (AASM) arousal criteria22 to investigate whether dream recall is heightened when the person is awakened immediately following an EEG-defined microarousal. Findings regarding the effects of salience, interference, and repression—the second step of the arousal–retrieval model—are also conflicting (for an overview, see reference 2). For example, interference reduced dream recall percentages in the sleep laboratory12 but did not seem to be of importance in explaining the variance in home dream recall.23 Whereas direct correlations between dream recall and stress measures were often not found, study participants often report that periods of stress are accompanied by increased dream recall.23,24 Repression as a trait measure was not related to dream recall in most of the studies.2 One can therefore conclude that the empirical evidence at least partially supports the arousal–retrieval model.
WAKING EXPERIENCE AND DREAMING: THE CONTINUITY HYPOTHESIS Although one can find evidence for a continuity between waking experience and dreaming in Freud’s Interpretation of Dreams (for example, the term “day residue” refers to many of his associations to his own dreams that are presented throughout the book),25 the continuity hypothesis was formally introduced into dream research by Hall and Nordby.26 The basic notion is that dreams reflect waking concerns and emotional preoccupations.27 Schredl28 pro-
posed a more-detailed model that includes several factors that can modulate the probability of specific experiences, thoughts, and feelings from waking life being incorporated into subsequent dreams. The model includes the following factors: exponential decrease of the incorporation rate of waking-life experiences into dreams with elapsed time, emotional involvement, type of waking-life experience, personality traits, and time of night. To test the continuity hypothesis, two different approaches are typically used: experimental manipulation (e.g., showing a film before sleep) or field study (e.g., collecting dreams after a major life event such as divorce). Whereas experimental studies29 have not found strong effects of presleep stimuli on dream content, field studies clearly demonstrate relationships between waking experience and dream content.30,31 One of the factors postulated by the continuity model—that emotional intensity of a waking life experience is directly related to the incorporation rate of this event into subsequent dreams—was confirmed by a diary study.32 The empirical evidence reviewed by Schredl28 indicates that the other factors of the model also seem important even though supportive systematic research is still lacking. Regarding the dream content of patients with sleep disorders, the continuity hypothesis stresses the importance of carefully eliciting patients’ waking-life experiences because it predicts that waking-life experiences unique to patients with sleep disorders (e.g., stress levels) will also be reflected in their dreams.
Insomnia Dream Recall Based on the arousal–retrieval model of dream recall and evidence obtained from healthy persons, one would expect that insomnia patients recall their dreams more often than do good sleepers. A questionnaire study of 137 insomnia patients found a relationship between the number of nocturnal wakefulness periods and dream recall.33 Whereas a small pilot study34 did not detect any differences in dream recall frequency between patients with primary insomnia and healthy controls, the first systematic study showed, as expected, that dream recall frequency was elevated in insomniacs compared to healthy controls.35 The fact that the group difference vanished when the frequency of nocturnal awakenings (questionnaire scale) was covaried in the statistical analysis supports the idea that heightened dream recall frequency is due to the frequency of nocturnal awakenings. A laboratory study including 26 patients with primary insomnia did not find differences in the recall of visual dreams after experimental REM awakenings or NREM awakenings.36,37 However, lower dream recall after spontaneous REM awakenings was found in the patients (28%) than in the healthy controls (66%). This finding should be viewed with caution because of methodologic issues, mainly the altered sleep patterns in the patient group, including shorter REM periods before the spontaneous awakenings and inadequate gender matching (higher dream recall in women).38 To summarize, dream recall elicited in the laboratory from insomniacs via an awakening technique does not
CHAPTER 52 • Dreams in Patients with Sleep Disorders 605
seem to differ from that of healthy controls, and the elevated home dream recall frequency for insomniacs might be explained by more frequent nocturnal awakenings. In clinical practice, insomnia patients often report that they must have slept because they remembered dreams: sleep state misperception (thinking that one is awake while the polysomnographic record indicates a sleep stage) is smallest for REM sleep.39 Nightmare Frequency and Negative Dream Emotions Two studies40,41 reported that persons with insomnia report nightmares more often than do patients without insomnia. However, both samples were not limited to patients with primary insomnia but also included patients with other diagnoses, such as depression. Because nightmare frequency is elevated in depression,42 these findings do not permit conclusions to be drawn about nightmare frequency in patients with primary insomnia. In another study, there were more negatively toned sleep-onset dreams in patients with insomnia, reflecting the presleep brooding or heightened cognitive arousal often present in these patients.43 However, these results were not replicated in a second study.44 More negatively toned night dreams were found in adolescents with sleeponset problems45 and in adult insomnia patients undergoing two diagnostic polysomnographic recording nights (without forced awakenings) in the sleep laboratory.35 In addition, negative dream emotions correlated with the number of waking life problems.35 Taking into account the fact that stressors or major life events can trigger insomnia, these findings are in line with the continuity hypothesis of dreaming.28 Dream Content Dream content analytic studies in patients with primary insomnia are scarce. A small pilot study34 including 44 diary dreams of six insomnia patients did not find any differences in dream length, dream emotions, and problems occurring in the dreams when compared with the dreams of healthy controls. The dream series of one patient, however, clearly reflected his waking-life problems: In the presence of my boss and several coworkers, I was unable to perform a repair job. After being verbally attacked by the boss, I told him that I would like to be placed in another department. Thinking about it, I regretted saying that because I felt that the job suits me and he is the one who is not qualified for the job because of his insufficient education.34, p. 143 This pilot study34 also showed that the number of dream persons was reduced in comparison with the dreams of healthy controls, a finding that fits the continuity hypothesis because the insomnia patients in this sample scored higher on introversion (personality questionnaire) than did the controls. Ermann46 studied the dream content of 26 insomnia patients obtained by REM awakenings in the sleep laboratory and after spontaneous awakenings during the night. The dreams of these patients more often contained negatives in self-description, such as low self-esteem, and negatives in dream descriptions, including words like no or never or references to something being missing. Schredl
606 PART I / Section 7 • Psychobiology and Dreaming Table 52-1 Dream Content in Patients with Insomnia and Healthy Controls Statistical Test VARIABLE Mean word count Realism or bizarreness
PATIENTS (N = 59)
CONTROLS (N = 30)
56.04 ± 47.42
45.34 ± 50.59
5.6
.0207
1.94 ± 0.70
1.60 ± 0.69
0.9
.3545
F =
P =
Positive emotions*
0.36 ± 0.78
0.67 ± 0.89
3.7*
.0284
Negative emotions*
0.93 ± 1.13
0.87 ± 1.03
0.2*
.3507
0.30 ± 0.58
2.4*
Problems* Health themes*
0.60 ± 0.75 16.9%
0.0%
.0607 .0120†*
Statistical test: analysis of co-variance with factors “diagnosis” and “gender” and with co-variates “age” and “mean word count” (factor “diagnosis” is depicted). *One-tailed. † Fisher’s exact test. Adapted from Schredl M, Schäfer G, Weber B, Heuser I. Dreaming and insomnia: dream recall and dream content of patients with insomnia. J Sleep Res 1998;7:191-198.
and colleagues35 were able to confirm that negatives in self-description were more prominent in patients’ dreams when compared to the dreams of healthy controls. However, the other previously reported findings of negatives in the dream description and reduced number of dream persons were not replicated. Their results are based on the analysis of dream reports of 59 insomnia patients recorded after undisturbed nights in the sleep laboratory. The patients reported longer dreams, fewer positive emotions, more problems within the dream, and more aggression and health-related themes than were present in the dreams of healthy controls (Table 52-1). Moreover, the occurrence of waking-life problems was significantly related to the occurrence of problems in their dreams (r = .357, P < .005, N = 50). Similarly, if the patients reported health problems, they dreamed about health-related issues more often (r = .255, P < .05, N = 50). The content analytic findings support the continuity hypothesis to some extent because current stressors that might play a role in etiology of the insomnia are reflected in some of the patients’ dreams (such as the dream example above). Within clinical practice, having patients report dreams might aid the diagnostic process in helping to identify current stressors. Furthermore, dreams related to these stressors might be useful within a cognitive-behavioral therapy that aims to reduce stress levels.
Sleep Apnea Syndrome Dream Recall Frequency Carrasco and colleagues47 postulated two contradictory mechanisms that might affect dream recall in sleep apnea patients. First, the cognitive impairment often found in sleep apnea patients48 might impair dream recall and, second, light sleep and frequent arousals might increase dream recall (compare with the findings for insomnia patients). Questionnaire studies that applied a retrospective dream frequency scale49 with high retest reliability50 have yielded mixed results. Whereas Schredl and colleagues51 reported increased dream recall frequency in a sample of 44 sleep apnea patients, a separate study52 found lower dream recall frequency in patients (n = 309) than in
healthy controls. A third study17 found no differences at all. This is in line with REM awakening studies47,53,54 that report similar recall rates for patients and for age-matched healthy controls: Schredl and coworkers found 64.2% recall for patients and 68.3% for controls,53 and Carrasco and colleagues found 51.5% recall for patients and 44.4% for controls.47 Furthermore, two studies52,55 did not find any relationship between dream recall frequency and sleep apnea parameters such as respiratory disturbance index or oxygen saturation nadir. Findings in this area indicate that there is no difference in dream recall between patients and controls, but systematic research that distinguishes between effects of the two postulated mechanisms (cognitive impairment, nocturnal awakenings) is still lacking. Future studies should link cognitive measures as well as sleep parameters to dream recall frequency simultaneously. Nightmares and Negative Dream Emotions In the 19th century, several researchers56-59 hypothesized that nightmares are caused by a shortage of oxygen. Using a cloth to block the mouth and nose, Boerner58 was able to induce nightmares in three different sleepers. To confirm or reject this hypothesis, the investigation of nightmare occurrence in patients with sleep apnea could be highly illuminating. De Groen and colleagues,60 indeed, reported a relationship among snoring, breathing pauses reported by the spouse, and nightmares in a sample of Dutch World War II veterans. Fifty-six percent of the sample, however, suffered from posttraumatic stress disorder, which limits generalization of the finding. Two studies61,62 have shown significant reductions in nightmare frequency after successful treatment of a comorbid sleep apnea syndrome in posttraumatic stress disorder patients. Taking the results reported next into account, one might speculate that posttraumatic nightmares are triggered by a different mechanism than idiopathic nightmares. Hicks and Bautista63 and Schredl64 did not find an association between snoring and nightmare frequency in a student sample. The first systematic study of nightmare frequency in sleep apnea patients52 found that on average,
nightmares occurred about once per month in the patient group (n = 309), which was comparable to the mean of the healthy controls after correcting for age, sex, and overall dream recall frequency. Moreover, nightmare frequency was not related to a respiratory disturbance index or the oxygen saturation nadir. Solely the presence of a psychiatric comorbidity like depression or anxiety disorder was associated with heightened nightmare frequency,52 a finding that is in line with studies of psychiatric patients.42 The findings indicate that sleep apnea patients do not suffer from nightmares caused by oxygen desaturation. Nevertheless, it would be interesting to further the research conducted by Boerner58 by applying a full-face mask during sleep, blocking the airway for short time periods and assessing reactions to the manipulation. This paradigm would induce breathing pauses without prior adaptation processes that might occur during gradual development of sleep apnea severity over time. Regarding negative dream emotions, Gross and Lavie54 reported that dreams were more negatively toned on nights with sleep apneas compared with nights with continuous positive airway pressure (CPAP) treatment. Their sample consisted of 33 patients already treated with CPAP for at least 2 months, and they were asked to sleep 1 night without CPAP for a dream recall night. Sleeping without the beneficial treatment, however, might have stimulated worries in these patients (high indices on this night: 218 ± 138 apneas per night) and, therefore, more negatively toned dreams on the nights with apneas might simply reflect these worries rather than apneic events. On the other hand, Carrasco and colleagues47 reported a significantly increased number of violent and highly anxious dreams in 20 never-treated patients with severe sleep apnea as compared to healthy controls and speculated as to whether a hyperactivation of the limbic system might explain this finding. More negatively toned dreams were also reported by 59 sleep apnea patients rating dreams recalled in the morning after a diagnostic night in the sleep laboratory.55 Because intensity of negative emotions was not related to symptom severity (respiratory disturbance index, oxygen saturation nadir51) one might speculate whether the more negatively toned dreams are explained by the continuity hypothesis, for example, they reflect patients’ daytime problems engendered by daytime sleepiness. Dream Content In 1965, Hobson, Goldfrank, and Snyder65 published a study investigating the relationship between respiration and mental activity in sleep. This research was stimulated by the concept of body-mind interaction during REM sleep; for example, if the dream ego looks at something, there should be related eye movements recordable from the sleeper. The research findings in this area (for reviews, see Erlacher66 and Schredl67) do not demonstrate a one-toone relationship between dreamed activities and physiologic parameters such as heart rate, leg electromyography (EMG), and eye movements; nonetheless, there is some evidence of a connection between dream content and sleep physiology. The following example illustrates the paradigm applied by Hobson, Goldfrank, and Snyder.65 The healthy young volunteer was awakened after a naturally
CHAPTER 52 • Dreams in Patients with Sleep Disorders 607
occurring breathing pause of about 10 seconds and was asked to report her dream experience. “It was a play, a person was being choked. That’s exactly when you called my name. I, by the way, was the actress that was being choked”65, p. 86 Overall, specific respiratory content (speech, laughter, crying, smoking, choking) was elicited after awakenings following apneic respiration more often than after periods of regular breathing (32.8% vs. 17.9%, P <.05). Whereas one might speculate that dreamed actions are responsible for changes in physiologic processes, the opposite is equally possible, namely, that physiologic processes affect dream content. The effect of external stimuli (auditory, tactile, olfactory, and kinesthetic) on dream content is well documented.68 Research on the effect of internal stimuli on dream content, however, is scarce. For example, Bokert69 found beverage and water themes in the dreams of thirsty subjects. In light of these two research themes (mind–body interactions and the effects of internal and external stimuli), the question arises whether breathing-related dream content occurs in patients with sleep apnea. Despite some very illustrative samples (see later), the results are not encouraging. In 24 diary dreams of five sleep apnea patients,34 in 44 REM and NREM awakening dreams of 33 patients,51 and in 34 REM awakening dreams of 20 patients,47 no references to respiratory events were found. Gross and Lavie54 and Schredl55 found at least some evidence of breathingrelated topics, but the differences did not reach significance. Here are two examples out of 59 dreams.55 A 39-year-old male sleep apnea patient with a respiratory disturbance index (RDI) of 68.1 apneas per hour and a maximal drop of blood oxygen saturation of 43%: During the dream I felt tied up or chained. I saw thick ropes around my arms and was not able to move. I experienced the fear of suffocation without being able to cope with the situation. Powerlessness and also resignation came up.55, p. 295 Another 39-year-old male patient with REM sleep– associated apneas, an RDI of 71.8, and an oxygen saturation nadir of 68% reported: I was diving without oxygen tanks and was gasping for breath. The way to the surface was far and I managed it just in time. After waking up I really gasped for breath.52, p. 207 Assuming that internal stimuli can affect dream content, it seems astonishing that apneas with such dramatic physiologic effects do not also appear in dreams more often. One plausible explanation might be that the mind adapts to the slow progress of apnea severity over the years. As mentioned, it could be informative to conduct a study in which participants wear a device (a full-face mask) that allows breathing to be blocked completely in order to investigate the effects of unadapted respiratory pauses on dream content. To summarize, a small number of patients report dreams related to their sleep apnea syndrome, but a general effect of sleep apnea on dream content has not been observed. Schredl and colleagues51 correlated respiratory disturbance
608 PART I / Section 7 • Psychobiology and Dreaming
indices with different dream characteristics and found a strong relationship with dream bizarreness (r = −.51, P < .005, N = 33), namely, high respiratory disturbance was associated with more-realistic and less-bizarre dreams. The hypothesis51 that microarousals terminating breathing pauses might interfere with the dreaming process seems worthy of further study. The finding of shorter-than-normal dream reports in sleep apnea patients34,53 might point to a similar conclusion because research70-72 indicates that the duration of undisturbed REM sleep is related to the length of the dream report. Carrasco and colleagues47 reported longer dreams in their sleep apnea patients than in healthy controls, but the mean dream length of the sleep apnea patients in this sample was comparable to that in previous studies (23.8 words34 versus 19.4 words54) whereas that of the controls (9.6 words) was much lower than normally found in healthy samples, which is 50 or more words per dream on average.68 One might speculate that the sleep fragmentation caused by apneas affects dream report length. On the other hand, it is plausible that memory deficits affect the dream recall process upon awakening. For instance, Schredl and coworkers73 reported a strong relationship between verbal short-term memory and dream length in healthy elderly persons. In future studies of sleep apnea and dreaming, cognitive measures should also be assessed to take this possibility into account. Effect of Continuous Positive Airway Pressure on Dreaming The treatment of sleep apnea syndrome with continuous positive airway pressure (CPAP) results in a dramatic change in sleep physiology (slow-wave sleep rebound, REM rebound, less-fragmented sleep) in addition to reduction of the respiratory disturbance index.47,74 The findings of Gross and Lavie54 did not clarify possible CPAP effects on dreaming because they studied previously treated patients who stopped using their CPAP masks for 1 night (for discussion of their findings, see earlier). Schredl and colleagues52 compared 15 patients with CPAP who were spending a control night in the sleep laboratory with patients who were undergoing diagnostic procedures for the first time. These patient groups did not differ with respect to dream recall frequency and nightmare frequency, although two patients did report subjective increases in dream recall frequency after starting CPAP treatment, and one patient experienced two nightmares on the first CPAP night. All were possibly due to REM rebound effects. A longitudinal study of the effects of CPAP on dreaming in a sample of 20 patients with severe sleep apnea (mean apnea–hypopnea index, 73.3) was carried out by Carrasco and colleagues.47 They found a decrease in dream recall on the first CPAP night but an increase in dream length and positively toned dreams. These results can be interpreted as an effect of slow-wave sleep rebound, which is associated with reduced dream recall and less-fragmented sleep. The positively toned dreams, especially those found after 3 months and after 2 years of CPAP treatment, might be explained by the continuity hypothesis because CPAP treatment is often perceived as being very beneficial in
patients with a severe sleep apnea syndrome. Thus, the possibility of increased limbic system activation during sleep in these patients as a cause of negatively toned dreams should be further examined.
Narcolepsy Although narcolepsy is a sleep disorder involving REM sleep, systematic research of dream recall and dream content in these patients is scarce. The dreams of patients with narcolepsy have been described as vivid and often disturbing,75-78 although Vogel79,80 found equal proportions of negative and positive emotions in their sleep-onset dreams. On the other hand, Mayer and colleagues,81 analyzing the hospital records of 106 narcolepsy patients, found a prevalence rate of nightmares of 41.5% compared to about 5% in the general population. Vogel79,80 reported that narcoleptic patients were more often aware of their state of consciousness during dreaming—that is, they knew that the dream experience was not real. A small pilot study82 investigated dream recall and dream content in narcoleptic patients more systematically. The sample of 23 patients showed higher dream recall frequency on a questionnaire measure and a tendency to report more negatively toned dreams upon awakening in the sleep laboratory than did healthy control subjects. Dream content analysis of 14 dreams recorded by eight patients during the laboratory diagnostic nights clearly showed that the dreams were more bizarre than those of the control subjects (Table 52-2). The following bizarre dream was reported by one 20-year-old female narcoleptic patient: I dreamt that I stepped out of the bright light of the lamp and slipped into another time period. I met my grandfather who I had never seen in my waking life and saw other persons from my hometown, much younger than today. With the help of friends I managed to travel back to the present time. I even brought some stuff from the past with me which my mother identified as her former belongings.82, p. 106 Two REM-awakening studies with 1583,84 and 17 patients85 with narcolepsy indicated that the percentage of recall after REM awakenings is very high (about 90%) and comparable to figures obtained from matched controls. Whereas dreams of the first REM period are longer in patients with narcolepsy,85 late-night dreams of the patient group tend to be shorter that those from the control group. However, correlations between sleep fragmentation (stage shifts, movements before awakening) and dream length or other dream characteristics were not found.83 In the patient group, sleep-onset REM dreams elicited during the day are more vivid and more intense (fear/anxiety and joy/ elation) than their nighttime dreams.84 Patients with narcolepsy show higher scores on a scale measuring reflective consciousness; that is, they are aware more often that they are dreaming (in both sleep-onset REM dreams and nighttime dreams) than are healthy controls.83 Despite the extensive methodology of the latter study, some questions were not answered, including effects of age on dream content (the sample included subjects from 17 to 70 years), effects of coping with the disorder (the sample consisted
CHAPTER 52 • Dreams in Patients with Sleep Disorders 609
Table 52-2 Dream Content of Patients with Narcolepsy and Healthy Controls ANCOVA VARIABLE
PATIENTS (N = 8)
HEALTHY CONTROLS (N = 30)
Word count
61.48 ± 56.68
45.34 ± 50.59
2.4
.1273
Bizarreness
2.56 ± 0.42
1.60 ± 0.69
10.9
.0023
F =
P =
Positive emotions
0.13 ± 0.35
0.67 ± 0.89
2.4
.1307
Negative emotions
1.00 ± 1.36
0.87 ± 1.08
0.0
.9343
−0.88 ± 1.55
−0.20 ± 1.25
0.4
.5578
Difference of emotions
*Analysis of co-variance with factor “diagnosis” (df = 1) and co-variates “age” and “word count.” ANCOVA, analysis of co-variance. Adapted from Schredl M. Dream content in narcoleptic patients: preliminary findings. Dreaming 1998;8:103-107.
mainly of well-adjusted members of the Norwegian Narcolepsy Association) and whether dream content differs in drug-naïve patients (most patients had discontinued their treatment). To summarize, dysregulation of the REM sleep system underlying narcolepsy also manifests in cognitive changes such as higher dream recall frequency and more negatively toned and bizarre dreams. Larger samples are needed to replicate the findings of these pilot studies.82,83,85 Because simple methods for coping with bad dreams and nightmares are available (e.g., imagery rehearsal therapy),86,86a it might be beneficial to speak with narcoleptic patients about their dream experiences in the course of diagnosis and treatment. The use of lucid dreaming as a treatment for nightmares87 might be especially well suited for these patients in light of their frequent awareness within the dream that they are dreaming.
Restless Legs Syndrome Schredl88 studied dream recall frequency in a sample of 131 patients with restless legs syndrome. Dream recall frequency (questionnaire measure) was not elevated in comparison with healthy controls, a finding that would have been predicted by the arousal–retrieval model of Koulack and Goodenough10 because the frequency of self-reported nocturnal awakenings was markedly higher in the patient group. The significant negative correlation between dream recall frequency and the index of periodic limb movements during sleep associated with arousals indicates that frequent arousals might interfere with dream recall or even with the dreaming process itself. Dream content analytic studies in patients with restless legs syndrome have not yet been published although it would be very interesting to investigate a possible link between dream content and limb EMG activity, especially in light of several studies89-91 that have demonstrated correlations between dreamed limb activity and leg or arm EMG recordings. Furthermore, it would be interesting to differentiate between direct associations between dream content and physiologically measured limb movement during sleep and the continuity effect: references to legs or arms might be more prominent in the dreams of this patient group because these patients are very preoccupied with this topic prior to sleep.
CONCLUSIONS Although the number of studies investigating dreaming in patients with sleep disorders is limited, overall the findings suggest that altered sleep physiology and other disorderrelated variables have effects on dream recall and dream content in these patients. The heightened dream recall frequency in insomnia patients supports the arousal–retrieval model of Koulack and Goodenough,10 namely, that nocturnal awakenings play an important role in explaining differences in dream recall. On the other hand, studies in patients with sleep apnea and restless legs syndrome clearly indicate that other factors such as cognitive dysfunction or microarousals play an important role. Thus, future studies should include cognitive measures and analyze the effects of microarousals92 on dream recall. Such studies would help to extend the present formulation of the arousal–retrieval model to account for the effects of sleep-related and cognitive variables. Although it may be preferable to use different methods to measure dream recall (questionnaire, diaries, forced awakenings in the sleep laboratory), correlations among these measures are quite high and have often yielded comparable findings.2 Nightmares are not directly caused by a shortage of oxygen—nightmare frequency is not elevated in sleep apnea patients—but the hypothesis put forward by Carrasco and colleagues47 concerning hyperactivity of the limbic system during REM sleep in these patients is an interesting topic for future research, especially if functional magnetic resonance imaging (fMRI) studies can be achieved. Narcoleptic patients will be very suitable for such studies because they fall asleep very quickly, often directly into a REM sleep episode. Dream content studies indicate that physiologic processes such as sleep apnea are somewhat reflected in dreams, but the relationships are rather weak.67 To assess possible adaptational processes, it would be useful to study healthy persons wearing devices (full-face masks) that block the airway for brief periods (10 or 20 seconds) during sleep. This might provide insights into the effects of internal stimuli on dream content. The findings of Hobson, Goldfrank, and Snyder65 and Schredl64 indicate that breathing pauses are related to dream content in healthy subjects.
610 PART I / Section 7 • Psychobiology and Dreaming
Some findings51,88 suggest that microarousals affect the dreaming process. Further studies of dream content in patients with sleep disorders will help to clarify whether altered sleep physiology has an effect on dream content and, more specifically, on the formal characteristics of dreams such as dream bizarreness.51 Systematic research in this area is, however, completely lacking. Because dream reports obtained in the sleep laboratory are strongly influenced by the setting (up to 50% of the dreams include laboratory references),93 it is also necessary to collect home dream reports to increase the generalizability of the laboratory findings. The continuity hypothesis28 is supported by findings from insomnia patients: Patients with more waking-life problems dream more often about these problems. Studying the dreams of patients with sleep disorders may thus be of clinical interest in providing clues to the specific, problematic, waking-life experiences of these patients, such as stressors and disorder-related distress. It would be useful to assess large samples of patients with different sleep disorders to determine whether disorderrelated symptoms such as sleepiness, concentration problems, or lack of energy are reflected in dream content. These findings could be combined with measures of distress to systematically test the model formulated by Schredl,28 namely, to determine whether emotional involvement affects the probability of dreaming about a particular experience or symptom. Regarding the negatively toned dreams of narcolepsy patients, it would be of great value to undertake clinical trials of imagery rehearsal therapy86 and training in lucid dreaming.87 Owing to the small number of studies in the field, additional research is needed to replicate and expand the findings reviewed in this chapter. Such efforts would help to refine the arousal–retrieval, salience, and continuity hypotheses, to deepen our knowledge about the dreaming process, and to provide further insight into the pathologies of patients with sleep disorders. ❖ Clinical Pearl Dream content in patients with sleep disorders reflects their awake experiences (e.g., current stressors) and rarely their abnormal physiologic events during sleep. For example, apnea patients seldom report nightmares or dreams of suffocating.
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32. Schredl M. Factors affecting the continuity between waking and dreaming: emotional intensity and emotional tone of the waking-life event. Sleep Hypnosis 2006;8:1-5. 33. Charney DS, Soldatos CR, Bixler EO, Kales A. Factors contributing to dream recall in insomniac subjects. Sleep Res 1977;6:126. 34. Schredl M. Traumerinnerungshäufigkeit und Trauminhalt bei Schlafgestörten, psychiatrischen Patienten und Gesunden. University of Mannheim: unpublished master thesis 1991. 35. Schredl M, Schäfer G, Weber B, Heuser I. Dreaming and insomnia: dream recall and dream content of patients with insomnia. J Sleep Res 1998;7:191-198. 36. Ermann M, Peichl J, Pohl H, Schneider MM, et al. Spontanerwachen und Träume bei Patienten mit psychovegetativen Schlafstörungen. Psychother Psychosom Med Psychol 1993;43:333-340. 37. Ermann M, Peichl J, Pohl H. Psychogene Schlafstörung als Traumstörung: Die Traumerinnerung bei Patienten mit psychovegetativen Schlafstörungen. In: Becker-Carus C, editor. Fortschritte der Schlafmedizin: Aktuelle Beiträge zur Insomnieforschung. Hamburg: LIT Verlag; 1994. p. 102-114. 38. Schredl M, Reinhard I. Gender differences in dream recall: a metaanalysis. J Sleep Res 2008;17:125-131. 39. Amrhein C, Schulz H. Selbstberichte nach dem Wecken aus dem Schlaf—ein Beitrag zur Wahrnehmung des Schlafes. Somnologie 2000;4:61-67. 40. Ohayon MM, Morselli PL, Guilleminault C. Prevalence of nightmares and their relationship to psychopathology and daytime functioning in insomnia subjects. Sleep 1997;20:340-348. 41. Hoffmann RM, Rasch T, Schnieder G. Fragebogen zur Erfassung allgemeiner Persönlichkeitsmerkmale Schlafgestörter (FEPS-I). Göttingen: Hogrefe; 1996. 42. Schredl M, Engelhardt H. Dreaming and psychopathology: dream recall and dream content of psychiatric inpatients. Sleep Hypnosis 2001;3:44-54. 43. Antrobus JS, Saul HN. Sleep onset: subjective behavioral and electroencephalographic comparisons. Waking Sleep 1980;4:259-270. 44. Freedman RR, Sattler HL. Physiological and psychological factors in sleep-onset insomnia. J Abnorm Psychol 1982;91:380-389. 45. Strauch I, Maier B, Kaiser F. Developmental aspects of sleep onset insomnia in adolescents. In: Koella WP, Rüther E, Schulz H, editors. Sleep 1984. Stuttgart: Gustav Fischer Verlag; 1985. p. 386-388. 46. Ermann M. Die Traumerinnerung bei Patienten mit psychogenen Schlafstörungen: Empirische Befunde und einige Folgerungen für das Verständnis des Träumens. In: Leuschner W, Hau S, editors. Traum und Gedächtnis: Neue Ergebnisse aus psychologischer, psychoanalytischer und neurophysiologischer Forschung. Münster: LIT Verlag; 1995. p. 165-186. 47. Carrasco E, Santamaria J, Iranzo A, Pintor L, et al. Changes in dreaming induced by CPAP in severe obstructive sleep apnea syndrome patients. J Sleep Res 2006;15:430-436. 48. Fulda S, Schulz H. Cognitive dysfunction in sleep disorders. Sleep Med Rev 2001;5:423-445. 49. Schredl M. Messung der Traumerinnerung: Skala und Daten gesunder Personen. Somnologie 2002;6:34-38. 50. Schredl M. Reliability and stability of a dream recall frequency scale. Percept Motor Skills 2004;98:1422-1426. 51. Schredl M, Kraft-Schneider B, Kröger H, Heuser I. Dream content of patients with sleep apnea. Somnologie 1999;3:319-323. 52. Schredl M, Schmitt J, Hein G, Schmoll T, et al. Nightmares and oxygen desaturations: is sleep apnea related to heightened nightmare frequency? Sleep Breath 2006;10:203-209. 53. Groß M. Dreams of patients with and without sleep apnea in the sleep laboratory. Haifa: Israel Institute of Technology, Research thesis; 1991. 54. Gross M, Lavie P. Dreams in sleep apnea patients. Dreaming 1994;4:195-204. 55. Schredl M. Träume und Schlafstörungen: Empirische Studie zur Traumerinnerungshäufigkeit und zum Trauminhalt von schlafgestörten PatientInnen. Marburg Germany: Tectum; 1998. 56. Waller J. Abhandlung über das Alpdrücken, den gestörten Schlaf, erschreckende Träume und nächtliche Erscheinungen. Frankfurt: Philipp Heinrich Guilhauman; 1824. 57. Strahl M. Der Alp, sein Wesen und seine Heilung. Berlin: Theod. Chr. Fr. Enslin; 1833. 58. Boerner J. Das Alpdrücken: Seine Begründung und Verhütung. Würzburg, Germany: Carl Joseph Becker; 1855.
CHAPTER 52 • Dreams in Patients with Sleep Disorders 611 59. Cubasch W. Der Alp. Berlin: Habel; 1877. 60. de Groen JHM, Op den Velde W, Hovens JE, Falger PR, et al. Snoring and anxiety dreams. Sleep 1993;16:35-36. 61. Youakam JM, Doghraniji K, Schutte SL. Posttraumatic stress disorder and obstructive sleep apnea syndrome. Psychosomatics 1998;39: 168-179. 62. Krakow B, Lowry C, Germain A, Gaddy L, et al. Retrospective study on improvements in nightmares and post-traumatic stress disorder following treatment for co-morbid sleep-disordered breathing. J Psychosom Res 2000;49:291-298. 63. Hicks RA, Bantista J. Snoring and nightmares. Percept Motor Skills 1993;77:433-434. 64. Schredl M. Snoring, breathing pauses, and nightmares. Percept Motor Skills 2008;106:690-692. 65. Hobson JA, Goldfrank F, Snyder F. Respiration and mental activity in sleep. J Psychiat Res 1965;3:79-90. 66. Erlacher D, Schredl M. Do REM (lucid) dreamed and executed actions share the same neural substrate? Int J Dream Res 2008;1: 7-14. 67. Schredl M. Body-mind interaction: dream content and REM sleep physiology. North Am J Psychol 2000;2:59-70. 68. Schredl M. Die nächtliche Traumwelt: Einführung in die psychologische Traumforschung. Stuttgart: Kohlhammer; 1999. 69. Bokert E. The effects of thirst and a related stimulus on dream reports. Dissertation Abstracts 1967;28:4753B. 70. Dement WC, Kleitman N. The relation of eye movements during sleep to dream activity: an objective method for the study of dreaming. J Exp Psychol 1957;53:339-346. 71. Dement WC, Wolpert EA. The relation of eye movements, body motility and external stimuli to dream content. J Exp Psychol 1958;55:543-553. 72. Hobson JA, Stickgold R. The conscious state paradigm: a neurocognitive approach to waking, sleeping, and dreaming. In: Gazzaniga MS, editor. The cognitive neurosciences. Cambridge, Mass: MIT Press; 1995. p. 1373-1388. 73. Schredl M, Schröder A, Löw H. Traumerleben von älteren Menschen—Teil 2: Empirische Studie und Diskussion. Z Gerontopsychol Psychiatr 1996;9:43-53. 74. Aldrich M, Eiser A, Lee M, Shipley JE. Effects of continuous positive airway pressure on phasic events of REM sleep in patients with obstructive sleep apnea. Sleep 1989;12:413-419. 75. Nixon OL, Pierce CM, Lester BK, Mathis JL. Narcolepsy. Nocturnal dream frequency in adolescents. J Neuropsychiatr 1964;5: 150-152. 76. Passouant P, Cadilhac J. Activite onirique et narcolepsie. J Psychol Norm Pathol 1967;64:171-187. 77. Roth B, Bruhova S. Dreams in narcolepsy, hypersomnia and dissociated sleep disorders. Exp Med Surg 1969;27:187-209. 78. Lee JH, Bliwise DL, Labret-Bories E, Guilleminault C, et al. Dreamdisturbed sleep in insomnia and narcolepsy. J Nerv Ment Dis 1993;181:320-324. 79. Vogel GW. Studies in psychophysiology of dreams: III. The dream of narcolepsy. Arch Gen Psychiat 1960;3:421-428. 80. Vogel GW. Mentation reported from naps of narcoleptics. Adv Sleep Res 1976;3:161-168. 81. Mayer G, Kesper K, Peter H, Ploch T, et al. Untersuchung zur Komorbidität bei Narkolepsiepatienten. Dtsch Med Wochenschr 2002;127:1942-1946. 82. Schredl M. Dream content in narcoleptic patients: preliminary findings. Dreaming 1998;8:103-107. 83. Fosse R. REM mentation in narcoleptics and normals: an empirical test of two neurocognitive theories. Conscious Cogn 2000;9: 488-509. 84. Fosse R, Stickgold R, Hobson JA. Emotional experience during rapid-eye-movement sleep in narcolepsy. Sleep 2002;25:724732. 85. Cipolli C, Bellucci C, Mattarozii K, Mazzetti M, et al. Story-like organization of REM-dreams in patients with narcolepsy-cataplexy. Brain Res Bull 2008;77:206-213. 86. Krakow B, Zadra A. Clinical management of chronic nightmares: imagery rehearsal therapy. Behav Sleep Med 2006;4:45-70. 86a. Aurora RN, Zak RS, Auerbach SH, et al. Standards of Practice Committee; American Academy of Sleep Medicine. Best practice guide for the treatment of nightmare disorder in adults. J Clin Sleep Med 2010;6:389-401.
612 PART I / Section 7 • Psychobiology and Dreaming 87. Spoormaker VI, Van den Bout J. Lucid dreaming treatment for nightmares: a pilot study. Psychother Psychosom 2006;75:389-394. 88. Schredl M. Dream recall frequency of patients with restless legs syndrome. Eur J Neurol 2001;8:185-189. 89. Wolpert EA. Studies in psychophysiology of dreams: II. an electromyographic study of dreaming. Arch Gen Psychiat 1960;2:231-241. 90. Grossman WI, Gardner R, Roffwarg HP, Fekek AF, et al. Relation of dreamed to actual movement. Psychophysiology 1972;9:118-119.
91. Gardner R, Grossman WI, Roffwarg HP, Weiner H. The relationship of small limb movements during REM sleep to dreamed limb action. Psychosom Med 1975;37:147-159. 92. Guilleminault C. EEG arousals: scoring rules and examples. Sleep 1992;15(2):173-184. 93. Schredl M. Laboratory references in dreams: methodological problem and/or evidence for the continuity hypothesis of dreaming? Int J Dream Res 2008;1:3-6.
Dreams and Nightmares in Posttraumatic Stress Disorder Thomas A. Mellman and Wilfred R. Pigeon Abstract Posttraumatic stress disorder (PTSD) develops in a significant minority of persons who are exposed to severely threatening trauma. Trauma-related nightmares appear to be specific to PTSD and can be a persisting and distressing symptom. Not all dream content reported by persons with PTSD is a direct representation of trauma memories, however. Stress and trauma appear to acutely affect the thematic content of dreams irrespective of whether the dreamer goes on to experience continuing emotional distress. Dreams that more specifically replicate the memory of the trauma during the early aftermath of exposure have been associated with the development of PTSD. In addition to indicating that stressful experiences are incorporated into dream content, findings from experimental and naturalistic studies further suggest that dreams can positively influence adaptation to stress and
REPLICATIVE-TRAUMA NIGHTMARES: HALLMARK OF A DISORDER? Posttraumatic stress disorder (PTSD) is a psychiatric condition that develops in some but not all persons who experience severely threatening traumatic experiences (see also Chapter 129). The diagnosis is based on persisting symptoms that include re-experiencing the trauma with intrusive images, flashbacks, or nightmares; emotional numbing and avoidance behavior; and heightened arousal. The course of PTSD can be self-limited, but in approximately a third of cases it persists for many years, and it often manifests with comorbid psychiatric disorders.1 The fourth edition of the Diagnostic and Statistical Manual (DSMIV-TR) specifically delineates “recurrent distressing dreams of the event” among re-experiencing symptoms.2 In an influential review and theoretical paper, Ross and colleagues emphasized the occurrence of “repetitive replicas” of trauma scenes as a feature of dreams that is virtually specific to PTSD, further referring to trauma nightmares as a “hallmark of the disorder.”3 Treating patients who have PTSD often leaves the clinician impressed with the impact of distressing dreams featuring traumatic experiences. Several studies support the specificity of the relationship between trauma-related nightmares and PTSD proposed by Ross’s group.3 Van der Kolk and colleagues4 reported that patients with combatrelated PTSD were more likely to indicate that their nightmares exactly or almost exactly replicated an actual event, as compared with nightmare sufferers who did not have PTSD. Mellman and coworkers5 surveyed combat veterans from clinical and nonclinical settings and found that nightmares about combat experiences were more specifically associated with PTSD than were nightmares on other topics. In an analysis of a large epidemiologic data-
Chapter
53
trauma. Persisting trauma-related nightmares might represent a failure of adaptive mechanisms. Findings from polysomnographic studies of PTSD have not been entirely consistent. More-recent studies suggest that the majority of nightmare episodes of study subjects with PTSD arise from REM sleep, although they can also be accompanied by NREM sleep. A more-fragmented pattern of REM sleep during the month following trauma is associated with the development of PTSD. In contrast to normal dreams, dreams in persons with PTSD often incorporate actual memories of frightening experiences. These features have implications for understanding dreams’ neurocognitive substrates. There is evidence that pharmacologic antagonism of noradrenergic receptors ameliorates nightmares in PTSD. Treatments that use cognitive restructuring of nightmare content have also yielded promising results.
base from Vietnam veterans, a measure that combined instances of nightmares related to military experiences and of distress from dreaming was strongly associated with PTSD.6 Thus there is consistent support for the theory that continuing representation of trauma memories in dreams is a feature of PTSD but not necessarily of trauma exposure absent the diagnosis. The aforementioned studies relied on retrospective and global, categorical assessments of dreams. Esposito and coworkers7 performed content analysis of dreams elicited from morning diaries in a group of combat veterans receiving treatment for PTSD. About half of subjects’ dreams contained direct references to combat experiences, and almost all of the dreams featured threat. The majority of dreams were also not unlike normal dream reports in containing implausible elements that were not representations of actual memories. Kramer and colleagues8 also found in a symptomatic combat veteran group that about half of the dreams elicited after awakenings in the laboratory setting referred to military experiences. These studies all focused on combat veterans many years after their combat experiences. Several studies have examined the influence of trauma on dream content during an acute phase following the traumatic event. In the 2 months following Hurricane Iniki, which struck Hawaii in 1992, dream questionnaires from 22 primary care patients were compared to a larger sample surveyed prior to the hurricane (N = 265). A significantly higher percentage of the posthurricane subjects reported that their dreams were related to general stressors (74% versus 48%) and to “especially stressful life experiences” (67% versus 37%), although only 13% reported dreams specific to the hurricane.9 Similarly, evacuees of the East Bay fire (Oakland and Berkeley, California, in 1991) were more likely to have recorded dreams in their home 613
614 PART I / Section 7 • Psychobiology and Dreaming
diaries with content related to death, disasters, and fires than were controls.10 Incorporation of trauma content in the dreams of recently traumatized children was reported by all 23 children kidnapped and buried underground in a trailer,11 in 8 of 10 who witnessed rapes,12 and in 63% of those on a playground during a sniper attack.13 Unfortunately, these studies did not relate dream content to PTSD or acute stress disorder status, although the study of the sniper attack did document higher rates of trauma dreams as a function of proximity to the threat. Mellman’s group14 elicited dream content from study participants during the acute aftermath of traumatic injury. A subgroup of the sample described dreams that were distressing and “highly similar” to the traumatic experience (17% of the sample; 56% of those who reported dreams). This group had more severe concurrent PTSD symptom ratings than the groups with other categories of dreams, and they had higher subsequent PTSD severity than the group that did not recall dream content.14 Thus, exposed populations tend to report dreams with specific trauma-related or thematically related content during the acute aftermath of disasters and other traumas, and dreams that are similar to the memory of the actual traumatic event are associated with the development of PTSD. Chronic PTSD is associated with recurring dreams that represent specific memories of a traumatic experience. However, the more comprehensive evaluations of dreams during chronic phases of PTSD document that salient dream content is not limited to representations of traumatic memories.
DREAM CONTENT WITH STRESS AND TRAUMA: BEYOND REPLICATION Although the issue of trauma replication has received the most attention, there are descriptions of other aspects of content in the literature on dreaming, nightmares, and PTSD. The boundaries of traumatic stress are not always clear, and the topic seems embedded in broader questions of stress and dreaming, including observations of the impact of stressful experiences on dreams, the influence of dreams on adaptation to stressful experiences, and content themes related to trauma exposure and PTSD beyond replication of trauma. Stress and Dream Content A number of studies of naturalistic stressors have suggested an impact of stressful waking experiences on dream content. For example, health-related stressors have been evidenced in the home dream content of patients awaiting surgery15 and in hospitalized burn patients.16 Dreams in pregnancy have been interpreted as reflecting concerns about the body and about the ability to mother and nurture.17 In addition, the dreams of women with stressful menstruation are more likely to contain emotional content and relationship themes during the peak hormonal phase compared with other days in the menstrual cycle.18 Academic and occupational stress might also influence dream content. Duke and Davidson19 found increased dream recall in a week before exams compared with a
control week in college students. In contrast, Delorme, Lortie-Lussier, and De Koninck20 found no difference in dream content involving exams or negative emotions 10 days before and after exam periods, although the authors failed to find a difference in the students’ reported stress levels between the two periods. During one of the worst weekly performances of the Dow Jones Industrial Average, significant correlations were found between stockbrokers’ stress levels and negative dream features, including recurrent nightmares, dreams of being chased, and dreams of falling.21 It has been noted that recurring dreams, which have more negative content than nonrecurring dreams,22 tend to be activated by stressful life experiences.23,24 In a community sample, subjects with active recurring dreams reported greater life stress in the prior 6 months and had more negative dream content than both former recurrent dreamers and dreamers who had never had recurrent dreams.23 These findings were replicated in two college student samples.25,19 In addition to these naturalistic observations, studies have used experimental induction of stress and examined dream content. Disturbing movies,26,27 sham intelligence exams,28,29 deprivation of liquids,30 and experimentally induced pain31 have all been incorporated into dreams collected in the sleep laboratory. Overall, experimental stressors are associated with subsequent dreams that are characterized by a negative tone. This almost uniform support for incorporation of stressful experiences into dream content contrasts somewhat with the debate and mixed findings around the broader question of whether dreams tend to incorporate recent experiences and waking concerns.32-36 Although there is evidence that relatively innocuous daytime events and concerns can be incorporated into dreams, it seems reasonable to infer from the studies we have reviewed that stressful waking experiences are more likely to be incorporated into dreams and have an impact on dream emotional content. This relationship of dream incorporation to emotional saliency has led researchers to invoke an emotional information processing function for dreaming.22,37-40 Although this contention is difficult to confirm, several lines of evidence support a relationship between dreams and adaptations to emotional stress. Dreams and Adaptation to Stress Two experimental studies suggest that dream content is related to adaptation to stress. In the study of liquid deprivation, subjects who had their thirst quenched in their dreams were less thirsty in the morning than those who had liquid in their dreams and remained unquenched or who had unrelated dreams.30 In one of the experiments that used viewing a disturbing film as a probe, subjects experimentally deprived of REM sleep were subsequently more distressed by the film than either a NREM-sleep interruption group or an uninterrupted sleep group.26 Naturalistic studies suggesting that dream incorporation can aid adaptive processing include several that found that references to drugs and alcohol in dreams are a positive predictor of abstinence,41-44 including smoking cessation.45 Cartwright and colleagues38 elicited dream reports following laboratory awakenings from REM sleep in men and
CHAPTER 53 • Dreams and Nightmares in Posttraumatic Stress Disorder 615
women going through divorce near the time of the initial breakup and one year later. Those who incorporated the ex-spouse into their dreams at the time of the breakup were less depressed and better adjusted at 12-month follow-up than those who did not. These two sets of observations might initially seem to contradict the observations reviewed earlier of an association between trauma-replicating dreams and the outcome of PTSD. The observations just reviewed, however, refer to incorporation of a reference or representation of a stressful situation and not necessarily the replication of events. For dreaming to influence emotional adaptation to stress, the neurocognitive activity of sleep must have an enduring influence on memory representations. Although the theory remains controversial, there is increasing support for a role for sleep in the consolidation and reprocessing of memory (i.e., learning) that is reviewed in preceding chapters of this text. Trauma, PTSD, and Content Themes Dow and colleagues46 studied depressed combat veterans with and without PTSD. They examined dreams collected from both groups in the sleep laboratory after awakenings from REM sleep. The PTSD group’s dreams were rated higher for anxiety and were more likely to have been set in the past. Another laboratory study of veterans found more frequent aggression in the dreams of subjects with combat-related PTSD compared to the dreams of healthy controls.47 Ratings for anxiety, aggression, and interpersonal conflicts were greater in the dreams of a symptomatic subgroup of Holocaust survivors.48 In a study of combat-related PTSD where dream recall was stimulated using diary records filled out in the morning, threatening content was observed in the majority of dreams (83%) with and without the presence of combat references.7 In contrast, although the dreams from five female college students with PTSD were found to be more vivid and descriptive than dreams from five matched controls, they were not more negative, repetitive, or oriented to the past.49 Studies relating dreams to trauma exposure in children have also described content themes beyond representation of the trauma. The dreams of Palestinian children exposed to ongoing civil and military violence, elicited by home diaries, contained more themes of aggression, persecution, and negative emotions than dreams recorded by children living in a more peaceful region.50 Kurdish children with trauma exposure evidenced more dreams with threat and aggression than either a nonexposed group or a control group from a peaceful country.51 Unfortunately, neither of these studies determined the PTSD status of their subjects. In our own study of patients with recent traumatic injuries, dreams contained less friendliness and sexuality compared with dreams from a normative sample of dreamers.52 The dreams of those who developed PTSD had more content related to general and physical misfortune, as well as more negative emotions, than those who did not develop PTSD. Thus, compared to other dreams, dreams after trauma have more general negative emotions, anxiety, threat, and aggression, and these appear to be most pronounced with PTSD.
POLYSOMNOGRAPHIC CORRELATES OF NIGHTMARES IN PTSD There is an association, albeit not an absolute one, between dreams—particularly those with content that is more elaborate, visual, emotional, and bizarre—and the REM sleep stage.53 Other sleep phenomena, such as night terrors and related parasomnias, arise from NREM sleep stages, particularly slow-wave sleep.54 Owing to the atypical aspects of dreams from patients with PTSD, there has been interest in determining their relationships to stages of sleep. It has been asserted that nightmares in PTSD are associated with NREM sleep. In one study, body movement occurred during stage 2 sleep when nightmares were reported in the morning.4 In another study, Kramer and Kinney55 studied a group of 24 subjects in the sleep laboratory and identified a subgroup of eight combat veterans with nightmare symptoms who reported the majority of their nightmares after awakening from stage 2 sleep. In contrast, the one spontaneous nightmare awakening that occurred during sleep recordings in a study by Ross and coworkers3 and three of the three recorded by Mellman’s group14 were preceded by REM sleep. Hefez and colleagues56 described a pattern of REM interruption insomnia in a PTSD group with nightmares. The largest sample of polysomnographically recorded spontaneous nightmares (N = 17) for PTSD patients was reported in an abstract by Woodward and colleagues.57 They indicated that the probability of REM sleep occurring in the 10 minutes preceding spontaneous awakenings with nightmares was 57%, whereas only 17% of total sleep was REM. The probability of sleep preceding nightmares featuring stage 2 (27%) was less than its percentage of total sleep. None of the nightmares emerged from slow-wave sleep. Thus on balance it seems that nightmares in PTSD tend to be preceded by REM sleep, but they sometimes emerge from other sleep stages (1 and 2). The characteristics of nightmares in PTSD, however, can contrast with normative features of dreams associated with REM sleep, such as a lack of correspondence to actual events, bizarreness, and mixing of time frames and contexts.53,58 The observations reviewed in previous sections of this chapter suggest that associative memory functions linked to REM sleep may facilitate emotional adaptation. We have previously described a relationship between the development of PTSD and dreams that were rated as being very similar to the trauma memory. Another aim of our study of acute trauma was to evaluate characteristics of REM sleep and their relationship to outcome following trauma by obtaining polysomnographic recordings close to the time of medical and surgical stabilization in patients receiving treatment for traumatic injuries. The injured patients who developed PTSD did not differ from those who did not develop PTSD with respect to general measures of sleep maintenance, amount of REM sleep, and increased eye-movement density (compared with uninjured controls). The group developing PTSD, however, spent significantly less uninterrupted time in REM sleep before shifting to waking or other EEG sleep stages. We hypothesized that this observed fragmentation of REM sleep may compromise REM sleep’s potentially adaptive memory-processing functions.59
616 PART I / Section 7 • Psychobiology and Dreaming
SUMMARY AND THEORETICAL IMPLICATIONS The representation of the memory of a traumatic experience in dreams is a distinguishing feature of PTSD. Although having characteristics different from those generally ascribed to dreams from the REM sleep stage, PTSD dreams appear most often to be associated with REM sleep, although they can emerge from stage 1 and 2 as well. Traumatic and stressful experiences appear to influence dream content whether or not people are successfully adapting emotionally. Findings suggest that nightmares that are replicative of the actual memory of the trauma experience are associated with the development of PTSD. When PTSD enters a chronic phase, trauma memories continue to be represented in recurring nightmares. Dream content of patients with established PTSD is not limited to trauma memories, however, and it might reflect the negative and restricted emotional state of the dreamer in other ways as well. The literature on stress and dreaming suggests that dream content reflects the emotional processing of the dreamer and that dreams potentially have a positive influence on emotional adaptation. In contrast, recurring nightmares in PTSD patients appear to reinforce the memory of the trauma and contribute to the dreamer’s distress. The distinguishing feature of replicating or representing the memory of the trauma over time might provide important clues as to what is not working in the dream life and the more general emotional memory processing of people with PTSD. Fosse and colleagues60 have found that dreams recalled by healthy college students often contain references to recent experiences, but the events’ representation in the dreams rarely corresponds to actual events. The researchers concluded that normal dreams are not episodic memories. Noncorrespondence to coherent whole-memory representations and other characteristics of dream mentation are thought to be consequent to the selective activation of neural structures during REM sleep. In the generally accepted model of sleep state regulation, neural activation during REM sleep is mediated by firing of cholinergic brainstem nuclei and is further facilitated by inhibition of noradrenergic firing.58 As has been discussed, the dreams that characterize PTSD are not necessarily unaltered replays of the traumatic event. Yet there is a tendency for dreams occurring with PTSD to contain more representations of events that include or are closer to unaltered memories (of traumatic events) than there is for normal dreams. Experimental evidence indicates that declarative memory for emotionally arousing stimuli is mediated by noradrenergic mechanisms.61 Therefore, impaired inhibition of noradrenergic tone during sleep could be a mechanism underlying the presence of episodic-like, fear-enhanced memories in dreams. Direct support for this hypothesis comes from evidence that pharmacologic blockade of noradrenergic stimulation with prazosin, an α1-noradrenergic antagonist, ameliorates nightmares in PTSD.62 There is a further consideration regarding an adaptive memory-processing function for REM sleep and REM
dreaming that may be impaired with PTSD. Normal dream mentation has a hyperassociative quality: characters, places, and sequences that are not typically linked in waking conscious thought tend to be juxtaposed in dreams.58 Foa and colleagues63 have suggested that one of the mechanisms of successful emotional processing during exposure therapy is the development of a new network of associations to the traumatic memories. Such a process may be facilitated by the normal neurocognitive characteristics of REM sleep and impaired by a more selective activation of trauma memories.
TREATMENT OF POSTTRAUMATIC NIGHTMARES AND RELATED SLEEP DISTURBANCES A number of treatments, particularly selective serotonin reuptake inhibitor antidepressants and cognitive behavior psychotherapies, have recently been documented to be effective for treating PTSD.64 Reports of the treatment studies typically indicate reduction of the severity of reexperiencing symptoms but do not specifically parcel out the treatment effects on nightmares. It is likely that nightmares tend to decrease in frequency and intensity as PTSD generally improves. Clinical experience and literature on the treatment of residual nightmare symptoms, however, suggest that nightmare symptoms can be inadequately responsive to first-line interventions for PTSD. Formulations discussed in preceding sections suggest pharmacologic and psychotherapeutic approaches for targeting PTSD nightmares. There is now clinical research evidence that supports efficacy of treatment strategies that are consistent with the previously stated theoretical for mulations. Raskind and coworkers62 followed up their preliminary studies suggesting amelioration of nightmare symptoms with α1-adrenergic blockade in a trial with a double-blind, placebo-controlled parallel-groups design that further supported prazosin treatment for nightmares and sleep disturbance in combat-related PTSD.64a A therapeutic effect of postsynaptic blockade of noradrenergic neurotransmission is consistent with the role for noradrenergic activity in mediating traumatic nightmares that was postulated in the previous section. Evaluations of other pharmacologic approaches to target nightmare symptoms of PTSD have mostly not been controlled. Anecdotal descriptions of benefits to nightmares have been made for other noradrenergic-suppressing agents (e.g., guanfacine),65 novel antipsychotic medications,66 antidepressants that feature postsynaptic serotonin antagonism (trazodone and nefazodone),67,68 and the serotonin antagonist cyproheptadine.69 Subsequent double-blind evaluations of cyproheptadine70 and guanfacine71 failed to find therapeutic effects for these medications. The idea that dreams are related to both successful and impaired patterns of emotional processing suggests that recurrent nightmares related to trauma might respond to psychotherapeutic interventions. In fact, several clinical trials have demonstrated good efficacy for nightmare interventions that are based on principles of exposure therapy or cognitive restructuring. Imagery-rehearsal therapy has
CHAPTER 53 • Dreams and Nightmares in Posttraumatic Stress Disorder 617
the largest evidence base to date.72-74 In this technique, patients first learn cognitive-behavioral strategies to manage unpleasant images during wakefulness before writing out the content of a distressing dream, rescripting the content any way they wish, and then rehearsing the images of the altered dream scenario. Successful variations on this approach include combining relaxation training and direct, repeated exposure to disturbing dream content with75 or without76 rescripting of the dreams, as well as an approach that uses lucid dreaming techniques,77 wherein patients learn to change dream content as the dream actually occurs. Overall, this set of interventions results in highly significant reductions in nightmare severity and frequency, with more modest improvements in insomnia and other symptoms of PTSD. At present none of these related approaches can be recommended as a first-line comprehensive treatment for PTSD. However, imagery-rehearsal therapy in particular is a practical brief treatment with a growing evidence base that appears particularly effective in targeting nightmare symptoms; it can be applied as a stand-alone intervention for nightmares. Imagery-rehearsal therapy has also been combined with cognitive-behavioral therapy for insomnia with good success.78,79 It may also be a useful adjunct to PTSD treatments. These psychotherapeutic nightmare interventions are consistent with principles from the established cognitive behavior treatments of PTSD that apply exposure or cognitive restructuring, or both, to trauma memories.64 That such techniques can be effectively applied directly to nightmare content (which in PTSD often features trauma memories) has important implications. One is that clinicians can be realistically hopeful about the potential for alleviating distressing nightmare symptoms. We have previously referred to the apparent paradox that stressrelated references in dreams are associated with positive outcome, whereas trauma-replicating nightmares are associated with PTSD. This paradox may be reconciled if the former dreams represent an adaptive emotional processing, possibly related to modification of associative networks, and the latter represent a failure of such a process. Studies of imagery rehearsal suggest that conscious exposure to the content of recurring distressing dreams, along with instruction to modify the dream scenario, facilitates movement toward the more adaptive response. That benefits of nightmare-focused interventions generalize to other symptom domains lends support to the idea of continuity between waking emotional life and dreaming. Dreams may also offer clinicians a unique window into patients’ emotional adaptation to trauma and stress along with the status of their processing of traumatic memories. The apparently robust association between PTSD and replays or representations of trauma memories in dreams further provides an important clue to understanding abnormalities of emotional memory processing that differentiate those who suffer with PTSD and those who are more resilient to adverse psychobiological consequences of trauma. It has been shown that poor sleep quality has a negative impact on the severity of PTSD symptoms.80 However
it is unclear whether treatment of the disturbed sleep per se (by medications or cognitive behavior therapy, without, for example, imagery-rehearsal therapy as mentioned earlier78,79) improves the general symptoms of PTSD, in particular the disturbing dream-related symptoms.
❖ Clinical Pearl The phenomenon of trauma replication in dreams is a distinguishing feature of posttraumatic stress disorder that has implications for understanding alterations of memory processing functions.
REFERENCES 1. Kessler RC, Sonnega A, Bromet E, Hughes M, et al. Posttraumatic stress disorder in the National Comorbidity Survey. Arch Gen Psychiatry 1995;52:1048-1060. 2. Diagnostic and statistical manual of mental disorders. 4th ed. Washington, DC: American Psychiatric Association; 1994. 3. Ross RJ, Ball WA, Sullivan KA, Caroff SN. Sleep disturbance as the hallmark of posttraumatic stress disorder. Am J Psychiatry 1989; 146:697-707. 4. van der Kolk B, Blitz R, Burr W, Sherry S, et al. Nightmares and trauma: a comparison of nightmares after combat with lifelong nightmares in veterans. Am J Psychiatry 1984;141:187-190. 5. Mellman TA, Kulick-Bell R, Ashlock LE, Nolan B, et al. Sleep events in combat-related post-traumatic stress disorder. Am J Psychiatry 1995;152:110-115. 6. Neylan TC, Marmar CR, Metzler TJ, Weiss D, et al. Sleep disturbances in the Vietnam generation: Findings from a nationally representative sample of male Vietnam veterans. Am J Psychiatry 1998;155:929-933. 7. Esposito K, Benitez A, Barza L, Mellman TA. Evaluation of dream content in combat-related PTSD. J Traumatic Stress 1999; 12:681-687. 8. Kramer M, Schoen LS, Kinney L. The dream experience in dream disturbed Vietnam veterans. In: van der Kolk BA, editor. Posttraumatic stress disorders: psychological and biological sequelae. Washington, DC: American Psychiatric Association; 1984. p. 82-95. 9. Pagel JF, Vann BH, Altomare CA. Reported association of stress and dreaming: community background levels and changes with disaster (hurricane Iniki). Dreaming 1995;5:43-50. 10. Siegel A. Dreams of firestorm survivors. In: Barrett D, editor. Trauma and dreams. Cambridge, MA: Harvard University Press; 1996. 11. Terr LC. Children of Chowchilla: a study of psychic trauma. Psychoanalytic Study Child 1979;34:547-623. 12. Pynoos RS, Nader K. Children who witness the sexual assaults of their mothers. J Am Acad Child Adolesc Psychiatry 1988;27: 567-572. 13. Nader K, Pynoos R, Fairbanks L, Frederick C. Children’s PTSD reactions one year after a sniper attack at their school. Am J Psychiatry 1990;147:1526-1530. 14. Mellman TA, David D, Bustamante V, Torres J, et al. Dreams in the acute aftermath of trauma and their relationship to PTSD. J Traumatic Stress 2001;14:241-247. 15. Berger L, Hunter I, Lane RW. The effect of stress on dreams. New York: International University Press; 1971. 16. Raymond I, Nielsen TA, Lavigne G, Choiniere M. Incorporation of pain in dreams of hospitalized burn victims. Sleep 2002;25: 765-770. 17. Maybruck P. Pregnancy and dreams. Los Angeles: Jeremy Tarcher; 1989. 18. Bucci W, Creelman ML, Severino SK. The effects of menstrual cycle hormones on dreams. Dreaming 1991;1:263-276. 19. Duke T, Davidson J. Ordinary and recurrent dream recall of active, past and non-recurrent dreamers during and after academic stress. Dreaming 2002;12:185-197. 20. Delorme M, Lortie-Lussier M, De Koninck J. Stress and coping in
618 PART I / Section 7 • Psychobiology and Dreaming the waking and dreaming states during an examination period. Dreaming 2002;12:171-183. 21. Kroth J, Thompson L, Jackson J, Pascali L, et al. Dream characteristics of stock brokers after a major market downturn. Psychol Rep 2002;90:1097-1100. 22. Zadra AL. Recurrent dreams: their relation to life events. In: Barrett D, editor. Trauma and dreams. Cambridge, MA: Harvard University Press; 1996. p. 231-267. 23. Brown RJ, Donderi DC. Dream content and self-reported well-being among recurrent dreamers, past recurrent dreamers, and nonrecurrent dreamers. J Pers Soc Psych 1986;50:612-623. 24. Cartwright RD. The nature and function of repetitive dreams: a survey and speculation. Psychiatry 1979;42:131-137. 25. Zadra AL, O’Brien S, Donderi DC. Dream content, dream recurrence, and well-being: a replication with a younger sample. Imagination Cog Pers 1998;17:293-311. 26. Greenberg R, Pillard R, Pearlman C. The effect of dream (stage REM) deprivation on adaptation to stress. Psychosom Med 1972; 34:257-262. 27. De Koninck JM, Koulac D. Dream content and adaptation to a stressful situation. J Abnorm Psych 1975;84:250-260. 28. Koulac D, Prevost F, De Koninck JM. Sleep, dreaming, and adaptation to a stressful intellectual activity. Sleep 1985;8:244-253. 29. Stewart DW, Koulack D. The function of dreams in adaptation to stress over time. Dreaming 1993;3:259-268. 30. Bokert E. The effects of thirst and a related stimulus on dream reports. Dissertation Abstracts 1967;28:4753B. 31. Nielsen TA, McGregor DL, Zadra A, Ilnicki D, et al. Pain in dreams. Sleep 1993;16:490-498. 32. Roussy F, Camirand C, Foulkes D, Koninck J, et al. Does early-night REM dream content reliably reflect presleep state of mind? Dreaming 1996;6:121-130. 33. Roussy F, Brunette M, Mercier P, Gonthier I, et al. Daily events and dream content: unsuccessful matching attempts. Dreaming 2000; 10:77-83. 34. Rados R, Cartwright RD. Where do dreams come from? A comparison of presleep and REM sleep thematic content. J Abnorm Psych 1982;91:433-436. 35. Marquardt CJG, Bonato RA, Hoffmann RF. An empirical investigation into the day-residue and dream-lag effects. Dreaming 1996; 6:57-65. 36. Saredi R, Baylor GW, Meier B, Strauch I. Current concerns and REM-dreams: a laboratory study of dream incubation. Dreaming 1997;7:195-208. 37. Breger L. Function of dreams. J Abnorm Psych Monograph 1969;72:1-28. 38. Cartwright RD. Dreams that work: the relation of dream incorporation to adaptation to stressful events. Dreaming 1991;1: 3-9. 39. Hartmann E. Nightmares after trauma as paradigm for all dreams: a new approach to the nature and function of dreaming. Psychiatry 1998;61:223-238. 40. Van de Castle RL. Our dreaming mind. New York: Ballantine Books; 1993. 41. Choi SY. Dreams as a prognostic factor in alcoholism. Am J Psychiatry 1973;130:699-702. 42. Christo G, Franey C. Addicts’ drug-related dreams: their frequency and relationship to six-month outcomes. Subst Use Misuse 1996; 31:1-15. 43. Reid SD, Simeon DT. Progression of dreams of crack cocaine abusers as a predictor of treatment outcome: a preliminary report. J Nerv Ment Dis 2001;189:854-857. 44. Hajek P, Belcher M. Dream of absent-minded transgression: an empirical study of a cognitive withdrawal symptom. J Abnorm Psychol 1991;100:487-491. 45. Persico AM. Predictors of smoking cessation in a sample of Italian smokers. Int J Addict 1992;27:683-695. 46. Dow BM, Kelsoe JR, Gillin JC. Sleep and dreams in Vietnam PTSD and depression. Biol Psychiatry 1996;39:42-50. 47. Lavie P, Katz N, Pillar G, Zinger Y. Elevated awaking thresholds during sleep: characteristics of chronic war-related posttraumatic stress disorder patients. Biol Psychiatry 1998;44:1060-1065. 48. Lavie P, Kaminer H. Dreams that poison sleep: dreaming in Holocaust survivors. Dreaming 1991;1:11-21. 49. Vinent MH, Smith CT. REM sleep processes and dream content in
posttraumatic stress disorder. Sleep 2000;23(S2):A101. 50. Punamaeki R. The relationship of dream content and changes in daytime mood in traumatized vs. non-traumatized children. Dreaming 1999;9:213-233. 51. Valli K, Revonsuo A, Pälkäs O, Ismail KH, et al. The threat simulation theory of the evolutionary function of dreaming: evidence from dreams of traumatized children. Conscious Cogn 2005 Mar;14(1): 188-218. 52. Pigeon WR, Mellman TA. Dream content in recently hospitalized trauma patients. Proceedings of the International Society of Trauma and Stress Studies. Baltimore, MD; 2002. p. 45. 53. Foulkes WD. Dream reports from different stages of sleep. J Abnorm Social Psychol 1969;65:14-25. 54. Fisher C, Kahn E, Edwards A, Davis DM. A psychophysiological study of nightmares and night terrors: the suppression of stage 4 night terrors with diazepam. Arch Gen Psychiatry 1973;28: 253-259. 55. Kramer M, Kinney L. Sleep patterns in trauma victims with disturbed dreaming. Psychiatr J Univ Ott 1988;13:12-16. 56. Hefez A, Metz L, Lavie P. Long-term effects of extreme situational stress on sleep and dreaming. Am J Psychiatry 1987;144:344347. 57. Woodward SH, Arsenault NJ, Michel GE, Santerre CS, et al. Polysomnographic characteristics of trauma-related nightmares. Sleep 2000;23(S2):A356. 58. Hobson JA, Stickgold R, Pace-Schott EF. The neuropsychology of REM sleep dreaming. Neuroreport 1998;9:R1-R14. 59. Mellman TA, Bustamante V, Fins AI, Pigeon WR, et al. REM sleep and the early development of posttraumatic stress disorder. Am J Psychiatry 2002;159:1696-1701. 60. Fosse MJ, Fosse R, Hobson JA, Stickgold RJ. Dreaming and episodic memory: A functional dissociation? J Cog Neurosci 2003; 15:1-9. 61. Cahill L, Prins B, Weber M, McGaugh JL. β-Adrenergic activation and memory for emotional events. Nature 1994;371:702-704. 62. Raskind MA, Peskind ER, Hoff DJ, Hart K, et al. A parallel group placebo controlled study of prazosin for trauma nightmares and sleep disturbance in combat veterans with post-traumatic stress disorder. Biol Psychiatry 2007;61(8):928-934. 63. Foa EB, Kozak MJ. Emotional processing of fear: exposure to corrective information. Psych Bull 1986;99:20-35. 64. Foa E, Keane TM, Friedman MJ, editors. Effective treatments for PTSD: practice guidelines from the International Society for Traumatic Stress Studies. New York: Guilford Press; 2000. 64a. Aurora RN, Zak RS, Auerbach SH, et al. Standards of Practice Committee; American Academy of Sleep Medicine. Best practice guide for the treatment of nightmare disorder in adults. J Clin Sleep Med 2010;6:389-401. 65. Horrigan JP. Guanfacine for PTSD nightmares. J Am Acad Child Adolesc Psychiatry 1996;35:975-976. 66. Leyba CM, Wampler TP. Risperidone in PTSD. Psychiatr Serv 1998;49:245-246. 67. Ashford JW, Miller TW. Effects of Trazodone on sleep in patients diagnosed with post-traumatic stress disorder (PTSD). J Contemporary Psychotherapy 1996;26(3):221-233. 68. Mellman TA, David D, Barza L. Nefazodone treatment and dream reports in chronic PTSD. Depress Anxiety 1999;9(3):146-148. 69. Brophy MH. Cyproheptadine for combat nightmares in posttraumatic stress disorder and dream anxiety disorder. Military Med 1991;156:100-101. 70. Jacobs-Rebhun S, Schnurr PP, Friedman MJ, Peck R, et al. Posttraumatic stress disorder and sleep difficulty. Am J Psychiatry 2000;157:1525-1526. 71. Neylan TC Lenoci M, Franklin KW, Metzler TJ, et al. Guanfacine does not improve symptoms of posttraumatic stress disorder. Am J Psychiatry 2006;163:2186-2188. 72. Krakow B, Hollifield M, Johnston L, Koss M, et al. Imagery rehearsal therapy for chronic nightmares in sexual assault survivors with posttraumatic stress disorder: a randomized controlled trial. JAMA 2001;286:537-545. 73. Forbes D, Phelps AJ, McHugh AF, Debenham P, et al. Imagery rehearsal in the treatment of posttraumatic nightmares in Australian veterans with chronic combat-related PTSD: 12-month follow-up data. J Traumatic Stress 2003;16:509-513. 74. Germain A, Nielsen T. Impact of imagery rehearsal treatment on
CHAPTER 53 • Dreams and Nightmares in Posttraumatic Stress Disorder 619
distressing dreams, psychological distress, and sleep parameters in nightmare patients. Behav Sleep Med 2003;1:140-154. 75. Davis JL, Wright DC. Randomised clinical trial for treatment of chronic nightmares in trauma-exposed adults. J Trauma Stress 2007; 20:123-133. 76. Burgess M, Gill M, Marks I. Postal self exposure treatment of recurrent nightmares: a randomised controlled trial. Br J Psychiatry 1998; 172:257-262. 77. Spoormaker VI, van den Bout J. Lucid dreaming treatment for nightmares: a pilot study. Psychoter Psychosom 2006; 75:389-394. 78. Germain A, Shear MK, Hall M, Buysse DJ. Effects of a brief behav-
ioral treatment for PTSD-related sleep disturbances: a pilot study. Behav Res Ther 2007; 45:627-632. 79. Krakow BJ, Melendrez DC, Johnston LG, Clark JO, et al. Sleep dynamic therapy for Cerro Grande fire evacuees with posttraumatic stress symptoms: a preliminary report. J Clin Psychiatry 2002;63: 673-684. 80. Belleville G, Guay S, Marchand A. Impact of sleep disturbances on PTSD symptoms and perceived health. J Nerv Ment Dis 2009;197(2):126-132.
Dreaming as a Mood-Regulation System Rosalind Cartwright Abstract Dream experience may be responsible for postsleep mood improvement in normal persons. Research studies support the mood-regulation function of dreaming in healthy subjects. Dysfunctions in overnight mood regulation are associated with short-term disrupted mood states. Longer-term failures to regulate emotion occur in several sleep disorders. An example of the latter is the reduced recall of dreams and lack of dream affect in severe major depression with typically low, unregulated, morning mood and early onset of the first rapid
That we feel and function better after a night of a sufficient number of hours of sleep has recently been supported in the Institute of Medicine report1 pointing out the negative impact on health and behavior of reducing the hours of sleep. A major focus of sleep research is investigating what it is about having 7 to 9 hours of sleep that restores physiologic and psychological functions. This is puzzling in light of the amount and regularity of rapid eye movement (REM) sleep—a complex state of high brain activation, motor inhibition, shutdown of afferent input, and experience of hallucinations2—and that it is REM sleep that is disproportionately reduced when total sleep hours are curtailed. This suggests that the loss of sufficient REM sleep, and the accompanying dreams, may well be implicated in some negative effects on health and behavior subsequent to widespread reduction in sleep hours. The prevailing theory of dreaming at the time of the discovery of REM sleep was that of Freud3 who stated that dreams were a mechanism for the expression of primitive unacceptable drives, and that this display in sleep allowed these drives to be partially gratified, preventing their intrusion into waking life. There were few research tests of the validity of this theory. Foulkes4 undertook such a test by tracing the development of dreaming in normal children studied in the laboratory. He describes his findings on preschool aged children through to late adolescence, showing dreaming to be a cognitive skill parallel to the waking level of cognitive development, and concluded that this failed to support a unique drive-regulatory function of dreaming. Given that his method required a verbal report of the experienced dream, a difficult task even for some adults, Foulkes left open the possibility that REM sleep may perform this affect-modulating function before youngsters have the cognitive skill to communicate this experience. Snyder5 extended the age group covered by Foulkes’s study by analyzing the content of the dreams of healthy young adults. His study provided two findings that contributed to the hypothesized mood-regulation function of dreams. The first was the presence in dreams of the dreamer as the main character in 95% of the reports 620
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54
eye movement (REM) period. Other sleep disorders with a failure to improve morning mood are the non-REM (NREM) parasomnias that abort the first REM episode and REM sleep behavior disorder, idiopathic nightmares, and posttraumatic stress disorder, all of which are associated with interruptions of REM sleep. These suggest that REM-associated dreaming has an active role in emotional modulation, but that this role can be dysfunctional owing to various inherent or acquired dysfunctions of sleep. Few studies have examined the content of dreams for their contribution to mood regulation in patients with sleep disorders.
from REM awakenings.5 The second was the direct expression of “unpleasant” emotion more than twice as often as pleasant emotion; fear and anxiety was the most common category, and anger was the next most common category.5 A common thread in current views of dream function is that dreams reflect recent emotion-related experience and connect this to the organized system of memories that define the self-concept. The recurrence of content patterns within the dreams of a night and between nights over time suggests that activation of dream images is not random. Globus proposed that “the periodic disturbances of REM … moves the [memory] networks towards … self consistency.”6, p. 134 Kramer7 tested this assertion using the Clyde Mood Scales8 before and after sleep and found that mood changed through the night and that dreaming seemed to be a problem-solving method that, when successful, resulted in increased happiness scores.7 Foulkes9 stated that “activation spreads according to preexisting patterns in symbolic memory” and “significant emotional life experiences may appear later in dreams when they serve as mnemonic references to those meaningful experiences organized by emotion.”9, p. 151 Thus there is some consensus that dreaming supports an identity-preserving function by downregulating affect that is disturbing to the organized self-system.
MOOD-REGULATION FUNCTION OF DREAMING IN NORMAL PERSONS That dream function improves postsleep mood has been supported by using four types of studies: home dreams recalled spontaneously, laboratory dreams collected by awakenings from REM periods, dreams reported during psychotherapy, and brain-imaging studies distinguishing areas that are activated and deactivated during REM sleep, NREM sleep, and waking. None of these data sources alone yields sufficient proof of the mood-regulating function of dreams, but the cumulative evidence across these independent sources does support this conclusion.
Evidence of Mood Regulation from SelfReported Home Dreams Some dreams are sufficiently unpleasant to abort sleep and awaken the sleeper prematurely with vivid recall of frightening content. This is the usual definition of a nightmare. Nightmares are common, affecting 2% to 6% of the overall population; are more frequent in children, women, and psychiatric patients; and have a negative relation to measures of mental health.10,11 Nightmare frequency compared between patients with and without laboratorydiagnosed insomnia found nightmares were more frequent in the insomnia group, but frequency was lower in those with reduced REM sleep.11 On a continuum of more unpleasant to more pleasant content, nightmares are at one extreme, bad dreams that do not wake the sleeper are at a mid point, and neutral or more pleasant dreams are at the opposite end. The frequency of the two types of unpleasant dreams correlate negatively with a self-report measure of well-being.12 Dreams recalled spontaneously by adults often have a negative affective tone. This contributes to their ability to be recalled. Individual differences in recall rates have been noted to be related to various personality traits and to specific states, although few of these correlations have stood up to replication. Dream recall has been noted to be higher in women and associated with a trait of their higher interest in their inner life. Recall has also been associated with a state of anxiety, which is linked to light sleep, higher rates of NREM dreams,13 and REM dreams with more intense negative affect. When these disturbing dreams exceed the capacity of sleep to contain them, a premature awakening from REM results in a failure of within-night mood regulation. However, failure to regulate negative mood on one night does not necessarily invalidate the mood-regulatory function. It might take more than one night to regulate a highly disturbing mood. Other possibilities are that the recall of negative dreams is an artifact of the method used to collect them. Researchers generally use questionnaires that ask for retrospective reports. A comparison of home dream reports to laboratory-collected dream reports show that home dream reports have more disturbing content.14 Because most sleep does not result in a premature REM awakening in fear, it is possible that dreaming is for the most part successful in regulating affect within the night or that the presleep affect might not require nightly regulating in healthy sleepers. In either case, waking without a change in mood when the mood was not elevated before sleep onset, or waking in a more positive mood when the presleep mood was only moderately elevated, was predicted in an early model of the relations of presleep mood, dream characteristics, and postsleep affect level.15 This model proposes: • Morning mood varies systematically with the degree and kind of presleep emotional state and the quality and quantity of sleep that follows. • When the mood before sleep is elevated and moderately negative, dream affect will show a progressive reduction within a normal night of sleep in healthy persons, resulting in a reduction in the negativity of morning mood from the presleep level.
CHAPTER 54 • Dreaming as a Mood-Regulation System 621
• When the degree of presleep affect is either highly elevated and negative in type or is not elevated in intensity above that person’s baseline and is neutral in type, the within-sleep dream affect sequence will be random from REM to REM and the morning mood will be unchanged. A review of studies when presleep affect level is expected to be elevated in intensity and negative in type have been examined for their findings relevant to these proposals. Following the 1989 San Francisco earthquake, frequency of nightmares was reported to increase to 40% among persons who were living in the area but not in a control group living remotely in Arizona, where the rate was 5%.16 A traumatic event plus helplessness to cope with it were the conditions implicated in the persistence of nightmares over 4 or more years in children who had been kidnapped and buried in an abandoned quarry for 2 days.17 The author suggests that the long delay in dream adaptation was a function of the children’s having had no previous solutions to such an event stored in their long-term memory, which were necessary to provide helpful dream images to defuse their fear. Children who witnessed the 9/11 New York City Twin Towers attack, some from their preschool across the street, were studied by interviewing the parents, the teachers, and the children over 4 years. Those who continued to have disturbed dreaming had a higher rate of a previous personal trauma—tonsillectomy, car accident, or dog bite—than did exposed children who did not have nightmares. The authors suggested that those with previous traumas had been “sensitized” to attend to frightening events.18 Among adults surveyed by Internet for nightmare frequency following 9/11, only men reported a significant increase.10 Nightmares are more frequent in young children and gradually reduce with age. The elderly have the lowest rate, suggesting nightmares relate negatively to the presence of learned coping behavior, which tends to increase with age. These naturalistic studies support a general trend for disturbing events to be followed by disturbed dreaming but do not provide sufficient data to be more than suggestive. Dreams Collected in the Sleep Laboratory Dreams in Subjects Undergoing Surgery Dream content reports were collected in the laboratory by Breger and colleagues19 before and after a planned stressful event: elective surgery. Although the dreams demonstrated the impact of surgery on the dreamers’ sense of personal integrity, this varied according to the meaning of this event to the person: whether it was anticipated to correct a problem or was a dreaded experience. This meaning was not directly represented in the dreams but was displayed metaphorically. This is one of the complications of dream research; the images are not realistic snapshots of waking events. They are more often compounds of new and old associated images and so require some unwrapping of their personal meaning. This poses problems for the reliability of scoring dream content. Winget and Kramer20 have provided a resource for this work in a book devoted to instruments for measuring dream content along with the reliability data available for each scale.
622 PART I / Section 7 • Psychobiology and Dreaming
Dreams in Depressed Subjects Sleep disorder clinicians have rarely applied sleep monitoring methods to study the dreams of patients presenting with various sleep disorders. Notable exceptions are work with major depression and nightmare patients. The finding that the classic timing of REM sleep is shifted to occur earlier in the sleep of those suffering a major mood disorder was noted by early sleep investigators.21,22 This was modeled as a phase advance of REM sleep by Wehr and coworkers23 and as a response to increased waking affect.24 There are other abnormalities of sleep in the depressed including an increased fragmentation of sleep, particularly of the REM periods. The percentage of rapid eye movements themselves is a good indicator of the general emotional or motivational turmoil in schizophrenics and in depressed patients.25 The density of rapid eye movements in REM episodes is more variable in the depressed subjects than in controls. These patients show periods when the eye movements are very sparse and periods of eye movement storms. These abnormalities suggest an explanation for the why depressed subjects have difficulty developing or reporting coherent dreams and consequently fail to regulate morning mood. Dream recall in depressed subjects is poor, even when they are awakened from REM. Most common are reports of no recall or a short report describing a single image with flat affect.26-28 This poverty of dreaming may be due to the observed disturbances—the frequent interruptions of REM sleep and the dysregulation of the release of rapid eye movements, allowing too few to supply the images or too many to allow time for the associations necessary to construct a dream scenario. Nofzinger and colleagues29 reported that patients in remission from depression show a reduction in eye movement density. Other aspects of sleep in depressed subjects prove to be more stable. Two of these, the poor quality of sleep and early onset of REM, typically remain after remission.30,31 The most robust of the markers, the reduced latency to the first REM, appears to represent a genetic vulnerability to depression in family members.32 Indrusky and Rotenberg33 studied patients who had major depression and found mood change based on the patients’ self-report of their morning mood as worse, the same, or better than before sleep. When morning mood was “better,” the eye movement density was low in the first REM period and increased across the night to be highest in the last REM period. This is similar to the eye movement distribution pattern of healthy subjects. In contrast, those whose mood either did not change or worsened overnight had high eye movement density in the first REM and a slow decrease from REM to REM, the opposite to that of control sleepers. Thus depressed patients whose within-night sequence of rapid eye movement density resembles that of healthy subjects are more likely to feel an improvement of mood on awakening next morning. This is consistent with the findings of mood improvement with this pattern reported by others.30,34 Dreams in Divorcing Subjects Marital separation or divorce is another disturbing life event that has been studied in the sleep laboratory for its impact on sleep and dreams and on overnight mood regu-
lation. Divorce has a lengthy time course allowing longitudinal study of changes in mood and adaptation to an identity change. There is a wide variance in emotional response to this event, from a relatively rapid adjustment to one that is long delayed and has serious emotional consequences. Clinical depression is common and has a strong effect on both sleep and dreaming. In one study of this series24,30,35-37 equal numbers of male and female subjects, 40 with untreated clinical depression secondary to the divorce and 30 nondepressed controls, were studied in the laboratory, with REM dreams collected at intake and, for 22 of 30 controls and 39 of 40 depressed subjects, 1 year later. Subjects rated their dream affect as pleasant, unpleasant, or neutral and whether the dream was unemotional, mildly emotional, or strongly emotional. The number of unpleasant dreams was significantly higher in the depressed group. Depressed subjects who dreamed of the ex-spouse were not more depressed than those who did not but had higher dream affect scores and no longer met depression criteria at the 1-year reassessment. Those who dreamed of the former partner with expressed emotion on the first REM collection night showed a within-the-night dream affect change from negative to positive. The difference in percentage of positive and negative affect ratings in the dream reports of the first half night and those in the second are seen in Figure 54-1. The discriminant function analysis testing whether the order of dream affect predicted remission from depression was highly significant. This withinsleep change in dream affect correctly classified the remission status of 72% of those initially depressed. This study was followed with a second study testing mood-regulation in a nondivorcing sample38 using the Profile of Mood States (POMS)39 and a current concerns questionnaire.40 Sixty high-functioning adults, with no present symptoms or history of depression, had dreams collected from each REM period and rated for affect. The group was stratified by presleep POMS Depression scale into two groups by intensity of mood: no elevation of depressed mood (N = 50) and mild elevation of depressed mood (N = 10). The no elevation group had more positive than negative dreams, with a flat distribution across the night, and those with mild elevation had a higher percentage of negative dreams in the first half of the night and a reduction of these and increase in the percentage of positive dreams in the last two dreams collected (Fig. 54-2). This supports that there is a within-night mood regulation process in normal persons. The reduction in POMS morning score suggests that within night dream affect change helps to reduce the level of the negative morning mood when the intensity of the mood is modestly elevated before sleep. The third study in this series,40-42 enrolled 30 divorcing volunteers with equal numbers of men and women. Twenty depressed subjects and 10 controls were tested for changes in mood regulation in relation to remission from depression after 5 months. The POMS before and after each night of laboratory sleep yielded 12 data points, showing successful mood regulation for those remitting and failure to change in those who did not remit. The contribution of dream content to remission was significant. The degree of the presleep waking concern about the former spouse from
CHAPTER 54 • Dreaming as a Mood-Regulation System 623
25
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% Affect reported
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Group 1 (not depressed) n = 22
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% Pos
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Figure 54-1 Dream affect in the first and second half of the night in three divorcing groups on the first dream-collection night. Group 1, not depressed (control); group 2,depressed subjects who remit; group 3, depressed subjects who do not remit.
the current concerns test40 and the total number of dreams of the ex-spouse in REM reports, the degree and type of affect expressed in the ex-spouse dreams, and the presence of older memory images in those dream reports were predicted to contribute to remission without treatment. The number of ex-spouse dreams was associated with successful regulation of disturbed morning mood, but only when these dreams included the expression of negative affect and older associated memories (Box 54-1).43,44 Dreams following Presleep Stress Breger, Reiman, and Lauer43 manipulated presleep stress levels in the laboratory to induce an increased negative state in healthy and depressed volunteers to investigate changes in sleep and dreams collected from the first and last REM period. Stress levels were measured by mood ratings; blood samples to measure cortisol, human growth hormone, and prolactin levels; and heart rate while the subjects watched a stressful movie and a neutral movie. Their predictions of differences in first and last dream reports following the two conditions and morning mood change were supported only in the healthy group, who showed a presleep physiologic and psychological stress reaction to the stressful movie. They had first dreams following the stress movie that were more anxious and aggressive, with higher self-participation than in their first dreams following the neutral movie. The dreams from the last REM showed improved mood in both conditions and a marked improvement in morning mood scores. The depressed group had few scorable dreams, although their self-reports of mood at each REM awakening were poorer from first to last experimental awakening. The authors conclude that the dreams of healthy subjects show within- night coping with stress leading to positive mood regulation, but dreams of depressed persons may actually promote depression. The small samples and the failure of the depressed group to report dreams are limitations of the study. Results Results from these various negative life event studies support the proposition that dreaming is generally responsive to new emotion-evoking situations requiring
Box 54-1 Examples of Dreams of Ex-spouse in Remitting and Nonremitting Depressed Subjects Example 1 This dream is from a depressed woman who did not remit: “I was dreaming about my husband dating this girl that he works with and him taking her out. That’s all I can remember.” (Question: Anything else?) “He was just taking her out, meeting her at our house. I was just sitting in my house, in my living room, and he was going out the door with this girl.” Comment: The spouse is present but no affect is expressed. There is only a single image without story development or any older memories. Example 2 This dream is from a depressed woman who was in remission at month 5: “I was fleeing from something with my daughter and son on a dark street in a suburban area, an Indian or Asian community with barbed wire around the fence. My son needed to use the bathroom and my daughter needed water for her dog. We knocked on the door of this house and an old woman answered and I asked her for help but a man came to the door and said “No.” I asked him “Why not?” and he said “You would have to be my wife.” I didn’t know what to do. Then we were backtracking through a field and there were shots being fired all around. Then we were in a room where a dance was being planned. I was telling my ex-husband that I would only be staying for 5 minutes and he said “Fine,” like he didn’t care. I knew that his new girlfriend would be there and they would be dancing. I felt resentful. I didn’t want to see that.” Comment: Here the spouse is present and the dreamer’s negative affect “resentful” is expressed. The historical elements are the setting of her former South African home where she is rejected as a nonwife when in danger and asking for help. This past is linked to a present image of the ex-husband who doesn’t care. Her changing role as now the primary caregiver in the family is linked to present marital dissolution.
624 PART I / Section 7 • Psychobiology and Dreaming 25 % Affect reported
% Affect reported
25 20 15 10 5
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Figure 54-2 Dream affect in first half and second half of the night of two groups of healthy volunteers with different presleep depression scores. Group 1 had no increase in intensity of depressed mood before sleep. Group 2 had a modest increase in intensity of depression score.
adaptation; however, there are individual differences. Those with “thin boundaries” are more likely to have high recall and increased dream intensity to levels that disrupt sleep,44 whereas others, like the depressed subjects, have low dream recall with dampened dream affect and lesselaborate dream construction. Both extremes, those with high and low affect in waking, display less mood regulation following sleep. It is those with moderate presleep mood disturbance who show the predicted dream response with progressive downregulation of mood. It is only in studies where dreams are retrieved in the laboratory that these within-the-night affect changes can be tested. If negative dream affect is not progressively reduced, and the content does not link present disturbing experiences to similar past events, mood regulation may require a therapeutic intervention. Mood Regulation in Office Dreams in Psychotherapy Psychotherapists who encourage patients to report dreams expect this will further their treatment goals. The assumption is that dreams give the therapist access to information about the emotional life that patients are unable or unwilling to verbalize directly; dreams are a short-cut to the affective or cognitive organizational patterns underlying the irrational anxieties and poor behavior choices that have brought patients to seek help. Here the emphasis is on how dreams reveal the way the patient’s past affective learning history influences their present behavior in a detrimental manner. Schredl’s group45 surveyed psychotherapists on their use of dreams in treatment. Both psychoanalytic and humanistic therapists report they work on dreams in 28% of their sessions. Seventy percent of those believed this work to be beneficial to their patients. With few exceptions,46,47 evidence from hypothesis-driven research of a direct benefit from therapeutic work with dreams is lacking. Support of this practice rests on abundant case reports illustrating dream interpretation furthers the insight of the therapist into their patient’s inner life. Evidence that this promotes better use of therapy hours, is instrumental in changing dysfunctional dreaming, and is responsible for subsequent
changes in waking emotional adaptation is at present correlational. Palombo48 proposed a mechanism to explain how dream interpretation helps to “restore and renew the incomplete self” by the analyst’s work interpreting the patient’s dreams, which leads the patient to have a “corrective” dream. This stimulates the same dream memory network, which incorporates the interpreted changes and produces a corrective dream that is now ready to respond more positively to a similar new emotion-evoking experience. This could be tested, but there has been no study published. A formal test of the idea that becoming aware of what one is dreaming is helpful to the process of initiating change in emotionally dysfunctional patients was conducted by Cartwright, Tipton, and Wicklund.46 Dream access was provided by 2 weeks of laboratory sleep with REM awakenings and by prompting dream recall next morning before treatment began for an experimental group of 12 patients. The effects of this intervention were compared to those of two control groups: One was awakened only in NREM sleep the same number of times as the experimental group at same time of night, and the other group went directly into treatment. All 36 subjects were selected by the intake worker as being poor risks for successful treatment based on their low score on a counseling readiness scale49 and judgment that they were not insightful, with poor skills for self-understanding. These subjects were predicted to drop out of treatment before receiving any benefit. The benefit criteria were remaining in treatment for at least 10 sessions and engaging in therapy-appropriate behavior such as discussing their feelings. The results of the research supported that increasing the patient’s access to their dreams and practice in recalling and discussing these was related to the patients staying in treatment and engaging in productive psychotherapy. Two unanticipated findings were that some in the experimental group failed to recall dreams even with REM awakenings, similar to patients with major depression, and a few in the NREM control group produced reports that were judged by blind raters to be dreams. These patients derived the same benefits from treatment that were expected only
for the experimental group. Those who were able to access their emotional issues through dream retrieval, whether from REM or NREM awakenings, progressed well in treatment. The dreams provided focus on an issue they explored in their treatment. Hill and colleagues have developed and tested a short treatment program focused on dreams called the Hill Cognitive-Experiential Dream Model.47,50,51 This is a threestage approach: exploration, insight, and action. The method is designed to elicit feelings in relation to the dream images by retelling a recalled home dream using the present tense as if it were being experienced in the hour and, with the therapist’s help, to explore how the images relate to their waking experience. Limitations of these types of studies include the experience level of the therapists, often students in training, and the clients themselves, who are also often student volunteers rather than real patients. Also the therapy is limited to one or only a few sessions of work on a single dream. Not having the opportunity to see the recalled dream in the context of the series of dreams occurring the same night limits the applicability of this method to the question of a within-sleep progressive mood regulation. Despite this, the model has potential for formalizing dream work and testing the effectiveness of practice in dream recall on improving waking mood regulation. A few treatment studies of nightmare sufferers using imagery rehearsal and desensitization techniques52,53 have reported positive results in reducing the frequency of nightmares. However, these rely on the patients’ reports and do not document changes in the experienced dreams. Dream Function Studied with Brain Imaging Brain-imaging studies are another source for understanding the function of dreaming from investigating where in the brain REM dreams are formed.54-59 Winson54 states that “dreams are a window on the neural processes whereby, from early childhood on, strategies of behavior are being set down, modified or consulted.”54, p. 204 Imaging has mapped the areas in which there is increased brain activation and deactivation occurring during REM sleep. The consensus of this work is that there is increased activation in the integrative visual cortex and the limbic and paralimbic systems and decreased activation in the dorsolateral prefrontal and parietal cortices, in comparison to the patterns during waking and in NREM sleep. This supports that REM dreaming displays emotional concerns in visual terms in a nonlogical structure. Solms56 has tracked the correlation between the sites of brain damage and changes in the dream experience reported by patients. He finds an intact dopaminergic tract to be basic to normal dreaming. This work has added to our knowledge base of how dreams are made but not why. A recent PET imaging study of depressed and control subjects indicates that patients show different patterns of glucose metabolic changes in the limbic and paralimbic systems in waking than they show in their first REM period.60 The lack of an increase in activation of the anterior cingulate in depressed persons was interpreted as perhaps related to the blunted responsive of these patients to emotionally salient information.
CHAPTER 54 • Dreaming as a Mood-Regulation System 625
MOOD REGULATION FUNCTION OF DREAMING IN PATIENTS WITH PARASOMNIAS The research in support of a mood-regulatory function of dreaming is strongest from the laboratory studies comparing normal sleepers to those with major depression. Although the dreaming patterns in other clinical disorders have not been studied in the same detail, there are indications of support also from the disturbed dreams acted out by patients with REM sleep behavior disorder (RBD).61 These patients explain their aggressive behavior as a response to their perceived need to defend themselves or to attack others on the basis of an ongoing threatening dream scenario. Similarly, NREM parasomnia patients might attack in a behavioral arousal that occurs in slowwave sleep prior to REM.62,63 This suggests that some waking experience with an affective charge continues into NREM sleep. Presumably this would stimulate a relevant memory network and initiate a mood-regulatory process, if REM sleep had not been aborted by the prior behavioral arousal. Although many NREM parasomnia events are benign, these may become dangerous to the patient or others. Sleep terrors are models of overwhelming fear. In neither sleepwalking nor sleep terrors are dream images being connected to a network of older memories that might diffuse the affect. Rather this is expressed in the arousal behavior. NREM parasomnias are more likely to occur in those genetically vulnerable to slow-wave sleep arousals when their presleep stress levels are high. Then the consequent sleep deprivation increases the pressure for more delta sleep, but the genetic flaw in controlling movement during deep sleep leads to partial arousals with motor behavior.64,65 The single photon emission computed tomography (SPECT) study by Bassetti and colleagues66 of a sleepwalker in action shows increased blood flow into the posterior cingulate cortex and decreases in the frontoparietal cortices. The nightmares in PTSD are another example of nonprogressive affect reduction. These vivid dreams are often repetitive and refer to some earlier life trauma that has left powerful images in long-term memory. These are associated to a current problem as if it, too, is life threatening.67 Sleep disorders that interrupt sleep such as REM sleep behavior disorder and NREM parasomnias prevent mood regulation. The effect of shortened total sleep, which does not allow time for end-of-night dreaming to complete the modulation of disturbed affect, may also be implicated in failures to improve morning mood. CLINICAL APPLICATIONS Sleep medicine clinicians rarely investigate their patients’ dreams for their contribution to the sleep complaint. Collecting dreams in the laboratory is costly and not usually covered by insurance. This makes systems for recording dreams in the home an option.68 The relevance of dream health to waking physical and mental health has been pointed out in a recent study.69 This topic has been given increased credence through recent studies of sleep-related learning and memory and by brain imaging. These studies
626 PART I / Section 7 • Psychobiology and Dreaming
have anchored the psychology of dreaming in science by supporting the contribution of REM sleep to enhanced learning70,71 and identifying the brain sites damaged in head-injury patients with subsequent distortions of dream experience. Future studies of patients should note if REM is misplaced in the sleep cycle, occurring too early or too late; if the eye movements are too sparse or too frequent; if the dreams are well or poorly constructed; and if the dreams fragment REM sleep or end the night too early. We also need to study the effects these REM and dream variables have on the waking emotional state that follows. The more we bring objective measurement to the question of dream function, the better will be the science base for applying this information to patient care.
❖ Clinical Pearl Dreaming has a sequential mood-regulatory effect when presleep negative mood is moderate. Dream content includes the expression of affect in relation to a current concern, and images from earlier similar experiences are integrated into the narrative. If presleep affect is highly elevated, dreams are increasingly negative within the night, resulting in a failure to downregulate morning mood.
REFERENCES 1. Institute of Medicine. Sleep disorders and sleep deprivation: an unmet public health problem. Washington: National Academies Press; 2006. 2. Antrobus J. Dreaming: cognitive processes during cortical activation and high afferent thresholds. Psychol Rev 1991;98:96-121. 3. Freud S. The interpretation of dreams (English translation). New York: Basic Books; 1954. 4. Foulkes D. Children’s dreams: longitudinal studies. New York: John Wiley and Sons; 1982. 5. Snyder F. The phenomenology of dreaming. In: Madow L, Snow L, editors. The psychodynamic implications of the physiological studies on dreams. Springfield, Ill: Charles C Thomas; 1970. p. 124-151. 6. Globus G. Connectionism and sleep. In: Moffitt A, Kramer M, Hoffman R, editors. The functions of dreaming. Albany, NY: State University of New York Press; 1993. p. 119-138. 7. Kramer M. The selective mood regulatory function of dreaming: an update and revision. In: Moffitt A, Kramer M, Hoffman R, editors. The functions of dreaming. Albany, NY: State University of New York Press; 1993. p. 139-195 8. Clyde D. Manual for the Clyde-Mood Scale. Miami: University of Miami Biometric Laboratory; 1963. 9. Foulkes D. Dreaming: a cognitive-psychological analysis. Hillsdale, NJ: Erlbaum; 1985. 10. Nielsen T, Stenstrom P, Levin R. Nightmare frequency as a function of age, gender and September 11, 2001: findings from an Internet questionnaire. Dreaming 2006;16:145-158. 11. Pagel JF, Shocknesse S. Dreaming and insomnia: polysomnographic correlates of reported dream recall frequency. Dreaming 2007; 17:140-151. 12. Zadra A, Donderi D. Nightmares and bad dreams: their prevalence and relationship to well-being. J Abnorm Psychol 2000;109: 273-281. 13. Brown J, Cartwright R. Locating NREM dreaming through instrumental responses. Psychophys 1978;15:35-39. 14. Weisz R, Foulkes D. Home and laboratory dreams collected under uniform sampling conditions. Psychophys 1970;6:588-597. 15. Cartwright R. The nature and function of repetitive dreams: a survey and speculation. Psychiatry 1979;42:131-137.
16. Wood J, Bootzin R, Rosenhan D. Effects of the 1989 San Francisco earthquake on frequency and content of nightmares. J Abnorm Psychol 1992;101:219-224. 17. Terr L. Chowchilla revisited: the effects of psychic trauma four years after a school-bus kidnapping. Am J Psychiatry 1983;140: 1543-1550. 18. Chemtob C, Nomura Y, Abromovitz R. Impact of conjoined exposure to the World Trade Center attacks and to other traumatic events on the behavioral problems of preschool children. Arch Ped Adoles Med 2008;162:126-133. 19. Breger L, Hunter I, Lane R. The effect of stress on dreams. Psychological Issues, Monograph 27. Guilford, Conn: International University Press; 1971. p. 96-181. 20. Winget C, Kramer M. Dimensions of dreams. Gainesville, Fla: University of Florida Press; 1979. 21. Mendels J, Hawkins D. Sleep and depression: a controlled EEG study. Arch Gen Psychiatry 1967;16:344-353. 22. Kupfer D. REM latency: a psychobiological marker for primary depressive disease. Biolog Psychiatry 1975;11:159-174 23. Wehr T, Wirz-Justice A, Goodwin F, et al. Phase advance of the circadian sleep-wake cycle as an anti-depressant. Science 1979; 206:710-713 24. Cartwright R. Early REM sleep: A compensatory change in depression? Psychiatry Res 1993;51:245-252. 25. Hauri P, Hawkins D. Phasic REM, depression, and the relationship between sleeping and waking. Arch Gen Psychiatry 1971;25:56-63. 26. Reimann D, Weigand M, Majer-Trendel K, et al. Dream recall and dream content in depressive patients, patients with anorexia nervosa and normal controls. In: Koella W, Obal F, Schulz H, et al, editors. Sleep ’86. New York: Gustav Fischer Verlag; 1988. p. 373-375. 27. Armitage R, Rochlen A, Fitch T, et al. Dream recall and major depression: a preliminary report. Dreaming 1995;5:189-198. 28. Cartwright R, Lloyd S, Knight S, Trenholme I. Broken dreams. Psychiatry 1984;47:251-259 29. Nofzinger E, Schwartz R, Reynolds CF, et al. Affect intensity and phasic REM sleep in depressed men before and after treatment with cognitive-behavioral therapy. J Consul Clin Psych 1994;62:8391. 30. Cartwright R, Kravitz H, Eastman C, et al. REM latency and recovery from depression: getting over divorce. Amer J Psychiatry 1991; 148:1530-1535. 31. Cartwright R. Rapid eye movement sleep characteristics during and after mood disturbing events. Arch Gen Psychiatry 1983;40: 197-201. 32. Giles D, Roffwarg H, Rush AJ. REM latency concordance in depressed family members. Biol Psychiatry 1987;22:910-914. 33. Indrusky P, Rotenberg V. Change of mood during sleep and REM sleep variables. Int J Psychiatry in Clin Pract 1998;2:47-51. 34. Kramer M. The dream experience: a systematic exploration. New York: Routledge; 2007. p. 167-187. 35. Cartwright R. Dreams that work: the relation of dream incorporation to adaptation to stressful events. Dreaming 1991;1:3-9. 36. Cartwright R, Wood E. Adjustment disorders of sleep: the effects of a major distressful event and its resolution. Psychiatry Res 1991;39:199-209. 37. Cartwright R, Young M, Mercer P, et al. Role of REM sleep and dream variables in the prediction of remission from depression. Psychiatry Res 1998;80:249-255. 38. Cartwright R, Luten A, Young M, et al. Role of REM sleep and dream affect in overnight mood regulation: a study of normal volunteers. Psychiatry Res 1998;81:1-8. 39. McNair D, Lorr M, Droppleman L. Profile of mood states. San Diego: Educational and Industrial Testing Service; 1981. 40. Cartwright R, Agargun M, Kirkby J, et al. Relation of dreams to waking concerns. Psychiatry Res 2006;141:261-270. 41. Cartwright R, Newell P, Mercer P. Dream incorporation of a sentinel life event and its relation to waking adaptation. Sleep Hypnosis 2001;3:25-32. 42. Cartwright R, Baehr E, Kirkby J, Friedman J. REM sleep reduction, mood regulation and remission in untreated depression. Psychiatry Res 2003;121:159-167. 43. Breger M, Reiman D, Lauer C. The effect of pre-sleep stress on subsequent sleep and dreams in healthy subjects and depressed patients. In: Koella W. Obal F, Schulz H, Sleep ’86. New York: Gustav Fischer Verlag; 1988. p. 84-86.
44. Hartmann E, Rosen R, Grace N. Contextualizing images in dreams: more frequent and more intense after trauma. Sleep 1998;21S:284. 45. Schredl M, Bohusch C, Kahl J, et al. The use of dreams in psychotherapy: a survey of psychotherapists in private practice. J Psychother Pract Res 2000;9:81-87 46. Cartwright R, Tipton L, Wicklund J. Focusing on dreams: a preparation program for psychotherapy. Arch Gen Psychiatry 1980;37: 275-277. 47. Hill CE, Zack J, Wonnell T, et al. Structured brief therapy with a focus on dreams or loss for clients with troubling dreams and recent loss. J Counsel Psychol 2000;47:90-101. 48. Palombo S. Dreaming and memory: a new information processing model. New York: Basic Books; 1978. 49. Gough H, Heilbrun A. The adjective check list. Palo Alto, Calif: Consulting Psychologists Press; 1983. 50. Hill C, editor. Dream work in therapy: facilitating exploration, insight and action. Washington, DC: American Psychological Association; 2004. 51. Crook-Lyon R, Hess S, Hill C, et al. Prediction of session process and outcomes in the Hill dream model: contribution of client characteristics and the process of the three stages, Dreaming 2006;16: 159-185. 52. Kellner R, Neidhardt J, Krakow B. Changes in chronic nightmares after one session of desensitization or rehearsal instructions. Am J Psychiatry 1992;149; 659-663. 53. Krakow B, Tandberg D, Cutchen L, et al. Imagery rehearsal treatment in chronic nightmares in PTSD: A controlled study. Sleep Res 1997;26:245. 54. Winson J. Brain and psyche. New York: Anchor Press; 1985. 55. Hobson A, Pace-Schott E, Stickgold R. Dreaming and the brain: toward a cognitive neuroscience of conscious states. In: Pace-Schott E, Solms M, Blagrove M, Iarnad S, editors. Sleep and dreaming: scientific advances and reconsiderations. Cambridge: Cambridge University Press; 2003. p. 1-50. 56. Solms M. Dreams and REM sleep are controlled by different brain mechanisms. In: Pace-Schott E, Solms M, Blagrove M, Harnad S, editors. Sleep and dreaming: scientific advances and reconsiderations. Cambridge: Cambridge University Press; 2003. p. 51-58. 57. Braun A, Blakin T, Wesenstein N, et al. Regional blood flow throughout the sleep-wake cycle. Brain 1997;120:1173-1197.
CHAPTER 54 • Dreaming as a Mood-Regulation System 627 58. Maquet P, Peters JM, Aerts J, et al. Functional neuroanatomy of human rapid eye-movement sleep and dreaming. Nature 1996;383: 163-166. 59. Nofzinger E, Mintun M, Wiseman M, et al. Forebrain activation in REM sleep: a FDG PET study. Brain Res 1997;770:192-201. 60. Nofzinger E, Buysse D, Germain A, et al. Increased activation of anterior paralimbic and executive cortex from waking to rapid eye movement sleep in depression. Arch Gen Psychiatry 2004;61: 695-702. 61. Schenck C, Bundle S, Patterson A, et al. Rapid eye movement sleep behavior disorder: a treatable parasomnia affecting older adults. JAMA 1987;257:1786-1789. 62. Cartwright R. Sleep-related violence: does the polysomnogram help establish the diagnosis? Sleep Med 2000;1:331-335. 63. Cartwright R. Sleepwalking violence: a sleep disorder, a legal dilemma and a psychological challenge. Am J Psychiatry 2004;161: 1149-1158. 64. Joncas S, Zadra A, Paquet J, et al. The value of sleep deprivation as a diagnostic tool in adult sleep walkers. Neurology 2002;58: 936-940. 65. Pilon M, Montplaisir M, Zadra A. Precipitating factors of somnambulism: impact of sleep deprivation and forced arousals. Neurology 2008;70:2284-2290. 66. Bassetti C, Vella S, Donati F, et al. SPECT during sleepwalking. Lancet 2000;356:484-485. 67. Kramer M. Nightmares in Vietnam veterans. J Am Acad Psychoanalysis 1987;15:67-81. 68. Lloyd S, Cartwright R. The collection of home and laboratory dreams by means of an instrumental response technique. Dreaming 1995;5:63-73. 69. King D, DeCicco T. The relationships between dream content and physical health, mood and self-control. Dreaming 2007;17: 127-239. 70. Stickgold R. Human studies of sleep and off-line memory reprocessing. In: Maquet P, Smith C, Stickgold R, editors. Sleep and brain plasticity. Oxford: Oxford University Press; 2003. p. 41-63. 71. Guiditta A, Mandile P, Montagnese P, et al. The role of sleep in memory processing: the sequential hypothesis. In: Maquet P, Smith C, Stickgold R, editors. Sleep and brain plasticity. Oxford: Oxford University Press; 2003. p. 157-178.
Why We Dream
Robert Stickgold and Erin J. Wamsley Abstract Historical models of dreaming have failed to achieve scientific validation. New models, built from studies in the cognitive neurosciences, are now being proposed. These are based on (1) the reactivation of learning-related neural networks during posttraining sleep in humans and rodents; (2) patterns of regional brain activation during wake, rapid eye movement (REM) sleep, and non-REM sleep in humans; (3) sleep-dependent learning and memory consolidation; and (4) cognitive
The search for an understanding of dreaming is thousands of years old. Three publications during the last 100 years have formed the core of most of the scientific discussion of this question. These include Freud’s Interpretation of Dreams,1 at the end of the 19th century; the report of a correlation between dreaming and the newly discovered rapid eye movement (REM) sleep,2 in the 1950s; and the proposal of the activation-synthesis model of dreams,3 in the 1970s, which argued that dreaming is initiated by random neural activity in the brainstem during REM sleep. As we enter the 21st century, however, there is precious little on which dream researchers agree. One relatively new approach has been to consider dreaming within a larger neurocognitive framework of offline memory processing during sleep. The rationale of this approach is that dreaming reflects the activity of the brain and that this activity necessarily includes the reactivation of memories and emotions from earlier experiences. Because any neural activity in the brain invariably leaves the activated networks altered, dreaming must modify the networks storing memories and emotions. Dreaming then becomes the conscious experiencing of these activated networks in the process of being modified.
BRAIN ACTIVITY DURING SLEEP To understand how dreams might be produced and the functions they may serve, it is important to understand how brain activity differs in wake, REM, and non-REM sleep. During the last decade, a series of positron emission tomography studies have shown that patterns of human brain activation differ across the states of waking, REM sleep, and non-REM sleep. Whereas regional cerebral blood flow is generally decreased during slow-wave sleep, entry into REM sleep leads to reactivation of some regions along with further deactivation of others. The pattern seen suggests a shift in global brain function in REM sleep away from conscious executive control (further decrease in dorsolateral prefrontal cortex activity) and toward hallucinatory (increased activity in sensory association cortices) and emotional (increased amygdala, anterior cingulate, and medial orbitofrontal cortex activity) processing.4-6 In concert with these changes in patterns of brain activity, 628
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performance in humans immediately after awakenings from non-REM and REM sleep. These data suggest that dreaming represents the conscious experience of brain mechanisms that perform offline emotional and memory reprocessing during sleep. At the same time, novel dream studies suggest that a multiplicity of memory functions are reflected in the formal properties and content of dreams, across sleep stages. Together, these findings suggest both a mechanism and function for dreaming.
cognitive testing performed immediately after awakenings from REM and non-REM sleep suggests that the sleeping brain is biased toward less common associations and more flexible cognitive processing.7,8 In both humans and rats, patterns of brain activity observed during waking appear to be “replayed” during sleep. In rats, simultaneous recordings from large numbers of hippocampal neurons have shown that specific patterns and neuronal firing sequences observed as the rats sought out food on a circular track were replayed during subsequent REM and non-REM sleep, with the speed of this reiteration differing distinctly between the two sleep states.9,10 In humans, positron emission tomography studies have shown that brain regions activated during learning of a task were selectively reactivated during the next night’s sleep.11,12 The discovery that brain networks involved in prior waking experience are reactivated during later sleep is paralleled by a growing body of evidence for sleepdependent memory consolidation.
SLEEP-DEPENDENT MEMORY CONSOLIDATION One interpretation of neural changes during sleep is that they reflect a homeostatic process working to restore the brain to the state it was in at the start of the previous day. This “rest” or “restorative” model of sleep argues that sleep serves to reverse deleterious changes that inevitably accrue across the day. However, a more powerful, pro gressive model suggests that these changes reflect offline processing of information obtained during the prior day— consolidating, integrating, and even actively reversing changes that occurred during waking. Dreaming, as well, might serve a homeostatic or a progressive function. Freud, for example, proposed a restorative model of dreaming, specifically considering but then rejecting any progressive model.1 In contrast, others have questioned13 or rejected14 the notion of any evolutionary function for dreams. Although the question of the function of dreaming remains unresolved, there is a growing consensus that sleep serves a function of offline memory processing (for reviews, see references 4 and 15). Sleep has been shown to enhance prior learning of perceptual and motor skills,16,17 paired word associates,18,19 and emotionally charged epi-
sodic memories20 and even to enhance mathematical insight.21 In relation to learning and memory consolidation, however, not all sleep is equal. For example, improvement on a motor skill task has been reported to correlate with amounts of late-night light (stage 2) non-REM sleep,22 but improvement on a visual perception task correlates with both late-night REM sleep and early-night slow-wave sleep.23-25 Others have found paired word associate learning to depend on early-night sleep18,19 and emotional declarative memory on late sleep (for review, see references 15 and 20). Brain mechanisms are clearly in place that would permit dreaming to be involved in a similar memory function, participating in (or at least reflecting) the reprocessing of memories from recent daytime experiences. Such a claim is reminiscent of Freud’s statement that “in every dream we may find some reference to the experiences of the preceding day [original emphasis],”1 although in some cases this reprocessing, identified by sleep-dependent learning enhancements, has been shown to continue for several nights after an initial learning experience (e.g., see reference 16), and lesser, incremental enhancements might even continue for years.26
SLEEP STAGES AND DREAM CONTENT If memory processes are differentially activated across sleep stages, and dreaming at least parallels and possibly contributes to these memory processes, one would expect to see changes in the content of dream reports collected from different sleep states. In its simplest form, this is exactly what is seen. Reports are more frequent after awakenings from REM sleep,27-30 and both REM and non-REM reports are more common when awakenings occur later in the night.31 Reports obtained from REM tend to be longer,32-34 more vivid, more story-like, and more bizarre29,30,35,36 than non-REM reports. Whereas it has been suggested that some of these differences merely reflect poorer recall after non-REM awakenings, little objective evidence supports such a claim, and other REM– non-REM differences are not amenable to such an explanation. For example, hallucinations are more prevalent in reports from REM sleep, whereas directed thinking is more common in non-REM sleep, a pattern that cannot be explained simply by poorer recall from one stage or another.37 Even at this level of analysis, there is the suggestion of homology between dream content and memory function in sleep. In REM sleep, dreams are (1) hallucinatory, (2) emotional, and (3) narrative, with (4) frequent fictive movements (for review, see reference 30). Similarly, REM is thought to facilitate consolidation of visual perceptual and emotional memories.15 In contrast, non-REM has been associated with sleep-dependent improvement on a range of hippocampus-dependent tasks, including the memorization of declarative information18,38 and navigation through spatial environments.12 Paralleling this mnemonic function, dream reports from non-REM tend to be realistic and thoughtlike and draw on material from recent episodic memory.39 There are notable exceptions (e.g.,
CHAPTER 55 • Why We Dream 629
improvement on a motor task correlates with late-night non-REM sleep, but REM dreams are decidedly more motoric), but the argument can be made that differences in memory functions across sleep stages are reflected in differences in dream content.
DREAMS AND MEMORY SYSTEMS Most models of dreaming implicitly assume that dreams are constructed from our memories, but they also recognize that this construction need not involve the transparent, direct incorporation of specific memories into the dream scenario. Freud, for example, emphasized that actual memories, events, and their associated emotions underwent “condensation” and “displacement” before appearing in dreams. Whereas he elaborated a complex theory of “dream work” to explain these alterations, modern cognitive neuroscience allows the formation of much simpler, evidence-based explanations. Specifically, dream construction does not include the veridical replay of complete “episodic” memories, as normally mediated by the hippocampus in waking life. Instead, dreams appear to be constructed from unbound fragments of various recent episodes,40 intermixed with remote memories, semantic memories (facts and general information), and representational memories (sensorimotor images) stored in and directly accessed in the neocortex.41 Within dream content, the distribution of these various types of memory sources appears to differ by sleep stage. Subjects identify episodic memory sources for dream elements more frequently after awakenings from sleep onset or non-REM sleep than after REM awakenings.39 This differential rate parallels the decline in directed thinking reported as subjects move from sleep onset to stage 2 non-REM and then into REM sleep.42,43 At the same time, the frequency of “generic semantic memory sources” is greater in REM than in non-REM sleep.39, p. 165 Episodic memories are clearly a source for the construction of dreams in both REM and non-REM sleep, but these episodes are not “replayed” during dreaming in their original form. In a study, subjects identified waking antecedents for 364 dream elements in 299 dream reports. When the extent of congruence between these dreams and their purported waking sources were analyzed,40 only 3% of dream elements were judged to have the same location, characters, and actions as the identified waking memory source. For this small percentage of reports, dream content may reflect the same hippocampus-mediated process of episodic recall that characterizes “remembering” during wakefulness. However, the majority of dreams appear to be composed of isolated fragments of recent episodes, recombined and interleaved with cortically mediated remote and semantic memories. Thus, “we dream about what happened, but not what actually occurred.”43, p. 24 What is most striking in this study is that whereas specific episodic memories do not appear unaltered in dreams, dreamers nonetheless identify with confidence particular episodes as the source of their dream elements. What, then, is the basis of this association? The features that showed highest congruence between dream element and putative waking source were (1) theme, (2) emotion, and (3) characters.40 Whereas the last of these is consistent with
630 PART I / Section 7 • Psychobiology and Dreaming
the reiteration of a specific episode, the first two are decidedly not. Thematic congruence might instead reflect the activity of the non–hippocampally mediated, strongly associatively linked, semantic memory system. The lack of episodic replay also raises new questions about dream formation. Whereas episodic memories recalled during wakefulness consist of events that unfold over time, the memory fragments seen in dreams are generally separated from their original temporal context. Although certain semantic memories of motor actions (how to swing a bat or to tie a shoe) have an inherent temporal structure, in general it remains unclear how the process of dream construction might go about putting episodic fragments and semantic elements together into a cohesive dream narrative that unfolds over time. At an even more fundamental level, it remains unclear how objects, characters, and actions would be bound together within such a dream scenario at all. There must be some mechanism at work that serves to bind together the disparate fragments composing a novel dream scenario, allowing its subsequent recall. During waking memory recall, the hippocampal episodic memory system functions to bind together the individual features of an event—the persons, places, things, and actions that make up an episodic memory. If the functioning of this memory system is altered by the particular neurochemical milieu of the sleep state, the mechanisms of binding and association during dreaming may be quite different from those that operate during our waking lives. It is to the nature of these associative processes that we now turn our attention.
ASSOCIATIVE NETWORKS IN SLEEP From a neuroscientific perspective, Freud’s “censorship,” “condensation,” and “displacement” can be supplanted by more useful neurocognitive models of how associative networks control the construction of dream scenarios. We have seen already that episodic and semantic memory fragments, divorced from their original spatial or temporal context, are a primary source material for dreams. However, there is clearly more to the process of dreaming than a “random” activation of isolated memory elements. Insofar as dreams are relatively coherent in space and time, some manner of associative structure must control the development of the dream scenario, constraining which memory elements become active during a particular dream and binding these elements together into an unfolding narrative. As in wakefulness, the activation of cortical networks in the sleeping brain is presumably constrained by a learned association structure established by a lifetime of waking experience. When one semantic network is activated in the cortex (e.g., kitchen), its experience-dependent connections to other networks will always activate certain related concepts (e.g., refrigerator) while inhibiting others (e.g., park bench). There is evidence, however, that the associative rules employed by the sleeping brain differ from those evident during waking cognition and also differ across sleep states (REM versus non-REM). What, then, is the nature of this associative processing during sleep? One approach to this question is to perform standard cognitive tests of associative memory immediately after
awakening from REM and non-REM sleep in the middle of the night, during the period of “sleep inertia” that precedes the return to full wakefulness,44 when the brain and mind still display properties of the previous sleep condition (see reference 45 for review) and regional brain activation has not returned to waking levels.46,47 Two such studies have found a bias toward the activation of less common associations after awakenings from REM sleep. In the first of these, subjects performed a semantic priming test within 2 to 3 minutes after being awakened from REM or stage 2 non-REM sleep. In the task, subjects see a “prime” word for 200 msec, followed by a target letter string that may or may not be a word, and must press one of two keys indicating whether or not the target string is a word, responding as quickly and accurately as possible. When reaction times for words (as opposed to nonwords) are analyzed, the speed of response is found to be proportional to the degree of relationship between the prime and target words.48-50 Thus, the response time to the target word mouse would be faster when preceded by a strongly related prime, such as cat, than a weakly related prime, such as fur, and faster yet than to an unrelated prime, such as mop. This enhancement in response rate is thought to reflect the automatic spread of activation from cortical networks representing the prime word to other neural ensembles representing the target word, a process that proceeds without intent or conscious awareness.51-53 The lesser enhancement seen with “weak” primes presumably reflects the reduced spread of activation to these less strongly associated neural ensembles. However, when the efficacy of such weak and strong primes was measured after awakenings from REM sleep, weak priming decreased reaction times by 24 msec (compared with unrelated primes), whereas strong priming decreased them by only a nonsignificant 3 msec, significantly less than the weak priming.8 The implication of these findings is that the spread of activation among neural ensembles is altered during REM sleep, such that normally weak associations become more readily activated than normally strong associations. Such an inversion of the normal pattern might be expected to have two effects on cognitive processes during sleep. Insofar as these associative networks control the development of dream scenarios, one would expect dreams to develop in bizarre and unpredictable ways, as is in fact the case; but such a shift in activation patterns would also foster creative processes, which act through the novel juxtaposition of known facts. Just such an effect was found in a second study, in which subjects awakened from REM or non-REM sleep attempted to solve anagram puzzles, unscrambling such letter strings as resmad to discover a scrambled word, in this case the word dreams. When awakened from REM sleep, subjects were able to solve 32% more anagrams in the allotted time than after awakening from stage 2 non-REM sleep,7 a finding consistent with the results of the semantic priming study. In an even more dramatic example of sleep’s ability to foster creative thinking, subjects taught a rote mathematical process were more than twice as likely to discover a shortcut that dramatically reduced the time required to complete the task if they were allowed a night of sleep between initial training and follow-up testing than if they were given an equivalent amount of wake time during the
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Table 55-1 Scrambled Object Transformations OBJECT 1
Table 55-2 Object Transformations
OBJECT 2 OBJECT 1
OBJECT 2
CORRECT SCORES
% CORRECT
Burlap sac
Bag
Georgia home
Bed
Burlap sac
Bag
Boston home
Bike
Bed
6
100%*
-size bed
6
100%*
Boston home
Georgia home
6
100%*
School bus
Building
Building
6
100%*
Beach
Car
Bike
6
100%*
Pool
Car wheels and frame
Cash machine
6
100%*
Car
Building
Intense combat video game
City bus
Lion (really a bed)
Pool
Beach
6
100%*
Flowers
Intense combat video game
Car
Car wheels and frame
5
83%*
Statue of a lamb
Figures
City bus
School bus
5
83%*
Flowers
Figures
5
83%*
Statue of a lamb
Lion (really a bed)
5
83%*
62
94%*
Building Car Cash machine
1 2
-size bed
Transformations involved the sudden and discontinuous change of objects in column 1 into those in column 2. Judges were instructed to match each initial object with its transformed product. From Rittenhouse CD, Stickgold R, Hobson JA. Constraint on the transformation of characters and objects in dream reports. Conscious Cogn 1994;3:100-113.
day or across a night.21 Perhaps most important, this discovery was made in the absence of any suggestion that there was a shortcut to be found. Thus, the sleeping brain appears to be able to search out and to find potentially valuable new associations without prior knowledge that such associations are to be found. Still, none of these studies actually examined dream content to determine whether there was even a correlation between such changes in cognitive processing and dreaming. One source of information about how associative processes function in dreaming is to look at the actual associations found in dream content, and there may be no better place to look than in the bizarreness of dreams, one of the most broadly studied of all dream features.1,36,54-56 In one description, bizarreness has been divided into three main categories—incongruities, discontinuities, and uncertainties.57-59 Within this construct, discontinuities provide a useful insight into the nature of bizarre dream associations. In a study of bizarre discontinuities involving the sudden and unexpected transformation of one object into another, judges were asked to match the original dream objects with their transformation products. When presented with the transformation pairs in scrambled lists (Table 55-1), judges could reliably identify the original transformations (Table 55-2).60 Thus, although the transformations were sudden, unexpected, and bizarre, some associative rules clearly guided the process, as related objects could be readily identified. Perhaps of more interest is the nature of the relationships. Such transformations could in theory be based on similarity of form or function or could be guided by associations learned through experience. For example, fire trucks and buses are related by similarity, whereas fire trucks and firefighters are related through a learned association. When the 11 transformations listed in Table 55-2 were analyzed, all object pairs (with the possible exception of
Total
1 2
*P < .0001. “Correct scores” is the number of judges (of six) who correctly matched the initial and transformed objects. From Rittenhouse CD, Stickgold R, Hobson JA. Constraint on the transformation of characters and objects in dream reports. Conscious Cogn 1994;3:100-113.
flowers–figures) were clearly related by similarity of form or function, and none were obviously related by learned association. Thus, at least in the case of such transformations, the nature of the associative processes involved appear to be partially explained.
DREAMING AND DECLARATIVE MEMORY PROCESSING DURING SLEEP A mounting body of evidence suggests that sleep is critically involved not only in the consolidation of simple visual and motor skills16,17 but also in the processing of complex, hippocampus-dependent declarative memory. Although early findings were mixed, more recent reports clearly demonstrate a role for non-REM sleep in hippocampusdependent memory consolidation.12,19,38,61,62 Several studies have now employed the “paired associate” learning paradigm to assess the contribution of sleep to declarative memory performance. In this task, subjects are presented with a series of word pairs, and after the entire list has been presented, they are shown the first word of each pair and asked to recall the second. An early study by Plihal and Born18 suggested that non-REM sleep early in the night is particularly beneficial for the consolidation of such word pair memory compared with the benefits of late-night REM sleep. Subsequent studies have consistently confirmed that a period of sleep, relative to wakefulness, benefits the retention of this type of memory38,63 and that experimental enhancement of slowwave activity enhances word pair recall.64 Although the majority of the emerging literature on declarative memory and sleep focuses on the memorization of verbal or visual stimuli, other research highlights the
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equally important role of sleep in the reorganization and transformation of declarative memories across time. For example, Ellenbogen and coworkers62 reported that sleep aids in the development of transitive inference in a paradigm in which subjects are asked to make judgments extending beyond material learned before sleep. Payne and colleagues65 have meanwhile observed that sleep facilitates extraction of the general theme of semantically related word lists. Other studies stress the role of sleep in the consolidation of spatial12 or contextual memory.66 In sum, a rapidly accumulating body of research demonstrates that complex, hippocampus-dependent learning is processed during human sleep. Might this reactivation and transformation of declarative memory be expressed within the content of dreams? In partial answer to this question, we discuss, in the following, evidence that intensive, engaging learning experiences are reliably expressed in the content of dreams during posttraining sleep.
INCORPORATION OF WAKING EVENTS INTO DREAMS Although many of the studies of dreaming described earlier reflect the incorporation of waking events into dreams, few involved experimental manipulations of waking events with the goal of influencing subsequent dream content (for review, see reference 67). A new line of research investigating this process has focused on hypnagogic dreams, which occur at sleep onset. In the first of these studies,68 subjects spent 2 to 3 hours per day playing the video game Tetris across 2 or 3 days. Three groups of subjects were studied: 12 subjects with no prior Tetris experience (novices), 10 with extensive Tetris experience (experts), and 5 dense amnesiacs with extensive medial temporal lobe damage resulting from anoxia or encephalitis (amnesiacs). The game involves manipulating game pieces as they “fall” from the top of the computer screen to the bottom in a central “play window.” Players can move pieces to the left or right and rotate them as they fall. Their goal is to rotate and to position the pieces so that they fill the space at the bottom of the screen without leaving gaps between pieces. On the evening of each day of game play, subjects were awakened repeatedly during the first hour of the night, always within 3 minutes of sleep onset, and asked to report any thoughts, feelings, or images from the prior sleep period. Nine of the novices (75%) and five of the experts (50%) reported visual images of the game in 9.8% and 4.8% of their sleep-onset reports, respectively. Taken together, 64% of the subjects reported instances of game imagery during the hypnagogic period, with images reported in 7.2% of their reports. Subjects reported remarkably similar imagery, seeing Tetris pieces falling in front of their eyes, occasionally rotating and fitting them into empty spaces. Among the 27 reports of imagery, there were no reports of seeing the larger picture surrounding the play window, the scoreboard, or the keyboard or of typing on the keyboard. There were only two reports of seeing a computer screen and none of seeing the desk or room. Thus, the imagery was limited to those aspects of the experience that were most salient and to which subjects presumably paid the most attention. As described before, here we again see that
dreams are not exact “replays” of waking experience but rather are composed of fragments of recent episodic material, intermingled with other content. Remarkably, three of five amnesiac patients also reported hypnagogic Tetris images, despite being unable to recall playing the game before or after the night’s sleep. This observation clearly indicates that the hippocampal memory system, which supports the encoding and recall of episodic memories during wakefulness, is not necessary for the construction of sleep-onset imagery related to recent experience. Indeed, the similarity of amnesiacs’ reports to those of control subjects was striking. Although unable to recall having played the game (or even to recognize the experimenter from session to session), patients nonetheless reported, for example, “little squares coming down on a screen,” and in one case, the subject explicitly stated that she had no knowledge of the source of the images. Thus, she was able to produce dream images of events for which she had no declarative knowledge. An additional point of note is that two of the five Tetris experts reported Tetris images explicitly described as being from earlier versions of the game, which they had not played in the last year. One subject reported imagery from a game version that she had not played since high school, 5 years earlier. Thus, sleep-onset dream imagery need not be determined only by recent sensory input but additionally can incorporate older, strongly associated memories. These last two findings, of (1) Tetris images in the dreams of amnesiacs and (2) the presence of images from previously encountered game versions, bear a striking resemblance to aspects of freudian dream theory. Freud’s belief that dream construction involved the reactivation, by events of the day, of memories from childhood finds support in the imagery of previously played versions of Tetris reported after a day with game play; but there is nothing of a negative, suppressed, forbidden, or sexual nature in the recalled and replayed memories seen in the dream. A more straightforward interpretation would be that associative processes, primed by the recently formed memories resulting from 2 to 3 hours of play earlier that day, reactivated strongly associated memories from childhood. This is what would be predicted on the basis of a progressive, associative model of dream construction, in which remote memory networks are updated on the basis of recent related experiences, here allowing more information from the earlier memories to be used while performing the newer version of the Tetris game. The case is similar for the findings with amnesiacs. Here, in perhaps the clearest form possible, dreams provide a royal path to the unconscious. With their inability to form new declarative memories, any incorporation of Tetris images into the dreams of these patients must reflect activation of memory systems that are not accessible through conscious search. Indeed, at least one patient explicitly reported a lack of knowledge of the waking source of the dream imagery. The fact that normal subjects produce similar images at similar rates suggests that even in normal subjects, these hypnagogic dreams are being constructed from memory systems unavailable to direct conscious recall. Whereas this model implies dream access to “the unconscious,” it is a very different unconscious from that proposed by Freud, one not fraught with
forbidden memories and desires, but rather one that evolved to provide us with useful semantic knowledge of the world around us. This fact is driven home even more forcefully by a study in which subjects were taught three nonsense sentences across a night, one immediately before going to sleep and two more after awakening from REM sleep.69 The nonsense sentences (translated from the original Italian) are In the bathroom the raven is painting a fish on a radio and spinning a bust on the custard. In the embers a poster is fining a parcel along the bridge and betting a tooth in the game. In a liter a cock is tricking a ruble from a palm and nursing a ball in a tub. Subjects were instructed to memorize the sentences, and after hearing one twice, they repeated it back as accurately as possible. When dream reports were collected after awakening from the next REM period, dream content was frequently judged as related to the previously memorized sentence. For example, after hearing the first sentence, with its reference to “painting a fish,” one subject reported “walking with a friend on the seashore.” Of course, such apparent associations can be spurious. Indeed, when judges scored dream reports from a control night, before subjects had heard any of the sentences, apparent associations were again found. However, the experimental design allowed one to use these rates of “pseudoincorporation,” obtained from the control night, to correct for such spurious associations, and when this is done, more than a third of all REM reports collected on the experimental night contained actual incorporations of elements from the learned sentence (72% of reports on the experimental night versus 39% on the control night; P < .01). Two features of these results are particularly striking. First, the simple act of intentional memorization seems to be sufficient to tag a memory for potential incorporation into subsequent dream content, even when the memory itself has no apparent meaning. Second, as with the previously described study of the incorporation of waking memories into nocturnal dreams,40 these incorporations are never in the form of an exact replay of the episode, for example, a report of memorizing a sentence. Instead, the brain seems to simply extract key elements of the memorized sentence (single words) and to incorporate them into an unrelated scenario. In fact, not only is the scenario changed, but the object is as well, so that the actual word from the memorized sentence (e.g., the fish) is replaced by a semantically related word (e.g., the seashore). This is different from what was seen in the hypnagogic Tetris dreams,68 but additional studies of sleep-onset imagery bridge this difference. In a related study, after training intensively on the downhill skiing arcade game Alpine Racer II, 65% of subjects reported images from the game in their subsequent hypnagogic dreams.70 These sleep-onset dream reports sometimes included places where they frequently crashed or a particularly steep slope, but the game images were again devoid of their original context, always being reported without the arcade game itself being seen or themselves
CHAPTER 55 • Why We Dream 633
playing it.70 In agreement with the findings of the Tetris study, subjects with prior downhill skiing experience also sometimes reported seeing images related not to the arcade game but to actual skiing experiences from their past. These observations thus extend the Tetris findings to a second game. In the case of Alpine Racer II, it was additionally observed that the nature of game-related sleep-onset imagery became more abstracted from the original experience across the course of the night. A subset of participants were allowed 2 hours of uninterrupted sleep at the start of each night, before being awakened and then, as they fell back asleep, reporting hypnagogic imagery at this later time. In this “delayed awakening” protocol, subjects reported dramatically fewer skiing images. Instead, they reported imagery more indirectly related to the game, for example, of “falling down a hill” or of “moving through some kind of forest” with their “entire upper body incredibly straight.”70 Thus, imagery related to recent experience appears to become more abstracted from the original memory source later in the night, a phenomenon also suggested in the transformation of “fish” into “seashore” in the study described above.69
EMOTION IN THE SLEEPING BRAIN REM dreaming is commonly associated with the experiencing of intense emotion. As such, emerging literature suggesting that sleep supports the reactivation and transformation of emotional memories, in particular, may be relevant to our understanding of the dreaming process. In one study,20 the recall of emotionally charged stories was selectively enhanced after REM sleep. In this protocol, subjects learned both neutral and emotional texts before sleep. Relative to wakefulness, periods of posttraining sleep rich in REM were particularly beneficial for these memories. Furthermore, memory for the emotional texts benefited from REM sleep to a greater degree than did neutral material. Remarkably, when the same research participants were again tested 4 years later,71 the beneficial influence of REM sleep versus wakefulness on memory for the original emotional (but not neutral) texts was maintained. Similarly, a study from Payne and colleagues72 demonstrated that sleep selectively enhances memory for emotional objects in the foreground of visual scenes, suggesting that sleep selects the information most relevant to an individual for further processing while allowing memory for less salient aspects of an experience to decay. These findings are in agreement with numerous studies that have suggested that dreaming represents a highly complex analysis and recasting of both memories and emotions67,73-78 and that dreaming acts to process the emotional content of events in an individual’s life. The most well-known example of emotional processing during sleep is perhaps also the least well understood. This is the phenomenon of “sleeping on a problem,” involving situations in which a difficult decision must be made. Anecdotal reports indicate that people can go to bed at night with such a problem on their mind and wake up the next morning with a clear choice in their mind. There are several features of this phenomenon that are worth noting. First, it is a remarkably robust effect, with most people
634 PART I / Section 7 • Psychobiology and Dreaming
casually surveyed believing that as often as not, it successfully yields results overnight. Second, the decision normally becomes apparent without an explicit rationale. People report knowing at a “gut level” that they have come to the correct decision but without a clear and rational justification for it. Third, there is usually considerable confidence that the decision reached is the correct one and little sense that further deliberation would be of any added benefit. At the same time, the process does not appear to be useful for the recall of forgotten information, such as a phone number or address. Rather, it serves to analyze available information to come to a decision on the basis of some sort of weighing of the relevant information. Whereas these features of the process are clear from anecdotal observations, it must be made clear that to our knowledge, no objective studies of the phenomenon have been made. Perhaps the closest we have at this time is the study of mathematical insight, described earlier.21
A NEUROCOGNITIVE MODEL OF DREAM CONSTRUCTION AND FUNCTION When memory networks are activated in the brain, they are inevitably altered. This is one of the most striking findings of cognitive neuroscience in the last decade. Indeed, it might be true that no neural circuits are ever activated without being at least subtly altered. This is true whether the activity of a particular circuit is perceived by the conscious mind or not. Thus, every time a child hears a sentence spoken, neural circuits are activated that over time will extract rules of grammar that will allow her to speak with nearly perfect use of that grammar, even though she may never explicitly know those rules or even be consciously aware that they exist. This is a hallmark of the brain’s construction—that it extracts similarities and rules without even knowing that they exist. This is exactly what was seen in the studies of mathematical insight21 and transitive inference,62 in which sleep was shown to dramatically facilitate this process. Of course, the activation of memory networks can also be accompanied by conscious experience, as is the case now, as you read and consider the arguments presented here. As there are distinct memory systems in the brain, some accessible to consciousness and some not,41 so also are there distinct mechanisms for activating and manipulating these memories, some of which are accessible to consciousness and some of which are not. So it should come as no surprise when we suggest, first, that dreaming must inevitably alter the memories accessed in the process of dream construction and, perhaps more important, that dreaming may be a byproduct of mechanisms that evolved to facilitate sleep-dependent memory consolidation and integration. As in wake, these mechanisms would often activate systems that remain outside of our awareness. This presumably is the case when a visual texture discrimination skill23 or a finger tapping motor sequence22 is consolidated during sleep. At other times, the sleep-dependent reactivation of memory networks might occur in a manner that brings the patterns of activation in these networks into
conscious awareness. When this happens, we dream, observing the flow of images, thoughts, and feelings that occur during this memory reactivation process; but critically, we do not necessarily see the changes in the memory systems that result from this process, and thus we see the content of dreams but neither their underlying purpose nor their ultimate effects. If one chose to, one could describe the dream content as “manifest content” and the underlying changes in memory systems as its “latent content.” The question of the function of dreaming may be reducible to a question of the function of the sleep-dependent memory processes that result in the conscious experience of dreaming. It is our belief that sleep has, as one of its most critical functions, the incremental modification of cortical networks. Such a model has been put forward in some detail by others.79 Because sleep has been shown to enhance (1) genetically preprogrammed but experientially controlled modification of visual circuitry during early development,80 (2) visual and motor skill learning,22,23 (3) emotional memories,20,72 (4) declarative and hippocampusdependent memories,12,18,38,62,63,66 and (5) mathematical insight,21 it would appear that sleep’s role in such processing spans an impressively wide range of brain circuits and functions. The question of dream function now becomes the question of which of these circuits and functions, when activated, enter our conscious awareness and whether this conscious awareness in turn has an impact on these brain circuits. Which circuits might be critical? On the basis of studies of neurologic patients, several discrete regions have been proposed81 to be responsible for consciousness, including several brainstem nuclei (including monoaminergic and cholinergic nuclei involved in control of the REM cycle), hypothalamus, superior colliculus, thalamus, somatosensory cortices (including the insula and medial parietal cortex), and cingulate cortex, and brain imaging studies provide evidence that many if not all of these areas are specifically activated during REM sleep.5 We propose that when these regions are sufficiently activated, consciousness arises in sleep as it does in waking, resulting in the phenomenon of dreaming. Thus, from one perspective, we dream because the necessary brain regions are appropriately activated; but from another perspective, dreaming is the appropriate activation of these regions. They become two levels of description of the same biological event. What function might these circuits serve? We have proposed elsewhere43 that dreaming occurs as the brain evaluates the potential value of novel forms of behavior, using, during REM sleep, the weak cortical associations preferentially activated in this state,8 in the absence of dorsolateral prefrontal cortex6,82,83 or hippocampal84,85 feedback, but in the presence of active error detection circuits in the anterior cingulate cortex,86 and affective evaluation of such errors by the amygdala and medial orbitofrontal cortex. As patterns of functional activation differ rather dramatically during non-REM sleep,82,87,88 the construction of dream experiences during this stage is likely to rely on at least a slightly different neural substrate. For example, during non-REM sleep, hippocampal output would be more likely to affect the dreaming process.84,89,90
CHAPTER 55 • Why We Dream 635
During REM dreaming, how might such a circuitry function? The inability of the dorsolateral prefrontal cortex to allocate attentional resources (and the dreaming brain classically pays little attention to bizarre incongruities in dreams) would be compounded by a relative inhibition of hippocampal output to the cortex.89 As a result, dreamed responses would have to be constructed from those primarily weak neocortical associations available during REM sleep,8 without the help of the directed (dorsolateral prefrontal cortex) recall of episodic (hippocampal) memories. Whereas the process of incorporation of these weak associates into the dream narrative remains unknown, we believe that associated emotions, mediated by both the amygdala and the medial orbitofrontal cortex, would play an important role. These responses would then, in turn, be reanalyzed by the anterior cingulate cortex error-detection circuitry. The consequence of this repeated modification and reanalysis of potential behaviors is twofold. At the brain level, we would see novel associations being activated within neocortical networks and being tested by an error-detection system that could adjust the strengths of these associations on the basis of the affective response to the imagined behavioral outcomes. At the conscious level, however, we would see classic REM dream construction. Situations would arise in the dream narrative without the dreamer’s appearing to participate in planning the course of events (dorsolateral prefrontal cortex inactive); the dreamer instead appears to simply respond emotionally to each turn of events (anterior cingulate cortex, orbitofrontal cortex, amygdala), not paying attention (dorsolateral prefrontal cortex) to incongruous or impossible twists in the plot (weak associations). The frequent perplexity that the dreamer experiences surrounding dream behavior suggests that as in waking, “the anterior cingulate cortex seems to come into play when rehearsed actions are not sufficient to guide behavior.”91 In the end, then, we propose that dreaming is simply the conscious perception of the stream of images, thoughts, and feelings evoked in the brain by one of many forms of offline learning and memory processes that occur during sleep. At the same time, it reflects one of the most sophisticated forms of processing that the brain performs—the analysis and interpretation of the events of our lives in a manner that provides meaning to these events and guides our future behavior. Whether assessing the chances of sexual conquest or the choices in a complex moral dilemma, the mechanism is the same, and it is quintessentially human.
❖ Clinical Pearl Emerging data suggest that dream experiences reflect the offline consolidation of recent memories during sleep. As such, studying dreaming may facilitate a greater understanding of the sleep-related processes underlying long-term memory formation, as well as the dysfunction of these processes in pathological conditions such as post-traumatic stress disorder.
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52. Collins JJ, Chow CC, Imhoff TT. Stochastic resonance without tuning. Nature 1995;376:236-238. 53. Posner MI, Snyder CRR. Attention and cognitive control. Information processing and cognition. The Loyola Symposium. Hillsdale, NJ: Erlbaum; 1975. 54. Casagrande M, Violani C, Lucidi F, Buttinelli E, et al. Variations in sleep mentation as a function of time of night. Int J Neurosci 1996; 85:19-30. 55. Foulkes D. Dream reports from different stages of sleep. J Abnorm Soc Psychol 1962;65:14-25. 56. Molinari S, Foulkes D. Tonic and phasic events during sleep: psychological correlates and implications. Percept Motor Skills 1969; 29:343-368. 57. Hobson JA, Hoffman SA, Helfand R, Kostner D. Dream bizarreness and the activation-synthesis hypothesis. Hum Neurobiol 1987;6:157164. 58. Mamelak AN, Hobson JA. Dream bizarreness as the cognitive correlate of altered neuronal behavior in REM sleep. J Cogn Neurosci 1989;1:201-222. 59. Williams J, Merritt J, Rittenhouse C, Hobson JA. Bizarreness in dreams and fantasies: implications for the activation-synthesis hypothesis. Conscious Cogn 1992;1:172-185. 60. Rittenhouse CD, Stickgold R, Hobson JA. Constraint on the transformation of characters and objects in dream reports. Conscious Cogn 1994;3:100-113. 61. Plihal W. Differential effects of early and late nocturnal sleep on the consolidation of declarative and nondeclarative memory. Frankfurt: Peter Lang; 1996. 62. Ellenbogen JM, Hu PT, Payne JD, Titone D, et al. Human relational memory requires time and sleep. Proc Natl Acad Sci U S A 2007; 104:7723-7728. 63. Ellenbogen JM, Hulbert JC, Stickgold R, Dinges DF, et al. Inter fering with theories of sleep and memory: sleep, declarative memory, and associative interference. Curr Biol 2006;16:1290-1294. 64. Marshall L, Helgadottir H, Molle M, Born J. Boosting slow oscillations during sleep potentiates memory. Nature 2006;444:610-613. 65. Payne JD, Propper R, Walker MP, Stickgold R. Sleep increases false recall of semantically related words in the Deese-RoedigerMcDermott memory task. Sleep 2006;29:A373. 66. Rauchs G, Orban P, Schmidt C, Albouy G, et al. Sleep modulates the neural substrates of both spatial and contextual memory consolidation. PLoS One 2008;3:e2949. 67. Lauer C, Riemann D, Lund R, Berger M. Shortened REM latency: a consequence of psychological strain. Psychophysiology 1987;24: 263-271. 68. Stickgold R, Malia A, Maguire D, Roddenberry D, et al. Replaying the game: hypnagogic images in normals and amnesiacs. Science 2000;290:350-353. 69. Cipolli C, Bolzani R, Tuozzi G, Fagioli I, et al. Active processing of declarative knowledge during REM-sleep dreaming. J Sleep Res 2001;10:277-284. 70. Wamsley EJ, Perry K, Djonlagic I, Reaven LB, et al. Cognitive replay of visuomotor learning at sleep onset: temporal characteristics and relation to task performance. Sleep 2010;33:59-68. 71. Wagner U, Hallschmid M, Rasch B, Born J. Brief sleep after learning keeps emotional memories alive for years. Biol Psychiatry 2006;60: 788-790. 72. Payne JD, Stickgold R, Swanberg K, Kensinger EA. Sleep preferentially enhances memory for emotional components of scenes. Psychol Sci 2008;19:781-788. 73. Berger M, Riemann D, Lauer C. The effect of presleep stress on subsequent sleep EEG and dreams in healthy subjects and the depressed. In: Koella WP, Obal F, Schulz H, Visser B, et al, editors. Sleep ’86. New York: Gustav Fischer Verlag; 1988. p. 84-86. 74. Cartwright R. Dreams that work: the relation of dream incorporation to adaptation to stressful events. Dreaming 1991;1:3-9. 75. Cartwright R, Newell P, Mercer P. Dream incorporation of a sentinel life event and its relation to waking adaptation. Sleep Hypnosis 2001;3:25-32. 76. Greenberg R, Pearlman CA. Cutting the REM nerve: an approach to the adaptive function of REM sleep. Perspect Biol Med 1974;17: 513-521. 77. van der Kolk B, Blitz R, Burr W, Sherry S, et al. Nightmares and trauma: a comparison of nightmares after combat with lifelong nightmares in veterans. Am J Psychiatry 1984;141:187-190.
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Impact, Presentation, and Diagnosis
Section
8
Beth A. Malow 56 Approach to the Patient with Disordered Sleep 57 Cardinal Manifestations of Sleep Disorders 58 Physical Examination in Sleep Medicine
59 Use of Clinical Tools and Tests in Sleep Medicine 60 Classification of Sleep Disorders 61 Epidemiology of Sleep Disorders
62 Sleep Medicine, Public
Policy, and Public Health 63 Sleep Forensics
Approach to the Patient with Disordered Sleep Beth A. Malow Abstract The evaluation of a patient with disordered sleep begins with the chief complaint, which can be classified into insomnia, daytime sleepiness, episodic nocturnal movements or behaviors, or a combination of these concerns. A thorough characterization of these concerns, coupled with a comprehensive sleep history that includes the daily schedule, bedtime routine, and morning and daytime symptoms, forms the foundation
Sleep disorders are common in the general population. They can contribute to impaired academic or occupational performance, accidents at work or while driving, and disturbances of mood and social adjustment. Marriages and relationships may be adversely affected by the disordered sleep of a spouse or bed partner. In addition, sleep disorders may lead to or exacerbate serious medical, neurologic, and psychiatric problems. The clinician should therefore take sleep complaints from a patient seriously and approach the evaluation of such problems in an orderly and systematic fashion. Patients who complain of disturbed sleep usually describe one or more of three types of problems: insomnia; abnormal movements, behaviors, or sensations during sleep or during nocturnal awakenings; or excessive daytime sleepiness (Table 56-1). These sleep complaints are not mutually exclusive, and a given sleep disorder may be associated with more than one type. For example, patients with sleep apnea may complain of insomnia, excessive daytime sleepiness, choking or gasping during the night, or all three. Those with narcolepsy may complain of sleep paralysis and hallucinations at sleep onset or on awakening, disrupted sleep, and daytime sleepiness. The foundation for the diagnosis of sleep disorders is the history of the sleep complaint. Ideally, the evaluation includes a history from the patient’s bed partner. Many sleep problems are not evident to the patient, and it is often
Chapter
56
for diagnosis. As in other fields of medicine, it is essential to consider other medical and psychiatric conditions, medication use, family history, social history including the psychosocial situation, review of systems, and physical examination before formulating a differential diagnosis and performing diagnostic studies. This systematic approach allows accurate diagnosis and specific interventions for many treatable sleep disorders.
the bed partner who has persuaded the patient to seek evaluation. The bed partner can comment on the intensity of snoring and the presence of nocturnal behaviors or events. Rounding out the clinical evaluation are the past medical history, family history, social history, general review of systems (Table 56-2), and physical examination. Table 56-3 provides a sample sleep review of systems. An assessment is then made on the basis of the clinical evaluation. In many cases, it is possible to make a definitive diagnosis and to begin treatment, whereas in others, the diagnosis is presumptive and must be confirmed or excluded by diagnostic studies. If the diagnosis is uncertain, a differential diagnosis is formulated and a plan is developed to determine a definitive diagnosis, if possible. The elements of the evaluation of patients with disordered sleep are reviewed in this chapter, and signs and symptoms that may point to a particular diagnosis are emphasized.
CHIEF COMPLAINT AND HISTORY Evaluation begins with the chief complaint, which provides a focus for delineating the patient’s concerns and eliciting the history. It is often useful to ask why the patient is seeking help at the present time, particularly if the problem has been of long standing. If the chief complaint is from the spouse or bed partner, it is important to determine whether the patient recognizes the problem, is 641
642 PART II / Section 8 • Impact, Presentation, and Diagnosis Table 56-1 Sleep Concerns, Including Leading Differential Diagnoses I’m Not Able to Fall Asleep or Stay Asleep. Psychophysiologic insomnia (often stress related) Inadequate sleep hygiene (poor sleep habits) Medications (corticosteroids) Neurologic disorder (Parkinson’s disease) Psychiatric disorder (anxiety, depression) Sleep apnea Restless legs syndrome I’m Too Sleepy during the Day. Insufficient sleep Sleep disruption due to obstructive sleep apnea, periodic limb movement disorder, or a medical condition Narcolepsy or other intrinsic hypersomnias Medications
Table 56-3 Sample Sleep Review of Systems Sleep Habits Bedtime on weekdays Bedtime on weekends Wake time on weekdays Wake time on weekends Time it takes to fall asleep Awakenings during the night Time it takes to fall back asleep Morning Symptoms Dry mouth Refreshed Morning headaches Nasal congestion
I Am Told I Do Unusual Things in My Sleep. Epileptic seizures NREM arousal disorders REM sleep behavior disorder Rhythmic movement disorder Psychogenic seizures
Daytime Functioning Sleepiness (specific situations when patient has fallen asleep) Falling asleep while driving Any accidents caused by sleepiness Memory problems Difficulty concentrating Fatigue Irritability Naps (how many, how long, dreams?)
Table 56-2 Sleep Disorders or Concerns Associated with Medical Disorders Encountered in the Review of Systems
Bed Partner’s Observations or What Patient Has Been Told Loudness of snoring (mild, moderate, severe) Witnessed apneas Choking or gasping Arousals
SLEEP DISORDER SYSTEM (SYMPTOM) OR CONCERN Constitutional (weight gain)
Obstructive sleep apnea
Head, eyes, ears, nose, throat (hypothyroidism)
Obstructive sleep apnea
Lungs (nocturnal dyspnea)
Sleep disruption
Heart (nocturnal angina)
Sleep disruption
Gastrointestinal (reflux)
Nocturnal choking
Genitourinary (nocturia)
Sleep disruption
Musculoskeletal (joint pain)
Insomnia, sleep disruption
Neurologic (neuropathic pain)
Insomnia, sleep disruption, restless legs syndrome
Psychiatric (anxiety or depression)
Insomnia, sleep disruption
unaware of it, or denies its existence. Many clinicians also obtain a brief patient profile during the interview that includes the patient’s age, sex, occupational or academic status, marital status, and living arrangements. The profile often includes valuable information about how the sleep concern is affecting the patient’s daily functioning (e.g., difficulty performing job responsibilities or participating in leisure activities with family). There are two kinds of nighttime symptoms: those that occur during sleep and those that occur during nocturnal awakenings. Symptoms that occur during sleep concern movements or behaviors and often are reported by the spouse or bed partner because the patient may be unaware of the episodes. Examples include snoring, cessation of breathing, twitching or kicking of the legs or arms, chewing movements, sleepwalking, sleeptalking, screams,
Sleep-Related Movements Periodic leg movements Leg cramps Restless legs symptoms Narcoleptic Symptoms Cataplexy Hallucinations Sleep paralysis Automatic behaviors Genitourinary System Nocturia Impaired sexual functioning Other Weight gain in recent years Sleepwalking Dream-enacting behavior
and violent behavior. Complaints that occur during nocturnal awakenings concern sensations or events that are evident to the patient and include headaches, wheezing or shortness of breath, palpitations, heartburn, leg cramps, and feelings of paralysis or numbness and tingling. Once the chief complaint is delineated, details concerning the sleep problem are sought, including its duration, the circumstances at its onset, the factors that lead to exacerbation or improvement, and any associated symptoms. The patient’s daily schedule is reviewed, including the usual bedtime and estimated time to sleep onset, the number and timing of awakenings, and the time of final awakening. Particularly in children, the bedtime routine, or lack thereof, should be assessed; this information may
CHAPTER 56 • Approach to the Patient with Disordered Sleep 643
suggest limit-setting sleep disorder. The method of awakening should be determined: spontaneous, with an alarm, or by a family member. The usual waking schedule should also be determined, including times of work, school, meals, and exercise. It is important to obtain detailed sleep–wake schedules in shift workers. A comparison of the patient’s weekday and weekend schedules may reveal significant variations in sleep timing that suggest a circadian rhythm sleep disorder (see Chapter 41) or insufficient sleep syndrome (see Chapter 6). Morning symptoms should be elicited, such as increased nasal congestion or dry mouth or morning headaches. These symptoms may support a diagnosis of obstructive sleep apnea. Daytime symptoms, including activities that tend to provoke sleepiness, should be investigated to characterize the severity of sleepiness. A comprehensive sleep history also includes questions about the frequency and duration of daytime naps and the presence or absence of cataplexy, hypnic hallucinations, sleep paralysis, and automatic behavior. Questions assessing the sleep setting may elicit information about factors that cause or aggravate sleep problems. Noise, extreme temperature, uncomfortable sleep surfaces, and frequently changing sleep conditions may all adversely affect sleep continuity and suggest an environmental sleep disorder. For patients with medical or psychiatric diseases, the degree of sleep disturbance usually varies with the severity of the underlying illness. For example, in patients with congestive heart failure, the degree of insomnia may correlate with the severity of orthopnea and paroxysmal nocturnal dyspnea. Similar relationships may occur in patients with sleep disturbance related to depression, asthma, gastroesophageal reflux, and arthritis. In patients with sleep apnea, daytime sleepiness may correlate with seasonal allergies, alcohol use, or other factors that worsen apnea. Insomnia Patients with insomnia usually complain that their nocturnal sleep is inadequate in some way. They may describe difficulty falling asleep, frequent awakening, or early morning awakening with inability to return to sleep. It is important to distinguish among these patterns of insomnia because they may have different causes. For example, awakenings from sleep due to obstructive sleep apnea may result in sleep maintenance insomnia but would not result in a patient’s complaining of lying awake for hours not being able to fall asleep. The description of insomnia and its course may help determine cause. For example, insomnia that began in early childhood and continues with few remissions may suggest idiopathic insomnia (see Chapter 75). The relation of insomnia to stress is also important. If the cause of the stress is clear, such as the recent death of a family member, the diagnosis is likely to be adjustment sleep disorder (see Chapter 75). In other patients, however, the nature of the stress may not be immediately apparent. Positive life events, such as a promotion at work or recent marriage, may not be recognized by the patient as stressful. Medical conditions, such as cancer and its treatment (see Chapter 123), pain syndromes (see Chapter 126), or gastrointestinal disease (see Chapter 127), may also cause or contribute to insomnia.
Specific questions may reveal maladaptive behaviors and thought patterns that contribute to sleep difficulties. People with insomnia may become aroused and anxious when they are preparing for sleep and may worry about their insomnia and its effects on performance at work or at home the following day. Some may sleep better in an unfamiliar sleep setting, which suggests heightened arousal, frustration, or anxiety in attempting to sleep in the usual environment; these characteristics suggest psychophysiologic insomnia (see Chapter 75). Irregular bedtimes, latenight exercise, caffeine use in the afternoon or evening, watching television in bed, or going from work directly to bed may interfere with sleep and suggest inadequate sleep hygiene (see Chapter 75). Systematic inquiry into the behaviors and thoughts that accompany nocturnal awakenings is useful and may reveal conscious or unconscious “rewards” for poor sleep. Awakenings followed by inability to return to sleep without eating or drinking alcohol suggest the nocturnal eating syndrome (see Chapter 94). Patients who report “resting” for up to 8 hours at night without sleeping or leaving the bed may have sleep state misperception. Excessive Sleepiness Patients with daytime sleepiness typically complain of drowsiness that interferes with daytime activities, unavoidable napping, or both. Falling asleep while driving or at other particularly inappropriate or dangerous times is often the impetus that brings the patient to the clinician. Some of these patients complain that they need more sleep at night or that daytime drowsiness occurs regardless of how much sleep is obtained at night. Patients may also complain of difficulty with concentration or memory or increased irritability. Children may exhibit hyperactivity rather than sleepiness. The situations associated with drowsiness and spontaneous sleep episodes help determine the severity of the problem. Drowsiness and naps either may be limited to sedentary situations in which falling asleep is socially acceptable, such as watching television or reading at home, or may occur at work, while driving, in conversation, at sitting on the toilet, or even during sexual intercourse. The differential diagnosis of excessive daytime sleepiness ranges from insufficient sleep to sufficient sleep that is disrupted by pathologic events, such as apneas, or neurologic disorders, such as narcolepsy. Inquiring about sleep routines and bedtimes and wake times is essential in excluding insufficient sleep as a cause of sleepiness. Asking patients who complain of sleepiness about other associated symptoms provides essential information. Loud snoring, gasping, snorting, and episodes of apnea suggest the diagnosis of obstructive sleep apnea syndrome (see Chapter 105). The relationship of snoring to body position should be determined; snoring may occur in all positions or only in the supine position. A history of episodic muscle weakness with buckling of the knees, laxity of the neck or jaw muscles, or complete loss of muscle tone associated with laughter, anger, or hearing or telling a joke suggests cataplexy and a diagnosis of narcolepsy1 (see Chapter 84). Episodes of partial or total paralysis at the onset or termination of sleep (sleep paralysis) and dreamlike auditory, visual, or tactile hallucinations occurring at sleep onset or
644 PART II / Section 8 • Impact, Presentation, and Diagnosis
on awakening (hypnagogic and hypnopompic hallucinations) also suggest narcolepsy. Questions assessing mood are needed to identify patients with sleep disorder associated with mood disorders (see Chapter 130). The sleep–wake schedule may also provide clues to the diagnosis. Short nocturnal sleep time, longer sleep on weekends or days off, and fewer symptoms during vacations when the sleep period is longer suggest the insufficient sleep syndrome. Circadian rhythm sleep disorders should be considered in patients with complaints of nocturnal insomnia and daytime sleepiness. Patients with delayed sleep phase syndrome (see Chapter 41) frequently complain of difficulty waking up, morning sleepiness and sluggishness, and difficulty falling asleep at night. Symptoms are worse on days when the patient must awaken by a set time to be at school or work. Patients with advanced sleep phase syndrome (see Chapter 41) may complain of evening sleepiness and early morning awakening. The patient’s occupation and social schedule may suggest diagnoses of shift-work sleep disorder (see Chapter 41) or jet lag syndrome (see Chapter 41). Nocturnal Movements, Behaviors, and Sensations Information from collateral sources is needed for evaluation of episodic movements and behaviors during sleep. The bed partner should be asked to describe behaviors and vocalizations during the episodes, to relate episodes to sleep onset and time of night, and to note the degree of the patient’s responsiveness during the episode. The patient’s ability to recall the events is also significant. Episodes of inconsolable screaming and amnesia during the first third of the night suggest sleep terrors (see Chapter 94); episodes of dream-enacting behavior associated with dream recall that occur toward the end of the sleep cycle suggest the rapid eye movement (REM) sleep behavior disorder (see Chapter 95). Epileptic seizures may occur at any time of the night and should be strongly considered if a history of stereotyped behavior or dystonic posturing is elicited (see Chapter 92). In patients whose symptoms occur during nocturnal awakenings, the relations to evening activities and medical or psychiatric conditions are often illuminating. Repeated awakenings from sleep with chest discomfort may suggest sleep-related gastroesophageal reflux, sleep disorder due to peptic ulcer disease (see Chapter 127), or nocturnal cardiac ischemia (see Chapter 116), depending on associated symptoms and underlying diseases. Similarly, complaints of choking during sleep may suggest obstructive sleep apnea syndrome when they are accompanied by snoring or sleep-related gastroesophageal reflux when they are accompanied by heartburn and a sour taste in the mouth.
MEDICATION USE AND PAST MEDICAL HISTORY Assessment of medication use is critical because of the wide variety of medications that alter sleep and wakefulness (see Chapter 132). Some medications, such as theophylline and other bronchodilators, directly affect sleep; others, such as diuretics, have indirect effects. Chronic sedative or hypnotic use also affects sleep (see Table 56-2). Because cold
preparations, appetite suppressants, antihistamines, and nonprescription sedatives and stimulants affect sleep, it is important to ask specifically about nonprescription as well as prescription medications and herbal supplements. Herbal supplements have a variety of sedating and stimulating effects on sleep, and patients often omit mention of them during a medical evaluation.2 In addition, illicit drugs, such as Ecstasy, can cause insomnia and altered mood in teenagers and young adults.3 Many illicit drugs affect sleep by acting on adrenergic, gamma-aminobutyric acid–ergic, and other receptors.4 The history of current or past medical, surgical, and psychiatric illnesses is a source of important information. Seizure disorders, parkinsonism and dementia, arthritic conditions, asthma, ischemic heart disease, migraine or cluster headache, compressive neuropathies, obstructive uropathy, and almost any painful illness can cause significant sleep disturbance. A variety of medical conditions, including hypothyroidism, acromegaly, Cushing’s syndrome, allergic rhinitis, and some of the mucopolysaccharidoses, may contribute to the development of obstructive sleep apnea syndrome. Anemia and renal disease may cause or exacerbate restless legs syndrome or periodic limb movement disorder. In infants and toddlers, milk and other food allergens may cause insomnia. Head trauma may lead to the postconcussion syndrome, often accompanied by disrupted sleep continuity. Information about tonsillectomy, cleft palate repair, nasal trauma or surgery, and other orofacial surgery is essential in patients with suspected obstructive sleep apnea syndrome. Anxiety disorders, including panic disorder, and mood disorders are psychiatric disturbances that are often accompanied by insomnia, and some patients with depression complain of excessive daytime sleepiness. Exacerbation of schizophrenia and other psychotic disorders is frequently associated with severe sleep disruption.
FAMILY HISTORY A history of disordered sleep in family members is important information. Specific inquiry should be made about the existence in family members of previously diagnosed sleep disorders or symptoms suggestive of narcolepsy, obstructive sleep apnea, periodic limb movements, enuresis, sleep terrors or sleepwalking, or insomnia. There is a strong genetic contribution to the development of narcolepsy (see Chapter 84), and genetic and familial influences sometimes have a role in the development and expression of obstructive sleep apnea (see Chapter 103) and some of the parasomnias.5 SOCIAL HISTORY Assessment of psychosocial, occupational, and academic functioning as well as of satisfaction with personal relationships can yield valuable information about the impact of disordered sleep on the patient’s life. When the chief complaint comes from the spouse or bed partner, the patient may have one of the many sleep disorders whose symptoms may not be noticed by the patient. However, the possibility of marital or relationship difficulties should also be considered and explored. In patients complaining
CHAPTER 56 • Approach to the Patient with Disordered Sleep 645
of excessive sleepiness, potential occupational hazards should be assessed, and special attention should be paid to the assessment of social and occupational functioning of shift workers. The ability of the work environment to provide support for the patient should be evaluated. For children and adolescents, school performance should be determined. Alcohol, caffeine, nicotine, and illicit drug use should be determined. Alcohol use or abuse may intensify snoring and obstructive sleep apnea, may be a contributor to insomnia, or may produce long-lasting changes in sleep patterns. Patients who drink heavily on the weekend may complain of sleepiness primarily during the early part of the week. Caffeine use produces significant sleep disturbance in susceptible persons, and nicotine dependency may lead to nocturnal awakenings. Cocaine, amphetamines, barbiturates, and opiates can be associated with major disruption of sleep architecture. Illicit drugs, such as Ecstasy, may be the cause of an altered mood or sleep schedule in a teenager.
REVIEW OF SYSTEMS The review of systems may uncover symptoms of medical illnesses that can cause or contribute to sleep disorders (see Table 56-2). Recent weight gain or increase in collar size increases the likelihood of obstructive sleep apnea syndrome. Particular attention should be paid to the cardiovascular and pulmonary systems because of their relation to breathing and oxygenation during sleep. Angina, orthopnea, paroxysmal nocturnal dyspnea, and wheezing may indicate that sleep disturbance is due to cardiac or pulmonary disease. Heartburn and reflux of gastric contents into the throat when the patient is recumbent may cause nocturnal choking episodes. Leg cramps and neuropathic pain may be accompanied by sleep disruption. Nocturia is a common cause of disturbed sleep, particularly in older men. Depression or anxiety can contribute to insomnia. PHYSICAL EXAMINATION Physical examination of the patient with disordered sleep begins with observation. Body habitus often provides clues to potential etiologic factors of sleep complaints; thus, obesity with distribution of fat around the neck or midriff suggests the diagnosis of obstructive sleep apnea. Psychomotor slowing, poor hygiene, downcast eyes, blunted affect, or sad facies may suggest major depression and its associated sleep disturbance. Examination of the head and neck is particularly important in patients with suspected obstructive sleep apnea. Mandibular hypoplasia, craniosynostosis, retrognathia, and other craniofacial abnormalities may indicate the presence of Pierre Robin syndrome, Treacher Collins syndrome, Crouzon’s disease, achondroplasia, or other skeletal disorders that are associated with an increased incidence of sleep-related respiratory disturbances. Boggy, edematous nasal mucosa in patients with allergies or deviation of the nasal septum after trauma may compromise nasal patency and predispose the patient to obstructive sleep apnea syndrome. Oropharyngeal findings suggestive of
obstructive sleep apnea include an elongated soft palate and uvula; edema and erythema of the peritonsillar pillars, uvula, soft palate, or posterior oropharynx; redundant pharyngeal mucosa; enlarged tongue; and enlarged tonsillar tissue. Examination of the neck may reveal an enlarged thyroid or prominent fatty infiltration suggesting the likelihood of excess retropharyngeal adipose tissue. Auscultation of the chest may reveal expiratory wheezes in patients with nocturnal asthma attacks. Thoracic abnormalities such as kyphoscoliosis may compromise ventilatory capacity, leading to hypoventilation and nocturnal breathing difficulties. Patients with severe obstructive sleep apnea may have findings consistent with right-sided heart failure, including hepatomegaly, ascites, and ankle edema. Cardiac complications of disordered breathing during sleep may be indicated by a cardiac thrust at the left sternal border as a result of right ventricular enlargement or in the left second intercostal space adjacent to the sternum as a result of pulmonary hypertension. Auscultation may reveal a prominent fourth heart sound originating from the enlarged right ventricle and murmurs of pulmonary or tricuspid valve insufficiency. On abdominal examination, hepatomegaly may suggest that alcohol abuse is contributing to sleep disturbance or, in conjunction with other findings, that congestive heart failure is a factor. Examination of the extremities may reveal joint swelling or deformity, decreased range of motion across affected joints, and thickening of synovial tissue in patients with disordered sleep due to arthritis. Findings on mental status testing and neurologic examination may indicate the presence of a psychiatric or neurologic disease that causes or contributes to disturbed sleep. Impairment of short-term memory, judgment, language functions, and abstract reasoning suggests the presence of a dementing illness that may cause insomnia or nocturnal confusion. Assessment of mood may suggest the presence of mania or depression, either of which may be associated with insomnia. Delusional thoughts and agitation may indicate that acute psychosis is the cause of insomnia. Reduced alertness with slurred speech and nystagmus may be signs of hypnotic or sedative abuse. Impaired sensation and reduced or absent tendon reflexes may indicate peripheral neuropathy, sometimes accompanied by nocturnal paresthesias or burning pain. Elements of the physical examination relevant to the sleep patient are covered in greater detail in Chapter 58.
FORMULATION AND DIAGNOSTIC STUDIES Once the initial evaluation is complete, the clinician generates a differential diagnosis. The International Classification of Sleep Disorders (ICSD-2) provides a comprehensive diagnostic approach and is discussed in detail in Chapter 60. On the basis of the relative likelihood of the diagnostic possibilities, appropriate diagnostic studies are ordered (see Chapter 59). Even when the diagnosis is clear, laboratory tests may be required to determine the severity of the condition before the clinician decides on the appropriate treatment. Additional diagnostic information can be obtained through the use of laboratory or radiologic investigations,
646 PART II / Section 8 • Impact, Presentation, and Diagnosis
sleep logs, and sleep laboratory studies. Radiologic and laboratory tests may clarify or refine the diagnosis or may indicate its severity. Thyroid function tests or pulmonary function tests may be indicated in some patients with suspected obstructive sleep apnea. If the diagnosis of narcolepsy is under consideration, tissue typing for specific human leukocyte antigens implicated in the genetics of narcolepsy is sometimes helpful. Uremia, anemia, iron deficiency, or other metabolic abnormalities may be present in patients with suspected periodic limb movement disorder or restless legs syndrome. Iron deficiency anemia contributing to restless legs syndrome may be due to low body stores of iron.6 Repeated blood donation has been associated with restless legs syndrome and periodic limb movements of sleep,7 perhaps because of reduced iron stores. A urine toxicology screen may be diagnostic in cases of insomnia or hypersomnia due to substance abuse. The sleep log is particularly useful in patients with insomnia or suspected circadian rhythm disturbances. Although a variety of sleep logs exist, a 2-week log in which the patient records bedtime, approximate time of sleep onset, times and durations of awakenings during the sleep period, final awakening time, and nap times during the day is commonly used. The sleep log may provide a new perspective on the sleep problem for both the clinician and the patient; some patients are surprised and relieved to note that their sleep is better than they believed. Polysomnography can provide confirmatory diagnostic evidence in cases of sleep apnea, narcolepsy, periodic limb movements, nocturnal seizures, and sleep terrors and helps determine the severity of these conditions. Its use in the evaluation of insomnia is somewhat controversial but may be beneficial, especially when sleep apnea, periodic limb movements, or sleep state misperception is suspected. The Multiple Sleep Latency Test, described in Chapters 59 and 143, can confirm excessive sleepiness, quantify its severity, and determine the pathologically early onset of REM sleep. This test is used the day after polysomnography. Ambulatory sleep–wake recordings, wrist actigraphy, portable monitoring devices that record esophageal acidity, electrocardiography, and extended electroencephalography with video monitoring are useful in selected patients.8
CONCLUSION Sleep disorders are prevalent in the general population and are common in patients who consult with physicians and other health care providers. Patients with complaints of sleep disturbance often present a diagnostic challenge to the clinician because of the many possible causes of symptoms and the patient’s inability to describe accurately events occurring during sleep. A systematic evaluation usually yields a provisional diagnosis or a set of diagnostic possibilities that can be confirmed or excluded with specific diagnostic tests. With accurate diagnosis and specific interventions, most sleep disorders are treatable. ❖ Clinical Pearl A complete sleep and medical history often yields a specific cause of the patient’s sleep complaint. For example, in patients complaining of excessive daytime sleepiness, the cause can often be pinpointed by close attention to the patient’s (and bed partner’s) account of nighttime symptoms, bedtime and wake time schedules, medications, and coexisting medical disorders.
REFERENCES 1. Anic-Labat S, Guilleminault C, Kraemer HC, Meehan J, et al. Validation of a cataplexy questionnaire in 983 sleep-disorders patients. Sleep 1999;22:77-87. 2. Gyllenhall C, Merritt SL, Peterson SD, Block KI, et al. Efficacy and safety of herbal stimulants and sedatives in sleep disorders. Sleep Med Rev 2000;4:229-251. 3. Yates KM, O’Connor A, Horsley CA. “Herbal ecstasy”: a case series of adverse reactions. N Z Med J 2000;113:315-317. 4. Giannini AJ. An approach to drug abuse, intoxication, and withdrawal. Am Fam Physician 2000;61:2763-2774. 5. Hublin C, Kaprio J. Genetic aspects and genetic epidemiology of parasomnias. Sleep Med Rev 2003;7:413-421. 6. Kryger MH, Otake K, Foerster J. Low body stores of iron and restless legs syndrome: a correctable cause of insomnia in adolescents and teenagers. Sleep Med 2002;3:127-132. 7. Kryger MH, Shepertycky M, Foerseter J, Manfreda J. Sleep disorders in repeat blood donors. Sleep 2003;26:625-626. 8. Collop NA. Portable monitoring for the diagnosis of obstructive sleep apnea. Curr Opin Pulm Med 2008;14:525-529.
Cardinal Manifestations of Sleep Disorders Bradley V. Vaughn and O’Neill F. D’Cruz Abstract Sleep disorders include a wide range of disorders that impair health and quality of life. Clinicians must efficiently identify individuals with sleep disorders and direct effective treatment of these disorders. The fundamental symptoms of sleep disorders include insomnia, hypersomnia, and unusual sleeprelated behaviors, but more subtle signs and symptoms may also provide clues to an underlying sleep dysfunction. Insomnia, a symptom of difficulty initiating or maintaining sleep with daytime sequelae, can be related to many contributing factors. Features that predispose to, precipitate, and perpetuate the insomnia can be identified in individuals who suffer from primary and secondary insomnias. Insomnia can have an intricate relationship to other medical and psychiatric disorders. Hypersomnia, often associated with excessive daytime sleepiness, consists of sleep propensity during the wake period. Sleepiness can be subjectively and objectively quantified to give clues differentiating this symptom from fatigue.
Sleep is essential to health, restoring properties that promote wakefulness and a sense of well-being. Sleep disturbance, however, frequently disrupts this sense of wellbeing and can result in a wide range of systemic and psychological symptoms. Sleep disruption frequently is manifested as intrusion of components of the sleep state into periods of wakefulness or vice versa. Beyond the medical manifestations, sleep disruption may impair work performance and psychosocial interactions. As we realize the connection of sleep to good health, we also recognize that sleep disruption may exacerbate symptoms of other diseases. These manifestations may present as worsening of a preexisting disorder or impairment of the patient’s ability to cope with its symptoms. The challenge for physicians is to recognize these manifestations and appropriately delineate them as related to dysfunction of sleep. Most patients referred to sleep centers present with one or a combination of three classic complaints: excessive sleepiness, difficulty attaining or sustaining sleep, or unusual events associated with sleep. These symptoms can be easily recognized as related to sleep and are not mutually exclusive. Patients may note more than one problem, such as difficulty sleeping at night and excessive sleepiness during the day. Others may complain of unusual events at night with daytime sleepiness or inability to sleep. Each of these symptoms conveys clues to the underlying pathologic process (Figs. 57-1 to 57-3). In this chapter, we review the cardinal manifestations of sleep disorders and address some of the key features that guide the clinician to pursue further diagnostic evaluations.
INSOMNIA Insomnia is the complaint of difficulty initiating or maintaining sleep or of unrefreshing sleep combined with daytime sequelae. This combination of poor nighttime
Chapter
57
Other symptoms, such as snoring, apnea, and morning headache, may indicate potential sleep-related breathing disorders or other medical problems. Cataplexy, as a symptom of sudden loss of muscle tone in relation to an emotional trigger, rarely occurs in isolation. In combination with excessive sleepiness, cataplexy should prompt an evaluation for narcolepsy. Restless legs syndrome, associated with discomfort and the urge to move extremities during periods of inactivity, is worse in the evenings and relieved with movement. Periodic limb movements in sleep can occur in association with restless legs syndrome and may involve movements of the upper or lower extremities. Other parasomnias, such as sleepwalking, sleep terrors, and dream enactment, require detailed description of the sleep-related behaviors to help differentiate potential causes. In this chapter, we review the major symptoms, discuss the physical findings, and highlight some of the key features of sleep disorders.
sleep with an adverse effect on daytime activities is important to establishment of the complaint as insomnia. The daytime manifestations of insomnia may take the form of excessive fatigue, impairment of performance, or emotional change. Individual sleep need may vary significantly. Some people may feel fine and note no impairment of performance with 5 hours of sleep per night, whereas others may need more than 9 hours to preserve daytime functioning. Thus, the requirement of daytime sequelae differentiates individual sleep need from the complaint of insomnia. Most people have an occasional night fraught with difficulty falling asleep or trouble maintaining sleep. These occasional nights might be closely linked to the surrounding events of the day, psychological challenges, or sudden changes in environment or medical condition. Surveys have shown that approximately 35% of individuals complain that their sleep is disrupted and that a smaller group, of approximately 10%, have a more persistent insomnia.1 For these patients, lack of “good-quality” sleep produces a greater disruption of life and may lead to more significant medical symptoms. As a symptom, insomnia is directly related to the patient’s perception of poor sleep. Patients with insomnia believe that the sleep disruption produces their excessive sleepiness, fatigue, lack of concentration, muscle aches, and depression. Patients with insomnia frequently will describe themselves as tense, anxious, nervous, tired, irritable, unable to relax, obsessively worried, and depressed. Many of these traits may predate the onset of the insomnia, but others may occur after the onset of the poor sleep. These individuals also believe that a good night’s sleep would reverse their symptoms. Patients with insomnia frequently give historical clues directed toward the mechanisms behind their insomnia. The symptom complex may indicate an underlying 647
648 PART II / Section 8 • Impact, Presentation, and Diagnosis
Excessive daytime sleepiness Circadian rhythm disturbance
Intrinsic sleep mechanism disorder
Sleep disturbance
Advanced sleep phase Delayed sleep phase Irregular sleep type Free running Shift work
Intrinsic issue
Extrinsic issue
Sleep apnea PLMD Hypoventilation GERD Pain CHF
Noise Temperature Light Bedding Allergen Bedpartners
Narcolepsy with cataplexy Narcolepsy without cataplexy Idiopathic hypersomnia Klein Levine Neurological disorders
Secondary to: Medications Herbs and supplements Recreational drugs Other medical disorders
Sleep deprivation
Fatigue
Volitional timing Work schedule Poor time management
Psychiatric and other medical issues
Figure 57-1 Diagnostic flow chart to approach excessive daytime sleepiness. CHF, congestive heart failure; GERD, gastroesophageal reflux disease; PLMD, periodic limb movement disorder.
Insomnia Sleep disturbance
Circadian rhythm disturbance
Advanced sleep phase Delayed sleep phase Irregular sleep type Free running Shift work
Intrinsic disturbances
Extrinsic issues (sleep hygiene)
Sleep apnea RLS Hypoventilation GERD Pain CHF Other medical disorders
Noise Temperature Light Bedding Allergen Bedpartners
Intrinsic sleep mechanism disorder
Idiopathis insomnia Paradoxical insomnia Psychophysiological insomnia
Secondary to: Medications Herbs and supplements Recreational drugs Other medical disorders
Psychiatric disorders
Psychological issues
Depression Anxiety Bipolar disorder PTSD Adjustment disorder
Sleep phobia Maladaptive behaviors or beliefs
Figure 57-2 Diagnostic flow chart to approach insomnia. CHF, congestive heart failure; GERD, gastroesophageal reflux disease; PTSD, posttraumatic stress disorder; RLS, restless legs syndrome.
Unusual events at night NREMrelated disorders
Sleep walking Sleep terrors Confusional arousals Sleep-related eating disorder
Evoked by: Sleep apnea RLS Hypoventilation GERD Pain CHF Other issues causing partial arousals
REMrelated disorders
Other parasomnias
Nightmares REM sleep behavior disorder Sleep paralysis
Exploding head syndrome Sleep-related hallucinations Catathrenia Enuresis
Movement disorders
Psychiatric disorders
Periodic limb Sleep-related movements dissociative Rhythmical move- disorder ment disorder Panic attacks Bruxism Leg cramps
Neurological issues
Epilepsy Encephalopathynocturnal confusion
Figure 57-3 Diagnostic flow chart to approach unusual nocturnal events. CHF, congestive heart failure; GERD, gastroesophageal reflux disease; NREM, non–rapid eye movement; REM, rapid eye movement; RLS, restless legs syndrome.
disorder related to primary failure of the sleep mechanics or one in which sleep disruption is the byproduct of another disorder. As sleep is an active process, neuronal networks involved with sleep induction must be engaged and networks involved in wakefulness must be diminished for sleep. Rarely do patients have just one factor responsible for their chronic insomnia. Most patients have factors
that put them at risk for development of insomnia, for initiation of the insomnia, and for perpetuation of the insomnia. The presence of predisposing, precipitating, and perpetuating factors emphasizes the nature of insomnia as an ongoing process, and clinicians need to search for these contributing factors to outline an effective treatment course (see Chapters 75, 77, and 78).
Epidemiologically, insomnia appears to be more common in women, older individuals, and those with psychiatric or chronic medical illness. Insomnia is also more common in those with lower socioeconomic status and poor education. Behavioral traits such as obsessivecompulsive nature, frequent rumination, and poor coping strategies and “hyperalert” individuals are correlated with greater risk for insomnia. “Hyperarousal” documented on recent neuroimaging studies may explain the neurophysiologic basis of these associated factors predisposing to chronic insomnia. Insomnia may be initiated by sudden changes in environment or challenges to the body or mind. These challenges may come in the form of acute medical illness, psychological or psychiatric events, shift in schedule, or changes in medications or supplements. Initiating events may play little role in the patient’s current ongoing process but give important clues to preventing further recurrence of the insomnia. Many patients, attempting to improve their sleep, will adopt behaviors that actually perpetuate the insomnia. Patients may employ rituals and endorse “remedies” that convert the short-term insomnia into a chronic form. During this evolution, the patient may take on changes in sleep schedule, depend on certain somnogenic substances, or develop secondary medical or psychological issues. Many of these behaviors conflict with typical sleep hygiene practices, producing an environment detrimental to sleep. Such maladaptive habits may occur during the day or night and include issues such as heavy caffeine or alcohol use, watching television or playing video games while in bed, and even eating or exercising during the usual sleep period. Some patients will describe that television or radio distracts them from intrusive thoughts. Others may develop sleep associations to counterbalance negative events. A subgroup of patients actually fear going to bed or have performance anxiety over the oncoming sleep period. This expectation of poor sleep promotes the apprehension toward sleep and may perpetuate counterproductive sleep rituals. These maladaptive behaviors become the predominant feature of psychophysiologic insomnia. Timing of the insomnia during the sleep period may also be helpful. Circadian rhythm disorders can masquerade as complaints of insomnia or excessive sleepiness, and patients with insomnia may develop dysfunction of their circadian rhythm. Difficulty with the onset of sleep suggests an underlying delayed sleep phase or occasionally depression in younger adults. Insomnia with early morning arousal raises the possibility of underlying depression or advanced sleep phase. Schedule changes, such as from jet lag or shift work, are important clues, and sleep diaries of bedtime and wake time can be useful in determining potential links to schedule or circadian rhythm issues. Perception of good sleep is an important factor in evaluating the complaint of insomnia. Some patients exaggerate their symptoms, whereas other patients may not perceive that they are asleep. Paradoxical insomnia is one form of the primary insomnias. Individuals who have this disorder display the normal physiologic parameters of sleep but do not recognize that they have slept. Other patients may endorse unrealistic expectations or unobtainable goals. Patients may assume that sleep should not be
CHAPTER 57 • Cardinal Manifestations of Sleep Disorders 649
interrupted by any arousals or that one must sleep a set number of hours. These beliefs can be easily addressed with education of the patient. Another primary insomnia, idiopathic insomnia, is not associated with clear inciting factors. These individuals usually have lifelong difficulty of sleep and may have significant family history. These primary insomnias are discussed further in Chapters 75 and 77. Medical or neurologic disorders may precipitate and perpetuate insomnia. Derangement of almost any system in the body can disrupt sleep. Patients with heart, liver, or renal failure or disturbances of the gastrointestinal system or pulmonary disease commonly complain of insomnia. Patients with fulminant rash or significant burns frequently note disturbed sleep, and urologic issues such as nocturia may provoke frequent arousals. Neurologic disorders also promote sleep disruption. Patients with neuromuscular disorders may have discomfort or inadequate ventilation at night that provokes insomnia. Some patients with stroke will note insomnia or sleep disruption after their vascular event. Paralysis from central or peripheral nervous system disorders can result in nighttime discomfort from inability to move. Patients with Parkinson’s disease may have akinesis, tremor, or medication effect, and patients with dementia may have circadian abnormalities that promote awakenings at night. Pain can disturb sleep and promotes insomnia. Musculoskeletal discomfort may become worse with periods of rest. Pain from entrapment neuropathies, such as carpal tunnel syndrome, is typically worse at night; headaches, such as cluster headache, and even pain related to increased intracranial pressure or brain mass lesions can become more intense during sleep. Restless legs produce significant discomfort and are classically worse in the evening, before the onset of sleep. Arthritis and other rheumatologic disorders frequently can disrupt sleep by increasing nighttime pain and stiffness. Nearly all of the psychiatric illnesses have some link to poor sleep. Patients with depression or anxiety disorders may have insomnia years before the presentation of the affective component. Although the cause and effect are still in debate, the association is clear. Insomnia may herald the onset of psychosis or mania. The clinician may uncover few physical findings in patients with insomnia. Anxious or hyperalert individuals may demonstrate mild tachycardia, rapid respiratory rate, or cold hands. These individuals may startle easily or be easily distracted during the interview. The clinician should look carefully for signs of obstructive sleep apnea, narrow airway, and obesity because these too can be manifested as insomnia. Signs of Cushing’s syndrome (round face and buffalo hump) or hyperthyroidism (tachycardia and excessive sweating) are important clues to an endocrine disorder. Each patient with insomnia should have a complete neurologic examination to look for potential neurologic lesions impairing sleep. This examination should include an assessment of cognition, mood, and affect. The Mini Mental State Examination is one tool that helps assess cognitive abilities and can be followed over time.2 Clinicians can also use the Minnesota Multiphasic Personality Inventory to identify personality and affect issues.
650 PART II / Section 8 • Impact, Presentation, and Diagnosis
EXCESSIVE DAYTIME SLEEPINESS Sleepiness is a common symptom noted by 5% to 20% of individuals.3,4 Most individuals can relate some instances of falling asleep when they intended to be awake. Sleepiness is a normal feeling as one approaches a typical sleep period or after prolonged wakefulness. Excessive sleepiness occurs when one enters sleep at an inappropriate setting or has episodes of unintentional sleep. Excessive sleepiness can occur in degrees. In mild sleepiness, one might fall asleep while reading a book or while sitting quietly. This degree of sleepiness may produce only limited impairment in the person’s perceived quality of life. Greater degrees of sleepiness may be associated with bouts of irresistible sleep or sleep attacks. Irresistible sleep may intrude on such activities as driving, having a conversation, or eating meals. This degree of sleepiness may place the patient at significant risk for accidents and have a major impact on the person’s health and sense of well-being. As with other subjective symptoms, an individual’s perception of sleepiness influences the complaint. Some patients may overreport the degree of sleepiness and note sleepiness even during periods of normal wakefulness. Other individuals may underreport and not recognize periods of sleepiness. For some of these individuals, sleepiness may be described as periods of lapse of attention or diminished cognitive abilities, such as missing an exit on the highway or brief delay in performing a task. Perception of sleepiness is also reduced with continued sleep deprivation. Individuals who are chronically sleep deprived become accustomed to their impairment and are less likely to recognize their degree of sleepiness. Clinicians should always question their hypersomnic patients for clues of potential sleep debt, dyssomnia, or medical or psychiatric causes. Sleep deprivation is common in our society, and patients should be queried about their schedule during the week and weekends. Information about sleep habits and environment may disclose important factors contributing to the sleepiness. Excessive sleepiness may result from a wide range of medical disorders and medication. Patients with heart, kidney, or liver failure and rheumatologic or endocrinologic disorders such as hypothyroidism and diabetes may note sleepiness and fatigue. Neurologic disorders, such as strokes, tumors, demyelinating diseases, and head trauma, can evoke excessive sleepiness. Sleepiness is frequently the cardinal symptom of many sleep disorders. Patients with sleep apnea and narcolepsy, restless legs syndrome– periodic limb movements, and even parasomnias may note excessive daytime sleepiness as their main complaint. Historical features of snoring, observed apneas, morning headaches, cataplexy, sleep paralysis, hypnagogic hallucinations, and confusion on arousals suggest contributions of a specific sleep disorder. Individuals with idiopathic hypersomnolence have unrelenting daytime sleepiness despite prolonged periods of sleep, which differentiates this disorder from sleep deprivation. Physical findings are few in patients with sleepiness. Frequent pauses, slowed responses, drooping eyelids, and repetitive yawning support the complaint of sleepiness. Patients may be asleep when the clinician enters the examination room, and some patients may show signs of chronic
sleepiness, such as dark circles under the eyes. The patient’s neurologic examination may show findings of inattentiveness or even brief “microsleeps.” Sleepiness can be quantified subjectively by questionnaires or by physiologic measures such as a multiple sleep latency test. The Epworth Sleepiness Scale is one example of a quantifiable subjective measure of sleepiness and has been translated into several languages (Table 57-1).5 In this scale, the individual is asked to rate on a scale of 0 to 3 (0, no chance; 3, high likelihood) the chance of dozing in a series of eight situations. This score has a modest correlation with physiologic measures of sleep but has a better correlation with the respiratory disturbance index in patients with obstructive sleep apnea (Table 57-2). Two quantitative tests exist to measure ability to fall asleep and to stay awake: Multiple Sleep Latency Test (MSLT) and Maintenance of Wakefulness Test (MWT). The MSLT quantifies objective sleepiness on the basis of the time to onset of physiologic changes associated with sleep. These changes include the absence of eye blinks, slow eye movements, slowing of the background electroencephalographic activity, and reduction in heart rate and respiration. The MSLT uses these physiologic markers to quantify the time to sleep. Unfortunately, the MSLT is not well correlated with daytime function, and there is significant overlap between individuals deemed “normal” and those deemed to have sleep disruption. The MSLT is a useful test for narcolepsy. The MWT quantifies the propensity to stay awake across four attempts in a dimly lit room. This test has not been extensively tested in relationship to daytime function. These tests are covered in greater detail in Chapter 143.
FATIGUE Many patients with excessive daytime sleepiness note fatigue and decreased energy. Patients may be aware of the lack of energy and not perceive the degree of sleepiness or confuse the symptom of fatigue with excessive sleepiness. These patients may not have an increased ability to fall asleep but believe that a good night’s sleep would improve their lack of energy. Although frequently noted in combination, fatigue is distinct from excessive sleepiness. The complaint of fatigue is a complex symptom related to the perception of lack of energy. Distinguishing sleepiness from fatigue can be difficult even for the most astute clinicians, but multiple sleep latency testing can be helpful. Patients with insomnia frequently complain of fatigue related to disrupted sleep. Fatigue can also be associated with a wide range of causes, separate from sleep disruption. Endocrinologic and metabolic disorders such as diabetes mellitus, cardiac failure, renal failure, liver failure, post– organ transplantation, and psychiatric disease such as depression can be associated with fatigue without sleepiness. SNORING Snoring is the sound created by turbulent airflow vibrating upper airway soft tissue. Usually more prominent during inspiration, snoring occurs in approximately 32% of adults and in more than 7% of children.6,7 Many adults have little
CHAPTER 57 • Cardinal Manifestations of Sleep Disorders 651
Table 57-1 The Epworth Sleepiness Scale Name: _____________________________________________________________________________________________________________________ Today’s date: ______________________________________________ Your age (years): ______________________________________________ Your sex (male = M; female = F): _____________________________________________________________________________________________ How likely are you to doze off or fall asleep in the following situations, in contrast to feeling just tired? This refers to your usual way of life in recent times. Even if you have not done some of these things recently, try to work out how they would have affected you. Use the following scale to choose the most appropriate number for each situation: 0 = would never doze 1 = slight chance of dozing 2 = moderate chance of dozing 3 = high chance of dozing SITUATION*
CHANCE OF DOZING
Sitting and reading
________
Watching TV
________
Sitting, inactive in a public place (e.g., a theater or a meeting)
________
As a passenger in a car for an hour without a break
________
Lying down to rest in the afternoon when circumstances permit
________
Sitting and talking to someone
________
Sitting quietly after a lunch without alcohol
________
In a car, while stopped for a few minutes in traffic
________
Thank you for your cooperation. *The numbers for the eight situations are added together to give a global score between 0 and 24. From Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991;14:540-545.
Table 57-2 Scores for Various Conditions: Ages and Epworth Sleepiness Scale Scores of Experimental Subjects AGE IN YEARS (MEAN ± SD)
EPWORTH SLEEPINESS SCALE SCORES (MEAN ± SD)
RANGE
SUBJECTS/DIAGNOSES
TOTAL NUMBER OF SUBJECTS (M/F)
Healthy control subjects
30 (14/16)
36.4 ± 9.9
5.9 ± 2.2
2-10
Primary snoring
32 (29/3)
45.7 ± 10.7
6.5 ± 3.0
0-11
Obstructive sleep apnea syndrome
55 (53/2)
48.4 ± 10.7
11.7 ± 4.6
4-23
Narcolepsy
13 (8/5)
46.6 ± 12.0
17.5 ± 3.5
13-23
Idiopathic hypersomnia
14 (8/6)
41.4 ± 14.0
17.9 ± 3.1
12-24
Insomnia
16 (6/12)
40.3 ± 14.6
2.2 ± 2.0
0-6
Periodic limb movement disorder
18 (16/2)
52.5 ± 10.3
9.2 ± 4.0
2-16
SD, standard deviation. From Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991;14:540-545.
knowledge or recognition of their snoring habits, and accounts from bed partners may be more helpful for the clinician. Snoring is usually worse in the supine position, after sleep deprivation or alcohol ingestion. Loud snoring may not disturb sound sleepers, but some patients may report complaints from family members and even neighbors. Snoring may continue for decades. Persistent loud snoring is a classic symptom of obstructive sleep apnea syndrome, but the absence of snoring does not exclude the diagnosis of apnea. Some patients have airway dynamics that are not conducive to production of snoring. This is especially true in patients who have had upper airway surgical procedures that eliminated flaccid tissue that can vibrate. Other individuals, such as those with neuromuscular disorders, may not generate enough force to produce turbulent airflow.
Snoring, for many people, produces little disruption in their lives, but snoring may have implications on overall health. Individuals who snore have a greater risk of vascular disease. Witnesses may be able to account for snoring occurring in bursts or associated with snorts, gasps, choking, body jerks, and movements. Patients may recall being awoken by their own gasps and relay symptoms of gastroesophageal reflux. These associated symptoms raise the suspicion of obstructive sleep apnea.
SLEEP APNEA Apnea is the absence of ventilation. In the sleep laboratory, apneas are defined by the cessation of breathing for more than 10 seconds and are usually associated with oxygen desaturation and arousal.8 Patients’ bed partners note that
652 PART II / Section 8 • Impact, Presentation, and Diagnosis Table 57-3 Key Features of the Berlin Questionnaire Height ________________________
Age ___________________
Weight ____________________
Gender _______________
Has your weight changed in the last 5 years?
Increase Decreased No change
Do you snore?
Yes No Do not know
Your snoring is
Slightly louder than breathing As loud as talking Louder than talking Very loud
How often do you snore?
Nearly every day 3 to 4 times per week 1 to 2 times per week 1 to 2 times per month Never or almost never
Has your snoring bothered other people?
Yes No
Has anyone noticed that you quit breathing during your sleep?
Almost every day 3 to 4 times per week 1 to 2 times per week 1 to 2 times per month Never or almost never
Are you tired or fatigued after your sleep?
Nearly every day 3 to 4 times per week 1 to 2 times per week 1 to 2 times per month Never or almost never
During your wake time, do you feel tired, fatigued, or not up to par?
Nearly every day 3 to 4 times per week 1 to 2 times per week 1 to 2 times per month Never or almost never
Have you ever fallen asleep while driving?
Yes No If so, how often does it occur? Nearly every day 3 to 4 times per week 1 to 2 times per week 1 to 2 times per month Never or almost never
Do you have high blood pressure?
Yes No Do not know
Modified from the Berlin Questionnaire; from the editors of Sleep and Breathing 2000;4:187-192, with the permission of Kingman P. Strohl.
the breathing has stopped or that the individual “holds their breath.” The events are aborted with a loud gasp, a snort, or the resumption of breathing. Some patients may have hundreds of events in a single night and are unable to obtain quality sleep because of the frequent arousals. These individuals are typically unaware of the arousals, but some may report occasional awakening with the gasp or snorts. Sleep apnea is classified in two major forms: obstructive and central. Obstructive apnea is the most common form of sleep apnea. These apneas are due to obstruction in the upper airway and more commonly noted during stage N1, N2, or rapid eye movement (REM) sleep. Snoring is a frequent associated complaint, but a wide variety of symptoms may be present. Some questionnaires, such as the Sleep Apnea
section of the Sleep Disorder Questionnaire or the Berlin Questionnaire inventory, a combination of items regarding snoring, witnessed apneas, body habitus, and associated disorders such as hypertension (Table 57-3),9,10 provide a summary score that correlates with presence of obstructive sleep apnea, but the questionnaires have been tested only in selected populations. Thus, the questionnaires themselves require further study and may not be appropriate for broad clinical use. The topics inventoried, however, are important and provide basic information intrinsic to the diagnosis. Astute clinicians should not exclude patients on the basis of a low score on a questionnaire. The physical examination may show structural evidence for airway obstruction. Many patients are obese and have a large neck or crowded upper airway, yet some have a normal body
habitus. Common structural abnormalities, such as narrow nasal passage, long soft palate, large tonsils, or retroflexed mandible leading to a small airway, contribute to airway obstruction. Sleep apnea is associated with significant health risks and lowers the quality of life of both the patient and bed partner. Recent evidence from the Sleep Heart Health Study indicates that hypopneas with 4% oxygen desaturation correlate with greater risk of vascular disease.11 These are discussed in greater detail in Chapter 116. Central apnea is the absence of ventilation without an effort to breathe. These patients have pauses in respiration also associated with oxygen desaturation and arousals. Central apneas can be caused by a neurologic abnormality in the brainstem or other areas involved in regulation of respiration. Cheyne-Stokes breathing can have features of both central and obstructive apnea. The classic pattern of crescendo-decrescendo breathing with a central apnea can be seen in individuals with heart failure, neurologic lesions, and metabolic or toxic encephalopathies. This pattern may be present only in sleep and signal underlying disease. Apneas may follow other neurologic events, such as nocturnal seizures, and are more prevalent after acute strokes and seizures. Central apnea is reviewed in Chapter 100.
MORNING HEADACHE Morning headache is a common symptom. More than 70% of the population has occasional headache; this symptom is relatively nonspecific. Morning headache is more specifically linked to sleep dysfunction. Characteristics of the headache, such as location, quality, and nature of pain, and potential associations can aid in determining the etiology. Approximately half of patients with obstructive sleep apnea and hypoventilation note morning headache that is usually dull and generalized and clears within an hour of waking. Patients with chronic obstructive pulmonary disease and obstructive sleep apnea may develop morning headache from the increase in carbon dioxide, low oxygen saturation, or vascular changes. Headache that awakens patients from sleep should always suggest further evaluation, potentially including head imaging. Patients with brain tumors frequently note worsening of headache at night. Patients with sinus disorders, muscle contraction headache, post–alcohol intake, and withdrawal from medication (rebound headache) may have distinct patterns. Cluster headaches are noted to occur in REM sleep. Hypnic headaches are brief sharp pains that awaken the patient.12 Headaches in sleep are discussed in greater detail in Chapter 126. CATAPLEXY Cataplexy is the abrupt loss of muscle tone triggered by strong emotional stimuli or physical exercise. Patients are aware of their surroundings and have clear memory for the complete events. Events can be triggered by a joke, surprise, anger, fear, or athletic endeavors. Individual experiences vary from a mild feeling of weakness to severe falls. Cataplectic attacks start during several seconds and may start with brief waves initially. Most symptoms start in the face and neck and then progress to the rest of the body. The events are generally brief, lasting less than 5 minutes.
CHAPTER 57 • Cardinal Manifestations of Sleep Disorders 653
Patients then regain muscle control and have no postictal confusion or deficits. Longer events may be ended with the patient’s entering sleep and then awakening. Examination of the patient during the cataplectic attack will demonstrate paralysis with diffuse hypotonia, absence of deep tendon reflexes, diminished corneal reflexes, preserved pupillary responses, and phasic muscle twitching. Phasic muscle twitching can occur as single jerks or repetitive muscle twitching and is most frequently seen in the face. The combination of excessive daytime sleepiness and cataplexy is nearly always related to narcolepsy. Cataplexy can rarely be seen as an isolated symptom suggestive of an underlying neurologic disorder. Maintenance of consciousness and memory helps differentiate these events from most seizures and syncope. The historical feature of clear emotional triggers differentiates cataplexy from vertebral basilar insufficiency and the group of neuromuscular disorders known to produce periodic paralysis. Cataplexy also is differentiated from myasthenia gravis by the abrupt onset and absence of muscle fatigue with repetitive stimulation that is typical of myasthenia gravis.
SLEEP PARALYSIS Sleep paralysis is an inability to move during the transition into or out of sleep. The association with intentional sleep distinguishes these events from cataplexy. Patients may describe complete awareness of their surroundings or feeling partially asleep with awareness but be unable to move even their fingers or to speak. Patients may try to scream but produce only a whisper. Some individuals will describe a feeling of suffocation and be able to resume breathing only when the event has passed. Patients frequently describe a strong feeling of impending doom, being chased, or having to escape imminent danger. On occasion, patients may note the feeling that someone else is in the bedroom. Auditory and tactile hallucinations may accompany the events, and patients may recount dramatic stories. These events can be emotionally profound and leave a lasting memory that patients vividly recall years later. Most sleep paralysis episodes last a few minutes and usually end after the patient is touched or is alerted to a sound. If the event is allowed to persist, the patient usually reenters sleep and awakens later. These events are experienced by many individuals after severe sleep deprivation, schedule disruption, or ingestion of alcohol and may be more frequently seen in patients with narcolepsy or depression. HYPNAGOGIC AND HYPNOPOMPIC HALLUCINATIONS Hallucinations can occur with sleep onset (hypnagogic) or at the end of sleep (hypnopompic). These hallucinations may include visual, auditory, or tactile components and may last seconds to minutes. The events occur at the transition between wake and sleep and incorporate some dreamlike features. They can be relatively pleasant or very terrifying and difficult to distinguish from reality. Patients may note a feeling of weightlessness, falling, flying, or outof-body experiences and may sometimes terminate with a sudden jerk (hypnic jerk). Visual hallucinations may be
654 PART II / Section 8 • Impact, Presentation, and Diagnosis
described as poorly formed colors and shapes or wellformed images of people and animals. The events are aborted once the patient awakens. Exploding head syndrome is a loud painless sound of explosion that occurs near sleep onset. This parasomnia is benign and may be associated with a hallucinatory flash of light. In the face of excessive daytime sleepiness, patients with hypnagogic hallucinations should be evaluated for narcolepsy. These events may be repetitive but are not usually stereotypical. This lack of stereotypical feature distinguishes these events from seizures. Individuals may experience these events after sleep deprivation or change in sleep schedule. Alcohol ingestion or withdrawal of REM suppressants may also evoke these events. The relationship of sleep to these hallucinations distinguishes them from hallucinations of psychosis and dementia. Hypnagogic hallucinations are shorter in duration than peduncular hallucinations.
AUTOMATIC BEHAVIOR Automatic behavior is purposeful but inappropriate activities that occur with the patient partially asleep. Patients relay stories of putting milk containers in the microwave oven, cereal bowls in the dryer, or even missing an exit on the highway. Sleep-deprived soldiers have been reported to continue marching in the wrong direction. Patients appear drowsy or groggy during the event and are usually partially or totally amnestic for the actual happenings. Events may last minutes to hours. They are more common in individuals with idiopathic hypersomnolence or narcolepsy but are also common in patients with delayed sleep phase. Most events are associated with non–rapid eye movement (NREM) sleep, but REM activity is witnessed in patients with narcolepsy. These events are distinguished from seizures by the lack of stereotypical behavior. Automatisms associated with seizures are usually stereotyped and repetitive, such as picking, rubbing, or lip smacking. Patients with sleeprelated automatic behavior appear sleepy but can be alerted and answer questions appropriately, in contrast to postictal confusion and metabolic or toxic encephalopathy. The quick return of orientation with a lack of bewilderment and anxiety also differentiates this from transient global amnesia. EXCESSIVE MOVEMENT IN SLEEP OR PARASOMNIA Individuals and bed partners may complain of frequent movement during the sleep period. In part, this complaint may be more concerning to the bed partner than to the patient. This is also a common complaint among patients who complain of insomnia and individuals with sleep apnea. Some individuals will complain of being active sleepers and imply that they are mentally active or have inability to turn off their mind. These individuals need an evaluation focusing on features of insomnia. Those who are physically active need evaluation for the movements or parasomnia. Parasomnia refers to undesirable physical or behavioral phenomena that occur predominantly during sleep. They
include disorders of arousals, such as sleepwalking and night terrors; sleep–wake transition disorders, such as sleeptalking and rhythmic movement disorder (e.g., head banging); and REM parasomnias, such as REM sleep behavior disorder. These behavioral events may mimic epileptic seizures or other psychiatric events. The parasomnias are covered in greater detail in Chapters 94 to 99. Key features of age at onset, time of night of the events, memory for the events, and family history are important in historically distinguishing the etiology of parasomnias. Stereotypical behavior, recurrence of the same behavior with each event, can also help in categorizing the events. Events such as periodic limb movements, rhythmic movement disorder, and epileptic seizures are stereotypical, whereas sleeptalking, sleepwalking, night terrors, and dream enactment incur different behavior with each event. Although historical features can be useful in distinguishing these disorders, most patients require polysomnographic recording to delineate the cause. Sleeptalking Sleeptalking is a relatively frequent event of utterances to coherent conversation during sleep. This usually occurs in the lighter stages of NREM sleep but can occur in REM (stage R) sleep. The patients have no memory of the events and may convey information that may have little resemblance to the truth. Sleeptalking in the absence of other sleep disturbances is of little medical concern. Sleepwalking Sleepwalking events are partial arousals typically from slow-wave sleep (stage N3) occurring during the first half of the sleep period. The events can be minor behaviors and movement or elaborate behaviors including dressing, unlocking locks, minor tasks, and even driving. Patients usually have little or no memory for the event. Patients can recall various feelings or impressions from the events, and some imagery is more common in adults. The patients do not exhibit significant tachycardia, sweating, or expression of fear. The lack of screaming and autonomic features differentiates sleepwalking from sleep terrors. Both children and adults with a history of recent sleepwalking should be questioned for signs of other sleep disorders. Any disorder evoking arousals may increase the likelihood of these events, and so patients should be carefully questioned for symptoms of other sleep disorders. Patients typically have normal neurologic examination findings during wakefulness. Sleep Terrors Sleep terrors are a more intense form of disorder of arousal with a predominance of autonomic expression. Witnesses rarely forget the patient’s sudden arousal accompanied by a piercing scream or cry, autonomic output, and behavioral manifestation of intense fear. The onset of the events is abrupt, and patients have tachycardia, tachypnea, flushing, diaphoresis, and mydriasis. The patients are confused and disoriented, and attempts to intercede may result in prolongation of the event and potential harm to the person trying to wake the patient. Patients can become violent, resulting in injury to the patient and bed partners. Less
than 1% of adults may have these events.13 They typically occur in the first third of the night, and patients have no memory for the events. Patients typically have a normal diurnal neurologic examination, and as with sleepwalking, patients should be questioned for the presence of other sleep disorders. Confusional Arousals and Sleep Drunkenness Confusional arousals can occur during any arousal from NREM sleep. These events are characterized by disorientation, slow speech and mentation, or inappropriate behavior. The patients have memory impairment for the event, and the events can be induced with forced arousal. The course of these events usually becomes less frequent with age but may remain stable in adulthood. Sleep drunkenness refers to inability to attain full alertness after an extended time of sleep. Patients are drowsy and disoriented and show signs of poor coordination. Patients with these events may note rising from a deep sleep feeling tired and having poor ability to concentrate and automatic behavior. This can be associated with dysfunction of the arousal system, such as is seen in idiopathic hypersomnolence, and patients should have a neurologic examination to look for a central nervous system process if these symptoms persist. Patients may have other behaviors that focus on specific themes. One group of individuals may have eating as sleep-related events as seen in sleep-related eating disorder. These patients will eat high-calorie, sometimes bizarre foods and have no or little memory. They have morning anorexia and unexplained weight gain. Another group may report episodes of sexual intercourse during sleep. Again, these individuals relate no memory for their events. Sleep-Related Groaning (Catathrenia) Rarely, patients or families may present because of repetitive nocturnal groaning. Bed partners usually express concern because the patients have long expiratory groans that sound mournful. The patient usually has no recollection of the sound nor any distress. Patients may have morning hoarseness, but no other detectable abnormalities are found on physical examination. These groaning events have been compared with central apneas.14 Dream-Related Movement REM sleep (stage R) is characterized by diffuse muscle atonia. Typically, only brief phasic muscle activity is noted during REM sleep. Some individuals or bed partners may note dream enactment behavior. These behaviors can include punching, kicking, leaping, running, talking, yelling, and any behavior that could occur during a dream. Bed partners are frequently injured, and patients may go to great lengths to prevent injury to themselves or bed partners. This dream enactment is commonly seen in REM sleep behavior disorder (RBD). This loss of REM sleep atonia appears as elaborate motor activity associated with dream mentation. Patients usually have a vivid recall of the actual dreams that correlates with the witnessed behavior. Dream recall is not uniformly noted, and patients may not be willing to talk about the dream that
CHAPTER 57 • Cardinal Manifestations of Sleep Disorders 655
led them to seek medical attention. These events occur more commonly in the latter half of the night but can occur any time that the patient enters REM sleep. Patients may have multiple events during a single night. Most cases begin in late adulthood, but children with symptoms of RBD have been described. RBD can be induced by medication, and cases have been reported of tricyclic antidepressants, monoamine oxidase inhibitors, and serotonin reuptake inhibitors causing RBD-like behavior. Acute forms of RBD can also occur during alcohol withdrawal and potentially benzodiazepine withdrawal. The more chronic form of RBD may have behaviors occurring for years before presentation for medical evaluation. RBD has been linked to alpha-synucleinopathies. This group of disorders includes parkinsonism, multiple system atrophy, and Lewy body dementia. Patients need a complete neurologic evaluation to look for signs of degenerative disorders. Other identifiable neurologic disorders, such as strokes, posterior fossa tumors, and demyelination, have been reported.15 Nightmares Nightmares or recurrent disturbing dream mentation can be a presenting symptom of sleep disturbance. The hallmark of nightmares is emotionally intense dreaming associated with fear, anxiety, anger, sadness, or other negative emotions. Individuals awaken from stage R or light NREM sleep to full alertness and usually recall the event immediately. Nightmares are most commonly associated with a psychologically disturbing event but may also be a result of medications, such as antihypertensives, antidepressants, or dopamine agonists. Nightmares can occur in patients with narcolepsy as well as in patients with sleep apnea. Rhythmic Movement Disorder Rhythmic movement disorder can be manifested as a variety of distracting behaviors that occur before sleep onset. The movements are stereotyped, usually involving large muscles, and are sustained into light sleep. Movements may include head banging, body rocking, leg rolling, humming, and chanting and are frequently more concerning to the bed partner and family than to the patient. Many patients are relatively unaware of the movement, and others will describe the movement as a calming effect or as a compulsion before sleep. This behavior is frequently seen in infants and young children, and the prevalence diminishes with age. It is more commonly seen in individuals with mental challenges or autism and is more prevalent in males. Emotional stress may provoke it. Patients can be easily alerted during the events, which helps differentiate these events from seizures. Bruxism Sleep bruxism can also occur as a rhythmic or repetitive movement during sleep.16 Grinding or clenching of the teeth during sleep may produce bizarre sounds, and patients can even rarely vocalize with the episodes. Patients may have abnormal wear of the teeth, jaw pain, headache, facial pain, or tooth pain. They may have hundreds of events per night, and the events increase with emotional stress. Some studies suggest that as many as 85% of the
656 PART II / Section 8 • Impact, Presentation, and Diagnosis
population grinds their teeth to some degree. These events often occur in children, and persistence of symptoms is occasionally associated with a familial tendency.
RESTLESS LEGS SYNDROME AND PERIODIC MOVEMENTS OF SLEEP Patients may complain of an unpleasant crawling, deep aching sensation in the legs or arms that is improved by motion of the extremities. Diagnostic criteria focus on four main symptoms: the sensation or urge to move the limbs that is worse with rest, improves with movement, and is more frequent in the evening.17 Patients with restless legs syndrome may relay that the discomfort can be debilitating at times, and some individuals are even driven to pursue extreme measures to decrease the symptoms. Most patients experience the symptoms while sitting or lying down and may complain of the need to walk or to have continuous movement of their legs. These symptoms can lead to individuals’ walking until the early morning hours or trying to sleep with continuous motion in their legs. Other individuals will use a combination of medication and alcohol to reduce the symptoms. Some patients note that their legs will move or dance on their own, indicating periodic limb movements in wakefulness. Restless legs syndrome usually occurs along with periodic movements of sleep. Periodic movements of sleep are repetitive stereotyped movements of the lower extremities that occur during sleep; they consist of the extension of the great toe with dorsiflexion of the ankle and flexion of the knee and hip. Patients or a bed partner may complain of kicking or arm movements at night. These movements may occur as periodic events or appear random. Movements can also occur in the arms and axial muscles. The individual movements are relatively brief, lasting 0.5 to 5.0 seconds, and occur at 5- to 90-second intervals. Although a majority of individuals with restless legs have periodic limb movements of sleep, only a minority of patients with periodic movements of sleep will have excessive daytime sleepiness or insomnia. Patients may be unaware of the movements, but bed partners usually are aware of the movements. Similar factors that provoke periodic limb movements increase the likelihood of restless legs syndrome. Periodic movements of sleep have been associated with uremia, peripheral vascular disease, anemia, arthritis, peripheral neuropathy, spinal cord lesions, antidepressants, and caffeine use. SYSTEMIC FEATURES The connection of good sleep to good health continues to expand our understanding of the importance of sleep. Sleep plays a role in endocrine regulation, weight, and metabolism and has been hypothesized to improve neuronal network proficiency and function. Therefore, sleep disorders may influence both regulatory processes and compensatory mechanisms. Sleep disorders may influence systemic disorders by three general mechanisms: directly cause the primary physiologic changes that result in systemic disease; exacerbate a preexisting disorder by altering a normal compensa-
tory mechanism; or be the hallmark symptom of the systemic disease, sharing a common pathophysiologic mechanism. Sleep disorders may result in systemic manifestations, as noted in sleep-related breathing disorders. Sleep-related disordered breathing can result in a variety of vascular and autonomic changes that increase the likelihood of hypertension and other vascular disorders. Physicians must question patients with high-risk disorders, including those with hypertension, vascular disease, heart disease, diabetes mellitus, and obesity, for symptoms of sleep dysfunction that may indicate sleep disorders acting as a cofactor. Sleep disorders, for example, obstructive sleep apnea or hypoventilation, may exacerbate underlying conditions such as hypertension, diabetes mellitus, congestive heart failure, epilepsy, and depression. Thus, the clinician must pay attention to aggravation of symptoms of medical, neurologic, or psychiatric dysfunction as a clue to disordered sleep. The interplay of sleep and brain function makes symptoms of neurologic and psychiatric disease a natural manifestation of sleep dysfunction. This has been documented in individuals with epilepsy as well as in those with symptoms of depression and anxiety. Patients may not be aware of the connection of sleep to their other medical problems or may not place emphasis on their sleep symptoms. Therefore, the clinician needs to consider the potential of sleep disturbance as an aggravating factor and to recognize the relationship of systemic findings to sleep disruption. Patients may also display a systemic illness that may share a common pathophysiologic mechanism with a sleep disorder. In individuals with anemia and restless legs, iron deficiency may be the common link, and thus appropriate treatment of the underlying cause may improve the symptoms of both. Last, the sleep symptom may be the hallmark of another process, as observed with REM sleep behavior disorder preceding the development of other neurologic disorders such as Parkinson’s disease. Although these symptoms may not be considered the typical cardinal manifestations of sleep disorders, they do represent an important aspect and entry point for patients into the medical system. Recognition of the systemic manifestations of sleep disorders is an important step in understanding the full relationship of sleep to the body.
PEDIATRIC CARDINAL MANIFESTATIONS Symptoms of sleep disorders in children can be strikingly different from those in adults and are likely to be overlooked or misinterpreted. Children can present with a range of physical and behavioral manifestations. In young children, sleep disturbances may present as poor growth, persistent fussiness, inconsolability, or increased oppositional behavior. School-aged children may exhibit suboptimal academic performance, inattention or hyperactivity, or daydreaming behavior in sedentary settings. Adolescents fall asleep in class and may present with affective symptoms that need to be differentiated from primary psychiatric disorders. In all ages, unrefreshing nocturnal sleep is often a clue to sleep disturbance. Although many of these symptoms are nonspecific, the clinician must be
CHAPTER 57 • Cardinal Manifestations of Sleep Disorders 657
aware of the role of sleep dysfunction in the genesis of the symptoms.
SUMMARY Sleep provides the benchmark for many aspects of our lives. The restorative powers of sleep improve our wakefulness and ability to attain higher level of functioning, whereas poor sleep has a negative impact on health, sense of well-being, and performance. Obvious manifestations of poor sleep, such as daytime sleepiness, insomnia, and sleep-related events, are the hallmark signs for further investigation. Our understanding of the intricate relationship of sleep and health must go beyond the most apparent manifestations of sleepiness. As astute clinicians, we must pay attention to the obvious and discrete signs; predominance of negative over positive memories, trouble with creative solutions, obesity, or poor healing may suggest sleep disruption. We must search for more clues that delineate the connection of sleep to health. Through the insight of the connection between sleep and the body, we will expand our recognition of these cardinal manifestations of sleep disorders. Identification of individuals who need further evaluation and application of appropriate therapies as described in the following chapters will aid both patients and society. ❖ Clinical Pearl Patients may accommodate to daytime sleepiness and fatigue or think that their symptoms are part of normal aging. One way to gauge this perspective is to ask patients to describe how they feel during certain activities, such as the process of getting up in the morning, or how they handle the situations in the Epworth Sleepiness Scale. Family members may be aware of behaviors before the patient and thus lend insight into the impact of the patient’s sleep situation.
REFERENCES 1. Roth T. Insomnia: definition, prevalence, etiology and consequences. J Clin Sleep Med 2007;3(Suppl):S7-S10. 2. Bleecker ML, Bolla-Wilson K, Kawas C, et al. Age-specific norms for the Mini-Mental State Exam. Neurology 1988;38: 1565-1568. 3. Millman RP; Working Group on Sleepiness in Adolescents/Young Adults; AAP Committee on Adolescence. Excessive sleepiness in adolescents and young adults: causes, consequences and treatment strategies. Pediatrics 2005;115:1774-1786. 4. Ohayon MM. From wakefulness to excessive sleepiness: what we know and still need to know. Sleep Med Rev 2008;12:129-141. 5. Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991;14:540-545. 6. Young T, Palta M, Dempsey J, et al. The occurrence of sleep disordered breathing among middle aged adults. N Engl J Med 1993;328:1230-1235. 7. Lumeng JC, Chervin RD. Epidemiology of pediatric obstructive sleep apnea. Proc Am Thorac Soc 2008;5:242-252. 8. Iber C, Ancoli-Israel S, Chesson A, Quan SF, for the American Academy of Sleep Medicine. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. Westchester, Ill: American Academy of Sleep Medicine; 2007. 9. Douglass AB, Bornstein R, Nino-Murcia G, et al. The Sleep Disorders Questionnaire. I: creation and multivariate structure of SDQ. Sleep 1994;17:160-167. 10. Netzer NC, Stoohs RA, Netzer CM, et al. Using the Berlin Questionnaire to identify patients at risk for the sleep apnea syndrome. Ann Intern Med 1999;131:485-491. 11. Punjabi NM, Newman AB, Young TB, et al. Sleep-disordered breathing and cardiovascular disease: an outcome-based definition of hypopneas. Am J Respir Crit Care Med 2008;177:1150-1155. 12. Silberstein SD, Lipton RB, Dalessio DJ, editors. Wolff’s headache and other head pain. 7th ed. New York: Oxford University Press; 2001. 13. Hublin C, Kaprio J, Partinen M, et al. Limits of self-report in assessing sleep terrors in a population survey. Sleep 1999;22:89-93. 14. Guilleminault C, Hagen CC, Khaja AM. Catathrenia: parasomnia or uncommon feature of sleep disordered breathing? Sleep 2008;31: 132-139. 15. Boeve BF, Silber MH, Saper CB, et al. Pathophysiology of REM sleep behaviour disorder and relevance to neurodegenerative disease. Brain 2007;130:2770-2788. 16. Lavigne GJ, Kato T, Kolta A, et al. Neurobiological mechanisms involved in sleep bruxism. Crit Rev Oral Biol Med 2003;14:30-46. 17. Hening WA, Allen RP, Chaudhuri KR, et al. Clinical significance of RLS. Mov Disord 2007;22(Suppl 18):S395-S400.
Physical Examination in Sleep Medicine Alon Y. Avidan and Beth A. Malow Abstract The physical examination of the patient presenting with sleep concerns often provides important supporting information for the diagnosis of a sleep disorder. In this chapter, the examination findings characteristic of the major categories of sleep
After obtaining the medical history, the clinician performs the physical examination, a key and necessary element in evaluating patients with sleep disorders. The examination may provide important clues that lead to elucidation of the etiology and pathophysiology of the sleep disorder. This will guide the clinician in determining what diagnostic tests will be ordered, what comorbidities require management, and ultimately what therapy will be employed. The physical examination is a critical component monitoring outcome to treatment of some sleep disorders.
SLEEP APNEA Obstructive sleep apnea (OSA) is associated with multiple anatomic risk factors. The main ones are obesity, as reflected by elevated body mass index, and increased neck circumference. However, many patients with OSA are not obese but may exhibit reduced oropharyngeal airspace, retrognathia, or micrognathia. In contrast, central sleep apnea usually presents with abnormalities reflective of impaired respiratory effort, including the manifestations of heart failure, central nervous system (CNS) disease, or neuromuscular disease. Hypoventilation may be secondary to obesity but may also reflect pulmonary disease or neuromuscular and chest wall disorders. We review the manifestations of sleep apnea on the basis of anatomic site. Overall Inspection Sleep apnea often presents in association with obesity, which increases the prevalence 10-fold (20% to 40%).1 Obesity and, in particular, the central type of obesity (Fig. 58-1) are significant risk factors for OSA.2 They impose increased pharyngeal collapsibility through mechanical compression of the pharyngeal soft tissues and decreased lung volume through CNS-acting signaling proteins (adipokines) that may alter airway neuromuscular control.2,3 OSA may independently predispose individuals to worsening obesity as a result of sleep deprivation, hypersomnia, and disrupted metabolism.4 Sleep apnea is also associated with endocrinopathies such as hypothyroidism5,6 and acromegaly.7 Hypothyroidism is a known cause of secondary OSA; oropharyngeal airway myopathy, edema, and obesity predispose patients to upper airway collapse and obstruction. Acromegaly results from excessive growth hormone, resulting in enlarged growth of the craniofacial bones, enlargement of the tongue (macroglossia), and thickening and enlarge658
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disorders are described and illustrated. These include findings observed in obstructive sleep apnea, central sleep apnea, hypoventilation syndromes, narcolepsy, restless legs syndrome, parasomnias, and bruxism.
ment of the laryngeal region; all of these factors can contribute to upper airway obstruction. Goiter, which is associated with acromegaly and hypothyroidism as well as a euthyroid state,8 can contribute to OSA (Fig. 58-2). Other conditions contributing to upper airway narrowing include Down syndrome and deposition disorders such as mucopolysaccharidosis and amyloidosis. Craniofacial Factors Cephalometric measurements reveal that subjects with OSA have significant changes in the size and position of the soft palate and uvula, volume and position of the tongue, hyoid position, and mandibulomaxillary protrusion compared with controls. Mandibular retrognathia (Fig. 58-3) and micrognathia (Fig. 58-4), which cause the tongue to rest in a more superior and posterior position, impinging on the upper airway, can be detected on examination, especially by observing the patient from the side. A scalloped tongue (Fig. 58-5) may accompany micrognathia. Men with retrognathia or micrognathia may grow a beard to compensate for this anatomic variant. Crowded teeth (Fig. 58-6) and overjet (Fig. 58-7), with the mandibular teeth excessively posterior to the maxillary teeth, often accompany retrognathia or micrognathia. Racial differences in cephalometric properties probably play a major role in conferring risk for OSA in the absence of obesity. For example, in Chinese patients with OSA, a more retropositioned mandible was associated with more severe OSA, after controlling for obesity.9 In Japanese patients with OSA, micrognathia was a major risk factor.10 Children and adults with Down syndrome frequently have sleep apnea most likely related to a combination of craniofacial abnormality and macroglossia. Patients with OSA have an increased pharyngeal narrowing ratio, which is defined as a ratio between the airway cross-section at the hard palate level and the narrowest cross-section from the hard palate to the epiglottis.11 Nasal Factors Examination of the nasal airway should focus on anatomic abnormalities that may contribute to nasal obstruction. These may be congenital, traumatic, infectious, or neoplastic in etiology (Fig. 58-8). Neck Circumference Increased neck circumference is an important risk factor for OSA. Patients with a neck circumference greater than
Figure 58-1 Central obesity in OSA. (From Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010.)
Figure 58-3 Mandibular retrognathia contributing to OSA. (From Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010.)
Figure 58-5 Scalloped tongue in a patient with OSA and micrognathia. The scalloping and furrow result from the tongue’s pressing against teeth (especially on the right side). In addition, the tongue is atrophied, raising the possibility of iron or vitamin B12 deficiency. (From Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010.)
CHAPTER 58 • Physical Examination in Sleep Medicine 659
Figure 58-2 Goiter. (From Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010.)
Figure 58-4 Mandibular micrognathia contributing to OSA. (From Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010.)
Figure 58-6 Crowded teeth indicate a small mandible, contributing to OSA. (From Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010.)
660 PART 2 / Section 8 • Impact, Presentation, and Diagnosis
Figure 58-7 Overjet contributing to OSA. (From Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010.)
Figure 58-9 Mallampati class I. (From Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010.)
Figure 58-8 Nasal pathology (trauma leading to broken nose) contributing to OSA. (From Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010.)
48 cm (19.2 inches) have a 20-fold increased risk of having OSA.12 Examination of the Pharynx There are two well-established classifications to determine the relation of the tongue to the pharynx. The Mallampati classification was first described as a method for anesthesiologists to predict difficult tracheal intubation.13 The Friedman classification identifies prognostic indicators for successful surgery for sleep-disordered breathing, combining palate position with tonsillar size.14 The Mallampati classification is as follows: Class I Soft palate, fauces, uvula, and posterior and anterior pillars are visible (Fig. 58-9). Class II Soft palate, fauces, and uvula are visible (Fig. 58-10).
Figure 58-10 Mallampati class II. (From Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010.)
Class III
Soft palate, fauces, and only base of uvula are visible (Fig. 58-11). Class IV Soft palate is not visible (Fig. 58-12). The Friedman classification is illustrated in Figure 58-13. Examination of the Tonsils Enlarged tonsils and adenoids are a major cause of airway obstruction and sleep apnea in children, but a minority of
CHAPTER 58 • Physical Examination in Sleep Medicine 661
Figure 58-12 Mallampati class IV. (from Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010.) Figure 58-11 Mallampati class III. (From Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010.)
adults may also have enlargement of these structures contributing to airway obstruction.15 Adenoids cannot be visualized in a routine physical examination, and the examination of tonsils may require use of a tongue blade. Tonsillar size is graded on a scale of 1 to 4 (Fig. 58-14). Neurologic Examination The neurologic examination may hold important clues to the presence of obstructive or central sleep apnea and hypoventilation syndromes. Features of neuromuscular disease evident on physical examination may indicate these syndromes. For example, progressive muscle atrophy and fasciculations of the hand (Fig. 58-15) or tongue may indicate amyotrophic lateral sclerosis. In amyotrophic lateral sclerosis, phrenic nerve dysfunction is common and results in diaphragmatic paralysis, with prominent hypoventilation during rapid eye movement (REM) sleep. In addition, coexisting OSA may occur in amyotrophic lateral sclerosis with bulbar involvement. Weakness of thoracoabdominal or respiratory accessory muscles, often with accompanying kyphoscoliosis, may be observed in poliomyelitis. Post polio syndrome, muscular dystrophies, myasthenia gravis, and metabolic myopathies may also be manifested with weakness of the chest wall musculature16 and diaphragm weakness. Myasthenia gravis (Fig. 58-16) may also involve facial structures, resulting in OSA. Craniofacial abnormalities may occur in myotonic dystrophy (Fig. 58-17) or muscular dystrophy; macroglossia may also occur (e.g., Duchenne’s muscular dystrophy).17 Finally, obesity (e.g., from steroid use or inactivity) may also contribute to sleep apnea in neuromuscular disease.
Friedman Palate Position I allows visualization of the entire uvula and tonsils/pillars.
Friedman Palate Position III allows visualization of the soft palate but not the uvula.
Friedman Palate Position II allows visualization of the uvula but not the tonsils.
Friedman Palate Position IV allows visualization of the hard palate only.
Figure 58-13 Friedman classification. (From Friedman M, Ibrahim H, Bass L. Clinical staging for sleep-disordered breathing. Otolaryngol Head Neck Surg 2002;127:13-21.)
662 PART 2 / Section 8 • Impact, Presentation, and Diagnosis
Tonsils, size 1, are hidden within the pillars.
Tonsils, size 2, extend to the pillars.
Figure 58-16 Facial muscle weakness in myasthenia gravis. (From Goldman L, Ausiello DA, editors. Cecil medicine, 23rd ed. Philadelphia: Elsevier; 2008.)
Tonsils, size 3, extend beyond the pillars, but not to the midline.
Tonsils, size 4, extend to the midline.
Figure 58-14 Tonsil size grading. (From Friedman M, Ibrahim H, Bass L. Clinical staging for sleep-disordered breathing. Otolaryngol Head Neck Surg 2002;127:13-21.)
Figure 58-15 Hand atrophy in amyotrophic lateral sclerosis. (From Goldman L, Ausiello DA, editors. Cecil medicine, 23rd ed. Philadelphia: Elsevier; 2008.)
Cardiopulmonary Examination The presence of congestive heart failure (see Chapter 122) indicates a high likelihood of central sleep apnea. Peripheral edema is a common finding in patients with obesity hypoventilation syndrome (as a manifestation of cor pulmonale) and in some patients with obstructive apnea who also have left ventricular cardiac failure. Resolution of peripheral edema with treatment correlates with clinical improvement. Chronic obstructive pulmonary disease (see Chapter 111) and asthma (see Chapter 111) are also seen in association with OSA.
Figure 58-17 Facial weakness and micrognathia in myotonic dystrophy. (From Bradley WG, Daroff RB, Fenichel G, Jankovic J, editors. Neurology in clinical practice, 5th ed. Philadelphia: Elsevier; 2008.)
NARCOLEPSY Physical findings in patients with idiopathic narcolepsy are nonspecific. Patients with narcolepsy tend to be obese, with increased predilection to non–insulin-dependent diabetes mellitus, and have a lower basal metabolism compared with controls.18,19 Children with obesity and
Figure 58-18 Tongue glossitis in iron deficiency.
precocious puberty should be screened for narcolepsy and cataplexy.20 Narcolepsy related to medical conditions (symptomatic narcolepsy) is seen in disorders such as CNS tumors, head trauma, multiple sclerosis, acute disseminated encephalomyelitis, CNS vascular disorders, encephalitis, and neurodegeneration.21 An abnormal neurologic examination can be an important sign that hypersomnia may be due to a CNS etiology.
RESTLESS LEGS SYNDROME The prevalence of restless legs syndrome (RLS) in type 2 diabetes is 17.7%,22 and the prevalence may be higher in patients with hereditary neuropathy.23 RLS occurs in about one third of patients with polyneuropathy,24 with preferential involvement of small sensory fibers. Electrophysiologic studies demonstrate that axonal neuropathy is common in RLS, which further necessitates comprehensive peripheral nerve evaluations in these patients.25 Reduced iron stores can also cause RLS. With iron deficiency, examination of the pharynx may reveal inflammation (redness) or loss or atrophy of the lingual mucosa indicating glossitis (Fig. 58-18). The patient may complain of a sore or tender tongue. On neurologic examination, symptoms include sensory loss, often described by patients as a sense of numbness or tingling. In the generalized polyneuropathies, symptoms frequently begin in the most distal aspect of the longest sensory fibers, which produce disturbances in sensation in the toes and feet. In addition to sensory loss, patients frequently complain of paresthesias and dysesthesias, often characterized by a sense of numbness, tingling, prickling, and pins-and-needles sensations. The sensory examination will often disclose a distal to proximal loss of the various sensory modalities. In certain polyneuropathies, pain predominates in the clinical picture, and the sensory examination tends to disclose deficits predominantly of pain and thermal sensation. When significant proprioceptive deafferentation occurs, patients may present with altered joint position sense that may be manifested as an ataxia or tremor of the affected limbs and an imbalance of gait and station.
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Pain may be a significant symptom for many patients with RLS in which the etiology is related to a polyneuropathy. It may be described as a dull aching sensation, an intense burning sensation, or, occasionally, intermittent lancinating pulses of pain. On occasion, patients notice that their skin is hypersensitive to tactile stimulation, such as from the touch of bed sheets or clothing or standing on their feet. Some patients note an exaggerated painful sensation resulting from any stimulus to the affected area, a form of pain termed allodynia. Various limb deformities and trophic changes may be observed in chronic polyneuropathies. Pes cavus, characterized by high arches and hammertoes, and the clawfoot deformity are typical foot deformities in hereditary polyneuropathies with childhood onset. These deformities are due to progressive weakness and atrophy of intrinsic foot muscles. A similar clawlike deformity may be observed in the hand. Autonomic involvement of a limb may cause the affected area to appear warm, red, and swollen at times and pale and cold at other times owing to dysregulation of small vessels due to autonomic denervation. Various trophic changes, including a tight, shiny skin, may occur. In patients who have had severe sensory loss in the limbs, the affected areas may be subject to incidental traumas, including burns, pressure sores, and other injuries that are not perceived by the patient, in whom repeated injuries and traumas may result in chronic infections and, when severe, lead to osteomyelitis. A clinical evaluation of peripheral neuropathy is provided by Kelly.26,27
PARASOMNIAS Nocturnal Eating Disorder and Sleep-Related Eating Disorder In nocturnal eating disorder, patients often manifest compulsive food-searching behaviors and a return to sleep after food ingestion. Body mass index was abnormally high in 6 of 10 patients after careful exclusion of both anorexia nervosa and bulimia.28 Sleep-related eating disorder, characterized by recurrent episodes of eating after an arousal from nighttime sleep with or without amnesia,29 may also result in obesity. REM Sleep Behavior Disorder Patients with idiopathic REM sleep behavior disorder (RBD) are frequently at risk for development of alphasynucleinopathies such as Parkinson’s disease, and the majority present with hyposmia (impaired smell), which is a potential preclinical nonmotor sign of the disease.30 Odor identification was also found impaired in Japanese patients with idiopathic RBD and Parkinson’s disease.31 Patients with multiple system atrophy may present with inspiratory stridor, which along with RBD may serve as a clue to the disease in a patient with autonomic failure.32 Sleep-Related Movement Disorders Bruxism Bruxism (see Chapter 99) represents a stereotyped movement disorder clinically characterized by grinding or clenching of the teeth during sleep. The sounds made by friction of the teeth are usually perceived by a bed partner as very unpleasant.33 The condition is typically brought to
664 PART 2 / Section 8 • Impact, Presentation, and Diagnosis
Figure 58-19 Bruxism with abnormal wear of the teeth.
the attention of the medical or dental practitioner in efforts to eliminate the disturbing sounds. Bruxism can lead to abnormal wear of the teeth (Fig. 58-19), periodontal tissue damage, or jaw pain. Other symptoms include facial muscle and tooth pain and headache. Bruxism induces dental damage with abnormal wear to the teeth and damage to the structures surrounding the teeth. Chronically, over time and when untreated, this leads to recession and inflammation of the gums, alveolar bone resorption, muscles of mastication hypertrophy, and temporomandibular joint disorders, often associated with facial pain. Additional physical findings include tenderness of the muscles of mastication (masseter, temporalis, pterygoid, sternocleidal), temporomandibular disorders, tongue indentation, subjective appreciation of a tense personality, and hypervigilant patient.34 Case reports in patients with bruxism demonstrate bilateral enlargement in the region of the mandibular angle, corresponding with the masseter hypertrophy.35 Children with bruxism have a significantly longer and higher palate in the sagittal plane and bigger dental arches compared with normal children.36 Psychiatric patients have a higher prevalence of bruxism and signs of temporomandibular disorders, possibly related to neuroleptic-induced phenomenon.37 ❖ Clinical Pearl Overall inspection of the patient, coupled with observation of craniofacial, nasal, and pharyngeal factors, allows detection of key risk factors for sleep apnea.
Acknowledgment Dr. Meir Kryger provided assistance with illustrations for this chapter. REFERENCES 1. Kyzer S, Charuzi I. Obstructive sleep apnea in the obese. World J Surg 1998;22:998-1001.
2. Schwartz AR, Patil SP, Laffan AM, et al. Obesity and obstructive sleep apnea: pathogenic mechanisms and therapeutic approaches. Proc Am Thorac Soc 2008;5:185-192. 3. Quinnell TG, Smith IE. Obstructive sleep apnoea in the elderly: recognition and management considerations. Drugs Aging 2004; 21:307-322. 4. Gami AS, Caples SM, Somers VK. Obesity and obstructive sleep apnea. Endocrinol Metab Clin North Am 2003;32:869-894. 5. Rosenow F, McCarthy V, Caruso AC. Sleep apnoea in endocrine diseases. J Sleep Res 1998;7:3-11. 6. Grunstein RR, Sullivan CE. Sleep apnea and hypothyroidism: mechanisms and management. Am J Med 1988;86:775-779. 7. Weiss V, Sonka K, Pretl M, et al. Prevalence of the sleep apnea syndrome in acromegaly population. J Endocrinol Invest 2000;23: 515-519. 8. Deegan PC, McNamara VM, Morgan WE. Goitre: a cause of obstructive sleep apnoea in euthyroid patients. Eur Respir J 1997; 10:500-502. 9. Lam B, Ooi CG, Peh WC, et al. Computed tomographic evaluation of the role of craniofacial and upper airway morphology in obstructive sleep apnea in Chinese. Respir Med 2004; 98:301-307. 10. Endo S, Mataki S, Kurosaki N. Cephalometric evaluation of craniofacial and upper airway structures in Japanese patients with obstructive sleep apnea. J Med Dent Sci 2003;50:109-120. 11. Koren A, Groselj LD, Fajdiga I. CT comparison of primary snoring and obstructive sleep apnea syndrome: role of pharyngeal narrowing ratio and soft palate–tongue contact in awake patient. Eur Arch Otorhinolaryngol 2009;266:727-734. 12. Flemons WW, Whitelaw WA, Brant R, et al. Likelihood ratios for a sleep apnea clinical prediction rule. Am J Respir Crit Care Med 1994;150(Pt 1):1279-1285. 13. Mallampati SR, Gatt SP, Gugino LD, et al. A clinical sign to predict difficult tracheal intubation: a prospective study. Can Anaesth Soc J 1985;32:429-434. 14. Friedman M, Ibrahim H, Bass L. Clinical staging for sleepdisordered breathing. Otolaryngol Head Neck Surg 2002; 127:13-21. 15. Zonato AI, Bittencourt LR, Martinho FL, et al. Association of systematic head and neck physical examination with severity of obstructive sleep apnea–hypopnea syndrome. Laryngoscope 2003;113:973980. 16. Culebras A. Sleep disorders and neuromuscular disease. Semin Neurol 2005;25:33. 17. Alves RS, Resende MB, Skomro RP, et al. Sleep and neuromuscular disorders in children. Sleep Med Rev 2009; 13:133-148. 18. Honda Y, Doi Y, Ninomiya R, et al. Increased frequency of non– insulin-dependent diabetes mellitus among narcoleptic patients. Sleep 1986;9(Pt 2):254-259. 19. Schuld A, Hebebrand J, Geller F, et al. Increased body-mass index in patients with narcolepsy. Lancet 2000;355:1274-1275. 20. Plazzi G, Parmeggiani A, Mignot E, et al: Narcolepsy-cataplexy associated with precocious puberty. Neurology 2006;66:15771579. 21. Nishino S, Kanbayashi T. Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/ orexin system. Sleep Med Rev 2005;9:269-310. 22. Merlino G, Fratticci L, Valente M, et al. Association of restless legs syndrome in type 2 diabetes: a case-control study. Sleep 2007;30: 866-871. 23. Hattan E, Chalk C, Postuma RB. Is there a higher risk of restless legs syndrome in peripheral neuropathy? Neurology 2009;72: 955-960. 24. Gemignani F, Brindani F. Restless legs syndrome associated with peripheral neuropathy. Eur J Neurol 2007;14:e9-e10. 25. Iannaccone S, Zucconi M, Marchettini P, et al. Evidence of peripheral axonal neuropathy in primary restless legs syndrome. Mov Disord 1995;10:2-9. 26. Kelly JJ. The evaluation of peripheral neuropathy. Part II: identifying common clinical syndromes. Rev Neurol Dis 2004;1:190-201. 27. Kelly JJ. The evaluation of peripheral neuropathy. Part I: clinical and laboratory evidence. Rev Neurol Dis 2004;1:133-140. 28. Spaggiari MC, Granella F, Parrino L, et al. Nocturnal eating syndrome in adults. Sleep 1994;17:339-344. 29. Howell MJ, Schenck CH, Crow SJ. A review of nighttime eating disorders. Sleep Med Rev 2009;13:23-34.
30. Stiasny-Kolster K, Clever SC, Moller JC, et al. Olfactory dysfunction in patients with narcolepsy with and without REM sleep behaviour disorder. Brain 2007;130(Pt 2):442-449. 31. Miyamoto T, Miyamoto M, Iwanami M, et al. Odor identification test as an indicator of idiopathic REM sleep behavior disorder. Mov Disord 2009;24:268-273. 32. Gaig C, Iranzo A, Tolosa E, et al. Pathological description of a non-motor variant of multiple system atrophy. J Neurol Neurosurg Psychiatry 2008;79:1399-1400. 33. Rugh JD, Harlan J. Nocturnal bruxism and temporomandibular disorders. Adv Neurol 1988;49:329-341.
CHAPTER 58 • Physical Examination in Sleep Medicine 665 34. Camparis CM, Formigoni G, Teixeira MJ, et al. Sleep bruxism and temporomandibular disorder: clinical and polysomnographic evaluation. Arch Oral Biol 2006;51:721-728. 35. Rispoli DZ, Camargo PM, Pires JL Jr, et al. [Benign masseter muscle hypertrophy.] Braz J Otorhinolaryngol 2008;74:790-793. 36. Restrepo CC, Sforza C, Colombo A, et al. Palate morphology of bruxist children with mixed dentition. A pilot study. J Oral Rehabil 2008;35:353-360. 37. Winocur E, Hermesh H, Littner D, et al. Signs of bruxism and temporomandibular disorders among psychiatric patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;103:60-63.
Use of Clinical Tools and Tests in Sleep Medicine Ronald D. Chervin Abstract A clinician confronted with a sleep-related complaint combines symptoms, signs, and test results to make a diagnostic assessment that will best serve the patient. When it is available, information about test performance characteristics, such as sensitivity, specificity, and predictive value, can be used more formally to decide on optimal approaches. Evaluations for obstructive sleep-disordered breathing start with a history and physical examination, which generate valuable information, although mathematical symptom-based models usually show inadequate specificity. Laboratory-based nocturnal polysomnography is a gold standard but not infallible. Final diagnostic decisions should be based on integration of multiple clinical and objective data points rather than on any specific cutoff for one specific variable, such as the apnea-hypopnea index. Evaluation for hypersomnolence also relies on historical symptoms, collected during an interview or by use of a ques-
This chapter focuses on the comparative value of different approaches to clinical assessment of sleep-related problems. The symptoms, signs, and test results relevant to particular sleep disorders are described in detail in other parts of this volume. This chapter, instead, highlights the clinical reasoning process by which a clinician challenged with a sleep complaint can combine information from different sources, appropriately weigh available evidence, and arrive at sound diagnoses and treatment plans. Data are reviewed on the value of test results in evaluations of four common clinical problems: suspected obstructive sleepdisordered breathing, hypersomnolence, insomnia, and parasomnias. The Standards of Practice Committee of the American Academy of Sleep Medicine reviews the value of clinical tests and publishes guidelines. A selection of evidence-based practice parameters and reviews can be accessed at http://www.aasmnet.org/Standards.aspx (Table 59-1). These are recommended to supplement overviews presented in this chapter.
EVALUATION FOR SLEEP-RELATED BREATHING DISORDERS History and Questionnaires Sleep-related breathing disorders are by far the most common class of disorders diagnosed at U.S. sleep centers, and obstructive sleep apnea (OSA) alone accounts for nearly 70% of all patients evaluated.1 The value of interview and questionnaire information has been studied with respect to polysomnographically confirmed diagnoses of OSA, a term now used to include the upper airway resistance syndrome, for which limited prior information also exists. For primary snoring, no objective measure has been shown to be better than subjective reports. Virtually no data are available on the utility of interviews and question666
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tionnaire. Objective testing with a Multiple Sleep Latency Test or one of its variants is particularly useful when a short mean sleep latency confirms excessive daytime sleepiness. Results must be interpreted carefully, especially when they are normal, because of potential confounds. The Multiple Sleep Latency Test is also useful in an assessment for narcolepsy, particularly in the absence of cataplexy. Evaluation for insomnia often relies solely on historical information. Sleep logs also can be helpful, and polysomnography is indicated when sleep-disordered breathing, periodic leg movements, or other occult sleep disorders may underlie the insomnia. Evaluation for a parasomnia often starts with a thorough history, obtained whenever possible from a bed partner in addition to the patient. Polysomnography may confirm a diagnosis or distinguish between several possibilities, although few data on test performance in these settings are published.
naires in the diagnosis of nonobstructive forms of sleeprelated breathing disorders. Subjective clinical impressions of OSA tend to have inadequate sensitivity (probability of a positive test result or assessment given that the disorder is present) and specificity (probability of a negative test result given that the disorder is absent). Combinations of some symptoms can have sensitivity above 0.90, but specificity is usually poor (Table 59-2). Performance of these models in clinical practice can be worse than originally reported.2 Most studies do not report the positive predictive value (PPV, probability that the disorder is present given a positive test result) and negative predictive value (NPV, probability that the disorder is absent given a negative test result). However, sensitivity and specificity data suggest that the NPV of some symptom combinations may be good, whereas the PPV is probably poor, especially when the prevalence of OSA in the tested population is not high.3 Accordingly, patients without a history suggestive of OSA usually do not receive further testing for it. Among patients referred for suspected OSA, models based on historical information may accurately classify a minority as apnea free without further tests.4 In practice, patients who do have symptoms of OSA generally are tested. Although, in general, the PPV of symptoms alone is not high, a minority of patients have a clinical presentation so convincing as to be essentially diagnostic. However, the International Classification of Sleep Disorders requires minimal polysomnographic criteria, in addition to symptoms, to establish a diagnosis of OSA.5 Tests in such cases may also serve to define the severity of OSA. In a patient with a history strongly suggestive of OSA, the diagnosis must still be suspected when it is not confirmed by a single polysomnogram (which is not infallible) and especially when it is not confirmed by a more abbreviated home sleep study.6
CHAPTER 59 • Use of Clinical Tools and Tests in Sleep Medicine 667
Table 59-1 Best Practice Guides (BPG), Clinical Guidelines (CG), Practice Parameters (P), and Reviews (R) TYPE
PUBLISHED (MONTH/YEAR)
CATEGORY
PAPER TITLE
BPG
8/2010
Nightmare Disorder
Best Practice Guide for the Treatment of Nightmare Disorder in Adults
BPG
2/2/10
REM Sleep Behavior Disorder
Best Practice Guide for the Treatment of REM Sleep Behavior Disorder (RBD)
CG
6/2009
Sleep-Related Breathing Disorders
Clinical Guideline for the Evaluation, Management and Long-Term Care of Obstructive Sleep Apnea in Adults
CG
10/2008
Insomnia
Clinical Guideline for the Evaluation and Management of Chronic Insomnia in Adults
CG
2/2008
Sleep-Related Breathing Disorders
Clinical Guidelines for the Manual Titration of Positive Airway Pressure in Patients with Obstructive Sleep Apnea
CG
12/2007
Sleep-Related Breathing Disorders
Clinical Guidelines for the Use of Unattended Portable Monitors in the Diagnosis of Obstructive Sleep Apnea in Adult Patients
P
11/2007
Circadian rhythm sleep disorders
Practice Parameters for the Clinical Evaluation and Treatment of Circadian Rhythm Sleep Disorders
R
11/2007
Circadian rhythm sleep disorders
Circadian Rhythm Sleep Disorders: Part I, Basic Principles, Shift Work and Jet Lag Disorders
R
11/2007
Circadian rhythm sleep disorders
Circadian Rhythm Sleep Disorders: Part II, Advanced Sleep Phase Disorder, Delayed Sleep Phase Disorder, Free-Running Disorder, and Irregular Sleep–Wake Rhythm
P
4/2007
Circadian rhythm sleep disorders
Parameters for the Use of Actigraphy in the Assessment of Sleep and Sleep Disorders: An Update for 2007
P
5/2003
Circadian rhythm sleep disorders
Practice Parameters for the Role of Actigraphy in the Study of Sleep and Circadian Rhythms: An Update for 2002
P
12/2007
Hypersomnias
Practice Parameters for the Treatment of Narcolepsy and other Hypersomnias of Central Origin
R
12/2007
Hypersomnias
Treatment of Narcolepsy and other Hypersomnias of Central Origin
P
11/2006
Insomnia
Practice Parameters for the Psychological and Behavioral Treatment of Insomnia: An Update
R
11/2006
Insomnia
Psychological and Behavioral Treatment of Insomnia: Update of the Recent Evidence (1998-2004)
P
9/2003
Insomnia
Practice Parameters for Using Polysomnography to Evaluate Insomnia: An Update
P
1/2005
MSLT/MWT
Practice Parameters for Clinical Use of the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test
R
1/2005
MSLT/MWT
A Review by the MSLT and MWT Task Force of the Standards of Practice Committee of the American Academy of Sleep Medicine: The Clinical Use of the MSLT and MWT
R
1/2005
MSLT/MWT
A Review by the MSLT and MWT Task Force of the Standards of Practice Committee of the American Academy of Sleep Medicine: The Clinical Use of the MSLT and MWT—Evidence Tables
P
10/2006
Pediatrics
Practice Parameters for Behavioral Treatment of Bedtime Problems and Night Wakings in Infants and Young Children
R
10/2006
Pediatrics
Behavioral Treatment of Bedtime Problems and Night Wakings in Infants and Young Children
R
10/2006
Pediatrics
Behavioral Treatment of Bedtime Problems and Night Wakings in Infants and Young Children—Evidence Table 2
P
4/2005
Polysomnography
Practice Parameters for the Indications for Polysomnography and Related Procedures: An Update for 2005
P
5/2004
Sleep-related movement disorders
Practice Parameters for the Dopaminergic Treatment of Restless Legs Syndrome and Periodic Limb Movement Disorder
R
5/2004
Sleep-related movement disorders
A Review by the Restless Legs Syndrome Task Force of the Standards of Practice Committee of the American Academy of Sleep Medicine: An Update on the Dopaminergic Treatment of Restless Legs Syndrome and Periodic Limb Movement Disorder
P
1/2008
Sleep-related breathing disorders
Practice Parameters for the Use of Autotitrating Continuous Positive Airway Pressure Devices for Titrating Pressures and Treating Adult Patients with Obstructive Sleep Apnea Syndrome: An Update for 2007 Continued
668 PART II / Section 8 • Impact, Presentation, and Diagnosis Table 59-1 Best Practice Guides (BPG), Clinical Guidelines (CG), Practice Parameters (P), and Reviews (R)—cont’d TYPE
PUBLISHED (MONTH/YEAR)
CATEGORY
PAPER TITLE
P
8/2006
Sleep-related breathing disorders
Practice Parameters for the Medical Therapy of Obstructive Sleep Apnea
R
8/2006
Sleep-related breathing disorders
P
3/2006
Sleep-related breathing disorders
Medical Therapy for Obstructive Sleep Apnea: A Review by the Medical Therapy for Obstructive Sleep Apnea Task Force of the Standards of Practice Committee of the American Academy of Sleep Medicine Practice Parameters for the Use of Continuous and Bilevel Positive Airway Pressure Devices to Treat Adult Patients with SleepRelated Breathing Disorders
R
3/2006
Sleep-related breathing disorders
Evaluation of Positive Airway Pressure Treatment for Sleep-Related Breathing Disorders in Adults
P
2/2006
Sleep-related breathing disorders
Practice Parameters for the Treatment of Snoring and Obstructive Sleep Apnea with Oral Appliances: An Update for 2005
R
2/2006
Sleep-related breathing disorders
Oral Appliances for Snoring and Obstructive Sleep Apnea: A Review
R
2/2006
Sleep-related breathing disorders
Oral Appliances for Snoring and Obstructive Sleep Apnea: A Review—Evidence Tables
MSLT, Multiple Sleep Latency Test; MWT, Maintenance of Wakefulness Test. Written by the Standards of Practice Committee of the American Academy of Sleep Medicine. Reviews, Practice Parameters, and Clinical Guidelines are generally available at http://www.aasmnet.org/Standards.aspx.
The diagnostic values of specific symptoms are difficult to judge on the basis of studies with significant methodological differences. The author’s clinical impressions are listed in Table 59-3, with reference to adults referred for sleep evaluations. These data are not quantitative, but they illustrate how PPV and NPV for the same symptom may differ substantially. Clinical value may be quite different in other populations. For example, among patients referred specifically for possible OSA, the symptom of excessive daytime sleepiness may7 or may not8 be useful in making the diagnosis, and a history of hypertension may be better than a report of snoring as an indication that OSA is present.9 In the community, the symptom with the highest predictive value for OSA is habitual snoring, although excessive daytime sleepiness and observed apneas are also useful.10 Little is known about the ability of historical symptoms to identify upper airway resistance syndrome and to distinguish it from OSA, and data to support the distinction appear not to have warranted separation of these diagnoses in the most recent nosology.5 The probability of upper airway resistance syndrome rather than more severe OSA may be increased by youth, female sex, functional somatic complaints, resting hypotension, and normal neck circumference. Patients with upper airway resistance syndrome appear more likely than those with more severe forms of OSA to have sleep-onset insomnia.11 The probability of upper airway resistance syndrome rather than primary snoring is increased by the presence of excessive daytime sleepiness or insomnia and may be increased by a history of hypertension, hypotension, dysmenorrhea, chronic fatigue syndrome, or bruxism.12-14 The likelihood of upper airway resistance syndrome rather than no sleep-disordered breathing is increased by a history of snoring, but
the absence of snoring may not diminish the probability of upper airway resistance syndrome as much as it does the probability of more typical OSA.13 Physical Examination Among variables related to body weight, neck circumference and body mass index (equal to weight in kilograms/ height in meters squared) correlate well with the presence and severity of OSA in the community.15 Among patients referred for possible OSA, these variables still may be useful, but their predictive value is not large except in extreme ranges.4,7,8,16-18 Patients with OSA who are not obese often have pharyngeal crowding, obstructed nasal passages, or other craniofacial abnormalities associated with narrowing of the upper airway.19 The predictive value of such findings may differ somewhat between men and women.20 The Mallampati score, which reflects oropharyngeal crowding on a 4-point scale, was found in a series of 137 adults referred for OSA to predict polysomnographic confirmation of OSA.21 Each 1-point increase in the score was associated with an odds ratio of 2.5 (95% CI [1.2, 5.0]) for OSA and predicted a 5-point higher apneahypopnea index (coefficient = 5.3 [0.2-10]), independent of many other physical findings and symptoms. Physical findings can also be combined into predictive quantitative models to aid in the diagnosis of OSA. One such model is based on body mass index, neck circumference, and bedside craniofacial measurements that include palatal height, maxillary intermolar distance, mandibular intermolar distance, and overjet.22 Among 300 sleep center patients, the model showed a sensitivity of 98% and a specificity of 100% for OSA. The PPV was 100% and the NPV was 89%. A second model is based on a modified Mallampati grade, tonsil size, and body mass index.23
Loud habitual snoring, observed apneas, sex, age, BMI Several snoring questions, observed apneas, sweat at night, history of hypertension, nasal obstruction, weight, years of smoking, age, BMI Observed apneas Snoring Falls asleep driving Predominant sleep position is supine
AHI ≥ 10
Followed ICSD101 criteria and had PSG, but PSG criteria not otherwise specified AHI ≥ 15
129 adults referred for nocturnal PSG
435 patients with specified sleep disorders and 84 normal control subjects
250 patients referred for suspected SDB
Douglass et al.,100 1994
Deegan and McNicholas,4 1996
Dealberto et al.,7 1994
Habitual snoring, observed gasping or choking, neck circumference, hypertension
AHI > 10
180 patients suspected of having sleep apnea
Flemons et al.,8 1994
Weight, height, sex, observed apneas, falling asleep while reading
116 patients referred for heavy snoring
Rauscher et al.,99 1993
Men, .70 Women, .47
Nocturnal breath-holding
Men, .85 Women, .88
.82
.94
.60
Men, .89 Women, .71
Disruptive snoring
AHI > 10
594 patients referred for suspected sleep apnea
Hoffstein and Szalai,18 1993
Men, .97 Women, .82
Usually has
SENSITIVITY
Any snoring
AHI ≥ 10
Age, sex, BMI, observed apneas, pharyngeal examination Subjective impression
1409 patients referred for sleep-related problems
Bliwise et al.,98 1991
MODEL
GOLD STANDARD
AHI > 10 on PSG
SUBJECTS
REFERENCE
Men, .76 Women, .81
.68
.45
.63
Men, .88 Women, .96
Men, .71 Women, .89
Men, .47 Women, .79
SPECIFICITY
Continued
PPV = .64, NPV = .53 PPV = .63, NPV = .56 PPV = 70, NPV = .51 PPV = .77, NPV = .47 with pretest probability of OSA = .54 and pretest probability of no OSA = .46
Men: PPV = .72, NPV = .87 with pretest probability of OSA = .42 Women: PPV = .31, NPV = .99 with pretest probability of OSA = .09
PPV* = .81 with pretest probability of OSA = .45 Model explained 34% of the variation in AHI
Regression model explained 36% of variability in square root transform of AHI
OTHER RESULTS PROVIDED
Table 59-2 Value of Historical or Questionnaire-Derived Diagnostic Information in the Diagnosis of Obstructive Sleep Apnea at Sleep Centers: Selected Studies Since 1990
CHAPTER 59 • Use of Clinical Tools and Tests in Sleep Medicine 669
Above plus BMI, age, neck circumference, and gender
.84 .93 1.00
.56 .43 .37
.60 .53 .49
with pretest probability of OSA/no OSA being: .69/.31 .40/.60 .22/.78
.81/.61 .52/.90 .31/1.00
.78/.44 .51/.76 .30/.89
.66 .74 .80
PPV/NPV: Snoring, tiredness, observed apneas, and high blood pressure
PPV = .87, NPV = .85 with 87% of patients correctly classified, pretest probability of OSA = .38 and pretest probability of no OSA = .62
PPV = .88, NPV = .98 Area under receiver operating curve = .94 with pretest probability of OSA = .65 This study trained a neural network to predict OSA based on 23 clinical variables
PPV = .89 with pretest probability of OSA = 0.69
OTHER RESULTS PROVIDED
AHI > 5, AHI > 15, or AHI > 30 (successively)
.91
.80
.77
SPECIFICITY
PSG:
.83
.99
.86
SENSITIVITY
*Depended on cutoff chosen for model results. AHI, apnea-hypopnea index (number of apneas or hypopneas per hour of sleep); BMI, body mass index; CPAP, continuous positive airway pressure; NPV, negative predictive value; PPV, positive predictive value; PSG, polysomnography; SDB, sleep-disordered breathing.
177 adult surgical patients seen in a preoperative clinic
Hypertension, observed apneas, Epworth Sleepiness Scale score, BMI
AHI > 30 on automatically titrating CPAP unit
Chung et al.,105,106 2008
23 variables including age, gender, frequent awakening, witnessed apneas, reported sleepiness, hypertension, alcohol use, smoking, BMI, blood pressure, pharynx crowding
AHI > 10 on PSG
207 patients referred for suspected SDB (model development); 102 similar patients (model testing)
Weight change, snoring, snoring loudness, snoring frequency, bothersome snoring, observed apneas, tiredness, tired after sleeping, falling asleep while driving, high blood pressure
AHI > 5 on cardiorespiratory portable monitor
744 primary care patients
Martínez García et al.,104 2003
MODEL
GOLD STANDARD
SUBJECTS
255 patients referred for suspected SDB (training set); 150 similar patients (model testing)
102
Kirby et al.,103 1999
Netzer et al., 1999
REFERENCE
Table 59-2 Value of Historical or Questionnaire-Derived Diagnostic Information in the Diagnosis of Obstructive Sleep Apnea at Sleep Centers: Selected Studies Since 1990—cont’d
670 PART II / Section 8 • Impact, Presentation, and Diagnosis
CHAPTER 59 • Use of Clinical Tools and Tests in Sleep Medicine 671
Table 59-3 Estimated Clinical Values of Specific Symptoms in the Diagnosis of Obstructive Sleep Apnea Syndrome, with Reference to Patients Referred to a Sleep Clinic Effect on Probability of OSA SYMPTOM
SYMPTOM PRESENT
SYMPTOM ABSENT
↑↑
↓↓↓
Loud snoring
↑↑↑
↓↓
Observed apneas
↑↑↑
↓
Habitual snoring
Sleepy while driving
↑↑
↓
Sleepy while reading
↑
↓↓
↑
↓
Dry mouth on awakening
↑↑
↓
Nocturia (>1 episode/night)
↑↑
↓
Excessive sweating at night
↑↑
↓
Nocturnal reflux
↑↑
↓
Sleep maintenance insomnia
↑↑
↓↓
Nocturnal restlessness
↑
↓↓
History of hypertension
↑↑
↓
History of stroke
↑↑
↓
Morning headaches
↑ ↑ ↑, large increase; ↑ ↑, moderate increase; ↑, little or no increase. ↓ ↓ ↓, large decrease; ↓ ↓, moderate decrease; ↓, little or no decrease.
This model showed a PPV of 90% and an NPV of 67%. A third model is based on simple neck profile, pharyngeal, and overbite scores; OSA was identified with 40% sensitivity and 96% specificity, which produced a PPV of 95% and an NPV of 49%.24 The neck profile measurement alone accurately excluded OSA in about one quarter of referred patients. Direct comparison of these three models is difficult because the studies used different recording techniques and criteria for OSA. Some physical findings other than craniofacial features and obesity also have value in the diagnosis of OSA. High blood pressure increases the chance that OSA will be present, especially among those persons who are less obese.25 Signs of neuropathy or neuromuscular disease also may increase the likelihood of OSA. Nocturnal Polysomnography A nocturnal, laboratory-based polysomnogram (PSG) is the most commonly used test in the diagnosis of OSA. The PSG often is considered a gold standard for OSA diagnosis, assessment of severity, and identification of some other sleep disorders that can accompany OSA. The PSG allows direct monitoring and quantification of respiratory events and physiologic consequences—such as hypoxemia, arousals, and awakenings—that are believed to cause daytime symptoms. A single-night PSG is usually sufficient to diagnose or to exclude OSA. However, the test is not infallible. Accuracy may be reduced by variability in biologic severity, laboratory equipment, human scoring, or scoring protocols. Night-to-night variability may be particularly high in subjects with low but clinically significant rates of apneas and hypopneas during sleep. In one study, when 11 patients thought likely to have OSA on clinical grounds were restudied after initial normal PSGs, 6 had OSA.26
Although standards for scoring normal sleep were consistent and widely accepted for 4 decades,27 their widespread application to abnormal sleep probably did not serve patient care optimally well. Furthermore, standards for scoring sleep-related breathing abnormalities were not specified in the same document and became far from uniform between laboratories. Variations in practice made interpretation of unfamiliar reports difficult. Most important, the definition of hypopnea varied considerably between laboratories.28 The definition of apnea also varied to some extent. Publication by the American Academy of Sleep Medicine in 2007 of new sleep scoring guidelines also included recommendations for polysomnographic equipment; scoring of abnormal respiratory events, electrocardiographic findings, movements, and arousals during sleep; and modifications necessary for children.29 These guidelines are required for sleep laboratories accredited by the Academy and thereby are serving to increase uniformity of procedures between laboratories in the United States. For sleep-disordered breathing, these guidelines also specify rules for optional scoring of respiratory event– related arousals (RERAs), defined by nasal or esophageal pressure monitoring, in the absence of apneas or hypopneas. Most laboratories report a summary measure, called the apnea-hypopnea index (AHI) or the respiratory disturbance index, that represents the sum total of apneas, hypopneas, and—sometimes in the second case—RERAs per hour of sleep. An index of this type is often given the most weight in interpretation of whether the study shows significant sleep-disordered breathing. Other commonly used results, the extent and frequency of oxygen desaturations, are also tallied and reported. Although the 2007 Manual has greatly advanced clinical care, it does have
672 PART II / Section 8 • Impact, Presentation, and Diagnosis
some limitations. The large majority of the recommendations were decided by consensus, in the absence of relevant published data, let alone outcome or evidence-based medicine. With respect to sleep-disordered breathing in particular, the hypopnea rule conforms to current Medicare billing requirements, but hypopneas leading to arousals or awakenings, in the absence of significant oxygen desaturation, are not recognized unless a rule labeled “alternative” is used. Furthermore, scoring of RERAs, by nasal or esophageal pressure monitoring, is “optional.” These multiple options, whether or not necessary given health care funding or widespread practice realities, leave significant disparities between laboratory practices, even among those accredited by the American Academy of Sleep Medicine. Furthermore, not all procedure details could be given in the Manual, and some are therefore left for individual laboratory directors to decide. As a result of this and also the imperfect reliability of PSGs, interpretation of PSG reports remains more complicated, especially when studies are performed by unfamiliar laboratories, and PSGs may not be definitive, particularly in borderline cases. Clinical information about the patient must still play an important role in establishing diagnoses and choosing appropriate management options. Specifically, despite researchers’ tendency to use a specified AHI threshold to define OSA, the clinician cannot succumb to the same temptation. An individual patient with an AHI of 40 is at risk for excessive daytime sleepiness and cardiovascular morbidity but may not have either. Conversely, a patient with an AHI of 2 may still have OSA (e.g., because of night-to-night variability in test results) or may have upper airway resistance syndrome with associated sleepiness and morbidity.13,14 Interpretation of a PSG without knowledge of the patient’s clinical presentation can lead to serious underdiagnosis and overdiagnosis. Many clinicians believe that an AHI above 5 suggests OSA, but a large population-based epidemiologic study found that only 22.6% of women and 15.5% of men who met this criterion clearly complained of daytime hypersomnolence.15 Some patients who meet polysomnographic criteria for OSA but do not complain of hypersomnolence have little to gain from treatment.30 Further research is needed to define and to improve the ability of PSGs to measure those aspects of sleepdisordered breathing that most affect health and daytime sleepiness. The AHI and minimum oxygen saturation do not correlate strongly with daytime sleepiness,31 although the AHI may correlate better with cardiovascular morbidity.25 Some patients with RERAs have excessive daytime sleepiness in the absence of a significant AHI.13 Esophageal pressure monitoring, a gold standard in assessment of respiratory effort, facilitates identification of such patients and is particularly helpful when sleep-disordered breathing is evaluated in patients who lack obvious symptoms and signs.12,32 However, criteria for abnormal esophageal pressure recordings, as defined by association with poor outcomes, remain to be studied more definitively. Nasal pressure monitoring may provide a well-tolerated alternative, but identification of more apneic events by this sensitive measure of airflow is not necessarily a diagnostic advantage; studies have yet to demonstrate improved prediction of outcomes, and initial comparisons to thermistor
results show correlations high enough (e.g., 0.90 or higher33) to suggest redundancy of information. Other polysomnographic measures that may (or may not) prove to enhance the ability of PSGs to predict outcomes of sleep-disordered breathing include end-tidal or transcutaneous carbon dioxide monitoring,34 pulse transit time,35 peripheral arterial tonometry,36 scoring of arousals,37 and analysis of respiratory cycle–related electroencephalographic changes.38 In short, the PSG is the single most useful and definitive test in the diagnosis of sleep-related breathing disorders, but the information it provides cannot be reliably interpreted by persons without experience in sleep medicine, summarized by any single number, or applied to patient care without careful use of additional clinical data. Failure to recognize these limitations, by health care policy makers or clinicians, could trigger unnecessary intervention or deprive a patient of effective treatment. Modified Forms of the Polysomnogram In comparison to the standard PSG, daytime nap studies and split-night studies may reduce costs and expedite evaluation. Studies of daytime PSGs have sometimes found a high NPV, with lower PPV, but inconsistent results and the lack of sufficient data explain why daytime PSGs have not generally been recommended.3 A successful split-night study may save a patient from a second night in the sleep laboratory. Initial studies of diagnostic accuracy and treatment outcomes appear promising.39 Although the preferred approach is separate, full night studies for diagnostic assessment and then positive airway pressure titration, split-night studies are now thought to be adequate alternatives in most cases.40 Portable Recording The wide range of recordings that can be performed during sleep in a patient’s home are designed primarily to test for OSA. Portable recordings usually are less costly than laboratory-based PSGs, and patients often prefer home studies to laboratory studies. However, the diagnostic value of unattended portable monitoring is reduced by the inability to make behavioral observations, to standardize recording conditions, to address technical problems, to make interventions during the night, or (in many cases) to monitor variables equivalent to those recorded in the laboratory setting. Portable studies that do not monitor signals necessary to identify sleep stages or leg movements may show respiratory events that cannot be assumed to have occurred during sleep and may fail to demonstrate disorders other than OSA. A Portable Monitoring Task Force of the American Academy of Sleep Medicine recommended home studies only after a comprehensive sleep evaluation by a clinician board eligible or certified in sleep medicine, and then supervised and interpreted by someone with the same level of specialty training.6 This is because published literature about the effectiveness of home studies usually included screening clinical evaluations, differential diagnoses can be broad, home studies must be interpreted with sufficient knowledge of their many limitations in addition to capabilities, and results must be integrated into the context of the patient’s history and physical examination. Under
CHAPTER 59 • Use of Clinical Tools and Tests in Sleep Medicine 673
these conditions, home studies can be used as an alternative to laboratory-based PSGs when the clinical judgment suggests that pretest probability of moderate to severe OSA is high. Home studies should generally not be used when the patient is a child or older person, significant health comorbidities (such as severe pulmonary disease, neuromuscular disease, or congestive heart failure) are present, additional sleep disorders besides OSA are suspected, or a screening process is needed for asymptomatic individuals, even if at risk because of comorbidities such as hypertension or obesity.6 Home studies may be indicated for patients who do not have access to laboratory-based PSG, cannot tolerate the procedure, or need follow-up assessment of response to non–positive airway pressure treatments of OSA. A recent randomized but not blinded clinical trial supported use of home oximetry as an alternative to more elaborate studies, but only in combination with a sleep specialist evaluation, threshold scores on several screening surveys, absence of significant comorbidities, and other circumstances that in combination applied to less than 4% of referred patients.41 Published guidelines for home studies recommend that at minimum they monitor airflow, respiratory effort, and blood oxygenation, and the equipment should be applied by a sleep technologist or health care practitioner with appropriate training.6 A normal home study generally must be confirmed by a more definitive laboratory-based sleep study. A suggested algorithm for use of home studies is shown in Figure 59-1. Despite limited validation data for many portable recording devices, those that have low costs, high sensitivities, and high specificities have convinced some clinicians that portable studies are cost-effective in comparison to PSGs. However, cost-effectiveness analyses have been scarce (see later). In some situations, home studies could increase costs, delay confirmatory laboratory testing, encourage treatment of patients with false-positive results, or allow development of medical morbidity from undiagnosed and therefore untreated OSA. Nonetheless, Medicare recently approved home studies for justification of the need for home use of continuous positive airway pressure. Coverage of the expense of home studies was motivated in part by evidence that gold standard PSG measures do not necessarily predict symptoms or response to treatment accurately. Whether positive airway pressure is justified by findings of home or laboratory studies, Medicare now requires posttreatment clinical verification that positive airway pressure is used and helpful for the individual patient. Studies of Airway Morphology Although imaging of the upper airway for research purposes has led to a better understanding of OSA pathophysiology, such studies are not routinely performed in diagnostic evaluations of patients, in part because findings that predict OSA or its severity with sufficient accuracy to allow use in management of individual patients have not been identified. However, cephalometric radiography and pharyngoscopy may be useful in preoperative identification of sites of obstruction and in selection of appropriate surgical procedures. The diagnostic value of
PORTABLE MONITORING DECISION TREE Patient presents to BCSS for evaluation of suspected OSA
Does the patient have a high pretest probability of moderate to severe OSA?
Evaluate for other sleep disorders, consider in-lab PSG
No
Yes Does patient have symptoms or signs of comorbid medical disorders?
Yes No
No Does patient have symptoms or Yes In-lab signs of comorbid polysomnography sleep disorders?
OSA diagnosed?
No Sleep study (PM or in-lab PSG)
PM
No
OSA diagnosed?
Yes
Yes
Treatment
Figure 59-1 Recommended use of home studies. BCSS, Boardcatified sleep specialist; OSA, obstructive sleep apnea; PM, portable monitoring; PSG, polysomnography. (Reprinted with permission from Collop NA, Anderson WM, Boehlecke B, et al. Clinical guidelines for the use of unattended portable monitors in the diagnosis of obstructive sleep apnea in adult patients. Portable Monitoring Task Force of the American Academy of Sleep Medicine. J Clin Sleep Med 2007;3:737-747.)
cephalometrics may be limited in part because only sagittal plane dimensions are provided, and coronal plane dimensions or volume may be more pertinent to OSA.42 Pharyngoscopy allows three-dimensional anatomic characterization, but whether airway collapse with Müller’s maneuver predicts response to uvulopalatopharyngoplasty is debated. Pharyngoscopy may be particularly valuable if it is performed during supine sleep.43 Techniques for quantitative computer-assisted videoendoscopic airway analysis are also being developed and have shown, for example, correlation between the extent of anatomic change after uvulopalatopharyngoplasty and improvement in the AHI.44 Computed tomography and magnetic resonance imaging studies can show upper airway morphology,42 and some authors suggest the potential for clinical usefulness,45 but the value of these techniques in the clinical setting is not well defined. In particular, it is uncertain that imaging techniques more sophisticated and expensive than cephalometric radiographs and pharyngoscopy provide additional, valuable clinical information.
674 PART II / Section 8 • Impact, Presentation, and Diagnosis
EVALUATION OF HYPERSOMNOLENCE History and Questionnaires The history provides important clues to the severity of hypersomnolence. Direct inquiry about sleepiness can be supplemented by questions about sleepiness in sedentary situations, such as driving, desk work, reading, or watching television. However, patients may report little of the excessive daytime sleepiness suggested by family members, clinical signs, or objective tests. Words other than sleepiness are often used by patients with sleep disorders to describe the chief complaint. Among 190 apneic subjects in one study, preferred terms included lack of energy (40%), tiredness (20%), fatigue (18%), and sleepiness (22%).46 Patients’ opinions about their own sleepiness sometimes show no significant association with results of the Multiple Sleep Latency Test (MSLT).47 Questionnaires such as the Epworth Sleepiness Scale48 and the Stanford Sleepiness Scale49 provide a more formal and perhaps reliable measure of excessive daytime sleepiness. The impact of sleepiness on activities of daily living can be assessed with the Functional Outcomes of Sleep Questionnaire.50 Epworth results correlate reasonably well with patients’ self-ratings for overall sleepiness but not well with MSLT results.51 Although the Epworth Sleepiness Scale and the Stanford Sleepiness Scale can have clinical utility, for example, in monitoring response to treatment over time, they do not substitute for well-validated objective measures of sleepiness. Unfortunately, the ability of subjective tests of sleepiness to predict future health outcomes remains largely unknown. Physical Examination Although the alerting effect of an examination obscures physical signs of sleepiness in most patients, overt signs of sleepiness—such as the inability to stay awake or to keep eyes open in the examination room—have high PPV and may obviate the need for additional tests. The examination may also help distinguish severe sleepiness from stupor due to neurologic impairment or drugs. Nocturnal Polysomnography Many patients referred to sleep centers for excessive daytime sleepiness have nocturnal sleep disorders, and polysomnography is often more notable for the manifestations of such disorders than for signs of excessive daytime sleepiness. Patients whose excessive daytime sleepiness is due to insufficient sleep can show shorter sleep latencies, increased sleep efficiency, decreased stage 1 sleep, and increased amounts of deep non–rapid eye movement (nonREM) sleep and REM sleep. The single polysomnographic variable that best reflects sleepiness, as measured by the mean sleep latency on the MSLT, is nocturnal sleep latency.52 Polysomnographic measures of sleep pathology, such as the AHI and minimum oxygen saturation, show only low magnitudes of correlation with MSLT results.53 Multiple Sleep Latency Test The mean sleep latency on the MSLT is the most commonly used objective measure in assessment of daytime sleepiness.54 The MSLT may contribute to diagnosis but
is usually not sufficient, alone, to establish a diagnosis. The mean sleep latency is most useful when it is clearly abnormally low. A patient with a mean sleep latency of 2 minutes on a properly performed MSLT is unlikely to be exaggerating a complaint of excessive daytime sleepiness, to suffer from fatigue rather than sleepiness, or to be free of any sleep disorder. The MSLT can help determine the clinical significance of a sleep disorder or assess response to treatment. As a general guideline, mean sleep latencies shorter than 8 minutes on a properly conducted MSLT are considered abnormal,54 and latencies shorter than 5 minutes are often taken to indicate severe excessive daytime sleepiness. However, proper interpretation of MSLT results requires integration of other factors and especially knowledge of the limitations of this test. Results may be misleading if they are affected by youth (different criteria apply for children), noise, anxiety, or atypical sleep on the previous night. Use of medications such as stimulants or antidepressants, their recent discontinuance, or inability to be weaned off them at least 10 days before testing can prevent administration of an MSLT or complicate interpretation of results. Sleep apnea and other sleep disorders may make sleep onset more difficult and thereby interfere with the test. In general, the NPV of a long mean sleep latency is less than the PPV of a particularly short mean sleep latency. When an MSLT is normal, clinicians must carefully consider other possible explanations before telling a subjectively sleepy patient that there is no objective evidence of excessive daytime sleepiness. Formal prospective studies of “real-life” outcomes associated with different mean sleep latencies are still needed, but until such data are available, clinicians should realize that MSLT results form a continuum without strictly interpretable cutoffs. Like most other physiologic tests, the MSLT is subject to test-retest biologic variation; a patient’s mean sleep latency may be 4 minutes on one day and 9 minutes on another without any intervening therapy. Communitybased samples of adults show mean sleep latencies of 8 minutes or less in well above 20% of subjects.55 High test-retest reliability among normal subjects56 does not necessarily generalize to patients.57 Interrater reliability can be excellent but adds another source of potential variation in test results. Finally, interpretation of the mean sleep latency on the MSLT must take into account available data on validity of the test. The most consistent data in support of the validity of the MSLT were generated in experiments with sleep deprivation, restriction, or fragmentation. However, in clinical practice, polysomnographic measures of the severity of sleep disorders may show small53,58 or insignificant52,59 correlation with MSLT results. A clinician should not be surprised when a patient with 8 apneic events per hour of sleep has a lower mean sleep latency than a patient who has 50 such events per hour of sleep. Furthermore, despite clear clinical improvement demonstrated by sleep apneic subjects and other patients treated for their sleep disorders, the MSLT does not always reflect the improvement.60,61 Evidence that mean sleep latency on the MSLT does not necessarily parallel other measures of sleepiness or reflect the patient’s symptoms may mean that the MSLT does not measure sleepiness precisely. However, the same
CHAPTER 59 • Use of Clinical Tools and Tests in Sleep Medicine 675
evidence can also be used to support the importance of the MSLT, which provides unique data not generated by other methods. Sleepiness may have several aspects, some of which are measured better by the MSLT and some by other means.62 The investigators who developed the MSLT originally described it as a measure of physiologic sleep tendency rather than a direct measure of sleepiness.63 The narrower concept may define an important part of the neurophysiologic state of sleepiness without capturing the entire concept. Use of the MSLT in the Diagnosis of Narcolepsy The MSLT criteria for narcolepsy—two or more sleeponset REM periods (SOREMPs) and a short mean sleep latency—were once thought to have high sensitivity and specificity. Original case series suggested that all narcoleptic subjects and virtually no normal controls had two or more SOREMPs64; the PPV of two or more SOREMPs for the diagnosis of narcolepsy was 98%, and the NPV was 89%.65 More recent studies did not find the SOREMP criteria to provide such diagnostic accuracy, partly because the most common reasons for sleep laboratory referral evolved. Two or more SOREMPs were found in 25% of 187 sleep apneic subjects,66 17% of 139 normal subjects,67 and only 83% of 200 narcoleptic subjects who had cataplexy.68 Among 2083 patients evaluated with MSLTs at one sleep center, the PPV of two or more SOREMPs was 57% and the NPV was 98%.69 Other combinations of MSLT and polysomnographic criteria may have additional utility.69 A positive MSLT result is essential to establish a diagnosis of narcolepsy without cataplexy and useful also in making a diagnosis of narcolepsy with cataplexy.5 However, the MSLT results cannot be used alone to diagnose narcolepsy; the presence of SOREMPs must be interpreted in conjunction with other clinical and polysomnographic findings. In particular, the criterion of two or more SOREMPs cannot be used to diagnose narcolepsy when the patient has untreated OSA, upper airway resistance syndrome, or other sleep disorders associated with SOREMPs. As an alternative to the MSLT, cerebrospinal fluid hypocretin-1 levels can be used to confirm narcolepsy with cataplexy. These levels are low (≤110 pg/ mL or one third of the mean for controls) in more than 90% of affected patients but almost never among patients without this diagnosis.5 Variations of the Multiple Sleep Latency Test and Other Physiologic Tests Results of the Maintenance of Wakefulness Test (MWT) can differ markedly from those of the MSLT,70 but whether the MWT results are more predictive of adverse effects of sleepiness in daily life remains unknown. Results of both the MWT and MSLT can be influenced by the patient’s motivation.71 The MWT results correlate with measures of sleep apnea severity to about the same extent as MSLT results do72 but may better reflect improvement with treatment.70 Shorter sleep latencies on MWTs correlate with increased errors on driving simulation tests.73,74 However, until MWT and MSLT results are shown to differ in a clinically meaningful way, the MSLT continues to offer advantages of more published experience, familiarity among clinicians, and relevance to the diagnosis of narco-
lepsy. The Federal Aviation Administration and other agencies may at times request or require an MWT, but given the dearth of proven real-life predictive value, the role of this test or the MSLT in predicting workplace safety remains controversial.75,76 Other MSLT modifications, for which limited validity data exist, include the assignment of a simple performance task during the nap attempts77; a formula to combine quantities of sleep stages attained on naps into an overall polygraphic score of sleepiness78; calculation of mean wake efficiencies (100% minus time asleep during nap attempt) as an alternative to mean sleep latencies79; definition of sleep onset by a subject’s failure to respond to an intermittent light signal80; and use of survival analysis methods to better incorporate information from nap attempts on which no sleep was obtained.81 In the clinical setting, none of these modifications has a well-established role in the evaluation of hypersomnolence; neither do a range of other physiologic tests, including pupillometry and brainstem auditory evoked potentials. A variety of performancebased tests are used, usually in research settings, to assess variables related to sleepiness. Examples are the Psychomotor Vigilance Task82 and the Steer Clear driving simulation test.83
EVALUATION OF INSOMNIA Like excessive daytime sleepiness, the complaint of inadequate, insufficient, or nonrestorative sleep can have many different causes. However, causes of insomnia are often diagnosed by history alone.84 In part because the gold standard is not a physiologic test, few data are available with which to assess the relative value of individual symptoms. Predictive values for some symptoms are likely to be high because symptoms define the disorders. When a history does not reveal a cause of the insomnia, polysomnography may be useful (see later), but referral to an appropriate specialist for further history taking and evaluation is sometimes necessary. For example, if the sleep clinician cannot thoroughly evaluate a patient for depression, a psychiatrist or psychologist may be better able to establish a diagnosis and treatment regimen that will lead to resolution of the patient’s insomnia. Psychometric tests can reveal cognitive differences between insomniac subjects and normal controls,85 but these tests are not commonly used for diagnostic purposes in the clinical sleep medicine setting. Sleep logs are an important tool in the evaluation of insomnia,86 but data on their predictive value have not been published. Logs are not necessary to establish the presence of insomnia but can help define severity and facilitate identification of causes such as inadequate sleep hygiene, delayed sleep phase syndrome, or psychophysiologic insomnia. The physical and mental status examinations may provide clues that the cause of a patient’s insomnia is an underlying medical or psychiatric illness, such as hyperthyroidism, asthma, benign prostatic hypertrophy, painful lumbar radiculopathy, arthritis, depression, or anxiety. The importance and focus of an examination vary according to what is learned from the history. A patient’s history and physical examination sometimes suggest that insomnia
676 PART II / Section 8 • Impact, Presentation, and Diagnosis
may be due to sleep-disordered breathing, periodic limb movement disorder, or uncertain causes. In such cases, polysomnography can be an important aid to diagnosis.87 If insomnia fails to respond to treatment for initial diagnoses, polysomnography also may be useful. Polysomnography may be indicated for patients who have precipitous arousals with violent or injurious behavior.84 Polysomnography may also be useful in some cases when sleep state misperception is suspected. However, injudicious use of polysomnography can sometimes enhance an insomniac person’s conviction that symptoms are due to physical rather than behavioral causes or lead to diagnoses that eventually prove irrelevant to the main complaint. Polysomnography is not indicated for routine evaluation of insomnia that is transient or chronic, due to psychiatric disorders, associated with dementia, or found in the many conditions (such as fibromyalgia) that are associated with the alpha-delta sleep pattern.84
EVALUATION FOR SUSPECTED PARASOMNIAS With the notable exception of REM sleep behavior disorder, parasomnias often can be diagnosed by history alone.5 Information obtained from a bed partner may contribute more than that obtained from the patient. Classic descriptions can be diagnostic for disorders such as sleep terrors, rhythmic movement disorder, sleep paralysis, sleep bruxism, and sleep enuresis. However, the history in such cases occasionally can be misleading, as when one patient’s nocturnal behaviors and bed wetting episodes were shown by polysomnography to occur only during wakefulness.88 Furthermore, some parasomnia presentations commonly lead to a differential diagnosis that frequently requires clarification by polysomnography. For example, the differential diagnosis for a middle-aged adult who presents with behavioral episodes at night may include not only sleepwalking but also REM sleep behavior disorder and complex partial seizures. The physical examination of patients evaluated for parasomnias can be useful, but its value is not well quantified. Some signs may suggest sleep apnea as an underlying trigger for confusional arousals, sleepwalking, sleep terrors, REM sleep behavior disorder, or nocturnal enuresis. Worn occlusive surfaces of molars can provide key evidence of sleep bruxism. The urogenital examination is important in patients thought to have impaired sleep-related penile erections, sleep-related painful erections, or sleep enuresis. Endocrine, cardiac, vascular, and neurologic examination findings can also show a cause of erectile dysfunction. A neurologic examination may suggest a primary cause of sleep enuresis or REM sleep behavior disorder. Similarly, appropriate laboratory findings may be helpful in some cases; for example, a urinalysis may reveal the cause of sleep enuresis. Few studies have examined the predictive value of polysomnography for parasomnia diagnoses. When the behavior in question occurs during polysomnography, the diagnostic value of the test is likely to be high, especially if appropriate additional recording devices, such as extra electroencephalographic leads, extra surface electromyographic leads, or video monitoring, are used.89 Unfortu-
nately, polysomnography often fails to document the behavior—especially in cases of suspected REM sleep behavior disorder, sleepwalking, night terrors, and epilepsy—either because the behavior does not occur on most nights or perhaps because the sleep laboratory is not an environment familiar to the patient. However, other findings during polysomnography can have positive predictive value. Examples include excessive limb twitching during REM sleep in a patient tested for REM sleep behavior disorder and spike and wave complexes in the electroencephalographic examination of a patient thought to have epilepsy. The electromyographic abnormalities in REM sleep behavior disorder can be quantified by eye or computer, in a manner that leads to good sensitivity (about 89% to 100% in a small series of patients with and without neurodegenerative disorders) and reasonable specificity (57% to 71%) against a clinical diagnosis based on accepted diagnostic criteria.90-92 For evaluation of parasomnias, the NPV of a completely normal study is less clear than the PPV of an abnormal study. In one series of 122 patients with suspected parasomnias, one or two nights of polysomnography with video monitoring contributed useful diagnostic information in more than 50% of the cases.89
BEYOND SENSITIVITY, SPECIFICITY, AND PREDICTIVE VALUE: DECISION AND COST-EFFECTIVENESS ANALYSES Data on sensitivity, specificity, pretest probability, and utility of outcomes can be used to construct a decision analysis. A clinical decision analysis typically models a choice between diagnostic and therapeutic alternatives. Logical rules are used to weigh information and to make the best decision for an individual patient.93 Decision analysis may be useful, for example, when one procedure has a high probability of a small benefit but an alternative has a low probability of a large benefit. Physicians often attempt a similar mental process but do not usually make optimal use of their own beliefs about probabilities and values of outcomes. Beyond utility, economic data on a procedure can include cost studies, cost-effectiveness analyses that compare different methods to achieve the same end, costutility analyses that compare costs per common unit of utility (often quality-adjusted life years), and cost-benefit analyses that compare monetary costs with monetary gains.94 Such studies require quantitative information on costs and outcomes, data that are not abundant for sleep disorders.95,96 Despite uncertainty of some important data points, one published cost-utility model focused on the decision of whether to diagnose OSA with the aid of a polysomnography, portable cardiorespiratory monitoring, or no ancillary test.97 Polysomnography generated higher utility than the other diagnostic options did, and the magnitude of the advantage of polysomnography easily justified the added initial expense. This result appeared to reflect the high utility of an OSA diagnosis and the expense of diagnostic mistakes. These findings highlight the importance of performing decision and cost-utility analyses before conclusions are made about relative values of diagnostic tests.
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❖ Clinical Pearl Evaluation of common sleep complaints is based on symptoms, signs, and test results, combined with an understanding of the diagnostic value that each type of data contributes.
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104. Martínez García MA, Soler Cataluña JJ, Román Sánchez P, et al. Clinical predictors of sleep apnea-hypopnea syndrome susceptible to treatment with continuous positive airway pressure. Arch Bronconeumol 2003;39:449-454. 105. Chung F, Yegneswaran B, Liao P, et al. STOP questionnaire—a tool to screen patients for obstructive sleep apnea. Anesthesiology 2008;108:812-821. 106. Chung F, Yegneswaran B, Liao P, et al. Validation of the Berlin questionnaire and American Society of Anesthesiologists checklist as screening tools for obstructive sleep apnea in surgical patients. Anesthesiology 2008;108:822-830.
Classification of Sleep Disorders Michael J. Thorpy Abstract The classification of sleep disorders is necessary to discriminate between disorders and to facilitate an understanding of symptoms, etiology, pathophysiology, and treatment. The earliest classification systems were largely organized according to the major symptoms (insomnia, excessive sleepiness, and abnormal events that occur during sleep), because the pathophysiologic basis for many of the sleep disorders was unknown. These three categories provide a classification system that is easily understood by physicians and that is useful for developing a differential diagnosis. With the development of modern sleep research, some categories can now be based on patho-
The classification of sleep disorders has been of particular interest to clinicians ever since sleep disorders were first recognized. The first major classification, the Diagnostic Classification of Sleep and Arousal Disorders, published in 1979,1 organized the sleep disorders into categories that formed the basis of the current classification systems. In 1990, the International Classification of Sleep Disorders (ICSD) was produced after a 5-year process, initiated by the American Sleep Disorders Association (ASDA), that involved the three major international sleep societies at that time: the European Sleep Research Society, the Japanese Society of Sleep Research, and the Latin American Sleep Society. It resulted in the production of a diagnostic and coding manual, the International Classification of Sleep Disorders: Diagnostic and Coding Manual.2 The ICSD classification, developed primarily for diagnostic, epidemiologic, and research purposes, has been widely used by clinicians and has allowed better international communication in sleep disorder research. In 2003, the American Academy of Sleep Medicine, formerly the ASDA, began a complete revision and update of the ICSD. The resulting text, the International Classification of Sleep Disorders, version 2 (ICSD-2), was published in 2005 (Table 60-1).3 The ICSD-2 classification lists 85 sleep disorders, each presented in detail and with a descriptive diagnostic text that includes specific diagnostic criteria. The ICSD-2 has eight major categories: the insomnias, sleep-related breathing disorders, hypersomnias of central origin, circadian rhythm sleep disorders, the parasomnias, sleep-related movement disorders, isolated symptoms that are apparently normal variants and unresolved issues, and other sleep disorders. Most of the world uses the ICD-10 for classification of diseases. The ICD-10 transition date in the USA is October 1, 2013. This chapter includes these ICD-10 sleep codes.3a
INSOMNIAS The insomnias are defined by a repeated difficulty with sleep initiation, duration, consolidation, or quality that occurs despite adequate time and opportunity for sleep, 680
Chapter
60
physiology. The International Classification of Sleep Disorders, version 2 (ICSD-2), published in 2005, combines a symptomatic presentation (e.g., insomnia) with one organized in part on pathophysiology (e.g., circadian rhythms) and in part on body systems (e.g., breathing disorders). This organization is necessary because of the varied nature of the sleep disorders and because the pathophysiology for many of the disorders is unknown. The ICSD-2 is not just a listing of the sleep disorders but is also a manual that lists relevant information on the diagnostic features and epidemiology to help the reader more easily differentiate between the disorders.
and they result in some form of daytime impairment (see Section 10). Insomnia complaints typically include difficulty initiating or maintaining sleep (or both), and they usually include extended periods of nocturnal wakefulness or insufficient amounts of nocturnal sleep. Occasionally, insomnia complaints are characterized by the perception of poor quality, or nonrestorative, sleep, even when the amount and quality of the usual sleep episode is considered to be normal or adequate. The insomnias can be either primary or secondary. Secondary forms can occur when the insomnia is a symptom of a medical or psychiatric illness, another sleep disorder, or substance abuse. Primary insomnias may have both intrinsic and extrinsic factors involved in their etiology, but they are not regarded as being secondary to another disorder. Primary Insomnia There are six types of primary insomnia. Psychophysiologic insomnia4,5 is a common form of insomnia that is present for at least 1 month and is characterized by a heightened level of arousal with learned sleep-preventing associations. There is an overconcern with the inability to sleep. Paradoxical insomnia (formerly known as sleep state misperception),6,7 is a complaint of severe insomnia that occurs without evidence of objective sleep disturbance and without daytime impairment to the extent that would be suggested by the amount of sleep disturbance reported. The patient often reports little or no sleep on most nights. It is thought to occur in up to 5% of insomniac patients. Adjustment sleep disorder8,9 is insomnia that is associated with a specific stressor. The stressor can be psychological, physiologic, environmental, or physical. This disorder exists for a short period, usually days to weeks, and usually resolves when the stressor is no longer present. Inadequate sleep hygiene10,11 is a disorder associated with common daily activities that are inconsistent with good-quality sleep and full daytime alertness. Such activities include irregular sleep onset and wake times, stimulating and alerting activities before bedtime, and substances (e.g., alcohol, caffeine, cigarette smoke) ingested around
CHAPTER 60 • Classification of Sleep Disorders 681
Table 60-1 ICSD-2 Sleep Disorder Categories and Individual Sleep Disorders SLEEP DISORDERS
ICD-9-CM
ICD-10-CM
Adjustment sleep disorder (acute insomnia)
307.41
F 51.02
Psychophysiologic insomnia
307.42
F 51.04
Paradoxical insomnia (formerly sleep state misperception)
307.42
F 51.03
Idiopathic insomnia
307.42
F 51.01
Insomnia due to mental disorder
307.42
F 51.05
V69.4
Z72.821
Insomnias
Inadequate sleep hygiene
307.42
—
Sleep-onset association type
Behavioral insomnia of childhood
—
Z73.810
Limit-setting sleep type
—
Z73.811
Combined type
—
Z73.812
Insomnia due to drug or substance
292.85
G47.02
Insomnia due to medical condition (code also the associated medical condition)
327.01
G47.01
Insomnia not due to a substance or known physiologic condition, unspecified
780.52
F51.09
Physiologic (organic) insomnia, unspecified; (organic insomnia, NOS)
327.00
G47.09
Primary central sleep apnea
327.21
G47.31
Central sleep apnea due to Cheyne Stokes breathing pattern
768.04
R06.3
Central sleep apnea due to high altitude periodic breathing
327.22
G47.32
Central sleep apnea due to a medical condition, not Cheyne-Stokes
327.27
G47.31
Central sleep apnea due to a drug or substance
327.29
F10-19
Primary sleep apnea of infancy
770.81
P28.3
Obstructive sleep apnea, adult
327.23
G47.33
Obstructive sleep apnea, pediatric
327.23
G47.33
Sleep-related nonobstructive alveolar hypoventilation, idiopathic
327.24
G47.34
Congenital central alveolar hypoventilation syndrome
327.25
G47.35
Sleep-related hypoventilation or hypoxemia due to pulmonary parenchymal or vascular pathology
327.26
G47.36
Sleep-related hypoventilation or hypoxemia due to lower airways obstruction
327.26
G47.36
Sleep-related hypoventilation or hypoxemia due to neuromuscular or chest wall disorders
327.26
G47.36
320.20
G47.30
Narcolepsy with cataplexy
347.01
G47.411
Narcolepsy without cataplexy
347.00
G47.419
Narcolepsy due to medical condition
347.10
G47.421
Narcolepsy, unspecified
347.00
G47.43
Recurrent hypersomnia
780.54
G47.13
Kleine-Levin syndrome
327.13
G47.13
Menstrual-related hypersomnia
327.13
G47.13
Idiopathic hypersomnia with long sleep time
327.11
G47.11
Idiopathic hypersomnia without long sleep time
327.12
G47.12
Behaviorally induced insufficient sleep syndrome
307.44
F51.12
Hypersomnia due to medical condition
327.14
G47.14
Hypersomnia due to drug or substance
292.85
G47.14
Sleep-Related Breathing Disorders Central Sleep Apnea Syndromes
Obstructive Sleep Apnea Syndromes
Sleep-Related Hypoventilation and Hypoxemic Syndromes
Sleep-Related Hypoventilation and Hypoxemia Due to a Medical Condition
Other Sleep-Related Breathing Disorder Sleep apnea or sleep-related breathing disorder, unspecified Hypersomnias of Central Origin
Continued
682 PART II / Section 8 • Impact, Presentation, and Diagnosis Table 60-1 ICSD-2 Sleep Disorder Categories and Individual Sleep Disorders—cont’d SLEEP DISORDERS
ICD-9-CM
ICD-10-CM
Hypersomnia not due to a substance or known physiologic condition
327.15
F51.1
Physiologic (organic) hypersomnia, unspecified (organic hypersomnia, NOS)
327.10
G47.10
Circadian rhythm sleep disorder, delayed sleep phase type
327.31
G47.21
Circadian rhythm sleep disorder, advanced sleep phase type
327.32
G47.22
Circadian rhythm sleep disorder, irregular sleep–wake type
327.33
G47.23
Circadian rhythm sleep disorder, free-running (nonentrained) type
327.34
G47.24
Circadian rhythm sleep disorder, jet lag type
327.35
G47.25
Circadian rhythm sleep disorder, shift-work type
327.36
G47.26
Circadian rhythm sleep disorders due to medical condition
327.37
G47.27
Other circadian rhythm sleep disorder
327.39
G47.29
Other circadian rhythm sleep disorder due to drug or substance
292.85
G47.27
Confusional arousals
327.41
G47.51
Sleepwalking
307.46
F51.3
Sleep terrors
307.46
F51.4
REM sleep behavior disorder (including parasomnia overlap disorder and status dissociatus)
327.42
G47.52
Recurrent isolated sleep paralysis
327.43
G47.53
Nightmare disorder
307.47
F51.5
Sleep-related dissociative disorders
300.15
F44.9
Sleep enuresis
788.36
N39.44
Sleep-related groaning (catathrenia)
327.49
G47.59
Exploding head syndrome
327.49
G47.59
Sleep-related hallucinations
368.16
R29.81
Sleep-related eating disorder
327.49
G47.59
Parasomnia, unspecified
227.40
G47.50
Parasomnia due to a drug or substance
292.85
G47.54
Parasomnia due to a medical condition
327.44
G47.54
Restless legs syndrome (including sleep-related growing pains)
333.49
G25.81
Periodic limb movement sleep disorder
327.51
G47.61
Sleep-related leg cramps
327.52
G47.62
Sleep-related bruxism
327.53
G47.63
Sleep-related rhythmic movement disorder
327.59
G47.69
Sleep-related movement disorder, unspecified
327.59
G47.90
Sleep-related movement disorder due to drug or substance
327.59
G47.67
Sleep-related movement disorder due to medical condition
327.59
G47.67
Long sleeper
307.49
R29.81
Short sleeper
307.49
R29.81
Snoring
786.09
R06.83
Sleeptalking
307.49
R29.81
Sleep starts, hypnic jerks
307.47
R25.8
Benign sleep myoclonus of infancy
781.01
R25.8
Circadian Rhythm Sleep Disorders
Parasomnias Disorders of Arousal (from Non-REM Sleep)
Parasomnias usually associated with REM sleep
Sleep-Related Movement Disorders
Isolated Symptoms, Apparently Normal Variants, and Unresolved Issues
Hypnagogic foot tremor and alternating leg muscle activation during sleep
781.01
R25.8
Propriospinal myoclonus at sleep onset
781.01
R25.8
Excessive fragmentary myoclonus
781.01
R25.8 Continued
CHAPTER 60 • Classification of Sleep Disorders 683
Table 60-1 ICSD-2 Sleep Disorder Categories and Individual Sleep Disorders—cont’d SLEEP DISORDERS
ICD-9-CM
ICD-10-CM
Other physiologic (organic) sleep disorder
327.8
G47.8
Other sleep disorder not due to a known substance or physiologic condition
327.8
G47.9
307.48
F51.8
Other Sleep Disorders
Environmental sleep disorder Sleep Disorders Associated with Conditions Classifiable Elsewhere Fatal familial insomnia
046.8
A81.8
Fibromyalgia
729.1
M79.7
345
G40.5
Sleep-related epilepsy Sleep-related headaches
784.0
R51
Sleep-related gastroesophageal reflux disease
530.1
K21.9
Sleep-related coronary artery ischemia
411.8
I25.6
Sleep-related abnormal swallowing, choking, and laryngospasm
787.2
R13.1
Other Psychiatric or Behavioral Disorders Commonly Encountered in the Differential Diagnosis of Sleep Disorders Mood disorders
—
—
Anxiety disorders
—
—
Somatoform disorders
—
—
Schizophrenia and other psychotic disorders
—
—
Disorders usually first diagnosed in infancy, childhood, or adolescence
—
—
Personality disorders
—
—
ICD-9, International Classification of Diseases, 9th Revision; ICD-10, International Classification of Diseases, 10th Revision; ICSD-2, International Classification of Sleep Disorders, Revised; NOS, not otherwise specified. Courtesy of the American Academy of Sleep Medicine, Chicago, Ill.
sleep time. These practices do not necessarily cause sleep disturbance in other people. For example, an irregular bedtime or wake time that produces insomnia in one person may not be important in another. Idiopathic insomnia12,13 is a long-standing form of insomnia that appears to date from childhood and has an insidious onset. Typically, there are no factors associated with the onset of the insomnia, which is persistent and without periods of remission. Behavioral insomnia of childhood14,15 includes limitsetting sleep disorder and sleep-onset association disorder. Limit-setting sleep disorder is a stalling or a refusing to go to sleep that is eliminated once a caretaker enforces limits on sleep times and other sleep-related behaviors. Sleeponset association disorder occurs when there is reliance on inappropriate sleep associations, such as rocking, watching television, holding a bottle or other object, or requiring environmental conditions such as a lighted room or an alternative place to sleep.
insomnia. The insomnia may be associated with the ingestion or discontinuation of the substance.20,21 Excessive use or dependency is not a feature of this diagnosis. Insomnia not due to a substance or known physiologic condition22,23 (formerly associated with other mental/behavioral factors) is the diagnosis applied when an underlying mental disorder is associated with the occurrence of the insomnia and when the insomnia constitutes a distinct complaint or focus of treatment. Differentiation between the two diagnoses, inadequate sleep hygiene and other insomnia due to a substance requires some elaboration. Caffeine ingestion in the form of coffee or soda can produce a disorder of inadequate sleep hygiene, if the intake amount is normal and within the limits of common use but the timing of ingestion is inappropriate. On the other hand, ingestion of caffeine in an amount that is considered excessive by normal standards can lead to a diagnosis of other insomnia due to a substance.
Secondary Insomnia The ICSD-2 classification lists several secondary insomnias. Insomnia due to medical condition16,17 is applied when a medical or neurologic disorder gives rise to the insomnia. The medical disorder and the insomnia type are given with the diagnosis. Insomnia due to drug or substance18,19 is applied when there is dependence on or excessive use of a substance such as alcohol, a recreational drug, or caffeine that is associated with the occurrence of the
SLEEP-RELATED BREATHING DISORDERS The disorders in this group are characterized by disordered respiration during sleep (see Section 13). Central apnea syndromes24,25 include those in which respiratory effort is diminished or absent in an intermittent or cyclic fashion as a result of central nervous system dysfunction. Other central sleep apnea forms are associated with
684 PART II / Section 8 • Impact, Presentation, and Diagnosis
underlying pathologic or environmental causes, such as Cheyne–Stokes breathing pattern26,27 or high-altitude periodic breathing.28,29 Primary Sleep Apneas Primary central sleep apnea is a disorder of unknown cause characterized by recurrent episodes of cessation of breathing during sleep without associated ventilatory effort. A complaint of excessive daytime sleepiness, insomnia, or difficulty breathing during sleep is reported. The patient must not be hypercapnic (Pco2 greater than 45 mm Hg). This diagnosis requires that five or more apneic episodes per hour of sleep be seen by polysomnography. Central sleep apnea resulting from the Cheyne–Stokes breathing pattern is characterized by recurrent apneas or hypopneas alternating with prolonged hyperpnea in which tidal volume waxes and wanes in a crescendo–decrescendo pattern. This pattern does not occur in rapid eye movement (REM) sleep but is characteristically seen in non-REM (NREM) sleep. The pattern is typically seen in medical disorders such as heart failure, cerebrovascular disorders, and kidney failure. Central sleep apnea resulting from high-altitude periodic breathing30,31 is characterized by sleep disturbance that is caused by cycling periods of apnea and hyperpnea without ventilatory effort. The cycle length is typically between 12 and 34 seconds. Five or more central apneas per hour of sleep are required to make the diagnosis. Most people have this ventilatory pattern at elevations greater than 7600 meters, and some have it at lower altitudes. A secondary form of central sleep apnea resulting from drug or substance (substance abuse)30,32 is most commonly associated with long-term opioid use. The substance causes a respiratory depression by acting on the mu receptors of the ventral medulla. A central apnea index of greater than 5 is required for the diagnosis. Primary sleep apnea of infancy31,33 is a disorder of respiratory control most often seen in preterm infants (apnea of prematurity), but it can occur in predisposed infants (apnea of infancy). This may be a developmental pattern, or it may be secondary to other medical disorders. Respiratory pauses of 20 seconds or longer are required for the diagnosis. Obstructive Sleep Apneas The obstructive sleep apnea syndromes include those in which there is an obstruction in the airway resulting in increased breathing effort and inadequate ventilation. Upper airway resistance syndrome has been recognized as a manifestation of obstructive sleep apnea syndrome and therefore is not included as a separate diagnosis. Adult and pediatric forms of obstructive sleep apnea syndrome are discussed separately because the disorders have different methods of diagnosis and treatment. Adult obstructive sleep apnea34,35 is characterized by repetitive episodes of cessation of breathing (apneas) or partial upper airway obstruction (hypopneas). These events are often associated with reduced blood oxygen saturation. Snoring and sleep disruption are typical and common. Excessive daytime sleepiness or insomnia can result. Five or more respiratory events (apneas, hypopneas, or respiratory effort–related arousals) per hour of sleep are required
for diagnosis. Increased respiratory effort occurs during the respiratory event. Pediatric obstructive sleep apnea36,37 is characterized by features similar to those seen in the adult, but cortical arousals might not occur, possibly because of a higher arousal threshold. At least one obstructive event, of at least two respiratory cycles’ duration, per hour of sleep is required for diagnosis. Hypoventilation and Hypoxemia Sleep-related hypoventilation and hypoxemic syndromes comprise five disorders associated with hypoventilation or hypoxemia during sleep. Idiopathic sleep-related nonobstructive alveolar hypoventilation refers to decreased alveolar hypoventilation resulting in sleep-related arterial oxygen desaturation in patients with normal mechanical properties of the lungs. Congenital central alveolar hypoventilation syndrome (CCHS)38,39 is a failure of automatic central control of breathing in infants who do not breathe spontaneously or who breathe shallowly and erratically. It is a failure of central automatic control of breathing. The hypoventilation begins in infancy, and it is worse in sleep than wakefulness. Hypoventilation and hypoxemic disorders are related to elevated arterial carbon dioxide tension (Paco2) or reduced oxygen saturation during sleep. Sleep-related hypoventilation or hypoxemia due to a medical condition is a subgroup of three disorders of impaired lung function or chest wall mechanics. Hypoventilation or hypoxemia related to pulmonary parenchymal or vascular pathology40,41 is due to disorders of interstitial lung disease such as interstitial pneumonitis or disorders such as sickle-cell anemia or other hemoglobinopathies. Sleep-related hypoventilation or hypoxemia due to lower airways obstruction is seen in patients with lower airway disease such as chronic obstructive lung disease (COPD) and emphysema, bronchiectasis, or cystic fibrosis. Sleep-related hypoventilation or hypoxemia due to neuromuscular and chest wall disorders is seen in disorders such as neuromuscular disease or kyphoscoliosis.42-47
HYPERSOMNIA OF CENTRAL ORIGIN The hypersomnia disorders are those in which the primary complaint is daytime sleepiness and the cause of the primary symptom is not disturbed nocturnal sleep or misaligned circadian rhythms. Daytime sleepiness is defined as the inability to stay alert and awake during the major waking episodes of the day, resulting in unintended lapses into sleep. Other sleep disorders may be present, and they must first be effectively treated. These are the hypersomnias that are not due to a circadian rhythm sleep disorder, sleep-related breathing disorder, or other cause of disturbed nocturnal sleep. Narcolepsy with cataplexy48,49 requires the documentation of a definite history of cataplexy (see Chapter 85). Narcolepsy without cataplexy50,51 is the diagnosis when cataplexy is not present but when the patient has sleep paralysis and hypnagogic hallucinations, with supportive evidence in the form of a positive multiple sleep latency test with a mean sleep latency of no more than 8 minutes and two or more sleep-onset REM periods. Narcolepsy due to
medical condition52,53 is the diagnosis applied to a patient with sleepiness who has a significant neurologic or medical disorder that accounts for the daytime sleepiness. Recurrent hypersomnia,54,55 also known as periodic hypersomnia, comprises two subtypes: Kleine-Levin syndrome and menstrual-related hypersomnia. Kleine-Levin syndrome, is associated with episodes of sleepiness together with binge eating, hypersexuality, or mood changes. Menstrual-related hypersomnia is recurrent episodes of hypersomnia that occur in association with the menstrual cycle. Episodes usually last approximately 1 week and resolve at the time of menses. Idiopathic hypersomnia with long sleep time56,57 is the classic form of idiopathic hypersomnia, characterized by a major sleep episode that is at least 10 hours in duration, whereas idiopathic hypersomnia without long sleep time58,59 is the more commonly seen disorder of excessive sleepiness with unintended naps that are typically unrefreshing (see Chapter 86). Behaviorally induced insufficient sleep syndrome60,61 occurs in patients who have a habitual short sleep episode and who sleep considerably longer when the habitual sleep episode is not maintained. Hypersomnia due to medical condition62,63 is hypersomnia that is caused by a medical or neurologic disorder. Cataplexy or other diagnostic features of narcolepsy are not present. Hypersomnia due to drug or substance64-67 is diagnosed when the complaint is believed to be secondary to current or past use of drugs. Hypersomnia not due to a substance or known physiologic condition68,69 is excessive sleepiness that is temporally associated with a psychiatric diagnosis.
CIRCADIAN RHYTHM SLEEP DISORDERS The circadian rhythm sleep disorders share a common underlying chronophysiologic basis. The major feature of these disorders is a persistent or recurrent misalignment between the patient’s sleep pattern and the pattern that is desired or regarded as the societal norm (see Chapter 41). Maladaptive behaviors influence the presentation and severity of the circadian rhythm sleep disorders. The underlying problem in the majority of the circadian rhythm sleep disorders is that the patient cannot sleep when sleep is desired, needed, or expected. The wake episodes can occur at undesired times as a result of sleep episodes that occur at inappropriate times; therefore, the patient might complain of insomnia or excessive sleepiness. For several of the circadian rhythm sleep disorders, once sleep is initiated, the major sleep episode is of normal duration with normal REM–NREM cycling. Delayed sleep phase type,70,71 which is more commonly seen in adolescents, is characterized by a delay in the phase of the major sleep period in relation to the desired sleep time and wake time, whereas advanced sleep phase type,72,73 which is more commonly seen in older adults, is characterized by an advance in the phase of the major sleep period in relation to the desired sleep time and wake-up time. An alteration in the homeostatic regulation of sleep may be responsible. However, the delayed and advanced sleep phase types can have a predominant influence caused by the person’s choice to remain awake late into the night or
CHAPTER 60 • Classification of Sleep Disorders 685
go to bed earlier associated with behavioral, social, or professional demands. The irregular sleep-wake type,74,75 a disorder that involves a lack of a clearly defined circadian rhythm of sleep and wakefulness, is most often seen in institutionalized older adults and is associated with a lack of synchronizing agents such as light, activity, and social activities. The free-running type76,77 or nonentrained type (formerly known as the non–24-hour sleep–wake syndrome) occurs because there is a lack of entrainment to the 24-hour period, and the sleep pattern often follows that of the underlying free-running pacemaker with a sequential shift in the daily sleep pattern. Circadian rhythm sleep disorders due to a medical condition78,79 are related to an underlying primary medical or neurologic disorder. A disrupted sleep–wake pattern leads to complaints of insomnia or excessive daytime sleepiness. Jet-lag type80,81 or jet-lag disorder, is related to a temporal mismatch between the timing of the sleep–wake cycle generated by the endogenous circadian clock produced by a rapid change in time zones. The severity of the disorder is influenced by the number of time zones crossed and the direction of travel, with eastward travel usually being more disruptive. Shift-work type82,83 is characterized by complaints of insomnia or excessive sleepiness that occur in relation to work hours that are scheduled during the usual sleep period. Other circadian rhythm sleep disorders not resulting from a known physiologic condition are irregular or unconventional sleep-wake patterns that can be the result of social, behavioral, or environmental factors.84,85 Noise, lighting, or other factors can predispose a person to develop this disorder. The appropriate timing of sleep within the 24-hour day can be disturbed in many other sleep disorders, particularly those associated with the complaint of insomnia. Patients with narcolepsy may have a pattern of sleepiness that is identical to that described as being caused by an irregular sleep-wake type. However, because the primary sleep diagnosis is narcolepsy, the patient should not receive a second diagnosis of a circadian rhythm sleep disorder unless the disorder is unrelated to the narcolepsy. For example, a diagnosis of jet-lag type could be stated along with a diagnosis of narcolepsy, if appropriate. Similarly, patients with mood disorders or psychoses can, at times, have a sleep pattern similar to that of delayed sleep phase type. A diagnosis of delayed sleep phase type would be coded only if the disorder is not directly associated with the psychiatric disorder. Some disturbance of sleep timing is a common feature in patients who have a diagnosis of inadequate sleep hygiene. Only if the timing of sleep is the predominant cause of the sleep disturbance and is outside the societal norm would the diagnosis be a circadian rhythm sleep disorder. Limit-setting sleep disorder is also associated with an altered time of sleep within the 24-hour day. If the setting of limits is a function of the caretaker, then the sleep disorder is more appropriately diagnosed as a limitsetting sleep disorder.
PARASOMNIAS The parasomnias are undesirable physical or experiential events that accompany sleep (see Section 12). These sleep
686 PART II / Section 8 • Impact, Presentation, and Diagnosis
disorders are not abnormalities of the processes responsible for sleep and awake states per se but are undesirable phenomena that occur predominantly during sleep. The parasomnias consist of abnormal sleep-related movements, behaviors, emotions, perceptions, dreaming, and autonomic nervous system functioning. They are disorders of arousal, partial arousal, and sleep-stage transition. Many of the parasomnias are manifestations of central nervous system activation. Autonomic nervous system changes and skeletal muscle activity are the predominant features. The parasomnias often occur in conjunction with other sleep disorders such as obstructive sleep apnea syndrome. It is not uncommon for several parasomnias to occur in one patient. Three parasomnias have typically been associated with arousal from non-REM sleep, the disorders of arousal. Confusional arousals86,87 are characterized by mental confusion or confusional behavior that occurs during or after arousal from sleep. These arousals are common in children and can occur not only from nocturnal sleep but also from daytime naps. They sometimes occur in association with obstructive sleep apnea syndrome. Sleepwalking88,89 is a series of complex behaviors that occur from sudden arousals from slow-wave sleep and result in walking behavior during a state of altered consciousness. Sleep terrors90,91 also occur from slow-wave sleep and are associated with a cry or piercing scream accompanied by autonomic nervous system activation and behavioral manifestation of intense fear. Patients may be difficult to arouse from the episode and when aroused can be confused and subsequently amnestic for the episode. These two disorders, sleepwalking and sleep terrors, often coexist together, and sometimes one form blends into the other or is difficult to distinguish from the other. Several parasomnias are typically associated with the REM sleep stage. Some common underlying pathophysiologic mechanism related to REM sleep may underlie these disorders. REM sleep behavior disorder (RBD)92,93 involves abnormal behaviors that occur in REM sleep and result in injury or sleep disruption. The behaviors are often violent, with dream enactment that is action filled. The disorder can occur in narcolepsy, and many patients with Parkinson’s disease have RBD. The delayed emergence of a neurodegenerative disorder can occur, especially in men older than 50 years. Recurrent isolated sleep paralysis94,95 can occur at sleep onset or on awakening and is characterized by an inability to perform voluntary movements. Ventilation is usually unaffected. Hallucinatory experiences often accompany the paralysis. Nightmare disorder96,97 is characterized by recurrent nightmares that occur in REM sleep and result in an awakening with intense anxiety, fear, or other negative feelings. Sleep-related dissociative disorders98,99 involve a disruption of the integrative features of consciousness, memory, identity, or perception of the environment. This disorder can occur in the transition from wakefulness to sleep or after an awakening from stage 1 or 2 sleep. A history of physical or sexual abuse is common in such patients. These patients fulfill the Diagnostic and Statistical Manual of Mental Disorders, fourth edition, text revision (DSM-IV-TR) criteria for dissociative disorder. Sleep enuresis100,101 is recurrent involuntary voiding that occurs during sleep. Enuresis
is considered primary in a child who has never been dry for 6 months or longer; otherwise, it is called secondary. Sleep-related groaning (catathrenia)102,103 is an unusual disorder in which there is a chronic, often nightly, expiratory groaning that occurs during sleep. The affected person is often unaware of the groaning. The disorder is rare and the pathophysiology is unknown. Exploding head syndrome104,105 is characterized by a loud imagined noise or sense of a violent explosion that occurs in the head as the patient is falling asleep or during waking in the night. Sleep-related hallucinations are hallucinatory experiences that occur at sleep onset or upon awakening. They may be difficult to distinguish from vivid dreams or nightmares but usually are complex images that occur when the patient is clearly awake. Sleep-related eating disorder106,107 involves recurrent eating and drinking episodes during arousals from nocturnal sleep. The eating behavior is uncontrollable, and often the patient is unaware of the behavior until the next morning. It can be associated with sleepwalking and can be induced by medication. Parasomnia due to a medical condition108,109 is the manifestation of a parasomnia associated with an underlying medical or neurologic disorder. Parasomnia due to a drug or substance110 is a parasomnia that has a close temporal relationship between exposure to a drug, medication, or biologic substance. Unspecified parasomnia111,112 is a parasomnia that occurs as a manifestation of an underlying psychiatric disorder.
SLEEP-RELATED MOVEMENT DISORDERS The sleep-related movement disorders are characterized by relatively simple, usually stereotyped movements that disturb sleep (see Chapter 90). Disorders such as periodic limb movement disorder and restless legs syndrome are classified in this section. Restless legs syndrome113,114 is characterized by a complaint of a strong, nearly irresistible urge to move the legs often accompanied by uncomfortable or painful symptoms. The sensations are worse at rest and occur more frequently in the evening or during the night. Walking or moving the legs relieves the sensation. Periodic limb movement disorder115,116 is an independent disorder of repetitive, highly stereotyped limb movements that occur during sleep. Periodic leg movements are often associated with restless legs syndrome. Sleep-related leg cramps117,118 are painful sensations that are associated with sudden intense muscle contractions, usually of the calves or small muscles of the feet. Episodes commonly occur during the sleep period and can lead to disrupted sleep. Relief is usually obtained by stretching the affected muscle. Sleeprelated bruxism119,120 is characterized by clenching of the teeth during sleep and can result in arousals. Often the activity is severe or frequent enough to result in symptoms of temporomandibular joint pain or wearing down of the teeth. Sleep-related rhythmic movement disorder121,122 is a stereotyped, repetitive rhythmic motor behavior that occurs during drowsiness or light sleep and results in large movements of the head, body, or limbs. The disorder is typically seen in children, but it can also be seen in adults. Head and limb injuries can result from violent movements.
Rhythmic movement disorder can also occur during full wakefulness and alertness, particularly in persons who are mentally retarded. Unspecified sleep-related movement disorder is a movement disorder that occurs during sleep and that is diagnosed before a psychiatric disorder can be ascertained. Sleep-related movement disorder due to a medical disorder appears to have a neurologic or medical basis. Sleeprelated movement disorder due to a drug or substance is a sleep disorder that appears to have a substance or drug as its basis.
OTHER SLEEP DISORDERS These disorders are difficult to fit into any other classification section. Environmental sleep disorder123,124 is a sleep disturbance that is caused by a disturbing environmental factor that disrupts sleep and leads to a complaint of either insomnia or excessive sleepiness. Isolated Symptoms, Apparently Normal Variants, and Unresolved Issues This section lists sleep-related symptoms that are in the borderline between normal and abnormal sleep. Sleep length and snoring are two examples. A long sleeper125,126 is a person who sleeps more in the 24-hour day than the typical person. Sleep is normal in architecture and quality. Usually, sleep lengths of 10 hours or greater qualify for this diagnosis. Symptoms of excessive sleepiness occur if the person does not get that amount of sleep. A short sleeper125,126 is a person with a routine pattern of obtaining 5 hours or less of sleep in a 24-hour day. In children, this sleep length can be 3 hours or less than the norm for the age group. Snoring127,128 is diagnosed when a respiratory sound is disturbing to the patient, a bed partner, or others. This diagnosis is made when the snoring is not associated with either insomnia or excessive sleepiness. Not only can snoring lead to impaired health but also it may be a cause of social embarrassment and can disturb the sleep of a bed partner. Snoring associated with obstructive sleep apnea syndrome is not diagnosed as snoring. Sleep talking129,130 can be either idiopathic or associated with other disorders such as RBD or sleep-related eating disorder. Sleep starts (hypnic jerks)131,132 are sudden brief contractions of the body that occur at sleep onset. These movements are associated with a sensation of falling, a sensory flash, or a sleep-onset dream. Benign sleep myoclonus of infancy133,134 is a disorder of myoclonic jerks that occur during sleep in infants. It typically occurs from birth to age 6 months and is benign and resolves spontaneously. Hypnagogic foot tremor and alternating leg muscle activation135,136 occurs at the transition between wake and sleep or during light NREM sleep. It is demonstrated by recurrent electromyographic (EMG) potentials in one or both feet that are in the myoclonic range of longer than 250 msec. Propriospinal myoclonus at sleep onset137,138 is a disorder of recurrent sudden muscular jerks in the transition from wakefulness to sleep. The disorder may be associated with severe sleep-onset insomnia. Excessive fragmentary myoclonus139,140 is small muscle twitches in the fingers, toes, or the corner of the mouth that do not cause actual
CHAPTER 60 • Classification of Sleep Disorders 687
movements across a joint. The myoclonus is often a finding during polysomnography that is often asymptomatic or can be associated with daytime sleepiness or fatigue. Other Organic Disorders Commonly Encountered in the Differential Diagnosis of Sleep Disorders Fatal familial insomnia141,142 is a progressive disorder characterized by difficulty in falling asleep and maintaining sleep that develops into enacted dreams or stupor. Autonomic hyperactivity with pyrexia, excessive salivation, and hyperhidrosis leads to cardiac and respiratory failure. The disease is caused by a prion and it leads eventually to death. Fibromyalgia is a disorder of widespread pain and muscle tenderness. It is usually associated with light and unrefreshing sleep. Sleep-related epilepsy143,144 is the diagnosis when epilepsy occurs during sleep. Several epilepsy types are associated with sleep, including nocturnal frontal lobe epilepsy, benign epilepsy of childhood with centrotemporal spikes, and juvenile myoclonic epilepsy. Sleep-related headaches145,146 are headaches that occur during sleep or on awakening from sleep. Chronic paroxysmal hemicrania, hypnic headache, or cluster headaches can all occur during sleep. Sleep-related gastroesophageal reflux147,148 is characterized by regurgitation of stomach contents into the esophagus during sleep. Shortness of breath or heartburn can result, but occasionally the disorder is asymptomatic. Sleep-related coronary artery ischemia149,150 is ischemia of the myocardium that occurs at night. Sleep-related abnormal swallowing, choking, and laryngospasm is a disorder in which patients report choking and difficulty breathing at night that may be due to pooling of saliva in the upper airway. Other Psychiatric or Behavioral Disorders Commonly Encountered in the Differential Diagnosis of Sleep Disorders This final section of the ICSD-2 lists the psychiatric diagnoses that are often encountered during an evaluation of sleep complaints. Many psychiatric disorders are associated with disturbances of sleep and wakefulness. The main sleep-related features are presented in this section. Psychiatric diagnoses that are discussed include mood disorders, anxiety disorders, somatoform disorders, schizophrenia and other psychotic disorders, disorders first diagnosed in childhood or adolescence, and personality disorders.151
CURRENT AND FUTURE CLASSIFICATION CONSIDERATIONS Comorbid Insomnia and Insomnia Research Criteria An outcome from the 2004 NIH consensus development conference on Insomnia was the promotion of the term, comorbid insomnia to distinguish insomnia due to other primary sleep disorders, medical, and psychiatric disorders and insomnia due to medication or drug use from primary insomnia.152,153 Primary insomnia is a term that has been used to apply to insomnia not due to another medical or psychiatric disorder, as compared to insomnia that is
688 PART II / Section 8 • Impact, Presentation, and Diagnosis
secondary to other disorders. Comorbid insomnia does not indicate whether the associated medical disorder is causative or coincidental. The term, primary insomnia is used in the ICD-10-CM and DSM-IV-TR classifications and has the benefit of being a more global classification of insomnia (Table 60-2). The term is compatible with the ICSD-2, which uses a more detailed subtyping of the sleep
disorders. The term, secondary insomnia is still appropriate for use when there is a clear development of insomnia related to the underlying medical or psychiatric disorder, such as one might see in pain disorders. The definition of insomnia as being a complaint of sleep onset, sleep maintenance, waking too early, or unrestorative sleep is less precise than that required for research in
Table 60-2 ICD-10-CM Sleep Disorders CODE
DESCRIPTION
F51: Sleep Disorders Not Caused by a Substance or Known Physiologic Condition F51.01
Primary insomnia
F51.02
Adjustment insomnia
F51.03
Paradoxical insomnia
F51.04
Psychophysiologic insomnia
F51.05
Insomnia due to other mental disorder
F51.09
Other insomnia not due to a substance or known physiologic condition
F51.1
Hypersomnia not due to a substance or known physiologic condition
F51.11
Primary hypersomnia
F51.12
Insufficient sleep syndrome
F51.13
Hypersomnia due to other mental disorder
F51.19
Other hypersomnia not due to a substance or known physiologic condition
F51.3
Sleepwalking (somnambulism)
F51.4
Sleep terrors (night terrors)
F51.5
Nightmare disorder
F51.8
Other sleep disorders not due to a substance or known physiologic condition
F51.9
Sleep disorder not due to a substance or known physiologic condition, unspecified
G47: Organic Sleep Disorders G47.0
Insomnia, unspecified
G47.01
Insomnia due to medical condition
G47.09
Other insomnia
G47.1
Hypersomnia, unspecified
G47.11
Idiopathic hypersomnia with long sleep time
G47.12
Idiopathic hypersomnia without long sleep time
G47.13
Recurrent hypersomnia
G47.14
Hypersomnia due to medical condition
G47.19
Other hypersomnia
G47.20
Circadian rhythm sleep disorder, unspecified type
G47.21
Circadian rhythm sleep disorder, delayed sleep phase type
G47.22
Circadian rhythm sleep disorder, advanced sleep phase type
G47.23
Circadian rhythm sleep disorder, irregular sleep–wake type
G47.24
Circadian rhythm sleep disorder, free running type
G47.25
Circadian rhythm sleep disorder, jet lag type
G47.26
Circadian rhythm sleep disorder, shift-work type
G47.27
Circadian rhythm sleep disorder in conditions classified elsewhere
G47.29
Other circadian rhythm sleep disorder
G47.30
Sleep apnea, unspecified
G47.31
Primary central sleep apnea
G47.32
High-altitude periodic breathing
G47.33
Obstructive sleep apnea (adult) (pediatric)
G47.34
Idiopathic sleep-related nonobstructive alveolar hypoventilation
G47.35
Congenital central alveolar hypoventilation syndrome
G47.36
Sleep-related hypoventilation in conditions classified elsewhere Continued
CHAPTER 60 • Classification of Sleep Disorders 689
Table 60-2 ICD-10-CM Sleep Disorders—cont’d CODE
DESCRIPTION
G47.37
Central sleep apnea in conditions classified elsewhere
G47.39
Other sleep apnea
G47.4
Narcolepsy and cataplexy
G47.41
Narcolepsy
G47.411
Narcolepsy with cataplexy
G47.419
Narcolepsy without cataplexy, NOS
G47.42
Narcolepsy in conditions classified elsewhere
G47.421
Narcolepsy in conditions classified elsewhere with cataplexy
G47.429
Narcolepsy in conditions classified elsewhere without cataplexy
G47.50
Parasomnia, unspecified
G47.51
Confusional arousals
G47.52
REM sleep behavior disorder
G47.53
Recurrent isolated sleep paralysis
G47.54
Parasomnia in conditions classified elsewhere
G47.59
Other parasomnia
G47.6
Sleep-related movement disorders
G47.61
Periodic limb movement disorder
G47.62
Sleep-related leg cramps
G47.63
Sleep-related bruxism
G47.69
Other sleep-related movement disorders
G47.8
Other sleep disorders
G47.9
Sleep disorder, unspecified
Z72.8: Problems Related to Sleep Z72.820
Sleep deprivation
Z72.821
Inadequate sleep hygiene
Z73.8: Other Problems Related to Life Management Difficulty Z73.810
Behavioral insomnia of childhood, sleep-onset association type
Z73.811
Behavioral insomnia of childhood, limit-setting type
Z73.812
Behavioral insomnia of childhood, combined type
Z73.819
Behavioral insomnia of childhood, unspecified type
insomnia. Specific research criteria have been developed for insomnia disorder.154 The criteria include a primary complaint of difficulty initiating sleep, maintaining sleep, waking too early, or unrestorative or poor quality sleep and a requirement that the sleep difficulty occurs despite adequate opportunity and circumstances for sleep, plus one or more complaints of daytime impairment due to the sleep difficulty. Specific research criteria have also been developed for primary insomnia, insomnia due to a mental disorder, psychophysiologic insomnia, paradoxical insomnia, idiopathic insomnia, insomnia related to periodic limb movement disorder, insomnia related to sleep apnea, insomnia due to medical condition and insomnia due to drug or substance, as well as diagnostic criteria for normal sleepers. Hypersomnia The diagnosis of narcolepsy with cataplexy is based upon the belief that most cases are due to loss of hypocretin possibly on an autoimmune basis.155 However, up to 10% of patients with narcolepsy and cataplexy have normal
hypocretin levels suggesting either a downstream problem with hypocretin, such as at the receptor level, or an alternative pathophysiologic mechanism.155 Another question is whether narcolepsy without cataplexy is the same disorder or a disorder based upon an entirely different pathophysiology. Most patients who have narcolepsy without cataplexy have intact hypocretin levels. Idiopathic hypersomnia, whether with or without long sleep time, is still poorly understood because there is no clear pathophysiologic mechanism.157 The genetic basis of the disorders needs to be determined. Whether idiopathic hypersomnia without long sleep time is a variant of narcolepsy without cataplexy is not yet determined. Parasomnia Catathrenia, a disorder with sleep-related moaning, has been suggested to be a variant of a sleep-related breathing disorder because treatment with continuous positive airway pressure has been reported to be successful.156 There has been described a classification of sleep-related sexual disorders and abnormal sexual behaviors.157 Many
690 PART II / Section 8 • Impact, Presentation, and Diagnosis
of the disorders occur out of sleep and are related to the parasomnias, particularly confusional arousals; however, other sleep-related sexual behavior is associated with seizure disorders or other sleep disorders such as KleineLevin syndrome, insomnia, or restless legs syndrome. Some abnormal sexual behaviors occur in narcolepsy, sleep-related dissociative disorders, and nocturnal psychotic disorders. Sleep-related painful erection, which has been well described in the literature, and sleep exacerbation of persistent sexual arousal syndrome, which is a rare condition with widely diverse causes, are two other sexual disorders that are rare but not included in the ICSD-2. A study of the interobserver reliability of the diagnostic criteria included in the 1997 revised version of the ICSD-I showed that the diagnostic criteria were less precise for sleepwalking, sleep terrors, nightmares, RBD, and sleep starts.158 Sleep terrors, nightmares, and RBD had a weak agreement mainly because of the first criterion that defines the phenomenon. In sleepwalking, the disagreement was due to the inclusion of amnesia in the criteria. ❖ Clinical Pearl The classification of sleep disorders allows accurate diagnosis, improved communication among physicians, and the standardization of data for research purposes. New sleep disorders have been recognized, and previous sleep disorders have been clarified with a better understanding of their diagnostic and epidemiologic features. The International Classification of Sleep Disorders, version 2, increases the refinement of sleep disorder diagnoses because of recent advances in sleep research. Referring to the ICSD-2 helps clinicians establish a rational differential diagnosis when evaluating patients.
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692 PART II / Section 8 • Impact, Presentation, and Diagnosis 94. Goode GB. Sleep paralysis. Arch Neurol 1962;6:228-234. 95. Ohayon MM, Zulley J, Guilleminault C, et al. Prevalence and pathologic associations of sleep paralysis in the general population. Neurology 1999;52;1194-1200. 96. Fisher CJ, Byrne J, Edwards T, et al. A psychophysiological study of nightmares. J Am Psychoanal Assoc 1970;18:747-782. 97. Levin R, Fireman G. Nightmare prevalence, nightmare distress, and self-reported psychological disturbance. Sleep 2002;25: 205-212. 98. Agargun MY, Kara H, Ozer OA, et al. Characteristics of patients with nocturnal dissociative disorders. Sleep Hypnosis 2001;3:131134. 99. Rice E, Fisher C. Fugue states in sleep and wakefulness: a psychophysiological study. J Nerv Ment Dis 1976;163:79-87. 100. Mikkelsen EJ, Rapoport JL. Enuresis: psychopathology, sleep stage, and drug response. Urol Clin North Am 1980;7:361-377. 101. Yeung CK. Nocturnal enuresis (bedwetting). Curr Opin Urol 2003;13:337-343. 102. De Roeck J, Van Hoof E, Cluydts R. Sleep-related expiratory groaning: a case report. Sleep Res 1983;12:237. 103. Vetrugno R, Provini F, Plazzi G, et al. Catathrenia (nocturnal groaning): a new type of parasomnia. Neurology 2001;56:681683. 104. Pearce JMS. Clinical features of the exploding head syndrome. J Neurol Neurosurg Psychiatry 1989;52:907-910. 105. Sachs C, Svanborg E. The exploding head syndrome: polysomnographic recordings and therapeutic suggestions. Sleep 1991;14: 263-266. 106. Birketvedt GS, Florholmen J, Sundsfjord J, et al. Behavioral and neuroendocrine characteristics of the night-eating syndrome. JAMA 1999;282:657-663. 107. Schenck CH, Mahowald MW. Review of nocturnal sleep-related eating disorders. Int J Eat Disord 1994;15:343-356. 108. Lugaresi E, Provini F. Agrypnia excitata: clinical features and pathophysiological implications. Sleep Med Rev 2001;5:313-322. 109. Silber MH, Hansen MR, Girish M. Complex nocturnal visual hallucinations. Sleep 2002;25:484. 110. Plazzi G, Montagna P, Meletti S, et al. Polysomnographic study of sleeplessness and oneiricisms in the alcohol withdrawal syndrome. Sleep Med 2002;3:279-282. 111. Ohayon MM, Priest RG, Caulet M, et al. Hypnagogic and hypnopompic hallucinations: pathological phenomena? Br J Psychiatry 1996;169:459-467. 112. Schenck CH, Mahowald MW. On the reported association of psychopathology with sleep terrors in adults. Sleep 2000;23:448449. 113. Ekbom KA. Restless legs syndrome. Neurology 1960;10:868-873. 114. Earley CJ. Restless legs syndrome. N Engl J Med 2003;348: 2103-2109. 115. Symonds CP. Nocturnal myoclonus. J Neurol Neurosurg Psychiatr 1953;16:166-171. 116. Picchietti DL, Walters AS. Moderate to severe periodic limb movement disorder in childhood and adolescence. Sleep 1999;22: 297-300. 117. Layzer RB, Rowland LP. Cramps. N Engl J Med 1971;285:3140. 118. Saskin P, Whelton C, Moldofsky H, et al. Sleep and nocturnal leg cramps. Sleep 1988;11:307-308. 119. Lavigne GJ, Kato T, Kolta A, et al. Neurobiological mechanisms involved in sleep bruxism. Crit Rev Oral Biol Med 2003;14:30-46. 120. Ware JC, Rugh J. Destructive bruxism: sleep stage relationship. Sleep 1988;11:172-181. 121. Dyken ME, Lin-Dyken DC, Yamada T. Diagnosing rhythmic movement disorder with video-polysomnography. Pediatr Neurol 1997;16:37-41. 122. Sallustro F, Atwell CW. Body rocking, head banging and head rolling in normal children. J Pediatr 1978;93:704-708. 123. Roth T, Kramer M, Trinder J. The effect of noise during sleep on the sleep patterns of different age groups. Can Psychiatr Assoc J 1972;17:SS197-SS201. 124. Thiessen GJ, Lapointe AC. Effect of continuous traffic noise on percentage of deep sleep, waking, and sleep latency. J Acoust Soc Am 1983;73:225-229. 125. Hartmann E, Baekeland F, Zwilling GR. Psychological differences between short and long sleepers. Arch Gen Psychiatry 1972; 26:463-468.
126. Webb WB. Are short and long sleepers different? Psychol Rep 1979;44:259-264. 127. Dalmasso F, Prota R. Snoring: analysis, measurements, clinical implications and applications. Eur Respir J 1996;9:146-159. 128. Jennum P, Hein HO, Suadicani P, et al. Snoring, family history, and genetic markers in men. The Copenhagen Male Study. Chest 1995;107:1289-1293. 129. Arkin AM. Sleep talking: a review. J Nerv Ment Dis 1966;143: 101-122. 130. Hublin C, Kaprio J, Partinen M, et al. Sleeptalking in twins: epidemiology and psychiatric comorbidity. Behav Genet 1998;28:289298. 131. Broughton R. Pathological fragmentary myoclonus, intensified sleep starts and hypnagogic foot tremor: three unusual sleep-related disorders. In: Koella WP, editor. Sleep 1986. New York: FischerVerlag; 1988. p. 240-243. 132. Oswald I. Sudden bodily jerks on falling asleep. Brain 1959;82: 92-93. 133. Coulter DL, Allen RJ. Benign neonatal sleep myoclonus. Arch Neurol 1982;39:191-192. 134. Resnick TJ, Moshe SL, Perotta L, et al. Benign neonatal sleep myoclonus: relationship to sleep states. Arch Neurol 1986;43:266268. 135. Chervin RD, Consens FB, Kutluay E. Alternating leg muscle activation during sleep and arousals: a new sleep-related motor phenomenon? Mov Disord 2003;18:551-559. 136. Wichniak A, Tracik F, Geisler P, et al. Rhythmic feet movements while falling asleep. Mov Disord 2001;16:1164-1170. 137. Montagna P, Provini F, Plazzi G, et al. Propriospinal myoclonus upon relaxation and drowsiness: a cause of severe insomnia. Mov Disord 1997;12:66-72. 138. Tison F, Arne P, Dousset V, et al. Propriospinal myoclonus induced by relaxation and drowsiness. Rev Neurol (Paris) 1998;154:423425. 139. Broughton R, Tolentino MA, Krelina M. Excessive fragmentary myoclonus in NREM sleep: a report of 38 cases. Electroencephalogr Clin Neurophysiol 1985;61:123-309. 140. Vetrugno R, Plazzi G, Provini F, et al. Excessive fragmentary hypnic myoclonus: clinical and neurophysiological findings. Sleep Med 2002;3:73-76. 141. Lugaresi E, Medori R, Montagna P, et al. Fatal familial insomnia and dysautonomia with selective degeneration of thalamic nuclei. N Engl J Med 1986;315:997-1003. 142. Montagna P, Gambetti P, Cortelli P, et al. Familial and sporadic fatal insomnia. Lancet Neurol 2003;2:167-176. 143. Provini F, Plazzi G, Tinuper P, et al. Nocturnal frontal lobe epilepsy: a clinical and polygraphic overview of 100 consecutive cases. Brain 1999;122:1017-1031. 144. Scheffer IE, Bhatia KP, Lopes-Cendes I, et al. Autosomal dominant nocturnal frontal lobe epilepsy: a distinctive clinical disorder. Brain 1995;118:61-73. 145. Dexter JD. Relationship between sleep and headaches. In: Thorpy MJ, editor. Handbook of sleep disorders. New York, Marcel Dekker, 1990. p. 663-671. 146. Evers S, Goadsby PJ. Hypnic headache—clinical features, pathophysiology, and treatment. Neurology 2003;60:905-909. 147. Nebel OT, Fornes MF, Castell DO. Symptomatic gastroesophageal reflux: incidence and precipitating factors. Am J Dig Dis 1976; 21:953-956. 148. Orr WC. Gastrointestinal functioning during sleep. In: LeeChiong TL, Sateia MJ, Carskadon MA, editors. Sleep medicine. Philadelphia: Hanley & Belfus; 2002. p. 463-470. 149. Nowlin JB, Troyer WG Jr, Collins WS, et al. The association of nocturnal angina pectoris with dreaming. Ann Intern Med 1965;63:1040-1046. 150. Verrier RL, Muller JE, Hobson JA. Sleep, dreams, and sudden death: the case for sleep as an autonomic stress test for the heart. Cardiovasc Res 1996;31:181-211. 151. Benca RM. Sleep in psychiatric disorders. Neurol Clin 1996; 14:739-764. 152. NIH State of the Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults statement. J Clin Sleep Med 2005;1(4):412-421. 153. NIH State-of-the-Science Conference Statement on manifestations and management of chronic insomnia in adults. NIH Consens State Sci Statements 2005;22(2):1-30.
154. Edinger JD, Bonnet MH, Bootzin RR, et al. American Academy of Sleep Medicine Work Group. Derivation of research diagnostic criteria for insomnia: report of an American Academy of Sleep Medicine Work Group. Sleep 2004;27(8):1567-1596. 155. Billiard M. Diagnosis of narcolepsy and idiopathic hypersomnia. An update based on the International Classification of Sleep Disorders, 2nd edition. Sleep Med Rev 2007;11(5):377-388. 156. Guilleminault C, Hagen CC, Khaja AM. Catathrenia: parasomnia or uncommon feature of sleep disordered breathing? Sleep 2008;31(1):132-139.
CHAPTER 60 • Classification of Sleep Disorders 693 157. Schenck CH, Arnulf I, Mahowald MW. Sleep and sex: what can go wrong? A review of the literature on sleep related disorders and abnormal sexual behaviors and experiences. Sleep 2007;30(6): 683-702. 158. Vignatelli L, Bisulli F, Zaniboni A, et al. Interobserver reliability of ICSD-R minimal diagnostic criteria for the parasomnias. J Neurol 2005;252(6):712-717.
Epidemiology of Sleep Disorders Markku Partinen and Christer Hublin Abstract Every day one third or more of the population suffers from some sleep disturbance and/or from abnormal daytime sleepiness. At least 10% of the population suffers from a sleep disorder that is clinically significant and of public health importance. Insomnia is the most common sleep disorder, followed by sleep-disordered breathing and restless legs syndrome. Sleep disorders are interrelated with medical and psychiatric disorders, such as arterial hypertension, cardiovascular and cerebrovascular diseases, morbid obesity, diabetes, metabolic syndrome, and depression. Many gender, socioeconomic, and also ethnic differences exist; and more epidemiologic and genetic epidemiologic studies are needed to understand reasons for these differences. In the 1980s, the large epidemiologic studies on sleep disorders were based on the 1979
Although sleep disorders are very common, rigorous epidemiologic studies in this field are fairly recent, in part because the discipline of sleep medicine is recent. In this chapter we present epidemiologic data important in the practice of sleep medicine. There are several excellent books of epidemiologic methods that are recommended.3-6
SLEEP DURATION Sleep duration is highly individual in all age groups, and it is clearly dependent on age. In the United States the relationship between age and the average sleep time is U-shaped, with a minimum 7.9 hours at age 45 to 54 years and a maximum (9.0 hours) at age 75 years or older.7 In addition to sleep disorders (e.g., insomniacs among short sleepers and hypersomniacs among long sleepers), there are also healthy subjects in the extreme groups: a few percent of the populations are so-called natural short sleepers or natural long sleepers (ICSD-2).2,8 Sleep duration can be considered as a lifestyle factor that is modulated by several background factors and by genotype. In a Finnish general-population study the most important and statistically independent determinants of short and long sleep duration were gender, physical tiredness, sleep problems, marital status, main occupation, and physical activity, but these accounted for only 16% of the variance in sleep duration.9 In the United States the largest reciprocal relationship to sleep was found for work time, followed by travel time, and only shorter than average (<7.5 hours) sleepers spent more time socializing, relaxing, and engaging in leisure activities, whereas both short (<5.5 hours) and long (≥ 8.5 hours) sleepers watched more television than average sleepers.7 The same study showed also significant differences in sleep length between weekdays and weekend (longest on Sunday [9.6 hours] and shortest on Friday [8.0 hours]). The effect of genetic aspects has been assessed in large twin cohorts. In the Finnish cohort, representative of the general population, a significant 694
Chapter
61
sleep disorders classification. In 1990,1 a new International Classification of Sleep Disorders (ICSD) was published. Its revised version from 20052 is now commonly used in sleep medicine. For statistical purposes the International Classification of Diseases, 10th revision (ICD-10) published by the World Health Organization, is commonly used especially in Europe and Asian countries. The Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV), published by the American Psychiatric Association, also includes criteria for diagnosing sleep disorders. The DSM-IV criteria have been commonly used especially in studies of insomnia. From the public health and clinical viewpoints, the most important problems related to sleep–wake disorders are insomnia, sleep deprivation, sleep-related breathing disorders, restless legs syndrome, excessive daytime sleepiness, and parasomnias.
hereditary effect was found on sleep length (overall heritability estimate h2 = 0.44) and sleep quality (h2 = 0.44).10 Similarly, in an Australian cohort, genetic influences accounted for at least 33% of the variance in sleep quality and sleep disturbance.11 There seem to be differences between populations and countries in the mean duration of sleep and trends in them. Among students from 24 countries, sleep was shortest in Japan (6.2 hours in men and 6.1 hours in women), and longest in Bulgaria (7.8 and 8.0 hours, respectively).12 In the United States the self-reported modal of sleep duration has been estimated to be about 8 hours in the 1960s,13 but more recent Gallup surveys have yielded estimates of about 7 hours or even less (National Sleep Foundation, 2005). However, based on reanalysis of all population-based surveys with information on sleep duration (>440,000 persons) in Finland from 1972 to 2005 the mean sleep duration was shortened only 18.3 minutes to about 7.3 hours.9 The same study showed that sleep was shortest and sleep complaints were most frequent among middle-aged employees. It is possible that changes in society (e.g., “24/7”) and working life (e.g., increase in irregular working hours and stress) have an effect on sleep and contribute to insufficient sleep, leading to fatigue and sleepiness during awake times.14 In Sweden, 12% of adults had persistent and considerable chronic sleep loss. In subjects without sleeping difficulties, the most common cause of insufficient sleep was too little time for sleep.15 In Finland, the prevalence of insufficient sleep, defined as a difference of at least 1 hour between the reported need for sleep and obtained sleep length, was 20.4% (16.2% in men; 23.9% in women). Almost half of those with insufficient sleep continued to have it 9 years later. One third of the liability to chronic insufficient sleep was attributed to genetic influences.16 Sleep duration is associated with different health outcomes. The first report was by Hammond in 1964, in
which there was a U-shaped curve between sleep length and risk of mortality, being lowest in those sleeping 7 hours.13 In the early 1980s a U-shaped curve was also found between sleep length and coronary heart disease.17 Later, more than 20 studies have been published on this topic, and the association between sleep length and mortality/ morbidity has been confirmed in many of them.18 The increases in risk have mostly been around 12%. There are also two studies with more than one assessment of sleep behavior,19,20 which may be of importance because in the other studies sleep length and sleep quality changed in one third during 6 years.20 The cause(s) and mechanism(s) of the association are poorly understood. Association with short sleep and sleep deprivation may be linked to dysfunction of the restorative function of sleep. Long sleep may be a consequence of a dysfunction/morbidity (e.g., increased levels of cytokines).21,22 Further long-term cohort studies enable better inferences about causal relationships. It is also important to study natural short and natural long sleepers who have had the same sleeping habits since an early age. Sleep length has also other interesting and important, yet complex associations. In a recent meta-analysis of short sleep and obesity (45 studies with more than 630,000 participants) there was a significantly increased risk both in children (pooled odds ratio [OR] = 1.89) and in adults (OR = 1.55) but the difficulty of causal inference was noted.23 On the other hand, in a clinical review, Marshall and coworkers considered the evidence in adults to be insufficient.24 The association between sleep length and type 2 diabetes has been found in several studies, indicating a 35% to 100% increase in risk for short sleepers25-27 and a 50% to 200% increase for long sleepers.26,27 There is some evidence about an association between sleep length and hypertension: in short sleepers, risks increased from 66%28 to 110%29; and in long sleepers, 19% to 30%28 increases have been reported. However, in some studies no significant association has been observed in elderly persons30 or after adjustment for known risk factors.31 In women, short and long sleep is associated with a 40% increase of risk of coronary heart disease.31,32
INSOMNIA AND USE OF HYPNOTIC AGENTS Insomnia is the most common sleep–wake-related complaint, and sleeping pills are among the most commonly prescribed drugs in clinical practice, especially at the primary health care level.32a Based on a large number of published epidemiologic studies we can generalize that the prevalence of symptoms of insomnia is about 30% among adults (Tables 61-1 and 61-2), and the prevalence of specific insomnia disorders varies between 5% and 10%.33,34 Symptoms of insomnia often persist, and earlier occurrence of insomnia increases the probability of insomnia in later life.35,36 There is some evidence that the occurrence of insomnia has increased during the past 30 years.9 Insomnia can be a symptom of an underlying problem with dozens of causes, or it can be a primary disease. Different questionnaires usually contain items about trouble falling asleep, trouble staying asleep, nocturnal awakenings, early morning awakening, and the use of hypnotic agents. The
CHAPTER 61 • Epidemiology of Sleep Disorders 695
number of urinary voids per night seems to be a good question. People remember easily how many times they wake because of the need to void. Waking up twice to void may not be bothersome. On the contrary, waking up twice or more without the need to void may reflect depression, brain hyperactivity, or some other underlying problem, and frequent (more than two times per night) nocturnal voiding may be a symptom of sleep apnea.37-39 The heterogeneity of the definitions and methods used is striking, but some clear trends can be seen. First, insomnia increases with age. About one third of subjects older than 65 years old have more or less continuous insomnia, although at very old age the levels may be lower. In Australia, insomnia was persistent in 16.2% of the communitydwelling population and 12.2% of the institutional residents. Altogether, 14.5% of the elderly subjects living in the community were using hypnotics regularly while the corresponding percentage was 39.7% among the institutional residents.40 In a large U.S. population–based study,41 the prevalence of insomnia was 7.5% and that of difficulty sleeping was an additional 22.4%. In children and adolescents, the prevalence of frequent insomnia is quite variable; in several studies, it is higher than 10%. In middle-aged populations, the frequency of longstanding insomnia seems to be around 10%. Trouble falling asleep seems to be the most common manifestation in younger age groups, whereas trouble staying asleep is the most frequent form of insomnia in middle-aged and elderly people.9,41-46 Second, there is a clear gender difference, with insomnia occurring about 1.5 times more often in women than in men; this is especially true in menopausal and postmenopausal women compared with middle-aged men. Third, seasonal differences, probably due to light exposure, can occur and the results are consistent in Nordic countries. In northern Norway, 41.7% of the women and 29.9% of the men had occasional insomnia.47 As a whole, complaints of insomnia were more common during the dark period of year than during other times of the year. In the Tromsø study, occurrence of insomnia during the midnight sun period (summer insomnia) decreased with age whereas the other seasonal types of insomnia increased with age.47 Fourth, comorbidity is very common. The association of psychiatric disorders, especially depression, with insomnia is well known. Primary insomnia and insomnia related to mental disorders are the two most common insomnia diagnoses listed in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).42 Insomnia is a frequent complaint among patients with different respiratory symptoms. In the study of Dodge and coworkers,, the prevalence of insomnia was 31.8% to 52.4% among adults with cough, dyspnea, or wheezing; among adults without respiratory symptoms, the prevalence was 25.8% to 26.2%.48 In a World Health Organization collaborative study, 25,916 primary health care attendees were evaluated (Üstün B, Worldwide Project on Sleep and Health; see www-websciences.org). Sleep problems were present in 27% of the patients. Of the patients with insomnia, 51% had a well-defined mental disorder according to the 10th edition of the Internal Classification of Diseases (ICD-10) that mainly included
696 PART II / Section 8 • Impact, Presentation, and Diagnosis Table 61-1 Occurrence of Insomnia REFERENCE (COUNTRY) Saarenpää-Heikkilä et al.64 1995 (Finland) Tynjälä et al.65 1993 (Finland)
NO. SUBJECTS 574
40,202
AGE RANGE (YR)
DEFINITION
METHODS
OCCURRENCE (%)
School-age children (7-17)
Sleeplessness
Questionnaire
Often or always: 4 (m), 5 (f) Sometimes: 61 (m), 57 (f)
School-age children (11-16)
Inability to fall asleep twice a week
Questionnaire (in nine countries)
11-12 yr: 16.4-33.2 13-14 yr: 11.5-25.3 15-16 yr: 10.8-26.6
Partinen and Rimpelä66 1982 (Finland)
2016
Population sample (15-64)
Insomnia daily or several times
Telephone interview weekly
7 (m), 9 (f) 15-24 yr: 5 25-44 yr: 6 45-64 yr: 14
Ford and Kamerow67 1989 (USA)
7954
Population sample (18-65+)
Ever a period of ≥2 weeks with trouble falling asleep, staying asleep, or waking up too early
Direct structured interview using diagnostic interview schedule (DIS)
7.9 (m), 12.1 (f)
Population sample (18+)
During the past year, ever having a period of ≥2 weeks or more with trouble falling asleep, staying asleep, or waking
Direct structured interview using DIS67 as in Ford & Kamerow67
All types: 11.9 Uncomplicated: 4.9 Complicated: 3.6
Weissman et al.68 1997 (USA)
10,533
Dodge et al.48 1995 (USA)
1667
Population sample (18-65+)
Current trouble falling asleep, staying asleep, or waking up too early
Questionnaire and interview
18-44 yr: 22.8 (m), 30.0 (f) 45-64 yr: 31.5 (m), 43.8 (f) >64 yr: 36.4 (m), 47.6 (f)
Morgan and Clarke69 1997 (England)
1042
Primary care (65-80+)
Patients with sleeping problems often or all the time
Questionnaire
65-69 yr: 33.2 (m), 44.1 (f) 70-74 yr: 39.4 (m), 44.4 (f) 75-79 yr: 11.2 (m), 30.8 (f)
982
Population sample (18+)
Insomnia (DSM-IV)
Telephone survey using Sleep-EVAL
DSM-IV: 11.7 Any type: 37.6
3030
Population sample (20+)
Insomnia of any type
Interview at home
22.3 (m), 20.5 (f) 20-39 yr: 18.1 40-59 yr: 18.9 60+ yr: 29.5 No stress: 15.9 Stress: 25.8
Population sample (20-100)
Insomnia Difficulty sleeping
Questionnaire (PSG in 1741)
Insomnia: 7.5 Difficulty sleeping: 22.4
Ohayon and Partinen43 2002 (Finland) Kim et al.70 2000 (Korea)
Bixler et al.41 2002 (USA)
16,583
Li et al.71 2002 (Hong Kong)
9851
Population sample Chinese (18-65)
Insomnia, DSM Preceding month ≥3 per week
Telephone survey
Insomnia: 11.9% Women: 1.6 × P (men) Increase with age
Morin et al.46 2006 (Canada)
2001
Population sample (18-91)
Insomnia, DSM-IV & ICD-10, ≥3 nights/wk
Telephone survey
Symptoms of insomnia: 29.9 Insomnia syndrome: 9.5
DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th ed; f, female; m, male.
CHAPTER 61 • Epidemiology of Sleep Disorders 697
Table 61-2 Occurrence of Symptoms of Insomnia Based on Different Types of Insomnia Complaints TROUBLE FALLING ASLEEP (%)
TROUBLE STAYING ASLEEP (%)
Questionnaire
1-2 nights/wk: 12.9 ≥3 nights/wk: 11.3
1-2 nights/wk: 6.0 ≥3 nights/wk: 6.5
Adolescents (13-15)
Interview
≥4 nights/wk: 9.1 (m), 10.0 (f)
≥4 nights/wk: 1.5 (m), 3.0 (f)
>4 nights/wk: 2.5 (m), 4.4 (f)
4972
Population sample (>14)
Telephone interview
Currently: 10.5 (m), 15.3 (f)
Currently: 16.4 (m), 24.8 (f)
Currently: 13.7(m), 17.8 (f)
Bixler et al.74 1979 (USA)
1006
Population sample (>18)
Sleep-EVAL questionnaire
Currently: 14.4 (about two thirds women)
Currently: 22.9 (about two thirds women)
Currently: 13.8 (about two thirds women)
Karacan et al.75 1983 (USA)
2347
Population sample (18-65+)
Interview
Often or always (no age effect): 6.0 (m), 11.2 (f)
Often or always Often or always (significant (significant increase with increase with age): 12.9 (m), age): 6.2 (m), 17.4 (f) 8.0 (f)
Ganguli et al.35 1996 (USA)
1050
Population sample (66-97)
Questionnaire
Sometimes or usually: 26.7 (m), 44.1 (f)
Sometimes or usually: 19.2 (m), 35.8 (f)
Sometimes or usually: 13.6 (m), 23.3 (f)
Blazer et al.76 1995 (USA)
3976
Population sample (≥65; EPESE)
Interview using a questionnaire
Blacks: 14.8 Whites: 16.3
Blacks: 19.9 Whites: 33.8
Blacks: 12.9 Whites: 16.0
Foley et al.77 1995 (USA)
9282
Population sample (≥65; EPESE)
Interview using a questionnaire
Most of the time: 19.2
Most of the time: 29.7
Most of the time: 18.8
Henderson et al.40 1995 (Australia)
869
Population sample (≥70)
Home interview, computer
Nearly every night over the previous 2 weeks: 5.1 algorithm
NA
Nearly every night over the previous 2 weeks: 2.6
Kim et al.70 2000 (Japan)
3030
Population sample (≥20)
Home interviews
7.0 (m) 9.4 (f) No stress: 4.1 Stress: 11.6
20-39 yr: 11.1 40-59 yr: 13.6 60+ yr: 22.6 No stress: 11.2 Stress: 18.3
20-39 yr: 5.1 40-59 yr: 6.7 60+ yr: 13.3 No stress: 6.0 Stress: 9.4
Ohayon and Partinen43 2002 (Finland)
982
Population sample (≥18)
Telephone survey using Sleep-EVAL questionnaire
≥3 nights/wk: 10.4 (m), 13.2 (f)
≥3 nights/wk: 30.2 (m), 33.0 (f)
≥3 nights/wk: 9.7 (m), 12.2 (f)
Li et al.71 2002 (Hong Kong)
9851
Population sample: Chinese (18-65)
Telephone survey Preceding month ≥ 3 nights/wk
≥3 nights/wk: 4.5 (4.1-5.0)
≥3 nights/wk: 6.9 (6.4-7.5)
≥3 nights/wk: 4.0 (3.6-4.4)
Morin et al.46 2006 (Canada)
2001
Population sample (18-91)
Telephone survey
≥3 nights/wk: 8.7 (7.4-9.9)
≥3 nights/wk: 6.4 (5.3-7.4)
≥3 nights/wk: 2.1 (1.5-2.8)
Gureje et al.78 2007 (Nigeria)
6752
Population sample (>18)
Face-to-face interviews
>2 wk/yr: 7.7
>2 wk/yr: 8.5
>2 wk/yr: 5.4
REFERENCE (COUNTRY)
NO. SUBJECTS
POPULATION (AGE RANGE, YR)
Blader et al.72 1997 (USA)
987
School-age children (5-12)
Morrison et al.73 1992 (Canada)
943
Ohayon et al.42 1997 (UK)
METHODS
EARLY MORNING AWAKENING (%)
EPESE, Established Populations for Epidemiologic Studes of the Elderly; f, female; m, male; NA, not applicable.
depression or anxiety, alcohol abuse, or both. Use of alcohol and over-the-counter medications to control insomnia is common. Also, somatic and psychological complaints as well as psychological stress are associated with a higher prevalence of insomnia.33,49-51 Fifth, social and occupational factors are important contributors to insomnia. Being unemployed or not married is associated with a higher prevalence of insomnia.14,52,53 In
a questionnaire survey of 6268 adults in 40 different occupations, 18.9% of bus drivers complained of having some or very much difficulty falling asleep. Among male executives and male physicians, the respective percentages were 3.7% and 4.9%. Disturbed nocturnal sleep was complained of the most often by male laborers (28.1% waking up at least three times a night) and female housekeepers (26.6%). Disturbed nocturnal sleep was rare among male physicians
698 PART II / Section 8 • Impact, Presentation, and Diagnosis
(1.6%), male executives (7.4%), female head nurses (8.9%), and female social workers (9.4%).54 Symptoms of workrelated stress and mental exhaustion are associated with insomnia.46,55-57 Use of Hypnotics In a nationally representative probability sample survey of noninstitutionalized adults, 3161 people 18 to 79 years old were surveyed.58 Insomnia afflicted 35% of all adults during the course of 1 year. During the year before the survey, 2.6% of adults had used a medically prescribed hypnotic agent; 0.3% of all adults and 11% of all users of hypnotic agents reported using the medication regularly for 1 year or longer. When anxiolytic and antidepressant agents were excluded, 4.3% of adults had used a medically prescribed hypnotic for sleep and 3.1% had used an overthe-counter sleeping pill. In a reanalysis of several studies published in Finland between 1972-2005 (251,083 subjects) the prevalence figures concerning the use of sleeping medicine at least once a week among adult population did not show any clear trend of increase; the figures varied between 4% and 6% from 1982 to 2002.9 In Sweden, 10,216 members of the Swedish Pensioners’ Association were surveyed.59 Hypnotic agents were used by 13.5% of the men and 22.3% of the women. Of the men aged younger than 70 years, 7.9% were receiving such treatment; of those 70 to 80 years old, 14.4% were using hypnotic agents; and of those 80 years old or older, 21.8% were taking hypnotic agents (P < .0001). The corresponding frequencies among women were 15.0%, 23.0%, and 34.9%, respectively (P < .0001). Hypnotic agents are used by many institutionalized elderly subjects even without insomnia. This raises an ethical question because the chronic use of hypnotic agents is associated with excessive mortality rates.60 In a excellent meta-analytic study of risks and benefits of hypnotics among elderly persons the number needed to treat for improved sleep quality was 13 and the number needed to harm for any adverse event was 6.61 An excellent way of tracking the use of hypnotic medication of the population is to count unit defined daily doses (DDD) from the sales statistics. When one knows the assumed average dose per day for each drug, sales per year, and population of the country, one can calculate DDD per 1000 inhabitants per day. In Finland, for all hypnotic agents, the rate in 1994 was 38 DDD/1000 inhabitants/ day. In 2002 the rate had increased to 53.4 DDD/1000 inhabitants/day. Since that time the use of hypnotics has remained about the same. In 2007 the rate was 53.8 DDD/1000 inhabitants/day.62 Benzodiazepines are available in all Scandinavian countries, and in 2001 the consumption of benzodiazepines (in DDD/1000 inhabitants/ day) was 14.9 in Denmark, 21.5 in Finland, 20.8 in Iceland, 13.1 in Norway, and 11.7 in Sweden.63 Respectively, the consumption of cyclopyrrolones was 17.7 in Denmark, 29.5 in Finland, 34.5 in Iceland, 20.9 in Norway, and 24.3 in Sweden.63
CIRCADIAN RHYTHMS AND THEIR DISORDERS Morningness/eveningness or “chronotype” is dependent on genetic, environmental, and age-related factors. Using
the Munich ChronoType Questionnaire in more than 55,000 persons, it has been found that the most frequent (about 15%) type has midsleep on free days at 4:14 am and about 35% earlier and 50% later.79 (Midsleep is the halfway point between sleep onset and sleep end.) Women reach their maximum in lateness at around 19.5 years and men at 21 years, and this sex difference disappears around the age of 50; and people older than 60 years of age, on average, become even earlier chronotypes than they were as children.79 In a Finnish population, morning type increased from 16% among 25- to 29-year olds to about 50% among those 65 years and older.80 Respectively, evening type was observed in 11% to 12% among 25- to 29-year olds and the minimum (6%-7%) was found among 55- to 59-year olds. The estimate for overall genetic effect was 49.7%.80 Studies on the prevalences of circadian rhythm sleep disorders are scarce. Delayed sleep phase syndrome has been found in 0.17% among Norwegians aged 18 to 67 years81 and in 0.13% among Japanese aged 15 to 54 years,82 and the number of cases seems to have increased in the past few decades,83 being about 1.66% in Japanese university students.84 In Europeans aged 15 to 18 years a circadian rhythm disorder was found in fewer than 0.5%.85 One study has suggested that the prevalence of shift-work sleep disorder is about 10%.86
EXCESSIVE SLEEPINESS AND HYPERSOMNIA The feeling of not being alert is common, occurring both as a physiologic everyday phenomenon and as a symptom of sleep disorders.1,2 In spoken language, this feeling is probably most often called sleepiness but the actual meaning varies. By definition, sleepiness implies an increased risk of falling asleep,2 but the complaint of sleepiness is sometimes used to describe physical tiredness, fatigue, and loss of mental alertness without an increase in sleep behavior— conditions often associated with a decreased ability to fall asleep, contrary to true sleepiness. Abnormal sleepiness is often called excessive daytime sleepiness (EDS), but also this condition is difficult to be defined, because falling easily asleep or inability to stay awake may be normal and a desired everyday phenomenon (e.g., in the evening when going to bed). EDS has also been labeled as a disease or a disorder, although it is a symptom of a sleep disorder or of another disease. Our own studies exemplify these problems.87 Among those reporting daytime sleepiness every or almost every day, 19.5% of women and 42.3% of men were frequent snorers (snoring on at least 3 nights per week), 25% had scores suggesting moderate to severe depression, 25% had insomnia at least every other day, 10% were regular hypnotic or tranquilizer users, and 10% reported insufficient sleep. Thus, a “tired” or “sleepy” (in the patient’s words) person may have insomnia and not EDS or hypersomnia. In practice, it must be remembered that descriptions of the symptoms are related to the person’s feelings, emotions, level of education, and cultural background. Sleep researchers usually talk about sleepiness when referring to poor vigilance, lack of alertness, and tendency to fall asleep, but traffic researchers often use the terms, fatigue
CHAPTER 61 • Epidemiology of Sleep Disorders 699
Table 61-3 Occurrence of Excessive Sleepiness REFERENCE (COUNTRY)
NO. SUBJECTS; AGE RANGE (YR)
DEFINITION OF SLEEPINESS (WORDING OF QUESTIONS)
METHODS
OCCURRENCE (%)
Excessive Sleep Time Karacan et al.99 1976 (USA)
1645; 18-70
Too much sleep
Questionnaire
0.3
Bixler et al.74 1979 (USA)
1006; 18-80
Sleeping too much
Questionnaire
Current: 4.2 (past 7.1) 18-30 yr: 9.9 31-50 yr: 2.3 51-80 yr: 1.8
Ford and Kamerow67 1989 (USA)
7954; 18-65
Ever a period of 2 wk or longer sleeping too much
Direct structured interview using diagnostic interview schedule
2.8 (m), 3.5 (f) 18-25 yr: 5.8 26-44 yr: 3.7 45-64 yr: 1.5 65+ yr: 1.6
Breslau et al.100 1996 (USA)
1007; 21-30
Definition and methods as in Ford and Kamerow67 (1989)
14.7 (m), 17.3 (f)
Ohayon et al.101 1997 (Great Britain)
4972; 15-100
Getting too much sleep
Telephone interview
3.2
Roberts et al.92 1999 (USA)
2730; 46-102
Sleeping too much nearly every day in the last 2 weeks
Questionnaire
6.0 and 1 year later 7.2, 7.4 (m) and 7.2 (f) 50-59-yr: 6.0 and 1 year later 7.1 60-69 yr: 5.5 and 5.2 70-79 yr: 8.4 and 10.3 80+ yr: 9.4 and 6.3
Saarenpää-Heikkilä et al.64 1995 (Finland)
574; 7-17
Sleeping in lessons often or always
Questionnaire (both subject and parents)
3 (m), 0 (f)
Partinen and Rimpelä66 1982 (Finland)
2016; 15-64
Involuntary sleep attacks daily or almost daily
Telephone interview
3.4 (m), 2.5 (f)
Kaneita et al.95 2005 (Japan)
28,714; 20-70+
Fall asleep when must not sleep
Questionnaire (e.g., when driving)
2.8 (m), 2.2 (f) 20-29 yr: 4.6 (m), 4.0 (f) 30-39 yr: 3.8 (m), 2.8 (f) 40-49 yr: 3.5 (m), 3.0 (f) 50-59 yr: 2.1 (m), 1.9 (f) 60-69 yr: 1.8 (m), 0.9 (f) 70+ yr: 0.9 (m), 0.7 (f)
Hays et al.96 1996 (USA)
3962; 65-85
Most of the time sleepiness, forcing to take a nap
Interview
25.2
Ganguli et al.35 1996 (USA)
1050; 66-97
Ever becoming uncontrollably sleepy so cannot help falling asleep
Interview
18.9 (no gender difference)
Saarenpää-Heikkilä et al.64 1995 (Finland)
574; 7-17
Sleepiness always or often
Questionnaire (both subject and parents)
20 (m), 22 (f)
Gaina et al.98 2007 (Japan)
9261; 12-13
Sleepiness
Questionnaire
Almost always: 20.7 (m), 29,6 (f) Often: 44.6 (m), 50.4 (f)
Chung and Cheung102 2008 (Hong Kong Chinese)
1629; 12-19
ESS >10
Questionnaire
41.9 (m < f)
Ohida et al.97 2004 (Japan)
106,297; 13-18
Excessively sleepy during the daytime always
Questionnaire
13-yr: 14-yr: 15-yr: 16-yr: 17-yr: 18-yr:
Sleep Attacks
Daytime Sleepiness
6.0 (m), 9.2 (f) 8.3 (m), 10.5 (f) 10.6 (m), 12.3 (f) 13.8 (m), 16.6 (f) 13.9 (m), 15.3 (f) 14.9 (m), 15.5 (f) Continued
700 PART II / Section 8 • Impact, Presentation, and Diagnosis Table 61-3 Occurrence of Excessive Sleepiness—cont’d DEFINITION OF SLEEPINESS (WORDING OF QUESTIONS)
METHODS
OCCURRENCE (%)
3871; 15-18
ESS >10
Questionnaire
14.9 (m), 18.2 (f)
Ohayon et al.101 1997 (Great Britain)
4952; 15-100
Feeling greatly sleepy daily for at least 1 month
Telephone interview using Sleep-EVAL expert system
4.4 (m), 6.6 (f)
Souza et al.104 2002 (Brazil)
408; 18-60+
ESS >10
Interview
18.9 18-29 yr: 19.3 30-39 yr: 17.9 40-49 yr: 15.1 50-59 yr: 26.3 60+ yr: 19.6
Hara et al.105 2004 (Brazil)
1066; 18-60+
Sleepiness during the previous month ≥3 times per week
Interview
16.8 18-29 yr: 30.7 30-44 yr: 29.6 45-59 yr: 25.7 60+ yr: 14.0
Hublin et al.87 1996 (Finland)
11,354; 33-60
Sleepiness daily or almost daily
Questionnaire
6.7 (m), 11.0 (f)
Joo et al.106 2008 (Korea)
4405; 40-69
ESS >10
Questionnaire
10.7 (m), 13.7 (f) 40-49 yr: 10.2 (m), 11.2 (f) 50-59 yr: 13.1 (m), 20.5 (f) 60+ yr: 8.8 (m), 13.3 (f)
Tsuno et al.107 2007 (France)
2259; 65-96
ESS >10
Questionnaire and clinical evaluation
12.0 (m), 6.0 (f)
REFERENCE (COUNTRY) Joo et al. (Korea)
103
2005
NO. SUBJECTS; AGE RANGE (YR)
ESS, Epworth Sleepiness Scale; f, female; m, male.
or drowsiness.88 Sleeping alleviates sleepiness at least temporarily whereas resting without sleep does not. Fatigue, on the contrary, may be alleviated by having a pause, resting, physical exercise, and management of stress. Chronic fatigue is usually multifactorial in etiology, and it is generally not relieved by usual restorative techniques.88 Fatigue (57%), tiredness (61%), and lack of energy (62%) may be more frequent complaints than sleepiness (47%) in patients with sleep apnea.89 Also in primary care, complaints of chronic fatigue may be more common (20%-25%) than complaints of excessive sleepiness (5%-15%).90,91 Table 61-3 provides a summary of studies on daytime sleepiness.35,64,66,67,74,87,92,95-107 Depending on the wording, there is approximately a 100-fold difference in occurrence, ranging from 0.3% to more than 30%, and in most of the studies the range is from 5% to 15%. The prevalences of excessive sleep time or hypersomnia-like states are mostly around 5% in adults (no studies on children), with no clear gender difference. The prevalence may be age dependent, although the results are conflicting (decreases67,74 or increases92,93). In the classic study by Ford and Kamerow,67 64% of hypersomniacs had a psychiatric disorder in two interviews with a 1-year interval, most commonly an anxiety disorder or major depression. Similar findings are
reported from many European countries.94 Studies with two assessments of excessive sleep have shown stability of the symptom in less than one third.92 Sleep attacks (involuntary sleep episodes during awake periods) also mostly seem to occur in a few percent of the population in all age-groups, with no clear difference between the sexes and with conflicting results as to age-dependence (decreases95 or increases35,96 with age). Frequent or excessive (subjective) daytime sleepiness occurs in 10% to 15%. It occurs more often in school-aged children (with large differences between studies in the same country97,98) or young adults than in middle-aged or older adults. In most studies, sleepiness is more prevalent among women than among men. The variability of the results in different studies can be explained by differences in the definition of sleepiness and by other methodological aspects. Comparison of the results is difficult, but real differences in different populations probably exist. One problem is how “excessive” is understood in different studies. In questionnaires, the word “excessive” is subjective, and it should be compared with something that the responder considers normal for him or her. There are no studies on the population prevalences of recurrent hypersomnia or idiopathic hypersomnia.
CHAPTER 61 • Epidemiology of Sleep Disorders 701
Table 61-4 Prevalence Studies on Narcolepsy-Cataplexy REFERENCE (COUNTRY)
FREQUENCY (PER 100,000)
95% CI*
BASE POPULATION (AGE RANGE, YR)
METHODS
Dement et al.123 1972 (USA)
50†
NA
NA (?) Bay area
Population sample Newspaper ad, telephone interview
Dement et al.124 1973 (USA)
67‡
NA
NA (?)
Population sample TV ad, telephone interview
9-230
12,469 (12-16)
Population sample Questionnaire, personal interview Personal interview
Honda109 1979, Honda et al.110 1983 (Japan)
160
Hublin et al.114 1994 (Finland)
26
0-56
11,354 (33-60) (Finnish twin cohort)
Population sample Questionnaire Ullanlinna Narcolepsy Scale Telephone interview Polygraphy HLA typing
Ohayon et al.118 1996 (UK)
40
0-96
4972 (15-100)
Population sample Telephone interview; Sleep-EVAL questionnaire
Silber et al.119 2002 (USA)
36
NC
97,667 (0-109) Olmsted County, Minnesota
Review of medical records covering 1960-1989
Wing et al.115 2002 (Hong Kong)
34
10-117
9851 (18-65)
Population sample (Chinese) as in Hublin et al.114 (1994)
Ohayon et al.94 2002 (five European countries)
47
NA
18,980 (15-100)
Population sample Telephone interview; Sleep-EVAL questionnaire
Shin et al.116 2008 (South Korea)
15
0-31
20,407 (14-19)
High school students as in Hublin et al.114 (1994)
Longstreth et al.120 2008 (USA)
22
19-25
1,366,417 (18 or more)
Physician-made diagnosis in one county covering 2001-2005
Heier et al.117 2009 (Norway)
22
6-80
8992 (20-60)
Population sample as in Hublin et al.114 (1994)
NA, not applicable; HLA, human leukocyte antigen. *95% confidence interval (CI) for the frequency of narcolepsy per 100,000 of population. † Estimated from San Francisco Bay area population (4 million), newspaper circulation (1.2 million), number of respondents (196) and interview-confirmed narcolepsy cases (114), and number of persons seeing/not seeing and responding/not responding to a control advertisement. ‡ Estimated from number of television homes in Los Angeles area (2,290,200), rating of number of viewers of the advertisement (56,576), number of respondents (165), and interview-confirmed narcolepsy cases (35); 30% sampling error and errors in making the diagnosis.
NARCOLEPSY AND NARCOLEPSY-LIKE SYMPTOMS There are about 30 studies published on the prevalence on narcolepsy (most of them on narcolepsy-cataplexy) with considerable differences in the figures. Highest prevalences (up to 30%) are based on questionnaire data without follow-up testing, and the next highest (0.2%-0.8%) on studies with self-reported diagnosis.108 In most studies with more intensive screening or clinical evaluation of suspected narcoleptics the prevalence of narcolepsy-cataplexy falls between 0.025% and 0.05%, or 25 to 50 per 100,000 population, and the 95% confidence intervals (CIs) for the frequencies overlap in the majority of them (Table 61-4). There are some exceptions. The highest figures are from Japan109,110 based on interviews of symptomatic schoolaged children selected by questionnaire, giving “a suspect
of narcolepsy” in 160 per 100,000 and a surprisingly high prevalence (7.6%) of “interview-confirmed cataplectic attacks,” which suggests criteria different from other studies. The lowest frequency (0.23 per 100,000) is found among Israeli Jews,111 but this was based on an extrapolation of sleep clinic samples to the entire population. However, narcolepsy is likely hugely underdiagnosed.111a The prevalence of narcolepsy-cataplexy seems to be consistent despite considerable differences methods, ethnic groups, and population frequencies of DQB1*0602, and so on between the studies.112 For example, there are three studies using a simple screening method called the Ullanlinna Narcolepsy Scale (UNS) developed and validated for population studies.113 It consists of 11 items assessing cataplexy-like symptoms and the tendency to fall asleep. Using the UNS, telephone interviews, and polygraphic confirmation of the diagnosis, the prevalence of narcolepsy
702 PART II / Section 8 • Impact, Presentation, and Diagnosis
with clinically significant cataplexy has been found to be of same order among adult Finns (26 per 100,000),114 adult Chinese in Hong Kong (34 per 100,000),115 Korean adolescents (15 per 100,000),116 and adult Norwegians (22 per 100,000).117 Similar prevalences have been obtained in Europeans using telephone interviews (Sleep-EVAL questionnaire) without any other examinations (40 or 47 per 100,000)94,118 and in the United States using a review of medical records (36 per 100,000)119 and physician-made diagnoses (22 per 100,000).120 There are only a couple of studies on narcolepsy without cataplexy, giving a prevalence of 20 per 100,000 in adults in the United States119 and 34 per 100,000 in Korean adolescents,116 which may be gross underestimations.112 However, it can be difficult to assess the true prevalence because diagnostic Multiple Sleep Latency Test criteria may be 100 times more prevalent in a population than narcolepsy.121 One study gives an incidence rate of 1.37 (0.74 for narcolepsy with cataplexy) per 100,000 persons per year. Some studies suggest that narcolepsy may be slightly more common in men.108 Analytic epidemiologic studies have found associations between narcolepsy and body mass index (BMI), immune responses, and stressful life events, but these may rather reflect consequences than cause of disease.108 Although typical cataplexy is pathognomonic of narcolepsy, mild forms are difficult to separate from similar physiologic phenomena. As mentioned, reports of EDS in the population are common. In Finland, 29.3% of the people reported (at least once during his or her lifetime) feelings of limb weakness associated with emotions.114 If this is considered as evidence of cataplexy and combined with the occurrence of daytime sleep episodes at least 3 days per week, 6.5% of the population would have fulfilled the minimal diagnostic criteria for narcolepsy of the International Classification of Sleep Disorders.114,122 Therefore, using only questionnaires in population studies may increase the risk of too high prevalence rates.
SNORING, SLEEP-DISORDERED BREATHING, AND SLEEP APNEA SYNDROME Habitual snoring is defined as snoring almost every night or every night or as snoring at least 5 nights per week. It is almost always present in patients with obstructive sleep apnea syndrome (OSAS). In the first large-scale epidemiologic study on snoring, about 24% of San Marino men and 14% of San Marino women were reported to habitually snore (Table 61-5125-137). In Finland, 9% of adult men and 3.6% of adult women snore always or almost always when asleep.125 A Syndrome or a Disease? Obstructive sleep apnea syndrome is a public health disease. It is the most common organic sleep disorder causing excessive daytime somnolence. Sleep-related breathing disorders (SRBD) and sleep-disordered breathing (SDB) refer to the same clinical disorder. In this chapter, we still use the term OSAS, although hypopneas are now included in the syndrome.
According to various cross-sectional studies, the lowest rates for the prevalence of OSAS among adult men are 1% to 4%. There is an age relationship, so the prevalence of OSAS among men 40 to 59 years old may be greater than 4% or 8%.133 OSAS is less common is younger and older age groups. After menopause, up to the age of 65, OSAS is almost as common among women as among men. Obstructive sleep apneas are part of the complex of heavy snorer’s disease as defined by Lugaresi and colleagues.138 Heavy snoring (i.e., partial upper airway obstruction), even without apneas, is associated with higher pulmonary arterial pressure, daytime sleepiness, arterial hypertension, and insulin resistance.139-143 Heavy snoring is also associated with case-fatality and short-term mortality after a first acute myocardial infarction.144 Visceral central body obesity, measured by waist circumference, is strongly related to SBD.145 Among morbidly obese patients the proper diagnosis may be morbid obesity with obstructive sleep apnea.146 Another example is acromegaly with symptomatic sleep apnea. This is analogous to a patient with a brain tumor who has symptomatic epilepsy. The primary diagnosis is brain tumor (e.g., glioma), and epilepsy is a secondary symptom caused by the brain tumor. The severity of sleep apnea must be properly quantified, not only by indices (e.g., apnea index [AI], apnea-hypopnea index [AHI], or respiratory disturbance index [RDI]) but also by the number of oxygen desaturations, presence of cardiovascular effects, and degree of daytime sleepiness. Snoring and sleep apnea are more common in the supine sleeping position than in the lateral positions. It is therefore necessary to give indices separately for supine and lateral sleeping positions. In clinical studies, sequential apnea indices should always be compared relative to sleeping position. The diagnostic criteria should also be adjusted for age. Bixler and associates147 studied 20- to 100-year-old men. The criteria for OSAS were an AHI of at least 10 in the sleep laboratory and fulfillment of clinical criteria, including the presence of daytime symptoms. OSAS was found in 3.3% of the sample, with its maximum among 45- to 64-year-old men. Although the prevalence of sleep apnea increases with age the clinical impact of apnea seems to decrease among elderly people.148-150 Prevalence of Sleep Apnea The first large epidemiologic polysomnographic study was conducted in Madison, Wisconsin.133 The authors estimated that 2% of women and 4% of men in the middleaged work force met the minimal diagnostic criteria for the sleep apnea syndrome, defined as an AHI of 5 and daytime hypersomnolence.133 Up to 9% of women and 24% of men had an AHI of 5 without daytime somnolence. On examination of the subgroup of patients between the ages of 50 and 60, 4% of women and 9.1% of men were found to have an AHI exceeding 15.133 In a large U.S. population– based study,140,147 clinically defined sleep apnea (AHI ≥ 10 and daytime symptoms) occurred in 3.9% of men and 1.2% of women. The peak prevalence, 4.7% (95% CI, 3.1% to 7.1%), was found among men aged 45 to 64 years. Among the 20- to 44-year olds and those older than 65
CHAPTER 61 • Epidemiology of Sleep Disorders 703
Table 61-5 Occurrence of Habitual Snoring
REFERENCE (POPULATION)
METHODS
1980 Lugaresi et al. (San Marino general population)
Interview
Partinen127 1982 (Army recruits)
DEFINITION/ WORDING OF HABITUAL SNORING
SEX
NO. SUBJECTS
AGE RANGE (YR)
PREVALENCE (%)
“Every night” (alternatives: no, sometimes, every
m
2858
3-94
24.1
f
2855
3-94
13.8
Questionnaire, clinical studies
Snoring always or almost always Snoring often or always
m
2537
18-29
Koskenvuo et al.125 1985 (Finnish population sample)
Postal questionnaire
“Snoring always or almost always”
m
3847
40-69
9
f
3864
40-69
3.6
Norton and Dunn 1985 (Canadian population sample)
Questionnaire filled during a medical visit
Snoring every night (reported by spouses)
m
1411 1211
3rd to 8th decade
13.2
f
Billiard et al.129 1987 (French army draftees)
Questionnaire completed under supervision
Snoring habitually
m
58,162
17-22
13.6
Gislason et al.130 1987 (Swedish men)
Postal questionnaire
“Loud and disturbing snoring” very often
m
4064
30-69
15.5
Cirignotta et al.131 1989 (Italian adults)
Postal questionnaire
Snoring always (alternatives: never, rarely,
m
1170
30-69
10.1
890
40-69
11.5
304
50-59
15.5
18 or older
10.2
126
128
2.9 9.5
5.6
Schmidt-Nowara et al.132 1990 (HispanicAmerican adults)
Interview using a questionnaire
“Regular and loud snoring” always (every night)
m
482
f
724
Young et al.133 1993 (state employees in Wisconsin)
Postal questionnaire (first stage of
Almost every night or every night snoring
m
1670
30-60
35
f
1843
30-60
28
Ali et al.134 1993 (English children)
Questionnaire filled by
“Snoring on most nights”
m, f
4-5
12.1
Jennum and Sjol135 1994 (Danish population sample)
Interview and clinical examinations
Snoring nightly (every night)
m
Total
30-60
19.1
f
1504
30-60
7.9
Kayukawa et al. (Japan, new outpatients)
Questionnaire, outpatient clinic visit
Habitual snoring
m
6445
Adults
16.0
Kaditis et al.136 2004 (Greek children and adolescents)
Questionnaire filled out by parents
Habitual snoring (snoring every night)
m, f
3680
1-18
1-6 yr: 5.3 7-12 yr: 4.0 13-18 yr: 3.8
Kuehni et al.137 2008 (English preschool children)
Population survey
Habitual snoring
m, f
6811
1-4
1 yr: 6.6 4 yr: 13.0
162
2000
782
5.4
f
years, the prevalence rate was 1.7%. Among women, the average prevalence was 1.2.140,147 In women, the prevalence of SDB increases after menopause; hormone replacement therapy is associated with lower occurrence of SDB.140,161 In the study by Bixler and coworkers.140 the prevalence of clinically defined sleep apnea among premenopausal women was 0.6%. Among postmenopausal women on hormone replacement therapy the prevalence was about the same (0.5%).140
6.5
The prevalence depends on the base population. OSAS is most frequent in persons 40 to 65 years old. One can safely estimate that the prevalence rate of OSAS in that age group is around 4% (3% to 8%) in men and 2% in women and that the absolute minimum prevalence of clinically significant OSAS is 1%. Among obese subjects, hypertensive persons, patients with adult-onset diabetes, and many patient groups with abnormal facial anatomy, the prevalence rates are significantly higher.
704 PART II / Section 8 • Impact, Presentation, and Diagnosis Table 61-6 Occurrence of Obstructive Sleep Apnea Syndrome REFERENCE (COUNTRY)
METHODS
NO. SUBJECTS
AGE RANGE (YR)
CRITERIA
PREVALENCE (%)
Lavie151 1983 (Israel)
Questionnaire for industrial workers of whom 78 subjects had PSG
1262 (m)
18-67
AI ≥ 10, symptomatic
3.5 (1.0-5.9)
Telakivi et al.152 1987 (Finland)
Questionnaire. PSG recordings and clinical examination for potential subjects
1939 (m)
30-69
Snoring, EDS, and RDI > 10
0.4-1.4
Gislason et al.153 1988 (Sweden)
Questionnaire. PSG recordings and clinical examination for potential subjects
3201 (m)
30-69
Snoring, EDS, and AHI > 10
0.7-1.9
Cirignotta et al.131 1989 (Italy)
Questionnaire, telephone survey. PSG recordings and clinical examination for potential subjects Ambulatory oximetry recordings at home
1170 (m)
30-39
AI > 10, symptomatic
0.2-1.0
40-59
AI > 10, symptomatic
3.4-5.0
60-69
AI > 10, symptomatic
0.5-1.1
35-65
ODI4 > 20, symptomatic
0.3
ODI4 > 10
1.0
Stradling and Crosby154 1991 (Great Britain)
893 (m)
Young et al.133 1993 (Wisconsin, USA)
A sample of state employees. PSG recordings and clinical
352 (m)
30-60
250 (f)
30-60
Olson et al.155 1995 (Australia)
Questionnaire and home sleep recordings
1233 (m)
35-69
Bixler et al.147 1998 (USA)
Telephone survey. Random sample of men aged 20-100 yr A sleep laboratory study (PSG) for a subsample of men
4364 (m) Subsample: 741
20-100
Marin et al.156 1997 (Spain)
Personal interview, clinical examination, home oximetry A population sample
597 (m)
>18
Bixler et al.140 2001 (USA)
Telephone survey Random sample of women
12,219 (f)
A sleep laboratory study (PSG) for a subsample of women
Subsample: 1000
Male office workers
784 (m)
Ip et al.157 2001 (Hong Kong, China) Ip et al.158 2004 (Hong Kong, China)
969 (f)
625 (f) 20-100
30-60
Questionnaire and PSG in 153 Community samples of women
854 (f)
30-60
Questionnaire and PSG in 106
ODI4 > 5
4.6
Hypersomnia and RDI ≥ 5
4.0 (m) 2.0 (f)
AHI ≥ 15
4-18
AHI ≥ 10
7-35
AHI ≥ 5
14-69
AHI > 10 and clinical criteria fulfilled with daytime symptoms
All: 3.3 45-64 yr: 47
Loud snoring + EDS + abnormal home oximetry
2.2 (m)
AHI > 10 and clinical criteria fulfilled with presence of daytime symptoms
All (f): 1.2
0.8 (f)
Premenopause: 0.6 Postmenopause without HRT: 2.7 With HRT: 0.5
AHI ≥ 5 + EDS
4.1
AHI ≥ 15 + EDS
3.1
AHI ≥ 5 + EDS
2.1
AHI ≥ 15 + EDS
0.8
Kim et al.159 2004 (South Korea)
Examination of 5020 Korean subjects A subsample of 457 had PSG
5020
40-69
AHI ≥ 5 + EDS
4.5 (m); 3.2 (f)
Reddy et al.160 2009 (New Delhi, India)
Random community sample Questionnaire and PSG in 360
2505
≥ 18
AHI ≥ 5 + EDS
4 (m); 1.5 (f)
AHI, apnea–hypopnea index; AI, apnea index; EDS, excessive daytime sleepiness; f, female; HRT, hormone replacement therapy; m, male; NA, not applicable; ODI4, oxygen desaturation index (≥4% desaturation); OSAS, obstructive sleep apnea syndrome; PSG, polysomnography; RDI, respiratory disturbance index.
Role of Obesity as a Risk Factor for Snoring and Sleep Apnea Obesity is the most important risk factor for snoring and sleep apnea. The association is found without exceptions, which does not, naturally, mean that lean people could not have OSAS. Neck size162 and especially waist circumference145,163 are related to severity of sleep apnea and may be better indicators than BMI. Other Risk Factors for Snoring and Sleep Apnea Alcohol increases upper airway resistance and tends to induce obstructive sleep apnea in healthy people and especially among chronic snorers. In Great Britain, one drink per day increased the odds of mild or worse SDB by 25% (OR = 1.25; 95% CI, 1.07-1.46) among men. Among women, minimal to moderate alcohol consumption was not significantly associated with increased risk of SDB.164 Other risk factors include large adenoids or tonsils, rhinitis, and other abnormalities in the upper airways, such as those found in different syndromes of dysmorphia and in the mentally disabled. Also, smoking,165 acromegaly,166,167 and amyloidosis168 are known risk factors for SDB. Organic solvent use was associated with increased prevalence of SDB in Sweden169 but not in Germany.170 Snoring and Sleep Apnea in Children Habitual snoring and sleep apnea during childhood (see Tables 61-5 and 61-6125-137,140,147,151-160) may be associated with significant harmful effects on health. Childhood obesity and adenotonsillar hypertrophy are among the most common associated factors.171 In an Italian study, 118 (7.3%) of 1615 children 6 to 13 years of age were often snorers.172 Children with rhinitis were more than twice as likely to be habitual snorers than others. A positive correlation between parental smoking and snoring in children exists. In Singapore, 6% of children snore habitually.173 In Iceland,174 the minimal prevalence of obstructive sleep apnea among children 6 months to 6 years old was 3.2%. In another study, significant sleep and breathing disorders occurred in 0.7% of 4- to 5-year olds.134 The prevalence of SBD among adolescents aged 12 to 16 years was similar to that reported for younger children. In Greece, a survey of 3680 people aged 1 to 18 years revealed a prevalence of habitual (every night) snoring of 5.3%, 4%, and 3.8% among 1- to 6-, 7- to 12-, and 13- to 18-year-old subjects, respectively.136 Sleepiness at school was more common in habitual snorers than in nonhabitual snorers (4.6 vs. 2%, P = .03). Based on 70 random polysomnographic recordings among the 307 snorers without adenoidectomy and/or tonsillectomy the estimated prevalence of OSAS was 4.3%. In a population survey of 6811 children aged 1 to 4 years in the United Kingdom (from parent’s reports) the prevalence of habitual snoring was 7.9%, and 0.9% of children were reported to have habitual snoring and sleep disturbance. Habitual snoring increased with age from 6.6% in 1-year olds to 13.0% in 4-year olds. Habitual snoring was associated with parent’s smoking, road traffic, single parenthood, white but not South Asian children, and socioeconomic deprivation.137 Atopy and respiratory infections were strongly associated
CHAPTER 61 • Epidemiology of Sleep Disorders 705
with snoring, but BMI was not,137 which shows that the association between childhood obesity and SBD is not simple.175 Sleep Apnea among Elderly People The prevalence of habitual snoring seems to decrease after the age of 65 or 70 years (see Table 61-5). According to Ancoli-Israel and colleagues,176 62% of elderly people have an RDI of at least 10. Bixler has emphasized the need to adjust the criteria for OSAS in elderly persons.147 A cohort of 198 noninstitutionalized elderly individuals (mean age at entry, 66 years) were followed up to 12 years.148 The mortality ratio for sleep apnea, defined as an RDI greater than 10, was 2.7 (95% CI, 0.95 to 7.47). In a cohort of 426 elderly people those with an RDI of 30 had significantly shorter survival. RDI was not an independent predictor of death among the elderly during 5 years follow-up after adjustment for age, cardiovascular disease, and pulmonary disease.149 The clinical significance of sleep apnea among elderly people remains open. Arterial Hypertension and Snoring An association between always or almost-always snoring and arterial hypertension exists. Among 41- to 60-year-old people in San Marino,126 hypertension was present in 15.2% of habitual snorers and in 7.5% of nonsnorers. In a cross-sectional study in Finland the odds of arterial hypertension were increased by 94% (OR 1.94) among habitual male snorers versus nonsnorers after adjustment for BMI and age.177 Case-control studies have shown that the prevalence of sleep apnea among patients with essential hypertension is around 30%. In another study,178 38% of the hypertensive subjects and 4% of normotensive subjects had an AHI of higher than 5.178 In middle-aged adults with drug-resistant hypertension the prevalence of OSA may be over 80%.179 There are now several studies, including prospective studies, showing that SDB in the form of habitual snoring or sleep apnea is a determinant of risk of arterial hypertension but occasional snoring is not associated with an increased risk.180-184 Snoring, Sleep Apnea, and Heart Disease An association of habitual snoring with electrocardiographic changes and arrhythmias has been reported.185 The association of snoring and ischemic heart disease was tested in a population consisting of 3847 men and 3664 women 40 to 69 years old. Reported angina pectoris was associated with habitual snoring among men (risk ratio, 1.9) but not among women (risk ratio, 1.2). The association was also found after adjustment for arterial hypertension and BMI.177 These results were confirmed in a prospective follow-up study of 4388 men 40 to 69 years old. The age-adjusted risk ratio of ischemic heart disease between often or always snorers and nonsnorers was 1.91 (1.18-3.09). An additional adjustment for BMI, history of arterial hypertension, smoking, and alcohol use decreased the risk ratio to 1.71 (0.96-3.05).186 In a casecontrol study with 50 patients with myocardial infarction and 100 control subjects, snoring every night was associated with myocardial infarction. The odds ratio was 2.35 (1.18-4.67) when patients were compared with both hospital control and population control subjects. Adjustment
706 PART II / Section 8 • Impact, Presentation, and Diagnosis
by smoking, arterial hypertension, diabetes mellitus, and alcohol consumption did not change results.187 In Australia, men with an AI of more than 5.3 had a 23.3-fold (95% CI, 3.9 to 139.9) risk of myocardial infarction than men with an AI of less than 0.4. The mean AI was 6.9 in patients with myocardial infarction versus 1.4 in the control subjects.188 The association was independent of age, BMI, arterial hypertension, smoking, and cholesterol level. Fifty patients 61 ± 6 years old with coronary artery disease were investigated prospectively. In 25 patients (50%), the AI was more than 10/hour sleep. EDS was exhibited by 8 of the 25 patients.189 Several cross-sectional and prospective studies have now confirmed that there is an association between habitual snoring, sleep apnea, and ischemic heart disease142,144,190-193 or congestive heart failure.194,195 The minimum prevalence of OSAS among patients with coronary disease can be estimated as about 16%. Snoring, Sleep Apnea, and Brain Infarction An association between cerebral infarction and habitual snoring has been found in many studies.196 In a casecontrol study of 50 male patients with brain infarction and 100 male control subjects,197 the risk ratio of brain infarction between habitual or often snorers and occasional or never snorers was 2.8. Between habitual snorers and occasional or never snorers, the risk ratio of stroke was 10.3. After adjustments for several confounding variables among 177 male patients and control subjects matched for age and sex, the independent odds ratio relating to snoring and stroke remained at 2.13.198 Other studies have provided supporting results. In Italy,199 the adjusted (age, gender, obesity, diabetes, dyslipidemia, smoking, use of alcohol, and hypertension) odds ratio for “often or always snoring” in relation to ischemic brain infarction was 1.9 (1.2-2.9). Neau and associates200 studied 133 patients 45 to 75 years old and 133 control subjects matched for age and sex. The prevalence of habitual snoring was 23.3% among patients with stroke and 8.3% among their controls. The odds ratio for habitual snoring was 3.4 (1.5-7.6). The odds ratio for “often or always snoring” was 1.7 (1.03-2.93). After adjustment for age, sex, arterial hypertension, cardiac arrhythmia, and obesity, the odds ratio of habitual snoring for stroke remained statistically significant (2.9; 1.3-6.8). The risk of ischemic stroke seems to be especially high among habitually snoring men with arterial hypertension.200 A significant association between occurrence of sleep apnea and ischemic stroke exists.201-204 The causal relationships remain still somewhat open.196,205 Snoring and Sudden Death An autopsy was performed in 460 consecutive cases of sudden death among 35- to 76-year-old men. The closest cohabiting person to each deceased man was interviewed. The mean age was 55.4 years, and the mean BMI was 26.3 kg/m2. Among the obese snorers (N = 82), apneas had been observed “occasionally,” “often,” or “habitually” in 49 cases. Death was classified as cardiovascular in 186 cases (40.4%). The cardiovascular cause of death was more common among the habitual and often snorers than among
occasional or never snorers. Habitual snorers died more often while sleeping. Habitual snoring was found to be a risk (OR 4.07; 1.45-11.45) for cardiovascular early morning death between 4 and 8 am.206 In a follow-up study of 34 obese men, a history of obstructive sleep apnea was a strong risk factor for sudden cardiovascular death. On autopsy, the degree of atherosclerosis was moderate in all cases.207 Snoring and Dementia The occurrence of snoring was studied in 46 patients with Alzheimer’s disease, in 37 patients with multiinfarct dementia, and in a random sample of 124 elderly community residents.208 The demented patients snored twice as frequently as the control subjects. No difference in the occurrence of snoring was found between the two types of dementia. Among 235 nursing home residents 70% had an AHI of 5. The presence of sleep apnea correlated with results of dementia rating scales.209,210 Clinical reports exist about associations between sleep apnea and dementia,210,211 but larger epidemiologic studies are lacking. Evolution of Obstructive Sleep Apnea Syndrome Evolution of OSAS and the effects of treatment are handled in greater detail elsewhere in this textbook. OSAS may be a lethal disease if not treated. There are several studies showing an increased risk of cardiovascular complications and death in patients with at least moderate (AI > 20) or severe (AI > 40) OSAS.212-216 Mortality of mild sleep apnea, with AHI less than 15, does not seem to differ significantly from the mortality of the average population.216 The increased risk is found especially among middle-aged people with SDB, but not in the elderly, in whom several other risk factors for cardiovascular disease and death coexist with OSAS.216 In a Swedish study of 3100 men aged 30 to 69 followed for 10 years, 213 men died, 88 of cardiovascular diseases. In that study, those with isolated snoring or excessive daytime sleepiness (EDS) displayed no significantly increased mortality but the combination of snoring and EDS was associated with a significant increase in mortality. The relative rates decreased with increasing age as in other studies.217 Men younger than the age of 60 with both snoring and EDS had an age-adjusted total death rate that was 2.7 times higher than men with no snoring or EDS (95% CI 1.6 to 4.5). The corresponding age-adjusted hazard ratio for cardiovascular mortality was 2.9 (1.3-6.7) for subjects with both snoring and EDS. Further adjustment for BMI and reported hypertension, cardiac disease, and diabetes reduced the relative mortality risk associated with the combination of snoring and EDS to 2.2 (1.3-3.8) and the relative risk of cardiovascular mortality to 2.0 (0.8-4.7).217 Continuous positive airway pressure (CPAP) is an effective and life-saving treatment of severe OSAS.218-221 Studies show that CPAP is effective in short-term trials in the treatment of mild sleep apnea.222-224 A few prospective follow-up studies142,221,225,226 have been published, but more well-done prospective epidemiologic studies are still needed, especially based on intention to treat analysis. Different surgical methods (e.g., uvulopalatopharyngoplasty,
CHAPTER 61 • Epidemiology of Sleep Disorders 707
Table 61-7 Prevalence of Restless Legs Syndrome REFERENCE (COUNTRY)
POPULATION; NO. SUBJECTS
METHODS, CRITERIA
PREVALENCE (%)
Ekbom230 1945 (Sweden)
Patients in a physician’s practice; N = 500
Presence of restless legs (original description)
5
Lavigne et al.233 1994 (Canada)
Population sample, age 18 yr+; N = 2019
Leg restlessness at bedtime, face-to-face interviews
10-15
Phillips et al.234 2000 (USA)
Kentucky random population of men and women, aged ≥ 18 yr, N = 1803
Telephone interview, presence of restless legs 5 or more times/month At least once per month
18-29 yr: 3 30-79 yr: 10 80+ yr: 19 All ages: 19.4
Rothdach et al.235 2000 and Berger et al.236 2002 (Germany)
German elderly population sample, age 65-83 years, N = 369
RLS-criteria and neurologic examination; IRLSSG criteria
Overall: 9.8 m: 6.1 f: 13.9 65-69 yr: 9.8 70-74 yr: 12.75 75+ yr: 7.4
Tan et al.237 2001 (Singapore)
General population sample, 155 subjects aged ≥ 55 yr and 1000 consecutive patients aged ≥ 21 yr in a health center
IRLSSG criteria
0.6 in the population; 0.1 among the patients
Ulfberg et al.238 2001 (Sweden)
A random sample of men in Sweden; N = 4000
IRLSSG criteria
5.8
Ulfberg et al.239 2001 (Sweden)
Random sample of women aged 18-64 yr in Sweden; N = 200
IRLSSG criteria
11.4
Ohayon and Roth240 2002 (5 European countries)
UK, Germany, Italy, Portugal, and Spain; N = 18,980; aged 15-100 yr
Telephone surveys, SleepEVAL questionnaire
RLS: 5.5 PLMD: 3.9 with ICSD criteria
Sevim et al.241 2003 (Turkey)
Turkish adults, N = 3234
IRLSSG criteria, face-to-face personal interviews
3.19
Bhowmik et al.242 2003 (India)
Case-control study. N = 121 hemodialysis patients and 99 control patients
Questionnaire with RLScriteria; ENMG
Patients on hemodialysis: 6.6 Control patients: 0.0
Nichols et al.243 2003 (USA)
A primary care patient population seen by family physicians, N = 2099
IRLSSG criteria, examined by family physicians
All 4 symptoms present: 24.0 Symptoms present at least weekly: 15.3
Suzuki et al.244 2003 (Japan)
Japanese pregnant women, N = 16,528
Questionnaire survey in 500 maternity services
19.9
Rijsman et al.245 2004 (The Netherlands)
Population of a health center in the Netherlands aged ≥ 50 yr; N = 1437
Questionnaire
7.1
Gigli et al.231 2004 (Italy)
N = 601 patients with endstage renal disease
IRLSSG criteria, questionnaire
21.5
Ulfberg, Nyström246 2004 (Sweden)
Blood donors, N = 946, aged 18-64 yr
IRLSSG criteria, questionnaire
f: 24.7 m: 14.7
Högl et al.247 2005 (Austria)
Population sample, aged 50-89 yr, N = 701
Interviews, clinical examination, laboratory
10.6
Allen et al.229 2005 (USA)
Population sample, aged > 18 yr, N = 15,391 (REST study)
IRLSSG criteria, questionnaire
RLS weekly: 5 RLS symptoms at least on 2 days per week: 2.7
Kim et al.248 2005 (South Korea)
Population sample, adults
IRLSSG criteria, questionnaire
f: 15.4 m: 8.5
Winkelman et al.249 2006 (USA)
Wisconsin Sleep Cohort, N = 2821
IRLSSG criteria, slightly modified, questionnaire
RLS at least weekly
Nomura et al.250 2008 (Japan)
N = 2812
Rural population telephone interview IRLSSG criteria, questionnaire
1.8
f: 14.2 m: 6.6
f: 11.2 m: 9.9 f: 2.3 m: 1.2
ICSD, International Classification of Sleep Disorders; IRLSSG, International Restless Legs Syndrome Study Group; PLMD, periodic limb movement disorder.
708 PART II / Section 8 • Impact, Presentation, and Diagnosis Table 61-8 Population Prevalences of Parasomnias* Childhood
PARASOMNIA
OCCURRENCE (%) ALWAYS OR OFTEN/NOW AND THEN/EVER
Adulthood OCCURRENCE (%) ALWAYS OR OFTEN/NOW AND THEN/EVER
REFERENCES
REFERENCES
Sleep terrors
0.9-1.8/8.4/ 28-39.8
264, 271-273
–/–/<1.0-2.2
274, 275
Sleepwalking
0.9-2.8/ 5.7-14.2/14.5-21
264, 266, 271-273
0.1-0.6/0.9-3/2
74, 266, 274-276
Confusional arousals
–/–/17.3
2
–/–/4.2
275
Isolated sleep paralysis
–/–/–
–
–/–/6.2-40
85, 277-280
Nightmares
1-10.9/17.8-32.0/ 37.2-78
270, 271, 273, 281, 282
0.9-5.8/8-29/5.3-68.8
74, 260, 270, 276, 283
Sleep-related hallucinations
–/–/–
–
Hypnagogic: 2.52.9/17.2-21.7/19.7— almost all hypnopompic: 0.9/5.7/6.6
118, 276, 284
Sleeptalking
3.9-13.9/23-59.8/ 84.4
264, 273, 281, 285, 286
1.5-2.1/4.4/5.3-50.0
74, 276, 285
Sleep enuresis
3.6-5.8/6.7-13/ 3.1-26.5
264, 267, 273, 281, 287-289
0.3/0.1/0.07-5.0
267, 290, 291
Sleep bruxism
4.7-6.4/17.3/ 39.1-45.6
264, 268, 273, 292
1.0-8.2/4.2/7.5-27.2
276, 293-295
*The lowest and the highest frequency of the original works (references) are given. “Childhood” refers to studies in populations aged up to about 15 years.
radiofrequency tissue ablation) are used to treat snoring and sleep apnea, but there are only a few studies with acceptable epidemiologic methodology. Weight loss and lifestyle change are effective.227,228
RESTLESS LEGS SYNDROME The prevalence of clinically significant restless legs syndrome (RLS), or Ekbom’s syndrome, among adults is probably 2% to 3%,229 which is close to Ekbom’s original estimations of about 5.4%.230 In earlier studies, RLS seemed to be less common in Asian countries than in Western world. When the same survey methods have been used, the occurrence of RLS seems to be quite similar all over the world. RLS is common. In general, the prevalence varies between 5% and 15%. The prevalence is higher among elderly people. In some patient groups, such as patients with end-stage renal disease in Western countries, the prevalence may be higher than 20%.231 Also more than 20% of pregnant women suffer from restless legs232 (Table 61-7229-231,233-250). REM SLEEP BEHAVIOR DISORDER In the current International Sleep Classification,2 REM sleep behavior syndrome (RBD) is considered a parasomnia, but it could also be classified as a sleep-related movement
disorder. RBD is an important topic in sleep medicine and also in movement disorders research because it seems to be a premonitory sign of Parkinson’s disease and alphasynucleinopathies.251-254 In clinical follow-up studies, 30% or more of subjects with RBD develop Parkinson’s disease within 7 years. RBD is also associated with cognitive decline in Parkinson’s disease, and it is commonly present in patients with multisystem atrophy and Lewy-body dementia.255-259 At the moment we lack population-based studies about the prevalence of RBD.
PARASOMNIAS Table 61-8 summarizes the prevalences of 10 parasomnias, mainly based on population studies.* The figures given must be regarded only as crude ratings. Most of the studies are retrospective questionnaire studies, and recall bias may affect results.259a For example, regarding nightmares there can be up to 10 times higher frequencies when using short follow-up (1 month vs. 1 year) and a log instead of a questionnaire.260,261 There is also an obvious risk that the parasomnias occur without being noticed. Unless a cohabiting person reports the occurrence the subject may be unaware of the symptoms of *See references 2, 74, 85, 118, 260, 264, 266-268, and 271-295.
CHAPTER 61 • Epidemiology of Sleep Disorders 709
sleeptalking or bruxism because of being asleep himself/ herself or of sleepwalking or sleep terror because of the impaired arousal and amnesia regarding the nocturnal episode. Moreover, because the frequency of parasomnias in children is strongly associated with age, it is difficult (or may even be misleading), for example, to give occurrence figures to sleep enuresis in “childhood.” Additionally, there are considerable methodological differences in the studies (e.g., definitions of specific parasomnias, questions asked also of parents). Co-occurrence of parasomnias is well-known, and the strongest associations are between sleeptalking, sleepwalking, nightmares, and sleep terrors.262-264 Parasomnias also run in families, and in genetic epidemiologic studies the proportions of total genetic variance in liability to certain parasomnias has been highest in childhood sleepwalking and enuresis (about two thirds)265-267 and 40% to 60% in childhood and adult sleeptalking, nightmares, and bruxism.265,268-270 The highest estimated proportions of shared genetic effects were between sleeptalking with sleepwalking (50%), with bruxism (30%), and with nightmares (26%).263 There are some association between parasomnias and psychopathology also based on population level. Serious psychiatric disorders (indicated by long-term antipsychotic medication and/or psychiatric hospitalization) are significantly associated with both childhood (OR ≤ 3.7) and adulthood (OR ≤ 5.9) nightmares occurring frequently, although this was the case only in the minority of the subjects (11.5% in childhood and 15.6% in adulthood nightmares in the most frequent categories).270 In sleeptalking, a similar association was found only in frequent talkers.269
❖ Clinical Pearl Because sleep disorders are very common in each age group, clinicians should inquire about their symptoms whenever evaluating new patients. The following possible problems should be investigated: 1. In young children • Trouble getting to sleep • Symptoms of insufficient sleep • Parasomnias • Excessive daytime sleepiness • Symptoms related to possible sleep apnea 2. In young and middle-aged adults: • Symptoms of insomnia • Excessive daytime sleepiness • Symptoms of restless legs syndrome • Sleep apnea 3. In older people: • Symptoms of insomnia • Excessive daytime sleepiness Chronic insomnia and chronic insufficient and/or poor sleep is related to many somatic and psychiatric disorders. Sleep-related issues should be part of routine clinical work and of all epidemiologic studies that investigate relationships between different exposures and outcomes.
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286. Reimao RN, Lefevre AB. Prevalence of sleep-talking in childhood. Brain Dev 1980;2:353-357. 287. Devlin JB. Prevalence and risk factors for childhood nocturnal enuresis. Ir Med J 1991;84:118-120. 288. Jarvelin MR, Vikevainen-Tervonen L, Moilanen I, et al. Enuresis in seven-year-old children. Acta Paediatr Scand 1988;77:148-153. 289. Yeung CK, Sreedhar B, Sihoe JD, et al. Differences in characteristics of nocturnal enuresis between children and adolescents: a critical appraisal from a large epidemiological study. BJU Int 2006;97: 1069-1073. 290. Bing MH, Moller LA, Jennum P, et al. Validity and reliability of a questionnaire for evaluating nocturia, nocturnal enuresis and sleepinterruptions in an elderly population. European Urology 2006; 49:710-719.
CHAPTER 61 • Epidemiology of Sleep Disorders 715 291. Burgio KL, Locher JL, Ives DG, et al. Nocturnal enuresis in community-dwelling older adults. J Am Geriatr Soc 1996;44: 139-143. 292. Barbosa Tde S, Miyakoda LS, Pocztaruk Rde L, et al. Temporomandibular disorders and bruxism in childhood and adolescence: review of the literature. Int J Pediatr Otorhinolaryngol 2008;72: 299-314. 293. Glaros AG. Incidence of diurnal and nocturnal bruxism. J Prosthet Dent 1981;45:545-549. 294. Hublin C, Kaprio J, Partinen M, et al. Sleep bruxism based on self-report in a nationwide twin cohort. J Sleep Res 1998;7: 61-67. 295. Ohayon MM, Li KK, Guilleminault C. Risk factors for sleep bruxism in the general population. Chest 2001;119:53-61.
Sleep Medicine, Public Policy, and Public Health James K. Walsh, William C. Dement, and David F. Dinges Abstract Sleep medicine comprises a sizable body of knowledge, and a significant portion relates to public health in a number of ways. The prevalence of sleep disorders and the widespread occurrence of sleep deprivation in modern society affect the public through industrial and transportation accidents and in reduced performance in the workplace and in educational settings. Sleep disturbances also may contribute to epidemic societal levels of hypertension and cardiovascular disease, obesity, and diabetes. In part, the failure of the biomedical
Sleep is among the most basic of human needs. Waking brain function and behavioral capability depend on obtaining adequate sleep quality and quantity each day. As amply illustrated throughout this book, a person’s sleep can be disrupted not only by pathologic processes but also by a person’s lifestyle and by societal demands on the sleep– wake schedule.1 When sleep disruption occurs, regardless of the reason, the consequences for the individual and in some circumstances for society can be serious. At present there is only limited recognition of this fundamental fact because of failure to translate advances in sleep science and medicine into educational programs and institutional action directed toward improved public health and safety. Sleep medicine constitutes an important public health resource because of the widespread and diverse ways sleep and sleepiness are related to public health and safety.1 Health professionals have always had a major role in decisions regarding public health issues. One does not have to look far to find cogent examples of behavioral and societal changes that were initiated by and through the health care system that reduced the prevalence of catastrophic outcomes. Physicians advanced the knowledge of linkages between “unseen” microbes and disease, which led to improvements in food preparation and waste disposal. Pulmonologists led the way in reducing cigarette smoking. Emergency department physicians helped implement mandatory seatbelt laws. These and many other public health initiatives have saved millions of lives and have improved the quality of life for many more. It can be argued that sleep loss and sleepiness are other “unseen” threats to public health. It is now appropriate and necessary to develop similar educational and regulatory approaches to improve society’s understanding of sleep and sleep disorders and to modernize public policies that affect the quantity and quality of sleep. By communicating what has been learned about the effects of sleep disturbances, sleep loss, and sleepiness on public health and safety, health care professionals can encourage behavior and contribute to the formulation of public policies that promote healthy sleep and prevent sleepiness on the job and during other safety-sensitive activities such as driving.2,3 716
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community to translate research advances into educational messages, interventional research, individual lifestyle changes, and institutional and public policies underlies the heavy public health burden. The modest responsiveness of policy makers in many industries and the government also contributes to the impact on public health. Health professionals in general, and sleep specialists specifically, are encouraged to participate in the communication of sleep medicine advances for the betterment of society.
The purpose of this chapter is to review aspects of sleep science and sleep medicine from a societal perspective and to facilitate translation of that knowledge into behavior and practices that will have a positive impact on public health. The public health benefits of enhanced application of research findings in various biomedical fields have received increasing attention.4
SLEEP IN MODERN SOCIETY Sleep, like many other aspects of human activity, has been irrevocably altered by the industrial revolution and its attendant artificial light and affordable energy. Aroundthe-clock operations are now commonplace, and the time traditionally allocated to sleep has given way to expanded hours for business, long commutes, recreation, and so on. As societies make the transition from agrarian economies to industrial economies, some of the more dramatic changes that occur involve sleep. For example, the transition to industrialization typically involves eliminating the daytime siesta and implementing shift work.5 The advent of highly technological societies has made inadequate daily sleep and substandard levels of waking alertness commonplace for many people. As a result, there is a risk of sleepiness-related human errors in many segments of society, such as public transportation, energy plants, security and public safety, and military operations. Errors in situations such as these can have catastrophic consequences. When such catastrophes have occurred on the night shift, such as the event at the Three Mile Island nuclear power plant and the grounding of the Exxon Valdez oil tanker, public trust in these industries has been undermined.1 Technological advances have markedly reduced or eliminated many sources of accidents, but sleep deprivation and its consequent fatigue and human error continue to contribute to performance failures and accidents throughout society.1,6 Automation has potentiated the negative effects of reduced alertness by increasing the monotony involved in many jobs, leaving people to stand vigil, an activity that is especially susceptible to elevated sleep pressure and sleepiness.7 At present, human error causes the majority
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(60% to 90%) of all industrial and transportation accidents.1,8 Although the proportion that is directly related to sleep loss, fatigue, and sleepiness is unknown, the economic and human impact is undoubtedly substantial. Unfortunately and ironically, nearly 100 years of technological advances aimed at improving life has been accompanied by a parallel reduction in societal priority for adequate sleep. For example, in 1913, 8- to 12-year-old schoolchildren slept an average of 10.5 hours per night9; by 1964, the average had dropped to 9.2 hours per night.10 In 1994, 13- to 14-year-olds averaged 7.7 hours on school nights and 9.5 hours on weekends.11 Failure to understand the effect of inadequate sleep on the entire 24-hour cycle has created a public health problem. Even modest amounts of daily sleep loss accumulate as a sleep debt that is manifest as an increasing tendency to fall asleep and a reduced level of neurobehavioral function.12,13 Although most people can resist this tendency under normal circumstances, when physical activity is low and circadian alerting effects are minimal, the likelihood of a lapse in vigilance, a microsleep, or a longer sleep episode can become high. People who are directly responsible for public health and safety, including but not limited to physicians and nurses, often work night shifts and long hours that make them prone to sleepiness-related errors.14 In work environments where sustained attention is necessary for safety, the probability of an accident rises and falls along with the biological tendency to fall asleep.15 Thus, catastrophic accidents related to sleepiness and fatigue do not occur at random throughout the day. Rather, they are more likely at times when human beings are most prone to sleep, between midnight and 8 am and between 1 and 3 pm.16
subsequently to improved public health, are instructive. For example, changes in societal behavior and institutional policies have now made it possible to limit the public health impact of communicable diseases. Similarly, changes in public policy have reduced motor vehicle crash fatalities and injuries due to alcohol. Fighting the most common cause of lung cancer required public health programs to warn consumers about the dangers of smoking and policies to create smoke-free environments. Considering the various areas of life in the 21st century that are especially vulnerable to sleepiness, it is apparent that untoward outcomes caused by sleepiness will persist until key scientific principles are translated into action for the betterment of public health. Sleep researchers and clinicians must encourage many components of society to promote individual and institutional behavior change (e.g., increasing habitual sleep duration, planning work schedules with consideration of human biology). Also, research efforts must be hastened to provide detailed information on the prevalence of sleeprelated mishaps and on the economic and personal consequences of inadequate sleep. This information is vital for designing approaches and targeting resources where they will be most likely to advance public health and safety. Much of what we know or suspect about the role of sleep and sleepiness in public and private catastrophes is gleaned inferentially from retrospective studies and time-of-day data. Recent prospective efforts to obtain data on sleepiness-related mishaps are providing evidence consistent with earlier work, and attempts to define the biological limits sleep places on the alertness and safety of operators in certain occupations are under way.3,6,19
THE CHALLENGE Most people, including many involved in public health and public policy, do not know the fundamentals of homeostatic sleep need and circadian physiology, and most remain unaware of, or choose to ignore, important relationships between sleepiness and human waking performance capacity. Societal ignorance about the importance of sleep stems in part from the relative recency of scientific and medical advances in this area. In addition, our educational systems have been slow to integrate into course work even the most fundamental principles of the field, such as that the effects of chronic sleep restriction on the ability to perform are cumulative (see Chapter 6), or that adolescents require much more sleep than they routinely obtain,17 or that driving while sleepy is as risky as driving while impaired by alcohol.18 Rather, if any sleep material is presented it tends to focus on descriptive information that is largely irrelevant to public health, such as sleep stages or dreaming. The challenge sleep specialists face is to develop methods to translate the body of sleep medicine knowledge into messages and strategies directed toward reducing or resolving the economic, social, health, and safety issues associated with insufficient or disrupted sleep. Inclusion of such messages at all levels and in all forms of education is essential if the knowledge of sleep science is to positively influence public health. Lessons from other areas of medicine that led to major societal policy and behavior changes, and
KEY AREAS FOR EDUCATION AND AWARENESS A number of sleep research areas have progressed to the degree that research findings can lead to improved public health if adequately translated to various segments of society and, if necessary, into improved public policy. Cardiovascular Disease Two lines of investigation implicate an association of cardiovascular disease and habitual sleep duration. First, acute periods of experimental sleep restriction produce increased blood pressure and heightened sympathetic nervous system activity,20,21 as well as elevated levels of inflammatory markers associated with cardiovascular risk.22 After recovery sleep, these physiologic measures return to baseline levels, suggesting a role for sleep in maintaining physiologic homeostasis. Second, epidemiologic studies demonstrate a relationship of sleep duration and the presence of hypertension23 and the incidence of hypertension.24 Another study of more than 71,000 female nurses found that both short and long self-reported sleep durations are associated with the risk of coronary heart disease during a 10-year follow-up period.25 Consistent with the latter finding are studies demonstrating that either short or long habitual self-reported sleep lengths are associated with an increase in all-cause mortality rates.26 Distinct from sleep duration per se, there is also convincing evidence that sleep-disordered breathing is a
718 PART II / Section 8 • Impact, Presentation, and Diagnosis
contributing factor to hypertension.27 Less well established are apparent associations between sleep-disordered breathing and coronary artery disease and heart failure.28 The likelihood of suffering a myocardial infarction varies significantly across time of day, with a peak between 8 and 10 am, which is 2 hours later than the morning peak for disease-related mortality.29 Circadian regulation may underlie the shape of the 24-hour pattern in disease-related mortality. Direct observations of platelet aggregability show diurnal variation, with a prominent morning peak.30 Moreover, disease-related mortality closely approximates the two-peak pattern throughout the 24-hour day that has been described for sleep tendency.31 Circadian and sleeprelated increases in plasma concentrations of molecules that potentiate blood clotting or vasospasm may play a role in these temporal relationships, because aspirin reduces mortality due to myocardial infarction primarily during the morning peak, which suggests that the morning peak may be related to heightened platelet aggregability.30 Sleep-disordered breathing may also play a role in the early-morning mortality peak of cardiovascular morbidity. Jennum and colleagues32 found that morning awake arterial blood pressure and nocturnal arterial blood pressure decreased with nasal continuous positive airway pressure treatment and concluded that these hemodynamic changes were associated with a treatment-related decrease in the number of sleep apnea events, a decrease in sympathetic activity, and an increase in parasympathetic activity. More evidence for the putative role of sleep apnea in the timing of deaths comes from work by Ancoli-Israel and colleagues, who reported that 24% of people older than 65 years had more than five apneic events per hour of sleep, and 62% had more than 10 respiratory disturbances (i.e., apneas plus hypopneas) per hour of sleep.33 The high prevalence of sleep apnea in older people might contribute to the shape of the 24-hour pattern in disease-related mortality. Metabolism, Obesity, and Diabetes Impaired glucose tolerance has been described in healthy subjects after 6 nights of restriction of sleep to approximately 4 hours per night.20 Combined with higher evening cortisol levels and reduced leptin secretion, the results suggest endocrine changes with acute sleep loss that are consistent with the development of diabetes. An epidemiologic study found sleep durations less than 6 or more than 9 hours to be associated with an increased prevalence of diabetes and impaired glucose tolerance.34 A growing body of evidence also supports a link between sleepdisordered breathing and insulin resistance, independent of degree of obesity.35 Thus, both short sleep and disrupted sleep associated with sleep-disordered breathing appear to be associated with endocrine and metabolic changes that may promote obesity and diabetes. Consistent with that interpretation is the observation of decreased nocturnal leptin levels during 3 consecutive nights of total sleep deprivation.36 Transportation Safety It is known that sleepiness represents a significant risk to driving safety and might pose as great a risk to driving safety as does alcohol.18,37 That sleep loss increases vehicular crash risk is evident in studies showing that crashes
were more likely in sleepy patients with untreated obstructive sleep apnea38 and in people sleeping less than 6 hours per night.39 Moreover, motor vehicle accidents do not occur randomly throughout the 24-hour day but tend to peak during early morning and midafternoon, in accordance with times of increased sleep propensity.16,40 Perhaps the most precise estimate of the influence of drowsy driving upon crash frequency is the 100-Car Naturalistic Driving study, which used vehicles equipped with cameras and other sensors to monitor driver behavior and vehicle performance during about 2 million miles of driving.41 Drowsiness was found to be a contributing cause in 22% of all motor vehicle crashes and 16% of nearcrashes. One study in Great Britain estimated that 27% of drivers who lost consciousness behind the wheel fell asleep, as opposed to fainting, having a seizure, or having a heart attack.42 Moreover, this 27% of motor vehicle accidents accounted for 83% of the fatalities. Other investigators have also observed a high rate of fatality in sleep-related accidents.43 The increased fatality rate is likely due to a combination of reduced vigilance, slowed reaction times, and loss of steering control (i.e., drift out of lane). Once a driver is sufficiently inattentive due to sleepiness, or has transitioned to sleep, there is little or no attempt to brake or otherwise avoid collision.40 Comparisons have been made between the behavioral impairment similarities of driving while excessively sleepy and driving under the influence of alcohol. In fact, if authorities determine that impairment from sleep deprivation has caused an accident, the driver can be considered negligent and held liable for civil and criminal penalties. However, the parallel with alcohol ends there. In contrast to measurement of breath or blood alcohol levels, accident investigators have no reliable objective measurement of the degree of sleepiness. Thus, errors due to falling asleep or impaired performance due to sleep deprivation must be inferred from the nature of the accident and the operator’s prior sleep–wake schedule. Impairment due to alcohol is heightened by sleep deprivation.18 It is not yet fully appreciated how great a contributory role sleepiness may have in the overall number of transportation accidents involving drug and alcohol use. In a study of fatal-to-the-driver truck accidents, the National Transportation Safety Board (NTSB) found that fatigue plus alcohol or drugs accounted for a large fraction of fatal accidents.42 We may speculate that sleepy persons operating a vehicle may be very susceptible to further impairment from consumption of even modest quantities of alcohol (or other depressant drugs). The first law to specifically criminalize drowsy driving was enacted by the state of New Jersey in 2003. Specifically, this legislation allows law enforcement officials to charge drivers with vehicular homicide if, after not sleeping for 24 hours or more, they cause a fatal accident. The legislation was termed “Maggie’s Law” after Maggie McDonnell, who was killed in a head-on collision in 1997 by a driver who had gone without sleep for 30 hours. Another legislative attempt to change the culture regarding drowsy driving was undertaken by the Sleep Research Society, the National Sleep Foundation, and the American Academy of Sleep Medicine when they jointly endorsed model legislation in Massachusetts to educate drivers about
CHAPTER 62 • Sleep Medicine, Public Policy, and Public Health 719
the hazards of drowsy driving, train police to recognize signs of drowsiness associated with sleep deprivation or sleep disorders, include collection of information relative to drowsy driving on all state motor vehicle accident forms, and establish the crime of falling asleep or being impaired by drowsiness or sleep deprivation while operating a motor vehicle. As a result of these efforts, the Junior Operators’ Law in the Commonwealth of Massachusetts was amended in 2007 to require that education regarding the hazards of drowsy driving be included in all driver education programs provided to junior operators in the Commonwealth, restrict junior operators from driving between 12:30 am and 5:00 am, and establish a special commission to study the impact of drowsy driving on highway safety and the effects of sleep deprivation on drivers while operating motor vehicles. Historically, the trucking industry has been a focus of regulation to prevent driving while fatigued. Each year in the United States there are approximately 4800 fatal crashes involving trucks, and many more nonfatal crashes. The NTSB reported a probable cause of fatigue in 57% of accidents that led to a truck driver’s death,42 although this percentage is not universally accepted by all public and private entities concerned with trucking safety. The term fatigue has been used throughout federal agencies to describe human performance failure attributable to a variety of factors. It is clear from the NTSB’s texts that their intended meaning of the term fatigue is most con gruent with what sleep specialists mean by the term sleepiness.1 When a truck driver dies in a crash, three or four other people are usually also killed. Depending on the involvement of other vehicles and the nature of the cargo, associated damage may be substantial. The mean cost of a crash involving a single large vehicle has been calculated to be $51,000, but when fatalities result, the cost per crash is estimated at $2.7 million.44 The trucking industry employs approximately 2.5 million drivers, operates 1 million motor carriers, and accounts for 10 billion miles per year of travel on U.S. highways. Trucks deliver products and materials to every segment of society, from local deliveries through transcontinental long hauls. There are economic incentives for driving long hours in some segments of the trucking industry. Several major studies on the quality and quantity of sleep in commercial truck drivers were completed in recent years. These studies show that sleep of truck drivers is often inadequate to ensure stable alertness and performance. In one study of 80 long-haul truck drivers operating on North American routes with four demanding driving schedules, drivers slept an average of only 4.8 hours per day.45 Despite general recognition of the effects of chronically inadequate sleep on performance and safety, federal regulations promulgated in 1939 remained unaltered for years. Perhaps the complexity of the problem and the understandable fear of harming such a vital industry delayed initiation of research and the revision of hours-of-service regulations directed toward reducing accidents due to sleepiness in truck drivers. In April, 2003, a revised Hours-of-Service Rule was announced by the Department of Transportation’s Federal Motor Carrier Safety Administration46 in response to a
congressional mandate in 1995. This new legislation allows long-haul drivers (i.e., those who do not routinely return to their home base after each driving shift) to drive a maximum of 11 hours per day after 10 consecutive off-duty hours; the old rule required only 8 hours off duty for sleep and recovery. In addition, in the new rule drivers are prohibited from driving after 14 hours on duty during a single shift, whereas the old rule allowed 15 hours on duty. Thus, the new rule allows more off-duty time for sleep and personal time (i.e., 14 hours on duty and 10 hours off duty), in contrast to the 23-hour pattern of the old rule (i.e., 15 hours on duty and 8 hours off duty). Finally, as in the earlier regulation, drivers may not drive after being on duty for 60 hours in a 7-consecutive-day period, or after 70 hours in an 8-day period. Enforcement of the new rule began January 4, 2004, and undoubtedly the impact on trucking safety will be closely monitored. Many in the sleep field contributed to the formulation of these new regulations—tangible evidence that we can and do have a public policy impact, which it is hoped will benefit public health. In addition to regulatory approaches, preventing the dangers of driving while impaired by sleepiness will require research on countermeasures such as drowsydriving detection technologies, roadside signs, safe sleeping areas, and tests to assess sleepiness. Advances in these areas may then require public policy changes and education. In addition, recognition and treatment of sleep apnea and other sleep disorders is crucial if the total health and economic impact is to be reduced. Recent projections suggest that more than 800,000 drivers were involved in sleep apnea–related vehicle crashes in 2000, and that those events cost $15.8 billion and 1400 lives that year.47 Further, treating all drivers having sleep apnea with continuous positive airway pressure would produce a net savings of approximately $11 million and save 960 lives each year. Many of the same issues pertaining to the role of work schedules and sleep in trucking safety are common to other commercial transportation modes. Sleep-related catastrophic accidents on the railroad have been identified, for example. The NTSB concluded that sleep deprivation with its related impairment was a primary cause in at least four catastrophic railroad accidents between 1987 and 1992. Maritime transportation typically involves 24-hour operations, and sleep deprivation has been the cause of several catastrophes. One of the most dramatic involved the grounding of the supertanker Exxon Valdez on Bligh Reef in Prince William Sound, Alaska, in March 1989. The NTSB determined that a “probable cause of the grounding of the Exxon Valdez was the failure of the third mate to properly maneuver the vessel because of fatigue and excessive work load.”48, p. v The grounding of the oil tanker World Prodigy off the coast of Rhode Island is another example of a major maritime accident involving fatigue due to sleep deprivation. The NTSB determined that the probable cause was the master’s impaired judgment from acute fatigue. The master had been awake for 36 hours at the time of the accident. There have been other summaries of fatigue-related performance failures in transportation modes that resulted in catastrophic outcomes.49
720 PART II / Section 8 • Impact, Presentation, and Diagnosis
In each of these transportation areas, little research has been conducted to identify effective measures to counter sleep-based fatigue. Impetus to begin such countermeasure research will be enhanced as more public attention focuses on human error accidents and as top management integrates the real costs of accidents due to sleepiness-based error into their overall plans for risk management. This has begun in many of these industries, under the aegis of “fatigue management.” As the essential principles and practices of fatigue management develop, it will be important for sleep scientists to translate research findings into policies and practices that limit sleep debt and provide maximum opportunity for recovery sleep. Moreover, sleepiness countermeasures should be data based, as well as reasonably feasible for the industry or occupation of concern. An area of fatigue management that has received growing federal attention in recent years concerns the development of technologies that detect or prevent sleepiness on the job. Fatigue management technologies fall into four broad categories: biomathematical models of human performance, readiness-to-perform and fitness-for-duty, workbased performance technologies, and online operator status monitoring technologies. Although such efforts have a long history, they have increased markedly recently owing to the prevalence and seriousness of fatigue-related crashes, the unreliability of subjective estimates of sleepiness or impairment, the potential of drowsiness detection technologies as alternatives (in part or in whole) to proscriptive hours of service, and the fact that technological advances have made the goal of online drowsiness detection feasible. As these technologies continue to develop, the sleep field should take an active role to ensure they meet stringent criteria for scientific validity, reliability, sensitivity, and specificity. In addition, there are substantive public policy questions that will have to be addressed concerning privacy, liability, and related legal issues in the use of sleepiness-prevention and drowsiness-detection technologies. Relieving Sleepiness with Naps: Aviation as a Case Study Although accidents caused by sleep-based fatigue imperil all modes of transportation, aviation is one mode that has a history of research on the nature of fatigue and on developing countermeasures, primarily through research initiatives at the National Aeronautics and Space Administration (NASA) Ames Research Center. One example of this work serves to illustrate how sleep science can be used to address policy (i.e., research undertaken to investigate job-specific strategies to reduce sleepiness in the work place). However, this example also serves to highlight the significant challenges involved in gaining acceptance of viable sleepiness countermeasures by government, industry, labor, and the public. For transmeridian flight crews, inadequate sleep has been a major source of fatigue. A multidisciplinary research effort was undertaken to evaluate the benefits to long-haul flight crews of preplanned naps while in the air.50 The results indicated not only that crew members could safely rotate, taking a brief (40-minute) nap period in flight, but also that the naps enhanced alertness of crews during
transmeridian flights. Interestingly, the brief naps did not totally eliminate the cumulative sleep debt of crews, but they did provide transient relief from in-flight fatigue, especially on night flights. Such a clear example of an evidenced-based approach to mitigating sleepiness on the job also exposes a problem in translating science into public policy. Although many European and Asian transcontinental air carriers have adopted planned cockpit napping, the Federal Aviation Administration, because of political concerns, has not yet approved it for U.S. carriers. Public policy change requires both evidence of the need and benefits of the proposed change, as well as the acceptance of evidenced-based research as the standard for implementing organizational change. Absence of the latter prevented U.S. policy makers from incorporating a viable fatigue counter measure in long-haul flight operations. Health Care Workers Health care workers can be on duty for extended shifts ranging in duration from 12 to 24 hours, with day and night shifts alternating as frequently as every few days. In any work situation, a tired and sleepy worker is less effective and at some point at higher risk for an error or accident. The nature of the risk depends on the nature of the work. When 24-hour operations are involved, the likelihood of cumulative sleep deprivation and working at an adverse circadian phase are considerable. The associated risks for diminished productivity, errors, and accidents are also higher. In 1984, Libby Zion, an 18-year-old college freshman, died in a hospital in New York City. A grand jury found that her death was due to an undiagnosed infection and blamed inadequate supervision of residents and resident fatigue for the failure to institute proper treatment. As a result, New York enacted laws to reduce the total number of hours that residents are permitted to work. The state of New Jersey followed in 2002 with a bill limiting residents’ work hours. In 2003 the Accreditation Council for Graduate Medical Education (ACGME) implemented standard requirements for work hours for all resident physicians.51 In brief, the ACGME regulations prescribe no more than an 80-hour work week, a maximum shift duration of 24 hours, at least 10 hours off between shifts, 1 day off per week, and overnight on-call assignment no more than every third night. In recent years, a series of landmark studies conducted by the Harvard Work Hours and Safety Group and others indicate that long resident physician work hours are associated with reduced well-being and more attentional failure, medical errors, motor and vehicle crashes.52-56 Interventional studies that compared traditional schedules with shorter shifts by interns in intensive care units found that the revised work hours result in more sleep, substantially fewer serious medical errors, fewer driving mishaps, and fewer attentional failures.57-59 Based upon these and other findings, the Institute of Medicine issued recommendations regarding resident work hours in 2008 to further address the effect of fatigue on patient and physician safety.60 Highlights of this report are the call for protected 5-hour sleep periods during long-duration work shifts, increased time off after night shifts and long-duration shifts, and a maximum of 4 consecutive night shifts.
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Although the costs and benefits of restricting work hours for physicians are being evaluated, we should note that the medical community has often used scientific knowledge as the basis for new policies and guidelines for physician behavior relative to improved public health. The widespread use of sterile technique in surgery and the modern emphasis on preventive medicine through smoking cessation are two of many examples of evidenced-based behavior changes. The obvious challenge is to balance the need for adequate sleep with minimal interference with the educational process and maintenance of a work environment that promotes high-quality health care.60a Hazardous Workplaces Sleep is inexorably intertwined with a large number of occupations that have a potential impact on public safety and health. It is not possible here to provide an exhaustive discussion, but some obvious examples other than those already mentioned include emergency operations and military conflict. Although the need to sustain wakefulness for prolonged periods of time may be obvious in a national disaster, the consequences of human error due to sleepiness and fatigue can be particularly serious in essential but nonemergency hazardous work environments that operate around the clock (e.g., nuclear power plants and plants producing hazardous or toxic chemicals). The early morning human errors that led to the on-site disaster at Three Mile Island61 and the environmental disaster at Chernobyl62 bear all the earmarks of sleepiness-related accidents. The sequence of decisions leading up to the space shuttle Challenger accident in 1986 is an example of sleep deprivation being contributory, if not causal, according to a supplemental report to the investigation.63 The senior manager’s decision to launch was based not on engineering or safety judgments but rather on other factors, including public image and preset schedules; the latter also was found to be contributory in the official investigation of the space shuttle Columbia investigation. In the case of the loss of Challenger, a presidential commission concluded that specific key managers had slept less than 2 hours the night before and had been on duty since 1 am on the day of the launch. The report stated that “time pressure, particularly that caused by launch scrubs and turnarounds, increased the potential for sleep loss and judgment errors” and that working “excessive hours, while admirable, raises serious questions when it jeopardizes job performance, particularly when critical management decisions are at stake.”63, p. G5 Such a cogent example serves to illustrate that any workplace in which the consequences of a human error can be catastrophic economically, environmentally, or physically must consider the role of sleep need in maintaining safe and effective functioning. Adolescents and Young Adults The prevalence of significant sleepiness associated with insufficient sleep is particularly high among adolescents and young adults. The adolescent years are accompanied by decreasing parental control, growing academic challenges, increasing social activities, and more employment opportunities. All of these forces tend to push sleep to a lower priority in time management. The net result is that
few adolescents obtain adequate sleep, especially during the school week. The resultant sleepiness increases the risk for fatigue-related motor vehicle accidents, contributes to negative mood, impairs memory and other measures of cognition, and increases use of stimulants and alcohol.64 Up to 40% of high school and college students are sleep deprived, and laboratory studies have documented performance impairments in them due to sleep loss.11 This age group is also heavily represented among those who have drowsy driving crashes.41 In addition, tired students are likely to have impaired motivation and unintended sleep episodes.65 Students earning Cs or below report obtaining less sleep and having more irregular sleep schedules than do students with higher grades, although a causal relationship has not been established. In an effort to address the problem of sleep-deprived adolescents, a Minneapolis school district delayed high school start times from 7:15 am to 8:40 am, resulting in students obtaining an hour more sleep per night and improved attendance rates.66 Another investigation suggests that delayed school start times may decrease the accident rates of young drivers.67 In response to such concerns, Congresswoman Zoe Lofgren introduced into the U.S. House of Representatives the “Zzz’s to A’s” resolution (H. Con. Res. 176) to draw the attention of policy makers to this important issue.
MAKING SLEEP A MATTER OF PUBLIC HEALTH AND PUBLIC POLICY Scientific advances in understanding sleep, sleepiness, and the impact of sleepiness on behavior and health need to be interpreted and communicated in ways that are useful to society. Without dissemination of the necessary knowledge and concepts, it is difficult to influence public consciousness and behavior. In some instances, our society faces problems related to sleep loss and sleepiness without the knowledge to formulate solutions. There have been some important milestones in the history of federal policy regarding sleep medicine and research. Many came about through effective communication of scientific knowledge by individuals or appointed representatives of the sleep research community to federal authorities, who then acted in the interests of the public. From the early 1970s, when the U.S. Food and Drug Administration developed guidelines for the evaluation of hypnotic medications, and moving to the present activities of the National Center for Sleep Disorders Research (NCSDR), our history has been one of activism and progress. Here we mention only a few of the important milestones. In 1979, the Surgeon General’s office created Project Sleep to focus further government attention on sleep research and sleep disorders. In 1984, the American Sleep Disorders Association created an active government affairs committee. The committee’s mandate was to provide all three branches of the government with up-to-date information on sleep physiology and current sleep research. Committee members gave congressional testimony and worked with regulatory and investigative agencies.
722 PART II / Section 8 • Impact, Presentation, and Diagnosis
In 1990, the Institute of Medicine prepared a research briefing entitled “Basic Sleep Research.” The briefing was prompted, in part, by the Institute of Medicine’s recognition that the continuation of basic sleep research in the United States was being threatened by limited training of young researchers, limited research funding, and attacks by animal rights groups on several basic sleep research programs. In an independent but complementary effort stimulated by the heightened federal interest in the impact of the sleep–wake cycle on society, the Office of Technology Assessment of the U.S. Congress conducted a major review of biological rhythms and their impact in the workplace.68 The National Sleep Foundation (www.sleepfoundation. org), an independent nonprofit organization whose mission includes improving public health and safety by achieving understanding of sleep and sleep disorders, was established by the American Academy of Sleep Medicine (AASM) in 1990. The National Sleep Foundation’s programs have contributed to a heightened public awareness of the importance of sleep for public health. The National Commission for Sleep Disorders Research (NCSDR), established by Congress, completed its comprehensive report of its findings in 1993. In the executive summary, the commission called for permanent and concerted government efforts in expanding basic and clinical research on sleep disorders as well as in improving public awareness of the dangers of inappropriate sleepiness. The NCSDR was subsequently created within the National Heart, Lung, and Blood Institute at the National Institutes of Health. The NCSDR’s mandate has been to conduct and support research, training, dissemination of health information, and other activities with respect to sleep disorders, including biological and circadian rhythm research, basic understanding of sleep, and chronobiology and to coordinate the sleep activities of other federal agencies. The legislation also mandated development of the National Sleep Disorders Research Plan. This plan was updated in 2003 and provides an excellent presentation of the progress in sleep research over the last several years, as well as detailing the key research and training recommendations for the future. The plan is available from http://www.nhlbi. nih.gov/health/prof/sleep/res_plan/index.html. Since the establishment of the NCSDR, total National Institutes of Health funding for sleep research has grown steadily; with estimates showing an increase from $75 million to more than $196 million during the period 1996 to 2004. Recognition of sleep medicine as a medical subspecialty has been significantly advanced through the efforts of the AASM. For example, in recent years the AASM has gained official recognition in the American Medical Association House of Delegates (1996), received approval of the ACGME for accreditation of sleep fellowship training programs (2003), and was accepted as a subspecialty by the American Board of Medical Specialties (2005). In 2006 the Institute of Medicine published the report “Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem,” which has prompted attention to fostering the development of academic sleep medicine programs.1 Beginning in 2006, the Centers for Disease Control and Prevention (CDC) greatly expanded its programs dealing
with sleep and sleep disorders. Among other objectives the CDC sleep team aims to strengthen surveillance research related to sleep at the national and state levels, promote science-based public policies that improve the sleep health of the nation, and advance strategies to reduce the impact of sleep deprivation upon the nation’s health and safety. The CDC also worked with the National Sleep Foundation in establishing the National Sleep Awareness Roundtable, a coalition of more than 20 organizations with common interests in promoting sleep health. In 2008, the Institute of Medicine released a report “Resident Duty Hours: Enhancing Sleep, Supervision, and Safety.” In this document the IOM panel proposes changes in graduate medical education work hours to lessen the impact of sleep loss upon patient and physician safety.60
CONCLUSION Sleepiness and inattention related to sleep loss and circadian rhythms adversely affect workers in many industries, as well as the general public, and lead to public health and safety problems. Evidence is accumulating that sleep disorders and restriction may be contributing factors not only to many errors and accidents but also to certain highly prevalent disease states that are major public health concerns, such as diabetes, obesity, and hypertension. For each of these societal concerns, sleep science must be translated to the general public, to biomedical researchers, and to those in policy positions for wiser public policy and the betterment of public health. Education and recognition of true risk are necessary first steps toward improved public health and formulation of wise public policy. Elementary and secondary level health and science classes clearly should include the critical messages of our field. The health impact of inadequate or disrupted sleep should be known as well as people know the negative effects of poor nutrition, inadequate exercise, or smoking. All opportunities should be taken to translate sleep science to engender behavior change of the general public. Communication of sleep science to researchers in other biomedical areas is also necessary to encourage the interdisciplinary approaches most likely to produce rapid advances in understanding sleep-related morbidity and its prevention. There is also ample precedent for health professionals to assume responsibility, both individually and collectively through their professional organizations, to take action to improve the health and safety of the public. This includes societal health in its broadest sense: the reduction of risk and the enhancement of quality of life. Indeed, the special expertise of sleep medicine professionals confers a unique and heightened set of obligations to address and to shape rational public policy. It is axiomatic that public policy does not change by itself. It is also axiomatic that public policy can change in a manner that is counterproductive or that poses a threat to the health of the public. There may be economic incentives involved in maintaining or increasing the risks associated with sleep deprivation. It is the responsibility of health professionals and biomedical organizations to foster knowledge transfer to the public, to industry, to policy makers, and to others in a position to influence public health and safety. By translating the
CHAPTER 62 • Sleep Medicine, Public Policy, and Public Health 723
scientific body of knowledge about sleep and its disorders, we may promote behavior change and the formulation of good public policy and as a result improve public health.
❖ Clinical Pearl Clinicians and researchers should contribute their knowledge and expertise to the development of public and institutional policies that will serve to improve public health and safety in areas such as educational systems, public utilities, transportation, and workplace safety. In the near future there may be an increasing role for sleep specialists in dealing with major public health issues such as obesity, hypertension, and diabetes.
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724 PART II / Section 8 • Impact, Presentation, and Diagnosis 45. Mitler MM, Miller JC, Lipsitz JJ, et al. The sleep of long-haul truck drivers. N Engl J Med 1997;337:755-761. 46. Department of Transportation, Federal Motor Carrier Safety Administration. Docket number FMCSA-97-2350. Federal Register 2003;68(81). Available at http://www.fmcsa.dot.gov/rulesregulations/administration/fmcsr/fmcsrguidedetails.aspx?rule_toc= 764§ion_toc=764. 47. Sassani A, Findley LJ, Kryger M, et al. Reducing motor vehicle collisions, costs, and fatalities by treating obstructive sleep apnea. Sleep 2004;27:453-458. 48. National Transportation Safety Board. Marine Accident Report: Grounding of the U.S. tankship Exxon Valdez on Bligh Reef, Prince William Sound, near Valdez, Alaska, March 24, 1989. NTSB/MAR90/04. Washington, DC: National Transportation Safety Board; 1990. 49. Lauber JK, Kayten PJ. Sleepiness, circadian dysrhythmia, and fatigue in transportation system accidents. Sleep 1988;11:503-512. 50. Rosekind MR, Graeber PC, Dinges DF, et al. Crew factors in flight operations: IX. Effects of planned cockpit rest on crew performance and alertness in long-haul operations. Moffett Field, Calif: NASA Ames Research Center; 1994. 51. Accreditation Council for Graduate Medical Education. Common duty hour standards for programs. Chicago: Accreditation Council for Graduate Medical Education; 2002. Available at http://www/ acgme.org/acWebsite/dutyHours/dh_Lang703.pdf. 52. Barger LK, Cade NT, Ayas JW, et al. Extended work shifts and the risk of motor vehicle crashes among interns. N Engl J Med 2005; 352(2):125-134. 53. Rothschild JM, Landrigan CP, Cronin JW, et al. The critical care safety study: the incidence and nature of adverse events and serious medical errors in intensive care. Critical Care Medicine 2005; 33(8):1694-1700. 54. Barger LK, Ayas JW, Cade NT, et al. Impact of extended-duration shifts on medical errors, adverse events, and attentional failures. PLoS Medicine 2006;3(12):2440-2448. 55. Lockley SW, Barger LK, Ayas NT, et al. Effects of health care provider work hours and sleep deprivation on safety and performance. The Joint Commission Journal on Quality and Patient Safety 2007;33(11 Suppl):7-18.
56. Philibert I. Sleep loss and performance in residents and nonphysicians: a meta-analytic examination. Sleep 2005;28(11):1392-1402. 57. Landrigan CP, Czeisler CA, Barger LA, et al. Effective implementation of work-hour limits and systemic improvements. The Joint Commission Journal on Quality and Patient Safety 2007;33(11 Suppl):19-29. 58. Landrigan CP, Rothschild JM, Cronin JW, et al. Effect of reducing interns’ work hours on serious medical errors in intensive care units. N Engl J Med 2004;351:1838-1848. 59. Lockley SW, Cronin JW, Evans EE, et al. Effect of reducing interns’ weekly work hours on sleep and attentional failures. N Engl J Med 2004;351:1829-1837. 60. Institute of Medicine. Resident duty hours. Enhancing sleep, supervision, and safety. Washington, DC: National Academies Press; 2008. 60a. Sharpe R, Koval V, Ronco JJ, et al. The impact of prolonged continuous wakefulness on resident clinical performance in the intensive care unit: a patient simulator study. Crit Care Med 2010;38: 766-770. 61. Moss TH, Sills DL. The Three Mile Island nuclear accident: lessons and implications. Ann N Y Acad Sci 1981;365:1-341. 62. U.S. Nuclear Regulatory Commission: report on the accident at the Chernobyl Nuclear Power Station. Washington, DC: U.S. Government Printing Office; 1987. 63. Presidential Commission. Report of the presidential commission on the Space Shuttle Challenger accident, vol 2, appendix G. Washington, DC: U.S. Government Printing Office; 1986. 64. Carskadon MA. Patterns of sleep and sleepiness in adolescents. Pediatrician 1990;17:5-12. 65. Morrison DN, McGee R, Stranton WW. Sleep problems in adolescence. J Am Acad Child Adolesc Psychiatry 1992;31:94-99. 66. Wahlstrom K, Davidson ML, Choi J, et al. School Start Time Study—executive summary, August, 2001. Available at http://www. cehd.umn.edu/CAREI/Reports/summary.html#SchoolStart. 67. Danner F, Phillips B. Adolescent sleep, school start times, and teen motor vehicle crashes. J Clin Sleep Med 2008;4:533-535. 68. U.S. Congress Office of Technology Assessment. Biological rhythms: implications for the worker. Washington, DC: U.S. Government Printing Office; 1991.
Sleep Forensics
Chapter
Michel A. Cramer Bornemann and Mark W. Mahowald
To blame a person is to express moral criticism, and if the person’s action does not deserve criticism, blaming him is a kind of falsehood, and is, to the extent the person is injured by being blamed, unjust to him. Sanford Kadish, 20001 Philosophers from time immemorial have been grappling with the mind–body dilemma, but recent advances in neuroscience have placed us on the verge of solving how our brains affect our minds and behavior. Neuroscience has developed powerful tools to investigate the neural activity underlying elementary aspects of physiology and behavior, and these tools have been further extended to encompass research into memory, executive function, and higher levels of cognition. Such innovative tools have also been applied to understanding the pathophysiology, diagnosis, and management of many clinical conditions including those found in sleep medicine. Not unexpectedly, sleep disorders, most notably parasomnias, have become increasingly invoked as a defense in legal cases with criminal allegations. Unfortunately, conflicts often arise as law in many ways is the polar opposite of neuroscience. Law usually requires dichotomies with an exacting all-or-none approach, whereas the modern scientist is comfortable describing nonstatic systems in multiple dimensions. Courts reach decisions savoring the adversarial bipartisan environment, whereas much of science is driven by consensus and supported by statistics on groups. Law covets tradition embodying centuries of thought and beliefs that resists change, compared with science, which values rapidly accelerating innovation. Lastly, law accepts cultural assumptions and commonsense that is largely based upon casual observation and unexamined conjecture, whereas science demands objectivity, reproducibility, and conscientious peer review. The developments in cognitive neuroscience unmistakably establish that consciousness exists on a spectrum and certainly is not a dichotomous proposition. The element of consciousness is an essential feature addressed in the courtroom of every criminal case, placing neuroscientific principles at the core of criminal law. In many ways the states resulting from incomplete transitions between sleep and wakefulness are unique experiments in nature providing the clinician scientist a direct window into the evanescent spectrum of consciousness with its associated expressions of human behavior. Thus, those asked to become engaged in sleep forensics would appear to be well poised at this intersection of law and neuroscience. In the developing field of sleep forensics, a medical expert called upon to investigate criminal allegations will need to do more than just evaluate for a possible sleep disorder because, ultimately, determining the defendant’s state of consciousness will prove pivotal. A conceptual
63
foundation would appear to be most beneficial to bridge this divide between neuroscience and law. Such a foundation should include familiarity with the evolution of legal thought, the historical development of sleep forensics, the neuroscience of consciousness, the relevant neuroscientific models of the types of behavior arising from sleep, as well as clinical guidelines to assist in determining purported acts of violence arising from sleep, and guidelines for the role of the sleep medicine specialist in an unfamiliar legal environment. Such an approach would enhance the role of the sleep medicine specialist as a resource to the legal community. It would begin to develop the framework for further research, particularly in parasomnias, and would facilitate the discourse related to the social implications concerning advances in cognitive neuroscience.
EVOLUTION OF LEGAL THOUGHT General Influenced by Sir Edward Coke, Chief Justice of the King’s Bench (1613), Anglo-American law defines criminal offenses whereby a person must be in a certain mental state, called the mens rea (guilty mind), necessary to have committed a crime and have accomplished the criminal act, called the actus reus (guilty act). Traditionally, intention is found within mens rea, and the physical part of the offense resides within actus reus. It is necessary to prove both essential elements to secure a conviction. Sir Nicolas Tindal established in 1843 what has become known as the M’Naghten Rules, which exculpates the defendant for an offense committed while the defendant was suffering from a disorder of reason or disease of the mind in a manner “as not to know the nature and quality of the act he was doing; or, if he did know it, that he did not know he was doing what was wrong.”2,3 From a neuroscientific perspective, the criminal act or actus reus component of the crime is of less interest than the essential element of mens rea in regard to both culpability and mechanism of behavior. Implementation of the M’Naghten Rules thereby becomes a watershed moment concerning the influence of neuroscience on criminal law as the mind—or that most complex of all organs, the brain— firmly becomes the linchpin in criminal law from which all is determined and to what degree. Consequently, with the growth and advances seen since the 1980s, neuroscience has only recently begun to appreciate its vast influence on society. Sleep The first appearance of the “sleepwalking defense” in an American court of law came in Massachusetts v Tirrell4 in 1846. In this landmark case, Rufus Choate, a skilled orator, innovative legal tactician, and U.S. senator, successfully 725
726 PART II / Section 8 • Impact, Presentation, and Diagnosis
employed the “insanity of sleep” defense to convince the jury to acquit Tirrell of homicide although Tirrell brutally killed the victim with a razor, almost severing her head from her body, set the horrifically bloody crime scene ablaze, and attempted to flee the country.5 In the mid to late 1800s there were no plausible medical explanations to account for sleepwalking, let alone account for complex violent actions that apparently arose from sleep and led to misfortune. Though such tragic circumstances resulting in death appear to be exceedingly rare, when presented to a court of law, as in HMS Advocate v Fraser (1878)6 and Fain v Commonwealth (1879),7 a homicide charge may be defended by pleas of a temporary “defect of reason” or “disease of mind.” Until physiologic aspects of sleep could be objectively measured and verified using validated neuroscientific instruments, defending, in the criminal court system, sleep-related violent, antisocial, and apparently bizarre behavior arising from sleep often meant associating such behavior with other, better-understood medical or psychiatric conditions for which sleep might not be related in that particular case, such as automatism versus insanity. A defense of automatism may be appropriate for allegations associated with behavior arising from epileptic seizures, fugue states, and limbic psychotic trigger reactions, whereas an insanity plea would likely find no opposition if the defendant acted in the throes of fulminant delusional paranoid schizophrenia. However, superimposing criminal allegations associated with sleep disorders upon the wellestablished legal models of “automatism” and “insanity” has led to unresolved ambiguities, uneven court processes, and ultimately unpredictable outcomes whereby even an acquittal can result in life-long incarceration in a mental health facility. The legal community’s perspective toward sleep began to shift in 1968 with Roger Broughton’s seminal publication characterizing the relationship among somnambulism, nightmares, confusional states of arousal, and rapid eye movement (REM) sleep.8 By creating a clear demarcation between sleep disorders and other medical or psychiatric conditions, this appears to be the first scientific sleep-related publication with direct legal implications, as supported by the Regina v Parks (1992),9 where Broughton served as an expert witness on behalf of the defense. It has been documented in this criminal case that the defendant drove in the early morning hours to the house of his wife’s parents. Apparently while still sleepwalking, the defendant was provoked to attack by his in-laws’ physical contact, whereby he then attacked both of them with a kitchen knife, killing his mother-in-law and leaving his father-inlaw seriously injured.10 The defendant was acquitted in a complete defense of all criminal charges, including homicide, in a courtroom jury trial whose rendering was eventually upheld by a landmark decision by the Supreme Court of Canada not to characterize sleepwalking as a mental health disorder. Though inherently multidisciplinary, somnology, when addressing the mental state with the ephemeral nature of consciousness, is best categorized as a subset within the greater field of neuroscience. Yet, despite ongoing scientific and medical advances within the field, the legal community remains bewildered in its approach toward sleep.
EVOLUTION OF CONSCIOUSNESS THOUGHT Waking Consciousness As mentioned, Anglo-American law has traditionally defined criminal offenses as requiring both an actus reus and a mens rea. The state (or prosecution) must prove both elements to secure a conviction. Regrettably, it has proved exceedingly difficult to establish either the precise meaning of these terms or the relationships connecting them. The American Law Institute’s Model Penal Code (MPC) attempts to provide guidance to these difficult relationships by substituting a relatively simplified set of terms and requirements for offense definitions. To secure a conviction in a criminal trial under the MPC, the state must prove all elements in the definition of the offense and must exhibit that the conduct was a voluntary act. Furthermore, the MPC includes a culpability requirement for each material element of the offense. Criminal law presumes that most human behavior is voluntary and that individuals are consciously aware of their acts. All criminal liability is based upon a voluntary act, or an omission to engage in a voluntary act that the defendant would otherwise have been capable of performing, that is composed of three key elements governed by Aristotelian rules of syllogistic logic: an internal event (volition), an external event (demonstration), and a causal connection (internal plus external events). Voluntariness is the first step in establishing mens rea; if that is successfully proved, the state proceeds to assess liability according to the four levels of culpability: purpose, knowledge, recklessness, and negligence. In criminal law, the level of culpability determines the category of homicide (murder, manslaughter, or negligent homicide) and the category directly influences the severity of punishment. Because voluntariness is absolutely fundamental to mens rea, it is surprising that the MPC never explicitly defines the term voluntary acts, but it does offer four examples of acts that are not voluntary including reflex convulsion; bodily movement during unconsciousness or sleep; bodily movement that is not otherwise not a product of the effort or determination of the actor, either conscious or habitual; and conduct during hypnosis or hypnotic suggestion.11,12 The MPC Commentaries offer further explanations but maintain vagueness to allow each court to render its own interpretation, particularly when addressing what would constitute “conscious” and “unconscious” bodily movements. As voluntariness is to mens rea, consciousness is to voluntary conduct. Despite the lack of clarity, criminal law must attempt to explain consciousness, and in this the MPC provides a clue with its decision to specifically cite hypnotic suggestion as an involuntary act, a striking reminder of the potent strength of the sphere of Freudian thought on the MPC’s advisory committee members.12 A comprehensive review toward a neuroscience of consciousness is well beyond the scope of this chapter. First, consciousness is a term that has varied meanings to neuroscientists, though in the legal realm its definition has held steadfast. In science, for example, consciousness may be used to indicate whether or not an individual is in a conscious state, as in whether it has been altered, reduced, or even
lost. On the other hand, consciousness may be a trait or an attribute of a psychological process, as in the ability to think, see, and feel consciously. With trait consciousness, further distinctions may be made between conscious representations, which are usually phenomenal and required conscious access. Unfortunately, a direct objective marker for the neural basis of state and trait consciousness that is independent of a person’s external expressions or behavior has yet to be determined. Nevertheless, the neuronal processes that mediate the required conscious access provide a prominent candidate in a network of frontoparietal cortical regions that play an important role in attentional and behavioral selection of incoming and stored information. Because the frontoparietal cortical regions govern behavioral selection, it is not surprising that this region becomes active when patients in a vegetative state recover or becomes further activated when healthy subjects perform demanding perceptual tasks. Sleep is regularly and actively induced by a shift in neuronal activity and neurotransmitter balance in brainstem nuclei. Functional neuroimaging studies performed on sleeping subjects reveal that during both REM and non-REM (NREM) sleep the prefrontal and parietal cortical regions become deactivated in comparison to the resting wakeful state.13-15 The most active regions during the resting wakeful state include the left dorsolateral and medial prefrontal areas, the inferior parietal cortex, and the posterior cingulate and precuneus.14 In REM sleep, despite overall increases in cerebral blood flow and energy demands, relatively low regional cerebral blood flow persists in prefrontal and parietal cortex.16 Consciousness involves awareness of our environment, awareness of our bodies, and introspection (self-awareness), and it can only fully occur when we are awake. Thus, in this regard, the frontal cortex would appear to be indispensable to consciousness. Another important region is the dorsal thalamus, the “gateway to the cortex,” and its accompanying “guardian of the gateway,” the reticular complex (part of which is often called the perigeniculate nucleus).17-20 Francis Crick believed that the input and output gating of the reticular complex were topographically arranged to approximate a map of the entire cortex. In his searchlight hypothesis, the reticular complex thereby was able to heat up the warmer parts of the thalamus and cool down the cooler parts so that “attention” would remain focused on the most active thalamocortical regions.21 Though the function of the thalamic reticular complex remains incompletely understood, as with the frontal cortex, it is essential for consciousness, whereas cerebellar circuits, in contrast, are not. Dreaming Consciousness The concept of consciousness was first put forth by influential American scientific psychologist and pragmatist William James (1842-1910). Consciousness has been subdivided into nine distinct components (Table 63-1), all of which are seamlessly integrated into our own personal conscious experience. What differentiates humans from other animals is language, which enriches the cognitive experience and allows humans to develop verbal and numeric abstractions. Thus, the animal models of consciousness are limited because they could never address the
CHAPTER 63 • Sleep Forensics 727
Table 63-1 The Nine Components of Consciousness COMPONENT
FUNCTION
Perception
Representation of input data
Attention
Selection of input data
Memory
Retrieval of stored representations
Orientation
Representation of time, place, and person
Thought
Reflection upon representations
Narrative
Linguistic symbolization of representations
Instinct
Innate propensities to act
Intention
Representation of goals
Volition
Decisions to act
full range of human cognitive experience that resides in the comparatively enormous cerebral cortex. It is obvious with sleep onset that sensory input is largely lost and our ability to interact with the external environment is curtailed. The conscious state paradigm outlined by J. Alan Hobson recognizes that all nine components of consciousness change to varying degrees as the brain changes state and does so in a repetitive and stereotyped manner over the sleep–wake cycle. Furthermore, consciousness is graded, and the state changes appear to be of such dramatic magnitude that strong inferences can be made about the major physiologic underpinnings of consciousness.22 The application of the conscious state paradigm has led Hobson to declare three important principles. First, as consciousness rides on the crest of the brain activation process, even a small perturbation in activation level leads to lapses in waking vigilance. Second, though consciousness may be largely deactivated, the brain remains highly active and is still capable of processing information. Functional imaging studies reveal that the brain remains about 80% active even when consciousness has largely subsided. Lastly, most brain activity is not associated with consciousness. In relation to its evanescence, consciousness “is a very poor judge of its own causation and of information processing by the brain.”22 There have been seismic shifts in cognitive neuroscience that the legal system has yet to appreciate and incorporate into the legal arena. Rather confusingly, the terms “conscious” and “unconscious” are still used in the lexicon of neuroscience, but the ideas and principles behind these terms have been substantially altered and continue to be refined, with one such example being Tononi’s information integration theory of consciousness.23,24 Advances in neuroscience since the 1980s support the existence of a continuum of conscious and unconscious processes and it has dispensed with Freudian-influenced psychoanalytic concepts and theories. The boundaries between our conscious and unconscious, as between wake and sleep, are permeable, dynamic, and interactive, and there is no valid scientific support for the sharp dichotomy as currently held by the MPC and the legal community. It is this model of permeability, or state dissociation, that will also assist in
728 PART II / Section 8 • Impact, Presentation, and Diagnosis Box 63-1 Conditions Associated with Automatic Behavior Arising from the Sleep Period Primary Sleep Disorders (Neurologic Conditions) Disorders of arousal • Confusional arousal • Sleep sex (sexsomnia) • Sleep terror • Somnambulism REM sleep behavior disorder Nocturnal seizures Compelling hypnagogic hallucinations Somniloquy Psychiatric Conditions Dissociative states (may arise exclusively from sleep) Post-traumatic stress disorder Malingering Munchausen’s syndrome by proxy Psychopathy REM, rapid eye movement.
the explanation of unusual, irrational, or bizarre human behavior in sleep forensics.
COMPLEX BEHAVIOR ARISING FROM SLEEP Increasingly, experts in sleep medicine are being called upon by attorneys to assist in reviewing legal cases, most of which involve behavior with criminal allegations. The variety of such cases is broad, though it is conventionally thought of as an evaluation for parasomnias as an explanation for a wide variety of violent types of behavior ostensibly arising from the sleep period, with hope that if such behavior is deemed sleep related, it may serve to completely exonerate the perpetrator. Some cases include a request to evaluate a driver’s lapses of waking vigilance resulting in tragic consequences, with an assessment of the defendant and Department of Transportation case files to determine whether or not the contributing sleep deprivation attained the standard to prosecute gross criminal negligence. Case requests to review bizarre nocturnal activities and associated rage reactions attributed to pharmaceutical agents such as benzodiazepines and, particularly, nonbenzodiazepine drugs are not uncommon. Incidents of violent sleep-related behavior have been reviewed in the context of automatic behavior in general, with many well-documented cases resulting from a wide variety of disorders. Conditions associated with violence related to the sleep period fall into two major categories: neurologic and psychiatric (Box 63-1). Those actions arising from a primary neurologic condition can be explained by applying conceptual approaches based on models of evanescent consciousness, the overlapping physiology of clinical disorders, and the platform of central pattern generators (CPSs) supported by semiotic neuroethology.
Consciousness as a Continuum From the notion that consciousness is graded and not dichotomous, Hobson developed the AIM concept, which undoubtedly explains many types of human experience and behavior previously enigmatic and formerly felt to be unrelated. This concept creates a four-dimensional “mind space” in time that is transformed by three variables: activation (A), input–output gating (I), and neuromodulation ratio (M) (as measured by the aminergic-to-cholinergic ratio). All of these determine changes in the state of consciousness, which in turn govern the oscillation from wake to sleep, and they can also account for the physiologic properties within each state.22 With this concept it also then follows that temporary nonhomeostatic conditions might arise in which the variables conspire with the final output expressed as kinds of behavior that are undesirable and without consciousness or memory; violent outbursts related to REM sleep behavior disorder are one such example. The recurrent recruitment of state-determining parameters is amazingly consistent. However, there are numerous clinical and experimental examples of dissociation of state components, simultaneous mixtures of clinical and neurophysiologic elements of the three states of being— wake, NREM sleep, and REM sleep. These fall into three categories, as reviewed by Mahowald and Schenck25 and include neuroanatomic lesions or stimulation, pharmacologic mechanisms, and sleep deprivation. Neuroanatomic lesions or stimulation include hypothalamic, thalamic, and brainstem manipulation or stimulation inducing state dissociation. Pharmacologic mechanisms include manipulation of the cholinergic or glutamate neurotransmitter systems resulting in a variety of state dissociations. As for sleep deprivation, recent studies by Montplaisir and colleagues suggest that sleepwalking results from a dysfunction of the mechanism responsible for sustaining stable slow-wave sleep and that sleepwalkers are particularly at risk when exposed to increased homeostatic sleep pressure.26 Both experimentally induced and naturally occurring state dissociations in animals serve to predict spontaneously occurring experiments in nature and drug-induced state dissociation in humans, which undoubtedly exist on a broad spectrum of expression. Such state dissociations are the consequence of timing or switching errors in the normal process of the dynamic reorganization of the CNS as it moves from one state (or mode) to another. Elements of one state persist, or are recruited, erroneously into another state, often with fascinating and dramatic consequences. The concept of state dissociation in humans helps to explain such phenomena as waking hallucinations, narcolepsy, REM sleep behavior disorder, lucid dreaming, out-of-body experiences, near-death experiences, repressed or recovered memories of childhood sexual abuse, alien abductions, and disorders of arousal (Fig. 63-1).27-31 The concept of state dissociation supports the notion that consciousness occurs on a continuum. Despite considerable attention in the popular media in the United States and the United Kingdom given to the association between alcohol and sleepwalking, there are no compelling scientific research data that support the notion
CHAPTER 63 • Sleep Forensics 729 Epilepsy
OVERLAPPING STATES Narcolepsy triad Hypnagogic hallucinations, sleep paralysis, cataplexy
Disorders of arousal (NREM) Confusional arousals Somnambulism Sleep terrors Sleep eating Sexsomnia
REM sleep behavioral disorder (RBD) Wake
Lucid dreaming, out-of-body experiences 2 REM
3 4
Parasomnia overlap syndrome status dissociatus
1
Paleomammalian (limbic system)
Frontolimbic seizures
Neomammalian Arousal
NREM Reptilian
Parasomnias
Asymptomatic (no conscious awareness)
Figure 63-1 Areas of overlap among states of being. (Modified from Mahowald MW, Schenck CH. Dissociated states of wakefulness and sleep. Neurology 1992;42:44-52).
that a reasonable amount of alcohol will either prime or trigger such an mixture of states such as sleepwalking or sleep sex.32,33 Fixed Action Patterns and Central Pattern Generators: A Neuroethologic Approach to Behavior The fact that violent or injurious behavior can arise in the absence of conscious wakefulness raises the crucial question of how such complex actions can occur. The widely held concept that the brainstem and other more “primitive” neural structures primarily participate in elemental or vegetative rather than behavioral activities is inaccurate. There is clear evidence that highly complex emotional and motor activities can originate from these more primitive structures without involvement of more rostral neural structures. Ethology is the study of whole patterns of animal behavior under natural conditions in a manner that highlights the functions and the evolutionary process of those patterns. With an ever-increasing physiologic approach through the application of refined and elegant laboratory research techniques to animal behavior, neurobiology and ethology have coalesced to develop neuroethology.34 An important behavior type in ethology is the fixed action pattern (FAP) which is an instinctive indivisible behavioral sequence that when initiated will run to full completion. FAPs are invariant and are produced by a neural network known as the innate releasing mechanism in response to an external stimulus known as a sign stimulus. FAPs are ubiquitous in the animal kingdom and are seen from invertebrates to higher primates. Movements resulting in FAPs may be initiated by CPGs: “Movements are generated by dedicated network of nerve cells that contain the information that is necessary to activate the different motor neurons in the appropriate sequence and intensity to generate motor patterns. Such networks are referred to as Central Pattern Generators.”35 Tassinari and coworkers, in their neuroethologic approach, recognized that motor events related to certain
Behaviors Bruxism—teeth grinding Oral automatisms (chewing, swallowing, lip-smacking)
Alimentary
Biting—flybiting Teeth chattering Faciomandibular Myoclonus
Defensive/ predatory
Universal facial expression (fear—pavor, etc.) and encoded vocalizations
Emotional
Pedalling (supine), Tetrapod progression (prone) Fugue—wandering Locomotory Cyclic legs movements Bimanual—bipedal activity Repetitive pelvic thrusting
Copulatory
Sleep
Figure 63-2 The emergence of innate primal behavior facilitated through central pattern generators from the arousal platform. (Adapted from Tassinari CA, Rubboli G, Gardella E, et al. Central pattern generators for a common semiology in fronto-limbic seizures and in parasomnias. A neuroethologic approach. Neurol Sci 2005;26:S225-S232).
epileptic seizures and parasomnias share very similar features suggesting a stereotyped inborn FAP, perhaps initiated by CPGs.36 Tassinari recognized CPGs as genetically determined neuronal aggregates in the mesencephalon, pons, and spinal cord that, from an evolutionary perspective, were linked with innate primal behavior essential for survival (e.g., feeding, locomotion, reproduction). In higher primates, CPGs are inhibited by the influence of neocortical control. Many of the CPGs are located in the brainstem and in close proximity to processes that govern the wake, NREM sleep, and REM sleep transitions. Despite diurnal neocortical inhibition, Tassinari provides a neuroethologic model whereby both epilepsy and sleep can lead to a temporary loss of control of the neomammalian cortex that is provided a pathway through a common arousal platform initiated by CPGs, which in turn triggers these FAPs (Fig. 63-2), resulting in the abrupt onset of bizarre motor or emotional expressions that are uncharacteristic of awake neocortical-mediated diurnal behavior. Tassinari’s concept of the role of CPGs and FAPs provides a physiologic explanation for parasomnias. As a neuroethologic concept, it also sets a framework for future research by promoting a naturalistic approach through observing behavior, including by methodical data collection, to better understand the spectrum of parasomnias for which the duration and complexity of behavior remain ill defined. This concept is particularly useful in sleep forensics because parasomnias and epileptic seizures tend to have patterned stereotyped actions without conscious awareness. When addressing criminal allegations and their potential association with sleep-related conditions, the sleep medicine specialist can use behavior pattern recognition, applying neuroethologic concepts that indicate process fractionation, and neurobehavioral investigative
730 PART II / Section 8 • Impact, Presentation, and Diagnosis
techniques. Such an approach could be particularly beneficial and would be consistent with the direction of current mainstream science.
THE DEVELOPMENT OF SLEEP FORENSICS Regina v Park9 facilitated ushering in the sleepwalking defense into the modern era, but the interface between law and science remains contentious due in part to conflicting philosophies, methodologies, and goals. Nonetheless, there is now a greater degree of civic responsibility placed upon the field of sleep medicine given the legal community’s growing recognition of sleep’s broad effects on behavior (or lack thereof) including parasomnias, cognitive impairment related to sleep deprivation, and pharmaceutical toxicity, to name a few. Thus, sleep forensics was born of the need to address civic responsibility while appreciating that advances in neuroscience have social implications, and it thereby attempts to facilitate discourse between the two disparate disciplines of law and sleep medicine within currently held rules of the legal system. Sleep forensics is defined as the application of the principles and tools of neuroscience as applied to somnology and sleep medicine. These principles and tools have been widely accepted under international peer review as means for investigating unusual, irrational, or bizarre human sleep-related behavior associated with alleged criminal activity that is to undergo further examination in a conflict resolution legal atmosphere or courtroom. The application of sleep forensics is best based upon an adaptable conceptual approach using the most current neuroscientific and clinical principles as opposed to a static condition that simply lists or highlights clinical disorders and extrapolates associations with criminal behavior. Such a dynamic approach applies current neuroscientific concepts of consciousness and sleep–wake state dissociation to sleep medicine. As a result, to effectively translate this information into the courtroom, attention must be given to the controversy between dynamic neuroscientific principles of consciousness, which contrast with static definitions put forth by the U.S. Model Penal Code. To assist in determining the putative role of an underlying sleep disorder in a specific violent act, guidelines should be proposed that are based upon international clinical experience that have undergone peer-review publication. The role of the sleep medicine specialist and recommendations for expert witness qualifications and testimony should be addressed to ensure that those who practice sleep forensics optimize dialogue and maintain ethical behavior so the process of law can proceed without hindrance. CLINICAL GUIDELINES TO ASSIST IN DETERMINING PURPORTED VIOLENCE ARISING FROM SLEEP Legal implications of automatic behavior have been discussed and debated in the medical and legal literature.37-41 As with automatisms not related to sleep, the identification of a specific underlying organic or psychiatric sleep and violence condition does not establish causality for any given deed. Two questions accompany each case of pur-
ported sleep-related violence: Directly addressing mens rea, is it possible for behavior this complex to have arisen in a mixed state of wakefulness and sleep without consciousness? Is that what happened at the time of the incident? The answer to the first is usually “yes.” The second can never be determined with certainty after the fact. To assist in determining the putative role of an underlying sleep disorder in a specific violent act, several clinical guidelines have been proposed.42-45 Research has shown certain features identify actions occurring as a result of a sleep disorder. • There should be reason by history to suspect a bona fide sleep disorder. Similar episodes, with benign or morbid outcome, should have occurred previously. (Disorders of arousal may begin in adulthood.) • The duration of the action is usually brief (seconds), though action of longer duration (minutes) does not necessarily exclude a sleep disorder or a sleep-related behavior. The action is usually abrupt, immediate, impulsive, and senseless—without apparent motivation. Although ostensibly purposeful, it is completely inappropriate to the total situation, out of (waking) character for the individual, and without evidence of premeditation. • The victim is someone who merely happened to be present, usually in close proximity, and who may have been the stimulus for the arousal. Sleepwalkers rarely, if ever, seek out victims.45,46 • Immediately following return of consciousness, there is perplexity or horror, and there is no attempt to escape, conceal, or cover up the action. There is evidence of lack of awareness on the part of the sleepwalker during the event. There is usually some degree of amnesia for the event, but this amnesia need not be complete. • In the case of sleep terrors, sleepwalking, or sleep inertia, the act may occur upon awakening (rarely immediately upon falling asleep) and usually at least 1 hour after sleep onset. It occurs upon attempts to awaken the subject. The action has been potentiated by sedative–hypnotics or by prior sleep deprivation. Voluntary intoxication by alcohol, or other illicit mindaltering intoxicants, precludes the sleepwalking defense. Of special note in legal cases involving voluntary intoxication and addressing consequent culpability, alcohol binge drinking has increasingly become a societal menace and is often misunderstood and underappreciated in its involvement with antisocial behavior. Binge drinking can be associated with blackouts, episodes of amnesia during which the person is capable of participating even in salient, emotionally charged events that he or she cannot remember. These memory impairments are primarily anterograde such that the alcohol impairs the ability to form memories while the person is intoxicated, but it does not erase memories formed before the toxic insult. An alcoholic blackout can manifest as a Korsakoff-like syndrome that can go undetected by law enforcement officers and health care providers not trained to evaluate this type of cognitive impairment. Several studies have shown a surprisingly high prevalence of alcoholic blackouts among social drinkers and college-age persons.47 Subsequent studies involving college students reported a high prevalence of risky behavior
during blackouts, including sexual activity with acquaintances and strangers, vandalism, and instigation of other violent activity.48 Although much is known about the effects of alcohol on reductions in motor performance, there is also compelling evidence that acute alcohol use impairs the performance of frontal lobe–mediated tasks such as those that require judgment and impulse control.49 Appreciating the neuroscience of alcoholic blackouts allows one to better understand the mechanisms of behavior that can proceed without consciousness, awareness, and proper executive function. Likewise, the alcoholic blackout also clearly represents one of the many types of behavior that can mimic parasomnia—types of behavior that are arguably exponentially much more prevalent and thus should be given appropriate weight when attributing likely cause in criminal allegations.32 The guidelines for determining the role of a sleep disorder in violence are purely meant to provide direction when beginning the review process to gauge whether or not a sleep disorder could be used as a possible defense. Once this question is answered, the strength of the argument to either support or refute the defendant’s claim should be used alongside current neuroscientific models of consciousness and behavior and further sustained with the medical expert’s wealth of specialized clinical experience.
THE ROLE OF THE SLEEP MEDICINE SPECIALIST Recent interest in the forensic aspects of parasomnias provides the sleep medicine professionals an opportunity to educate and assist the legal profession in cases of sleeprelated violence. One infrequently used tactic to improve scientific testimony is to use a court-appointed impartial expert. Volunteering to serve as a court-appointed expert, rather than as one appointed by either the prosecution or defense, might encourage this practice. Other proposed measures include the development of a specific section in scientific journals dedicated to expert witness testimony extracted from public documents with request for opinions and consensus statements from appropriate specialists or the development of a library of circulating expert testimony that could be used to discredit irresponsible professional witnesses. Good science is not determined by the credentials of the expert witness but by scientific consensus. To address the problem of junk science in the courtroom, many professional societies are calling for, and some have developed guidelines for, expert witness qualifications and testimony. The American Academy of Sleep Medicine’s stance on expert witness testimony is to accept opinions held by the American Medical Association (AMA) in their 2004 Report of the Council on Ethical and Judicial Affairs.50 Similarly, influenced by both American Academy of Neurology and the AMA, the following guidelines should serve as a compass. Expert Witness Qualifications Expert witnesses should have a current, valid, unrestricted medical license. Expert witnesses testifying about sleep medicine should be diplomates of the American Board of Sleep Medicine or should have passed the American Board
CHAPTER 63 • Sleep Forensics 731
of Internal Medicine specialty examination in sleep medicine. Membership into the Sleep Research Society is strongly encouraged. An expert witness in sleep medicine must be a recognized resource within the sleep medicine community and should have been actively involved in clinical practice in a manner consistent with the requirement of the criminal case at the time of the event. Given the essential position of mens rea in criminal law and the pivotal role of levels of consciousness, an expert witness must have significant direct experience in either neurology or neuroscience. Guidelines for Expert Testimony Expert testimony must be impartial. The ultimate test for accuracy and impartiality is a willingness to prepare testimony that could be presented unchanged for use by either the plaintiff or the defendant. Fees should relate to time and effort and should not be contingent upon the outcome of the claim. Fees should not exceed 20% of the practitioner’s annual income. The practitioner should be willing to submit such testimony for peer review. To establish consistency, the expert witness should make records from his or her previous expert witness testimony available to the attorneys and expert witnesses of both parties. The expert witness must not become a partisan or advocate in the legal proceeding. It is not the role of the medical expert to win the case for a client, although it is not uncommon to use irrelevant disingenuous technicalities in an attempt to deceive so as to attain an advantage to secure the decision. Instead, the salient ethical decision for those who assume this mantle of medical expert witness is to recognize and value the privileged position given within our society as an educator inside the legal system by promoting current published peer-reviewed science and minimizing bias while rendering an opinion. The role of the expert witness is therefore to attempt to succinctly and clearly communicate scientifically valid information to the jury, who in turn determines culpability based upon this information. The weight of the decisions of either guilt or innocence should never rest in the hands of medical experts, whose task is to contribute to the due process of an efficient and functional legal system by ensuring that the jury is educated and well informed.51
CONCLUSION Advances in neuroscience are increasing our understanding of how the brain enables action, including everything from simple movement, to thought, to the diurnal and nocturnal variability of wake–sleep processing. We appear to be closing in on the idea that humans are a determined system. Such scientific advance comes at a cost, as the societal and cultural implications have yet to be understood or even conceived.52 However, the legal community is aware of the implications of this new neuroscience, because science directly challenges the law’s currently held constructs of consciousness as defined by mens rea and the voluntary act requirements. To study these problems, the John D. and Catherine T. MacArthur Foundation has established the Law and Neuroscience Project in 2007 (www.lawandneuroscienceproject.org), comprising
732 PART II / Section 8 • Impact, Presentation, and Diagnosis
40 neuroscientists, legal specialists, and philosophers.53 Two important concepts to be incorporated into the legal community are that consciousness is not all-or-none but occurs on a spectrum, and consciousness can be dissociated from behavior. Sleep forensics does more than provide medical expert testimony in individual legal cases. This chapter provides a definition and a conceptual approach for the formal development of the field of sleep forensics so that it serves as a resource to the legal community so that its complex and important position at the intersection of neuroscience and law can be appreciated. With this appreciation comes significant social responsibility. Applying process fractionation, much can be learned about consciousness from sleep physiology, particularly in mixed states. The growth of cognitive neuroscience will continue to change our understanding of what it means to be human, and as a result the law will have to change in conformity with it. The conceptual approach to sleep forensics encourages further research to define and characterize mixed states of wake and sleep and the parasomnias. Understanding all of these are beneficial in understanding the spectrum of complex human behavior. Close collaboration among basic neuroscientists, sleep medicine clinicians, and the legal community will facilitate the development of a commonly shared concept of consciousness and culpability. ❖ Clinical Pearls In a court of law, the undisciplined use of scientific technical data is a real concern, especially given the public misperception that science is a field that deals with absolute certainties when in actuality it is a field that reflects probabilities of occurrence. In many ways, the legal community has misrepresented the nature of science for many years and continues to attempt to do to so in an admittedly adversarial environment. One problem with presenting results of scientific research is a condition called brain overclaim syndrome.54 In general, the public has an overfascination with new developments in science and often assumes statements of scientific evidence are true, even when the statements cannot be conceptually or empirically sustained. Studies have shown, for example, that the results of a simple experiment in cognitive psychology is more positively evaluated and considered important if a brain scan is included in the report of the results.55 In a sleep-related example, a review has clearly established that polysomnography performed after the fact is of absolutely no value in determining whether the accused was sleepwalking at the time of the criminal activity. Even frank sleepwalking during a formal sleep study would only indicate that the person was a sleepwalker, not that sleepwalking was involved at the time of the crime.56
REFERENCES 1. Kadish SH. Moral excess in the criminal law. McGeorge Law Review 2000;32:1-17. 2. West DJ, Walk A. Daniel McNaughton: His trial and the aftermath. Ashford, England: Gaskell Books for British Journal of Psychiatry; 1977.
3. Queen v M’Naghten, 8 Eng. Rep. 718 (H.L. 1843). 4. Massachusetts v. Tirrell (1846). 5. Knappman EW. Great American trials: from Salem witchcraft to Rodney King. Detroit: Visible Ink; 1994. p. 429. 6. Yellowlees D. Homicide by a somnambulist. J Ment Sci 1878; 24:451-458. 7. Fain v. Commonwealth, 78 Ky. 183 (Ky. 1879) 8. Broughton RJ. Sleep disorders: disorders of arousal? Enuresis, somnambulism, and nightmares occur in confusional states of arousal, not in “dreaming sleep.” Science 1968;159:1070-1078. 9. Regina v. Parks, [1992] 2 S.C.R. 871 (Canada). 10. Broughton R, Billings R, Cartwright R, et al. Homicidal somnambulism: a case report. Sleep 1994;17:253-264. 11. Model Penal Code. American Law Institute, 1962. 12. Denno DW. Crime and consciousness: science and involuntary acts. Minnesota Law Review 2002;87:269-400. 13. Maquet P, Peters J-M, Aerts J, et al. Functional neuroanatomy of human rapid-eye-movement sleep and dreaming. Nature 1996; 383:163-166. 14. Maquet P. Functional neuroimaging of normal human sleep by positron emission tomography. J Sleep Res 2000;9:207-231. 15. Braun AR, Balkin TJ, Wesensten NJ, et al. Regional cerebral blood flow throughout the sleep-wake cycle. Brain 1997;120: 1173-1197. 16. Steriade M. Corticothalamic resonance, states of vigilance and mentation. Neuroscience 2000;101:243-276. 17. Sumitomo I, Nakamura M, Iwama K. Location and function of the so-called interneurons of rat lateral geniculate body. Exp Neurol 1976;51:110-123. 18. Ohara PT, Lieberman AR, Hunt SP, et al. Neural element containing glutamic acid decarboxylase (GAD) in the dorsal lateral geniculate nucleus of the rat; immunohistochemical studies by light and electron microscopy. Neuroscience 1983;8:189-211. 19. Houser CR, Vaughn JE, Barber RP, et al. GABA neurons are the major cell type of the nucleus reticularis thalami. Brain Res 1980; 200:341-354. 20. Ohara PT, Sefton AJ, Lieberman AR. Mode of termination of afferents from the thalamic reticular nucleus in the dorsal lateral geniculate nucleus of the rat. Brain Research 1980;197:503-506. 21. Crick F. Function of the thalamic reticular complex: the search light hypothesis. Proc Natl Acad Sci U S A 1984;81:4586-4590. 22. Hobson JA. Normal and abnormal states of consciousness. In: Velmans M, Schneider S, editors. The Blackwell companion to consciousness. Malden, Mass: Blackwell; 2007. p. 101-113. 23. Tononi G. The information integration theory of consciousness. In: Velmans M, Schneider S, editors. The Blackwell companion to consciousness. Malden, Mass: Blackwell; 2007. p. 287-299. 24. Tononi G. Consciousness as integrated information: a provisional manifesto. Biol Bull 2008;215:216-242. 25. Mahowald MW, Schenck CH. Dissociated states of wakefulness and sleep. In: Lydic R, Baghdoyan HA, editors. Handbook of behavioral state control: cellular and molecular mechanisms. Boca Raton, Fla: CRC Press; 1999. p. 143-158. 26. Zadra A, Pilon M, Montplaisir J. Polysomnographic diagnosis of sleepwalking: effects of sleep deprivation. Ann Neurol 2008;63: 513-519. 27. Mahowald MW, Schenck CH. Dissociated states of wakefulness and sleep. Neurology 1992;42:44-52. 28. Mahowald MW, Schenck CH. Dissociated states of wakefulness and sleep. In: Lydic R, Baghdoyan HA, editors. Handbook of behavioral state control: cellular and molecular mechanisms. Boca Raton, Fla: CRC Press; 1999. p. 143-158. 29. Nelson KR, Lee SA, Schmitt FA. Does the arousal system contribute to near death experience? Neurology 2006;66:1003-1009. 30. McNally RJ, Clancy SA. Sleep paralysis, sexual abuse, and alien abduction. Transcultural Psychiatry 2005;42:113-122. 31. McNally RJ, Clancy SA. Sleep paralysis in adults reporting repressed, recovered, or continuous memories of childhood sexual abuse. J Anxiety Disord 2005;19:595-602. 32. Pressman MR, Mahowald MW, Schenck CH, et al. Alcohol-induced sleep-walking or confusional arousal as a defense to criminal behavior: a review of scientific evidence, methods and forensic implications. J Sleep Res 2007;16:198-212. 33. Pressman MR, Mahowald MW, Schenck CH, et al. No scientific evidence that alcohol causes sleepwalking. J Sleep Res 2008;17: 473-474.
34. Lehner PN. Handbook of ethological methods. 2nd ed. New York: Cambridge University Press; 1996. 35. Grillner S. The motor infrastructure: from ion channels to neuronal networks. Nat Rev Neurosci 2003;4:573-586. 36. Tassinari CA, Rubboli G, Gardella E, et al. Central pattern generators for a common semiology in fronto-limbic seizures and in parasomnias. A neuroethologic approach. Neurol Sci 2005;26: s225-s232. 37. Whitlock F. Criminal responsibility and mental illness. London: Butterworths; 1963. 38. Prevezer S. Automatism and involuntary conduct. Crim Law Rev 1958;361-367. 39. Fitzgerald P. Voluntary and involuntary acts. In: Guest A, editor. Essays in jurisprudence. Oxford: Oxford University Press; 1961. p. 1-28. 40. Shroder O, Mather NJ. Forensic psychiatry. In: Camps FE, editor. Gradwohl’s legal medicine. Chicago: A John Wright and Sons; 1976. p. 494-519. 41. Schopp RF. Automatism, insanity, and the psychology of criminal responsibility. New York: Cambridge University Press; 1991. 42. Bonkalo A. Impulsive acts and confusional states during incomplete arousal from sleep: criminological and forensic implications. Psychiat Q 1974;48:400-409. 43. Ohayon MM, Caulet M, Priest RG. Violent behavior during sleep. J Clin Psych 1997;58:369-376. 44. Mahowald MW, Bundlie SR, Hurwitz TD, et al. Sleep violence— forensic science implications: polygraphic and video documentation. J Forensic Sci 1990;35:413-432. 45. Pressman MR. Disorders of arousal from sleep and violent behavior: the role of physical contact and proximity. Sleep 2007;30(8):10391047.
CHAPTER 63 • Sleep Forensics 733 46. Schenck CH, Arnulf I, Mahowald MW. Sleep and sex: what can go wrong? A review of the literature on sleep related disorders and abnormal sexual behaviors and experiences. Sleep 2007;30:683-702. 47. Wechsler H, Lee JE, Kuo M, et al. Trends in college binge drinking during a period of increased prevention efforts. Findings from 4 Harvard School of Public Health College Alcohol Study Surveys: 1993-2001. J Amer Coll Health 2002;50:203-217. 48. White AM, Jamiesom-Drake DW, Swartzwelder HS, et al. Prevalence and correlates of alcohol-induced blackouts among college students: results of an e-mail survey. J Amer Coll Health 2002;51: 117-131. 49. Weissenborn R, Duka T. Acute alcohol effects on cognitive function in social drinkers: their relationship to drinking habits. Psychopharmacology 2003;165:306-312. 50. Goldrich MS. Report of the Council on Ethical and Judicial Affairs. CEJA Report 12-A-04 (Committee on Constitution and Bylaws). http://www.ama-assn.org/ama1/pub/upload/mm/369/12a04.pdf (accessed 1/11/2010). 51. Cramer Bornemann M. Health law: role of the expert witness in sleep-related violence trials. American Medical Association J Ethics 2008;10:571-577. 52. Churchland PS. The impact of neuroscience on philosophy. Neuron 2008;60:409-411. 53. Gazzaniga MS. The law and neuroscience. Neuron 2008;60:412-415. 54. Morse SJ. Brain overclaim syndrome and criminal responsibility: a diagnostic note. Ohio State J Crim Law 2006;3:397-412. 55. Weisberg DS, Keil FC, Goodstein J, et al. The seductive allure of neuroscience explanations. J Cogn Neurosci 2008;20:470-477. 56. Pressman MR. Factors that predispose, prime, and precipitate NREM parasomnias in adults: clinical and forensics implications. Sleep Med Rev 2007;11:5-30.
Occupational Sleep Medicine 64 Introduction 65 Performance Deficits during
Sleep Loss: Effects of Time Awake, Time of Day, and Time on Task 66 Fatigue and Performance Modeling 67 Fatigue, Performance, Errors, and Accidents
68 Fatigue Risk Management 69 Drowsy Driving 70 Sleep and Performance
Monitoring in the Workplace: The Basis for Fatigue Risk Management 71 Shift Work, Shift-Work Disorder, and Jet Lag
Introduction
Gregory Belenky and Torbjörn Åkerstedt Abstract Occupational sleep medicine is a new field within the specialty of sleep medicine. It is developing from multiple basic and clinical strands yielding applications in both operational (normative, workplace) and clinical environments. In its most basic form, occupational sleep medicine studies work as it affects sleep and sleep-related physiology both in terms of direct effects on performance and in terms of direct and indirect (through impaired safety) effects on health. Good performance translates into safety and productivity. All the chapters in this occupational sleep medicine section discuss the sleep and circadian rhythm effects variously on performance, productivity, safety (and, thus, indirectly on health), and well-being in the operational (workplace) context. Several of the chapters touch on the direct effects of sleep on health (see Chapters
Occupational sleep medicine is concerned with performance, productivity, safety, health, and well-being in the workplace or operational environment as affected by sleep restriction, circadian rhythm phase, and workload. The operational environment is defined as a work setting in which human performance plays a critical role and there is a high risk that if human performance degrades the system will fail. In the operational environment, the human in the operational loop has limited time to decide and act upon a course of action.1 Operational environments include military operations, maritime (including intracoastal and riverine) operations, medicine, the various modes of land transportation, aviation, security work, energy generation, resource extraction (mining, drilling), financial markets, and industrial production. 734
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72 Sleep Problems in First
Responders and the Military
73 Pharmacologic Management of Performance Deficits Resulting from Sleep Loss and Circadian Desynchrony 74 Sleep, Stress, and Burnout
Chapter
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71, 72, and 74). Three chapters outside of this section have a primary focus on the direct effects of sleep on health (see Chapters 25 to 27). Occupational sleep medicine will likely contribute to and be in part enabled by the development and implementation of individual, continuous, unobtrusive biomedical status monitoring, including in all probability monitoring of sleep–wake history, for use as input to biomathematical modeling predicting performance. We envision occupational sleep medicine being integrated into enterprisewide systems of fatigue risk management (see Chapters 66 and 70). In the modern corporate environment, fatigue risk management is typically folded into safety management. Occupational sleep medicine will develop as a subset of sleep medicine with ties to occupational medicine and industrial and organizational psychology.
In these settings, operational demands (shift timing and duration; work intensity, difficulty, and complexity) degrade performance directly through the effects of workload and circadian timing and indirectly by reducing the amount of time available for sleep, and thus total sleep time, a primary determinant of alertness and performance.1
FATIGUE AS A FUNCTION OF SLEEP–WAKE HISTORY, CIRCADIAN RHYTHM, AND WORK LOAD In the workplace, termed here the operational environment, we speak of fatigue defined subjectively by self-report and objectively as degraded performance. Fatigue, so
defined, is the end result of a common pathway integrating multiple factors. These factors include time awake (sleep–wake history), time of day (circadian rhythm), and workload (time on task, task intensity, and task complexity) (see Chapter 65). Also relevant to the generation of fatigue in the workplace are the clinical causes of excessive work-shift sleepiness (see Chapters 4 to 6, 57, and 75). Effective implementation of fatigue risk management in the operational environment will require a systematic understanding of the interaction of the multiple factors causing fatigue, perhaps by means of integrating these factors into biomathematical models predicting performance. In evaluating fatigue and excessive work-shift sleepiness in the workplace, the occupational sleep medicine physician should screen for and treat the clinical causes of sleepiness and fatigue, including obstructive sleep apnea, other sleep disorders, and insomnia (see Sections 10 and 13) in addition to providing a broader occupational consultation.
MANAGING SLEEP AND CIRCADIAN RHYTHM–RELATED FATIGUE RISK Fatigue-related performance decrements include lapses in attention, slowed reaction time, and impaired anticipation, planning, and judgment (see Chapter 66). Fatigue degrades the ability to observe, orient, decide, and act (OODA). The concept of the OODA loop was developed as a tool for analyzing relative advantage in air-to-air combat and has been extended to operational performance in general.2,3 Biomathematical models integrating circadian variations in alertness and its mirror, sleep propensity, with homeostatic sleep–wake regulation and sleep inertia—in effect encapsulating what is currently known in the science of sleep, circadian rhythms, and fatigue—have been effective in predicting operational performance, which is useful in comparing one potential schedule to another and could be integrated into software systems for rostering and scheduling to manage fatigue and its operational consequences in the workplace. Fatigue as a function of extended work hours and shift work is ubiquitous, and fatigue-related degradation in cognitive performance is common. Yet errors and incidents are uncommon and accidents are, fortunately, rare. How are we to understand this? A reasonable hypothesis is that the outcome of human performance is stochastic, depending upon both variability in internal state and variability in environmental demands. Thus, only when the internal stochastic process of lapsed attention or slowed response coincides with a period of high cognitive demand will an error occur, and only if this error is system critical will an incident or accident occur (see Chapter 67). This concept of the intersection of lapsing of attention or slowing of response time (or both) with a critical event is important operationally and clinically and suggests that past avoidance of accidents in the fatigued state does not guarantee future safety. Fatigue risk management is emerging as the applied, normative arm of occupational sleep medicine. Fatigue in the workplace has been traditionally—and is still to this day—managed with one-size-fits-all prescriptive hours-of-service rules that specify shift duration, between-
CHAPTER 64 • Introduction 735
shift intervals, and within-shift breaks. These hours-ofservice rules are typically blind to the human circadian rhythm in sleep propensity and performance and the increasing homeostatic drive for sleep from extended waking, and they are thus likely to be overly restrictive at some times and unsafe at other times. Hours of service represent a single and brittle line of defense against fatigue-related error, incident, and accident. Fatigue risk management is based on the scientific understanding of the dynamics of sleep loss and recovery and provides an alternative to the prescriptive hours-of-service approach (see Chapter 68). Fatigue risk management is a layered defense in depth against error, incident, and accident. In its basic form, fatigue risk management ensures an adequate sleep opportunity in terms of duration and placement with respect to the circadian rhythm; ensures that personnel are making good use of the sleep opportunity; and evaluates, given the sleep opportunity and the use made of it, how well personnel are performing in the workplace. Unlike hours-ofservice regulations, fatigue risk management is evidence based and entails iterative evaluation and improvement. As our understanding of the dynamics of sleep and performance becomes deeper and more comprehensive, including, for example, the effects of workload and individual differences in response to fatigue-related factors, our ability to implement fatigue risk management will correspondingly improve.
DROWSY DRIVING Drowsy driving and falling asleep behind the wheel cause upwards of 20% of vehicular accidents and translate into accident-related morbidity and mortality (see Chapter 69). Driving extended hours and driving through the night are associated with sleepiness and circadian-related fatigue and fatigue-related accidents. Depressant drugs, sleep-disordered breathing, and narcolepsy all increase the risk of sleepiness and sleepiness-related crashes. Objective measures of sleepiness, including the Multiple Sleep Latency Test and the Maintenance of Wakefulness Test, are valuable clinical tools that can be used to predict vehicular accident risk. Effective treatment of sleepdisordered breathing and other sleep disorders reduces this accident risk. The potential for drowsy driving in professional drivers has led to suggestions that governments include some screening for sleep disorders in the periodic medical evaluations that professional drivers undergo. To date there are no transnational, agreed-upon standards for such evaluation. Nor, when a sleep disorder is discovered, is there agreement on what constitutes effective treatment and when a driver may return to work. As part of the clinical practice of sleep medicine, sleep medicine physicians should carefully evaluate patients for risk for accident from drowsy driving. Public service campaigns against drowsy driving, including information on the dangers of driving drowsy; the risks when driving of combining sleep loss with alcohol; and the value of countermeasures such as getting adequate sleep, avoiding driving during the circadian low, and the tactical use of napping and caffeine, can be of great value.
736 PART II / Section 9 • Occupational Sleep Medicine
MONITORING SLEEP AND WORKPLACE PERFORMANCE One possible implementation of fatigue risk management includes using measures of sleep–wake history as input into biomathematical models predicting individual performance. In turn, workplace measures of alertness and performance could be used in a process of iterative model validation and improvement. Such models could be integrated into the objective function of rostering and scheduling software, creating and updating fatigue-friendly rosters and schedules in real time. There is evidence suggesting the utility of this approach in the form of studies that objectively measure sleep and performance in the workplace and adjust work schedules in the light of these measurements (see Chapters 68 and 70). SHIFT WORK, SHIFT-WORK SLEEP DISORDER, AND JET LAG In current industrial economies, shift work and travel across time zones and the attendant sleep restriction and circadian rhythm disruption are common (see Chapter 71). The circadian rhythm resynchronizes over days to the new time zone but does not resynchronize while working the night shift. Some people tolerate shift work and the attendant disconnection between the behavioral sleep–wake cycle and the underlying circadian physiology better than others. In a real sense, night-shift workers are continuously jet lagged, with chronic circadian desynchrony and associated daytime (off shift) insomnia and nocturnal (on shift) excessive sleepiness. This insomnia and excessive sleepiness, when severe, is diagnosed as shift-work sleep disorder. Among shift workers, those more vulnerable to shift-work sleep disorder are those older than 50 years and those who are morning types (those who have an earlymorning circadian preference). A variety of treatments both singly and in combination can mitigate shift-work sleep disorder. These include nocturnal bright light, daytime sleep in darkness, and stimulants to maintain alertness while on shift at night and sleep-inducing medications to maintain and extend sleep off shift during the day. Successful night-shift workers are often able to supplement their main morning sleep period with a late afternoon nap and even naps at night while on shift (if permitted at their workplace) thus increasing their total sleep time over 24 hours. Similar to shift-work sleep disorder, though self-limited, jet lag is characterized by excessive daytime sleepiness, nocturnal insomnia, and, in contrast to shift-work sleep disorder, gradually resynchronizing circadian desynchrony. Like shift work and shift-work sleep disorder, jet lag can lead to serious cognitive and performance impairment. Westward travel is generally better tolerated than eastward travel, perhaps because the circadian clock, having a slightly longer than 24-hour period, makes it easier for most people to stay up late and sleep in than to go to bed early and get up early. Multiple approaches to mitigation are possible. Appropriately timed bright light exposure can facilitate resynchronization. Sleep-inducing agents, including the chronobiotic melatonin, can promote out-of-phase sleep, reduce daytime sleepiness, and perhaps
speed resynchronization. As in drowsy driving, naps and caffeine can be effective countermeasures to excessive daytime sleepiness.
POLICE, FIRST RESPONDERS, AND THE MILITARY Police, first responders, and military personnel constitute critical operational populations. They are required to work extended hours and do shift work often without even the protection of traditional hours-of-service regulations (see Chapter 72). Police, first responders, and soldiers find their health and safety impaired by extended duty hours, night work, sleep restriction, and circadian disruption. Sleep loss and fatigue in these operational personnel can impair judgment and interfere with the appropriate exercise of restraint in the use of force or judgment in the use of lifesaving interventions, often with severe and enduring adverse consequences. A concatenation of social, organizational, and individual factors promotes fatigue in these occupational groups and interacts with sleep disorders to degrade performance, impair productivity and safety, and increase morbidity and mortality. Sleep medicine physicians should see working with operational agencies as an opportunity to extend and improve patient care and to improve public safety. Work with such agencies is an opportunity to do useful individual clinical work and to advise on organizational fatigue risk management. PHARMACOLOGIC MANAGEMENT OF SLEEP AND FATIGUE As indicated earlier, extended work hours, shift work, and travel across time zones entail sleep restriction, working at adverse circadian phase, and circadian desynchrony. Adequate sleep and rapid resynchronization are the best solutions, but they are not always achievable, at least in the short term. As a short-term or intermittent intervention, stimulant drugs and sleep-inducing drugs may be useful in getting normal amounts of out-of-phase sleep and sustaining performance in the face of sleep restriction and working at adverse circadian phase (see Chapter 73). SLEEP, STRESS, AND BURNOUT Stress appears to play a major role in the etiology of insomnia (see Chapter 74). Both cross-sectional and prospective studies support this connection. Anxious, worried thoughts at bedtime in the form of ruminating over anticipated next-day stress appear to be the link between stress and insomnia. In addition, sleep loss and stress may synergize as both serve to increase cortisol secretion, promote dyslipidemia, and increase insulin resistance, and both are implicated in type 2 diabetes and heart disease. Burnout is a result of chronic stress and is characterized by extreme fatigue, impaired cognition, and depressed mood. These symptoms of burnout are associated with severe sleep disturbance in the form of sleep fragmentation, increased sleep latency, and reduced slow-wave sleep. Sleep loss and sleep disturbance appear to be necessary preconditions for burnout to occur. It is tempting to see burnout as the end of a long chain of events beginning with stress, passing
through stress-induced insomnia and sleep disturbance, and leading finally to burnout. Burnout, as well as more moderate influences of stress on restitution, is related to increased levels of sickness absence and should be considered in patients with unusually high levels of sickness absence. Stress and social requirements also cause sleep restriction, which results in fatigue similar to that caused by irregular work hours.
THE SCIENCE AND ART OF OCCUPATIONAL SLEEP MEDICINE Occupational sleep medicine is a new field within sleep medicine with ties to occupational medicine and industrial and organizational psychology. Occupational sleep medicine concerns itself with maintaining performance, productivity, safety, health, and well-being in the workplace through individual and system-wide interventions mitigating the deleterious effects of sleep loss, circadian desynchronization, and other fatigue-related and health-related factors. Occupational sleep medicine is advancing in several areas including fatigue risk management, preventing drowsy driving, mitigating shift-work sleep disorder and jet lag, understanding and tailoring behavioral and pharmacologic interventions toward special populations (police, first responders, and military personnel), and investigating the causal chain linking stress, sleep loss, and burnout. Traditional sleep medicine focuses on diagnosis and treatment of sleep disorders, thereby improving performance, productivity, safety, health, and well-being. Complementing the clinical practice of sleep medicine,
CHAPTER 64 • Introduction 737
occupational sleep medicine is increasingly relevant not only to sustaining performance, productivity, and safety in the workplace but also to maintaining health across the span of a career spent working fatigue-producing schedules and shifts. Occupational sleep medicine clearly informs the newly emerging art and science of fatigue risk management. Fatigue risk management aims to apply the concepts and facts of basic and applied sleep science to create sleepfriendly rosters and schedules for industry. In one possible instantiation, measurement of sleep–wake history, circadian phase, and performance is done through personal, unobtrusive biomedical status monitoring, and these data are used as input to biomathematical models encapsulating sleep science and integrated into the rostering and scheduling optimization created by modern rostering and scheduling software systems. Under the aegis of occupational sleep medicine, sleep medicine physicians in academic sleep medicine programs and in clinical sleep medicine laboratories can expand their activities to include consultation to industries and occupational groups on the screening, diagnosis, and treatment of sleep disorders and the implementation of organizational fatigue risk management. REFERENCES 1. Wesensten NJ, Belenky G, Balkin TJ. Cognitive readiness in networkcentric operations. Parameters: U.S. Army War College Quarterly 2005;35(1):94-105. 2. http://en.wikipedia.org/wiki/John_Boyd_(military_strategist) 3. Boyd CR. The fighter pilot who changed the art of war. New York: Little, Brown; 2002.
Performance Deficits during Sleep Loss: Effects of Time Awake, Time of Day, and Time on Task Thomas J. Balkin Abstract
Chapter
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The deleterious effects of sleep loss on various aspects of cognitive performance have been well known for a long time, but epidemiologic findings suggest that sleep loss continues to be a common phenomenon that exacts a considerable toll on society. Over the past decade, significant progress has been made toward elucidating the physiologic basis of sleepiness and the physiologic (e.g., regional brain activity) correlates of sleepiness-induced
performance deficits. Future progress depends on an improved understanding and appreciation of the interactions between sleep loss and task-related variables such as time on task and workload, the circadian rhythm of alertness, and individual differences in resilience during sleep loss. It is anticipated that advances in these areas will culminate in the development of valid and reliable performance prediction models that will be applied widely to improve safety, health, and quality of life.
Awareness of the deleterious effects of sleep loss have grown steadily over the past decade. Awareness has been bolstered by public educational campaigns by the National Sleep Foundation, the National Sleep Disorders Center at the National Institutes of Health (NIH), and other likeminded organizations; by publication of the Institute of Medicine’s report Sleep Disorders and Sleep Deprivation: An Unmet Public Health Problem (2006)1; and by findings from epidemiologic studies linking reduced average daily sleep duration with potential health consequences including obesity, diabetes,2 and reduced longevity.3 However, the most widely appreciated and most extensively researched effects of sleep loss are its acute and profound effects on alertness and performance, with performance defined generally as goal-directed behavior requiring mental effort. Although difficult to estimate, it is likely that sleepiness-induced performance deficits cost the world economy hundreds of billions of dollars per year in accidents, direct health care costs, and lost operational efficiency and productivity. This can be inferred from the fact that significant sleepiness is experienced at least occasionally by everyone and may be experienced chronically by a considerable portion of the adult population. According to the 2004-2006 National Health Interview Survey, approximately 21% of adults in the United States typically obtain 6 or fewer hours of sleep per 24 hours4—considerably less than the 7 to 8 hours of sleep that is recommended.5 And if those with sleep disorders (e.g., sleep apnea, insomnia) are considered along with those who are chronically sleep restricted for other reasons (e.g., shift work), it is estimated that as many as 70 million Americans experience chronic sleep loss5 and therefore may experience correspondingly increased sleepiness and impaired performance on a daily basis. In this chapter, the state of the science relating sleep loss and performance is summarized, and issues pertaining to the application of this knowledge to real-world, operational environments are discussed.
THE NATURE OF SLEEPINESSINDUCED PERFORMANCE DEFICITS Cognitive performance is not solely a function of sleepiness, and it is therefore not simply a direct reflection of level of sleepiness. But level of sleepiness—as determined by duration of prior sleep, time since awakening, and phase of the circadian rhythm of alertness— does affect performance on a variety of tasks in a predictable manner. Thus, for example, average reaction time performance on the psychomotor vigilance test (PVT) increases in a dose-dependent fashion with decreasing amounts of nighttime sleep and increasing levels of sleepiness across multiple days of sleep restriction.6,7 Sleepiness-induced declines in average performance are not, however, the result of a wholesale shift in the entire distribution of reaction times, but rather reflect increased variability in the distribution of reaction times—the result of an increasing proportion of relatively long reaction times intermixed with “normal” reaction times (i.e., reaction times within the range typical for normal alertness). Based largely on this observation, it has been suggested that the increased response variability that characterizes sleep loss is most likely a manifestation of a reduced level of stability in the physiologic processes by which wake fulness is maintained—specifically, that it is caused by intermittent intrusion of sleep-onset mechanisms into wakefulness.8,9 It has been proposed that the physiologic basis of this state instability may be a toggle switch (of the sort proposed by Saper and colleagues10), in which sleeppromoting neurons within the ventral lateral preoptic nucleus and monoaminergic wake-promoting neurons inhibit each other, resulting in stable sleep when the former neurons are more active, stable wakefulness when the latter are more active, and relative instability as the activity levels and influence of these two cell groups on the toggle switch approaches parity.11
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FUNCTIONAL BRAIN IMAGING STUDIES OF SLEEPINESS AND PERFORMANCE Functional brain imaging techniques have shown that sleep loss results in reduced brain activation, with greatest reductions manifest in prefrontal cortex, inferior parietal and superior temporal cortex, and thalamus.12 Based on such findings, it has proved possible to predict specific sleep loss–induced deficits in various aspects of performance. For example, noting that sleep deprivation results in reduced metabolic activity in specific regions of the prefrontal cortex known to mediate specific aspects of cognitive performance and perception, it has been predicted and confirmed that sleep deprivation causes deficits in executive mental functions such as decision making,13 moral judgment,14 and humor appreciation15 and that it results in reduced ability to differentiate odors.16 Although such studies clearly suggest a relationship between the absolute level of activity in specific brain regions and cognitive performance, the relationship between regional brain activation and performance is not always straightforward. In an elegant series of studies, Drummond and coworkers17-19 demonstrated not only that sleepiness-related performance deficits are associated with region-specific deficits in activation but also that the ability to maintain baseline-level performance on specific tasks during sleep deprivation was associated with relative activation of cortical regions that were not significantly activated during performance of the same task in the well-rested state. Subjects whose functional magnetic resonance imaging (fMRI) images revealed such new regional relative activations during sleep deprivation were better able to maintain task performance than were those whose fMRI images failed to reveal similar new activations. This suggests that individual differences in ability to recruit resources from other brain regions might underlie task-specific individual differences in resilience during sleep loss. The relationship between sleepiness and performance is perhaps best illustrated during the first several minutes after awakening, when sleep inertia effects are manifest. The term sleep inertia refers to the immediate postawakening period that is characterized by profound sleepiness and
performance deficits, which rapidly dissipate over 20 minutes or more of continuous wakefulness.20 Sleep inertia constitutes a unique and somewhat paradoxical state because it is a period of profound sleepiness and performance deficits without a correspondingly profound sleep debt. That is, actual sleep debt is at a local minimum immediately upon awakening (by virtue of the recuperation obtained during the preceding sleep period) but it takes 20 minutes or more of continuous wakefulness before the normal correspondence between sleep debt and alertness level is reestablished. Therefore, functional brain imaging studies during the immediate postawakening period characterize a sleep-sated (but sleepy) brain that is ascending toward alertness, rather than a sleep-deficient, sleepy brain struggling to remain awake (as during sleep-deprivation studies).21 A comparison of the regional cerebral blood flow pattern during the sleep inertia period versus previous studies of sleep deprivation and non–rapid eye movement (NREM) sleep reveal that sleep-deprived wakefulness is characterized by global reductions in brain activity (relative to normal, well-rested wakefulness), with the greatest reductions evident in heteromodal (primarily prefrontal) association cortices and thalamus.12 A similar pattern is evident when comparing slow-wave sleep to normal wakefulness: global deactivation (albeit of a greater magnitude than during sleep-deprived wakefulness), with the greatest deactivations evident in anterior (prefrontal) cortical regions and centrencephalic regions, including the thalamus.22 In contrast, the immediate postawakening (sleep inertia) period is characterized by bidirectional changes in regional cerebral blood flow, with waxing activity in anterior cortical regions and waning activity in centrencephalic regions across the first 5 to 20 minutes of wakefulness (Fig. 65-1).23 Because deactivated prefrontal cortex is the only common finding during these three states (sleep-deprived wakefulness, sleep, and sleep inertia), it can be surmised that sleepiness and its attendant performance deficits are ultimately and specifically a function of activity in the prefrontal cortices. Changes in the pattern of interregional functional connectivity across the first 20 minutes of wakefulness (i.e., during the time period when sleepiness and performance
+4.0 +1.0 −1.0 −4.0 z = −19
z = −7
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z = +32
Figure 65-1 Brain map depicting changes in regional cerebral blood flow (rCBF) between 5 and 20 minutes after awakening from stage 2 sleep. Values are z-scores representing the significance level of changes in proportionally normalized rCBF in each voxel when scans acquired at 20 minutes versus 5 minutes (baseline) are contrasted. Positive scores reflect increases in relative blood flow from 5 to 20 minutes after awakening; negative scores reflect concomitant relative decreases during this period. The range of scores is coded in the color table, with red designating z-scores greater than +4.0 and purple designating z-scores of less than −4.0. (Brain map from Balkin, TJ, Braun, AR, Wesensten, NJ, et al. The process of awakening: a PET study of regional brain activity patterns mediating the reestablishment of alertness and consciousness. Brain 2002;125:2308-2319.)
740 PART II / Section 9 • Occupational Sleep Medicine
deficits are known to dissipate most rapidly) confirm a primary role of the prefrontal cortices, revealing that some of the most robust changes in functional connectivity patterns across the first 20 minutes of wakefulness center on this region: A negative correlation between activity in the prefrontal cortex and reticular formation at 5 minutes after awakening dissipates by 20 minutes after awakening. Conversely, activity in the caudate and prefrontal cortex is not significantly correlated at 5 minutes after awakening, but it is positively and robustly correlated at 20 minutes after awakening.23 In contrast, a positive, relatively stable correlation of activity in the anterior cingulate cortex and prefrontal cortex across the 20 minute postawakening period suggests that this functional relationship probably does not mediate alertness and performance but might instead be part of the pattern of functional connectivity that underlies conscious wakefulness itself, which is also, of course, a basic requirement for goal-directed performance. The bidirectional results found in this study suggest that alertness—and by extension, performance on tasks that are affected by fluctuations in alertness—are ultimately and specifically a function of the activity and interregional connectivity patterns of the heteromodal association cortices, including most prominently the prefrontal cortices.
INFLUENCE OF THE CIRCADIAN RHYTHM OF ALERTNESS ON PERFORMANCE The circadian rhythm of alertness has been well described (for review, see reference 24 and see Section 5). Briefly, output from the suprachiasmatic nucleus (SCN) of the hypothalamus drives a variety of body functions on an approximately 24-hour rhythm. Core body temperature follows a 24-hour rhythm, rising throughout the day to peak in the evening and subsequently declining to a trough in the morning; cognitive performance parallels fluctuations in temperature.25 In the absence of sleep, subjective26 and objective27 sleepiness (as well as performance) continue to track this rhythm. The three-process model of alertness28 provides a convenient framework for conceptualizing the main factors that interactively mediate sleepiness and performance. In this model, which is an extension of the two-process model,29 Process S is an exponential function representing the sleep homeostat, a reflection of the underlying physiologically based need for sleep.30 Process S thus increases across the waking period, reflecting an increasing physiologic need for sleep. Process W reflects the temporary performance deficits and sleepiness that characterize the first approximately 20 minutes of wakefulness.20 Because sleep need immediately upon awakening must be at a local minimum (i.e., Process S must be at a local minimum) it is likely that Process W reflects the residual (and waning during wakefulness) influence of sleep maintenance mechanisms.21 Process C is the circadian factor, a sinusoidal function with a peak (acrophase) in the evening hours and a nadir in the early morning hours. From an evolutionary standpoint, Process C can be thought of as an adaptively useful physiologic opponent to Process S, consolidating
wakefulness during daytime hours and sleep during nighttime hours in diurnal animals such as humans.31 Functionally, sleepiness and its attendant performance deficits can be conceptualized as the product of the combined effects of Processes S, C, and (during the immediate postawakening period) W. The desynchrony between circadian phase and work–sleep schedule associated with shift work can result in reduced performance and alertness during the night shift and cumulative sleep loss resulting from inadequate daytime sleep. Regardless of total amount of sleep lost, human performance declines in the early morning hours when the circadian rhythm of alertness is approaching or at its nadir; in a complementary manner, daytime sleep is impaired during the ascending phase of the circadian rhythm of alertness, and sleep at this time of the day is typically shorter, more fragmented, and therefore less recuperative. Under normal (nonlaboratory) conditions, the circadian rhythm of alertness is primarily influenced by the timing of daily light exposure.32
TIME ON TASK (FATIGUE) EFFECTS Wilkinson33,34 showed that long duration (i.e., 30 to 40 minutes), boring tasks are especially sensitive to sleep deprivation, and performance decrements are less likely to occur during the first 5 to 10 minutes of task performance than later in the testing period. It has been hypothesized that decreased performance on tasks such as these are the result of the unmasking of latent sleepiness: The stimulation provided by performing the task at hand is so low that it fails to provide an effective counterbalance to the expression of physiologic sleepiness (i.e., sleepiness determined by sleep debt).35 In this scenario, performance deficits do not necessarily reflect a reduced underlying capacity to perform the task at hand, but rather they reflect a sort of reprioritization under which sleepiness (to an extent primarily determined by extant sleep debt and circadian phase) is allowed to emerge, and the propensity to initiate sleep essentially competes with the desire to continue performing the task at hand. In contrast, time-on-task effects (here referred to as fatigue effects) are conceptualized as arising from cognitive work-related depletion of cognitive resources over time— resources that, unlike those mediating sleepiness, only require rest (time off task) to effect recuperation. But how do we know that this conceptualization is correct, that fatigue effects and sleepiness are not physiologically equivalent? That is, how do we know that increased cognitive workload does not actually increase subsequent sleepiness, or that increased sleepiness does not represent depletion of exactly the same pool of cognitive resources that are depleted by extended performance of cognitively challenging tasks? The answer is: Because fatigue effects are reversed by rest (time off task), even during sleep deprivation. Figure 65-2 depicts minute-by-minute mean response speed on the 10-minute PVT, which was administered every 2 hours across 40 hours of continuous wakefulness.36 It can be seen that time-on-task effects were evident before significant sleep loss—that is, from 8:00 am to midnight on day 1—and that sleep deprivation exacerbates the time-on-task effect. For example, comparison of the performance change
CHAPTER 65 • Performance Deficits during Sleep Loss: 741
PVT SPEED 10-MIN BLOCKS ACROSS 40 HOURS OF TOTAL SLEEP DEPRIVATION 3.5
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across the 10-minute PVT at 8:00 am on day 1 versus 8:00 am on day 2 suggests differences not only at minute 1 of the PVT (which, because of the relatively short time on task at this point, probably reflects a relatively pure effect of sleep loss) but also differences in the rate at which performance declined across the 10-minute test. Also noteworthy is the extent to which performance on the PVT recovered from minute 10 on one trial to minute 1 on the next, even though there was no intervening sleep. This was evident even when the apparent circadian trend suggested increasing sleepiness between trials. Thus, mean speed on the PVT at minute 1 on the 6 am test was greater than mean speed at minute 10 on the 4 am test, even though overall performance declined across this time period. Therefore, two opposing trends are clearly evident in the performance data during the early morning hours: First, there is an overall decline in PVT performance, most likely reflecting the combined effects of approaching the nadir of the circadian rhythm of alertness and the continuing accrual of sleep debt. But riding over this trend is also a clear fatigue effect: Average performance declines across each 10-minute PVT session, followed by apparent recovery during the intervening time-off-task rest period, revealing a restorative effect of rest even as sleep debt continues to accrue. If fatigue and sleepiness were the same phenomenon, one would not expect to see this interaction. The results depicted in Figure 65-2 clearly show that sleepiness interacts with time on task and that considerable (albeit short-lived) recovery of PVT performance during sleep deprivation can be realized with simple rest (wakeful-
ness without sleep). But these results still leave open the possibility that such fatigue effects are motivational; for example, the decrements across each 10-minute PVT represent growing within-session boredom with the task, and the recovery that is evident from the end of one PVT session to the beginning of the next PVT session merely reflects some temporary dissipation of that boredom. However, another line of evidence suggests that withinsession decrements are probably not wholly due to motivational changes or mounting boredom with the task at hand. That fatigue effects are, in fact, due to depletion of a physiologically based cognitive resource (rather than merely reflecting an increasing motivational disinclination to perform a particular task over time) is suggested by findings that performance of subsequent unrelated tasks are also negatively affected by having previously performed a fatiguing task. Such findings suggest that performance of one task reduces the available pool of general cognitive resources available for performing a second task. For example, a crossover study design was used to compare the effects of a fatiguing simulated driving task (during which performance on an additional, secondary visual detection task was required) versus a control driving task that was identical except that there was no secondary task. Toward the end of each simulated drive, a third task that involves detecting visual stimuli in the periphery of the visual display was introduced. It was found that inclusion of the secondary task resulted in poorer performance on the third task, suggesting that the subjects’ previous exposure to the secondary task had, in fact, been more fatiguing or more depleting of cognitive resources.
742 PART II / Section 9 • Occupational Sleep Medicine
Similarly, in a study comparing the effects of relatively demanding versus nondemanding mental workdays, it was found that performance on a subsequent (postworkday) memory-search task was relatively impaired, with longer reaction times and more errors, following the more demanding workdays.37 Thus, as shown with the previously mentioned driving study,38 greater fatigue was inferred from the finding that relatively increased prior cognitive load subsequently resulted in performance deficits. From a practical standpoint, the extent to which sleepiness and fatigue interact to produce performance deficits is an important issue, because sleep loss typically results from an externally imposed (occupational) requirement to remain awake for an extended period, performing goaldirected or work-related tasks. Thus, studies in which the effects of sleep loss on the performance of tasks are administered nearly continuously most closely replicate realworld operational conditions. In one such study,39 subjects performed cognitively demanding work on a nearly continuous basis across 54 hours of wakefulness, with occasional administration of subjective rating scales (including mood, fatigue, and sleepiness scales) and with short breaks for meals and personal hygiene. The study design was quasi-experimental40 because it included no comparison condition in which work was performed at a slower pace. Nevertheless, by assessing the relative rates of performance decline from this study with those of previously published sleep-deprivation studies in which similar performance measures had been administered, analyses suggested that sleep deprivation–induced decrements were exacerbated by sustained cognitive work, an effect that was hypothesized to be due to differential workload-dependent depletion rates of unspecified cognitive resources. Thus, it can be concluded that fatigue is manifested by deficits in subjective capacity and corresponding decrements in overt performance. There is also a physiologic basis to fatigue effects, reflecting depletion of unspecified physiologic resources during performance of cognitive tasks; and fatigue varies as a function of workload (the product of time on task and task complexity), and, in sharp contrast to sleepiness, is reversed by simple rest, defined as time off task. Both fatigue and sleepiness result in performance deficits, and performance deficits are synergistically exacerbated when conditions that produce both are present.
THE NONSPECIFICITY OF SLEEP LOSS–INDUCED PERFORMANCE DEFICITS The implication from a plethora of studies conducted over the years—and especially from more recent studies—is that a wide array of cognitive abilities are degraded by sleep loss. In fact, the array of cognitive abilities apparently decremented by sleep loss is so extensive that it is reasonable to posit that sleep loss exerts a nonspecific effect on cognitive performance—in other words, that it impairs some essential capacity that is basic to cognitive performance in general. From the preceding sections, it is clear that sleep loss might be expected to result in performance deficits for any task that is mediated by prefrontal cortices; that is, essentially all cognitive tasks.
Although it would be interesting from a scientific standpoint, it is not logically possible to compare and contrast the extent to which any two cognitive abilities (e.g., attention and memory) are differentially affected by sleep loss. This is because one cannot quantify the extent to which a particular performance measure actually reflects a particular hypothetical construct. For example, although it is reasonable to operationally define short-term memory as performance on a visual matching to sample test in one study, and as performance on a word list recall test in another study, it would not be logical to assert that performance on one test is a better or more accurate measure of short-term memory than performance on the other. This is because short-term memory (like attention, problem solving, and other mental abilities) is a hypothetical construct, a concept that is not directly observable or measureable. Furthermore, it has been shown that the sensitivity of a particular measure to sleep loss is not only a function of the cognitive ability (hypothetical construct) it represents; it is also a function of the test parameters used. For example, manipulation of session duration, amount of feedback provided during tests, and other measures can affect the sensitivity of a performance measure to the effects of sleep loss.33,34 For these reasons, metrics like effect size are useful for comparing the sensitivity of specific tests administered with a specific set of test parameters under specific sleeploss conditions, but they cannot be used as a basis for comparing the extent to which sleep loss more generally affects one cognitive ability versus another. At best, cognitive tests administered during sleep loss can be considered probes of general brain state,41 rather than absolute scales that reflect the extent to which sleep loss affects specific cognitive abilities.42 Thus, as implied earlier, any task performance that is mediated by prefrontal cortex might be expected to be decremented by sleep loss, but the extent to which a specific performance decrement is manifested will be a function of the specific parameters of the test used to measure performance.
PERFORMANCE PREDICTION MODELING The ultimate utility of efforts to specify and quantify the relationship between sleepiness and performance will be realized with the development of mathematical performance prediction models.42 It is anticipated that such models will someday be widely used to predict the timing and severity of performance deficits in a variety of environments to optimize work–rest schedules and to optimize the dosing and timing of countermeasure application.43 (See Chapter 73 for a discussion of countermeasures.) In addition to the conceptually and practically difficult problem of determining just how performance should be operationally defined in such models (i.e., determining the relationship between such operational definitions and actual, real-world operational performance), the utility of models predicting the effects of sleep on performance will also depend upon the extent to which model parameters can be tweaked to predict the performance capacity of each individual operator (rather than predicting mean group
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performance). This will mean, for example, that model parameters will need to be determined to account for traitlike individual differences in sensitivity or resilience to the effects of sleep loss,44 individual differences in sensitivity to fatigue countermeasures like caffeine,45 and both the recent and long-term sleep–wake history of the individual operator whose performance capacity is being predicted. Thus, model development will be facilitated by improved understanding and quantification of the processes by which sleep loss affects performance and subsequent sleep restores performance capacity and by advances in mathematical approaches to modeling itself (e.g., improvements in techniques to individualize model parameters).
CONCLUSION Realization of the goal of developing valid and reliable individualized performance prediction models will be facilitated by advances in understanding the physiologic underpinnings of sleepiness and its effects on performance capacity, understanding and quantifying the interactions between sleepiness and other performance-decrementing factors like time on task, understanding the basis of individual differences in resilience during sleep loss, and developing improved mathematical modeling techniques.46,47 It is likely that advancement will occur in a stepwise, iterative fashion as mathematical models that constrain relevant physiologic models (and vice versa) are devised and tested experimentally. Ultimately, the development and application of valid and reliable performance prediction models will be a boon to society, resulting in improved individual and public health, improved workplace safety and efficiency (and thus productivity and profitability), and an enhanced quality of life for all. ❖ Clinical Pearl In the operational environment, sleepiness-related performance deficits are typically the result of interactions involving multiple factors such as recent and long-term sleep–wake history, the circadian rhythm of alertness, effects of time on task, cognitive workload, and individual differences in resilience and sensitivity to sleep loss. Such factors should be taken into consideration when devising operational work–rest schedules and when assessing individual patients who complain of deficits in alertness and performance.
Disclaimer This material has been reviewed by the Walter Reed Army Institute of Research, and there is no objection to its presentation or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the position of the U.S. Department of the Army or the U.S. Department of Defense. REFERENCES 1. Institute of Medicine of the National Academies. Sleep disorders and sleep deprivation: an unmet public health problem. Washington, DC: National Academies Press; 2006.
2. Knutson KL, Van Cauter E. Associations between sleep loss and increased risk of obesity and diabetes. Ann N Y Acad Sci 2008;1129:287-304. 3. Ferrie JE, Shipley MJ, Cappuccio FP, et al. A prospective study of change in sleep duration: associations with mortality in the Whitehall II cohort. Sleep 2007;30:1659-1666. 4. Schoenborn CA, Adams PF. Sleep duration as a correlate of smoking, alcohol use, leisure-time physical inactivity, and obesity among adults: United States, 2004-2006. Health E-Stat (May, 2008) [document on the Internet]. Available at: http://www.cdc. gov/nchs/products/pubs/pubd/hestats/sleep04-06/sleep04-06.htm. Accessed September 15, 2009. 5. National Heart, Lung, and Blood Institute. Your guide to healthy sleep. National Institutes of Health. NIH Pub No. 06-5271. Department of Health and Human Services. November 2005. 6. Belenky GL, Wesensten NJ, Thorne D, et al. Patterns of performance degradation and restoration during sleep restriction and subsequent recovery: a sleep dose-response study. J Sleep Res 2003; 12:1-12. 7. Van Dongen HP, Maislin G, Mullington JM, et al. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 2003;26(2):117-126. 8. Doran SM, Van Dongen HPA, Dinges DF. Sustained attention performance during sleep deprivation: evidence of state instability. Arch Ital Biol 2001;139:253-267. 9. Durmer JS, Dinges DF. Neurocognitive consequences of sleep deprivation. Semin Neurol 2005;25:117-129 10. Saper CB, Chou TC, Scammell TE. The sleep switch: hypothalamic control of sleep and wakefulness. Trends Neurosci 2001;24:726731. 11. Olofsen E, Van Dongen HP, Mott C, et al. Current approaches and challenges to development of an individualized sleep/performance prediction model (manuscript in preparation). 12. Thomas M, Sing H, Belenky G, et al. Neural basis of alertness and cognitive performance impairments during sleepiness. I. Effects of 24 h of sleep deprivation on waking human regional brain activity. J Sleep Res 2000;9:335-352. 13. Killgore WDS, Balkin TJ, Wesensten NJ. Impaired decision-making following 49 hours of sleep deprivation. J Sleep Res 2006;15:7-13. 14. Killgore WDS, Killgore DB, Day LM, et al. The effects of 53 hours of sleep deprivation on moral judgment. Sleep 2007;30:345-352. 15. Killgore WDS, McBride SA, Killgore DB, et al. The effects of caffeine, dextroamphetamine, and modafinil on humor appreciation during sleep deprivation. Sleep 2006;29:841-847. 16. McBride SA, Balkin TJ, Kamimori GH, et al. Olfactory decrements as a function of sleep deprivation. J Sens Stud 2006;21:456-463. 17. Drummond SP, Gillin JC, Brown GG. Increased cerebral response during a divided attention task following sleep deprivation. J Sleep Res 2001;10:85-92. 18. Drummond SP, Brown GG, Stricker JL, et al. Sleep deprivationinduced reduction in cortical functional response to serial subtraction. Neuroreport 1999;10:3745-3748. 19. Drummond SP, Brown GG, Gillin JC, et al. Altered brain response to verbal learning following sleep deprivation. Nature 2000;403: 655-657. 20. Lubin A, Hord D, Tracy M, et al. Effects of exercise, bedrest, and napping on performance during 40 hours. Psychophysiology 1976;13: 133-139. 21. Balkin TJ, Badia P. Relationship between sleep inertia and sleepiness: Cumulative effects of four nights of sleep disruption/restriction on performance following abrupt nocturnal awakenings. Biol Psychol 1988;27:245-258. 22. Braun AR, Balkin TJ, Wesenten NJ, et al. Regional cerebral blood flow throughout the sleep-wake cycle. An H215O PET study. Brain 1997;120:1173-1197. 23. Balkin TJ, Braun, AR, Wesensten, NJ, et al. The process of awakening: a PET study of regional brain activity patterns mediating the reestablishment of alertness and consciousness. Brain 2002;125: 2308-2319. 24. Fuller PM, Gooley JJ, Saper CB. Neurobiology of the sleep-wake cycle: sleep architecture, circadian regulation, and regulatory feedback. J Biol Rhythms 2006;21:482-493. 25. Wright KP Jr, Hull JT, Czeisler CA. Relationship between alertness, performance, and body temperature in humans. Am J Physiol Regul Integr Comp Physiol 2002;283:R1370-R1377.
744 PART II / Section 9 • Occupational Sleep Medicine 26. Babkoff H, Caspy T, Mikulincer M. Subjective sleepiness ratings: The effects of sleep deprivation, circadian rhythmicity and cognitive performance. Sleep 1991;14:534-539. 27. Richardson GS, Carskadon MA, Orav EJ, et al. Circadian variation of sleep tendency in elderly and young adult subjects. Sleep 1982;5:S82-S94. 28. Folkard S, Akerstedt T. Towards a model for the prediction of alertness and/or fatigue on different sleep/wake schedules. In: Oginski A, Pokorski J, Rutenfranz J, editors. Contemporary advances in shiftwork. Krakow: Medical Academy; 1987. p. 231-240. 29. Borbely AA. A two-process model of sleep regulation. Hum Neurobiol 1982;1:195-204. 30. Beersma DG. Models of human sleep regulation. Sleep Med Rev 1998;2:31-43. 31. Dijk DJ, Czeisler, CA. Paradoxical timing of the circadian rhythm of sleep propensity serves to consolidate sleep and wakefulness in humans. Neurosci Lett 1994;166:63-68. 32. Czeisler CA, Kronauer RE, Allan JS, et al. Bright light induction of strong (type 0) resetting of the human circadian pacemaker. Science 1989;244:1328-1333. 33. Wilkinson RT. Effect of sleep deprivation on performance and muscle tensions, In: Wolstenholme G, O’Connor M. editors. The nature of sleep. Boston: Little, Brown; 1960. p. 329-336. 34. Wilkinson RT. Interaction of lack of sleep with knowledge of results, repeated testing, and individual differences. J Exp Psychol 1961;62:263-271. 35. Carskadon MA, Dement WC. The multiple sleep latency test: What does it measure? Sleep 1982;5:S67-S72. 36. Wesensten NJ, Belenky G, Thorne DR, et al. Modafinil vs. caffeine: effects on fatigue during sleep deprivation. Aviat Space Environ Med 2004;75:520-525. 37. Schellekens JM, Sijtsma GJ, Vegter E, et al. Immediate and delayed after-effects of long lasting mentally demanding work. Biol Psychol 2000;53:37-56.
38. Desmond PA, Matthews G. Implications of task-induced fatigue effects for in-vehicle countermeasures to driver fatigue. Accid Anal Prev 1997;29:515-523. 39. Angus R, Heslegrave R. Effects of sleep loss on sustained cognitive performance during a command and control simulation. Behav Res Methods 1985;17:55-67. 40. Campbell DT, Stanley JC. Experimental and quasi-experimental designs for research. Chicago: Rand McNally; 1963. 41. Dinges D, Kribbs N. Performing while sleepy: effects of experimentally induced sleepiness. In: Monk T, editor. Sleep, sleepiness and performance. Chichester, UK: John Wiley & Sons; 1991. p. 97-128. 42. Neri D. Preface: Fatigue and modeling workshop, June 13-14, 2002. Aviat Space Environ Med 2004;75:A1-A3. 43. Balkin TJ, Kamimori GH, Redmond DP, et al. On the importance of countermeasures in sleep and performance models. Aviat Space Environ Med 2004;75:A155-A157. 44. Van Dongen HP, Baynard MD, Maislin G, et al. Systematic interindividual differences in neurobehavioral impairment from sleep loss: evidence of trait-like differential vulnerability. Sleep 2004;27: 423-433. 45. Balkin TJ, Bliese PD, Belenky G, et al. Comparative utility of instruments for monitoring sleepiness-related performance decrements in the operational environment. J Sleep Res 2004;13:219-227. 46. Van Dongen HP, Mott CG, Huang JK, et al. Optimization of biomathematical model predictions for cognitive performance impairment in individuals: accounting for unknown traits and uncertain states in homeostatic and circadian processes. Sleep 2007;30: 1129-1143. 47. Rajaraman S, Gribok AV, Wesensten NJ, Balkin TJ, Reifman J. An improved methodology for individualized performance prediction of sleep-deprived individuals with the two-process model. Sleep 2009;32:1377-1392.
Fatigue and Performance Modeling Steven R. Hursh and Hans P.A. Van Dongen Abstract Fatigue leads to lapses in attention, slowed reactions, and impaired reasoning and decision making and has been shown to contribute to accidents, incidents, and errors in a host of industrial and military settings. Several research initiatives have been directed toward developing biomathematical models of fatigue that could be used to predict performance changes in the laboratory and in the workplace. Validated models could be incorporated into scheduling tools to obviate fatigue in operational settings. Most of the available models of fatigue and performance are based on three basic com-
Most physiology-based biomathematical models of fatigue and performance have three general components commonly accepted as critical to the modulation of sleep and performance.1-6 A circadian process influences both performance and sleep regulation. This process is presumed to mirror physiologic activation apparent in measuring body core temperature and various hormones, such as melatonin. Performance increases with circadian activation, and propensity to sleep decreases. A second process tracks the occurrence of sleep and maintains a homeostatic balance of performance capacity that is replenished while asleep and depleted while awake. This sleep–wake homeostatic process depends on hours of sleep, hours of wakefulness, and current sleep debt from prior days. Performance decreases with homeostatic depletion, and propensity to sleep increases. A third process causes a temporary degradation in performance immediately after awakening, a process called sleep inertia, which depends on depth of sleep at the time of awakening and dissipates with time since awakening on a time scale of minutes to a few hours. Performance depends on the combined action (summation) of these three underlying processes: the circadian process, the balance of the sleep–wake homeostatic process, and sleep inertia. Recent advances have refined the mathematical representations of these three components, have added interaction terms between the components, and have added factors to adjust for chronic sleep restriction, dynamic variations in circadian phase including the influence of light exposure, and methods to estimate patterns of sleep under specific work schedules.2,7-11
COMPONENTS OF A FATIGUE MODEL To illustrate the modeling approach shared in general form by a range of three-process models,2,4-6 the Sleep, Activity, Fatigue, and Task Effectiveness (SAFTE) model
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ponents: circadian variations in alertness and sleep propensity, homeostatic sleep–wake regulation, and sleep inertia. These processes vary over time as a function of sleep–wake patterns, and they combine to produce changes in subjective alertness and cognitive performance capacity. Present-day models have been shown to be useful predictors of average performance of groups under variations in sleep opportunities or work schedules, and recent advances provide methods to further refine these biomathematical models to enhance accuracy of prediction for individuals.
will be used in this chapter. The components of this model are diagrammed in Figure 66-1. Circadian Oscillators Performance while awake and the drive to sleep are both controlled, in part, by a circadian process.4,12,13 Performance and alertness reach a peak in the early evening, about 7 pm, and fall to a minimum at about 4 am for a person entrained to a sleep period of 11 pm to 7 am. There is a secondary peak in the morning at about 10 am, and a secondary minimum (dip) in the early afternoon at about 2 pm. This is shown in Figure 66-2, which displays alertness ratings from shift workers working around the clock.14 Negatively correlated with this alertness pattern is a tendency to fall asleep that reaches a peak at about the same time performance and alertness reach a trough. The existence of both a major and a minor peak in performance with corresponding troughs between them is often modeled as the result of two linked harmonic oscillations (cosine functions), one with a period of 24 hours and the other with a period of 12 hours. This results in a combined function that resembles the daily variation in alertness and in body temperature (see Fig. 66-2).14 Other models use a limit cycle or Van der Pol oscillator that yields a function of similar form.15 Most fatigue models assume that the same underlying arousal oscillator drives both variations in predicted cognitive function and sleep propensity. Differences between the temperature profile, a purely circadian marker, and the alertness function in Figure 66-2 reflect the fact that alertness and performance are affected by both the circadian process and the sleep–wake homeostatic process, discussed later.1 The amplitude of the circadian process may be dependent on the level of sleep debt modeled by the sleep–wake homeostatic process.16,17 The phase (timing) of the circadian process is driven largely by environmental factors, 745
746 PART II / Section 9 • Occupational Sleep Medicine
Sleep regulation
level.8,24 The achievement of an equilibrium state at some level below the fully rested level implies a feedbackmodulated control system. Modeling this phenomenon has led to much new activity in model development.2,8,11,27,28 Beneficial sleep accumulation does not start immediately upon retiring to sleep. There is a minimal delay required to achieve a restful sleep state. This factor accounts for the penalty during recuperation (see Fig. 66-1) that is caused by sleep in an environment that leads to frequent interruptions (sleep fragmentation).
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such as the timing of sleep and (sun)light exposure,9,18 but it also has an individual trait component expressed as morningness and eveningness.19,20 Sleep–Wake Homeostatic Regulation The control of sleep and its influence on cognitive capacity is usually modeled as a homeostatic process.13,21-23 One way to conceptualize this process is through a sleep reservoir (see Fig. 66-1). A fully rested person has a certain performance capacity represented by the reservoir capacity. While awake, units of this reservoir are depleted according to a performance use function. While asleep, units of capacity are added to replenish the reservoir and restore the capacity to perform and be alert. The rate of accumulation for each minute of sleep is driven by two factors: circadian variation and the current sleep deficit, which is the shortage in the current level of the reservoir. Because the rate of accumulation to the reservoir is in part regulated by feedback concerning the current level of the reservoir, the process is homeostatic. Laboratory studies have revealed that chronic sleep restriction leads to cumulative alertness and performance deficits.24-26 However, when less than adequate sleep is possible, performance does not decline to floor levels but rather declines to a suboptimal plateau or equilibrium
Sleep Inertia A third factor diagrammed in Figure 66-1 is the temporary disturbance in performance that often occurs immediately following awakening, called sleep inertia.22,29 It is typically modeled as an exponentially decreasing performance deficit.2,30,31 The duration of this phenomenon is approximately between 30 minutes and 2 hours depending on the depth of sleep at the time of awakening and possibly other independent factors.32 Sleep inertia is discussed briefly in chapter 38. Due to its relatively short duration it is not always relevant in operational contexts, and in some biomathematical fatigue models it is not included.8,33,10
MODULATION OF PERFORMANCE Performance and alertness are modeled as the combined effect (typically calculated as the sum) of the mathematical functions for the circadian oscillator, the sleep–wake homeostatic reservoir, and sleep inertia immediately following awakening. The sum of the homeostatic process with the circadian process produces a performance function with two nadirs, one in the late night and early morning and a smaller one in the early afternoon. The two process functions are shown in the top panel of Figure 66-3. During the first part of a waking period, the circadian process increases (growing activation) and the homeostatic process decreases (reservoir depletion). When summed, the changes are roughly offsetting, leading to fairly constant daytime performance with a minor dip in the afternoon when the circadian process has a plateau. After the evening peak in the circadian process around 7 pm, both the circadian process and homeostatic process are declining and the combination leads to a precipitous loss of alertness and performance up to the time of (spontaneous) sleep onset. During sleep, the circadian process decreases (declining activation) and the homeostatic process increases (restoration of reservoir level). After the early morning nadir in the circadian process, both the circadian and homeostatic processes are rising, up to the time of spontaneous awakening in the morning.1 Combined (summated), the two processes produce the performance profile depicted in the bottom panel of Figure 66-3. RECUPERATION DURING SLEEP During sleep, the sleep–wake homeostatic reservoir is replenished. The rate by which the reservoir is filled depends on the prior sleep debt as reflected in the current level of the reservoir. A large reservoir deficit leads to an increased rate of replenishment; a small deficit leads to a reduced rate of replenishment. The rate of replenishment
CHAPTER 66 • Fatigue and Performance Modeling 747
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Figure 66-3 The circadian and sleep–wake homeostatic processes affecting performance (cognitive effectiveness). Graphs based on SAFTE model simulations of a schedule of 16 hours of wake and 8 hours of sleep, with sleep starting at 11 pm. Performance predictions during sleep are nominal, because they cannot actually be observed during the sleep state.
also appears to be modulated by the circadian variation in sleep propensity34 and may follow the circadian pattern of sleep propensity35,36 (the inverse of the circadian pattern of activation in the top panel of Fig. 66-3). The net effect is a more-or-less steady homeostatic reservoir accumulation through a normal night (see top panel of Fig. 66-3), which is in line with studies that have documented an approximately linear relationship between sleep duration and performance recuperation.25,37 The homeostatic regulation of sleep38 leads to the existence of equilibrium states under conditions of chronic sleep restriction.8 If a subject is scheduled to take less than an optimal amount of sleep each night (less than the nominal requirement of approximately 8 hours), for example, 4 hours per day, the reservoir initially loses more units during the waking period than are made up during the sleep period. This results in a sleep debt at the end of the sleep period that accumulates over days.24,25 However, since the rate of accumulation during sleep increases with sleep debt, eventually, the rate of accumulation increases so that 4 hours of sleep makes up for 20 hours of wakeful-
ness. At this point, the reservoir reaches an equilibrium state over days and no further debt is accumulated, although the initial deficit persists as long as the person remains on this schedule. The sleep–wake homeostatic process is not infinitely elastic; there appears to be a limit to the rate of accumulation. For example, in the SAFTE model, any schedule that provides less than about 4 hours of sleep per day will not reach an equilibrium state and performance capacity will gradually deplete entirely. Physiologic model analyses have provided further evidence that there is such a bifurcation (i.e., qualitative change in behavior) for the homeostatic process when sleep is reduced to less than approximately 4 hours (for the average person).8 Laboratory studies of chronic sleep restriction have revealed cumulative changes in performance and slower rates of recovery than might be expected from brief periods of total sleep deprivation.24,25 These long-lasting effects of chronic sleep restriction suggest that some aspect of sleep– wake homeostasis undergoes a gradual change that is slow to recover.2,27 This phenomenon, which until recently was not captured in models of fatigue and performance,39 has prompted modelers to revise their sleep–wake homeostatic processes by adding a new, long-term process.2,8,27,28 Within the context of the SAFTE model, a gradual downregulation of the sleep reservoir capacity during chronic sleep restriction accounts for the long-term change. It has the effect of gradually reducing the contribution of sleep to the reservoir because the target capacity has been reduced. When sleep durations return to the nominal value of approximately 8 hours per day, the downregulation of the reservoir capacity is gradually reversed. The implication is that after a period of chronic sleep restriction, it takes multiple days of recovery sleep to restore performance to baseline levels.8,24 The time of day also affects the recuperative potential of a sleep period. For a person given 8 hours of sleep per day from 11 am until 7 pm, performance reaches a peak about 4 hours after awakening (9 pm), after which performance rapidly declines during the late night and early morning hours to a strong minimum at about 5 am, as illustrated in Figure 66-4, bottom panel. This pattern is substantially different from the performance pattern seen after nighttime sleep (see Fig. 66-3) and results from two factors. First, sleep propensity is diminished for sleep periods during the day, resulting in less physiologic sleep and therefore less homeostatic reservoir replenishment; that is, the reservoir level does not return to 100% (see Fig. 66-4, top panel). Second, circadian activation reaches its minimum in the early morning hours, at the same time that the sleep–wake homeostatic reservoir is increasingly depleted. This pattern has strong implications for performance under shift schedules that require daytime sleep. It is well documented that most mistakes on the night shift occur during the early morning hours,36,40 and fatigue and performance models predict this outcome. Furthermore, the pattern illustrated in Figure 66-4 is likely to be a bestcase scenario because studies indicates that shift workers seldom achieve 8 hours of sleep during the daytime hours, as sleep propensity is insufficient to overcome environmental interference factors such as daylight and social activities and circadian modulation.41,42
748 PART II / Section 9 • Occupational Sleep Medicine CIRCADIAN AND HOMEOSTATIC COMPONENTS OF PERFORMANCE 8 hr sleep at 11 AM 120 100
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sleep opportunities, further decisions are made about when to sleep, representing sleep habits. These habits might include such factors as the preferred bedtime, the normal duration of sleep on work and rest days, the minimum duration of a nap, and any time during the day that a person normally uses for personal activities and not sleep. The sleep estimation algorithm combines these parameters with considerations of typical circadian factors modulating the timing and duration of sleep during opportunities afforded by the work schedule.11,44
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Figure 66-4 The circadian and sleep–wake homeostatic processes affecting performance (cognitive effectiveness) when 8 hours of sleep occurs during the day starting at 11 am. Graphs are based on SAFTE model simulations.
SLEEP ESTIMATION Fatigue and performance models rely on accurate knowledge or reliable estimation of sleep times and durations to predict performance correctly. Sleep timing and duration can be estimated mathematically using the two-process model of sleep regulation (see Chapter 37).43 However, this model does not take into account social and other nonbiological constraints on sleep.44 For this reason, biomathematical models applied to work schedules may make use of an alternative method for estimating potential sleep given the available sleep opportunities. One approach for estimating potential sleep involves modeling the observed likelihood of sleep, as recorded by means of diaries or actigraphy (see Chapter 147), in field studies in the operational environment at hand.45 This approach assumes that the occurrence of major sleep episodes is largely the result of a decision to sleep aided by the physiologic propensity to sleep. A sleep estimation algorithm is developed that attempts to simulate the decision processes that govern when a person would seek sleep. Sleep is assumed not to occur during work or commuting to work; these periods limit sleep opportunities. Within
ADAPTATION OF CIRCADIAN PHASE When people move to another time zone or alter work patterns so that sleep and wake occur at different times of day, the internal circadian oscillator that modulates alertness and performance shifts to this new schedule. During the period of adjustment, subjects experience performance degradation, disrupted mood, and feelings of dysphoria, collectively termed jet lag (see Chapter 71).46-49 Several fatigue models can simulate this process and automatically adjust the phase of the circadian rhythm to coincide with the activity pattern. This feature is critical for accurately predicting the effects of moving to a new time zone or changing to a new and regular work pattern, such as changing from the day shift to the night shift.42 The inputs to the fatigue model that induce a phase shift vary across models. Research suggests that a major driver of circadian phase is exposure to bright light50—especially the blue part of the spectrum51—like sunlight (see Chapter 35). There are models that take direct measurement of light exposure as input and use that to stimulate changes in circadian phase.5,52 Other models use a surrogate for sunlight measurement.2,7,11,53 In the SAFTE model, it is assumed that the probability of bright light exposure is proportional to the time spent awake during daylight hours. Hence, the model adjusts the rate of phase change based on the proportion of waking time that occurs during the daylight hours. This simplification eliminates the need to take continuous measurements of light to drive the circadian process, but it also limits the ability of the model to consider light exposure when light is deliberately manipulated as a countermeasure.54,55 The timing of the sleep period can itself also drive circadian adjustment,11,56 suggesting that the interaction between the circadian oscillator and the sleep–wake homeostatic process is fundamentally bidirectional. PREDICTING PERFORMANCE Biomathematical fatigue models simulate the dynamic interplay of circadian variations in alertness and sleep propensity, homeostatic sleep–wake regulation supporting performance capacity, and short-term sleep inertia following awakening. Specific models differ in the way these three factors are represented and combined mathematically. The predictions of fatigue models also vary with the units of the model and the specifics of the underlying functions. For example, the fundamental predictions of the SAFTE model are in terms of changes in cognitive speed, expressed as percentage of baseline performance
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CHAPTER 66 • Fatigue and Performance Modeling 749
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Figure 66-6 Fatigue model predictions for group-average (N = 12) cognitive performance during 54 hours of total sleep deprivation (beginning at 7 am), compared to actual observations59 for several cognitive measures (diamonds, circles, and triangles) and mean cognitive performance (squares) expressed relative to baseline. Model predictions were made with the SAFTE model (solid line) with a reservoir depletion rate of 1.1% per hour.2 ♦ serial reaction time; + decoding problem performance; ж encoding problem performance; auditory vigilance; logical reasoning.
when well rested. This measure corresponds to speed of response on a psychomotor vigilance test (PVT)57 computed as percent change in speed from the best performance of a fully rested person during a normal day. Studies that have included other cognitive tests along with the PVT have shown them to be highly correlated, with the PVT showing the greatest sensitivity to sleep deprivation.58 When predicting group averages, translation functions can be used to calculate other performance metrics such as lapse likelihood, reaction time, and mean cognitive throughput on other cognitive tests, such as serial addsubtract, choice reaction time, logical reasoning, and code substitution (Fig. 66-5).24 To illustrate the potential of fatigue models to accurately predict performance under a variety of sleep–wake and work schedules, we consider two specific examples. The first example concerns performance changes observed on a variety of cognitive tasks during a period of total sleep deprivation in a laboratory.59 In Figure 66-6, these observations are compared to the predictions of a fatigue model. The model predictions conform to the means of the performance observations with 98% of the variance explained. The second example deals with chronic sleep restriction, as encountered in demanding civilian and military schedules that provide less than the optimal approximately 8 hours of sleep a day for extended periods of time. Figure 66-7 shows performance observations (daytime averages) obtained during a laboratory dose-response study involving 7 days of sleep restriction to 3 hours, 5 hours, 7 hours, or 9 hours per day, preceded by 3 baseline days and followed by 3 recovery days each with 8 hours of time for sleep per day.24 In the figure, the observations are compared to the predictions of the fatigue model, which explains 94% of the variance.
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110 95 80 65 50 B1 B2 B3 E1 E2 E3 E4 E5 E6 E7 R1 R2 R3 Day Figure 66-7 Fatigue model predictions for group-average psychomotor vigilance test (PVT) performance (averaged within each day) across 3 baseline days (B1-B3) with 8 hours for sleep; 7 experimental days (E1-E7) with daily sleep restricted to 3 hours (circles, N = 13), 5 hours (diamonds, N = 13), 7 hours (triangles, N = 14), or 9 hours (squares, N = 16); and 3 recovery days (R1-R3) with 8 hours for sleep.24 Model predictions were made with the SAFTE model (solid lines).2
FATIGUE MODELING APPLIED TO OPERATIONAL SETTINGS Most fatigue models are optimized to predict changes in cognitive performance as measured by standard laboratory tests performed under controlled laboratory conditions. It is assumed that these tests measure changes in the fundamental capacity to perform a variety of tasks that rely, more or less, on the cognitive skills of detection, discrimination, reaction time, mental processing, reasoning, and decision making. However, specific operational tasks vary in their reliance on these skills, and deficits in cognitive capacity might not produce identical reductions in the capacity to perform all operational tasks. It is reasonable to assume, however, that the changes in task performance
750 PART II / Section 9 • Occupational Sleep Medicine
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would be correlated with changes in the underlying cognitive capacity. That this analysis is not unreasonable can be demonstrated in job task simulator experiments. For example, Figure 66-8 illustrates that there is a systematic relationship between predicted performance for the PVT and driving simulator accident data from subjects given varying amounts of daily sleep for a week.60 Prediction of operational task performance could be used to design improved work schedules, alter the timing of critical tasks to coincide with periods of optimal performance, or introduce countermeasures to prevent errors and accidents. Fatigue and performance models also offer flexible, physiology-based ways to optimize safety and performance beyond what prescriptive hours-of-service regulations can provide. Currently, fatigue modeling can predict risk of impairment in a given work–rest or wake– sleep schedule; guide the effective implementation of fatigue countermeasures; function as a component of fatigue risk management systems (see Chapter 68); inform, supplement, or substitute hours-of-service policies and regulations; aid in post-hoc investigations of incidents and accidents; and function as an educational tool for understanding fatigue and its consequences.
LIMITATIONS AND ENHANCEMENTS OF FATIGUE MODELS Fatigue modeling is becoming a valuable tool for fatigue risk management (see Chapters 67 and 68). It is also an evolving science and has limitations that should be noted.39,61,62 Some limitations to consider when evaluating a fatigue model include: • Validity and accuracy of the model relative to observations in laboratory or field studies; • Domain of generalizability, or to what extent the model is applicable in sleep–wake and work scenarios beyond those used in its development; • Balance between sensitivity and specificity, namely between being too liberal or conservative in identifying
periods with increased performance impairment versus being too liberal or conservative in identifying periods with reduced performance impairment. These fatigue modeling issues, among others, were examined in the international Fatigue and Performance Modeling Workshop (June 13 to 14, 2002, in Seattle) and documented in the proceedings of that meeting.63 Since then, the various existing fatigue models have been further developed, making some of the information in the proceedings outdated, but the volume still provides valuable documentation for fatigue and performance modeling as a developing science. The accuracy of any model depends on the accuracy of the major inputs to the model. In operational settings, one of the key inputs is the pattern of sleep achieved under a work schedule. In laboratory studies, models of performance can make use of precise polysomnographic estimates of sleep. Such data are seldom available in operational settings, but a variety of other techniques can be used to estimate sleep, such as recording sleep with an actigraph (see Chapter 147), using sleep diaries, and using an algorithmic sleep estimator. Algorithmic sleep estimation can be sufficient to detect elevated accident risk64 (see Chapter 67), but the predictions will necessarily be imperfect given the errors in sleep estimation. Such estimates may be sufficient for large groups of workers where errors might cancel; they could prove problematic for persons with idiosyncratic sleep patterns. Similarly, measures of circadian rhythm are rarely available in the operational environment, and thus fatigue models must estimate the phase and amplitude of the circadian process from the timing of sleep, light exposure, or other environmental drivers of biological rhythms. Such estimates might be sufficient for large groups, but they would likely be inadequate for specific employees, who may be morning or evening types or otherwise shifted in circadian phase.19 Additional information from the employees (e.g., sleep–wake history) would be required to reduce this source of error. Another major input to any fatigue model involves the initial states. These reflect the sleep debt (reservoir level), circadian phase, and other relevant variables that provide the starting point from which predictions are made. Often the initial states are unknown and assumptions need to be made. The accuracy of these assumptions may have a large impact on the accuracy of predictions, although in threeprocess models the importance of the accuracy of initial states tends to diminish over time.65 Individual differences in responses to sleep loss and circadian timing (e.g., in shift work)66 represent a substantial source of uncertainty in fatigue models, which are developed primarily to predict group-average performance. Individual differences can be accounted for broadly by reflecting the expected distribution of performance outcomes in the model predictions, based on the individual variability of performance changes observed in laboratory studies.11 This provides insight into the range of effects to be expected under a specific sleep–wake and work schedule, but it does not provide information about where any specific person would fall in that range. Individual differences in vulnerability to sleep loss have been demonstrated to be traitlike,67 and thus predictable on a subject-specific basis. Two complementary strategies
CHAPTER 66 • Fatigue and Performance Modeling 751
exist to enhance a fatigue model for prediction at the level of individual persons. The first is to incorporate candidate predictors of vulnerability, such as morningness or eveningness,19,20 basal sleep need, or job experience, into the fatigue model equations.62 To date, no predictors have been demonstrated to explain a significant portion of the interindividual variability, but research efforts are ongoing.68 The second strategy is to tailor the parameters of the fatigue model to the person under consideration through (real-time) feedback of performance observations from the person. Thus far, one viable algorithm for this has been developed based on Bayesian statistics.69 It provides, as a bonus feature, performance predictions with confidence intervals, which indicate the statistical certainty level of the predictions. Fatigue models are designed to predict cognitive capacity either in terms of some objective measure of performance or in terms of subjective reports of alertness. Reductions in capacity will have varying impacts on the ability to perform specific tasks or elevate the risk of making an error or, more rarely, causing an accident.64 It is important to keep in mind what the nominal prediction outcome of a model is, and to what extent this may carry over to other aspects of performance or safety. Extensions of fatigue modeling for predicting operational risk are discussed in Chapter 67. The basic three-process fatigue model assumes that the magnitude of fatigue is independent of the nature of activities while awake. However, fatigue varies with the demands of the job: It increases with time on task,70 with successive duty periods in shift work,71 with the number of flight segments during an air crew duty period, and so on. Conversely, fatigue diminishes with rest breaks and days off.72,73 Other modulators of fatigue, such as pharmacologic countermeasures (e.g., caffeine), are also not covered by threeprocess fatigue models. Thus, predictions of fatigue models must be interpreted as representing the fundamental cognitive capacity of a group or person as driven by the enduring biological forces in the underlying physiologic mechanisms. How this affects performance depends just as much on the nature of the tasks and on the circumstances at hand. ❖ Clinical Pearl Fatigue from sleep loss and circadian displacement results in large and sustained changes in cognitive performance as observed in experiments and as simulated by biomathematical models. Biomathematical models of fatigue and performance can be valuable tools on multiple levels. For the individual, models demonstrate the general relationship between sleep– wake patterns and potential impact on performance and alertness, which can guide clinical, professional, and personal decision making regarding improved sleep habits and application of countermeasures to prevent performance errors. For employers, regulatory agencies, and practitioners in occupational medicine, models can guide the design of better work schedules to reduce performance errors and accidents, improve the health and well-being of employees, and advance public safety.
REFERENCES 1. Van Dongen HPA, Dinges DF. Sleep, circadian rhythms, and psychomotor vigilance. Clin Sports Med 2005;24:237-249. 2. Hursh SR, Redmond DP, Johnson ML, et al. Fatigue models for applied research in warfighting. Aviat Space Environ Med 2004;75: A44-A53. 3. Achermann P, Borbély A. Combining different models of sleep regulation. J Sleep Res 1991;1:144-147. 4. Folkard S, Åkerstedt T. A three-process model of the regulation of alertness and sleepiness. In: Ogilvie R, Broughton R, editors. Sleep, arousal and performance: problems and promises. Boston: Birkhauser; 1991. p. 11-26. 5. Jewett ME, Kronauer RE. Interactive mathematical models of subjective alertness and cognitive throughput in humans. J Biol Rhythms 1999;14:588-597. 6. Belyavin AJ, Spencer MB. Modeling performance and alertness: The QinetiQ approach. Aviat Space Environ Med 2004;75:A93A103. 7. Hursh SR, Balkin TJ, Miller JC, et al. The fatigue avoidance scheduling tool: modeling to minimize the effects of fatigue on cognitive performance. SAE Trans 2004;113:111-119. 8. McCauley P, Kalachev LV, Smith AD, et al. A new mathematical model for the homeostatic effect of sleep loss on neurobehavioral performance. J Theor Biol 2009;256:227-239. 9. St Hilaire MA, Klerman EB, Khalsa SBS Jr, et al. Addition of a nonphotic component to the light-based mathematical model of the human circadian pacemaker. J Theor Biol 2007;247:583-599. 10. Roach GD, Fletcher A, Dawson D. A model to predict work-related fatigue based on hours of work. Aviat Space Environ Med 2004; 75:A61-A69. 11. Hursh SR, Eddy DR. Fatigue modeling as a tool for managing fatigue in transportation operations. In: Transportation Development Centre. Transport Canada. Proceeding of the 2005 International Conference on Fatigue Management in Transportation Operations, Seattle (USA), September 2005, 1-19 (TP 14620E). 12. Monk T. The arousal model of time of day effects in human performance efficiency. Chronobiologia 1982;9:49-54. 13. Daan S, Beersma DGM, Borbély AA. Timing of human sleep: recovery process gated by a circadian pacemaker. Am J Physiol 1984;246:R161-R178. 14. Monk T, Embry D. A field study of circadian rhythms in actual and interpolated task performance. In: Reinberg A, Vieux N, Andlauer P, editors. Night and shift work: biological and social aspects. Oxford: Pergamon Press; 1981. p. 473-480. 15. Jewett ME, Forger DB, Kronauer RE. Revised limit cycle oscillator model of human circadian pacemaker. J Biol Rhythms 1999;14: 493-499. 16. Van Dongen HPA, Dinges DF. Investigating the interaction between the homeostatic and circadian processes of sleep-wake regulation for the prediction of waking neurobehavioural performance. J Sleep Res 2003;12:181-187. 17. De Boer T, Vansteensel MJ, Détári L, et al. Sleep states alter activity of suprachiasmatic nucleus neurons. Nat Neurosci 2003;6:10861090. 18. Halberg F, Halberg E, Barnum CP, et al. Physiological 24-hour periodicity in human beings and mice, the lighting regimen and daily routine. In: Withrow RB, editor. Photoperiodism and related phenomena in plants and animals, vol. 55. Washington, DC: American Association for the Advancement of Science; 1959. p. 803. 19. Horne JA, Östberg O. A self-assessment questionnaire to determine morningness–eveningness in human circadian rhythms. Int J Chronobiol 1976;4:97-110. 20. Kerkhof GA, Van Dongen HPA. Morning-type and evening-type individuals differ in the phase position of their endogenous circadian oscillator. Neurosci Lett 1996;218:153-156. 21. Åkerstedt T, Folkard S. Validation of the S and C components of the three-process model of alertness regulation. Sleep 1991; 19:1-6. 22. Folkard S, Åkerstedt T. Towards a model for the prediction of alertness and/or fatigue on different sleep/wake schedules. In: Oginski A, Pokorski J, Rutenfranz J, editors. Contemporary advances in shiftwork research. Kraków: Medical Academy; 1987. p. 231-240. 23. Achermann P, Borbély AA. Simulation of daytime vigilance by the additive interaction of a homeostatic and a circadian process. Biol Cybern 1994;71:115-121.
752 PART II / Section 9 • Occupational Sleep Medicine 24. Belenky G, Wesensten NJ, Thorne DR, et al. Patterns of performance degradation and restoration during sleep restriction and subsequent recovery: a sleep dose-response study. J Sleep Res 2003; 12:1-12. 25. Van Dongen HPA, Maislin G, Mullington JM, et al. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 2003;26:117-126. 26. Carskadon MA, Dement WC. Cumulative effects of sleep restriction on daytime sleepiness. Psychophysiology 1981;18:107-113. 27. Johnson ML, Belenky G, Redmond DP, et al. Modulating the homeostatic process to predict performance during chronic sleep restriction. Aviat Space Environ Med 2004;75:A141-A146. 28. Åkerstedt T, Ingre M, Kecklund G, et al. Accounting for partial sleep deprivation and cumulative sleepiness in the three-process model of alertness regulation. Chronobiol Int 2008;25:309-319. 29. Lubin A, Hord D, Tracy ML, et al. Effects of exercise, bedrest and napping on performance decrement during 40 hours. Psychophysiology 1976;13:334-339. 30. Achermann P, Werth E, Dijk DJ, et al. Time course of sleep inertia after nighttime and daytime sleep episodes. Arch Ital Biol 1995; 134:109-119. 31. Jewett ME, Wyatt JK, Ritz-De Cecco A, et al. Time course of sleep inertia dissipation in human performance and alertness. J Sleep Res 1999;8:1-8. 32. Dinges DF. Are you awake? Cognitive performance and reverie during the hypnopompic state. In: Bootzin RR, Kihlstrom JF, Schacter D, editors. Sleep and cognition. Washington, DC: American Psychological Association; 1990. p. 159-175. 33. Moore-Ede M, Heitmann A, Guttkuhn U, et al. Circadian alertness simulator for fatigue risk assessment in transportation: application to reduce frequency and severity of truck accidents. Aviat Space Environ Med 2004;75:A107-A118. 34. Dijk DJ, Czeisler CA. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci 1995;15:3526-3538. 35. Monk T. Circadian aspects of subjective sleepiness: a behavioral messenger? In: Monk T, editor. Sleep, sleepiness and performance. Chichester, UK: Wiley; 1991. p. 39-63. 36. Lavie P. The 24-hour sleep propensity function (SPF): practical and theoretical implications. In: Monk T, editor. Sleep, sleepiness and performance. Chichester, UK: Wiley; 1991. p. 65-93. 37. Mollicone DJ, Van Dongen HPA, Rogers NL, et al. Response surface mapping of neurobehavioral performance: testing the feasibility of split sleep schedules for space operations. Acta Astronaut 2008;63:833-840. 38. Borbély A, Achermann P. Concepts and models of sleep regulation: an overview. J Sleep Res 1992;1:63-79. 39. Van Dongen HPA. Comparison of mathematical model predictions to experimental data of fatigue and performance. Aviat Space Environ Med 2004;75:A15-A36. 40. Folkard S, Monk T. Shiftwork and performance. Human factors 1979;21:483-492. 41. Budnick LD, Lerman SE, Baker TL, et al. Sleep and alertness in a 12-hour rotating shift work environment. J Occup Med 1994;36: 1295-1300. 42. Monk TH. What can the chronobiologist do to help the shift worker? J Biol Rhythms 2000;15:86-94. 43. Borbély AA, Achermann P. Sleep homeostasis and models of sleep regulation. J Biol Rhythms 1999;14:557-568. 44. Kandelaars KJ, Fletcher A, Dorrian J, et al. Predicting the timing and duration of sleep in an operational setting using social factors. Chronobiol Int 2006;23:1265-1276. 45. Pollard JK. Locomotive engineer’s activity diary (Report No. DOT/ FRA/RRP-96/02). Washington, DC: US Department of Transportation; 1996. 46. Klein K, Wegmann H, Athanassenas G, et al. Air operations and circadian performance rhythms. Aviat Space Environ Med 1976;47: 221-229. 47. Graeber RC. Recent studies relative to the airlifting of military units across time zones. In: Scheving LE, Halberg F, editors. Chronobiology: principles and applications to shifts in schedules. Rockville, Md: Sijthoff & Noordhoff; 1980. p. 353-370.
48. Haus E, Halberg F. The circadian time structure. In: Scheving LE, Halberg F, editors. Chronobiology: principles and applications to shifts in schedules. Rockfield, Md: Sijthoff & Noordhoff; 1980. p. 47-94. 49. Reilly T, Waterhouse J, Edwards B. Jet lag and air travel: implications for performance. Clin Sports Med 2005;24:367-380. 50. Czeisler CA, Allan JS, Strogatz SH, et al. Bright light resets the human circadian pacemaker independent of the timing of the sleepwake cycle. Science 1986;233:667-671. 51. Brainard GC, Sliney D, Hanifin JP, et al. Sensitivity of the human circadian system to short-wavelength (420-nm) light. J Biol Rhythms 2008;23:379-386. 52. Van Dongen HPA, Robinson BM, Dinges DF. Astronaut scheduling assistant: predicting neurobehavioral impairment under altered sleep/wake conditions. Aviat Space Environ Med 2006;77:234-235. 53. Åkerstedt T, Folkard S, Portin C. Predictions from the three process model of alertness. Aviat Space Environ Med 2004;75:A75-A83. 54. Samel A, Wegmann HM. Bright light: a countermeasure for jet lag? Chronobiol Int 1997;14:173-183. 55. Boivin DB, James FO. Light treatment and circadian adaptation to shift work. Ind Health 2005;43:34-48. 56. Santhi N, Duffy JF, Horowitz TS, et al. Scheduling of sleep/darkness affects the circadian phase of night shift workers. Neurosci Lett 2005;384:316-320. 57. Dinges DF, Powell JW. Microcomputer analyses of performance on a portable, simple visual RT task during sustained operations. Behav Res Meth Instr Comp 1985;17:652-655. 58. Balkin TJ, Bliese PD, Belenky G, et al. Comparative utility of instruments for monitoring sleepiness-related performance decrements in the operational environment. J Sleep Res 2004;13:219-227. 59. Angus R, Heslegrave R. Effects of sleep loss on sustained cognitive performance during a command and control simulation. Behav Res Meth Instr Comp 1985;17:55-67. 60. Balkin T, Thorne D, Sing H, et al. Effects of sleep schedules on commercial driver performance. (Report No. DOT-MC-00-133). Washington, DC: U.S. Department of Transportation, Federal Motor Carrier Safety Administration; 2000. 61. Mallis MM, Mejdal S, Nguyen TT, et al. Summary of the key features of seven biomathematical models of human fatigue and performance. Aviat Space Environ Med 2004;75:A4-A14. 62. Dinges D. Critical research issues in development of biomathematical models of fatigue and performance. Aviat Space Environ Med 2004;75:A181-A191. 63. Neri DF. Preface: Fatigue and Performance Modeling Workshop, June 13-14, 2002. Aviat Space Environ Med 2004;75:A1-A3. 64. Hursh SR, Raslear TG, Kaye AS, et al. Validation and calibration of a fatigue assessment tool for railroad work schedules, summary report. (Report No. DOT/FRA/ORD-06/21). Washington, DC: Federal Railroad Administration; 2006. 65. Van Dongen HPA, Mott CG, Huang JK, et al. Confidence intervals for individualized performance models. Sleep 2007;30:1083. 66. Van Dongen HPA. Shift work and inter-individual differences in sleep and sleepiness. Chronobiol Int 2006;23:1139-1147. 67. Van Dongen HPA, Baynard MD, Maislin G, et al. Systematic interindividual differences in neurobehavioral impairment from sleep loss: evidence of trait-like differential vulnerability. Sleep 2004;27: 423-433. 68. Van Dongen HPA, Vitellaro KM, Dinges DF. Individual differences in adult human sleep and wakefulness: leitmotif for a research agenda. Sleep 2005;28:479-496. 69. Van Dongen HPA, Mott CG, Huang JK, et al. Optimization of biomathematical model predictions for cognitive performance impairment in individuals: accounting for unknown traits and uncertain states in homeostatic and circadian processes. Sleep 2007;30: 1129-1143. 70. Bills AG. Fatigue in mental work. Physiol Rev 1937;17:436-453. 71. Folkard S, Åkerstedt T. Trends in the risk of accidents and injuries and their implications for models of fatigue and performance. Aviat Space Environ Med 2004;75:A161-A167. 72. Folkard S, Tucker P. Shift work, safety and productivity. Occup Med 2003;53:95-101. 73. Tucker P, Lombardi D, Smith L, et al. The impact of rest breaks on temporal trends in injury risk. Chronobiol Int 2006;23:14231434.
Fatigue, Performance, Errors, and Accidents Hans P.A. Van Dongen and Steven R. Hursh Abstract Fatigue caused by extended work hours and shift work induces cognitive performance deficits and increases risk of human error, incidents, and accidents. Fatigue results from the interaction of sleep-homeostatic and circadian drives for sleepiness with time on task and cumulative duty time effects. Hours-ofservice rules typically only regulate duty hours, leaving homeostatic and circadian factors unaddressed. Human error due to fatigue is fundamentally stochastic, which has made it difficult to demonstrate the role of fatigue in specific accident cases. Self-reported, subjective sleepiness cannot be relied upon in this context, because it has a low correlation with
In large-scale correlational studies, sleepiness-inducing schedules including extended work hours and shift work have been linked to increased risk of human error, incidents, and accidents,1-5 thus leading to reduced safety and productivity.6-9 Yet, any given sleepy person does not simply by being sleepy make errors or cause accidents; and conversely, any person who is fully alert does not necessarily perform his or her tasks without errors. In investigations of specific accidents, establishing a causal relationship with sleepiness is often a tenuous endeavor, even if the presence of sleepiness—or “fatigue” as it is typically referred to in operational settings—is itself undisputed. There are two major reasons for this. First, fatigue is rarely the only reason for accidents to occur; multiple, diverse factors ranging from personnel shortages to equipment failures and safety check overrides typically combine with human error to lead to adverse outcomes. Second, human error due to fatigue is fundamentally stochastic. In this chapter, fatigue as a risk factor for errors and accidents is explored in terms of the sleep–wake-related regulation and expression of sleepiness.
SLEEP, CIRCADIAN, AND TIME-ONTASK FACTORS MODULATING RISK OF ERRORS AND ACCIDENTS Sleep homeostasis and circadian rhythmicity interact to determine sleepiness and performance capability (see Chapter 38). Sleepiness changes as a function of time awake, with longer wakefulness inducing a progressively increasing sleep drive. Sleepiness also varies as a function of time of day, with nighttime on the biological clock resulting in elevated sleep drive. As a consequence, alertness level and performance capability are reduced when working extended hours involving sleep loss and when working at night or in the early morning.10,11 Moreover, chronic sleep loss leads to cumulative degradation of performance across days to weeks.12,13 It has been documented that the circadian (time of day) variation in performance is associated with a circadian rhythm in accident rates and injuries.3,14 Much less evidence is available for a relation-
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actual performance impairment. It is posited that fatigue results in an accident when fatigue-induced, randomly occurring periods of inattentiveness coincide with high cognitive demands while the impact of human error is significant. Biomathematical models of fatigue and performance have been successfully applied to forecast the risk of accidents. Such models may thus be used to help improve performance and safety in operational settings. Clinicians should discuss the risk of errors and accidents due to fatigue with their patients and should explain that because of the stochastic nature of human error, past performance or safety does not guarantee future performance or safety.
ship of accidents and injuries with homeostatic (time awake) changes in performance. However, a relationship between homeostatic sleepiness drive and accident risk might be inferred from statistics on road crashes attributed to the driver having fallen asleep.15,16 Although definitive evidence is lacking, it would be reasonable to assume that the same interaction between homeostatic and circadian processes that increases sleepiness and decreases performance capability also increases the risk of errors and accidents. Hours-of-service regulations and policies for operational settings tend to ignore homeostatic and circadian factors and rather focus on duty time. There are good reasons for this. Dealing with homeostatic and circadian effects would require regulating how much and when people are awake, which would be nearly impossible to enforce outside work hours. In addition, even when nominal alertness levels are high, performance deteriorates as a function of time on task.17 This phenomenon extends to duty hours: Generally, the longer the work period, the more performance degrades.18 This effect is evident in the effectiveness of rest breaks as a countermeasure to performance degradation.19 Performance degradation also accumulates across consecutive work shifts,20,21 as illustrated in Figure 67-1. Thus, restricting work hours limits performance impairment and helps to reduce incidents and accidents.22 Homeostatic and circadian drives for sleep interact with the time-on-task effect, however, such that when sleepiness is increased, performance degrades faster across task duration (see Chapter 65). Sleep homeostasis and circadian rhythms likewise interact with the effect of the duration of work.20 Thus, hours-of-service regulations may be only partially effective when they ignore homeostatic and circadian factors. They can be inadequate in night and shiftwork settings, while potentially being overly restrictive during normal daytime operations. In addition, hoursof-service regulations do little to protect workers from fatigue during the commute to and from work.23-25 Although the terminology used in the literature, in policy documents, and in jurisprudence is varied and 753
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inconsistent, it is useful here to define “fatigue” as the combined influence of sleep homeostasis, circadian rhythm, and time on task on performance capability. So defined, fatigue may be seen as an index of basal risk of errors and accidents. This broadly incorporates effects of sleep disorders and other illnesses as well: Many clinical conditions cause fatigue through disruptions of sleep homeostasis or circadian rhythmicity (as discussed in several other chapters in this volume). There are additional, indirect effects of sleep loss on accident risk. Sleepiness tends to promote impulsivity and risk taking,26-28 and impairs self-monitoring of error.29,30 To what extent these effects contribute to incidents and accidents beyond the direct effects of sleep loss on performance is unknown, although risk taking and fatigue have been noted to be a deadly combination in young male drivers.31,32 A variety of other factors unrelated to sleep–wake contribute to the risk of errors and accidents in operational environments33-35 and on the road.36 These include task demands, prior training and experience, safety measures, risks inherent in the tasks at hand, and others, as discussed elsewhere.37-39
FATIGUE, PERFORMANCE IMPAIRMENT, AND WAKESTATE INSTABILITY It is not well understood why persons impaired by sleep loss, adverse circadian timing, or long duty hours appear to have poor awareness of their performance impairment and increased risk of error, and they do not take steps to avoid accidents and get out of harm’s way. Investigations of automobile drivers about whether or not individual drivers are prospectively aware of their own deficits have yielded mixed results.40-44 Laboratory sleep-deprivation studies have revealed that there are systematic disconnects between self-reported subjective sleepiness and objectively measured performance deficits. For instance, there are considerable individual differences in accident-proneness45,46 and substantial, traitlike differences in the level of
sleepiness and in the level of performance impairment people experience as a consequence of sleep deprivation.47 However, the correlation between individual differences in subjective sleepiness on the one hand, and individual differences in objective performance impairment47,48 or driving simulator accidents49 on the other hand, is low. In addition, chronic sleep restriction leads to cumulative performance deficits, but these deficits are not tracked accurately by subjective sleepiness.13 As a result, people cannot unequivocally be expected to assess their own risk level accurately.50,51 Detailed examination of moment-to-moment fluctuations in cognitive processing may yield some insight into this matter. Figure 67-2 shows reaction times on a 10-minute psychomotor vigilance test (PVT), a simple reaction time test with stimuli appearing randomly at intervals of 2 to 10 seconds. The test was administered every 2 hours during an 88-hour period of laboratorycontrolled sleep deprivation.52 In Figure 67-2, one subject’s raw data at 12, 36, and 60 hours awake (i.e., at 24-hour intervals) are displayed. At 12 hours awake, reactions times are consistently short (predominantly in the range of 200 to 250 msec), representing optimal performance capability. At 36 hours awake, some reaction times are longer, indicating occasional errors of omission (lapses of attention). In addition, there are a few false starts—these reflect errors of commission.52 At 60 hours awake there are many more errors of omission, and errors of commission are also still present. Error responses are increasingly prevalent toward the end of the 10-minute test duration, which reflects the time-on-task effect.17,52 Note, however, that normal responses continue to be mixed in with the error responses. From moment to moment, it is unpredictable whether a response will involve an error or not. This illustrates that performance impairment due to fatigue is a stochastic phenomenon. The random variability in performance impairment during sleep deprivation has been theorized to be due to wake-state instability: moment-to-moment fluctuations brought about by an “elevating homeostatic drive for sleep, resulting in rapid and uncontrolled sleep initiation, which subjects seek to resist using increasingly greater compensatory effort to perform.”52 In this view, performance lapses are caused because the brain is effectively (if not actually) falling asleep in part or in whole for a brief period52,53 during otherwise normal (albeit effortful) wakefulness. If this explanation is correct, then a sleep-deprived person might not be aware of any performance deficits because concurrently he or she is unable to perceive any errors of omission. This could provide an explanation for the discrepancy between subjective (i.e., perceived) sleepiness and actual performance deficits from sleep loss. In accordance with the time-on-task effect (or “vigilance decrement”54), performance impairment is minimal when a task is just begun, and only exposed more substantively when task duration is extended (see Fig. 67-2, middle and bottom panels). This might provide a further explanation for the discrepancy between subjective sleepiness and objective performance impairment in situations where tasks are typically brief and distinct and the time-on-task effects are limited. Such an explanation implicitly assumes that subjective awareness of sleepiness is driven by
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perception of one’s cognitive performance. Indeed, knowledge of performance level interacts with the effects of sleep deprivation,55 and subjects calibrate their self-reported sleepiness after receiving performance feedback (see Fig. 38-1). However, it should be noted that this recalibration is short-lived, and subjects quickly revert back to what appears to be a distinct, internal subjective state (see chapter 38). The PVT is a task requiring sustained attention to perform, and it is therefore sensitive to lapses of attention.54 Indeed, the effects of sleep deprivation are readily exposed on the PVT56 (after the first 1 or 2 minutes of task duration have passed), as is illustrated in Figure 67-2. Many occupationally relevant tasks ranging from systems monitoring to threat detection also require sustained attention57 and are likewise vulnerable to the adverse consequences of sleep loss.58,59 In modern operational settings with high degrees of automation, such tasks are prevalent. Automation and other technological innovations have broadly improved safety, but by shifting performance demands to sustained-attention tasks, they may have simultaneously increased the likelihood of human error.60 The paradoxical result is that serious accidents are increasingly rare, but when they do occur, their outcomes are often dramatic and costly.61
PREDICTING ACCIDENTS Because accidents are rare and ostensibly randomly occurring events, it has remained difficult to predict the risk of fatigue-induced accidents despite increasing knowledge of the processes underlying fatigue. Even when considering incidents more broadly by including near-accidents (“near-misses”62) and other performance errors, a relationship between fatigue level and accident rate is still difficult to discern and even considered by some to be controversial.63 Consideration of the stochastic nature of performance impairment due to fatigue, as discussed earlier, may shed some light on this issue. Using the PVT as an assay of performance impairment,57 the series of reaction times in a test bout may be seen as a record of task inattentiveness (sampled randomly every 2 to 10 seconds). Assuming for illustration purposes that the same pattern of cognitive function could apply during a given job task, then the observed reaction times (minus ~250 msec necessary for responding even when fully alert) would indicate the intervals of inattentiveness (lapses of attention) during the task at hand. When the demands for cognitive processing are high during such an interval of inattentiveness, human error would occur. And if the impact of human error at that specific time is high, then an accident could take place.
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For example, if the task involves driving a car, and an interval of inattentiveness coincides with the approach to an intersection with a stop sign, then the detection and processing of the stop sign would fail and the intersection would be crossed without braking: human error. If at the same time another car enters the intersection as well, a collision could ensue: an accident. Yet, if no other car had been nearby, or of there had been no intersection, or if the interval of inattentiveness had occurred a little earlier or later, then no accident would have occurred. In this view of the relationship between fatigue and accidents, illustrated in Figure 67-3, it is necessary for a period of inattentiveness, high cognitive demands, and significant impact of error to all line up temporally in order for fatigue-induced impairment to actually result in an accident. Indeed, the same circumstances—same level of fatigue, same task demands, and same impact of error—can happen many times without noticeable consequences, until one day, due to a small difference in the timing of attentional lapses, suddenly a major accident occurs. Such appears to have been the case with the crash of Comair flight 5191 at the Blue Grass Airport in Lexington, Kentucky, in the early morning of August 27, 2006. The pilots as well as the air traffic controller failed to notice that the plane, a commercial jet requiring a long runway,
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Figure 67-3 Schematic of the (speculative) mechanism by which fatigue contributes to accidents. Top, Stochastically occurring intervals of inattentiveness across a 10-minute span of task performance taking place at 60 hours of total sleep deprivation. Longer bars represent slowed responses indicating attentional lapses (taken from Figure 67-2). Middle, Hypothetical pattern of changing cognitive demands across the duration of the task. Bottom, Hypothetical level of impact a human error would have over the course of the task. In this view of how fatigue contributes to accident causation, intervals of inattention when cognitive task demands are high lead to human error, which in turn, if the impact of error is considerable, results in an accident. Thus, for fatigue to actually lead to an accident, attentional lapses must line up temporally with high cognitive processing demands and high impact of human error—in this case at the dotted line.
was erroneously positioned on a general aviation runway that was much too short for takeoff. The plane crashed about half a mile past the end of the runway, killing 49 people. Both pilots as well as the air traffic controller were fatigued due to extended work hours and the early time of day of the scheduled flight. Runway choice at the airport required considerable cognitive processing because the taxiway signage was poor at the time; the appearance of the runways is similar both from the holding point and from the beginning of the take-off roll; the entry points from the taxiway to the two runways are close together; and the taxi to the holding point is short, leaving little time for completing checklists and for orientation and decision making. Furthermore, the impact of human error was clearly substantial. These critical factors coincided and precipitated the tragic event. Yet, the same circumstances were present at the Blue Grass Airport almost every morning, without any other crash. What exactly made the difference on the fateful morning of August 27, 2006, is impossible to ascertain. Inferring from the conceptual framework sketched out in Figure 67-3, though, it would seem that by chance the pilots’ and air traffic controller’s fatigue-induced intervals of inattentiveness overlapped with the critical periods of cognitive processing that should have flagged the incorrect choice of runway and prevented the accident.
MODELING SLEEP–WAKE–WORK AND ACCIDENT RISK Figure 67-3 may serve as a heuristic for understanding the complex relationship between fatigue and accidents. It illustrates that accident risk, while fundamentally stochastic, is proportional to both total time of inattentiveness (cumulative lapse time) and density of critical task events (i.e., prior risk or exposure64). Given information about the latter, it may be possible to predict accident risk by predicting cumulative lapse time. There is a strong correlation between the number of lapses of attention and their duration,65 and so mathematical models capable of predicting PVT lapse counts could serve this purpose. Several biomathematical models of fatigue and performance based on the neurobiology of sleep–wake regulation (see Fig. 38-5) can predict PVT lapses for a number of different sleep–wake scenarios66 and may thus be useful in this context (see Chapter 66 for a more detailed discussion). Some successful applications of sleep–wake biomathematical models of fatigue for predicting accidents have been documented.4,67 Even so, the usability of fatigue and performance models for predicting accident risk has been questioned.20 A reason is that under conditions of (presumably) near-constant operational conditions, the daily peak in published trends for accident frequency in 8-hour shift systems is around midnight,3,20 which is several hours earlier than the circadian peak in performance impairment (see Chapter 38). However, interpreting the timing of the daily peak in accident frequency in circadian terms only is not likely to be appropriate. Morning, afternoon, and night shifts are typically accompanied by different sleep–wake behavior, and thus sleep homeostasis also
80% 65%
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plays a role. Furthermore, in just about any operational setting it is difficult to establish the temporal consistency of (or correct for the temporal variation in) other factors that contribute to accident risk. One way to circumvent the difficulties of disentangling the various factors that contribute to incidents and accidents and that are or are not related to fatigue is to predict accident risk on the basis of descriptive modeling of published incident data. This idea has led to a risk index for assessing work schedules.3,21,68 Because this approach is purely descriptive, however, its generalizability across different shift systems is uncertain. Prediction strategies based on the neurobiology of sleep–wake and fatigue give greater confidence that findings for one shift system will generalize to another, because the underlying mechanisms involved do not change. For the purpose of predicting accidents with a biomathematical model of fatigue and performance based on sleep– wake, accident risk may be defined as an odds ratio.69 This odds ratio is expressed as the percentage of accidents cooccurring with a given range of predicted fatigue (incidence level) divided by the percentage of time spent working in that range of predicted fatigue (exposure level). For example, if 20% of accidents occur in a particular range of predicted fatigue while 10% of work time is spent in this range of predicted fatigue, then that specific range of fatigue is associated with a doubling (odds ratio 2) of accident risk. A study published by the Federal Railroad Administration (FRA) applied this technique to validate accident risk predictions made with a biomathematical model of fatigue and performance.4 The data set at hand concerned 400 human-factors accidents and 1000 non–human-factors accidents in railroad operations. The SAFTE fatigue model70 was used to predict operator performance, on an effectiveness scale from 0 (worst) to 100 (best), at the time of the accidents. The model predictions were based solely on the work histories and estimated sleep opportunities of the locomotive crew in the 30 days leading up to each of the accidents. The results of this analysis indicated that there was a significant, high correlation between reduced predicted crew effectiveness (i.e., increased fatigue) and the risk of a human-factors accident, as displayed in Figure 67-4. No significant relationship was expected, and none was found, for non–human-factors accidents. At predicted effectiveness scores below 70, the risk of human-factors accidents was elevated above chance level and was greater than the mean risk of non–human-factors accidents.71 At such low levels of predicted effectiveness, accident cause codes (defined by the FRA to indicate the factors that caused the accident, such as passing a stop signal or exceeding authorized speed) were of the sort expected to be related to fatigue, which confirmed that the detected relationship between accident risk and predicted effectiveness was meaningful. A significant relationship was also found between reduced predicted crew effectiveness (fatigue) and increased accident damage costs. Human-factors accident costs were 2.5 times greater when predicted effectiveness was below about 77.5 as compared to above 90. Figure 67-5 shows the relationship between predicted effectiveness and
CHAPTER 67 • Fatigue, Performance, Errors, and Accidents 757
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Predicted crew effectiveness Figure 67-4 Human-factors accident risk, from aggregated data of five railroads, at specific predicted ranges of decreasing effectiveness (increasing fatigue). The diagonal line indicates the linear relationship between predicted crew effectiveness and relative risk (r = −0.93). A relative risk of 0% corresponds to an odds ratio of 1, which is the chance level of risk. Less than 0% is reduced risk; greater than 0% is elevated risk. A relative risk of 65% means that accidents were 65% more frequent than chance.
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Predicted crew effectiveness Figure 67-5 Human-factors accident risk and damage risk as a function of predicted ranges of decreasing effectiveness (increasing fatigue). The zero line represents a risk level equal to the overall (average) risk. #, frequency of accidents; $, damage costs.
damage risk (i.e., the combination of the risk of humanfactors accidents and their damage costs). The significant relationships revealed in this FRA study confirm that accident risk can be predicted, at least to some extent, on the basis of fatigue as predicted from sleep– wake–work schedules. The specific risks associated with given levels of predicted fatigue are likely to be occupation-specific and related to the demands of the job, and data from rail operations should not be used to predict
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risks for other occupations. Nonetheless, it is likely that systematic relationships between predicted fatigue and risk of accident and damage exist in almost any occupational setting. Initiatives to avoid work schedules that induce high levels of fatigue should thus result in a beneficial reduction in risk for any safety-sensitive job.
CONCLUSION Fatigue is believed to be involved in hundreds of thousands of road accidents each year, and it has been cited as a contributing factor in occupational disasters such as the meltdown of the Chernobyl nuclear reactor, the grounding of the Exxon Valdez oil tanker, and the illadvised launch of the Challenger space shuttle. Fatigue from sleep loss and circadian factors—and, by extension, fatigue from sleep disorders—combines with the effects of time on task and duty hours to induce performance impairment and thereby increases risk of errors and accidents. It should be clear that the various factors contributing to accident risk must be considered simultaneously because they interact. For example, the maximum length of a work shift considered to be safe would vary according to the circadian timing of the shift. Present-day workhour regulations tend to consider risk factors independently,3 and as mechanisms for promoting safety and productivity they can thus be ineffective by in some circumstances being too liberal and in other circumstances being overly restrictive. The concepts laid out in this chapter are part of a developing science and, in part, await substantiation with further experimental data. They may nevertheless be used as a heuristic for understanding how fatigue leads to accidents, how the temporal changes in accident risk arise, and how the stochastic nature of performance impairment induced by fatigue contributes to the rare and seemingly unpredictable nature of accidents. Such information is important for implementing fatigue risk management (see Chapter 68), and for the cost–benefit or actuarial analyses that justify the allocation of resources to fatigue risk management. At the level of individuals, the consequences of fatigue and the need to intervene remain difficult to gauge. A clinician seeing patients experiencing fatigue should have discussions with them about the risk of errors and accidents and should document this in their files. The clinician may try to determine the risk level by asking questions about the type of job, nature of job (safety sensitive, mission critical), level of exposure, history of incidents or “near misses,” safety measures that could be put in place (e.g., rest breaks, ergonomic tools), habitual sleep–wake and work schedules, length of commute to and from work, and likely outcomes if an adverse event were to occur. It is important to explain that a patient’s own subjective evaluation of his or her impairment resulting from fatigue may be inaccurate and, because of the stochastic nature of human error, past performance or safety does not guarantee future performance or safety. Bringing these issues to the attention of the patients may prompt them to make behavioral changes and may thereby help to reduce their fatigue-related risk of errors and accidents.
❖ Clinical Pearl Fatigue from sleep loss, circadian misalignment, and sleep disorders, in conjunction with time on task, duty hours, and consecutive work shifts, results in cognitive impairment and contributes to errors, incidents, and accidents. In general, individuals cannot be relied upon to accurately selfestimate their accident risk, but increased risk can be predicted using biomathematical models of fatigue and performance.
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23. Rogers A, Holmes S, Spencer M. The effect of shiftwork on driving to and from work. J Hum Ergol (Tokyo) 2001;30:131-136. 24. Barger LK, Cade BE, Ayas NT, et al. Extended work shifts and the risk of motor vehicle crashes among interns. N Engl J Med 2005; 352:125-134. 25. Åkerstedt T, Peters B, Anund A, et al. Impaired alertness and performance driving home from the night shift: a driving simulator study. J Sleep Res 2005;14:17-20. 26. Roehrs T, Greenwald M, Roth T. Risk-taking behavior: effects of ethanol, caffeine, and basal sleepiness. Sleep 2004;27:887-893. 27. Acheson A, Richards JB, De Wit H. Effects of sleep deprivation on impulsive behaviors in men and women. Physiol Behav 2007; 91:579-587. 28. Venkatraman V, Chuah YML, Huettel SA, et al. Sleep deprivation elevates expectation of gains and attenuates response to losses following risky decisions. Sleep 2007;30:603-609. 29. Scheffers MK, Humphrey DG, Stanny RR, et al. Error-related processing during a period of extended wakefulness. Psychophysiology 1999;36:149-157. 30. Tsai LL, Young HY, Hsieh S, et al. Impairment of error monitoring following sleep deprivation. Sleep 2005;28:707-713. 31. Åkerstedt T, Kecklund G. Age, gender and early morning highway accidents. J Sleep Res 2001;10:105-110. 32. Hutchens L, Senserrick TM, Jamieson PE, et al. Teen driver crash risk and associations with smoking and drowsy driving. Accid Anal Prev 2008;40:869-876. 33. Vernon HM. The causation of industrial accidents. J Ind Hygiene 1923;5:14-18. 34. Oginski A, Oginski H, Pokorski J, et al. Internal and external factors influencing time-related injury risk in continuous shift work. Int J Occup Safety Ergon 2000;6:405-421. 35. Fortson KN. The diurnal pattern of on-the-job injuries. Monthly Labor Rev 2004;Sept:18-25. 36. Vivoli R, Bergomi M, Rovesti S, et al. Biological and behavioral factors affecting driving safety. J Prev Med Hyg 2006;47:69-73. 37. Stellman JM, editor. Encyclopaedia of occupational health and safety. 4th ed. Geneva: International Labour Office; 1998. 38. Burns T. Serious incident prevention: how to sustain accident-free operations in your plant or company. 2nd ed. Houston: Gulf; 2002. 39. Whittingham RB. The blame machine: why human error causes accidents. Boston: Elsevier; 2004. 40. Arnold PK, Hartley LR, Corry A, et al. Hours of work, and perceptions of fatigue among truck drivers. Accid Anal Prev 1997;29: 471-477. 41. Reyner LA, Horne JA. Falling asleep whilst driving: are drivers aware of prior sleepiness? Int J Legal Med 1998;111:120-123. 42. Nabi H, Guéguen A, Chiron M, et al. Awareness of driving while sleepy and road traffic accidents: prospective study in GAZEL cohort. Br Med J 2006;333:75. 43. Kaida K, Åkerstedt T, Kecklund G, et al. Use of subjective and physiological indicators of sleepiness to predict performance during a vigilance task. Ind Health 2007;45:520-526. 44. Kaplan KA, Itoi A, Dement WC. Awareness of sleepiness and ability to predict sleep onset: can drivers avoid falling asleep at the wheel? Sleep Med 2007;9:71-79. 45. Mitler MM, Miller JC, Lipsitz JJ, et al. The sleep of long-haul truck drivers. N Engl J Med 1997;337:755-761. 46. Howard ME, Desai AV, Grunstein RR, et al. Sleepiness, sleep-disordered breathing, and accident risk factors in commercial vehicle drivers. Am J Respir Crit Care Med 2004;170:1014-1021. 47. Van Dongen HPA, Baynard MD, Maislin G, et al. Systematic interindividual differences in neurobehavioral impairment from sleep loss: evidence of trait-like differential vulnerability. Sleep 2004;27: 423-433.
CHAPTER 67 • Fatigue, Performance, Errors, and Accidents 759 48. Leproult R, Colecchia EF, Berardi AM, et al. Individual differences in subjective and objective alertness during sleep deprivation are stable and unrelated. Am J Physiol Regul Integr Comp Physiol 2003;284:R280-R290. 49. Ingre M, Åkerstedt T, Peters B, et al. Subjective sleepiness and accident risk avoiding the ecological fallacy. J Sleep Res 2006;15: 142-148. 50. Van Dongen HPA, Vitellaro KM, Dinges DF. Individual differences in adult human sleep and wakefulness: leitmotif for a research agenda. Sleep 2005;28:479-496. 51. Van Dongen HPA. Shift work and inter-individual differences in sleep and sleepiness. Chronobiol Int 2006;23:1139-1147. 52. Doran SM, Van Dongen HPA, Dinges DF. Sustained attention performance during sleep deprivation: evidence of state instability. Arch Ital Biol 2001;139:253-267. 53. Krueger JM, Rector DM, Roy S, et al. Sleep as a fundamental property of neuronal assemblies. Nat Rev Neurosci 2008;9:910-919. 54. Kribbs NB, Dinges DF. Vigilance decrement and sleepiness. In: Harsh JR, Ogilvie RD, editors. Sleep onset mechanisms. Washington, DC: American Psychological Association; 1994. p. 113-125. 55. Wilkinson RT. Interaction of lack of sleep with knowledge of results, repeated testing, and individual differences. J Exp Psychol 1961; 62:263-271. 56. Balkin TJ, Bliese PD, Belenky G, et al. Comparative utility of instruments for monitoring sleepiness-related performance decrements in the operational environment. J Sleep Res 2004;13:219-227. 57. Dorrian J, Rogers NL, Dinges DF. Psychomotor vigilance performance: neurocognitive assay sensitive to sleep loss. In: Kushida CA, editor. Sleep deprivation. Clinical issues, pharmacology, and sleep loss effects. New York: Marcel Dekker; 2005. p. 39-70. 58. Edkins GD, Pollock CM. The influence of sustained attention on railway accidents. Accid Anal Prev 1997;29:533-539. 59. Basner M, Rubinstein J, Fomberstein KM, et al. Effects of night work, sleep loss and time on task on simulated threat detection performance. Sleep 2008;31:1251-1259. 60. Dinges DF. An overview of sleepiness and accidents. J Sleep Res 1995;4(Suppl. 2):4-14. 61. Leger D. The cost of sleep-related accidents: a report for the National Commission of Sleep Disorders Research. Sleep 1994;17:84-93. 62. Powell NB, Schechtman KB, Riley RW, et al. Sleepy driver nearmisses may predict accident risks. Sleep 2007;30:331-342. 63. Webb WB. The cost of sleep-related accidents: a reanalysis. Sleep 1995;18:276-280. 64. Chapman R. The concept of exposure. Accid Anal Prev 1973; 5:147-156. 65. Lim J, Dinges DF. Sleep deprivation and vigilant attention. Ann N Y Acad Sci 2008;1129:305-322. 66. Van Dongen HPA. Comparison of mathematical model predictions to experimental data of fatigue and performance. Aviat Space Environ Med 2004;75:A15-A36. 67. Åkerstedt T, Connor J, Gray A, et al. Predicting road crashes from a mathematical model of alertness regulation—the Sleep/Wake Predictor. Accid Anal Prev 2008;40:1480-1485. 68. Folkard S, Lombardi DA. Modelling the impact of the components of long work hours on injuries and “accidents.” Am J Ind Med 2006;49:953-963. 69. Sackett DL, Haynes RB, Guyatt GH, et al. Clinical epidemiology. Boston: Little, Brown; 1991. 70. Hursh SR, Balkin TJ, Miller JC, et al. The fatigue avoidance scheduling tool: modeling to minimize the effects of fatigue on cognitive performance. SAE Trans 2004;113:111-119. 71. Hursh SR, Redmond DP, Johnson ML, et al. Fatigue models for applied research in warfighting. Aviat Space Environ Med 2004; 75:A44-A53.
Fatigue Risk Management
Philippa Gander, R. Curtis Graeber, and Gregory Belenky Abstract The traditional approach to managing workplace fatigue risk has been to impose regulatory limits on hours worked and breaks within and between work periods (hours-of-service regulations). However, this approach does not address all the known causes of fatigue-related performance impairment and represents a single-layer defensive strategy within an organization. Fatigue risk management systems (FRMSs) are a flexible alternative approach that are based on scientific understanding of the dynamics of sleep loss and recovery and of the modulating influence of the circadian system on performance capacity. FRMSs are data driven, monitoring where fatigue risk occurs and where safety may be jeopardized, and
In February 2008, the U.S. National Transportation Safety Board issued a notice for aviation, “Most Wanted Transportation Safety Improvement,” that sought to reduce accidents and incidents caused by human fatigue. A stated objective was to “set working hour limits for flight crews, aviation mechanics, and air traffic controllers based on fatigue research, circadian rhythms, and sleep and rest requirements.” Working-hours limits (also known as hours-of-service regulations) are the traditional approach to managing workplace fatigue, with a history dating back to the industrial revolution in Britain and the first Factory Acts in the early 19th century.1 This chapter reviews a new approach: fatigue risk management systems (FRMSs), which have evolved from advances in sleep science and in safety science, notably better understanding of human error in the etiology of accidents, and the practice of risk assessment and management. Central concepts in FRMS are that: • human functional capacity is variable (both between individuals and across time); • some of this variability is predictable from prior sleep history and the phase of the circadian pacemaker; and • to maintain safety, systems are needed to mitigate both the risk of fatigue-related functional impairment and its consequences. The FRMS approach is developing most rapidly in the transportation sector, and this chapter focuses on examples from transportation. It begins by outlining a theoretical framework for fatigue risk management, based on a comprehensive definition of fatigue that incorporates both the traditional understanding of fatigue in occupational safety and more recent understanding of the importance of adequate sleep for maintaining waking function. The sleep science that underpins FRMS is then considered, followed by a review of the safety science that is also integral to the FRMS approach. We introduce some examples of new regulations for different transport modes that permit FRMS as an alternative to compliance with prescriptive hours-of-service regulations. 760
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they include a layered system of defensive strategies to mitigate measured fatigue risk. The effectiveness of FRMS will improve as their implementation and evaluation expands and as the scientific knowledge base improves. Further research is needed to clarify the dynamics of sleep loss and recovery, their effects on different types of performance, the importance of individual variability (including trait differences and age-related changes), and how degraded performance of individual workers affects workplace teams and safety. In addition, the FRMS approach faces the challenge of changing the traditional roles of regulators, companies, and employees in regard to safety management.
Fatigue risk management systems are a new approach that will continue to evolve. The chapter concludes with a discussion of some areas that have potential for improving the effectiveness of FRMS. These include addressing scientific knowledge gaps; ensuring that regulators, employers, and employees have an adequate understanding of the causes and consequences of fatigue; addressing the challenges of changing traditional roles among these parties; and consideration of issues around cost, equity, and evaluation of FRMS.
A THEORETICAL FRAMEWORK The definition of fatigue is an ongoing academic debate.2 From a scientific perspective, the term may be problematic, but its usage is widespread and long-standing in occupational safety. Nevertheless, a clear working definition of fatigue is a prerequisite for developing systems to manage it in the workplace. In the practical context of managing safety, the focus is on human functional capacity. Thus, we here use the following working definition: Fatigue is the inability to function at the desired level because physical and mental exertion (of all waking activities, not only work) exceeds current capacity. The effects of fatigue can be measured as changes in brain function (for example waking EEG power spectra, sleep latency), behavior (including performance on standard tests), or subjective experience. The underlying construct is simple—fatigue is the result of work demands exceeding current performance capacity, due to inadequate recovery opportunities, particularly for sleep. Factors known to affect performance capacity include: • fluctuations across the daily cycle of the circadian biological clock (hence the risk of fatigue is greater when performance capacity is reduced during biological night); • restricted sleep causes a cumulative, dose-dependent reduction in performance capacity;
• as continuous time awake increases, performance capacity decreases; and • as continuous time on a task increases, performance capacity decreases. The rate of this decline is influenced by the intensity of work demands (workload). There is evidence from laboratory and field studies that these factors interact. For example, in a large diary study of fatigue ratings made by air traffic controllers at the end of each period of active controlling (interspersed with breaks) across duty periods, the following factors were independently associated with the level of fatigue: time of day; self-rated workload; time since coming on duty; duration of continuous wakefulness; and duration of the active operational duty period.3,4 The effects of time on duty and time of day appeared to be additive, such that highest fatigue ratings occurred at the end of long duty periods that finished around 6 am. Under low-workload conditions, fatigue ratings remained relatively stable for continuous work periods up to 4 hours long, but when workload was high, there was a rapid increase in fatigue after 2 hours of continuous work. These effects of workload became more evident after controllers had been awake for at least 12 hours, so the effects were more marked on the afternoon shift than on the morning shift. The timeof-day variation in fatigue ratings was also influenced by workload, being more marked at low and high levels of workload than at intermediate levels. Fatigue is thus multifaceted and complex. The definition encompasses the aspects of fatigue that have been identified in transportation hours-of-service regulations since the 1930s, namely time-on-task fatigue (addressed by limits on daily work hours and requirements for regular breaks during work) and acute and chronic fatigue (addressed by limits on minimum rest breaks away from work and cumulative total work hours per week or per month). In addition, the definition encompasses more recent understanding of the modulating influence of the circadian pacemaker on performance and the vital importance of adequate sleep in restoring and maintaining all aspects of waking function. The definition also highlights an aspect of fatigue that differentiates it from most other workplace hazards (such as noise, vibration, toxic substances), where exposure is limited to the workplace. In contrast, fatigue is also affected by activities and choices made outside of work, sometimes described as a “whole of life issue.” Thus, the management of fatigue risk is, of necessity, a shared responsibility between employers and employees. The notion of the inability to function at the desired level recognizes that responsibility for fatigue-related impairment can vary. It may be the result of an employer’s imposing excessive work demands or inadequate recovery opportunities (both during work and between work periods). However, fatigue-related impairment can also result from less-than-optimal use of rest opportunities by an employee. Thus, the definition implies the need for careful evaluation of the contribution of the actions of an individual employee, as well as work demands and safety systems present, in the analysis of fatigue-related accidents. This is consistent with the view that human error should be the starting point for safety analysis, rather than the end point.5
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DYNAMICS OF SLEEP LOSS AND RECOVERY Modern approaches to fatigue risk management seek to incorporate scientific understanding of the dynamics of sleep loss and recovery and their effects on performance capacity. Most of the this understanding comes from controlled experimental studies, and it is important to keep in mind that laboratory studies simulate only limited aspects of work demands and typically seek to exclude the more complex psychosocial context of people’s daily lives. However, only controlled laboratory studies can unravel the dynamics of the different physiologic systems that generate fluctuating performance capacity, and they are therefore essential for improving FRMS. The following sections summarize key areas of sleep research that have lead to the FRMS approach. Effects of Total Sleep Deprivation and Sleep Restriction An extensive body of experimental evidence indicates that performance capacity is affected by sleep loss (acute and chronic), extended time awake, circadian variation, workload (task demands, task complexity), time on task, and their interactions6-15 (also see Chapter 65). The effects of total sleep deprivation in the laboratory are wellcharacterized. However, fewer experimental studies have addressed the affects of chronic sleep restriction,6,11,12,16 which is more common in 24/7 operations than total sleep deprivation.14,17 Figure 68-1 illustrates the effects of a week of chronic sleep restriction on performance on a psychomotor vigilance test (PVT) averaged across four tests per day. The protocol began with 3 days with 8 hours time in bed (TIB), followed by 7 experimental days (E1-E7) during which groups had 9 hours TIB (n = 16), 7 hours TIB (n = 16), 5 hours TIB (n = 16), or 3 hours TIB (n = 18). All groups then had three recovery days (R1-R3) with 8 hours TIB. Figure 68-1 clearly illustrates that the effects of restricted sleep are cumulative and dependent on sleep dose. A similar protocol studied the effects of 4, 6, or 8 hours TIB per night over 14 days and likewise found cumulative, dose-dependent effects of chronic sleep restriction.12 An unresolved question is whether or not performance stabilizes during prolonged sleep restriction, albeit at a lower level than when subjects are well rested. In Figure 68-1, performance of the 7-hour and 5-hour TIB groups appears to stabilize over the final few days of sleep restriction. However in the study with 4-, 6-, or 8-hour TIB groups, performance continued to degrade across the entire 14 days of sleep restriction.12 Because sleep restriction is considered to be endemic in modern industrialized societies, this issue has important implications for FRMS. The effects of sleep restriction on performance in the laboratory may represent a best-case scenario when compared to the effects of sleep restriction on performance in the workplace. A study of the PVT performance of 20 anesthesiology specialists found that postduty reaction speed declined linearly across 12 consecutive working days, even although they averaged only 0.6 hours less sleep (measured by actigraphy) than on days off.18 This
762 PART II / Section 9 • Occupational Sleep Medicine
Mean speed (1/RT*1000)
4.50 4.25 4.00 3.75 3.50 3.25 3.00 2.75 2.50 2.25 B E1 E2 E3 E4 E5 E6 E7 R1 R2 R3 Day 9 hr time in bed 7 hr time in bed 5 hr time in bed 3 hr time in bed Figure 68-1 Daily mean performance on the 10-minute psychomotor vigilance task (PVT) during one condition of sleep augmentation (9 hr time in bed/night) and three conditions of sleep restriction (7 hr time in bed/night, 5 hr time in bed/night, or 3 hr time in bed/night) across seven consecutive experimental days (E1-E7). The experimental period is preceded by a baseline day with 8 hr time in bed/night (B) and is followed by three recovery days (R1-R3) again with 8 hr time in bed/night in a total of 66 subjects divided between sleep-dose conditions. This sleep dose-response study shows sleep dose-dependent degradation of performance with decreasing sleep doses yielding decreasing performance. The PVT metric used is the reciprocal of reaction time (1/RT) times 1000. (Belenky G, Wesensten NJ, Thorne DR, et al. Patterns of performance degradation and restoration during sleep restriction and subsequent recovery: a sleep dose-response study. J Sleep Res 2003;12:1-12.)
suggests that the demands of clinical workload may have exacerbated the effects of sleep restriction on PVT performance. Sleep restriction experiments in the laboratory focus on the performance of individual subjects, and very little research has addressed the effects of sleep restriction on teams undertaking complex work. A simulation study with 67 Boeing B747-400 crews demonstrated that sleep loss increased the number of errors made by a two-person cockpit team.19 Paradoxically however, greater sleep loss among first officers improved the rate of error detection, although greater sleep loss among captains led to a higher likelihood of failure to resolve detected errors. Greater sleep loss was also associated with changes in decision making, including a tendency toward choosing lower-risk options. Influence of Task Type These simulator study findings are consistent with evidence from behavioral studies indicating that more-complex cognitive tasks, particularly tasks that involve executive functions dependent upon the prefrontal cortex, are more severely affected by sleep loss than are simpler tasks.20,21 These observations are further supported by positron emission tomography (PET) studies confirming that sleep deprivation decreases brain activation during subsequent wake (as measured by fludeoxyglucose [18F-FDG] uptake), with the greatest decreases occurring in the prefrontal
cortex.22 This brain area mediates complex cognitive performance including attention, vigilance, situational awareness, anticipation, and judgment. On the other hand, PET studies of the sleeping brain show that the prefrontal cortex is deactivated to the greatest extent during sleep, remaining deactivated during both rapid eye movement (REM) sleep and non-REM (NREM) sleep.23-25 Taken together, the imaging studies suggest that the brain regions involved in higher order complex cognitive performance are most affected by sleep deprivation and have the greatest need for sleep-mediated recuperation. A graphic illustration of the possible safety consequences comes from debriefings following friendly fire incidents during Operation Desert Storm, which indicated that sleep deprivation contributed to Bradley fighting vehicle and M1 tank crews becoming misoriented to the battlefield (a complex mental task involving situational awareness) and mistook friend for foe.26 They were, however, able to shoot straight (a simple task involving putting cross-hairs on the target and squeezing the trigger). This combination of degradation in complex task performance coupled with relative preservation of simple task performance led to their firing upon and destroying friendly vehicles and causing friendly casualties. Individual Differences in Sensitivity to Sleep Loss Studies with healthy young adults indicate that some people are much more resistant to the effects of sleep loss on performance than others.27,28 This is an enduring individual trait that is independent of prior sleep history and is stable across repeated exposures to sleep loss.27 These findings potentially have significant implications for FRMS in workforces where it is not ethically or financially possible to select for the resilient few. Other aspects of individual variability that may be relevant for FRMS include differences in the basal level of alertness, in the amount of sleep needed to be fully rested, and in aspects of the circadian pacemaker including its phase position relative to the day–night cycle and its rate of adjustment to altered sleep–wake schedules.29 There also appear to be stable traitlike differences among people in the effects of sleep restriction on their self-rated sleepiness, fatigue, and mood. However, these subjective measures do not reliably reflect impaired waking function during chronic sleep restriction,29,30 which suggests that fatigued people in the workplace might not be able to reliably assess their own level of functioning. Acknowledging this limitation, subjective assessment data may nevertheless be of value in FRMS because they have the advantages of being easy and cheap to collect, and a worker’s perception of fatigue will arguably affect his or her use of countermeasure strategies. Restorative Value of Sleep The amount and quality of sleep needed for full recovery of waking function is an issue of central importance in managing fatigue risk. Recovery from total sleep deprivation is typically complete with 1 to 2 days of unrestricted sleep.15 However, in the experiment illustrated in Figure 68-1, the performance of all the sleep-restricted groups failed to recover fully after 3 nights of 8 hours’ TIB. This
Role of the Circadian Pacemaker The relevance of the circadian pacemaker to fatigue risk management is twofold: it modulates performance capacity directly (see Chapter 65), and it modulates the amount of
sleep that can be obtained during a given rest period and thus also affects performance capacity indirectly. Fatigue risk increases when work requirements dictate that a person must be awake during the part of the circadian cycle that is optimal for sleep, which is also when performance capacity passes through its daily nadir. In most shift-work situations, the circadian pacemaker tends to be drawn back to its normal phase position (with sleep at night) regardless of the work–rest schedule, because it is sensitive to environmental time cues (particularly light) that do not change with the work–rest schedule.31 In contrast, the circadian pacemaker can adapt after transmeridian flight because it is eventually re-entrained to its preferred phase position by the local time cues, if a person remains in the new time zone long enough and attempts to live on local time. During international longhaul trips, commercial airline pilots seldom spend long enough in any time zone to become adapted to local time, effectively combining shift work and jet lag.32,49 Figure 68-2 illustrates the interaction between the duration of a rest break and the part of the circadian cycle that it includes, in determining the total amount of sleep obtained by pilots attempting to sleep on board Boeing 747-400 aircraft.50 The curves are fitted to data from a retrospective questionnaire survey of British Airways pilots operating in three- or four-person crews on long-haul flights of 8 to 14 hours and crossing +9 to −8 time zones.
MANAGING FATIGUE RISK The degraded performance of fatigued employees reduces the safety margin in operations where human performance is critical to system performance, particularly when there is limited time in which to decide and act.51 Inadequate performance of fatigued operators is increasingly cited as 5 Duration of sleep (hr)
suggests that recovery from chronic sleep restriction may take longer. It is also possible that 8 hours of TIB might not have been sufficient to allow full recovery sleep for some participants. This issue is directly relevant to work schedules where people are expected to experience sleep restriction (when work times overlap usual sleep times). Unrestricted nights of sleep are needed periodically to permit full recovery. These recovery breaks need to occur at intervals appropriate to the level of ongoing sleep restriction and thus the rate of accumulation of impairment. Sleep architecture typically returns to normal with 2 nights of unrestricted sleep, with rebound of slow-wave sleep predominant on the first recovery night and REM rebound on the second.15 On this basis, it is typically recommended that work schedules need to provide at least two consecutive nights of unrestricted sleep at regular intervals to prevent the cumulative effects of chronic sleep restriction. Another key question relevant to FRMS is whether the same amount of sleep obtained in several episodes is as restorative as a single consolidated period of sleep at night. It is relatively common for people whose work pattern cuts across their normal sleep time to attempt to sleep at least twice in 24 hours, known as split sleep.31,32 In some cultures, split sleep (at night and with an afternoon nap) is also traditional.33 By definition, at least one of a set of split sleep periods must occur outside the optimum nocturnal window for sleep that is defined by the circadian pacemaker. This question was addressed in a study that evaluated the effects of 10 consecutive days of nocturnal anchor sleep (4.2, 5.2, 6.2, or 8.2 hours in bed) centered around 2:00 am, coupled with either a diurnal nap (0.4, 0.8, 1.2, 1.6, 2.0, or 2.4 hours in bed) centered around 2:00 pm or with no nap.34,35 Across the 18 different combinations of nocturnal and nap sleep times examined, the total amount of sleep obtained was largely independent of the pattern of sleep across the 24-hour day–night cycle, but it was strongly related to the total amount of time in bed (which ranged from 4.2 hours to 8.2 hours in the different protocols).34 Performance impairment (on the PVT and a digit symbol substitution task) and subjective sleepiness (Stanford Sleepiness Scale) were also independent of the pattern of sleep across the 24-hour day–night cycle and had a nearlinear relationship to total sleep time.35 Thus, under conditions of chronic sleep restriction, this study suggests that there is no disadvantage to having a flexible division of sleep across the 24-hour day–night cycle if the major sleep period occurs at night. There is also substantial evidence that even short naps (30 minutes or so) provide some benefit, improving performance after both normal and restricted nights of sleep.36-43 The restorative value of sleep is known to be compromised by higher frequency interruptions (at least every few minutes). Among young adults, experimental sleep fragmentation leads to increased sleepiness and degradation of performance and mood.15,44-46 Sleep also becomes more fragmented with increasing age,47 but the significance of this for waking function remains unclear.48
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4 3 2 1 0 14
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Time of sleep (hr) 6-hr rest period 5-hr rest period 4-hr rest period
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Figure 68-2 Prediction of the amount of sleep obtained during in-flight rest breaks, depending on when sleep starts (x axis, based on the pilot’s home time zone as a surrogate measure for circadian phase) and the length of the break (y axis). Data from 428 outbound flights from London and 423 return flights to London. (Safety Regulation Group, UK Civil Aviation Authority. Aircrew fatigue: a review of research undertaken on behalf of the UK Civil Aviation Authority. CAA Paper 2005/04. Available at: http://www.caa.co.uk/application.aspx?catid=33&page type=65&appid=11&mode=detail&id=1942. Accessed September 12, 2009.)
764 PART II / Section 9 • Occupational Sleep Medicine
a causal factor in catastrophic accidents.26,52,53 At the population level, a case-control study has estimated that motor vehicle crashes resulting in injury could be reduced by 19% on a metropolitan road network if drivers did not drive when they felt sleepy, when they had slept 5 hours or less in the last 24 hours, or between 2:00 am and 5:00 am.54 A fatigue-related incident or accident can be viewed as the final point in a causal chain of events or hazard trajectory that penetrates all the defenses present in the system to control that hazard.55 A series of defensive layers can be implemented to limit the likelihood of a fatigue-related incident or accident (a defenses-in-depth approach), including: • providing adequate opportunities for sleep (level 1 defense, partially addressed by traditional hours-of-service regulations); • processes for confirming that adequate sleep is obtained (level 2 defense); • processes to detect behavioral symptoms of fatigue (level 3 defense); • processes for detecting fatigue-related errors (level 4 defense); and • processes for investigating fatigue-related incidents (level 5 defense). No single level of defenses is impenetrable. However, in a system with four levels of defense, even if each level has only 50% sensitivity for detecting fatigue, only about 6% of cases will remain undetected. The concept of defenses in depth is central to fatigue risk management systems. Sleep science is not yet able to reliably predict the level of fatigue-related impairment of an individual at a given point in time. Estimating the risk of a fatigue-related accident at a given point in time is even more complex and depends on the context in which the fatigued person is working (see Chapter 67, this volume). However, in a defenses-in-depth approach, additional defensive layers can be implemented to compensate for scientific uncertainty. As scientific understanding improves, the effectiveness of the overall system for reducing fatigue risk also improves. Safety Management Systems Ideally, fatigue risk management systems are one component in a broader safety management system that addresses the full range of hazards in a given work environment. Safety management systems are becoming more formalized across a range of industries. For example, standards for safety management systems in the aviation industry are specified in a manual published by the International Civil Aviation Organization (ICAO).56 To identify hazards, ICAO identifies three types of tools: reactive analysis, normal activity analysis, and proactive analysis. Reactive analysis is based on reporting systems. For example, a voluntary reporting system ensures that crewmembers can report possible fatigue-related incidents without fear of retribution, in addition to the mandatory reporting required for more serious safety incidents. Normal activity analysis uses questionnaires or routine observations. This provides data for the analysis of trends in fatigue risk and does not rely on fatigue levels reaching a threshold where accidents or reportable safety events occur. For FRMS, it is possible to take advantage of
modern onboard technologies that continuously record a vast array of flight data. These data are already being assessed on a routine basis to proactively correct shortcomings in flight operations before safety issues arise. The challenge for FRMS is to link crew fatigue to identified incidents of exceeding established flight safety parameters. Proactive analysis occurs whenever a significant change is introduced. For example, appropriately validated biomathematical models can be used to estimate likely fatigue levels on a new route or as a result of a significant schedule change. In a system with multiple layers of defense, models do not have to be perfect to be useful, so long as other defenses are adequate to detect and manage where model predictions are unreliable. As model predictive capability improves, the effectiveness of the overall system for reducing fatigue risk improves. Once a register of hazards has been established, risk management aims at minimizing the safety impact of those hazards. In its guidance material, ICAO identifies three levels of safety management. First is suppression of risk, for example in FRMS by eliminating schedules that are associated with high levels of fatigue. Second is mitigation of the risk of fatigue, for example by providing education on personal strategies to improve sleep, or in long-haul aviation providing additional crew members and the opportunity for in-flight sleep, or ensuring that schedules include layovers that permit sufficient time for recovery sleep. Third is strategies to maintain operational safety when crewmembers are fatigued, for example through the use of automation or task rotation. This level is critical because fatigue risk cannot be eliminated by the first two levels, particularly fatigue caused by nonwork factors. Consistent with these considerations, we here define an FRMS as a scientifically based and flexible alternative to rigid work time limitations that provides a layered system of defenses to minimize, as far as is reasonably practicable, the adverse effects of fatigue on workforce alertness and performance and the safety risk that this represents. A strength of this approach is that it does not rely on a priori decisions about the factors most likely to be causing fatigue, in contrast to the traditional prescriptive hours-ofservice limits, which focus on duration of work and rest. Instead, the FRMS is data driven, monitoring where fatigue risk occurs and where safety may be jeopardized and generating new scheduling solutions or other strategies to mitigate measured fatigue risk. At the same time, the FRMS provides operators with flexibility to seek the most efficient safe crewing solutions to meet operational needs. Fatigue risk management systems are not envisaged as a one-size-fits-all approach. They differ according to the regulatory framework under which an organization operates; the complexity, scale, and nature of its operations; the operational reliability required; and the particular demographics of its workforce. A detailed example of a comprehensive FRMS for aviation operations has been published by the Flight Safety Foundation.57 The Role of Regulation Concerns about the risk that fatigued people pose to others are particularly acute in sectors such as health care and public transportation, where consumers must trust that
they will receive safe, effective service. A key contributor to confidence in the safety of public transportation is the expectation that governments have a duty to regulate the activities of transport companies to limit the societal risk posed by fatigue-impaired transport workers. Interestingly, the same logic has not usually been applied to health care services. The traditional regulatory approach in transportation has been to impose prescriptive limits on the duration of work and the duration of breaks within and between work periods. A fundamental problem with this approach is that even within one industry sector, regulators are being asked to clearly define the limits of acceptable performance or the levels of fatigue that cause performance to become unacceptable in every context across a broad range of operations.58 On the other hand, from a regulator’s perspective, hours-of-service regulations provide clear standards for judging violations and deciding culpability in legal contexts, whether or not the prescribed limits are scientifically defensible. The challenge for FRMSs is to achieve a level of trust in the protection they offer that is at least equivalent to that enjoyed by hours-of-service regulations among both governments and the public. A number of countries have begun developing legislation that enables transport operators to develop an FRMS as an alternative to complying with the prescriptive hoursof-service limits to manage the risks associated with operator fatigue. Examples include the mandatory Great Barrier Reef Pilotage Safety Management Code (Australian Maritime Safety Authority, 1999), the Australian Federal Model Rail Safety Bill (2006), the UK Railways and Other Guided Transport Systems (Safety) Regulations (2006), and the Australian Transport Council National Heavy Vehicle Accreditation Scheme (2007). In 2006, the ICAO established a Fatigue Risk Management Sub-Group (FRMSG) of the Operations Panel to develop an international regulatory framework for fatigue risk management in commercial aviation. States can choose to adopt ICAO regulatory frameworks, and it is expected that states will need clear guidance to enable regulators to accredit and audit FRMSs. In general, the development and implementation of FRMSs seems to be proceeding more rapidly in countries that already have the principles of duty of care and shared responsibility for safety included in their general occupational safety and health legislation (for example, Australia, New Zealand, and the United Kingdom), than in countries that do not (for example the United States).
CHALLENGES Fatigue risk management systems represent a new approach to an increasingly complex health and safety issue. Consequently, although there is a strong evidence base to support the principles behind FRMSs, practical experience with their implementation is more limited. There are a number of key areas where advances have potential to improve effectiveness of FRMS. In the interim, as knowledge and practice improves, FRMSs are designed with multiple defensive layers to manage uncertainties. In contrast, although traditional hours-of-service regulations face some of the same challenges, they offer only a single rigid defensive layer against fatigue-related risk.
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Scientific Knowledge Gaps Chronic sleep restriction is the most common sleep disturbance associated with 24/7 operations, and the U.S. National Sleep Disorders Research Plan identifies studies of the performance effects of sleep restriction as the highest research priority.59 Individual differences in susceptibility to fatigue-related performance impairment need to be better understood, including the extent of traitlike differences27,28 and whether aspects of experience can mitigate any risk associated with age-related changes in sleep and performance capacity.48,60-62 The safety hazards represented by fatigued employees in different workplaces remain poorly understood. This can be addressed through experimental studies focusing on the effects of sleep restriction on different types of performance and communication, simulation studies of the effects of fatigue on the functioning of workplace teams, and careful investigation and analysis of fatiguerelated incidents and accidents. The relationship between individual fatigue and system safety is likely to be very complex in ultrasafe systems63 such as commercial aviation, where multiple layers of operational defenses (e.g., automation, teamwork, procedures) reduce the probability of having an accident attributable uniquely to an error made by a fatigued employee. All current biomathematical models focus on predicting individual performance based on sleep history or work history, which is a limitation that needs to be recognized when they are used in the context of FRMSs. Knowledge Transfer Successful implementation of FRMSs requires that regulators, employers, and employees have a sufficient understanding of the causes and consequences of fatigue to meet their responsibilities in relation to the FRMS. However, as with other areas relating to human factors in safety, this is an unfamiliar area for many organizations and employees. Accredited, competency-based education and training programs are needed. Evaluation of the effectiveness of training is also a neglected area, with conflicting findings that may be linked to the type of training and the presence or absence of other ongoing strategies to maintain awareness of fatigue risk in an organization.64,65 Changing Roles and Competing Interests Fatigue risk management systems shift the locus of responsibility for safety away from the regulator and toward employers and employees. This is consistent with the philosophy behind much recent occupational health and safety legislation, namely that permitting industry to selfregulate fosters greater ownership of safety by industry and that those who create the risk are best placed to manage it.66 However, this shift also implies modification of the traditional roles of all parties. An important subtext is that safety considerations should be separated from industrial bargaining and remuneration. Fatigue risk management systems can help support this culture shift because fatigue risk management is, of necessity, a shared responsibility, and the scientific knowledge base provides neutral ground on which to build a collaborative approach. For example, fatigue is inevitable in 24/7 operations
766 PART II / Section 9 • Occupational Sleep Medicine
because of the innate preference for sleep at night, which is driven by the circadian pacemaker. From a regulatory perspective, considerable expertise is required to accredit and audit complex fatigue management systems. In addition, an FRMS is typically introduced as an alternative means of compliance that companies can seek to use if they wish to operate outside the existing hours-of-service limits. Having multiple compliance regimens running in parallel may place considerable extra demands on regulators and enforcement agencies. Diverse and influential nonprofit organizations engaged in advocacy are putting forward strong views relevant to hours-of-service regulations and FRMS. These include the National Sleep Foundation and the Truck Safety Coalition, which represents a partnership between the Citizens for Reliable and Safe Highways (CRASH) and the Parents Against Tired Truckers (PATT). Cost There is a concern that FRMS may shift regulatory costs from the government to the operators. As a counterexample, the low-cost carrier EasyJet has implemented an innovative FRMS that has enabled it to work outside the current flight and duty time limitations and to negotiate substantial savings in insurance premiums.67 The costs of developing a safety case and implementing and running an FRMS may be disproportionately heavy for smaller operators, which could be seen as inequitable if an FRMS gives larger companies a competitive edge. There is still very little information on whether the FRMS approach can be scaled to the needs of smaller organisations.68 Evaluation Evaluation of the effectiveness of FRMS (or other safety management systems) for improving safety remains an important challenge, both because they are relatively new and because multiple factors are likely to contribute to changes in safety in complex operations across time.69 However, data to address this issue will accrue as more FRMSs are implemented, because ongoing internal evaluation is an intrinsic feature of FRMS and regulatory audits provide opportunities for external evaluation. Sharing information and experience across an industry sector would greatly facilitate the evaluation and improvement of FRMS.
CONCLUSIONS Fatigue risk management systems represent a new approach that seeks to integrate advances in sleep science and in safety science to reduce the occupational hazard of workplace fatigue. Clinical sleep services clearly have a role in FRMS, in the diagnosis, treatment, and return to work (where possible) of employees whose sleep disorders put them at elevated risk for fatigue-related occupational accidents.70 On the other hand, long waiting lists and high costs can be a significant disincentive for disclosure by an employee who is experiencing chronic sleep problems. Employees may also be facing loss of their livelihood if there are medical standards for fitness to work (for example in commercial driving and aviation). Sleep clinicians need to be involved in a comprehensive approach to these issues.
Acknowledgement The ideas and constructs presented here have developed through collaborative projects and discussions with many academic colleagues, industry partners, and regulatory agencies over a number of years. Most recently, we acknowledge the stimulation and challenge provided by fellow participants in the Hopkinton Conference on Future Directions in Fatigue and Safety Research (November 13-14, 2008) sponsored by the Liberty Mutual Research Institute for Safety. Responsibility for the content of the chapter rests with the authors.
❖ Clinical Pearl Fatigue risk management systems are a new approach to managing the safety risk represented by fatigued employees in the workplace. FRMSs use sleep science to help identify times across a duty cycle when fatigue risk is likely to be elevated and to inform the design of better work schedules to improve opportunities for recovery sleep. Fatigue risk is elevated for people with sleep disorders that compromise the restorative value of sleep. For these people, diagnosis, treatment, and managed return to work (where possible) are integral to fatigue risk management.
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14. Dinges, DF, Rogers, NL, Baynard MD. Chronic sleep deprivation. In: Kryger MK, Roth T, Dement WC, editors. Principles and practice of sleep medicine. 4th edition. Philadelphia: Elsevier Saunders; 2005. p. 67-76. 15. Bonnet MH. Acute sleep deprivation. In: Kryger MK, Roth T, Dement WC, editors. Principles and practice of sleep medicine. 4th ed. Philadelphia: Elsevier Saunders; 2005. p. 51-66. 16. Balkin T, Thorne D, Sing H, et al. Effects of sleep schedules on commercial motor vehicle driver performance. Walter Reed Army Institute of Research under DOT Contract DTFH61-94-Y-00090, Report No. DOT-MC-00-133, May 2000. 17. National Sleep Foundation. National Sleep Foundation Sleep in America Poll 2005. Available at: http://www.sleepfoundation. org/article/sleep-america-polls/2005-adult-sleep-habits-and-styles. Accessed September 12, 2009. 18. Gander PH, Millar MA, Webster C, et al. Sleep loss and performance of anaesthesia trainees and specialists. Chronobiol Int 2008;25:1-15. 19. Thomas MJW, Petrilli RM, Lamond NA, et al. Australian long haul fatigue study. In: Enhancing safety worldwide. Proceedings of the 59th Annual International Air Safety Seminar, Paris, October 23-26, 2006. Red Hook, NY: Curran Associates, Inc.; 2007. 20. Harrison Y, Horne JA. The impact of sleep deprivation on decision making: a review. J Exp Psychol Appl 2000;6:236-249. 21. Nilsson JP, Soderstrom M, Karlsson AU, et al. Less effective executive functioning after one night’s sleep deprivation. J Sleep Res 2005;14:1-6. 22. Thomas ML, Sing HC, Belenky G, et al. Neural basis of alertness and cognitive performance impairments during sleepiness. I. Effects of 24 h of sleep deprivation on waking human regional brain activity. J Sleep Res 2000;9:335-352. 23. Braun AR, Balkin TJ, Wesenten NJ, et al. Regional cerebral blood flow throughout the sleep-wake cycle. An H215O PET study. Brain 1997;120(Pt 7):1173-1197. 24. Braun AR, Balkin TJ, Wesensten NJ, et al. Dissociated pattern of activity in visual cortices and their projections during human rapid eye movement sleep. Science 1998;279:91-95. 25. Balkin TJ, Braun AR, Wesensten NJ, et al. The process of awakening: a PET study of regional brain activity patterns mediating the reestablishment of alertness and consciousness. Brain 2002;125: 2308-2319. 26. Belenky G, Marcy SC, Martin JA. Debriefings and battle reconstructions following combat. In: Martin JA, Sparacino L, Belenky G, editors. The Gulf War and mental health: a comprehensive guide. Westport, Conn: Praeger; 1996. p. 105-113. 27. Van Dongen HPA, Baynard MD, Maislin G, et al. Systematic interindividual differences in neurobehavioral impairment from sleep loss: evidence of trait-like differential vulnerability. Sleep 2004; 27:423-433. 28. Van Dongen HPA, Vitellaro KM, Dinges DF. Individual differences in adult human sleep and wakefulness: leitmotif for a research agenda. Sleep 2005;28:479-496. 29. Van Dongen HPA. Shift work and inter-individual differences in sleep and sleepiness. Chronobiol Int 2006;23:1139-1147. 30. Leproult R, Colecchia EF, Berardi AM, et al. Individual differences in subjective and objective alertness during sleep deprivation are stable and unrelated. Am J Physiol Regul Integr Comp Physiol 2003;284:R280-R290. 31. Gander PH, Gregory KB, Connell LJ, et al. Flight crew fatigue IV: overnight cargo operations. Aviat Space Environ Med 1998;69: B26-B36. 32. Gander PH, Gregory KB, Miller DL, et al. Flight crew fatigue V: long-haul air transport operations. Aviat Space Environ Med 1998; 69:B37-B48. 33. Webb WB, Dinges DF. Cultural perspectives on napping and the siesta. In: Dinges DF, Broughton RJ, editors. Sleep and alertness: chronobiological, behavioral and medical aspects of napping. New York: Raven Press; 1989. p. 247-266. 34. Mollicone DJ, Van Dongen HPA, Dinges DF. Optimizing sleep/ wake schedules in space: sleep during chronic nocturnal sleep restriction with and without diurnal naps. Acta Astronaut 2007;60: 354-361. 35. Mollicone DJ, Van Dongen HPA, Rogers NL, et al. Response surface mapping of neurobehavioural performance: testing the feasibility of split sleep schedules for space operations. Acta Astronaut 2008;63:833-840.
CHAPTER 68 • Fatigue Risk Management 767 36. Takahashi M, Fukuda H, Arito H. Brief naps during post-lunch rest: effects on alertness, performance, and autonomic balance. Eur J Appl Physiol 1998;78:93-98. 37. Hayashi M, Ito S, Hori T. The effects of a 20-min nap at noon on sleepiness, performance and EEG activity. Int J Psychophysiol 1999;32:173-180. 38. Takahashi M, Arito H. Maintenance of alertness and performance by a brief nap after lunch under prior sleep deficit. Sleep 2000; 23:1-7. 39. Tietzel AJ, Lack LC. The short-term benefits of brief and long naps following nocturnal sleep restriction. Sleep 2001;24:293-300. 40. Tietzel AJ, Lack LC. The recuperative value of brief and ultra-brief naps on alertness and cognitive performance. J Sleep Res 2002; 11:213-218. 41. Brooks A, Lack L. A brief afternoon nap following nocturnal sleep restriction: which nap duration is most recuperative? Sleep 2006;29:831-840. 42. Philip P, Taillard J, Moore N, et al. The effects of coffee and napping on nighttime highway driving: a randomized trial. Ann Intern Med 2006;144:785-791. 43. Signal TL, Gander PH, Anderson H, et al. Scheduled naping as a countermeasure to sleepiness air traffic controllers. J Sleep Res 2009;18:11-19. 44. Gillberg M. Sleepiness and its relation to the length, content, and continuity of sleep. J Sleep Res 1995;4(S2):37-40. 45. Stepanski EJ. The effect of sleep fragmentation on daytime function. Sleep 2002;25:268-276. 46. Stepanski EJ. Sleep fragmentation, sleep deprivation, or both. J Clin Sleep Med 2006;2:479. 47. Redline S, Kirchner HL, Quan SF, et al. The effects of age, sex, ethnicity, and sleep-disordered breathing on sleep architecture. Arch Int Med 2004;164:406-418. 48. Gander PH, Signal TL. Who is too old for shift work? Towards better criteria. Chronobiol Int 2008;25:199-213. 49. Spencer MB, Stone BM, Rogers AS, et al. Circadian rhythmicity and sleep of aircrew during polar schedules. Aviat Space Environ Med 1991;62:3-13. 50. Safety Regulation Group, UK Civil Aviation Authority. Aircrew fatigue: a review of research undertaken on behalf of the UK Civil Aviation Authority. CAA Paper 2005/04. Available at: http://www. caa.co.uk/application.aspx?catid=33&pagetype=65&appid=11&mod e=detail&id=1942. Accessed September 12, 2009. 51. Wesensten NJ, Belenky G, Balkin TJ. Cognitive readiness in network-centric operations. Parameters: US Army War College Quarterly 2005;35:94-105. 52. Mitler MM, Carskadon MA, Czeisler CA, et al. Catastrophes, sleep, and public policy: consensus report. Sleep 1988;11:100-109. 53. Folkard S, Lombardi DA, Tucker PT. Shiftwork: safety, sleepiness and sleep. Industrial Health 2005;43:20-23. 54. Connor J, Norton R, Ameratunga S, et al. Driver sleepiness and risk of serious injury to car occupants: population based case control study. BMJ 2002;324:1125-1129. 55. Dawson D, McCulloch K. 2005. Managing fatigue: it’s about sleep. Sleep Med Rev 2005;9:365-380. 56. International Civil Aviation Authority. Safety Management Manual (SMM). Doc. 9859 AN 460. Montreal: International Civil Aviation Authority; 2006. 57. Flight Safety Foundation. Fatigue risk management system helps ensure crew alertness, performance. Flight Safety Digest 2005;26: 16-19. 58. Gander PH. Fatigue management in air traffic control: the New Zealand approach. Transport Res Part F 2001;4:49-62. 59. National Center for Sleep Disorders Research. National Sleep Disorders Research Plan. NIH Publication No. 03-5209 2003. Available at: http://www.nhlbi.nih.gov/health/prof/sleep/res_plan/index.html. Accessed September 12, 2009. 60. Amalberti R. The paradoxes of almost totally safe transportation systems. Safety Science 2001;37:109-126. 61. Gander PH, Nguyen D, Rosekind MR, et al. Age, circadian rhythms, and sleep loss in flight crews. Aviat Space Environ Med 1993; 64:189-195. 62. Bonnefond A, Harma M, Hakola T, et al. Interaction of age with shift-related sleep–wakefulness, sleepiness, performance, and social life. Exp Aging Res 2006;32:185-208. 63. Taylor JL, Kennedy Q, Noda A, et al. Pilot age and expertise predict flight simulator performance. Neurology 2007;68:648-654.
768 PART II / Section 9 • Occupational Sleep Medicine 64. Folkard S. Transport: rhythm and blues: the 10th Westminster Lecture on transport safety. London: Parliamentary Advisory Council for Transport Safety; 1999. p. 1-32. 65. Gander PH, Marshall NS, Bolger W, et al. An evaluation of driver training as a fatigue countermeasure. Transport Res Part F 2005; 8:47-58 66. Robens Lord A. Safety and health at work. Report of the committee 1970-1972. London: Her Majesty’s Stationery Office; 1972. 67. Stewart S. An integrated system for managing fatigue risk within a low cost carrier. In: Enhancing safety worldwide: proceedings of the 59th Annual International Air Safety Seminar, Paris, October 23-26, 2006. Red Hook, NY: Curran Associates, Inc; 2007.
68. Signal TL, Ratieta D, Gander PH. Flight crew fatigue management in a more flexible regulatory environment: an overview of the New Zealand aviation industry. Chronobiol Int 2008;25:373-388. 69. Transport Canada. Moving forward changing the safety and security culture—a strategic direction for safety and security management. Transport Canada Publication TP 14678; 2007. Available at: http:// www.tc.gc.ca/publications/app/en/corral.asp?itemid=50889&tpnum ber=14678&language=US&source=istore. Accessed September 12, 2009. 70. Parks P, Durand G, Tsismenakis AJ, Vela-Bueno A, Kales S. Screening for obstructive sleep apnea during commercial driver medical examinations. J Occup Environ Med 2009;51:275-282.
Drowsy Driving
Pierre Philip, Patricia Sagaspe, and J. Taillard Abstract Drowsiness and falling asleep at the wheel are now identified as the reasons for many fatal crashes and traffic accidents. For years, fatigue has been associated with the risk of accidents but the causes of fatigue were unclear. Extended hours and nocturnal driving have been associated with accidents, but few reports differentiate fatigue from sleepiness. In the early 1990s, researchers using epidemiologic data began investigating sleepiness and sleep deprivation as causes of accidents. Falling asleep at the wheel associated with sleep restriction and nocturnal driving has been incriminated in 20% of traffic accidents. Drugs affecting the central nervous system (i.e., benzodiazepines, narcotic analgesics, and antihistamines), nocturnal breathing disorders, and narcolepsy also have been associated with an increased risk of accidents. Interestingly, chronic daytime sleepiness in monotonous circumstances (i.e., watching television or reading) is not associated with accident risk but situational sleepiness (i.e., drowsy driving) increases the risk of accidents very significantly. Several articles show that objective measures of sleepiness such as the Multiple Sleep Latency Test or Maintenance of Wakefulness Test can predict accident rates or deteriorated driving performance. Further studies before and after treatment are required in patients with obstructive sleep apnea as well as other types of sleep disorders involving drowsy driving
Traffic accidents are an increasing cause of death and injury in the world, and major countries have launched road safety campaigns in recent decades to decrease mortality and morbidity on their roads.1 Alcohol and excessive speed have been highlighted in the past years as major killers, but quite surprisingly the health status of drivers has received little attention as a cause of accidents. For many years fatigue has been associated with an increased risk of accidents, but the causes were unclear. Extended or nocturnal work or driving was associated with accidents, but few reports differentiated fatigue, which is usually seen as due to driving time, from sleepiness, which is due to reduced sleep,2 extended time awake and/or being awake at the circadian trough,3 or drugs. Epidemiologic studies from the 1990s showed that sleep-related accidents represent up to 20% of all traffic accidents in industrial societies.4-6 Although drowsiness7-9 has been identified as the reason behind fatal road crashes and many industrial accidents,10 many people drive when alertness is at its lowest level. A case-control study6 has shown that driving between 2 and 5 o’clock in the morning multiplies 5.6-fold the risk of traffic accidents and that being sleepy at the wheel multiplies eightfold the risk of accidents, which gives a clear measure of the associated risk of drowsy driving. An Internet-based survey11 showed that inappropriate line crossings related to drowsy driving was a good
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(e.g., periodic leg movement syndrome, hypersomnia, insomnia, circadian rhythm disorders). This issue of evaluation is particularly crucial because studies show a major intersubject variability in response to sleep loss or sleep fragmentation. Treatments improving daytime vigilance (e.g., continuous positive airway pressure [CPAP] in obstructive sleep apnea) significantly reduce the risk of traffic accidents for a reasonable cost. On the other hand, drugs that promote alertness have never been evaluated regarding their protective effects with respect to sleep-related accidents. Many countries systematically evaluate medical disorders in professional drivers, but the criteria are still very heterogeneous; and an effort toward harmonization would be very beneficial, especially in Europe and the United States where drivers can cross several countries or states, each of which having different rules. Drowsy driving is still underdiagnosed, and sleep disorders are not well enough explored and treated in the exposed population of sedentary men. Sleep physicians also tend to pay insufficient attention to the problem of road safety in their clinical evaluation of nonprofessional drivers, and better awareness by the health community should help in reducing the risk of accidents. Public campaigns integrating notions of sleep hygiene and countermeasures (naps and coffee) as well as promotion of sleep medicine to combat drowsy driving could significantly improve road safety.
predictor of future sleep-related accidents, and a Swedish epidemiologic study showed that more than 40% of the reported incidents involved crossing of the far right line before awaking and 16% involved crossing of the center line.12 Although both the European Union and the United States have launched public campaigns to make their citizens aware of the risk of drowsy driving (e.g., the U.S. National Sleep Foundation “Drive Alert–Arrive Alive” campaign), a major problem remains in the identification of patients or behaviors at risk for traffic accidents and the best way to reduce this risk by appropriate countermeasures. In this review we present an update on the relationship between the extrinsic or intrinsic sleep disorders, drug intake, and traffic accidents, the present state of knowledge, and what major studies are needed to improve our patients’ safety.
PREVALENCE AND ASSOCIATED RISKS Rest/Activity Patterns Behavioral changes affecting the sleep–wake pattern help explain sleep-related accidents. Studying large populations of drivers,13,14 we demonstrated that long-distance driving was very frequently associated with sleep curtailment. 769
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Several experimental studies showed that sleep restriction15 or nocturnal driving16 could drastically alter driving performances (i.e., number of inappropriate highway line crossings). Sleep deprivation affects not only the general population of automobile drivers but also many professional drivers all over the world. A study on professional truck drivers17 demonstrated a mean duration of sleep of 4.78 hours/day in a 5-day period. Fifty-six percent of drivers presented at least 6 noncontinuous minutes of electroencephalographic (EEG)-recorded sleep while driving. The vast majority of these microsleep episodes occurred during the late night and early morning. Not only do professional drivers have to drive under sleep restriction, health care workers are also affected by sleep loss and drive frequently after a night on call. A prospective survey18 in 2737 residents reported detailed information about work hours, work shifts of an extended duration, and documented motor vehicle accidents. The odds ratios for reporting a motor vehicle accident and for reporting a near-miss incident after an extended work shift, as compared with a shift that was not of extended duration, were 2.3 (95% confidence interval [CI], 1.6 to 3.3) and 5.9 (95% CI, 5.4 to 6.3), respectively. In 2008, researchers in one study19 showed that extensive nocturnal driving dramatically worsens driving performance. Eight hours of nocturnal driving increase sixfold the number of inappropriate highway line crossings compared with a 2-hour nocturnal driving session (3 to 5 am). These results suggest that fatigue related to driving duration is amplified at night so maximal driving duration should be shorter at night than during the day. Sleep Disorders Of all sleep disorders, obstructive sleep apnea syndrome is possibly the most studied pathologic process with regard to traffic accidents. Indeed, several studies performed in the past 20 years show a clear relationship between sleep disorders and traffic accidents.20-26 In a study comparing patients with sleep apnea to controls to evaluate the additional accident risk related to sleep-disordered breathing,27 patients with an apneahypopnea index (AHI) of 10 or higher had an odds ratio of 6.3 (95% CI, 2.4 to 16.2) for having a traffic accident as compared with those without sleep apnea. Researchers in another study28 found increased accident risk in 460 apneic patients, although only the most severe patients (AHI > 30) presented an accident risk factor higher than that of the controls. In a third study,29 the investigators performed an integrated analysis of recordings of sleeprelated breathing disorders and self-reported automotive and company-recorded automotive accidents in 90 commercial long-haul truck drivers. In this study, truck drivers with sleep-disordered breathing had a twofold higher accident rate per mile than drivers without sleep-disordered breathing. In contrast to the study cited earlier,28 accident frequency was not dependent on the severity of the sleeprelated breathing disorder.30 In another study on professional drivers,8 over 20% of long-haul drivers reported having dozed off at least twice while driving. Near misses due to dozing off had occurred in 17% of these drivers. There is debate about
the best predictive symptom for risk of sleep-related accidents. Surprisingly, excessive daytime sleepiness per se as measured by the Epworth Sleepiness scale (ESS) has not been associated with accident risk in apneic patients.27 This finding could be explained by a low percentage of chronically sleepy drivers (9% scored themselves above 10 at the ESS) in the studied population. In a case-control study31 of a series of 189 consecutive patients and a control group of 40 hospital staff workers, the best predictors of traffic accidents were self-reported sleepiness while driving (odds ratio [OR] 5; 95% CI, 2.3-10.9), having quit driving because of sleepiness (OR 3; 95% CI, 1.1-8.6), and being currently working (OR 2.8; 95% CI, 1.1-7.7). In a similar vein, a sample of 4002 randomly selected drivers32 were interviewed to define the prevalence of drivers who are habitually sleepy while driving. The habitually sleepy drivers reported a significantly higher frequency of vehicular accidents than control subjects (adjusted OR 13.3; CI, 4.1-43.0) and had a significantly higher prevalence of respiratory sleep disorders than control subjects. The authors concluded that habitually sleepy drivers are a large group (1 in 30 drivers) who are involved in severalfold more vehicular accidents than control subjects. More recently, in a meta-analysis33 on sleep apnea and driving risk, 23 of 27 studies and 18 of 19 studies with control groups found a statistically significant increased risk, with many of the studies finding a twofold to threefold increased risk. Sleep apnea is not the only disease responsible for excessive daytime sleepiness. Narcolepsy is a major disorder responsible for excessive daytime sleepiness, and it has also been studied as a risk factor for traffic accidents. Narcoleptic patients present a higher risk of sleep-related accidents than apneic subjects.21 The proportion of individuals with sleep-related accidents are 1.5- to 4-fold greater in the hypersomnolent patients than in the control group. Apneic and narcoleptic individuals account for 71% of all sleep-related accidents. The results of multiple sleep latency tests (MSLT) did not correlate with the rate of accidents among sleepy patients. However, the number of patients in the study with MSLTs was quite limited (46 apneic, 22 narcoleptic, 17 other causes of excessive daytime sleepiness), which could explain the lack of power of the study. It is worth noting that in all sleep disorders, victims of accidents presented with sleep latencies shorter than those of controls. Elevated risks for motor vehicle accidents due to sleepiness and cataplexy have been reported for persons with untreated narcolepsy.34 In one study,35 researchers compared the performance on the Divided-Attention Driving Test (DADT) of 21 male patients with obstructive sleep apnea, 21 sex-matched controls, and 16 narcoleptic patients. Narcoleptic patients were younger and sleepier than the obstructive sleep apnea patients. The tracking error was much worse in patients than in control subjects (228 ± 145 cm for obstructive sleep apnea vs. 196 ± 146 for narcolepsy vs. 71 ± 31 for controls; P < .001). Further studies on narcolepsy and hypersomnia are urgently needed to improve the understanding of the driving risk of these patients.
EVALUATION OF RISK IN PATIENTS WITH SLEEPINESS WHILE DRIVING Two studies31,32 concluded that asking a subject about excessive sleepiness while driving may better predict which subjects with sleep-disordered breathing have accidents than asking about overall sleepiness. For this reason, a thorough clinical interview can usefully evaluate patients’ driving risks in a vast majority of cases. Nevertheless, this strategy relies on a truthful, subjective assessment by the driver talking to the physician. Deceit cannot be excluded, especially in drivers dependent on their driving license for their job. Very few studies have investigated the relationship between objective measurement of sleepiness (MSLT or MWT scores) and driving performance. In a study41 of the Wisconsin Sleep Cohort, the authors found a correlation between MSLT scores and driving accidents in male apneic drivers. One study42 compared the MWT score with performance on a driving simulator in healthy sleep-deprived volunteers and found the first evidence of the predictive value of the MWT for driving performances. When additional studies were performed in a driving simulator and in real driving experiments, they confirmed that MWT scores are significantly associated with impaired driving (i.e., inappropriate highway line crossings) (Fig. 69-1).43,44 Further data are needed to understand the predictive value of the MWT on accidental risk in large cohorts of apneic and narcoleptic patients. IMPACT OF TREATMENT AND COUNTERMEASURES ON ACCIDENT RISK Given the sleep-related risk, a major question is how can accidents involving these patients be reduced? Uvulopalatopharyngoplasty was evaluated as a therapeutic strategy to reduce accidental risk.45 The authors compared the car accident rate of 56 apneic patients for the first 5 years after this surgery with the rate of the 5 years immediately before the operation. The risk of accidents of apneic patients was compared with that of a control group of subjects followed for nasal surgery. The reported habitual sleepiness while driving had disappeared in 87% (P < .001) of drivers who had the problem preoperatively, and the accident risk reduction (corrected for mileage) in patients was almost four times greater than the reduction in control subjects (P < .001) after surgery. Several studies investigating the impact of continuous positive airway pressure (CPAP) on traffic accidents46-48
Mean number of inappropriate line crossings (ILC)
Drugs Even if many publications36-40 associate central nervous system drugs and risk of accidents, very few data show a link between sleep-related accidents and drug intake. Indirect factors such as the type of drugs responsible for traffic accidents (i.e., hypnotics and benzodiazepines) suggest that sleepiness could be the major cause for drug-related accidents, but further evidence is needed.
CHAPTER 69 • Drowsy Driving 771
*
3 *
*
*
2
1
0 Very sleepy Sleepy Alert (0–19 min) (20–33 min) (34–40 min)
Controls
Maintenance of wakefulness test scores Figure 69-1 Mean number of inappropriate line crossings (ILC) during real driving (mean ± SE) in the three sleep latency groups on the Maintenance of Wakefulness Test (MWT) and in healthy controls. *P < .05. (From Philip P, Sagaspe P, Taillard J, et al. Maintenance of Wakefulness test, obstructive sleep apnea syndrome, and driving risk. Ann Neurol 2008;64:410-416.)
have confirmed that this therapy is associated with a reduction in the risk of motor vehicle accidents due to obstructive sleep apnea. No study has yet demonstrated in narcoleptics or hypersomnia patients the impact of drugs taken to promote alertness on accident rates. Although cold air or listening to the radio has not demonstrated any efficacy, coffee and naps are very efficient in combating sleepiness at the wheel.16,49-51 We have shown that subjects should select specific countermeasures according to their age or individual physiology.52 Indeed, a cup of coffee containing 200 mg of caffeine significantly improves performance in both young (20 to 25 years) and middle-aged participants (40 to 50 years) on nighttime highway driving performances, whereas a 30-minute nap is more efficient in younger than in middle-aged drivers.
DRIVING LICENSE REGULATIONS Excessive daytime sleepiness and several sleep disorders have been targeted by experts as medical conditions affecting driving skills. As part of the COST Action B-26, a review paper53 looked at driving license regulations in 25 European countries. Excessive daytime sleepiness is mentioned as a medical handicap for driving in 9 countries (Belgium, Finland, France, Germany, Hungary, the Netherlands, Spain, Sweden, the United Kingdom), whereas sleep apnea syndrome is mentioned in 10 countries (Belgium, Finland, France, Germany, Hungary, the Netherlands, Spain, Sweden, the United Kingdom, Poland). In all these European countries a patient with untreated obstructive sleep apnea syndrome is considered unfit to drive. However, even when excessive daytime sleepiness or sleep apnea is mentioned, no criteria for assessment of the sleep disorder are given. Finally, medical qualification of the physician applying the law is not clearly defined.
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Implications for the patients and the physicians are also very different in each country. In the vast majority of European Union countries, once a diagnosis of sleep disorder is made it is the physician’s responsibility to inform the administrative authorities issuing driving licenses of the driver’s condition. This is not the case in 4 countries (Belgium, France, Germany, and The Netherlands), where the physician is expected to inform the patient, but not the authorities, that he or she is unfit to drive. Medicolegal authorizations for driving once diagnosed with a sleep disorder rely on a certificate delivered by a general practitioner or specialist (pulmonologist or neurologist) in 8 countries (Belgium, Finland, France, Germany, Hungary, Spain, the United Kingdom, Poland). This certificate is based on a patient’s clinical improvement and therapeutic compliance, but in 2 countries the final decision for fitness to drive relies on the patient’s self-evaluation. Despite available scientific evidence,33 many countries in Europe do not yet include sleep apnea or excessive daytime sleepiness as risk factors for traffic accidents. A unified European directive seems desirable and should include several sleep disorders and excessive daytime sleepiness in the list of medical conditions adversely affecting driving skills.54 Nonprofessional and professional drivers are not subjected to the same medical evaluations. Frequency and type of evaluation differ dramatically. Commercial drivers have a major motivation to keep their driving license, and this can affect their reports of symptoms during the medical evaluation. In addition, Europe and the United States differ in how the driver’s income is calculated. In Europe, drivers are paid by the hour with a limit on the number of hours that can be driven in a day. In the United States, although there is a daily limit on driving and on duty hours, drivers are paid by the mile and thus are effectively encouraged to achieve the longest distance per day to maximize their income. Thus, it would appear that the risk of fatigue is higher in the United States. In addition to these differences in calculating pay, health status is also approached differently. Several states within the United States require physicians to report if a professional driver is affected by a sleep disorder. Such a reporting requirement can have dramatic consequences for the driver’s continued employment. The 1991 U.S. Department of Transportation Federal Highway Administration Recommendations reference a 1988 conference on Neurological Disorders and Commercial Drivers that recommended that a person with a diagnosis of narcolepsy be disqualified from driving commercially.55 This restrictive attitude regarding clinical conditions and driving fitness is not followed in Europe. As recommended by the task force of the American College of Chest Physicians,56 apneic professional drivers are submitted to a more permissive regulation than narcoleptic drivers and can go back to work after appropriate treatment. An apneic driver should be diagnosed by a physician and the diagnosis confirmed by polysomnography, preferably in an accredited sleep laboratory and by a certified sleep specialist. A full-night study should be done unless a split-
night study is indicated (severe obstructive sleep apnea identified after at least 2 hours of sleep). Treatment (with CPAP) should be started as soon as possible (i.e., within 2 weeks of the sleep study). At a minimum of 2 weeks after initiating therapy, but within 4 weeks, the driver should be re-evaluated by the sleep specialist and compliance assessed. If the driver is compliant, the driver can return to work but should be initially certified for no longer than 3 months. Such an approach reduces health care and disability costs.57 In Europe, driving regulations are similar to U.S. recommendations for apneic commercial drivers with minor changes in terms of period of evaluation (e.g., 1 year in France). Finally, whereas some countries consider sleepiness while driving as the major problem regarding driver safety, only France requires an objective quantification of alertness (the Maintenance of Wakefulness Test) to evaluate fitness to drive. This specific position refers to the frequent combination of sleep disorders and poor sleep hygiene in truck drivers. To ensure legal protection for drivers and physicians, French experts estimated that it was mandatory to demonstrate objectively that patients respond to treatment before allowing them to drive again. In case of a sleep-related accident in treated drivers, physicians could not be sued for insufficient efficacy of treatment and patients should not be prosecuted for misreporting the beneficial effects of treatments.
FUTURE CONSIDERATIONS Although much has already been done in this field, many questions remain unanswered. At the diagnostic level there is still no simple objective measure to quantify the risk to our patients as are available for other accident risk factors (e.g., using a breathalyzer for alcohol testing). Ideally, we need a “somnotest” to quantify the driving risk, but up to now driving simulators or EEG measures have provided only indirect and variable estimation of the driving risk and are obviously not practicable for field use outside the clinic or laboratory. Treatments other than CPAP or uvulopalatopharyngoplasty could provide an interesting alternative to prevent accidents, but there are still no data on the impact of alertness substances on the driving risk of apneic individuals and oral appliances have not yet been studied regarding driving risk. Studying the impact of extensive driving in treated and untreated patients is also a key factor in the research agenda because of the high prevalence of sleep-disordered breathing in professional drivers. More studies are needed to better define the phenotype of apneic individuals involved in traffic accidents. Whereas only 1 patient of 30 with sleep-disordered breathing is a victim of a sleeprelated accident, it is urgent to track these subjects and develop special evaluations plus driving recommendations (e.g., no nocturnal driving) for these drivers. New pharmacologic countermeasures should be tested, and interindividual response rates to these countermeasures need to be developed. Finally, public campaigns on the risks of drowsy driving and the effectiveness of naps and coffee as countermeasures need to be released in every country.
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❖ Clinical Pearl Drowsiness and sleeping at the wheel are now identified as the reasons behind many fatal traffic accidents. Drowsiness from sleep restriction and nocturnal driving have been incriminated in 20% of traffic accidents. Drugs affecting the central nervous system, sleep-disordered breathing, and narcolepsy have also been associated with an increased risk of accidents. Caffeine or naps have shown a great efficacy to decrease driving impairment in sleepy drivers, but medical treatments such as CPAP are also effective to decrease accidental risk in those with sleep apnea. Many countries systematically evaluate medical disorders among professional drivers, but criteria are still very heterogeneous and an effort toward harmonization would be very beneficial. Objective measurements of sleepiness such as the Maintenance of Wakefulness Test can provide important information in addition to questions on subjective sleepiness while driving. Finally, public awareness on the danger of drowsy driving needs to be reinforced and physicians should play a key role in these educational programs.
REFERENCES 1. World Health Organization. World report on road traffic injury prevention. Geneva: WHO; 2004. 2. Jewett ME, Dijk DJ, Kronauer RE, et al. Dose-response relationship between sleep duration and human psychomotor vigilance and subjective alertness. Sleep 1999;22:171-179. 3. Dijk DJ, Czeisler CA. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci 1995;15:3526-3538. 4. Horne JA, Reyner LA. Sleep related vehicle accidents. BMJ 1995; 310:565-567. 5. Philip P, Vervialle F, Le Breton P, et al. Fatigue, alcohol, and serious road crashes in France: factorial study of national data. BMJ 2001;322:829-830. 6. Connor J, Norton R, Ameratunga S, et al. Driver sleepiness and risk of serious injury to car occupants: population based case control study. BMJ 2002;324:1125. 7. Connor J, Whitlock G, Norton R, et al. The role of driver sleepiness in car crashes: a systematic review of epidemiological studies. Accid Anal Prev 2001;33:31-41. 8. Hakkanen H, Summala H. Sleepiness at work among commercial truck drivers. Sleep 2000;23:49-57. 9. Hakkanen H, Summala H. Fatal traffic accidents among trailer truck drivers and accident causes as viewed by other truck drivers. Accid Anal Prev 2001;33:187-196. 10. Mitler MM, Carskadon MA, Czeisler CA, et al. Catastrophes, sleep, and public policy: consensus report. Sleep 1988;11:100-109. 11. Powell NB, Schechtman KB, Riley RW, et al. Sleepy driver nearmisses may predict accident risks. Sleep 2007;30:331-342. 12. Sagberg F. Road accidents caused by drivers falling asleep. Accid Anal Prev 1999;31:639-649. 13. Philip P, Ghorayeb I, Stoohs R, et al. Determinants of sleepiness in automobile drivers. J Psychosom Res 1996;41:279-288. 14. Philip P, Taillard J, Guilleminault C, et al. Long distance driving and self-induced sleep deprivation among automobile drivers. Sleep 1999;22:475-480. 15. Philip P, Sagaspe P, Moore N, et al. Fatigue, sleep restriction and driving performance. Accid Anal Prev 2005;37:473-478. 16. Philip P, Taillard J, Moore N, et al. The effects of coffee and napping on nighttime highway driving: a randomized trial. Ann Intern Med 2006;144:785-791. 17. Mitler MM, Miller JC, Lipsitz JJ, et al. The sleep of long-haul truck drivers. N Engl J Med 1997;337:755-761.
18. Barger LK, Cade BE, Ayas NT, et al. Extended work shifts and the risk of motor vehicle crashes among interns. N Engl J Med 2005;352:125-134. 19. Sagaspe P, Taillard J, Åkerstedt T, et al. Extended driving impairs nocturnal driving performances. Plos One 2008;3:e3493. 20. American Thoracic Society. Sleep apnea, sleepiness, and driving risk. Am J Respir Crit Care Med 1994;150:1463-1473. 21. Aldrich MS. Automobile accidents in patients with sleep disorders. Sleep 1989;12:487-494. 22. Findley LJ, Unverzagt ME, Suratt PM. Automobile accidents involving patients with obstructive sleep apnea. Am Rev Respir Dis 1988;1 38:337-340. 23. Cassel W, Ploch T, Peter JH, et al. [Risk of accidents in patients with nocturnal respiration disorders]. Pneumologie 1991;45 (Suppl. 1):271-275. 24. Haraldsson P-O, Carenfelt C, Diderichsen F, et al. Clinical symptoms of sleep apnea syndrome and automobile accidents. ORL J Otorhinolaryngol Relat Spec 1990;52:57-62. 25. Philip P. Sleepiness of occupational drivers. Ind Health 2005;43: 30-33. 26. Powell NB, Schechtman KB, Riley RW, et al. Sleepy driving: accidents and injury. Otolaryngol Head Neck Surg 2002;126: 217-227. 27. Teran-Santos J, Jimenez-Gomez A, Cordero-Guevara J. The association between sleep apnea and the risk of traffic accidents. Cooperative Group Burgos-Santander. N Engl J Med 1999;340:847-851. 28. George CF, Smiley A. Sleep apnea and automobile crashes. Sleep 1999;22:790-795. 29. Stoohs RA, Bingham LA, Itoi A, et al. Sleep and sleep-disordered breathing in commercial long-haul truck drivers. Chest 1995; 107:1275-1282. 30. George CF. Sleep apnea, alertness, and motor vehicle crashes. Am J Respir Crit Care Med 2007;176:954-956. 31. Lloberes P, Levy G, Descals C, et al. Self-reported sleepiness while driving as a risk factor for traffic accidents in patients with obstructive sleep apnoea syndrome and in non-apnoeic snorers. Respir Med 2000;94:971-976. 32. Masa JF, Rubio M, Findley LJ. Habitually sleepy drivers have a high frequency of automobile crashes associated with respiratory disorders during sleep. Am J Respir Crit Care Med 2000;162:1407-1412. 33. Ellen RL, Marshall SC, Palayew M, et al. Systematic review of motor vehicle crash risk in persons with sleep apnea. J Clin Sleep Med 2006;2:193-200. 34. Bartels EC, Kusakcioglu O. Narcolepsy: a possible cause of automobile accidents. Lahey Clin Found Bull 1965;14:21-26. 35. George CF, Boudreau AC, Smiley A. Comparison of simulated driving performance in narcolepsy and sleep apnea patients. Sleep 1996;19:711-717. 36. Barbone F, McMahon AD, Davey PG, et al. Association of roadtraffic accidents with benzodiazepine use. Lancet 1998;352:13311336. 37. Leveille SG, Buchner DM, Koepsell TD, et al. Psychoactive medications and injurious motor vehicle collisions involving older drivers. Epidemiology 1994;5:591-598. 38. Hemmelgarn B, Suissa S, Huang A, et al. Benzodiazepine use and the risk of motor vehicle crash in the elderly. JAMA 1997; 278:27-31. 39. Hauser RA, Gauger L, Anderson WM, et al. Pramipexole-induced somnolence and episodes of daytime sleep. Mov Disord 2000; 15:658-663. 40. Hu PS, Trumble DA, Foley DJ, et al. Crash risks of older drivers: a panel data analysis. Accid Anal Prev 1998;30:569-581. 41. Young T, Blustein J, Finn L, et al. Sleep-disordered breathing and motor vehicle accidents in a population-based sample of employed adults. Sleep 1997;20:608-613. 42. Banks S, Catcheside P, Lack LC, et al. The Maintenance of Wakefulness Test and driving simulator performance. Sleep 2005;28: 1381-1385. 43. Sagaspe P, Taillard J, Chaumet G, et al. Maintenance of Wakefulness Test as a predictor of driving performance in patients with untreated obstructive sleep apnea. Sleep 2007;30:327-330. 44. Philip P, Sagaspe P, Taillard J, et al. Maintenance of Wakefulness test, obstructive sleep apnea syndrome, and driving risk. Ann Neurol 2008;64:410-416. 45. Haraldsson PO, Carenfelt C, Lysdahl M, et al. Does uvulopalatopharyngoplasty inhibit automobile accidents? Laryngoscope 1995; 105:657-661.
774 PART II / Section 9 • Occupational Sleep Medicine 46. Krieger J, Meslier N, Lebrun T, et al. Accidents in obstructive sleep apnea patients treated with nasal continuous positive airway pressure: a prospective study. The Working Group ANTADIR, Paris and CRESGE, Lille, France. Association Nationale de Traitement a Domicile des Insuffisants Respiratoires. Chest 1997;112: 1561-1566. 47. George CF. Reduction in motor vehicle collisions following treatment of sleep apnoea with nasal CPAP. Thorax 2001;56:508-512. 48. Sassani A, Findley LJ, Kryger M, et al. Reducing motor-vehicle collisions, costs, and fatalities by treating obstructive sleep apnea syndrome. Sleep 2004;27:453-458. 49. Reyner LA, Horne JA. Evaluation of “in-car” countermeasures to sleepiness: cold air and radio. Sleep 1998;21:46-50. 50. Garbarino S, Mascialino B, Penco MS, et al. Professional shift-work drivers who adopt prophylactic naps can reduce the risk of car accidents during night work. Sleep 2004;27:1295-1302. 51. Reyner LA, Horne JA. Suppression of sleepiness in drivers: combination of caffeine with a short nap. Psychophysiology 1997;34:721-725. 52. Sagaspe P, Taillard J, Chaumet G, et al. Aging and nocturnal driving: better with coffee or a nap? A randomized study. Sleep 2007; 30:1808-1813.
53. Alonderis A, Barbe F, Bonsignore M, et al. Medico-legal implications of sleep apnoea syndrome: driving license regulations in Europe. Sleep Med 2008;9:362-375. 54. Rodenstein D. Driving in Europe: the need of a common policy for drivers with obstructive sleep apnoea syndrome. J Sleep Res 2008; 17:281-284. 55. Booker HE, Hauser WA, Chrokroverty S, et al. Executive summary: conference on neurological disorders and commercial drivers. Washington, DC: U.S. Department of Transportation; 1988, p 8. 56. Hartenbaum N, Collop N, Rosen IM, et al. Sleep apnea and commercial motor vehicle operators: statement from the joint task force of the American College of Chest Physicians, the American College of Occupational and Environmental Medicine, and the National Sleep Foundation. Chest 2006;130:902-905. 57. Hoffman B, Wingenbach DD, Kagey AN, Schaneman JL, Kasper D. The long-term health plan and disability cost benefit of obstructive sleep apnea treatment in a commercial motor vehicle driver population. J Occup Environ Med 2010;52:473-477.
Sleep and Performance Monitoring in the Workplace: The Basis for Fatigue Risk Management Jennifer McDonald, Dipali Patel, and Gregory Belenky Abstract Managing fatigue to reduce the risk of error, incident, and accident will depend on the evidence base built upon monitoring sleep and performance in the workplace. Fatigue, defined objectively as degraded operational performance, is a function of sleep, circadian rhythm, and workload. In the operational (field or workplace) environment, sleep can be measured subjectively by self-report or objectively using field- or workplace-friendly technology such as wrist actigraphy. Performance can be measured subjectively by self-report or objectively by performance measures added to the workplace (e.g., the psychomotor vigilance task), or measurement can be derived from the actual work performed using embedded metrics (e.g., lane deviation in commercial trucking). Sleep and performance studies conducted in the workplace reveal that performance is impaired by sleep loss and that performance is restored by sleep (main sleep period and
Imagine a near future in which unobtrusive, continuous, personal biomedical status monitoring is ubiquitous. A personal biomedical status monitor could measure a host of parameters, including metabolic indices (e.g., blood glucose, caloric expenditure), cardiovascular parameters (e.g., blood pressure, electrocardiogram), and inflammatory markers (e.g., C-reactive protein). It could guide medical treatment in the chronically ill, help sustain health and well-being in the healthy, and, combined with objective measures of work performance, sustain productivity and safety in the workplace. Components of such a system are already in use (e.g., continuous glucose monitoring in patients with diabetes, electrocardiographic monitoring to trigger defibrillation in patients with arrhythmias). With respect to occupational sleep medicine, comprehensive biomedical status monitoring could include measurement of sleep–wake history (e.g., by actigraphy) and circadian phase (method to be developed) and could be used as input for biomathematical models predicting, in real time, fatigue-related performance decrements. These predicted individual performance decrements, calibrated and validated against embedded-in-the-workplace measures of performance (e.g., changes in lane deviation in commercial drivers, flight operations quality assurance [FOQA] data in commercial pilots) and integrated into the objective function of existing commercial rostering and scheduling software, could enable the implementation of system-wide fatigue risk management systems to improve safety and productivity. Such fatigue risk management systems could be capable of continuous, real-time optimization and reoptimization of rosters and schedules ensuring the best possible sleep opportunity, monitoring the use made of this opportunity, and monitoring actual performance in the workplace.
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naps). It appears that it is total sleep in 24 hours that determines performance and that an amount of actual sleep split into two or three sleep periods is as performance sustaining as the same amount of actual sleep consolidated into a single sleep period. Sleep and performance studies conducted in the workplace can inform the development of interventions to counteract the effects of fatigue on workplace performance, a primary intervention being to provide adequate opportunity for and proper circadian placement of sleep, including both main sleep period and naps. It is possible to imagine a system of workplace fatigue risk management using real-time measurement of sleep and performance as inputs to biomathe matical models predicting performance and using these performance predictions to optimize scheduling in real time. Such fatigue risk management would preserve performance, productivity, and safety, and would likely sustain long-term health and well-being in working people.
Fatigue risk management, as conceptualized here, will depend on the real-time, objective measurement of sleep– wake history, circadian phase, and performance. In anticipation of fatigue risk management through monitoring of personal biomedical status, prediction of performance, and integration of predictions into rostering and scheduling software, this chapter reviews the findings of field studies on the effects of shift timing and duration and subsequent sleep on postsleep performance. Granted that the findings of such studies are very much after the fact compared to the real-time optimization through measurement envisioned here, they nevertheless give an idea of what is to come and suggest the utility of such studies in developing evidence-based fatigue risk management (see Chapter 68).
SLEEP, CIRCADIAN RHYTHM, WORKLOAD, AND OPERATIONAL PERFORMANCE Sleep and Sleep Loss Sleep loss (sleep deprivation and sleep restriction) leads to fatigue, operationally defined subjectively by self-report and objectively by degraded alertness and cognitive performance. Sleep loss related fatigue is largely a function of three interacting factors: sleep–wake history, circadian rhythm, and workload (see Chapter 65). Performance and its inverse, sleep propensity, vary over the 24-hour period of a day, in parallel with the sinusoidal circadian rhythm in core body temperature.1 Working night shifts or travelling across time zones disrupts the normal relationship between sleep and work timing and the circadian rhythm and impairs sleep, alertness, and performance 775
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(see Chapter 71). Workload—roughly task duration, complexity, and intensity—contributes to performance degradation by increasing effects of time on task and decreasing sleep opportunity.2 In addition, there are enduring individual differences in response to sleep loss and in the relationship of circadian phase to the light dark cycle.3 Laboratory studies have demonstrated that both acute total sleep deprivation and chronic partial sleep restriction lead to declines in alertness and cognitive performance, well-being, and health. Acute total sleep deprivation degrades cognitive performance linearly over days, modulated within days by the circadian rhythm, with a loss in the capacity to do useful mental work of 17% to 25% per day.4,5 Mild, moderate, and severe sleep restriction (7, 5, or 3 hours in bed per night for 7 days, respectively) leads to sleep-dose-dependent decreases in performance over time in comparison to baseline or to sleep augmentation (9 hours in bed per night).6 For 7 and 5 hours in bed per night, performance appears to stabilize at lower levels after 3 or 4 days, but for 3 hours in bed per night, performance continues to degrade across the 7-day experimental period. In a parallel study, chronic sleep restriction of 6 and 4 hours in bed per night for 14 days led to cognitive decrements comparable to 1 to 2 days of total sleep deprivation, also in a sleep-dose-dependent manner.7 Even mild sleep restriction (7 hours in bed per night) degraded performance over time.6 In the first study,6 at the end of the 7-day sleep restriction period participants were allowed 8 hours in bed per night recovery sleep for 3 nights. In contrast to acute total sleep deprivation, where recovery is complete in 1 to 2 days, performance in the 7, 5, and 3 hour time in bed groups did not recover over the 3-day recovery period. Sleep loss and fatigue lead to decreased efficiency and productivity in the workplace, increased accidents, and economic losses, in the form of additional costs to employers and employees and to society as a whole.8 Furthermore, sleep loss is associated with significant adverse effects on mental and physical health, including weight gain and obesity,9 hypertension and cardiovascular problems,10 gastrointestinal disease, chronic fatigue, substance and alcohol abuse, family problems, and mood difficulties.11 Thus, the adverse effects of sleep loss and sleep loss–related fatigue are varied and far reaching. Circadian Rhythm The circadian rhythm (the sinusoidal 24-hour rhythm of the endogenous biological clock) modulates alertness, performance, and sleep propensity (see Section 5). The circadian rhythms in performance and sleep propensity parallel the circadian rhythm in core body temperature. The rhythm in performance peaks subsequent to the peak in the circadian temperature rhythm and troughs subsequent to the trough in circadian temperature rhythm. Performance is modulated by circadian rhythm both when persons are well rested and when they are sleep deprived or sleep restricted. With respect to sleep propensity, it is difficult to fall asleep and to stay asleep when core body temperature is rising or high; it is easy to fall asleep and to stay asleep when core body temperature is falling or low. In modulating fatigue risk, the circadian rhythm
modulates the risk of injury, a correlate of decreased performance. Risk of injury increases depending on the shift worked, with the lowest rates of injury risk on morning shifts and highest rates on night shifts.12 Injury rates on the job are highest during the late night and early morning circadian low.12 Mild to moderate sleep loss, common for night shift workers who typically experience restricted sleep during the day,13 leads to declines in performance.6 Thus, both sleep–wake history and the circadian rhythm modulate alertness, sleep propensity, and performance. Workload and Operational Environment Workload is not well defined and not easily measured in either laboratory or field. As an expedient, studies have equated workload with work task duration. Five factors are related to workload that operate to impair performance.14 These include time on task, task sequence, time of day, number of tasks performed, and whether sleep loss is partial or total. Fatigue as a result of time on task has been shown to be relieved by breaks within the shift.9 Thus, fatigue from time on task recovers after a simple break from the task and does not require sleep. In contrast, fatigue and performance decrements related to time awake can only be reversed by sleep.15 Overall, the fatigue resulting from working long hours or overtime shifts increases the risk of accident.16 Workload, time of day, and sleep loss all interact to affect performance. The operational environment is defined as a work setting in which human performance plays a critical role and there is a high risk that if human performance degrades the system will fail. In the operational environment, the human in the operational loop has limited time to decide and act upon a course of action.2 Operational environments include military operations, maritime operations, medicine, the various modes of land transportation, aviation, security work, energy generation, resource extraction (e.g., mining), financial markets, and industrial production. In these settings, the operational demands described previously (shift timing and duration, work intensity, and difficulty and complexity of the work tasks) degrade performance directly through the effects of workload and indirectly by reducing the amount of time available for sleep, thus reducing total sleep time, a primary determinant of alertness and performance.2 Degraded operational performance leads to a loss in productivity and a decrease in safety through increased risk of error, incident, and accident. Human error, with sleep loss as a contributing factor, has led to major disasters, including Chernobyl, Three Mile Island, and the Exxon Valdez,12 and probably the Challenger launch decision. Risk of accident increases approximately 18% on afternoon shifts and 30% on night shifts compared to risk on morning shifts, with risk increasing across successive nights worked.12 A significant increase in injury rates results from degraded operational performance.17 This risk extends past the end of the shift. The rate of motor vehicle accidents following night shift work is greater than that following day shift work.18 Thus, decreased operational performance resulting from fatigue decreases safety and productivity, increases the risk of error, incident, and accident, and can generate large economic losses.
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TECHNIQUES FOR MEASURING SLEEP AND PERFORMANCE IN THE OPERATIONAL ENVIRONMENT Historical Perspective In the 1980s, when one of us (G.B.) was directing the U.S. Army’s research program in sleep and performance, measuring sleep in the field environment by actigraphy was a relatively young, developing technology. We proudly presented our early field actigraph studies to U.S. Army Major General Maxwell Thurman, the then U.S. Army Deputy Chief of Staff for Personnel. General “Max” was not impressed. He harrumphed and said, “I don’t care how much they sleep, I want to know how well they perform.” An actigraphically recorded sleep–wake history is a marvel of applied information technology, but in itself an actigraphically derived sleep–wake history does not say much about the wearer’s performance. In response to General Max’s challenge, we developed a mathematical model that used sleep–wake history and estimated circadian phase as its inputs and yielded a minute-by-minute prediction of performance as its output. Our model and other similar models have become commercial products with application in the developing field of fatigue risk management.2,19 General Max would have been pleased: With actigraphy we will know how much people sleep, and applying mathematical models to the actigraphic data we will be able to predict how well they will perform. Measuring Sleep Sleep can be measured objectively using polysomnography (PSG) and actigraphy, and it can be measured subjectively using a sleep diary or other means of self-report. Polysomnography is the standard for sleep measurement in laboratory studies of sleep and performance. Using a network of electrodes, PSG measures the electrical potentials of the brain, eyes, and muscles and can determine sleep–wake status and the stages of sleep (see Chapter 141).20 PSG is not practical for data collection during field studies of sleep and performance, especially field studies attempting to capture running sleep–wake histories in multiple subjects over weeks and months. Actigraphy can accurately measure total sleep time and is validated as a measure of total sleep time against PSG (see Chapter 147).20 Thus, actigraphy can reliably (relative to PSG) assess the duration of main sleep periods and supplemental naps and thus provide a running sleep–wake history. The actigraph is a small, self-contained, wristwatch-size device worn on the nondominant wrist that sums arm movements over consecutive 60-second epochs, generating a minute-by-minute record of activity that can be scored for sleep–wake state by a validated sleep-scoring algorithm. This method can be used to collect continuous sleep–wake history data over consecutive 24-hour periods for weeks at a time and allows collection of an objective record of sleep–wake history (main sleep periods and naps) comparable to that obtained by PSG in a laboratory study.20 Sleep diaries allow a participant to record sleep time for a given time period based upon his or her subjective sense and recollection. Sleep diaries offer the advantages of being easy to implement and inexpensive. Sleep diaries can be useful as adjuncts to actigraphy because they can bridge
periods of data lost through actigraph malfunction or the actigraph being off the wrist. Performance and Total Sleep Time in 24 Hours Studies have demonstrated that performance is a function of total sleep time in 24 hours, regardless of whether the sleep is consolidated or split21 and irrespective of sleep stages (e.g., rapid eye movement [REM] sleep or non-REM [NREM] sleep and its stages). It does not appear to matter whether sleep is obtained in a single consolidated sleep bout or distributed in two or three bouts over 24 hours (split sleep). Given equal total sleep time, split sleep appears to sustain performance as well as sleep consolidated into a single sleep bout.21 Thus, total sleep time measured by actigraphy can be used to predict performance in operational settings.20,22 Performance and Napping Napping is potentially an effective way to augment total sleep time and improve performance in shift workers whose main sleep period occurs during the day and at an adverse circadian phase. Indeed, with any worker experiencing sleep restriction, napping to supplement the main sleep period improves performance.23,24 Napping may be the most effective way to counter fatigue, improving performance by increasing total sleep time.13 Total sleep time per 24 hours, including both main sleep period and napping, is the key to performance. Added, Simulator-Derived, and Embedded Performance Metrics Alertness and, broadly speaking, cognitive performance (attention, vigilance, learning, and memory) can be measured in the field by added, simulator-derived, or embedded performance metrics. Added metrics are those that are not intrinsic to the workplace and include self-report, laboratory tests ported to personal digital assistants (PDAs) and similar devices, and paper-and-pencil testing. Added metrics typically lack ecological validity. Simulator-derived metrics include performance in simulated work environments (e.g., driving simulators in commercial trucking, flight simulators in commercial aviation). Embedded performance metrics are taken from the workplace (e.g., lanedeviation sensors in commercial trucking, FOQA data in commercial aviation, and evaluation of workplace performance by expert raters). Embedded metrics are those intrinsic to the workplace and are almost by definition ecologically valid. An example of a laboratory test ported to a PDA to measure performance in field studies is the psychomotor vigilance task (PVT).25 The PDA-based PVT is a portable, self-contained, simple reaction time test that measures the ability to sustain attention and vigilance over time and is sensitive to time awake (sleep–wake history, sleep loss), time of day (circadian rhythm), and time on task (workload).26 Paper-and-pencil testing can include neuropsychological performance measures. Performance measures added to the work environment have been used in studies with medical residents.27 These added performance measures typically interrupt the normal flow of work and generally lack ecological validity.
778 PART II / Section 9 • Occupational Sleep Medicine
In contrast to added performance metrics, embedded performance metrics (e.g., lane deviation and FOQA) do not interrupt the flow of work and add ecological validity. Embedded metrics include measures of performance that can be derived from job performance, such as medical errors committed,28 observed attentional failures,29 injuries at work,30 critical incidents,31 performance of military tasks in field training exercises,32,33 driving errors,34,35 and, in commercial aviation, automated flight data recording.36 Finally, performance measures taken from workplace simulations (e.g., driving simulators) may be used in both field and laboratory studies. These add a degree of ecological validity to the investigation because they are designed to recreate in simulation actual job duties. Examples include studies investigating simulated motor vehicle driving,37 simulated train driving,38 simulated medical procedure completion,39 and simulated military operations.32,33
A REVIEW OF FIELD SLEEP AND PERFORMANCE STUDIES The literature on field studies of sleep and performance spans 50 years and involves diverse populations and a variety of methods. Recent studies have supported the development of systems for fatigue risk management within or as an alternative to prescriptive hours-of-service rules. These studies include work with medical professionals, commercial long-haul truck drivers, shift workers, and employees working extended hours (those who work long shifts or more than one shift per job per day). A focus of study has been medical professionals, with an emphasis on obtaining the evidence base to develop public policy with respect to medical residents’ work hours.18,28,29 The majority of these studies focus on the relationship between work hours and performance rather than the relationship between sleep and performance. The performance measures used fall largely into the three categories mentioned earlier: added metrics, embedded metrics, and metrics drawn from simulator performance. In studies showing a link between longer work hours and degraded performance, this link is presumably mediated by a combination of sleep loss, adverse circadian rhythm phase, and time on task. Similar to research with medical professionals, sleep and performance studies with commercial truckers have as their rationale relevance to safety and public policy development. Studies of driving performance have shown that long hours on duty or decreased sleep opportunity result in decreased vigilance as measured by PVT performance and speed limit violations,34 greater attentional lapses as measured by electrooculography (EOG),40 increased selfreported sleepiness,18 increased incidents or accidents,31 and increased lane deviation and speed variability.35 Similar studies have been conducted in the rail industry measuring sleep time, sleep opportunity, attention, and performance relevant to train conducting.34,38 Research on other shift workers has focused on schedule optimization and safety, with measurements concentrated on hours worked and hours slept. Night-shift workers suffer from chronic sleep restriction engendered by attempting daytime sleep at what is, in effect, an adverse circadian phase.23 Studies in shift workers have shown,
using either self-report or objective measures of sleep, a decrease in total sleep time in 24 hours due to hours worked or type of shift.41 Using objective measures of sleep, some studies find that working the night shift impairs sleep and degrades performance,41 and others find no relationship.42 In studies of night shift workers without objective measures of sleep, some have found degraded performance,43 and others have found no change.44 Another population of interest for objective work hours, sleep, and performance studies is workers who work extended work hours, either by virtue of working extended shifts or by working multiple shifts in one 24-hour period (e.g., working a double shift or holding two jobs). The literature on extended work hours is limited.45
METHODOLOGICAL FACTORS IN FIELD STUDIES OF SLEEP AND PERFORMANCE The methodological factors necessary for good field studies of sleep and performance include ecological validity, objective measures of sleep, objective measures of performance that are sensitive to sleep loss, control for circadian factors, and, if possible, an adequately rested control group.46 Studies in Military Field Training Exercises In the mid to late 1970s, researchers in the United Kingdom conducted two studies of sleep and performance in military field training exercises (Exercises Early Call I and Early Call II).32,33 These studies used objective metrics of performance including added, embedded, and simulated measures of performance and objective measures of sleep. In Early Call I, three platoons of airborne infantry, sleep condition randomized by platoon, were allowed a zero, 1.5-hour, or 3-hour sleep opportunity each night over a 10-day period. In Early Call II, soldiers were deprived of all sleep for 90 hours and then allowed a 4-hour sleep opportunity each night for the next 6 days. In both Early Call I and II, ecologically valid complex task performance (e.g., shooting at targets popping up at random) declined more than simple task performance (e.g., shooting a tight cluster of rounds at a fixed stationary target) during sleep loss. From Early Call I and II, it was concluded that soldiers were ineffective after 48 hours without sleep. From Early Call II, it was concluded that 4 hours of sleep opportunity produced recovery in cognitive functioning approximating values obtained during the control condition before sleep deprivation. This latter conclusion from Early Call II needs qualification. On closer examination, the daily 4-hour sleep opportunity in this study only partially restored performance after prolonged total sleep deprivation. Studies of Physicians in Training In medical settings, a substantial body of evidence demonstrates that sleep loss leads to decreased safety for patients, physicians, and the general public. Medical residents’ work schedules combine those of rotating shift workers and employees working extended hours, and have similar degrees of sleep loss and subjective complaints.47 Residents on call demonstrate decreased sleep as measured by
CHAPTER 70 • Sleep and Performance Monitoring in the Workplace: The Basis for Fatigue Risk Management 779
Table 70-1 Medical Residents’ Work, Sleep, and Medical Errors Work Schedule PARAMETER
TRADITIONAL*
INTERVENTION†
Work (hours/week)
84.9 (range, 74.2-92.1)
65.4 (range 57.6-76.3)
Maximum shift (hours)
34
16
Sleep (hours/day)
6.6 ± 0.8
7.4 ± 0.9
Serious medical errors per 1000 patient-days
136
100
*Work schedule allowed a maximum of 34 consecutive hours on duty and averaging 85 hours on duty per week. † Work schedule limited to a maximum of 16 consecutive hours on duty and averaging 65 hours on duty per week. Summarized from Landrigan CP, Rothschild JM, Cronin JW, et al. Effect of reducing interns’ work hours on serious medical errors in intensive care units. N Engl J Med 2004;351:1838-1848; and Lockley SW, Cronin JW, Evans EE, et al. Effect of reducing interns’ weekly hours on sleep and attentional failures. N Engl J Med 2004;351: 1829-1836.
actigraphy and decreased performance as measured by the PVT.48 Effect of Sleep on Task Performance Twenty medical interns (physicians in their first year of postgraduate of training) were compared working an “intervention” schedule (limited to a maximum of 16 consecutive hours on duty and averaging 65 hours on duty per week) versus working a “traditional” schedule (allowed a maximum of 34 consecutive hours on duty and averaging 85 hours on duty per week).28,29 Each intern served as his or her own control in this within-subjects design. On the intervention schedule the interns averaged more sleep than on the traditional schedule (7.4 ± 0.9 hours per day of sleep on the intervention schedule versus 6.6 ± 0.8 hours per day of sleep on the traditional schedule). In association with the decrease in maximum consecutive hours worked, reduction in hours worked per week, and increase in hours slept per day, interns made substantially fewer serious medical errors (100 medical errors per 1000 patient-days on the intervention schedule versus 136 medical errors per 1000 patient-days on the traditional schedule)28 (Table 70-1). Further investigations based on survey data from 2737 physicians in postgraduate training supported and extended these findings.28,29 These additional studies found that working extended hours (24 hours or more) compared to working a normal day shift increased automobile crashes, near misses, and falling asleep while driving.18 Working extended hours was also associated with increased medical errors, attentional failures (e.g., falling asleep during lectures, rounds, and patient care, including surgery), and fatigue-related adverse events resulting in fatality.”49 Finally, working extended hours was related to increased incidence rates of percutaneous needle sticks.30 These studies18,28-30,49 indicate a risk to physicians, patients, and
the general public from physicians working extended hours. They demonstrate that performance is impaired with extended work hours and (given the attentional failures) the ability to learn is likely impaired as well. Similarly, medical residents working a heavy call rotation (averaging 90 hours of work per week) showed degraded attention, vigilance, and simulated driving performance similar to those of persons with a blood alcohol concentration of 0.04 to 0.05 g/100 mL.46 These residents were less able to maintain speed and lane position, and they experienced more off-road accidents in the driving simulator after being on this heavy call rotation than residents working light call (averaging 44 hours of work per week). Further, when compared to the effects of alcohol ingestion, residents working heavy call had similar crash rates, attentional lapses, and slowing of reaction time, as well as 30% greater simulated speed variability. Effect of Sleep on Cognitive Performance Medical residents work extended hours providing patient care, and concurrently they are expected to learn new skills and new information. Alertness and attentional performance can be reliably measured using the PVT.25 Measuring learning and memory requires other tests. A meta-analysis of 60 studies investigating cognitive performance in health care professionals indicated that cognitive performance decreases with sleep loss.27 In health care professionals, vigilance and complex task performance appear to be more vulnerable to sleep loss than other functions.50 Consistent findings have come from studies using intelligence tests. Scores on an intelligence test taken after five consecutive day shifts were higher than scores obtained after five consecutive night shifts.51 This is consistent with findings from a study in medical residents in which the effect of one night’s sleep loss on test scores from the American Board of Family Practice In-Training Examination reduced the apparent level of training of these residents from 3 years to 1 year.52 Of the studies cited, only one made objective measures of sleep loss (measured through continuous PSG).29 One of the studies51 did not obtain any measure of sleep, and the remaining studies relied on self-reported sleep hours. Just one of the studies assessed the effects of chronic sleep restriction,53 the type of sleep loss engendered by extended work hours and shift work and typical of the schedules worked by medical residents. A Series of Field Studies in Other Industries Investigations with nonmedical shift workers include a series of studies by researchers investigating the relation of on-the-job sleepiness to total sleep time obtained while being on call or working the night shift.54-56 In railway locomotive engineers (train drivers), subjective and objective sleepiness increased during a night train trip.54 These data provide an indication of operational errors made when train drivers become fatigued, the prime example from this study being two drivers failing to respond to signals despite the presence of an observer.
780 PART II / Section 9 • Occupational Sleep Medicine
Ship engineers in the merchant marine on or off call for shipboard malfunctions were studied.55 While the time of going to bed and time of rising did not differ between on-call nights and nights free from duty, total sleep time was reduced by 1.5 hours on the on-call nights. This sleep reduction was due to the time spent responding to alarms while on call. A third study56 investigated paper mill workers who worked on a continuously rotating three-shift system (shift start times at 6 am, 2 pm, and 10 pm), working 2 to 4 days on each shift. PSG recordings were taken from these workers during two 24-hour periods, once while working nights and once while working afternoons. Consistent with the increased sleepiness while working the night shift54 and disturbed, truncated sleep while on call,55 it was found that the day sleep associated with night shift work was 2 hours shorter than the night sleep associated with afternoon shift work. Additionally, although no workers napped during the day while working afternoon shifts, 28% of the night-shift workers took an afternoon nap averaging 44 minutes in duration, and 20% of the night shift workers had a sleep period averaging 43 minutes while on duty during the night shift. When nap length was included in the total sleep time length, the total sleep time difference between nappers and nonnappers disappeared. Another study42 focused on how sleep and performance are affected by changing from a rotating three-shift schedule (8 hours per shift) to a rotating two-shift schedule (12 hours per shift), with total hours worked per week held constant. There was no increase in accidents when working the longer shift. Subjectively, workers felt they had improved sleep and more time with friends and family on the longer shift because they worked fewer days per week. There was a reduction in napping frequency when working the 12-hour shift schedule, from about 50% of workers taking an off-duty nap when on the 8-hour shift schedule compared to about 25% of workers on the 12-hour shift schedule. Night shift work was the focus of further studies in this series, including a study57 investigating adjustment to the night shift in oil rig workers in the North Sea working a 2-week schedule of 12-hour shifts, with the first week being a night shift (6:30 pm to 6:30 am) and the second week being a day shift (6:30 am to 6:30 pm). Using actigraphy to measure sleep and a 5-minute reaction-time task to measure performance, the authors found that unlike other field studies, and similar to laboratory studies in which the light–dark cycle is reversed, personnel appeared to adapt to night shift work as indicated by increasing sleep time and improving performance across successive days on the night shift. This successful adaptation was likely due to study participants living and working indoors so that moving to the night shift was accompanied by a reversal of the normal diurnal light– dark cycle. Driving Home after the Night Shift An additional experiment was conducted to investigate the effects of driving home following night-shift work.58 Shift workers participated in daytime simulated driving follow-
ing either a normal night of sleep or a night of night-shift work. The study found an increase in incidents while driving after working the night shift (7.6 ± 2.1) relative to driving following a night of sleep (2.4 ± 1.1). There were more accidents while driving after working the night shift. Blink duration was also longer after working the night shift. Subjective sleepiness was higher following the night shift than it was following a normal night of sleep. A follow-up analysis of these data40 found a relationship between ratings on the Karolinska Sleepiness Scale (KSS) with the objective driving measure of lateral position and duration of eye blink. More Studies in Train Drivers Sleep and performance in train drivers has been studied in simulated59 and actual extended railroad operations.34 Simulated train driving occurred in an 8-hour simulated shift testing period, with a daytime driving period following a night’s sleep and a nighttime driving period after drivers had worked two consecutive night shifts. For this study, the researchers calculated a fatigue score for each subject’s session based on a fatigue performance prediction model, the Fatigue Audit InterDyne (FAID) model.60 Attention and alertness, as measured by the PVT, decreased significantly as model-predicted fatigue increased. Additionally, extreme speed violations and penalty brake applications increased as fatigue increased. Fuel use and braking errors increased at low and moderate fatigue levels but decreased at high levels of fatigue. This improvement in measured driving performance at high fatigue levels may be associated with decreases in driving safety, as the authors postulate that these apparent improvements in driving performance reflect cognitive disengagement, a passive coping mode, in which the train drivers “let the train run itself.” Researchers34 conducted a field study of sleep and performance with 10 train drivers on a 106-hour relay that included an 18-hour layover. Each driver was run through two conditions: early schedule (those who drove immediately) and late schedule (those who rested in the crew van first). The relay operation began at 9:30 am and involved 8-hour shift rotations, with five or six between-shift rest opportunities available depending upon the shift schedule worked. There was an 18-hour layover before the return journey. Drivers had worse performance on the late schedule compared to the early schedule. Drivers obtained 4.86 ± 1.02 hours of sleep per 24 hours during the early rotation and 5.14 ± 0.40 hours total sleep per 24 hours during the late rotation. Drivers in this study favored use of a split-sleep strategy, consistent with other studies.21,61,62 Performance was not adversely affected by split sleep. It may be that the drivers’ splitting their sleep resulted in more optimal placement of sleep opportunity, thus improving subsequent performance. Finally, extended work hours in train drivers have been studied.63 Researchers found that early in the roster (including three 8-hour sleep opportunities) and late in the roster (including two 8-hour sleep opportunities) drivers obtained similar amounts of sleep during the trip (3.9 ± 1.1 hours and 4.2 ± 1.2 hours per sleep opportunity respectively); however, early-roster drivers’ sleep amounts
CHAPTER 70 • Sleep and Performance Monitoring in the Workplace: The Basis for Fatigue Risk Management 781
per sleep opportunity decreased as the trip progressed. PVT lapses for the late-roster drivers were more frequent toward the end of the trip, and alertness was lower in the final PVT.
mance prediction models.20,65 Further validation and development of these models through evidence gathered in field studies of sleep and performance will enable fatigue risk management.
USEFULNESS OF FIELD STUDIES OF SLEEP AND PERFORMANCE Field studies, such as those described here, provide us with information regarding sleep and performance in the workplace. In general, they support findings from laboratory studies. In some cases, field studies go beyond simple confirmation of laboratory work and reveal phenomena not found in laboratory studies (e.g., successful adjustment to night shift).57 Extended work hours and work during the night shift lead to decreased sleep and decreased performance, which in turn likely lead to increased risk of errors, incidents, and accidents. When interventions that improve scheduling and create more optimal sleep opportunities are implemented, sleep time increases and errors, incidents, and accidents decrease. These studies suggest the importance of investigating not only acute total sleep deprivation but also chronic partial sleep restriction, the latter being a more common occurrence in operational environments. Field studies of sleep and performance have application to the broader issues of sleep and performance including making public policy, developing standards of fitness for duty, optimizing schedules, and educating shift workers, and are essential to the emerging art and science of fatigue risk management. A notable success in the translation of research into recommendations for practice is the effect of field studies of sleep and performance in medical house staff on the recent Institute of Medicine report on resident duty hours.64
THE FUTURE OF SLEEP AND PERFORMANCE MONITORING IN THE WORKPLACE We anticipate that objective and subjective monitoring of sleep and performance in the workplace will play an increasingly important role in fatigue risk management to manage sleep and duty times to sustain optimal performance given operational constraints. Already studies of fatigue risk management are providing guidance for operational intervention and the construction of public policy around issues of fatigue in the workplace. Integrating such an approach and screening for sleep disorders management into the workplace may reduce health care and disability costs, and absenteeism.66
❖ Clinical Pearls Split sleep (two or three episodes in 24 hours) seems to be as effective as consolidated sleep in sustaining performance; thus, when the main sleep period is restricted or truncated, napping is an effective strategy to sustain performance. Measuring sleep and performance in the operational environment can provide the evidence base for safety and performance-enhancing changes in rostering and scheduling.
REFERENCES
SLEEP AND PERFORMANCE STUDIES AND THE MANAGEMENT OF FATIGUE-ASSOCIATED RISK OF ERROR, INCIDENT, AND ACCIDENT Sleep and performance studies in operational environments are the evidence base for managing fatiguerelated risk. The degraded alertness and cognitive performance resulting from sleep loss is largely a function of three factors: sleep–wake history, circadian rhythm, and workload (see Chapter 65). Certain aspects of the operational environment (e.g., working night shifts, transmeridian travel, shift timing and duration) can negatively affect those factors through disrupting circadian rhythms, increasing time-on-task effects, and decreasing the opportunity for sleep. The incorporation of fatigue risk management systems into an operational framework will translate the findings from the studies cited here into practical application in the 24/7 work environment and provide the evidence base for fatigue risk management and optimization of rostering and scheduling. Sleep–wake histories recorded in field studies can be used to predict performance on a minute-to-minute basis through the use of biomathematical sleep/perfor-
1. Van Dongen HPA, Dinges DF. Sleep, circadian rhythm, and psychomotor vigilance. Clin Sports Med 2005;24:237-249. 2. Wesensten NJ, Belenky G, Balkin TJ. Cognitive readiness in network-centric operations. Parameters 2005;94-105. 3. Van Dongen HPA, Baynard MD, Maislin G, et al. Individual differences in neurobehavioral impairment from sleep loss: evidence of a trait-like differential vulnerability. Sleep 2004;27:423-433. 4. Thomas ML, Sing HC, Belenky G, et al. Neural basis of alertness and cognitive performance impairments during sleepiness. I. Effects of 24 h of sleep deprivation on waking human regional brain activity. J Sleep Res 2000;9:335-352. 5. Thorne DR, Genser S, Sing H, et al. Plumbing human performance limits during 72 hours of high task load. In: Forshaw SE, editor. Proceedings of the 24th Defense Research Group Seminar on the Human as a Limiting Element in Military Systems. Toronto, Canada: Defense and Civil Institute of Environmental Medicine (DCIEM); 1983. p. 17-40. 6. Belenky G, Wesensten NJ, Thorne DR, et al. Patterns of performance degradation and restoration during sleep restriction and subsequent recovery: a sleep dose-dependent study. J Sleep Res 2003;12:1-12. 7. Van Dongen HPA, Maislin G, Mullington JM, et al. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 2003;26:117-126. 8. Folkard S, Lombardi DA, Tucker PT. Shiftwork: sleepiness and sleep. Industrial Health 2005;43:20-23. 9. Knutson K, Spiegel K, Penev P, et al. The metabolic consequences of sleep deprivation. Sleep Med Rev 2007;11:163-178.
782 PART II / Section 9 • Occupational Sleep Medicine 10. Meier-Ewert HK, Ridker PM, Rifai N, et al. Effect of sleep loss on C-reactive protein, an inflammatory marker of cardiovascular risk. J Am Coll Cardiol 2004;43:678-683. 11. Costa G, Akerstedt T, Nachreiner F, et al. Flexible working hours, health, and well-being in Europe: some considerations from a SALTSA project. Chronobiol Int 2004;21:831-844. 12. Folkard S, Tucker P. Shift work, safety, and productivity. Occup Med 2003;53:95-101. 13. Akerstedt T. Shift work and disturbed sleep/wakefulness. Occup Med 2003;55:89-94. 14. Balkin TJ, Bliese PD, Belenky G, et al. Comparative utility of instruments for monitoring sleepiness-related performance decrements in the operational environment. J Sleep Res 2004;13: 219-227. 15. Dawson D, McCulloch K. Managing fatigue: it’s about sleep. Sleep Med Rev 2005;9:365-380. 16. Dembe AE, Erickson JB, Delbos RB, et al. The impact of overtime and long work hours on occupational injuries and illnesses: new evidence from the United States. Occup Environ Med 2005;62: 588-597. 17. Brogmus G, Maynard W. Safer shift work through more effective scheduling. Occup Health Safety 2006;75:16. 18. Barger LK, Cade BE, Ayas NT, et al. Extended work shifts and the risk of motor vehicle crashes among interns. N Engl J Med 2005;352:125-134. 19. Mallis MM, Mejdal S, Nguyen TT, et al. Summary of the key features of seven biomathematical models of human fatigue and performance. Aviat Space Environ Med 2004;75:A4-A14. 20. Ancoli-Israel S. Actigraphy. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep med. 4th ed. Philadelphia: Elsevier Saunders; 2005; p. 1459-1467. 21. Belenky G, Hursh SR, Fitzpatrick J, et al. Split sleeper berth use and driver performance: a review of the literature and application of a mathematical model predicting performance from sleep/wake history and circadian phase. Report prepared for The American Trucking Associations. Sleep and Performance Research Center, Washington State University, Spokane, Wash, February 2008. 22. Wesensten NJ, Balkin TJ, Belenky G. Does sleep fragmentation impact recuperation? A review and reanalysis. J Sleep Res 1999;8: 237-245. 23. Akerstedt T. Is there an optimal sleep-wake pattern in shift work? Scand J Work Environ Med 1998;24:18-27. 24. Dhand R, Sohal H. Good sleep, bad sleep! The role of daytime naps in health adults. Curr Opin Pulmon Med 2006;12;379-382. 25. Dinges DF, Powell JW. Microcomputer analyses of performance on a portable, simple visual RT task during sustained operations. Behav Res Methods Instrum Comput 1985;17:652-655. 26. Wesensten NJ, Belenky G, Thorne DR, et al. Modafinil versus caffeine: effects on fatigue during sleep deprivation. Aviat Space Environ Med 2004;75:520-525. 27. Philibert I. Sleep loss and performance in residents and nonphysicians: a meta-analytic examination. Sleep 2005;28:13921402. 28. Landrigan CP, Rothschild JM, Cronin JW, et al. Effect of reducing interns’ work hours on serious medical errors in intensive care units. N Engl J Med 2004;351:1838-1848. 29. Lockley SW, Cronin JW, Evans EE, et al. Effect of reducing interns’ weekly hours on sleep and attentional failures. N Engl J Med 2004;351: 1829-1836. 30. Ayas NT, Barger LK, Cade BE, et al. Extended work duration and the risk of self-reported percutaneous injuries in interns. JAMA 2006;296:1055-1062. 31. Hanowski RJ, Hickman J, Fumero MC, et al. The sleep of commercial vehicle drivers under the 2003 hours-of-service regulations. Accid Anal Prev 2007;39:1140-1145. 32. Haslam DR. Sleep loss, recovery sleep and military performance. Ergonomics 1982;25:163-178. 33. Haslam DR. The military performance of soldiers in sustained operations. Aviat Space Environ Med 1984;216-221. 34. Darwent D, Lamond N, Dawson D. The sleep and performance of train drivers during an extended freight-haul operation. Appl Ergon 2008;39:614-622. 35. Marcus CL, Loughlin GM. Effect of sleep deprivation on driving safety in housestaff. Sleep 1996;19:763-766.
36. US General Accounting Office. Aviation safety: US efforts to implement flight operations quality assurance programs. Flight Safety Foundation Digest 1998;17:1-36. 37. Akerstedt T, Peters B, Anund A, et al. Impaired alertness and performance driving home from the night shift: a simulator study. J Sleep Res 2005;14:17-20. 38. Thomas GR, Raslear TG, Kuehn GI. The effects of work schedule on train handling performance and sleep of locomotive engineers: a simulator study. (Report No. DOT/FRA/ORD-97-09). Washington, DC: Department of Transportation; 1997. 39. Grantcharov TP, Bardram L, Funch-Jensen P, et al. Laparoscopic performance after one night call in a surgical department: a prospective study. BMJ 2001;323:1222-1223. 40. Ingre M, Akerstedt T, Peters B, et al. Subjective sleepiness, simulated driving performance and blink duration: examining individual differences. J Sleep Res 2006;15:47-53. 41. Signal TL, Gander PH. Rapid counterclockwise shift rotation in air traffic control: effects on sleep and night work. Aviat Space Environ Med 2007;78:878-885. 42. Lowden A, Kecklund G, Axelsson J, et al. Change from an 8-hour shift to a 12-hour shift, attitudes, sleep, sleepiness and performance. Scand J Work Environ Health 1998;24:69-75. 43. Smith L, Totterdell P, Folkard S. Shiftwork effects in nuclear power workers: a field study using portable computers. Work Stress 1995;9:235-244. 44. Peacock B, Glube R, Miller M, et al. Police officers’ response to 8 and 12 hour shift schedules. Ergonomics 1983;26:479-493. 45. Rosa RR. Performance, alertness, and sleep after 3-5 years of 12 h shifts: a follow-up study. Work Stress 1991;5:107-116. 46. Arnedt JT, Owens J, Crouch M, et al. Neurobehavioral performance of residents after heavy night call vs. after alcohol ingestion. JAMA 2005;294:1025-1033. 47. Epstein R, Tzischinsky O, Herer P. Can we consider medical residents as shift workers? J Hum Ergol 2001;30:375-379. 48. Saxena AD, George CFP. Sleep and motor performance in on-call internal medicine residents Sleep 2005;28:1386-1391. 49. Barger LK, Ayas NT, Cade BE, et al. Impact of extended-duration shifts on medical errors, adverse events, and attentional failures. PLoS Med 2006;3:2440-2448. 50. Rollinson DC, Rathlev NK, Moss N, et al. The effects of consecutive night shifts on neuropsychological performance of interns in the emergency department: a pilot study. Ann Emerg Med 2003;41: 400-406. 51. Dula D, Dula N, Hamrick C, et al. The effect of working serial night shifts on the cognitive functioning of emergency physicians. Ann Emerg Med 2001;38:152-155. 52. Jacques CH, Lynch JC, Samkoff JS. The effects of sleep loss on cognitive performance of resident physicians. J Fam Prac 1990;30:223-229. 53. Hawkins MR, Vichick DA, Silsby HD, et al. Sleep and nutritional deprivation and performance of house officers. J Med Educ 1985;60:530-535. 54. Torsvall L, Akerstedt T. Sleepiness on the job: continuously measured EEG changes in train drivers. Electroencephalogr Clin Neurophysiol 1987;66:502-511. 55. Torsvall L, Akerstedt T. Disturbed sleep while being on-call: an EEG study of ships’ engineers. Sleep 1988;11:35-38. 56. Torsvall L, Akerstedt T, Gillander K, et al. Sleep on the night shift: 24 hour EEG monitoring of spontaneous sleep/wake behavior. Psychophysiology 1989;26:352-358. 57. Bjorvatn B, Stangenes K, Oyane N, et al. Subjective and objective measures of adaptation and readaptation to night work on an oil rig in the North Sea. Sleep 2006;29:821-829. 58. Akerstedt T, Peters B, Anund A, et al. Impaired alertness and performance driving home from the night shift: a simulator study. J Sleep Res 2005;14:17-20. 59. Dorrian J, Hussey F, Dawson D. Train driving efficiency and safety: examining the cost of fatigue. J Sleep Res 2007;16:1-14. 60. Dawson D, Fletcher A. A quantitative model of work-related fatigue I: background and definition. Ergonomics 2001;44:144163. 61. Mollicone DJ, Van Dongen HPA, Dinges DF. Optimizing sleep wake schedules in space: sleep during chronic nocturnal sleep restriction with and without diurnal naps. Acta Astronaut 2007;60: 354-361.
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62. Mollicone DJ, Van Dongen HPA, Rogers NL, et al. Response surface mapping of neurobehavioral performance: testing the feasibility of split sleep schedules in space operations. Acta Astronaut 2008;63:833-840. 63. Lamond N, Darwent D, Dawson D. Train drivers’ sleep and alertness during short relay operations. Appl Ergon 2005;36: 313-318. 64. Institute of Medicine: Resident duty hours: enhancing sleep, supervision, and safety. Washington, DC: National Academies Press; 2008.
65. Hursh SR, Raslear TG, Kaye AS, et al. Validation and calibration of a fatigue assessment tool for railroad work schedules, a summary report. (Report No. DOT/FRA/ORD-06/21). Washington, DC: US Department of Transportation; 2006. 66. Hoffman B, Wingenbach DD, Kagey AN, Schaneman JL, Kasper D. The long-term health plan and disability cost benefit of obstructive sleep apnea treatment in a commercial motor vehicle driver population. J Occup Environ Med 2010;52:473-477.
Shift Work, Shift-Work Disorder, and Jet Lag Christopher L. Drake and Kenneth P. Wright Jr. Abstract Shift work and travel across time zones are commonplace in industrialized society. Adjustment to these circadian challenges requires abrupt and often large shifts in physiology to match behavioral changes in the timing of sleep–wake schedules. There are clear individual differences in the ability to adapt to this mismatch between circadian physiology and sleep–wake behavior. These differences can impact several areas of functioning, including the sleep–wake, cardiovascular, and gastrointestinal systems in certain individuals. Among the most common consequences of working at night are insomnia and excessive sleepiness, which contribute to other morbidity (e.g., accidents) and are the defining symptoms of shift-work sleep disorder (SWD). Those older than age 50 years and individuals with an early morning circadian preference appear more vulnerable to these effects of shift work. For the subset of individuals with SWD there remains a need to deconstruct the morbidity of the disorder into its causal components (i.e., insomnia, excessive sleepiness, and circadian desynchrony) and their interaction. Effective treatments for symptoms of SWD are available and include the use of nocturnal bright light and daytime darkness as well as sleep- and wake-
The increased use of technologies such as artificial light and jet aircraft have increased exposure to sleep–wake schedules that oppose internal circadian physiology. The ever-increasing societal pressure in industrialized countries to abandon the customary 9-to-5 workday results in job-driven schedules and sleep times that are at odds with endogenous rhythms, which are tightly regulated by the suprachiasmatic nucleus, the “master” biological clock. The abnormal sleep and wakefulness patterns experienced by shift workers are associated with significant morbidity and mortality. Although other chapters in this volume address the physiologic basis for conditions such as jet lag and shift-work disorder (SWD) in terms of biological regulation of the circadian system, the discussion in this chapter bridges basic science and laboratory studies and explores the implications of the underlying physiology to patient and public health. A summary is provided of available laboratory and field-based occupational health data that can inform the clinician and the patient as to clinical issues central to SWD and travel across time zones (jet lag).
SHIFT WORK Prevalence The current total working population of the United States is approximately 145.9 million.1 The prevalence of shift work (i.e., permanent night, rotating, and evening shifts) is difficult to determine. Estimates vary depending on the definition employed and the region studied, but U.S.based estimates suggest that nearly 20% of employed 784
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enhancing medications. The efficacy of such treatments for morbidity outside the sleep–wake system remains to be demonstrated. Jet lag is a common problem and symptoms include gastrointestinal disturbance, daytime fatigue, sleepiness, and insomnia. Cognitive impairments associated with jet lag can have serious consequences, resulting in drowsy driving and impaired decision-making. Because the average period of the circadian clock is longer than 24 hours, jet lag is typically worse after eastward than westward travel. Interventions such as the use of appropriately timed bright light and darkness can improve circadian adaptation to time zone changes. Other interventions including sleep-promoting agents and melatonin and its agonists (during the biological daytime) may promote sleep but may not improve wakefulness in the new time zone. Melatonin agonists are available, but no clinical trials have been reported to date regarding the efficacy of these medications for the treatment of jet lag. Preadaptation of the circadian clock, use of caffeine, and brief naps in the new time zone are useful countermeasures to promote wakefulness after jet travel across time zones and its associated sleep loss.
adults are shift workers. The proportion may be higher if workers with early-morning shifts and infrequent or irregular shifts are included. In the United States today, 17.7% to 25.9% of the total workforce start shifts between 2 pm and 6:30 am.2 These data suggest that between 25.8 and 37.8 million U.S. adults are shift workers on a regular or rotating basis. Data from other countries also indicate that a high prevalence of the population is engaged in shift work: in the United Kingdom, estimated prevalence is 22%; in Australia, 13%; in Greece, 25%; and in Finland, 25%.3,4 Not all individuals exposed to shift work develop SWD. Many factors, including scheduling differences, shift frequency, shift duration, family/social responsibilities, and differences in sleep and circadian physiology can affect an individual’s response to shift work and hence the development of SWD. These same factors are important influences on the development of jet lag and its impact on work performance and health. Types Although the literature is not always precise in defining shift work in terms of start times, the following classifications are based not only on statistics from the U.S. Department of Labor but also with respect to differences in circadian physiology. Night-Shift Workers Night-shift workers with regular start times between 6 pm and 4 am make up an estimated 4.25% of the total U.S. workforce.5 However, this is a conservative estimate because it does not include variable shift schedules.
Although some have speculated that permanent night work may have benefits in terms of circadian adjustment to shift work relative to variable shift schedules and have advised shift workers to stay on a night-shift schedule on days off, there is little support for this contention.6 Indeed, both objective and subjective measurements show that night shifts result in greater loss of total sleep time than eveningand slow rotating-shift schedules.7-9 Sleep loss accumulates and its impact grows over successive night shifts. The result is a buildup of homeostatic sleep debt combined with the effects of circadian misalignment, with both having serious implications for productivity and safety in shift workers. In fact, sleep loss alone has been shown to impair alertness and performance, including driving ability, as much as alcohol intake associated with a breath ethanol concentration up to 0.19%.10 Not surprisingly, the night shift produces the greatest degree of sleepiness relative to daytime work, evening shifts, and even rotating shifts, with the sleepiness greatest during the early morning hours close to commute times.11,12 Early Morning-Shift Workers The International Classification of Sleep Disorders (ICSD) classifies early morning shifts as those starting between 4 am and 7 am.13 This is the most common alternate work shift with at least 18.1 million U.S. workers (12.4% of the workforce) falling into this category.5 Given these start times many early morning-shift workers wake before 5 am. As a consequence, these workers are likely to be on the road at their nadir of circadian alertness and may also be particularly sleep deprived, owing to their early time of rising. This is consistent with the high rate of excessive sleepiness reported in this population.14 Using objective measures of sleep, Kecklund and colleagues showed that early morning-shift workers accrue significantly less sleep than those who work during the day; stage 2 and rapid eye movement (REM) sleep were particularly reduced.14 Indeed, their sleep disturbance is close to that of permanent night workers.15 These factors, coupled with severe sleep inertia at that hour,16 suggest that early morning-shift workers may have the highest risk of all workers for automotive accidents. Further examination of the prevalence of excessive sleepiness and resultant risk of accidents in this specific population is needed. Evening/Afternoon-Shift Workers Evening-shift workers with regular start times between 2 pm and 6 pm make up 4.3% of all U.S. workers5 and can be impaired in terms of social isolation and quality of life.17 Although the literature clearly documents the presence of significant morbidity in shift workers, not all shifts are associated with these effects. In fact, the average eveningshift worker actually sleeps 7.6 hours/night,8 which is longer than most day workers (6.8-7.0 hours/night).12 As noted, the human circadian pacemaker has an intrinsic period that is on average slightly longer than 24 hours.18 The resulting tendency to delay internal rhythms combined with schedules that allow later morning wakeup times may account for the increased total sleep time of evening-shift workers. However, some evening-shift workers have shortened sleep times due to family obliga-
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tions that require earlier wakeup times on days off that could result in significant impairment over time. Rotating-Shift Workers The U.S. population is estimated to include 4 million rotating-shift workers (approximately 2.7% of the total workforce),2 but nearly all shift workers could be considered to have rotating schedules because most (particularly married workers) revert to a normal pattern of nocturnal sleep during days off. Nonetheless, even on their days off, rotating-shift workers remain sleepier than daytime workers.19 In a meta-analysis of sleep patterns, workers on rotating shifts had nearly as much sleep reduction as permanent night workers relative to day workers.8 Workers with regular rotating shift schedules face additional challenges related to the speed and direction of shift rotations. Rapid shift rotations (e.g., multiple rotation within a week) are associated with reduced total sleep duration compared with slower rotations (e.g., at least 3 weeks per shift schedule).8 In terms of direction, both rapid clockwise and counterclockwise rotations negatively impact total sleep duration and increase circadian misalignment.20 These effects are thought to be less severe for workers experiencing a clockwise rotation because of the natural tendency of the circadian clock to delay to a later time18 and increased time between shifts. However, shift direction and duration may interact, with findings from at least one controlled study showing that clockwise and counterclockwise rotations in rapidly rotating shift systems are not significantly different in terms of either total sleep duration or degree of excessive sleepiness.21 Some individuals have circadian clock periods that are shorter than 24 hours, and they would be expected to adapt more easily to counterclockwise shift rotations. Prior to a counterclockwise rotation, 80% to 90% of workers nap before the midnight shift, as opposed to only 40% to 60% before a clockwise rotation, which may help to ameliorate some of the expected impairments in sleep and sleepiness during a counterclockwise rotation. This interpretation is also consistent with numerous studies demonstrating the beneficial effects of napping among shift workers.22,23 Circadian Misalignment and Effects of Light Exposure Human physiology is organized by the internal circadian clock such that sleep and its associated functions are promoted during the biological night, when levels of the hormone melatonin are high, and wakefulness and its associated functions are promoted during the biological day, when endogenous melatonin levels are low.24 The internal circadian clock in humans has a period that is on average slightly longer than 24 hours,18 and thus the average adult requires the phase and period of his or her internal clock to be reset on a daily basis to remain entrained to the 24-hour day.25 Light is the dominant environmental time cue that entrains the human circadian clock to the 24-hour day, and the timing of light exposure will determine whether the internal clock is phase delayed or advanced (Fig. 71-1).26 Circadian misalignment can be caused by schedules induced by shift work and jet travel that rapidly alter exposure to environmental time cues and require wakefulness during the biological night and
Maximum phase advance with melatonin
Maximum phase advance with light
Phase shift
Delay westward
Advance eastward
786 PART II / Section 9 • Occupational Sleep Medicine
Maximum phase delay with light
14 17 20 23 2
Maximum phase delay with melatonin 5
8 11 14 17 20 23
Approximate clock hour for someone with a bedtime at 24:00 hr Figure 71-1 Schematic representation of the phase response curves to 1 day of light exposure (6.7 hrs) (blue line) and 3 days of 3 to 5 mg of exogenous melatonin administration (red line) when the circadian system is entrained to local environmental time. The circadian phase resetting response to light and melatonin depends on the internal biological time of exposure. Generally, bright light exposure before habitual bedtime and several hours thereafter will induce the largest westward phase delays, whereas bright light exposure just before the habitual time of awakening and several hours thereafter will induce the largest eastward phase advances. The time at which phase delays cross over to phase advances is on average about 2.5 hours before the habitual time of awakening in young adults and about 2 hours in older adults.153 Therefore, bright light exposure too close to the crossover point may shift the circadian phase in a direction opposite to what is desired. Opposite to the effects of light, ingestion of exogenous melatonin in the late afternoon will induce the largest eastward phase advances, whereas melatonin ingestion shortly after the habitual time of awakening and several hours thereafter will induce the largest westward phase delays. The time at which melatonin-induced phase delays change to phase advances is, on average, in the early afternoon.103,104
sleep during the biological day. The resulting circadian misalignment associated with shift work and jet lag can produce significant morbidity associated with disturbed sleep, impaired alertness, as well as a direct effect of circadian misalignment. Morbidity Associated with Shift Work Sleepiness and Insomnia Among the most common problems experienced by shift workers are excessive sleepiness and insomnia, resulting from imposition of a sleep–wake schedule that opposes the body’s internal circadian clock.27,28 For example, measures of sleepiness in anesthesia residents demonstrate impaired alertness after a single night shift similar to levels observed in sleep disorders.29 Chronic shift work tends to increase the sleepiness, because shift workers may further deprive themselves of sleep by reducing the amount of time spent in bed during the day.30 This is understandable, because everyday domestic activities are likely to conflict with the opportunity for sleep. In addition, it is difficult to maintain sleep when the circadian clock is promoting wakefulness.27,28 Shift workers may also remain awake longer when changing from one shift schedule to another, producing a
further accumulation of sleep debt. Difficulty rapidly shifting the circadian clock combined with erratic exposure to light in shift workers31 also places significant restrictions on adapting biological rhythms to shift-work schedules. Thus, in some workers, both sleep disturbance and sleepiness continue even after months or years of shift work. Reduced Alertness and Accidents Converging evidence from controlled laboratory settings, large epidemiologic studies, and clinical samples has established an incontrovertible link between shift work and accidents.32,33 In a classic study, Smith and colleagues demonstrated that working a night shift increased on-road accidents by 50%.34 In a recent study of a large sample of nurses, 79.5% of those working the night shift reported at least one drowsy driving incident, equal to an increased odds ratio (OR) of 3.96 (95% confidence limit [CI] = 3.244.84) relative to nurses working a day shift.35 Residents who have frequent on-call schedules have 6.7 times the risk of motor vehicle accidents compared with those working less-demanding call schedules.36 Others have shown that risk increases nearly 10% for every extended shift worked in a month.37 Sleepiness-related impairment is not confined to motor vehicle accidents; for example, findings from studies of medical personnel have also demonstrated an increased number of accidents associated with the use of sharp instruments and items (percutaneous injuries),38 medication and diagnostic errors,39 and increased patient death rates associated with extended and unconventional shift schedules.40 These findings are not surprising in light of a study by Arnedt and colleagues showing that residents on heavy call rotations have driving impairments similar to residents on light call rotations with a blood alcohol concentration of 0.05%.41 In industrial settings, the risk of both accidents and injuries increases by more than 30% on the night shift; moreover, it increases over successive night shifts and rises exponentially with successive hours on a shift.32 Major catastrophes such as those at Three Mile Island, at Chernobyl, and from the Exxon Valdez oil spill have all occurred during the night shift, drawing increased attention to both the risks and costs associated with shift work schedules.42,43 The cost of sleepiness-related accidents in the United States is estimated at up to $40 billion per year, representing 24% of the total cost of traffic accidents in the United States.44 These data suggest that the economic savings associated with shift work for specific industries should be carefully weighed against the overall cost to society. Work Productivity and Quality of Life The negative impact of shift work is not limited to adverse events. It also affects productivity. An association of shift work with reduced dexterity and efficiency,45 impaired threat detection,46 and lower productivity47 has been demonstrated. Thus, overall worker productivity is significantly reduced during the night shift in a broad range of occupational settings.42 There is also evidence for increased absenteeism in night workers compared with day workers, particularly for those experiencing insomnia and/or excessive sleepiness.12
The negative effects of shift work affect the family system as well as the individual’s quality of life.48 Studies show a 57% higher divorce rate,49 reduced job satisfaction,50 and reduced family and social interaction.12 Findings from a 5-year longitudinal study demonstrated a relationship between parental shift work and poor school performance and behavioral problems in children 5 to 12 years old after controlling for a number of demographic variables.51 The reader is also referred to more extensive reviews on work-related and quality-of-life variables in shift workers.48 Health Effects of Shift Work A wealth of information documents the negative health effects associated with shift work. Notable are a 36% to 60% increased risk of breast cancer in large prospective studies,52,53 a fourfold increased risk of duodenal ulcers verified by endoscopy,54 and increased cardiovascular morbidity and mortality,55-57 including atherosclerosis and myocardial infarction.55 Poor eating habits58 and other adverse health behaviors among shift workers may account for some of the increased morbidity. Moreover, findings from one study demonstrated that a weekly 12-hour shift in the light–dark cycle relative to endogenous circadian rhythms decreased survival by 11% in hamsters with cardiomyopathic heart disease.59 This finding suggests that these morbidities are not simply related to health habits but may be inherently related to misalignment of circadian rhythms and the sleep–wake cycle. With respect to the risk of breast cancer, investigators have suggested that reduced free radical scavenging due to suppression of the hormone melatonin by nocturnal light exposure, thereby reducing its potential tumor-inhibiting effects, could be a mediating factor.60 Findings of reduced breast cancer risk by 20% to 50% in blind women61 and an inverse relationship between level of blindness and cancer risk62 provide some support for this hypothesis. Finally, data suggest that the risk of cancer increases with the number of years on shift work.52
SHIFT-WORK DISORDER Individuals on the same shift schedule differ dramatically in response to shift work with regard to two of the most common consequences, excessive sleepiness and insomnia.12,63 The inability of a subset of individuals to tolerate shift work may be related, in part, to findings from several laboratory studies indicating that most night workers do not fully adapt their internal circadian rhythms to their adjusted sleep–wake schedule.64 The subgroup of nonadapted workers have reduced daytime sleep relative to those whose melatonin profiles showed rapid shifts in response to night work.65 Individual differences in vulnerability to insomnia, vulnerability to excessive sleepiness, and/or differences within the circadian system itself (i.e., period, amplitude, response to light) may account for the adverse response to shift work. Data suggest approximately 50% genetic heritability estimates for vulnerability to insomnia.66 Because this vulnerability can be elicited by a circadian challenge such as a major shift in the sleep–wake cycle,67 individual vulnerability to sleep disturbance remains a plausible determi-
CHAPTER 71 • Shift Work, Shift-Work Disorder, and Jet Lag 787
nant of shift-work tolerance. However, studies of trait vulnerability to sleep disturbance68,69 have yet to be performed in shift workers. Individuals also differ in the degree to which sleep loss impairs alertness and performance.70 Vulnerability to sleep loss is related to at least one genetic variant in the coding region of the circadian clock gene PER3.71 Furthermore, in one study of shift workers, increased perceived need for sleep was associated with intolerance for shift work.63 In terms of the circadian system, findings from one study suggested that individuals unable to tolerate shift work had an observed oral temperature and grip strength rhythm that appeared to be different from 24 hours, pointing toward a proclivity to circadian desynchrony in nontolerant workers.72 One predictor of shift tolerance is circadian preference (i.e., morningness/eveningness),73 a heritable trait linked to a length polymorphism in the PER3 gene74 and the intrinsic period of the circadian clock.75 Morningtype individuals tend to have a reduced tolerance for shift work compared with evening type individuals.76 Moreover, the fact that older individuals tend to be more morning types77 may partly explain the age-related reduced ability to cope with shift work and jet lag.78 A reduced capacity for older individuals to shift their endogenous circadian rhythms in response to moderate light levels is also a possible contributing factor for shift work intolerance in that population (>50 years old).79 Finally, in tightly controlled laboratory settings, clock gene expression shows considerable intersubject variability after a night-shift schedule in comparison to a daytime work schedule.80 The presence of these individual differences in the circadian and sleep–wake system response to shift work81 led to the development of diagnostic criteria for SWD (Table 71-1).13 Individuals diagnosed with SWD are unable to tolerate the effects of a shift-work schedule13 and may present with excessive sleepiness or insomnia despite adequate time in bed (∼7 to 8 hours), stable sleep schedules, and the absence of other sleep disorders. Although few studies specifically address SWD, the sleep of these individuals likely includes sleep fragmentation, early final awakenings, and an inability to remain awake during the early morning work/commute hours.82 These deficits can impact job performance, driving safety, quality of life, work satisfaction, and health.12,63 In addition to further research on the sleep and alertness of individuals with SWD, a major challenge for future studies will be to determine which specific morbidities are associated with insomnia versus excessive sleepiness versus both symptoms of the condition, versus a direct effect of circadian misalignment. Prevalence Because few shift workers have been reported to fully adjust their internal circadian rhythms to that of the imposed shift-work schedule, the prevalence of SWD would be expected to be high.6 Clinical evaluation of insomnia and excessive sleepiness in shift workers is necessary to determine the actual prevalence of SWD, but few population-based data are available. In one representative sample, the prevalence of the disorder has been conservatively estimated at 14% to 32% of night-shift workers and 8% to 26% of rotating-shift workers.12
788 PART II / Section 9 • Occupational Sleep Medicine Table 71-1 Diagnostic Criteria for Shift-Work Disorder International Classification of Sleep Disorders Criteria (ICSD-2): General Criteria for Any Circadian Rhythm Sleep Disorder A. There is a persistent or recurrent pattern of sleep disturbance due primarily to one of the following: i. Alterations of the circadian time-keeping system. ii. Misalignment between the endogenous circadian rhythm and exogenous factors that affect the timing or duration of sleep. B. The circadian-related sleep disruption leads to insomnia, excessive sleepiness, or both. C. The sleep disturbance is associated with impairment of social, occupational, or other areas of functioning. Specific Criteria for Circadian Rhythm Sleep Disorder, Shift-Work Type (327.36)* A. There is a complaint of insomnia or excessive sleepiness that is temporally associated with a recurring work schedule that overlaps the usual time for sleep. B. The symptoms are associated with the shift work schedule over the course of at least 1 month. C. Sleep log or actigraphy monitoring (with sleep diaries) for at least 7 days demonstrates disturbed circadian and sleep-time misalignment. D. The sleep disturbance is not better explained by another current sleep disorder, medical or neurological disorder, mental disorder, medication use, or substance use disorder. Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR): Diagnostic Criteria for Circadian Rhythm Sleep Disorder (307.45) A. A persistent or recurrent pattern of sleep disruption leading to excessive sleepiness or insomnia that is due to a mismatch between the sleep-wake schedule required by a person’s environment and his or her circadian sleep-wake pattern. B. The sleep disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. C. The disturbance does not occur exclusively during the course of another sleep disorder or other mental disorder. D. The disturbance is not due to the direct physiological effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition. Specify Type: Shift-Work Type: insomnia during the major sleep period or excessive sleepiness during the major awake period associated with night shift work or frequently changing shift work. *ICD-9 code: 327.36 Circadian rhythm sleep disorder, shift-work type
Morbidity In addition to sleep–wake disturbances, Gumenyuk and colleagues have shown that persons with SWD have significant alterations in neurophysiologic measures of attention and memory relative to night-shift controls without SWD.82a In a comparison of shift workers with and without SWD, those with SWD had a higher prevalence of ulcers.12 In addition, affected individuals exhibited higher rates of absenteeism and significant difficulties with family and social activities compared with shift workers without SWD. Higher rates of major depression were also found
in individuals with SWD. A relationship has also been found between reduced satisfaction with the work schedule and excessive sleepiness on the night shift.63 Not surprisingly, individuals with SWD report higher rates of sleepiness-related accidents than non-SWD controls or day workers. While increased rates of heart disease have been found in shift workers, this morbidity may not be directly related to the excessive sleepiness or sleep disturbance characteristic of SWD.12 However, additional studies with patients meeting diagnostic criteria are needed before definitive conclusions regarding unique morbidity in SWD (as opposed to shift work per se) can be determined. Clinical Evaluation SWD can be diagnosed by a thorough sleep history, although polysomnography may be indicated if there is a high suspicion of another sleep disorder (e.g., obstructive sleep apnea).83 The clinical evaluation of SWD is similar to that of other sleep disorders, particularly the other circadian rhythm sleep disorders covered in Chapter 41. However, the evaluation of the shift worker requires careful attention to additional details related to the effects of the work–sleep schedule on cognitive, social, and healthrelated functioning. Insomnia and the ability to maintain wakefulness, particularly during sedentary activities (e.g., commute home from work), should be carefully assessed, because SWD patients have a twofold increase in sleepiness-related accidents compared with shift workers who do not meet diagnostic criteria.12 The use of a sleep diary with a focus on regularity, duration, and timing of bed times and actigraphy over 1 to 2 weeks are helpful to confirm the degree and pattern of sleep disturbance and circadian disruption.84 The timing of obtaining this information should include periods of being on the work schedule that produces the symptom-complex. Fatigue is often confused with sleepiness and is a common presenting complaint by patients.85 If fatigue is present, an important differential diagnosis in the shift worker is major depressive disorder.12 As opposed to excessive sleepiness, patients with mental or muscle fatigue (as opposed to sleepiness) may find that sedentary activities or rest without sleeping may improve their symptoms. On the other hand, patients with excessive sleepiness often state that sedentary activities or “rest” periods exacerbate their complaint. This is an important distinction to make, because patients frequently do not recognize that dozing off in such situations is abnormal. The judicious use of brief, well-validated, and standardized tools for the assessment of sleepiness cannot be overemphasized.84 The Epworth Sleepiness Scale (ESS) is particularly helpful in this regard and can be performed easily in most clinical settings. A score of greater than 10 on the ESS is generally considered clinically important. Using ESS cutoffs, prevalence rates of excessive sleepiness of up to 44% have been reported,12 compared with a consistently lower prevalence (24% to 33%) in representative samples of daytime workers.12,86,87 Assessment tools such as the Insomnia Severity Index and the Pittsburgh Sleep Quality Index are patient-administered tools helpful for determining the extent and relative impact of sleep disturbance.88 Practical issues regarding their implementation are discussed in detail in Chapter 77.
Extensive clinical guidelines for the general evaluation of insomnia, including its relation to functioning, have been published and should be considered when evaluating a shift worker.89 Patient difficulty initiating or maintaining sleep is important when considering appropriate treatment strategies. In contrast to medium-acting compounds (halflife of 5 to 12 hours), short-acting hypnotics (i.e., half-life of 1.5 hours) may have little benefit in shift workers with isolated sleep maintenance problems (i.e., difficulty staying asleep with no problems falling asleep). However, residual sedation should be considered when using longer-acting hypnotic medications because shift workers frequently have shorter sleep periods compared with day workers. Behavioral treatment of insomnia in shift workers may be helpful, but specific approaches (e.g., relaxation therapy, stimulus control techniques), have not been systematically evaluated. A thorough history of the patient’s recent work schedule is also essential to diagnosis, because many types of shift schedules, particularly rapidly backward rotating schedules, can cause significant sleep disturbance and excessive sleepiness.90 If an evening-shift worker presents with excessive sleepiness or insomnia, causes other than the effects of circadian misalignment due to shift work should be considered because evening shifts are not as likely to cause SWD as other types of shift schedules. However, additional research is needed to determine whether SWD is common in evening workers with a strong morning circadian phase preference or high social/domestic demands. The clinician also needs to be aware of potential psychological (i.e., depression), gastrointestinal, cardiovascular, and cancer risks of shift work; and workers should have regular physical examinations that include attention to these conditions.91 The health risk related to substance use for insomnia (e.g., illicit drugs and alcohol), poor diet, and nicotine use common in shift workers should also be addressed during the clinical evaluation. Finally, educating the shift worker with regard to appropriate sleep hygiene practices with an emphasis on adequate sleep opportunity is highly beneficial. Treatment Because the specific pathophysiology of SWD is unknown, treatment is necessarily targeted at either of the two symptoms or directly at the trigger itself (i.e., circadian misalignment). A cardinal feature of the disorder is that symptoms are directly linked to the shift-work schedule and thus likely to remit after returning to daytime work.13 Short of going off the night shift, occupational adjustments such as slower rotations with weeks spent on a particular shift, moving to an evening shift, changing from backward to forward shift rotation, and incorporating increased worker control by allowing “self-scheduling” of shifts may be of some benefit.92 However, in most cases clinical intervention is needed because occupational constraints generally prevent scheduling adjustments or a return to a diurnal schedule. Even before the diagnosis of SWD is made, the clinician must address all potential safety concerns. Indeed, the threshold for immediate treatment intervention should be lower in a shift worker presenting with excessive sleepiness while driving and for occupations in which performance is
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critical for individual or public safety.13 Shift workers typically have a chaotic sleep–wake schedule and may drastically curtail their time in bed in an attempt to meet their social, occupational, and daily obligations. This may be due to a short shift transition, long overtime hours to keep up with work demands, a second job, or staying awake to engage in normal social activities during the day. All of these factors can make it difficult for the shift worker to get enough sleep. Clearly, even shift workers need 7 to 8 hours of time in bed (i.e., sleep opportunity) per day. The clinician needs to address this issue with each patient. Circadian Interventions Interventions, particularly appropriately timed bright light aimed at shifting endogenous rhythms, have been extensively studied in shift workers. Exposure to bright light in the evening near habitual bedtime and for several hours thereafter will induce a phase delay of internal biological time, whereas exposure to bright light in the morning from approximately 2 hours before habitual wake time and thereafter will induce a phase advance (see Fig. 71-1). In general, for every hour of properly timed exposure to bright light, there is a 0.5-hour shift in internal biological time. Using these principles, bright light interventions aimed at producing phase delays of the circadian pacemaker (e.g., light during the first half of the night shift and daytime darkness) have been shown to improve daytime sleep and nocturnal functioning.93,94 In an early landmark study, Czeisler and colleagues treated circadian misalignment due to shift work with exposure to 7.5 hours of bright light (7,000-12,000 lux) on 4 consecutive nights in the laboratory and scheduled sleep in darkness between 9 am and 5 pm at home.93 In comparison to a control group exposed to room light (∼150 lux) and unscheduled sleep, those treated had a 9.6-hour delay (i.e., to a later hour) of their circadian rhythms (i.e., temperature, cortisol, alertness). They also averaged 2 hours more sleep during the day and showed improved nocturnal alertness and cognitive performance. Additional studies supporting this observation are thoroughly reviewed elsewhere.95 Despite the ability to achieve large phase shifts in controlled laboratory environments, producing complete circadian adaptation in most shift workers in the field is difficult.96-100 Phase shifting requires extensive control over environmental light and darkness (i.e., dark goggles and bright light), which may not be practical in all real-world settings. Furthermore, complete circadian phase reversals are likely to be “maladaptive” because family and social obligations may force patients to revert to a diurnal schedule on their days off. Recognition of practical limitations regarding continuous bright light exposure (e.g., 6 to 8 hours at ∼10,000 lux) and the limitations of complete phase shifts has led some investigators to study the sleep and performance effects of using brief intermittent light exposure to induce a “compromise” circadian phase (i.e., moderate but stable delays) compatible with permanent night work and common day schedules on days off. In a study by Smith and Eastman,101 subjects engaged in three simulated night shifts (11 pm to 7 am) followed by 2 “weekend” days off with a final episode of four additional night shifts, closely
790 PART II / Section 9 • Occupational Sleep Medicine
simulating the variable sleep–wake schedule of shift workers that often occurs in the real world. Subjects were exposed to brief light pulses during the night (15 minutes each hour; total light exposure duration of 1.25 hours per shift) and wore sunglasses while outside, with the goal of achieving a moderately delayed or “compromise” circadian phase position in which the lowest point of alertness would occur just a few hours after their shift work ended (∼10 am). The intervention produced a larger delay in onset of melatonin secretion from 9 pm to 4:30 am (∼7.5-hour delay) compared with the control group (∼3.5-hour delay). Sleep duration as determined by actigraphy and sleep logs improved in the delayed group relative to the controls. Treatment also resulted in better and more consistent psychomotor performance. Importantly, delayed circadian phase was positively correlated with improved sleep even in the control group (r = 0.65), suggesting that some individuals benefit from even small delays in circadian phase and emphasizing potentially important individual differences in the response to large and abrupt circadian shifts of the sleep–wake cycle. Although the effectiveness of this intervention for SWD needs to be studied, maintaining stable circadian delays of about 4 hours improves sleep and cognitive performance during a shift-work schedule. Compounds with phase-shifting properties (e.g., chronobiotics) may also be beneficial for shift workers. Exogenous melatonin is perhaps the strongest nonphotic time cue in humans. Normally, endogenous melatonin levels rise about 2 hours before habitual bed time,102 remain high across the night, and decline again near the habitual time of awakening. Use of exogenous melatonin to shift circadian rhythms generally follows the reciprocal of the phaseresponse curve for light (see Fig. 71-1). Thus, melatonin ingested during the biological day can be used to phase advance or phase delay the circadian phase.103,104 Properly timed exogenous melatonin administration for 3 days can lead to an approximate 1.5-hour shift in internal biological time.103 However, for melatonin to be an effective phase resetting agent, control over light exposure appears necessary because bright light can counter the phase shift produced by melatonin. In a recent controlled study, 4 days of treatment with 1, 2, or 4 mg of the melatonin agonist ramelteon had significant phase-advancing effects of 80 to 90 minutes when normal sleep–wake schedules were abruptly shifted by 5 hours.105 Although these effects may have more practical applications for circadian rhythm disorders such as delayed sleep phase syndrome and jet lag,106 in which modest shifts in the circadian pacemaker may improve symptoms, melatonin or melatonin agonists may still provide benefits in patients with SWD via the sleep-promoting and phaseshifting properties of these compounds.107,107a,107b In studies of shift work, melatonin (0.5 to 3 mg) was able to improve circadian adaptation through phase delays or advances depending on the time of administration.94,107 However, it must be emphasized that although chronobiotic compounds may have some benefits in shift workers, these will generally be easily counteracted by inappropriate exposure to the more powerful zeitgeber, daylight during the early morning hours. Melatonin does exert some performance impairment at doses as low as 5 mg, suggesting caution if wakefulness is intended to be maintained for more than 30
minutes after administration.107 Finally, no large-scale clinical trials have evaluated the effectiveness or safety of melatonin use, which should be discussed with the patient’s physician. In the United States, melatonin is available as a dietary supplement. There are available melatonin preparations that are certified for purity and dosage level, and such a preparation should be used. Use of melatonin to induce and maintain sleep as opposed to phase-shifting properties is reviewed later. Findings from studies have also demonstrated the ability of exercise interventions to delay circadian rhythms.108 However, without adequate control over light exposure, the usefulness of such interventions alone may be limited, owing to the extensive time required for significant phaseshifting effects and the potential counteractive effects of daytime light exposure on circadian adjustment in shift workers. Improving Diurnal (and Nocturnal) Sleep Shift workers should be encouraged to attempt sleep immediately after the night shift and to maintain a sleepconducive environment during their sleep time, using light-blocking shades, ear plugs, and a comfortable eye mask. If near-complete circadian alignment is achieved in a shift worker, improvements in daytime sleep do occur.93,109 However, the practical limitations of circadian interventions often prevent complete alignment (e.g., diurnal light exposure), thus necessitating interventions directly targeting sleep improvement. Owing to a lack of circadian adjustment in shift workers, sleep disturbance typically occurs during the latter half of daytime sleep.109 Use of two sleep periods: (1) an “anchor” sleep period of about 4 hours that represents a time of day (e.g., 8 am to 12 pm) when the shift worker is instructed to “always sleep” regardless of it being a workday or day off and (2) another 3- to 4-hour sleep period taken at irregular times depending on the work schedule may help to stabilize circadian rhythms and increase sleep duration for a given 24-hour period.110 Although the ability of melatonin to produce circadian phase shifts is limited when control over light exposure is difficult or when endogenous melatonin is present,107 exogenous melatonin doses between 1 and 10 mg and melatonin agonists, administered during the biological day when endogenous melatonin levels are low, can increase total sleep time even at doses as low as 0.3 mg.107a,107b,111,112 In terms of shift workers, some improvements in sleep have been shown with melatonin at doses between 5 and 10 mg,113,114 whereas others using subjective measures of sleep115,116 or lower doses (∼2 mg) have not found soporific effects.117 Studies in diagnosed SWD patients are needed because some of the subjects in previous studies may not have had significant sleep disturbance. Use of the benzodiazepine triazolam in individuals on a simulated shift-work schedule was shown to be beneficial for improving sleep during the daytime hours (30 to 60 minutes/day) but showed minimal to no effects on alertness during the night.118,119 The use of newer benzodiazepine receptor agonists have produced essentially similar results on subjective reports of daytime sleep120 and slight improvements in nocturnal performance but evidence for worsened mood.121 Individuals diagnosed with SWD may show greater benefits, but this has yet to be demonstrated.
Despite its sedative properties, the use of alcohol as a hypnotic in SWD should be strongly discouraged, particularly owing to the resultant fragmentation of sleep in the second half of the night after alcohol administration, a time when sleep is uniquely vulnerable to disruption in this population.122 Napping during the day before the night shift and for brief episodes during the night have been effective as countermeasures to improve alertness and performance in a number of studies.22,23,123 In two recent studies, the combination of an evening nap and caffeine (∼250 to 350 mg) 30 minutes before the night shift was particularly beneficial for improving alertness and performance for up to 3 nights.124 Findings from one recent study in shift workers who were professional drivers demonstrated that a clinically feasible combination of brief naps (2 at 20 minutes each) and a short light exposure period (10 minutes, 5000 lux) can reduce polysomnographically measured falling asleep at the wheel.23 Pharmacologically Enhancing Alertness Many individuals who experience sleepiness take stimulants such as caffeine or amphetamines. Caffeine can be used to improve wakefulness and performance during the biological night.124,125 Although prenap caffeine may be beneficial in reducing the performance-impairing effects of sleep inertia after brief naps,126 this approach has yet to be tested in patients with SWD. In a study by Wyatt and colleagues, low-dose caffeine (0.3 mg/kg/hr) administered over several periods of extended wakefulness (∼29 hours) helped subjects remain awake and improved memory and psychomotor performance.127 Overall, stimulant drugs have several disadvantages that offset their ability to enhance alertness, including the development of tolerance and withdrawal in the case of caffeine128 and the high potential for abuse of Schedule II medications such as amphetamines and methylphenidate.129,130 Benzodiazepine receptor agonists have been shown to improve daytime sleep in simulated shift-work environments,118,119 yet these medications do not normalize nocturnal alertness.118,121,131 Consequently, medications indicated for enhancing alertness in SWD have been used to promote nocturnal wakefulness in patients.83 A study on the use of modafinil for treatment of SWD provides evidence for its therapeutic benefit in occupationally related outcomes, including sleepiness while driving. In that study, 204 patients who met the criteria for SWD were given either 200 mg of modafinil or a placebo for 3 months during the clinical field trial.132 The group taking modafinil showed significant improvement over those taking the placebo in psychomotor vigilance and drowsy driving on the commute home, among other endpoints. Patients also had significant reductions in objectively defined sleepiness on the Multiple Sleep Latency Test during the night shift, although alertness levels did not normalize to those seen during typical daytime assessments. Importantly, modafinil did not have detrimental effects on subsequent daytime sleep when taken at the beginning of the night.132 Armodafinil, the longer lasting isomer of modafinil, has also been shown to be effective for the treatment of excessive sleepiness in SWD and has reduced the level of sleepiness during the commute home.132a It has been FDA
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approved for use in SWD and shown to significantly improve excessive sleepiness, overall clinical condition, and performance in this patient population.132a Additional studies regarding pharmacologic treatment of circadian desynchrony are reviewed in Chapter 73. Enhancing Alertness with Combined Treatments Several investigations have examined the efficacy of combined treatments for promoting wakefulness during the biological night. Combined treatments studied include caffeine and bright light,125 caffeine and naps,124 and naps and modafinil.133 Such wakefulness promoting treatment combinations have been reported to be better than the use of either treatment alone (Video 71-1). Management Guidelines for Shift-Work Sleep Disorder In light of the paucity of clinical tools for assessing and treating SWD, we have proposed a brief set of clinical guidelines (Table 71-2). These are based on established circadian principles, the rich literature on morbidity associated with shift work, and data from the few currently available studies on the assessment and treatment of SWD and tolerance to shift work. Several highly useful clinical case reviews from initial evaluation through treatment follow-up are presented in Chapter 72, with specific reference to high-risk occupations.
JET LAG Many millions of people travel via jet plane each year. Jet lag results from a mismatch between internal biological time and environmental time caused by rapid eastward or westward travel across multiple time zones. Disturbed and/ or shortened sleep duration before and during travel also contribute to jet lag symptoms. Symptoms include daytime fatigue and sleepiness and insomnia in the new time zone. Gastrointestinal disturbance is common and may be related to individuals eating at a biological time when the body is not prepared to intake nutrition.134,135 Daytime sleepiness can lead to difficulties concentrating and can impair tasks such as driving and decision-making. Although the circadian principles used in the management of jet lag are similar to those of shift work, environmental cues often support adaptation after travel to a different time zone. Thus, jet lag symptoms typically subside in a few days but in some cases can last for weeks. Circadian misalignment and the symptoms of jet lag occur because immediately after eastward jet travel attempts at sleep in the new time zone are made at the new environmental bedtime before the beginning of the biological night of the traveler. Sleep in the new time zone is thus disturbed, and such sleep disruption contributes to subsequent daytime sleepiness and reports of fatigue. Daytime sleepiness and fatigue also occur because wakefulness occurs during the biological night. Individual differences in the ability to sleep during the biological day (vulnerability to insomnia) and to maintain alert wakefulness during the biological night (vulnerability to sleep deprivation) may also contribute to jet lag symptoms. The cognitive impairments associated with jet lag can have serious consequences, resulting in drowsy driving or flying
792 PART II / Section 9 • Occupational Sleep Medicine Table 71-2 Clinical Guidelines for Assessment and Management of SWD Assessment I. Determine circadian misalignment (sleep diaries and or actigraphy) II. Assess sleep disturbance A. Determine difficulty falling asleep, staying asleep, or having nonrestorative sleep (both during daytime and nighttime sleeps) B. Measure degree of alertness C. Assess falling asleep during inappropriate circumstances or times (ESS), with special attention to drowsy driving D. Determine important job-related factors: duration of commute after shift, number of consecutive shifts, type of shift, time between shifts III. Determine impact on social and domestic responsibilities.150 Management91 I. Shift workers should have regular physicals with attention to psychological (i.e., depression), gastrointestinal, cardiovascular, and potential cancer risks of shift work91 A. Sleep-related comorbidity: determine risk of sleep disordered breathing, restless legs syndrome, or other potential sleep disorder B. Other comorbidity: identify medical or psychiatric disorders which may contribute to the symptoms of insomnia or excessive sleepiness II. Determine if removal from shift work is appropriate or practically feasible If patient meets criteria for a diagnosis of shift work disorder, cessation of the shift work schedule should be the first option discussed with the patient III. Determine patient-specific therapeutic approach A. Circadian adaptation 1. Consider individual difference factors (e.g., age, phase preference) 2. Consider compromise phase position (e.g., partial phase delay using bright light during first half of night and increased darkness during daytime) 3. Night workers—on days off adopt a late sleep schedule (i.e., bedtime 3-4 AM) B. Symptom management 1. Insomnia a. Sleep hygiene i. Target inappropriate sleep hygiene and encourage use of eye mask, ear plugs, and light blocking shades during daytime sleep b. Sleep maintenance a primary concern i. Consider intermediate half-life (5-8 hours) acting hypnotic ii. Consider melatonin treatment for daytime sleep (∼3 mg) c. Sleep initiation problems i. Consider short-acting hypnotic d. Sleep problems on days off i. Consider fixed sleep–wake schedule and consider anchor sleep 2. Excessive sleepiness (i.e., Epworth Sleepiness Scale Score <10) a. Address sleep disturbance if present b. Consider wake-enhancing medication prior to shift (e.g., modafinil, armodafinil) or off-label stimulants (e.g., amphetamine, methylphenidate) c. Prophylactic nap prior to work shift d. Judicious use of brief to moderate length naps (30 to 60 minutes) with recognition of risk of sleep inertia (consider prenap caffeine to reduce sleep inertia) e. Consider combined treatment strategies during the work shift (alerting medications, bright light, and naps) IV. Address additional work, social, and domestic factors A. Social/family/psychological: improve balance between family/social, work, and sleep time and treat psychosocial stress, depression, or marital discord if present,150 educate patient’s family regarding shift workers need of protected time for sleep. B. Health and safety: improve healthy eating habits with respect to regularity and timing relative to the major sleep period (not within 2 to 4 hours of bedtime), reduce inappropriate substance use, increase exercise at appropriate times (not within 2 to 4 hours of bedtime), educate on risks of drowsy driving and critical times of performance vulnerability. C. Work-related: reduce number of consecutive shifts (<4),150 reduce shift duration (<12 hr), clockwise rotation,151 adequate time between shifts (>11 hours),150 move heavy workload outside circadian nadir (4 to 7 AM), commute time (longer = greater accident risk), move to day or evening shift,8 consider incorporation of a shift-work awareness program152
accidents, impaired decision-making for the business traveler, and impaired athletic performance. In other cases, jet lag can be an inconvenience leading to difficulty staying awake when sight-seeing, attending the theater, or when having a meal. Sleepiness and fatigue also increase the performance-impairing effects of alcohol.136-138 Jet lag is often reported to be worse after eastward than westward travel. Westward travel may generally be easier because the average period of the circadian clock in humans is longer than 24 hours and thus there is a biological tendency for bedtime and waking to be later. However, 20%
to 25% of humans have a shorter than 24-hour clock139 and they may find it easier to adapt to eastward travel. Treatment Successful treatment requires a detailed history and knowledge of circadian physiology and of countermeasures to improve sleep, wakefulness, and circadian adaptation. Most evidence for jet lag treatments comes from laboratory studies. Currently, there are no medications approved by the U.S. Food and Drug Administration (FDA) for the treatment of jet lag syndrome.
Promoting Sleep during Flight and in the New Time Zone The traveler should be educated on environmental factors that can be controlled to promote sleep140 (see Chapter 80). Most flights eastward from the United States to Europe are scheduled at night. Eyeshades and earplugs or noise canceling headphones may help sleep during flight. Alcohol should be avoided during the flight. Although alcohol shortens sleep latency, it disrupts sleep continuity.122 Direct overnight flights provide more opportunity to sleep during travel than do itineraries with multiple stops. On arrival, it is often recommended to immediately adapt to the new bed time and awakening times of the new time zone. Exogenous melatonin can shorten sleep latency and increase sleep duration in a dose-dependent manner when taken during the biological daytime.107,111,112 Thus, if sleep is attempted during the biological daytime while in flight and/or in the new time zone, melatonin may be used to improve sleep quality and duration. Melatonin should be tried in the home time zone before use during travel to determine the response to the chosen dose. Melatonin agonists, such as ramelteon107a and tasimelteon,107b are reported to improve sleep during the biological daytime, and thus they may be useful in the treatment of jet lag. In a clinical trial, ramelteon (1 mg) was reported to shorten the latency to sleep compared to placebo after eastward air travel across five time zones (from Hawaii to the East Coast of the United States).140a As of 2010, ramelteon and tasimelteon do not have specific FDA indication for jet lag. Over-the-counter (OTC) sleep aids have not been tested to determine their effectiveness in treating jet lag. Several benzodiazepine receptor agonists prescribed as hypnotics have been tested in simulated and actual jet lag trials. Findings from these studies indicate that sleep is improved during jet travel,141,142 but there is little evidence that subsequent wakefulness is improved by these or other sleep medications in jet lag. In addition, the side effects of both OTCs and hypnotics need to be considered (e.g., cognitive and balance impairments). Promoting Wakefulness during Flight in the New Time Zone Most flights westward from Europe to the United States are scheduled during the daytime. Staying awake until bedtime in the new time zone should promote sleep. Brief naps (e.g., 15 to 20 minutes) when in flight during westward travel and in the new time zone after eastward or westward travel are likely to be effective at promoting subsequent wakefulness.143,144 Longer daytime naps may impair subsequent nighttime sleep and cause a greater degree of sleep inertia145 on awakening from the nap. Caffeine is perhaps the most commonly used self-selected countermeasure to promote wakefulness during jet travel. Based on sleep deprivation and simulated jet travel studies, caffeine can help to promote wakefulness when it occurs during the biological night.125,127,146 Regardless of intervention, travelers should be warned about the risks of drowsy driving. Circadian Adaptation Adjustment of the circadian system to a new time zone often takes days, with approximately 1 day required for each time zone crossed. Proper timing of bright light expo-
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sure and dim light/darkness can quicken adaptation of the internal circadian clock to the new time zone (see Fig. 71-1). Exogenous melatonin may also help to shift the circadian clock during jet travel. The timing of melatonin administration to induce phase shifts is opposite to that of light (see Fig. 71-1). For example, if a westward phase delay is desired, exposure to dim light/darkness and melatonin in the morning will likely facilitate a delay induced by exposure to bright light at night (Figs. 71-2 and 71-3). Partial Preflight Circadian Adaptation Partial preadaptation of the jet traveler’s circadian clock before travel147,148 may shorten the duration of jet lag symptoms. Partial preadaptation involves going to bed and waking up earlier for 1 or 2 days before eastward flight or going to bed and waking up later before westward flight combined with properly timed exposure to light (see Fig. 71-3). Earlier awakening before eastward flight should be combined with exposure to bright light (e.g., a sunrise walk or turning up the lights in the house) and exposure to dim light at night. Later bed and wake times before westward flight should be combined with exposure to bright light in the evening and exposure to dim light in the morning. Because space limitations prevent a full case presentation, the reader is referred to the successful assessment and treatment of a clinical case described in detail by Wright.149
794 PART II / Section 9 • Occupational Sleep Medicine
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Figure 71-3 Circadian adaptation during jet travel. When traveling eastward, the jet traveler needs to advance the timing of his or her sleep schedule as well as the phase of the internal circadian clock so that both occur earlier. In the current example of a trip from Denver, Colorado, USA, to Prague, Czech Republic, the primary plane flight to Frankfurt (long black arrows) occurs during the beginning of the biological night when endogenous melatonin levels are high (green line). The traveler should sleep as much as possible on the plane flight to reduce the negative impact of sleep deprivation during jet travel. Exogenous melatonin taken shortly after boarding the plane may help the traveler fall asleep earlier than normal when endogenous melatonin levels are low. In this example, the traveler spends several hours in Frankfurt before the flight connection to Prague. Light exposure during most of the biological night will induce a westward phase delay, opposite to what is needed for an eastward shift, thus the traveler should avoid exposure to bright light (sun with sunglasses) and wear an eye mask or sunglasses until after the habitual time of awakening in the home time zone. Then, the traveler should expose himself or herself to bright light (sun without sunglasses and light bulb) to facilitate the eastward phase advance of the circadian clock. Sleep timing should be consistent with the local time zone in Prague, and melatonin may again help phase shift the clock and promote sleep onset if taken when endogenous melatonin levels are low. The next day, the traveler should at first continue to avoid exposure to bright light. Each day, the time of exposure to bright light can be moved earlier by 1 to 2 hours per day. When traveling westward, the jet traveler needs to delay the timing of his or her sleep schedule as well as the phase of the internal circadian clock so that both occur later. In the current example of a trip from Prague to Denver, plane flights occur across the biological day when endogenous melatonin levels are low and the traveler should remain awake for much of the trip, assuming sleep was adequate prior to travel. Caffeine and/or a nap can help to improve subsequent wakefulness. Exposure to bright light should occur across the entire plane flight and until just before bedtime in the new time zone to facilitate a westward phase delay.
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CONCLUSIONS Shift work can have debilitating consequences due to chronic sleep disruption, social isolation, and circadian misalignment.154 The negative effects of shift work impact the gastrointestinal, cardiovascular, and other physiologic systems.155 Although the direct relation between disruptions of the sleep and circadian systems and these morbidities needs further study, circadian and sleep adaptation to shift work can be improved using interventions that target these systems. Impaired alertness may need to be addressed despite circadian and sleep-related interventions. In individuals with SWD, treatment should be directed at circadian adjustment to the shift-work schedule and at the patient presenting with symptoms of excessive sleepiness and/or sleep disruption. Although data in patients diagnosed with SWD are limited, successful treatment approaches include FDA-approved alertness-enhancing medications, prophylactic naps, and bright light exposure/ darkness when appropriate.
❖ Clinical Pearls Shift Work Shift work disrupts sleep and circadian rhythms and increases the risk for cardiovascular disease, gastrointestinal disorders, and cancer. The careful application of circadian principles (timed bright light exposure, darkness, and melatonin) can improve adjustment to shift work. Melatonin and hypnotic medications may provide additional benefit in some individuals. Treatment with FDA-approved alerting medication is useful in patients with shift-work disorder. Jet Lag Rapid eastward or westward travel across multiple time zones induces circadian misalignment, which produces insomnia, daytime sleepiness, impaired driving performance, and impaired cognition. Circadian adaptation to the new time zone requires appropriately timed exposure to light and darkness. Inappropriately time exposure to light can shift the circadian clock in the wrong direction and prolong jet lag symptoms. Wakefulness and sleep-promoting countermeasures can be used to address symptoms of daytime sleepiness and sleep disruption during travel and in the new time zone.
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Sleep Problems in First Responders and the Military Bryan Vila and Charles Samuels Abstract Fatigue is one of the most common health and safety hazards faced by police officers, as well as other first responders and military personnel in similar operational environments. Whether caused by extended-duty hours, night work, lack of rest, or circadian disruption, fatigue contributes to high levels of mortality and morbidity in these occupational groups. It also degrades cognitive performance, differentially impairing the parts of the brain that are most important for making sound judgments, deciding on appropriate courses of action, and exercising restraint in the face of threat and provocation. This impairment is particularly problematic in civilian police work, which we use here as a general model for all first responders and the military. Police, just like military personnel assigned to ground counterinsurgency operations and peacekeeping assignments, often face aggressors who are
Police officers in the United States, Canada, and many other industrialized nations often are overly fatigued because of long and erratic work hours, shift work, and insufficient sleep. These factors likely contribute to elevated levels of morbidity and mortality, psychological disorders, and family dysfunction observed among police. Fatigue-related impairments to officer performance and decision-making can generate unexpected social and economic costs because of the sensitivity, risks, and potential consequences of their actions.1 Managing police fatigue requires balancing the biological and social needs of police officers against those of the organizations that employ them and the communities they serve. Police work is one of the most critical and expensive government activities. Communities must have sufficient officers on duty at any moment to respond to emergencies, prevent crime, and arrest offenders, but not so many that public resources are wasted. To complicate matters, the need for police services fluctuates across the day, week, and season. This scheduling problem is compounded by the complexities of managing fatigue and work hours. If officers are impaired by fatigue, they become less alert, their cognitive and physical abilities decline, their moods worsen, and they become less able to deal with stress. This reduces both public and officer safety because risks of job-related accidents, injuries, errors, and misconduct increase. Over the long term, chronic sleep loss makes officers more vulnerable to illness, chronic disorders, and certain kinds of cancers. Fatigue also corrodes the quality of family and social interactions that help ground officers and buffer the impact of repeated exposure to a toxic work environment over the course of a decades-long career. Preventive measures and treatment require consideration of these systematic processes that cause sleep loss and interfere with recuperation as well as the internal systems associated with patients in distress.
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72
difficult to distinguish from bystanders in ambiguous, fastpaced, and complex situations in which they must identify and neutralize threats. The consequences of either failing to exercise restraint and minimize civilian casualties or failing to effectively neutralize an enemy can be equally dire—for operators on the ground and for strategic objectives. Analogous challenges confront other first responders and military specialties. Because the social, organizational, and individual causes of sleep loss among these occupational groups are inextricably linked, in this chapter a review is presented of the systematic interactions that must be taken into account to understand and treat sleep problems and disorders among this critical population. How such an approach provides opportunities for sleep physicians to improve both patient treatment and public health by working with operational agencies is discussed.
PREVALENCE OF SLEEP LOSS, MORTALITY, AND MORBIDITY Officers whose sleep is chronically disrupted by personal characteristics, off-duty choices, or employer scheduling and work-hour practices suffer from disproportionately high levels of cardiovascular, gastrointestinal, and metabolic diseases; chronic insomnia, sleep apnea, and other sleep disorders; and psychological disorders, depression, suicide, and family dysfunction.2-11 Research linking long and erratic work hours to these sorts of disorders is substantial and compelling.1,12 Shorter-term links between sleep loss and the sorts of on-the-job accidents and injuries that most frequently kill or seriously harm police officers also are well documented1,12,13 Figures 72-1 and 72-2 show the sources of on-the-job injury and death for police officers. In Figure 72-1, note that felonious killings of police officers have declined steadily during the past 27 years, likely as a consequence of improvements in training, tactics, and soft body armor. Accidents tend to account for a larger proportion of officer deaths than do felonies, and accidents are largely dominated by nonfelonious vehicular accidents. Accidents have declined much less during this period despite major improvements in vehicle safety, such as crash-resistant designs, air bags, shoulder harnesses, radial tires, antilock braking systems, and disk brakes. Reported suicide rates, which are available only from 1984 to 1998,14 tend to account for slightly more officer deaths annually than either felonious killing or accidents. However, suicide deaths are systematically underreported because cultural and economic incentives produce a substantial bias for full reporting of felony and accidental deaths and against full reporting of officer suicides. Figure 72-2 illustrates common causes of police on-thejob fatalities as well as injuries that were sufficiently serious 799
Deaths/100K full-time sworn police
800 PART II / Section 9 • Occupational Sleep Medicine
throughout their careers. Moreover, they do so in highly unstructured, variable, risky, and unpredictable situations that require both expert judgment and decision-making and great self-restraint. After chairing a congressional panel on the impact of sleep on society, here’s how Dr. William C. Dement, one of the most distinguished figures in sleep medicine, summarized this issue20:
25 Felonies Accidental Suicide
20
15
10
5 1980
1984
1988
1992
1996
2000
2004
Figure 72-1 Police officers killed per capita in the United States, by cause. (Felonies and accidents from FBI, LEOKA data, 1980-2007; suicides from CDC, NOMS data, 1984-1998.)
0%
10%
20%
30%
40%
50%
Assault, violence Vehicle accident Aircraft accident Struck by vehicle Fell, jumped Physical stress, overexertion Exposure to fire and hazardous substances Struck by, contact with object Other
Line-of-duty fatalities Occupational injuries
Figure 72-2 Causes of police injuries and fatalities in which work time was lost. (National Law Enforcement Officer Memorial Fund, 1995-2002.)
to require lost work time. Note that both tend to be dominated by accidents of the sort that are made more hazardous by sleep loss and disruption15-17 as well as circadian factors, which accidents track closely.13,18 Despite this evidence, police in the United States and Canada continue to compound the unavoidable physical insults of shift work with large amounts of overtime.19-21 Most officers assigned to patrol and detective assignments will at times work 16 or more consecutive hours and sometimes more than 24 hours straight. As with most occupations, a small proportion of the officers in most departments work a large proportion of the overtime. Extreme examples of officers working more than 3000 hours of overtime per year have been reported regularly during the past decade.22 On top of these practices, many officers also work second jobs, about which almost no hard data are available. The burden borne by officers and their families as a consequence of work-hour practices is similar to that of other occupational groups.1 However, unlike occupations in which shift work and long, erratic work hours tend to be limited to the first few years of one’s career, police and many first responders often work while sleep deprived
Police work is the one profession in which we would want all practitioners to have adequate and healthful sleep to perform their duties at peak alertness levels. Not only is fatigue associated with individual misery, but it can also lead to counterproductive behavior. It is well known that impulsiveness, aggression, irritability and angry outbursts are associated with sleep deprivation.
IMPLICATIONS FOR OTHER FIRST RESPONDERS AND THE MILITARY The police may be seen as a model occupational group for understanding the impact of sleep loss on other first responders such as firefighters and field emergency medical personnel.23 This model also is increasingly applicable to military operational environments that involve small ground units rather than massed armies, navies, and air forces. The challenges of new operational roles such as such as those faced by small infantry units involved in urban counterinsurgency patrols and roadblocks, peacekeeping, and nation building are more akin to police work than traditional infantry combat.24 As in police work, the tactical and strategic success of these endeavors requires an exquisite balance between the use of aggression and restraint.25-28 Success often hinges on the performance of low-ranking infantry and security personnel operating in small, relatively autonomous units. These troops often must make difficult and complex decisions about the use of deadly force in fluid, ambiguous, and emotionally charged situations. To be effective, they must find and neutralize enemies who are embedded within the general civilian population without alienating that population. This means that they must build strong relationships with local people by fostering public perceptions of their civility and professionalism as well as the justice and fairness of their actions, even as they do things that are intrusive and unpleasant for the individuals they delay, confront, or detain. Failure to strike an effective balance between aggression and restraint in these challenging tactical situations can carry deadly consequences for troops on the ground and for the public they are attempting to win over. It also can lead to serious tactical, operational, and even strategic setbacks. Performance Challenges and Sleep Loss Sleep loss degrades the ability of first responders and many military occupational specialties to respond to the challenges they face in operational environments. The immediate effects of sleep-related performance decrements increase risks of death or serious injury to operators, their peers, and bystanders whom they encounter. Longer-term health risks for these occupational groups are a function of the duration and frequency of exposure. Table 72-1 provides examples of the typical duration of operational
CHAPTER 72 • Sleep Problems in First Responders and the Military 801
Table 72-1 Illustrative Examples of Typical Duration of Operational Deployments and Frequency of Sleep-Related Insults and Hazards in Operational Settings among Selected First Responder and Military Occupational Specialties* OCCUPATIONAL SPECIALTY AND DURATION OF OPERATIONAL DEPLOYMENT
FIREFIGHTER (CAREER)
EMERGENCY MEDICAL TECHNICIAN (CAREER)
INFANTRYMAN (≤12 MO)
SHIPBOARD SAILOR (13 TO 36 MO)
MILITARY PILOT (CAREER)
SPECIAL OPERATIONS (≤12 MO)
**
*
*
***
***
***
**
Work/sleep schedule disruption
***
***
***
***
***
***
***
Day sleep
***
**
***
**
**
***
***
Time zone change
*
*
*
**
**
***
*
Sleep opportunities restricted to <6 hr/day
***
*
***
***
*
*
***
Consecutive work >36 hr
*
*
**
**
*
*
**
Consecutive work >24 hr
**
**
***
**
*
*
***
Stress from hazardous or emotionally intense incident
***
***
***
***
*
*
***
Sleep disrupted by emergency action
*
***
***
**
*
*
**
Domestic life disruption
***
***
***
***
***
***
***
Physical exercise opportunity restriction
***
*
**
*
*
*
*
Adequate, good quality food unavailable
***
*
*
**
*
*
**
FREQUENCY DURING DEPLOYMENT
POLICE OFFICER (CAREER)
Permanent sleep schedule change
*Does not include personnel assigned to administrative duties. ***, frequent; **, occasional; *, infrequent.
deployments and the typical frequency of sleep-related insults and hazards in operational settings among selected first responder and military occupational specialties. Note how some occupational groups’ exposure to sleep-loss– related risk factors are much more episodic whereas others face many of the same challenges throughout their careers. Although space limitations preclude a detailed discussion of the specific consequences of sleep loss for each occupational group, the discussion that follows illustrates the immediate and long-term consequences of sleep loss on police officers. Those same consequences may be extrapolated to other first responders and military specialties as long as the frequency and duration of exposure are taken into account.
Police officers are faced with an extraordinarily variable array of situations that require them to exercise discretion to solve problems effectively and justly. Society delegates great power to them in order to handle emergencies that often are nuanced, unpleasant, and dangerous. Officers are allowed substantial discretion in the use of these powers as they confront, detain, ticket, and arrest people; mediate disputes; direct traffic; and assist people in crisis. Individual officers decide when and how to drive emergency vehicles, confront disturbed and violent individuals, make arrests, and use deadly force. Many of their most difficult and complex decisions are made in fluid, ambiguous, and emotionally charged situations in which lives, property, and liberty can be lost in a split second. Errors
802 PART II / Section 9 • Occupational Sleep Medicine
made in the gray area between black-letter law and the hard concrete of the streets put police officers’ lives and their careers at risk and endanger the citizens they are sworn to protect. A large body of scientific research makes it clear that shift work and the kinds of long, erratic hours that many officers routinely work tend to interfere with precisely those parts of the brain that are most important for making morally charged decisions in dynamic, stressful situations. Sleep loss impairs rational decision-making in part because it differentially affects the frontal lobes of the brain where moral reasoning, planning, weighing of consequences, and self-control are centered and skilled movements are orchestrated. Many laboratory studies confirm that sleep loss affects a broad range of skills associated with decision-making, including insight, risk assessment, innovation, communication, and mood control.29 In fact, brain imaging studies demonstrate that lack of sleep has a disproportionate effect on the prefrontal cortex—the “executive” region of the brain where problems are solved and prioritized according to moral and situational criteria and where consequences are considered and responses are planned and coordinated.12 This suggests that even though tired cops may still be able to perceive a great deal about a situation because some parts of their brains are functioning well, they will be less likely to make sound decisions about what to do. Recent studies also suggest that they may be more likely to make hasty moral decisions and engage in riskier behavior.30,31 Decision-Making Chronic sleep loss reduces the ability to think clearly, handle complex cognitive tasks, and solve problems.12,32 Basic skills (e.g., marksmanship, emergency driving, and routine enforcement or public safety activities) rely heavily on abilities acquired through rote training, repetition to ingrained automatic responses, or unhurried rationalanalytic approaches to choosing from among alternative courses of action. These basic skills clearly tend to be degraded by sleep loss.33-35 However, the impact of sleep loss is likely to be even greater on the highly nuanced skills and expertise that police officers and similar occupations employ in emergency situations. Emergency responses in stressful, rapidly evolving and complex situations characterized by ambiguity, high risk, and personal threat require great expertise to avoid catastrophic outcomes36-38 and to apply complex rules of engagement quickly in complex and volatile naturalistic settings.39,40 Sleep loss degrades both routine decision-making skills and the ability to apply expertise in critical field situations, and it also diminishes critical abilities to modulate mood and arousal, especially in highly emotional confrontations and when being assaulted.41-45 The frequency, types, and locations of events that drive police judgments, decisions, and actions tend to differ with the daily, weekly, and seasonal rhythms of society. These shifting demands for service must be matched with efficient staffing and scheduling patterns that, in turn, limit officer opportunities for sleep and determine how much circadian disruption they must endure. This system of relationships must be taken into account to effectively manage,
prevent, and treat police officers’ sleep deprivation and sleep disorders.
SYSTEMATICALLY MANAGING, PREVENTING, AND TREATING SLEEP-DEPRIVED POLICE Shift Work: Interaction between the Organization and the Individual The quality of fit between police scheduling and staffing and the moving target of demand for services has profound implications for sleep loss. Poorer fit increases disruption of work schedules, generates more overtime work, and increases instances in which officers work longer shifts, multiple shifts, or lose days off. All of these increase sleep loss, increase circadian disruption, generate additional stress in officers’ lives, and reduce opportunities for sleep and recuperation. They also contribute to unexpected staff vacancies associated with illness, accidents, injuries, burnout, and early retirement. (Some police agencies in the United States report average daily absenteeism rates that range from 30% to 45% due to sick call-ins, occupational injuries, and similar causes.) Filling these vacancies generates more overtime and circadian disruption, creating a vicious cycle in which long and erratic work hours reduce the number of staff available for work, which, in turn, increases the prevalence of long and erratic work hours. Until recently, this sort of human resource management problem could be solved by hiring more officers whenever the costs associated with overtime premium pay exceeded the overhead associated with recruiting and training new officers.46 Now, however, demographic shifts and demands for police involvement in solving a wider array of community problems has left managers “fishing” for many more qualified recruits than the human resource pool can provide. Police departments across the United States and Canada are struggling to meet recruiting goals, generally with little success.19,47,48 Researchers are engaged with police in an attempt to understand the health and human performance consequences of long and erratic work shifts in police work. A major goal of this research is to provide evidence-based policy guidance on deployment strategies and standards of practice.20,49 Until now, demand for services and staffing levels generally were the only variables considered when assessing how efficiently an organization was deploying its personnel. Increasingly, however, managers and policymakers are coming to understand that officer performance, health, and safety also are critically important for community protection and safety. The essential insight here is that tired cops tend to be less able to serve their community than those who are adequately rested. This puts officer sleep loss and disruption front and center as a research and policy issue. The heart of this investigative endeavor is the need to understand the complex interaction between the community, the police agency, and police officers. As Figure 72-3 illustrates, the ability to provide sufficient police services is a function of both the number of officers assigned to work at a particular time and the work capacity of those officers. Understaffing results in more
CHAPTER 72 • Sleep Problems in First Responders and the Military 803
Box 72-1 Key Points
Management
Policing services provided
Community service needs
Understaffing
Officer work capacity × N officers
Overwork and job stress Health/wellness Nutrition
Resiliency Sleep
Sleep
Coping
Physical activity
Domestic life
Domestic life
Circadian phase
Figure 72-3 Conceptual model of interactions between needs of officers, police organizations, and communities.
work load, longer work hours, and greater risk to officers, resulting in more job stress. How these occupational demands affect individual officers depends on how resilient or susceptible they are, that is, how well they cope with both on-the-job challenges and the impact of those challenges on their personal lives. An officer’s ability to cope with the demands of shift work and long work hours is affected by sleep, circadian, and domestic factors.50 Because all of these factors interact, the cumulative effects of chronic sleep deprivation and circadian desynchrony tend to reduce resiliency and thus work capacity. Shift work, long work hours, overwork, and job stress also tend to undermine overall health and well-being because they interfere with the basic triad of human behaviors that are necessary for optimal health and wellness— good nutrition, physical activity, and a connected social life. Late-night shift workers often have difficulty obtaining nutritious food, and circadian disruption interferes with good eating habits. Furthermore, shift work and long or erratic work hours make it difficult to find sufficient time to sleep, recover, exercise, and interact with others. From a health and wellness perspective, sleep provides the foundation for recovery that enables people to maintain good health. The cumulative effects of chronic sleep deprivation and circadian desynchrony thus tend to reduce work capacity by diminishing overall health and wellness (Box 72-1). Repeated exposure to the sleep/circadian-related stress of shift work and long, erratic work hours throughout an officer’s career may affect his or her longevity in the pro-
1. Research evidence to date identifies three key factors associated with negative health and human performance outcomes in shift work: (a) extended hours of service, (b) limited recovery time, and (c) time on task. 2. The social, organizational, and individual causes of sleep loss among police and similar occupational groups are systematically linked, so they should be dealt with by striking a careful balance between the needs of society and the impact of shift work and long work hours on officers’ health and performance. 3. Shift length and rotation policies should be developed to fit the unique needs of each community and its police officers. There is no one ideal system for shift work. 4. The development of shift scheduling strategies and staff deployment models in police agencies requires both operational expertise and human factors expertise. Sleep physicians should participate in the scheduling/deployment process as advocates for police officers and experts on health and human performance issues. By doing so, they prevent health and wellness problems and help improve officer performance. 5. Diagnosing and treating sleep disorders in police officers often can benefit from understanding how occupational factors affect resilience, health, and wellness. Excessive overtime, frequent shift changes, and secondary employment are especially problematic in conjunction with sleep disorders. 6. Determination of “fitness for duty” requires the expertise of occupational physicians and is their responsibility. Sleep specialists should provide occupational medicine physicians with appropriate fitness-to-work recommendations regarding shift-work–related sleep disorders. 7. Appropriate management of sleep factors, circadian factors, and sleep disorders can mitigate the need for occupational accommodation and leaves of absence.
fession, in addition to health, safety, and survival.11 Police agencies that take a comprehensive approach to staffing that manages sleep and work-hour issues effectively can conserve human capital by improving retention and reducing lost work days, disability claims, and requests for accommodation. They also may improve recruitment— often from agencies with less desirable work-hour practices. This intimate and complex set of relationships must be taken into account when attempting to address human factors associated with shift work in police work and similar occupations. In sleep medicine, the traditional view of shift work focused on the relationship of sleep factors, circadian factors, and domestic demands, with the outcome being the shift worker’s ability to cope with these competing demands. Just as traditional police management models overlooked sleep and circadian issues, sleep medicine’s
804 PART II / Section 9 • Occupational Sleep Medicine
view failed to account for the interplay between the community, the police union/association, the police agency, and the individual. Truncated models such as these ignore important opportunities for preventing and treating sleep disorders and associated health problems. They also overlook critical opportunities for managing risks and human resources more effectively. Comprehensive models that consider demand for services, staffing, and human factors can improve individual health care, public health, and the management of scarce public resources. As Figure 72-3 emphasizes, adequately rested officers multiply the effective strength of a police force—just as adequate sleep can drastically improve the quality of officers’ lives.51,52 The comprehensive approach that we advocate provides clinicians, executives, and policymakers with measurable, objective outcomes that are useful for managing shift work in a way that maximizes health, safety, and performance. It also is the only approach that systematically attempts to optimize community well-being, organizational efficiency, and worker health and wellness. From a practical standpoint, this makes it easier to manage the competing interests of community, management, labor organizations, and individual officers because it provides them with a common ground for negotiating changes that help mitigate or minimize the unhealthy effects of shift work. Shift Work: The Individual Based on the proposed model, an officer’s resilience to repeated exposure to sleep restriction, circadian dysrhythmia, and domestic disturbance resulting from shift work and erratic work hours can be enhanced by addressing: (1) intrinsic sleep disturbance in the form of primary sleep disorders and (2) extrinsic factors related to the maintenance of general health. The relationship of sleep to cardiovascular disease, diabetes mellitus, and obesity has been well established in the sleep and medical literature.53,54 Figure 72-4 illustrates this system of relationships.55 The high prevalence of cardiovascular/metabolic disease in police officers is currently the focus of three major studies: the Buffalo Cardio-Metabolic Occupational Police Stress (BCOPS), the Calgary Police Service Health and Human Performance Research Initiative (CPS/HHPRI), and the Harvard Work Hours and Safety Group Police Study (HWHSGPS). Early results support the observation that cardiovascular and metabolic disease and sleep-disordered breathing are prevalent in this population.6,7,9,48,56 HWHSGPS researchers have established a high prevalence of primary sleep disorders (38.4%) and, in particular, sleep-disordered breathing (35.1%) based on a survey of 4471 police officers in the United States and Canada.9 This result has been corroborated in a smaller pilot study in the Calgary Police Service55 and the preliminary findings of the BCOPS study (Tables 72-2 and 72-3). Officers working night shifts also have been shown to acquire less sleep per day (44% higher prevalence of less than 7 hours per day than day-shift officers) and to have a higher prevalence of snoring, a risk factor for sleepdisordered breathing (16% higher prevalence than dayshift officers), both of which may increase risks of vascular disease.6,57,58 Therefore, reasonable interventions that can
Sleep restriction (sleep debt) Sleep disruption (nonrestorative sleep)
Circadian dysrhythmia: • Shift work • Night owl • Mood disorder
↑ Hyperaroused state ↑ Sympathetic tone ↑ Cortisol
↑ Increased appetite ↓ Leptin (resistance) ↑ Ghrelin
↑ Consume calorie-dense foods ↑ Central deposition of visceral fat
Adjusted neck circumference >43 cm58
Sleep-disordered breathing
Waist circumference >88 cm, >102 cm
Metabolic disregulation
Figure 72-4 Conceptual model of relationship of sleep restriction and disruption to metabolic disregulation, obesity, and sleep-disordered breathing.55
improve an officer’s ability to cope with the inherent rigors of shift work include screening for primary sleep disorders, managing sleep restriction, and minimizing circadian disturbance. Recovery, which is a function of sleep and rest, is critical for maintaining general health. Shift work often interferes with sleep, which forms the platform on which nutrition and physical activity interact with domestic life factors. Based on the current evidence, primary care, occupational medicine, and sleep physicians can help minimize and mitigate the negative effects of shift work and erratic work hours in police by: • Screening clinically for primary sleep disorders • Screening specifically for sleep-disordered breathing • Educating officers about the importance of managing chronic cumulative sleep debt • Educating officers about the connection between weight control, obesity, metabolic syndrome, cardiovascular disease, and sleep/circadian factors • Motivating officers to do their best with regard to behaviors over which they have at least partial control (i.e., physical activity, nutrition, rest and sleep) Police agencies also can contribute to this effort by conducting educational programs that reinforce the importance of getting adequate sleep. This combination of physician and agency interventions can help officers focus on critical factors that will improve their ability to withstand the rigors of shift work in a challenging work environment. Shift Work: The Organization Sleep physicians should be aware that both management and labor share responsibility for mitigating the impact
24
3-7 times/wk
50 24
<1-2 times/wk
3-7 times/wk
50 24
<1-2 times/wk
3-7 times/wk
50 23
<1-2 times/wk
3-7 times/wk
50 24
<1-2 times/wk
3-7 times/wk
50 24
<1-2 times/wk
3-7 times/wk
48 24
<1-2 times/wk
3-7 times/wk
24
3-7 times/wk
Ptrend
13 48
Never
<1-2 times/wk
Ptrend
13
Never
Ptrend
15
Never
Ptrend
15
Never
Ptrend
15
Never
Ptrend
15
Never
Ptrend
15
Never
.002
0.85 (0.01)
.004
0.24 (0.004)
0.22 (0.003)
.010
0.23 (0.004)
0.22 (0.003)
0.21 (0.010)
.002
.004 0.22 (0.006)
40.3 (0.8)
37.8 (0.6)
36.8 (1.0)
.006
0.55 (0.01)
0.52 (0.01)
0.50 (0.02)
.225
0.87 (0.01)
42.0 (0.8)
38.9 (0.6)
38.0 (1.1)
<.001
0.56 (0.01)
0.52 (0.01)
0.49 (0.01)
.038
0.88 (0.02)
0.85 (0.01)
0.85 (0.02)
.002
<.001 0.82 (0.02)
21.7 (0.7)
20.1 (0.5)
22.8 (0.6)
20.6 (0.4)
18.7 (0.8)
<.001 19.0 (0.7)
95.6 (2.3)
89.2 (1.7)
85.2 (2.8)
.003
109.9 (2.2)
105.6 (1.6)
99.0 (2.4)
90.2 (1.7)
84.9 (3.0)
.001
112.3 (1.8)
106.2 (1.2)
100.5 (2.6)
.002
<.001 102.8 (2.2)
29.6 (1.0)
26.8 (0.7)
30.9 (0.8)
27.5 (0.6)
25.4 (1.2)
MEAN (SE) 25.9 (1.0)
MODEL 2 MEAN (SE)
MODEL 1
SNORING
4
4
67
4
4
67
4
4
71
4
4
71
4
4
70
4
4
71
4
4
71
4
4
71
NO.
*Anthropometric measures, on the whole, predict pretest probability of obstructive sleep apnea.
Neck-to-height ratio
Neck circumference
Waist-to-height ratio
Waist-to-hip ratio
Abdominal height
Waist circumference
Hip circumference
50
<1-2 times/wk
Ptrend
15
Never
Body mass index
NO.
FREQUENCY OF SLEEP PROBLEMS
ANTHROPOMETRIC OBESITY MEASUREMENTS*
7
.156
0.24 (0.011)
0.23 (0.011)
0.22 (0.003)
.206
42.0 (2.0)
40.3 (2.0)
39.4 (0.5)
.847
0.53 (0.03)
0.52 (0.03)
0.52 (0.01)
.665
0.83 (0.04)
0.88 (0.04)
0.85 (0.01)
.283
22.6 (1.6)
21.1 (1.6)
20.9 (0.4)
.868
92.7 (6.5)
93.2 (6.5)
91.6 (1.5)
.366
112.1 (4.6)
105.4 (4.6)
107.8 (1.1)
.235
30.8 (2.2)
28.3 (2.2)
28.1 (0.5)
MEAN (SE)
MODEL 1
.316
0.23 (0.011)
0.23 (0.010)
0.22 (0.004)
.275
40.3 (1.8)
39.7 (1.7)
38.4 (0.6)
.844
0.54 (0.03)
0.52 (0.03)
0.53 (0.01
.622
0.84 (0.03)
0.87 (0.03)
0.85 (0.01)
.254
22.1 (1.5)
21.0 (1.4)
20.5 (0.5)
3
13
74
3
13
74
3
13
78
3
13
78
3
13
77
3 .845
13
92.7 (5.6)
78
3
13
78
3
13
78
NO.
93.4 (5.3)
91.6 (1.8)
.391
111.0 (4.7)
106.6 (4.5)
107.0 (1.5)
.312
29.9 (2.2)
28.6 (2.0)
27.7 (0.7)
MEAN (SE)
MODEL 2
STOP BREATHING
.057
0.25 (0.013)
0.23 (0.006)
0.22 (0.003)
.096
43.3 (2.4)
40.3 (1.2)
39.2 (0.5)
.200
0.57 (0.04)
0.52 (0.02)
0.52 (0.01)
.764
0.86 (0.05)
0.84 (0.02)
0.85 (0.01)
.091
23.8 (1.8)
20.6 (0.9)
20.6 (0.4)
.265
99.2 (7.5)
91.1 (3.6)
90.6 (1.4)
.105
115.9 (5.4)
107.8 (2.6)
106.8 (1.1)
.108
32.0 (2.5)
29.0 (1.2)
27.8 (0.5)
MEAN (SE)
MODEL 1
.042
0.25 (0.013)
0.24 (0.007)
0.22 (0.003)
.023
43.2 (2.0)
41.0 (1.1)
38.5 (0.5)
.089
0.58 (0.04)
0.53 (0.02)
0.52 (0.01)
.606
0.87 (0.03)
0.87 (0.02)
0.85 (0.01)
.014
24.3 (1.6)
20.5 (0.9)
20.2 (0.4)
.068
101.0 (6.1)
92.8 (3.4)
89.8 (1.6)
.036
116.7 (5.5)
106.5 (3.1)
104.9 (1.4)
.036
32.3 (2.5)
28.9 (1.4)
27.1 (0.6)
MEAN (SE)
MODEL 2
GASPING FOR BREATH
Table 72-2 Adjusted Mean Values of Anthropometric Obesity Measurements among Police (Models 1 and 2) Stratified According to Symptoms of Sleep-Disordered Breathing
CHAPTER 72 • Sleep Problems in First Responders and the Military 805
806 PART II / Section 9 • Occupational Sleep Medicine Table 72-3 Association of Sleep Quality and Quantity in Police Officers Who Work Night Shifts Compared with Those Who Work Day/Afternoon Shifts* SLEEP QUALITY/QUANTITY
At night, my sleep disturbs my bed partner’s sleep.
MODEL 1
MODEL 2
MODEL 3
PR
95% CI
PR
95% CI
PR
95% CI
0.93
0.65-1.33
0.99
0.68-1.45
0.94
0.62-1.43
I am told I snore in my sleep.
1.26
1.12-1.41
1.21
1.06-1.38
1.16
1.00-1.33
I am told I stop breathing in my sleep.
0.53
0.07-3.95
0.67
0.08-5.68
0.59
0.02-14.3
I suddenly wake up gasping for breath during the night.
0.27
0.04-1.89
0.25
0.03-1.89
0.27
0.03-2.67
I have or have been told that I have restless legs.
1.26
0.64-2.45
0.91
0.46-1.80
1.02
0.53-1.95
I feel tired upon awakening and want to go back to sleep.
0.99
0.83-1.18
0.97
0.82-1.16
0.97
0.81-1.16
I am very sleepy during the daytime and struggle to stay awake.
0.91
0.64-1.30
0.83
0.58-1.19
0.90
0.62-1.32
Hours of sleep per 24-hour period during the previous week (<7 vs. ≥7)
1.46
1.09-1.94
1.35
0.99-1.85
1.44
1.00-2.07
PR, prevalence ratio; CI, confidence interval. Results obtained from Poisson regression models: Model 1, unadjusted; Model 2, adjusted for years of service; Model 3, adjusted for years of service, depression, body mass index, physical activity, and gender. *Night-shift officers tend to snore more and get less sleep than dayshift officers.6
of shift work and erratic work hours. Policy makers, police executives, officers, and their families need to understand the implications of empirical evidence to make good decisions about work-hour issues. Efforts to translate knowledge to practice should emphasize the impact that shift work and erratic work hours have on human performance and health. And they should provide practical solutions that help strike a balance between the sometimes competing needs of officers and the communities they serve. Shift-work management strategies must go beyond the current focus on identifying an “ideal shift” because shift work itself has not been shown to be associated with morbidity,17 although total hours of work per week and amount of time available for recovery have been. In addition, wellness and health promotion programs need to broaden their focus to include sleep and circadian factors as well as nutrition, activity, and stress reduction. As Figure 72-3 illustrates, the rigors of shift work in police work require a broad-based and comprehensive approach to be effective. Exemplary Unified Approach An example of the unified approach we advocate is the Calgary Police Service (CPS) Health and Human Performance Research Initiative. This effort, which grew out of the 2001 CPS Patrol Officers Shift Schedule Review (POSSR),51,52 is a long-term research and knowledge transfer project. One of the key POSSR recommendations was that the CPS enlist a sleep specialist and knowledgetransfer expert to help the service develop and evaluate new shift schedules that were sensitive to officer health and human performance issues. Perhaps the most unique aspect of this initiative is the knowledge transfer component, which uses new scientific evidence as it emerges to develop educational programs. These educational programs guide CPS efforts to change how police officers,
labor leaders, and managers view shift-work management and related health and human performance issues. The CPS Health and Human Performance Research Initiative is a comprehensive, collaborative effort by all stakeholders that recognizes that they each have a stake in developing strategies for managing shift work and that cooperation is vital for long-term success. Another important aspect of this initiative is that it has support from high-ranking labor and management leaders who have been instrumental in maintaining its momentum. The success of this approach has drawn the attention of other police agencies, several of which are developing fatigue management strategies that fit their own resources, needs, and organizational cultures. In each of these efforts, sleep and occupational physicians, along with knowledgetransfer experts, provide critical expertise and advice.
❖ Clinical Pearl A comprehensive program of fatigue risk management for police officers and other first responders should include: • Screening all officers for primary sleep disorders and specifically for sleep-disordered breathing due to the high prevalence of sleep disordered breathing in this population • Emphasizing the importance of managing day and night sleep environment, cumulative sleep debt, early signs of chronic sleep deprivation, and symptoms of shift-work sleep disorder • Providing educational material for officers and their families for the purpose of preventing and mitigating the health and human performance consequences of shift work.
CHAPTER 72 • Sleep Problems in First Responders and the Military 807
REFERENCES 1. Caruso CC, Bushnell T, Eggerth D, et al. Long working hours, safety, and health: toward a national research agenda. Am J Indust Med 2006;49:930-942. 2. Franke WD, Anderson DF. Relationship between physical activity and risk factors for cardiovascular disease among law enforcement officers. J Occup Med 1994;36:1127-1132. 3. Franke WD, Cox DF, Schultz DP, et al. Coronary heart disease risk factors in employees of Iowa’s department of public safety compared to a cohort of the general population. Am J Ind Med 1997;31: 733-777. 4. Gershon RM, Lin S, Li X. Work stress in aging police officers. J Occup Environ Med 2002;44:160-167. 5. Liberman A, Best S, Metzler T, et al. Routine occupational stress and psychological distress in police. Policing 2002;25: 421-439. 6. Charles LE, Burchfiel CM, Fekedulgen D, et al. Shift work and sleep: the Buffalo Police Health Study. Policing 2007;30:215-227. 7. Charles L, Violanti J, Burchfiel C, et al. Obesity and sleep: the Buffalo Police Health Study. Policing 2007;30:203-214. 8. Neylan TC, Metzler MA, Best SR, et al. Critical incident exposure and sleep quality in police officers. Psychosom Med 2002;64: 345-352. 9. Rajaratnam S, Barger L, Lockley S, et al. Screening for sleep disorders in North American police officers. Sleep 2007;30(Abstract Suppl):A209. 10. Toch H. Stress in policing. Washington, DC: American Psychological Association; 2002. 11. Violanti JM, Vena JE, Petralia S. Mortality of a police cohort: 19501990. Am J Ind Med 1998;33:366-373. 12. Durmer J, Dinges D. Neurocognitive consequences of sleep deprivation. Semin Neurol 2005;25:117-129. 13. Caruso CC, Hitchcock EM, Dick RB, et al. NIOSH publication No. 2004-143: overtime and extended work shifts: recent findings on illnesses, injuries and health behaviors. Available at: http://www.cdc. gov/niosh/docs/2004-143. Accessed October 31, 2008. 14. Centers for Disease Control, National Occupational Mortality Survey. Available at: http://www.cdc.gov/niosh/topics/surveillance/ NOMS. Accessed October 31, 2008. 15. Dembe AE, Erickson JB, Delbos RG, et al. The impact of overtime and long work hours on occupational injuries and illnesses: new evidence from the United States. Occup Environ Med 2005;62: 588-597. 16. Folkard S, Tucker P. Shift work, safety and productivity. Occup Med (Lond) 2003;53:95-110. 17. Costa G. Shift work and occupational medicine: an overview. Occup Med (Lond) 2003;53:83-88. 18. Folkard S, Lombardi DA, Spencer MB. Estimating the circadian rhythm in the risk of occupational injuries and accidents. Chronobiol Int 2006;23:1181-1192. 19. Vila B. Impact of long work hours on police officers and the communities they serve. Am J Ind Med 2006;49:972-980. 20. Vila B. Tired cops: the importance of managing police fatigue. Washington, DC: Police Executive Research Forum; 2000. 21. Vila B, Morrison GB, Kenney DJ. Improving shift schedule and work-hour policies and practices to increase police officer health, safety and performance. Police Q 2002;5:1:4-24. 22. Vila B, Moore JM. Police long work hours: causes, consequences and alternatives. In: Burke R, Cooper C, editors. The long hours work culture: causes, consequences and choices. Bingly, UK: Emerald Publishing; 2008. p. 183-201. 23. Elliot DL, Kuehl KS. Effects of sleep deprivation on fire fighters and EMS responders, final report. Fairfax, Va: International Association of Fire Chiefs; 2007. 24. West B. The strongest tribe: war, politics, and the endgame in Iraq. New York: Random House; 2008. p. 21. 25. U.S. Army US. Marine Corps. Counterinsurgency, FM 3-24/MCWP 3-33.5. Washington, DC: Department of Defense; 2006. 26. U.S. Marine Corps. Small wars manual, NAVMC 2890. Washington, DC: U.S. Government Printing Office; 1940. 27. Parks WH. Deadly force is authorized. U.S. Naval Institute Proceedings 2001; vol. 127/1. Available at: http://www.usni.org/Proceedings/ Articles01/PROparks1.html. Accessed October 23, 2008. 28. Martins MS. Deadly force is authorized, but also trained. The Army Lawyer 2001; DA PAM 27-50-346 2001. Available at: http://www.
au.af.mil/au/awc/awcgate/army/roe_article.pdf. Accessed October 23, 2008. 29. Harrison Y, Horne JA. The impact of sleep deprivation on decision making: a review. Exp Psychol Appl 2000;6:236-249. 30. Killgore WD, Balkin TJ, Wesensten NJ. Impaired decision making following 49 hours of sleep deprivation. J Sleep Res 2005; 14:1-7. 31. Killgore WDS, Kilgore DB, Day LM, et al. The effects of 53 hours of sleep deprivation on moral judgment. Sleep 2007;30: 345-352. 32. Koslowsky M, Babkoff H. Meta-analysis of the relationship between total sleep deprivation and performance. Chronobiology Int 1992; 9:132-136. 33. Williamson AM, Feyer AM. Moderate sleep deprivation produces impairments in cognitive and motor performance equivalent to legally proscribed levels of alcohol intoxication. Occup Environ Med 2000;57:649-655. 34. Dawson D, Reid K. Fatigue, alcohol and performance impairment. Nature 1997;388:235. 35. Belenky G, Wesensten NJ, Thorne DR. Patterns of performance degradation and restoration during sleep restriction and subsequent recovery: a sleep dose-response study. J Sleep Res 2003;12:112. 36. Perrow C. Normal accidents: living with high-risk technologies. New York: Basic Books; 1984. 37. Klinger D. Social theory and the street cop: the case of deadly force. In: Ideas in American policing, No. 7. Washington, DC: Police Foundation; 2005. 38. Hammond KR. Judgments under stress. New York: Oxford University Press; 2000. 39. van den Bosch K, Riemersma JBJ. Reflections on scenario-based training in tactical command. In: Schiflett SG, Elliott LR, Salas E, Coovert MD, editors. Scaled worlds: development, validation and applications. Burlington, Vt: Ashgate; 2001. p. 1-21. 40. Ericsson KA, Smith J, editors. Toward a general theory of expertise: prospects and limits. Cambridge, UK: Cambridge University Press; 1991. 41. Pilcher JJ, Huffcutt AI. Effects of sleep deprivation on performance: a meta-analysis. Sleep 1996;19:318-326. 42. Sparks K, Cooper C, Fried Y, et al. The effects of hours of work on health: a meta-analytic review. J Occup Org Psychol 1997; 70:391-408. 43. Roman V, Hagewoud R, Luiten PG, et al. Differential effects of chronic partial sleep deprivation and stress on serotonin-1A and muscarinic acetylcholine receptor sensitivity. J Sleep Res 2006;15: 386-394. 44. Poissonnet CM, Vernon M. Health effects of work schedules in healthcare professions. J Clin Nursing 2000;9:13-23. 45. Salazar MK, Beaton R. Ecological model of occupational stress: application to urban firefighters. AAOHN J 2000;48:470479. 46. Vila B. Tired cops: probable connections between fatigue and the performance, health, and safety of patrol officers. Am J Police 1996;15(2):51-92. 47. Ruecker RC. Discover policing: a nationwide recruitment initiative for your agency and the entire police profession. Open letter to members of the International Association of Chiefs of Police, November 1, 2008. Available at: http://www.DiscoverPolicing.org. 48. Vila BJ, Kenney DJ, Morrison GB, et al. Evaluating the effects of fatigue on police patrol officers: final report. Washington, DC: National Institute of Justice; 2000. 49. Violanti JM, Burchfiel CM, Miller DB, et al. The Buffalo Cardio-Metabolic Occupational Police Stress (BCOPS) Pilot Study: methods and participant characteristics. Ann Epidemiol 2006;16: 148-156. 50. Monk T. Shift work: basic principles. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine. 4th ed. Philadelphia: Elsevier Saunders; 2005. p. 674. 51. Smith RB, Haddow R, Johnston A. Patrol officer shift schedule review. Calgary Police Service, Research and Development Section; May 2002. 52. Smith RB, Haddow R, Johnston A. Patrol officer shift schedule review: appendices. Calgary Police Service, Research and Development Section; May 2002. 53. Ha M, Park J. Shiftwork and metabolic risk factors of cardiovascular disease. J Occup Health 2005;47:89-95.
808 PART II / Section 9 • Occupational Sleep Medicine 54. Jennings RJ, Muldoon MF, Hall M, et al. Self-reported sleep quality is associated with the metabolic syndrome. Sleep 2007;30:219-223. 55. Samuels CH. Sleep and weight control: a wake-up call. Can J Diagn 2005;(June):75-79. 56. Samuels CH, Dirks-Farley S, Seib M, et al. A cross-sectional study of the prevalence of cardiovascular/metabolic risk and sleep/fatigue related impairment in the Calgary Police Services District Sergeants and Duty Inspectors. Sleep 2007;30(Abstract Suppl):A48.
57. Drager LF, Genta PR, Pedrosa RP, et al. Characteristics and predictors of obstructive sleep apnea in patients with systemic hypertension. Am J Cardiol 2010;105:1135-1139. 58. Li C, Hoffstein V. Snoring. In: Kryger MH, Roth T, Dement WC, editors. Principles and practice of sleep medicine, 5th ed. Philadelphia: Elsevier Saunders; 2011. p. 1172-1182.
Pharmacologic Management of Performance Deficits Resulting from Sleep Loss and Circadian Desynchrony Nancy J. Wesensten Abstract Extended work hours result in sleep loss. Shift-work hours/ time zone travel results in circadian desynchrony (which in turn also leads to sleep loss via impaired sleep). The only permanent solution to sleep loss is sleep itself, and the ideal solution to circadian desynchrony is rapid readjustment of the
Contemporary work hours are characterized by roundthe-clock shifts (evenings and nights), extended shifts (>8 hours), and duty cycles extending beyond the 5-day work week. Consequently, sleep loss–induced performance and alertness deficits have become a widespread problem, particularly for evening- and night-shift workers who additionally suffer sleep loss due to an inability to obtain sufficient daytime sleep. Performance and alertness deficits not only decrease worker productivity but also put the worker at substantially increased risk for accidents. Because nonpharmacologic/behavioral interventions for improving performance and alertness are largely ineffective, problems often must be treated using stimulant agents to maintain safe levels of performance and alertness or sleep-inducing agents to induce off-duty sleep. In this chapter, general guidelines are presented for the use of stimulants and sleep-inducing agents to manage cognitive performance deficits associated with sleep loss and circadian desynchrony in healthy adults (a detailed review of the circadian influence on sleepiness, alertness, and neurobehavioral performance can be found in Chapter 38). The goal of this chapter is to outline issues to be considered when using these agents to treat either excessive sleepiness on the job or difficulty sleeping. It is noted at the outset that pharmacologic agents should be considered a temporary, shortterm solution within the broader context of an overarching fatigue mitigation plan aimed at maintaining optimal amounts of daily sleep. Both total sleep deprivation and chronic, restricted sleep degrade alertness and cognitive performance. Additionally, sleep loss interacts with time of day (or circadian phase) to affect alertness and performance: sleep loss effects can be viewed as “overlying” the circadian-driven, rhythmic 24-hour improvements and decrements in cognitive performance and alertness (see Chapter 65). Figure 73-1A illustrates a simple schematic of the usual relationship between the sleep–wake period and the circadian system: performance and alertness improvements are driven across daytime hours (i.e., the ascending phase of the circadian rhythm), whereas the ability to sleep is optimal during nighttime hours (i.e., the descending phase of the circadian rhythm). Figure 73-1B illustrates the shifted relationship
Chapter
73
circadian system. In lieu of these preferred strategies and as components of a broad-based fatigue mitigation strategy, pharmacologic agents can be used in the short term to maintain cognitive performance and alertness (stimulants) and to improve sleep (sleep inducers).
between sleep–wake pattern and the circadian system after transmeridian travel (e.g., an 8-hour time zone advance) or shift work: because the circadian system does not immediately readjust, the individual is now attempting to (1) maintain wakefulness and perform optimally during the descending phase of the circadian rhythm and (2) sleep during the ascending phase of the circadian rhythm. Under these conditions, performance and alertness during waking hours is degraded; and sleep during the designated sleep period is degraded in that the ability to both initiate and maintain sleep is impaired.1 Consequently, although a person may spend 8 hours in bed, he or she may accumulate only 4 to 5 hours of sleep. These two problems characterize shift-work sleep disorder: excessive sleepiness during the work shift and insomnia during the sleep period.2 Even in the absence of circadian misalignment, extended work hours alone lead to sleep loss by decreasing the time available to sleep. As noted earlier, sleep loss directly degrades cognitive performance and alertness and it also exacerbates the circadian rhythm in sleep propensity. The ideal (and permanent) solution to extended work hours and lack of adequate sleep is sleep itself. Likewise, the ideal solution to circadian desynchrony would be a treatment that rapidly readjusts the circadian system to nighttime work hours or, in the case of transmeridian travel, to a new time zone. The operational realities, however, are that individuals sometimes must forego adequate sleep; and currently no “magic bullet” exists for rapidly re-entraining the circadian system (furthermore, in the case of night-shift work, due to social/family demands individuals often switch back to normal daytime hours on days off, thus reversing any re-entrainment that may have begun over the work week). Therefore, short-term pharmacologic solutions to these problems are a critical component of fatigue management. Evidence is overwhelming that central nervous system (CNS) stimulants exert measurable positive effects on mental operations and that sleep-inducing agents exert measurable positive effects on sleep. These solutions are discussed next. Nonpharmacologic solutions are not discussed here: the interested reader is referred elsewhere.3-7 809
810 PART II / Section 9 • Occupational Sleep Medicine
1200
0000
1200
0000 Time of day
1200
0000
1200
1200 2000
0000 0400
1200 2000
0000 0400
1200 2000
0000 0400
1200 2000
New local time following 8-hour time zone advance Body temp Performance and alertness Sleep Work
Figure 73-1 A, Optimal 24-hour alignment among the sleep– wake period, the work period, and underlying circadian rhythms. Under these conditions, cognitive performance and alertness are maximal during working hours and sleep is easily initiated and maintained during the sleep period. B, Alignment of the sleep–wake period, the work period, and underlying circadian rhythms during night-shift work or after an 8-hour time zone advance. Under these conditions, working hours occur during the descending phase of the circadian rhythm, resulting in impaired cognitive performance and alertness; likewise, the sleep period occurs during the ascending phase of the circadian rhythm, resulting in difficulties initiating and maintaining sleep.
PHARMACOLOGIC STRATEGIES FOR IMPROVING COGNITIVE PERFORMANCE Central nervous system stimulants include both overthe-counter (e.g., caffeine) and U.S. Food and Drug Administration (FDA)-approved prescription agents (e.g., dextroamphetamines, modafinil, and methylphenidate). Ideally, a CNS stimulant would maintain cognitive per formance while causing few unwanted side effects (e.g., headaches, jitteriness, nausea) at efficacious doses. The stimulants discussed in this section meet these criteria (for further discussion of efficacy and side effect issues, see Chapter 45). Putative cognitive enhancers and nutraceuticals are not discussed here because there is no evidence that, in humans, such compounds objectively improve cognitive performance decrements associated with sleep loss and circadian desynchrony.8 Caffeine Caffeine is a widely available over-the-counter CNS stimulant that exerts its effects by acting as an antagonist at brain adenosine receptors.9 Antagonism at these receptors
reduces brain adenosine transmission, stimulating wakefulness; and, conversely, brain adenosine agonists enhance brain adenosine transmission, inducing sleep. In sleep-deprived and sleep-restricted volunteers, caffeine has been shown to improve performance on a variety of cognitive tasks (e.g., simple and complex reaction time, logical reasoning, mathematical processing, digit span), most notably improving reaction time. Accuracy of performance is generally unaffected by sleep loss. Caffeine also improves the ability to stay awake under sleep-conducive conditions. Caffeine’s effects in warding off sleep and stimulating alertness are dose dependent and persist for a duration consistent with caffeine’s pharmacokinetic profile: the lowest dose of caffeine that effectively improves performance during sleep loss is approximately 100 mg with a duration of effect of 4 to 6 hours.10 Caffeine is effective both as a single bolus11 or when administered as appropriately timed, smaller doses.12,13 The timed, smaller-dose strategy makes most sense for operational use because (1) it reduces the likelihood of undesirable side effects such as nausea and jitteriness that are seen with higher (e.g., 300 mg and above) caffeine doses and (2) at smaller doses the likelihood of the individual being able to sleep should such an opportunity present itself is greater. Sustainedrelease formulations of caffeine have been shown to increase caffeine’s duration of action14; however the utility of such a formulation is unclear because caffeine is easily re-dosed and extended duration of action may be a hindrance if an opportunity for sleep presents itself. Like all currently available stimulants, caffeine can interfere with sleep if the sleep period falls within the duration of caffeine’s pharmacologic effects.15 The question of whether caffeine actually restores performance or merely reverses caffeine withdrawal has been raised.16,17 However, caffeine has been shown to be similarly efficacious in reversing the performance degrading effects of sleep loss in both nonusers and habitual users.18 Caffeine is available in tablet/pill and chewing gum formulations. With the gum formulation, some caffeine is absorbed through the oral mucosa, resulting in more rapid delivery and performance improvement.19 Modafinil Modafinil is an FDA-approved treatment of sleepiness associated with narcolepsy, shift-work sleep disorder, and sleep apnea. The mechanism of action by which modafinil exerts its stimulant effects is unclear but may include direct or indirect effects on noradrenergic, dopaminergic (specifically, the dopamine transporter), GABAergic, glutaminergic, histaminergic, and hypocretin systems.20 Modafinil is a Schedule IV compound. The recommended modafinil dosage for shift-work sleep disorder is 200 mg taken approximately 1 hour before the work shift. In contrast to clinical studies, results from laboratory studies in normal volunteers of modafinil in sleep loss have shown dose-dependent performance improvements in doses ranging from 100 to 400 mg. Higher doses also translate into a longer duration of action (e.g., up to 8 hours),21 which is consistent with modafinil’s half-life of 13 to 14 hours.22 In a simulated night-shift work study,23 modafinil 200 mg was administered at 10:00 pm (2200h) across four
CHAPTER 73 • Pharmacologic Management of Performance Deficits 811
consecutive “night shifts” (11:00 pm to 7:30 am), followed by daytime sleep (6 to 8 hours time in bed beginning at 8:00 am). Modafinil, 200 mg, sustained psychomotor vigilance performance at near-baseline levels. It also was shown to improve performance on tasks of executive function including the Torrence Test of Creative Thinking— Verbal (verbal fluency, flexibility, and originality), the Wisconsin Card Sorting Task (planning, mental flexibility, set-shifting, and concept formation), and the Haylings Sentence Completion Test (measuring the ability to inhibit verbal responses).23 Modafinil also improves the ability to stay awake under sleep-conducive conditions (sleep loss and adverse circadian phase) in a dose-dependent fashion.24 Like caffeine, modafinil can impair sleep if the sleep period is initiated within modafinil’s duration of action.25 Although modafinil’s low abuse potential profile makes it more attractive than other controlled stimulants (e.g., dextroamphetamine, methylphenidate), it has yet to be determined whether modafinil provides any performance, subjective side effect, or abuse potential advantage over noncontrolled stimulants such as caffeine.21 Dextroamphetamine Dextroamphetamine is an agonist of brain dopamine receptors where it exerts widespread effects. Because dextroamphetamine is FDA approved only for narcolepsy and attention deficit disorder with hyperactivity, it will not be reviewed thoroughly here. A full discussion of dextroamphetamine and its effects in sleep loss can be found elsewhere.26 Briefly, results of laboratory studies have shown that, like caffeine and modafinil, dextroamphetamine is efficacious for restoring cognitive performance degraded by total sleep loss,27 its effects are dose dependent,27 and its effects are comparable in duration to those of modafinil.21 Summary and Future Directions Caffeine is safe, effective, and available over the counter in several formulations and has been demonstrated to counteract impaired cognitive performance and alertness resulting from sleep loss and circadian desynchrony (e.g., jet lag, shift work). Caffeine’s short half-life also makes it attractive for use on 8- and 12-hour shifts because caffeine will have cleared from the body by the end of the shift. In most instances, caffeine is the agent of choice for improving cognitive performance and alertness during extended work hours and during shift work. In more severe cases (e.g., shift-work sleep disorder), the prescription agent modafinil is a viable option. In recent years, whether stimulant agents restore all aspects of cognitive performance impaired by sleep loss— most notably the so-called executive functions such as judgment, decision-making, and situational awareness— has been brought into question by the Tarnak Farms incident of April 17, 2002. In that incident, American Air Force pilots flying F-16s over the Khandahar region in Afghanistan mistook a live-fire friendly force ground exercise as a surface-to-air attack and dropped a laser-guided bomb, killing four Canadian soldiers. At issue was whether the dextroamphetamine (“Go-pills”) the pilots took to remain awake during the flight impaired their judgment, as the pilots claimed in their defense. Although it is unlikely
that dextroamphetamine played more than a minor role (if any), this single incident raised questions about stimulant effects on executive functions that are just beginning to be addressed in laboratory studies. As more is learned about the neurobiology, neurochemistry, and neuropharmacology underlying sleep and wakefulness, other potential wake-promoting agents will likely be developed. These may include drugs targeting the central histaminergic28 and orexin/hypocretin29 systems. For a discussion of basic mechanisms and pharmacology of wake-promoting agents, see Chapter 44.
PHARMACOLOGIC STRATEGIES FOR IMPROVING SLEEP Even when sleep time is available, sleep may be unlikely; for example, the sleep period may occur when it is unlikely that the person will be able to sleep due to time of day and consequent non–sleep-conducive circadian phase.30 Also, the sleep environment may be nonconducive to sleep (e.g., due to noise, lighting, ambient temperature, anticipation of being called to work). Under these conditions and particularly when individuals attempt to sleep at a low-sleep propensity circadian phase, nonpharmacologic strategies (e.g., ear plugs, room darkening) may not be sufficient. Improving sleep using a sleep-inducing agent may be of value. The following criteria are considerations for selecting a sleep-inducing agent with a view toward improving performance: the agent increases recuperative sleep time (by decreasing time spent awake and in nonrecuperative stage 1 sleep); the agent possesses a rapid onset of action; and, if the available sleep period is of limited duration, a short duration of action. Prescription Sleep-Inducing Agents Currently available over-the-counter sleep aids contain substances (e.g., antihistamines or pain relievers) that induce feelings of sedation, but these sleep aids do not increase recuperative sleep time. In contrast, prescription sleep inducers (hypnotics) have been shown to increase recuperative sleep time,31 and most (including those in the benzodiazepine drug class and nonbenzodiazepines such as zolpidem and zopiclone) act as agonists at the brain benzodiazepine receptor32 (see also Chapters 42 and 43). First-generation hypnotics such as flurazepam possessed a long duration of action well beyond the normal sleep period, whereas newer compounds such as zaleplon possess half-lives less than 2 hours. The variety of prescription hypnotics with differing half-lives allows for the hypnotic to be tailored to the available sleep period duration to avoid residual sedation. The ideal sleep-inducing agent should not impair performance on awakening, particularly if the individual has to awaken and perform within the compound’s duration of action. To date, no such compound exists: a hypnotic’s performance-impairing effect (the most notable for benzodiazepine receptors being impaired memory consolidation) appears to be directly (functionally) coupled with its sleep-inducing properties,33 and therefore the potential for performance impairment exists so long as the compound is still in the body—and particularly around the time of
812 PART II / Section 9 • Occupational Sleep Medicine
peak effect. The latter has potentially serious negative performance consequences under operational conditions.34 However, as long as an adequate sleep opportunity follows ingestion of a hypnotic, the likelihood of performance impairment on resuming work is minimized. Melatonin Hundreds of peer-reviewed papers have addressed the issue of whether orally administered exogenous melatonin improves sleep and hastens readjustment of body temperature, alertness, performance, and so on, after shift work or time zone travel.35,36 There is evidence that melatonin possesses some sleep-promoting effects; however, few studies have been published in which melatonin has been directly compared with prescription hypnotics across a range of doses. Thus, the efficacy of melatonin versus prescription hypnotics is still unclear.37,38 Summary and Future Directions At sufficient doses, prescription sleep-inducing agents increase recuperative sleep time under non–sleep-conducive conditions. Because, depending on the dose, sleepinducing agents impair cognitive performance (especially acquisition of new memories), they should only be used in conjunction with sufficient down time. In most instances, sleep-inducing agents can be administered according to labeling instructions (e.g., zolpidem, 10 mg taken 30 minutes before bedtime). Higher doses may be required in young, healthy adults and/or under particularly nonconducive conditions.33 When properly used according to packaging directions, sleep-inducing agents are both safe and effective. Pharmacologically managing both the excessive sleepiness and insomnia associated with circadian desynchrony might seem the best approach; however, there are few published studies in this area. Results of one study suggested a synergistic benefit of zolpidem-induced sleep followed by caffeine or modafinil-enhanced wakefulness39; however, results of another study indicated that including a sleep-inducing agent for increasing sleep conferred no additional benefit for enhancing alertness over a stimulant alone.40 However, data are lacking on cognitive performance- and alertness-improving efficacy of a combination hypnotic/stimulant approach across a variety of compounds and dose ranges.
CONCLUSION Extended work hours can result in partial sleep deprivation, which in turn contributes to cognitive performance and alertness deficits. Although the ideal solution to extended work hours is more sleep, in the short term stimulants such as caffeine can be used to manage fatigue. Travel across time zones and shift work results in partial sleep deprivation as well as circadian desynchrony, the latter also contributing substantially to cognitive performance and alertness deficits. After travel across time zones, individuals eventually resynchronize to the new local time. During the transition period, stimulants can be used to improve cognitive performance during the new local day and sleep-inducing agents can be used to increase recuperative sleep time during the new local night. In contrast
to time zone travel, evidence suggests that circadian adaptation to shift work is unlikely (perhaps owing to the light– dark cycle remaining out of phase and to social and familial conflicts with daytime sleep), and shift-work sleep disorder can result. In cases in which excessive sleepiness cannot be successfully combated with caffeine, modafinil may be considered. A combination of a hypnotic to improve sleep and a stimulant to improve performance may confer more benefits than either compound alone, but such an approach has yet to be evaluated across a range of compounds and dosages.
❖ Clinical Pearl The ideal strategy for maintaining optimal cognitive performance and alertness is sleep. However, in the short term, stimulants such as caffeine can be used to temporarily sustain performance and alertness during inevitable sleep loss or circadian desynchrony, and sleep-inducing agents can be used to induce sleep when a sleep period becomes available but sleep is unlikely due to environmental conditions or circadian desynchrony.
Disclaimer This material has been reviewed by the Walter Reed Army Institute of Research, and there is no objection to its presentation and/or publication. The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or as reflecting the position of the U.S. Department of the Army or the U.S. Department of Defense. REFERENCES 1. Sack RL, Auckley D, Auger RR, et al. Circadian rhythm sleep disorders: I. Basic principles, shift work and jet lag disorders. An American Academy of Sleep Medicine review. Sleep 2007;30:1460-1483. 2. American Academy of Sleep Medicine. International classification of sleep disorders, revised: diagnostic and coding manual. Chicago: American Academy of Sleep Medicine; 2001. 3. Skene DJ. Optimization of light and melatonin to phase-shift human circadian rhythms. J Neuroendocrinol 2003;15:438-441. 4. Touitou Y, Bogdan A. Promoting adjustment of the sleep-wake cycle by chronobiotics. Physiol Behav 2007;90:294-300. 5. Horne J, Reyner L. Vehicle accidents related to sleep: a review. Occup Environ Med 1999;56:289-294. 6. Batejat DM, Lagarde DP. Naps and modafinil as countermeasures for the effects of sleep deprivation on cognitive performance. Aviat Space Environ Med 1999;70:493-498. 7. Bonnet MH, Gomez S, Wirth O, et al. The use of caffeine versus prophylactic naps in sustained performance. Sleep 1995; 18:97-104. 8. Wesensten NJ, Reichardt RM, Balkin TJ. Ampakine (CX717) effects on performance and alertness during simulated night shift work. Aviat Space Environ Med 2007;78:937-943. 9. Nehlig A, Daval JL, Debry G. Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic, and psychostimulant effects. Brain Res Rev 1992;17:139-170. 10. Kamimori GH, Penetar DM, Headley DB, et al. Effect of three caffeine doses on plasma catecholamines and alertness during prolonged wakefulness. Eur J Clin Pharmacol 2000;56:537-544. 11. Penetar D, McCann U, Thorne D, et al. Caffeine reversal of sleep deprivation effects on alertness and mood. Psychopharmacology 1993;112:359-365.
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12. Kamimori GH, Johnson D, Thorne D, et al. Multiple caffeine doses maintain vigilance during early morning operations. Aviat Space Environ Med 2005;76:1046-1050. 13. Wyatt JK, Cajochen C, Ritz-De Cecco A, et al. Low-dose repeated caffeine administration for circadian-phase dependent performance degradation during extended wakefulness. Sleep 2004;27:374-381. 14. Sicard BA, Perault MC, Enslen M, et al. The effects of 600 mg of slow release caffeine on mood and alertness. Aviat Space Environ Med 1996;67:859-862. 15. Muehlbach MJ, Walsh JK. The effects of caffeine on simulated nightshift work and subsequent daytime sleep. Sleep 1995;18:22-29. 16. Jarvis MJC. Does caffeine intake enhance absolute levels of cognitive performance? Psychopharmacology 1993;101:160-167. 17. Juliano LM, Griffiths RR. A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features. Psychopharmacology 2004;176:1-29. 18. Attwood AS, Higgs S, Terry P. Differential responsiveness to caffeine and perceived effects of caffeine in moderate and high regular caffeine consumers. Psychopharmacology 2007;190:469-477. 19. Kamimori GH, Karyekar CS, Otterstetter R, et al. The rate of absorption and relative bioavailability of caffeine administered in chewing gum versus capsules to normal healthy volunteers. Int J Pharm 2002;234:159-167. 20. Ballon JS, Feifel D. A systematic review of modafinil: potential clinical uses and mechanisms of action. J Clin Psychiatry 2006;67: 554-566. 21. Wesensten N, Killgore W, Balkin T. Performance and alertness effects of caffeine, dextroamphetamine, and modafinil during sleep. J Sleep Res 2005;14:255-266. 22. Moachon G, Kanmacher I, Clenet M, et al. Pharmacokinetic profile of modafinil. Drugs Today 1996;32:327-337. 23. Walsh JK, Randazzo AC, Stone KL, et al. Modafinil improves alertness, vigilance, and executive function during simulated night shifts. Sleep 2004;27:434-439. 24. Wesensten NJ, Belenky G, Kautz MA, et al. Maintaining alertness and performance during sleep deprivation: modafinil versus caffeine. Psychopharmacology 1999;159:238-247. 25. Buguet A, Montmayeur A, Pigeau R, et al. Modafinil, d-amphetamine and placebo during 64 hours of sustained mental work: II. Effects on two nights of recovery sleep. J Sleep Res 1995;4:229-241. 26. Bonnet MH, Balkin TJ, Dinges DF, et al. The use of stimulants to modify performance during sleep loss: a review by the Sleep Depriva-
tion and Stimulant Task Force of the American Academy of Sleep Medicine. Sleep 2005;28:1163-1187. 27. Newhouse PA, Belenky G, Thomas M, et al. The effects of d-amphetamine on arousal, cognition, and mood after prolonged total sleep deprivation. Neuropsychopharmacology 1989;2:153-164. 28. Stocking EM, Letavic MA. Histamine H3 antagonists as wakepromoting and pro-cognitive agents. Curr Top Med Chem 2008; 8:988-1002. 29. Jones BE. Modulation of cortical activation and behavioral arousal by cholinergic and orexinergic systems. Ann N Y Acad Sci 2008; 1129:26-34. 30. Lavie P. Ultrashort sleep-waking schedule. III. “Gates” and “forbidden zones” for sleep. Electroencephalogr Clin Neurophysiol 1986;63:414-425. 31. Roth T. A physiologic basis for the evolution of pharmacotherapy for insomnia. J Clin Psychiatry 2007;68(Suppl. 5):13-18. 32. Lu J, Greco MA. Sleep circuitry and the hypnotic mechanism of GABAa drugs. J Clin Sleep Med 2006;2:S19-S26. 33. Balkin TJ, O’Donnell VM, Wesensten N, et al. Comparison of the daytime sleep and performance effects of zolpidem versus triazolam. Psychopharmacology 1992;107:83-88. 34. Penetar DM, Belenky G, Garrigan JJ, et al. Triazolam impairs learning and fails to improve sleep in a long-range aerial deployment. Aviat Space Environ Med 1989;60:594-598. 35. Srinivasan V, Pandi-Perumal SR, Trahkt I, et al. Melatonin and melatonergic drugs on sleep: possible mechanisms of action. Int J Neurosci 2009;119:821-846. 36. Hardeland R, Poeggeler B, Srinivasan V, et al. Melatonergic drugs in clinical practice. Arzneimittelforschung 2008;58:1-10. 37. Paul MA, Gray G, MacLellan M, et al. Sleep-inducing pharmaceuticals: a comparison of melatonin, zaleplon, zopiclone, and temazepam. Aviat Space Environ Med 2004;75:512-519. 38. Wesensten NJ, Balkin TJ, Reichardt RM, et al. Daytime sleep and performance following a zolpidem and melatonin cocktail. Sleep 2005;28:93-103. 39. Batéjat D, Coste O, Van Beers P, et al. Prior sleep with zolpidem enhances the effect of caffeine or modafinil during 18 hours continuous work. Aviat Space Environ Med 2006;77:515-525. 40. Hart CL, Haney M, Nasser J, et al. Combined effects of methamphetamine and zolpidem on performance and mood during simulated night shift work. Pharmacol Biochem Behav 2005;81: 559-568.
Sleep, Stress, and Burnout
Torbjörn Åkerstedt, Aleksander Perski, and Göran Kecklund Abstract Long-term exposure to stress is usually seen as a major cause of insomnia. Cross-sectional studies consistently support this view and demonstrate close relations between reported stress and impaired sleep. Prospective studies are rare, however, but the few that are available indicate that new cases of insomnia follow increases in prior stress at work. With respect to polysomnography, minor effects, such as a slightly increased sleep latency or sleep efficiency, follow periods of increased stress. The level of stress in these studies is usually rather modest, however. One key factor seems to be worries at bedtime, often related to upcoming difficulties during the subsequent day: anticipatory stress seems to be important and often involves bedtime rumination. One interesting link between sleep loss and stress is their similarity of endocrine/metabolic effects. Both involve increased levels of cortisol, lipids, and insulin resistance, for example. Furthermore, typical “stress diseases” such as cardiovascular disease or type 2 diabetes are linked also to prior sleep disturbance. Burnout, a characteristic outcome of long-time exposure to stress involves extreme fatigue, cognitive impairment, and lowered mood. Patients with burnout also show pronounced sleep fragmentation,
From a general perspective, psychosocial stress refers to the “the rate of wear and tear in the organism,” and the biological definition of stress refers to the nonspecific response to any demand5 to increase the chances of successful handling of a threatening situation. Contemporary physiologic stress models derive from the pioneering work of Cannon6 and of Selye.5 Cannon6 developed the concept of the “fight–flight” response, which linked the emotional perception of a “threat” to physiologic changes in the periphery. Selye7 proposed a model of stress, the general adaptation syndrome, which was composed of three stages—alarm, resistance, and exhaustion—and reflected the physiologic nonspecific response to a challenge. The resistance stage of the general adaptation syndrome has extreme energy requirements, which, if persistent over time, deplete the person’s capacity and leads to exhaustion. Markers of the fight–flight response are the catecholamines epinephrine and norepinephrine and other physiologic indicators associated with the autonomic nervous system.8,9 The hypothalamic-pituitary-adrenocortical (HPA) axis is also fundamental in the stress reaction. When the sympathetic-adrenal-medullary system is activated and neuropeptides such as corticotropin-releasing hormone (CRH) and vasopressin are released, they, in turn, stimulate release of adrenocorticotropic hormone (ACTH) into the general blood circulation within the pituitary.9,10 Long-term effects of stress are described by the term allostasis, which refers to the ability of the body to increase or decrease the activation level of vital functions to new steady states dependent on the characteristics of the chal814
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increased sleep latency, reduced sleep efficiency, and reduced slow-wave sleep. Sleep impairment seems to be a prerequisite for developing burnout. It is concluded that there is supporting evidence that stress affects sleep negatively but that we know too little about the details of the effects. The details include the critical levels and durations of stress necessary to cause insomnia and the process of the development of stress-related insomnia across time. Stress research often refers to the observation that repeated stress with insufficient restitution in between episodes of stress will lead to a gradual increase in physiologic activation and eventually an allostatic upregulation of wear and tear.1 Although the duration or type of rest in-between bouts of stress may be important factors, it is obvious that sleep is one of the major physiologic means of restitution.2 This involves the elimination of subjective or behavioral fatigue, the physiologic substrates of this elimination, and the peripheral physiologic changes that maintain proper metabolic balance and a well-functioning immune system. The amount of available data on stress and sleep is relatively modest, however.3,4 Some of the findings are summarized here.
lenge and the person’s emotions and appraisal of the event.1 The resulting allostatic load represents the cumulative cost to the body when the systems start to malfunction after a stressful event. It is suggested that serious pathophysiology can occur if overload is not relieved in some way.1 One of the outcomes may be insomnia. With respect to working life there are systematic theories, however. One of the leading ones in work stress research is the so-called demand/control model.11,12 According to this model, high demand and low decision latitude have been found predictive of cardiovascular and other types of stress diseases.13-15 Another approach is that of the “effort/reward model,” which focuses on the contrast between demands and resources.16 Resources include salary, career opportunity, and other rewards. In this model, “immersion” has an important role, representing major commitment of effort. Immersion (or commitment) involves experiences of “not being able to stop thinking of work in the evening” or “starting to think of work immediately on awakening,” for example. Another important work-related factor may be the amount of social support received at work. Several studies have indicated the impact of lack of such support on cardiovascular disease, depression, and other outcomes.12,17
THE CROSS-SECTIONAL CONNECTION BETWEEN STRESS AND SLEEP Considering the physiologic activation involved in the stress response it seems logical to expect a connection
with sleep disturbances. In fact, stress is considered the primary cause of persistent psychophysiologic (primary) insomnia.18 The evidence is, however, surprisingly modest, at least in terms of systematic studies of causal relations in a longitudinal perspective. Cross-sectional epidemiologic studies are readily available, however. They indicate a strong link between questionnaires on stress and sleep.19-26 There are far fewer studies on stress and sleep using polysomnography (PSG). However, Shaver and associates27 studied women with insomnia and did not find that stress ratings differed from those of good sleepers. Differences were found, however, in neuroendocrine activation and similar measures, suggesting increased stress. With respect to the particular character of the stress involved, Ribet and colleagues21 studied more than 21,000 subjects in France, using a sleep disturbance index and logistic regression analysis. It was found that shift work, a long work week, exposure to vibration, and “having to hurry” appeared to be the main risk factors for reports of impaired sleep, when controlled for age and gender. The demand component of the demand/control model of stressful work conditions has also been shown to have a link to reported sleep impairment.19-23 In Åkerstedt and associates,22 it was found that the strongest item of the demand index was “having to exert a lot of effort at work,” not simply “having too much to do,” for example. The distinction may be interpreted as a lot of work per se may not be the key factor but that the response to the work situation is more important. It was also found that when the item “not being able to stop thinking about work in the evening” was added to the regression this variable became the most important predictor of disturbed sleep. Again, it is the response to the work load that predicts sleep impairment. The effort-reward imbalance has also been related to disturbed sleep.28 With regard to socioeconomic group, sleep complaints are more frequently found in blue-collar workers. Thus, Partinen and coworkers29 investigated several occupational groups and found disturbed sleep to be most common among manual workers and much less so among physicians or managing directors. Geroldi and associates30 found in a retrospective study of older individuals (older than 75 years) that former white-collar workers reported better sleep than blue-collar workers. Kupperman and colleagues31 reported fewer sleep problems in subjects who were satisfied with their work. On the whole, bluecollar workers exhibit higher levels of stress than whitecollar workers but the origins seem more related to living conditions in general (e.g., economy, social situation, neighborhood) than work stress. Social support is usually seen as a countervailing force in demand/control models and seems to counteract the effects of high demands.17 Lack of social support may thus function as a risk factor for disturbed sleep.32 Nordin and associates33 demonstrated an interactive effect on sleep between social support, high demands at work, and lack of control. In a second study the same group showed that disturbed sleep may be a mediator between poor social support and coronary heart disease.33 Poor social support
CHAPTER 74 • Sleep, Stress, and Burnout 815
has been associated for instance with sleep complaints in Vietnam War veterans.34
THE PROSPECTIVE CONNECTION BETWEEN STRESS AND SLEEP The question if stress actually causes impaired sleep can only be resolved in longitudinal studies. One such study is that of Dahlgren and colleagues,35 who followed whitecollar workers before and during a period of intense work stress. Reported sleep duration and sleep quality (by sleep diary) was reduced, as was evening alertness. The latter was probably due to the intense work pressure. Finally, the cortisol pattern was flattened. In another study, Sadeh and associates36 found reduced sleep (by actigraphy and diary ratings) during a period of examination stress. Still, with both studies it is not clear if some of the reduced sleep could be partly due to simply trading sleep time for more study time rather than stress affecting the ability to sleep. Linton and coworkers37 studied employees with no reported initial sleeping problems and found that 14.3% developed a sleeping problem during the ensuing year. Even when controlling for possible confounders, stress in the form of a “poor” psychosocial work environment doubled the risk of developing a sleep problem. In a similar vein, Jansson and associates38 showed the effects of present stress on later complaints of disturbed sleep. The results showed that among individuals with no insomnia at baseline, high work demands increased the risk of developing insomnia 1 year later. Among participants with insomnia at baseline, high leader support decreased the risk of still reporting insomnia at follow-up. Finally, low influence over decisions and high work demands were related to the maintenance of insomnia. In another longitudinal study, Vahtera and colleagues showed that the effect of a self-rated tendency to respond strongly to stress predicted later sleep disturbances as a response to negative life events.39 This points to a consistent pattern of disturbed sleep in response to stress. Similarly, Drake and coworkers showed that those who reported a higher habitual sleep vulnerability to stress also showed longer sleep latency and lower sleep efficiency on the first night in the sleep laboratory.40 This suggests that sleep vulnerability to stress is somewhat of a trait. The scale Ford Insomnia Response to Stress (FIRST, from the Ford hospital) has also been shown to predict long sleep latency in response to caffeine.40 In the earlier mentioned study by Sadeh and associates,36 it was demonstrated that a stronger sleep duration response to examination stress was seen in those individuals who showed a high emotion-focused coping. Åkerstedt and colleagues41 recorded sleep in the home of 50 participants on four occasions across several weeks and showed that nighttime ratings of stress/worries at bedtime were related to reduced sleep efficiency, increased wake time after sleep onset and increased latency to slowwave sleep. Every-3-hour ratings of “stress” in the sleep diary were also increased both on the day before and the day after this sleep. Also in this study, differential vulnerability was seen. Those individuals who showed an increase in stress ratings showed a significantly higher level of
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depression on the Hospital Depression and Anxiety Scale.42 In other PSG studies, sleep on the night before an important examination43 and also before a day of skydiving44 was investigated. The results indicate a slightly negative effect on sleep efficiency and the amount of deep sleep. In addition, a number of early laboratory studies of stress and sleep have been performed but the stressors have been rather artificial (e.g., an unpleasant movie) and the results are unclear.45 It is probably the case that the stressor needs to be of some significance to the individual to have any effect on PSG measures of sleep. There are also studies of the effects of major life events, including stressors at the national/societal level. Cernovsky and coworkers46 demonstrated a clear increase in population-wide negative life events preceding an outbreak of insomnia. Haynes has shown similar results.47 The economic recession in Finland in 1993 was apparently related to reported reductions in sleep quality.48 It has also been shown that sleep is disturbed in response to threats to national security, for example, after the nuclear accident at the facility at Three Mile Island and during the scud missile attacks on Israel during the Gulf War.49,50 The effect of losing a life partner has in one study been shown to have surprisingly modest effects, and then mainly an increase in rapid-eye-movement (REM) intensity.51
RUMINATION AND ANTICIPATION Indirectly, many of the studies just described suggest that it is not the stress experience itself that impairs sleep but rather the anticipation of untoward events and worries about the immediate future. Examinations, high work demands, and external threats are likely to cause this type of worried anticipation. Cropley and colleagues52 coupled the relation between strain and poor sleep in teachers to rumination. The previous cross-sectional study by Åkerstedt and associates22 found that not being able to turn off thoughts of work in the evening was strongly related to subjectively disturbed sleep. This may manifest itself as a form of rumination, and rumination is seen as a major cause of disturbed sleep.53 Hall and coworkers26 have demonstrated in a cross-sectional study that intrusive thoughts at bedtime are related to increased alpha and beta power in the subsequent sleep EEG. Similarly, increased cognitive arousal at bedtime is related to increased sleep latency.47,54 Closely related to rumination is the worrying and the tension before sleep owing to a very early (and unpleasant) time of awakening before an unusually early morning shift.55,56 The resulting sleep contained less slow-wave sleep, which supports the notion that it is the anticipation of difficulties that is important in the stress reaction. A similar study was carried out with machine officers on container ships.57 Sleep recorded during a night on call (but without any call occurring) showed a reduction of slow-wave sleep and a corresponding increase in stage 2 sleep. Also, heart rate was increased. This was interpreted as an activation in the face of a possibility that the alarm would sound, which happened on average every second night on call. In the previously mentioned study on stress/
worries at bedtime,41 sleep recordings preceded by moderately increased subjective “stress/worries” at bedtime showed a moderate impairment, which may be interpreted as due to rumination. Interestingly, Meerlo and colleagues58 have shown that intense stress increases deep sleep in rats. Presumably this is due to the increase in the metabolic rate of the central nervous system due to the stress, without any anticipatory component. Whether stress has a similar effect on humans is unknown, but several studies in humans have shown that brain use (increased mental activity) leads to more intense sleep59 and that nonuse leads to reduced sleep intensity.60 The observations on the effects of brain use could mean that acute stress will improve subsequent sleep as long as there is no remaining negative anticipation. This question has not been addressed, however.
POSTTRAUMATIC STRESS Posttraumatic stress disorder (PTSD) is another wellestablished cause of disturbed sleep, even if many of the more common indicators of sleep quality (e.g., sleep latency, efficiency of sleep, total length of sleep, and amount of slow-wave sleep) are only moderately affected61-64 and sometimes not affected at all.65 Instead, these studies suggest that the major effect of PTSD is to disturb REM sleep by either increasing or decreasing its duration and by increasing its intensity. It also increases the number of awakenings. The unpleasant dreams associated with traumatic memories also tend to produce conditioned avoidance responses in affected individuals, resulting in postponements on a daily basis of retiring or of even entering the sleeping area. The effects on sleep seem to mediate long-term health effects.66 SLEEP PHYSIOLOGY THAT SEEMS TO LINK SLEEP WITH STRESS Insights into the connection between sleep and stress may also be obtained through comparing the physiologic changes during sleep or after sleep loss with those of stress. Among the basic observations on sleep physiology is the reduction of rectal temperature, rate of breathing, heart rate, blood pressure, and so on that occur during non– REM (NREM) sleep.67 In adults, the first part of sleep is characterized by increased growth hormone (GH) release (together with increased slow-wave sleep and low levels of REM sleep) and suppressed secretion of the hormones of the HPA system.68,69 This means that CRH, ACTH, and cortisol are suppressed. These changes directly oppose the effects of stress. GH promotes protein synthesis, which means that it is essential for growing and for repairing tissue. When sleep is prevented, cortisol secretion will increase70 and the rate of sleep fragmentation (microarousals) is related to increased levels of cortisol.71 Thus, sleep reduction has effects similar to those of stress. The secretion of GH, on the other hand, is strongly reduced if no sleep occurs.72 Sleep not only regulates stress hormone secretion but also is affected by it. Thus GH-releasing hormone (GHRH) causes increased slow-wave sleep and GH secretion, as well
as reduced cortisol levels in men but not in women.68 CRH exerts the opposite effects. It appears that the quality of sleep partly depends on an interaction of GHRH and CRH. The reduced glucose clearance after sleep loss70,73 also possibly reflects similar changes as a result of stress.2 The immune system is strongly suppressed by stress, via, for example, increased activation of the HPA axis.2 On the other hand, reduced or fragmented sleep causes increased levels of proinflammatory cytokines such as interleukin1β, interleukin-6, and tumor necrosis factor-alpha.74,75 Hall and associates have suggested that disturbed sleep may serve as a mediator in the link between stress and the immune system.76 Essentially, lack of sleep seems as linked with the metabolic syndrome as does stress.77,78
SIMILARITY OF MORBIDITY DUE TO STRESS AND SLEEP LOSS Poor sleep is associated with an increased prospective risk of diseases that are classic “stress diseases.” This association holds true for myocardial infarction, particularly when poor sleep is combined with increased resting heart rate—a marker of sympathetic overactivity.79 Also, hypertension is increased in both short and long sleepers.80 In women undergoing rehabilitation from a myocardial infarction, the risk of recurrent myocardial events is increased in selfreported poor sleepers.81 In addition, the frequent occurrence of waking and feeling exhausted in the morning is a predictor of subsequent myocardial infarction.82 The exhausted state is also associated with reduced amounts of sleep stages 3 and 4.83 Also, diabetes, another classic “stress disease,” has a relationship with sleep. For example, patients with type 2 diabetes report more sleep problems than nondiabetic subjects.84 This finding could be partly confounded by obesity or by obstructive sleep apnea. However, in a prospective follow-up study of healthy middle-aged men from Malmö, Sweden, it was shown that the 12-year risk of developing type 2 diabetes was independently predicted by selfreported difficulties in falling asleep and by elevated resting heart rate, after full adjustment for obesity, lifestyle factors, and other risk factors.85 One possible explanation is obstructive sleep apnea, which was not measured in the Malmö study, but another possibility would be chronic low-grade inflammation, both linked to insomnia and risk of type 2 diabetes. Short sleep duration is also involved in the metabolic syndrome.77 BURNOUT AND SLEEP Recently, there has been considerable interest in the problem of “burnout” in western countries. This has been particularly so in Sweden because of burnout’s contribution to the large increase in long-term sickness absence from work that occurred over the past 15 years.86,87 The concept of burnout describes a state of “chronic depletion of an individual’s energetic resources”88 and is usually conceived of as an outcome of prolonged occupational stress.89,90 Originally, the symptoms were seen as occurring only in people-oriented (e.g., nursing, social services, edu-
CHAPTER 74 • Sleep, Stress, and Burnout 817
cation) occupations90 but have since been found in virtually all types of work.91,92 The characteristic symptoms of burnout are persistent and excessive fatigue, emotional exhaustion, and cognitive dysfunction.93,94 Frequently, the condition also includes components of depersonalization or cynicism toward clients/patients and reduced personal efficacy, with a tendency to evaluate oneself negatively.90 However, no single conceptualization is accepted as standard, and in the 10th revision of the International Classification of Diseases (ICD10)95 burnout is broadly defined as “a state of vital exhaustion” (category # Z73.0). Recently, exhaustion syndrome has been established as a diagnosis in the Swedish version of the ICD-10 classification system (KSH97, category #F43.8A).96 Burnout is not a diagnostic entity in the ICD-9, which is used in the United States. Perhaps the closest diagnosis is “ICD 309 Adjustment reaction: includes reaction to chronic stress.” The physiologic mechanism behind the fatigue in burnout has not been identified, but the role of long-term stress suggests that the HPA axis is involved.97,98 Several studies seem to find a blunted cortisol response in the dexamethasone suppression test.99,100 In the former study a reduction of hippocampal size was also observed. This is interesting in relation to the links between circulating cortisol levels and impaired cognitive function,101,102 because the latter is a characteristic symptom in burnout. The other persistent finding is the exaggerated cortisol release at awakening, suggesting increased anticipation of stress. This response has been mainly observed among female patients with exhaustion syndrome.103 Also, increased activity of proinflammatory hormones has been suggested.103 Even if some endocrine and links between chronic stress exposure and burnout have been established, the results do not seem robust in the sense that they might “explain” the symptoms. An alternative or complementary factor could be disturbed sleep. It has recently been demonstrated that burnout scores are closely related to reports of disturbed sleep.103,104 There are, as yet, only a couple of studies of sleep in burnout using PSG. In one investigation of young individuals in the Internet technology industry with high burnout scores105 an increased level of sleep fragmentation was found. Also, sleepiness ratings (taken every 3 hours during waking) were increased during the working week compared with normal individuals but sleepiness during the days off fell only marginally, whereas in normal individuals there were dramatic decreases in sleepiness on days off. In a study of individuals on long-term sick leave with a diagnosis of burnout, a similar increase in sleep fragmentation was seen, but also lower sleep efficiency, more wake time after sleep onset, a doubled sleep latency, and reduced amounts of stages 3 and 4 sleep.106 The fragmentation of sleep was highly correlated with morning levels of cortisol, lipids, and other stress-related variables.71 A qualitative approach to a subsample of the patients just discussed showed that they described long periods of stress before becoming burnt out, that self-imposed sleep reduction was used to obtain more time to carry out work
818 PART II / Section 9 • Occupational Sleep Medicine
tasks, and that suddenly they “stopped sleeping.”107 The latter was followed by extreme fatigue, which brought them to medical attention, resulting in a diagnosis of burnout. The fragmentation and reductions in sleep efficiency suggest a link to the fatigue and performance impairment in burnout. Such links are well established in experimental sleep research.108-110 If there is a causal link between burnout and sleep one should see at least the latter predict the former in longitudinal studies. This has been demonstrated in one study.111 The persons who benefited poorly from sleep at baseline had higher exhaustion levels at follow-up than those who benefited from sleep. Trouble falling asleep and less refreshing sleep at baseline hampered eventual full work resumption. Armon and colleagues112 complicated interpretations by finding that burnout and insomnia recursively predict each other’s development and intensification over time, thus suggesting that either might be a risk factor for the other across time. But this study has been conducted with previously healthy workers and burnout patients. Finally, recovery from burnout was found to be linked to improvements in sleep fragmentation, sleep efficiency, and sleep latency. The degree of reduction in sleep fragmentation correlated with the reduction in fatigue, and the latter correlated with return to work after being on long-term sick leave.113
MEASURING STRESS From the previous discussion it may be obvious that “stress” has had many meanings. It was previously defined as an activating response to demands. In many of the previously mentioned studies this may mean high levels on the demand/control questionnaire and/or common sense notions that the anticipation of an examination or of sky diving should be stressful. Very seldom has the concept of stress per se been used. The reason may be that there is no generally accepted operational scale for measuring stress. There have been several such attempts, but they have taken very broad approaches and frequently include many nonspecific consequences of stress. For example, the Perceived Stress Questionnaire (PSQ)114 contains 20 items such as “tension,” “worries,” and “joy” in addition to items on pressure and demands. The Perceived Stress Scale (PSS)114 contains 14 items such as “upset,” “on top of things,” and “nervous” in addition to items on demands and stress. The Stress Response Inventory (SRI) contains 39 items, including scales on depression, frustration, anger, and others.115 The Calgary Symptoms of Stress Inventory116 is a similar scale. Because these types of scales combine the cause (e.g., stress, demands, pressure) with the effects (e.g., anger, anxiety) they are not well suited for use in cause-and-effect studies of, for example, stress and sleep. Understanding the role of stress in sleep disorders probably requires the development of unambiguous instruments for measuring stress. CONCLUSION Although there seems to be clear evidence of stress causing impaired sleep we still know very little about the effects on
sleep architecture, at what level or type of stress sleep is impaired, and after what duration semichronic levels occur, causing insomnia. We also lack information on what contributes to vulnerability. Apparently, there is a need for long-duration longitudinal studies. When meeting a patient who suffers from insomnia that may be stress related, the clinician may find it useful to conduct a structured stress interview around the patient’s life situation. In our experience, much information may be gained from questions that focus on preoccupation with work and presence of ruminations and worries about the immediate future. It may be phrased: “Are you often unable to stop thinking about work in the evening?” Another area to explore with patients is work pressure. This may be phrased: “Do you have to exert a lot of effort at work,” “do you get enough time for sleep, or “do you reduce sleep duration to make room for work?” For treatment of sleep problems due to stress, the reader is referred to the chapter on psychological treatment for sleep disturbances (see Chapter 79). However, it might also be useful to refer the patient to a short stress management course (based on cognitive therapy), which is often efficient in reducing sleep problems and may well be combined with cognitive behavior therapy for sleep disorders. The stress management courses usually involve stress reduction techniques, teaching basic life hygiene, as well as relaxation techniques to improve bedtime practices. Two groups of patients with extreme stress problems will demand special attention: patients with PTSD117 and patients with work-related burnout. In those patients a sleep treatment based on cognitive techniques (see Chapter 79) may greatly contribute to their chances to be free of their primary disease.
❖ Clinical Pearl Insomnia is often a result of long-term exposure to stress. Even modest amounts of day-to-day variations in stress may significantly affect sleep architecture. Patients with complaints of incapacitating fatigue (e.g., burnout) should be investigated for disturbed sleep and long-term exposure to stress. From the point of view of prevention, as well as treatment, it is important to realize that impaired sleep results from anticipatory stress. Stress that has been dealt with, and is out of the system, may even improve sleep.
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CHAPTER 74 • Sleep, Stress, and Burnout 819 4. Åkerstedt T. Psychosocial stress and impaired sleep. Scand J Work Environ Health 2006;32:493-501. 5. Selye H. The stress of life. New York: McGraw Hill; 1956. 6. Cannon WB. The emergency function of the adrenal medulla in pain and the major emotions. Am J Physiol 1914;33:356-372. 7. Selye H. The general adaptation syndrome and the diseases of adaptation. J Clin Endocrinol 1946;6:117-231. 8. Brown MR. Neuropeptide-mediated regulation of the neuroendocrine and autonomic responses to stress. In: McCubbin J, Kaufman P, Nemeroff C, editors. Stress, neuropeptides, and systemic disease. San Diego: Academic Press; 1991. p. 73-93. 9. Dunn AJ, Berridge CW. Physiological and behavioral responses to corticotropin-releasing factor administration: is CRF a mediator of anxiety or stress responses? Brain Res Rev 1990;15:71-100. 10. Rock JP, Oldfield EH, Schulte HM, et al. Corticotropin releasing factor administered into the ventricular CSF stimulates the pituitary-adrenal axis. Brain Res 1984;323:365-368. 11. Karasek RA. Job demands, job decision latitude and mental strain: implications for job redesign. Admin Sci Q 1979;24:285308. 12. Theorell T. The demand-control-support model for studying health in relation to the work environment: an interactive model. In: Orth-Gomér K, Schneiderman N, editors. Behavioral medicine approaches to cardiovascular disease prevention. Mahwah, NJ: Lawrence Erlbaum Associates; 1996. p. 69-85. 13. Alfredsson L, Spetz C-L, Theorell T. Type of occupation and nearfuture hospitalization for myocardial infarction and some other diagnoses. Int J Epidemiol 1985;14:378-388. 14. Hammar N, Alfredsson L, Theorell T. Job characteristics and the incidence of myocardial infarction. Int J Epidemiol 1994;23: 277-284. 15. Toomingas A, Theorell T, Michélsen H, et al. Associations between self-rated psychosocial work conditions and musculoskeletal symptoms and signs. Scand J Work Environ Health 1997; 23:130-139. 16. Siegrist J. A theory of occupational stress. In: Dunham J, editor. Stress in the workplace: past, present and future. London: Whurr Publishers; 2000. p. 52-65. 17. Karasek R, Theorell T. The demand-control-support model and CVD. Occup Med 2000;15:78-83. 18. Morin CM, Rodrigue S, Ivers H. Role of stress, arousal, and coping skills in primary insomnia. Psychosom Med 2003;65:259267. 19. Urponen H, Vuori I, Hasan J, et al. Self-evaluations of factors promoting and disturbing sleep: an epidemiological survey in Finland. Soc Sci Med 1988;26:443-450. 20. Ancoli-Israel S, Roth T. Characteristics of insomnia in the United States: results of the 1991 National Sleep Foundation survey: I. Sleep 1999;22(Suppl. 2):S347-S353. 21. Ribet C, Derriennic F. Age, working conditions, and sleep disorders: a longitudinal analysis in the French cohort E.S.T.E.V. Sleep 1999;22:491-504. 22. Åkerstedt T, Knutsson A, Westerholm P, et al. Sleep disturbances, work stress and work hours: a cross-sectional study. J Psychosom Res 2002;53:741-748. 23. Morphy H, Dunn KM, Lewis M, et al. Epidemiology of insomnia: a longitudinal study in a UK population. Sleep 2007;30:274-280. 24. Doi Y, Minowa M, Tango T. Impact and correlates of poor sleep quality in Japanese white-collar employees. Sleep 2003;26: 467-471. 25. Kalimo R, Tenkanen L, Härmä M, et al. Job stress and sleep disorders: findings from the Helsinki Heart Study. Stress Med 2000;16:65-75. 26. Hall M, Buysse DJ, Nowell PD, et al. Symptoms of stress and depression as correlates of sleep in primary insomnia. Psychosom Med 2000;62:227-230. 27. Shaver JL, Johnston SK, Lentz MJ, et al. Stress exposure, psychological distress, and physiological stress activation in midlife women with insomnia. Psychosom Med 2002;64:793-802. 28. Fahlén G, Knutsson A, Richard P, et al. Effort-reward imbalance, sleep disturbances and fatigue. Int Arch Occup Environ Health 2006;79:371-378. 29. Partinen M, Eskelinen L, Tuomi K. Complaints of insomnia in different occupations. Scand J Work Environ Health 1984;10: 467-469.
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820 PART II / Section 9 • Occupational Sleep Medicine 59. Horne JA, Minard A. Sleep and sleepiness following a behaviourally “active” day. Ergonomics 1985;28:567-575. 60. Huber R, Ghilardi MF, Massimini M, et al. Arm immobilization causes cortical plastic changes and locally decreases sleep slow wave activity. Nat Neurosci 2006;9:1169-1176. 61. Ross RJ, Ball WA, Dinges DF, et al. Motor dysfunction during sleep in posttraumatic stress disorder. Sleep 1994;17:723-732. 62. Mellman TA, Nolan B, Hebding J, et al. A polysomnographic comparison of veterans with combat-related PTSD, depressed men, and non-ill controls. Sleep 1997;20:46-51. 63. Dow BM, Kelsoe JR, Gillin JC. Sleep and dreams in Vietnam PTSD and depression. Biol Psychiatry 1996;39:42-50. 64. Pillar G, Malhotra A, Lavie P. Post-traumatic stress disorder and sleep—what a nightmare! Sleep Med Rev 2000;4:183-200. 65. Klein E, Koren D, Arnon I, et al. Sleep complaints are not corroborated by objective sleep measures in post-traumatic stress disorder: a 1-year prospective study in survivors of motor vehicle crashes. J Sleep Res 2003;12:35-41. 66. Mohr D, Vedantham K, Neylan T, et al. The mediating effects of sleep in the relationship between traumatic stress and health symptoms in urban police officers. Psychosom Med 2003; 65:485-489. 67. Snyder F, Hobson JA, Morrison DF, et al. Changes in respiration, heart rate, and systolic blood pressure in human sleep. J Appl Physiol 1964;19:417-422. 68. Steiger A. Sleep and the hypothalamo-pituitary-adrenocortical system. Sleep Med Rev 2002;6:125-138. 69. Steiger A, Antonijevic IA, Bohlhalter S, et al. Effects of hormones on sleep. Horm Res 1998;49:125-130. 70. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999;354:14351439. 71. Ekstedt M, Åkerstedt T, Söderström M. Microarousals during sleep are associated with increased levels of lipids, cortisol, and blood pressure. Psychosom Med 2004;66:925-931. 72. Van Cauter E, Latta F, Nedeltcheva A, et al. Reciprocal interactions between the GH axis and sleep. Growth Horm IGF Res 2004;14: S10-S17. 73. Knutson KL, Spiegel K, Penev P, et al. The metabolic consequences of sleep deprivation. Sleep Med Rev 2007;11: 163-178. 74. Vgontzas AN, Papanicolaou DA, Bixler EO, et al. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab 1997;82:1313-1316. 75. Vgontzas AN, Bixler EO, Chrousos GP. Sleep apnea is a manifestation of the metabolic syndrome. Sleep Med Rev 2005;9:211224. 76. Hall M, Baum A, Buysse DJ, et al. Sleep as a mediator of the stressimmune relationship. Psychosom Med 1998;60:48-51. 77. Hall MH, Muldoon MF, Jennings JR, et al. Self-reported sleep duration is associated with the metabolic syndrome in midlife adults. Sleep 2008;31:635-643. 78. Jennings JR, Muldoon MF, Hall M, et al. Self-reported sleep quality is associated with the metabolic syndrome. Sleep 2007; 30:219-223. 79. Nilsson P, Nilsson J-Å, Hedblad B, et al. Sleep disturbances in association with elevated pulse rate for the prediction of mortality—consequences of mental strain? J Intern Med 2001;250: 521-529. 80. Gottlieb DJ, Redline S, Nieto FJ, et al. Association of usual sleep duration with hypertension: the Sleep Heart Health Study. Sleep 2006;29:1009-1014. 81. Leineweber C, Kecklund G, Janszky I, et al. Poor sleep increases the prospective risk for recurrent events in middle-aged women with coronary disease. The Stockholm Female Coronary Risk Study. J Psychosom Res 2003;54:121-127. 82. Appels A, Schouten E. Waking up exhausted as risk indicator of myocardial infarction. Am J Cardiol 1991;68:395-398. 83. van Diest R, Appels WP. Sleep physiological characteristics of exhausted men. Psychosom Med 1994;56:28-35. 84. Nilsson P, Rööst M, Engström G, et al. Incidence of diabetes in middle-aged men is related to resting heart rate and difficulties to fall asleep. In: Helsinki: 7th International Congress of Behavioural Medicine. 2002. [Abstract].
85. Nilsson PM, Rööst M, Engström G, et al. Incidence of diabetes in middle-aged men is related to sleep disturbances. Diabetes Care 2004;27:2464-2469. 86. Weber A, Jaekel-Reinhard A. Burnout syndrome: a disease of modern societies? Occup Med 2000;50:512-517. 87. RFV. Långtidssjukskrivna—egenskaper vid 2003 års RFV-LSundersökning. [Long-term sickness absence.] Riksförsäkringsverket [Health Insurance Board]: Stockholm: 2003. p. 19. 88. Shirom A. Burnout in work organizations. In: Robertson CL, editor. International review of industrial and organizational psychology. New York: John Wiley & Sons; 1989. p. 25-48. 89. Freudenberger HJ. Staff burn-out. J Soc Issues 1974;30:159165. 90. Maslach C, Jackson S. The measurement of experienced burnout. J Occup Behav 1981;2:99-113. 91. Maslach C, Jackson SE, Leiter MP. Maslach burnout inventory manual. 3rd ed. Palo Alto, Calif: Consulting Psychologists Press; 1996. p. 52. 92. Kalimo R. Knowledge jobs—how to manage without burnout? Scand J Work Environ Health 1999;25(Special issue):605-609. 93. Melamed S, Kushnir T, Shirom A. Burnout and risk factors for cardiovascular diseases. Behav Med 1992;18:53-60. 94. Kushnir T, Melamed S. The Gulf War and its impact on burnout and well-being of working civilians. Psychol Med 1992;22:987995. 95. World Health Organization. International statistical classification of diseases and related health problems, 10th revision. Geneva: World Health Organization; 1992. 96. Socialstyrelsen. Ändringar i och tillägg till Klassifikation av sjukdomar och hälsoproblem 1997 (KSH97)—systematisk förteckning. 2005. [Board of Health. Change in the classification of diseases] Available at http://www.sos.se/epc/klassifi/KSHandr.htm. 97. Rosmond R, Björntorp P. Låg kortisolproduktion vid kronisk stress [Low cortisol production and chronic stress]. Lakartidningen 2000;97:4120-4124. 98. McEwen BS, Seeman T. Protective and damaging effects of mediators of stress. Ann N Y Acad Sci 1999;896:30-47. 99. Rydmark I, Wahlberg K, Ghatan PH, et al. Neuroendocrine, cognitive and structural imaging characteristics of women on long-term sick leave with job stress-induced depression. Biol Psychiatry 2006;60:867-873. 100. Sonnenschein M, Mommersteeg PM, Houtveen JH, et al. Exhaustion and endocrine functioning in clinical burnout: an in-depth study using the experience sampling method. Biol Psychol 2007;75:176-184. 101. Lupien S, Lecours A, Lussier I, et al. Basal cortisol levels and cognitive deficits in human aging. J Neurosci 1994;14:2893-2903. 102. Lupien SJ, de Leon M, de Santi S, et al. Cortisol levels during human aging predict hippocampal atrophy and memory deficits. Nat Neurosci 1998;1:69-73. 103. Grossi G, Perski A, Evengård B, et al. Physiological correlates of burnout among women. J Psychosom Res 2003;55:309-316. 104. Melamed S, Ugarten U, Shirom A, et al. Chronic burnout, somatic arousal and elevated salivary cortisol levels. J Psychosom Res 1999;46:591-598. 105. Söderström M, Ekstedt M, Åkerstedt T, et al. Sleep and sleepiness in young individuals with high burnout scores. Sleep 2004;17: 1369-1377. 106. Ekstedt M, Söderström M, Åkerstedt T, et al. Disturbed sleep and fatigue in occupational burnout. Scand J Work Environ Health 2006;32:121-131. 107. Ekstedt M, Fagerberg I. Lived experiences of the time preceding burnout. J Adv Nurs 2004;49:59-67. 108. Van Dongen HP, Maislin G, Mullington JM, et al. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 2003;26:117-126. 109. Bonnet MH. Sleep deprivation. In: Kryger M, Roth T, Dement W, editors. Principles and practice of sleep medicine. Philadelphia: Saunders; 1994. p. 50-67. 110. Bonnet MH, Arand DL. The consequences of a week of insomnia. Sleep 1996;19:453-461. 111. Sonnenschein M, Sorbi MJ, Verbraak MJ, et al. Influence of sleep on symptom improvement and return to work in clinical burnout. Scand J Work Environ Health 2008;34:23-32.
112. Armon G, Shirom A, Shapira I, et al. On the nature of burnoutinsomnia relationships: a prospective study of employed adults. J Psychosom Res 2008;65:5-12. 113. Ekstedt M, Söderström M, Akerstedt J. Sleep physiology in recovery from burnout. Biol Psychol 2009;82:267-273. 114. Cohen S, Kamarck T, Mermelstein R. A global measure of perceived stress. J Health Soc Behav 1983;24:385-396. 115. Koh KB, Park JK, Kim CH, et al. Development of the stress response inventory and its application in clinical practice. Psychosom Med 2001;63:668-678.
CHAPTER 74 • Sleep, Stress, and Burnout 821 116. Carlson LE, Thomas BC. Development of the Calgary Symptoms of Stress Inventory (C-SOSI). Int J Behav Med 2007;14:249256. 117. Aurora RN, Zak RS, Auerbach SH, et al. Standards of Practice Committee; American Academy of Sleep Medicine. Best practice guide for the treatment of nightmare disorder in adults. J Clin Sleep Med 2010;6:389-401.
Insomnia
Section
Daniel J. Buysse 75 Insomnia: Recent Developments and Future Directions 76 Insomnia: Epidemiology and Risk Factors 77 Insomnia: Diagnosis, Assessment, and Outcomes 78 Models of Insomnia
79 Psychological and
Behavioral Treatments for Insomnia I: Approaches and Efficacy 80 Psychological and Behavioral Treatments for Insomnia: Implementation and Specific Populations
81 Pharmacologic
Treatment of Insomnia: Benzodiazepine Receptor Agonists 82 Pharmacologic Treatment: Other Medications 83 Treatment Guidelines for Insomnia
Insomnia: Recent Developments and Future Directions Daniel J. Buysse
Research and clinical practice in insomnia have shown steady progress since the fourth edition of Principles and Practice of Sleep Medicine. These developments and the current state of knowledge are discussed in greater detail in the individual chapters in this section. This introductory chapter highlights and succinctly summarizes some of the most significant new findings and trends in four areas of insomnia: epidemiology; diagnosis and assessment; pathophysiology and biological findings; and treatment (Box 75-1). One landmark event since the publication of the previous edition of this textbook was the 2005 State of the Science (SOS) Conference on Manifestations and Management of Chronic Insomnia in Adults, sponsored by the National Institutes of Health and supported by the American Academy of Sleep Medicine and the Sleep Research Society. The SOS conference summarized the state of clinical research and practice in insomnia and provided a guideline for future investigation.1 More specifically, the SOS conference recognized the substantial prevalence of insomnia, the need for further studies on longitudinal course, and the utility of the concept of “comorbid insomnia,” in contrast to the established notions of “secondary” versus “primary” insomnia (Video 75-1). The SOS conference reaffirmed the efficacy and limitations of currently available behavioral and pharmacologic treatments and emphasized the need for better evidence on the efficacy and safety of the many nonapproved drugs used to treat insomnia. Finally, the SOS conference called for the development of new pharmacologic agents with different mechanisms of action and for comparative efficacy trials involving both medications and behavioral treatments. Supported by MH024652, AG020677, and MH078961.
822
10
Chapter
75
EPIDEMIOLOGY Studies of insomnia epidemiology continue to document the high prevalence of the condition, as well as the variability in prevalence and incidence estimates based on the particular definition of insomnia used (see Chapter 76). A relative weakness in the epidemiology of insomnia concerns the sparse information regarding the longitudinal course of the disorder. However, studies from various countries using both cross-sectional and true longitudinal designs continue to demonstrate that insomnia is often a highly persistent condition, with approximately 40% of individuals reporting insomnia for 1 year or longer.2-4 It has long been recognized that insomnia is often comorbid with other psychiatric and medical conditions. More detail has begun to emerge regarding the strength of these associations.5 Most significantly, substantial evidence continues to accumulate documenting insomnia as a risk factor for subsequent mental disorders such as depression and their persistence.6,7 Insomnia has also been demonstrated to be a risk factor for adverse outcomes in depression, such as suicidal ideation in adolescents with depression.8 The links between insomnia and physical health remain less well defined, with evidence for and against risk for hypertension.9,10 Finally, evidence of the functional consequences of insomnia has become more refined and specific regarding quality of life, health care costs and utilization, sick leave, and disability.11-14 DIAGNOSIS AND ASSESSMENT The International Classification of Sleep Disorders, second edition (ICSD-2), was published in 2005.15 Although it
CHAPTER 75 • Insomnia: Recent Developments and Future Directions 823
Box 75-1 Recent Developments in Insomnia Research and Practice Epidemiology • Additional evidence regarding the prevalence of insomnia symptoms and disorder • New evidence regarding the chronicity and course of insomnia • Additional evidence regarding the association between insomnia and mental and physical disorders Diagnosis and Assessment • Publication of International Classification of Sleep Disorders, 2nd edition • Published recommendations for standard research assessment of insomnia • New studies on neurocognitive symptoms and impairments • New qualitative research on insomnia symptoms • Development and validation of insomnia rating scales Pathophysiology • Further investigation of hypothalamic-pituitaryadrenal axis function in insomnia • New imaging studies to characterize brain structure and sleep and waking brain function in insomnia • Development of animal models, including a plausible stress model in rats Treatment • Further demonstration of cognitive behavioral treatment efficacy and effectiveness • Application of cognitive behavioral treatments to new comorbid populations • Shortened forms of cognitive behavioral treatments • Further investigation of comparative treatment efficacy and combination strategies for behavioral and pharmacologic treatments • Development of new benzodiazepine receptor agonists and modified formulations of existing agents (e.g., modified release, sublingual) • Development and clinical trials of other potential hypnotic drug classes, including antihistaminic, tricyclic, serotonin 5-HT2A receptor antagonists, orexin receptor antagonists, GABA reuptake inhibitors, and extrasynaptic GABA receptor agonists • Development of treatment guidelines
retains basically the same categories of insomnia as its predecessor, the ICSD-2 for the first time also specifies criteria for general insomnia disorder, which are common to all of the specific insomnia subtypes (Video 75-2). The criteria for general insomnia disorder emphasize not only the nighttime sleep complaint but also the presence of adequate opportunity for sleep and of specific types of daytime impairments. In this regard, the criteria follow closely with the research diagnostic criteria for insomnia published in 2004.16 The general insomnia disorder and research diagnostic criteria present specific diagnostic guidelines appropriate for both clinical and research use. However, operationalizing the impairment criteria and
adequate opportunity for sleep will require further effort. The development of the Diagnostic and Statistical of Mental Disorders, fifth edition (DSM-V), the nosology used in the psychiatric community, is currently underway, with an anticipated publication date of 2012. The DSM-V sleep disorders work group is actively collaborating with the sleep medicine community and the American Academy of Sleep Medicine to ensure compatibility of different diagnostic systems. Increasing attention has focused not only on the nighttime symptoms of insomnia but also on the daytime characteristics. The studies have included those focusing on the daytime symptoms of mood and attention difficulties17 but also on the documentation of impaired performance using neuropsychiatric assessments.18-20 These studies show that insomnia sufferers have worse self-reported mood and performance, as well as greater variability of self-reported and objective impairments, compared with controls. Neuropsychological impairments appear to be most notable with complex tasks requiring shifting in task strategy, a function attributable to dorsolateral prefrontal cortex control. These deficits are associated with prefrontal hypoactivation on functional magnetic resonance imaging studies and suggest that impairments diminish with successful cognitive behavioral treatment.21 Strategies developed in the field of sleep and learning have also been applied to insomnia, with some preliminary evidence again documenting impairments in insomnia.22 A number of new rating scales for insomnia symptoms and impairments have been published or are under development. The Insomnia Severity Index23,24 has increasingly gained wide acceptance as an outcome measure in pharmacologic and behavioral treatment studies of insomnia. Qualitative research involving focus groups and patient interviews has also been used more widely for developing new patient report outcomes,25,26 in keeping with the U.S. Food and Drug Administration (FDA) Draft Guidance on Patient-Reported Outcome Measures.27 Additional rating scales developed with such techniques are under development by a number of academic and industry research groups. Finally, an attempt to standardize research assessments for insomnia was published in 2006.28 One of the outcomes of this consensus process was the development of a standard sleep diary format, which was presented in preliminary form at the SLEEP 2008 meeting and is currently being finalized.
PATHOPHYSIOLOGY AND BIOLOGICAL FINDINGS Insomnia has long been considered to be a disorder of hyperarousal (see Chapter 78). Additional work has investigated the role of the hypothalamic-pituitary-adrenal axis in insomnia, both through physiological studies measuring the status and responsiveness of this system29 as well as the preliminary use of a corticotropin-releasing hormone antagonist to treat insomnia.30 The studies suggest that activation of the hypothalamic-pituitary-adrenal axis may contribute to the development of insomnia. Quantitative electroencephalography has long been used as a potential marker of hyperarousal and or
824 PART II / Section 10 • Insomnia
diminished homeostatic sleep drive. New evidence continues to suggest increased high frequency activity in at least some patients with insomnia, although the relationship of this finding to specific clinical features is less clear.31 Additional work in the neuroanatomy and functional neuroanatomy of insomnia has also been conducted, concurrent with important developments in basic sleep–wake neurobiology. For the first time, chronic insomnia has been associated with reduced hippocampal volume.32 Other techniques have also suggested abnormal brain function in insomnia. For instance, a magnetic resonance spectroscopy (MRS) study suggested decreased gamma-aminobutyric acid (GABA) in insomnia patients compared with controls, with a strong inverse correlation between data content and wakefulness after sleep onset.33 Positron emission tomography studies have shown a similar association between wake time after sleep onset (self-reported and polysomnographic) and glucose metabolism during non–rapid eye movement (NREM) sleep of brainstem, diencephalic, prefrontal, and limbic arousal systems.34 Plausible animal models of insomnia have also been developed and refined in the past several years that will provide insights into the pathophysiology of insomnia beyond those that can be achieved with human studies alone. Animal models include fear-conditioning studies in mice, which results in sleep disturbances similar to those observed in posttraumatic stress disorder with insomnia.35 A genetic screening technique has been used to identify and selectively breed Drosophila characterized by short sleep, prolonged sleep latency, sleep interruption, and waking consequences.36 This model provides the opportunity to examine not only genetic association with insomnia but also functional consequences of sleep disturbance and sleep loss in terms of gene regulation, gene products, and synaptic plasticity.37,38 A rodent model of behaviorally induced insomnia has also been described.39 The rat model of insomnia is associated with simultaneous activation of sleep-active and wake-active centers in the brain during NREM sleep. These findings may be a good model of the human condition of insomnia, in which individuals may perceive themselves as being awake during polysomnographically defined sleep. Finally, additional work has continued regarding psychological models of insomnia in humans. In particular, new work has been focused on cognitive components of insomnia, including the development of safety responses and the involvement of selective attention as potential mechanisms for perpetuating insomnia.40,41
TREATMENT Behavioral Treatment The efficacy of cognitive behavioral treatment for insomnia (CBTI) has by now been well documented in both recent and older studies.42,43 The emphasis in more recent clinical trials has been the use of CBTI for insomnia with comorbid conditions, including medical disorders and psychiatric disorders such as depression.44 Another emphasis in recent behavioral treatment studies has been on alternate delivery forms and alternate practitioner types. For instance, CBTI has been investigated in brief treatment
forms45,46 and in combination with other techniques such as mindfulness meditation.47 Additional work has also been published on the comparative efficacy of CBTI and medication48 and on optimal combination treatment strategies of CBTI with medication for short- and long-term outcomes.49 The behavioral sleep medicine field continues to debate the role of doctoral level clinical psychologists versus other practitioners, such as master’s level nurses, social workers, and other clinicians.50 A number of excellent treatment manuals51-53 and patient-focused guides54 to CBTI have been published. Pharmacologic Treatment Pharmacoepidemiologic data continue to show that zolpidem, now available in generic formulations, is the most widely prescribed hypnotic in the United States. However, other nonapproved medications, such as sedating antidepressants and antipsychotics, hold considerable market share as well. Benzodiazepine receptor agonists are summarized in Chapters 42 and 81 and other drugs used as hypnotics are discussed in Chapter 82. The NIH SOS Conference pointed to the lack of efficacy data with medications not approved as hypnotics; this continues to be the case, with no new clinical large clinical trials using these agents within the past 5 years. However, low-dose doxepin, a tricyclic antidepressant, is being actively investigated for the treatment of insomnia. Preliminary studies, with doses of 3 and 6 mg show reductions in wake time after sleep onset across the sleep period.55 At these very low doses, doxepin appears to have high specificity for histamine-1 receptors, with little other neurotransmitter effect. Although no new benzodiazepine receptor agonists have been approved in the United States, clinical trials with the alpha1-selective agent indiplon suggest that it has a short duration of action and similar efficacy to other benzodiazepine receptor agonists when administered before sleep or as needed after awakening from sleep.56-58 The first modified release preparation of zolpidem was marketed in the United States beginning in 2005. A low-dose, sublingual preparation of zolpidem has also been developed and evaluated for administration in the middle of the night, with promising initial results on subsequent sleep latency, sleep time, and sleep quality.59 Hypnotics with other mechanisms of action have also been developed. Ramelteon, a selective melatonin MT1/ MT2 receptor agonist, was approved and marketed in the United States beginning in 2005. Clinical trials show that ramelteon primarily has effects on sleep latency, rather than wakefulness after sleep onset.60-62 Other melatonin receptor agonists are also under clinical development. In addition to benzodiazepine receptor agonists, other drugs with mechanisms of action related to gammaaminobutyric acid (GABA) and neurotransmission have also been investigated. Trials of tiagabine, a GABA reuptake inhibitor, showed inconsistent effects on sleep latency and wakefulness after sleep onset but more consistent increases in slow-wave sleep.63-65 Additional concerns were raised regarding side effects such as new-onset seizures, and development of this drug as a hypnotic has been halted. Similarly, gaboxadol, an extrasynaptic GABA receptor agonist, showed initial efficacy regarding wakefulness after
CHAPTER 75 • Insomnia: Recent Developments and Future Directions 825
sleep onset and increased slow-wave sleep66,67 but was halted in clinical development because of concerns regarding potential side effects. Antagonists or inverse agonists of serotonin 5-HT2A receptors are also being developed for insomnia. One of these, APD125, showed promising initial findings,68 but clinical development was halted after limited efficacy in subsequent clinical trials. Low-dose doxepin was approved by the FDA in 2010. Finally, orexin antagonists are also being developed for the treatment of insomnia. However, these drugs are still likely to be several years away from approval and clinical use.69
Although insomnia is the most common sleep disorder, progress regarding its fundamental characteristics seems to have occurred at a slower rate than that of many other sleep disorders. Nevertheless, tangible progress is being made in the key areas of epidemiology, assessment, pathophysiology, and treatment. It is hoped that the next edition of Principles and Practice of Sleep Medicine will again be able to present new findings in each of these areas to guide clinicians and researchers.
DEVELOPMENT OF TREATMENT GUIDELINES Although the efficacy of behavioral and pharmacologic treatments for insomnia is well established, there have been very few empirical studies addressing which treatment is best suited to which patient (see Chapter 83). Likewise, there has been very limited work regarding treatment sequencing in the event that a given treatment does not result in a satisfactory clinical outcome. The American Academy of Sleep Medicine has developed treatment guidelines for the evaluation and management of chronic insomnia in adults.70 Additional clinical trials data will contribute to the refinement of these guidelines.
REFERENCES
FUTURE DIRECTIONS Based on the current status of the field, it is possible to speculate on some future directions for research in a clinical practice. First, it seems likely that additional studies will be conducted to investigate the longitudinal course of insomnia and the relationship between insomnia and comorbid conditions. More specifically, studies examining whether treatment of insomnia affects the outcome of comorbid conditions is an important area of active investigation. Second, more sophisticated self-report measures of daytime and nighttime symptoms of insomnia are being developed. In addition, use of objective markers of insomnia, such as quantitative sleep electroencephalography, may become more commonplace, at least in research studies. Functional imaging studies to assess daytime function in insomnia, and the effects of treatments, also seems to be a particularly fruitful area of investigation, which interacts with recent developments in the field of sleep and learning. Third, additional work on animal models of insomnia and biological correlates in humans is likely to provide important new insights into pathophysiology. In addition, studies of genetic associations with insomnia within families, the general population, and animal models, may yield important clues regarding the pathophysiology and consequences of insomnia. Finally, in the area of treatment, development of additional treatment guidelines is clearly needed. New pharmacologic agents with targets other than the GABA receptor are under development. For behavioral treatment, the main challenges revolve around dissemination and practical application of known efficacious treatments.
Acknowledgments The section editor gratefully acknowledges editorial assistance from Melissa Shablesky-Cade. 1. National Institutes of Health. NIH State-of-the-Science Conference statement on manifestations and management of chronic insomnia in adults. Bethesda, Md; 2005. 2. Roth T, Jaeger S, Jin R, et al. Sleep problems, comorbid mental disorders, and role functioning in the national comorbidity survey replication. Biol Psychiatry 2006;60:1364-1371. 3. Jansson-Frojmark M, Lindblom K. A bidirectional relationship between anxiety and depression, and insomnia? A prospective study in the general population. J Psychosom Res 2008;64:443-449. 4. Morin CM, Belanger L, LeBlanc M, et al. The natural history of insomnia: a population-based 3-year longitudinal study. Arch Intern Med 2009;169:447-453. 5. Taylor DJ. Insomnia and depression. Sleep 2008;31:447-448. 6. Buysse DJ, Angst J, Gamma A, et al. Prevalence, course, and comorbidity of insomnia and depression in young adults. Sleep 2008;31: 473-480. 7. Pigeon WR, Hegel M, Unutzer J, et al. Is insomnia a perpetuating factor for late-life depression in the IMPACT cohort? Sleep 2008;31: 481-488. 8. Liu X. Sleep and adolescent suicidal behavior. Sleep 2004;27: 1351-1358. 9. Phillips B, Buzkova P, Enright P. Insomnia did not predict incident hypertension in older adults in the cardiovascular health study. Sleep 2009;32:65-72. 10. Vgontzas AN, Liao D, Bixler EO, et al. Insomnia with objective short sleep duration is associated with a high risk for hypertension. Sleep 2009;32:491-497. 11. Ozminkowski RJ, Wang S, Walsh JK. The direct and indirect costs of untreated insomnia in adults in the United States. Sleep 2007;30: 263-273. 12. Leger D, Scheuermaier K, Philip P, et al. SF-36: Evaluation of quality of life in severe and mild insomniacs compared with good sleepers. Psychosom Med 2001;63:49-55. 13. Sivertsen B, Overland S, Bjorvatn B, et al. Does insomnia predict sick leave? The Hordaland Health Study. J Psychosom Res 2009;66: 67-74. 14. Overland S, Glozier N, Sivertsen B, et al. A comparison of insomnia and depression as predictors of disability pension: the HUNT Study. Sleep 2008;31:875-880. 15. American Academy of Sleep Medicine. The international classification of sleep disorders, 2nd ed (ICSD-2): diagnostic and coding manual. Westchester, Ill: American Academy of Sleep Medicine; 2005. 16. Edinger JD, Bonnet MH, Bootzin RR, et al. Derivation of research diagnostic criteria for insomnia: report of an American Academy of Sleep Medicine Work Group. Sleep 2004;27:1567-1596. 17. Buysse DJ, Thompson W, Scott J, et al. Daytime symptoms in primary insomnia: a prospective analysis using ecological momentary assessment. Sleep Med 2007;8:198-208. 18. Haimov I, Hanuka E, Horowitz Y. Chronic insomnia and cognitive functioning among older adults. Behav Sleep Med 2008;6:32-54. 19. Edinger JD, Means MK, Carney CE, et al. Psychomotor performance deficits and their relation to prior nights’ sleep among individuals with primary insomnia. Sleep 2008;31:599-607. 20. Altena E, Van Der Werf YD, Strijers RL, et al. Sleep loss affects vigilance: effects of chronic insomnia and sleep therapy. J Sleep Res 2008;17:335-343.
826 PART II / Section 10 • Insomnia 21. Altena E, Van Der Werf YD, Sanz-Arigita EJ, et al. Prefrontal hypoactivation and recovery in insomnia. Sleep 2008;31:1271-1276. 22. Nissen C, Kloepfer C, Nofzinger EA, et al. Impaired sleepassociated memory consolidation in primary insomnia. Sleep 2006;29:1068-1073. 23. Morin CM. Insomnia: psychological assessment and management. New York: Guilford Press; 1993. 24. Bastien CH, Vallieres A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med 2001;2:297-307. 25. Harvey AG, Stinson K, Whitaker KL, et al. The subjective meaning of sleep quality: a comparison of individuals with and without insomnia. Sleep 2008;31:383-393. 26. Carey TJ, Moul DE, Pilkonis P, et al. Focusing on the experience of insomnia. Behav Sleep Med 2005;3:73-86. 27. U.S. Department of Health and Human Services FDA Center for Drug Evaluation and Research, U.S. Department of Health and Human Services FDA Center for Biologics Evaluation and Research, U.S. Department of Health and Human Services FDA Center for Devices and Radiological Health. Guidance for industry: patientreported outcome measures: use in medical product development to support labeling claims: draft guidance. Health Quality Life Outcomes 2006;4:79. 28. Buysse DJ, Ancoli-Israel S, Edinger JD, et al. Recommendations for a standard research assessment of insomnia. Sleep 2006;29: 1155-1173. 29. Richardson GS. Human physiological models of insomnia. Sleep Med 2007;8(Suppl 4):S9-S14. 30. Buckley T, Duggal V, Schatzberg AF. The acute and post-discontinuation effects of a glucocorticoid receptor (GR) antagonist probe on sleep and the HPA axis in chronic insomnia: a pilot study. J Clin Sleep Med 2008;4:235-241. 31. Buysse DJ, Germain A, Hall ML, et al. EEG spectral analysis in primary insomnia: NREM period effects and sex differences. Sleep 2008;31:1673-1682. 32. Riemann D, Voderholzer U, Spiegelhalder K, et al. Chronic insomnia and MRI-measured hippocampal volumes: a pilot study. Sleep 2007;30:955-958. 33. Winkelman JW, Buxton OM, Jensen JE, et al. Reduced brain GABA in primary insomnia: preliminary data from 4T proton magnetic resonance spectroscopy (1H-MRS). Sleep 2008;31:1499-1506. 34. Nofzinger EA, Nissen C, Germain A, et al. Regional cerebral metabolic correlates of WASO during sleep in insomnia. J Clin Sleep Med 2006;2:316-322. 35. Sanford LD, Yang L, Tang X. Influence of contextual fear on sleep in mice: a strain comparison. Sleep 2003;26:527-540. 36. Shaw PJ, Cirelli C, Greenspan RJ, et al. Correlates of sleep and waking in Drosophila melanogaster. Science 2000;287:1834-1837. 37. Donlea JM, Ramanan N, Shaw PJ. Use-dependent plasticity in clock neurons regulates sleep need in Drosophila. Science 2009;324: 105-108. 38. Gilestro GF, Tononi G, Cirelli C. Widespread changes in synaptic markers as a function of sleep and wakefulness in Drosophila. Science 2009;324:109-112. 39. Cano G, Mochizuki T, Saper CB. Neural circuitry of stress-induced insomnia in rats. J Neurosci 2008;28:10167-10184. 40. Semler CN, Harvey AG. Daytime functioning in primary insomnia: does attentional focus contribute to real or perceived impairment? Behav Sleep Med 2006;4:85-103. 41. Spiegelhalder K, Espie C, Nissen C, et al. Sleep-related attentional bias in patients with primary insomnia compared with sleep experts and healthy controls. J Sleep Res 2008;17:191-196. 42. Morgenthaler T, Kramer M, Alessi C, et al. Practice parameters for the psychological and behavioral treatment of insomnia: an update. An American Academy of Sleep Medicine report. Sleep 2006;29: 1415-1419. 43. Morin CM, Bootzin RR, Buysse DJ, et al. Psychological and behavioral treatment of insomnia: an update of recent evidence (19982004). Sleep 2006;29:1398-1414. 44. Manber R, Edinger JD, Gress JL, et al. Cognitive behavioral therapy for insomnia enhances depression outcome in patients with comorbid major depressive disorder and insomnia. Sleep 2008;31:489-495. 45. Edinger JD, Wohlgemuth WK, Radtke RA, et al. Dose-response effects of cognitive-behavioral insomnia therapy: a randomized clinical trial. Sleep 2007;30:203-212.
46. Germain A, Moul DE, Franzen PL, et al. Effects of a brief behavioral treatment for late-life insomnia: preliminary findings. J Clin Sleep Med 2006;2:403-406. 47. Ong JC, Shapiro SL, Manber R. Combining mindfulness meditation with cognitive-behavior therapy for insomnia: a treatment-development study. Behav Ther 2008;39:171-182. 48. Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA 2006;295:2851-2858. 49. Morin CM, Vallieres A, Guay B, et al. Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: a randomized controlled trial. JAMA 2009;301:2005-2015. 50. Perlis ML, Smith MT. Editorial: how can we made CBT-I and other BSM services widely available? J Clin Sleep Med 2008;4:11-13. 51. Morin CM, Espie CA. Insomnia: a clinical guide to assessment and treatment. New York: Kluwer Academic/Plenum Publishers; 2003. 52. Perlis ML, Smith MT, Jungquist C, et al. Cognitive behavioral treatment of insomnia: a session-by-session guide. New York: Springer Verlag; 2005. 53. Edinger JD, Carney CE. Overcoming insomnia: a cognitive-behavioral therapy approach workbook (treatments that work). Oxford, UK: Oxford University Press; 2008. 54. Glovinsky P, Spielman A. The insomnia answer. New York: Berkley Publishing Group; 2006. 55. Roth T, Rogowski R, Hull S, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in adults with primary insomnia. Sleep 2007;30:1555-1561. 56. Rosenberg R, Roth T, Scharf MB, et al. Efficacy and tolerability of indiplon in transient insomnia. J Clin Sleep Med 2007;3:374-379. 57. Walsh JK, Moscovitch A, Burke J, et al. Efficacy and tolerability of indiplon in older adults with primary insomnia. Sleep Med 2007;8: 753-759. 58. Roth T, Zammit GK, Scharf MB, et al. Efficacy and safety of asneeded, post bedtime dosing with indiplon in insomnia patients with chronic difficulty maintaining sleep. Sleep 2007;30:1731-1738. 59. Roth T, Hull SG, Lankford DA, et al. Low-dose sublingual zolpidem tartrate is associated with dose-related improvement in sleep onset and duration in insomnia characterized by middle-of-the-night (MOTN) awakenings. Sleep 2008;31:1277-1284. 60. Erman M, Seiden D, Zammit G, et al. An efficacy, safety, and dose-response study of ramelteon in patients with chronic primary insomnia. Sleep Med 2006;7:17-24. 61. Roth T, Seiden D, Sainati S, et al. Effects of ramelteon on patientreported sleep latency in older adults with chronic insomnia. Sleep Med 2006;7:312-318. 62. Roth T, Seiden D, Wang-Weigand S, et al. A 2-night, 3-period, crossover study of ramelteon’s efficacy and safety in older adults with chronic insomnia. Curr Med Res Opin 2007;23:1005-1014. 63. Walsh JK, Zammit G, Schweitzer PK, et al. Tiagabine enhances slow wave sleep and sleep maintenance in primary insomnia. Sleep Med 2006;7:155-161. 64. Walsh JK, Randazzo AC, Frankowski S, et al. Dose-response effects of tiagabine on the sleep of older adults. Sleep 2005;28:673-676. 65. Roth T, Wright KP, Walsh J. Effect of tiagabine on sleep in elderly subjects with primary insomnia: a randomized, double-blind, placebo-controlled study. Sleep 2006;29:335-341. 66. Deacon S, Staner L, Staner C, et al. Effect of short-term treatment with gaboxadol on sleep maintenance and initiation in patients with primary insomnia. Sleep 2007;30:281-287. 67. Lankford DA, Corser BC, Zheng YP, et al. Effect of gaboxadol on sleep in adult and elderly patients with primary insomnia: results from two randomized, placebo-controlled, 30-night polysomnography studies. Sleep 2008;31:1359-1370. 68. Rosenberg R, Seiden DJ, Hull SG, et al. APD125, a selective serotonin 5-HT(2A) receptor inverse agonist, significantly improves sleep maintenance in primary insomnia. Sleep 2008;31:1663-1671. 69. Roecker AJ, Coleman PJ. Orexin receptor antagonists: medicinal chemistry and therapeutic potential. Curr Top Med Chem 2008;8: 977-987. 70. Schutte-Rodin S, Broch L, Buysse D, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med 2008;4:487-504.
Insomnia: Epidemiology and Risk Factors
Kenneth L. Lichstein, Daniel J. Taylor, Christina S. McCrae, and Megan E. Ruiter Abstract Chronic, clinically significant insomnia approaches 10% prevalence, and moderately frequent insomnia symptoms appear in a much larger number of persons. Advancing age, female gender, and low socioeconomic status are the strongest insomnia correlates. Some variant of hyperarousal is a broadly
Insomnia is the most common sleep disorder and is among the most prevalent of all mental health disorders. However, at the core of the challenge in evaluating the epidemiology of insomnia is demarcating the border between insomnia complaints and clinical insomnia. Twenty-six percent of people complain of difficulty falling asleep and 42% complain of difficulty staying asleep at least a few nights a week.1 These survey results illuminate the potential grandiose magnitude of insomnia, but they also serve to caution us that a sleep complaint alone does not in itself rise to the standard of clinical insomnia. Indeed, if treatment-seeking behavior is a proxy for clinical significance, a more-constrained picture emerges. Only 13% of persons complaining of insomnia seek professional treatment, though this rate increases with insomnia severity and advancing age.2 It should be immediately apparent that complexities impede efforts at clarifying the epidemiology of insomnia. This chapter enumerates such obstacles and presents a summary of current knowledge on the epidemiology and risk factors of insomnia.
EPIDEMIOLOGY Definition of Insomnia Defining insomnia is a complex task for several reasons. First, insomnia can occur as a symptom, a disorder, or both. Second, insomnia that begins as a symptom of another disorder often evolves over time into a disorder in its own right. Third, as a disorder, insomnia is heterogeneous, because it has varying durations, types, and etiologies. The durations include acute (1 month or less), intermittent, and chronic (6 months or more). Types include sleep-onset insomnia, sleep-maintenance insomnia, early morning awakening, or some combination of these. Etiologic categories include primary insomnia and insomnia comorbid with another condition. Given this complexity, it is not surprising that the literature contains numerous definitions of insomnia, ranging from the broad and inclusive to the narrow and exclusive. For example, some epidemiologic studies have relied on
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76
recognized candidate accounting for insomnia risk factors. Precise mechanisms and causal paths with respect to insomnia correlates and risk factors are poorly understood. The highest priorities for future research are a standard definition of insomnia, longitudinal studies, and more attention to monitoring psychological and medical comorbidity, ethnicity, and genetic variables.
respondents to provide their own definitions by simply asking whether or not they have trouble sleeping,3 whereas other studies have defined insomnia more narrowly using quantitative severity threshold criteria, such as greater than 30 minutes of sleep-onset latency or wake time after sleep onset.4 Unfortunately, the study of insomnia has been hampered by such varied definitions of insomnia as evidenced by a review of epidemiologic studies in which prevalence rates in the general population ranged from 4% to 48% depending on the definition used.5 Efforts to standardize insomnia criteria6 might prove helpful in the future. A consensus has begun to emerge in the literature that the core symptoms of insomnia include at least one sleep symptom and one wake symptom. The sleep symptom(s) include a report of difficulty initiating or maintaining sleep, early morning awakening, or nonrestorative or nonrefreshing sleep. The wake symptom(s) include a report of sleep-associated daytime impairment, such as sleepiness, fatigue, mood disturbance, cognitive difficulties, social impairment, or occupational impairment.7 Research supports the clinical utility of considering associated daytime impairment, because persons with both sleep and wake symptoms are more likely to seek treatment than those who report sleep symptoms alone.8 In a formal attempt to improve standardization, sensitivity-specificity analyses were performed on data from 61 clinical trials conducted during the 1980s and 1990s. The aim of these analyses was to determine common practices for defining quantitative criteria for the diagnosis of chronic insomnia: frequency (insomnia symptoms occur at least 3 nights a week), severity (sleep-onset latency or wake time after sleep onset of at least 31 minutes per night), and duration (insomnia symptoms have been present for at least 6 months).9 The American Academy of Sleep Medicine took another notable, formal attempt at standardization in 1999 by appointing a work group to develop research diagnostic criteria (RDC) for insomnia.10 In 2004, this work group published their recommendations, which included a universal definition for chronic insomnia (plus RDC for nine specific diagnostic types and normal control samples; Box 76-1). 827
828 PART II / Section 10 • Insomnia Box 76-1 Research Diagnostic Criteria: Universal Definition for Insomnia Disorder Patient must report difficulty initiating or maintaining sleep, waking up too early, or chronically nonrestorative or poor-quality sleep. Sleep difficulty occurs despite adequate opportunity and circumstances for sleep. Patient must report sleep-related daytime impairment involving one or more of the following: • Fatigue or malaise • Attention, concentration, or memory problems • Social or vocational dysfunction or poor school performance • Mood disturbance or irritability • Daytime sleepiness • Reduced motivation, energy, or initiative • Proneness for errors or accidents at work or while driving • Tension headaches, and/or gastrointestinal symptoms in response to sleep loss • Concerns or worries about sleep Adapted from Edinger JD, Bonnet MH, Bootzin RR, et al. Derivation of research diagnostic criteria for insomnia: report of an American Academy of Sleep Medicine Work Group. Sleep 2004;27:1567-1596.
Evaluation Epidemiological data have traditionally relied on selfreport data because large-scale data collection using objective methods (polysomnography [PSG] or actigraphy) is expensive and cumbersome. Further, self-report instruments better capture sleep perception than objective methods, and the subjective view may have greater import for insomnia than objective assessment.6 Self-reported accounts of one’s sleep experiences are necessarily retrospective in nature. However, the time period over which published studies have asked subjects to provide sleep estimates has varied widely—from 1 year to the previous night.4 Because asking respondents to provide single-point estimates of their sleep over extended time periods (days, months, years) poses specific methodologic limitations that are less of a concern when data is estimated for the previous night, the term prospective takes on a different connotation when referring to the epidemiology literature. Specifically, prospective typically refers to a future event, but in this context, it is used to refer to sleep diary data that collects information on sleep from the night just completed. This distinction is important, because sleep diaries allow researchers to capitalize on the immediacy of retrospective data. A review of the typical methodology used by 42 studies conducted during the mid 1970s through 2002 revealed that the overwhelming majority (n = 40) relied on retrospective assessment using either an interview or selfadministered survey to collect data at a single point in time.4 At that time, only two studies had used a prospective assessment approach, collecting daily sleep diaries for 1 week.11,12 Subsequently, an epidemiologic study was reported that used 2 weeks of daily sleep diaries.4
The heavy reliance on retrospective assessment is problematic because of the increased risk of recall errors and unreliability when respondents are asked to provide sleep estimates over long periods of time. The recall bias introduced by retrospective estimates may produce overestimates of insomnia symptoms. Retrospective estimates of total sleep time and number of awakenings are poorly correlated with similar sleep diary estimates,13 and PSG sleep variables correlate better with daily sleep diaries than with retrospective reports.14 Additionally, retrospective estimates can introduce unreliability, because single point estimates may be susceptible to situational influences that are temporary. Momentary emotional states (e.g., workrelated stress, depressed mood) tend to influence recall more than do routine experiences. Recency bias can also introduce unreliability because participants can exhibit a tendency to respond based on their previous night’s sleep. Another problem plaguing some retrospective studies is the absence of a specified time period of assessment. For example, some studies asked respondents to report how they “usually” or “generally” sleep. Prospective assessment using at least 1 week of sleep diaries, preferably 2, avoids or reduces many of the limitations inherent in retrospective assessment.15 It also allows a richer characterization of sleep, because sleep diaries provide detailed quantitative descriptions (i.e., sleep-onset latency, wake time after sleep onset, number of awakenings, total sleep time, sleep efficiency) and information on type of insomnia (i.e., onset, maintenance, terminal). Prevalence Nowhere is the impact of inconsistent definitions and assessment more evident than in the wide range of insomnia prevalence estimates (4% to 48%) available for the general population.5 In a review5 of more than 50 epidemiologic studies of insomnia based on samples or populations from around the world, this review provides prevalence rates for each of four main definitional categories and three subcategories. As illustrated in Table 76-1, prevalence rates drop precipitously as the stringency of criteria increase. Applying the most lenient criteria—presence of insomnia symptoms without any frequency or severity qualifiers—prevalence rates of up to 48% were found, whereas the most restrictive criteria—insomnia diagnosis based on DSM-IV-TR criteria7—revealed more modest prevalence rates of about 6%. Notably, prevalence rates also stabilized as criteria tightened so that the rates reported for the studies using DSM-IV-TR criteria demonstrated a narrow 2-point range (4.4% to 6.4%), whereas those examining insomnia symptoms demonstrated the greatest variability, with a broad 38-point range (10% to 48%). The overwhelming majority of studies included in this review used some type of retrospective assessment. This is not surprising given the large degree of overlap between the studies reviewed by Ohayon5 and the Lichstein and colleagues4 review previously discussed. Given the importance of the distinction between retrospective and prospective assessment, it seems prudent to examine the prevalence of insomnia when prospective assessment is used. This discussion focuses on the Lichstein and colleagues study,4
CHAPTER 76 • Insomnia: Epidemiology and Risk Factors 829
Table 76-1 Prevalence Rates by Four Main Definitional Categories and Three Subcategories
Table 76-2 Prevalence of Insomnia by Insomnia Type
DEFINITION
TYPE
DEFINITION
Onset
Satisfies quantitative criteria for onset insomnia only (SOL ≥31 min, ≥3 nights a week)
22.8
Maintenance
Satisfies quantitative criteria for maintenance insomnia only (WASO ≥31 min, ≥3 nights a week)
31.6
Mixed
Does not separately satisfy quantitative criteria for onset or maintenance insomnia, but has at least 3 insomnia nights a week (1 or 2 nights of SOL ≥31 min, and 1 or 2 nights of WASO ≥31 min)
16.9
Combined
Separately satisfies quantitative criteria for both onset and maintenance insomnia (SOL ≥31 min, ≥3 nights a week, and WASO ≥31 min, ≥3 nights a week)
28.7
PREVALENCE (%)
Definitional Categories DSM-IV insomnia diagnosis (n = 5)
4-6
Dissatisfaction with sleep quantity or quality (n = 11)
8-18
Insomnia symptoms plus daytime consequences (n = 8)
9-15
Insomnia symptoms* (n = 21)
10-48
Insomnia Symptoms (Subcategories) Insomnia symptoms only
30-48
Insomnia symptoms plus frequency criteria (≥3 nights/week or often/ always)
16-21
Insomnia symptoms plus severity criteria (moderately to extremely)
10-28
*Insomnia symptoms included difficulty initiating or maintaining sleep. Some studies also included nonrestorative sleep as a symptom. DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision. Adapted from Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev 2002;6: 97-111.
which used a stratified random sampling procedure to recruit at least 50 men and 50 women in each age decade from 20 to 29 years to 80+ years from Memphis, Tennessee, and neighboring suburbs. Although at least two other studies11,12 have used prospective assessment, this study was chosen because it provides the strongest methodological rigor of the prospective studies. Specifically, this study used random-digit dialing sampling, 2 weeks of sleep diaries, quantitative insomnia criteria including daytime impairment, and sampling across a broad age range and among different ethnic groups. The overall prevalence of insomnia, weighted by gender and age, was 15.9%. This rate is higher than expected based on Ohayon’s documentation of the decrease in rate with increased methodological rigor. The reason underlying the difference in rates between the 4% to 6% rates found in studies using DSM-IV-TR criteria and the approximately 16% rate found in this study using empirically based quantitative criteria and prospective assessment is unclear. This study also provides novel information on the prevalence of four unique insomnia types (Table 76-2). Comorbidities Comorbid insomnia is an important topic that has not received much attention in the epidemiology literature. This is because historically, insomnia occurring in the context of another disorder (medical or psychiatric) has been viewed as a symptom of that disorder and labeled secondary insomnia. Unfortunately, it is difficult to determine whether insomnia is a symptom secondary to another disorder or a separate disorder (comorbid), because
PREVALENCE (%)
SOL, sleep-onset latency; WASO, wake after sleep onset. Adapted from Lichstein KL, Durrence HH, Riedel BW, et al. Epidemiology of sleep: age, gender, and ethnicity. Mahwah, NJ: Erlbaum; 2004.
insomnia that initially occurs secondary to some other condition often becomes an independent problem or a partially independent problem that shares a reciprocal relationship with the original primary disorder. In recognition of the difficulty inherent in drawing conclusions about causality, a 2005 NIH State-of-the Science Consensus panel16 recommended that the term comorbid insomnia replace the term secondary insomnia. Greater focus on comorbid insomnia in the epidemiology literature is warranted because of its common occurrence, potentially accounting for up to 90% of insomnia in the general population.17,18,19 The most common comorbidities associated with insomnia are psychiatric disorders, including anxiety, depression, panic disorder, adjustment disorder, somatoform disorders, and personality disorders. Comorbidity rates between insomnia and psychiatric distress, particularly anxiety and depression,20,21 have been found to be as high as 77% in clinical cases.20 However, epidemiologic studies examining the association between clinically significant levels of anxiety and depression and insomnia in the general population have revealed lower rates. One study22 examined
830 PART II / Section 10 • Insomnia
comorbidity between insomnia and mental disorders in a representative French cohort (n = 5622). Of their total sample, 17.7% fit one of six DSM-IV-TR insomnia categories. Of subjects with a diagnosis of insomnia, only 7.3% qualified for a diagnosis of primary insomnia. However, even in those participants, the prevalence of subclinical depressive or anxiety symptoms was extremely high (90%). The distribution of the remaining 92.7% of participants with insomnia into the four other diagnostic categories was as follows: • Insomnia related to a depressive disorder: 8.1% • Insomnia related to an anxiety disorder: 8.4% • Depressive disorder accompanied by insomnia symptomatology: 10% • Anxiety disorder accompanied by insomnia symptomatology: 37.7% Another study23 found similar rates for depression and anxiety. Specifically, they found 20% percent of people with insomnia displayed clinically significant depression and 19.3% demonstrated clinically significant anxiety. People with insomnia were 10 times more likely to have depression and 17 times more likely to have anxiety than normal sleepers. Medical conditions that commonly co-occur with insomnia include arthritis, cancer, hypertension, chronic pain, coronary heart disease, and diabetes. Several studies have examined the association of insomnia and medical conditions in older persons. For example, in a crosssectional study of 9000 persons 55 to 84 years of age, Foley and colleagues24 found an association between history of insomnia and difficulties with activities of daily living, respiratory symptoms, and other health problems, including hypertension, heart disease, cancer, stroke, diabetes, and hip and other fractures. A 3-year follow-up (N = 6800) revealed that heart disease, stroke, hip fracture, and respiratory symptoms were associated with incident insomnia.
Heart disease, diabetes, respiratory symptoms, and stroke were also associated with the maintenance of insomnia.25 The 2003 National Sleep Foundation’s Sleep in America Survey found that 69% of respondents with one or more sleep problems also had four or more medical conditions.26 Only 36% of those with no major medical conditions reported sleep problems. Several other studies have examined adults across the lifespan. In a survey of 3161 adults19 18 to 79 years of age, those who reported insomnia symptoms (difficulty falling asleep, difficulty staying asleep, or waking too early) were more likely to report having two or more health problems than were normal sleepers. A study of 12,643 Hungarians27 found that people with insomnia exhibited greater use of health care, in terms of sick leave, emergency department visits, and hospitalization, than normal sleepers. Another study28 focused on prevalence rates of medical problems in persons with insomnia in the general population. Controlling for anxiety, depression, and symptoms of other sleep disorders, they found persons with insomnia had a higher prevalence of comorbid medical problems than did persons without insomnia (Table 76-3). Additionally, persons with chronic medical problems had a higher prevalence of insomnia than did people without those problems (Table 76-4). Demographics Aging Insomnia symptoms are a substantial health concern among older adults. Report of at least one insomnia complaint of varying frequency is common in the United States24,29,30 and in other countries,11,31 with a similar prevalence range of 30% to 60%. The prevalence of chronic insomnia, variously defined and assessed, among the elderly has been found to range from 12% to 41%.17,24,30,31,32,33
Table 76-3 Prevalence of Medical Problems in Persons with or without Insomnia Prevalence of Medical Problem (%)
Odds Ratio (95% CI)
MEDICAL PROBLEM
PWI
PNI
UNADJUSTED
Heart disease
21.9
9.5
2.68 (1.58-4.53)
2.27 (1.13-4.56)‡
2.17 (1.01-4.67)
2.58 (0.98-6.82)
Cancer
ADJUSTED* †
8.8
4.2
43.1
18.7
3.29 (2.16-5.01)†
Neurologic disease
7.3
1.2
6.24 (2.09-18.59)
4.64 (1.37-15.67)‡
Breathing problems
24.8
5.7
5.43 (3.06-9.62)†
3.78 (1.73-8.27)§
Urinary problems
19.7
9.5
2.35 (1.37-4.01)§
3.28 (1.67-6.43)§
Diabetes
13.1
5.0
2.88 (1.48-5.63)§
1.80 (0.78-4.16)
Chronic pain
50.4
18.2
4.56 (3.00-6.94)
3.19 (1.92-5.29)†
Gastrointestinal
33.6
9.2
4.97 (3.05-8.12)
Any medical problem
86.1
48.4
Hypertension
‡
3.18 (1.90-5.32)† §
†
3.33 (1.83-6.05)†
†
6.63 (3.93-11.18)
†
5.17 (2.93-9.12)†
*Adjusted for depression, anxiety, and sleep disorder symptoms. † P < .001. ‡ P < .05. § P < .01. CI, confidence interval; PNI, people not having insomnia; PWI, people with insomnia. Adapted with permission from Taylor DJ, Mallory LJ, Lichstein KL, et al. Comorbidity of chronic insomnia with medical problems. Sleep 2007;30:213-218.
CHAPTER 76 • Insomnia: Epidemiology and Risk Factors 831
Table 76-4 Prevalence of Insomnia in People in Persons with or without Medical Disorders Medical Problem DISEASE
Insomnia Prevalence*
Odds Ratio (95% CI)
PWP (NO.)
PWOP (NO.)
PWP (%)
PWOP (%)
UNADJUSTED
ADJUSTED*
Heart disease
68
470
44.1
22.8
2.68 (1.58-4.53)‡
2.11 (1.07-4.15)§
Cancer
29
509
41.4
24.6
2.17 (1.01-4.67)§
2.50 (1.01-6.21)§
134
404
44.0
19.3
3.29 (2.16-5.01)‡
3.19 (1.87-5.43)‡
Neurologic disease
15
523
66.7
24.3
6.24 (2.09-18.59)||
5.21 (1.22-22.21)§
Breathing problems
57
481
59.6
21.4
5.43 (3.06-9.62)‡
2.79 (1.27-6.14)§
Urinary problems
65
473
41.5
23.3
2.35 (1.37-4.01)||
3.51 (1.82-6.79)‡
Diabetes
38
500
47.4
23.8
2.88 (1.48-5.63)||
2.03 (0.86-4.79)
142
396
48.6
17.2
4.56 (3.00-6.94)‡
3.16 (1.90-5.27)‡
83
455
55.4
20.0
4.97 (3.05-8.12)‡
3.00 (1.66-5.43)‡
312
226
37.8
8.4
6.63 (3.93-11.18)‡
5.26 (2.82-9.80)‡
Hypertension
Chronic pain Gastrointestinal problems Any medical problem
CI, confidence interval; N/A, not applicable; PWP, people who reported having the medical problem; PWOP, people who did not report having medical problem. *Percentage of people with or without that particular disease who report insomnia. † Adjusted for depression, anxiety, and sleep disorder symptoms. ‡ P < .001 § P < .05. || P < .01. Adapted with permission from Taylor DJ, Mallory LJ, Lichstein KL, et al. Comorbidity of chronic insomnia with medical problems. Sleep 2007;30:213-218.
Epidemiology surveys have concluded that the prevalence of insomnia increases with advancing age.5 These findings are corroborated by studies on the incidence rates of insomnia in the elderly. Three such studies have found average yearly incidence rates of chronic insomnia in the range of 3.6% to 7% in older adults.17,25,34 One of the studies was longitudinal34 and determined that incident insomnia increases with age and nearly doubles in the 75 and older age group. Similarly, Foley and colleagues25 found that men 85 years and older had higher incidence rates than any other age group; however, both sexes did not have significantly different incidence rates until that age. The odds ratio (OR) of having persistent insomnia increases 1.1-fold each decade of life.35 The presence of depressed mood is a predictor of new difficulties with sleep, and the absence of it predicts remission.25 Thus, depression in the elderly may be an important factor in the development of chronic insomnia. Some studies have questioned the common finding of age-correlated prevalence. Chronic insomnia may be associated with health complications that are at greater risk of occurring as one ages.36 Correspondingly, evidence indicates that older adults who remain physically and mentally active do not show an increase in prevalence of chronic
insomnia as compared to younger adults.37,38 Other noteworthy predictors of insomnia in the elderly are female gender, mood disorders, poor perceived health, bodily pain, stressful life events, somatic complaints, and memory problems.26,33 Gender Overall, insomnia is more commonly found in women than in men. Lichstein and colleagues4 reported overall prevalence rates for insomnia and insomnia symptoms by gender based on their review of 42 epidemiology studies (33 of which reported gender comparisons; Table 76-5). Results from their own prospective epidemiology study further support the overall greater prevalence of insomnia in women (Fig. 76-1). There was no reliable difference in the sleep (e.g. sleep-onset latency, total sleep time) of men and women with diagnosed insomnia. This study also provides a decade-by-decade breakdown of insomnia prevalence for women and men. With the exception of the decade 30 to 39 years, women exhibited greater prevalence of insomnia than men across the lifespan. Specifically, insomnia prevalence rates for women ranged from 12% (20 to 29 and 30 to 39 years) to 41% (80+ years). For men, rates ranged from 6% (20 to 29 years) to 23% (70 to 79 and 80+ years).
832 PART II / Section 10 • Insomnia Table 76-5 Overall Prevalence Rates for Insomnia and Insomnia Symptoms by Gender INSOMNIA (%)
DIFFICULTY INITIATING SLEEP (%)
DIFFICULTY MAINTAINING SLEEP (%)
EARLY-MORNING AWAKENING (%)
Women
18.2
15.4
17.6
13.6
Men
12.4
11.4
13.2
11.8
Adapted from Lichstein KL, Durrence HH, Riedel BW, et al. Epidemiology of sleep: age, gender, and ethnicity. Mahwah, NJ: Erlbaum; 2004.
50 Men Women
Percent insomnia
40 30 20 10 0 20
30
40
50
60
70
80
Lower boundary of age decade Figure 76-1 Insomnia prevalence by sex and age. Each value on the abscissa represents the beginning of an age decade as in 20 (to 29) and 30 (to 39). (Data from Lichstein KL, Durrence HH, Riedel BW, et al. Epidemiology of sleep: age, gender, and ethnicity. Mahwah, NJ: Erlbaum; 2004.)
A meta-analysis39 examined 29 published epidemiologic studies (N = 1,265,015; female subjects = 718, 828, male subjects = 546,187) to estimate sex differences in the risk of insomnia. Women exhibited a higher risk ratio (RR, 1.4) for insomnia than men. Women’s risk ratio varied depending on the sample size and strength of methodology of the studies included in the analyses. Specifically, women exhibited a higher risk ratio in larger studies with more rigorous methodology (RR, 1.64) than in smaller, less-rigorous studies (RR, 1.32). As in prior results,4 this female preponderance in the risk of insomnia was evident across elderly (65 years or older), middle-aged (31 to 64 years), and young adult (15 to 30 years) age groups. Ethnicity Ethnicity may be an important explanatory factor as indicated by one study40 that found it accounts for 20% of the variance in insomnia. Most epidemiologic data on ethnicity and insomnia have focused on comparing whites and African Americans. One review of the literature41 determined that insomnia is likely to be more severe and more prevalent among African Americans than among whites. One study4 observed a bimodal pattern among African Americans, with insomnia peaks occurring during ages 30 to 50 years and 70 to 80 years.
One well-replicated finding is that older whites report more insomnia symptoms than African Americans.4,24,32,42 Despite the apparent consistency across this large age span, some data reveal that age and gender may be important moderators in the resulting ethnic difference. Middle-aged African Americans tend to have a higher rate of insomnia symptoms than whites,4,43 and African American women tend to sleep worse than African American men and whites.24,44 Reported severity of insomnia symptoms, determined by sleep diary and daytime functioning data, may also be greater in African Americans than whites, regardless of prevalence.4 Census and community data on sleep disturbance across a variety of countries that vary in their ethnic distribution reveal that the prevalence of insomnia is comparable. For example, rates of insomnia from countries with mostly white populations are roughly similar to those found in countries dominated by people of mostly Asian descent. Researchers in France cite prevalence rates of 9%,45 whereas data from an elderly Chinese population show a prevalence of 8.9%,31 and the prevalence rate in the general Japanese population has been reported at 21.4%.46 Education and Socioeconomic Status Epidemiologic studies have consistently shown that education and socioeconomic status predict sleep quality. Persons with lower socioeconomic status report more difficulty falling and staying asleep, more frequent early morning awakenings, and increased daytime sleepiness than do those with higher socioeconomic status.47 Among older women,48 higher income predicted better objective (reduced sleep latency and increased sleep efficiency) and subjective (lower Pittsburgh Sleep Quality Index [PSQI] global scores) sleep. Similarly, more years of education were associated with better objective (reduced sleep latency and increased sleep efficiency) and subjective (sleep efficiency) sleep. Importantly, these associations persisted after adjustments for potential confounders, including age, marital status, medication use, smoking, and use of alcohol, tobacco, or caffeine. Mezick and colleagues49 examined the association between socioeconomic status on objective (9 nights of actigraphy; 2 nights of in-home PSG) and subjective (PSQI) sleep in 187 adults (41% African American, mean age = 59.5 ± 7.2 years). Lower socioeconomic status was associated with longer actigraphically measured latency, more wake after sleep onset as measured by PSG, and poorer sleep quality on the PSQI. Another study50 investigated insomnia and related impairment. Persons with lower individual and household education were
CHAPTER 76 • Insomnia: Epidemiology and Risk Factors 833
significantly more likely to experience insomnia and also reported greater insomnia-related impairment. Importantly, education level was related to insomnia even after controlling for ethnicity, gender, and age.
with modest evidence for difficulty initiating sleep and early-morning awakenings also increasing with age. Other research shows that perhaps this relationship is overstated. After controlling for important comorbidities, such as health problems, some studies have shown that age is no longer a significant risk.36,37,38
RISK FACTORS A risk factor is a condition or status that is related to increased risk for developing some disease at a later time. Using longitudinal data is the best way to determine risk, but it is costly and time consuming to collect. Another common method for inferring risk status is through crosssectional, retrospective studies, asking participants with and without a disease of interest (e.g., insomnia), what problems they had before the onset of the disease. This method is less reliable than the longitudinal study because of a variety of problems with retrospective bias.51 Unfortunately, most of the data regarding insomnia risk factors use cross-sectional data (i.e., single time point), making these variables in actuality correlates or comorbidities of insomnia. This approach cannot be used to determine risk-factor status because data on both variables (i.e., condition and disease) are obtained simultaneously, which does not allow a temporal evaluation of which came first, which is necessary to determine direction of risk. One caveat to this statement is where the correlate is a relatively static condition or status (i.e., sex, ethnicity, age, genetics). Static Risk Factors for Insomnia Sex, age, and ethnicity are risk factors for insomnia and as well as central epidemiologic characteristics. These topics were discussed in detail in the earlier epidemiology section and are given briefer treatment here to minimize redundancy. Gender Women are far more likely to report insomnia than men. However, it is likely some other unmeasured factor is accounting for this relationship. For instance, it has been theorized that fluctuating hormone levels might play a role increasing the propensity for women to report mental health disorders.52 This is particularly relevant for insomnia and sleep in general because several hormones (e.g., melatonin and cortisol) do interact with sleep scheduling, including onset and offset. Others theorize that women are more at risk for developing mental health problems because they use different coping styles, being more likely to ruminate on their problems whereas men are more apt to distract themselves or use drugs and alcohol to cope.53 This theory appears to be in line with those models of insomnia that assume worry and rumination predispose or perpetuate insomnia. Finally, women may be exposed to higher levels of stressful events,54 which are also theorized to precipitate insomnia episodes. Age In the past, increasing age was thought to be an independent risk factor for insomnia. One review4 of 20 studies found that the majority of studies (60%) showed an increase of prevalence and severity of insomnia with age. In this review, difficulty maintaining sleep increased with age,
Ethnicity To briefly summarize the thrust of the findings presented in the epidemiology section, insomnia is more: • Severe in African Americans, particularly African American women • Prevalent in older whites compared to older African Americans • Prevalent in middle-aged African Americans compared to middle-aged whites Some limitations of these results include confounding between lower socioeconomic status and ethnicity, and the higher health-related concerns in minority groups. Genetics Although little is known about the genetics of insomnia, there is a growing interest in the area. Two older epidemiologic twin studies reported higher concordance rates of sleep complaints among monozygotic twins compared to dizygotic twins, with heritability estimates in the range of 0.2 to 0.4.55,56 These studies unfortunately did not use standard diagnostic criteria for insomnia. A more recent study57 found a concordance rate of 0.57 for insomnia defined as having trouble falling asleep or staying asleep “often” or “always.” Though this definition is more precise than previous studies, it still does not meet research diagnostic criteria,9,10 making the results somewhat unreliable and difficult to compare to future studies that are expected to use such definitions. Further, the authors did not control for other mental or physical illnesses, which could be the cause of insomnia and the reason for concordance. Familial aggregation is a type of statistical analysis where one determines if a disorder (i.e., insomnia) occurs more commonly in members of a family than among nonrelated persons. Although this method is somewhat weaker than the twins studies, these studies also show evidence of familial aggregation of insomnia.58,59 For example, familial aggregation accounted for 37.2% of individual vulnerability to stress-induced sleep disturbance, after controlling for age, gender, shift schedule, and psychiatric history.59 Based on the whole of these results, it is reasonable to assume that there is some genetic risk for developing insomnia. To date, however, the data are of questionable quality, making it difficult to determine the exact level of risk posed and which genes in particular are responsible. Modifiable Risk Factors for Insomnia Hyperarousal All of the models of insomnia (i.e., physiologic, behavioral, cognitive, and neurocognitive) assume some degree of hyperarousal as a predisposition or risk factor for the onset of insomnia. To date, virtually all of the evidence for this relationship has been cross-sectional.60,61 The absence of longitudinal evidence to explicate these associations makes it impossible to delineate causal paths.
834 PART II / Section 10 • Insomnia
Stress and Life Events Most models of insomnia assume that high stress or stressful life events are risk factors for the onset of insomnia. This area has actually received mixed support. Most earlier studies did not assess for this construct, but within those that did, stressful life events were only mildly related to the onset of insomnia.62 Newer studies show that one reason this relationship was weak in the past is because an anxious predisposition is a moderator of the relationship: People high in anxiety are more likely to develop a sleep disturbance after a stressful life event than those low in anxiety over 5-year follow-up.63 Transient Insomnia Transient insomnia is a short-term comorbid insomnia thought to be instigated by an aggravating event that resolves upon the extinction of that event.64 Transient insomnia is argued to be a significant risk factor in developing chronic insomnia such that greater episodic occurrence fosters further syndrome progression.64,65 At present, the only objective data that support this view find that previous transient insomnia episodes and poor sleep hygiene and beliefs significantly predicted the incidence of insomnia after discharge from a moderate hospital stay.66 In contrast, age, sex, type of surgery, length of hospital stay, and severity of hospital sleep disturbance did not predict incident insomnia. Medical Comorbidities Medical comorbidities are ubiquitous in insomnia. One could argue that even though this is based mostly on crosssectional data, when insomnia prevalence runs five times the population prevalence in such conditions as pain67 and cancer,68 it is safe to assume that at least severe medical conditions are a risk factor for subsequent insomnia. Although one would assume numerous types of medical problems would be a risk factor for at least transient insomnia, there is limited research to confirm this assumption. The few salient longitudinal studies do conclude that medical status is an insomnia risk factor. A study33 in adults 50 years and older found that one or more chronic medical conditions was a significant risk factor (OR, 1.3 to 3.8) for developing insomnia at 1-year follow-up. Another study69 of a biracial cohort (N = 2315) found that respiratory symptoms were a risk factor for development of insomnia in African Americans alone (OR, 1.1 to 1.7), physical disability was a risk factor for whites alone (OR, 1.1 to 3.1), and poor perceived health was a risk factor for both cohorts (OR, 1.1 to 5.0). These authors69 also found that improvement of perceived health improved the odds of remission of insomnia (OR, 1.1 to 5.8) in the white group but not in the African American group. The most detailed of these studies was completed in a group of adults aged 65 years and older.24 After controlling for depressed mood, this study found that respiratory symptoms, fair to poor perceived health, and physical disability, were associated with increased risk of insomnia. Improved self-perceived health, stable or improving physical functioning, and no new medical diagnoses were all associated with remission of insomnia.
Psychological Comorbidities Examining the risk relationship between insomnia and psychological disorders is complicated. Insomnia is a symptom of most psychological disorders, raising the possibility that these disorders cause insomnia. However, it is also true, as is discussed later, that insomnia is a risk factor for some of these disorders. To date, few longitudinal studies have evaluated if psychological disorders place a person at more risk of developing insomnia. One study33 did show that “mood disturbance” increased the risk (OR, 1.1 to 2.0) of developing insomnia at 1-year follow-up in adults at least 50 years old. Another study69 showed that depressed mood greatly increased the risk (OR, 1.4 to 8.6) of developing insomnia at follow-up. Interestingly, remission of depressed mood did not significantly improve the odds of remission of insomnia (OR, 0.5 to 2.9), which raises questions about the directionality and independence of these two disorders. A concurrent study24 found that depressed mood posed a significant risk (OR, 2.7 to 4.5) for the onset of insomnia. Again, remission of depression did not improve odds of remission of insomnia. These authors also noted that only a quarter of people who developed insomnia over the follow-up period also developed depression and vice versa. Hypotheses for How Risk Factors Result in Chronic Insomnia Spielman’s70 model of the development of insomnia is essentially a diathesis-stress model. It proposes that certain predispositions exist that make people more susceptible to developing diseases. There is some evidence that there are individual differences in the reactivity of sleep to stressors such as phase advancement (eastward time zone travel), first night effect, and caffeine administration near bedtime, where some sleepers continued to have good sleep despite the presence of these stressors whereas others responded with sleep loss.71,72 Increased sleep reactivity can predispose a person to respond with transient insomnia to a number of precipitating factors. However, the subsequent perpetuating factors garnered from these bouts of insomnia can catalyze the insomnia into chronicity. This process is conceptualized in the kindling hypothesis.65 Recurrent episodes of transient insomnia kindle the development of chronic insomnia so that these bouts, over time, become progressively more independent from precipitating stress-related triggers and deteriorate the body’s adaptive stress response system. The episodes can become more dependent on perpetuating factors such as worry about sleep ability and daytime consequences of sleep loss73 or maladaptive sleep-related behavior such as increased time in bed and activities conducted in the bedroom. Insomnia as a Risk Factor Evidence Several studies have begun to investigate insomnia as a risk factor for the development of other difficulties. One review74 found that insomnia was a consistent risk factor for depression, anxiety disorders, other psychological dis-
orders, alcohol abuse or dependence, drug abuse or dependence, and suicide. Newer evidence has extended these results to adolescents, showing that a self-report of insomnia symptoms in adolescents is a risk factor for depression and substance abuse in young adults.75 These results must be tempered with the knowledge that significant weaknesses existed in the studies reviewed. The main weaknesses were inadequate definition of insomnia and inadequate control for alternative explanations. Despite these limitations, this review suggests that insomnia is a risk factor for poor mental health. To date, the strongest evidence of insomnia as a risk factor is in the arena of depression. Sleep problems are some of the most prevalent complaints in patients with major depressive disorder (MDD), with as many as 84% reporting insomnia.17,76,77 Insomnia appears to be more than just a symptom of depression, and therefore may deserve special attention in the treatment of MDD. One indication of this is that insomnia is a risk factor for the development of MDD, where people with insomnia are 3.95 to 39.8 times more likely to develop MDD than people without insomnia (see reference 74 for a review). There is also evidence that sleep progressively worsens before the onset of MDD.76 Several studies78,79 have also found that the persistence of insomnia is a risk factor for decreased depression treatment response. In addition, insomnia appears to be associated with more frequent relapse and recurrence of MDD.80,81 Hypotheses for Why Insomnia Is a Risk for Other Disorders If one did hypothesize that insomnia has a causal link with these disorders, the relationship would probably best fit into the diathesis-stress model of disease acquisition,82 whereby predisposition to a certain disease and stress created by biological, behavioral, or social factors serves is a catalyst for development of the disease. In such a case, the stress created by insomnia aggravates or serves as a catalyst for the development of a predisposed disease (e.g., depression). One could imagine a scenario where someone overwhelmed with the hopelessness they feel regarding nightly insomnia and spending hours awake ruminating on depressive cognitions could be pushed into a depression.
CONCLUSIONS There exists a large body of work on the epidemiology and risk factors for insomnia providing a strong general understanding of these matters but providing poor precision. Pressing concerns that future research should be responsive to include using a standard definition of insomnia (and consensus recommendations6 are an important step toward this goal) and more careful documentation of salient variables such as psychological or medical comorbidity, ethnicity, and genetic variables. Equally important, no amount of cross-sectional data can substitute for hitherto scarce longitudinal studies. Though costly and time-consuming, longitudinal studies are the next great frontier in advancing understanding of epidemiology and risk factors for insomnia.
CHAPTER 76 • Insomnia: Epidemiology and Risk Factors 835
❖ Clinical Pearls Though the epidemiology literature is burdened by lack of consistency in defining insomnia, it appears that the prevalence of chronic, clinically significant insomnia approaches 10%, and the prevalence of persons experiencing at least moderately frequent insomnia symptoms is probably three times this rate. Advancing age, female gender, and low socioeconomic status are the strongest correlates or risk factors for insomnia, although it is premature to infer causal influence. Hyperarousal in its many forms is the dominant model for understanding insomnia risk factors, but the mediator or moderator influences associated with this mechanism are poorly understood, as are causal paths. Insomnia is itself a risk factor for psychiatric disorders, mainly depression.
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836 PART II / Section 10 • Insomnia Influence of previous complaints of insomnia. Arch Intern Med 1992;152:1634-1637. 19. Mellinger GD, Balter MB, Uhlenhuth EH. Insomnia and its treatment. Prevalence and correlates. Arch Gen Psychiatry 1985;42: 225-232. 20. Buysse DJ, Reynolds CF 3rd, Kupfer DJ, et al. Clinical diagnoses in 216 insomnia patients using the International Classification of Sleep Disorders (ICSD), DSM-IV and ICD-10 categories: a report from the APA/NIMH DSM-IV Field Trial. Sleep 1994;17:630637. 21. Mendelson WB. Experiences of a sleep disorders center: 1700 patients later. Cleve Clin J Med 1997;64:46-51. 22. Ohayon MM, Caulet M, Lemoine P. Comorbidity of mental and insomnia disorders in the general population. Compr Psychiatry 1998;39:185-197. 23. Taylor DJ, Lichstein KL, Durrence HH, et al. Epidemiology of insomnia, depression, and anxiety. Sleep 2005;28:1457-1464. 24. Foley DJ, Monjan AA, Brown SL, et al. Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep 1995;18:425-432. 25. Foley DJ, Monjan A, Simonsick EM, et al. Incidence and remission of insomnia among elderly adults: an epidemiologic study of 6,800 persons over three years. Sleep 1999;22:S366-S372. 26. Foley D, Ancoli-Israel S, Britz P, Walsh J. Sleep disturbances and chronic disease in older adults—results of the 2003 National Sleep Foundation Sleep in America Survey. J Psychosom Res 2004; 56:497-502. 27. Novak M, Mucsi I, Shapiro CM, et al. Increased utilization of health services by insomniacs—an epidemiological perspective. J Psychosom Res 2004;56:527-536. 28. Taylor DJ, Mallory LJ, Lichstein KL, et al. Comorbidity of chronic insomnia with medical problems. Sleep 2007;30:213-218. 29. Ancoli-Israel S, Roth T. Characteristics of insomnia in the United States: Results of the 1991 National Sleep Foundation Survey. I. Sleep 1999;22:S347-S353. 30. Schubert CR, Cruickshanks KJ, Dalton DS, et al. Prevalence of sleep problems and quality of life in an older population. Sleep 2002;25: 889-893. 31. Liu X, Liu L. Sleep habits and insomnia in a sample of elderly persons in China. Sleep 2005;28:1579-1587. 32. Blazer DG, Hays JC, Foley DJ. Sleep complaints in older adults: a racial comparison. J Gerontol 1995;50A:M280-M284. 33. Roberts RE, Shema SJ, Kaplan GA. Prospective data on sleep complaints and associated risk factors in an older cohort. Psychosom Med 1999;61:188-196. 34. Morgan K. Daytime activity and risk factors for late-life insomnia. J Sleep Res 2003;12:231-238. 35. Morphy H, Dunn KM, Lewis M, et al. Epidemiology of insomnia: a longitudinal study in a UK population. Sleep 2007;30:274-280. 36. Vitiello MV, Moe KE, Prinz PN. Sleep complaints cosegregate with illness in older adults: clinical research informed by and informing epidemiological studies of sleep. J Psychosom Res 2002;53: 555-559. 37. Ohayon MM. Prevalence of DSM-IV diagnostic criteria of insomnia: distinguishing insomnia related to mental disorders from sleep disorders. J Psychiatr Res 1997;31:333-346. 38. Ohayon MM, Zulley J, Guilleminault C, et al. How age and daytime activities are related to insomnia in the general population: consequences for older people. J Am Geriatr Soc 2001;49:360-366. 39. Zhang B, Wing YK. Sex differences in insomnia: a meta-analysis. Sleep 2006;29:85-93. 40. Jean-Louis G, Magai C, Casimir GJ, et al. Insomnia symptoms in a multiethnic sample of American women. J Womens Health 2008; 17:15-25. 41. Durrence HH, Lichstein KL. The sleep of African Americans: a comparative review. Behav Sleep Med 2006;4:29-44. 42. Jean-Louis G, Magai C, Consedine NS, et al. Insomnia symptoms and repressive coping in a sample of older black and white women. BMC Womens Health 2007;7:1-9. 43. Katz DA, McHorney CA. Clinical correlates of insomnia in patients with chronic illness. Arch Inter Med 1998;158:1099-1107. 44. Kripke DF, Brunner R, Freeman R, et al. Sleep complaints of postmenopausal women. Clin J Womens Health 2001;1:244-252. 45. Leger D, Guilleminault C, Dreyfus JP, et al. Prevalence of insomnia in a survey of 12,778 adults in France. J Sleep Res 2000;9:35-42.
46. Kim K, Uchiyama M, Okawa M, et al. An epidemiological study of insomnia among the Japanese general population. Sleep 2000;23: 1-7. 47. Sekine M, Chandola T, Martikainen P, et al. Explaining social inequalities in health by sleep: the Japanese civil servants study. J Public Health (Oxf) 2006;28:63-70. 48. Friedman EM, Love GD, Rosenkranz MA, et al. Socioeconomic status predicts objective and subjective sleep quality in aging women. Psychosom Med 2007;69:682-691. 49. Mezick EJ, Matthews KA, Hall M, et al. Influence of race and socioeconomic status on sleep: Pittsburgh SleepSCORE project. Psychosom Med 2008;70:410-416. 50. Gellis LA, Lichstein KL, Scarinci IC, et al. Socioeconomic status and insomnia. J Abnorm Psychol 2005;114:111-118. 51. Korotitsch WJ, Nelson-Gray RO. An overview of self-monitoring research in assessment and treatment. Psychol Assess 1999;11: 415-425. 52. Seeman MV. Psychopathology in women and men: focus on female hormones. Am J Psychiatry 1997;154:1641-1647. 53. Nolen-Hoeksema S. Sex differences in unipolar depression: evidence and theory. Psychol Bull 1987;101:259-282. 54. McGrath E, Keita GP, Strickland BR, Russo NF. Women and depression: risk factors and treatment issues: final report of the American Psychological Association’s National Task Force on Women and Depression. Washington, DC: American Psychological Association; 1990. 55. Heath A, Kendler K, Eaves L, Martin N. Evidence for genetic influences on sleep disturbance and sleep pattern in twins. Sleep 1990; 13:318-335. 56. McCarren M, Goldberg J, Ramakrishnan V, Fabsitz R. Insomnia in Vietnam era veteran twins: influence of genes and combat experience. Sleep 1994;17:456-461. 57. Watson NF, Goldberg J, Arguelles L, Buchwald D. Genetic and environmental influences on insomnia, daytime sleepiness, and obesity in twins. Sleep 2006;29:645-649. 58. Dauvilliers Y, Morin C, Cervena K, et al. Family studies in insomnia. J Psychosom Res 2005;58:271-278. 59. Drake CL, Scofield H, Roth T. Vulnerability to insomnia: the role of familial aggregation. Sleep Med 2008;9:297-302. 60. Bonnet MH, Arand DL. Hyperarousal and insomnia: state of the science. Sleep Med Rev 2010;14:9-15. 61. Perlis ML, Smith MT, Andrews PJ, et al. Beta/gamma EEG activity in patients with primary and secondary insomnia and good sleeper controls. Sleep 2001; 24:110-117. 62. Bastien CH, Vallieres A, Morin CM. Precipitating factors of insomnia. Behav Sleep Med 2004;2:50-62. 63. Vahtera J, Kivimaki M, Hublin C, et al. Liability to anxiety and severe life events as predictors of new-onset sleep disturbances. Sleep 2007;30:1537-1546. 64. Vander Wal GS, Ruiter ME, Lichstein KL. Transient insomnia: a behavioral sleep medicine perspective. In: Pandi-Perumal SR, Verster JC, Monti J, et al, editors. Sleep disorders: diagnosis and therapeutics. London: Informa; 2008. p. 70-79. 65. Drake CL, Roth T. Predisposition in the evolution of insomnia: Evidence, potential mechanisms, and future directions. Sleep Med Clin 2006;1:333-349. 66. Griffiths MF, Peerson A. Risk factors for chronic insomnia following hospitalization. J Adv Nurs 2005;49:245-253. 67. Smith MT, Haythornthwaite JA. How do sleep disturbance and chronic pain inter-relate? Insights from the longitudinal and cognitive-behavioral clinical trials literature. Sleep Med Rev 2004;8: 119-132. 68. Lee K, Cho M, Miaskowski C, Dodd M. Impaired sleep and rhythms in persons with cancer. Sleep Med Rev 2004;8:199-212. 69. Foley DJ, Monjan AA, Izmirlian G, et al. Incidence and remission of insomnia among elderly adults in a biracial cohort. Sleep 1999; 22(Suppl. 2):S373-S378. 70. Spielman AJ, Caruso LS, Glovinsky PB. A behavioral perspective on insomnia treatment. Psychiatr Clin North Am 1987;10:541-553. 71. Bonnet MH, Arand DL. Caffeine use as a model of acute and chronic insomnia. Sleep 1992;15:526-536. 72. Bonnet MH, Webb WB, Barnard G. Effect of flurazepam, pentobarbital, and caffeine on arousal threshold. Sleep 1979;1:271-279. 73. Jansson M, Linton SJ. The development of insomnia within the first year: a focus on worry. Br J Health Psychol 2006;11:501-511.
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74. Taylor DJ, Lichstein KL, Durrence HH. Insomnia as a health risk factor. Behav Sleep Med 2003;1:227-247. 75. Roane BM, Taylor DJ. Adolescent insomnia as a risk factor for early adult depression and substance abuse. Sleep 2008;31:13511356. 76. Perlis ML, Giles DE, Buysse DJ, et al. Self-reported sleep disturbance as a prodromal symptom in recurrent depression. J Affect Disord 1997;42:209-212. 77. McCall WV, Reboussin BA, Cohen W. Subjective measurement of insomnia and quality of life in depressed inpatients. J Sleep Res 2000; 9:43-48. 78. Buysse DJ, Frank E, Lowe KK, et al. Electroencephalographic sleep correlates of episode and vulnerability to recurrence in depression. Biol Psychiatry 1997;41:406-418.
79. Dew MA, Reynolds CF 3rd, Houck PR, et al. Temporal profiles of the course of depression during treatment. Predictors of pathways toward recovery in the elderly. Arch Gen Psychiatry 1997; 54:1016-1024. 80. Ohayon MM, Roth T. Place of chronic insomnia in the course of depressive and anxiety disorders. J Psychiatr Res 2003;37:9-15. 81. Taylor DJ, Walters H, Krebaum S, et al. Does residual insomnia predict depressive relapse and recurrence in cognitive therapy responders [Abstract]. Sleep 2004;27(Abstract Suppl.):A346. 82. Monroe SM, Simons AD. Diathesis-stress theories in the context of life stress research: implications for the depressive disorders. Psychol Bull 1991;110:406-425.
Insomnia: Diagnosis, Assessment, and Outcomes Allison G. Harvey and Arthur J. Spielman Abstract The evaluation of insomnia should take place within two general frameworks: The one is the 3P model that classifies case material into predisposing, precipitating, and perpetuating factors, and the other is the context of the insomnia, considering stage of development, social situation, and culture. The sleep history can be facilitated by the use of a formatted questionnaire that systematically surveys key issues. A sleep diary filled out each day is one of the most useful ways to evaluate the problem and track the effect of interventions. The use of polysomnography and actigraphy are not routinely recommended. A dual approach to assessment is suggested that uses a wide lens to establish the broad thematic structure of the problem (e.g., what part of the night is disturbed, daytime
The goal of this chapter is to provide a comprehensive overview of the diagnosis of insomnia, the clinical assessment of insomnia, and the measurement of outcome and to provide a guide as to how to select from the growing array of assessment tools available. The focus is on the adult insomnia patient. The full assessment described here takes between 60 and 120 minutes, depending on the complexity of the patient’s insomnia. Given that many professionals needing to assess insomnia are time pressed, a quick assessment guide is included as Box 77-1. The information within Box 77-1 is elaborated in the text and can be used as a checklist or guide for the broad domains that should be covered during an assessment.
DIAGNOSING INSOMNIA Insomnia is an ongoing difficulty getting to sleep, staying asleep, waking up too early, or waking up and feeling that the sleep obtained is not restorative. In addition to the sleep complaint, the person with insomnia reports daytime impairment and has an adequate opportunity for sleep.1 Three classification systems offer specific diagnostic criteria for insomnia. The Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR)2 and the International Classification of Diseases, 10th revision (ICD-10),3 offer a small number of broad categories based on current symptoms and functioning, but the International Classification of Sleep Disorders, second version (ICSD-2),4 offers a larger number of subtypes that require the assessor to make judgments about the causes of the insomnia. Table 77-1 lists the key features of the ICSD-2 diagnoses, and Table 77-2 summarizes the diagnostic codes of the ICSD-2 and the DSM-IV-TR. Research is needed to determine the validity and reproducibility of both the broad categories and the subtypes. The Duke Structured Interview for Sleep Disorders (DSISD) is a structured series of questions that helps the clinician to efficiently establish DSM-IV-TR, ICSD-2, 838
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activities that affect sleep, thoughts about sleep, worries about the daytime functional deficits, sleep–wake habits). The other approach is pointedly personal and uses a focused lens that dissects a particular night of insomnia—and the subsequent day—to catch the weave of events and mental responses that locate the targets for treatment within the vicious cycle created by the interaction between poor sleep and psychological reactions. Attention needs to be paid in the evaluation to comorbid conditions such as psychiatric, sleep and medical disorders. Consistent with the consensus of the field it is assumed that these disorders can trigger, contribute to, or be unrelated to the insomnia. During and after treatment, conducting an evaluation of progress refines our understanding of effectiveness.
and research diagnostic criteria (RDC) insomnia diagnoses. Each section of the interview starts with a screening question. If this is endorsed, a series of follow-up questions are asked. If the screen is not endorsed the follow-up questions are skipped and the assessor moves to the screening question in the next category. The DSISD is divided into three sections: insomnia diagnoses, other sleep disorders (e.g., dyssomnia), and sleep disorders associated with excessive daytime sleepiness. The DSISD has been found to be effective for identifying those meeting criteria for an insomnia disorder.5 Note that insomnia symptoms are a feature of a range of other sleep disorders. For example, insomnia is listed as a feature of various sleep-related breathing disorders, circadian rhythm disorders, sleep-related movement disorders, and the parasomnias (e.g., nightmare disorder and sleep-related breathing disorder). Such symptoms can arise, at least in part, from the precipitating factors that are also a feature of the insomnia disorders (e.g., hyperarousal, conditioning).
CLINICAL ASSESSMENT Recommendations for the standard research assessment of insomnia have been published.6 This was the result of a detailed review of the literature and an expert consensus process involving an evidence-based quantitative review of the available methods. Table 77-3 summarizes the measures selected by this process. Although these are recommendations for research contexts, they serve as a useful guide for clinicians to select from the vast array of instruments available. In this section a step-by-step guide to the completion of a clinical assessment of an insomnia patient is provided. Obtaining information via a multiple-method approach that includes using established interviews and questionnaires is recommended. The goal is to establish a diagnosis and a formulation and to obtain sufficient information to
CHAPTER 77 • Insomnia: Diagnosis, Assessment, and Outcomes 839
Box 77-1 Quick Assessment Guide Circumstances Surrounding Onset Age of onset Precipitating event(s) Sudden or gradual onset Duration Type Ongoing difficulty getting to sleep (obtain time estimate) Ongoing difficulty staying asleep (obtain time estimate) Ongoing difficulty waking up too early (obtain time estimate) Ongoing difficulty waking up and feeling that the sleep obtained is not restorative (obtain time estimate) Severity, Frequency, and Course Every night Episodic Specific nights Specific situations Seasonal variation Daytime Consequences Fatigue Sleepiness Napping Cognition, performance, and mood Past Treatments Type Adequacy of trial Efficacy Factors That Ameliorate Sleep in nonhabitual environments Sleep before a day with no commitments Other factors Factors That Exacerbate Sleep on Sunday nights Anxiety when seeing the clock at night Other factors Medical Factors Pain, discomfort Treatments that interfere with sleep Pharmacologic Considerations Activating drugs or sedating drugs that break down the regularity of the sleep–wake cycle Side effects History of using hypnotics Psychiatric Factors Key Features of Depression Mood • Sadness • Crying • Inability to enjoy oneself • Irritability • Reduced motivation • Diurnal mood variation (worse in the morning) Cognitive features • Reduced attention and concentration • Reduced speed of processing
• Preoccupations • Guilt • Hopelessness • Helplessness • Worthlessness • Catastrophic thinking Physiologic features • Reduced or increased appetite • Diminished sex drive • Poor sleep • Early morning awakening • Psychomotor agitation or lethargy • Increased fatigue Other features • Social withdrawal • Suicidal thoughts, intentions, plans, and attempts Key Features of Anxiety Exaggerated worry Tension and irritability Restlessness Headaches Trembling Sweating Sleep disturbance Work Factors Stress Work schedule incompatible with sleep schedule Family and Social Factors Stressful life events (past stressful events may be precipitants, and present stressful events may be perpetuators). Childhood habit of staying up late • With a parent who was a “night owl” • Waiting for a parent to return from late night drinking, etc. Comorbid Sleep Disorders Periodic limb movement disorder (movements, particularly legs, during sleep) Sleep apnea (snoring, daytime sleepiness) Restless legs syndrome (sensory discomfort/restlessness in limbs when sedentary) Perpetuating Factors Behavioral Practices intended to improve sleep • Going to bed early • Staying in bed late • Increasing time in bed • Falling asleep with TV or radio left on • Staying in bed during awakenings • Getting extra sleep during the weekends Practices intended to counter fatigue • Napping, dozing • Increasing caffeine ingestion • Lying down to rest • Decreasing physical activity Cognitive Anxiety • Worry about consequences of insomnia (fatigue, performance deficits, health, appearance) Continued
840 PART II / Section 10 • Insomnia Box 77-1 Quick Assessment Guide—cont’d • Worry about sleeplessness (“I’ll never get to sleep tonight”) • Worry about the self (“I’m not together, I can’t even sleep like a normal person,” “My sleep is out of control, just like my life”) False beliefs • Misconceptions about sleep (“Everybody sleeps 8 hours,” “I can’t function on less than 7 hours of sleep”) • Catastrophizing (“Insomnia is ruining my life”)
• Requirements for sleep (“I cannot sleep without sleeping pills,” “I must sleep alone”) Other • Alcohol • Noise • Pets sleeping in the same bed • Clock watching during the night • Getting home late without enough time to wind down
Table 77-1 Key features of ICSD-2 Insomnia Diagnoses INSOMNIA DIAGNOSIS
KEY FEATURES
307.41 Adjustment sleep disorder
Associated with a specific stressor
307.42 Psychophysiologic insomnia
Heightened arousal and learned sleep-preventing associations
307.42 Paradoxical insomnia
Subjective report of severe sleeplessness not congruent with the absence or minor degree of daytime impairment
327.02 Insomnia due to a mental disorder
Associated with mental disorder, but the insomnia constitutes a distinct complaint
307.42 Idiopathic insomnia
Onset in infancy or early childhood
V69.4 Inadequate sleep hygiene
Associated with activities that are inconsistent with optimal sleep
V69.5 Behavioral insomnia of childhood
The result of inappropriate sleep associations or inadequate limit setting
292.85 Insomnia due to a drug or substance
Disruption to sleep due to a drug or substance (prescribed, over-the-counter, or recreational)
327.01 Insomnia due to a medical condition
Associated with a coexisting medical disorder or other physical issue
780.52 Insomnia not due to a substance or physiologic condition, unspecified
Unable to be classified elsewhere but suspected to be associated with a mental disorder, psychological factor, or sleep-disruptive practice
327.00 Physiologic (organic) insomnia, unspecified
Unable to be classified elsewhere but suspected to be associated with a medical disorder, physiologic state, or substance
Table 77-2 Diagnostic Coding of Subtypes of Insomnia ICSD-2* INSOMNIA CATEGORIES
DSM-IV-TR† INSOMNIA CATEGORIES
307.41 Adjustment sleep disorder
307.42 Primary insomnia
307.42 Psychophysiologic insomnia
307.42 Primary insomnia
307.42 Paradoxical insomnia
307.42 Primary insomnia
307.42 Idiopathic insomnia
307.42 Primary insomnia
327.02‡ Insomnia due to a mental disorder
307.42 Insomnia related to another mental disorder
V69.4 Inadequate sleep hygiene V69.5 Behavioral insomnia of childhood 292.85 Insomnia due to a drug or substance
292.89 Substance-induced sleep disorder, insomnia type
327.01‡ Insomnia due to a medical condition
780.52 Sleep disorder due to a general medical condition, insomnia type
780.52 Other insomnia not due to a substance or physiological condition, unspecified 327.00 Organic insomnia, unspecified *American Academy of Sleep Medicine. International classification of sleep disorders (ICSD): diagnostic and coding manual, 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005. † American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed, text rev. Washington, DC: American Psychiatric Association; 2000. ‡ Code the primary condition first and the insomnia second (e.g., dysthymic disorder, 300.4, Insomnia due to a mental disorder, 327.02). Alternatively, one of the following codes may be used: ICD-10 Insomnia Categories,3 F51.0 Nonorganic sleep disorders, G47.0 Organic sleep disorders.
CHAPTER 77 • Insomnia: Diagnosis, Assessment, and Outcomes 841
Table 77-3 Recommended Research Measures for Insomnia6 DIAGNOSIS
MEASURES
NO. OF ITEMS
FORMAT
Disorders Insomnia and other sleep disorders
Clinical history or questionnaire for sleep disorders using ICSD-2 criteria Clinical history or questionnaire for Research Diagnostic Criteria for Insomnia (RDC-I)
Psychiatric disorders
Structured interview (SCID I)34 or psychiatric history or questionnaire
Medical disorders
Medical history or questionnaire
Current medications and substances
List of medications (history, participantgenerated list)
Sleep and Insomnia Symptoms Global sleep and insomnia symptoms
Pittsburgh Sleep Quality Index35
24
Severity and frequency ratings, symptom checklists, global score, and subscale scores
Insomnia Severity Index36
15
Severity ratings, symptom checklists
20
Five subscales: General fatigue, physical fatigue, mental fatigue, reduced motivation, and reduced activity
Daily self-report of sleep
Sleep diary
Objective sleep
Screening PSG PSG as dependent measure
Rest–activity pattern
Actigraphy
Waking Correlates and Consequences of Insomnia Fatigue
Multidimensional Fatigue Inventory37
9
or Fatigue Severity Scale38 Mood
Quality of life and function
Total score
Inventory of Depressive Symptomatology39
30
Severity ratings, total score
Beck Depression Inventory II40
21
Severity ratings, total score
State-Trait Anxiety Inventory41
40
State and trait anxiety, total score
SF-3642
36
Grouped into eight dimensions
PSG, polysomnography.
devise a treatment plan. Devising a treatment plan involves identifying the chain of factors that contribute to insomnia. If the context allows, ideally the assessment should begin before the first visit. It can be expedient and helpful to send some of the questionnaires, as well as the sleep diary, to be completed before the first meeting. At the outset it can be valuable to warn the patient that the assessment will be comprehensive, detailed, broad and potentially personal. Theoretical Guide The 3P model,7 also referred to as the three-factor or Spielman model, is a heuristic device around which to guide an assessment of insomnia. The 3P model is a diathesis-stress model that includes predisposing, precipitating, and perpetuating factors (Fig. 77-1). The predisposing factors can be biological (e.g., regularly elevated cortisol),
psychological (e.g., tendency to worry) or social (e.g., work schedule incompatible with sleep schedule). Precipitating factors, such as stressful life events, then trigger the acute onset of insomnia. Perpetuating factors, such as maladaptive coping skills or an extension of time in bed, can then contribute to the acute insomnia’s developing into a chronic or longer-term disorder. Within this framework, predisposing factors represent a constant vulnerability for insomnia. Precipitating factors trigger acute insomnia, but the influence of these factors diminishes over time, whereas perpetuating factors then come into play and serve to maintain the insomnia. The perpetuating factors are typically the targets of treatment. Developing hypotheses about the predisposing, precipitating and perpetuating factors will help the clinician weave the connections between the premorbid picture of sleep, the initial insomnia, changes over time, and the current sleep disturbance. An appreciation of the blend of predisposing, triggering, and perpetuating factors will also
Insomnia severity
842 PART II / Section 10 • Insomnia
complex interplay of behavioral, emotional, cognitive, and biologic factors. More detail on the assessment of each of these potential contributors is provided later.
Perpetuating Precipitating Predisposing e.g., naps Insomnia threshold
e.g., stress
e.g., arousal Time
Figure 77-1 The 3P model: Predisposing, precipitating, and perpetuating factors contributing to insomnia over time.
help with selecting a set of interventions that address different components of the problem. Developmental, Social, and Cultural Context It is easy to be so focused on intraindividual factors that the complex nature of the sleeping environment can be neglected. Sleep always occurs in a developmental, social, and cultural context that has a unique meaning or appraisal for each patient.7a The age of the patient can reveal possible developmental challenges and identify parts of the assessment discussed later that will need to be emphasized. For example, among older adults, the assessment of medical conditions and the possible contribution of medication use to the insomnia must be considered. Among adults in their middle years, the sleeping context of possibly sharing the bed or having their sleep interrupted by infants or children might need to be considered, and the stress of managing career, financial pressure, and family responsibilities may be critical. In young adults studying at university, a lateto-bed and late-to-rise sleep habit may be a contributor. And as young adults make the transition from school to their first full-time employment, a discrepancy between bedtime and wake times on weekdays and weekends can create a vicious cycle culminating in severe insomnia. Clinical Interview Focusing on the Night S LEEP H ISTORY The sleep history is also a time to begin to obtain information about predisposing, precipitating, and perpetuating factors. There is surprisingly little research delineating the factors that predispose people to insomnia. A short selfreport questionnaire has been developed and tested that predicts the vulnerability to stress-related insomnia in persons not complaining of insomnia. The Ford Insomnia Response to Stress Test (FIRST) is composed of nine Likert-type questions that have been shown to predict sleep disturbance on the first night in the laboratory, increased difficulty falling asleep when challenged by caffeine, and higher sleep latencies on a multiple sleep latency test (suggesting hyperarousal).8,9 In terms of precipitating factors, Bastien and colleagues10 have reported the most common precipitants to be family, health, and work or school events. The perpetuating factors typically include a
C URRENT S LEEP It can be valuable to take both a wide-lens and a focusedlens approach to the assessment of the current sleep schedule. The wide-lens approach is a broad overview and involves asking patients to retrospectively recall their sleep before it became a problem. Typically the focus is on the past week or the past month. The focused lens approach concentrates more specifically on a particular typical night of insomnia. The broad overview starts by determining which of the following is the patient’s predominant complaint: not enough sleep, trouble falling asleep, difficulty staying asleep, early morning awakening, light or nonrefreshing sleep, inability to sleep without sleeping pills, or sleep that is unpredictable. Then the interview moves becomes more specific by obtaining information about the frequency of nights of insomnia and the night-to-night variability.11 There are several other topics to systematically work through. Sleep topics include the time the patient retires to bed (many patients go to bed very early in an attempt to maximize the amount of sleep they obtain), the activities engaged in once in bed, the time of lights out and how the decision to turn the lights out is made, and sleep-onset latency (the difference between the time of lights out and the time of falling asleep). Waking topics include the number, timing, and duration of awakenings and the experience of awakenings, particularly any distress experienced and how the patient copes. Wake-up time could be determined by environmental disturbances and can be variable or unvarying, which suggests a circadian component to the insomnia. Out of bed time should be examined: Does the patient linger in bed and occasionally fall back to sleep? If so, this suggests poor sleep hygiene. Determine total sleep time: Does it vary on the weekdays versus the weekends? If so, this gives a clue that work stress may be contributing or that circadian factors such as a delayed sleep phase may need to be considered.11 In addition, an appreciation of what sleep and daytime functioning were like before the onset of the sleep problem provides a comparison for assessing response to treatment. The focused-lens approach involves a detailed functional analysis of a typical recent night. The goal is to build up a picture of how various emotional, behavioral, and cognitive processes are linked to, and feed into, one another.12 It essentially involves a detailed discussion of a recent, specific, typical night of poor sleep. A very specific episode is a situation that happened on one particular day (e.g., last Monday) and at a particular time (e.g., while trying to get to sleep). Focusing on this night, spend a few minutes asking questions to start to get an idea of the contexts, such as: “How was your day?” and “What had you been doing in the evening?” These questions help to determine antecedents or events that might have had a bearing on the insomnia experienced that night (e.g., conflict with spouse, late exercise session). Then obtain a very detailed description of exactly what happened and the consequences of it. By working through the events and the corresponding thoughts, feelings, and activities across a
CHAPTER 77 • Insomnia: Diagnosis, Assessment, and Outcomes 843
night, a vicious cycle can be drawn out demonstrating their contribution to the insomnia.12
tronic options are available15 that can increase efficiency and accuracy (because the data are time stamped, ensuring the diary really is completed each morning). The instructions given to the patient for completing the diary emphasize that it is important to complete the diary every morning soon after waking. When reviewing a completed diary, observe the type of sleep difficulty. For example, Figure 77-2A was completed by a patient with a sleep-onset and a wake-aftersleep-onset problem. Figure 77-2B was completed by a patient who has a tendency toward a delayed phase (bedtimes in the early hours of the morning). Other features to watch for include bedtimes that are very late at night, advanced phase (early bedtimes before 9 pm, for example), and variability in sleep across days (especially between weekdays and weekends). It is also helpful and informative for eliciting perpetuating factors to ask questions to ascertain the circumstances surrounding particularly difficult nights. The enhanced awareness arising from self-monitoring can have a therapeutic effect.16 Following several days of diary keeping patients can realize, from their written records, that they obtained more sleep than they initially thought and thus they became less anxious about their sleep problem, which in turn creates a psychological state that is more conducive to sleep. Other patients, through
QUESTIONNAIRE MEASURES
As indicated in Table 77-3, two questionnaires have been recommended as measures of global sleep and insomnia symptoms. The Pittsburgh Sleep Quality Index surveys the last month and the Insomnia Severity Index surveys the past week. These are both efficient and valuable measures for assessing the severity of insomnia. They are also sensitive to improvement following treatment.13 SLEEP DIARY
The sleep diary is perhaps the most helpful tool for assessing the current sleep problem. Several options are available. The need for a standard sleep diary has been recognized and is being addressed by a work group of experts in the field.14 The sleep diary is less influenced by the nuances of failures in memory and information processing biases. In retrospective reports that require patients to average over the past week or past month, the depiction will be inadvertently influenced by the most salient and the most recent nights. Recording sleep in a daily sleep diary, completed immediately on waking, can overcome this limitation. The completion of a paper version is inexpensive and easy to use, but increasingly Web-based and elec-
In the morning, fill out the information for the prior night...
Tuesday 3/25
/
/
/
/
/
/
/
1. Yesterday, I napped from ____ to ____ (Note the times of all naps)
13:50 to 14:30
13:30– 14:00
—
—
—
—
—
—
2. Yesterday, I took ___ mg of medication and/or ___ oz of alcohol as sleep aid.
Halcion 0, 125 mg
—
—
—
—
—
—
—
3. Last night, I went to bed and turned the lights off at ___ o’clock (AM or PM).
22hr 45 23hr 15
23:30 23:55
23:00 23:25
23:00 23:20
22:33 23:03
22:43 23:02
22:30 00:05
22:03 22:30
4. After turning the lights off, I fell asleep in ____ minutes.
40 min
45
30
45
75
10
20
5
5. My sleep was interrupted ____ times (specify number of nighttime awakenings).
3
2
1
2
4
1
3
1
6. My sleep was interrupted for ___ minutes (specify duration of each awakening).
10 5 45
15 25
10
15 30
10 15 30 15
30
10 20 40
30
7. Last night, I left my bed ____ times.
3
1
—
1
2
1
1
1
6:15
3:47
4:24
3:48
5:02
5:13
5:21
5:41
6:30
7:00
7:00
7:00
—
—
7:00
6hr 40
6:38
7:13
7:01
7:15
7:45
8:12
7:13
11. When I got up this morning I felt ____ (answer on a 1 to 5 scale; 1 = exhausted, 5 = refreshed).
2
1
1
1
1
3
2
3
12. Overall, my sleep last night was ____ (answer on a 1 to 5 scale; 1= restless, 5 = very sound).
3
1
1
1
1
3
1
3
night mo/day
8. This morning, I actually awoke at ___ o’clock (note time of last awakening). 9. This morning I had planned to wake up at ___ o’clock AM or PM (or leave blank if you did not plan a specific time). 10. This morning, I actually got out of bed at ___ o’clock (specify the time).
A
Figure 77-2 Sleep diaries. A, Sleep-onset latency and wake-after-sleep-onset problem. Continued
844 PART II / Section 10 • Insomnia
In the morning, fill out the information for the prior night...
night mo/day
Tuesday 3/25
/
/
/
/
/
/
/
1. Yesterday, I napped from ____ to ____ (Note the times of all naps)
13:50 to 14:30
—
—
12:00–1:00
—
—
—
—
2. Yesterday, I took ___ mg of medication and/or ___ oz of alcohol as sleep aid.
Halcion 0, 125 mg
0
0
0
0
0
0
0
3. Last night, I went to bed and turned the lights off at ___ o’clock (AM or PM).
22hr 45 23hr 15
11
1:00
3:30
12:00
3:00
2:00
1:00
PM
AM
AM
AM
AM
AM
AM
4. After turning the lights off, I fell asleep in ____ minutes.
40 min
1hr 40
40
25
20
30
40
30
5. My sleep was interrupted ____ times (specify number of nighttime awakenings).
3
4
2
1
3
2
5
1
6. My sleep was interrupted for ___ minutes (specify duration of each awakening).
10 5 45
35
30
10
20
20
30
20
7. Last night, I left my bed ____ times.
3
2
1
1
1
2
2
1
6:15
8 AM
8 AM
10 AM
9 AM
11 AM
9 AM
8 AM
8 AM
8 AM
10 AM
9 AM
11 AM
9 AM
8 AM
8:30
8:30
10:05
9:10
12:00
9:20
8:30
AM
AM
AM
AM
PM
AM
AM
8. This morning, I actually awoke at ___ o’clock (note time of last awakening). 9. This morning I had planned to wake up at ___ o’clock AM or PM (or leave blank if you did not plan a specific time). 10. This morning, I actually got out of bed at ___ o’clock (specify the time).
B
6hr 40
PM
11. When I got up this morning I felt ____ (answer on a 1 to 5 scale; 1 = exhausted, 5 = refreshed).
2
1
1
1
2
1
1
2
12. Overall, my sleep last night was ____ (answer on a 1 to 5 scale; 1= restless, 5 = very sound).
3
2
3
1
1
1
1
1
Figure 77-2, cont’d B, Inadequate opportunity to sleep.
keeping the diary, realize that they sleep worse when their sleep schedule is irregular, which leads them to make a schedule adjustment, which in turn improves sleep. It is helpful to ask the patient to continue to complete the diary across the course of treatment as a means of monitoring progress and adjusting treatment recommendations. Keep in mind that the diary questions can be individualized on the basis of issues discovered during the clinical assessment that are to be targeted in treatment (e.g., for some patients, add questions about daytime energy levels). Focusing on the Day Evidence is accruing from qualitative and quantitative studies indicating the importance of daytime symptoms to the experience of insomnia.17,18 The daytime impairments fall into several broad categories: fatigue, sleepiness, impaired performance, mood disturbance, decreased motivation, and anxiety. The daytime consequences can be more severe than one would expect from the degree of nighttime disturbance, which has led to questions about whether inadequate sleep is the only determinant of the daytime symptoms. Indeed, correlational research has indicated associations between psychological variables and impaired daytime functioning19 and theoretical discussions specifically highlight a role for behavioral, cognitive, and emotional factors that amplify daytime distress in insomnia.16,20,21
The sleep history interview should include an assessment of daytime functioning. Also, using the methods just discussed, taking a wide lens as well as a focused lens to the assessment of current daytime functioning yields helpful information for identifying daytime perpetuating factors and for planning the intervention. In addition, the Pittsburgh Sleep Quality Index (PSQI) and the Insomnia Severity Index (ISI) include questions on daytime functioning. Table 77-3 also lists a number of measures of specific domains of daytime functioning to assess: fatigue, mood, and quality of life and function. It can also be helpful to devise a diary to be completed before bedtime that asks questions about daytime functioning. Comorbid Disorders Comorbid Psychiatric Disorders Insomnia is commonly comorbid with a range of psychiatric disorders. Insomnia is explicitly listed in the DSMIV-TR as a symptom in 18 disorders (Box 77-2 lists some of the most common comorbid psychiatric disorders). Moreover, although insomnia is not listed as a formal symptom, it is a known common feature of a range of other psychiatric disorders including social phobia, panic disorder, autism, chronic pain, and the eating disorders. Rates of comorbidity between insomnia and psychiatric disorders among those presenting to a health facility average 53%, and among community samples the average is 42%.22 The rates of co-occurrence are even higher when
CHAPTER 77 • Insomnia: Diagnosis, Assessment, and Outcomes 845
Box 77-2 Medical and Psychiatric Conditions Commonly Comorbid with Insomnia Medical Conditions* Comorbid sleep disorders (e.g., sleep apnea, restless legs syndrome, periodic limb movement) Neurologic (e.g., headache, stroke, seizure disorders, brain injury, dementia, Parkinson’s disease) Cardiovascular (e.g., angina, congestive heart failure) Reproductive (e.g., pregnancy, menopause) Pulmonary (e.g., asthma, emphysema) Digestive (e.g., irritable bowel syndrome, peptic ulcer) Arthritis and other musculoskeletal disorders Endocrine disorders (e.g., diabetes mellitus) Nocturia, incontinence, enuresis and other genitourinary disorders Psychiatric Conditions Mood disorders • Major depressive disorder • Dysthymic disorder • Bipolar disorder • Seasonal affective disorder Anxiety disorders • Generalized anxiety disorder • Posttraumatic stress disorder (nightmares and flashbacks of the trauma while trying to sleep) Attention-deficit/hyperactivity disorder Eating disorders • Bulimia nervosa • Anorexia nervosa Adjustment disorder Personality disorder *Adapted from Schutte-Rodin S, Broch L, Buysse DJ, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med 2008;4:487-504.
subthreshold yet clinically significant insomnia is recognized. A widely held assumption is that insomnia is secondary to, or an epiphenomenon of, the so-called primary psychiatric disorder. Consequently, complaints of insomnia have tended to be dismissed or regarded as trivial by both patients and their caregivers or, at most, seen as a byproduct of the coexisting disorder. In contrast, evidence is accruing to indicate that insomnia is an important but underrecognized mechanism in the multifactorial cause and maintenance of psychiatric disorders23,24 and, when present, should be targeted in treatment. The value of this approach is illustrated by studies comparing depressed patients who are treated only for their depression (with an antidepressant) versus depressed patients who are treated for both the depression (with an antidepressant) and the insomnia (with either a hypnotic or cognitive behavior therapy for insomnia). The combined approach was superior for both depression and insomnia outcomes.25 Current research standards recommend that comorbid psychiatric disorders be assessed with the Structured Clinical Interview for Diagnosis (SCID) or a psychiatric history along with questionnaire measures of mood such as the
Inventory of Depressive Symptomatology or the Beck Depression Inventory II and the State Trait Anxiety Inventory (see Table 77-3). Comorbid Sleep Disorders Patients with periodic limb movement disorder (PLMD) commonly present with symptoms of insomnia such as trouble staying asleep and nonrestorative sleep. Those affected can have hundreds of movements or brisk extensions of the feet during the night; it is not uncommon for these movements to be associated with a hundred or more brief arousals. On occasion, a limb movement produces a shift to a full awakening. Therefore, the patient is usually unaware of these limb movements. The clinician needs to infer their presence from the bed partner’s report, for example that the patient is a restless sleeper or kicks during the night. Of course, overnight polysomnographic testing provides objective evidence of PLMD, but insurance reimbursement limitations can preclude ordering a sleep study to investigate clinical suspicion of the disorder. Therefore, in many cases PLMD underlying a complaint of insomnia might remain covert. Research has shown that an arousal (cortical or subcortical) might precede the leg movement.26 This suggests that it is not the limb movement that shakes the sleeper awake but rather that the ascent from sleep toward waking is primary. Restless legs syndrome (RLS) is a complaint of sensory discomfort or restlessness in the limbs (usually the legs) when sedentary. It commonly becomes more pronounced in the evening, and it is relieved by movements such as walking, tapping or stretching. In some RLS patients the discomfort is sufficient to interfere with falling asleep. Therefore, when these patients complain of sleep-onset insomnia, the culprit is clear. Although the vast majority of patients with obstructive sleep apnea and other sleep-related breathing disorders chiefly complain of sleepiness, some report trouble sleeping as a prominent problem. Anecdotal evidence suggests that early in the course of the development of sleep-related breathing disorders, trouble sleeping is more likely to be experienced compared to when these disorders have become firmly established. Comorbid Medical Disorders A list of some of the most common comorbid medical conditions is summarized in Box 77-2. Pain, discomfort, and treatment side effects of medical disorders are often problematic for sleep, and therefore an assessment of medical history, current health, and medication use is essential. For medications, obtain information about the type, amount, time of administration, frequency of use, side effects, withdrawal effects on discontinuation, and degree of drug tolerance. A physical examination has been recommended as part of the routine evaluation of insomnia, especially to detect comorbid disorders. When taking a history of hypnotic use be sure to ask how and when they decide to take the medication. If the patient starts the night by trying to fall asleep without a sleeping pill and then lies in bed worrying about whether or not sleep will come and whether or not to take a pill, the patient might wait several hours and then take a pill and then suffer sedating effects on waking.
846 PART II / Section 10 • Insomnia Table 77-4 Measures of Perpetuating Factors SCALE NAME (SOURCE)
NO. OF ITEMS
FORMAT
Beliefs about Sleep 30
Beliefs and Attitudes about Sleep Scale43 Sleep Locus of Control Scale
8
44
Visual analogue scale Six-point ratings of truth of statements
Sleep-Incompatible Behavior Sleep Behavior Self-Rating Scale45
20
Frequency ratings
Sleep Behavior Self-Rating Scale-Revised46
27
Frequency ratings
Sleep Hygiene Awareness and Practice Scale47
31+
Frequency and effect on sleep ratings
Sleep Hygiene Questionnaire48
10
Yes/no
Sleep Hygiene Index49
13
Frequency ratings
Pre-Sleep Arousal Scale50
16
Five-point severity ratings
Arousability Predisposition Scale51
12
Frequency ratings
Sleep Disturbance Questionnaire52
12
Five-point severity ratings
Sleep Disturbance Questionnaire52
12
Five-point severity ratings
Pre-Sleep Arousal Scale53
16
Five-point severity ratings
Sleep Hygiene
Arousal
Worry, Managing Thoughts
Anxiety and Preoccupation about Sleep Questionnaire
10
Ten-point ratings of truth of statements
Thought Control Questionnaire55
35
Four-point frequency ratings
Glasgow Content of Thought Inventory56
25
Four-point frequency ratings
30
Five-point ratings of truth of statements
54
Attentional Bias Sleep Associated Monitoring Index57 Sleep Effort Glasgow Sleep Effort Scale58
7
Frequency ratings
Safety Behavior Sleep-Related Behaviors Questionnaire59
Perpetuating Factors Up to this point in the clinical assessment, the assessor will have already developed hypotheses about potential perpetuating factors. In addition, a combination of questionnaire measures and a detailed functional analysis is recommended (described earlier as the focused lens approach). Table 77-4 summarizes some of the most commonly used questionnaire measures to identify perpetuating factors. Questionnaires rely on the assumption that patients can accurately introspect about and report what can be very subtle phenomena. Thus, skilled questioning and setting self-monitoring tasks must supplement the questionnaire assessment of perpetuating factors. The sleep diary is of course a self-monitoring questionnaire that is invaluable for detecting perpetuating factors (e.g., going to bed too early). Testing Polysomnography Because the diagnosis of insomnia relies solely on a subjective complaint, PSG is not needed or recommended for the standard evaluation of insomnia.27 However, PSG
58
Five-point ratings of truth of statement
should be conducted for patients who report symptoms of other sleep disorders (e.g., periodic limb movement disorder, sleep-disordered breathing) or who do not respond to standard insomnia treatment. In the latter case a comorbid sleep disorder may be present but covert, especially when there is no bed partner who can observe and complain about the symptoms. Major limitations include expense and discomfort. Hence PSG is typically only conducted for 1 or 2 nights. Given that most of the diagnostic criteria for insomnia require 3 or 4 nights of insomnia per week, it is possible that PSG inadequately captures the sleep problem. Moreover, in some cases sleeping in the laboratory can exaggerate sleep problems—the first night effect—or, in other cases, can result in better sleep than the patient typically gets at home—the reverse night effect. The latter may be explained by removing the patient from his or her bedroom, an environment that has become associated with anxiety and not sleeping. Actigraphy An alternative objective assessment of sleep is the use of actigraphy. Actigraphy has increasingly been employed in
CHAPTER 77 • Insomnia: Diagnosis, Assessment, and Outcomes 847
an attempt to overcome shortcomings associated with PSG. Actigraphs are wristwatch-like devices that provide an estimate of the sleep–wake cycle via movement detectors (accelerometers). Within is a sensor, a processor, and sufficient memory to record for up to several weeks. The processor samples physical motion and translates it to digital data. It summarizes the frequency of physical motions into epochs of specified time duration and stores the summary in memory. These data are then downloaded, and automatic scoring methods (algorithms) are used to derive levels of activity and inactivity and to generate various sleep–wake parameters. Relative to PSG, actigraphy is considerably less expensive and less intrusive, and it provides the opportunity to continuously monitor patients over long time periods in their normal environment. According to two comprehensive reviews by the American Sleep Disorders Association,28,29 actigraphy is considered a useful and acceptable instrument to measure sleep–wake schedule and sleep quality. Actigraphy is appropriate for examining sleep variability (i.e., night-to-night variability) in patients with insomnia.29,30 Although there is considerable evidence validating actigraphy in normal sleepers, data that test the validity of actigraphy for patients with chronic insomnia are lacking. This is important, because accuracy may be lower for insomnia patients because they can lie still for long periods without sleeping. However, two studies have reported preliminary promising data,31,32 although both reports emphasize that the type of actigraph and the scoring algorithm used can result in substantial scoring differences. Another study indicated that increasing the number of nights recorded improves the reliability of actigraphy in insomnia samples.33 As for the sleep diary, the actigraphy record can be used to observe the type of sleep difficulty. For example, Figure 77-3 was completed by a patient with a wake-after-sleeponset problem. It can also be useful to compare the sleep diary and the actigraphy record for evidence of paradoxical insomnia (an insomnia complaint without evidence of objective sleep disturbance).
TREATMENT OUTCOME Detailed recommendations for reporting the outcome of treatment for insomnia have been offered by Buysee and colleagues.6 Although these are focused on reporting the outcome of research studies, they are also useful for monitoring and reporting outcomes in clinical practice.
Changes to diagnostic status should be noted. Specifically, does the patient continue to meet criteria for insomnia? Quantitative improvement to sleep should be reported via the change in scores on the PSQI or the ISI, as well as by reporting pretreatment and posttreatment sleep parameters scored from the sleep diary. The latter should include bedtime, final wake time, arising time, sleep-onset latency (how many minutes it takes to fall asleep, starting from the moment of intention to fall asleep), number of awakenings (excluding the final awakening before the final arising), wake after sleep onset (total amount of time awake during the night, excluding sleep-onset latency and terminal wake time), terminal wake time (amount of awake time between the final awakening and the time of getting out of bed), total sleep time, sleep efficiency (calculated as total time asleep divided by total time in bed × 100), sleep quality (typically a rating from −5 [poor sleep quality] to +5 [good sleep quality]), the timing and duration of naps or daytime sleep episodes, and the day-to-day variability of each of these measures. Quantitative improvement to daytime functioning should be reported relative to pretreatment levels, which may have included measures of fatigue, mood, or quality of life and functioning (listed in Table 77-3). Also, reviewing changes to the items assessing daytime functioning on the PSQI and the ISI can be very informative.
SUMMARY The development of the field of sleep disorders since the 1980s has helped shape a refined understanding of insomnia and its determinants. Standardized diagnostic schemes, a heuristic model of insomnia, and widely used assessment techniques have begun to create a shared view of and approach to insomnia. This chapter provides the reader with the concepts and tools needed to perform a comprehensive and useful evaluation of the insomnia patient.
❖ Clinical Pearl A thorough evaluation that identifies predisposing, precipitating, and perpetuating factors (the 3Ps) of insomnia helps establish a valid diagnosis. In addition, a refined focus on perpetuating factors identifies both major and minor contributions to the current sleep disturbance. Addressing the perpetuating features produces rapid improvement, and attention to all three targets creates a comprehensive treatment approach that improves sleep for the long term.
REFERENCES 12:00 AM
6:00 AM
Figure 77-3 Actigraphy: Wake-after-sleep-onset problem.
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30. Sadeh A, Acebo C. The role of actigraphy in sleep medicine. Sleep Med Rev 2002;6(2):113-124. 31. Jean-Louis G, Zizi F, von Gizycki H, Hauri P. Actigraphic assessment of sleep in insomnia: application of the Actigraph Data Analysis Software (ADAS). Physiol Behav 1999;65:659-663. 32. Lichstein KL, Stone KC, Donaldson J, et al. Actigraphy validation with insomnia. Sleep 2006;29:232-239. 33. Van Someren E. Improving actigraphic sleep estimates in insomnia and dementia: how many nights? J Sleep Res 2007;16:269-275. 34. First MB, Gibbon M, Spitzer RL, Williams JBW. Structured Clinical Interview for DSM-IV Axis I Disorders SCID I: clinician version, administration booklet. Washington, DC: American Psychiatric Press, 1997. 35. Buysse DJ, Reynolds CF 3rd, Monk TH, et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28(2):193-213. 36. Bastien CH, Vallieres A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med 2001;2(4):297-307. 37. Smets EM, Garssen B, Bonke B, De Haes JC. The Multidimensional Fatigue Inventory (MFI) psychometric qualities of an instrument to assess fatigue. J Psychosom Res 1995;39(3):315-325. 38. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989;46(10): 1121-1123. 39. Rush AJ, Gullion CM, Basco MR, et al. The Inventory of Depressive Symptomatology (IDS): psychometric properties. Psychol Med 1996;26(3):477-486. 40. Beck AT, Steer RA, Ball R, Ranieri W. Comparison of Beck Depression Inventories-IA and -II in psychiatric outpatients. J Pers Assess 1996;67(3):588-597. 41. Spielberger CD, Gorsuc R, Lushene RE. Manual fro the state-trait anxiety inventory. Palo Alto, CA: Consulting Psychologists Press; 1970. 42. Ware JE, Snow KK, Kosinski M. SF-36 health survey: manual and interpretation guide. Boston: Health Institute, New England Medical Center; 1993. 43. Morin CM. Insomnia: psychological assessment and management. New York: Guilford Press; 1993. 44. Vincent N, Sande G, Read C, Giannuzzi T. Sleep locus of control: report on a new scale. Behav Sleep Med 2004;2:79-93. 45. Kazarian SS, Howe Mg, Csapo KG. Development of the Sleep Behavior Self-Rating Scale. Behav Ther 1979;10:412-417. 46. Kohn L, Espie CA. Sensitivity and specificity of measures of the insomnia experience: a comparative study of psychophysiologic insomnia, insomnia associated with mental disorder and good sleepers. Sleep 2005;28:104-112. 47. Miles I. Sleep Questionnaire and Assessment of Wakefulness (SQAW). In: Guilleminault C, editor. Sleeping and waking disorders: indications and techniques. Menlo Park, CA: Addison–Wesley; 1982. p. 384-413. 48. Lacks P. Behavioral treatment for persistent insomnia. New York: Pergamnon Press; 1987. 49. Mastin DF, Bryson J, Corwyn R. Assessment of sleep hygiene using the Sleep Hygiene Index. J Behav Med 2006;29:223-227. 50. Nicassio PM, Mendlowitz DR, Fussell JJ, Petras L. The phenomenology of the pre-sleep state: the development of the pre-sleep arousal scale. Behav Res Ther 1985;23(3):263-271. 51. Coren S. Prediction of insomnia from arousability predisposition scores: scale development and cross-validation. Behav Res Ther 1988;26(5):415-420. 52. Espie CA, Brooks DN, Lindsay WR. An evaluation of tailored psychological treatment of insomnia. J Behav Ther Exp Psychiatry 1989;20(2):143-153. 53. Nicassio PM, Mendlowitz DR, Fussell JJ, Petras L. The phenomenology of the pre-sleep state: the development of the pre-sleep arousal scale. Behav Res Ther 1985;23:263-271. 54. Tang NK, Harvey AG. Correcting distorted perception of sleep in insomnia: a novel behavioural experiment? Behav Res Ther 2004; 42:27-39. 55. Ree MJ, Harvey AG, Blake R, et al. Attempts to control unwanted thoughts in the night: development of the thought control questionnaire—insomnia revised (TCQI-R). Behav Res Ther 2005;43: 985-998.
CHAPTER 77 • Insomnia: Diagnosis, Assessment, and Outcomes 849
56. Harvey KJ, Espie CA. Development and preliminary validation of the Glasgow Content of Thoughts Inventory (GCTI): a new measure for the assessment of pre-sleep cognitive activity. Br J Clin Psychol 2004;43:409-420. 57. Semler CN, Harvey AG. Monitoring for sleep-related threat: a pilot study of the Sleep Associated Monitoring Index (SAMI). Psychosom Med 2004;66:242-250.
58. Broomfield NM, Espie CA. Towards a valid, reliable measure of sleep effort. J Sleep Res 2005;14:401-407. 59. Ree MJ, Harvey AG. Investigating safety behaviours in insomnia: the development of the sleep-related behaviours questionnaire (SRBQ). Behav Change 2004;21:26-36.
Models of Insomnia
Chapter
Michael Perlis, Paul J. Shaw, Georgina Cano, and Colin A. Espie Up until the late 1990s there were only two models regarding the etiology and pathophysiology of insomnia. The relative lack of theoretical perspectives was due to at least three factors. First, the widespread conceptualization of insomnia as owing directly to hyperarousal may have made it appear that further explanation was not necessary. Second, the long-time characterization of insomnia as a symptom carried with it the clear implication that insomnia was not itself worth modeling as a disorder or disease state. Third, for those inclined toward theory, the acceptance of the behavioral models (i.e., the 3P behavioral model and the stimulus control model1,2), and the treatments that were derived from them, might have had the untoward effect of discouraging the development of alternative or elaborative models. Since the 1990s there has been a proliferation of theoretical perspectives on the etiology and pathophysiology of insomnia that includes ten human models* and three animal models. In this chapter, six models (Box 78-1) are described and critiqued: the classic 3P behavioral model,1 the stimulus control model,2 and four models that are arguably the most influential of the modern perspectives†: the neurocognitive model,3 the psychobiological inhibition model,4 the Drosophila model,5,6 and the cage exchange model.7
THE DEFINITION OF INSOMNIA Currently, insomnia is conceptualized in terms of chronicity, type, and subtype. Chronicity refers to whether the insomnia is acute or chronic. Type refers to the forms of insomnia that have been identified as distinct nosologic entities including (for adults) idiopathic insomnia, psychophysiologic insomnia, paradoxical insomnia, insomnia due to inadequate sleep hygiene, and insomnia comorbid with medical or psychiatric illness. Subtype refers to the insomnia phenotype (initial, middle, late, or mixed insomnia). The formal definition of these entities, and discussion about their orthogonality and clinical utility, may be found elsewhere in this volume. What is relevant for the present chapter is that these diagnostic distinctions exist and thus must be taken into account by the various models; that is, each model must indicate which type of insomnia (and subtype, if pertinent) is being modeled. THE STIMULUS CONTROL MODEL Basic Description Stimulus control, as originally described by Bootzin,2 is based on the behavioral principle that one stimulus may elicit a variety of responses, depending on the conditioning *A complete listing of theories and models, along with citations, is contained in Appendix 1 on the website. † Although it is difficult to assess which models are the most influential, one approach would be based on a citation index metric. Using this index, it does indeed appear that the four contemporary models described in this chapter are the most influential.
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history. A simple conditioning history, wherein a stimulus is always paired with a single behavior, yields a high probability that the stimulus will yield only one response. A complex conditioning history, wherein a stimulus is paired with a variety of behaviors, yields a low probability that the stimulus will yield only one response. In persons with insomnia, the normal cues associated with sleep (e.g., bed, bedroom, bedtime, etc.) are often paired with activities other than sleep. For instance, in an effort to cope with insomnia, the patient might spend a large amount of time in the bed and bedroom awake and engaging in activities other than sleep. The coping behavior appears to the patient to be both reasonable (e.g., staying in bed at least permits the patients to rest) and reasonably successful (engaging in alternative activities in the bedroom sometimes appears to result in cessation of the insomnia). These practices, however, set the stage for stimulus dyscontrol, the lowered probability that sleep-related stimuli will elicit the desired response of sleepiness and sleep. Figure 78-1 provides as schematic representation of stimulus control and stimulus dyscontrol. Strengths and Weaknesses The treatment that is derived from stimulus control theory is one of the most widely used behavioral treatments, and its efficacy has been well established.8-12 The success of the therapy, however, is not sufficient evidence to say that stimulus dyscontrol is the factor, or one of the factors, responsible for predisposition to, the precipitation of, or the perpetuation of insomnia.* This is the case because the therapy includes active components that are not based solely on learning or behavioral theory. For instance, the treatment specifies that the patient should spend awake time somewhere other than the bed and that the sleep schedule should be fixed. These two interventions also influence the homeostatic and circadian regulation of sleep. Thus, the efficacy of stimulus control therapy does not necessarily provide evidence for the stimulus control model. In fact, one investigation found that the reverse of stimulus control instructions also improved sleep continuity.13 Another limitation of the stimulus control perspective is that it focuses solely on instrumental conditioning. That is, there are activities that can be engaged in that reduce or enhance the probability of the occurrence of sleep. The original model does not explicitly delineate how classical conditioning might also be an operational factor. That is, the regular pairing of the physiology of wake with sleeprelated stimuli might lead to a scenario where sleep-related stimuli become conditioned stimuli for wakefulness. This latter possibility, although not part of the classical stimulus control perspective, is clearly consistent with it. *The conceptual time frame for causality in terms of “predisposition, precipitation, and perpetuation” was first articulated as part of the 3P model. It is used in this context to illustrate the complexity of modeling what “causes” insomnia.
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Box 78-1 Potential Implications for Treatment of Insomnia Stimulus Control Model One unexplored implication for treatment is that physically altering the sleep environment may be helpful (e.g., paint the room a different color) Spielman Model The 3P model suggests that insomnia is perpetuated by sleep extension and thus should be managed with treatment protocols that restrict time in bed (i.e., compress the sleep period). One implication for treatment is that sleep compression need not occur in a radical fashion, but could be accomplished over days or weeks.19 Neurocognitive Model The neurocognitive model suggests that patients with insomnia suffer from an attenuation of the normal mesograde amnesia of sleep. One unexplored implication for treatment is that potentiation of the normal mesograde amnesia of sleep via the use of more traditional hypnotics (e.g., benzodiazapines with effects on long-term memory) might serve to augment clinical gains, if not in general, then at least in patients with substantial sleep state misperception. Psychobiological Inhibition Model According to the psychobiological inhibition model, chronic insomnia is less a hyperarousal disorder and more a disorder characterized by the failure to inhibit wakefulness. One implication for treatment is that persistent wakefulness may be the result of hypersecretion of orexin, and thus orexin antagonism might have a place in the management of insomnia. Drosophila Model The Drosophila model suggests that there may be a strong genetic component to insomnia that may be related to reduced sleep ability. One implication of the model is that it, like the 3P model, suggests that sleep opportunity should be a major focus for treatment. Cage Exchange Model The cage exchange model suggests that insomnia represents a hybrid state, one that is, from a neurobiological perspective, part wake and part sleep. One implication for treatment, which has not yet been tested empirically, is that corticotropin releasing hormone antagonist represent an alternative way of alleviating disturbed sleep continuity.
Implications for Current and Future Research and Therapeutics Given the efficacy of stimulus control therapy, as it is classically rendered, it would be useful to determine how much treatment outcome from cognitive behavior therapy (CBT) owes to the manipulation of this factor. One way to assess the relative importance of stimulus control would be as part of a dismantling study. To date no such study has been conducted as a single, large-scale, randomized trial.* Alternatively, experimental studies could be used to
STIMULUS CONTROL Good Stimulus Control
Stimulus Dyscontrol
Odds 1 in 2
Odds 1 in 8 Eat in bed Read in bed Watch TV in bed
Bedroom bedtime
Sex Sleep
Bedroom bedtime
Sex Sleep Work in bed Worry in bed Clean bedroom
Figure 78-1 The instrumental conditioning perspective on stimulus control. Left, Good stimulus control: The bedroom is tightly coupled with sleep and sex where, given the orthogonality and equal probability of events, the probability of association of bedroom to sleep is 1 in 2. Right, Stimulus dyscontrol: The bedroom is no longer a strong associate of sleep and sex where, given the orthogonality and equal probability of events, the probability of association of bedroom to sleep is 1 in 8. The treatment implication of stimulus dyscontrol is the voluntary elimination of the nonsleep associations except for sex, which should result in instrumental conditioning.
determine which, if any, specific stimuli are most associated with sleep continuity disturbance and whether alteration of these stimuli produces enhanced clinical gains.
THE 3P MODEL The 3P behavioral model,1 also known as the Spielman model, the three-factor model, or the behavioral model is the first fully articulated model of insomnia to gain widespread acceptance. The model delineates how insomnia occurs acutely and how acute insomnia becomes chronic and self-perpetuating. The model is based on the interaction of three factors. The first two factors (the predisposing and precipitating factors) represent a stress-diathesis conceptualization of how insomnia comes to be expressed. The third factor (the perpetuating factor) represents how behavioral considerations modulate chronicity. A schematic representation of this model is presented in Figure 78-2. Basic Description Predisposing factors extend across the entire biopsychosocial spectrum. Biological factors are likely to include increased basal metabolic rate, hyperreactivity, and/or fundamental alterations to the neurotransmitter systems associated with sleep and wakefulness.* Psychological factors include *The possibility of altered neurotransmission in insomnia (e.g., reduced GABAnergic tone) was recently explored by Winkelman and colleagues. See SLEEP 31(11)2008:1499-1506.
852 PART II / Section 10 • Insomnia
Perpetuating Precipitating Predisposing
Threshold
Premorbid
Acute
Early
Chronic
Figure 78-2 The classic 1987 rendition of the 3P model. There is a more recent representation of the model in Chapter 144. The reader is encouraged to compare the two versions of the model. The differences (e.g., allowing the predisposing factors to be represent as variable with time), while subtle, are theoretically important.
worry or the tendency to be excessively ruminative. Social factors, although rarely a focus at the theoretical level, include such things as the bed partner keeping an incompatible sleep schedule or social pressures to sleep according to a nonpreferred sleep schedule (e.g., child rearing). Precipitating factors, as the name implies, are acute occurrences that trigger disturbance of sleep disturbance. The primary triggers are thought to be related to life stress events (including medical and psychiatric illness). Perpetuating factors refer to the actions the insomniac person adopts that are intended to compensate for, or cope with, sleeplessness. Research and treatment have focused on three kinds of perpetuating factors: the practice of nonsleep activities in the bedroom, the tendency to stay in bed while awake, and the tendency to spend excessive amounts of time in bed. Stimulus control speaks to the first two of these considerations (as reviewed earlier). The classic version of the 3P model focuses primarily on the last of these considerations. Excessive time in bed (or sleep extension) refers to the tendency of patients with insomnia to go to bed earlier or to get out of bed later or to engage in napping. The patient enacts such changes (compensatory activities) to increase the opportunity to get more sleep; these changes are likely highly self-reinforcing (in the short term) because they allow lost sleep to be “recovered” and the daytime effects of lost sleep to be ameliorated. The tendency toward sleep extension is, in the long term, problematic. Sleep extension leads to a mismatch between sleep opportunity and sleep ability.1,14 The greater the mismatch, the more likely the person will spend prolonged periods wake during the given sleep period, and that this will occur regardless of what predisposed the individual to the insomnia and precipitated it. Strengths and Weaknesses The greatest strengths of the 3P model is that the therapy based on the theory (sleep restriction) is conceptually appealing to sleep medicine clinicians and scientists, the model is highly face valid for patients (especially when it is delivered as part of therapy), and the therapy itself (which is also compatible with, and a logical clinical application of, the two-process model of normal sleep15) appears
to be very efficacious. The equivocation regarding efficacy represents one of the models weaknesses. There have been very few studies evaluating sleep restriction therapy as a monotherapy,8,9 and no studies evaluating the relative efficacy of sleep restriction therapy (using dismantling designs) as component of CBT. It is therefore difficult to assess the extent to which treatment efficacy supports the 3P model itself. Further, even if there were large-scale studies showing that sleep-restriction therapy produces large effects, the validation of the model would still require empirical studies (see later). The model (while compatible with the two-process model of sleep–wake regulation) does not explicitly take into account the influences of the circadian system and sleep–wake homeostasis. Further, the model does not provide a detailed account of how one transitions from good sleep to acute insomnia (i.e., how does the precipitating factor precipitate disturbance of sleep continuity?). In the original model it is implied that the predisposition to insomnia varies across patients but is a trait factor (static over time) within the individual patient. Presumably the postulated between-subject variability means that some patients are not prone to insomnia, some are marginally at risk, and still others are at high risk. Although it stands to reason that the vulnerability for insomnia exists on a continuum (i.e., is normally distributed), it is also plausible that everyone is at risk for acute insomnia and that this is so to the extent that insomnia represents an adaptive response to stress (i.e., real or perceived threat prevents the inhibition of wakefulness; this idea is addressed by the cage exchange model and the psychobiological inhibition model). The postulate of within-subject variability (risk being static over time) also may be open to question. Some predispositions may be indeed be hardwired (addressed by the Drosophila model) but it also stands to reason that some predispositions vary over the lifespan (e.g., new sleep environments or partners, pregnancy or childrearing, altered hormonal status, effects of aging. The newer rendition of the 3P model (reviewed in Chapter 144) reconciles this issue by explicitly allowing predisposing factors to vary with time).16 As with stimulus control, the 3P model focuses on instrumental conditioning. It does not explicitly take into account the role of classical conditioning in chronic insomnia, i.e., the likely possibility that the regular co-occurrence of wakefulness with sleep-related stimuli might lead to a second-order, and perhaps more virulent, perpetuating factor: conditioned wakefulness or conditioned arousal. The 3P model does provide a conceptual framework for understanding types or subtypes of insomnia. For example, it addresses why some subjects have psychophysiologic insomnia as opposed to paradoxical insomnia and why, in either case, the insomnia is expressed as one phenotype as opposed to another (initial versus middle versus late insomnia). Implications for Current and Future Research and Therapeutics Most of the tenets of the 3P model are untested and await empirical demonstrations. Several avenues for research are possible. Family studies or medical anthropology studies could be used to evaluate the predisposition toward
insomnia. Stress-induction studies in good sleepers, like those, for example, conducted by Hall and colleagues,17,18 could be use to produce acute insomnia and to evaluate how a variety of biopsychosocial factors mediate the magnitude of the stress response. Longitudinal studies could be used to confirm whether the putative perpetuating factor of sleep extension does indeed mediate the transition from acute to chronic insomnia. As for therapeutics, the 3P model has served as the conceptual basis for one treatment modality in particular: sleep restriction. This therapy, while believed by many to be the single most potent component of CBT, was developed to target one particular factor (of the three) and only as it is expressed in one particular form (i.e., sleep extension). This may explain the overall value of multicomponent CBT in that the other treatment components, it can be argued, address other perpetuating factors (e.g., stimulus control addresses engaging in nonsleep activities in the bedroom, cognitive therapy addresses the problem of catastrophic or dysfunctional thinking about insomnia, sleep hygiene addresses the misuse of counterfatigue measures). Thus, the question at hand is: In what ways might the 3P model lend itself to identifying alternative treatment targets with standard or alternative methods?19 One possibility is to develop therapies or adapt existing therapies to target predisposing factors. Such treatments could be used to increase treatment response, decrease the risk for reoccurrence (as an adjuvant to traditional CBT), or prevent first episodes of insomnia. In the case of treatment response, depotentiation of predisposing factors might serve to augment outcomes to the extent that they are more, as opposed to less, operational. Treatment response may be boosted if the patient is hypermetabolic by nature by providing relaxation training, if the patient is anxious by nature by providing anxiolytic treatments (medical or psychotherapeutic), or if the patient is (for social reasons) sleeping in a nonpreferred sleep phase by providing some form of chronotherapy (e.g., progressive shifts in sleep scheduling, bright light treatment, or adjuvant treatment with melatonin). In the case of preventing relapse, one could address the factors discussed earlier or could develop interventions to prevent perpetuating factors from becoming operational during recurrence (new episodes of acute insomnia). In this instance the tendency toward sleep extension could be considered a predisposing factor. This being the case, a brief behavioral intervention could be designed that specifically targets sleep extension as a means for coping with acute insomnia. Alternatively (or in addition), rational approaches to fatigue management could be developed, such as giving instructions on how to compensate for shortterm sleeplessness in a way that allows normal sleep homeostasis. In the case of prophylaxis, it might well be possible to prevent many cases of chronic insomnia by replacing sleep hygiene with an empirically validated set of rules.
THE NEUROCOGNITIVE MODEL Basic Description The neurocognitive model3 is based on, and is an extension of, the 3P behavioral model as described by Spielman and colleagues.1 The central tenets of the model include:
CHAPTER 78 • Models of Insomnia 853
• a pluralistic perspective of hyperarousal (cortical, cognitive and somatic arousal); • the specification that cortical arousal (as opposed to cognitive or somatic arousal) is central to the etiology and pathophysiology of insomnia; • the proposition that cortical arousal, in the context of chronic insomnia, occurs as a result of classical conditioning and permits cognitive processes that do not occur with normal sleep; • the proposition that sleep initiation and maintenance problems do not occur because of hyperarousal per se but because of increased sensory and information processing at sleep onset and during non–rapid eye movement (NREM) sleep; • the suggestion that sleep state misperception derives from increased sensory and information processing at during NREM sleep or the attenuation of the normal mesograde amnesia of sleep. As with the “3P” behavioral model of insomnia, it is posited that acute insomnia occurs in association with predisposing and precipitating factors and that chronic insomnia occurs in association with perpetuating factors.1 The primary perpetuating factor is a form of instrumental conditioning that occurs with sleep extension. The neurocognitive model posits that classical conditioning can also serve as perpetuating factor for chronic insomnia and stipulates that hyperarousal needs to be construed and assessed in terms of its component domains: cognitive, somatic, and cortical arousal. With these considerations in mind, it is suggested that repeated pairing of sleep-related stimuli with insomniarelated wakefulness (arousal) ultimately causes sleeprelated stimuli to elicit (or maintain) higher than usual levels of cortical arousal at around sleep onset or during the sleep period. This form of arousal is not thought to be paralleled by somatic arousal (which is posited to be more characteristic of acute insomnia) and is thought to precede, and act as the biological substrate for and precipitant of, cognitive arousal in the context of chronic insomnia. Conditioned cortical arousal is, in turn, hypothesized to contribute to disturbance of sleep continuity or to sleep state misperception via enhanced sensory processing, enhanced information processing, and long-term memory formation. Enhanced sensory processing (detection of endogenous or exogenous stimuli and, potentially, the emission of startle or orienting responses) around sleep onset and during NREM sleep is thought to directly interfere with sleep initiation or maintenance. Enhanced information processing (detection of, and discrimination between, stimuli and the formation of a short term memory of the stimulating events) during NREM sleep is thought to blur the phenomenologic distinction between sleep and wakefulness and thus contributes to sleep state misperception. Enhanced long-term memory (detection of, and discrimination between, stimuli and recollection of the stimulating event hours after its occurrence) around sleep onset and during NREM sleep is thought to interfere with the subjective experience of sleep initiation and duration and thus contributes to the discrepancies between subjectively and objectively assessed sleep continuity.
854 PART II / Section 10 • Insomnia
Predisposing factors Biopsychosocial factors
Physical psychiatric illness
Precipitating event Acute biopsychosocial stress
Perpetuating factors Sleep extension (primary) Sleep stimuli as CSs (secondary)
Neurocognitive factors Conditioned arousal Somatic Cortical Cognitive
Cognitive alterations Sensory processing Information processing and Short-term memory formation Long-term memory formation
Chronic insomnia Can’t fall asleep Wake up frequently Perceived wakefulness vs. PSG sleep Sleep state misperception Overestimation of wakefulness Underestimation of sleep
Figure 78-3 The neurocognitive model shown here differs from prior versions in several ways: Dotted lines are provided to highlight feedback loops; solid lines represent feedforward loops. The examples provided for perpetuating factors have been changed. The primary factor is designated as sleep extension (previously denoted as increased time in bed and staying awake in bed). The secondary factor is designated as sleep stimuli as conditioned stimuli. This is meant to represent when sleep stimuli become conditioned stimuli for wakefulness (arousal). CSs, conditioned stimuli; PSG, polysomnographic.
Conditioned cortical arousal is hypothesized to be selfreinforcing, and for essentially two reasons. First, because sleep-related stimuli (X) act as conditioned stimuli for cortical arousal (Y), the pairing is self-reinforcing. That is, if X elicits Y, and the occurrence of Y reinforces the association of X and Y, then pairing is self-reinforcing. Second, because cortical arousal permits processes associated with wakefulness, it is likely that the elicited arousal will, on each occasion, be amplified because of ongoing sensory processing, enhanced information processing, and longterm memory formation. Taken together, these considerations virtually guarantee that the insomnia will, in the absence of its original precipitants, continue unabated and will not be subject to extinction, as usually occurs with classical conditioning. See Figure 78-3 for a schematic representation of the model.
Strengths and Weaknesses Strengths In general, the major strengths of the neurocognitive model are that it allows a pluralistic perspective on the concept of arousal; it does not require that hyperarousal be so intense as to directly interfere with sleep initiation and maintenance but instead posits that arousal only be sufficiently intense as to permit processes that are characteristic of wakefulness and can perpetuate wakefulness (stimulus detection, startle, orienting, stimulus identification, intention or action, and long-term recall); it delineates a mechanism beyond that of instrumental conditioning (i.e., classical conditioning as a perpetuating factor); it specifies how chronic insomnia takes on a life of its own (i.e., is self-reinforcing), and its hypotheses are falsifiable. Two lines of research (indirect and direct) provide support for the model. The indirect evidence derives from observations about the effects of sleep on long-term memory in good sleepers and perceived wakefulness during sleep recorded on a polysomnograph (PSG) in patients with insomnia. With respect to the former, there is good evidence that normal sleepers cannot recall information from periods immediately prior to sleep,20-23 during sleep,24-28 or during brief arousals from sleep.29,30 Thus, normal sleep is indeed characterized by a dense amnesia for events occurring at around sleep onset and during sleep. With respect to the latter, there is substantial evidence that when awakened from PSG-defined sleep, patients with insomnia (as opposed to good sleepers) tend to perceive themselves to be awake rather than asleep.31-38 This tendency, better known as sleep state misperception, is consistent with the neurocognitive model’s perspective regarding sensory and information processing during sleep. That is, if one cue for “knowing” that one is asleep is the lack of awareness for events occurring during sleep, and if it is the case that patients with insomnia exhibit increased levels of sensory and information processing during sleep, then it would be expected that the greater level of awareness for events occurring during PSG-defined sleep serves to blur the phenomenologic distinction between sleep and wakefulness so that patients with insomnia would have difficulty indentifying PSG sleep as sleep. In this instance, what remains open to question is whether sleep state misperception can be correlated with objective measures of cortical arousal—such as by quantitative electroencephalography (qEEG), analyses of cyclic alternating pattern (CAP), or brain metabolic functional imaging—or with objective measures of increased sensory and information processing during sleep (i.e., via evoked-response potentials [ERPs]). The direct evidence pertains to whether patients with insomnia exhibit increased cortical or central nervous system (CNS) arousal as measured by qEEG and positron emission tomography (PET), increased sensory or information processing as measured by ERPs, an attenuation in the normal mesograde amnesia of sleep, or association between sleep state misperception and objective measures of cortical arousal or ERP abnormalities. Patients with primary insomnia have been found to exhibit higher levels of cortical arousal (in terms of increased NREM highfrequency EEG) as compared to good sleepers39-43 or patients with insomnia comorbid with major depression.43a
Cortical arousal (as well as increased activity involving subcortical areas and circuits) has also been observed in patients with insomnia using PET techniques.44,45 Altered sensory and information processing have been observed with ERPs.46-47 Correlational analyses provide evidence that that beta and gamma activity is negatively associated with the perception of sleep quality17,48 and is positively associated with the degree of subjective-objective discrepancy.43 There is some evidence that patients with sleep state misperception disorder (paradoxical insomnia) have been found to exhibit more beta and gamma EEG activity than good sleepers or patients with primary insomnia.49 One study shows that patients with insomnia are better able to recognize word stimuli played during sleep-onset intervals and during early NREM sleep. This latter finding provides support for the hypothesis that there is an attenuation in the normal mesograde amnesia that accompanies sleep in patients with chronic insomnia. Weaknesses The primary limitations of the neurocognitive model are its failure to adequately account for the transition from good sleep to acute insomnia (like the 3P behavioral model, it primarily describes chronic insomnia), the importance of circadian and homeostatic influences on sleep, and the possibility that cortical arousal constitutes a permissive factor for worry, rumination, and monitoring behavior. The original model does not clearly address whether conditioned cortical arousal represents hyperarousal or the newer concept of the failure to inhibit wakefulness. With respect to this last point, the summary endeavors to clarify this issue by suggesting that chronic insomnia (versus acute insomnia) is perpetuated by a form of conditioned arousal that is more akin to alert wakefulness than to hyperarousal (physiologic and neurobiological states that occur with flight-or-fight–type stress responses). Finally, whereas the neurocognitive model does provide a conceptual framework for two types of insomnia (psychophysiologic and paradoxical insomnia) and how insomnia becomes self perpetuating (via classical conditioning), the model does not explicitly address how it is relevant for the other insomnia types or subtypes. Implications for Current and Future Research and Therapeutics There is evidence supporting the viability of the neurocognitive model, but many of the model’s central tenets require further empirical validation. Apart from the research required to support the behavioral base of the model, further work is needed showing that cognitive processes (sensory and information processing and long-term memory) are reliably altered during the sleep period in patients with chronic insomnia and that altered cognitive processing has clear neurobiological concomitants (e.g., altered metabolic activity in specific brain regions) and functional consequences (sleep continuity disturbance and sleep state misperception). Novel experimental paradigms need to be developed to test the model’s core hypotheses. For example, if classical conditioning is an operative factor, experimental paradigms could also be used to evaluate whether sleep-related stimuli may be conditioned to elicit wakefulness. Experi-
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ments of this type will most likely need to be conducted in animals because they run the risk of experimental effects persisting beyond the conduct of the experiment itself. If mesograde amnesia is a primary determinant of perceived sleep quantity and quality, it should also be possible to assess the relative importance of this factor using compounds that promote amnesia (with or without sedative properties) in combination with the manipulation of situation cues. Experiments of this type will need to be conducted in humans given the centrality of self-reported sleep continuity. The neurocognitive model may provide some insight into the potential mechanisms of action of existing therapeutics and also some guidance regarding potential targets for new treatments. In the case of existing therapeutics, pharmacotherapy might effective to the extent that the various compounds block sensory and information processing or promote amnesia within the sleep period. This idea, first espoused by Mendelson,50-55 seems probable given the effects of benzodiazepines and benzodiazepine receptor agonists on arousal thresholds and memory formation. Sleep restriction therapy might also work via these mechanisms to the extent that this treatment modality serves to deepen sleep (augment the endogenous form of sleep-related mesograde amnesia). Potential avenues for new medical treatments include the assessment of compounds that have greater-thannormal amnestic potential for their efficacy as hypnotics, provided that such effects can be limited to the desired sleep period and the use of diurnal stimulant therapy to promote wake extension and thereby their potential to diminish nocturnal cortical arousal via increased sleep pressure. Potential avenues for behavioral treatment include inpatient protocols that use more-intensive forms of sleep restriction therapy to promote counterconditioning, such as what is now being done with intensive sleep retraining therapy.56
THE PSYCHOBIOLOGICAL INHIBITION MODEL Basic Description The psychobiological inhibition model15 states that stressful life events precipitate both physiologic and psychological arousal, and the consequences of this are the occurrence of selective attending to the life stressor and the occurrence of insomnia symptoms. In the case of acute insomnia, it is thought that physiologic or psychological arousal is sufficient to interfere with the normal homeostatic and circadian regulation of sleep (i.e., is sufficient to prevent the normal inhibition of wakefulness). The acute insomnia might resolve or be perpetuated based on the extent to which the stress state resolves and the patient does not attend to the acute insomnia. The shift of attention from the life stressor, implicitly or explicitly, to the insomnia symptoms is posited to be the critical event that transitions acute insomnia to a form of sleep disturbance that is selfperpetuating. A schematic representation of the model is presented in Figure 78-4. This model substantially distinguishes itself from earlier perspectives in three fundamental and related ways. First, the point of departure for the model is the
856 PART II / Section 10 • Insomnia
Stressful life event
Psychological and physiologic correlates of stress
Selective attention toward stressors
ADJUSTMENT INSOMNIA
Arousal perpetuates sleep disturbance
Inhibition of sleep-related dearousal
Selective attention SHIFT
Insomnia symptoms
A1 Impilicit shift toward sleep cues
Recovery of normal sleep
A2 Expilicit shift toward sleep cues PSYCHOPHYSIOLOGIC INSOMNIA
I Expilicit intention
E Sleep effort Figure 78-4 Proposed evolution of psychophysiologic insomnia from adjustment insomnia following the attention-intentioneffort (A-I-E) pathway.
psychobiological framework for normal sleep that is inherent in the stimulus control perspective4 and formally delineated in the two-process model of sleep–wake regulation.57 Second, it is proposed (and was the first etiologic model to do so) that persistent sleep continuity disturbance occurs in relation to a failure to inhibit wakefulness (as opposed to conditioned hyperarousal). Third, the model is focused on how cognitive factors (as opposed to behavioral or physiologic factors) serve to perpetuate insomnia. Psychobiological Framework for Normal Sleep Espie4,58 suggests that for normal sleepers, homeostatic and circadian processes default to good sleep, not to insomnia, and that like other neurobehavioral systems, this is ensured by plasticity and automaticity. Plasticity refers to the ability of the sleep system to adjust to, and/or accommodate, situational factors that disrupt normal sleep-wake functioning (e.g., circumstances that require that sleep be temporarily foreshortened or extended). In transient or acute insomnia, the norm would be the recovery of good sleep, reflecting the system’s plasticity in function. Automaticity refers to the involuntary nature of sleep initiation and sleep maintenance. That is, that sleep is initiated and maintained automatically by the well-established conditioned associations between sleep-related stimuli and sleep and by the twoprocess system that governs the timing and duration of sleep and wake. Thus, under normal circumstances, sleep occurs passively (without attention, intention, or effort).
Insomnia as the Failure to Inhibit Wakefulness The majority of insomnia models conceptualize insomnia as a disorder of hyperarousal. That is, the inability to initiate or maintain sleep derives from the occurrence of a level of arousal that is simply incompatible with sleep, where such arousal occurs acutely in relation to stress and chronically in relation to behavioral factors58 or classical conditioning. Espie, however, has proposed an important alternative point of view, suggesting that insomnia occurs in association with a failure to inhibit wakefulness. That is, the psychobiological inhibition model suggests that in the early stages of chronic insomnia, problems with sleep initiation or sleep maintenance can occur because of fundamental alteration in the functioning of the neurobiological mechanisms that normally inhibit wakefulness and permit sleep to occur. Such an alteration is likely to be systemic; it occurs with real or perceived threat and is part of the larger flight-or-fight response. This alteration, which should dissipate along with the resolution of the acute stressor, may be potentiated by cognitive processes. Cognitive Factors Trigger the Failure to Inhibit Wakefulness The failure to inhibit wakefulness (in the context of chronic insomnia) is hypothesized to result from three related cognitive phenomena collectively referred to as the attentionintention-effort (A-I-E) pathway.4 Each of the three phenomena are thought to act in concert, and in a hierarchical fashion, to transition acute stress-induced insomnia into a form of insomnia that is self-perpetuating. This is thought to occur as follows. First, when the person is unable to sleep, his or her attention is drawn to an otherwise automatic process. The very process of attending, in turn, prevents perceptual and behavioral disengagement. Second, because a primary function of attention is to promote action in response to perceived need or threat, an intentional (purposive) process is initiated that acts to further inhibit the normal downregulation of arousal. Third, when the person is unable to sleep, active effort is expended trying to fall asleep, and this effort, like enhanced attention and intention, serves only to further prevent the inhibition of wakefulness. In sum, the psychobiological inhibition model provides a generic common pathway to chronic insomnia. Insomnia occurs in a persistent fashion when there is a sufficient level of attention, intention, or effort to outweigh good stimulus control or the intrinsic drives of the two-process system. Strengths and Weaknesses Strengths There is substantial support, in general, for the concept that attention bias or selective attention plays a role in mental illness.59 It has been found to be operational for a wide range of psychiatric disorders including panic disorder, hypochondriasis, eating disorders, obsessional disorders, generalized anxiety disorder, and posttraumatic stress disorder.60-64 In fact, the data within these domains are sufficiently compelling that it has been argued that attention bias may have a causal role in most, if not all, anxiety disorders.63 The concept is that the anxious person is preoccupied with danger and threat and thus
selectively attends to threat-related stimuli as he or she perceives that the danger is imminent but also potentially avoidable. Attention bias has also been implicated in habit and dependence disorders. In this case, however, attention is not focused on threat-related stimuli per se but instead on the object of the addiction.64 For example, in alcoholism, patients are thought to selectively attend to alcohol-related cues and that this form of attention bias can moderate or mediate addiction by producing craving. In the case of insomnia, attention bias is likely to operate in a manner akin to anxiety and dependence disorders (attention to threat or object of craving), and this might account for the nosologic requirement that insomnia (psychophysiologic insomnia) include “excessive focus on, and heightened anxiety about, sleep”.64, p. 7 Apart from the general perspective that attention bias is relevant for mental disorders, there is also a significant amount of experimental evidence supporting the psychobiological inhibition model, and especially with respect to sleep-related attention bias and sleep-related effort. To date eight studies have been conducted whose findings reliably indicate: • sleep-related mental preoccupation may be associated with the transition from acute to persistent insomnia in cancer patients65; • subjects with psychophysiologic insomnia exhibit heightened levels of attention bias as compared to good sleepers and subjects with delayed sleep phase syndrome66,67; • attention bias to sleep-related stimuli detected in patients with psychophysiologic insomnia may be driven by threat57,67-69; • there are positive linear relationships between sleeprelated attentional bias and self-reported sleep quality and sleepiness; • subjects with psychophysiologic insomnia exhibit “effortful preoccupation with sleep.”70 Another strength of the psychobiological inhibition model is that it allows an objective means of indexing cognitive processes in insomnia. In practice, insomnia patients complain primarily of mental events interfering with sleep, including intrusive thoughts, racing thoughts, increased worry, and the inability to disengage attending to environmental noise or bodily sensations. Although such mental events appear central to the experience of insomnia, their assessment has relied primarily on selfreport measures. Thus, a major strength of the psychobiological inhibition model is it concepts may be operationally defined and tested with objective measures like the computerized emotional Stroop task, the induced-change blindness task, and the dot probe task. Finally, and perhaps most important, a major strength of the psychobiological inhibition model is the extent to which one of its central tenets (inhibition of wakefulness) is supported by both animal and human data. In the case of the former, the cage exchange model7 serves to highlight that there is indeed a neurobiological substrate for the concept of the failure to inhibit wakefulness and it appears to be dysregulated in rodents exposed to the cage-exchange paradigm. In humans, studies using evoked response potential methodology46,47 suggest that patients with
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insomnia exhibit a diminished capacity to inhibit exterioception. Limitations Much of psychobiological inhibition model and the A-I-E pathway that remains to be validated (particularly the intention and effort components). Moreover, studies conducted in Glasgow now need to be replicated and extended by other research groups. An important consideration for subsequent studies will be the extent to which the psychobiological inhibition model and the A-I-E pathway apply across the range of primary insomnia types (e.g., psychophysiologic insomnia versus idiopathic and paradoxical insomnias) and the insomnia subtypes (initial, middle and late insomnias). Finally, and perhaps most difficult, is the need to create conceptualizations and measures that allow a clear distinction between, and an assessment of, the relative importance of the two primary concepts now thought to undergird the incidence and severity of insomnia: arousal or hyperarousal and the failure to inhibit wakefulness (or function typical of wakefulness). Implications for Current and Future Research and Therapeutics As previously suggested, the psychobiological inhibition model offers a generic common pathway to insomnia. Consequently, the model can accommodate a common pathway explanation for the effectiveness of many existing elements of cognitive behavioral therapy for insomnia (CBT-I). The model’s potential explanatory power, however, is not limited to elements of CBT-I but also likely extends to potential mechanisms of action for existing medical therapeutics. With respect to CBT-I, any behavioral or cognitive intervention that augments the inhibition of wakefulness should permit the reinstatement of normal sleep. Sleep restriction might exert its therapeutic effects via the reinstatement of sleep automaticity. That is, sleep restriction serves to increase homeostatic pressure for sleep to a point where sleep will occur inevitably and without attention, intention, or effort. Stimulus control may strengthen adaptive and automatic dearousal associations of bed and sleep and thereby diminish the conditioning effects that inhibit downregulation. Finally, relaxation, distraction, and imagery methods might reduce worry about sleep, and paradoxical intention methods might entirely refocus the A-I-E pathway away from sleep preoccupation. With respect to the medical management of insomnia, the psychobiological inhibition model suggests that the mechanisms for existing therapies reside in their capacity to promote relaxation, inhibit exterioception, and derail sleep-related attention, intention, and effort. Clearly these are features of traditional sedatives (e.g., barbiturates, benzodiazepines, and benzodiazepine receptor agonists) but also might apply to the off-label use of antipsychotics (e.g., quetiapine, olanzapine). Finally, the model also offers a perspective that might allow the development of new approaches. From the CBT or psychotherapeutic point of view, the psychobiological inhibition model clearly carries with it the suggestion that sensory gating training or (alternatively) mindfulness therapies may be successfully used to treat insomnia. From the
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pharmacologic point of view, the psychobiological inhibition model clearly carries with it the suggestion that it may be productive to antagonize wake-promoting or wakeconsolidating systems and that one such approach would be via orexin antagonism.
THE DROSOPHILA MODEL Basic Description The conceptual basis for the Drosophila model (as an analogue of human insomnia) is that insomnia occurs, in part, in relation to predisposing factors. This fundamental tenet of the behavioral model suggests that chronic insomnia may have a genetic component and that a portion of the variance in the incidence of insomnia71,72 should be related to factors that are heritable, for example, the strength and plasticity of the sleep system, the trigger threshold for and intensity of the flight-or-fight response, or the strength and plasticity of sleep homeostasis and circadian processes. Consistent with this point of view is that insomnia tends to run in families and that persons with a family history of insomnia are more anxious and prone to stress-related sleep disturbances.73,74 Thus, if insomnia results, in part, from predisposing trait characteristics, the identification of the underlying mechanisms should be feasible using genetic strategies. Given the complexity and number of traits observed for insomnia, it seems unlikely that single gene mutations will result in an animal model that adequately captures the human condition. An alternative approach is to identify natural variants in a population that simultaneously exhibit several behavioral characteristics of insomnia. The phenotypic variation in these individuals is likely to be the result of minor changes in many genes and as a consequence is more likely to reflect the diversity of the human disorder.75 The natural polygenic variation can be amplified over successive generations using laboratory selection and can be identified using whole-genome arrays.76 This is the approach that undergirds the Drosophila model. Evaluation of a normative dataset of wild-type Canton-S (Cs) Drosophila indicated that they display a sufficient range of sleep times and activity levels to make them suitable for laboratory selection (Figure 78-5A, green bars). Drosophila that demonstrated reduced sleep time in combination with increased sleep latency, reduced sleep bout duration, and elevated levels of waking activity (insomnia-like, referred to as ins-l flies) were selected and bred over successive generations. As seen in Figure 78-5B, total sleep time was progressively reduced during selection and stabilized after 60 generations. At generation 65, more than 50% of ins-l flies obtained less than 60 minutes of sleep in a day, and the distribution of sleep times was shifted dramatically to the left (see Fig. 78-5A, pink bars). Not surprisingly, the decrease in sleep time (or increase in total wake time) in selected Drosophila came primarily at the expense of nighttime sleep (see Fig. 78-5C). As with human insomnia, ins-l flies showed increased latency from lights off to the first sleep bout of the night (see Fig. 78-5D), suggesting that they have difficulty initiating sleep.77 The ins-l flies also exhibited difficulties maintaining sleep as evidenced by an inability to consolidate sleep into long bouts (average sleep bout duration; see Fig. 78-5E).7 The maximum episode of
consolidated sleep that can be generated by an ins-l fly is only 36 ± 9 minutes versus 257 ± 22 minutes in Cs flies. In addition to disrupted sleep, the ins-l flies exhibit increased locomotor activity during waking (1.86 ± 0.03 crossings) compared to Cs flies (1.42 ± 0.05 crossings). To assess the extent to which the sleep patterns of the selectively bred Drosophila represent a reasonable analogue of human insomnia (chronic insomnia), the sleep of the ins-l Drosophila was evaluated for chronicity (i.e., stability of the abnormal sleep pattern over the life span) and wake state of the ins-l Drosophila was evaluated for evidence that the altered form of sleep was associated with daytime consequences (i.e., fatigue, sleepiness, impaired concentration or memory) or health outcomes (increased mortality). With respect to chronicity, it was found that the sleep profile remained stable in ins-l Drosophila over time. Total sleep for three representative ins-l flies and one Cs fly are shown in Figure 78-5F. These three ins-l flies obtained a total of 358 ± 128 minutes of sleep during their first 20 days of life (and this appears stable with time) versus 17,567 ± 655 minutes of sleep over the same time period in the Cs flies (and this appears to trend downward with aging). Thus, the observed stability of the sleep profile of the ins-l flies may be viewed as chronic (i.e., the sleep disturbance does not spontaneously remit with time). With respect to daytime consequences, the two types of Drosophila were evaluated for sleepiness, learning impairment, and motor or coordination difficulties. Sleepiness was assessed using a biomarker for sleepiness (amylase).6 As seen in Figure 78-5G, ins-l flies show elevated levels of amylase relative to Cs flies, suggesting that they experience sleepiness (or increased sleep drive) during their primary wake period. Learning was assessed using aversive phototaxic suppression (APS).78 In this task, flies learn to avoid a light that is paired with an aversive stimulus (quinine or humidity). In this paradigm it was shown that APS is sensitive to both sleep loss and sleep fragmentation.79 For example, as seen in Figure 78-5H, learning is significantly impaired in the shortest sleeping ins-lshort flies compared to Cs controls. To determine whether the selection protocol generated poor-learning Drosophila as a phenotype independent from the observed sleep deficit, learning in longsleeping ins-l flies was also evaluated. Longer sleeping siblings maintained their ability to learn, indicating that the selection procedure did not inadvertently, and independent of sleep, contribute to poor learning. Motor and coordination difficulties were assessed by quantifying the number of spontaneous falls in young age-matched Cs and ins-l flies walking for 30 minutes in an obstacle-free environment. Cs flies rarely fall under these conditions. In contrast, ins-l flies often lose their balance (see Fig 78-5I). Finally, health consequences were assessed in terms of mortality via a measure of lifespan duration. This approach derives from the epidemiologic studies in humans that suggest that sleep duration and insomnia are associated with an increased risk of all-cause mortality and reduced lifespan.80 Accordingly, one would predict that if the selected lines have insomnia or are getting less sleep than they need, they would have a shortened lifespan. As seen in Figure 78-5J, this is indeed the case. It should be noted that the reduced lifespan observed in the ins-l flies is not a result of decreased fitness.
CHAPTER 78 • Models of Insomnia 859
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Figure 78-5 A, Frequency distribution of total sleep time in 60 min bins in wild type Cs flies (n = 1000) and in ins-l flies at generation 65 (n = 364). B, Total sleep time in males (n = 40) and females (n = 40) for successive generations of ins-l flies. C, Daily total sleep time is shown for 37 days in one Cs and three ins-l flies. D, Sleep in min/hr for 24 hr in Cs flies (n = 32) and ins-l flies (n = 32). The gray rectangle represents lights off. E, Sleep latency is increased in ins-l flies (n = 28) versus Cs flies (n = 33). F, Average sleep bout duration is reduced during the dark period in ins-l flies (n = 32) versus Cs flies (n = 32). G, Amylase mRNA levels are elevated in ins-l flies (% of Cs expression) at ZT0-1. H, Learning in Cs flies, longer-sleeping ins-l flies (average daily sleep time, 347 ± 55 min), and short-sleeping ins-l flies (average daily sleep time, 26 ± 7min) (n = 10 for each group) I, Number of falls during 30 minutes in Cs flies (n = 20) and ins-l flies (n = 18). J, Representative survival curve of aging ins-l compared to Cs flies (30 flies/group). *P < .05; error bars represent standard error of the mean.
In sum, the selection procedure was effective in producing animals with reduced total sleep time, increased sleep latency, and shortened sleeping bout duration. These sleep effects were found to be persistent and were associated with a variety of sequelae including diurnal sleepiness, impaired learning, motor or coordination difficulties, and increased mortality. Taken together, these findings suggest that the Drosophila model is a reasonable analogue of human insomnia (chronic insomnia). Strengths and Weaknesses A major strength of the Drosophila model is its approach: a naturally occurring set of sleep parameters (parameters that are commonly found in human insomnia) were operationally defined for use in the fly and amplified over successive generations using laboratory selection. Not only is the selection procedure an ideal one for a genetic study of insomnia, but also the use of multiple parameters ensures
that the analogue condition more closely resembles the human expression of the disorder. Another strength of the model is the effort to demonstrate that the aggregate phenotype also exhibited daytime deficits with respect to sleepiness, learning impairment, coordination difficulties, and reduced lifespan. One weakness of the model is the inability to establish (as with any animal model) the subjective complaint of insomnia. Another weakness is a level of insomnia severity that is not analogous to that seen in humans: Total sleep times are a fraction of the total sleep time seen in non–ins-l flies. This might suggest to some that the selection process produced a new class of sleep mutant as opposed to an idiopathic form of insomnia. The demonstration of sleepiness the ins-l flies are controversial. The consensus view (based on the use of the multiple sleep latency test [MSLT]) is that patients with chronic insomnia do not exhibit pathologic sleepiness. Finally, the method of
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assessment of sleepiness is also somewhat controversial to the extent that amylase is also used as a biomarker for stress.81-84 Implications for Current and Future Research and Therapeutics There are a variety of possible directions for future research. Given the complexity of insomnia, it is likely that independent selections would potentially yield alternative outcomes. That is, the genes identified in the ins-l flies might only represent one potential pathway to insomnia. Thus, a greater understanding of insomnia may be advanced with additional selected lines. Further, the use of molecular-genetic and genomic strategies such as Affymetrix arrays, suppressor screens, and genetic mapping may be useful for the identification of the genes that are associated with the various aggregate phenotypes. Given this latter strategy, it is important to acknowledge that gene profiling in Drosophila obtained by laboratory selection is likely to reveal two classes of genes: those that are causative for a given behavior and those that are a consequence of the behavioral change.85 Most studies have focused on identifying genes that are causative for a given behavior.76,86,87 However, given that extended waking results in substantial physiologic impairment,88,89 including death,90,91 the latter set of genes may also be particularly important in the context of insomnia.
THE CAGE EXCHANGE MODEL OF ACUTE INSOMNIA Basic Description A rat model of acute stress–induced insomnia has been developed using a species-specific psychological stressor, cage exchange. The aim of this model was to identify the brain circuitry activated in rats experiencing stress-induced insomnia to better understand the neurobiological basis of acute insomnia. In the cage-exchange paradigm, stress is induced by manipulating the social context rather than by applying a continual physical stressor (e.g., tone, shock).7,44 This is accomplished by transferring a male rat from his home cage, at the peak of the sleep period, to a soiled cage previously occupied by another male rat. Because rats are very territorial, exposure to the olfactory and visual cues of a competitor, even in its absence, induces a stress fight-orflight response including activation of the autonomic nervous system and the hypothalamic-pituitary-adrenal axis and sustained wakefulness. Several hours later, when the physiologic indicators of acute stress are attenuated, this manipulation induces a late period of disturbed sleep. The brain circuitry activated during this late period of disturbed sleep was assessed by examining the expression of Fos, a transcription factor widely used as a marker of neuronal activity. Increased activation was observed in the cerebral cortex, limbic system, some arousal groups (locus coeruleus and tuberomamillary nucleus), and part of the autonomic system. Surprisingly, there was also simultaneous activation of the sleep-promoting areas: the ventrolateral preoptic area (VLPO) and the median preoptic nucleus. This coactivation results in a unique pattern of brain activity that differs from those observed during wake
or normal sleep, because the sleep circuitry appears to be like that in a sleeping rat, whereas the arousal system and the cortex show a level of activation similar to those of wakefulness. The high level of cortical activation (as measured by Fos) was also associated with high-frequency EEG activity (distinctive of wakefulness) during NREM sleep. The co-occurrence of high-frequency EEG activity and traditional sleep frequencies also appears to represent a novel intermediate state that differs from both normal EEG sleep and wakefulness. Subsequent experiments revealed that inactivation of discrete limbic or arousal regions, via cell-specific lesions or pharmacologic inhibition, allowed the recovery of specific sleep parameters and changed the pattern of brain activity in the cage-exchange paradigm.7 This suggests that stress-induced insomnia requires the occurrence of a cascade of neuronal events along with the normal propensity for sleep. This cascade likely includes sensory inputs (olfactory and visual cues of a competitor) that activate limbic areas, which in turn activate part of the arousal system that subsequently activates the cerebral cortex. This latter event (cortical activation) may be measured as high-frequency EEG activity during NREM sleep, and it is eliminated after inactivating parts of the arousal system, which supports the proposed pattern of brain activation represented in Figure 78-6. The proposition that this particular stress paradigm can induce a novel intermediate state needs to be considered within the context of normal sleep–wake control,92,93 as the Species-specific stressor +
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Figure 78-6 Putative circuitry involved in stress-induced insomnia: The olfactory signals are conveyed to the limbic system, which in turn activates the arousal and autonomic systems, as well as nonorexin neurons in the lateral hypothalamus. The cerebral cortex becomes highly activated by inputs from the arousal system and the lateral hypothalamus, which generates the high-frequency activity observed during NREM sleep. The reciprocal inhibition between the sleep and arousal systems would ordinarily prevent co-activation, but the homeostatic and circadian pressure keep the sleep system activated, whereas stress activates the arousal system, resulting in a unique pattern of brain activity.
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existence of such a state represents an aberration of what is considered normal sleep and wake. As proposed by Saper and colleagues,93 in normal animals there is a reciprocal inhibitory innervation between the main sleep-promoting neuronal group (VLPO), whose neurons are active during sleep, and the neuronal groups that compose the arousal system—the histaminergic tuberomammillary nucleus, the serotoninergic dorsal raphe, and the noradrenergic locus coeruleus—whose neurons are active during wakefulness. The authors have proposed that this reciprocal inhibition provides a control system that is analogous to an electrical flip-flop switch. In this case, when one side is strongly activated, it inhibits and deactivates the other side, which decreases the inhibitory input to itself (disinhibition) and reinforces its own activity. In the absence of other factors, this configuration renders a bistable circuit (stable in one or the other state), with rapid and complete transitions between states and no occurrence of intermediate states (co-activation). The circuit is switched from one state to the other due to the strong inputs generated by the gradual buildup of the circadian and homeostatic pressures. As summarized by Saper: When this pressure to change becomes great enough, the same feedback properties that allow the flip-flop circuit to resist change will suddenly give way and rapidly produce a reversal of firing patterns. The flip-flop switch therefore changes behavioral state infrequently but rapidly, in contrast to the homeostatic and circadian inputs, which change continuously and slowly.93, p. 729 In this context, the simultaneous activation of the VLPO and the arousal system in the cage-exchange paradigm is surprising. A possible explanation is that during stressinduced insomnia, the VLPO is fully activated because of both the homeostatic and circadian drives, but it is unable to turn off the arousal system because this is being excited intensely by inputs from the cortical and limbic systems. At the same time, the arousal system cannot turn off the VLPO because it is highly active owing to the stronger homeostatic pressure caused by the fact that the stressed rats are partially sleep deprived. This results in the simultaneous activation of opposing systems that normally are not activated in tandem, and the bistable circuit becomes inherently unstable: The switch is forced into an intermediate position. This scenario is represented in Figure 78-7. Strengths and Weaknesses The rat model’s cage exchange paradigm has several strengths. One is the conceptualization of insomnia as part of, or precipitated by, the flight-or-fight response. It uses a psychosocial stressor (perceived territorial threat) to induce sleep continuity disturbance, and it successfully produces a form of acute insomnia that includes both initial and late subtypes. It identifies specific neuronal effects within regions implicated in the regulation of sleep and wakefulness and produces quantitative EEG findings that are consistent with those found in human insomnia. Its overall findings are consistent with the conceptualization of insomnia as a disorder of hyperarousal, and it neuronal findings suggest that acute insomnia is a hybrid state resulting from the co-activation of systems that normally function in bistable fashion.
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Figure 78-7 During normal sleep, the circadian and homeostatic drives enhance the activity of the sleep-promoting areas and simultaneously inhibit the arousal system, favoring the sleep state (the homeostatic effect is mediated in part by adenosine acting on A1 and A2a receptors). Stress activates part of the arousal system via cortical and limbic inputs, and this activation opposes the direction of the circadian and homeostatic drives. In stress-induced insomnia, the cortical, limbic, and arousal activation persists, but the homeostatic pressure is stronger than usual because the rats are partially sleep deprived; the circadian drive still favors the sleep state. Because these two forces are opposing and strong, the sleep–wake switch is forced into an unstable position, allowing the emergence of an intermediate state in which both sleep and wake circuitries are activated simultaneously, but each state is unable to sufficiently inhibit the other to prevent it from firing. His, histamine; LC, locus coeruleus; NE, norepinephrine; TMN, tuberomammillary nucleusVLPOc, ventrolateral preoptic nucleus core; VLPOex, ventrolateral preoptic nucleus extended.
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The characterization of acute insomnia as part of (or as a consequence of) the flight-or-fight response is particularly useful. This suggests that insomnia may be, as a transitory phenomenon, an adaptive response to perceived threat94 and is consistent with Richardson’s95 proposal that insomnia reflects the overactivity of systems extrinsic to the sleep–wake circuitry that can temporally override normal sleep–wake control to facilitate a more imperative function, the stress response. The suggestion that acute insomnia exists as a hybrid state represents an important refinement of the concept of hyperarousal and is consistent with the transition probability model described by Merica and colleagues96,97 and with Espie’s concept that insomnia occurs in association with a failure to inhibit wakefulness.4,58 The rat model of acute insomnia does have some limitations. As with the Drosophila model, it is unable to establish the subjective complaint of insomnia, and as an analogue of acute insomnia, it might not be relevant for assessing chronic insomnia, which many would argue is the more clinically relevant condition. Although there is no question that modeling chronic insomnia (e.g., using a conditioning paradigm) would be useful, the acute model might nevertheless serve as a guide for what to expect in chronic insomnia. For example, the model clearly identifies brain regions of interest and clearly delineates one kind of pathology that may be characteristic of both acute and chronic insomnia, namely, the co-activation of both sides of the flip-flop switch. Another limitation of the model may be its reliance on the Fos measure. Not all neuronal groups express Fos in association with action potential activity. Thus, this might limit the resolution of the neurobiological effects of the cage-exchange paradigm to regions that express Fos. Implications for Current and Future Research and Therapeutics Observations from the rat model might help to identify putative targets for pharmacologic manipulation that can guide the development of new therapies. One essential finding is that the sleep-promoting neuronal groups are fully active in the rat model, and the problem seems to be the anomalous residual activation of the arousal and limbic systems at a time they should be completely off. This suggests that shutting down the residual activity of these systems might be a better approach to treat stress-induced insomnia (and perhaps chronic insomnia) rather than potentiation of the sleep system. Further, identifying the phenotype of these neurobiological abnormalities may be helpful in the search for more-specific pharmacologic treatments, which may, in turn, yield fewer unwanted side effects.
CONCLUSION The neurocognitive model, psychobiological inhibition model, and the cage exchange model share at least two central tenets: Stress (threat or perceived threat) is a major precipitant of acute insomnia, and chronic insomnia involves a hybrid state where there are simultaneously higher than normal levels of CNS activation and a
failure to inhibit processes normally associated with wakefulness. The neurocognitive model and the psychobiological inhibition model differ with respect to the role of cognitive processes as they occur in chronic insomnia. The psychobiological inhibition model allows mental activity and cognitive processes to assume a central role in perpetuating insomnia: The person is awake because he or she is worrying or is attending to not sleeping. The neurocognitive model takes into account cognitive processes but does not ascribe a primary role to such phenomena: One is worrying or is attending to not sleeping because he or she is awake. Thus, cognitive phenomena serve as the flame for the psychobiological inhibition model and wind to the flame for the neurocognitive model. The cage exchange model differs from the human models, at the conceptual level, because of its mechanistic emphasis on the sleep switch (as opposed to functional or environmental factors) and dysregulation of the sleep switch as it occurs acutely with homeostatic and circadian dysregulation. This difference is, however, not as profound as one might think. The question is what happens over time? Is it possible that rodents can develop chronic insomnia, and if so does this occur in a fashion that is analogous to, or relevant for, the human condition ? In the absence of data, it stands to reason that the conditioning factors that appear to be operative with human insomnia are also likely to be operational in the rodent. If true, an animal model of chronic insomnia is possible and may be used to explore the effects of conditioned arousal or conditioned wakefulness on brain function, physiology, and anatomy. In the end, the differences in emphasis among the neurocognitive model, the psychobiological inhibition model, and the cage exchange model might not be a matter of which is correct but rather at what point the various models are more or less relevant. The assessment of such a proposition awaits empirical assessment, such as a large-scale natural history study focused on the factors that mediate the transitions from good sleep to acute insomnia and from acute insomnia to chronic insomnia. It stands to reason that stress response, attention bias, conditioning, and altered neurobiology all play a role across the trajectory from acute to chronic insomnia. Finally, there is the Drosophila model. At first glance it appears that this model highlights an entirely different component or phase of the disease process (genetic predisposition) and as such is potentially more relevant for idiopathic insomnia and has little overlap with models that are almost entirely focused on the precipitation and perpetuation of insomnia in the context of psychophysiologic or paradoxical insomnia. This, however, might not be the case. The Shaw Drosophila model might also be relevant for issues pertaining to the precipitation and perpetuation of insomnia. This may be true because the selective breeding paradigm might have resulted in a fundamental alteration of the strength and plasticity of the sleep system, the trigger threshold for and intensity of the flight-or-fight response, or the robustness of sleep or circadian processes. It is also possible that the selective breeding paradigm (particularly the short sleep aspect) might have itself directly predisposed the animals to insomnia. That is,
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Shaw and colleagues bred short sleepers without altering the environment (duration of the light–dark cycles) in such a way as to be compatible with short sleep. Thus, as with humans, it is possible that the insomnia was expressed as a result of a mismatch between sleep ability and sleep opportunity. In humans with psychophysiologic (and potentially paradoxical) insomnia, this mismatch is posited to result from sleep extension (activities enacted to recover lost sleep). In the Drosophila model the mismatch might occur because the animal cannot escape the environmental imperative for sleep. As with the above speculation, this concept also awaits an empirical evaluation; in this case one where the light–dark cycles may be altered to match sleep–wake propensity or where an opportunity is provided for the fly to manipulate its environment so as to allow light and dark exposure on demand. Under such conditions, if negative consequences are attenuated, this would suggest that the Drosophila model is also relevant for the primary insomnias. Acknowledgement The authors thank Dan Buysse for his feedback on this chapter. His insights and challenging perspective served to make this work immeasurably better.
❖ Clinical Pearls While many consider theory and experimental models of clinical entities to be largely academic enterprises, this is far from the case for the models summarized in the present chapter. Each model clearly suggests one or more targets for treatment, which might or might not be currently addressed by current therapeutics.
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864 PART II / Section 10 • Insomnia 38. Rechtschaffen A, Monroe L. Laboratory studies of insomnia. In: Kales A, editor. Sleep: physiology and pathology. Philadelphia: JB Lippincott; 1969. p. 158-169. 39. Freedman R. EEG power in sleep onset insomnia. Electroencephalogr Clin Neurophysiol 1986;63:408-413. 40. Merica H, Gaillard JM. The EEG of the sleep onset period in insomnia: a discriminant analysis. Physiol Behav 1992;52:199-204. 41. Merica H, Blois R, Gaillard JM. Spectral characteristics of sleep EEG in chronic insomnia. Eur J Neurosci 1998;10:1826-1834. 42. Lamarche CH, Ogilvie RD. Electrophysiological changes during the sleep onset period of psychophysiological insomniacs, psychiatric insomniacs, and normal sleepers. Sleep 1997;20:724-733. 43. Perlis ML, Smith MT, Orff HJ, et al. Beta/Gamma EEG activity in patients with primary and secondary insomnia and good sleeper controls. Sleep 2001;24:110-117. 43a. Fernandez-Mendoza J, Vela-Bueno A, Vgontzas AN, Ramos-Platón MJ, et al. Cognitive-emotional hyperarousal as a premorbid characteristic of individuals vulnerable to insomnia. Psychosom Med 2010;72(4):397-403. 44. Nofzinger EA, Buysse DJ, Germain A, et al. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry 2004;161:2126-2129. 45. Nofzinger EA, Buysse DJ, Germain A, et al. A comparison of regional cerebral metabolism across waking and NREM sleep between primary insomnia and major depression. Sleep 2005;28:A232-A233. 46. Bastien CH, St Jean G, Morin CM, et al. Chronic psychophysiological insomnia: hyperarousal and/or inhibition deficits? An ERPs investigation. Sleep 2008;31:887-898. 47. Yang CM, Lo HS. ERP evidence of enhanced excitatory and reduced inhibitory processes of auditory stimuli during sleep in patients with primary insomnia. Sleep 2007;30:585-592. 48. Nofzinger EA, Price JC, Meltzer CC, et al. Towards a neurobiology of dysfunctional arousal in depression: the relationship between beta EEG power and regional cerebral glucose metabolism during NREM sleep. Psychiatry Res 2000;98:71-91. 49. Krystal AD, Edinger JD, Wohlgemuth WK, Marsh GR. NREM sleep EEG frequency spectral correlates of sleep complaints in primary insomnia subtypes. Sleep 2002;25:630-640. 50. Mendelson W, Martin J, Stephens H, et al. Effects of flurazapam on sleep, arousal threshold, and perception of being asleep. Psychopharmacology (Berl) 1988;95:258-262. 51. Mendelson W. Do studies of sedative/hypnotics suggest the nature of chronic insomnia. In: Monplasir J, Godbout R, editors. Sleep and biological rhythms. New York: Oxford University Press; 1990. p. 209-218. 52. Mendelson W, Maczaj M. Effects of triazolam on the perception of sleep and wakefulness in insomniacs. Ann Clin Psychiatry 1990;2:211-216. 53. Mendelson W. Pharmacologic alteration of the perception of being awake. Sleep 1993;16:641-646. 54. Mendelson W. Hypnotics and the perception of being asleep. ASDA News 1994;1:33. 55. Mendelson WB. Effects of time of night and sleep stage on perception of sleep in subjects with sleep state misperception. Psychobiology 1998;26:73-78. 56. Harris J, Lack L, Wright H, et al. Intensive sleep retraining treatment for chronic primary insomnia: a preliminary investigation. J Sleep Res 2007;16:276-284. 57. Marchetti LM, Biello SM, Broomfield NM, et al. Who is pre-occupied with sleep? A comparison of attention bias in people with psychophysiological insomnia, delayed sleep phase syndrome and good sleepers using the induced change blindness paradigm. J Sleep Res 2006;15:212-221. 58. Espie CA. Insomnia: conceptual issues in the development, persistence, and treatment of sleep disorder in adults. Annu Rev Psychol 2002;53:215-243. 59. Shiffrin RM, Schneider W. Controlled and automatic human information-processing 2. Perceptual learning, automatic attending, and a general theory. Psychol Rev 1977;84:127-190. 60. Mogg K, Bradley BP. A cognitive-motivational analysis of anxiety. Behav Res Ther 1998;36:809-848. 61. Williams JMG, Watts FN, MacLeod CM, Mathews A. Cognitive psychology and emotional disorders. 2nd ed. New York: John Wiley; 1997. 62. Mathews A, MacLeod C. Cognitive approaches to emotion and emotional disorders. Annu Rev Psychol 1994;45:25-50.
63. Dalgleish T, Watts FN. Biases of attention and memory in disorders of anxiety and depression. Clin Psychol Rev 1990;10:589-604. 64. Lusher J, Chandler C, Ball D. Alcohol dependence and the alcohol Stroop paradigm: evidence and issues. Drug Alcohol Depen 2004;75:225-231. 65. Taylor LM, Espie CA, White CA. Attentional bias in people with acute versus persistent insomnia secondary to cancer. Behav Sleep Med 2003;1:200-212. 66. Jones BT, Macphee LM, Broomfield NM, et al. Sleep-related attentional bias in good, moderate, and poor (primary insomnia) sleepers. J Abnorm Psychol 2005;114:249-258. 67. MacMahon KMA, Broomfield NM, et al. Attention bias for sleeprelated stimuli in primary insomnia and delayed sleep phase syndrome using the dot-probe task. Sleep 2006;29(11):1420-1427. 68. Woods H, Marchetti LM, Biello SM, Espie CA. The clock as a focus of selective attention in those with primary insomnia: an experimental study using a modified Posner paradigm. Behav Res Ther 2009;47:231-236. 69. Spiegelhalder K, Espie C, Riemann D. Is sleep-related attentional bias due to sleepiness or sleeplessness? Cognition & Emotion 2009;23:541-550. 70. Broomfield NM, Espie CA. Toward a valid, reliable measure of sleep effort. J Sleep Res 2005;14(4):401-407. 71. Heath AC, Kendler KS, Eaves LJ, Martin NG. Evidence for genetic influences on sleep disturbance and sleep pattern in twins. Sleep 1990;13:318-335. 72. Watson NF, Goldberg J, Arguelles L, Buchwald D. Genetic and environmental influences on insomnia, daytime sleepiness, and obesity in twins. Sleep 2006;29:645-649. 73. Drake CL, Scofield H, Roth T. Vulnerability to insomnia: the role of familial aggregation. Sleep Med 2008;9:297-302. 74. Beaulieu-Bonneau S, LeBlanc M, Merette C, et al. Family history of insomnia in a population-based sample. Sleep 2007;30:1739-1745. 75. Greenspan RJ. The flexible genome. Nat Rev Genet 2001;2:383387. 76. Dierick HA, Greenspan RJ. Molecular analysis of flies selected for aggressive behavior. Nat Genet 2006;38:1023-1031. 77. Andretic R, Shaw PJ. Essentials of sleep recordings in Drosophila: moving beyond sleep time. Methods Enzymol 2005;393:759-772. 78. Le Bourg E, Buecher C. Learned suppression of photopositive tendencies in Drosophila melanogaster. Anim Learn Behav 2002;30:330-341. 79. Seugnet L, Suzuki Y, Vine L, et al. D1 receptor activation in the mushroom bodies rescues sleep-loss-induced learning impairments in Drosophila. Curr Biol 2008;18:1110-1117. 80. Tamakoshi A, Ohno Y. Self-reported sleep duration as a predictor of all-cause mortality: results from the JACC study, Japan. Sleep 2004;27:51-54. 81. Granger DA, Kivlighan KT, el Sheikh M, et al. Salivary alphaamylase in biobehavioral research: recent developments and applications. Ann N Y Acad Sci 2007;1098:122-144. 82. Nater UM, La Marca R, Florin L, et al. Stress-induced changes in human salivary alpha-amylase activity—associations with adrenergic activity. Psychoneuroendocrinology 2006;31:49-58. 83. Dantzer R, Kalin N. Salivary biomarkers of stress: cortisol and alphaamylase. Psychoneuroendocrinology 2009;34:1. 84. DeCaro JA. Methodological considerations in the use of salivary alpha-amylase as a stress marker in field research. Am J Hum Biol 2008;20:617-619. 85. Robinson GE, Grozinger CM, Whitfield CW. Sociogenomics: social life in molecular terms. Nat Rev Genet 2005;6:257-270. 86. Edwards AC, Rollmann SM, Morgan TJ, Mackay TF. Quantitative genomics of aggressive behavior in Drosophila melanogaster. PLoS Genet 2006;2:e154. 87. Sorensen JG, Nielsen MM, Loeschcke V. Gene expression profile analysis of Drosophila melanogaster selected for resistance to environmental stressors. J Evol Biol 2007;20:1624-1636. 88. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999;354:1435-1439. 89. Van Dongen HP, Maislin G, Mullington JM, Dinges DF. The cumulative cost of additional wakefulness: dose-response effects on neurobehavioral functions and sleep physiology from chronic sleep restriction and total sleep deprivation. Sleep 2003;26:117-126. 90. Rechtschaffen A, Bergmann BM, Everson CA, et al. Sleep deprivation in the rat: X. Integration and discussion of the findings. Sleep 1989;12:68-87.
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CHAPTER 78 • Models of Insomnia 865 95. Richardson GS. Human physiological models of insomnia. Sleep Medicine 2007;8:S9-S14. 96. Merica H, Fortune RD. A neuronal transition probability model for the evolution of power in the sigma and delta frequency bands of sleep EEG. Physiol Behav 1997;62:585-589. 97. Perlis ML, Merica H, Smith MT, Giles DE. Beta EEG activity and insomnia. Sleep Med Rev 2001;5:365-376.
Psychological and Behavioral Treatments for Insomnia I: Approaches and Efficacy Charles M. Morin Abstract Insomnia can be triggered by a variety of precipitating events, but when it becomes a persistent problem, psychological and behavioral factors are almost always involved in perpetuating or exacerbating sleep disturbances over time. Effective management of persistent insomnia must address these perpetuating factors, which can involve sleep scheduling factors, poor sleep habits, conditioning, hyperarousal, excessive worrying, and erroneous beliefs about sleep. Psychological and behavioral therapies for persistent insomnia include sleep restriction, stimulus control therapy, relaxation training, cognitive therapy, and a combination of those methods, referred to as cognitive behavior therapy (CBT). Evidence from controlled clinical trials indicates that the majority of patients (70% to 80%) with persistent insomnia respond to treatment, and approximately half of them achieve clinical remission. Treatment produces significant improvements of sleep-onset latency, wake after sleep onset, sleep
CURRENT TREATMENT PRACTICES Insomnia is a common condition and carries a significant psychosocial, medical, and economic burden. Despite its high prevalence and negative impact, insomnia often remains unrecognized and untreated. Most patients who initiate treatment do so without professional consultation and often resort to a host of alternative remedies (herbal or dietary supplements) that have unknown risks and benefits.1 When insomnia is brought to professional attention, typically to a primary care physician, treatment is often limited to medication. Although hypnotic medications are clinically indicated and useful in selected situations, psychological and behavioral factors are almost always involved in perpetuating sleep disturbances,2-4 and these factors must be addressed for effective management of chronic insomnia. With solid evidence supporting their efficacy and acceptability by patients, as well as their relative lack of adverse effects, psychological and behavioral therapies are increasingly recognized as valid therapeutic approaches and are often the treatments of choice for persistent insomnia.5 This chapter describes validated psychological and behavioral interventions and summarizes the evidence regarding their efficacy and generalizability. Clinical issues related to implementing treatment and feasibility of treatment are briefly addressed, because these issues are the focus of another chapter. TREATMENTS Treatment options for insomnia can be divided in three broad classes of interventions including psychological and behavioral therapies, pharmacotherapy, and a variety of 866
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efficiency, and sleep quality. These benefits are paralleled by reductions of daytime fatigue, psychological symptoms, and use of hypnotics. Changes in sleep patterns are well sustained after completing therapy. Treatment outcomes have been documented primarily with prospective sleep diaries; studies using polysomnography and actigraphy have also shown sleep improvements but of smaller magnitude. Psychological and behavioral therapies should be the firstline therapy for persistent insomnia. Specific indications include both primary insomnia and insomnia comorbid with medical and psychiatric disorders, insomnia in older adults, and insomnia associated with chronic hypnotic usage. Despite strong evidence supporting their efficacy and effectiveness, psychological and behavioral approaches remain under utilized by health care practitioners. An important challenge for the future will be to disseminate more effectively these evidence-based therapies and increase their use in routine clinical practice.
complementary and alternative therapies. This chapter is about psychological and behavioral interventions that have been validated in controlled clinical trials for persistent insomnia. These methods include sleep restriction, stimulus control therapy, relaxation-based interventions, cognitive strategies, sleep hygiene education, or a combination of these, which is often referred to as cognitive behavior therapy (CBT). Sleep hygiene education, although useful, must be distinguished from more formal CBT because sleep hygiene education is often insufficient to treat chronic insomnia. A summary of these interventions is provided in Box 79-1; more extensive descriptions are available in other sources.4,6,7 Rationale and Indications The main targets of CBT include factors (psychological, behavioral, cognitive) that perpetuate or exacerbate sleep disturbances. Such features may include sleep scheduling factors, poor sleep habits, conditioning, hyperarousal, faulty beliefs and excessive worrying about sleep, and inadequate sleep hygiene practices (see Chapters 77 and 78).2,4,8-10 Although numerous factors (e.g., life events, medical illness) can precipitate insomnia, when it becomes a persistent problem, psychological and behavioral factors are almost always involved in perpetuating it over time, hence the need to target those factors directly in treatment. CBT does not seek, however, to alter personality traits that might predispose to insomnia. Insight-oriented psychotherapy focusing on such predisposing variables may be useful in some patients, but there has been no controlled evaluation of its efficacy specifically for insomnia. The main indication for CBT is persistent insomnia, both for primary insomnia and insomnia occurring in the
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Box 79-1 Psychological and Behavioral Treatments for Persistent Insomnia Sleep Restriction A method designed to restrict time spent in bed (i.e., the sleep window) as close as possible to the actual sleep time, thereby strengthening the homeostatic sleep drive. This sleep window is then gradually increased over a period of a few days or weeks until optimal sleep duration is achieved. Stimulus Control A set of instructions designed to reinforce the association between the bed and bedroom with sleep and to re-establish a consistent sleep–wake schedule: • Go to bed only when sleepy • Get out of bed when unable to sleep • Use the bed/bedroom for sleep only (no reading, watching TV, etc.) • Arise at the same time every morning • No napping Relaxation Training Clinical procedures (e.g., progressive muscle relaxation, meditation) aimed at reducing autonomic arousal, muscle tension, and intrusive thoughts interfering with sleep. Most relaxation procedures require some professional guidance initially and daily practice over a period of a few weeks. Cognitive Therapy Psychological approach using socratic questioning and behavioral experiments to reduce excessive worrying about sleep and to reframe faulty beliefs about insomnia and its daytime consequences. Usually requires a trained and skilled clinician. Additional cognitive strategies may involve paradoxical intention technique to alleviate performance anxiety associated with the attempt to fall asleep. Sleep Hygiene Education General guidelines about health practices (e.g., diet, exercise, substance use) and environmental factors (e.g., light, noise, excessive temperature) that may promote or interfere with sleep. This may also include some basic information about normal sleep and changes in sleep patterns with aging. Cognitive Behavior Therapy A multimodal intervention combining some of the above cognitive and behavioral (e.g., stimulus control, sleep restriction, relaxation) procedures.
context of another medical or psychiatric disorder. It is also indicated for insomnia in older and in younger adults, and for patients with prolonged use of hypnotics, although chronic use of hypnotics can interfere with CBT’s objectives. There is no absolute contraindication to using CBT. Sleep restriction is contraindicated in patients with a history of seizures, some parasomnias (e.g., sleepwalking), or bipolar illness because sleep restriction can lower the threshold for a seizure or sleepwalking episode and might exacerbate a manic episode. Sleep restriction should also be used cautiously with patients who need to drive
or operate heavy equipment and with those who might otherwise be at increased risk for falling asleep during the day. Some stimulus control procedures (e.g., getting out of bed when unable to sleep) should be used with caution with the frail elderly, who may be at risk for falls when getting out of bed.11 Sleep Restriction There is a natural tendency among persons with insomnia to increase the amount of time they spend in bed simply to rest or provide more opportunity for sleep. Although this strategy may be effective in the short term, in the long run it is more likely to result in fragmented and poorquality sleep. Sleep restriction therapy consists of curtailing the amount of time spent in bed as close as possible to the actual amount of time asleep.12 Time in bed is subsequently adjusted on the basis of sleep efficiency (ratio of total sleep time per time in bed × 100%) for a given period, usually the preceding week. For example, if a person reports sleeping an average of 6 hours per night out of 8 hours spent in bed, the initial prescribed sleep window (i.e., from initial bedtime to final arising time) would be 6 hours. The subsequent allowable time in bed is increased by about 15 to 20 minutes for a given week when sleep efficiency exceeds 85%, it is decreased by the same amount of time when sleep efficiency is lower than 80%, and it is kept stable when sleep efficiency falls between 80% and 85%. Adjustments are made periodically (weekly) until optimal sleep duration is achieved. Changes to the prescribed sleep window can be made at the beginning of the night (i.e., postponing bedtime), at the end of the sleep period (i.e., advancing arising time), or at both ends. Some variations in implementation might involve changing the time in bed on the basis of a moving average of the sleep efficiency (e.g., the past 3 to 5 days) or changing it on a weekly basis regardless of changes in sleep efficiency.13 Sleep restriction improves sleep continuity through two complementary mechanisms: It strengthens the homeostatic sleep drive through a mild sleep deprivation, and it alleviates some of the sleep anticipatory anxiety by changing the patient’s focus of attention (i.e., asking to stay up later rather than going to bed early). To prevent excessive daytime sleepiness, time in bed should not be reduced to less than 5 hours per night, regardless of the number of hours of sleep reported by the patient. This caution is particularly indicated for those whose jobs require operating motor vehicles or who have duties in which drowsiness may be a danger to the patient or others. Stimulus Control Therapy Stimulus control therapy14 involves five instructions designed to reassociate temporal (bedtime) and environmental (bed and bedroom) stimuli with rapid sleep onset and to establish a regular circadian sleep–wake rhythm. These are: • Go to bed only when sleepy—not just fatigued, but sleepy. • Get out of bed when unable to sleep (e.g., after 20 minutes), go to another room, and return to bed only when sleep is imminent.
868 PART II / Section 10 • Insomnia
• Curtail all sleep-incompatible activities, overt and covert: no eating, watching television, listening to the radio, or planning or problem solving in bed. • Arise at a regular time every morning regardless of the amount of sleep the night before. • Avoid daytime napping. Persons with insomnia often develop apprehension around bedtime and the bedroom and come to associate this particular time of the day and environment with the frustration of being unable to sleep. Over time, the presleep rituals usually associated with relaxation and sleep become cues or stimuli for worrying and wakefulness. This conditioning process can take place over several weeks or months. In addition, many insomniac patients display poor sleep habits that initially emerge as a means of coping with sleep disturbances. For example, poor sleep at night can lead to daytime napping or sleeping late on weekends in an effort to catch up on lost sleep. Such persons might lie in bed for prolonged periods trying to force sleep, only to find themselves becoming more awake. Stimulus-control procedures are designed to recreate a positive association between the presleep rituals and the bedroom environment. Stimulus control instructions appear quite simple on paper; however, the challenge for clinicians is to foster strict compliance with these instructions. Several consultation visits held on a weekly or biweekly basis are often necessary to assist patients in implementing these behavioral changes. When combined with sleep restriction, some of the stimulus-control procedures may be less relevant or even in conflict (e.g., going to bed only when sleepy, when the prescribed sleep window is fixed). Such situations might occur early on in treatment when time in bed is significantly reduced; as the sleep window is increased, all these procedures become more relevant. Also, daytime napping is usually discouraged in the treatment of insomnia, but a short nap in midday may be permissible in the early phase of sleep restriction, particularly in older adults, if it helps improve compliance with the adjusted sleep window at night. This option is usually phased out by midtreatment. Relaxation-Based Interventions Because stress, tension, and anxiety are often contributing factors to sleep disturbances, relaxation is probably the most commonly used intervention for insomnia. The goal of this treatment is to reduce arousal at bedtime or on nighttime awakening. Among the different relaxation interventions, some methods (e.g., progressive muscle relaxation, autogenic training) focus primarily on reducing somatic arousal, whereas attention-focusing procedures (e.g., imagery training, meditation, thought stopping) target mental arousal in the form of worries, intrusive thoughts, or a racing mind.15,16 Mindfulness therapy is another form of relaxation that has been evaluated in the management of insomnia.17 Biofeedback is designed to train patients to control some physiologic parameters (e.g., tension, using electromyography) through visual or auditory feedback; despite its popularity in the 1980s, this method is not commonly used today. Most relaxation procedures are equally effective for treating insomnia. Selection of a particular method (e.g.,
progressive muscle relaxation versus meditation) should be based on the subtype of arousal (autonomic versus cognitive) interfering with sleep, although these often overlap, as well as on the patient’s preference and skills in learning the technique. There is no formal contraindication to using relaxation, but some patients—those who tend to be perfectionists—might have a paradoxical response and actually become more anxious when trying to relax. The most critical issue is to ensure diligent and daily practice of the selected method for at least 2 to 4 weeks and to keep the focus on reducing arousal rather than on inducing sleep. Professional guidance is often necessary during initial training. Sometimes, it is necessary to implement a more comprehensive stress-management program involving relaxation and other therapeutic components, such as time management and problem-solving training. Cognitive Therapy Cognitive therapy for insomnia seeks to alter sleep-disruptive cognitions (e.g., beliefs, expectations) and maladaptive cognitive processes (e.g., excessive self-monitoring, worrying) through socratic questioning and behavioral experiments.10,18 The basic premise of this approach is that appraisal of a given situation (sleeplessness) can trigger negative thoughts and emotions (fear, anxiety) that are incompatible with sleep. For example, when a person is unable to sleep at night and worries about the possible consequences of sleep loss on the next day’s performance, a spiral reaction is set off that feeds into a vicious cycle of emotional distress, increased arousal, and more sleep disturbance. Likewise, upon night waking, a person may engage in self-monitoring (e.g., clock watching to check how many hours are left in the night) and safety activities (e.g., trying to stop thinking), which can prolong the nocturnal awakenings.8 Cognitive therapy is designed to short-circuit the selffulfilling nature of this vicious cycle through verbal interventions and behavioral homework. Some therapeutic targets for cognitive restructuring include unrealistic expectations (“I must get my 8 hours of sleep every night”), faulty causal attributions (“My insomnia is entirely caused by a biochemical imbalance”), and amplification of the consequences of insomnia (“After a poor night’s sleep, I am unable to function the next day”). There are several key messages to communicate to patients in the context of cognitive therapy: • Keep realistic expectations with regard to sleep requirements and daytime energy. • Do not blame insomnia for all daytime impairments because there may be other explanations (worries about family, conflicts with coworkers) for these deficits. • Never try to sleep, because it is likely to exacerbate sleep difficulties. • Do not give too much importance to sleep. Although sleep should be a priority, it should not become the central point of life. • Do not catastrophize after a poor night’s sleep. Insomnia is very unpleasant, but it is not necessarily dangerous to health, at least not in the short term. • Develop some tolerance to the effects of insomnia. If you are predisposed to insomnia, it is likely that you will remain vulnerable to sleep disturbances
CHAPTER 79 • Psychological and Behavioral Treatments for Insomnia I: Approaches and Efficacy 869
even after treatment and you might as well develop strategies to cope with these occasional nights of poor sleep. In addition to these verbal interventions, behavioral experiments can be helpful to change a person’s beliefs about sleep and insomnia. For example, if a patient is convinced that bed rest is a good strategy to conserve energy, a behavioral experiment is designed to test the validity of this belief: The patient is instructed to engage specifically in this strategy (bed rest) on a day following insomnia and, on another day, to engage in the opposite behavior, such as performing a series of activities designed to generate energy after a poor night’s sleep (e.g., exercising, meeting with friends, doing errands). Such homework assignments can be quite effective to change a person’s belief about ways to preserve or generate energy in the context of insomnia.19 Additional cognitive strategies may be useful in treating insomnia. For instance, paradoxical intention is a procedure designed to eliminate performance anxiety. In the context of insomnia, any attempt to control or induce sleep voluntarily is likely to generate performance anxiety and to delay sleep onset. With paradoxical intention, the patient is instructed to remain passively awake and to give up any effort (intention) to fall asleep, the rationale being that good sleepers do not make any effort to fall asleep. To minimize worrying and mental activity interfering with sleep, it is also helpful to instruct patients to set aside a time and a place (other than bedtime and the bedroom) to write down thoughts or worries of the day and plans for the next day. Imagery techniques can also be useful to block out such unwanted presleep thoughts.20 Sleep Hygiene Education Sleep hygiene education is intended to provide information about lifestyle (diet, exercise, substance use) and environmental factors (light, noise, temperature) that might either interfere with or promote better sleep.16 It could also include general sleep-facilitating recommendations, such as allowing enough time to relax before bedtime, avoiding clock watching, and maintaining a regular sleep schedule. Some of these instructions overlap with other behavioral procedures. Sleep hygiene guidelines include: • Avoid stimulants (e.g., caffeine, nicotine) for several hours before bedtime. • Avoid alcohol around bedtime, because it fragments sleep. • Exercise regularly (especially in late afternoon or early evening). • Allow at least a 1-hour period to unwind before bedtime. • Keep the bedroom environment quiet, dark, and comfortable. • Maintain a regular sleep schedule. Although inadequate sleep hygiene is rarely the primary cause of insomnia, it can potentiate sleep difficulties caused by other factors or can interfere with treatment progress. Even when patients are well informed about the detrimental impact of poor sleep hygiene, they might not maintain good sleep hygiene practices. Thus, it is important to directly address these factors in therapy. On the other hand, although sleep-hygiene education may be helpful for mild insomnia, it is rarely sufficient for more severe insom-
nia, which requires more directive and potent behavioral interventions.21,22 A didactic approach can also be used to provide basic information about normal sleep, individual differences in sleep needs, and changes in sleep physiology with aging. This information is useful to help some patients distinguish clinical insomnia from normal (age-related) sleep disturbances. Such knowledge can prevent excessive worry and concern, which can themselves lead to clinical insomnia. Multifaceted Cognitive Behavior Therapy Single interventions described to this point are not incompatible with each other and can be combined effectively. Multicomponent therapy is becoming the preferred approach to treating insomnia. In a systematic review of the literature, 26 of 37 clinical studies conducted between 1999 and 2004 had evaluated a multicomponent approach for persistent insomnia.22 This approach typically included a behavioral (stimulus control, sleep restriction, and, sometimes, relaxation), a cognitive (cognitive restructuring therapy), and an educational component (sleep hygiene), hence the term cognitive behavior therapy (CBT). This multimodal approach is appealing because it addresses different insomnia features with different therapeutic recommendations, which is consistent with a multidimensional etiologic model of insomnia (see Chapter 78).2-4,8 Complementary and Alternative Therapies Several complementary and alternative therapies, within the nondrug domain, have been used in the treatment of chronic insomnia. These include acupuncture, tai chi, hypnosis, exercise, and electrosleep therapy. Although potentially useful in clinical practice, those methods have not been evaluated as extensively in controlled studies as the other interventions previously described.
TREATMENT OUTCOME EVIDENCE Evidence for Efficacy Several meta-analyses21,23-25 and systematic reviews22,26 have summarized the findings from clinical trials evaluating the efficacy and psychological and behavioral therapies for insomnia. Evidence from these different sources shows that treatment produces reliable changes in several sleep parameters (Fig. 79-1), including sleep latency (effect sizes, 0.41 to 1.05), wake after sleep onset (0.61 to 1.03), number of awakenings (0.25 to 0.83), total sleep time (0.15 to 0.49), and sleep quality ratings (0.94 to 1.14). These effect sizes are considered large (Cohen’s effect size d > 0.8) for sleep latency, wake after sleep onset, and sleep quality and moderate (d > 0.5) for other sleep parameters. When transformed into a percentile rank, these data indicate that approximately 70% to 80% of patients with insomnia benefit from treatment. These effect sizes are similar to those obtained for benzodiazepine-receptor agonists,24,27 with a slight advantage for CBT on measures of sleep onset latency and sleep quality and for pharmacotherapy on total sleep time. In terms of absolute changes, treatment reduces subjective (sleep diary) sleep latency and time awake after sleep
870 PART II / Section 10 • Insomnia
1.19
Effect size
1.2 1 Large 0.8 Medium
0.6 0.4
0.94
0.84 0.66 0.46
Small 0.2
Sl ee la p-o te n nc se y t W sl ak ee e p af on te se r t N aw um ak be en r o in f To gs ta tim l sle e ep Sl ee p qu al ity
0
Figure 79-1 Mean effect size (reported as a standardized z score) across sleep parameters. These effect sizes are pooled across three meta-analyses. (Data from Morin CM, Culbert JP, Schwartz SM. Nonpharmacological interventions for insomnia: a meta-analysis of treatment efficacy. Am J Psychiatry 1994;151:1172-1180; Murtagh DR, Greenwood KM. Identifying effective psychological treatments for insomnia: a meta-analysis. J Consult Clin Psychol 1995;63:79-89; and Smith MT, Perlis ML, Park A, et al. Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia. Am J Psychiatry 2002;159:5-11.)
onset from an average of 60 to 70 minutes at baseline to about 35 minutes after treatment. Total sleep time is increased by an average of 30 minutes, from 6 to 6.5 hours after treatment, with additional gains made after treatment is completed. Thus, for the average patient with persistent insomnia, often exceeding 10 years in duration, CBT may be expected to reduce sleep latency and wake after sleep onset by an average of about 50% and to bring the absolute values of those sleep parameters below or near the 30-minute cutoff criterion initially used to define sleep-onset or sleep-maintenance insomnia. Treatment effects are generally equivalent for sleep-onset and sleepmaintenance problems, although no study has targeted specifically the early-morning awakening problems. Overall, findings from meta-analyses represent fairly conservative estimates of treatment effects, because they are based on group averages pooled across all psychological and behavioral interventions, insomnia diagnoses (i.e., primary and comorbid), and age groups. Although the majority of patients benefit from treatment, only about half of them achieve full remission, and a significant number continue to experience residual sleep disturbances.22,28,29 Treatment outcome has been documented primarily with prospective daily sleep diaries, although several studies have complemented those findings with polysomnography (PSG)30-32 and actigraphy.33-35 In general, the magnitude of improvements is smaller on PSG measures, but those changes tend to parallel sleep improvements reported in daily sleep diaries. For example, in a study of older adults with sleep-maintenance insomnia,30 average baseline values for wake after sleep onset were 62 minutes for diaries and 73 minutes for PSG measures. Posttreatment values were 29 minutes for the diary and 35 minutes for PSG, yielding improvement rates of 54% and 51%, respectively, for the two assessment methods. In another study,34 sleep efficiency increases of 8% and 12% were
obtained for PSG and diary measures, respectively, after CBT. Collectively, these findings indicate that CBT not only alters sleep perception on daily diaries but also produces objective changes on EEG-defined sleep-continuity measures. Except for a modest increase in stages 3 and 4 after sleep restriction, there are few changes in sleep stages with CBT. In addition to showing robust changes on sleep–wake parameters, CBT has produced some improvements on secondary end points including the insomnia symptoms severity, sleep quality, fatigue, quality of life, sleep-related beliefs, and psychological symptoms (anxiety and depression). These findings are discussed later. Table 79-1 summarizes the main features (patients’ demographics, diagnosis, types of treatment, and outcomes) of selected randomized clinical trials evaluating the efficacy of psychological and behavioral treatments for primary and comorbid insomnia.36-49 This is only a sample of the more than 60 published studies in the last decade; other studies not listed in this table, as well as other sources of evidence (e.g., meta-analyses), are used in the following discussion. Generalizability of Treatment Effects to Comorbid Insomnia Insomnia is often a pervasive problem among patients with medical or psychiatric conditions.5 Although it is generally assumed that the sleep disturbance will remit with appropriate treatment of the comorbid condition, insomnia can persist and is even a risk factor for future relapse, for instance, of major depression. Thus, an important question is whether these patients with comorbid disorders can also benefit from CBT for insomnia.50 Several clinical case series29,51-55 suggest that patients with medical and psychiatric conditions can also benefit from insomnia-specific treatment, even though the outcome with those patients is more modest compared to patients with primary insomnia. Recent randomized, controlled studies have also shown that CBT is effective for treating insomnia associated with chronic pain,56 fibromyalgia,40 cancer,41,46 and various medical conditions in older adults.27,37,44,46,57,58 For example, the data shown in Figure 79-2 illustrate changes in insomnia severity (as rated by patients, clinicians, and spouses) over time with CBT. These sleep improvements were paralleled by reductions of depressive and fatigue symptoms. Another study43 showed that CBT had an augmentation effect when used in combination with antidepressant medication in the treatment of insomnia comorbid with major depression. The addition of CBT for insomnia, relative to antidepressant therapy alone, resulted in higher remission rates of depression (61.5% versus 33.3%) and insomnia (50% versus 7.7%) and larger improvements in measures of sleep continuity. In general, the findings from studies of comorbid insomnia indicate that baseline and posttreatment scores on insomnia measures are usually more severe among patients with comorbid disorders, but the absolute changes on those outcomes are comparable to those among patients with primary insomnia. To optimize treatment response, it may be necessary to adapt these interventions to Text continued on p. 879
SAMPLE SIZE
45
75
201
Bastien et al. (2004)36
Edinger et al. (2001)32
Espie et al. (2007)33
Primary Insomnia
AUTHOR(S) (YEAR)
68.2
46.7
64
% WOMEN
54
55.8
41.8
MEAN AGE (YR)
PATIENTS
Primary and comorbid insomnia
Primary insomnia
Primary insomnia
DIAGNOSIS
CBT Usual care from primary care physician
CBT Progressive muscle relaxation Placebo (psychological)
Individual CBT Group CBT Self-help CBT and telephone support
TREATMENT CONDITIONS
Table 79-1 Randomized Clinical Trials of Cognitive Behavior Therapy
5 weekly 1-hr grouptherapy sessions
6/6
8
TREATMENT (WK/HR)
6
6
6
FOLLOW-UP (MO)
Sleep diaries, actigraphy, PSQI, SF-36
Sleep diaries, PSG, BDI, Insomnia Symptom Questionnaire
Sleep diaries, ISI; DBAS, BAI, BDI
OUTCOME MEASURES
Continued
CBT patients improved significantly more than usual care patients on subjective SOL, WASO, and SE Greater changes for CBT on actigraphy measures for WASO but not for SOL or SE Better treatment response for CBT on secondary measures of PSQI and SF-36 (mental health and energy/ vitality subscales)
CBT produced larger subjective ↓ of WASO (54%) than relaxation training (16%) or placebo (12%) PSG changes were smaller, but CBT was also more effective Sleep changes maintained at 6-mo f/u
No group differences on main sleep variables; average SE ↑ of 13% and TWT ↓ by 83 min across 3 treatments ISI, DBAS, BAI, and BDI scores ↓ in all conditions TST ↑ at f/u Treatment benefits were maintained at 6-mo f/u
OUTCOMES
CHAPTER 79 • Psychological and Behavioral Treatments for Insomnia I: Approaches and Efficacy 871
SAMPLE SIZE
63
89
SAMPLE
AUTHOR(S) (YEAR)
Jacobs et al. (2004)37
Lichstein et al. (2001)13
AUTHOR(S)
%
68
47.1
MEAN AGE (YR)
MEAN
PATIENTS
74
70
% WOMEN
PATIENTS
Primary insomnia
Primary insomnia
DIAGNOSIS
TREATMENT
Relaxation Sleep restriction Placebo (psychological)
CBT CBT + medication (zolpidem, 5-10 mg) Sleep hygiene + medication (zolpidem, 5-10 mg) Placebo (medication)
TREATMENT CONDITIONS
Table 79-1 Randomized Clinical Trials of Cognitive Behavior Therapy—cont’d
TREATMENT
FOLLOW-UP
12
12
8
6
FOLLOW-UP (MO)
TREATMENT (WK/HR)
OUTCOME
Sleep diaries, PSG, ESS, DBAS, Insomnia Impact Scale, Fatigue Severity Scale
Sleep diaries, BDI, Profile of Moods State Scale
OUTCOME MEASURES
Sleep restriction and relaxation more effective than placebo on sleep continuity variables at posttreatment and f/u No significant gains in daytime functioning No significant change on PSG measures All groups (including placebo) improved on the secondary sleep variables Sleep restriction produced best outcomes at f/u
CBT produced best improvements on SOL and SE, and TST ↑ in all conditions, with largest gain (78 min) in the medication only group No group difference on mood measures Treatment benefits maintained at f/u for CBT and CBT + medication conditions More CBT patients achieved clinically significant changes on SOL and SE measures
OUTCOMES
872 PART II / Section 10 • Insomnia
46
SIZE
47.8
WOMEN 60.8
AGE (YR) Primary insomnia
DIAGNOSIS CBT Medication (zopiclone, 7.5 mg) Placebo (medication)
CONDITIONS
Currie et al. (2004)39
60
30
43.3
Insomnia and alcohol dependence
CBT (with relaxation) Self-help CBT and telephone support Wait list control
Insomnia Comorbid with Medical, Psychiatric, and Substance Abuse Disorders
Sivertsen et al. (2006)38
(YEAR)
6
6
(WK/HR)
(MO)
6
6
Sleep diaries, actigraphy, ISI, PSQI, BDI, alcohol relapses
Sleep diaries, PSG
MEASURES
Continued
Participants receiving CBT ↑ SE by 7.5% to 10% and ↓ SOL by 18 minutes, with ↓ of ISI and PSQI scores Gains maintained (with further improvement on the ISI) at f/u 15% of participants had relapses with alcohol, no difference among the three conditions
No significant group differences on diary measures, except for CBT patients spending less time awake at f/u relative to medicated patients On PSG measures, CBT and medication more effective than placebo in ↓ SE; CBT more effective than both drug conditions in ↓ total wake time and ↓ SWS
OUTCOMES
CHAPTER 79 • Psychological and Behavioral Treatments for Insomnia I: Approaches and Efficacy 873
150
SAMPLE
AUTHOR(S)
47
Edinger et al. (2005)40
Espie et al. (2008)41
SAMPLE SIZE
AUTHOR(S) (YEAR)
%
61
48.6
MEAN AGE (YR)
MEAN
PATIENTS
68.7
95.7
% WOMEN
PATIENTS
Insomnia and cancer
Insomnia and fibromyalgia
DIAGNOSIS
TREATMENT
CBT Treatment as usual
CBT Sleep hygiene Usual care for fibromyalgia
TREATMENT CONDITIONS
Table 79-1 Randomized Clinical Trials of Cognitive Behavior Therapy—cont’d
TREATMENT
5 weekly group sessions delivered by oncology nurses
6
TREATMENT (WK/HR)
FOLLOW-UP
—
6
FOLLOW-UP (MO)
OUTCOME
Sleep diaries, actigraphy, QOL, fatigue, psychological symptoms
Sleep diaries, actigraphy, pain, mood, insomnia questionnaires, SF-36
OUTCOME MEASURES
CBT produced significant ↓ of SOL, WASO (diary and actigraphy), and SE (diary) compared to no change in usual care patients; these benefits were sustained at f/u Significant improvements also noted on measures of fatigue (mean effect size, 0.82), anxiety and depressive symptoms (0.52, 0.59), and QOL (range, 0.16-1.17)
CBT more effective than usual care on measures of SOL (diary and actigraphy), SE (diary), and TWT (diary); sleep hygiene patients did not differ from the other two groups More CBT patients achieved clinically meaningful treatment response (57%) relative to sleep hygiene education (17%) or the usual care group (0%) CBT and sleep hygiene improved more on most secondary measures relative to controls
OUTCOMES
874 PART II / Section 10 • Insomnia
49
30
Manber et al. (2008)43
SIZE
Lichstein et al. (2000)42
(YEAR)
61
48
WOMEN
35
68.6
AGE (YR)
Insomnia and comorbid major depression
Insomnia comorbid with medical or psychiatric conditions
DIAGNOSIS
Medication (escitalopram) for depression and CBT for insomnia Medication (escitalopram) for depression and placebo (psychological)
Multicomponent (stimulus control, relaxation, sleep hygiene education); Wait-list control
CONDITIONS
7/9
4
(WK/HR)
(MO) 3
Hamilton Rating Scale for Depression, sleep diaries, actigraphy, ISI
Sleep diaries, STAI, GDS, Insomnia Impact Scale
MEASURES
Continued
Relative to antidepressant alone, addition of CBT for insomnia resulted in higher remission rates of depression (61.5% vs 33.3%) and insomnia (50% vs. 7.7%) and larger improvement in diary and actigraphy measures of TWT and SE, but not for TST
No difference in outcome between insomnia secondary to medical or psychiatric disorders Larger improvements for treated patients relative to controls on WASO and SE measures SOL ↓ and TST ↑ in both conditions at posttreatment 57% of treated patients achieved clinical improvement compared with 19% of control patients; no significant change on secondary measures
OUTCOMES
CHAPTER 79 • Psychological and Behavioral Treatments for Insomnia I: Approaches and Efficacy 875
67.4
92
57
Rybarczyk et al. (2005)44
Savard et al. (2005)45
54.1
69
MEAN AGE (YR)
Insomnia in women with breast cancer
Insomnia comorbid with medical disorders
DIAGNOSIS
AUTHOR(S)
Belleville et al. (2007)46
SAMPLE
53
%
55.3
MEAN
PATIENTS
64.2
Chronic hypnotic use and insomnia
Insomnia in Older Adults and Chronic Hypnotic Users
100
% WOMEN
SAMPLE SIZE
AUTHOR(S) (YEAR)
PATIENTS
TREATMENT
Gradual hypnotic withdrawal with self-help CBT Gradual hypnotic withdrawal
CBT Wait-list control
CBT Stress management and wellness training (placebo control)
TREATMENT CONDITIONS
Table 79-1 Randomized Clinical Trials of Cognitive Behavior Therapy—cont’d
TREATMENT
8 weeks
8
8/16
TREATMENT (WK/HR)
FOLLOW-UP
12
FOLLOW-UP (MO)
OUTCOME
Sleep diaries, ISI, BDI, STAI, SF-36
Sleep diaries, PSG, ISI, Hospital Anxiety and Depression Scale, Multidimensional Fatigue Inventory, QOL
Sleep diaries, PSQI, ISI, DBAS, POMS, pain questionnaires, SF-36
OUTCOME MEASURES
Hypnotic use ↓ in both conditions, from nearly nightly use at baseline to 1/wk at posttreatment Addition of CBT produced more improvements of SE and TWT; TST remained stable throughout withdrawal in both conditions
CBT patients achieved significantly better responses than controls on sleep diary and ISI measures, lower frequency of medicated nights, lower depression and anxiety symptoms, and higher QOL at posttreatment Therapeutic effects were well maintained at f/u
CBT produced larger improvements compared to control on measures of SOL (effect size, 0.64), WASO (0.58), SE (0.77), but not TST (0.08) Greater changes noted for CBT on the PSQI (0.81), ISI (1.02), and DBAS (1.07) No significant changes on pain measures
OUTCOMES
876 PART II / Section 10 • Insomnia
209
76
Morin et al. (2004)48
SIZE
Morgan et al. (2003)47
(YEAR)
50
67.5
WOMEN
62.5
65.5
AGE (YR)
Chronic hypnotic use and insomnia
Chronic use of hypnotics and insomnia
DIAGNOSIS
CBT Medication taper Combined CBT + medication taper
CBT and medication withdrawal No treatment control
CONDITIONS
10
3 mo
(WK/HR) 6
12
(MO)
Sleep diaries, PSG, ISI, BAI, BDI, benzodiazepine use
PSQI, SF-36, use of hypnotic medication, treatment costs
MEASURES
Continued
All three groups ↓ quantity (90%) and frequency (80%) of benzodiazepine use, but more participants receiving the combined intervention were drug-free at posttreatment Modest changes in sleep during initial withdrawal, but participants receiving CBT reported greater sleep improvements relative to patients receiving medication taper alone Improvements reported on secondary variables (ISI, BAI BDI) in all three groups, with gains maintained through f/u
CBT produced significant improvements in PSQI (global, SOL, SE) and ↓ of hypnotic use More CBT patients (39%) than controls (11%) achieved at least a 50% ↓ or no hypnotic use at 6-mo f/u Lower SF-36 vitality scale at the 3-mo f/u in CBT than in control group Greater costs for CBT initially, but longer term cost offsets due to ↓ of sleep medication usage
OUTCOMES
CHAPTER 79 • Psychological and Behavioral Treatments for Insomnia I: Approaches and Efficacy 877
47
Soeffing et al. (2008)49
63.8
% WOMEN 64.2
MEAN AGE (YR) Chronic hypnotic use and insomnia
DIAGNOSIS Multicomponent treatment (relaxation training, stimulus control, sleep hygiene) Placebo (faked biofeedback)
TREATMENT CONDITIONS 8/8
TREATMENT (WK/HR)
FOLLOW-UP (MO)
Sleep diaries, SF-36, ESS, Insomnia Impact Scale, FSS, STAI
OUTCOME MEASURES
Active treatment produced better improvements relative to control on measures of SOL (effect size, 0.55), WASO (0.53), and SE (0.89) No significant change on secondary end points, including use of sleep medication, except for an ↑ in fatigue in treated patients.
OUTCOMES
↑, increase; ↓, decrease or reduction; BAI, Beck Anxiety Inventory; BDI, Beck Depression Inventory; CBT, cognitive behavior therapy; DBAS, dysfunctional beliefs and attitudes about sleep; ESS , Epworth Sleepiness Scale; FSS, Fatigue Severity Scale; f/u, longest available follow-up; GDS, Geriatric Depression Scale; ISI, Insomnia Severity Index; POMS, Profile of Mood States; PSG, polysomnography; PSQI, Pittsburgh Sleep Quality Index; QOL, Quality of Life; SE, sleep efficiency; SF-36, 36-Item Short-Form Health Survey; SOL, sleep onset latency; STAI, StateTrait Anxiety Inventory; SWS, slow-wave sleep; TST, total sleep time; TWT, total wake time; WASO, wake after sleep onset.
SAMPLE SIZE
AUTHOR(S) (YEAR)
PATIENTS
Table 79-1 Randomized Clinical Trials of Cognitive Behavior Therapy—cont’d
878 PART II / Section 10 • Insomnia
CHAPTER 79 • Psychological and Behavioral Treatments for Insomnia I: Approaches and Efficacy 879
20 CBT WLC
Score
16 12 8 4
P (c ost on -tx t.) 3fo M llo on w th -u p 6fo M llo on w th -u p 12 fo -M llo o w nth -u p
P po os st t-t w x ai or tin g
Pr etx
0
A
Time 20
Score
16 12 8 4
B
P (c ost on -tx t.) 3fo M llo on w th -u p 6fo M llo on w th -u p 12 fo -M llo o w nth -u p
P po os st t-t w x ai or tin g
Pr
e-
tx
0
Time 20
Score
16 12 8 4
Pr
e-
tx Po po s st t-t w x ai or tin g Po (c st on -tx t.) 3fo M llo on w th -u p 6fo M llo on w th -u p 12 fo -M llo o w nth -u p
0
C
Time
Figure 79-2 Changes in Insomnia Severity Index (ISI) total scores over assessment periods. A, ISI—patient. B, ISI— clinician. C, ISI—significant other. Patients initially assigned to the waiting-list control group received treatment after the initial waiting period (Reproduced with permission from Savard J, Simard S, Ivers H, Morin CM. Randomized study on the efficacy of cognitive-behavioral therapy for insomnia secondary to breast cancer, part I: sleep and psychological effects. J Clin Oncol 2005;23:6083-6096.).
disease-specific conditions50; for example, the addition of a fatigue-management module to standard CBT has proved helpful for insomnia comorbid with cancer45 and traumatic brain injury.52 Treatment of Insomnia in Older Adults Insomnia is age-related, and its treatment in older adults is receiving increasing attention from clinical investigators. For example, 9 of 37 treatment studies conducted between 1999 and 2004 were specifically with older adults.22 Two evidence-based review papers concluded that psychological and behavioral treatments are effective for managing insomnia in older adults. A meta-analysis25 showed robust
treatment effects in sleep continuity (mean effect sizes, 0.52 for sleep latency and 0.64 for time awake after sleep onset) and sleep quality (0.76) for older adults, with similar effects for CBT, relaxation, and behavioral approaches. Another systematic review reported that multimodal CBT and sleep restriction or sleep compression met criteria for empirically validated therapies, but there was not adequate evidence to support cognitive therapy, relaxation, and sleep hygiene education as stand-alone interventions for insomnia in older adults.59 Insomnia in the elderly is more likely to be comorbid with another medical condition or even another sleep disorder than to be primary. The presence of a comorbid medical disorder, however, is not a contraindication to using CBT for insomnia, unless it is a progressive and unstable medical illness. There is increasing evidence that psychological and behavioral approaches are effective for insomnia in the context of other medical and, to a lesser extent, psychiatric conditions.35,42,44,57,60 One study44 found that older adults with chronic obstructive pulmonary disease, osteoarthritis, or coronary artery disease responded equally well to group CBT relative to control patients. In addition to improving sleep continuity, treatment of insomnia in the elderly is usually associated with enhanced sleep satisfaction and quality of life. When patients are considered for CBT, they might already have been on hypnotic medication for a long period, which in itself can represent a challenge for clinicians. This clinical situation is more common in older adults, but it can occur with all age groups. Several studies have shown that a supervised, structured, and time-limited withdrawal program, with or without cognitive behavior therapy, can facilitate discontinuation of hypnotic medications among patients with prolonged use.46-49 In a study of 76 older adults who had used benzodiazepines for insomnia for nearly 20 years, treatment was effective to reduce both the quantity (90% reduction) and the frequency (80% reduction) of medication use, and 63% of the patients were drug-free within the 10-week intervention.48 The addition of CBT to the withdrawal program minimized rebound insomnia and reduced worries about drug discontinuation. Initial Treatment Response versus Long-Term Outcome Because insomnia is often a recurrent or persistent problem and CBT is a brief intervention, it is important to evaluate outcome beyond initial treatment. A robust finding across clinical trials is that sleep improvements achieved with CBT are well sustained after treatment is completed.21-23,26 Although sleep restriction can yield modest increases (and even a reduction) of sleep time during initial therapy, there is generally an increase at follow-up, with sleep time often exceeding 6.5 hours. Long-term outcome must be interpreted cautiously, however, because few studies report long-term follow-up and, among those that do, attrition rates increase substantially over time. In addition, it is important to keep in mind that patients with chronic insomnia, even those who benefit from short-term therapy, might remain vulnerable to recurrent episodes of insomnia in the long term.58,61 The addition of maintenance therapy in the form of booster therapy sessions might facilitate
880 PART II / Section 10 • Insomnia
better integration of newly learned self-management skills and contribute to improved long-term outcome.62 Clinical Significance Despite reliable and durable changes produced by CBT on sleep parameters, there is less information about the impact of these changes on daytime functioning. Some studies have shown reductions of fatigue, anxiety, and depression symptoms and improved quality of life (see Table 79-1).15,28,36,37,45,63 There is no documentation, however, that sleep improvements produce meaningful changes on performance-based measures of cognitive functioning. Despite frequent reports of cognitive impairments among insomnia patients, there is no evidence that treatment improves such functions as attention, concentration, and memory. It is unclear whether these negative findings are due to the absence of objective deficits at baseline or are due to the selection of measures that are not sensitive enough to detect such deficits. Nonetheless, it remains essential to document outcome beyond reduction of insomnia symptom because it is often the perceived consequences of insomnia rather than insomnia per se that prompt treatment seeking. Investigators should incorporate multiple outcome measures including sleep, functional impairments, psychological symptoms, and quality of life.64,65 Comparative Efficacy of Single Therapies Although multimodal CBT is becoming the standard approach in the field, there have been no dismantling studies to isolate the relative efficacy and unique contribution of each component. Nonetheless, studies comparing the relative efficacy of single therapies have found that stimulus control and sleep restriction therapies are more effective than relaxation alone, which, in turn, is more effective than sleep hygiene education.21-23,26 Sleep restriction tends to produce better outcomes than stimulus control in terms of sleep efficiency and continuity, but it also decreases sleep time during initial treatment. Relaxation methods focusing on cognitive arousal (e.g., reducing intrusive thoughts) yield slightly greater improvements than those targeting somatic arousal. Sleep hygiene education, when used alone, produces little effect on sleep and insomnia symptoms; this didactic approach should be seen as a minimal intervention. Cognitive therapy, although increasingly used as one therapeutic component of multimodal interventions,22 has been evaluated as a single treatment in only one study.19 Preliminary results suggest that it is particularly useful for addressing daytime impairments associated with insomnia. Based on criteria set forth by the American Psychological Association, there are currently five interventions that have sufficient evidence to meet criteria for well-established psychological treatment for insomnia: CBT, sleep restriction, stimulus control, relaxation, and paradoxical intention.22 When the evidence is evaluated specifically with older adults, only CBT, sleep restriction, and stimulus control meet similar efficacy standards.59 Treatment Specificity and Mechanisms of Changes Although there is strong evidence supporting the efficacy of CBT, there is little information about the mechanisms
responsible for sleep improvements. With a few notable exceptions, which have used attention–placebo conditions,13,34 most CBT trials have used wait-list control groups, precluding the unequivocal attribution of treatment effects to any specific therapeutic ingredient. The lack of a pill–placebo control equivalent in psychological treatment studies makes it difficult to determine what percentage of the variance in outcomes is the result of specific clinical procedures (e.g., restriction of time in bed, cognitive restructuring), the measurement process (e.g., selfmonitoring), or nonspecific factors (e.g., therapist attention, patients’ expectations). This issue of mechanisms of changes has been addressed indirectly by examining predictors of changes and by surveying patients about their perception of the most effective treatment components. In a follow-up study of patients who had completed CBT for insomnia,66 the most critical ingredients associated with long-term improvements were stimulus control and sleep restriction, followed by cognitive restructuring. Relaxation was the most commonly endorsed component (79% of respondents), but it did not predict improvement in any of the sleep variables. Other studies have examined the association between changes in sleep beliefs and attitudes and sleep improvements. Reductions of dysfunctional sleep cognitions during treatment were correlated with sleep improvements after treatment, and fewer dysfunctional cognitions after treatment were associated with better maintenance of sleep changes over time.67 In a series of 89 patients with primary and comorbid insomnias,68 there were more treatment responders among those who received the cognitive therapy component (83%) than among those who did not (56%). With increasing evidence that central nervous system hyperarousal is implicated in insomnia,69,70 more attention is needed to identify the biological, as well as the psychological, mechanisms responsible for sleep changes. Combined Cognitive Behavior Therapy and Medication CBT and medication can play a complementary role in the management of insomnia. Medication produces fast symptomatic relief and CBT yields durable benefits over time. Thus, combined approaches should, in principle, optimize outcome by capitalizing on the more immediate and potent effects of medication and the more sustained effects of CBT. Few studies have directly evaluated the combined and differential effects of behavioral and pharmacologic therapies for insomnia.16,30,31,37,38,71-75 Three studies compared triazolam with relaxation or sleep hygiene,16,71,72 and six other studies compared CBT with temazeam,30,31 zolpidem,37,62 or zopiclone.38,74 Collectively, the evidence from those studies indicates that both treatment modalities, when used singly, are effective in the short term. Medication produces rapid improvements, but these benefits are also quickly lost after the drug is discontinued. Sleep improvements obtained with CBT take longer, but they are also well sustained even after treatment. There is a slight additive effect of combined approaches relative to medication alone, but not necessarily relative to CBT alone. The long-term impact of combined versus single approaches is more equivocal. Some studies71,72 indicate
CHAPTER 79 • Psychological and Behavioral Treatments for Insomnia I: Approaches and Efficacy 881
that a combined intervention (e.g., triazolam plus relaxation) produces more sustained benefits than medication alone, and others16,30,31 report more variable long-term outcomes. Treatment responses vary across individual patients; some patients retain their initial sleep improvements, but others return to their baseline values. Because of the mediating role of psychological factors in chronic insomnia, behavioral and attitudinal changes appear essential to sustain improvements in sleep patterns. When behavioral and drug therapies are combined, patients’ attributions of the initial benefits may be critical in determining long-term outcomes. Attribution of therapeutic benefits to the medication alone, without integration of self-management skills, can place a patient at greater risk for insomnia recurrence after the drug is discontinued. In addition, there is a risk that the availability of medications might undermine the patient’s effort and motivation to implement behavioral changes in sleep habits and sleep scheduling. Thus, despite the intuitive appeal of combining therapies, it is not entirely clear when, how, and for whom combining CBT and medication is indicated. Additional research is needed to examine optimal methods for combining or integrating these therapies.75 Rather than initiating and discontinuing treatment simultaneously, it may be preferable to introduce treatment sequentially in order to optimize outcome.76 One study has examined the impact of different treatment sequences when combining CBT with medication.74 The optimal sequence appeared to be when CBT was introduced early on in treatment, either before or concurrently with medication. In another study,62 medication had a modest augmentation effect on CBT, primarily in terms of improving total sleep time, but this added benefit may be important given that the sleep-restriction component of CBT reduces total sleep time during the initial course of therapy and could lead some patients to discontinue therapy prematurely. The best long-term sequence was a combined approach followed by CBT alone (i.e., drug tapering). Efficacy versus Effectiveness Because the main entry point for professional insomnia treatment is typically in primary care medicine, it is important to examine whether treatment validated in academic research centers is also effective in various clinical settings. Several effectiveness trials28,33,77 in which CBT was implemented in the context of primary care practices or sleep clinics15,68 have yielded results comparable to those obtained with patients treated within more-controlled research protocols. Brief consultation models involving one or two consultations have also been used successfully in primary care78 and in specialty sleep clinics.79 Finally, the effectiveness of insomnia treatment provided in behavioral sleep medicine clinics has been shown in several clinical replication series.15,29,51 Group therapy can be a cost-effective method to deliver CBT for insomnia in clinical settings. Although it might not provide the same flexibility, group therapy is generally as effective as individual therapy.36 Self-help approaches using printed materials or videotapes can also be useful in insomnia treatment.63,80 For example, studies46,63 have shown that a self-help treatment program, consisting of six printed booklets mailed weekly to participants was effec-
tive to treat insomnia and to reduce use of hypnotics; the addition of professional guidance in the form of brief telephone consultation added to the initial outcomes. Another study documented the benefits of an Internet-based intervention.81-83 Collectively, the evidence indicates that CBT for insomnia is effective not only in the context of controlled research studies but also in various clinical settings such as in primary care and in behavioral sleep medicine clinics. Self-help materials, brief consultations, group therapy, and even the Internet, can enhance treatment access and facilitate its implementation in clinical practice. Clinical and Practical Considerations Psychological and behavioral approaches to treating primary insomnia are time limited, structured, and sleep focused.4 For typical patients with chronic insomnia, direct consultation time takes between 4 and 6 hours per patient, which is usually spread over a treatment period of 6 to 8 weeks.34 The amount of direct clinical contact and the number of follow-up visits is likely to vary as a function of several factors including insomnia severity, comorbidity, use of hypnotic medications, and the patient’s motivation and education. This treatment period is considerably shorter than for other forms of psychotherapy, and it is shorter than behavioral approaches applied to other health and psychological problems (e.g., chronic pain, anxiety, depression). The success of CBT depends largely on the patient’s willingness to comply with the recommended self-management procedures. For this reason, it is particularly important to schedule follow-up visits after the initial evaluation to address compliance issues. Although treatment is generally well accepted by patients, it is more time consuming and requires more effort than drug therapy, both for clinicians and patients. Thus, compliance might not always be optimal. Given the multifactorial nature of insomnia, it is often necessary to combine several clinical procedures rather than to rely on a single treatment modality. Sleep restriction is almost always relevant for any insomnia patient, and the use of this procedure early in therapy is likely to produce rapid therapeutic benefits. Some stimulus control procedures (e.g., getting out of bed when unable to sleep) might not be necessary early on when the initial sleep window is restricted to 5 to 6 hours per night, but those procedures become particularly relevant as the sleep window is increased. Relaxation is helpful for persons with elevated tension or anxiety; however, caution is needed because some patients have a paradoxical response and become more anxious. Cognitive therapy is particularly helpful to challenge some misconceptions about sleep and daytime impairments, to alleviate emotional distress, and to minimize recurrence of sleep disturbances over time. For milder forms of insomnia, basic sleep hygiene education may be sufficient, whereas moresevere insomnia often requires multimodal interventions and more frequent follow-up visits.
SUMMARY AND CONCLUSION Significant advances have been made in the development and validation of nonpharmacologic therapies for insom-
882 PART II / Section 10 • Insomnia
nia. With increasing research-based evidence supporting its efficacy and acceptability, CBT is now recognized as a valid therapeutic approach and often is the treatment of choice for persistent insomnia.84 However, there is still a major gap between research evidence and actual clinical practices in that very few clinicians, other than behavioral sleep medicine specialists, use this therapeutic approach in their clinical practice. Important challenges remain for professional sleep organizations and public health decision makers to promote wider dissemination and use of psychological and behavioral therapies for managing insomnia.
❖ Clinical Pearl Sleep scheduling factors, conditioning, hyperarousal, and misconceptions about sleep are important contributing factors to persistent insomnia. Effective clinical management of insomnia must address those perpetuating factors. CBT is an effective and wellaccepted therapeutic approach for persistent insomnia, and sleep improvements are well sustained over time.
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37. Jacobs GD, Pace-Schott EF, Stickgold R, Otto MW. Cognitive behavior therapy and pharmacotherapy for insomnia: a randomized controlled trial and direct comparison. Arch Intern Med 2004;164: 1888-1896. 38. Sivertsen B, Omvik S, Pallesen S, Bjorvatn B, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA 2006;295: 2851-2858. 39. Currie SR, Clark S, Hodgins DC, El-Guebaly N. Randomized controlled trial of brief cognitive-behavioural interventions for insomnia in recovering alcoholics. Addiction 2004;99:1121-1132. 40. Edinger JD, Wohlgemuth WK, Krystal AD, Rice JR. Behavioral insomnia therapy for fibromyalgia patients: a randomized clinical trial. Arch Intern Med 2005;165:2527-2535. 41. Espie CA, Fleming L, Cassidy J, Samuel L, et al. Randomized controlled clinical effectiveness trial of cognitive behavior therapy compared with treatment as usual for persistent insomnia in patients with cancer. J Clin Oncol 2008;26:4651-4658. 42. Lichstein KL, Wilson NM, Johnson CT. Psychological treatment of secondary insomnia. Psychol Aging 2000;15:232-240. 43. Manber R, Edinger JD, Gress JL, San Pedro-Salcedo MG, et al. Cognitive behavioral therapy for insomnia enhances depression outcome in patients with comorbid major depressive disorder and insomnia. Sleep 2008;31:489-495. 44. Rybarczyk B, Stepanski E, Fogg L, Lopez M, et al. A placebo-controlled test of cognitive-behavioral therapy for comorbid insomnia in older adults. J Consult Clin Psychol 2005;73:1164-1174. 45. Savard J, Simard S, Ivers H, Morin CM. Randomized study on the efficacy of cognitive-behavioral therapy for insomnia secondary to breast cancer, part I: sleep and psychological effects. J Clin Oncol 2005;23:6083-6096. 46. Belleville G, Guay C, Guay B, Morin CM. Hypnotic taper with or without self-help treatment: a randomized clinical trial. J Consult Clin Psychol 2007;75:325-335. 47. Morgan K, Thompson J, Dixon S, Tomeny M, et al. Predicting longer-term outcomes following psychological treatment for hypnoticdependent chronic insomnia. J Psychosom Res 2003;54:21-29. 48. Morin CM, Bastien C, Guay B, Radouco-Thomas M, et al. Randomized clinical trial of supervised tapering and cognitive behavior therapy to facilitate benzodiazepine discontinuation in older adults with chronic insomnia. Am J Psychiatry 2004;161:332-342. 49. Soeffing JP, Lichstein KL, Nau SD, McCrae CS, et al. Psychological treatment of insomnia in hypnotic-dependant older adults. Sleep Med 2008;9:165-171. 50. Smith MT, Huang MI, Manber R. Cognitive behavior therapy for chronic insomnia occurring within the context of medical and psychiatric disorders. Clin Psychol Rev 2005;25:559-592. 51. Perlis M, Aloia M, Millikan A, Boehmler J, et al. Behavioral treatment of insomnia: a clinical case series study. J Behav Med 2000;23: 149-161. 52. Ouellet MC, Morin CM. Efficacy of cognitive-behavioral therapy for insomnia associated with traumatic brain injury: a single-case experimental design. Arch Phys Med Rehabil 2007;88:1581-1592. 53. Arnedt JT, Conroy D, Rutt J, Aloia MS, et al. An open trial of cognitive-behavioral treatment for insomnia comorbid with alcohol dependence. Sleep Med 2007;8:176-180. 54. Germain A, Shear MK, Hall M, Buysse DJ. Effects of a brief behavioral treatment for PTSD-related sleep disturbances: a pilot study. Behav Res Ther 2007;45:627-632. 55. Taylor DJ, Lichstein KL, Weinstock J, Sanford S, et al. A pilot study of cognitive-behavioral therapy of insomnia in people with mild depression. Behav Ther 2007;38:49-57. 56. Currie SR, Wilson KG, Pontefract AJ, deLaplante L. Cognitivebehavioral treatment of insomnia secondary to chronic pain. J Consult Clin Psychol 2000;68:407-416. 57. Pallesen S, Nordhus IH, Kvale G, Nielsen GH, et al. Behavioral treatment of insomnia in older adults: an open clinical trial comparing two interventions. Behav Res Ther 2003;41:31-48. 58. Buysse DJ, Angst J, Gamma A, Ajdacic V, et al. Prevalence, course, and comorbidity of insomnia and depression in young adults. Sleep 2008;31:473-480. 59. McCurry SM, Logsdon RG, Teri L, Vitiello MV. Evidence-based psychological treatments for insomnia in older adults. Psychol Aging 2007;22:18-27.
60. Germain A, Moul DE, Franzen PL, Miewald JM, et al. Effects of a brief behavioral treatment for late-life insomnia: preliminary findings. J Clin Sleep Med 2006;2:403-406. 61. Morin CM, Belanger L, Leblanc M, Ivers H, et al. The natural history of insomnia: a population-based, three-year longitudinal study. Arch Intern Med. 2009;169:447-453. 62. Morin CM, Vallières A, Guay B, Ivers H, et al. Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: a randomized controlled trial. JAMA 2009;301:2005-2015. 63. Mimeault V, Morin CM. Self-help treatment for insomnia: bibliotherapy with and without professional guidance. J Consult Clin Psychol 1999;67:511-519. 64. Morin CM. Measuring outcomes in randomized clinical trials of insomnia treatments. Sleep Med Rev 2003;7:263-279. 65. Buysse DJ, Ancoli-Israel S, Edinger JD, Lichstein KL, et al. Recommendations for a standard research assessment of insomnia. Sleep 2006;29:1155-1173. 66. Harvey L, Inglis SJ, Espie CA. Insomniacs’ reported use of CBT components and relationship to long-term clinical outcome. Behav Res Ther 2002;40:75-83. 67. Morin CM, Blais F, Savard J. Are changes in beliefs and attitudes about sleep related to sleep improvements in the treatment of insomnia? Behav Res Ther 2002;40:741-752. 68. Verbeek I, Schreuder K, Declerck G. Evaluation of short-term nonpharmacological treatment of insomnia in a clinical setting. J Psychosom Res 1999;47:369-383. 69. Winkelman JW, Buxton OM, Jensen JE, Benson KL, et al. Reduced brain GABA in primary insomnia: preliminary data from 4T proton magnetic resonance spectroscopy (1H-MRS). Sleep 2008;31:14991506. 70. Nofzinger EA, Buysse DJ, Germain A, Price JC, et al. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry 2004;161:2126-2128. 71. McClusky HY, Milby JB, Switzer PK, Williams V, et al. Efficacy of behavioral versus triazolam treatment in persistent sleep-onset insomnia. Am J Psychiatry 1991;148:121-126. 72. Milby JB, Williams V, Hall JN, Khuder S, et al. Effectiveness of combined triazolam–behavioral therapy for primary insomnia. Am J Psychiatry 1993;150:1259-1260. 73. Rosen RC, Lewin DS, Goldberg L, Woolfolk RL. Psychophysiological insomnia: combined effects of pharmacotherapy and relaxationbased treatments. Sleep Med 2000;1:279-288. 74. Vallieres A, Morin CM, Guay B. Sequential combinations of drug and cognitive behavioral therapy for chronic insomnia: an exploratory study. Behav Res Ther 2005;43:1611-1630. 75. Stepanski E, Wyatt JK. Controversies in the treatment of primary insomnia. Sleep Med 2000;1:259-261. 76. Morin CM. Combined therapeutics for insomnia: should our first approach be behavioral or pharmacological? Sleep Med 2006;7(Suppl. 1):S15-S19. 77. Espie CA, Inglis SJ, Harvey L. Predicting clinically significant response to cognitive behavior therapy for chronic insomnia in general medical practice: analysis of outcome data at 12 months posttreatment. J Consult Clin Psychol 2001;69:58-66. 78. Edinger JD, Sampson WS. A primary care “friendly” cognitive behavioral insomnia therapy. Sleep 2003;26:177-182. 79. Hauri PJ. Consulting about insomnia: a method and some preliminary data. Sleep 1993;16:344-350. 80. Riedel BW, Lichstein KL, Dwyer WO. Sleep compression and sleep education for older insomniacs: self-help versus therapist guidance. Psychol Aging 1995;10:54-63. 81. Ström L, Pettersson R, Andersson G. Internet-based treatment for insomnia: a controlled evaluation. J Consult Clin Psychol 2004; 72:113-120. 82. Ritterband LM, Thorndike FP, Gonder-Frederick L, et al. Efficacy of an Internet-based behavioral intervention for adults with insomnia. Arch Gen Psych 2009;66:692-698. 83. Vincent N, Lewycky S. Logging on for better sleep: RCT of the effectiveness of online treatment for insomnia. Sleep 2009;32: 807-815. 84. Babson KA, Feldner MT, Badour CL. Cognitive behavioral therapy for sleep disorders. Psychiatr Clin North Am 2010;33:629-640.
Psychological and Behavioral Treatments for Insomnia II: Implementation and Specific Populations
Chapter
80
Jack D. Edinger, Melanie K. Means, Colleen E. Carney, and Rachel Manber Abstract As evidenced by the preceding chapter, psychological and behavioral insomnia therapies have a strong legacy of research support. Moreover, many of the stand-alone (e.g., stimulus control, sleep restriction) and multicomponent (e.g., cognitive behavior therapy) forms of these treatments now are regarded as well-established therapies that can and should be considered as first-line or adjunctive therapies for many treatment-seeking insomnia patients. As a result, clinicians face
INTERVENTION TOOLS The psychological and behavioral insomnia therapies include a somewhat diverse group of treatments (e.g., relaxation training, stimulus control, cognitive therapy, sleep restriction).1,2 Research and clinical experience with these treatments has produced a number of helpful tools for identifying treatment targets, monitoring adherence and response, and delivering and reinforcing treatment instructions. In this section, we discuss some of the more commonly used clinical tools for implementing these therapies. Sleep Diaries A sleep diary is a standard intervention tool. It provides a daily log or a recording of sleep from the patient’s perspective. Sleep diaries are a mainstay of insomnia assessment and treatment. They quantify the severity of the sleep disorder, help in determining the diagnosis and conceptualizing the case, guide the implementation of behavioral interventions by allowing tracking of progress and adjustment of the behavioral instructions, and reliably measure treatment outcomes.3 They are also useful in identifying problems in adhering to treatment, such as a failure to follow a prescribed sleep schedule. Sleep diaries provide a more accurate and detailed depiction of sleep patterns compared to a patient’s retrospective report.4 They are inexpensive and are as easily administered as a paper questionnaire. There are many published versions available, which differ slightly in the type or amount of information obtained.1,2,4-8 In efforts to standardized insomnia research, recommendations for the type of information obtained from a sleep diary have been proposed.3 At a minimum, these variables include time and duration of naps, bedtime, latency to sleep onset, number of awakenings, wake time during the night, time of final awakening, rise time, total sleep time, sleep efficiency percentage, and sleep quality rating. A traditional sleep diary that meets these standard criteria is presented in Figure 80-1.2 884
pragmatic nuts-and-bolts considerations and decisions when using these therapies. This chapter provides a description of some tools commonly employed in implementing these therapies and discusses several implementation issues the clinicians might wish to consider. The latter discussion includes issues such as the format and dosing of treatment, patients’ acceptance of and adherence to treatment, and the usefulness of these treatments among insomnia patients with comorbid psychiatric and medical conditions and various age groups.
Sleep diaries are available in a number of formats to meet the needs of different populations. For example, The National Sleep Foundation has developed three sleep diary versions geared toward adults, teenagers, and children. The three versions are accessible via the Internet.9 The American Academy of Sleep Medicine also offers a downloadable sleep diary. In this sleep diary, patients are instructed to fill in blocks of time slept (Fig. 80-2).10 This format can provide a richer picture of sleep patterns for patients who have difficulty accurately completing the traditional diary, such as those who have highly erratic sleep patterns or are shift workers. Disadvantages of the traditional paper sleep diary include inaccurate or incomplete patient-recorded values, inability to monitor or confirm daily completion, the clinician’s time required for scoring, and the potential for scoring errors. Newer technologies, such as computerized sleep diaries on hand-held electronic devices and daily patient phone calls to interactive voice recording systems, circumvent many of these disadvantages but are not yet widely available for patient care.11-13 Thus, paper versions of sleep diaries remain the most readily available for assessing insomnia problems, identifying behavioral treatment targets, and tracking treatment responses and adherence. Actigraphy Actigraphy is an objective measurement method that assesses limb movement activity via a small recording device typically worn on the wrist (see Chapter 147). Recorded data are subjected to a proprietary algorithm that produces estimates of sleep–wake variables. Current standards of practice outline the primary roles of actigraphy in insomnia as the characterization of circadian or sleep patterns and the evaluation of treatment response.14 Although practice standards for actigraphy recommend a minimum recording period of 72 hours,15 periods of 1 to 2 weeks are preferable.3 It is essential for sleep diaries to accompany actigraphy, so that bed times, rise times, and times the device was removed can be determined. Because
CHAPTER 80 • Psychological and Behavioral Treatments for Insomnia II: Implementation and Specific Populations 885
Examples Day of the week
Monday
Sun
Mon
Tues
Wed
Thur
Fri
Sat
Calendar date
3/25/96
8/3
8/4
8/5
8/6
8/7
8/8
8/9
1. Yesterday I napped from ___ to ___ (note time of all naps).
1:30–2:45
––
––
––
––
––
––
1:30– 2:15 PM
2. Last night I took ___ mg of ___ or ___ of alcohol as a sleep aid.
Ambien 5 mg
None
None
Wine 4 oz
None
None
None
None
3. Last night I turned off the lights and attempted to fall asleep at ___ (AM or PM?)
11:30 PM
4. After turning off the lights it took me about ___ minutes to fall asleep.
40 min
25 min
35 min
20 min
45 min
60 min
20 min
35 min
5. I woke from sleep ___ times. (Do not count your final awakening here.)
2 times
1
1
1
2
2
1
1
6. My awakenings lasted ___ minutes. (List each awakening separately.)
25 min 40 min
35 min
25 min
45 min
20 min 20 min
10 min 10 min
60 min
40 min
7. Today I woke up at ___ (AM or PM?) NOTE: this is your final awakening.
6:30 AM
7:00 AM
6:30 AM
8:30 AM
7:00 AM
6:45 AM
6:30 AM
8:15 AM
8. Today I got out of bed for the day at ___ (AM or PM?)
7:15 AM
7:00 AM
7:00 AM
8:30 AM
7:30 AM
7:15 AM
7:00 AM
9:00 AM
9. I would rate the quality of last night’s sleep as: 1 = very poor 4 = good 2 = poor 5 = excellent 3 = fair
3
3
3
4
3
2
3
4
10. When I awoke today I felt: 1 = not at all rested 4 = rested 2 = slightly rested 5 = well rested 3 = somewhat rested
2
2
2
3
3
2
2
3
PM
For clinic use only
11:00 PM 11:30 PM 10:30 PM 11:00 PM 11:00 PM 10:30 PM 11:30 PM
Figure 80-1 Traditional sleep diary.
actigraphy tends to interpret wakeful stillness in bed as sleep, its validity in insomnia patients is less robust than in sleepers without insomnia.3 Among the many advantages of actigraphy are its unobtrusive nature and ease of use. It can be used in the home environment over extended time periods to capture the night-to-night variability in sleep patterns characteristic of insomnia.15a Because actigraphs record continuously, they provide information on 24-hour rest and activity patterns, allowing unreported daytime sleep episodes to be detected. Actigraphy may also be useful in monitoring adherence to behavioral treatment recommendations and for identifying occasions when violations of those recommendations occur.16 Actigraphy provides streamlined electronic data collection and analysis, a feature that may be of value in clinical and research applications.
Written Behavioral Prescriptions and Instruments for Home Use The success of behavioral insomnia therapy depends on the patient’s ability to implement therapeutic techniques in the home environment. Patients may be more successful in adhering to behavioral insomnia recommendations if they understand and accept the rationale behind the therapy instructions. This knowledge is particularly salient for treatment recommendations that are counterintuitive, such as directives to limit time in bed and leave the bedroom if not sleeping. Indeed, as has been demonstrated in cognitive behavior therapy (CBT) for depression,17 a patient’s acceptance of the treatment rationale enhances likelihood of a positive treatment outcome. Furthermore, providing a written summary of behavioral prescriptions helps the
886 PART II / Section 10 • Insomnia
AM E
A CAN CAD RI WAKE
Y EM
TWO-WEEK SLEEP DIARY
SLEEP
IN E
OF
Instructions: SL EEP MEDIC 1. Write the date, day of the week, and type of day: Work, School, Day Off, or Vacation. 2. Put the letter “C” in the box when you have coffee, cola or tea. Put “M” when you take any medicine. Put “A” when you drink alcohol. Put “E” when you exercise. 3. Put a line (|) to show when you go to bed. Shade in the box that shows when you think you fell asleep. 4. Shade in all the boxes that show when you are asleep at night or when you take a nap during the day. 5. Leave boxes unshaded to show when you wake up at night and when you are awake during the day.
Mon.
Work
E
|
11 AM
10
9
8
7
6 AM
5
4
3
2
1 AM
Midnight
11 PM
10
9
8
7
5
4
3
2
6 PM A
C M
Week 2
Week 1
Sample
1 PM
Today’s Day of Type of day date the Work, week School, Off, Vacation
Noon
Sample entry below: On a Monday when I worked, I jogged on my lunch break at 1 PM, had a glass of wine with dinner at 6 PM, fell asleep watching TV from 7 to 8 PM, went to bed at 10:30 PM, fell asleep around midnight, woke up and couldn’t get back to sleep at about 4 AM, went back to sleep from 5 to 7 AM, and had coffee and medicine at 7:00 in the morning.
Figure 80-2 Analog sleep diary offered by the American Academy of Sleep Medicine (http://www.sleepeducation.com/pdf/ sleepdiary.pdf).
patient review and remember the information discussed during the therapy session. Figures 80-3 through 80-5 exemplify handouts that can facilitate the implementation of some behavioral treatments. Of these, sleep restriction and stimulus control are efficacious stand-alone therapies but are more commonly folded into an omnibus multicomponent CBT for insomnia. Discussions of how these various treatment components are used in combination are provided in several available therapist guidebooks.1,2,18,19 Sleep Restriction In its original version,20 sleep restriction based the initial time-in-bed prescription on the average total sleep time estimated from 2 weeks of sleep logs. However, 4.5 hours was set as the minimum time in bed. Patients were instructed to go to bed 15 minutes earlier if, after 5 days,
sleep efficiency (based on subjective reports) was greater than 90%. If sleep efficiency was less than 85%, time in bed was decreased; no change was made if sleep efficiency fell between 85% and 89%. Although the general principle of sleep restriction (that of inducing mild sleep deprivation to consolidate sleep and improve sleep efficiency) endures today, many clinicians relax the original sleep restriction protocol in order to promote patient adherence.1,8,21,22 Morin1 provides guidelines for implementing sleep restriction that include flexibility in restricting time in bed to what the patient can tolerate, increasing time in bed (after the initial restriction) at predetermined time intervals rather than in response to sleep efficiency improvements in some clinical situations, adjusting the frequency of time in bed alterations based on patient comfort, giving patients control in selecting bedtime and rising time, and reassuring the patient about
CHAPTER 80 • Psychological and Behavioral Treatments for Insomnia II: Implementation and Specific Populations 887
The following rationale is provided for a patient whose sleep logs show an average total sleep time of 6 hours, with an average time in bed of 8 hours) Restrict the time you spend in bed to the actual amount of sleep you get. Since you average only 6 hours of sleep per night out of 8 hours spent in bed, your task consists of curtailing the time you spend in bed to these 6 hours. There is no reason for staying in bed any longer than that, since the remaining time is spent awake anyway. Spending excessive amounts of time lying down attempting to relax, rest, nap, or simply find a comfortable body position fragments rather than consolidates sleep. Although it may have been a useful coping strategy early on, it is most likely contributing to maintaining the sleep problem currently. As your sleep becomes more efficient, you will gradually be allowed to spend more time in bed. Quoted from: Morin CM. Insomnia: psychological assessment and management. New York: Guilford Press, 1993. p. 1141. Figure 80-3 Sleep-restriction rationale.
1. Lie down intending to go to sleep only when you are sleepy. (The goal of this rule is to help the patients become more sensitive to internal cues of sleepiness so that they will be more likely to fall asleep quickly when they go to bed.) 2. Do not use your bed for anything except sleep; that is, do not read, watch television, eat, or worry in bed. Sexual activity is the only exception to this rule. On such occasions, the instructions are to be followed afterward when you intend to go to sleep. (The goals here are to have activities that are associated with arousal occur elsewhere and to break up patterns that are associated with disturbed sleep. If bedtime is the only time patients have for thinking about the day’s events and planning the next day, they should spend some quiet time doing that in another room before they go to bed. Many people who do not have insomnia read or listen to music in bed without problem. This is not the case for insomniacs, however. This instruction is used to help those who have sleep problems establish new routines to facilitate sleep onset.) 3. If you find yourself unable to fall asleep, get up and go into another room. Stay up as long as you wish and then return to the bedroom to sleep. Although we do not want you to watch the clock, we want you to get out of bed if you do not fall asleep immediately. Remember the goal is to associate your bed with falling asleep quickly! If you are in bed more than about 10 minutes without falling asleep and have not gotten up, you are not following this instruction. (In order to associate the bed with sleep and disassociate it from the frustration and arousal of not being able to sleep, the patients are instructed to get out of bed after about 10 minutes [20 minutes for those over 60 years old]. This is also a means of coping with insomnia. By getting out of bed and engaging in other activities, patients are taking control of their problem. Consequently, the problem becomes more manageable and the patient is likely to experience less distress.) 4. If you still cannot fall asleep, repeat Step 3. Do this as often as is necessary throughout the night. (See rationale for #3 above.) 5. Set your alarm and get up at the same time every morning irrespective of how much sleep you got during the night. This will help your body acquire a consistent sleep rhythm. (Insomniacs often have irregular sleep rhythms because they try to make up for poor sleep by sleeping late or napping the next day. Keeping consistent wake times helps patients develop consistent sleep rhythms. In addition, the set wake times mean that the patients will be somewhat sleep-deprived after a night of insomnia. This will make it more likely that they will fall asleep quickly the following night, strengthening the cues of the bed and bedroom for sleep. Often insomniacs will want to follow a different sleeping schedule on weekends or nights off than they do during the work week. It is important to have as consistent a schedule as possible, seven nights a week. In our experience, a deviation of no more than one hour in the wake time on days off does not produce problems in establishing a consistent rhythm.) 6. Do not nap during the day. (The goals of this rule are to keep insomniacs from disrupting their sleep patterns by irregular napping and to prevent them from losing the advantage of the sleep loss of the previous night for increasing the likelihood of faster sleep onset the following night. A nap that takes place seven days a week at the same time would be permissible. For those elderly insomniacs who feel that they need to nap, a short daily afternoon nap of 30 to 45 minutes or the use of 20 to 30 minutes of relaxation as a nap substitute is recommended.) Reprinted from: Bootzin RR. Cognitive-behavioral treatment of insomnia: knitting up the ravell’d sleave of care. In: Kenny DT, Carlson JG, McGuigan FJ, Sheppard JL, editors. Stress and health: research and clinical applications. Amsterdam, Netherlands: Harwood Academic Publishers; 2000. (p. 243-266). Figure 80-4 Stimulus control rationale and treatment instructions.
888 PART II / Section 10 • Insomnia
The sorts of daytime activities in which you engage, the foods and beverages you consume, and the surroundings in which you sleep may all influence how well you sleep at night and how you feel in the daytime. Thus, you may benefit from making some changes to your lifestyle and bedroom to promote better sleep. 1. Limit your use of caffeinated foods and beverages such as coffee, tea, soft drinks, and chocolate. Caffeine is a stimulant that may make it harder for you to sleep well at night. Caffeine stays in your system for several hours after you consume it. Therefore, we recommend that you limit caffeine to the equivalent of no more than 3 cups of coffee per day and that you not consume caffeine in the late afternoon or evening hours. 2. Limit your use of alcohol. Alcoholic beverages may make you fall asleep more easily. However, alcohol also causes sleep to be much more broken and far less refreshing than normal. Therefore, we recommend against using much alcohol in the evening or using alcohol as a sleep aid. 3. Try some regular moderate exercise such as walking, swimming, or bike riding. Generally, such exercise performed in the late afternoon or early evening leads to deeper sleep at night. Also, improving your fitness level will likely improve the quality of your sleep. However, avoid exercise right before bed because it may make it harder to get to sleep quickly. 4. Make sure your bedroom is quiet and dark. Noise and even dim light may interrupt or shorten your sleep. 5. Make sure the temperature in your bedroom is comfortable. Generally, temperatures above 75 degrees Fahrenheit cause unwanted awakenings from sleep. During hot weather, we suggest you use an air conditioner to control the bedroom temperature. 6. Try a light bedtime snack that includes such items as cheese, milk, or nuts. These foods contain chemicals that your body uses to produce sleep and may help bring on drowsiness. Adapted from Edinger J, Carney C. Overcoming insomnia: a cognitive-behavioral therapy approach therapist guide (treatments that work). New York: Oxford University Press, 2008. Figure 80-5 Sleep hygiene Instructions and rationale.
the transient side effect of daytime sleepiness. He also provides an excellent description of the therapeutic rationale (see Fig. 80-3). The treatment rationale for sleep restriction is particularly important for patients to understand, because reducing time spent in bed seems counterintuitive and often contradicts strategies they have tried on their own to manage insomnia. Considering the sleep diary data in Figure 80-1, sleep restriction may be implemented as follows. In this example, the average time in bed is 8.6 hours, and total sleep time is 7 hours. Sleep efficiency is thus calculated as 81.5%. The initial time in bed prescription would be set for 7 hours. The patient would be encouraged to anchor a rise time close to his or her typical rise time, such as 7:00 am. A recommended bedtime, then, would be set at midnight. This schedule is adjusted as needed based on the therapeutic response over the course of subsequent weeks. However, insomnia patients as a group tend to underestimate sleep time, although there are admittedly exceptions to this rule.23 Moreover, the sleep-restriction approach outlined here is fairly strict and does not consider normal sleep-onset time or normative amounts of wakefulness during the night. For this reason, it has been suggested2 that it may be reasonable to add 30 minutes to the average sleep time derived from a pretreatment diary to provide a more realistic initial time in bed prescription. Using this more lenient approach, the initial time in bed prescription would be set at 7.5 hours in the above example. Stimulus Control The stimulus control instructions originally published by Bootzin in the 1970s essentially have remained unchanged since then.24 The instructions to the patient, along with
the rationale for each instruction, are reproduced in Figure 80-4.5 As noted earlier, stimulus control and sleep restriction may be used together in multicomponent insomnia treatments. In such applications it is necessary to slightly alter the stimulus control instruction to go to bed at night when sleepy. This is true particularly when sleepiness occurs too early to allow adherence to the sleep schedule required for sleep restriction. For such instance, patients are told to go to bed when sleepy, but not before the earliest bedtime recommended by the sleep-restriction schedule. Thus, bedtime recommended as part of sleep restriction can be viewed as the earliest allowed bedtime, but the patient could choose to stay up later on a given night when not sufficiently sleepy at that time. Sleep Hygiene Sleep hygiene practices are broadly defined and vary among clinicians, but most recommendations cover four core areas: keeping regular bed and rise times, maintaining a comfortable sleep environment, curbing substance use (e.g., alcohol, nicotine, caffeine), and exercising.25 When included as part of a multicomponent treatment package, recommendations about bed and rise times might not be included because they are already subsumed under the stimulus-control and sleep-restriction instructions. A sample sleep hygiene patient handout is presented in Figure 80-5. This handout includes the rationale for each recommendation. Sleep hygiene practices can be assessed with questionnaires such as the Sleep Hygiene Index26 or the Sleep Hygiene Awareness and Practice Scale.27 Riedel28 has developed a sleep hygiene checklist that can be implemented along with a sleep diary to monitor sleep hygiene over time.
CHAPTER 80 • Psychological and Behavioral Treatments for Insomnia II: Implementation and Specific Populations 889
Sleep Education Including a component of sleep education can set the stage for cultivating positive patient expectations and maximizing treatment adherence. Sleep education may include information about normative sleep patterns, circadian functioning, homeostatic sleep drive, the effects of sleep loss, and realistic sleep expectations.2
Worry management techniques are likely most helpful to reduce presleep cognitive arousal and worry, but they have not been shown to produce large improvements in sleep.34 Nonetheless, management of cognitive and emotional complaints is a worthwhile endeavor because patients identify it as one of the most common contributors to insomnia.35
Additional Educational Resources Patient-oriented educational resources in the public domain (e.g., websites, pamphlets, self-help books) are widely available at minimal cost and can reinforce or supplement nonpharmacologic insomnia treatments. The American Academy of Sleep Medicine (www.sleepeducation.com), National Sleep Foundation (www.sleepfoundation.org), and American Insomnia Association (www. americaninsomniaassociation.org) are three leading American organizations that disseminate public information regarding insomnia.
Thought Records Thought records are a classic cognitive therapy tool for modifying negative thinking.36 Maladaptive thinking styles have been implicated in a variety of disorders including insomnia.30,37-39 The negative sleep-related thoughts and beliefs in insomnia do not appear to be simply attributable to the high rate of comorbid disorders with a similarly unhelpful cognitive style.40 Negative thoughts and moods can exert reciprocal negative influences on each other, and both can perpetuate insomnia. The purpose of the thought record is to observe the connections between negative thoughts and distress and to challenge and interrupt this process. The observation is achieved via prospective monitoring using a specially designed worksheet divided into columns. Several versions of thought records are available, including a version specifically designed for use with insomnia patients.2 The first three columns of a typical thought record are labeled Situations, Mood and Mood Intensity Rating (0% to 100%), and Thoughts. Observing which situations (column 1) tend to give rise to distress (column 2), and subsequent negative thoughts (column 3) can provide insight into a seemingly automatic cognitive-emotional process. Although observing these connections can be helpful in initiating cognitive change, the main use of the thought record is to actively challenge unhelpful thoughts. Unhelpful thoughts about sleep are rated as more compelling or more believable by primary30,37-39 and comorbid insomnia groups40 relative to their good-sleeper counterparts. More specifically, people with insomnia have been shown to have cognitions that overestimate the negative effects of insomnia, focus on the belief that sleep is out of one’s control, are rigid or are unrealistic expectations about how much sleep is needed for functioning, and are misconceptions about the causes of insomnia.30,37-39 Whereas some of these beliefs may be true to varying degrees, the cognitive inflexibility or degree to which people with insomnia adhere to such thoughts perpetuate or exacerbate insomnia and are thus unhelpful. To modify these cognitions, patients are asked to challenge unhelpful thoughts using a series of questions. For example, after a poor night’s sleep insomnia sufferers may struggle with the negative thought, “I’ll never be able to make it through the day.” A question to explore with patients whether they have had any experiences that show this thought has not been true 100% of the time. Is it guaranteed that a poor night’s sleep will prevent them from functioning? Will they be able to function but perhaps it will be more difficult? Are there times when they had a good day even after a poor night or a poor day after a good night’s sleep? Are there strategies they have used in the past to be able to cope with the negative effects of their insomnia? Could they see how this thought becomes a self-fulfilling prophecy? This line of Socratic
Cognitive Therapy Tools Psychological and behavioral therapies for insomnia also address cognitions that interfere with sleep, mostly by increasing cognitive arousal, which is incompatible with sleep. Cognitive therapy for insomnia is typically combined with the behavioral methods discussed earlier. Below are a few tools that can help implement this aspect of therapy. Structured Problem-Solving Worry or problem-solving in the presleep period is one of the strongest cognitive predictors of delayed sleep onset latency.29 For patients who tend to worry in bed, a variety of intervention strategies have proved useful including relaxation (reviewed in a previous chapter) and techniques more directly focused on sleep-disruptive cognitions.30-33 One of the original problem-solving cognitive strategies is a presleep writing procedure developed by Espie and colleagues32; this technique is similar to a procedure called constructive worry.34 This procedure involves a relatively simple structured problem-solving technique. In constructive worry, patients reporting that worries follow them to bed are asked to set aside some time several hours before bedtime (i.e., usually in the early evening) to complete a homework assignment. The homework is completed using a worksheet that is divided into two columns. The first column is labeled “Concerns” and the second column is labeled “Solutions.” In the Concerns column, patients list worries that have the greatest likelihood of keeping them awake at night. In the Solutions column, patients generate the next, immediate step they can take toward the ultimate goal of solving the problem. Patients are instructed not to write down the ultimate end solution, as they may view this solution as out of reach or difficult to implement. They are refocused on the most immediate step in the sequence. When there are no apparent solutions to solve a problem, patients are encouraged to write down an acceptance-based or self-care strategy. For example, the worry may be that their terminally ill pet will die tonight. This upsetting prospect may have no apparent solution. In such a case, it is helpful to write down plans to implement coping strategies such as calling a friend for moral support.
890 PART II / Section 10 • Insomnia
questioning is aimed at modifying thoughts and thus improving the patient’s mood. The level of mood disturbance would be expected to improve if the thought mentioned is modified to, “I don’t feel well now, but I’ve always made it through, and things tend to get better as the day goes on anyway.” There are very few studies evaluating the relative contribution of cognitive restructuring to CBT for insomnia. A recent pilot study of cognitive therapy produced strong posttreatment effect sizes on daytime and nighttime functioning,41 although these findings can be viewed as preliminary only. Clinical trials testing CBT have shown that CBT produces declines in the belief of unhelpful sleeprelated thoughts,30,42 and the posttreatment modification of such maladaptive cognitions relates to other indices of clinical improvement.30,38,42,43 Thus, the sort of cognitive restructuring described is often viewed as a useful component of the overall insomnia treatment process.
METHODS OF DELIVERING TREATMENT As summarized in the previous chapter, the psychological and behavioral insomnia therapies, and particularly multicomponent CBT protocols, are currently regarded as wellestablished, efficacious insomnia treatments. In addition to their demonstrated efficacy, these treatments afford the practitioner and patient considerable flexibility in regard to their method of delivery. Indeed, the literature suggests that therapeutic modality (i.e., individual versus group), the type of provider delivering treatment, and the means by which treatment instructions are communicated can all vary such that a multitude of treatment delivery options can be considered for these therapies. The following text provides descriptions of several of these delivery methods and considers their advantages, disadvantages, and general efficacy. Individualized Treatment Perhaps the best tested and most commonly used method of delivering psychological or behavioral insomnia therapies has been via individualized treatment consisting of one-on-one sessions between a therapist and single patient. Most published studies that provide descriptions of this form of treatment delivery have employed doctoral-level psychotherapists or psychology graduate students as therapists primarily because the psychological or behavioral insomnia therapies have, for the most part, been developed by psychologists. As suggested by several meta-analyses and systematic reviews, such individualized behavioral insomnia treatment has proven efficacious for short-term and longer-term insomnia management using stand-alone behavioral insomnia therapies (relaxation training, sleep restriction, paradoxical intention, and stimulus control) and multimodal CBT protocols.44-49 Most available descriptions of the multiple-component interventions are derived from clinical trials that outline a fixed treatment package provided on a fixed schedule, usually in four to eight sessions occurring at predetermined intervals. However, in clinical practice, patients’ treatment needs vary, so pretreatment case formulations are typically conducted to decide on the specific treatment
components and duration of treatment provided. Although no consensus clinical guidelines exist for matching treatment components to patients, some previous clinic-based studies50,51 describe flexible treatment packages that allow the treatment to be tailored to the patient. One advantage of individualized treatment is its fit within traditional medical and mental health outpatient settings wherein one-on-one meetings between providers and patients are the norm. Individualized treatment offers reasonable treatment scheduling flexibility subject to the common availability of the provider and patient, and it requires only the limited office space to accommodate the patient and provider. It also allows maximum flexibility in tailoring treatment to best address each individual patient’s problematic sleep-related cognitions and behavior. However, compared to other treatment delivery methods, individualized treatment is relatively costly to the patient and arguably is an inefficient use of the relatively limited number of providers (largely psychologists and other doctoral-level sleep specialists) who have expertise with behavioral insomnia therapies. Some patients prefer individual therapy over other forms of treatment despite its high cost, so the patient’s preferences may guide the choice of this approach when knowledgeable providers are available. Group Treatment Protocols Because providing behavioral insomnia therapy through an individual treatment format is a relatively costly and inefficient form of treatment delivery, various alternate and more cost-efficient delivery methods have been developed. By far the most common alternative delivery format is group therapy. Most previously described group treatment protocols have been CBT or other multicomponent packages that are typically provided in four to eight treatment sessions to a group of patients. Table 80-1 lists and briefly describes a sampling of these group protocols. No one standard brand of group therapy has been employed universally for treating insomnia. However, the descriptions show that group therapy protocols characteristically include an amalgam of such well-established, stand-alone insomnia treatments as stimulus control, relaxation training, and sleep restriction, and these components are often supplemented by sleep education, sleep hygiene instructions, and cognitive therapy. Thus, the group protocols are typically omnibus and include treatment components with well-established efficacy for treating chronic insomnia. Results of previous meta-analyses44,47 and critical reviews45,46 suggest that group therapy is an efficacious delivery format for behavioral insomnia therapy. Whether group and individual insomnia treatment are equally efficacious is not clear. Some previous meta-analytic results44 suggest a slight superiority of individually administered treatments over group therapy for insomnia treatment. However, conclusions about the relative efficacy of individual and group insomnia treatment based on metaanalyses should be considered cautiously because such conclusions are based on comparisons of studies that employed different therapists, different patient samples, and often different treatment packages. More informative are randomized trials that provide direct comparisons of group and individual therapy within the same study.
CHAPTER 80 • Psychological and Behavioral Treatments for Insomnia II: Implementation and Specific Populations 891
Table 80-1 Sampling of Psychological and Behavioral Group Therapy Paradigms for Insomnia NO. OF PATIENTS PER GROUP
CITATION
NO. OF SESSIONS
TREATMENT COMPONENTS
TYPES OF PATIENTS
Backhaus et al.183
6
Sleep education Sleep hygiene Progress relaxation Cognitive relaxation Stimulus control Sleep restriction Cognitive therapy
Primary insomnia
4-8
PhD clinical psychologist
Bootzin and Stevens162
6
Stimulus control Bright light Sleep hygiene Cognitive therapy Mindfulness-based stress reduction
Teenage substance abusers
2-6
Advanced psychology graduate student
Epstein and Dirksen55
4, plus 2 phone follow-ups
Sleep education Sleep hygiene Stimulus control Sleep restriction
Breast cancer survivors
4-8
Master’s-level clinical nurse specialist
Espie et al.56
6
Sleep information Sleep hygiene Stimulus control Sleep restriction Relaxation Cognitive therapy
Medical clinic patients with primary insomnia
4-6
Health visitors (nurses)
Morin et al.77
8
Sleep education Sleep hygiene Stimulus control Sleep restriction Cognitive therapy
Primary insomnia
4-6
PhD clinical psychologists
Ong et al.83
7
Sleep education Deep breathing and mental imagery Stimulus control Sleep restriction Cognitive restructuring
Clinically referred mixed insomnia subtypes
8-15
Licensed PhD clinical psychologist
Rybarczyk et al.184
8
Sleep education Sleep hygiene Stimulus control Sleep restriction Cognitive therapy Relaxation
Older mixed medical patients with insomnia
5-6
PhD clinical psychologists
Verbeek et al.185
6
Psychoeducation Stimulus control Sleep restriction Relaxation Cognitive therapy Medication withdrawal
Clinically referred primary insomnia
5-7
PhD-level therapists
Studies of this nature have been generally absent from the literature, although one such trial52 showed comparable outcomes for individualized and group CBT for insomnia provided by the same set of therapists. More comparisons of this nature are needed before confident conclusions can be drawn regarding the relative efficacy of these two methods of delivering treatment. What is clear is that group therapy represents a reasonably efficacious way of delivering insomnia treatment and has several advantages that make it an attractive treatment medium. First, because a limited number of providers are competent in behavioral insomnia therapies, group treat-
TYPE OF PROVIDER
ment gives multiple patients access to a single trained provider and thus entails a relatively efficient use of the provider’s time. Because of this efficiency, group treatment is generally a less-expensive treatment alternative for the patient and third-party payers. Furthermore, the group milieu, composed of many patients with the same sorts of sleep difficulties, offers individual patients some sense of validation and social support that they would likely not derive from individualized treatment. These nonspecific factors are likely to enhance treatment outcomes for at least a portion of those who attend group insomnia therapies.
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Group treatment offers less scheduling flexibility than one-on-one therapy, and it may afford patients less individualized attention. It may be difficult for all patients to attend all sessions at prescheduled times, and if patients miss group sessions, individual makeup sessions may be needed to help patients catch up with the rest of the group after an absence. Group treatment may be optimized by individual prescreening of participants to identify those with special treatment needs (e.g., uncontrolled comorbid psychiatric or medical disorders) or who might be disruptive to the group process. Furthermore, group treatment requires a meeting room large enough to accommodate at least one therapist and several patients. The space requirement and the desirability of minimizing the time patients wait for a new group to form can render group treatment unfeasible in some small office settings, both in terms of space and patient volume. Nonetheless, group therapy is a viable treatment alternative that has a place in many clinical venues. Delivery by Nontraditional Providers The ranks of sleep specialists who are experts in the behavioral insomnia therapies is currently very limited.53 In efforts to facilitate broad dissemination of behavioral insomnia treatments, some investigators have examined whether nontraditional therapists can effectively deliver these interventions. Because insomnia sufferers typically present first in primary care settings, it seems reasonable to consider using health care professionals (e.g., nurses and family physicians) who are not sleep specialists to provide behavioral interventions. Several studies have demonstrated that various general health care staff including family physicians,54 nurses,55-57 nondoctoral rural mental health clinic staff such as mental health counselors and social workers,58 and primary care counselors59 can effectively administer treatments such as stimulus control and multicomponent CBT in general practice settings. In several of these trials, the nontraditional therapists received training and supervision from an experienced sleep psychologist, so that the therapists employed could be considered specialist provider extenders. This model in which the behavioral sleep medicine specialist assumes a trainer or consultant role might represent a reasonable alternative to higher-priced specialty care and might prove useful for optimal dissemination of the behavioral insomnia therapies in primary care and other traditional medical settings. Collaboration between a specialist consultant and nonspecialist medical office personnel who deliver treatment has obvious appeal. This delivery model represents an efficient use of behavioral sleep medicine specialists and assures that their expertise is made available, albeit indirectly, in medical settings where most treatment-seeking insomnia patients present for help.60 The training of existing licensed health care personnel to deliver behavioral insomnia therapies also seems reasonable given the relevant training most such professionals have in providing related health care activities. At least one study57 using this delivery method noted treatment effect sizes that fall short of those usually reported for efficacy studies in which more-traditional therapists (psychologists or psychology graduate students) were employed. Whether such differences in treatment outcome are due to “therapist effects”
or the presence of more diverse and difficult-to-treat patients encountered in the primary care setting is difficult to determine. Only through future studies that directly compare traditional and nontraditional therapists will this question be answered. When such nonspecialists as family physicians or nurses can be properly trained and given access to a specialist in the behavioral insomnia therapies for consultation, this sort of delivery method seems a reasonable alternative to consider. However, the more difficult and complex insomnia cases seen in such settings might ultimately benefit by more direct contact with behavioral sleep medicine specialists.53 Delivering Treatment Outside of the Office The various approaches discussed thus far provide a number of delivery methods for disseminating behavioral insomnia treatments. However, these options considered collectively might not meet the needs of all insomnia sufferers. Given the 10% to 15% prevalence61-63 of chronic insomnia in the general population and the limited number of skilled providers, many patients do not have easy access to such treatment. Others with limited financial resources (e.g., the poor and uninsured) might not have sufficient financial resources to seek professional help for their insomnia. Some insomnia sufferers initially prefer to use self-help approaches with limited or no provider contact and thus might resist presenting to clinical settings for insomnia treatment. Several investigators have tested less expensive treatment delivery methods that can be largely initiated in the home by patients themselves. Mimeault and Morin,64 for example, tested a booklet of self-help CBT instructions, used independently or with therapist guidance provided through phone consultations, against a wait-list control group. Compared to the control condition, those treated with the self-help therapy showed substantially greater sleep improvements, and these improvements were maintained at a 3-month follow-up. The addition of phone consultations with a therapist conferred some advantage over the self-help booklet alone at posttreatment evaluation, but these benefits disappeared by follow-up. In another study, Currie and colleagues65 compared individual behavioral insomnia therapy, treatment with a selfhelp manual, and a waiting list condition for ameliorating insomnia in a group of recovering alcoholics. Results showed treated patients achieved significantly greater improvements than controls, but no significant differences were noted between the in-person individual therapy and home-administered self-help program. Bastien and coworkers52 found comparable effectiveness of insomnia CBT provided in individual sessions, group meetings, or a self-help format aided by telephone consultation. Rybarczyk’s group66 tested a home-based video CBT program for treating older insomnia patients who had comorbid medical conditions. Whereas this treatment produced greater improvements in sleep and waking functioning than did a wait-list condition, the improvements noted fell short of those achieved with CBT delivered faceto-face in a classroom setting. Considered collectively, these findings suggest that self-administered behavioral insomnia treatments are promising, although contact with
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a therapist via phone consultation may be needed to improve outcome. To determine whether behavioral insomnia treatments can be delivered effectively without direct interaction between the patient and a therapist, some investigators have tested treatment protocols provided through mass media dissemination. In perhaps the largest single treatment study to date, Oosterhuis and Klip67 tested a behavioral insomnia therapy provided via a series of eight 15-minute educational programs broadcast on radio and television in the Netherlands. More than 23,000 people ordered the accompanying course material, and data from a random subset of these showed that improvements in sleep and reductions in hypnotic use, medical visits, and physical complaints were achieved among those who took part in this program. However, given the single group nature of their design, it is impossible to discern how these results might compare to more conventional treatments. Three studies68,68a,68b have tested self-help interactive CBT programs delivered to insomnia patients via the Internet. The first of these studies showed little benefit of this approach relative to a no treatment condition, but the latter two studies showed more favorable results for the Internet-delivered intervention. These results collectively suggest that at least some patients benefit by this form of self-help treatment. Summary The most-tested and well-established forms of delivery are the individual and group therapy protocols directed by those with extensive training backgrounds in providing psychotherapy in general and the behavioral insomnia therapies specifically. Treatment delivery approaches that diverge from that common paradigm through their use of alternative providers or no direct provider contact at all currently have much less empirical support. This does not mean they are not effective, at least for a subset of insomnia sufferers. However, a number of questions remain unanswered: Which alternate treatment delivery methods are most efficacious and cost effective? Who is likely to benefit from self-help approaches and who is not? Does treatment failure with one of the nontraditional or self-help approaches adversely affect a patients’ treatment expectations and subsequent response to a more intensive traditional behavioral insomnia treatment? Are patients harmed in any way by the relatively untested nontraditional approaches? Addressing questions such as these would be useful in determining which the treatment delivery methods can be considered viable and reasonable choices for those who seek treatment.
TREATMENT DOSING In addition to considering the various methods and providers that can be used to deliver the psychological and behavioral insomnia therapies, it is also important to consider what constitutes the proper or optimal dose of such treatments. Previous studies with multiple-component CBT for insomnia have shown efficacy for such interventions delivered in one, two, four, six, and eight individualized sessions and five to eight group sessions. Yet, little is known about how many individual and group sessions are
needed on average to achieve optimal treatment outcomes. Despite the ample number of exemplary dose-response studies extant in the pharmacology literature,69 research specifically designed to determine the optimal dosing for any of the psychological and behavioral insomnia therapies has generally been lacking. The lone exception to this oversight is a recently published study by Edinger and colleagues70 conducted to determine the optimal dosing of their CBT model delivered in an individual therapy format. In this study, patients with primary insomnia were randomly assigned to a notreatment control (wait-list) or to active treatment comprising one session, two sessions (weeks 1 and 5), four sessions (every other week) or eight (weekly) sessions of CBT delivered over an 8-week period. Results showed that subjective (sleep diary) and objective (actigraphic) sleep measures favored the one- and four-session CBT doses over the other CBT doses and wait-list control. However, comparisons of pretreatment data with data acquired at the 6-month follow-up showed that only the four-session group maintained significant improvements in objective wake time and sleep efficiency measures over time. Moreover, a notably greater percentage of those assigned to the four-session condition achieved more than 50% reduction in the study’s primary sleep outcome measure, subjective wake time after sleep onset, than did those in the other conditions. Considered collectively, this study’s findings imply that for the specific CBT model tested, a dose of four sessions delivered on an every-other-week schedule appears optimal. In addition to providing one model of ascertaining doseresponse curves for behavioral insomnia therapies, this study highlights at least two important dosing factors that can be considered in treatment delivery. The first is the total number of sessions delivered and the second is the interval at which consecutive sessions are scheduled. In the paradigm considered, treatment information and instructions are delivered by an expert therapist, and then the patient implements the strategies learned from the therapist at home and becomes self-sufficient in using them. As suggested in the dosing study,70 the four-session dosing, which provides therapist contact every other week, might offer the patient the optimal balance between therapist guidance and patient independence so self-sufficiency with the treatment strategy is realized. However, the study tested only one of the many available behavioral insomnia treatments and CBT paradigms, so little is currently known about what represents the optimal dosing of the range of individual and group treatments available. A more-recent study71 showed that those with insomnia comorbid to a psychiatric condition had somewhat less impressive treatment outcomes than did primary insomnia patients in response to the four-session CBT model.70 Thus, insomnia diagnosis or comorbidities may be important factors that affect the optimal dosing of psychological and behavioral insomnia therapies. A final consideration pertinent to the discussion of treatment dosing is the observation that some abbreviated interventions are highly effective, at least for those with primary insomnia. Two studies72,73 have tested very similar condensed (two-session) versions of multicomponent behavioral insomnia therapies that included sleep
894 PART II / Section 10 • Insomnia PRETREATMENT–TO–FOLLOW-UP SLEEP EFFICIENCY CHANGES: SLEEP LOG ACBT
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Figure 80-6 A, Changes in sleep efficiency and ISQ scores shown by each study patient. B, Increases in sleep log efficiency measures. ACBT, abbreviated cognitive behavior insomnia therapy; Pre-Tx, pretreatment; ISQ, Insomnia Symptom Questionnaire, an instrument designed to assess severity of sleep–wake symptoms of insomnia; SHC, sleep hygiene control intervention. (From Edinger JD, Sampson WS. A primary care “friendly” cognitive behavioral insomnia therapy. Sleep 2003;26:177-182.)
education and modified stimulus control and sleeprestriction strategies. In the former, the condensed CBT proved significantly superior to a sleep hygiene control for improving subjective sleep measures and global insomnia symptoms. Figure 80-6, which shows case-by-case changes in measures of sleep efficiency and insomnia symptoms, exemplifies the study’s findings. In the latter study, Germain and colleagues73 showed that a brief behavioral treatment outperformed a sleep information control therapy across a variety of outcome measures. Figure 80-7, which shows the treatment effect sizes for the brief behavioral therapy relative to a control condition, suggests reasonably impressive outcomes can be achieved with a fairly minimal inter-
vention. Considered together, these studies imply that relatively effective low-dose multicomponent psychological and behavioral insomnia therapies can be developed. Nevertheless, additional studies are needed to determine how these abbreviated treatment models compare to higher doses of the more complex unabridged psychological and behavioral insomnia therapies available.
TREATMENT ACCEPTABILITY AND ADHERENCE ISSUES The ultimate success of psychological and behavioral treatments for insomnia relies on patients’ willingness to accept
CHAPTER 80 • Psychological and Behavioral Treatments for Insomnia II: Implementation and Specific Populations 895
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Figure 80-7 Treatment effect sizes for brief behavioral insomnia therapy. Effect sizes shown are for a brief behavioral insomnia therapy relative to an information control therapy. SE%, sleep efficiency percentage; PSQI, Pittsburgh Sleep Quality Index; WASO, wake-time-after-sleep onset. (Findings from Germain A, Moul D, Franzen P, et al. Effects of brief behavioral treatment for late-life insomnia: preliminary findings. J Clin Sleep Med 2006;2[4]:403-406.)
and engage in the treatment process as well as their ability and motivation to implement the treatment components at home. The importance of factors related to treatment acceptability and adherence is gaining in recognition. Treatment Acceptability Patients’ preferences and values play a critical role in treatment acceptance.74 The most efficacious treatments, if not palatable to patients, will have little clinical utility. To assess patients’ attitudes toward insomnia treatments, Morin and colleagues1,75 developed The Insomnia Treatment Acceptability Scale. This scale asks respondents to rate their opinions of CBT versus a pharmacologic intervention for insomnia. Community samples of adults with insomnia rate the CBT intervention as more acceptable, more suitable for sleep difficulties, more likely to be effective in the long term, less likely to produce side effects, and more likely to improve daytime functioning compared to a hypnotic medication.75,76 Additional studies have confirmed patients’ preference for psychological or behavioral insomnia therapies over medications. In a study of older adults with insomnia, those randomized to receive CBT reported greater satisfaction with treatment than those receiving pharmacotherapy.77 A survey of hospitalized inpatients taking benzodiazepines for insomnia revealed a strong preference for nondrug treatment alternatives; 67% of those surveyed reported they would try an alternative treatment in the hospital if one were available, and most (82%) viewed these alternatives as “healthier” than benzodiazepines.78 When considering the range of psychological and behavioral therapies available, these patients reported the strongest preferences for sleep hygiene and relaxation, with sleep restriction and stimulus control holding the least appeal.78 A few studies have compared patient preferences after treatment with various psychological and behavioral approaches. In one such study, insomnia patients rated their satisfaction with CBT treatment components (sleep hygiene, stimulus control, sleep restriction, cognitive
therapy, relaxation training, and medication tapering) after participation in a group CBT treatment.76 Sleep hygiene was rated as the most liked and most useful element, whereas sleep restriction was rated lowest. Interestingly, sleep restriction, but not sleep hygiene, was related to symptom improvement. In another investigation comparing sleep hygiene, meditation, and stimulus control as treatments for chronic insomnia, participants in the sleep hygiene group were the least satisfied with their treatment at posttreatment review despite similar sleep improvements in all three groups.79 Collectively, these findings imply that most patients prefer psychological and behavioral treatments over medications. Some patients prefer treatment components that are not necessarily the most efficacious ones, perhaps because they are easier to implement. Sleep restriction seems to be unpopular with patients, perhaps due to its counterintuitive nature and their difficulty adhering to it. The implementation of sleep restriction might require a particular focus on the therapeutic rationale to foster its acceptance among patients. Treatment Adherence It is not difficult to appreciate the central importance of treatment adherence in ensuring the success of psychological and behavioral insomnia therapies. These treatments require considerable commitment from the patient, and adherence is recognized as one of the most critical factors affecting treatment success.80,81 It has been estimated that approximately 15% of research participants fail to complete behavioral insomnia therapy.82 This rate can approach 40% in clinical populations.82,83 Factors that have been linked to attrition include greater sleep impairment, poorer perceived general health, higher levels of depression, lessfavorable ratings of psychological and behavioral insomnia treatment, and greater tendency to view the therapist as critical and confrontive.82-86 Sleep diaries are the most common method of monitoring adherence to some behavioral treatments, although other intervention tools (e.g., actigraphy, patient checklists, provider checklist) can provide supplemental information. Studies reporting adherence to psychological and behavioral insomnia treatments in research participants are encouraging,77,87-89 but less-favorable outcomes are reported in clinical samples.81 The percentage of patients reporting continued adherence to treatment recommendations at long-term follow-up seemingly varies as a function of the specific treatment considered. Harvey and colleagues90 noted that patients’ reported adherence to 10 different CBT treatment components varied from 19% to 74% at a 1-year posttreatment follow-up. Similarly, Engle Friedman and coworkers91 found that 73% of the patients they treated reported continued use of stimulus control at a 2-year follow-up, whereas only 53% reported continued use of relaxation, and 38% reported continued use of sleep hygiene. Such usage patterns are important to consider because higher adherence is related to better treatment outcomes.88 Despite its importance, there is little evidence-based information on promoting adherence. One study implicated a benefit of modafinil in improving adherence to CBT.92 General suggestions for promoting adherence have
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included providing the treatment rationale, discussing adherence directly with the patient, enlisting the support of the patient’s family, providing encouragement, soliciting the patient’s commitment through a verbal or written contract, encouraging questions from the patient, understanding the patient’s expectations, and setting realistic goals.1,81,93 Adherence strategies targeting specific treatment components are described elsewhere.1,2
APPLICATIONS TO PATIENTS WITH COMORBID PSYCHIATRIC CONDITIONS Insomnia is highly prevalent as a coexisting complaint in association with various psychiatric and medical disorders94,95; in fact, such forms of insomnia are far more common than primary insomnia.96,97 Despite its prevalence, there has been scant research on the efficacy of psychological and behavioral treatments for this form of insomnia, probably due to the dated notion that insomnia is merely a symptom of the comorbid condition, particularly when it is concurrent with a psychiatric disorder. Traditionally, management of such forms of insomnia entailed treating the suspected “primary” condition with the expectation that the insomnia would remit once the associated “primary” disorder was resolved. However, this approach ignored observations that a sizable group of people continue to suffer from insomnia as a clinically significant residual symptom after remission from the “primary” disorder.98-102 Such findings imply that insomnia often becomes either partially or totally independent from the comorbid psychiatric condition and persists as a separate disorder worthy of independent clinical attention. In addition, insomnia can be a predictor of poorer response to treatment of the coexisting condition.103,104 As a result of these observations, there has been increasing recognition that insomnia should be regarded as a comorbid disorder when observed in patients with concurrent conditions such as the major psychiatric disorders.105 Pharmacologic treatment studies have suggested that adding a treatment of insomnia to the treatment of the comorbid psychiatric disorders produces better results than treating the comorbid disorder alone.106-108 However, there are drawbacks to some pharmacologic approaches, including possible dependence, unknown polypharmacy effects in patients with complex disorders, and shorter durability of posttreatment effects (relative to psychological treatments such as CBT).109 Because the psychological or behavioral insomnia therapies have comparable shortterm efficacy, better durability, and fewer safety concerns than do the pharmacologic approaches, they are attractive alternative (or augmenting) strategies for insomnia management. Before discussing the application of such treatments to persons with comorbid insomnia, it seems prudent to consider whether patients with comorbid insomnia have the same purported insomnia-maintaining factors targeted by the psychological or behavioral insomnia therapies as do patients with primary insomnia. If the patients with comorbid insomnia manifest the same cognitive and behavioral treatment targets shown by patients with primary insomnia, then they should benefit from the psychological and
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Figure 80-8 Possible etiologic pathways for comorbid insomnias. *Stress may be in the form of an internal (e.g., hormonal change) or external (e.g., interpersonal conflict) event that can directly cause sleep disruption or can cause a comorbid condition. Compensatory activities or arousing cognitions (or both) are thought to play a role in causing or maintaining the insomnia. The stressor might also operate through a moderator variable (i.e., a shared vulnerability trait) of insomnia and the comorbid illness.
behavioral insomnia treatments. Research has found that is the case.110 For example, patients with insomnia and comorbid depression exhibit similar levels of unhelpful, sleep-disruptive beliefs as do their primary insomnia counterparts.39,111 Moreover, patients with depression and clinically significant insomnia display at least as many sleep-disruptive activities and similarly elevated sleep effort as do patients with primary insomnia alone.111 Given that primary insomnia and comorbid insomnia have many shared perpetuating factors, we might expect a cognitive behavioral conceptualization of comorbid insomnia to look something like the model contained in Figure 80-8. In this conceptualization, stress may be an endogenous event (e.g., a change in neurochemical activity) or a life event (e.g., the birth of a baby). Whether the stressor is an external life event or a physiologic event, it can directly cause either sleep disruption or the comorbid disorder. Alternatively, the stressor might operate through a moderator variable (i.e., a shared vulnerability trait) of insomnia and the comorbid condition. Several potential moderator variables exist including ruminative tendency112 or specific maladaptive beliefs.39,113 Once sleep disruption occurs, attempts at coping or compensating for the sleep loss result in behaviors such as sleeping in, increasing time in bed, using alcohol or sleep aids, or avoiding obligations or socializing. Such actions may be linked to circadian or homeostatic disruption, increased arousal, or reinforcement of beliefs that one is helpless to cope with sleep loss. These factors have been posited as perpetuating factors in insomnia.1,20,24,113-115 Insomnia would be expected to exert negative influence on the comorbid disorder, and in some cases it could cause the disorder. Thus, even in cases where a comorbid disorder might have initially caused the sleep disruption, cognitive and behavioral factors can become perpetuating factors for an insomnia that remains after the comorbid condition remits. To date, there have been only a few studies investigating psychological and behavioral insomnia therapies among patents with comorbid psychiatric conditions.94,116,117 However, it is promising to note that these studies have reported moderate to large posttreatment effect sizes in patients with comorbid insomnia.110 A number of insomnia treatment studies have focused specifically on the effects
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of treating the insomnia that occurs with major depressive disorder (MDD). This is probably because of the important link posited between insomnia and depression. The vast majority of people with depression present with sleep complaints. So common is this association that there is a well-documented tendency in physicians to presume that an insomnia complaint is diagnostic of a major depressive episode even in the absence of other MDD diagnostic criteria.118,119 Indeed, insomnia can predate and predict initial MDD onset61,120,121 and can persist as a clinically significant condition long after the associated MDD episode remits.99,102,122 In addition to a likely etiologic relationship, insomnia predicts poorer response to depression treatment,103,123,124 and treatment of insomnia appears to enhance response of depression symptoms to treatment.107,125-127 Given these observations, a substantial portion of the comorbid insomnia treatment studies have focused on insomnia comorbid to depression. In one case-series study, bibliotherapy CBT was tested in those with insomnia and depression, and results showed improvements in both sleep and depression symptoms.128 Similarly, a case series study of persons with comorbid insomnia and MDD showed that CBT was effective for improving both sleep and mood.129 In the only published randomized, controlled trial testing CBT in those with depression and insomnia, Manber and colleagues126 reported that augmentation of antidepressant medication with CBT produced a far greater remission rate (depression remission rate, 61.5%) than antidepressant therapy and a sham behavioral control therapy (depression remission rate, 33%). Whereas the few studies conducted have mainly focused on depression, a review of psychological interventions for insomnia130 suggests that there is emerging support for CBT and other psychological and behavioral insomnia therapies in persons with mixed psychiatric comorbidities.82,94,129,131,132 Relatively few studies have examined the application of these treatments with other psychiatric disorders occurring comorbid to insomnia. CBT has been used effectively in persons with posttraumatic stress disorder (PTSD)133 and in persons in recovery from alcohol abuse.65,134 Elements of CBT have also been incorporated into an effective nocturnal panic disorder treatment protocol.135 Given the promising results thus far, much more controlled and systematic research is needed to test the applicability and efficacy of psychological and behavioral insomnia therapies associated with other psychiatric conditions. In a comprehensive review of the subject, Smith, Huang, and Manber110 suggested that there may be unique delivery issues with comorbid populations. However, evidence has not been reported in support of this idea. Trials investigating whether the insomnia of persons with comorbid psychiatric conditions can be treated as effectively with the psychological and behavioral treatments originally designed for primary insomnia patients132 have produced promising results. Higher degrees of psychopathology at baseline do not preclude patients from responding to such insomnia therapies.132 In other words, baseline psychopathology does not predict whether someone is a responder to these treatments or not. More research is needed to understand whether changes to traditional psychological and behav-
ioral insomnia therapies are needed for the most optimal response in patients with comorbid conditions. Nonetheless, preliminary studies support the use of these treatments to address the sleep complaints in persons with accompanying psychiatric disorders.
APPLICATIONS TO PATIENTS WITH COMORBID MEDICAL CONDITIONS There is mounting evidence that psychological and behavioral therapies for insomnia are effective for people with a variety of comorbid medical conditions including cancer, chronic pain, autoimmune diseases, and human immunodeficiency virus (HIV) infection (see Smith and colleagues110 for a review). Adaptations of standard psychological and behavioral insomnia therapies to specific populations with comorbid medical disorders may include adding components to address disease-specific symptoms, such as fatigue and pain, or using psychological and behavioral principles to address adaptation to the disease and factors that could interfere with adherence to treatment.110 In some studies, researchers adapted standard psychological or behavioral insomnia therapies to the population studied, but this has not been a consistent practice. For instance, in the context of breast cancer, some protocols have used cognitive and behavioral principles to directly address fatigue136,137 and others have not,138 yet all protocols reported improvement in sleep. Research concerning use of psychological or behavioral interventions for insomnia in patients with medical comorbidities has not directly tested the utility of specific treatment adaptations, but phenomenological studies and our collective clinical experience lead us to point to several issues that are relevant to its implementation when insomnia is present in the context of medical diseases. The Impact of Disease-Specific Symptoms on Insomnia Sleep of patients with medical disorders can be disrupted by physical discomfort, including pain, night sweats, cough, dyspnea, nocturia, and diarrhea. The clinician needs to ensure that these symptoms are adequately managed, because they often cannot be fully addressed with cognitive and behavioral principles. The most common of these symptoms is pain. In addition to the direct impact of pain on sleep, patients’ reactions to pain contribute to insomnia indirectly. This is also true for fatigue, which, like pain, is common in several medical disorders. Common reactions to these two symptoms include spending more than usual time in bed at night, using the bed during the day for resting or napping, or using the bed and bedroom as a headquarters for daily activities. These reactions can contribute to insomnia by weakening the sleep drive or by rendering the bed a poor stimulus for sleep. Some patients, particularly those with HIV, use large amounts of caffeine as a measure to counter fatigue,139,140 a practice that can interfere with sleep at night. In addition, because impaired sleep quality magnifies pain141,142 and is associated with reduced energy the next day, patients are concerned that a night of poor sleep will be followed by increased pain or fatigue on the following day. These concerns are often exaggerated
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(catastrophic cognitions) and contribute to insomnia by creating sleep anticipatory anxiety. The means by which pain and fatigue contribute to insomnia can be addressed with a number of the available cognitive and behavioral techniques commonly employed with insomnia patients. Stimulus control strengthens the bed and bedroom as cues for sleep, and sleep restriction increases the sleep drive. Sleep hygiene addresses excessive and untimely caffeine consumption and is a particularly relevant component of treatment for patients with HIV. Cognitive restructuring modifies sleep-interfering beliefs related to pain and fatigue by providing a realistic perspective regarding the relationship between sleep and these symptoms and setting behavioral experiments to test this relationship.137 In addition, the tendency to overly attribute pain and fatigue to sleep loss stems, in part, from failure to distinguish between sleepiness and fatigue. It is therefore particularly important to clarify this distinction for patients with medical comorbidities. Addressing Pain and Fatigue with Psychological and Behavioral Strategies Behavioral treatment components that are not included in standard psychological or behavioral protocols for insomnia can be used to modify sleep-interfering behavior that is associated with pain and fatigue. Increasing Activities Behavioral activation is an intervention that encourages increased engagement in active rather than sedentary pastimes, identifies obstacles to daytime activities, and helps work around these obstacles. Behavioral activation could be easily integrated into a psychological or behavioral insomnia therapy when pain and fatigue are associated with significant reduction in activities. Used in such situations, behavioral activation can help break the vicious cycle connecting low level of activity to physical deconditioning, which further reduces activity level.143 Exercise is a specific form of behavioral activation that has shown efficacy for pain management144 and reduction of daytime fatigue. Moderate exercise (55% to 75% of maximum heart rate) is safe and well tolerated by many patients with medical comorbidities, including cancer survivors with various cancer diagnoses. It effectively reduces cancer-related fatigue during and after cancer treatment, with similar results for different cancer treatments (surgery, transplant, chemotherapy, radiation therapy, and hormone therapy),145 though effect sizes among cancer patients are small.146 In the context of pain, paced behavioral activation and moderate exercise are often included in psychological and behavioral therapies for pain management.147 Scheduling Short Naps Scheduling naps is a good counterfatigue measure,148 although caution should be used so napping does not interfere with sleep drive at night. When napping is a consideration for selected patients, it may be best to schedule short naps early in the day so as to minimize negative effects on nighttime sleep. In addition to being an effective counter-fatigue measure, scheduled naps can increase selfefficacy by reducing the need to cancel scheduled daytime activities because of overwhelming fatigue.
Other Considerations for Patients with Chronic Pain Hypersensitivity to environmental stimuli, such as noise and uncomfortable temperature, is common among patients with chronic pain and predicts poor sleep quality.110 A white-noise device can address auditory environmental disruptions to sleep by masking extraneous sounds and might help patients with pain maintain sleep. This suggestion has face validity but it has not been empirically tested. Likewise, encouraging proper temperature regulation to maintain a comfortable sleeping environment is often useful. In addition to these environment-focused strategies, person-focused techniques such as relaxation training and cognitive distraction strategies are also useful for pain management in many patients.147 Cognitive Issues in Insomnia Related to Medical Treatment Medical treatment, including certain antiretroviral medications, cancer chemotherapy, and radiation therapy, can disrupt sleep and lead to increased fatigue. When disturbed sleep is known to be a transient treatment-related side effect, development of chronic insomnia can be prevented by educating and preparing patients for this eventuality and discouraging the use of compensatory coping strategies that could perpetuate the sleep problem. However, when disease-specific factors affect adherence to the insomnia treatment, they need to be addressed as part of the overall insomnia-management strategy. In some cases, standard behavioral strategies need to be altered somewhat so as not to lead to exacerbation of the comorbid medical condition. Presented here are a few issues to consider in applying the psychological and behavioral insomnia treatments to patients with comorbid medical conditions. Excessive Concern about Sleep Overconcern that insufficient sleep will worsen medical disease, impede healing, or lead to a recurrence of the medical problem can increase sleep-related performance anxiety and worry about sleep. These concerns need to be addressed because they can lead to reluctance to restrict time in bed, as required by sleep-restriction therapy, or reluctance to get out of bed when unable to sleep, as required by stimulus control. Helping the patient challenge these beliefs via use of thought records or other formal cognitive therapy and education can be useful to overcome treatment resistance in many patients with comorbid medical disorders. Unhelpful Sleep-Related Beliefs Some studies suggest that patients with insomnia that is comorbid with fibromyalgia or other medical or mental disorders have higher scores on measures of dysfunctional beliefs and attitudes about sleep.39 These beliefs are presumed to contribute to or perpetuate the insomnia of these patients. Thus, cognitive therapy might need to be emphasized and play a large role in managing insomnia with these patients. Admittedly, the importance of targeting sleep-interfering thoughts when using psychological or behavioral insomnia therapies with these populations has not been specifically evaluated. Nonetheless, because
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reductions in sleep-disruptive beliefs have been linked to sleep improvements in primary insomnia,30,41,42 such cognitive changes would be expected to be critical to patients with comorbid insomnia. Alterations in Standard Behavioral Instructions Pain and fatigue can contribute to insomnia severity and chronicity and can interfere with adherence to psychological and behavioral prescriptions by contributing to reluctance to curtail time in bed. Moreover, sleep deprivation is can be associated with hyperalgesic responses and can impair the functioning of endogenous pain-inhibitory systems.149 The tendency of insomniac patients to underestimate their total sleep times might mean that sleep restriction could lead to sleep loss and might need to be modified or replaced by sleep-compression therapy.150 Sleep compression gradually shortens sleep opportunity over a 5-week period, instead of drastically curtailing the sleep opportunity window precipitously at the onset of therapy.150 However, studies that used sleep restriction with chronic pain patients have not reported a worsening in pain. Moreover, sleep compression has not been tested specifically for insomnia associated with pain. Given the state of the science with respect to this issue, the best approach is to be cognizant of this potential difficulty and use clinical judgment when implementing this component of treatment. Sometimes psychological and behavioral therapies need to be modified to ensure they do not negatively affect the comorbid disease. For example, when applying sleep restriction in patients with a seizure disorder, it is important to know that sleep deprivation lowers seizure threshold.151,152 Addressing Psychological Reactions to the Comorbid Medical Disease Patients’ psychological reactions to their diseases, particularly depression and anxiety (including panic), are common153-155 and can contribute to sleep disturbance in patients with medical comorbidities. It is therefore important to assess patients for such emergent conditions and treat or refer patients who show such psychiatric symptoms when indicated.
USE WITH YOUNGER AND OLDER ADULTS Normal sleep and the experience of insomnia are affected by maturational and life span issues. Psychological and behavioral treatments for insomnia during childhood actively involve the parents and are based on principles of learning and behavior change, such as reinforcement, extinction, and shaping. Young Children The implementation of psychological and behavioral treatment for the problems of preschool and younger children was recently reviewed by Mindell and colleagues.156 The most important issues that need to be addressed when treating insomnia in school-age children include nighttime fears,157 scary dreams,158 and parenting, particularly limit setting regarding the timing and location of sleep.159 Psy-
chological interventions to address nighttime fear include self-control training (e.g., rewards for nocturnal “brave” behavior), desensitization, relaxation, positive self-statements, and positive reinforcement.160 Behavioral treatments are also effective for treating sleep problems in children with mental retardation.161 For example, faded bedtime with response cost combines elements from sleep restriction and stimulus control. It consists of restricting time in bed by delaying bedtime and then gradually advancing bedtime if needed as sleep improves or further delaying bedtime if difficulty falling asleep persists. In addition, the child is removed from the bed if sleep is not initiated within 15 minutes (response cost). This procedure has been shown to improve sleep more than regularizing bedtime and rising time.161 Adolescents The most prominent issues that need to be considered when using psychological and behavioral treatments of insomnia in adolescents include their tendency to engage in various sleep-disruptive practices (irregular sleep–wake schedules with marked differences between school and weekend nights, and use of substances such as caffeine, alcohol, and drugs), emergence of delayed sleep phase tendencies, and daytime sleepiness.162,163 These factors are interconnected and, therefore are best addressed together. Irregular sleep schedules produce phase delay in adolescents164; phase delay leads to difficulty falling asleep at night and waking up in the morning; and difficulties initiating sleep on school nights lead to sleep deprivation and associated sleepiness during the day. In addition, to cope with insomnia and daytime sleepiness, adolescents may use stimulants to increase daytime alertness and alcohol and marijuana to decrease sleep onset. Many of the same factors are relevant to young college students as well. A number of behavioral treatment options need to be considered when treating insomnia in adolescents and college students including regularizing sleep schedules (previously shown to improve sleep and decrease daytime sleepiness in young adults165), morning bright light exposure (previously shown to improve sleep in adults with sleep onset insomnia166), and attention to substance use. In addition, when treating adolescents’ insomnia, the clinician needs to assess factors such as late night use of electronic devices (e.g., cell phones and Internet) that contribute to difficulty relaxing at bedtime and thus contribute to sleeponset difficulty. Currently there are no published controlled studies demonstrating the efficacy of psychological and behavioral therapies for insomnia in adolescents. One uncontrolled study combined sleep hygiene, stimulus control, morning exposure to bright light, cognitive therapy, and mindfulness-based stress reduction for adolescents who completed a substance-abuse program and experienced insomnia or daytime sleepiness.162 The study encountered high dropout and adherence issues that might be unique to the sample. Nevertheless, results showed that those who attended at least four of the six treatment sessions experienced meaningful improvements in sleep, leading the authors to conclude that “the same techniques that work for adults, are effective for adolescents.”162
900 PART II / Section 10 • Insomnia
Older Adults Reviews and meta-analyses have supported the efficacy of cognitive behavioral therapies for insomnia in older adults.45,49,167-171 Recent studies suggest that psychological and behavioral therapies such as CBT for insomnia are effective for older adults even when they have hypnoticdependent insomnia172 or when the intervention is very brief (two sessions).73 Several factors specific to older adults need to be considered when implementing psychological and behavioral insomnia therapies. These include comorbid medical diseases and life changes that can weaken the homeostatic and circadian regulation of sleep.173 The latter set of factors includes decreased physical activity, social isolation, and reduced exposure to light, which are particularly relevant to residents of assisted-living facilities and people with dementia, including Alzheimer’s disease. Effective psychological and behavioral treatment of older adults with dementia include decreasing in-bed time during the day, increasing physical activity and social activation, ensuring daily exposure to sunlight (or artificial light), providing structured bedtime routines, and decreasing nighttime noise and light and involving the caregivers in institutional settings.174-176 However, evidence on the efficacy of single components of these protocols is sparse and often mixed. Current evidence shows that increasing social activities improves nocturnal sleep176 and introducing structured social activities increases slow-wave sleep and improved memory.173 On the other hand, a review of the literature on bright light therapy for older adults with dementia concluded that there is no adequate evidence of the effectiveness of this therapy in managing sleep.177 Whereas lowimpact aerobics, brisk walking, and tai chi improves sleep of sedentary older adults with moderate sleep disturbance,178,179 little is known about exercise and tai chi as a single-component intervention for older adults with an insomnia disorder. Passive body heating has been used successfully to improve sleep in older women180,181 and in patients with vascular dementia.182 This behavioral procedure consists of immersing the body in 40° C water for 30 minutes 1.5 to 2 hours before bedtime, and it is hypothesized to operate through its action on the thermoregulatory, circadian, and autonomic systems. It remains to be determined whether such findings can be translated into practical suggestions (e.g., taking a warm bath in the evening) that can be used as a reliable method for managing insomnia complaints in older adults.
SUMMARY AND CONCLUSIONS Psychological and behavioral insomnia therapies have a strong research legacy that supports their widespread use in clinical practice. Clinicians wishing to use these treatments have a number of useful tools that aid their implementation including sleep diaries, written behavioral prescriptions, structured cognitive exercises, and, for selected patients, actigraphy. These treatments can be delivered in different formats, in limited doses, and by various provider types, but the involvement of a specialist in behavioral sleep medicine either as a consultant or as a therapist appears to enhance treatment outcome. The
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CHAPTER 80 • Psychological and Behavioral Treatments for Insomnia II: Implementation and Specific Populations 903
118. Haponik E, Frye A, Richards B, et al. Sleep history is neglected diagnostic information. J Gen Intern Med 1996;11:759-761. 119. Krupinski J, Tiller JW. The identification and treatment of depression by general practitioners. Aust NZ J Psychiatry 2001;35: 827-832. 120. Chang PP, Ford DE, Mead LA, et al. Insomnia in young men and subsequent depression. The Johns Hopkins Precursors Study. Am J Epidemiol 1997;146:105-114. 121. Perlis M, Giles DE, Buysse DJ, et al. Self-reported sleep disturbance as a prodromal symptom in recurrent depression. J Affect Dis 1997;42:209-212. 122. Manber R, Rush AJ, Thase ME, et al. The effects of psychotherapy, nefazodone, and their combination on subjective assessment of disturbed sleep in chronic depression. Sleep 2003;26:130-136. 123. Buysse DJ, Tu XM, Cherry CR, et al. Pretreatment REM sleep and subjective sleep quality distinguish depressed psychotherapy remitters and nonremitters. Biol Psychiatry 1999;45:205-213. 124. Thase ME, Buysse DJ, Frank E, et al. Which depressed patients will respond to interpersonal psychotherapy? The role of abnormal EEG sleep profiles. Am J Psychiatry 1997;154(4):502-509. 125. DiMascio A, Weissman MM, Prusoff BA, et al. Differential symptom reduction by drugs and psychotherapy in acute depression. Arch Gen Psychiatry 1979;36:1450-1456. 126. Manber R, Edinger JD, Gress JL, et al. Cognitive behavioral therapy for insomnia enhances depression outcome in patients with comorbid major depressive disorder and insomnia. Sleep 2008;31(4):489-495. 127. Thase ME, Rush AJ, Manber R, et al. Effects of nefazodone and cognitive behavioral analysis system of psychotherapy, singly and in combination, on insomnia associated with chronic depression. J Clin Psychiatry 2002;63(6):493-500. 128. Morawetz D. Depression and insomnia: what comes first? Aust J Counsel Psychol 2003;3:19-24. 129. Dashevsky BA, Kramer M. Behavioral treatment of chronic insomnia in psychiatrically ill patients. J Clin Psychiatry 1998;59(12): 693-699. 130. Morin CM, Bootzin RR, Buysse DJ, et al. Psychological and behavioral treatment of insomnia: update of the recent evidence (1998-2004). Sleep 2006;29(11):1398-1414. 131. Dopke CA, Lehner RK, Wells AM. Cognitive-behavioral group therapy for insomnia in individuals with serious mental illnesses: a preliminary evaluation. Psychiat Rehabil J 2004;27:235-242. 132. Verbeek I, Schreuder K, Declerck G. Evaluation of short-term nonpharmacological treatment of insomnia in a clinical setting. J Psychosom Res 1999;47:369-383. 133. Krakow B, Johnston L, Melendrez D, et al. An open-label trial of evidence-based cognitive behavior therapy for nightmares and insomnia in crime victims with PTSD. Am J Psychiatry 2001; 158(12):2043-2047. 134. Arnedt JT, Conroy D, Rutt J, et al. An open trial of cognitivebehavioral treatment for insomnia comorbid with alcohol dependence. Sleep Med 2007;8(2):176-180. 135. Craske MG, Lang AJ, Aikins D, Mystkowski JL. Cognitive behavioral therapy for nocturnal panic. Behav Ther 2005;36:43-54. 136. Savard J, Simard S, Ivers H, Morin C. Randomized study on the efficacy of cognitive-behavioral therapy for insomnia secondary to breast cancer, part I sleep and psychological effects. Arch Intern Med 2005;23:6083-6096. 137. Quesnel C, Savard J, Simard S, et al. Efficacy of cognitive-behavioral therapy for insomnia in women treated for nonmetastatic breast cancer. J Consult Clin Psychol 2003;71:189-200. 138. Dirksen SR, Epstein DR. Efficacy of an insomnia intervention on fatigue, mood and quality of life in breast cancer survivors. J Adv Nurs 2008;61(6):664-675. 139. Lee KA, Portillo CJ, Miramontes H. The influence of sleep and activity patterns on fatigue in women with HIV/AIDS. J Assoc Nurses AIDS Care 2001;12(Suppl):19-27. 140. Dreher HM. The effect of caffeine reduction on sleep quality and well-being in persons with HIV. J Psychosom Res 2003;54: 191-198. 141. Affleck G, Urrows S, Tennen H, et al. Sequential daily relations of sleep, pain intensity, and attention to pain among women with fibromyalgia. Pain Med 1996;68:363-368. 142. Raymond I, Nielsen TA, Lavigne G, et al. Quality of sleep and its daily relationship to pain intensity in hospitalized adult burn patients. Pain 2001;92:381-388.
143. Sharpe M, Hawton K, Simkin S, et al. Cognitive behavior therapy for the chronic fatigue syndrome: a randomized controlled trial. BMJ 1996;321:22-26. 144. Busch AJ, Barber KA, Overend TJ, et al. Exercise for treating fibromyalgia syndrome: Cochrane Database Systematic Review; 2007. 145. Mustian KM, Morrow GR, Carroll JK, et al. Integrative nonpharmacologic behavioral interventions for the management of cancerrelated fatigue. Oncologist 2007;12(Suppl 1):52-67. 146. Schmitz KH, Holtzman J, Courneya KS, et al. Controlled physical activity trials in cancer survivors: a systematic review and meta-analysis. Cancer Epidemiol Biomarkers Prev 2005;14(7): 1588-1595. 147. Morley S, Eccleston C, Williams A. Systematic review and metaanalysis of randomized controlled trials of cognitive behaviour therapy and behaviour therapy for chronic pain in adults, excluding headache. Pain 1999;80(1):1-13. 148. Driskell JE, Mullen B. The efficacy of naps as a fatigue countermeasure: a meta-analytic integration. Hum Factors 2005;47(2): 360-377. 149. Kundermann B, Krieg JC, Schreiber W, Lautenbacher S. The effect of sleep deprivation on pain. Pain Res Manag 2004;9(1):25-32. 150. Lichstein KL, Riedel BW, Wilson NM, et al. Relaxation and sleep compression for late-life insomnia: a placebo-controlled trial. J Consult Clin Psychol 2001;69:227-239. 151. Fountain NB, Kim JS, Lee SI. Sleep deprivation activates epileptiform discharges independent of the activating effects of sleep. J Clin Neurophysiol 1998;15:69-75. 152. Colombo C, Benedetti F, Barbini B, et al. Rate of switch form depression into mania after therapeutic sleep deprivation in bipolar depression. Psychiatry Res 1999;86(3):267-270. 153. Palermo TM, Toliver-Sokol M, Fonareva I, Koh JL. Objective and subjective assessment of sleep in adolescents with chronic pain compared to healthy adolescents. Clin J Pain 2007;23(9):812820. 154. Zgierska A, Brown RT, Zuelsdorff M, et al. Sleep and daytime sleepiness problems among patients with chronic noncancerous pain receiving long-term opioid therapy: a cross-sectional study. J Opioid Manag 2007;3(6):317-327. 155. Tsao JC, Dobalian A, Moreau C, Dobalian K. Stability of anxiety and depression in a national sample of adults with human immunodeficiency virus. J Nerv Ment Dis 2004;192:111-118. 156. Mindell JA, Kuhn B, Lewin DS, et al. Behavioral treatment of bedtime problems and night wakings in infants and young children. Sleep 2006;20(10):1263-1276. 157. Muris P MH, Ollendick TH, King NJ, Bogie N. Children’s nighttime fears: parent–child ratings of frequency, content, origins, coping behaviors and severity. Behav Res Ther 2001;39(1):13-28. 158. Muris P, Merckelbach H, Gadet B, Moulaert V. Fears, worries, and scary dreams in 4- to 12-year-old children: their content, developmental pattern, and origins. J Clin Child Psychol 2000;29(1): 43-52. 159. Hurwitz T, Mahowald M, Kuskowski M, Engdahl B. Polysomnographic sleep is not clinically impaired in Vietnam combat veterans with chronic posttraumatic stress disorder. Biol Psychiatry 1998;44: 1066-1073. 160. Sadeh A. Cognitive-behavioral treatment for childhood sleep disorders. Clin Psychol Rev 2005;25(5):612-628. 161. Piazza CC, Fisher WW, Sherer M. Treatment of multiple sleep problems in children with developmental disabilities: faded bedtime with response cost versus bedtime scheduling. Develop Med Child Neurol 1997;39(6):414-418. 162. Bootzin RR, Stevens SJ. Adolescents, substance abuse, and the treatment of insomnia and daytime sleepiness. Clin Psychol Rev 2005;25:629-644. 163. Crowley SJ, Acebo C, Carskadon MA. Sleep, circadian rhythms, and delayed sleep phase in adolescence. Sleep Med 2007;8(6): 602-612. 164. Yang CM, Spielman AJ, D’Ambrosio P, et al. A single dose of melatonin prevents the phase delay associated with a delayed weekend sleep pattern. Sleep 2001;24(3):272-281. 165. Manber R, Bootzin RR, Acebo C, Carskadon MA. The effects of regularizing sleep–wake schedules on daytime sleepiness. Sleep 1996;19:432-441. 166. Lack LC, Wright HR. Treating chronobiological components of chronic insomnia. Sleep Med 2007;8(6):637-644.
904 PART II / Section 10 • Insomnia 167. Montgomery P, Dennis J. A systematic review of non-pharmacological therapies for sleep problems in later life. Sleep Med Rev 2004;8(1):47-62. 168. Nau SD, McCrae CS, Cook KG, Lichstein KL. Treatment of insomnia in older adults. Clin Psychol Rev 2005;25(5):645-672. 169. Pallesen S, Nordhus IH, Kvale G. Nonpharmacological inter ventions for insomnia in older adults: a meta-analysis of treatment efficacy. Psychother: Theory Res Pract Train 1998;35:472-482. 170. Pallesen S, Nordhus IH, Kvale G, et al. Behavioral treatment of insomnia in older adults: An open clinical trial comparing two interventions. Behav Res Ther 2003;41:31-48. 171. McCurry SM, Logsdon RG, Teri L, Vitiello MV. Evidence-based psychological treatments for insomnia in older adults. Psychol Aging 2007;22(1):18-27. 172. Soeffing JP, Lichstein KL, Nau SD, et al. Psychological treatment of insomnia in hypnotic-dependant older adults. Sleep Med 2008;9(2):165-171. 173. Naylor E, Penev P, Orteba L, et al. Daily social and physical activity increases slow wave sleep and daytime neuropsychological performance in the elderly. Sleep 2000;23(1):1-9. 174. McCurry SM, Gibbons LE, Logsdon RG, et al. Nighttime insomnia treatment and education for Alzheimer’s disease: a randomized, controlled trial. J Am Geriatr Soc 2005;53(5):793-802. 175. Alessi CA, Martin JL, Webber AP, et al. Randomized, controlled trial of a nonpharmacological intervention to improve abnormal sleep–wake patterns in nursing home residents. J Am Geriat Soc 2005;53(5):803-810. 176. Richards KC, Beck C, O’Sullivan PS, Shue VM. Effect of individualized social activity on sleep in nursing home residents with dementia. J Am Geriatr Soc 2005;53(9):1510-1517.
177. Forbes D, Morgan DG, Bangma J, et al. Light therapy for managing sleep, behaviour, and mood disturbances in dementia. Cochrane Database Syst Rev 2004;(2):CD003946. 178. King A, Oman R, Brassington G, et al. Moderate-intensity exercise and self-rated quality of sleep in older adults. A randomized controlled trial. JAMA 1997;277:32-37. 179. Li F, Fisher KJ, Harmer P, et al. Tai chi and self-rated quality of sleep and daytime sleepiness in older adults: a randomized controlled trial. J Am Geriatr Soc 2004;52(6):892-900. 180. Dorsey CM, Lukas SE, Teicher MH, et al. Effects of passive body heating on the sleep of older female insomniacs. J Geriatr Psychiatry Neurol 1996;9(2):83-90. 181. Dorsey CM, Teicher MH, Cohen-Zion M, et al. Core body temperature and sleep of older female insomniacs before and after passive body heating. Sleep 1999;22(7):891-898. 182. Mishima Y, Hozumi S, Shimizu T, et al. Passive body heating ameliorates sleep disturbances in patients with vascular dementia without circadian phase-shifting. Am J Geriatr Psychiatry 2005; 13(5):369-376. 183. Backhaus J, Hohagen F, Voderholzer U, Riemann D. Long-term effectiveness of a short-term cognitive-behavioral group treatment for primary insomnia. Eur Arch Psychiatry Clin Neurosci 2001; 251:35-41. 184. Rybarczyk B, Lopez M, Benson R, et al. Efficacy of two behavioral treatment programs for comorbid geriatric insomnia. Psychol Aging 2002;17:288-298. 185. Verbeek IH, Konings GM, Aldenkamp AP, et al. Cognitive behavioral treatment in clinically referred chronic insomniacs: group versus individual treatment. Behav Sleep Med 2006;43(3):135-151.
Pharmacologic Treatment of Insomnia: Benzodiazepine Receptor Agonists James K. Walsh and Thomas Roth Abstract Considerable evidence indicates that the benzodiazepine receptor agonists (BzRAs) are efficacious in the treatment of insomnia, whether primary or comorbid, chronic or transient. Limited data suggest a substantial degree of effectiveness in clinical use. BzRAs are also generally safe as commonly used in clinical practice. Research refutes the common concerns of
A 2005 National Institutes of Health State of the Science Conference concluded that the benzodiazepine receptor agonists (BzRAs) were the only drugs for which adequate scientific evidence exists to support their use for chronic insomnia.1 This chapter reviews what is known about efficacy, effectiveness, and safety of the nine BzRAs approved for the treatment of insomnia by the United States Food and Drug Administration (FDA). A number of other BzRAs are approved for the treatment of insomnia in other countries, and research with those drugs is highly consistent with the data reviewed herein. In addition, implementation and assessment strategies for the pharmacologic treatment of insomnia are discussed. The group of drugs referred to as “benzodiazepine receptor agonists” are categorized according to the welldescribed common mechanism of action of these medi cations. All BzRAs act as allosteric modulators of gamma-aminobutyric acid (GABA) activity by binding to inotropic benzodiazepine receptors at the GABAA receptor complex. BzRAs serve to further open chloride ion channels and facilitate GABA inhibitory activity. Some of these drugs (Table 81-1) have a benzodiazepine chemical structure (i.e., estazolam, flurazepam, quazepam, temazepam, triazolam) and others do not (i.e., eszopiclone, zaleplon, zolpidem). BzRAs demonstrate affinity for four benzodiazepine receptor subtypes (referred to as α1, α2, α3, and α5) located at the GABAA pentameric complex. Benzodiazepines tend toward comparable affinity for the four receptor subtypes, whereas the affinities of zolpidem and zaleplon for the α1 subtype are higher than for other subtypes. Eszopiclone shows less preference for α1, having some activity at α2 or α3 (or both). The functional significance of these binding differences for effect on sleep in humans remains unclear. In contrast, preclinical investigations of knock-in rodent strains suggest different functional characteristics of the benzodiazepine receptor subtypes.2 The most clinically relevant differences among BzRAs are associated with pharmacokinetic properties of the drugs, particularly duration of drug action. Elimination characteristics, commonly reflected by elimination halflife, is the most significant pharmacokinetic property related to duration of action, but distribution characteristics (for single doses) and absorption contribute, although to a much lesser degree. Of course as with all biological systems, substantial individual differences exist in the
Chapter
81
tolerance, misuse, and abuse by insomnia patients. Sufficient differences in pharmacokinetic profiles exist among the BzRAs to provide physicians with therapeutic options that have differing durations of action. Several investigations indicate that treatment of insomnia with BzRAs produces improvement in daytime symptoms as well as nighttime symptoms of insomnia, and they might also reduce the severity of comorbid illnesses.
metabolism and elimination of BzRAs, with about a 30% intersubject variability that translates into individual differences in duration of action among patients and hence associated efficacy and safety. Finally, factors other than pharmacokinetics also influence duration of action, in particular drug dose and formulation (e.g., extended release, sublingual absorption). Of the available BzRA hypnotics in the United States, the most rapidly eliminated drugs used at recommended doses in healthy adults have estimated durations of action in the range of 2 to 5 hours (zaleplon) and 4 to 7 hours (triazolam, zolpidem), whereas the slowly eliminated drugs (including active metabolites) appear to have durations of action of 24 hours or more (flurazepam, quazepam). Estazolam, temazepam, and eszopiclone have intermediate durations of action. A number of BzRAs are available in other countries for the treatment of insomnia. They include the short-acting midazolam and brotizolam, intermediate-acting zopiclone, loprazolam, lormatazepam, and long-acting flunitrazepam and nitrazepam. All are benzodiazepines except zopiclone, a cyclopyrrolone, of which eszopiclone is the active stereoisomer. The BzRAs are generally recommended as first-line hypnotics for several reasons. All BzRAs have been shown to be efficacious, although there are some differences among drugs, associated with pharmacokinetic properties, and marketed dose. Compared with other central nervous system (CNS) drug classes, the margin of safety or therapeutic index (i.e., the effective dose relative to lethal dose) is wide.3 For example, barbiturates have margins of safety on the order of two to four times the effective dose, whereas for BzRAs, the margin of safety can be as great as 100. Abuse of or dependence on BzRAs is uncommon in the therapeutic context, most likely accounted for by the relatively mild reinforcing effects and self-administration patterns. Summaries of the efficacy, effectiveness, and safety characteristics of BzRAs follow. Unless otherwise stated, the summary material refers to the FDA-approved dosages of the drugs.
EFFICACY AND EFFECTIVENESS Traditional measures of hypnotic efficacy include polysomnographic (PSG) or patient estimates of induction and 905
906 PART II / Section 10 • Insomnia Table 81-1 Characteristics of Benzodiazepine Receptor Agonists with an FDA Indication for Insomnia GENERIC NAME
RECEPTOR BINDING SPECIFICITY
DOSE RANGE (MG)
ELIMINATION HALF-LIFE (HR)
Estazolam
Nonspecific
1-2
10-24
CYP3A
Flurazepam
Nonspecific
15-30
48-120*
CYP3A4
Temazepam
Nonspecific
15-30
8-20
None
Triazolam
Nonspecific
0.125-0.25
2-6
CYP3A4
Quazepam
Nonspecific
7.5-15
39-73*
Eszopiclone
GABAA, α1,2,3
1-3
Zaleplon
GABAA, α1
5-20
Zolpidem
GABAA, α1
5-10
Zolpidem extended-release
GABAA, α1
6.25-12.5
6 1
METABOLISM
Not available CYP3A4, CYP2E1 Minor: CYP3A4
1.5-2.4
CYP3A4, CYP2C9
1.6-4.5
CYP3A4, CYP2C9
CYP, cytochrome P-450 (letters and numbers refer to specific CYP enzymes); GABAA, gamma-aminobutyric acid, type A receptor complex. *Refers to elimination half-life of active metabolite.
maintenance of sleep. Sleep latency (or latency to persistent sleep), whether given by PSG or self-report, is the standard sleep induction variable and addresses a patient’s difficulty falling asleep. Number of awakenings and wake after sleep onset (WASO) are the most common sleep maintenance measures addressing patients’ reports of difficulty staying asleep. Total sleep time and sleep efficiency reflect both sleep induction and sleep maintenance properties. Qualitative measures of efficacy such as morning ratings of sleep quality, sleep depth, or global impression ratings performed by either the clinician or the patient are also used in efficacy trials. Given the variability of individual nights, efficacy is evaluated by averaging across nights and in many cases across a week. Importantly, patient-reported data are typically collected using diaries or questionnaires with an electronic time stamp to determine the time the evaluation was completed. Given the desire to maximize objective data and to minimize costs, the monitoring of movements or activity with a wrist-worn sensor (actigraphy) has also been used to evaluate hypnotic efficacy. However, to date, actigraphy has been shown to be sensitive only to timing and duration of sleep. This makes actigraphy especially valuable in evaluating efficacy in insomnia that is comorbid with circadian rhythm disorders (e.g., phase-delay syndrome) Primary Insomnia Most insomnia clinical trials have documented the efficacy of hypnotics using patients’ reports, PSG, or both, in patients with primary insomnia. A meta-analysis of clinical trials with benzodiazepines and zolpidem found that these drugs in aggregate produce reliable improvements in the sleep of persons with chronic insomnia. Importantly, the median duration of the studies included in the analysis was only 1 week.4 Other meta-analyses5-8 largely concur regarding short-term efficacy. However, the utility of metaanalyses to assist the clinician is fairly low, because they combine data from several different drugs with widely different pharmacokinetics, which affects the outcome variables examined in the meta-analysis. Additionally, two or more doses of a drug may be included in the analysis. It is much more instructive to examine the strengths and weaknesses of individual drugs as opposed to generalizing across
all drugs in a category. Simply put, meta-analyses tell us about the pharmacology of a group of drugs, but they are not informative about the properties of individual drugs or what the best drug is for a given patient. Later, similarities among BzRAs are discussed, but important differences among drugs will be emphasized. At appropriate doses all of the BzRA hypnotics reduce sleep latency, and most increase total sleep time. The exception is zaleplon, which does not reliably increase total sleep time. The reduction of sleep latency is attributable to a rapid onset of hypnotic effect. Specific sleepmaintenance variables, as distinct from total sleep time, have begun to receive attention. Investigations assessing number of awakenings or WASO typically find that the longer the drug’s duration of action (i.e., the longer the half-life or the higher the dose, or both), the more likely it is that the drug will show efficacy on these measures. At doses within the therapeutic range, a dose-response effect is observed on efficacy measures, and little additional effect is generally apparent at supratherapeutic doses. As might be expected, sleep latency shows a relatively flat doseresponse curve, and WASO and total sleep time show more pronounced dose-response curves. Tolerance is defined as a reduction of a drug’s effect with repeated administration of a constant dose, or the need to increase the dose to sustain a specific level of effect. Despite frequent speculations in the medical literature, tolerance to the hypnotic effects of BzRAs does not develop in subjects in the vast majority of studies, at least for therapeutic doses and for the periods of time that have been studied. Investigations that are often cited as evidence for developing tolerance, such as the one by Mitler and colleagues,9 show gradual improvement in sleep over time in the placebo group, in the face of a constant effect in the drug group, resulting in loss of statistical significance between groups. Yet the within-group comparison of an early drug effect versus a late drug effect fails to show any change in drug activity with repeated use. Thus, it cannot be concluded that tolerance has developed, but rather that unspecified changes occur over time with placebo, such as spontaneous remission, regression to the mean (if there are sleep-disruption criteria for entering the study), sleep hygiene influences inherent in protocol adherence,
CHAPTER 81 • Pharmacologic Treatment of Insomnia: Benzodiazepine Receptor Agonists 907
Comorbid Insomnia Comorbid insomnia refers to insomnia coexistent with other medical or psychiatric conditions. Although BzRAs have not been extensively studied in patients with comorbid insomnia, the published data indicate improvements in sleep similar to those seen with primary insomnia. One of the earliest studies relevant to BzRA efficacy in comorbid insomnia examined rheumatoid arthritis patients with insomnia using PSG techniques. Triazolam 0.25 mg was found to reduce sleep latency and number of awakenings and to increase total sleep time across six nights of treatment.22 Zolpidem 10 mg increased total sleep time and improved sleep quality in a 4-week placebo-controlled study in depressed patients with refractory insomnia despite adequate control of depressive symptoms with selective serotonin reuptake inhibitor (SSRI) medication.23 Figure 81-3 contains total sleep time data and wake after sleep time values during that 4-week study. Preliminary reports indi-
SLEEP LATENCY 80 Placebo Eszopiclone
Minutes (median)
70 60 50 40
*
30
*
*
*
*
*
20 10 0 Baseline Month Month Month Month Month Month 1 2 3 4 5 6
A
WASO 45 40 Minutes (median)
Hawthorne effects, and true placebo effects.10 This is further evidenced by the fact that patients rarely escalate the nightly use of hypnotics even with long-term use.11 Nearly 30 years ago, Oswald and colleagues12 reported that lormetazepam and nitrazepam, two benzodiazepines available in some European countries, retained their effect by some patient estimates of hypnotic efficacy during 24 weeks of nightly use. More recently, in rigorous PSG studies, zolpidem 10 mg and zaleplon 10 mg were shown to retain efficacy for 5 weeks of nightly use.13,14 A 2003 landmark study of several hundred patients with primary insomnia showed continued hypnotic efficacy of eszopiclone for 6 months of nightly use.15 Patient reports of sleep latency and WASO were significantly reduced with eszopiclone 3 mg as compared with placebo at each monthly time point. Total sleep time, number of awakenings, and sleep quality were also better than with placebo at each monthly time point. These 6-month findings have been replicated by Walsh and colleagues16 and are shown in Figure 81-1. Examination of open-label extension data of the 2003 6-month, eszopiclone study suggested sustained efficacy for a total of 12 months.17 Other evidence for sustained efficacy of nightly BzRA use includes a 3-month trial with indiplon, a nonmarketed hypnotic.18 Efficacy of nonnightly use of zolpidem 10 mg has been investigated for up to 12 weeks.19,20 In these studies, ratings of sleep latency, total sleep time, number of awakenings, and sleep quality were all improved on nights when zolpidem was taken (an average of 3 or 4 nights per week), as compared with placebo (also an average of 3 or 4 nights per week). Additionally, investigator global ratings, which considered both medication nights and no-medication nights, indicated reduced insomnia severity with zolpidem. Total sleep time data on nights when a pill (either zolpidem or placebo) was taken or not taken during an 8-week study are shown in Figure 81-2. Importantly, an examination of sleep on nights when no drug was taken immediately after a zolpidem night failed to reveal evidence of rebound insomnia.14 A 6-month study with an extendedrelease formulation of zolpidem used 3 to 7 nights per week has generated similar results over the duration of the study.21
35 30 25 20
*
15
*
*
*
*
*
10 5 0
B
Baseline Month Month Month Month Month Month 1 2 3 4 5 6
TOTAL SLEEP TIME 410 Minutes (median)
390
*
*
*
*
*
*
370 350 330 310 290
C
Baseline Month Month Month Month Month Month 1 2 3 4 5 6
Figure 81-1 Median values for key hypnotic efficacy measures at baseline and during months 1 to 6 of double-blind treatment for eszopiclone (red) and placebo (green) groups. A, Sleep latency. B, Wake after sleep onset; C, Total sleep time. *Change from baseline P value versus placebo <.0001. (Adapted from Walsh JK, Krystal AD, Amato DA, et al. Nightly treatment of primary insomnia with eszopiclone for six months: effect on sleep, quality of life and work limitations. Sleep 2007; 30:959-968.)
cate that zolpidem extended-release coadministered with escitalopram improves subjective measures of sleep in patients with comorbid depression24 and in those with comorbid anxiety.25 A number of studies have been conducted to assess efficacy of eszopiclone in comorbid insomnia. Eszopiclone
908 PART II / Section 10 • Insomnia 420
a
Minutes
400 380 c
360
d
340 b
320 300 BSLN
1-2
3-4
5-6
7-8
Disc
Study week
Figure 81-2 Mean subjective total sleep time for 8 weeks. a, Zolpidem pill nights (green line and green circles). b, zolpidem no-pill nights (blue line and blue circles). c, Placebo pill nights (red line and red squares). d, Placebo no-pill nights (yellow line and yellow squares). P < .001 for A versus C and for A versus B, each at study periods 1-2, 3-4, 5-6, and 7-8 weeks. BSLN, baseline (both groups receive placebo, doubleblind); DISC, discontinuation week during which both groups received placebo, double-blind. (Adapted from Walsh JK, Roth T, Randazzo AC, et al: Eight weeks of non-nightly use of zolpidem for primary insomnia. Sleep 2000;23:1087-1096.)
60
TST
Mean change from baseline
50 40
*
*
*
*
30 20 10 0 WASO
−10 −20 −30 −40
* 1
* 2
* 3
* 4
Treatment week Zolpidem 10 mg Placebo Figure 81-3 Mean weekly change from baseline values for reported total sleep time TST, (upper panel) and wake after sleep onset WASO, (lower panel) in patients with clinically significant insomnia despite effectively treated depressive disorders (treated with fluoxetine, sertraline, or paroxetine). Patients were randomized in double-blind fashion to either zolpidem 10 mg or placebo. *Indicates the weekly zolpidem value is significantly different from the corresponding placebo value, P < .05. (Adapted from Asnis GM, Chakraburtty A, DuBoff EA, et al. Zolpidem for persistent insomnia in SSRI-treated depressed patients. J Clin Psychiatry 1999; 60:68-76).
combination therapy with fluoxetine was superior to fluoxetine and placebo in improving sleep in patients with newly diagnosed major depressive disorder and comorbid insomnia.26 In addition, the combination-therapy group was found to have a significantly greater reduction in depressive symptoms, a higher rate of remission, and a faster time
to the onset of the antidepressant effect. Similarly, eszopiclone co-therapy with escitalopram was superior to escitalopram plus placebo in improving the sleep of patients with insomnia and generalized anxiety disorder,27 and anxiety and depressive symptoms were reduced further in patients receiving co-therapy. Finally, insomnia patients treated with eszopiclone 3 mg for 4 weeks during perimenopause or early menopause reported significantly improved sleep throughout the trial, but in addition they had significant improvements in mood, quality of life, and menopause-related symptoms (Fig. 81-4).28 Effectiveness Studies Studies of treatment efficacy enroll a selected homogenous sample using a variety of exclusion criteria (e.g., for concomitant medications, many medical conditions) and using highly controlled methods, compare treatment effects to placebo or other active treatments, often examining a limited number of outcome variables. In contrast, investigations of treatment effectiveness include patient samples, which are much more representative of clinical practice (few exclusion criteria) and the degree of experimental control is minimal. Often no control group is used, and the outcome focus is not only on efficacy measures but also on treatment adherence, patient satisfaction, and quality of life. Hypnotic effectiveness trials, per se, have not been carried out. However, some reports provide information on hypnotic use in the general population that might approximate reports of clinical investigations of effectiveness. Using an epidemiologic methodology, Ohayon and colleagues29 reported that of 532 patients describing chronic insomnia and long-term use of hypnotic medications to help them sleep, 67% rated their sleep quality as improved “a lot,” and only 14.4% reported little or no improvement with medication. Balter and Uhlenhuth30 interviewed subjects who in the past year either reported significant trouble with insomnia or had taken a medication to help them sleep. They found very high satisfaction rates among users of hypnotics when they asked, “Taking into account both the positive effects on your sleep and daytime functioning and any negative effects you may have experienced, would you take this medication again for the same purpose?” Affirmative responses were received from 84% of those taking triazolam, 82% for flurazepam, 74% for temazepam, and 61% for over-the-counter aids. In summarizing the findings of this intensive interview study, the authors concluded that “the benefits of treatment with prescription hypnotics are substantial and far outweigh the risks as defined in this study.” It is important to recognize that in both of these studies, the cited data were obtained from either current users of sleep-promoting medications or those who had used them at some time in the past year. In these studies, the severity or nature of the insomnia is not characterized, nor are the duration, dose, or pattern of hypnotic use or other aspects of the patients. Clearly, effectiveness data in the management of insomnia needs to be an important future research priority. Long-term open-label studies conducted in both adult and elderly subjects in outpatient settings also provide some information about effectiveness.17,31-34 Zolpidem, zaleplon, and eszopiclone have been evaluated over periods
CHAPTER 81 • Pharmacologic Treatment of Insomnia: Benzodiazepine Receptor Agonists 909
Vasomotor
Psychosocial
Physical
Sexual
0
Least squares mean
−0.2 −0.4 P = .63
−0.6
P = .61
−0.8
P = .04
−1 Placebo Eszopiclone
−1.2
A
−1.4
P = .003
Total
Psychological
Somatic
Vasomotor
Sexual
0 −0.5
P = .9
P = .09
Least squares mean
−1 P = .03
−1.5 −2 −2.5 −3
P = .009
−3.5 −4
B
−4.5
P = .03
Figure 81-4 Menopause outcomes after 4 weeks of treatment with eszopiclone 3 mg. A, Change in menopause-specific quality of life at week 4. B, Change in Greene Climacteric Scale at week 4. Data presented are least square means ± standard error of the means. P values reflect change from baseline using analysis of covariance. (Adapted from Soares CN, Joffe H, Rubens R, et al. Eszopiclone in patients with insomnia during perimenopause and early postmenopause: a randomized controlled trial. Obstet Gynecol 2006;108(6):1402-1410).
of 6 to 12 months in such studies. In general, patients and physicians report sustained benefit of BzRAs for the duration of the studies, without adverse reactions unique to long-term use. The generalizability of results and the confidence level regarding any conclusions drawn must be tempered by the self-selection of those remaining in these open-label studies. Impact on Daytime Symptoms of Insomnia and Comorbid Conditions Diagnostic criteria of insomnia include some form of subjective daytime impairment perceived to be consequent to the sleep disruption, such as fatigue, sleepiness, concentration and memory problems, and mood changes. If the daytime impairment is mediated by the insufficient or disturbed sleep, it should be possible to demonstrate a reduction of impairment with improved sleep. Elimination or reduction of the daytime problem could be viewed as another measure of treatment efficacy. Until recently, few studies have shown daytime consequences of insomnia,
especially on laboratory-based tasks of psychomotor and cognitive performance. There is growing evidence, however, that in addition to the perceived daytime dysfunction, insomnia patients have a substantially increased risk of future mood and other psychiatric disorders,35-38 higher rates of health care use and health care costs,39-42 elevated risk of falling,43-45 reduced quality of life,46,47 and increased absenteeism from work.39,48,49 Cognitive impairments are reported less often, but recent investigations have differentiated insomniac subjects from normal sleepers.50,51 Until recently, the focus of research on the daytime effects of BzRAs used to treat insomnia was the assessment of residual sedation rather than relief of daytime symptoms or other consequences. However, the few studies that have systematically assessed patient-reported daytime measures generally show improvement. For example, in the two 6-month eszopiclone studies of patients with primary insomnia previously discussed,15,16 patients’ reports of daytime alertness, ability to function during the daytime,
910 PART II / Section 10 • Insomnia
and physical sense of well-being were all significantly better in the eszopiclone group than in the placebo group. The waking impact of chronic comorbid insomnia may differ from that of primary insomnia. For example, patients with insomnia and periodic limb movement disorder52 and those with insomnia and rheumatoid arthritis53 have been shown to have lower than optimal daytime alertness as determined by multiple sleep latency test (MSLT) scores, which improve significantly after 6 nights of treatment with triazolam. Three studies of older adult patients showed increased daytime alertness on the MSLT resulting from increased sleep consolidation and duration with BzRA treatment.54-56 In part, then, the difficulty in finding systematic daytime impairment in chronic insomnia may be the result of differing daytime consequences in subgroups of insomniac patients.
SAFETY In general, BzRAs are well tolerated, with few significant safety concerns. For example, adverse reactions recorded in clinical trials or in clinical practice are seen in the minority of patients, the severity is most commonly rated as mild, and reactions rarely result in abandoning the study or treatment. For inpatient use in a large academic hospital, the median rate of adverse events, across all hypnotics, was found to be about 1 in every 10,000 doses.57 Data on the incidence of abuse of hypnotic medications, independent of other sedatives, is not available. However, a study in Switzerland in the early 1980s indicated that abuse of all benzodiazepines (not limited to use as a hypnotic) occurred at the rate of only two per 10,000 prescriptions.58 More recently, a population-based study in the United States indicated that 2.3% of the population reported nonmedical use of sedatives and tranquillizers, and approximately 0.002% of the population met criteria for substance abuse.59 The adverse events associated with BzRAs are related to peak plasma concentration (e.g., amnesia, ataxia), which is highly associated with dose, and to duration of action (e.g., daytime hangover), which is primarily determined by elimination half-life and dose. Specific safety concerns for hypnotics and their potential mediators are discussed later. Residual Effects Many of the side effects associated with BzRAs are mediated by their desired pharmacologic activity, sedation.60 Residual sedation, which is merely a prolongation of the hypnotic effect of the drug into the wake period, results in adverse reactions such as drowsy feelings, sleepiness, and impairment in psychomotor performance and driving. The likelihood of residual sedation is determined by the duration of drug activity, which in turn is determined by the elimination half-life and the dose of the drug. Many studies using the MSLT, performance assessments, and simulator or on-road driving tests have shown differences in residual effects between short- and long-acting drugs and between different doses of the same drug. Amnestic Effects Another side effect that is, in part, related to the sedative effects of hypnotics is anterograde amnesia. Anterograde amnesia is memory failure for information presented after
administration of the drug. It is associated with all sedatives, including all the BzRAs, alcohol, and barbiturates. The extent of amnesia is related to the plasma concentration of the drug. That is, the proximity of information input to peak plasma concentration determines the degree of amnesia, and higher doses, which increase plasma concentration, are associated with both a greater degree of amnesia and a higher prevalence of amnestic events.61,62 Furthermore, maintaining wakefulness for 10 to 15 minutes after presentation of memory material, rather than allowing a drug-induced rapid sleep onset, attenuates the amnesia.63 It is important to recall that sleep itself has amnestic effects. It is not uncommon for people to awake in the middle of the night, and if they fall back to sleep rapidly (within about 5 to 7 minutes) they do not remember the awakening. Thus, the promotion of rapid sleep onset as well as a direct drug effect combine to produce the risk of amnesia. There have been reports of global amnesia or traveler’s amnesia.64 These reports are anecdotal and describe persons forgetting long periods of wakefulness after ingestion of a BzRA. These reports tend to be associated with higher doses, drug taken in combination with another CNS depressant drug or alcohol, or drug taken during a period of sleep deprivation. Discontinuation Effects The most commonly cited discontinuation effect of BzRA hypnotics is rebound insomnia. Rebound insomnia is defined as a worsening of sleep relative to the patient’s status before starting treatment. Unlike other discontinuation effects, rebound insomnia only lasts for 1 or 2 nights after the hypnotic is discontinued. Rebound insomnia can occur even after 1 or 1 nights’ hypnotic use65 and does not increase in severity with the number of repeated nights of use, at least within the time frame of a few weeks of nightly use. Rebound insomnia is more likely to occur after high doses of short- and intermediate-acting BzRAs. It does not occur with long-acting drugs because of the gradual decline in plasma concentration that is inherent in the pharmacology of such drugs. Similarly, it can be minimized with short- and intermediate-acting drugs by gradually tapering the dose over a few nights. A reduction of one clinical dose per week is usually recommended. Importantly, rebound usually can be avoided by using the lowest effective dose. A critical distinction between rebound and recrudescence is necessary. Recrudescence is a return of symptoms to pretreatment level. This should be expected because the BzRAs manage the symptoms, and hence drug discontinuation is associated with return of symptoms. One must differentiate rebound insomnia from a withdrawal syndrome. A withdrawal syndrome is the appearance of a new cluster of symptoms (not present before treatment) that are unpleasant and generally last a few days to a few weeks rather than 1 or 2 days. Rebound insomnia is the brief (1 or 2 nights) exacerbation of the original symptom. It does not reflect the presence of a withdrawal syndrome, which would involve the appearance of new symptoms lasting for more than a night or two. Also, rebound insomnia does not increase the likelihood of hypnotic self-administration and behavioral dependence.65 Withdrawal has been found with short-acting and with long-acting BzRAs, unlike rebound insomnia. Withdrawal
CHAPTER 81 • Pharmacologic Treatment of Insomnia: Benzodiazepine Receptor Agonists 911
phenomena are typically associated with long-term use and importantly can occur with clinical doses. The patient’s expectancies can also play a role in the experience of rebound insomnia. Discontinuing placebo pills, that is, stopping pill-taking per se, has been found to produce a sleep disturbance.66 Abuse Potential Dependence on hypnotic medication has continued to be a concern despite only anecdotal evidence to support the concern. Epidemiologic data from representative population samples indicate that the majority of patients do not persist in taking hypnotics for long periods because about 70% use them for 2 weeks or less.67,68 A percentage of patients use them nightly on a chronic basis (for months or years), but with rare dose escalation.30 It is unlikely that this pattern of use reflects physical or psychological dependence given the absence of dose escalation and nontherapeutic use of the medications. Although there are reports of physical dependence at therapeutic doses in long-term daytime use of benzodiazepines, none have been reported in 6- to 12-month studies of BzRA hypnotic use. Daytime studies of the reinforcing effects of these drugs indicate that they have a low to moderate behavioral dependence liability.69 Studies of their behavioral dependence liability in the context of their use as hypnotics have come to a similar conclusion.66,70 Among individual patients, the rate of hypnotic administration varies with the severity of the sleep disturbance; within an individual patient, rate of administration depends on the degree of sleep disturbance the prior night.71 Dose escalation in controlled trials (as in the clinical situation) does not occur, and daytime use is uncommon.72 The same is true for normal volunteers; the population that best corresponds with patients being treated for transient insomnia. Insomniac patients who do take hypnotic medication during the daytime show the physiologic hyperarousal discussed previously.72 Hypnotic self-administration in insomniac patients is best explained by therapy-seeking behavior, in that it does not lead to dose escalation, it rarely generalizes to daytime use (i.e., it does not occur outside the therapeutic context), and the rate of self-administration varies as a function of the severity of the sleep problem. Falls, Cognitive Effects, and Other Considerations for Older Adults Given the age-related prevalence of insomnia, older adults represent a significant fraction of those using hypnotic medications (see Chapter 80 for more on treatment of insomnia of older patients). The therapeutic index for hypnotics in this population is probably narrower than for younger adults because of the increased prevalence in older patients of medical, neurologic, and primary sleep disorders, the common use of concomitant medications (particularly other drugs active on the CNS), and changes in drug metabolism and excretion. Drugs that are primarily metabolized by conjugation are potentially safer for older patients and patients with liver disease. The pharmacokinetics of oxidatively metabolized drugs are altered in these two categories of patients, resulting in increased area under the plasma concentration curve. For some drugs (e.g., triazolam), this alteration is a
consequence of increasing the peak plasma concentration, and for others (e.g., flurazepam) it is a consequence of extending the duration of significant blood levels. The lower recommended dose for most hypnotics when treating older patients is related in part to these kinetic changes. However, it is also thought that even with comparable blood levels, the elderly are more sensitive to drug effects. A number of investigations have demonstrated an increased risk of falls for institutionalized older adults taking benzodiazepines and other psychotropic medications, without regard for the condition being treated or when the medication was taken. Results of early studies of community-dwelling older adults are inconsistent,73-75 but recent large-scale studies suggest elevated risk. Kelly and colleagues76 found an elevated risk of an injurious fall for seven categories of medications. When controlling for comorbid illness, the elevated risk remained significant for narcotics, antidepressants, and anticonvulsants but not hypnotics. Ensrud and colleagues77 reported an elevated risk for falls in older women taking antidepressants (selective serotonin reuptake inhibitors tricyclic antidepressants), anticonvulsants, and benzodiazepines, but not narcotics. Data from the same study, however, showed that risk for a fracture was elevated for those taking narcotics and antidepressants but it was not affected by use of benzodiazepines and anticonvulsants.78 Long-acting sedative drugs have been reported to increase risk for falls more than short-acting drugs, but recent data have not borne out this difference.77 It is important to understand that a variety of CNS-active medications statistically increase fall rates in older adults, and antidepressants often have the highest risks.79,80 Investigators have begun to assess the risk of falls in insomniac patients with or without pharmacologic treatment for insomnia. Brassington and coworkers43 found that reported sleep problems, but not use of psychotropic medication, was an independent risk factor for falls in a large sample of community-dwelling adults aged 64 to 99 years. In another recent study, the risk for falls was statistically significant for patients who had insomnia and did not use hypnotics and for those with insomnia that persisted despite hypnotic use but not for patients who used hypnotics but did not have insomnia. One interpretation of these findings is that if the hypnotic relieves the insomnia, the hypnotic is not a risk factor for falling.44 Stone and colleagues studied community-dwelling older women and reported that short sleep duration and fragmented sleep, determined by actigraphy, were associated with an increased risk of falls, independent from benzodiazepine and other BzRA use.45 Future investigations will need to carefully differentiate between sleep disturbance and its treatment in evaluating contributing factors to falls. Long-term use of benzodiazepines has been reported to be associated with cognitive decline in older adults,81 although this is certainly not a universal finding.82 The nature of these investigations (which are predominantly cross-sectional and retrospective) does not allow conclusions regarding causality, because it is extremely difficult to implement proper controls for the aging process, the disease being treated, exposure to other drugs, and other factors. The cognitive changes are often subtle,83 and the
912 PART II / Section 10 • Insomnia
clinical significance of these effects has been questioned.84 Nevertheless, the possibility that cognitive decline might at least in part be attributable to use of hypnotics, or any psychotropic medication, should be kept in mind by the clinician prescribing chronic therapy in the elderly. However, withholding hypnotic treatment because of the anticipation of cognitive effects does not appear to be warranted on the basis of available information regarding magnitude of risk. Complex Behavior in Sleep Reports of idiosyncratic side effects associated with BzRA hypnotics, and other drugs, have appeared periodically in the public press. These reports of “global amnesia,” “somnambulism,” and “sleep-related eating disorders” are anecdotal. Peer reviewed case reports describing unusual behavior concurrent with BzRA use also have appeared in the medical literature. Although case reports provide more detail and presumably more-accurate information, including assessment of other contributing factors, the level of scientific evidence ascribed to case reports is low. Until a higher level of scientific evidence becomes available through placebo-controlled investigations, the actual risk of complex behavior in sleep and global amnesia will remain unknown. Even if adequate surveillance data were available to assess event frequency, the risk of an event cannot be determined unless the rate of exposure to various medications is known. Moreover, the dose consumed and concomitant substances ingested at the time of the event are unknown. Somnambulism has been reported with zolpidem and zaleplon.85,86 These episodes of somnambulism have occurred in persons taking two to three times the clinical doses of the drug, in persons who have a prior history of somnambulism, and in persons who have experienced prior traumatic head injury. Zolpidem-associated somnambulism also has been reported in combination with antidepressant medications and alcohol. In a clinical context, somnambulism is believed to be associated with incomplete arousal from sleep. Although BzRAs increase somnambulism, alcohol and sleep deprivation also produce partial arousals and increase the likelihood of a somnambulistic event. Sleep-related eating disorder associated with ingestion of BzRAs has also been reported.87,88 It is disputed whether sleep-related eating disorder is a disorder of partial arousal from sleep with altered levels of consciousness or is the psychiatric disorder of nocturnal eating with awareness and recall. Sleep-related eating disorder is hypothesized to share a common pathophysiology with somnambulism. Zolpidem was reported to exacerbate sleep-related eating disorder and in several cases to induce it de novo. In some of these cases doses of zolpidem greater than 10 mg were being used, and in other cases there was use of sedating antidepressants. Sleep-related eating disorder also has been reported with triazolam. A common thread links much of this case-report information: excessive hypnotic activity or sleep drive. The excessive hypnotic activity can occur as a result of high doses, clinical doses in vulnerable persons (i.e., those who have a past history of sleep disorders or brain injury), the combination of clinical or high doses with prior sleep deprivation caused by stress or
illness, or the combination of clinical or high doses with the prior consumption of alcohol. Mortality Examination of mortality risk associated with use of medication taken for insomnia and other indications often shows an elevated risk, the explanation for which is unknown.89-91 Clearly, these findings merit investigation of the mediators and nature of the risk. However, a number of factors limit the conclusions that can be drawn from currently available data. The epidemiologic nature of the studies (as opposed to controlled experimental trials) prevents any conclusions regarding causality or mediators. It is also important to remember that 90% of insomniac patients have a comorbid condition, and typically they have more than one. Thus the mediators of the mortality is not clear. It would be important to look at the risk in terms of specific causes of mortality. The exact medications responsible for the elevated mortality risk are not constant from study to study, and, in fact, they are often unknown. Data for one study were collected in 1959 to 1960,89 when barbiturates were the most commonly used hypnotics; for the second90 data were collected in 1982, when benzodiazepines were the most commonly used hypnotics. Several studies also did not differentiate between prescription and nonprescription drugs. All investigations concluding that an elevated mortality risk exists must include any medication the respondent reports as being taken for sleep, whether a hypnotic or not, and whether the prescribing physician actually intended another indication. The only study that obtained reasonable verification of the actual drugs being taken by respondents found that sedative-hypnotics were not associated with an increased mortality risk. Rather “other drugs” taken for sleep, which in that study were often analgesics, showed a statistically higher mortality risk.92 Long-term, controlled investigations would be needed (although ethical considerations clearly are of concern) to clarify whether any medication used to promote sleep increases mortality risk, or whether the statistical risk is explained by the poor health of the users of sleeppromoting drugs, or by other factors. Alternatively, longitudinal population-based studies aimed at answering this question could better define the risk. Such a study would need to identify the specific hypnotic drug being taken, pattern of drug taking, other drugs being taken, and the nature of the comorbid disorders and should institute adequate experimental and statistical control to allow reasonable inferences about the data.
CONSIDERATIONS FOR PHARMACOTHERAPY Hypnotic therapy should be considered for insomnia when the patient is significantly distressed by the presence or possibility of disturbed sleep, or when the physician judges the sleep disturbance to be deleterious to the patient’s overall safety or health. The 2005 National Institutes of Health (NIH) state of the science report on the management of chronic insomnia1 concluded that BzRAs are the only medications with an established scientific basis (i.e.,
CHAPTER 81 • Pharmacologic Treatment of Insomnia: Benzodiazepine Receptor Agonists 913
clearly defined risk and benefit by dose) for use for insomnia. Thus, for most patients with chronic insomnia, pharmacotherapy should be initiated with a BzRA at the lowest effective dose for the shortest clinically necessary period of time. There is also widespread agreement that BzRA hypnotics are an appropriate therapy for short-term insomnia. The specific BzRA should be carefully chosen, considering the pharmacokinetics of the drug and the patient characteristics (e.g., age, nature of the sleep problem, concurrent illness). The dose and treatment regimen should be individualized, agreed to by the patient, and most importantly monitored by the physician. The hypnotic should be taken only at the time and frequency agreed on. The initial dose should be the lowest clinically indicated dose, and the clinician and patient should jointly determine effectiveness of that dose soon after treatment is initiated (e.g., after 3 to 5 nights). The dose can then be adjusted as appropriate based on both efficacy and safety reports from the patient. Patients should generally not be allowed to adjust the dose themselves, particularly during the early portion of therapy, because a fluctuating dose makes interpretation of clinical response very difficult. Hypnotics can be prescribed to be taken nightly, on a predetermined intermittent schedule (e.g., every third night), or as needed. With the exception of zaleplon, all medications should be taken only when the patient has the opportunity to stay in bed 7 to 8 hours. Zaleplon has been evaluated in middle-of-the-night dosing protocols (i.e., medication is administered with 5 hours or less of time in bed remaining) and been found to improve sleep in the remaining time without residual effects the next morning.93,94 If nightly hypnotic use is not desirable for individual patients, they can be instructed to attempt sleep without medication and, if unsuccessful, to take the drug later, provided there are 4 to 5 hours remaining before they must rise. Thus, in cases of sleep-maintenance insomnia characterized only by a middle-of-the-night awakening, or in cases of intermittent sleep-onset insomnia, middle-of-the-night administration should be considered. The physician should specifically inquire about the aspects of sleep and daytime function that were most problematic for the patient before treatment, rather than relying solely on global statements. A sleep diary can be helpful for comparing pretreatment and posttreatment symptoms. In reasonably healthy persons, monthly visits should be sufficient to identify most potential adverse effects. For older adults or others at increased risk for drug interactions, alterations in drug metabolism, incoordination, or cognitive problems, close follow-up is recommended throughout the period that hypnotics are administered. Discontinuation of therapy should be considered if symptoms occur that may be side effects of the medication, to confirm whether they are indeed related to the medication. After longer-term use, gradual discontinuation, via dose tapering at a rate of one clinical dose per week, is a reasonable practice. The primary contraindications to BzRA hypnotic therapy are concomitant illnesses, such as obstructive sleep apnea, substance abuse disorder, or advanced liver disease. All sedative medications have the potential to worsen sleep apnea by blunting arousal from sleep, although central
apnea has been reduced by BzRAs in some investigations.95 The dependence liability of BzRAs and other sedative drugs, although not high, leads to the conclusion that most patients with a history of alcoholism or drug abuse should not receive BzRAs in outpatient settings without close supervision. Caution is advised for moderate users of alcohol because of additive sedative effects with hypnotics, which narrows the wide margin of safety described earlier. Because most BzRAs undergo hepatic metabolism, advanced liver disease requires the use of a lower dose or avoidance of these medications. Pharmacotherapy for insomnia during pregnancy is also contraindicated; the teratogenic effects of all psychoactive drugs are a matter of concern. People who may be required to awaken and perform duties in the middle of the night should avoid CNS-depressant drugs when on call. All hypnotics have the potential to disrupt alertness and cognitive function for the duration of the sedative activity of the drug, and they can affect motor function.
CONCLUSION Despite significant advances in understanding the neurobiological mechanisms of sleep and arousal, which involve multiple neural systems, attempts to produce novel drug treatments for insomnia have met with limited success to date. As of this writing, the BzRAs remain the most effective, safest, and best-understood therapeutic agents for the treatment of insomnia. ❖ Clinical Pearl Extensive efficacy and safety evidence supports the use of benzodiazepine receptor agonists for the treatment of insomnia for as long as it is clinically warranted. Convincing evidence for use of other available medications (e.g., sedating antidepressants) is not currently available. The duration of action between different benzodiazepine receptor agonists varies greatly, and therefore the desired duration of sleep-promoting action and the need for morning alertness should guide the clinician in the choice of a medication for each person.
REFERENCES 1. National Institutes of Health. State of the Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults statement. J Clin Sleep Med 2005;1:412-421. 2. Mohler H, Fritschy JM, Rudolph U. A new benzodiazepine pharmacology. J Pharmacol Exp Ther 2002;300:2-8. 3. Greenblatt DJ, Shader RI. Benzodiazepines in clinical practice. New York: Raven Press; 1974. 4. Nowell PD, Mazumdar S, Buysse DJ, et al. Benzodiazepines and zolpidem for chronic insomnia: a meta-analysis of treatment efficacy. JAMA 1997;278:2170-2177. 5. Buscemi N, Vandermeer B, Friesen C, et al. The efficacy and safety of drug treatments for chronic insomnia in adults: a meta-analysis of RCTs. J Gen Intern Med 2007;22:1335-1350. 6. Dündar Y, Dodd S, Strobl J, et al. Comparative efficacy of newer hypnotic drugs for the short-term management of insomnia: a systematic review and meta-analysis. Hum Psychopharmacol 2004;19: 305-322.
914 PART II / Section 10 • Insomnia 7. Smith MT, Perlis ML, Park A. Comparative meta-analysis of pharmacotherapy and behavior therapy for persistent insomnia. Am J Psychiatry 2002;159:5-11. 8. Glass J, Lanctôt KL, Herrmann N, et al. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ 2005;331:1169. 9. Mitler MM, Seidel WF, Van Den Hoed J, et al. Comparative hypnotic effects of flurazepam, triazolam, and placebo: a long-term simultaneous nighttime and daytime study. J Clin Psychopharmacol 1984;4:2-13. 10. Mccall WV, Perlis ML, Tu X, et al. A comparison of placebo and no-treatment during a hypnotic clinical trial. Int J Clin Pharmacol Ther 2005;43:355-359. 11. Balter MB, Uhlenhuth EH. New epidemiologic findings about insomnia and its treatment. J Clin Psychiatry 1992;53(Suppl. 12):34-39. 12. Oswald I, French C, Adam K, et al. Benzodiazepine hypnotics remain effective for 24 weeks. BMJ 1982;284:860-863. 13. Scharf MB, Roth T, Vogel GW, et al. A multicenter, placebo-controlled study evaluating zolpidem in the treatment of chronic insomnia. J Clin Psychiatry 1994;55:192-199. 14. Walsh JK, Vogel GW, Scharf M, et al. A five week, polysomnographic assessment of zaleplon 10 mg for the treatment of primary insomnia. Sleep Med 2000;1:41-49. 15. Krystal AD, Walsh JK, Laska E, et al. Sustained efficacy of eszopiclone over 6 months of nightly treatment: results of a randomized, double-blind, placebo-controlled study in adults with chronic insomnia. Sleep 2003;26:793-799. 16. Walsh JK, Krystal AD, Amato DA, et al. Nightly treatment of primary insomnia with eszopiclone for six months: effect on sleep, quality of life and work limitations. Sleep 2007;30:959-968. 17. Roth T, Walsh J, Krystal A, et al. An evaluation of the efficacy and safety of eszopiclone over 12 months in patients with chronic primary insomnia. Sleep Med 2005;6:487-495. 18. Scharf MB, Black J, Hull S, et al. Long-term nightly treatment with indiplon in adults with primary insomnia: results of a double-blind, placebo-controlled, 3-month study. Sleep 2007;30:743-752. 19. Walsh JK, Roth T, Randazzo AC, et al. Eight weeks of non-nightly use of zolpidem for primary insomnia. Sleep 2000;23:1087-1096. 20. Perlis M, McCall WV, Krystal A, et al. Long-term, non-nightly administration of zolpidem in the treatment of patients with primary insomnia. J Clin Psychiat 2004;65:1128-1137. 21. Krystal AD, Erman M, Zammit GK, et al. ZOLONG Study Group. Long-term efficacy and safety of zolpidem extended-release 12.5 mg, administered 3 to 7 nights per week for 24 weeks, in patients with chronic primary insomnia: a 6-month, randomized, double-blind, placebo-controlled, parallel-group, multicenter study. Sleep 2008; 31:79-90. 22. Walsh JK, Muehlbach MJ, Lauter SA, et al. Effects of triazolam on sleep, daytime sleepiness, and morning stiffness in patients with rheumatoid arthritis. J Rheumatol 1996;23:245-252. 23. Asnis GM, Chakraburtty A, DuBoff EA, et al. Zolpidem for persistent insomnia in SSRI-treated depressed patients J Clin Psychiatry 1999;60:68-76. 24. Fava M, Asnis G, Shrivastaava R, et al. Improved insomnia symptoms and daily functioning in patients with comorbid major depressive disorder and insomnia following zolpidem extended-release 12.5 mg and escitalopram co-treatment. Sleep 2008;31:A324 25. Sheehan D, Asnis G, Shrivastava R, et al. Zolpidem extended-release 12.5 mg co-adiministered with escitalopram improves insomnia symptoms and next-day functioning in generalized anxiety disorder comorbid with chronic insomnia. Sleep 2008;31:A325. 26. Fava M, McCall WV, Krystal A, et al. Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry 2006;59:1052-1060. 27. Pollack M, Kinrys G, Krystal A, et al. Eszopiclone coadministered with escitalopram in patients with insomnia and generalized anxiety disorder. Arch Gen Psychiatry 2008;65:551-562. 28. Soares CN, Joffe H, Rubens R, et al. Eszopiclone in patients with insomnia during perimenopause and early postmenopause: a randomized controlled trial. Obstet Gynecol 2006;108:1402-1410. 29. Ohayon MM, Caulet M, Arbus L, et al. Are prescribed medications effective in the treatment of insomnia complaints? J Psychosom Res 1999;47:359-368. 30. Balter MB, Uhlenhuth EH. The beneficial and adverse effects of hypnotics. J Clin Psychiatry 1991;52(Suppl):16-23.
31. Kummer J, Linden J, Eich FX, et al. Long-term polysomnographic efficacy and safety of zolpidem in elderly psychiatric in-patients with insomnia. J Int Med Res 1993;21:171-184. 32. Maarek L, Cramer P, Coquelin JP, et al. The safety and efficacy of zolpidem in insomnia patients: a long-term open study in general practice. J Int Med Res 1991;20:162-170. 33. Schlich D, L’Heritier C, Coquelin JP, et al. Long-term treatment of insomnia with zolpidem: a multicentre general practitioner study of 107 patients. J Int Med Res 1991;19:271-279. 34. Ancoli-Israel S, Richardson GS, Mangano RM, et al. Long-term use of sedative hypnotics in older patients with insomnia. Sleep Med 2005;6:107-113. 35. Perlis ML, Giles DE, Buysse DJ, et al. Self-reported sleep disturbance as a prodromal symptom in recurrent depression. J Affect Disord 1997;42:209-212. 36. Agargun MY, Kara H, Solmaz M. Sleep disturbances and suicidal behavior in patients with major depression. J Clin Psychiatr 1997;58:249-251. 37. Chang PP, Ford DE, Mead LA, et al. Insomnia in young men and subsequent depression. The Johns Hopkins Precursors Study. Am J Epidemiol 1997;146:105-114. 38. Breslau N, Roth T, Rosenthal L, et al. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry 1996;39:411-418. 39. Ozminkowski RJ, Wang S, Walsh JK. The direct and indirect costs of untreated insomnia in adults in the United States. Sleep 2007;30:263-273. 40. Hatoum HT, Dong SX, Darnia CM, et al. Insomnia, health-related quality of life, and healthcare resource consumption: a study of managed care enrollees. Pharmacoeconomics 1998;14:629-647. 41. Simon GE, VonKorff M. Prevalence, burden, and treatment of insomnia in primary care. Am J Psychiatry 1997;154:1417-1423. 42. Leger D, Guilleminault C, Bader G, et al. Medical and socio-professional impact of insomnia. Sleep 2002;25:625-629. 43. Brassington GS, King AC, Bliwise DL. Sleep problems as a risk factor for falls in a sample of community-dwelling adults aged 64-99 years. J Am Geriatr Soc 2000;48:1234-1240. 44. Avidan AY, Fries BE, James ML, et al. Insomnia and hypnotic use, recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes. J Am Geriatr Soc 2005;53: 955-962. 45. Stone KL, Ancoli-Israel S, Blackwell T, et al. Actigraphy-measures sleep characteristics and risk of falls in older women. Arch Intern Med 2008;168:1768-1775. 46. Katz DA, McHorney CA. The relationship between insomnia and health-related quality of life in patients with chronic illness. J Fam Pract 2002;51:229-235. 47. Zammit GK, Weiner J, Damata N, et al. Quality of life in people with insomnia. Sleep 1999;22(Suppl. 2):S379-S385. 48. Leger D, Massuel MA, Mellaine A. The SISYPHE Study Group. Professional correlates of insomnia. Sleep 2006;29:171-178. 49. Godet-Cayre V, Pelletier-Fluery N, Le Valliant M, et al. Insomnia and absenteeism at work. Who pays the cost? Sleep 2006;29: 179-184. 50. Edinger JD, Means MK, Carney CE, et al. Psychomotor performance deficits and their relation to prior nights’ sleep among individuals with primary insomnia. Sleep 2008;31:599-607. 51. Altena E, Van Der Werf YD, Strijers RLM, et al. Sleep loss affects vigilance: effects of chronic insomnia and sleep therapy. J Sleep Res 2008;17:335-343. 52. Doghramji K, Browman CP, Gaddy JR, et al. Triazolam diminishes daytime sleepiness and sleep fragmentation in patients with periodic limb movements in sleep. J Clin Psychopharmacol 1991;11;284290. 53. Walsh JK, Muehlbach MJ, Lauter SA, et al. Effects of triazolam on sleep, daytime sleepiness, and morning stiffness in patients with rheumatoid arthritis. J Rheumatol 1996;23:245-252. 54. Carskadon MA, Seidel WF, Greenblatt DJ, et al. Daytime carryover of triazolam and flurazepam in elderly insomniacs. Sleep 1982;5:361-371. 55. Roehrs T, Zorick F, Wittig R, et al. Efficacy of a reduced triazolam dose in elderly insomniacs. Neurobiol Aging 1985;6:293-296. 56. Walsh JK, Salked L, Knowles LJ, et al. Treatment of eldery primary insomnia patients with EVT 201 improves sleep initiation, sleep maintenance, and daytime sleepiness. Sleep Med 2010;11:23-30.
CHAPTER 81 • Pharmacologic Treatment of Insomnia: Benzodiazepine Receptor Agonists 915
57. Mendelson WB, Thompson C, Franko T. Adverse reactions to sedative/hypnotics: three years’ experience. Sleep 1996;19:702-706. 58. Ladewig D. Abuse of benzodiazepines in western European society: incidence and prevalence, motives, drug acquisition. Pharmacopsychiatria 1983;16:103-106. 59. Becker WC, Fiellin DA, Desai RA. Non-medical use, abuse and dependence on sedatives and tranquilizers among U.S. adults: psychiatric and socio-demographic correlates. Drug Alcohol Depend 2007;90:280-287. 60. Roth T, Roehrs T. Issues in the use of benzodiazepine therapy. J Clin Psychiatry 1992;53:S14-S18. 61. Roth T, Roehrs TA, Stepanski EJ, et al. Hypnotics and behavior. Am J Med 1990;8:43S-46S. 62. Greenblatt D, Harmatz JS, Shapiro L, et al. Sensitivity to triazolam in elderly. N Engl J Med 1991;324:1691-1698. 63. Roehrs T, Zorick F, Sicklesteel J, et al. Effects of hypnotics on memory. J Clin Psychopharmacol 1983;3:310-313. 64. Morris HH 3rd, Estes ML. Traveler’s amnesia. Transient global amnesia secondary to triazolam. JAMA 1987;258:945-946. 65. Roehrs T, Vogel G, Roth T. Rebound insomnia: its determinants and significance. Am J Med 1990;88:39S-42S. 66. Roehrs T, Merlotti L, Zorick F, et al. Rebound insomnia and hypnotic self administration. Psychopharmacology 1992;107:480484. 67. Mellinger GD, Balter MB, Uhlenhuth EH. Insomnia and its treatment. Arch Gen Psychiatry 1985;42:225-232. 68. Roehrs T, Hollebeek E, Drake C, et al. Substance use for insomnia in metropolitan Detroit. J Psychosom Res 2002;53:571-576. 69. Griffiths RR, Johnson MW. Relative abuse liability of hypnotic drugs: a conceptual framework and algorithm for differentiating among compounds. J Clin Psychiaty 2005;66(Suppl. 9):31-41. 70. Roehrs T, Pedrosi B, Rosenthal L, et al. Hypnotic self administration and dose escalation. Psychopharmacology 1996;127:150-154. 71. Roehrs T, Bonahoom A, Pedrosi B, et al. Disturbed sleep predicts hypnotic self administration. Sleep Med 2002;3:61-66. 72. Roehrs T, Bonahoom A, Pedrosi B, et al. Nighttime versus daytime hypnotic self-administration. Psychopharmacology 2002;161:137142. 73. Campbell AJ, Borrie MJ, Spears GF. Risk factors for falls in a community based prospective study of people 70 years and older. J Gerontol 1989;44:M112-M117. 74. Tinetti ME, Speechley M, Ginter SF. Risk factors for falls among elderly persons living in the community. N Engl J Med 1988;319: 1701-1707. 75. Nevitt MC, Cummings SR, Kidd S, et al. Risk factors for recurrent nonsyncopal falls: a prospective study. JAMA 1989;261:26632668. 76. Kelly KD, Pickett W, Yiannakoulias N, et al. Medication use and falls in community-dwelling older persons. Age Ageing 2003;32: 503-509. 77. Ensrud KE, Blackwell TL, Mangione CM, et al. Central nervous system-active medications and risk for falls in older women. J Am Geriatr Soc 2002;50:1629-1637.
78. Ensrud KE, Blackwell TL, Mangione CM, et al. Central nervous system active medications and risk for fractures in older women. Arch Intern Med 2003;163:949-957. 79. Kallin K, Lundin-Olsson L, Jensen J, et al. Predisposing and precipitating factors for falls among older people in residential care. Public Health 2002;116:263-271. 80. Thapa PB, Gideon P, Cost TW, et al. Antidepressants and the risk of falls among nursing home residents. N Engl J Med 1998;339: 875-882. 81. Paterniti S, Dufouil C, Alperovitch A. Long-term benzodiazepine use and cognitive decline in the elderly: the Epidemiology of Vascular Aging Study. J Clin Psychopharmacol 2002;22:285-293. 82. Allard J, Artero S, Ritchie K. Consumption of psychotropic medication in the elderly: a re-evaluation of its effect on cognitive performance. Int J Geriatr Psychiatry 2003;18:874-878. 83. Curran HV, Collins R, Fletcher S, et al. Older adults and withdrawal from benzodiazepine hypnotics in general practice: effects on cognitive function, sleep, mood and quality of life. Psychol Med 2003; 33:1223-1237. 84. McAndrews MP, Weiss RT, Sandor P, et al. Cognitive effects of longterm benzodiazepine use in older adults. Hum Psychopharmacol 2003;18:51-57. 85. Yang W, Dollear M, Muthukrishnan SR. One rare side effect of zolpidem-sleepwalking: a case report. Arch Phys Med Rehabil 2005;86:1265-1266. 86. Liskow B, Pikalov A. Zaleplon overdose associated with sleepwalking and complex behavior. J Am Acad Child Adolesc Psychiatry 2004;43:927-928 87. Morgenthaler TI, Silber MH. Amnestic sleep-related eating disorder associated with zolpidem. Sleep Med 2002;3:323-327. 88. Vetrugno R, Manconi M, Ferini-Strembi LF, et al. Nocturnal eating: sleep-related eating disorder or nocturnal eating syndrome? A videopolysomnographic study. Sleep 2006;29:949-954. 89. Kripke DF, Simons RN, Garfinkel L, et al. Short and long sleep and sleeping pills: is increased mortality associated? Arch Gen Psychiatry 1979;36:103-116. 90. Kripke DF, Klauber MR, Wingard DL, et al. Mortality hazard associated with prescription hypnotics. Biol Psychiatry 1998;43: 687-693. 91. Hublin C, Partinen M, Koskenvuo M, et al. Sleep and mortality: a population-based 22-year follow-up study. Sleep 2007;30:12451253. 92. Rumble R, Morgan K. Hypnotics, sleep, and mortality in elderly people. J Am Geriatr Soc 1992;40:787-791. 93. Walsh JK, Pollak CP, Scharf MB, et al. Lack of residual sedation following middle-of-the-night zaleplon administration in sleep maintenance insomnia. Clin Neuropharmacol 2000;23:17-21. 94. Danjou P, Paty I, Fruncillo R, et al. A comparison of the residual effects of zaleplon and zolpidem following administration 5 to 2 hrs before awakening. Br J Clin Pharmacol 1999;48:367-374. 95. Bonnet MH, Dexter JR, Arand DL. The effect of triazolam on arousal and respiration in central sleep apnea patients. Sleep 1990; 13:31-41.
Pharmacologic Treatment: Other Medications Andrew D. Krystal Abstract Many agents other than benzodiazepine receptor agonists (BzRAs) are used in the treatment of insomnia. This includes agents classified as antidepressants, antipsychotics, antihistamines, anticonvulsants, melatonin agonists, and herbals as well as chloral hydrate and sodium oxybate. These agents vary in the extent to which studies have been carried out of their efficacy and safety in the treatment of insomnia. By and large, the empirical support for the efficacy and safety of the BzRAs is far greater than for the non-BzRA agents. Exceptions to this include doxepin, trimipramine, melatonin, and ramelteon. Each of the non-BzRA agents has unique properties that should be considered when determining whether they might be useful for the treatment of a given patient with insomnia. These properties include the time to maximum blood level
The predominant treatments for insomnia in the 20th century were medications that bind to the benzodiazepine binding site on the gamma-aminobutyric acid (GABA) receptor complex.1-3 These agents, often referred to as benzodiazepine receptor agonists (BzRAs), are discussed in detail in the preceding chapter. Their therapeutic effects in insomnia patients occur through enhancing the inhibitory effects of GABA, which is believed to be the neurotransmitter that is most important for promoting sleep.1,2,4 Because of the longstanding widespread use of BzRAs, this mechanism and the clinical properties of these agents have become synonymous with insomnia pharmacotherapy. Experience with these agents suggests that insomnia agents have effects that are proportional to their serum level (maximal effect occurs at peak blood level), have abuse potential, and have daytime sedation and psychomotor impairment as their primary potential side effects.2,3 There are agents used to treat insomnia that improve sleep by other mechanisms than enhancing GABA-ergic inhibition, and their clinical properties differ from those of the BzRAs. These agents act via a variety of mechanisms and represent at least 11 different medication classes. The mechanisms of their therapeutic effects on insomnia include melatonin receptor agonism, serotonin receptor antagonism, histamine receptor antagonism, and possibly antagonism of norepinephrine, dopamine, and acetylcholine receptors.3 In addition, these agents have a diverse set of other pharmacologic effects that contribute to their side-effect profile and are responsible for their effects on conditions other than insomnia.3 In fact, all of these agents, with the exception of the melatonin receptor agonist ramelteon, are indicated for use in conditions other than insomnia by the U.S. Food and Drug Administration (FDA). As a result, they are not usually categorized as insomnia therapies but are referred to as 916
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82
(Tmax), the half-life (T1/2), their means of metabolism, evidence for efficacy in the treatment of insomnia, known adverse effects profile, and therapeutic effects on conditions that cooccur with insomnia. In addition, in some clinical circumstances non-BzRAs are preferred over BzRAs, including intolerance of BzRAs, nonresponse to BzRAs, the treatment of insomnia in substance abusers, allergy-associated sleep disturbance, insomnia occurring with psychosis, insomnia occurring with mania or hypomania, insomnia occurring with depression where single-agent therapy is desired, and insomnia occurring with chronic pain where single-agent therapy is desired. Awareness of the characteristics of the non-BzRA agents and the clinical circumstances where they might be the preferred pharmacotherapy are important for optimizing the pharmacotherapy of insomnia in clinical practice.
antidepressants, anxiolytics, antipsychotics, anticonvulsants, or antihistamines. The pharmacology of these agents is reviewed in Chapter 43. In this chapter, I discuss these agents, focusing on their clinical effects and their potential utility in the clinical treatment of insomnia.
MELATONIN AND MELATONIN RECEPTOR AGONISTS Melatonin Overview Melatonin is a hormone that is primarily produced by the pineal gland. The release of this hormone occurs during the period of darkness from sundown to sunrise. When taken orally, melatonin appears to have sleep-enhancing and circadian rhythm modifying effects. The circadian rhythm effects of melatonin are discussed in Chapter 36. Here we discuss the sleep-enhancing effects. Melatonin is available as an over-the-counter (OTC) medication. It has a time to maximum concentration (Tmax) of approximately 0.5 hours and an elimination half-life (T1/2) of roughly 1 hour (Table 82-1).5 A BzRA with such a pharmacokinetic profile would be expected to be have a short duration of effect and be best suited to treating sleeponset problems. However, this cannot be assumed with melatonin, which works by a mechanism that differs from that of the BzRAs. Melatonin binds to melatonin receptors, predominantly MT1/MT2 receptors; the mechanism by which these receptors affect sleep is unknown, though it is clear that the sleep enhancement of this agent is divorced from the serum level. A dose-response relationship does not appear to exist for melatonin, and the means to determine optimal dosing are lacking. Further complicating optimizing the use of melatonin, a number of studies have shown that the
FDA INDICATION
MDD
MDD, anxiety
MDD
MDD
MDD
Amitriptyline
Doxepin
Trimipramine
Trazodone
Mirtazapiine
Sedating Antidepressants
MEDICATION
7.5-30
25-150
25-100
1-25
10-100
INSOMNIA DOSAGE (MG)
0.25-2
1-2
2-8
1.5-4
2-5
TMAX (HR)
20-40
7-15
15-40
10-50
—
0/1
2/2
5/5
10-100 —
T1/2 (HR)*
EFFICACY IN PLACEBOCONTROLLED INSOMNIA TRIALS
Sedation, dry mouth, increased appetite; weight gain; constipation
Sedation, dizziness, headache, dry mouth, blurred vision, OH, priapism
Sedation, dizziness; weight gain, OH, dry mouth, blurred vision, constipation, urinary retention
Sedation, dizziness; weight gain, OH, dry mouth, blurred vision, constipation, urinary retention
Sedation, dizziness, weight gain, OH, dry mouth, blurred vision, constipation, urinary retention
MOST COMMON SIDE-EFFECTS
Table 82-1 Medications Other than Benzodiazepine Receptor Agonists Used in the Treatment of Insomnia
Patients with suspected bipolar disorder; liver disease; kidney disease
Liver disease, kidney disease, suspected bipolar disorder
History of MI, ischemia, or conduction abnormalities Closed-angle glaucoma, decreased GI motility, urinary retention, hypotension History suggestive of bipolar disorder, Parkinson’s disease, seizure disorder, liver disease
History of MI, ischemia, or conduction abnormalities; closed-angle glaucoma; decreased GI motility; urinary retention; hypotension; history suggestive of bipolar disorder; Parkinson’s disease; seizure disorder; liver disease
History of MI, ischemia, or conduction abnormalities; closed-angle glaucoma; decreased GI motility; urinary retention; hypotension; history suggestive of bipolar disorder; Parkinson’s disease; seizure disorder; liver disease
RELATIVE CONTRAINDICATIONS
Continued
Insomnia comorbid with MDD; Insomnia comorbid with SBD
Insomnia comorbid with MDD; insomnia comorbid with substance abuse
Insomnia comorbid with MDD, chronic pain, or anxiety
Efficacy with relative absence of side effects at 1-6 mg Insomnia comorbid with MDD, chronic pain, or anxiety Treatment of early morning awakenings
Insomnia comorbid with MDD, chronic pain, or anxiety
MOST PROMISING CLINICAL USE
CHAPTER 82 • Pharmacologic Treatment: Other Medications 917
Schizophrenia, mania, MDD
Quetiapine
Partial seizures, pain
Fibromyalagia, pain, partial seizures
Partial seizures
Gabapentin
Pregabalin
Tiagabine
Anticonvulsants
Schizophrenia, mania
FDA INDICATION
Olanzapine
Antipsychotics
MEDICATION
2-16
50-300
100-900
25-200
2.5-20
INSOMNIA DOSAGE (MG)
1-1.5
1
3-3.5
1-2
4-6
TMAX (HR)
8
4.5-7
5-9
7
20-54
T1/2 (HR)*
EFFICACY IN PLACEBOCONTROLLED
2/4
1/1
0/1
—
—
EFFICACY IN PLACEBOCONTROLLED INSOMNIA TRIALS
Sedation, nausea, dizziness, seizures
Sedation, dizziness, dry mouth, cognitive impairment; increased appetite; discontinuation effects
Sedation, dizziness, ataxia, diplopia
Sedation, OH, dry mouth, tachycardia, weight gain
Sedation, agitation, dizziness, constipation, OH, akathisia, weight gain; increased incidence of cerebrovascular events in dementia patients
MOST COMMON SIDE-EFFECTS
Liver disease
Kidney impairment, risk of substance abuse
Kidney impairment
Patients with liver disease, hypotension, cerebrovascular disease, heart failure, history of MI or ischemia, or conduction abnormalities
Patients with dementia, liver disease, prostatic hypertrophy, closedangle glaucoma, paralytic ileus, urinary retention, hypotension, history of MI, ischemia, or conduction abnormalities
RELATIVE CONTRAINDICATIONS
Table 82-1 Medications Other than Benzodiazepine Receptor Agonists Used in the Treatment of Insomnia—cont’d
Insomnia in patients with partial seizures.
Insomnia in patients with pain, fibromyalgia, partial seizures.
Insomnia in patients with pain, partial seizures, alcohol dependence or alcohol withdrawal.
Insomnia in patients with psychosis, mania-spectrum, anxiety, or comorbid MDD
Insomnia in patients with psychosis, mania-spectrum, anxiety
MOST PROMISING CLINICAL USE
918 PART II / Section 10 • Insomnia
FDA INDICATION
INSOMNIA DOSAGE (MG)
Insomnia
Ramelteon
Insomnia (OTC)
Doxylamine
Narcolepsy
Sodium oxybate
2000-4500
250-2000
25-50
25-50
8
0.3-10
0.6-1
T1/2 (HR)*
0.5-0.8
0.5
1.5-2.5
2-2.5
1/2
—
2/2
4/4
13/14
INSOMNIA TRIALS
0.3-1.2 —
7-10
10-12
5-11
0.7-0.95 0.8-2
0.3.-1
TMAX (HR)
Headache, nausea, dizziness, drowsiness; discontinuation effects.
Sedation, nausea, diarrhea, parasomnias, renal damage may occur with chronic use; discontinuation effects.
Sedation, dizziness, dry mouth, blurred vision, constipation, urinary retention
Sedation, dizziness, dry mouth, blurred vision, constipation, urinary retention
Drowsiness, fatigue, dizziness
Headache, sedation
MOST COMMON SIDE-EFFECTS
Those vulnerable to respiratory depression, including SDB, COPD, or hypoxemia of any cause; those at risk for substance abuse
Neonates; persons at risk for substance abuse or suicide; persons with gastritis, intermittent porphyria, liver failure, or kidney failure
Severe liver failure, closed-angle glaucoma, asthma, COPD, bladder obstruction, GI obstruction, ileus, urinary retention
Severe liver failure, closed-angle glaucoma, asthma, COPD, bladder obstruction, GI obstruction, ileus, urinary retention
Severe liver failure
Persons attempting to conceive
RELATIVE CONTRAINDICATIONS
Insomnia in fibromyalgia patients; sleep disturbance in narcolepsy patients
—
Insomnia in those with allergy or upper respiratory infections
Insomnia in those with allergy or upper respiratory infections
Sleep-onset insomnia, insomnia comorbid with COPD, SDB
Chronic sleep-onset insomnia in children, persons with Alzheimer’s dementia, and children with neurodevelopmental disorders
MOST PROMISING CLINICAL USE
COPD, chronic obstructive pulmonary disease; GI, gastrointestinal; MDD, major depressive disorder; MI, myocardial infarction; OH, orthostatic hypotension; OTC, over-the-counter; SDB, sleep-disordered breathing. *Includes active metabolites.
Insomnia, alcohol withdrawal, anxiety
Chloral hydrate
Other Drugs
Allergy, insomnia (OTC)
Diphenhydramine
Antihistamines
Hormone (OTC)
Melatonin
Melatonin and Melatonin Receptor Agonists
MEDICATION
CHAPTER 82 • Pharmacologic Treatment: Other Medications 919
920 PART II / Section 10 • Insomnia
timing of sleep enhancement that occurs with melatonin depends on the time of day of administration and might not be manifest for as long as 3 hours after dosing despite achieving maximal serum concentration in approximately 30 minutes.6-8 As a result, attention must be given to the time of day that this agent is administered as well as the relationship of the time of administration to desired sleepenhancing effect. The doses administered in placebo-controlled trials ranged from 0.1 mg to 75 mg; however, the majority of studies used doses in the range of 2 to 6 mg. The timing of administration varied from 30 minutes to 3 hours before bedtime. There was no clearly predominant administration time. The primary metabolism of melatonin occurs via cytochrome P-450 (CYP) 1A2 and 2C19 isoenzymes, so the elimination of melatonin would be expected to be affected by factors that modify the function of these isoenzymes.9 Evidence of Efficacy Placebo-controlled studies of the effects of melatonin on sleep have been carried out in a number of different subject populations, including adults without sleep complaints; children, adults, and elderly persons with insomnia; patients with Alzheimer’s dementia; patients with insomnia comorbid with medical illnesses; patients with mood disorders, schizophrenia, or attention-deficit/ hyperactivity disorder; and children with neurodevelopmental disorders.10-24 However, our ability to draw conclusions from these studies is limited because they employed widely varying melatonin dosages and different melatonin formulations (immediate and delayed release), and they varied substantially in the timing of melatonin administration.25,26 Despite these limitations, the available self-report, polysomnographic, and actigraphic data suggest that melatonin tends to have a therapeutic effect on sleep onset that is greater and more consistent than its effects on the ability to stay asleep or on the duration of sleep.10,12,14,18,19,27-31 Profile of Adverse Effects No substantive risks of melatonin have been identified. However, no large-scale systematic studies assessing the adverse effects of melatonin have been carried out. The most commonly reported side effect is headache.12 Slowing of reaction time and sedation has been observed with melatonin following daytime administration, which could impair ability to function.6,32,33 Melatonin is nonreinforcing, so abuse potential is minimal. There does not appear to be physiologic or psychological dependence occurring with melatonin therapy, though this has not been systematically evaluated. The longest studies of nightly melatonin therapy have been 8 weeks in duration.11,24 Potential Clinical Utility Melatonin appears to have primary use in addressing problems of sleep onset. It is relatively unusual in that data exist suggesting that it can be safely administered to children, those with Alzheimer’s dementia, and children with neurodevelopmental disorders,10-24 though the degree of therapeutic effects in these populations is not well established. Given the absence of abuse potential, this medication
would also be reasonable to use in patients prone to substance abuse; however no studies of melatonin treatment have been carried out in this population. A number of studies suggest that melatonin regulates reproductive function in both males and females. Some evidence suggests that higher melatonin levels may be associated with reversible inhibition of spermatogenesis and ovulation.34-37 On this basis some have suggested that those who are trying to conceive should avoid taking melatonin.36,37 Ramelteon Overview Ramelteon is an agonist at MT1 and MT2 melatonin receptors which has a Tmax of 0.75 to 1 hour and a T1/2 of 1 to 2.5 hours.38 Based on this pharmacokinetic profile, like melatonin, ramelteon would be expected to have effects primarily on sleep onset. Indeed, it is approved by the FDA with an indicated use of treatment of sleep-onset difficulty. Ramelteon, like melatonin, has no clear dose-response relationship; however, a therapeutic dosage of 8 mg and timing of dosing 30 minutes before bedtime has been established.3 Primary metabolism of ramelteon occurs via the CYP isoenzymes CYP1A2, CYP2C, and CYP3A4 so that factors that affect these isoenzymes would be expected to alter the metabolism of ramelteon.39 Evidence of Efficacy In placebo-controlled trials, ramelteon has consistently been found to shorten sleep latency, with an accompanying increase in total sleep time.3 These effects have been more consistent on polysomnographic than self-reported measures of sleep. Therapeutic effects on the ability to stay asleep have generally not been noted. Profile of Adverse Effects Ramelteon is generally well tolerated. Doses up to 64 mg are associated with no substantive increase in adverse effects. The most common side effects reported with ramelteon include headache, dizziness, somnolence, fatigue, and nausea.40,41 There is no evidence for abuse potential or tolerance developing with this medication in studies as long as 5 weeks.40,41 Statistically significant, though not clinically significant, elevations of prolactin have been noted with ramelteon compared with placebo in women receiving 6 months of nightly treatment with 16 mg.42 Several studies suggest that ramelteon does not exacerbate breathing problems when used in those with sleep-disordered breathing and mild to moderate chronic obstructive pulmonary disease.43,44 Potential Clinical Utility Ramelteon is indicated solely for the treatment of sleep-onset difficulties. The data in patients with sleepdisordered breathing and chronic obstructive pulmonary disease suggests that ramelteon can be safely used in these patient populations when treatment of sleep-onset insomnia is indicated.43,44 The absence of abuse potential suggests that this medication could also be used in persons prone to substance abuse, though no studies of the treatment of insomnia with ramelteon have been carried out in this population.
Ramelteon is relatively free of contraindications. The only relative contraindication to use is severe liver failure.
SEDATING ANTIDEPRESSANTS A number of agents that are approved by the FDA for the treatment of depression are used in relatively lower dosages for the treatment of insomnia.3 In fact, for some of these agents, their use in low dosage for insomnia therapy exceeds their use for alleviating depression.45 These agents have therapeutic effects on sleep by blocking the receptors of a number of key wake-promoting neurotransmitters including serotonin, norepinephrine, and histamine.3,46 The antidepressants most commonly used to treat insomnia include tricyclic antidepressants—most notably doxepin, trimipramine, and amitriptyline—the chlorophenyl piperazine, trazodone, and the tetracyclic antidepressant mirtazapine.3 Tricyclic Antidepressants: Doxepin, Amitriptyline, Trimipramine Overview Three tricyclic antidepressants are used relatively often for the treatment of insomnia, presumably due to the sedating effects noted when they have been used to treat major depression: doxepin, amitrityline, and trimipramine.3,45,47 Interactions with the tricyclic antidepressants can occur via effects on their predominant metabolic pathways, which involve the CYP3A4, CYP2C19, CYP2D6, and CYP2C9 isoenzymes.48,49 By affecting these isoenzymes or altering hepatic blood flow, a number of factors can increase blood levels of tricyclic antidepressants including age, antipsychotic medications, methylphenidate, fluoxetine, paroxetine, cimetidine, diltiazem, and grapefruit juice.50 There is also genetic variation in the capacity to metabolize tricyclic antidepressants in the population, which leads to substantial person-to-person differences in the relationship between dosage and therapeutic and adverse effects.50a Amitriptyline, doxepin, and trimipramine reach their maximum serum concentration Tmax in 1.5 to 6 hours after oral ingestion and have T1/2 on the order of 10 to 50 hours.48-50 Evidence of Efficacy These agents have been reported to have therapeutic effects on indices of sleep onset and maintenance in depressed patients.51 In addition, a number of placebocontrolled trials of the treatment of insomnia have been carried out with doxepin and trimipramine. Trimipramine dosed from 50 to 200 mg has been evaluated in two studies in primary insomnia patients and noted to lead to improved sleep quality and polysomnographic sleep efficiency compared with placebo, though no effect on sleep-onset latency was observed.52,53 Doxepin has been evaluated in three studies at a dosage of 25 to 50 mg and found to improve sleep quality and reported daytime well-being, as well as polysomnographic indices of sleep onset and maintenance compared with placebo.52,54-56 More recently, doxepin has been evaluated in placebo-controlled trials in insomnia patients at dosages of 1 to 6 mg.57,58 Because doxepin’s predominant pharmacologic effect is the blockade of H1 histamine receptors, as
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the dosage is decreased, doxepin becomes an agent with increasingly specific H1 antagonist effects.59 The studies carried out with doxepin 1 to 6 mg have identified evidence of self-reported and polysomnographic efficacy in indices of sleep onset and maintenance with particular effects on maintenance of sleep.57,58 Notably, the therapeutic effects appear to be largest in the last third of the night, and of particular note they are greatest in the last hour (hour 8) of the night.57 This suggests a dissociation of the clinical effects from the serum blood level, because the peak blood level occurs between 1.5 and 4 hours after dosing. At the same time, 1 to 6 mg of doxepin was not associated with significant sedation or impairment when subjects were tested after waking 1 hour after the peak sleep-enhancing effect.57 No daytime somnolence was noted as an adverse effect more frequently than placebo in these studies, despite the relatively long half-life of this agent. The absence of daytime impairment with doxepin 1 to 6 mg suggests that an increase in wake-promoting neurotransmitter activity occurs after waking that counteracts the H1 antagonism. Low-dose doxepin was approved by FDA as a hypnotic in 2010. Profile of Adverse Effects The side effects of the tricyclic antidepressants primarily derive from their blockade of H1 histaminergic, M1 muscarinic cholinergic, serotoninergic (5-HT2) and α1 and α2 adrenergic receptors, which results in their being associated with sedation, orthostatic hypotension (and the attendant risk of falls), weight gain, dry mouth, constipation, urinary retention, and cardiac dysrhythmias (increased heart rate and impairment of cardiac electrical conduction, which can lead to heart block in some instances), exacerbation of narrow-angle glaucoma, and, rarely, seizures and anticholinergic delirium.46,49 It is important to note that these effects are dose dependent, and most published literature with these agents relates to their use in dosages used to treat depression and not the lower dosage ranges more commonly used in the treatment of insomnia. The best data on the adverse effects of tricyclic antidepressants when used in lower dosages for insomnia therapy exist for doxepin. In dosages of 1, 3, and 6 mg, doxepin has a remarkably favorable side-effect profile, in contrast with the side effects noted with its antidepressant use.57,58 In particular, the available data suggest that doxepin is not associated with significant weight gain, it does not appear to be associated with substantive daytime impairment or sedation, and anticholinergic effects appear to be uncommon. Potential Clinical Utility It is natural to consider the use of these antidepressants in patients with insomnia associated with depression. However, it is important to bear in mind that there are no data indicating that an antidepressant effect occurs with the dosages of these agents that are generally used to treat insomnia. Furthermore, it is possible that in this dosage range monotherapy with these agents might not have antidepressant effects, but a therapeutic effect on depression might be seen when they are combined with a nonsedating antidepressant (e.g., selective serotonin reuptake inhibitor or serotonin-norepinephrine reuptake inhibitor). However,
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there may be increased risks when combining these agents.60 Tricyclic antidepressants have also been used commonly in the treatment of anxiety and chronic pain and may be useful for treating sleep problems associated with these conditions; however, as with depression, dosage may be an important consideration.61 Given the lack of abuse potential, the tricyclic antidepressants are a possible option for treating the sleep difficulties of substance abusers. Doxepin dosed from 1 to 6 mg appears to have unique potential for treating sleep difficulties in the latter part of the night and early morning period. Because low-dose doxepin is also a relatively selective H1 antihistamine, it may be useful in patients who have insomnia occurring in conjunction with allergies. Relative contraindications to the use of tricyclic antidepressants derive from their risks of cardiac arrhythmias, anticholinergic effects, seizures, and orthostatic hypotension.46,49 Because of these risks, tricyclic antidepressants should be used with caution in those with a history of myocardial infarction, ischemia, or conduction abnormalities; closed-angle glaucoma; decreased gastrointestinal motility; urinary retention; hypotension; or seizure disorder. Antidepressants should be used with caution in patients with bipolar disorder because of the increased risk of precipitating mania.62 Also, based on the metabolism of the tricyclic antidepressants, significant liver disease is a relative contraindication to their use. The risks and associated relative contraindications of these agents are dose related and might not be relevant in the lower dosages often used to treat insomnia. Trazodone Overview Trazodone has the distinction of being the agent most often used off-label in the treatment of insomnia.45 It is generally used at a dosage of 200 to 600 mg in the treatment of depression, but the dosage used to treat insomnia typically ranges from 25 to 150 mg. With a Tmax of 1 to 2 hours and a T1/2 of 7 to 15 hours, trazodone has the potential to have therapeutic effects on initiating and maintaining sleep.3 Trazodone is primarily metabolized via CYP3A4 and CYP2D6 pathways and can have significant interactions with other agents that are associated with these liver cytochrome systems.3 Trazodone has one active metabolite, methyl-chlorophenylpiperazine (mCPP).63 Significant variation in the effects of trazodone occur because many factors can affect the metabolism of trazodone and mCPP, including genetic polymorphisms that are common in the general population.64 Evidence of Efficacy The primary evidence of a sleep-enhancing effect of trazodone is that sedation was a commonly reported side effect in trials where this agent was studied as a treatment for depression. Few studies of the use of trazodone in insomnia patients have been carried out. A small placebo-controlled study in abstinent alcoholics (N = 16) found significant improvement in sleep efficiency and awakenings compared with placebo.65 A double-blind, placebo-controlled, crossover study was carried out in 17 patients with depression who had insomnia while being
treated with fluoxetine or bupropion.66 Compared with placebo, trazodone significantly improved the Pittsburgh Sleep Quality Index and the sleep items of the Yale–New Haven Hospital Depressive Symptom Inventory. One study of the treatment of patients with primary insomnia was also carried out with trazodone.67 This was a parallel group, 2-week study comparing trazodone 50 mg, placebo, and zolpidem 10 mg. A number of sleep parameters were significantly improved compared with placebo for both trazodone and zolpidem in the first week of treatment; however, by the second week these differences were not significant due to improvement in the placebo-treated patients. Profile of Adverse Effects The most common side effects occurring with trazodone include sedation, dizziness, headache, dry mouth, blurred vision, and orthostatic hypotension. Weight gain occurs in some cases. Some patients who take trazodone have relatively diminished capacity to metabolize mCPP due to genetic or other factors, and these patients are likely to experience anxiety or insomnia. Priapism, a painful sustained erection, is a relatively uncommon side effect of trazodone that can require surgical intervention and can lead to impotence.68 There is no evidence that trazodone has significant abuse potential. Potential Clinical Utility As with other antidepressants, it is natural to consider using trazodone in patients with insomnia associated with depression. One study demonstrates the safe and effective use of trazodone in depressed patients treated with fluoxetine or bupropion.66 However, trazodone may be associated with increased risks when combined with other antidepressants. Further, it is unlikely to have significant antidepressant effects when used as monotherapy in the dosing range generally used to treat insomnia (50 to 150 mg), though whether it has antidepressant effects when used in combination with other antidepressants is unknown. Given the lack of abuse potential, trazodone is reasonable to consider in patients with substance use disorders. In this regard, one study that was carried out in abstinent alcoholics reported a therapeutic effect on sleep and a reasonable safety profile.65 Trazodone should be used with caution in those at risk for falls because of the risk of orthostatic hypotension. Trazodone should also be administered judiciously in men due to the risk of priapism. Like any antidepressant, trazodone should be used with caution in those with bipolar disorder because of the increased risk of precipitating mania.62 Also based on the metabolism of trazodone, significant liver or kidney disease is a relative contraindication. Mirtazapine Overview Mirtazapine is FDA approved for the treatment of major depression in dosages of 7.5 to 45 mg. The dosages generally used to treat insomnia are 7.5 to 30 mg. It has been suggested that the sedating effects diminish in dosages greater than 30 mg due to increasing adrenergic effects.69 The antidepressant, sleep enhancing, and adverse effects
of this agent derive from antagonism of adrenergic (α1 and α2), serotoninergic (5-HT2 and 5-HT3), and histaminergic (H1) receptors.70 Interactions with mirtazapine can occur via effects on liver enzymes CYP2D6, CYP3A4, and CYP1A2.3 The Tmax of this agent is 15 minutes to 2 hours, and the T1/2 is 20 to 40 hours.3 Evidence of Efficacy Mirtazapine has not been evaluated in a placebo-controlled trial in insomnia patients. Evidence that this agent has sleep-onset and sleep-maintenance enhancing effects have been noted in open-label studies of depressed patients and normal sleepers and one double-blind, randomized study comparing the sleep effects of this agent to fluoxetine.71-73 Profile of Adverse Effects The predominant side effects of mirtazapine are increased appetite and weight gain, dry mouth, and constipation.69 Consistent with the sleep-enhancing effects of this agent, sedation is also a common adverse effect of treatment. Mirtazapine is not associated with significant abuse potential or with cardiac or sexual adverse effects. Potential Clinical Utility Because of the antidepressant effects of mirtazapine, it is particularly well suited for use in patients with insomnia occurring with major depression. A study suggesting that mirtazapine might decrease the apnea–hypopnea index in those with significant sleep-disordered breathing suggests that this agent should be considered in patients who have insomnia comorbid with sleep-disordered breathing.74 The lack of abuse potential of this agent also suggests its use in those with insomnia who are at risk for substance abuse, though there are no studies of the use of mirtazapine in this population. Mirtazapine has few relative contraindications. Like other antidepressants, it should be used with caution in those with bipolar disorder because of the risk of precipitating mania.62 It should also be used with caution in those with obesity, liver disease, and kidney disease.
ANTIPSYCHOTICS Overview Antipsychotic agents are sometimes used to treat insomnia in clinical practice.45 Generally, these agents are used in dosages that are lower than typically used in their FDA-approved indications, which include the treatment of psychotic disorders (including schizophrenia and schizo affective disorder), mania, and in some cases bipolar and unipolar major depression. The antipsychotic agents most commonly used to treat insomnia include quetiapine and olanzapine.45,75 When used to treat insomnia, quetiapine is generally dosed from 25 to 250 mg, and olanzapine is typically administered at a dosage of 2.5 to 20 mg. The primary effects of these agents are antagonism of dopamine, histamine (H1), serotonin, muscarinic, cholinergic, and adrenergic (α1) receptors.3 Olanzapine has a Tmax of 4 to 6 hours and T1/2 of 20 to 54 hours, which makes it relatively unlikely to be effective
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for sleep-onset difficulty when taken near bedtime; however it is likely to have a prolonged sleep-enhancing effect.3 Olanzapine elimination may be affected by factors that alter the liver enzymes CYP1A2 and CYP2D6. Because of this, there is slower elimination among female patients, tobacco smokers, and persons of Japanese descent. Quetiapine, with a Tmax of 1 to 2 hours and a T1/2 of approximately 7 hours, has the potential to improve sleep onset as well as sleep maintenance based on pharmacokinetics. The metabolism of quetiapine may be affected by factors that alter the CYP3A4 and CYP2D6 liver enzymes.3 Evidence of Efficacy There has yet to be a placebo-controlled trial of the use of any antipsychotic agent for the treatment of primary insomnia patients.3 However, quetiapine 25 to 75 mg was found to improve self-reported and polysomnographic indices of sleep in an open-label study in primary insomnia patients.76 Both quetiapine and olanzapine have been found to improve sleep in small studies of normal sleepers.75 These agents have also been found to improve sleep in open-label and placebo-controlled studies in patients with schizophrenia, mania, bipolar depression, and unipolar depression.75,77,78 Profile of Adverse Effects The primary side effects of the antipsychotic agents used to treat insomnia include orthostatic hypotension, dizziness, dry mouth, constipation, blurred vision, urinary retention, increased appetite, weight gain, and sedation.75 Because antipsychotics antagonize dopamine receptors, they can lead to extrapyramidal side effects such as parkinsonism, acute dystonic reactions, akathisia, and tardive dyskinesia.76 However, these side effects are relatively uncommon in the newer antipsychotic agents, which include those most commonly used to treat insomnia. Olanzapine has also been associated with cognitive impairment, glucose intolerance, and an elevated risk of mortality among patients with dementia.79 Antipsychotic agents do not have significant abuse potential. Potential Clinical Utility Antipsychotic agents are best suited for treating insomnia occurring in persons with psychosis or bipolar disorder. Quetiapine is also FDA approved for treating bipolar and unipolar major depression, suggesting its potential use for treating insomnia occurring in patients with these disorders. Given the lack of abuse potential, antipsychotics have potential for use in patients who have insomnia and who are prone to substance abuse. Because of their adverse effect profiles, antipsychotic agents commonly used to treat insomnia should be used with caution in those with a history of myocardial infarction, ischemia, or conduction abnormalities; closed-angle glaucoma; decreased gastrointestinal motility; urinary retention; or hypotension. These agents should also be used with caution in those with liver disease or in whom weight gain would be of significant concern. Olanzapine is also relatively contraindicated in patients with dementia because of a reported increase in risk of mortality in this population.79
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ANTICONVULSANTS Gabapentin and Pregabalin Overview Gabapentin and pregabalin are structural analogues of gamma-aminobutyric acid (GABA) but are thought to exert their primary central nervous system effects by binding to the alpha-2-delta subunit of N-type voltagegated calcium channels, thereby diminishing the release of glutamate and norepinephrine.80,81 Gabapentin and pregabalin are approved by the FDA, with indicated use for treating partial seizures and pain. Pregabalin is also indicated for treating fibromyalgia. These agents are also used to treat insomnia, periodic limb movement disorder, restless legs syndrome, and bipolar disorder. Gabapentin has a Tmax of 3 to 3.5 hours and a T1/2 of 5 to 9 hours and is generally used at a dosage of 100 to 900 mg for insomnia therapy. Because of its relatively slow absorption, gabapentin is relatively less likely than other agents to improve sleep onset when taken at bedtime. Pregabalin is more rapidly absorbed, with a Tmax of 1 hour and T1/2 of 4.5 to 7 hours. Both agents are eliminated renally, so factors that affect renal function can affect the elimination of these agents.80,81 Evidence of Efficacy Although neither gabapentin nor pregabalin has been evaluated in a placebo-controlled trial of the treatment of primary insomnia, evidence of a sleep-enhancing effect has been noted in studies of the treatment of normal sleepers, pain patients, patients with restless legs syndrome, and epilepsy patients.82-85 Gabapentin was also found to improve sleep in a small placebo-controlled trial of the treatment of insomnia occurring in alcohol-dependent persons.86 A small open-label pilot study also suggests that gabapentin might be useful in treating alcohol withdrawal.87 Profile of Adverse Effects The most common adverse effects of gabapentin are sedation, dizziness, ataxia, and diplopia. Pregabalin’s most common side effects include sedation, dizziness, dry mouth, cognitive impairment, and increased appetite. Rarely, leukopenia has been noted with these agents. Gabapentin appears to have minimal abuse potential; however, abuse potential may be a consideration with pregabalin.88 Potential Clinical Utility Gabapentin and pregabalin should be considered for treating insomnia occurring in patients with pain or partial seizures because of their efficacy in the treatment of those conditions. Pregabalin, an FDA-approved treatment for fibromyalgia, should be considered when treating patients with insomnia occurring with fibromyalgia. Both agents may be useful in treating patients with insomnia occurring with restless legs syndrome or periodic limb movement disorder. Based on the two small studies, gabapentin is potentially useful in treating insomnia occurring in alcohol-dependent persons and those undergoing alcohol withdrawal. Given this potential and the absence of abuse potential, gabapentin may also be useful in the treatment
of the insomnia that commonly occurs in abstinent alcoholics. Because both of these agents are renally eliminated, they should be used with caution in patients with renal impairment or where there is any factor that impedes renal function. Caution should also be used when prescribing pregabalin to abuse-prone patients. Tiagabine Overview Tiagabine is a GABA reuptake inhibitor that is FDA approved for treating partial seizures. It has been evaluated for the treatment of insomnia at dosages from 2 to 16 mg.89,90 Tiagabine has a Tmax of 1 to 1.5 hours and a T1/2 of approximately 8 hours. It is primarily metabolized by the liver CYP3A4 isoenzyme, and, as a result, factors that affect that enzyme can affect the elimination of tiagabine Evidence of Efficacy Tiagabine has been evaluated in four placebo-controlled trials of the treatment of primary insomnia in adults and the elderly.89-92 Although this agent reliably increases slow-wave sleep in a dose-dependent manner, it has not led to improvement in indices of sleep onset and has not consistently improved measures of sleep maintenance compared with placebo. Profile of Adverse Effects The most frequent side effects of tiagabine in placebocontrolled trials were sedation, dizziness, and nausea. There is also a small risk of precipitating seizures with this medication. Potential Clinical Utility Tiagabine could be considered in patients who require treatment for partial seizures and who have accompanying insomnia. Tiagabine should be used with caution in patients with significant liver disease.
ANTIHISTAMINES The designation of an agent as an antihistamine generally reflects that the agent was developed and/or marketed with the treatment of allergies as its primary intended use. However, many agents that are potent antagonists of the H1 histamine receptor were developed to treat other conditions and are not generally referred to as “antihistamines.” This includes the antidepressants doxepin and mirtazapine, which have more selective H1 antagonist effects than any agents designated as antihistamines, as well as antipsychotics including olanzapine and quetiapine.3 Agents designated as antihistamines that cross the blood–brain barrier include diphenhydramine, doxylamine, chlorpheniramine, and hydroxyzine. Of these, the agents most commonly used to treat insomnia are diphenhydramine and doxylamine, constituents of nearly all overthe-counter insomnia medications. Diphenhydramine Overview Diphenhydramine is generally dosed at 25 to 50 mg for the treatment of insomnia. H1 antagonism is its greatest
effect, and muscarinic cholinergic antagonism is the next most important effect of diphenhydramine.92a,92b This agent has a Tmax of 2 to 2.5 hours and a T1/2 of 5 to 11 hours.3 The elimination of diphenhydramine primarily involves hepatic metabolism by the CYP2D6, CYP1A2, CYP2C9, and CYP2C19 isoenzymes.3 Evidence of Efficacy Sleep-enhancing effects of diphenhydramine have been observed in placebo-controlled trials of sleep disturbance in a mixed group of psychiatric patients, outpatients in a primary care practice, nursing home residents, and primary insomnia patients.93-97 The effects on sleep maintenance appear to be more consistent than the effects on sleep onset. While this may, at least in part, reflect that the Tmax is 2 hours, a greater effect on the maintenance of sleep than on sleep initiation was also noted with doxepin when dosed in a range where it is a highly selective H1 antagonist. In a study examining the sedating effects associated with daytime dosing of diphenhydramine, a sedating effect seen on the first day of treatment was no longer seen on the fourth day of treatment.98 Profile of Adverse Effects The most important adverse effects of diphenhydramine include: sedation, dizziness, psychomotor impairment, cognitive impairment, dry mouth, blurred vision, constipation, urinary retention, and weight gain. Less commonly, diphenhydramine is associated with agitation and insomnia. Diphenhydramine does not have substantial abuse potential. Potential Clinical Utility The most promising use of diphenhydramine would be expected to be in the treatment of persons with sleep difficulty occurring in conjunction with allergy symptoms or upper respiratory infections. The only data relevant to this potential use is a study of 100 children with nocturnal cough in which diphenhydramine did not improve sleep compared with placebo according to parents’ reports.99 The primary relative contraindications to diphenhydramine use are closed-angle glaucoma, decreased gastrointestinal motility, urinary retention, asthma, chronic obstructive pulmonary disease, and severe liver disease. Doxylamine Overview The characteristics of doxylamine are very similar to those of diphenhydramine. It is generally used for insomnia in the same dose range (25 to 50 mg) and has a T1/2 of 10 to 12 hours. Doxylamine has a slightly faster absorption, with a Tmax of 1.5 to 2.5 hours.3 The primary elimination of doxylamine occurs through the CYP2D6, CYP1A2, CYP2C9 liver isoenzymes. Evidence of Efficacy No studies of the treatment of insomnia with doxylamine have been carried out. However, there is one double-blind, placebo controlled trial demonstrating a significant therapeutic effect on self-reported sleep with doxylamine 25 mg in 2931 postoperative patients.100
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Profile of Adverse Effects The adverse-effects profile of doxylamine is essentially the same as for diphenhydramine, with the exception that case reports document that coma and rhabdomyolysis occasionally occur with the use of doxylamine.101 Potential Clinical Utility The most promising clinical use of doxylamine is as a treatment for insomnia in those with associated allergy symptoms or upper respiratory infections. Relative contraindications to the use of doxylamine are the same as with diphenhydramine: closed-angle glaucoma, decreased gastrointestinal motility, urinary retention, asthma, chronic obstructive pulmonary disease, and severe liver disease.
CHLORAL HYDRATE Overview Chloral hydrate is thought to exert its effect via its metabolite trichloroethanol, which modulates GABAA receptors in a manner that appears to be related to the barbiturates.102 The Tmax of the active metabolite of chloral hydrate is approximately 30 minutes and the T1/2 is 7 to 10 hours. The dosage range for the treatment of insomnia is 250 mg to 2 g. Trichloroethanol undergoes hepatic conjugation with subsequent renal elimination. Evidence of Efficacy Chloral hydrate has been the subject of placebo-controlled trials in elderly insomnia patients and mildly demented older adults.103,104 Of these studies, a significant advantage over placebo was only found in the trial carried out in the mildly demented patients.104 Profile of Adverse Effects The primary adverse effects of chloral hydrate include sedation, nausea, diarrhea, psychomotor impairment, and parasomnias.102 There is significant abuse and dependence potential with this agent.102 Liver and kidney damage can also occur with chloral hydrate treatment. There is a significant risk of death with overdoses of chloral hydrate.102 Potential Clinical Utility Given the potential for serious adverse effects with this agent and that there are no conditions where it has unique efficacy, it has been reasonably argued that this agent should not used to treat insomnia.102 Although chloral hydrate is not recommended for insomnia therapy, in some conditions its use is of special concern. This includes those at risk for suicide, neonates, persons prone to substance abuse, those with gastritis, patients with intermittent porphyria, and those with liver or kidney failure.
SODIUM OXYBATE Overview Sodium oxybate is indicated for the treatment of cataplexy and daytime sleepiness in those with narcolepsy. The mechanisms of action of this agent are unknown. It is dosed in the range of 2.5 to 4.5 grams. The Tmax is 0.5 to 0.8 hours and the T1/2 is 0.3 to 1.2 hours.51 Because the half-life is so short, it is dosed both at bedtime and again
926 PART II / Section 10 • Insomnia
in the middle of the night. The metabolism of sodium oxybate is incompletely understood; however, enzymatic breakdown appears to be the most important element, involving a cytosolic enzyme, gamma-hydroxybutyrate dehydrogenase, and a mitochondrial transhydrogenase. Evidence of Efficacy Sleep-promoting effects of sodium oxybate have been demonstrated in terms of both onset and maintenance of sleep in placebo-controlled trials in patients with narcolepsy and fibromyalgia.105,106 No trials of this agent have been carried out in any other groups of insomnia patients. Profile of Adverse Effects The primary adverse effects of sodium oxybate are headache, nausea and vomiting, excess salivation, parasomnias, and amnesia. Sodium oxybate has significant abuse and dependence potential. It can lead to coma and delirium in overdose.51 Potential Clinical Utility Sodium oxybate should be considered as a potential therapy for the treatment of sleep disturbance in narcolepsy patients and in those with fibromyalgia. Because of the side-effect profile of sodium oxybate, it has a number of relative contraindications including in patients vulnerable to respiratory depression, those with sleep-disordered breathing, patients with chronic obstructive pulmonary disease, and those at risk for substance abuse.51
HERBALS Safety and Limitations The use of plants for medicinal purposes dates back to antiquity. In the United States, herbals that do not claim that they treat a disorder are regulated differently than drugs are. Such herbals are regulated by the Dietary Supplement Health and Education Act (DSHEA) of 1994 and not according to the procedures the FDA employs for approving and overseeing prescription medications. Although herbal dietary supplements undergo regulation in terms of safety, it is critical to note that manufacturers of herbal remedies are not required to provide data on the safety, efficacy, or purity of their products. As a result, the constituents, effectiveness, and side-effects profile of any given product remains uncertain.107 Further complicating the situation for practitioners and consumers is that for many herbals the active constituents and their interactions are not fully established. At the same time, as plant derivatives, the constituents of herbal preparations vary depending on the particular species of plant, where and when it was cultivated, and how it was processed.107 Despite these limitations, herbal medications are frequently used around the world for the treatment of insomnia. Valerian is one of the most common herbal insomnia therapies. It must be understood that this review is limited by uncertainty as to identity of the active constituents and the composition of any of the valerian preparations studied.
Valerian Overview Valerian is an herbal substance derived from a plant of the Valeriana genus, which includes more than 150 plants that grow in temperate regions in North America, Europe, and Asia.107 Of these plants, the most commonly used for medicinal purposes is Valeriana officinalis L. It is believed that this substance has been used for therapeutic purposes for more than 1000 years. Because the active ingredients of valerian are unknown, it is not possible to establish its pharmacokinetics or route of metabolism. The dosages of valerian most commonly employed in studies of insomnia treatment are 400 to 900 mg/day. Evidence of Efficacy Because of the uncertainty as to the dosing of active ingredients in the preparations of valerian studied, we are limited to assessing the evidence for efficacy in the group of placebo-controlled studies of insomnia treatment carried out with valerian as a whole. Although a few studies have reported a therapeutic effect on sleep, the majority of placebo-controlled trials of the treatment of insomnia with valerian preparations have failed to find a therapeutic benefit over placebo.108-111 At this point it must be concluded that the efficacy of valerian in the treatment of insomnia is not established. Profile of Adverse Effects Valerian preparations have been associated with few side effects. Most studies have noted comparable rates of adverse effects in subjects treated with valerian or placebo. There is no evidence for significant abuse potential, and daytime sedation appears to be relatively uncommon. Potential Clinical Utility Given the uncertainty as to the efficacy of valerian preparations, it makes sense to limit the clinical use of this herbal therapy to persons who are specifically interested in using an herbal treatment for their insomnia. Four cases of hepatitis have been reported in persons taking valerian in combination with skullcap, another herbal therapy.107 The role of valerian in causing the hepatitis is uncertain; however, it is recommended that caution be used when combining valerian with skullcap and when treating patients with liver disease.
SUMMARY OF CLINICAL CIRCUMSTANCES WHERE OTHER AGENTS MIGHT BE PREFERRED As discussed earlier, in a number of circumstances the agents reviewed in this chapter might be preferred over BzRAs for the treatment of insomnia. One of these is where patients appear to be not responsive to or intolerant of several BzRAs. The other circumstances include the treatment of insomnia in substance abusers, allergyassociated sleep disturbance, insomnia occurring with psychosis, insomnia occurring with mania or hypomania, insomnia occurring with major depression where singleagent therapy is desired, and insomnia occurring with chronic pain where single-agent therapy is desired.
Substance-Use Disorders Unlike the BzRAs, nearly all of the agents discussed in this chapter have minimal abuse potential. As a result, they might be preferred in the treatment of those with a predisposition to substance abuse or those who are experiencing insomnia in the setting of substance abuse. The exceptions to this are sodium oxybate and chloral hydrate, both of which have abuse potential. Among the non-BzRAs without abuse potential, only gabapentin and trazodone have been studied for the treatment of insomnia in substance-abuse populations. Gabapentin was found to improve sleep and have an acceptable safety profile in small studies of alcohol-dependent persons and those going through alcohol withdrawal. Trazodone was found to be an effective treatment for insomnia in abstinent alcoholics in a placebo-controlled study. The utility of other nonBzRAs in the treatment of insomnia in those with substance use disorders remains to be evaluated. Allergy-Associated Sleep Disturbance A number of the non-BzRA agents appear to have sleepenhancing effects as well as significant antihistaminergic effects (H1 antagonism). As a result, they might be expected to be particularly useful in the treatment of insomnia occurring in association with allergies. These agents include doxepin, mirtazapine, diphenhydramine, doxlamine, amitriptyline, trimipramine, trazodone, olanzapine, and quetiapine. No placebo-controlled trials of the treatment of insomnia occurring with allergic rhinitis have been carried out. Insomnia Occurring with Psychosis Quetiapine and olanzapine are agents with antipsychotic efficacy that have been used to treat insomnia. The sleepenhancing effects of these agents have been demonstrated in trials in normal sleepers or small open-label studies in those with schizophrenia.75 Olanzapine and quetiapine are agents that should be considered for treating sleep disturbance in persons with psychosis. No placebo-controlled trials of the treatment of insomnia in patients with psychosis have been carried out. Insomnia Occurring with Mania or Hypomania Quetiapine and olanzapine also are indicated for the treatment of mania. These agents would be natural to consider for addressing sleep difficulties in persons with mania or hypomania, although no systematic trials of their effects specifically on sleep in this setting have been carried out. Single-Agent Therapy of Insomnia Occurring with Major Depression There is empirical evidence that several BzRAs may be effective and safe for the treatment of insomnia occurring with major depression. These studies have evaluated eszopiclone, zolpidem, zolpidem CR, and clonazepam as adjunctive therapy to antidepressant medications.3 However, there may be some instances where single-agent therapy that addresses both the depression and the sleep disturbance is preferred. Such instances include those
CHAPTER 82 • Pharmacologic Treatment: Other Medications 927
where cost or the complexity of the medication regimen are primary concerns. The importance of the complexity of the medication regimen is that it can contribute to nonadherence in some patients, particularly those whose cognitive function is impaired. In such instances, a single agent that has established antidepressant effects as well as sleep-enhancing effects would be preferred. Of the non-BzRAs discussed in this chapter, a number of agents have demonstrated antidepressant effects and are, therefore, promising for use in this setting. These include amitriptyline, trimipramine, doxepin, mirtazapine, trazodone, and quetiapine. Of these, only trimipramine and doxepin have been found to have efficacy in the treatment of insomnia in placebo-controlled trials. Another consideration is that for some agents, the antidepressant dosage is substantially higher than what is typically used to treat insomnia. Such a difference in dosage range precludes their utility for single-agent therapy of insomnia and depression or anxiety. Agents where the dosing range for depression and insomnia are not substantially different and, as a result, could be considered for this purpose include trimipramine, doxepin, amitriptyline, mirtazapine, and quetiapine. Single-Agent Therapy of Insomnia Occurring with Chronic Pain The BzRAs eszopiclone and triazolam have been found to be safe and effective for the treatment of insomnia occurring with chronic pain.3 However, as with singleagent therapy for insomnia occurring with depression, in some circumstances single-agent therapy for insomnia occurring with chronic pain is desirable. Agents with sleepenhancing effects that appear to have therapeutic effects on chronic pain include amitriptyline, doxepin, trimipramine, gabapentin, and pregabalin. Although none of these medications has been evaluated in controlled trials for the treatment of insomnia occurring with chronic pain, these agents could be considered for use when single-agent therapy for these conditions is indicated.
SUMMARY AND CONCLUSIONS A number of agents other than BzRAs are used in the treatment of insomnia. This includes agents classified as antidepressants, antipsychotics, antihistamines, anticonvulsants, melatonin agonists, herbals, and chloral hydrate and sodium oxybate. These agents vary in the extent to which studies have been carried out of their efficacy and safety in the treatment of insomnia. By and large, the empirical support for the efficacy and safety of the BzRAs is far greater than for the non-BzRA agents. Exceptions to this include doxepin, trimipramine, melatonin, and ramelteon. Each of the non-BzRA agents has unique properties that should be considered when determining whether they might be useful for treating a given patient who has insomnia. In addition, in some clinical circumstances non-BzRAs are preferred over BzRAs. Awareness of the characteristics of the non-BzRA agents and the clinical circumstances where they might be the preferred pharmacotherapy are important for optimizing the pharmacotherapy of insomnia in clinical practice.
928 PART II / Section 10 • Insomnia ❖ Clinical Pearl Although the empirical support for the efficacy and safety of BzRAs in the treatment of insomnia is generally stronger than for non-BzRAs, there are some clinical circumstances where non-BzRAs would be preferred over BzRAs, including intolerance of BzRAs, nonresponse to BzRAs, the treatment of insomnia occurring with substance-use disorders, allergyassociated sleep disturbance, insomnia occurring with psychosis, insomnia occurring with mania or hypomania, insomnia occurring with depression where single-agent therapy is desired, and insomnia occurring with chronic pain where single-agent therapy is desired.
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99. Paul I, Yoder KE, Crowell KR, et al. Effect of dextromethorphan, diphenhydramine, and placebo on nocturnal cough and sleep quality for coughing children and their parents. Pediatrics 2004;114:e85e90. 100. Smith G, Smith PH. Effects of doxylamine and acetaminophen on postoperative sleep. Clin Pharmacol Ther 1985;37:549-557. 101. Koppel C, Tenczer J, Ibe K. Poisoning with over-the-counter doxylamine preparations: an evaluation of 109 cases. Hum Toxicol 1987;6:355-359. 102. Gauillard J, Cheref S, Vacherontrystram MN, et al. Chloral hydrate: a hypnotic best forgotten? Encephale 2002;28(3 Pt. 1):200-204. 103. Piccione P, Zorick F, Lutz T, et al. The efficacy of triazolam and chloral hydrate in geriatric insomniacs. J Int Med Res 1980;8: 361-367. 104. Linnoila M, Viukari M, Numminen A, et al. Efficacy and side effects of chloral hydrate and tryptophan as sleeping aids in psychogeriatric patients. Int Pharmacopsychiatry 1980;15:124-128. 105. Scrima L, Hartman PG, Johnson FH, et al. The effects of gammahydroxybutyrate on the sleep of narcolepsy patients: a double-blind study. Sleep 1990;13:479-490. 106. Scharf M, Baumann M, Berkowitz DV. The effects of sodium oxybate on clinical symptoms and sleep patterns in patients with fibromyalgia. J Rheumatol 2003;30:1070-1074. 107. Krystal A, Ressler I. The use of valerian in neuropsychiatry. CNS Spectr 2001;6:841-847. 108. Lindahl O, Lindwall L. Double blind study of a valerian preparation. Pharmacol Biochem Behav 1989;32:1065-1066. 109. Taibi D, Vitiello MV, Barsness S, et al. A randomized clinical trial of valerian fails to improve self-reported, polysomnographic, and actigraphic sleep in older women with insomnia. Sleep Med 2009;10:319-328. 110. Jacobs B. An Internet-based randomized, placebo-controlled trial of kava and valerian for anxiety and insomnia. Medicine (Baltimore) 2005;84:197-207. 111. Coxeter PD, Schluter PJ, Eastwood HL, et al. Valerian does not appear to reduce symptoms for patients with chronic insomnia in general practice using a series of randomised n-of-1 trials. Complement Ther Med 2003;11:215-222.
Treatment Guidelines for Insomnia Michael J. Sateia and Daniel J. Buysse Abstract Treatment guidelines are evidence and consensus-based recommendations that are intended to guide clinical practice. Guidelines are particularly important in areas where multiple efficacious treatments exist but data regarding comparative efficacy may be sparse. Previous chapters have described the substantial body of evidence regarding the efficacy and safety of behavioral and pharmacologic treatments for chronic insomnia. However, despite these data, clinicians continue to use a number of less rigorously evaluated medications for the treatment of insomnia. Moreover, relatively few data are available to describe the comparative efficacy of different
THE ROLE OF CLINICAL PRACTICE GUIDELINES Clinical medicine is often characterized by uncertainties regarding diagnosis, selection of appropriate treatment, and measurement of outcomes for individual patients. The boundaries of one diagnosis versus another, even against no diagnosis at all, can be difficult to ascertain. In the field of insomnia, for instance, distinguishing a person with chronic sleep-onset insomnia from someone with delayed sleep phase disorder can be quite challenging. Likewise, multiple efficacious treatments are often available for a particular condition. This is certainly true for insomnia, with multiple behavioral and pharmacologic treatments demonstrating short-term and long-term efficacy data. What is considerably more challenging is trying to determine which treatment is best suited for which particular patient based on that patient’s preferences, the characteristics of their disorder, and the availability of treatments. Having instituted a treatment, it can also be challenging to determine when a patient has derived sufficient benefit to continue a treatment, or whether discontinuing treatment or switching to an alternate modality may be indicated. Clinical practice guidelines are designed to assist the clinician with such challenges. The Institute of Medicine (IOM) defined practice guidelines as “systematically developed statements to assist practitioner and patient decisions about appropriate healthcare for specific clinical circumstances.”1,2 Practice guidelines can be classified into a number of categories, such as assessment of therapeutic effectiveness, counseling, diagnosis, evaluation, management, prevention, rehabilitation, risk assessment, screening, technology assessment, and treatment.3 In its original report, the IOM distinguished practice guidelines from related concepts including medical review criteria, standards of quality, and performance measures. The distinctions among these concepts are summarized in Box 83-1. In addition to defining practice guidelines, the IOM also identified eight attributes of good practice guidelines. These include validity, reliability or reproducibility, clinical applicability, clinical flexibility, clarity, multidisciplinary process, scheduled review, and documentation.
Chapter
83
treatments, or the process by which a clinician should choose one treatment versus another. This chapter reviews general principles regarding the use of treatment guidelines in clinical medicine and the recommendations from the American Academy of Sleep Medicine’s clinical guideline for the evaluation and management chronic insomnia in adults. The guideline emphasizes a thorough initial evaluation of patients with chronic insomnia; first-stage treatment with either behavioral treatment or a benzodiazepine receptor agonist medication; repeated evaluations of efficacy and side effects; and changes in therapy for nonresponse. Future research will guide refinements of this initial guideline.
This outline has been widely adopted in many areas of clinical medicine, including sleep medicine. The National Guideline Clearinghouse (NGC) (www. guideline.gov) is a website supported by the Agency for Healthcare Research and Quality (AHRQ). As of January 2009, the National Guideline Clearinghouse listed more than 2400 practice guidelines from 48 recognized clinical specialties, including sleep medicine. The NGC archives, summarizes, and classifies guidelines. It also provides a number of tools including a glossary, links to related websites, and specific tools for submitting guidelines. The NGC uses a standard summary format for clinical guidelines, including categories such as methodology, recommendations, evidence supporting the recommendations, identifying information of the sponsoring organizations and authors, and availability. At the center of all clinical practice guidelines is some type of systematic review, which refers to a summary of the clinical literature providing a critical assessment and evaluation of all research studies that address a particular clinical issue.4 Systematic reviews often, but not always, include quantitative analyses of data, such as metaanalyses. In addition, practice guidelines must use some specific method for formulating recommendations. These may range from informal expert consensus, to more standardized methods such as the Delphi method, nominal group technique, or a consensus development conference.3 In applying guidelines and other methods of evidencebased medicine, it is also important to recognize that many factors beyond data from clinical trials influence clinical decision making. For example, the patient’s preferences, characteristics, and ability to implement a treatment; the clinician’s expertise; the availability of a treatment; and cost are all important considerations. As stated succinctly by Haynes and colleagues, “Evidence does not make decisions, people do.”5 The American Academy of Sleep Medicine (AASM) provides two types of documents to guide clinical decision making. The first are standards of practice parameters, which provide physicians with clear recommendations for evaluating and managing patients with sleep disorders 931
932 PART II / Section 10 • Insomnia Box 83-1 Definitions of Practice Guidelines and Related Constructs Practice Guidelines Systematically developed statements to assist practitioner and patient in forming decisions about appropriate health care for specific clinical circumstances. Medical Review Criteria Systematically developed statements that can be used to assess the appropriateness of specific health care decisions, services, and outcomes. Standards of Quality Authoritative statements of minimum levels of acceptable performance or results, excellent levels of performance or results, or the range of acceptable performance or results. Performance Measures Methods or instruments to estimate or monitor the extent to which the actions of a health care practitioner or provider conform to practice guidelines, medical review criteria, or standards of quality. Adapted from Institute of Medicine. Clinical practice guidelines: directions for a new program. Washington, DC: National Academy Press; 1990.
based on current scientific evidence in the medical literature.6 Practice parameters follow the AHRQ and NGC guidelines, and are based on exhaustive reviews of the scientific literature conducted by a task force of experts. These practice parameters undergo internal and external peer review before publication and are reviewed and updated every 3 to 5 years. The second type of guideline provided by the AASM is clinical guidelines, which are designed to provide comprehensive recommendations for evaluation, diagnosis, treatment, and follow-up for patients with sleep disorders. Clinical guidelines are designed for areas in which a lower degree of evidence may be present or in which greater individual decision making is required. Clinical guidelines incorporate the AASM’s evidence-based practice parameters and supplement them with consensus-based recommendations from a task force of experts. Clinical guidelines include methods for diagnosis, treatment options, and recommended long-term management strategies. To date, the AASM has issued two clinical guidelines, both published in the Journal of Clinical Sleep Medicine.7,8 In 2008, the AASM released its Clinical Practice Guideline for evaluating and managing chronic insomnia in adults.7 The strengths and limitations of the available evidence make this topic a very appropriate one for clinical guidelines. Strengths of the current available data include a large number of efficacy trials regarding both behavioral and pharmacologic treatments for insomnia. However, many limitations also exist. There is considerably less evidence for actual effectiveness of these trials, namely, efficacy in usual care settings. Although some case series have been reported for behavioral treatment of insomnia,9 systematic effectiveness trials are not yet available. There is also fairly limited evidence regarding the direct comparative efficacy of
different modalities of treatment, including direct comparisons of behavioral and pharmacologic treatments (see Chapter 79). There is very little systematic evidence regarding the matching of specific patient characteristics with specific treatments in order to achieve optimal outcomes. Although pharmacologic treatment efficacy trials often select patients with certain characteristics, such as sleep-onset insomnia, this is not equivalent to determining differential efficacy among subgroups of patients. Likewise, there are small studies suggesting superiority of one form of behavioral or psychological treatment versus another, but no large-scale studies have been conducted. There is very little evidence regarding true long-term outcomes of insomnia treatments. Some behavioral treatment studies have examined follow-up intervals of up to 2 years,10,11 and some purely retrospective observational studies have examined pharmacologic treatment outcomes over approximately 10 years.12 However, these do not amount to systematic examinations of long-term effectiveness in actual patient populations. Thus, the treatment of insomnia presents a combination of areas with substantial evidence, and areas of relatively little evidence, making it well-suited to the development of a clinical practice guideline.
DEVELOPMENT OF INSOMNIA CLINICAL GUIDELINES Recognizing the need for systematic guidelines in evaluating and managing insomnia, and aware of the paucity of sound evidence in many related areas, the AASM appointed a task force of content experts to develop a uniform set of recommendations for the comprehensive assessment and treatment of patients with chronic insomnia. The task force was instructed to derive evidence-based recommendations from existing practice parameters, where such parameters existed, and to develop consensus-based guidelines in the absence of these standards. The guidelines were to be based in the diagnostic classification system for insomnia of the International Classification of Sleep Disorders, second edition (ICSD-2). The consensus process began with a systematic literature review for the period 1999 to 2006 (supplementing and updating reviews of previous practice parameters). The resulting literature was reviewed for relevance and sorted by task force members, who were assigned specific areas of focus. A modified nominal group process technique was used in developing consensus. Members generated comprehensive lists of potential diagnostic and therapeutic strategies that were subsequently ranked by all task force members. Based on these rankings and subsequent discussion, specific guidelines were developed. Areas in which previous evidence-based parameters existed were not altered. The guidelines are identified as evidence-based (with level of recommendation)13 or consensus-based. Throughout the rest of the chapter, the type of recommendation— Consensus, Guideline, or Standard—is indicated in parentheses. The guidelines were reviewed by outside content experts and members of the AASM board of directors.
CHAPTER 83 • Treatment Guidelines for Insomnia 933
Consider Insufficient sleep
Insomnia symptoms
Evaluate for: • Other primary sleep disorders • Primary medical, psychiatric, and substance-induced disorders
Consider Short sleeper
Consider Insomnia due to another disorder
Evaluate for primary insomnia disorders Figure 83-1 Summary of AASM Insomnia Guideline assessment flowchart
The AASM guidelines provide recommendations for a comprehensive approach to the assessment and treatment of patients with chronic insomnia. As such, they do not address management issues for acute insomnia, nor are they directly relevant to managing insomnia in children. Evaluation The evaluation section of the guidelines is based on previously published evidence-based standards of practice14,15 and consensus of the task force. Figure 83-1 summarizes the guideline recommendations. The central tenet of this section is that “insomnia is primarily diagnosed by clinical evaluation through a thorough sleep history and detailed medical, substance, and psychiatric history” (standard). This evaluation process can be organized into three major areas: characterization of the insomnia complaint and the consequences thereof; comprehensive assessment of sleep–wake schedule, behavior, and related symptoms; and medical and psychiatric history and examination. These inquiries may be supported by a number of questionnaires and instruments that provide additional information regarding the insomnia condition, other sleep-related symptoms (e.g., sleepiness), psychological state, daytime function, and quality of life. Very little evidence exists regarding the impact of various approaches to evaluation on outcome, and therefore the specific guidelines in this area are largely consensus based. As discussed in previous chapters, ICSD-2 establishes requirements not only of a subjective complaint of sleep disturbance but also of adequate opportunity and circumstances to sleep and the presence of daytime consequences that are attributable to the insomnia condition. Characterization of the insomnia problem is, in many respects, no different from that for any symptom: What is the nature of the symptom (sleep initiation or maintenance problems or early awakening)? When and how did the problem begin (life circumstances, precipitants)? How often does it occur? Does the sleep disturbance vary over time and, if so, are there predictors of that variability (course and progression, ameliorating or exacerbating factors)? How does the condition affect the patient’s life
(daytime consequences)? What does the person do, think, and feel in response to the problem (associated attitudes and behavior)? This issue of the patient’s response to the insomnia is if particular importance in that it is an individual patient’s behavioral, cognitive, and emotional response to the sleep disturbance that strongly influences development, course, and, eventually, therapeutic outcome. Inquiry regarding previous therapeutic interventions and outcomes informs both diagnosis and future therapy. A careful history of the sleep–wake schedule, including naps, is a recommended component of the evaluation (consensus). This process is aided greatly by requesting that patients complete a sleep log or diary over a one- to twoweek period. Sample instruments are widely available. Sleep diaries are useful in several respects. Although still subjective, they tend to provide a more accurate assessment of the patient’s actual sleep–wake patterns than retrospective estimates obtained during a clinical interview. They provide information critical to the diagnosis of circadianrhythm sleep disorders and can help to shed light on associated types of behavior or patterns that serve to perpetuate the sleep problem. The guidelines advise that diaries should be obtained both before and during treatment of chronic insomnia. In addition to these features, the guidelines also emphasize the importance of assessing other sleep, psychiatric, and physical symptoms. The fundamental issue is whether there is any indication of other primary sleep disorders or comorbid medical, neurologic, or psychiatric conditions that might contribute to the insomnia complaint. The most common areas of inquiry include sleep-related breathing disorders (snoring, observed apnea, nocturnal dyspnea), movement disorders (e.g., restless legs, periodic limb movements), and parasomnias (e.g., nightmares). Further, other nocturnal medical symptoms, such as pain, gastroesophageal reflux, urinary frequency, dyspnea, cough, or hot flushes may be important comorbid factors that contribute to the insomnia. The majority of chronic insomnia is comorbid with another medical, substance, or psychiatric problem, so detailed history in each of these areas is necessary (standard). In most patients these associated disorders have been previously diagnosed, but the clinician must be attentive to the possibility of previously undiagnosed disorders, especially as depression, anxiety disorders, or occult medical problems (e.g., thyroid disease). Focused physical examination and mental status should complement the history. Finally, a review of current and previous substance use, including prescription, over-the-counter, and illicit drugs is necessary. This must also include the most widely used sleep aid, alcohol, and the most widely used stimulant, caffeine. See Chapter 77 for additional discussion of common comorbidities. Numerous questionnaires related to insomnia and comorbid conditions are available, with varying degrees of validation. The management guidelines identify several of the most widely used and well-validated instruments (consensus). The Insomnia Severity Index16 is a seven-item, patient completed questionnaire that has been applied extensively as a measure of subjective severity. The Pittsburgh Sleep Quality Index17 is a 24-item patient-reported measure of global sleep quality and disturbance. The
934 PART II / Section 10 • Insomnia
Dysfunctional Beliefs and Attitudes Scale18 helps the clinician identify maladaptive cognitions that serve to maintain the insomnia problem and can guide cognitive therapeutic interventions. The Epworth Sleepiness Scale19 represents an important tool in screening for pathologic sleepiness, the presence of which may suggest other sleep related disorders (e.g., obstructive sleep apnea) as comorbid factors in the insomnia presentation. Beyond these sleep-specific instruments, other measures such as the Beck Depression Inventory20 and the State-Trait Anxiety Inventory21 are intended to alert the clinician to comorbid psychopathology. Finally, widely used quality-of-life assessments such as the Medical Outcomes Study 36-item Short Form Survey (SF-36)22,23 and the Fatigue Severity Scale24 allow the clinician to further evaluate the degree of dysfunction and impairment associated with the insomnia condition. As for objective physiologic assessments, the guidelines reaffirm the previously established principle that polysomnography is not indicated in the routine evaluation of insomnia (standard). Polysomnography may, however, be indicated in the presence of symptoms suggesting other sleep disorders such as breathing disturbance (e.g., snoring, observed apnea), movement disorder (e.g., repetitive limb movement) or parasomnia (e.g., dream-enacting behavior). Actigraphy, a potentially useful tool for assessing possible circadian abnormalities or for tracking therapeutic outcomes, is recommended as an option. Other laboratory tests are indicated only when there is a suspicion of other medical disorders (consensus). Diagnosis The consensus guidelines for diagnosis of insomnia are based on the ICSD-2 diagnostic system. A diagnostic algorithm, based on previous published practice parameters,14,15 provides clinicians with a specific framework for the diagnostic process; multiple diagnoses can coexist. Specific insomnias and related comorbidities are discussed at length elsewhere. Treatment The guidelines for treatment consist of four sections: general principles, psychological and behavioral therapies, pharmacologic therapies, and combined treatment modalities. All but the psychological and behavioral therapy section are consensus based, because no practice parameters have been issued in other areas. The guidelines emphasize that the overall therapeutic goals are twofold: to improve sleep quantity and quality and to reduce daytime consequences of insomnia and improve function. More specific goals and treatment principles stem largely from evaluation approaches. These include ongoing assessment of specific sleep complaints (e.g., time to fall asleep, time awake after sleep onset, frequency of awakening); readministration of sleep–wake logs, questionnaires, and other instruments, tailored to the specific patient, presentation, and course of treatment; routine follow-up that is most frequent during active treatment phases (e.g., every week to month) and becomes gradually less frequent as the condition stabilizes (e.g., every 6 months). As noted earlier, we lack sufficient scientific data, at present, to clearly define optimally effective management
Insomnia disorder
Optimize treatment for other disorders
Evaluate tx options (cost, preference, availability)
Behavioral treatment
Combined behavioralpharmacological treatment
CBT-I • Evaluate tx response • Re-evaluate dx • Consider switching tx modality
Pharmacologic treatment
BzRA or ramelteon
Other behavioral treatment
Second BzRA or ramelteon
Other behavioral treatment
Sedating antidepressant
BzRA + Sedating antidepressant
Other drugs
Figure 83-2 Summary of AASM Insomnia Guideline treatment flowchart.
of chronic insomnia, especially in regard to specific therapeutic strategies. Although substantial information exists concerning the efficacy of various individual pharmacologic agents and cognitive behavioral therapies from controlled trials, we lack a clear understanding of the most appropriate first-line therapeutic interventions, whether and how various therapies should be combined, how the variability in patients’ characteristics and presentation should dictate treatment decisions, and what outcomes should be tracked. Thus, although these guidelines offer general recommendations for treatment, the clinician must recognize these inherent limitations. For these reasons, the guidelines recommend that when any individual therapeutic intervention or combination of interventions has been unsuccessful, other treatments, combinations of treatments, or reassessment must be considered. The AASM Treatment Guideline for Insomnia is summarized in Figure 83-2. Psychological and Behavioral Therapies These therapies, most often subsumed under the term cognitive behavior therapy for insomnia (CBT-I), have undergone extensive evaluation in the treatment of primary
and, to a lesser extent, comorbid insomnia (see Chapters 79 and 80 for a detailed discussion). They have welldemonstrated efficacy in reducing sleep latency, wake after sleep onset, and awakenings and in increasing sleep efficiency and total sleep time. Subjective improvements in sleep quality are also reported. Most of these outcome measures have been based on subjective reports, although a number of studies also demonstrate objective (polysomnographic) improvements, which are typically smaller. The gains derived from these treatments have been shown to be durable in follow-up studies of up to 24 months. In light of this evidence, the clinical guidelines for insomnia indicate that these treatments should be used for managing chronic primary and comorbid insomnia, including in older adults and in persons who chronically use hypnotics (standard). The standards-of-practice paper for these therapies advises that there is insufficient evidence “to recommend one single therapy over another, or to recommend single therapy versus a combination of psychological and behavioral interventions.” Nevertheless, the guidelines, consistent with the practice parameters, recommend that the therapeutic approach should include at least one intervention with the highest level of evidence (stimulus control or relaxation therapy) or combined treatment with stimulus control, sleep restriction, and cognitive therapy (with or without relaxation) (standard). Other multicomponent therapies, or sleep restriction, paradoxical intention, or biofeedback, used alone, have lesser levels of evidence but have been shown to be effective (guideline). Sleep hygiene education is employed almost ubiquitously, in various forms, in the management of insomnia. While promotion of healthy sleep practices is unquestionably a desirable goal, there is little evidence that these practices alone are efficacious in the treatment of chronic insomnia (consensus). Within the field of sleep medicine, sleep hygiene education is most often employed as a part of a multicomponent strategy, although its relative contribution, even in this application, is uncertain. Pharmacologic Therapies To date, no practice parameters on pharmacotherapy for chronic insomnia have been issued. Although there are a great many clinical trials of hypnotic medications, these are, for the most part, treatment trials of individual medications that do not fully inform us about the relative effectiveness and merits of one medication versus another or the effectiveness of these agents in comparison to other, nonpharmacologic interventions. The consensus recommendation of the chronic insomnia task force was that whenever medication is used in the treatment of chronic insomnia, it should be supplemented by CBT-I to the extent that is possible within a given treatment arena. Treatment decisions for patients with chronic insomnia are complex and should inevitably vary with the characteristics of the patient and the particular symptom presentation, comorbidities, and patient preferences. This is particularly applicable to the decision of whether to prescribe medication and, if so, what medication should be prescribed. Therefore, the guidelines state that the choice of medication should be dictated by the aforementioned considerations, as well as prior treatment
CHAPTER 83 • Treatment Guidelines for Insomnia 935
response, contraindications, and potential drug-drug interactions, side effects, and cost (consensus). Benzodiazepine receptor agonists (BzRAs), including true benzodiazepines and nonbenzodiazepine drugs, have been the most extensively studied hypnotics. Their demonstrated efficacy in these studies, coupled with the relative safety of this class as a whole, is the primary reason that BzRAs are the recommended first-line pharmacotherapy for chronic insomnia (consensus). The melatonin agonist ramelteon is also recommended as a first-line choice. The primary difference among the BzRAs is duration of action (although differences in nonhypnotic properties, e.g., in anxiolytic activity, might also result from receptor subtype specificity). The guidelines recommend that a short- to intermediate-acting agent (e.g., zolpidem, eszopiclone, zaleplon, temazepam) be used as first-line therapy. The specific choice should be dictated by the nature of the symptoms: The shortest-acting drugs such as zaleplon or ramelteon are most appropriate for isolated sleep-initiation problems, whereas agents with somewhat longer half-lives, such as eszopiclone or zolpidem CR, are more suitable for sleep-maintenance problems. When any given BzRA or melatonin agonist is not effective, an alternative medication from this class should be tried (consensus). Sedating antidepressants (ADs) have been widely used as alternatives to standard hypnotic medications, despite a limited amount of evidence supporting their efficacy or safety for this indication. These medications are not recommended as first-line pharmacotherapy, but they may be indicated as monotherapy, or in combination with other medications, when first-line treatment has not been effective (consensus). This may be especially true in the management of sleep disturbance associated with comorbid psychiatric conditions such as depression, when low-dose sedating antidepressants may be combined with therapeutic dosages of other antidepressants, or sleep disturbance associated with substance-use disorders, in which BzRAs are relatively contraindicated. Much of the available evidence regarding use of these agents, especially trazodone, is derived from such applications. Numerous other prescription medications, including antiepileptic medications (e.g., gabapentin) and antipsychotics (e.g., quetiapine), have been used for their sedating effects in comorbid disorders associated with insomnia. The guidelines note that scant evidence supports this use and recommends that these agents be employed cautiously and, in most cases, only when they have a clear therapeutic effect on the primary condition, as well as the sleep disturbance. Over-the-counter medications and nutritional supplements, with few exceptions, have not been subjected to controlled evaluation of their efficacy for chronic insomnia, nor have safety considerations been adequately addressed. Hence, these agents are not recommended in the management of chronic insomnia (consensus). Finally, certain broad recommendations apply to the use of medications for chronic insomnia. Patients must be educated about the medication, side effects, and potential complications. Clear treatment goals should be established and patients must be followed and repeatedly assessed with regard to those goals, as well as possible side effects. As
936 PART II / Section 10 • Insomnia
previously noted, psychological and behavioral therapies should be offered whenever available. Minimum dosages of medication should be used, and efforts should be made over time to reduce or discontinue medications as the clinical situation permits. In some cases, chronic administration of hypnotic medication may be necessary when other treatments have been ineffective for long-term control of the insomnia. In such cases, patients must be followed closely and reassessed periodically for emergence of complications or new comorbidities. Chronic administration may be nightly, although intermittent chronic use (e.g., every other night) has also proved efficacious. Several studies that compare individual pharmacotherapy or CBT-I to combined treatment have been conducted. The majority of these studies have been limited to comparisons of short-term hypnotic treatment with standard courses of CBT-I. They have not shown any consistent evidence of superiority of combined treatment to individual treatment (consensus). These investigations have also suggested that improvements achieved following a course of CBT-I are more sustained than those following a time-limited course of medication or (more recently) a longer course of intermittent medication use.11 No comparisons between CBT-I and longterm nightly administration of sleep medication have been conducted.25
OPEN QUESTIONS, CHALLENGES, AND FUTURE DIRECTIONS Although the AASM Clinical Practice Guideline provides a starting point for systematic clinical management for chronic insomnia, the recommendations in this guideline will change as further information becomes available. Specific areas that are likely to require revision with further information include the following: • Further evidence regarding the utility and clinical impact of various insomnia subtypes versus more general insomnia diagnosis • Evidence regarding the impact of specific patient and symptom characteristics on treatment outcome with different specific treatments • The differential efficacy of specific behavioral and pharmacologic treatments, according to specific patient characteristics • The effectiveness of common treatments in actual clinical practice • The impact of insomnia treatment on other health indicators and comorbidities • The role of newly developed pharmacologic and behavioral treatments • The applicability of specific treatments to routine care settings in clinical medicine The continued collection of systematic evidence regarding diagnosis and treatment has the potential to improve patient outcomes. In a sense, the AASM Clinical Practice Guidelines on the management of insomnia should be viewed as a reasonable first step, but certainly not the final one, in the optimal clinical management of this most common sleep disorder.
❖ Clinical Pearl Clinical guidelines aid clinicians in systematic patient evaluation, treatment, and diagnosis, particularly in conditions such as chronic insomnia, where several options or uncertainties exist. The AASM clinical guideline on chronic insomnia represents a first step toward such standardization, but it should be viewed as a living document. Future data will likely lead to more specific recommendations regarding the appropriate clinical scenarios for each type of treatment.
REFERENCES 1. Institute of Medicine. Clinical practice guidelines: directions for a new program. Washington, DC: National Academy Press; 1990. 2. Institute of Medicine. Changing the health care system: models from here and abroad. New York: National Academy Press, National Academy of Sciences; 1994. 3. The National Guideline Clearinghouse. http://www.guideline.gov/ resources/glossary.aspx Accessed September 28, 2009. 4. U.S. Department of Health and Human Services. Agency for Healthcare Research and Quality. http://www.ahrq.gov/tools.cfm Accessed September 28, 2009. 5. Haynes RB, Devereaux PJ, Guyatt GH. Physicians’ and patients’ choices in evidence-based practice. BMJ 2002;324:1350. 6. American Academy of Sleep Medicine. http://www.aasmnet.org/ Print.aspx Accessed September 28, 2009. 7. Schutte-Rodin S, Broch L, Buysse D, et al. Clinical guideline for the evaluation and management of chronic insomnia in adults. J Clin Sleep Med 2008;4:487-504. 8. Adult Obstructive Sleep Apnea Task Force of the American Academy of Sleep Medicine. Clinical guideline for the evaluation, management and long-term care of obstructive sleep apnea in adults. J Clin Sleep Med 2009;5:263-276. 9. Espie CA, Macmahon KM, Kelly HL, et al. Randomized clinical effectiveness trial of nurse-administered small-group cognitive behavior therapy for persistent insomnia in general practice. Sleep 2007;30:574-584. 10. Morin CM, Colecchi C, Stone J, et al. Behavioral and pharmacological therapies for late-life insomnia: a randomized controlled trial. JAMA 1999;281:991-999. 11. Morin CM, Vallieres A, Guay B, et al. Cognitive behavioral therapy, singly and combined with medication, for persistent insomnia: a randomized controlled trial. JAMA 2009;301:2005-2015. 12. Mendelson WB. Long-term follow-up of chronic insomnia. Sleep 1995;18:698-701. 13. Sackett DL. Rules of evidence and clinical recommendations for the management of patients. Can J Cardiol 1993;9:487-489. 14. Chesson A, Hartse K, Anderson WM, et al. Practice parameters for the evaluation of chronic insomnia. An American Academy of Sleep Medicine report. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep 2000;23:237-241. 15. Sateia MJ, Doghramji K, Hauri PJ, et al. Evaluation of chronic insomnia. An American Academy of Sleep Medicine review. Sleep 2000;23:243-308. 16. Bastien CH, Vallieres A, Morin CM. Validation of the Insomnia Severity Index as an outcome measure for insomnia research. Sleep Med 2001;2:297-307. 17. Buysse DJ, Reynolds CF, Monk TH, et al. The Pittsburgh Sleep Quality Index: a new instrument for psychiatric practice and research. Psychiatry Res 1989;28:193-213. 18. Morin CM, Vallieres A, Ivers H, et al. Dysfunctional attitudes and beliefs about sleep (DBAS): validation of a brief version (DBAS-16). Sleep 2003;26:A294. 19. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540-545. 20. Beck AT, Steer RA, Brown GK. Manual for Beck Depression Inventory II (BDI-II). San Antonio, Tex: Psychology Corporation; 1996.
21. Spielberger CD. State-trait anxiety inventory for adults: permissions set, manual, test booklet, and scoring key. Redwood City, Calif: Mind Garden; 1983. 22. Ware JE, Sherbourne CD. The MOS-36-Item short form health survey (SF-36): I. Conceptual framework and item selection. Med Care 1992;30:473-483. 23. McHorney CA, Ware JE, Raczek AE. The MOS 36-Item ShortForm Health Survey (SF-36): II. Psychometric and clinical tests of
CHAPTER 83 • Treatment Guidelines for Insomnia 937 validity in measuring physical and mental health constructs. Med Care 1993;31:247-263. 24. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989;46:1121-1123. 25. Pinto LR Jr, Alves RC, Caixeta E, et al. New guidelines for diagnosis and treatment of insomnia. Arq Neuropsiquiatr 2010;68:666-675.
Neurologic Disorders Jacques Montplaisir 84 Narcolepsy:
Pathophysiology and Genetic Predisposition 85 Narcolepsy: Diagnosis and Management 86 Idiopathic Hypersomnia 87 Parkinsonism
88 Sleep and Stroke 89 Sleep and
91 Alzheimer’s Disease and
Neuromuscular Diseases
90 Restless Legs Syndrome
and Periodic Limb Movements during Sleep
Abstract In international classifications, narcolepsy with and without cataplexy are now considered two different diagnostic entries. In almost all cases with cataplexy and in a minority of cases without cataplexy, narcolepsy is associated with a deficiency in the hypothalamic neuropeptide system hypocretin (orexin). The hypocretin deficiency can be assessed by the demonstration of very low to undetectable hypocretin-1 in the cere brospinal fluid (CSF), a test more specific than the multiple sleep latency test but only recommended in selected cases. These cases also carry the human leukocyte antigen (HLA) DQB1*0602, a subtype present in 25% of white controls, and are associated with genetic polymorphisms located in the T-cell receptor alpha (TCA) locus. Both genetic and environmental factors are implicated in predisposition to the disease. The HLA and TCA association
In its classical definition, narcolepsy is characterized by “excessive daytime sleepiness that typically is associated with cataplexy and other rapid eye movement (REM) sleep phenomena such as sleep paralysis and hypnagogic hallucinations”.1 Cataplexy, the sudden occurrence of muscle weakness in association with laughing, joking or anger, has long been considered the core pathognomonic symptom for the disorder.2-5 A broader definition of narcolepsy includes patients with sleepiness and abnormal REM sleep, such as sleep-onset REM periods (SOREMPs) during the multiple sleep latency test (MSLT), sleep paralysis, or hypnagogic hallucinations (narcolepsy without cataplexy). Disturbed nocturnal sleep is mentioned less often but is also common.2-6 The definition of narcolepsy is being revised due to rapidly evolving scientific discoveries. Studies indicate that in most narcolepsy cases with cataplexy, and in fewer cases without cataplexy, a deficiency in the neuropeptide system, hypocretin is causal.7-12 A tight genetic association with the 938
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Other Dementias 92 Epilepsy, Sleep, and Sleep Disorders 93 Other Neurological Disorders
Narcolepsy: Pathophysiology and Genetic Predisposition Emmanuel Mignot
Section
Chapter
84
indicate an autoimmune basis for the hypocretin cell destruction. Rare cases of narcolepsy secondary to genetic, tumoral, traumatic, or inflammatory disorders, many of which were shown to affect the hypothalamus or the hypocretin system, have also been reported, although it is becoming increasingly clear that decreased CSF hypocretin-1 can also occur nonspecifically in cases with severe brain pathology. Treatments to date are pharmacologically based and do not directly act on the hypocretin system. Stimulant compounds mostly increase alertness by activating dopaminergic transmission, and antidepressant therapy reduces cataplexy by increasing adrenergic transmission. The mode of action of gamma-hydroxybutyrate (sodium oxybate), a treatment for cataplexy and disturbed nocturnal sleep, is uncertain but may involve gamma-aminobutyric acid B (GABAB) receptors. Novel therapies involving hypocretin supplementation and histamine H3 antagonism are under development.
human leukocyte antigen (HLA) DQB1*0602 is also found in patients with cataplexy,13,14 suggesting an autoimmune mediation of the hypocretin cell loss. As a result, in the most recent revision of the International Classification of Sleep Disorders, narcolepsy with and without cataplexy have been separated (Table 84-1).1 Narcolepsy treatments have also rapidly evolved, yet all remain based on symptoms. Available therapeutic options support the concept of a REM sleep and sleepiness duality in the symptoms of narcolepsy.15 Excessive daytime sleepiness is typically treated by amphetamine-like stimulants or modafinil. These compounds are effective in reducing daytime sleepiness but have little effect on cataplexy and abnormal REM sleep.4 Conversely, the most commonly used anticataplectic treatments, antidepressant drugs, alleviate cataplexy and other REM sleep abnormalities but have little effect on daytime sleepiness.4 A newly approved medication, gamma-hydroxybutyric acid (GHB or sodium oxybate), is effective in alleviating disturbed nocturnal
CHAPTER 84 • Narcolepsy: Pathophysiology and Genetic Predisposition 939
Table 84-1 International Classification of Sleep Disorders CONDITION
DIAGNOSTIC CRITERIA
PATHOPHYSIOLOGY
Narcolepsy with cataplexy
Presence of definite cataplexy (and usually abnormal MSLT)
95% with hypocretin deficiency and DQB1*0602
Narcolepsy without cataplexy
MSLT: SL ≤8 min, ≥2 SOREMPs No or unclear cataplexy
Unknown, heterogeneous 16% hypocretin deficiency 40% HLA-DQB1*0602
Secondary narcolepsy
As for other forms of narcolepsy but with other conditions (e.g., neurologic)
With or without hypocretin deficiency; various disorders (see Table 84-4)
Idiopathic hypersomnia
No cataplexy, no SOREMPs during the MSLT
Unknown, likely heterogeneous
For details, see International classification of sleep disorders. Diagnostic and coding manual. Chicago: American Academy of Sleep Medicine; 2005. HLA, human leukocyte antigen; MSLT, multiple sleep latency test; REM, rapid eye movement; SL, sleep latency; SOREMP, sleep-onset REM period.
sleep, cataplexy, and to a lesser extent daytime sleepiness. In this chapter, information regarding the pathophysiology and pharmacology of narcolepsy is reviewed. The clinical, diagnostic, and therapeutic aspects are discussed elsewhere16 and are not reviewed here.
ANIMAL MODELS OF NARCOLEPSY In the last 20 years, narcolepsy research has been facilitated by the existence of a unique animal model, canine narcolepsy. Narcolepsy was first reported in two dogs by Knecht17 and Mitler18 in 1973. Early attempts to establish genetic transmission were unsuccessful, suggesting a nongenetic etiology in most cases of canine narcolepsy. In 1975, two narcoleptic Doberman pinschers were reported in a single litter.19 Subsequent breeding experiments found autosomal recessive transmission with full penetrance, allowing the establishment of a Doberman pinscher colony at Stanford University (Video 84-1). Familial canine narcolepsy was also reported in Labrador retrievers and dachshunds.19,20 Experiments indicate that animals heterozygous for the canine narcolepsy gene have subclinical abnormalities such as increased daytime sleepiness. In heterozygous animals, the administration of drugs that increase cholinergic and reduce monoaminergic transmissions (manipulations known to promote REM sleep) has been shown to induce cataplexy at specific developmental times.21 The parallel between human and canine narcolepsy is striking. In MSLT-like procedures, narcoleptic canines have been shown to have short sleep and REM latencies.15 Twenty-four–hour recording studies show increased sleep fragmentation and proportionally more daytime sleep in narcoleptic than in control animals.22 Finally, as in human narcolepsy, sudden episodes of muscle weakness akin to cataplexy can be observed in association with strong positive emotions, most typically during the presentation of appetizing food or while at play (Fig. 84-1). These episodes usually last a few seconds and preferentially affect the hind legs, neck or face. Cataplexy may also escalate into complete muscle paralysis with abolition of tendon reflexes. During these episodes, the animal is conscious and most often able to visually track nearby movement (for video, see http://med.stanford.edu/school/Psychiatry/
Figure 84-1 Narcoleptic Doberman pinschers in the middle of a cataplectic attack. Note eyes are open. Autosomal recessive forms of canine narcolepsy are due to mutations in the hypocretin receptor-2 gene.
narcolepsy/moviedog.html). Polygraphic recording indicates a desynchronized, wakelike EEG pattern at the onset of cataplexy, followed by increased theta activity and genuine REM sleep in long-lasting episodes.23 A typical picture of narcoleptic canines in the midst of a cataplectic attack is presented in Figure 84-1. The cause of autosomal recessive canine narcolepsy was identified through positional cloning.20,24 The pathology was found to be due to mutations in a receptor for the newly identified neuropeptide system hypocretin (hypocretin receptor-2). Three different mutations causing a complete dysfunction of the receptor were identified in Doberman pinscher, Labrador retriever, and dachshund pedigrees.20,24 Sporadic cases of canine narcolepsy were later shown to be associated with low CSF and almost absent brain hypocretin peptide content,25 as found in human narcolepsy.8,9 Several rodent models of narcolepsy are now also available. Chemelli and colleagues26 developed preprohypocretin knockout mice, reporting fragmented sleep and rapid transitions from wake into REM sleep. A reversible state of physical paralysis akin to cataplexy or sleep paralysis was also observed.26 In another model, a toxic transgene derived from an ataxin-3 human gene mutation, was driven by the hypocretin promoter, resulting in narcoleptic mice
940 PART II / Section 11 • Neurologic Disorders
lacking hypocretin-containing cells.27 A rat model with partial hypocretin cell loss28 and mice lacking either of the two hypocretin receptors, hypocretin-1 and hypocretin-2, are now also available.29,30 In these models, only hypocretin receptor-2 knockout animals experience behavioral arrest episodes similar to cataplexy. Interestingly however, hypocretin receptor-1 knockout animals have fragmented sleep patterns but no behavioral arrest episodes.30 It is also suggested that hypocretin receptor-2 knockout animals are less affected than hypocretin peptide knockout animals, suggesting a role for HCRTR1 in increasing the severity of the phenotype.29 The use of these new rodent models, together with developments that make it possible to increase firing rate selectively in hypocretin cells through optogenic stimulation,31 is revolutionizing research in this area. Importantly, however, whereas it is clear that rodent hypocretin models all have a narcolepsy-like phenotype, it is difficult to differentiate cataplexy from REM sleep transitions or sleep paralysis at sleep onset. The link between behavioral arrest and positive emotions is unclear, and pharmacologic characterization has not been performed in narcoleptic rodents. Further, humans are more genetically diverse than inbred rodent lines and have distinct ecological niches, most likely explaining interspecies differences in the regulation of hypocretin.32 As an example, depriving mice of food for up to 31 hours has been shown to induce wakefulness, most likely because of the acute need to search for food, an effect abolished in mice lacking hypocretin.33 Yet, metabolically, mice have high demands and low metabolic reserves, unlike humans. Further, in contrast to these results, patients with hypocretin-related narcolepsy often use food restriction to stay awake, and they have binge-eating abnormalities, especially at night.34-36 Similarly, we found that the small decreases in food intake found in rodents with hypocretin deficiency could largely be explained by wake fragmentation in these models.37 Finally, as discussed later, pharmacologic responses can vary across species. As an example, the alpha2 antagonist yohimbine is a strong wake-promoting compound and anticataplectic agent in canines, yet it has only marginal if any effect in humans.15 The hypocretin system is ancient phylogenetically. It has been found in all mammals studied to date and in amphibians and fish but not in insects. Anatomically however, in zebrafish, a teleost vertebrate, hypocretin cells do not project heavily onto monoaminergic neurons in contrast to mammals. Further, hcrtr2-mutated zebrafish have disturbed sleep but not impaired daytime activity, suggesting a somewhat distinct physiologic role,38 although this is debated.39 These results suggest substantial interspecies differences in sleep and wake regulatory networks that are important to consider in the quest to understand the function of sleep.40
PHARMACOLOGY OF NARCOLEPSY Adrenergic Uptake Inhibition Mediates the Anticataplectic Effects of Antidepressants In the past, the most commonly prescribed anticataplectic agents were tricyclic antidepressants. More recently, more selective monoaminergic reuptake inhibitors have become
available. These compounds have a complex pharmacologic profile that includes monoamine (serotonin, norepinephrine, epinephrine, and dopamine) uptake inhibition and, for older tricyclic antidepressants, cholinergic, histaminic, and alpha-adrenergic blocking effects.15,41,42 Cataplexy is difficult to quantify in humans (because it is unpredictable) and mouse models (because it is difficult to differentiate from REM sleep or sleep paralysis), but this symptom can be easily measured in narcoleptic canines using a simple behavioral tool, the food-elicited cataplexy test. In this test, pieces of dog food are lined up on the floor and the animal is released into the room.15 A normal animal will complete the test in less than 10 seconds, whereas narcoleptic subjects, excited by the food, exhibit multiple partial or complete attacks that can be recorded in number and duration. This test has been used to pharmacologically dissect the mode of action of currently prescribed anticataplectic agents.15 In narcoleptic canines, results have shown that inhibition of adrenergic but not dopaminergic or serotoninergic uptake or other properties is critical to explain therapeutic efficacy for antidepressant compounds.41,42 This observation fits well with available human pharmacologic data15 (Box 84-1). Indeed, protriptyline, desipramine, viloxazine, and atomoxetine, four adrenergic-specific uptake blockers with no effect on serotonin transmission, are effective and potent anticataplectic agents (see Box 84-1). In contrast, escitalopram, zimelidine, fluoxetine, and other selective serotonin reuptake inhibitors (SSRIs) are either inactive or only active on cataplexy at relatively high doses, an effect probably mediated by the weak adrenergic uptake effects of these compounds and their metabolites in several cases.41 Alternatively, it may be that in humans, blocking the serotonin reuptake site has minor therapeutic effects on cataplexy in contrast to canines, because of increased genetic diversity in humans or species differences. The observation that adrenergic uptake blockers are anticataplectic agents correlates well with the potent inhibitory effects of these compounds on REM sleep. It is well established that adrenergic transmission is reduced during REM sleep.43 Firing rate in the locus coeruleus has also been shown to decrease during cataplexy in narcoleptic canines.44 Adrenergic uptake blockers might thus increase activity in adrenergic projection sites involved in REM sleep regulation. This effect would reverse the effect of decreased locus coeruleus impulse flow normally occurring during natural REM sleep. The fact that serotoninergic uptake blockers, also known to have inhibitory effects on REM sleep, have less or no effect on cataplexy is more surprising. Like adrenergic cells of the locus coeruleus, serotoninergic cells of the raphe nuclei dramatically decrease their activity during REM sleep.43 This discrepancy could be explained by a preferential effect of serotoninergic projections on REM sleep features other than atonia, for example in the control of eye movements. In this model, adrenergic projections may be more important than serotoninergic transmission in the regulation of REM sleep atonia and thus cataplexy.41 In favor of this hypothesis, one experiment has shown that serotoninergic activity does not decrease during cataplexy in narcoleptic canines,45 in contrast with locus coeruleus activity.44
CHAPTER 84 • Narcolepsy: Pathophysiology and Genetic Predisposition 941
Box 84-1 Pharmacologic Properties of Commonly Prescribed Treatments Stimulants Amphetamine Increases MAO release (DA > NE >> 5-HT) Blocks MAO reuptake and MAO at high doses d-Isomer is more specific for dopaminergic transmission and is a better stimulant compound Methamphetamine More lipophilic than amphetamine Increased central penetration Proportionally fewer peripheral side effects More potent Methylphenidate Blocks MAO uptake at lower dose than amphetamine Slightly less effect on MAO release Short half-life Pemoline Inhibits dopamine uptake Low potency Hepatotoxicity Selegiline (l-Deprenyl) MAO-B inhibitor In vivo conversion into amphetamine Modafinil and Armodafinal Fewer peripheral side effects Mode of action debated Anticataplectic Compounds Venlafaxine Specific serotonin and adrenergic reuptake blocker (5-HT = NE) Very effective Some nausea
Fluoxetine Specific serotonin uptake blocker (5-HT >> NE = DA) Active metabolite norfluoxetine has more adrenergic effects High therapeutic doses are often needed Protriptyline Tricyclic antidepressant MAO uptake blocker (NE >> 5-HT > DA) Anticholinergic effects Imipramine Tricyclic antidepressant MAO uptake blocker (NE = 5-HT > DA) Anticholinergic effects Desipramine is an active metabolite Desipramine Tricyclic antidepressant MAO uptake blocker (NE >> 5-HT > DA) Anticholinergic effects Clomipramine Tricyclic antidepressant MAO uptake blocker (5-HT > NE >> DA) Anticholinergic effects Desmethylclomipramine (NE >> 5-HT > DA) is an active metabolite No specificity in vivo Other Medications Sodium Oxybate Might act via GABAB or hydroxybutyrate receptors Reduces dopamine release
via
specific
gamma-
Atomoxetine Specific adrenergic reuptake blocker (NE) Normally indicated for attention-deficit/hyperactivity disorder Also effective on daytime sleepiness DA, dopamine; GABA, gamma-aminobutyric acid; 5-HT, serotonin; MAO, monoamine oxidase; NE, norepinephrine. For details, see references 15, 40, 41, and 45-48.
Increased Dopaminergic Transmission Mediates the Wake-Promoting Effects of Currently Prescribed Stimulant Compounds Commonly prescribed stimulant compounds include amphetamine-like drugs, such as dextroamphetamine, methamphetamine, methylphenidate, pemoline, and modafinil (see Box 84-1). Like tricyclic antidepressants, amphetamine-like drugs are nonspecific pharmacologically. Their main effect is to globally increase monoaminergic transmission by stimulating monoamine release and blocking monoamine reuptake. Abuse and dose escalation can occur with amphetamine, especially in patients without cataplexy. Less abuse is reported with methylphenidate, and modafinil is not believed to be addictive.
Studies have shown that the wake-promoting effect of these compounds is secondary to stimulation of dopamine release and inhibition of reuptake.46,47 The mode of action of modafinil is debated, but this compound also selectively inhibits dopamine uptake.48 All these compounds are ineffective in dopamine transporter knockout mice, suggesting a primary mediation of wake promotion via dopaminergic systems.47 Interestingly, compounds selective for dopaminergic transmission have no effect on cataplexy, whereas amphetamine-like compounds with combined dopaminergic and adrenergic effects have some anticataplectic properties at high doses.41,49 Adrenergic effects of amphetamine-like stimulants also correlate with the respective effects of these compounds on normal REM sleep.15,49 Dopaminergic-specific uptake blockers have
942 PART II / Section 11 • Neurologic Disorders
little effect on REM sleep when compared to adrenergic or serotoninergic compounds.15 The most important effects of dopaminergic uptake blockers are to reduce total sleep time and slow-wave sleep.50 This preferential effect of dopaminergic uptake blockers on non-REM (NREM) sleep correlates with electrophysiologic data. As opposed to adrenergic or serotoninergic neurons, the firing rate of dopaminergic neurons is known to remain relatively constant during REM sleep.51,52 Interestingly, studies in humans and narcoleptic canines have shown that large doses of stimulants are needed to polygraphically normalize narcoleptic subjects. In our narcoleptic Doberman population, doses equivalent to 60 mg/day were needed to reduce daytime sleep to control levels.22 In both control and narcoleptic animals, however, the dose-response curves for modafinil or amphetamine were parallel. This result suggests that there is no difference in sensitivity to stimulants in narcoleptic animals but rather that higher doses are needed in narcoleptic animals because of their extreme baseline sleepiness.22 However, one study has suggested increased wake-promoting effects of modafinil in rodents with hypocretin deficiency.53 Sodium Oxybate (Gamma-Hydroxybutyrate) Sodium oxybate, also called gamma-hydroxybutyrate (GHB), is a sedative anesthetic compound known to increase slow-wave sleep and, to a lesser extent, REM sleep.15 Abuse in the context of rave parties has been reported, and prescription of the compound is highly regulated, with centralized distribution. Because slow-wave sleep is associated with growth hormone (GH) release, GHB also induces GH release and has been abused by athletes. When administered at night, it consolidates sleep and improves daytime functioning. Because of its short half-life (~30 min), it must be administered twice a night. Interestingly, cataplexy and daytime alertness also improve over time, sometimes producing a full therapeutic effect only after several months of treatment and dose adjustments.16 The mode of action of GHB on sleep and narcolepsy is unclear. GHB has a major effect on dopamine transmission, reducing firing rate and raising brain content of dopamine.15,54 Other effects on opioid, glutamatergic, and cholinergic transmission have been reported.54 Specific GHB receptors have been identified, but the compound is also a GABAB agonist.54 Most studies to date suggest that the sedative-hypnotic effect is mediated via GABAB agonist activity.54,55 Whether this effect also mediates the anticataplectic effects after long-term administration is unknown. Other Known Modulators of Narcolepsy Symptoms The effects of more than 200 compounds with various modes of action have been examined in human patients and narcoleptic canines.15 In almost all cases except a few, similar effects were found in humans and canines.15 Almost all the effects have been reported for monoaminergic and cholinergic compounds. With cataplexy being easier to study than sleep in canines, most studies have also focused on cataplexy rather than sleepiness. For cataplexy, the findings were generally consistent with pharmacologic studies
of REM sleep. As is the case for REM sleep, the regulation of cataplexy is modulated positively by cholinergic systems and negatively by monoaminergic tone.15 Muscarinic M2 or M3 receptors mediate the cholinergic effects, and monoaminergic effects are mostly modulated by postsynaptic adrenergic alpha1 receptors and presynaptic D2 or D3 autoreceptors.15 A number of studies have shown abnormal cholinergic and monoaminergic receptor density and neurotransmitter levels in brain and CSF samples human or canine narcolepsy.15,56-68 Local injection studies in selected brain areas of narcoleptic canines have also shown functional relevance for some of these abnormalities.69-71 As a result, cholinergic hypersensitivity, dopaminergic abnormalities, and decreased histaminergic tone are likely to be critical downstream mediators of the expression of the narcolepsy symptomatology.68-71 The cholinergic and monoaminergic imbalances observed in narcolepsy are best illustrated by the finding that in asymptomatic animals heterozygous for the hcrtr2 mutation, a combination of cholinergic agonists with an alpha1 blocker or a D2 or D3 agonist can trigger cataplexy.21 A possible application of these findings is illustrated by the recent development of histaminergic H3 antagonists, drugs that are known to stimulate histamine release via the H3 receptor, as novel wake-promoting stimulants for the treatment of narcolepsy.72
HYPOCRETIN AND INVOLVEMENT IN NARCOLEPSY Anatomy and Physiology of the Hypocretin Neuropeptide System The hypocretin/orexin system was discovered almost simultaneously by two groups of scientists, hence the two conflicting names. De Lecea and colleagues first isolated the prepro-hypocretin transcript (clone 35) and suggested the existence of two resulting processed neuropeptides sharing extensive homology with each other and weak homology with secretin.73 These neuropeptides were called Hypocretin 1 and Hypocretin 2, to indicate hypothalamic peptides of the incretin family. Using cell lines expressing various orphan G protein–coupled receptors (GPCR), Sakurai and coworkers screened tissue extracts for GPCR agonist activity.74 Two mature peptides stimulating the orphan HFGAN72 GPCR cell line were isolated and called Orexin-A and B.74 The name was chosen from Greek orexis (“appetite”) based on associated studies suggesting stimulation of appetite after central administration. A second receptor with high homology with HFGAN72 was also identified by homology. The two G protein– coupled receptors were initially called orexin receptor 1 and 274 but their official names are HCRTR1 and HCRTR2 in genetic databases. HCRTR1 (OxR1) binds hypocretin-1 (OxA) selectively, whereas HCRTR2 (OxR2) binds both hypocretin-1 (OxA) and hypocretin-2 (OxB) with similar affinity.74 The two receptors mostly couple with Gq and stimulate cellular activity in most cell types.75-77 Only a few thousand cell bodies containing these two peptides are found in the entire brain, all within the perifornical area of the posterior hypothalamus. Contrasting with this discrete perikaria localization, the neurons project widely in the central nervous system.75-77 Limbic system
CHAPTER 84 • Narcolepsy: Pathophysiology and Genetic Predisposition 943
areas (including amygdala and nucleus accumbens), monoaminergic cell groups (adrenergic locus coeruleus, serotoninergic raphe nuclei, dopaminergic ventral tegmental area and substantia nigra, histaminergic tuberomammillary nuclei), intrahypothalmic nuclei, and various periventricular organs are densely innervated.75-77 Hypocretin immunoreactive varicose terminals are also seen in the cerebral cortex, spinal cord, and thalamus. The strongest extrahypothalamic prepro-hypocretin immunoreactive projection is found in the locus coeruleus. Hypocretin has also been suggested to be present in selected peripheral tissue (testis, gut) at very low levels of expression. Hypocretin Deficiency and Human Narcolepsy and Cataplexy As expected from the observation that most cases of human narcolepsy are sporadic and not fully genetic, as in dogs or mice, an extensive genetic screening study did not identify numerous prepro-hypocretin, hcrtr1, or hcrtr2 mutations in human narcolepsy.8,78,79 Surprisingly, even familial cases of narcolepsy (some of which were HLA-DQB1*0602 negative) did not have any hypocretin mutations, suggesting further heterogeneity in genetic cases.8 Rather, only a single case with a signal peptide mutation of the preprohypocretin gene was identified. This case has an extremely early onset (6 months), severe narcolepsy and cataplexy, DQB1*0602 negativity, and undetectable levels of hypocretin-1 in cerebrospinal fluid (CSF).8 This observation indicates that hypocretin system gene mutations can cause narcolepsy, as in animal models. Following on the cloning of the canine narcolepsy gene, we have also found that most patients who have sporadic HLA-DQB1*0602–positive narcolepsy with cataplexy have undetectable hypocretin-1 levels in the CSF.7-12,80 Follow-up neuropathologic studies in 10 narcoleptic patients also indicated dramatic loss of hypocretin-1, hypocretin-2, and prepro-hypocretin mRNA in the brain and hypothalamus of narcoleptic patients (Fig. 84-2).8,9 These subjects have no hypocretin gene mutations and a peripubertal or postpubertal disease onset81 as opposed to a 6-month onset in patients with a prepro-hypocretin mutation.8 Together with the tight HLA association,13,14 a likely pathophysiologic mechanism in most narcolepsy patients could thus involve an autoimmune alteration of hypocretin-containing cells in the CNS. Hypocretin Transmission in Sleep Regulation The potential role of hypocretin in the regulation of normal sleep is only beginning to emerge. Central (intracerebroventricular or local injections) but not peripheral administration of hypocretin-1 stimulates wakefulness and reduces REM sleep. Hypocretin antagonists promote NREM and REM sleep, including in humans. In rats and monkeys, cisternal CSF hypocretin-1 fluctuates, with maximal levels at the end of the active period (night in rodents) and minimum levels at the end of the inactive period (amplitude is 40%).82 Using in vivo dialysis, a similar profile is observed in rat brain tissue extracellular fluid.83 In diurnal, wake-consolidated squirrel monkeys, cisternal hypocretin-1 levels also peak in the late evening, around bedtime (amplitude ≥40%).84 These results suggest
NARCOLEPTIC CONTROL
f
1 cm
f
1 cm
Figure 84-2 Hypocretin (hcrt) and melanin-concentrating hormone (MCH) expression studies in the hypothalamus of control and narcoleptic subjects. Hypocretin and MCH neurons are intermingled in this region of the hypothalamus. Staining of adjacent brain sections for MCH is shown for comparison as a control. Prepro-hypocretin mRNA molecules are detected in the hypothalamus of control (right) but not narcoleptic subjects. MCH mRNA molecules are detected in the same region in both control and narcoleptic sections. f, fornix. Scale bar represents 10 mm. (Derived from Peyron C, Faraco J, Rogers W, et al. A mutation in a case of early onset narcolepsy and a generalized absence of hypocretin peptides in human narcoleptic brains. Nat Med 2000;6[9]:991-997, with modifications.)
that hypocretin may be important to promote wakefulness in the evening in humans. In this model, hypocretin would oppose the sleep debt that has accumulated since early morning, allowing a constant level of wakefulness through the day.84 Additional studies suggest that diurnal fluctuations in hypocretin release are driven both directly by the circadian clock and indirectly by the increased sleep debt.32 It is also still uncertain at this stage how hypocretin release and activity fluctuates across the various sleep stages (REM versus NREM). In lumbar CSF, hypocretin-1 only has limited diurnal fluctuation (10%), suggesting a dampening and delay of changes when reaching the lumbar sack (minimal levels in morning).85,86 This finding is important practically because time of CSF collection has no significant effect for purposes of diagnosing narcolepsy.10,87 The most dense reported hypocretin projections are to the monoaminergic cell groups of the locus coeruleus (norepinephrine), substantia nigra and ventral tegmental area (dopamine), raphe magnus (serotonin), and tuberomammillary (histamine) neurons. Dopamine and histamine cell groups have one of the highest densities of hypocretin-2 receptors88 and may be especially important.75-77,89 Increased dopamine level in the amygdala is one of the most consistent neurochemical abnormalities reported in canine narcolepsy.56,58 Decreased histamine levels are also observed in the brain of narcoleptic canines.68 In vivo dialysis studies have indicated a critical role for the dopamine mesolimbic and mesocortical system in regulating alertness and triggering cataplexy by emotions. Histaminergic transmission has long been recognized as a critical wake-promoting neurotransmitter.90 Dopamine and histaminergic projections may thus be centrally involved in controlling both cataplexy and alertness.
944 PART II / Section 11 • Neurologic Disorders
Similar to REM sleep, cataplexy is controlled by pontine cholinergic REM-on cells and aminergic locus REM-off cells.15 Removing hypocretin-excitatory projections to monoamine cell groups could decrease monoaminergic tone and produce a cholinergic-aminergic imbalance consistent with sleepiness and abnormal REM sleep in narcolepsy. Hypocretin projections to the basal forebrain area, an area with cholinergic hypersensitivity in narcoleptic animals, are also likely to be involved.69,70 It is also likely that hypocretin is critical to the integration of sleep regulation with metabolic status, although the importance of this effect could depend on the species.
GENETIC ASPECTS OF HUMAN NARCOLEPSY Familial Aspects of Human Narcolepsy The familial occurrence of narcolepsy and cataplexy was first reported in 1877 by Westphal.91 Since then, numerous case reports have appeared in the literature. Until recently, narcolepsy was considered a familial disorder. More recent studies have shown that earlier reports were often confounded by unrecognized obstructive sleep apneas. One frequently cited publication by Krabbe and Magnussen92 reports that “narcoleptic” (obese) relatives of a narcoleptic proband would frequently fall asleep while playing cards, falling forward on the table, snoring loudly and becoming cyanotic during the episodes. In more recent studies, the risk of a first-degree relative to develop narcolepsy and cataplexy has been shown to be only 1% to 2% (see reference 93 for review). A larger portion of relatives (4% to 5%) may have isolated daytime sleepiness, when other causes of daytime sleepiness have been excluded.93 These figures are important to keep in mind because they are helpful in reassuring patients regarding the risk to their children and relatives. A 1% to 2% risk is 10- to 40-fold higher than in the general population but remains manageable. A 4% to 5% risk for daytime sleepiness is not negligible, but similar values have been reported for excessive daytime sleepiness in the general population independent of narcolepsy.94-96 Twin Studies and Environmental Factors in Narcolepsy The only systematic twin study available was performed by Hublin and colleagues in white Finns.96 All three twins identified were from dizygotic pairs, so the protocol was not informative to establish concordance in monozygotic twins. Twenty monozygotic twin reports are available in literature (see reference 93 for review). Five to seven are discordant for narcolepsy, depending on how strictly concordance is determined clinically.93,97-99 Most cases of human narcolepsy therefore require the influence of environmental factors for the pathology to develop. This is also substantiated by the fact that onset is not at birth but rather in adolescence,6,81 suggesting the existence of triggering factors. The nature of the environmental factor involved is still unknown. Factors often cited are head trauma,100-102 sudden change in sleep–wake habits98,103 or various infections.104,105 These factors may be involved, but studies all use a retrospective design, limiting the value of any reported differ-
ence. Some studies have suggested increased incidence of narcolepsy in persons born in March and decreased incidence in persons born in September, suggesting the influence of perinatal factors,81,106,107 as reported in other autoimmune diseases. Human Narcolepsy, Human Leukocyte Antigen, and the Immune System The observation that narcolepsy is associated with HLA DR2 and DQ1 was first reported in Japan in 1983.108,109 It was quickly confirmed in Europe and North America; 90% to 100% of all patients with cataplexy carry the HLA DR2 subtype.13,14,110-116 Because many diseases associated with HLA (also called major histocompatibility complex [MHC]) are known to be autoimmune diseases, this discovery led to the hypothesis that narcolepsy might result from an autoimmune insult within the CNS. The finding of hypocretin cell loss in human narcolepsy8,9 suggests that the autoimmune process could target this small population of hypothalamic neurons. Attempts at verifying an autoimmune mediation have generally been disappointing.116-120 Human narcolepsy is not associated with any striking pathologic changes in the CNS or with increased incidence in the occurrence of oligoclonal bands in the CSF.116-119 Gliosis in brains of human narcoleptics has been reported8,9,121 but remains controversial, as are imaging findings suggesting macroscopic hypothalamic changes.122-124 Similarly, peripheral immunity does not seem to be altered even around disease onset.116,117 Lymphocyte CD4/CD8 populations, various autoantibody levels, erythrocyte sedimentation rate, and C-reactive protein are within the normal range and were found not to change up to a year after disease onset. Since this discovery, HLA DR and DQ typing has changed from serologic to molecularly based, and the broad DR2 and DQ1 subtypes have been further divided into DR15, DQ6, and then DRB1*1501, DQA1*0102, and DQB1*0602 (Fig. 84-3). The key gene involved was next found to be DQB1*0602, a subtype of DQ1. This is especially important in African-American patients, many of whom are DQB1*0602 positive but DR2 negative.13,14,125,126 Subjects were also found to be DQA1*0102 positive,13,14,125,126 a less-specific marker than DQB1*0602. Novel DNA markers developed in the HLA DQ region have been tested to further map the narcolepsy susceptibility region within the DQA1-DQB1 interval.127,128 This segment was entirely sequenced and shown to contain no new genes.128 It is also worth noting that in all narcolepsy susceptibility DR-DQ haplotypes identified, both DQA1*0102 and DQB1*0602 are present,125 thus suggesting that the active DQA1*0102/DQB1*0602 heterodimer is necessary for disease predisposition. A number of other DR-DQ haplotypes in the population carry DQA1*0102 without DQB1*0602, and those do not predispose to narcolepsy.126 Conversely, although DQB1*0602 subjects are almost always DQA1*0102 positive, rare haplotypes with DQB1*0602 but without DQA1*0102 are observed in the control population but not in narcoleptic patients.126 Both the DQA1*0102 and the DQB1*0602 alleles might thus be needed for predisposition.126 Findings in families and in unrelated patients also suggest that most if not all the DQB1*0602/DQA1*0102
CHAPTER 84 • Narcolepsy: Pathophysiology and Genetic Predisposition 945
DQA1
DQB1 12 Kb Serologic typing
DRB1 85 Kb
DQ6 DNAbased typing DQB1*0602 and DQA1*0102
DR5
DR2
DQ1
DQ5
DR15
DR16
DR11
DR12
Other DQB1*06 DRB1*1502 and DQA1*01 (Asians) subtypes DRB1*1101 DRB1*1501 African Americans (Whites and Asians) DRB1*1503 (African Americans)
Figure 84-3 Human leukocyte antigens (HLAs) DR and HLA DQ alleles typically observed in narcolepsy. The genes for the DR and DQ alleles are located very close to each other on chromosome 6p21. These genes encode heterodimeric HLA proteins composed of an α and a β chain. In the DQ locus, both the DQα and DQβ chains have numerous polymorphic residues and are encoded by two polymorphic genes, DQA1 and DQB1, respectively. Polymorphism at the DR(αβ) level is mostly encoded by the DRB1 gene, so only this locus is depicted in this figure. DQB1*0602, a molecular subtype of the serologically defined DQ1 antigen, is the most specific marker for narcolepsy across all ethnic groups. It is always associated with the DQA1 subtype, DQA1*0102. In whites and Asians, the associated DR2 subtype DRB1*1501 is typically observed with DQB1*0602 (and DQA1*0102) in narcoleptic patients. In African Americans, either DRB1*1503, a DNA-based subtype of DR2, or DRB1*1101, a DNA-based subtype of DR5, are most often observed together with DQB1*0602. Other DRB1 alleles (DRB1*0301, DRB1*0806, DRB1*08del, DRB1*12022 and DRB1*1602) have been observed together with DQB1*0602 in much rarer cases.
alleles present in the population predispose equally to narcolepsy. One such finding comes from multiplex families, in which several patients are DQB1*0602 positive. In many cases, DQB1*0602 has been inherited from different branches of the family (for example in one case from the father and the other case from the mother) and are thus not identical by descent (IBD).93 It has been shown that subjects homozygous for DQB1*0602 have a twofold to fourfold increased risk for developing narcolepsy when compared to DQB1*0602 heterozygotic subjects.14,128 Finally, risk in DQB1*0602 heterozygotic persons is modulated by the other DQB1 allele. Most notably, risk is increased in DQB1*0602/DQB1*0301 heterozygotes and reduced in DQB1*0602/DQB1*0601 and DQB1*0602/ DQB1*0501 heterozygotes.14,129 Overall, the data accumulated to date strongly suggest that the HLA-DQ alleles themselves (most notably DQB1*0602 and DQA1*0102) rather than a yet-unknown genetic factor in the region predispose to narcolepsy. Human Leukocyte Antigen and Narcolepsy in Clinical Practice The usefulness of HLA typing in clinical practice is limited by several factors. First, the HLA association is very high (greater than 90%) only in narcoleptic patients with clearcut cataplexy.13 Clear-cut cataplexy is defined as episodes of muscle weakness triggered by laughter, joking, or anger. Muscle weakness episodes triggered by anger, stress, other negative emotions or physical or sexual activity might not
be cataplexy if joking or laughing is not also mentioned as a triggering factor.4 In patients without cataplexy or with doubtful cataplexy, HLA DQB1*0602 frequency is also increased (40% to 60%) but many patients are DQB1*0602 negative.13 Secondly, a large number of controls (approximately 12% in Japanese, 25% in whites and Chinese, 38% in African Americans) have the HLA DQB1*0602 marker without having narcolepsy. Finally, a few rare patients with clear-cut cataplexy do not have the HLA DQB1*0602 marker.130 Despite these limitations, HLA typing is probably most useful in atypical cases or in narcolepsy without definite cataplexy. A negative result should lead the clinician to be more cautious in excluding other possible causes of daytime sleepiness such as abnormal breathing during sleep. In practical terms, it is always more useful to request HLA DQB1*0602 high-resolution typing rather than DR typing to confirm the diagnosis of narcolepsy. If a patient is homozygous for DQB1*0602, the narcolepsy diagnosis is even more probable. A study has shown that 18% to 30% of narcoleptic subjects are DQB1*0602 homozygous versus 0% to 4% in African-Americans and white controls.14,128 In whites, DR2 and DQB1*0602 typing is almost equivalent, and it is probably unnecessary to retype patients who have been shown to be DR2 (or DR15, or DRB1*1501) positive using serologic typing techniques. Most white subjects with DR2 are also DQB1*0602 positive, but the situation is somewhat different in Asians and African Americans. It is not necessary to test for DQA1*0102, because almost all subjects with DQB1*0602 are also DQA1*0102 positive. Most HLA typing laboratories also do not routinely type for DQA1. HLA DQB1*0602 Negativity HLA DQB1*0602-negative subjects with typical and severe cataplexy have been reported, but these subjects are exceptionally rare.130 An increase in DQB1*0301 has been suggested in these cases but needs further substantiation.14 Most of these patients have normal CSF hypocretin-1, suggesting a different pathophysiology (Fig. 84-4).10 Interestingly, two partially concordant monozygotic twins reported in the literature were DQB1*0602 negative.93 A number of DQB1*0602 negative families (with normal CSF hypocretin-1) have been reported in which narcolepsy with cataplexy seems to be transmitted as a highly penetrant autosomal dominant trait, and many patients experience narcolepsy and cataplexy whereas other family members have sleepiness and documented REM abnormalities during the MSLT.10,93 These results emphasize the fact that HLA typing and CSF hypocretin-1 results should be interpreted in conjunction with a careful family history. HLA DQB1*0602-negative subjects with cataplexy have also been reported in the context of posttraumatic narcolepsy in the United States.99 This finding would need confirmation in other cultures because the issue could easily be confounded by medicolegal factors in North America. Genetic Factors other Than Human Leukocyte Antigen Genetic factors other than HLA-DQ and DR are likely to be involved in predisposition to narcolepsy. The increased
946 PART II / Section 11 • Neurologic Disorders 700
Lumbar CSF hypocretin-1 (pg/mL)
600 500
59% (41)
92% (37)
31% (22) 10% (7)
8% (3)
100% (9)
91% (84) 7% (6) 2% (2)
nt ro
Co
Co
nt ro
ls (5 6 HL A– ls ( ) Na 18 rc H o LA w/ +) C Na at rc (H o LA w/ Na –) C at rc o ( H w/ L A+ o Na Ca ) rc t o w/ (HL A– o Ca ) t( HL A+ ) IH (H LA –) IH (H LA +) KL S OS (8) AS (3 6) RL S ( In so 20) m ni a( 9)
0
6% (13)
100
93% (192) 1% (1)
200
81% (22)
300
7% (2) 11% (3)
400
Figure 84-4 Lumbar cerebrospinal fluid (CSF) hypocretin-1 concentrations in controls versus subjects with narcolepsy and other sleep disorders (from an update of the Stanford Center for Narcolepsy Research database). Each point represents the concentration of hypocretin-1 as measured in unextracted lumbar CSF of a single subject. Subjects are differentiated according to HLA DQB1*0602 status and include controls; samples were taken during both night and day. Patients are classified according to the International Classification of Sleep Disorders,1 but cases without cataplexy are subdivided into cases with atypical (triangle) and no cataplexy (squares). Clinical subgroups include narcoleptic subjects (Narco) with (w) and without (w/o) cataplexy, idiopathic hypersomnia (IH), periodic hypersomnia (KLS; Kleine-Levin syndrome), obstructive sleep apnea syndrome (OSAS), restless legs syndrome (RLS), and insomnia. Secondary narcolepsy/hypersomnia cases are not included. In the text, levels are described as low (<110 pg/mL), intermediate (111-200 pg/mL), or normal (>200 pg/mL). Note that these values are largely artificial and are meant to represent approximately 30% of mean control value as tested in a given center using direct radioimmunoassay and a set of healthy controls. Mean CSF hypocretin-1 concentration was not significantly different between HLA DQB1*0602-positive and HLA DQB1*0602-negative controls. The percentage and number of subjects is specified for each group of subjects according to the two CSF hypocretin thresholds. (Data derived from Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol 2002;59[10]:1553-62; Bassetti C, Gugger M, Bischof M, et al. The narcoleptic borderland: a multimodal diagnostic approach including cerebrospinal fluid levels of hypocretin-1 (orexin A). Sleep Med 2003;4[1)]7-12; Hong SC, Lin L, Jeong JH, et al. A study of the diagnostic utility of HLA typing, CSF hypocretin-1 measurements, and MSLT testing for the diagnosis of narcolepsy in 163 Korean patients with unexplained excessive daytime sleepiness. Sleep 2006;29[11]:1429-38; and Lin L, Mignot E. Human leukocyte antigen and narcolepsy: Present status and relationship with familial history and hypocretin deficiency. In: Bassetti C, Billiard M, Mignot E, editors. Narcolepsy and hypersomnia. New York: Informa Health Care; 2007. p 411-426.)
familial risk in first-degree relatives (10-fold in Japanese, 20-fold to 40-fold in whites) cannot be explained solely by the sharing of HLA subtypes, estimated to explain a twofold to threefold increased risk.93 Additionally, the existence of HLA-negative families suggests disease heterogeneity and the possible involvement of other genes. Linkage
analysis in HLA-DQB1*0602-positive Japanese families has suggested the existence of a susceptibility gene on 4q13-23.131 A possible association with tumor necrosis factor α (TNF-α) gene polymorphism (independent of HLA) has also been suggested.132-134 Other results indicate that a polymorphism in the catechol-O-methyltransferase (COMT) gene, a key enzyme in the degradation of catecholamines, might also modulate disease severity.135,136 More recently, studies have moved toward systematic genome coverage using genome-wide association (GWA) designs.137,138 In the study of 222 patients and 389 controls and replication in 159 patients versus 190 controls, Miyagawa’s group139 found involvement of rs5770917, a polymorphism located between CPT1B and CHKB, two genes that regulate cholinergic metabolism or beta-chain fatty acid oxidation, respectively. A similar effect of rs5770917 (and a significant HLA association) was also observed in cases with essential hypersomnia syndrome, a milder form of narcolepsy without cataplexy defined in Japan by sleepiness, refreshing naps, and no cataplexy,138 suggesting a disease continuum. Although the effect occurs weakly in Koreans,139 the same polymorphism had no effect in a large sample of whites.140 In a second, larger GWA study in whites, Hallmayer140 found a solid association with polymorphisms in the T-cell receptor α (TCRA) locus, with highest significance at rs1154155 (average allelic odds ratio [OR], 1.69; genotype OR 1.94 and 2.55, P < 10-21, 1830 subjects, 2164 controls). In contrast to the Miyagawa study,139 the finding replicated extremely strongly in all ethnic groups, most notably Asians. Surprisingly, it is the first documented genetic involvement of the TCRA locus, the major receptor for HLA-peptide presentation, in any disease. In contrast to HLA (which can be expressed in many cells), the T-cell receptor protein is only expressed in T lymphocytes, thus this finding demonstrates that narcolepsy must be autoimmune or immune related. Because it is still unclear how specific HLA alleles confer susceptibility to more than 100 HLA-associated disorders,141 narcolepsy will provide new insights on how interactions between HLA and T-cell receptors contribute to organ-specific autoimmune targeting.
CLINICAL OVERLAPS OF THE HYPOCRETIN DEFICIENCY SYNDROME CSF Hypocretin-1 Testing in Narcolepsy The observation that cerebrospinal fluid (CSF) hypocretin-1 levels are decreased in patients with narcolepsy provides a new test to diagnose this disorder (Table 84-2, Fig. 84-4). Using a large sample of patients and controls, we have conducted a quality receiver operating curve (QROC) analysis to determine the CSF hypocretin-1 values most specific and sensitive to diagnose narcolepsy.10 A cutoff value of 110 pg/mL was the most predictive overall (30% of mean control values). A majority of samples had undetectable levels (less than 40 pg/mL in most assays), and a few samples had detectable but very diminished levels. None of the patients with idiopathic hypersomnia, sleep apnea, restless legs syndrome, or insomnia had
CHAPTER 84 • Narcolepsy: Pathophysiology and Genetic Predisposition 947
Table 84-2 Sensitivity and Specificity of Diagnostic Tests NARCOLEPSY WITH CATAPLEXY TEST
SENSITIVITY‡
SPECIFICITY§
NARCOLEPSY WITHOUT CATAPLEXY* SENSITIVITY‡
SPECIFICITY§
IDIOPATHIC HYPERSOMNIA† SENSITIVITY‡
SPECIFICITY§
HLA
89.3% (822/1291)
76.0% (1291)
45.4% (306/1291)
76.0% (1291)
17.7% (62/1291)
76.0% (1291)
MSLT
87.9% (964/1095)
96.9% (1095)
N/A
96.9% (1095)
N/A
96.9% (1995)
Hcrt ≤ 110 pg/mL
83.3% (233/182)
100%
14.8% (162/182)
100%
0.0% (49/182)
100%
Hcrt ≤ 200 pg/mL
85.0% (233/182)
98.9%
22.8% (162/182)
98.9%
6.1% (49/182)
98.9%
CSF, cerebrospinal fluid; Hcrt, CSF hypocretin-1; HLA, human leukocyte antigen; MSLT, multiple sleep latency test; N/A, not applicable as part of the clinical definition; SOREMP, sleep-onset REM period; CSF hypocretin-1 data from the Stanford Center for Narcolepsy Research database and CSF from healthy control subjects (volunteers or subjects undergoing spinal surgery). HLA data from the Stanford Center for Narcolepsy Research database and ethnically matched controls: Mignot E, Lin L, Rogers W, et al. Complex HLA-DR and -DQ interactions confer risk of narcolepsy-cataplexy in three ethnic groups. Am J Hum Genet 2001;68:686-699. MSLT data from the Stanford Center for Narcolepsy Research database, and 1095 random controls from Mignot E, Lin L, Finn L, et al. Correlates of sleep-onset REM periods during the multiple sleep latency test in community adults. Brain 2006;129(Pt. 6):1609-1623; and Singh M, Drake CL, Roth T. The prevalence of multiple sleep-onset REM periods in a population-based sample. Sleep 2006;29:890-895. *Narcolepsy with atypical and no cataplexy are grouped as narcolepsy without cataplexy per American Academy of Sleep Medicine. International Classification of Sleep Disorders, 2nd ed, Diagnostic and Coding Manual. Westchester, Ill: American Academy of Sleep Medicine; 2005. † Idiopathic hypersomnia includes both patients as defined by a positive MSLT or with prolonged sleep time independent of MSLT results. A positive MSLT is a mean sleep latency ≤8 min and ≥2 SOREMPs for narcolepsy without cataplexy, and mean sleep latency ≤8 min and <2 SOREMPs in idioathic hypersomnia per American Academy of Sleep Medicine. International classification of sleep disorders, 2nd ed, Diagnostic and coding manual. Westchester, Ill: American Academy of Sleep Medicine; 2005. ‡ Numbers in parentheses indicate the number of patients and the corresponding number of controls used to calculate sensitivity. § Numbers in parentheses indicate the number of controls used to calculate specificity.
abnormal hypocretin levels. This study has now been updated to include a significantly larger sample (see Fig. 84-3). Testing in Narcolepsy with Cataplexy Using the 110 pg/mL cutoff, the measurement was especially predictive in patients with definite cataplexy (100% specificity, 83% sensitivity). Sensitivity and specificity are higher for this test than for the MSLT (see Table 84-2). In most case series, approximately 12% of subjects who have narcolepsy with cataplexy or hypocretin deficiency do not have a positive MSLT. For the patient, the diagnostic value of CSF hypocretin-1 measurements needs to be weighed against the trauma associated with obtaining cerebrospinal fluid. Lumbar punctures are well known to be safe, but post–lumbar puncture headaches are often observed.142 Such headaches are positional, possibly severe, and can last several days. They are always self-limited and rarely require a blood patch. In our experience, headaches are manageable if patients are clearly warned of such risks and are told that lying down almost always relieves symptoms, at least temporarily. Using a double-needle atraumatic technique, which facilitates dural puncture with a 24- to 25-gauge blunt needle, also decreases the likelihood of post–lumbar puncture headache to 2%. We do not advocate testing CSF hypocretin-1 levels in all patients (Table 84-3). Even in patients with cataplexy where the CSF test is most predictive, the MSLT is still advised. It should follow nocturnal polysomnography, allowing the identification of concurrent sleep disorders such as sleep-related breathing disorders and periodic limb movement disorder (PLMD), both of which can be associ-
ated with narcolepsy and can contribute to daytime sleepiness independently. Sleep-related breathing disorder is not uncommon in these patients, who have a higher mean body-mass index than controls and must be identified and treated to reduce known complications of sleep apnea. A rational argument can be made that neither the MSLT nor CSF hypocretin-1 testing results will affect treatment plans in patients with straightforward sleepiness and clearcut cataplexy. In fact, the MSLT is not required for the diagnosis of narcolepsy if clear, definite cataplexy is present. However, in many patients presenting with cataplexy, collection of objective data is still recommended. In these cases, CSF hypocretin-1 testing may be most helpful when the MSLT is difficult to conduct or interpret (see Table 84-3). The trauma associated with the lumbar puncture must be balanced against the risk of misdiagnosing narcolepsy and possibly introducing lifelong treatment in a patient who is not narcoleptic. Testing in Narcolepsy without Cataplexy or with Atypical or Dubious Cataplexy CSF hypocretin-1 measurements have a more limited predictive power in patients with atypical or absent cataplexy. Specificity of the CSF hypocretin-1 measurement is still extremely high (99%), but sensitivity is low (16%)10 (see Fig. 84-3), and most patients have normal levels.10-12 Raising the cutoff of CSF hypocretin-1 to 200 pg/mL after demonstrating HLA positivity increases sensitivity to 41%, suggesting that 200 pg/mL may be more appropriate in these cases after HLA typing (see Table 84-2).143 The low positivity of the CSF test in patients without clear cataplexy is plainly a dilemma for the clinician because there
948 PART II / Section 11 • Neurologic Disorders Table 84-3 Advantages and Disadvantages of Selected Diagnostic Procedures for Narcolepsy DISADVANTAGES AND LIMITATIONS
SUGGESTED INDICATIONS
Highly specific in cases with cataplexy
Very low sensitivity; 8%-38% of the population is positive Only 40% positive in cases without cataplexy
Very limited interest Can only assist the diagnosis; should not be used to formally diagnose narcolepsy To use before lumbar puncture for CSF hypocretin-1 assessment If negative, almost certainly CSF hypocretin-1 will be normal
Sleep latency ≤8 min ≥2 SOREMPs
Identifies concurrent sleep disorders (e.g., SDB) Safe and painless measures of physiologic tendency to sleepiness independent of any biological cause By definition, positive in cases without cataplexy Available and recognized by insurance companies and other professionals
Cannot be interpreted if sleep was insufficient or disturbed before the MSLT Cannot be conducted in patients on stimulants or antidepressants 15% false negative in narcolepsy with cataplexy False positive in sleep apnea, sleep deprivation, adolescents Not validated in young children Difficult to conduct in very young children and complex cases (e.g., psychiatric) Expensive
Most cases, especially patients without cataplexy
Direct assay: <110 pg/mL
Highly specific (99%) and sensitive (87%) in patientswith typical cataplexy Biologically based, definitive test for narcolepsy
Highly specific (99%) but low sensitivity (16%) in patients without cataplexy or with atypical cataplexy Painful, long-lasting post-LP headache can occur Contraindications (i.e., anticoagulants, high-pressure hydrocephalus) Assay not widely available and not standardized Should be interpreted together with the clinical context if a severe brain pathology is present (e.g., coma, GuillainBarré syndrome, head trauma) Intermediary values (110-200 pg/mL) of unknown significance
Some patients with cataplexy with severe SDB or insomnia , making the MSLT difficult to interpret Young children unable to follow MSLT instructions (e.g., <7 years old) Recent onset with a negative MSLT Patients treated with psychotropic drugs (e.g., antidepressants) and unwilling to interrupt treatment Patients with cataplexy in whom narcolepsy is still suspected despite a negative MSLT Patients unable to afford the cost of an MSLT Patients with complex associated psychiatric, neurologic, or medical disorders (e.g., secondary narcolepsy) Treatment failures in need of reevaluation (e.g., patients with cataplexy taking high-dose stimulants without positive response)
PROCEDURE
RESULT
ADVANTAGES
HLA-DQ typing
Positive for DQB1*0602
MSLT following nocturnal polysomnography*
CSF hypocretin-1 measurements
CSF, cerebrospinal fluid; HLA, human leukocyte antigen; LP, lumbar puncture; MSLT, multiple sleep latency test; SDB, sleep-disordered breathing; SOREMP, sleep-onset REM period. *Other polygraphic tests of possible diagnostic value, such as continuous 24-hour sleep recording studies, are not discussed.
CHAPTER 84 • Narcolepsy: Pathophysiology and Genetic Predisposition 949
is more often a need for a definitive diagnosis in these atypical cases. The MSLT is a generally more useful first step, because it will help determine diagnosis and treatment strategies (see Table 84-3). If a lumbar puncture is required, HLA typing is useful as a first step, because almost all patients who have narcolepsy and low CSF hypocretin-1 levels are also HLADQB1*0602 positive10-12,144; five exceptions have been reported (out of several hundred patients with low hypocretin), including one case where cataplexy was very mild and atypical.8,10,143,144 We estimate that the probability of observing low levels (less than 110 pg/mL) in HLAnegative patients without cataplexy to be less than 0.1%. Most patients with no cataplexy and low CSF hypocretin-1 levels are children who develop cataplexy later in the course of the disease.10,145,146 Therefore, we generally advise that young children with excessive daytime sleepiness but without cataplexy undergo CSF hypocretin-1 testing. Patients in whom there is a suspicion that cataplexy is present but not clearly reported should also undergo CSF hypocretin-1 testing (see Table 84-3). Intermediate Levels The diagnostic value of low CSF hypocretin-1 (less than 110 pg/mL) has been established, but all healthy control values have been shown to be above 200 pg/mL10 (see Fig. 84-4). In rare cases of narcolepsy with cataplexy, and possibly more often in cases without cataplexy,143 we found hypocretin-1 levels between these two values, raising the possibility of partial hypocretin deficiency.10 Such values should, however, be cautiously interpreted, because in a large series of patients with various neurologic disorders we found that up to 15% had CSF hypocretin-1 values within this intermediate range; most of these cases represented severe brain pathology, most notably head trauma, encephalitis, and subarachnoid hemorrhage.80,143 Decreased hypocretin-1 levels in these patients might reflect damage to hypocretin-1 transmission, or they may be related to changes in CSF flow. Other authors have shown that CSF hypocretin-1 increases with locomotor activity and decreases with treatment with serotonin reuptake inhibitors (but never to near-undetectable, narcolepsy-like levels).85 Therefore, the finding of hypocretin-1 levels in this intermediate range should alert the clinician to the possibility of underlying brain pathology, which might require additional clinical evaluation, laboratory testing, or imaging. Whether genuine hypocretin deficiency explains abnormal sleep in these neurologic disorders is in need of further investigation.143 Secondary Narcolepsy Historical Perspective Another potential application for CSF hypocretin-1 testing lies in the complex field of narcolepsy and hypersomnia related to neurologic disorders associated with trauma, tumor, infection, degenerative diseases, and genetic disorders (Box 84-2). von Economo was the first to suggest that narcolepsy might have its origins in the posterior hypothalamus and in some cases a secondary etiology. In his classic study of encephalitis lethargica, von Economo recognized three categories of patients: a group with hypersomnia and eye movement abnormalities (somno-
lent-ophthalmoplegic), a group with insomnia and hyperkinetic movement disorder (sometimes with reversal of the sleep cycle), and a group with parkinsonism (amyostaticakinetic, often as a residual form).147,148 Neuropathologic studies revealed involvement of the midbrain periaqueductal gray matter and posterior hypothalamus in the hypersomnolent variant (with extension to the oculomotor nuclei, explaining the oculomotor symptoms). Involvement of the anterior hypothalamus with extension into basal ganglia was observed in the insomnia variant (explaining the commonly co-occurring chorea). This led von Economo to speculate that the anterior hypothalamus contained a sleep-promoting area and that an area spanning from the posterior wall of the third ventricle to the third nerve (encompassing part of the posterior hypothalamus and the periaqueductal midbrain region) was involved in promoting wakefulness. The cause of idiopathic narcolepsy that had been described some 50 years earlier91 was also speculated to involve this general area.148 This hypothesis was further refined by others, who noted that tumors or lesions located close to the third ventricle were also associated with secondary narcolepsy.100,149 A postulated hypothalamic cause of narcolepsy was widespread until the 1940s but was subsequently ignored during the psychoanalytic boom to be replaced by the brainstem hypothesis.150 Only two cases of postencephalitis genuine narcolepsy with cataplexy had even been clearly documented, and in one case reversal of symptoms was reported with recovery.151,152 Hypocretin Studies Reports of third-ventricle lesions (hypothalamus and upper midbrain) in association with narcolepsy (such as tumors) have been described since the 1930s.147-153 Narcolepsy-like symptoms have also been reported after traumatic brain injury, acute disseminated encephalomyelitis, hypothalamic sarcoidosis or histiocytosis X, and in association with multiple sclerosis and Parkinson’s disease.143,154,155 In some cases, lesions of the hypothalamic hypocretin centers have been clearly identified using MRI, as in bilateral multiple sclerosis or anti–aquaporin-4 lesions in the hypothalamus and tumors of the third ventricle.87,143,154-161 Cataplexy may be present in these cases, and CSF hypocretin-1 levels may be either in the narcolepsy range (less than 110 pg/mL), or in the intermediate range (see Box 84-2).10,87,156-160 Similarly, postmortem studies have shown a 30% and 50% decrease in hypocretin cell counts in Huntington’s and Parkinson’s disease,143 respectively, with maintenance of normal CSF hypocretin-1 levels.10 Such intermediate or normal levels might reflect damage to nearby hypocretin projection sites, with sufficient preservation of cell bodies to maintain detectable levels of hypocretin-1. Alternatively (or additionally), other regions in the upper midbrain might also contribute to the symptomatology, especially sleepiness, as initially proposed by von Economo. Therefore, as illustrated above, CSF hypocretin-1 levels might potentially prove helpful in complex clinical situations in which the history, polysomnographic, or MSLT data are difficult to interpret (see Table 84-3). Box 84-2 outlines results obtained to date with hypocretin studies in these various secondary etiologies, and Table 84-4 illustrates the possible value of such a test in selected cases.
950 PART II / Section 11 • Neurologic Disorders Box 84-2 CSF Hypocretin-1 Measurements in Secondary Narcolepsy and Hypersomnia* Secondary Hypersomnia Hypocretin-1 Less than 110 pg/mL Acute disseminated encephalomyelitis with sleepiness (n = 1) Autosomal dominant cerebellar ataxia, deafness, and narcolepsy (n = 3, including one family) Hypothalamic tumor (after removal) (n = 2) Large pituitary adenoma with probable hypothalamic involvement (n = 1) Late-onset congenital hypoventilation syndrome (n = 1) Multiple sclerosis with bilateral hypothalamic plaques (n = 1) Myotonic dystrophy type 1 (n = 1) Paraneoplastic syndrome with anti-Ma2 and sleepiness, possible cataplexy (n = 4) Prader-Willi syndrome (n = 1) Steroid-responsive encephalopathy associated with autoimmune thyroiditis (n = 1) Whipple’s disease with CNS involvement (with hypersomnia) (n = 1) Intermediate Hypocretin-1 Levels (110 to 200 pg/mL) Diencephalic stroke with hypothalamic and midbrain lesions (sequela) (n = 1) Head trauma (sequela) (n = 1) Myotonic dystrophy type 1 (n = 2) Niemann-Pick type C with cataplexy (n = 2) Prader-Willi syndrome (n = 1)
Normal Hypocretin-1 Levels (Greater than 200 pg/mL) Acute disseminated encephalomyelitis with sleepiness (n = 1) HIV encephalopathy with sleepiness (n = 1) Hypersomnia with depression (n = 6) Hypersomnia with Parkinson’s disease (n = 3) Myotonic dystrophy type 1 (n = 3) Neurocysticercosis cysts in the hypothalamus and other locations (n = 1) Niemann-Pick type C without cataplexy (n = 1) Narcolepsy-cataplexy after irradiation of the hypothalamus (n = 1) Pontine lesion (n = 1) Thalamocortical stroke (n = 1) Other Pathologies with Intermediate Hypocretin-1 Levels†,‡ Traumatic brain injury (numerous cases, probably transitory) Various neoplasms of the brain (numerous cases) Encephalitis of infectious origin (numerous cases) Guillain-Barré syndrome and other inflammatory neuropathies (numerous cases) Pathologies with Low Hypocretin-1 Levels† Guillain-Barré syndrome (n = 7) (transitory, unknown significance) Myxedema coma, no clinical doumentation (n = 1) Posttraumatic head injury trauma coma (n = 1)
*Patients who were tested at Stanford University or in centers that used the same standard CSF samples for comparisons are included; measurements in other laboratories cannot be compared. † These patients did not report sleep symptoms but might have had them. ‡ In another case of Whipple’s disease with long-lasting resistant insomnia without hypersomnia, intermediate CSF hypocretin levels were found. This might reflect more-complex hypothalamic damage that could include the anterior hypothalamus. CSF, cerebrospinal fluid; HIV, human immunodeficiency virus.
Additional studies are needed to expand upon these anecdotal reports, to determine whether these changes in CSF hypocretin-1 levels truly represent abnormalities in their respective cells or their projections, or rather if they simply represent a nonspecific finding.143,154 Narcolepsy and Cataplexy in Syndromic Associations of Likely Genetic Origin Genetic disorders such as Coffin-Lowry syndrome,162 Moebius syndrome,163 Norrie’s disease,163 Prader-Willi syndrome.10 Niemann-Pick type C,10,164-167 and myotonic dystrophy168 have been reported to be associated with daytime sleepiness, SOREMPs, and cataplexy-like symptoms. CSF hypocretin-1 has been measured in cases of Niemann-Pick type C, a condition where oculomotor symptoms are common, and intermediate levels have been found in some patients with cataplexy.10,164,165 This condition is remarkable because cataplexy is clear, often triggered by typical emotions (laughing) and partially responsive to anticataplectic treatment. Some diseases are associated with the development of both narcolepsy and sleep-disordered breathing, such as myotonic dystrophy168 and Prader-Willi syndrome10; in such cases, primary
hypersomnia should only be diagnosed if excessive daytime sleepiness does not improve after adequate treatment of sleep-disordered breathing. We have explored CSF hypocretin-1 levels in such cases and have found that most patients have normal or intermediate CSF hypocretin-1 levels (greater than 110 pg/mL).10,164 HLA may be negative or positive (by chance in these cases). Two interesting genetic associations should be mentioned, because they might reflect the existence of rare narcolepsy-plus syndromes with hypocretin deficiency of genetic origin. In one family described in Spain, several members were found who were HLA-DQB1*0602 negative and hypocretin deficient and who had narcolepsy with cataplexy association with obesity and type 2 diabetes. Similarly, Melberg’s group169 described a family that included numerous HLA-negative patients with ataxia, deafness, and narcolepsy with cataplexy associated with undetectable CSF hypocretin-1. Finally, in one case of late-onset congenital hypoventilation syndrome, a disorder with reported hypothalamic abnormalities,170 we found very low CSF hypocretin-1 levels in a patient with otherwise unexplained sleepiness and cataplexy-like episodes.10 Excellent response to anticataplectic therapy was observed in this case.
CHAPTER 84 • Narcolepsy: Pathophysiology and Genetic Predisposition 951
Table 84-4 CSF Hypocretin-1 and HLA Results: Selected Examples in Secondary Narcolepsy and Hypersomnias CLINICAL CASE
CSF HYPOCRETIN-1
HLA
MSLT
NOTES
8-year-old white boy without cataplexy (onset within 6 months)
88 pg/mL
Pos
Pos
Diagnostic for narcolepsy, treatment with modafinil, later in association with venlafaxine
17-year-old boy with rape hallucinations; suspicious and difficult to interview; possible cataplexy
Undetectable (<40 pg/mL)
Pos
Refused
Narcolepsy associated with psychosis
16-year-old girl with a 5-year history of depression and drug-resistant insomnia; cataplexy on interview
Undetectable (<40 pg/mL)
Pos
Impossible to stop medications, not done
Diagnostic for narcolepsy, now successfully treated with sodium oxybate, modafinil, and atomoxetine
32-year-old man, after resection of hypothalamic pharyngioma; very impaired, possible cataplexy
152 pg/mL
Neg
Impossible to conduct, too impaired
Questionable narcolepsy; possibly lesions of other areas; partial effect of stimulants
33-year-old woman successfully treated with d-amphetamine and fluoxetine; recently moved to the area; no cataplexy
Undetectable (<40 pg/mL)
Pos
Not interpretable, was taking medication
Diagnostic for narcolepsy No change in treatment, but considering modafinil
15-year-old girl with sleepiness, no cataplexy
310 pg/mL
Pos
Pos
Narcolepsy without cataplexy Treatment with modafinil
67-year-old man, narcolepsy without cataplexy, diagnosed at age 50, AHI = 25 events/hr, noncompliant with CPAP, currently with falls not triggered by laughing
Undetectable (<40 pg/mL)
Pos
Pos
First tried venlafaxine without effect, then sodium oxybate with very positive response
Positive test result criteria: HLA, HLA-DQB1*0602-positive; MSLT, sleep latency <8 min, ≥2 SOREMPs AHI, apnea–hypopnea index; CPAP, continuous positive airway pressure ventilation; CSF, cerebrospinal fluid; HLA, human leukocyte antigen; MSLT, multiple sleep latency test; Neg, negative; Pos, positive; SOREMP, sleep-onset REM period.
HYPOCRETIN COMPOUNDS AS POTENTIAL THERAPEUTIC TARGETS Experiments aimed at studying the effects of hypocretin on sleep after nasal, systemic, and central administration (e.g., intracerebroventricular injection or local perfusion in selected brain areas) have been conducted.171-173 Central administration of hypocretin-1, for example in the ventricle of wild-type rodents or normal canines, is strongly wake-promoting172 and reverses cataplexy and sleep abnormalities in narcoleptic rodents.174 The effect is likely to be at least in part mediated by the HCRTR2 because intra crebroventricular hypocretin-1 at the same dose (10 to 30 nmol) has no effect in HCRTR2-mutated narcoleptic canines.175 Interestingly, hypocretin-2 administration has few if any central effects even in normal animals, most probably not because it is inactive but because it is biologically unstable and rapidly degraded. The instability might also explain why hypocretin-1 but not hypocretin-2 is detectable in native CSF.175 Experiments conducted after intravenous administration of hypocretin-1 have been performed in HCRTR2mutated canines and in two hypocretin-deficient narcoleptic dogs. In spite of a previous report,171 we were unable to detect any significant effect even at extremely high doses in hypocretin receptor-2 mutated animals.172 This result was not surprising considering the lack of effects after central administration of the same dose in these animals
lacking HCRTR2 (see earlier). More interestingly, a possible very slight and short-lasting suppression of cataplexy was observed in a single hypocretin-deficient narcoleptic animal at extremely high doses.160 The effect of intranasal hypocretin-1 in rodents and humans has been studied173 with the hope that hypocretin-1 would penetrate into the brain via the olfactory nerve endings. Although we found central uptake of radiolabeled hypocretin counts in rodents, in vivo experiments did not reveal any behavioral effects. In contrast, another study found a significant reversal of MRI abnormalities induced by sleep deprivation after intranasal administration,173 a finding that suggests the need to conduct similar studies in narcoleptic patients. We also examined the possibility of intrathecal administration by implanting a Medtronic pump with catheterization of the cisterna magna in a single hypocretin-deficient narcoleptic canine.176 Our hope was that at a high dose, some reverse flow would occur back into deeper brain structure, providing therapeutic relief. A positive result would have had therapeutic application, because these pumps are often used in humans to treat pain or spasticity using intrathecal administration. Disappointingly, however, we did not observe any significant effect on cataplexy,176 probably because the hypocretin did not diffuse in upper ventricular compartments. Additional studies using intraventricular rather than intracisternal injections will be needed to verify that hypocretin-deficient narcoleptic canines are responsive to supplementation.
952 PART II / Section 11 • Neurologic Disorders
CONCLUSION Narcolepsy is both a common neurologic disorder and a model disorder to further our understanding of REM sleep and regulation of sleepiness. Since the 1960s, research in the area has been greatly facilitated by the existence of a canine narcolepsy model, now rapidly replaced by rodent models. Narcolepsy with cataplexy is most commonly caused by a loss of hypocretin-producing cells in the hypothalamus. Low CSF hypocretin-1 can be used to diagnose the condition. The disorder is associated with HLADQB1*0602 and TCRα polymorphisms, indicating that the cause of most of these cases is an autoimmune destruction of these cells. Studies in narcoleptic canines have substantiated a tight parallel between the pharmacologic control of cataplexy and that of REM sleep. Using this model, it was found that the mode of action of stimulant medications is presynaptic stimulation of dopaminergic transmission, and anticataplectic compounds exert their therapeutic effects primarily via adrenergic uptake inhibition. The hypocretin system sends strong excitatory projections onto monoaminergic cells. The loss of hypocretin is likely to create a cholinergic monoaminergic imbalance in narcolepsy. Abnormally sensitive cholinergic transmission and depressed dopaminergic and histaminergic transmission are believed to underlie abnormal REM sleep and daytime sleepiness in canine narcolepsy. Whereas most cases of narcolepsy with cataplexy are caused by hypocretin cell loss, some patients with cataplexy and most patients without cataplexy have normal CSF hypocretin-1 levels. This might reflect disease heterogeneity or a partial loss of hypocretin neurons without significant CSF hypocretin-1 decrements. A critical area in need of further inquiry is the role of CSF hypocretin-1 testing in predicting therapeutic response to medications already in use to treat the symptoms of narcolepsy.87 It might be possible to develop an assay that could reliably measure hypocretin-1 in plasma, and such an assay would be extremely useful if low levels are observed in narcolepsy.87 Measuring hypocretin-1 levels might someday facilitate development of therapies that can interrupt or delay the development of disease. Experience suggests that a subset of patients without cataplexy (including those with idiopathic hypersomnia), or patients with an unclear clinical diagnosis of narcolepsy, may be more resistant to stimulant treatment, leading to management difficulties. Additional work comparing drug responses in patients with and without hypocretin deficiency is needed. There is increasing evidence that narcolepsy is an autoimmune disorder or involves an infectious agent, with participation of the immune system.140,177 Explaining the link between the HLA–TCR association and hypocretin deficiency must be a high priority. It may be possible to use CSF hypocretin-1 testing to evaluate the extent of hypocretin cell loss in early stages of the disease (e.g., in children), thus facilitating the development of treatments that may be able to arrest or at least delay disease progression. Similar strategies using immunosuppression have been used in other autoimmune diseases, such as type 1 diabetes mellitus. In one case, 2 months after an abrupt onset, we tried high-dose prednisone but did not observe
significant effects on symptoms and CSF hypocretin-1 levels145; however, in this case, very low hypocretin-1 levels were already observed, suggesting the possibility that the cells had already been irreversibly damaged. In other subjects with recent onset, intravenous immunoglobulin administration was reported to have positive effects in some but not all open-label studies,178-181 suggesting the need for placebo-controlled studies.182 We anticipate that in time, patients at risk for narcolepsy will be identified through genetic typing, monitored with biomarkers (e.g., measuring T-cell populations bearing specific TCR idio types, occurrence of specific infections), thereby allowing early intervention to arrest immune destruction of hypocretin cells. ❖ Clinical Pearl Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and abnormal transitions to REM sleep. When cataplexy is present, the cause is almost always an immune-mediated destruction of hypocretin cells in the hypothalamus, an abnormality that can be documented by measuring CSF hypocretin-1. The treatment of narcolepsy typically uses drugs from two or three of the following drug classes: antidepressants (for cataplexy, acting on adrenergic and serotoninergic uptake), modafinil or amphetamine-like stimulants (for sleepiness, most likely acting on dopamine), and sodium oxybate (a sedative acting on all symptoms, most likely acting on GABAB receptors).
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118. Black JL 3rd, Krahn LE, Pankratz VS, et al. Search for neuronspecific and nonneuron-specific antibodies in narcoleptic patients with and without HLA DQB1*0602. Sleep 2002;25:719-723. 119. Overeem S, Geleijins K, Garssen MP, et al. Screening for antiganglioside antibodies in hypocretin-deficient human narcolepsy. Neurosci Lett 2003;341:13-16. 120. Scammell TE. The frustrating and mostly fruitless search for an autoimmune cause of narcolepsy. Sleep 2006;29:601-602. 121. Thannickal TC, Siegel JM, Nienhuis R, et al. Pattern of hypocretin (orexin) soma and axon loss, and gliosis, in human narcolepsy. Brain Pathol 2003;13:340-351. 122. Kaufmann C, Schuld A, Pollmacher T, et al. Reduced cortical gray matter in narcolepsy: preliminary findings with voxel-based morphometry. Neurology 2002;58:1852-1855. 123. Draganski B, Geisler P, Hajak G, et al. Hypothalamic gray matter changes in narcoleptic patients. Nat Med 2002;8:1186-1188. 124. Overeem S, Steens SC, Good CD, et al. Voxel-based morphometry in hypocretin-deficient narcolepsy. Sleep 2003;26:44-46. 125. Mignot E, Lin X, Arrigoni J, et al. DQB1*0602 and DQA1*0102 (DQ1) are better markers than DR2 for narcolepsy in Caucasian and black Americans. Sleep 1994;17(Suppl. 8):S60-S67. 126. Mignot E, Kimura A, Lattermann A, et al. Extensive HLA class II studies in 58 non-DRB1*15 (DR2) narcoleptic patients with cataplexy. Tissue Antigens 1997;49:329-341. 127. Ellis MC, Hetisimer AH, Ruddy DA, et al. HLA class II haplotype and sequence analysis support a role for DQ in narcolepsy. Immunogenetics 1997;46:410-417. 128. Pelin Z, Guilleminault C, Risch N, et al. HLA-DQB1*0602 homozygosity increases relative risk for narcolepsy but not disease severity in two ethnic groups. US Modafinil in Narcolepsy Multicenter Study Group. Tissue Antigens 1998;51:96-100. 129. Hong SC, Lin L, Lo B, et al. DQB1*0301 and DQB1*0601 modulate narcolepsy susceptibility in Koreans. Hum Immunol 2007;68: 59-68. 130. Mignot E, Lin X, Kalil J, et al. DQB1-0602 (DQw1) is not present in most nonDR2 Caucasian narcoleptics. Sleep 1992;15:415-422. 131. Nakayama J, Miura M, Honda M, et al. Linkage of human narcolepsy with HLA association to chromosome 4p13-q21. Genomics 2000;65:84-86. 132. Hohjoh H, Terada N, Nakayama T, et al. Case-control study with narcoleptic patients and healthy controls who, like the patients, possess both HLA-DRB1*1501 and -DQB1*0602. Tissue Antigens 2001;57:230-235. 133. Kato T, Honda M, Kuwata S, et al. Novel polymorphism in the promoter region of the tumor necrosis factor alpha gene: no association with narcolepsy. Am J Med Genet 1999;88:301-304. 134. Wieczorek S, Gencik M, Rujescu D, et al. TNFA promoter polymorphisms and narcolepsy. Tissue Antigens 2003;61:437-442. 135. Dauvilliers Y, Neidhart E, Billiard M, et al. Sexual dimorphism of the catechol-O-methyltransferase gene in narcolepsy is associated with response to modafinil. Pharmacogenomics J 2002;2: 65-68. 136. Dauvilliers Y, Neidhart E, Lecendreux M, et al. MAO-A and COMT polymorphisms and gene effects in narcolepsy. Mol Psychiatry 2001;6:367-472. 137. Kawashima M, Tamiya G, Oka A, et al. Genomewide association analysis of human narcolepsy and a new resistance gene. Am J Hum Genet 2006;79:252-263. 138. Miyagawa T, Honda M, Kawashima M, et al. Polymorphism located between CPT1B and CHKB, and HLA-DRB1*1501-DQB1*0602 haplotype confer susceptibility to CNS hypersomnias (essential hypersomnia). PLoS ONE 2009;4:e5394. 139. Miyagawa T, Kawashima M, Nishida N, et al. Variant between CPT1B and CHKB associated with susceptibility to narcolepsy. Nat Genet 2008;40:1324-1328. 140. Hallmayer J, Faraco J, Lin L, et al. Narcolepsy is strongly associated with the TCR alpha locus. Nature Gen 2009. 141. Shiina T, Hosomichi K, Inoko H, et al. The HLA genomic loci map: expression, interaction, diversity and disease. J Hum Genet 2009;54:15-39. 142. Evans RW. Complications of lumbar puncture. Neurol Clin 1998;16:83-105. 143. Bourgin P, Zeitzer JM, Mignot E. CSF hypocretin-1 assessment in sleep and neurological disorders. Lancet Neurol 2008;7:649662.
144. Dalal MA, Schuld A, Pollmacher T. Undetectable CSF level of orexin A (hypocretin-1) in a HLA-DR2 negative patient with narcolepsy-cataplexy. J Sleep Res 2002;11:273. 145. Hecht M, Lin L, Kushida CA, et al. Immunosuppression with prednisone in an 8-year-old boy with an acute onset of hypocretin deficiency/narcolepsy. Sleep 2003;26:809-810. 146. Kubota H, Kanbayashi T, Tanabe Y, et al. Decreased cerebrospinal fluid hypocretin-1 levels near the onset of narcolepsy in 2 prepubertal children. Sleep 2003;26:555-557. 147. von Economo C. Encephalitis lethargica ITS sequelae and treatment. London: Oxford University Press; 1931. 148. von Economo C. Sleep as a problem of localization. J Nerv Ment Dis 1930;71:249-259. 149. Daniels LE. Narcolepsy. Medicine 1934;13:1-122. 150. Mignot E. A hundred years of narcolepsy research. Arch Ital Biol 2001;139:207-220. 151. Symonds CP. Narcolepsy as a symptom of encephalitis lethargica. Lancet 1926;12:1214-1215. 152. Adie WJ. Idiopathic narcolepsy: a disease sui generis; with remarks on the mechanism of sleep. Brain 1926;49:257-306. 153. Aldrich MS, Naylor MW. Narcolepsy associated with lesions of the diencephalon. Neurology 1989;39:1505-1508. 154. Nishino S, Kanbayashi T. Symptomatic narcolepsy, cataplexy and hypersomnia, and their implications in the hypothalamic hypocretin/orexin system. Sleep Med Rev 2005;9:269-310. 155. Fronczek R, Baumann CR, Lammers GJ, et al. Hypocretin/orexin disturbances in neurological disorders. Sleep Med Rev 2009;13: 9-22. 156. Arii J, Kanbayashi T, Tanabe Y, et al. A hypersomnolent girl with decreased CSF hypocretin level after removal of a hypothalamic tumor. Neurology 2001;56:1775-1776. 157. Dempsey OJ, McGeoch P, De Silva RN, et al. Acquired narcolepsy in an acromegalic patient who underwent pituitary irradiation. Neurology 2003;61:537-540. 158. Kato T, Kanbayashi T, Yamamoto K, et al. Hypersomnia and low CSF hypocretin-1 (orexin-A) concentration in a patient with multiple sclerosis showing bilateral hypothalamic lesions. Intern Med 2003;42:743-745. 159. Kubota H, Kanbayashi T, Tanabe Y, et al. A case of acute disseminated encephalomyelitis presenting hypersomnia with decreased hypocretin level in cerebrospinal fluid. J Child Neurol 2002;17: 537-539. 160. Scammell TE, Nishino S, Mignot E, et al. Narcolepsy and low CSF orexin (hypocretin) concentration after a diencephalic stroke. Neurology 2001;56:1751-1753. 161. Nozaki H, Shimohata T, Kanbayashi T, et al. A patient with antiaquaporin 4 antibody who presented with recurrent hypersomnia, reduced orexin (hypocretin) level, and symmetrical hypothalamic lesions. Sleep Med 2009;10:253-255. 162. Nelson GB, Hahn JS. Stimulus-induced drop episodes in CoffinLowry syndrome. Pediatrics 2003;111:197-202. 163. Parkes JD. Genetic factors in human sleep disorders with special reference to Norrie disease, Prader-Willi syndrome and Moebius syndrome. J Sleep Res 1999;8(Suppl. 1):14-22. 164. Kanbayashi T, Abe M, Fujimoto S, et al. Hypocretin deficiency in Niemann-Pick type C with cataplexy. Neuropediatrics 2003; 34:52-53. 165. Vankova J, Stepanova I, Jech R, et al. Sleep disturbances and hypocretin deficiency in Niemann-Pick disease type C. Sleep 2003; 26:427-430. 166. Oyama K, Takahashi T, Shoji Y, et al. Niemann-Pick disease type C: cataplexy and hypocretin in cerebrospinal fluid. Tohoku J Exp Med 2006;209:263-267. 167. Smit LS, Lammers GJ, Catsman-Berrevoets CE. Cataplexy leading to the diagnosis of Niemann-Pick disease type C. Pediatr Neurol 2006;35:82-84. 168. Martinez-Rodriguez JE, Lin L, Iranzo A, et al. Decreased hypocretin-1 (Orexin-A) levels in the cerebrospinal fluid of patients with myotonic dystrophy and excessive daytime sleepiness. Sleep 2003; 26:287-290. 169. Melberg A, Ripley B, Lin L, et al. Hypocretin deficiency in familial symptomatic narcolepsy. Ann Neurol 2001;49:136-137. 170. Katz ES, McGrath S, Marcus CL. Late-onset central hypoventilation with hypothalamic dysfunction: a distinct clinical syndrome. Pediatr Pulmonol 2000;29:62-68.
956 PART II / Section 11 • Neurologic Disorders 171. John J, Wu MF, Siegel JM. Systemic administration of hypocretin-1 reduces cataplexy and normalizes sleep and waking durations in narcoleptic dogs. Sleep Res Online 2000;3:23-28. 172. Nishino S, Fujiki N, Yoshida Y, et al. The effects of hypocretin-1 in hypocretin receptor-2 mutated and hypocretin deficient narcoleptic dogs. Sleep 2003;26(Suppl.):A287. 173. Deadwyler SA, Porrino L, Siegel JM, et al. Systemic and nasal delivery of orexin-A (hypocretin-1) reduces the effects of sleep deprivation on cognitive performance in nonhuman primates. J Neurosci 2007;27:14239-14247. 174. Mieda M, Willie JT, Hara J, et al. Orexin peptides prevent cataplexy and improve wakefulness in an orexin neuron-ablated model of narcolepsy in mice. Proc Natl Acad Sci U S A 2004;101:4649-4654. 175. Yoshida Y, Fujiki N, Maki RA, et al. Differential kinetics of hypocretins in the cerebrospinal fluid after intracereroventricular administration in rats. Neurosci Lett 2003;346:182-186. 176. Schatzberg SJ, Barrett J, Cutter K, et al. The effect of hypocretin replacement therapy in a 3-year-old Weimaraner with narcolepsy. J Vet Intern Med 2004;18:586-588.
177. Jackson MW, Reed JH, Smith AJ, et al. An autoantibody in narcolepsy disrupts colonic migrating motor complexes. J Neurosci 2008;28:13303-13309. 178. Fronczek R, Verschuuren J, Lammers GJ. Response to intravenous immunoglobulins and placebo in a patient with narcolepsy with cataplexy. J Neurol 2007;254:1607-1608. 179. Valko PO, Khatami R, Baumann CR, et al. No persistent effect of intravenous immunoglobulins in patients with narcolepsy with cataplexy. J Neurol 2008;255:1900-1903. 180. Dauvilliers Y, Carlander B, Rivier F, et al. Successful management of cataplexy with intravenous immunoglobulins at narcolepsy onset. Ann Neurol 2004;56:905-908. 181. Plazzi G, Poli F, Franceschini C, et al. Intravenous high-dose immunoglobulin treatment in recent onset childhood narcolepsy with cataplexy. J Neurol 2008;255:1549-1554. 182. Valko PO, Khatami R, Baumann CR, Bassetti CL. No persistent effect of intravenous immunoglobulins in patients with narcolepsy with cataplexy. J Neurol 2008 Dec;255:1900-1903.
Narcolepsy: Diagnosis and Management Christian Guilleminault and Michelle T. Cao Abstract Narcolepsy is a syndrome with a prevalence close to 0.04%. It is a chronic neurologic sleep disorder resulting from the abnormal regulation of the sleep–wake cycle, resulting in abnormal sleep tendencies, including excessive daytime sleepiness, disturbed nocturnal sleep, and manifestations related to rapid eye movement (REM) sleep such as cataplexy (an abrupt drop in muscle tone), sleep paralysis, and hypnopompic or hypnagogic hallucinations. Its peak age of onset is the second decade. Multiple sleep latency testing following overnight polysomnography shows short sleep latencies (mean sleep latency
Gélineau1 first coined the term narcolepsy in 1880 to designate a pathologic condition characterized by irresistible episodes of sleep periods of short duration recurring at close intervals. Although Westphal2 and Fisher3 previously published reports of patients with sleepiness and episodic muscle weakness, Gélineau was the first to characterize narcolepsy as a distinct syndrome. He wrote that falls, or “astasias” sometimes accompanied attacks. Henneberg later referred to these attacks as cataplexy.4 In the 1930s, Daniels5 emphasized the association of daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations. Referring to these symptoms as “the clinical tetrad,” Yoss and Daly6 and Vogel7 reported nocturnal sleep-onset rapid eye movement (REM) periods (SOREMPs) in narcoleptic patients, a finding confirmed in the following years.8-11 The current definition of narcolepsy strongly emphasizes the dysfunction of REM sleep, but it ignores the notion that genetic factors are often involved in the development of narcolepsy. Moreover, although most cases of narcolepsy are idiopathic, secondary causes of narcolepsy have been described.12 The discovery of the hypocretin (orexin) mutation in narcoleptic Doberman pinschers led to a better understanding of the syndrome and changed, to some degree, our approach to diagnosis and treatment of disorders of excessive daytime sleepiness, particularly narcolepsy. Because hypocretins are involved in many hypothalamic functions, narcolepsy may be considered more than just a disorder of sleep. In addition, it may be considered a syndrome of instability of wake and sleep stages rather than merely a disorder of dysfunctional REM sleep: Patients have the capacity to achieve wakefulness, non-REM (NREM) sleep, and REM sleep, but they are unable to maintain the state. They appear to lack the modulator responsible for maintaining the active sleep state long enough for the normal physiologic switches to change the state. Thus, patients with narcolepsy dissociate into the various states of consciousness at inappropriate times. This dissociation is often incomplete, leading to a mixture of normal and abnormal states of consciousness,
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≤8 minutes) and two or more sleep-onset REM periods (SOREMPs). The treatment of narcolepsy has improved in recent years, with the newest compounds providing fewer side effects than the classic stimulants for excessive daytime somnolence and tricyclic antidepressants for cataplexy. Modafinil and armodafinil improve daytime somnolence, and sodium oxybate improves both cataplexy and daytime somnolence. Narcolepsy is a complex syndrome that involves dysfunction in the timing of changes in wake and sleep stages. Medications with an alerting effect can help but do not completely control the multifaceted problems associated with this syndrome.
such as cataplexy, which represents a combination of the waking state and the paralysis of REM sleep.13
CLINICAL FEATURES The International Classification of Sleep Disorders includes two entities: narcolepsy with cataplexy and narcolepsy without cataplexy.14 The classic tetrad for narcolepsy includes excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic hallucinations (Video 85-1). Automatic behavior and disrupted nighttime sleep also commonly occur. Not all of these symptoms are present in all patients. Many of the symptoms of narcolepsy can occur in any person who is severely sleep deprived; only cataplexy is unique to narcolepsy. Sleepiness Unwanted episodes of sleep recur several times a day not only under favorable circumstances, such as during monotonous sedentary activity or after a heavy meal, but also in situations in which the patient is fully involved in a task. The duration of these sleep attacks can vary from a brief episode of a few seconds to several minutes, if the patient is in an uncomfortable position, to longer than an hour if the patient is reclining. Narcoleptic patients characteristically wake up feeling refreshed, and there is a refractory period of one to several hours before the next episode occurs. These relatively short but refreshing naps can help differentiate patients with narcolepsy from patients with idiopathic hypersomnia, who take long and unrefreshing naps. Despite having sleep attacks during the day, narcoleptic patients generally do not spend a greater amount of time sleeping than people without narcolepsy. Apart from sleep attacks, patients might feel abnormally drowsy, resulting in poor performance at work, memory lapses, and even gestural, ambulatory, or speech automatisms. Cataplexy Cataplexy occurs in 60% to 70% of narcoleptic patients.15,16 Cataplexy is an abrupt and reversible decrease or loss 957
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of muscle tone, most commonly elicited by emotional responses such as laughter, anger, or surprise. It can involve certain muscles or the entire voluntary musculature. Most typically, the jaw sags, the head falls forward, the arms drop to the side, and the knees unlock or buckle (Video 85-2). Awareness is preserved throughout the attack. The severity and extent of cataplectic attacks can vary from a state of absolute powerlessness, which seems to involve the entire voluntary musculature, to a limited involvement of certain muscle groups, or to no more than a fleeting sensation of weakness extending more or less throughout the body. Although the extraocular muscles supposedly are not involved, weakness can occur, and the patient might complain of blurred vision. Complete paralysis of extraocular muscles has never been reported, although the palpebral muscle may be affected. Speech may be impaired and respiration can become irregular during an attack. Long breathing pauses have never been recorded, but short pauses similar to those seen during nocturnal REM sleep in healthy subjects can occur. Speech may be broken or slurred because of intermittent weakness affecting the arytenoid muscles. If the weakness involves only the jaw or speech, the subject might have wide masticatory movement or an unusual attack of stuttering speech. Rarely in a cataplectic attack, there is a complete loss of muscle tone that can lead to total body collapse, and serious injuries such as skull or other bone fractures can occur. However in most cases, cataplectic attacks are not that extreme and might even go unnoticed by persons nearby. An attack might consist of only a slight buckling of the knees. Patients might perceive this abrupt and shortlasting weakness and simply stop or stand against a wall. If the attack involves the upper limbs, the patient might complain of “clumsiness,” reporting activity such as dropping cups or plates or spilling liquids when surprised, laughing, and so forth. As seen during nocturnal REM sleep, the abrupt muscle inhibition is interrupted by sudden bursts of muscle tone returning, which at times even seem enhanced. The short cataplectic attacks are the most common manifestation of cataplexy. Because they do not resemble the classic full-blown attack of cataplexy, they are often missed even by skilled physicians without the aid of electromyographic recording. By the same token, the skilled physician must be cautious not to overdiagnose as cataplexy normal phenomena such as the “rubber knees” that precede the anxiety of public speaking or “rolling on the ground laughing.” The duration of each cataplectic attack—whether partial or complete—is variable, lasting from a few seconds to 30 minutes, but in most cases 30 seconds to 2 minutes. Attacks can be elicited by emotion or stress. Laughter and anger seem to be the most common triggers, but these attacks can also be induced by a feeling of elation while listening to music, reading a book, or watching a movie. Cataplexy can be induced merely by remembering a happy or funny situation, and it occurs rarely without clear precipitating acts or emotions, particularly if the patient is sleepy. It often occurs when the patient is telling a joke and even when the patient simply anticipates saying something humorous.
Status cataplecticus is a rare manifestation of cataplexy. It is characterized by prolonged cataplexy lasting hours, confining the patient to the bedroom. Sleep Paralysis This is a terrifying experience that occurs in the narcoleptic patient upon falling asleep or awakening. Patients find themselves paralyzed, suddenly unable to move the limbs, speak, or even breathe deeply. This state is often accompanied by hallucinations. During an episode of sleep paralysis, the patient is unable to move the extremities, speak, or open the eyes, although he or she is fully aware of the condition and able to recall it completely later. In many episodes of sleep paralysis, but especially the first occurrence, the patient may be subjected to extreme anxiety associated with the fear of dying. This anxiety is often greatly intensified by the terrifying hallucinations that can accompany the sleep paralysis. Patients often interpret the experience as being “scared stiff.” With more experience with the phenomenon, however, the patient usually learns that episodes are brief and benign, rarely lasting longer than a few minutes and always ending spontaneously. Sleep paralysis can occur as an independent and isolated phenomenon, and 3% to 5% of the general population may be affected by it. Hallucinations Sleep onset, either during daytime naps or at night, may be unpleasant due to vivid auditory or visual hallucinations, known as hypnagogic hallucinations (Video 85-3). Similar hallucinations can occur upon awakening; these hypnopompic hallucinations may be more characteristic of narcolepsy than the hypnagogic ones. The visual hallucinations usually consist of simple forms (colored circles, parts of objects, and so forth) that are either constant or changing in size. The image of an animal or a person can occur abruptly and more often in color. Auditory hallucinations are also common, although other senses are seldom involved. The auditory hallucinations can range from a collection of sounds to an elaborate melody. The patient may also be frightened by threatening sentences or harsh invective. Often hypnopompic hallucinations are perceived as so vividly realistic that the patient acts on them upon awakening. For example, patients with narcolepsy have been known to call the police due to intruders being in the home, only to discover after authorities have searched the house that it was all a hallucination. The exact boundary between hypnagogic and hypnopompic hallucinations and dreams is not a clear one. In some cases of unrecognized narcolepsy with daytime hypnagogic or hypnopompic hallucinations, the patient may be mistakenly determined to have a delusional psychosis.17 Another common and interesting type of hallucination reported at sleep onset involves elementary cenesthopathic feelings (i.e., experiencing picking, rubbing, or light touching), changes in location of body parts (e.g., arm or leg), or feelings of levitation or extracorporeal experiences (e.g., moving the body in space or floating above the bed) that may be quite elaborate. For example, the patient might report, “I am above my bed and I can also see my body below” or “I am a few feet up and people are jumping over my body.” The association of sleep paralysis has led
researchers to postulate gamma loop involvement in some of these hallucinations. The abrupt motor inhibition that involves the spinal cord motor neurons can lead to significant decrease in the feedback of information that is normally used by the central nervous system (CNS) to gauge the position of the body and the relation of the limb segments to each other. Sleep Disruption Narcolepsy patients commonly experience disturbed nocturnal sleep. Night sleep is often interrupted by repeated awakenings and sometimes accompanied by terrifying dreams. Ironically, patients complain of difficulty falling asleep and staying asleep at night, although they might fall asleep repeatedly during the daytime. Rarely, insomnia with secondary daytime tiredness is the initial complaint. The sleep disruption may be enhanced by the presence of periodic limb movements, which appear to be common in these patients. These movements can be associated with typical episodes of REM sleep behavior disorder.
ONSET OF CLINICAL SYMPTOMS The first symptom often develops near the age of puberty; the peak age at which reported symptoms occur is 15 to 25 years, but narcolepsy and other symptoms have been noted as early as 2 years, and at 6 months of age in the case with hypocretin gene mutation.18 A second, smaller peak of onset has been noted between 35 and 45 years and near menopause in women. In those who developed narcolepsy at age 60 years or later, cataplexy was the most common initial symptom.19 There is often a marked delay of more than 10 years before diagnosis is made, especially if cataplexy is initially absent (Video 85-4).20 A survey of 157 narcoleptic patients found that the majority experienced symptoms before 30 years of age; only 21% of the patients had their first symptom after 30 years of age.19 Excessive daytime sleepiness and irresistible sleep attacks usually occur as the first symptoms, either independently or associated with one or more symptoms. They are enhanced by high environmental temperature, indoor activity, and idleness. Symptoms might abate with time but never phase out completely. Attacks of cataplexy usually appear in conjunction with abnormal episodes of sleep but can occur as long as 20 years later. They occasionally occur before the abnormal sleep episodes, in which case they are a major source of difficulty in diagnosis. They can vary in frequency from a few episodes during the subject’s entire lifetime to one or several episodes per day. Cataplectic attacks have an overall tendency to decrease in frequency with aging. Hypnagogic and hypnopompic hallucinations and sleep paralysis do not affect all subjects, are often transitory, and occur commonly in the general population.21 Disturbed nocturnal sleep seldom occurs in the first stages and usually worsens with age.22 Narcolepsy leads to a variety of complications, such as accidents related to driving or operating machines; difficulties at work leading to disability, forced retirement, or job dismissal; impotence; and depression.23
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DIAGNOSTIC PROCEDURES Evaluating Sleepiness The Stanford Sleepiness Scale,24 a seven-point scale, was developed to quantify the subjective sleepiness of patients throughout the day, but it is often difficult for patients to accurately rate themselves every 15 to 20 minutes. The Epworth Sleepiness Scale (ESS) is also used as an index of subjective sleepiness (see Chapter 143). The ESS is not validated in children. The Pediatric Daytime Sleepiness Scale, a validated scale, is more appropriate for use in children and teenagers. Several tests have been designed to evaluate sleepiness objectively. The multiple sleep latency test (MSLT; see Chapter 143) was designed to measure physiologic sleep tendencies in the absence of alerting factors.25 This test consists of five scheduled naps, usually at 10 am, noon, and 2, 4, and 6 pm, during which the subject is polygraphically monitored in a comfortable, soundproof, dark bedroom, while wearing street clothes. The MSLT records the latency for each nap (time between lights out and sleep onset), the mean sleep latency, and the presence or absence of REM sleep during any of the naps.26 On the basis of polygraphic recording, REM sleep that occurs within 15 minutes of sleep onset is considered a SOREMP.27 After each 20-minute monitoring period, patients stay awake until the next scheduled nap. In the normal population, MSLT scores vary with age, and puberty is a critical landmark. Prepubertal children between the ages of 6 and 11 years appear to be hyperalert. In postpubertal subjects, mean MSLT scores under 8 minutes are generally considered to be in the pathologic range; those over 10 minutes are considered to be normal. When the range is between 8 and 10 minutes, age factors interact, so the test must be interpreted with greater care; mean scores of 8 to 10 minutes represent a gray area.28 An MSLT performed alone has drawbacks: it measures sleepiness regardless of its cause, which may simply be sleep deprivation. The MSLT also ignores repetitive microsleeps that can lead, in borderline cases, to daytime impairment not scored by conventional analysis. To be clinically relevant, the test must be conducted under specific conditions. Subjects must have abstained from medication for a sufficient period (usually 15 days) so that drug interaction is avoided. On the basis of sleep diaries, their sleep–wake schedules are stabilized. On the night preceding the MSLT, the subjects undergo a standard nocturnal polysomnogram. Throughout the total nocturnal sleep period, any sleep-related biologic abnormalities responsible for sleep fragmentation and sleep deprivation are recorded. The nocturnal polysomnogram can indicate the underlying cause of sleepiness; the MSLT indicates the severity of the problem. Once the nocturnal sleep recording has eliminated specific diseases, the MSLT confirms the diagnosis of narcolepsy with the presence of two or more SOREMPs and a mean sleep latency of 8 minutes or less. Browman and colleagues29 proposed adding to the MSLT a test for maintaining wakefulness (MWT). The MWT tests the patient’s ability to remain awake in a comfortable sitting position in a dark room for five 20-minute trials given at 10 am, noon, and 2, 4, and 6 pm. The MWT
960 PART II / Section 11 • Neurologic Disorders
may be helpful in specific pharmacologic trials, in evaluating response to a treatment for alertness, and in evaluating the risk of falling asleep associated with specific jobs or activities, but it has proved to be unsatisfactory as a diagnostic procedure.29 Traditionally, the test is composed of five nap opportunities at 2-hour intervals, similar to the MSLT. Each opportunity for sleep lasts 20 minutes. More recently, the test consists of four 40-minute sessions administered at 2-hour intervals, with a cutoff point around 30 minutes before falling asleep. MWT is typically useful in distinguishing between a pathologic process and normality. Another procedure that has been used to document sleepiness is a continuous 24- or 36-hour polysomnogram that provides information about the number, duration, times, and types of daytime sleep episodes, as well as documenting nighttime sleep disruptions. In addition, this long polysomnographic recording can identify the dissociated REM sleep–inhibitory process characterizing cataplexy by showing the absence of chin and muscle twitches, which are typical of REM sleep, in the awake patient. These recordings may be performed using ambulatory equipment. Diagnosing Narcolepsy By consensus, the diagnosis of narcolepsy requires a clinical history of excessive daytime sleepiness and a positive MSLT, with a mean sleep latency of no more than 8 minutes and two or more SOREMPs.14 However, there is controversy concerning the criteria needed to confirm narcolepsy in patients with excessive daytime sleepiness. There is a progressive decrease in the number of SOREMPs and an increase in the mean sleep latency on the MSLT as a function of age, suggesting that the current criteria used for diagnosis may be too stringent in older patients.30 Clinicians and researchers in Japan have indicated that their U.S. counterparts have given too much credit to polysomnographic criteria and the presence of two or more SOREMPs on MSLT.31 General population investigations have shown that normal subjects can have two or more SOREMPs, and there seems to be a greater chance of having narcolepsy with the presence of two or more SOREMPs, but the likelihood of having narcolepsy in relation to an increasing number of SOREMPs is unknown.32 In Japan, a positive history of cataplexy associated with excessive daytime sleepiness is systematically required for the diagnosis of narcolepsy.31 Undoubtedly, the presence of cataplexy is pathognomonic of narcolepsy, but it may be difficult to rely on this criterion alone, particularly when cataplexy is partial (i.e., limited to the head and neck or neck and upper arms). Anic-Labat and colleagues33 developed a self-administered questionnaire that validated cataplexy in 1000 subjects. Moscovitch and coworkers34 also cautioned against the diagnosis of narcolepsy if excessive daytime sleepiness and two or more SOREMPs at MSLT are the only positive findings. These authors found that only 84% of the persons with complaints of excessive daytime sleepiness and documentation of cataplexy had two or more SOREMPs on MSLT, a replication of findings by Van den Hoed and
colleagues28 10 years earlier. They found that all subjects with excessive daytime sleepiness and cataplexy had two or more SOREMPs at one MSLT if the MSLT was repeated daily for 4 days. Moscovitch and coworkers34 recommended that the term narcolepsy be used only when excessive daytime sleepiness and at least a positive history of cataplexy are associated with two or more SOREMPs. If there is no history of cataplexy, a more descriptive term such as excessive daytime sleepiness with several SOREMPs could be used, even if other symptoms such as sleep paralysis or hypnagogic hallucinations exist. Narcolepsy occurs sporadically in 99% of patients, but genetic factors probably play a role in which environ mental factors to act on. Genetic testing has been used to aid in the clinical diagnosis of narcolepsy. The HLA DQB1*0602 is the most specific genetic marker for narcolepsy across all ethnic groups, and it is found in 95% of narcoleptic patients with cataplexy.35,36 Mignot’s group35 showed that 40% of subjects with narcolepsy and no cataplexy were positive for the human leukocyte antigen (HLA) DQB1*0602, and the HLA is positive in 18% to 35% of the general population (without narcolepsy or cataplexy). Thus, genetic testing alone is not sufficient for the diagnosis of narcolepsy. The systematic requirement of a positive history of cataplexy would eliminate subjects in the developing phase of the syndrome, which can take several years. However, the use of strict criteria will allow better epidemiologic studies to be conducted. Subjects would be classified as narcoleptic only after the presence of excessive daytime sleepiness and cataplexy had been reported and abnormal daytime alertness had been confirmed by polysomnographic recording with MSLT. The discovery of cerebrospinal fluid (CSF) hypocretin (orexin) has led to a new diagnostic approach. In 1998, two different groups independently discovered that a hypothalamic peptide neurotransmitter (named hypocretin by one group and orexin by the other)37,38 played a major role in maintenance of wakefulness. Hypocretin is produced exclusively by a group of neurons located in the lateral hypothalamus and has projections widely throughout the CNS.39 In 1999 Stanford researchers discovered an autosomal recessive mutation in the hypocretin receptor 2 gene (HCRTR2) responsible for narcolepsy in canines.40 This discovery identified hypocretins as the major sleepmodulating neurotransmitter.40 However, narcolepsy in humans is not a result of gene mutations; rather, narcoleptic humans were found to have very low levels of CSF hypocretin. Hypocretin neurons and functions are selectively damaged in patients with narcolepsy, although the cause is still unknown.39 By performing a lumbar puncture, a very low or nonexistent level of hypocretin can confirm the diagnosis of narcolepsy with cataplexy.40-43 CSF hypocretin-1 levels less than 110 ng/L (measured using the Stanford University technique), have a high positive predictive value (94%) for narcolepsy with cataplexy.39,44 Currently, CSF hypocretin measurement is the most accurate diagnostic technique available; however, narcolepsy is recognized in a low percentage (less than 9%) of subjects despite normal levels of CSF hypocretin. In rare
CHAPTER 85 • Narcolepsy: Diagnosis and Management 961
cases, low CSF hypocretin levels may be due to GuillainBarré syndrome, brain tumors, encephalitis, vascular diseases, and brain trauma.39
Box 85-1 Examples of Initial Treatment Packages for Children
TREATMENT At present, there is no cure for narcolepsy. The goal of all therapeutic approaches is to control narcoleptic symptoms and allow the patient to have a full personal and professional life.44a Other sleep disorders may co-exist (Video 85-5). Treatment goals specifically include control of excessive daytime sleepiness, cataplexy attacks, hypnagogic or hypnopompic hallucinations, sleep paralysis, improvement in nocturnal sleep, and psychosocial difficulties. Drug prescriptions must take into account possible side effects because narcolepsy is a lifelong illness and patients have to receive medication for years. Tolerance or addiction can occur with some compounds. In addition, hypertension, abnormal liver function, and psychosis are the most commonly reported complications associated with the long-term use of stimulant medications. The treatment of narcolepsy must balance maintaining an active life with avoiding side effects and developing tolerance to medications.45 Behavioral Approaches Part of the difficulty in treating patients who have narcolepsy involves the patient’s frustration over the delay in diagnosis. In 500 narcoleptic patients surveyed in United States in the 1980s, the mean time to diagnosis from symptom onset was 15 years. The consequence of this, particularly in a young patient, is the development of reactive depressive symptoms. One of the most important initial treatments is a referral to patient support groups organized by sleep disorders centers, such as the National Sleep Foundation or the Narcolepsy Network. Other support groups exist in most western European countries and in North America. The American Academy of Sleep Medicine is an integral resource. Career counseling is also important because patients and their employers must be educated regarding jobs that patients with narcolepsy should avoid, including shiftwork, on-call schedules, driving and the transportation industry, or any job necessitating continuous attention for long hours without breaks, particularly under monotonous conditions. Some of these difficulties can be overcome if the employer recognizes the importance of short 15 to 20 minute naps every 4 hours during the daytime. In addition to scheduled naps, other important behavioral treatment targets include following a regular sleep–wake schedule, avoiding frequent time zone changes, and practicing good sleep hygiene. Pharmacologic Treatments Table 85-1 lists currently available drugs for narcolepsy. Boxes 85-1 and 85-2 list the treatment protocols for adults and children. All Major Symptoms of Narcolepsy S ODIUM O XYBATE In 1979, Broughton and Mamelak46 first suggested that sodium oxybate (gamma-hydroxybutyrate [GHB])
Prepubertal Children General Measures Contact school to alert teachers Nap at lunch time and 4 or 5 PM Medications for Sleepiness Modafinil 100-200 mg* Armodafinil 50-250 mg Sodium oxybate (GHB) 6-8 g Methylphenidate 5 mg (2-4 tablets†) Atomoxetine 10-25 mg Medications for Cataplexy‡ Sodium oxybate (GHB) 6-8 g Venlafaxine 75-150 mg in the morning Fluoxetine 10-20 mg in the morning Clomipramine 50 mg at bedtime Pubertal Children General Measures Contact school to alert teachers Nap at lunch time and 4 or 5 PM Emphasize need for a regular nocturnal sleep schedule Try to obtain 9 hours of nocturnal sleep Medications for Sleepiness Modafinil 100-400 mg* Armodafinil 50-250 mg Sodium oxybate (GHB) 6-9 g Methylphenidate 5 mg (2-6 tablets†) or 20 mg sustained-release tablet in the morning (on empty stomach) Atomoxetine 10-25 mg Medications for Cataplexy‡ Sodium oxybate (GHB) 6-9 g Venlafaxine 75-150 mg in the morning Fluoxetine 10-40 mg in the morning *Modafinil is started at 100 mg in the morning for 5 days, and a second dose of 100 mg is then added at lunch time, if needed. This is usually sufficient in prepubertal children. Pubertal children might require a further increase (after 5 days) to an additional 100 mg in the morning and, if still needed later, another 100 mg at noon. † Usually 10 mg when waking up on an empty stomach, 5 mg around lunch time, and 5 mg at 3 PM. ‡ The use of antidepressants for cataplexy is not approved by the Food and Drug Administration (FDA). No medications have specifically received approval by the FDA for use in narcoleptic patients younger than 16 years.
improved cataplexy, daytime sleepiness, and disturbed nocturnal sleep in patients with narcolepsy. GHB is a naturally occurring CNS metabolite that is found in highest concentrations in the hypothalamus and basal ganglia and acts as a sedative to consolidate REM sleep. It is now the major treatment of choice for narcolepsy with cataplexy. In addition to its use as an anticataplectic medication, it also improves excessive daytime sleepiness and disturbed nocturnal sleep. GHB treats cataplexy through an unknown mechanism that is thought to be related to its consolidation of REM sleep or to a secondary interaction with dopamine secretion.46-51
962 PART II / Section 11 • Neurologic Disorders Box 85-2 Examples of Initial Treatment Packages for Adults General Measures Avoid shifts in sleep schedule Avoid heavy meals and alcohol intake Regular timing of nocturnal sleep: 10:30 PM to 7 AM Naps: Strategically timed naps if possible (e.g., 15 min at lunchtime, 15 min at 5:30 PM) Medications for Sleepiness The effects of stimulant medications vary widely among patients. The dosing and timing of medications should be individualized to optimize performance. Additional doses, as needed, may be suggested for periods of anticipated sleepiness. • Modafinil* 100-200 mg (taken when waking up in the morning) and 100-200 mg at lunchtime, or • Armodafinil* 50-250 mg (taken once in the morning) • Sodium oxybate (GHB)† at bedtime • Dosage must start low at 2.25 g taken twice while in bed (at bedtime and 2.5-4 hours after bedtime); increase to total dosage of 5 to 6 g within 2-4 weeks. • The initial dose is usually an ineffective dose, so keep increasing as indicated on package until 3 g at bedtime and 3 g 2.5 to 4 hours after bedtime. This is a therapeutic dose. Depending on response, dosage can be increased to 9 g total daily dose. Do not increase over 9 g because of risk of serious side effects during sleep. • Improvement in cataplexy is seen much faster than on daytime sleepiness. Slowly decrease medication taken for daytime sleepiness only when therapeutic dosage of GHB has been reached. As it takes up to 2 months to see a good response on daytime sleepiness, sodium oxybate is normally used with modafinil for the first 2 months.
• Methylphenidate 5 mg (3 or 4 tablets; 10 mg when waking up; 5 mg 30 min before lunch; 5 mg near 3 PM; better action is always obtained if the drug is taken on an empty stomach) or 20 mg SR morning (on an empty stomach) If Persistent Difficulties • Modafinil 200 mg in the morning and 200 mg at lunchtime with further increase to 300 mg at morning and lunchtime (total daily dosage 600 mg), or • Add sodium oxybate (GHB) at bedtime: dosage must start low as indicated above, or • Methylphenidate (SR): 20 mg in the morning; 5 mg after noon nap; 5 mg at 4 PM, or • Atomoxetine (more in teenagers): start at 0.5 mg/kg within one week to appropriate dosage of 1 to 1.2 mg/kg taken in the morning If No Response • Dextroamphetamine sulfate (will induce rebound hypersomnia), or • Dexedrine Spansule, SR: 15 mg on awakening; 5 mg after noon nap; 5 mg at 3:30 or 4 PM (or 15 mg at awakening and 15 mg after noon nap) Medications for Cataplexy‡ • Sodium oxybate (see above) • Venlafaxine 75-300 mg • Fluoxetine 20-60 mg Drugs below are used much less today: • Clomipramine 75-125 mg • Viloxazine 150-200 mg • Imipramine 75-125 mg
*Modafinil and Armodafinil work best in naive subjects. It should be the drugs of first choice in children and adults. † Response to sodium oxybate is slow. ‡ Medications may be taken in the evening near bedtime (GHB, clomipramine, imipramine); only in the morning (fluoxetine), or in the morning and at lunchtime (viloxazine, venlafaxine). Tricyclic medications, despite efficacy, should be third-line medications because of side effects. The use of antidepressants for cataplexy is not approved by the U.S. Food and Drug Administration (FDA). The only medications specifically approved for use in narcolepsy by the FDA are modafinil and GHB (for cataplexy). GHB, gamma-hydroxybutyrate; SR, sustained-release tablet.
In its endogenous form (gamma-hydroxybutyrate), it is a neurotransmitter and neuromodulator that affects dopamine, serotonin, gamma-aminobutyric acid (GABA), and endogenous opioids. It is postulated to act through its own receptors and via stimulation of GABAB receptors. GHB binds to GABAB receptors with low affinity. At a dose of 30 mg/kg, it has been shown to induce a normal sequence of NREM and REM sleep in normal volunteers that lasts 2 to 3 hours. GHB has been part of multicenter studies in the United States and has shown long-term efficacy.50,52 The drug is normally taken at bedtime, with the patient already in bed to avoid falls. A second dose is taken approximately 2.5 to 4 hours after the first one while the patient is in bed. Its half-life is 90 to 120 minutes. The effective dose varies from 6 to 9 g, with a small increase in nocturnal total sleep time and a decrease in sleep paralysis, hypnagogic hallucinations, and nightmares. There is a progressive increase of dose intake over 6 to 8 weeks.
The initial dosing is usually too low to have a therapeutic effect, particularly on daytime sleepiness. This progressive effect indicates that the therapeutic effect is an indirect one. It can take 2 to 3 months to see the full effects of the medication on daytime alertness. All patients subjectively report progressive improvements in feeling rested upon awakening. Overall, a positive effect on cataplexy is reported. The response is gradual but is seen much more rapidly than the effect on alertness, with a significant decrease in the frequency of cataplectic attacks. As mentioned previously, these gradual effects, particularly on sleepiness, mean that patients must initially take other alerting agents, temporarily, to control sleepiness. If patients wake up in the middle of the night, they may be confused and disoriented, and they may have episodes of enuresis, particularly at a high dosage of 9 g and also during initial use of the drug. A transient worsening of cataplexy during the nocturnal
CHAPTER 85 • Narcolepsy: Diagnosis and Management 963
Table 85-1 Narcolepsy Drugs Currently Available
DRUG
USUAL DOSAGE* (ALL DRUGS ADMINISTERED ORALLY)
Treatment of Excessive Daytime Sleepiness Stimulants† Modafinil
100-600 mg/day
Armodafinil
50-250 mg/day
Sodium oxybate (GHB)
6-9 g/day (divided in two doses)
Methylphenidate
10-60 mg/day
Atomoxetin
10-25 mg/day
Dextroamphetamine
5-60 mg/day
Methamphetamine
20-25 mg/day
Treatment of Auxiliary Effects (e.g., Cataplexy) Sodium oxybate (GHB)
6-9 g/day (divided in two doses)
Antidepressants‡ without Atropinic Side Effects Venlafaxine
75-300 mg/day
Fluoxetine
20-60 mg/day
Viloxazine
50-200 mg/day
Antidepressants‡ (with Atropinic Side Effects, used much less today) Protriptyline
2.5-20 mg/day
Imipramine
25-200 mg/day
Clomipramine
25-200 mg/day
Desipramine
25-200 mg/day
*Occasionally, depending on clinical response, the dose may be outside the usual dosage range. † Most stimulants should be administered in divided doses, commonly in the morning and at lunch time. This is recommended for amphetamines and modafinil. Methylphenidate has a fast elimination rate; the slow-release (SR) formula may be helpful in the morning (e.g., 20 mg SR). If administered by 5 mg increments, the usual timing of methylphenidate administration is every 3 to 4 hours until 3 pm. ‡ The use of antidepressants for cataplexy is not approved by the U.S. Food and Drug Administration (FDA). The only medications specifically approved for use in narcolepsy by the FDA are modafinil and gamma-hydroxybutyrate (sodium oxybate).
period can occur. Nausea may be seen with a high dosage, as well as sluggishness in the early mornings. Patients generally prefer this drug to the anticataplectic drugs because there are fewer side effects. In clinical trials, GHB has demonstrated a dose-related efficacy in cataplexy and daytime sleepiness, with no acute rebound effect following withdrawal after 4 weeks of therapy. There is a sustained increase in efficacy on cataplexy over 12 months, with maintenance of efficacy on daytime sleepiness. GHB shows a dose-related increase in slow-wave sleep and reduction in nocturnal awakenings at doses of 7.5 to 9 g. Studies have not shown negative effects on respiratory parameters.50-60 GHB is not recommended in pregnancy.
A TOMOXETINE Atomoxetine, the specific noradrenergic reuptake inhibitor also used in the treatment of cataplexy, has been effective in improving daytime sleepiness, particularly in children. Atomoxetine may be prescribed as the one medication to deal with both main symptoms, but it is clearly less effective than modafinil and sodium oxybate in older teenagers and adults.61,62 S ELEGILINE Selegiline is a potent irreversible monoamine oxidase-B (MAO) inhibitor. Its active metabolites are l-amphetamine and l-methamphetamine. The drug has anticataplectic effects and improves excessive daytime sleepiness at a starting dose of 20 mg/day with a maximum recommended dose of 40 mg/day.61,62 Adverse effects include sympathomimetic and multiple drug to drug interactions. To avoid risk of hypertensive emergencies, a diet low in tyramine is recommended. Excessive Daytime Sleepiness M ODAFINIL Modafinil is the first-line pharmacologic treatment for excessive daytime sleepiness and irresistible episodes of sleep in narcoleptic patients.62a Modafinil is a wakepromoting drug whose mechanism is unknown, but it has been hypothesized to selectively activate wake-generating sites in the hypothalamus. Modafinil’s mechanism of action is different from that of the amphetamines.63 The data are controversial on the role of dopamine in mediating the wake-promoting effects of modafinil.64,65 In narcoleptic dogs, the drug increases extracellular dopamine in independent of hypocretin receptor-2.64 In DAT (dopamine transporter) knockout mice, the lack of response to the wake-promoting action of modafinil suggests that dopamine transporters do play a role and are necessary for wake-promoting actions of this drug.64 Results from several multicenter studies indicate that modafinil had a significant impact on the objective measures of sleepiness and improves wakefulness in narcoleptic patients; however, the improvement noted on MSLT was never normalized. This suggests that narcolepsy is a complex disorder in which mechanisms underlying daytime sleepiness are not yet well understood. Modafinil has no known anticataplectic effects or other REM-related sleep symptoms. The most important benefit of modafinil is its relative lack of side effects. It is not addictive and therefore has a low potential for abuse. There is no reported evidence showing that tolerance develops to the effects of modafinil on excessive daytime sleepiness. Headache is the most common complaint, followed by nervousness, nausea, and dry mouth. These symptoms can be reduced by a slow and progressive increase in dosage. Blood pressure should be monitored because the drug can cause elevated pressures. Most European studies suggest twice-daily administration, in the morning and at lunch time. Its elimination half-life is 10 to 12 hours. Modafinil can be administered concurrently with anticataplectic medications without problems. Modafinil can reduce the efficacy of oral contraceptives, and therefore patients need to be warned and advised on additional forms of protection.
964 PART II / Section 11 • Neurologic Disorders
Switching patients from a stimulant medication to modafinil can lead to the reappearance of narcoleptic symptoms. Patients who have been taking a daily dose of amphetamines of 45 mg or more complain of less control over sleepiness when switched to modafinil. Another problem encountered in the switch from amphetamines to modafinil is the reappearance of cataplectic attacks and, more rarely, sleep paralysis in patients whose narcolepsy was previously well controlled with a combination of stimulants and anticataplectic agents, or by amphetamines alone. Amphetamines have a direct impact on the norepinephrine synapse, thereby helping to control cataplexy and sleep paralysis. Modafinil has none of these activities. With the switch to modafinil, patients who had mild REM sleep–related symptoms controlled on amphetamine might experience an abrupt recurrence of these symptoms at the time of the switch of medication and might need an adjunct compound temporarily. In patients already taking an anticataplectic drug simultaneously, an increase in the daily intake of this medication may be necessary. The combination of modafinil and venlafaxine has provided good results in these specific cases. Modafinil produces best results in stimulant-naive patients. Black and Houghton performed a double-blind, placebo-controlled comparison trial of modafinil, GHB, or the combination for the treatment of excessive daytime sleepiness in 270 adult narcoleptic patients and found that both drugs are effective in treating excessive daytime sleepiness and are additive when used together.66 Both the stimulant medications and the anticataplectic drugs are hepatically metabolized, so any liver dysfunction affects both classes of drug. Thus, regular liver function tests are recommended. A RMODAFINIL Armodafinil is the R-enantiomer of the racemic modafinil.66a In 2007 armodafinil was approved for the treatment of excessive daytime sleepiness in narcoleptic patients. In a multicenter, randomized, double-blind, placebocontrolled trial of 196 subjects with narcolepsy, armodafinil significantly improved excessive daytime sleepiness throughout the day.61,67,68 The R-enantiomer has a half-life of 10 to 14 hours compared to a half life of 3 to 4 hours for the S-enantiomer. Plasma concentrations in humans have been found to be higher during wakefulness later in the day compared to modafinil. The usual dosing is 50 to 400 mg/day. Side effects are similar to modafinil’s, which include headache, nausea, dizziness, and insomnia. No parallel studies comparing modafinil to armodafinil have been published. A MPHETAMINES AND A MPHETAMINE- L IKE C ENTRAL N ERVOUS S YSTEM S TIMULANTS Amphetamines were first proposed as a treatment of excessive daytime sleepiness in narcolepsy by Prinzmetal and Bloomberg in 1935, and the first addiction to amphetamine was reported in 1939.69 Known as CNS stimulants, amphetamine-like drugs including methylphenidate, dextroamphetamine, and methamphetamine increase the release of dopamine, norepinephrine, and serotonin and inhibit the reuptake of amines by the dopamine transporter. These drugs increase sleep-onset and REM sleep
latency, and they reduce sleepiness and the percentage of REM sleep. Because they stimulate norepinephrine release and have dopaminergic activity, amphetamines and methylphenidate have the greatest impact on daytime sleepiness. In standard doses, amphetamines can enhance performance in simple motor and cognitive tasks; improve coordination; and increase strength, endurance, and mental and physical alertness, especially in monotonous situations.70 In adults, methylphenidate and amphetamines at dosages of more than 60 mg/day do not significantly improve excessive daytime sleepiness without long-term side effects, including frequent worsening of the nocturnal sleep disruption, higher frequencies of psychosis, paranoia, alcohol or polydrug abuse, and psychiatric hospitalizations. Rebound hypersomnia is more common with higher dosages of amphetamines. These stimulants have a high potential for abuse and development of tolerance, and therefore they should be administered at the lowest effective doses. The drug is usually administered in three divided doses, with a maximum of 20 mg in the morning, 20 mg at lunchtime, and 20 mg at 3 pm—never later. Therefore, short naps are necessary. The combination of pharmacologic agents and two short naps provides the best daily response to excessive daytime sleepiness, with no stimulant drug taken after 3 pm. The slow-release form may provide gradual and delayed response during the daytime. The association between anticataplectic drugs and amphetamine-like medications can enhance the anticataplectic effect of the stimulant medication.71 Our patients subjectively rate the effectiveness of methylphenidate on a similar level to modafinil. None of the currently available stimulants, including modafinil, has been tested in parallel with a placebo control or in comparison with each other in the narcoleptic population. Cataplexy and REM Sleep–Related Symptoms Investigations have shown that muscle atonia is normally associated with REM sleep; REM-associated muscle atonia occurs at inappropriate times during wakefulness in narcoleptic patients and is responsible for cataplexy. Several neurotransmitter systems have been identified that affect the inhibitory pathways involving the lower motor neurons, particularly muscarinic cholinergic and noradrenergic systems at the a1b and D2 receptor levels but also glycinergic and glutaminergic receptors. The best medications for cataplexy are those that target these receptors with the fewest side effects.72 M ONOAMINE N ONSPECIFIC U PTAKE I NHIBITORS Tricyclic antidepressants were the first medications used to treat cataplexy. The older tricyclics include imipramine, clomipramine, and protryptiline.73,74,75 Tricyclic antidepressants inhibit monoamine (serotonin, norepinephrine, dopamine) reuptake and block cholinergic, histaminic, and α-adrenergic transmission, and they were the first drugs of choice, particularly protryptiline. However, they have significant anticholinergic side effects including dry mouth, sweating, constipation, tachycardia, difficulty urinating, and particularly sexual dysfunction that led to impotence in more than 40% of male narcoleptic patients. Most
tricyclic antidepressants with significant anticholinergic side effects are now used as a last resort. S ELECTIVE S EROTONIN R EUPTAKE I NHIBITORS Selective serotonin reuptake inhibitors have an active noradrenergic reuptake blocker metabolite, the prototype being fluoxetine and its active metabolite norfluoxetine.76 Based on our experience, we recommend starting with 20 mg fluoxetine in the morning and increasing to 60 to 80 mg/day in two divided doses. Fluvoxamine at 25 to 200 mg/day has been shown to be mildly effective on cataplexy. This class is less efficacious in treating cataplexy but has fewer side effects than tricyclics. Adverse effects include CNS excitation, nausea, and sexual difficulties. Tolerance to this class does not develop. N OREPINEPHRINE AND S EROTONIN U PTAKE I NHIBITORS These newer antidepressants have been found to be effective for cataplexy, sleep paralysis, and hypnagogic and hypnopompic hallucinations. They are the recommended drugs because they have fewer side effects and greater efficacy. The most commonly used drug of this class is venlafaxine, a potent inhibitor of serotonin and noradrenergic reuptake and a weak inhibitor of dopamine reuptake. At a dose of 75 to 150 mg, venlafaxine has been the most widely used of these compounds both in adults and in children; it has shown good response and is better tolerated than the tricyclics. It has no significant activity for muscarinic, cholinergic, H1 histaminergic, and α1adrenergic receptors. Atomoxetine (18 to 100 mg once a day or in two divided doses) is a highly specific noradrenergic reuptake inhibitor and has been tried in cases of resistant cataplexy after failure of fluoxetine, venlafaxine, and other serotonin reuptake inhibitors. The decision to select sodium oxybate or venlafaxine as a treatment for cataplexy is not based on data but mostly related to socioeconomic rationale. The advantage of venlafaxine is its ease of prescription and timing of intake of the medication during wakefulness. The advantage of sodium oxybate is its slow but significant impact on daytime sleepiness and the possibility that after 2 to 3 months the patient needs to take only one medication for both cataplexy and daytime sleepiness. Serotonin and noradrenalin reuptake inhibitors and selective serotonin reuptake inhibitors are category C drugs when used during the last trimester of pregnancy. They can lead to serious respiratory and feeding side effects in the neonate immediately after birth. Pregnant women might need to be progressively withdrawn from these medications before the third trimester of pregnancy. The withdrawal must be slow to avoid a marked cataplexy rebound that usually occurs on day 3 or 4 and peaks near day 10 after completion of withdrawal. Investigative Agents Emerging treatments under investigation for narcolepsy include hypocretin-based therapies, hypocretin gene therapy, stem cell transplantation, immunotherapy, thyrotropin analogues and promoters, and histamine (H3) antagonists.61,77,77a A major limitation to hypocretin-1 replacement therapy is that it has to cross the blood–brain barrier to reach the CNS. Therapies exploring modalities
CHAPTER 85 • Narcolepsy: Diagnosis and Management 965
for drug delivery are becoming of interest. Possible hypocretin replacement therapies include intranasal and intracerebroventricular administration.78 Gene therapy as a treatment for hypocretin deficiency has been a topic of research. Mieda and colleagues79 conducted a study on genetic rescue in mice with ablated hypocretin neurons, highlighting viral vectors as a potential future treatment for hypocretin-deficient narcoleptic patients. There is some evidence that thyrotropin and thyrotropin agonists have stimulant, antidepressant, and neurotrophic effects, thus making this a possible treatment modality for narcolepsy. Thyrotropin has been shown to increase wakefulness and decrease cataplexy in canine narcolepsy.80 There is ongoing research on the histaminergic system and its action on hypocretin signaling for promoting wakefulness.81,82 Histamine H3 receptors are abundant in the CNS and are inhibitory autoreceptors. A novel investigative agent, thioperamide, a potent H3 antagonist, significantly enhances wakefulness in hypocretin-deficient (orexin-deficient) narcoleptic mice, raising the possibility that H3 antagonists may be useful in treating excessive daytime sleepiness in human narcoleptics.83 Autoimmune destruction of hypocretin neurons resulting in low or undetectable CSF hypocretin levels and associated clinical symptoms of narcolepsy has been hypothesized. In a case report, Lecendreux and colleagues used high-dose intravenous immunoglobulin (IVIg) and corticosteroids in a 10-year old boy within 2 months after onset of narcolepsy, with improvement in cataplexy and daytime sleepiness.84 In another case report, Hecht’s group performed a 3-week trial of high-dose prednisone (1mg/kg/day) in an 8-year old boy with 2 months of hypocretin-deficient narcolepsy. CSF hypocretin levels and the boy’s clinical symptoms did not improve. At present, IVIg and corticosteroids are not recommended, and further trials are needed to determine the possible role of these two drugs in the treatment of narcolepsy.85 Further review of new insights on the pathophysiology and investigational treatment approaches for this rare disease has recently been published.77 Medication Side Effects Common side effects have been well described in previous reports, but some side effects that are rarely mentioned may be more important in narcoleptic patients, such as the appearance of periodic limb movements during sleep. This syndrome is related to the increase in muscle tone induced by these compounds during sleep and can lead to a significant fragmentation of sleep. Levodopa or other dopamine agonists (e.g., pramipexole, pergolide, and ropinirole) may be useful.86,87 Another rare side effect worth mentioning is the development of REM sleep behavior disorder, particularly in older subjects. Classically, tricyclic antidepressants and serotonin reuptake inhibitors “decrease” REM sleep. These drugs eliminate or decrease the muscle atonia of REM sleep and dissociate REM sleep (i.e., electroencephalographic pattern of REM sleep without muscle atonia). Although the absence of muscle atonia limits the ability to score this stage as REM sleep using the international
966 PART II / Section 11 • Neurologic Disorders
rules,26 the electroencephalographic pattern and dream state of REM persist. Thus, the patient can act out his or her dreams. Although REM sleep behavior disorder is a separate sleep disorder, it can occur in narcoleptic patients who already have dysfunction of muscle tone control with cataplexy, and this tendency may be enhanced with anticataplectic drugs. It is unclear if long-term use of anticataplectic drugs favors this complication. Rebound cataplexy and other REM-related symptoms such as sleep paralysis and hypnagogic or hypnopompic hallucinations can be seen with abrupt drug withdrawal. These medications should be withdrawn slowly; the recommended withdrawal schedule is one dose every 4 days. Patients must be warned about this side effect and prohibited from driving during the withdrawal period. When switching medications, our experience has been to add the second drug 16 to 24 hours after interrupting the previous medication.88 Treatment in Children Based on our clinical experience of more than 1000 adults and children with narcolepsy, we recommend modafinil for the treatment of excessive daytime sleepiness in children with narcolepsy. A study of 13 children (mean age
11.0 ± 5.3 years) taking modafinil (346 ± 119 mg/day) showed reduction in sleep attacks in 90% of subjects, prolongation of sleep latency (from 6.6 ± 3.7 min to 10.2 ± 4.8 min, P = .02), and appeared to be safe and well tolerated (mean treatment duration, 15.6 ± 7.8 months).89 Modafinil seems to work best when administered morning and noon, but this may be a problem with children, so a single dose in the morning may be prescribed. The drawback of single-dose administration is that the therapeutic effect might not last late into the day. A 5-mg methylphenidate tablet may be added when the child returns from school, if needed. The drug must not be given too late to avoid inducing sleep-onset insomnia. If modafinil cannot be prescribed, methylphenidate is the second best option; it has a short half-life and is available in a slow-release form.90 In children, the recommended dose is based on weight, and we try to maintain a maximum of 30 mg/day administered as the slow-release form. The drug is given in the morning (15 mg) and at lunchtime (15 mg maximum) in the best case, or as a 20- or 30-mg slow-release preparation in the morning. Guidelines for diagnosis, treatment, and follow-up of narcolepsy in children have been provided by Guilleminault and Pelayo.91
❖ Clinical Pearls Narcolepsy is characterized by the clinical tetrad of excessive daytime sleepiness, cataplexy, sleep paralysis, and hypnagogic or hypnopompic hallucinations, but not all of these must be present for the diagnosis of narcolepsy. The nighttime sleep of a patient with narcolepsy is often disrupted by frequent awakenings. Patients with narcolepsy typically have two or more sleep-onset REM periods and a mean sleep latency 8 minutes or less on the multiple sleep latency test (MSLT). The MSLT must be preceded by a nighttime polysomnogram to exclude more common causes of daytime sleepiness. Patients who have narcolepsy with cataplexy usually have absent or very low levels of hypocretin in their cerebrospinal fluid. Cataplexy is defined as a loss of muscle tone, usually triggered by humor or anger. Cataplexy is not associated with loss of consciousness.
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The effectiveness of short naps (15 to 20 minutes) in treating daytime sleepiness should not be underestimated, and this should be made clear to the patient’s employer. GHB (sodium oxybate) has been found to be effective in treating cataplexy without the negative side effects associated with the older tricyclics and the serotoninnorepinephrine reuptake inhibitors. It is also effective in treating excessive daytime sleepiness and disturbed nocturnal sleep, and it is the only drug available that can effectively treat both cataplexy and excessive daytime sleepiness. Modafinil has been found to be effective in treating excessive daytime sleepiness without the negative side effects associated with older stimulants.
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Idiopathic Hypersomnia Claudio L. Bassetti and Yves Dauvilliers
Abstract Idiopathic hypersomnia is a rare and not uncommonly familial disorder characterized by excessive daytime sleepiness with long and unrefreshing naps, prolonged and undisturbed nocturnal sleep, and great difficulty waking up (sleep drunkenness) after sleep. The 2005 International Classification of Sleep Disorders recognizes also a second form of idiopathic hypersomnia without long sleep time. High sleep efficiency and slow-wave sleep percentages on polysomnography, decreased mean sleep latencies (without sleep-onset rapid eye movement [REM] sleep) on multiple sleep latency test (MSLT), prolonged times “asleep” on actigraphy, and normal cerebrospinal fluid levels of hypocretin-1 are typically observed. The pathophysi-
HISTORY The term idiopathic hypersomnia was used as early as 1829 (“die idiopathische chronische Schlafsucht”) for excessive daytime sleepiness of undetermined origin.1 Bedrich Roth was the first in the late 1950s to describe a syndrome that was characterized by excessive daytime sleepiness, prolonged sleep, and sleep drunkenness and by the absence of sleep attacks, cataplexy, sleep paralysis, and hallucinations. The of independent sleep drunkenness and hypersomnia with sleep drunkenness were initially suggested.2-5 Overlapping features with narcolepsy were identified from the beginning and led to the use of such labels as essential narcolepsy, independent narcolepsy, and non–rapid eye movement (NREM) sleep narcolepsy.6,7 Other terms including idiopathic central nervous system hypersomnolence, functional hypersomnia, hypersomnia with automatic behavior, harmonious hypersomnia, and idiopathic hypersomnia (in the 1990 edition of the International Classification of Sleep Disorders [ICSD]) were also put forward. The 2005 version of the ICSD suggests differentiating between idiopathic hypersomnia with long sleep time (the polysymptomatic classic form of idiopathic hypersomnia) and idiopathic hypersomnia without long sleep time (the monosymptomatic form). The absence of a biological marker for the disorder and the better identification over the last several decades of other potential causes of nonstructural excessive daytime sleepiness, including subtle forms of sleep-disordered breathing and chronic sleep insufficiency (behaviorally induced sleep insufficiency syndrome), raise questions about the true frequency and clinical picture of idiopathic hypersomnia. EPIDEMIOLOGY Idiopathic hypersomnia is rare, and its incidence is usually overestimated. In the absence of systematic studies, the exact prevalence of idiopathic hypersomnia is unknown. Reports suggest that patients with idiopathic hypersomnia represent only about 1% of patients seen in neurologic
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ology of idiopathic hypersomnia is unknown but might include genetic factors and deficient monoaminergic neurotransmissions. Idiopathic hypersomnia is a diagnosis of exclusion, and a broad differential diagnosis including atypical forms of depression and behaviorally induced sleep should always be considered. Response to stimulants is variable and remissions are possible. In the clinical practice of sleep medicine, one of the most frustrating diagnoses to make (and for the patient to receive) is idiopathic hypersomnia. The dissatisfaction stems from diagnostic uncertainty, unclear natural history and unpredictable response to treatment. This chapter gives an overview on epidemiology, pathogenesis, clinical features, diagnostic workup, treatment, and prognosis of this disorder.
sleep centers and are 5 to 10 times less common than patients with narcolepsy.8,9 Hence, the prevalence of idiopathic hypersomnia in the general population may be estimated at around 50 per million, a figure much lower than the 300 to 600 per million suggested until the early 1980s.4,5,10 Only about one fourth of patients with idiopathic hypersomnia diagnosed according to ICSD criteria present the classic or polysymptomatic form.8 In a large series published in 2007, patients with idiopathic hypersomnia represented 1% of 6000 patients seen at a single respiratory sleep center. Because idiopathic hypersomnia is 60% as prevalent as narcolepsy, questions about the diagnostic accuracy arise.11 The age of onset of symptoms varies, but it is commonly between 10 and 30 years. In contrast to narcolepsy with cataplexy, the age of onset is sometimes difficult to pinpoint due to the insidious onset of the condition over several weeks or months. Once established, symptoms are generally stable and long lasting. Spontaneous improvement in excessive daytime sleepiness may be observed in up to one quarter of patients.8,11,12 A female preponderance was found in some but not all series.8,11-13 In one to two thirds of cases (see later), idiopathic hypersomnia is familial.
PATHOGENESIS Genetic and Environmental Factors The disorder is familial in 50% to 60% of cases, most commonly in the classic (polysymptomatic) form. On rare occasions, idiopathic hypersomnia and narcolepsy occur in the same family.8,9,14 An autosomal dominant mode of inheritance has been discussed, and females may be more affected.13 In a few series, an association with diabetes or obesity was observed.8,15 Given the existence of overlapping features between idiopathic hypersomnia and narcolepsy (see later), there has been an interest in potential human leukocyte antigen (HLA) markers for idiopathic hypersomnia. Despite reports of an increase in HLA DQ1,8 DR5 and Cw2,16 and 969
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DQ317 and of a decrease of Cw3,18 no consistent findings have emerged. HLA typing currently does not play a role in the diagnosis of idiopathic hypersomnia. Serum total IgG levels were recently reported in 159 Japanese with narcolepsy-cataplexy patients positive for the HLA-DQB1*0602 allele, 28 idiopathic hypersomnia patients with long sleep time, and 123 healthy controls (HLA-DQB1*0602 present in 45 of them). The distribution of serum IgG was significantly different among healthy controls (11.66 ± 3.55 mg/ml and 11.45 ± 3.43 for HLApositive and HLA-negative subjects, respectively), narcolepsy patients (9.67 ± 3.38), and idiopathic hypersomnia patients (13.81 ± 3.80). In addition, idiopathic hypersomnia patients showed high IgG3 and IgG4 level, low IgG2 level, and IgG1/IgG2 imbalance.18a Hypersomnia usually starts insidiously. Occasionally, excessive daytime sleepiness is first experienced after transient insomnia, abrupt changes in sleep–wake habits, overexertion, general anesthesia, viral illness or mild head trauma.8 Cerebrospinal fluid (CSF) analyses in idiopathic hypersomnia have shown normal cell counts, cytology, and protein content. Neurochemistry Montplaisir and coworkers found a decrease in dopamine and indole-3-acetic acid in both idiopathic hypersomnia and narcolepsy.19 Faull and colleagues found similar mean concentrations of monoamine metabolites in subjects with narcolepsy or idiopathic hypersomnia and with controls but—using a principal component analysis—they also found a dysregulation of the dopamine system in narcolepsy and dysregulation of the norepinephrine system in idiopathic hypersomnia.20-22 These metabolic data suggest the possibility of a dysfunction of aminergic arousal systems in idiopathic hypersomnia. Additional experimental and human data give some support to this hypothesis. In the cat, both hypersomnia and disturbances of monoamine metabolites can be induced by a lesion of ascending noradrenergic pathways.23 In humans, decreased CSF levels of histamine were found in patients with excessive daytime sleepiness including narcolepsy and idiopathic hypersomnia.24,25 Finally, the hypothesis of a dysfunctional dopaminergic transmission has been confirmed also by positron emission tomography (PET) studies.26 Most studies found normal levels of CSF hypocretin-1 in idiopathic hypersomnia.15,27-29 In the absence of clear cutoffs for normal levels and considering differences in diagnostic criteria, reports of diminished levels of hypocretin-1 and hypocretin-2 levels must be interpreted with caution.30,31 Neurophysiology Homeostatic and circadian disturbances of sleep regulation as well as deficient arousal systems have been postulated in idiopathic hypersomnia. An abnormally high level of slowwave activity (SWA), due either to an abnormally slow decay of SWA or to a normal decay of an enhanced level of SWA, was found by some authors.32,33 More-recent studies did not confirm these data. Reports of increased
sleep spindle activity at the beginning and at the end of sleep and of a delayed start (and decline) of melatonin and cortisol secretion suggest a primary circadian deficit in idiopathic hypersomnia.34 Unfortunately, core temperature recordings have not been reported in idiopathic hypersomnia to date. The detection after awakening of delayed and smaller P300 potentials in idiopathic hypersomnia documents a cortical activation problem in these patients without, however, giving any clue about its origin.33,35
CLINICAL FEATURES Excessive Daytime Sleepiness Patients describe a constant, daily excessive daytime sleepiness that only rarely leads to involuntary naps (“sleep attacks”). The Epworth Sleepiness Scale score is typically high (>11/24). As with other forms of excessive daytime sleepiness, alcohol, exercise, heavy meals, and warm environments can accentuate excessive daytime sleepiness. Paradoxically, sleep deprivation is often well tolerated by patients with idiopathic hypersomnia. Daytime drowsiness leads to naps that are prolonged (typically longer than 1 hour) and usually unrefreshing. The unrefreshing quality of napping and the sleep drunkenness associated with awakenings lead patients to fight sleepiness as long as they can. Patients who do not nap are particularly prone to episodes of drowsiness and automatic behavior, which are usually signaled by blank stares. During these episodes, patients act in an unplanned and often inappropriate way. Patients have reported finding themselves miles from their homes while driving or performing inappropriate actions such as sprinkling salt on coffee, putting dirty plates in a clothes dryer and turning on the machine, writing incoherent sentences during classes, having loud and irrelevant bursts of speech, and so on. Amnesia of such occurrences is the rule, although patients are usually aware that they have had one of their “drowsy” episodes when they are later confronted with the results of their automatic behavior. A few patients with idiopathic hypersomnia may occasionally report episodes of irresistible sleep episodes as well as short and refreshing naps.8 The existence, on the other hand, of patients who have narcolepsy with cataplexy with nonimperative excessive daytime sleepiness, prolonged naps, and prolonged nocturnal sleep proved the existence of an overlap between narcolepsy and idiopathic hypersomnia, as suggested also by the occurrence of both conditions in the same family (see earlier). In a comparison of 62 patients with idiopathic hypersomnia and 50 controls, patients were able to focus only for 1 hour (versus 4 hours in the controls) and felt more sedated in darkness, in a quiet environment, and when listening to music or conversation. Patients were also more frequently evening type and more alert in the evening than in the morning.35a Nocturnal Sleep Nocturnal sleep often is typically subjectively long and undisturbed, with more than 10 hours of sleep. A few patients report sleep times of 12 to 19 hours per day on weekends and during holidays. Because most patients do
not report improvement of excessive daytime sleepiness with prolonged sleep, history of extreme sleep times (sleep longer than 12 hours per day) is uncommon.8 In a comparison of 62 patients with idiopathic hypersomnia and 50 controls, patients slept 3 hours more on weekends, on holidays, and in the sleep unit than on working days.35a Awakening after nocturnal sleep is typically difficult. Sleep drunkenness (also called syndrome d’Elpénor, after the youngest of Ulysses’ comrades, who killed himself during an episode of incomplete awakening) is reported by 40% to 60% of patients,5,8,11 but can be seen also in other forms of excessive daytime sleepiness. Patients are hard to awaken; they can be aggressive and verbally and physically abusive during that twilight state if they are awakened, even at their own request. The patient may be confused and unable to react adequately to external stimuli upon awakening. The sleep inertia (time to get going) in the morning may be as long as 2 to 3 hours. Sleep drunkenness can also be noted when patients are awakened from naps. Associated Features Sleep paralysis and hallucinations are typical for narcolepsy with cataplexy, but they are not exceptional in patients with idiopathic hypersomnia.8,29,36 Cataplexy-like episodes and nightmares are also possible. Depressive symptoms were noted in 15% to 25% of patients in Roth’s series and confirmed in later studies.5,8,14,37,38 Mood changes not qualifying for the diagnosis of affective disorder can precede or follow the onset of excessive daytime sleepiness and evolve independently. The presence of major depression signs are, however, not compatible with the diagnosis of idiopathic hypersomnia (see later). Headache is a common symptom in patients with excessive daytime sleepiness. Migraine-type and tension-type headaches are reported in about 30% of patients with idiopathic hypersomnia. Pain complaints of other localizations are occasionally observed. Neurovegetative symptoms such as cold hands or feet, lightheadedness on standing up (orthostatic hypotension), or syncope have been observed.3,8,12,39,40 The incidence of neurovegetative symptoms is, however, similar in narcolepsy and in idiopathic hypersomnia.12 An increased body mass index has been noted in a few series.8,15 The overall psychosocial handicap of patients with idiopathic hypersomnia is similar to that of patients with narcolepsy.41
DIAGNOSIS Clinical Criteria The current ICSD (2005) gives diagnostic criteria for idiopathic hypersomnia. The patient complains of excessive daytime sleepiness that has lasted for more than 3 months. The patient has prolonged nocturnal sleep for more than 10 hours in the polysymptomatic form or has normal nocturnal sleep of 6 to 10 hours for the oligosymptomatic form. Other causes of excessive daytime sleepiness are excluded by polysomnography. Findings on polysomnography include short sleep latency, a major sleep period of more than 10 hours, with laborious wakening in the morning or from naps, in the polysymptomatic form, or a
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major sleep period of 6 to 10 hours in the oligosymptomatic form. Findings on the multiple sleep latency test (MSLT) are a mean sleep latency less than 8 minutes and one or no sleep-onset rapid eye movement (REM) period (SOREMP). The patient’s hypersomnia is not better explained by another sleep disorder, by a medical, neurologic, or mental disorder, or by medication use or substance abuse. Given the possibility of behaviorally induced insufficiency sleep syndrome (BIISS) and circadian disorders, the patient should be set on a regular sleep–wake schedule and complete sleep diaries (or actigraphy, see later) for at least 2 weeks before polysomnography. Drugs known to affect sleep, sleep latency, and daytime alertness must be carefully evaluated and should be withdrawn for a minimum of 2 weeks before objective tests. It may be helpful to obtain a urine toxicology sample for drug testing at the time of polysomnography/MSLT. Polysomnography Polysomnographic findings of idiopathic hypersomnia include a short sleep latency, a high sleep efficiency (usually more than 90%), and increased amounts of deep (slowwave) NREM sleep (Figs. 86-1 and 86-2).3,8,11,40 These findings are nonspecific and can be seen also in patients with BIISS (see later). Amounts of sleep spindles (throughout the sleep period or at the beginning and end of the night) have been occasionally reported to be elevated in idiopathic hypersomnia (Fig. 86-3).9,42 Sleep-onset REM episodes are rare, and specific sleep abnormalities should be absent. Typically the arousal, apnea hypopnea, and periodic limb movements in sleep (PLMS) indexes are lower than 5 to 10/hour. Some authors believe, however, that PLMS in patients who have excessive daytime sleepiness—but not restless legs syndrome— does not necessarily preclude the diagnosis of idiopathic hypersomnia. Higher PLMS indexes have been observed in a few patients who otherwise satisfy all other criteria for idiopathic hypersomnia.8,11,43,44 Multiple Sleep Latency Test A multiple sleep latency test (MSLT) is usually conducted the day following polysomnography. The mean sleep latency score is typically less than 8 minutes. A few patients with idiopathic hypersomnia have mean sleep latencies of less than 5 minutes.8,11 SOREMPs occur in 3% to 4% of naps, never more than once.8,11 Subjective awareness of sleep during naps is higher than in narcoleptic patients. MSLT is of limited diagnostic value in idiopathic hypersomnia with long sleep time. The first reason is the usual difficulty to keep the patient awake before the test and between sessions of the test. The second one is the obligation to wake up the patient in the morning to perform MSLT, thus precluding the recording of the prolonged nighttime sleep, the typical symptom of idiopathic hypersomnia with long sleep time. Regarding these limits, several patients have normal mean sleep latency on conventional MSLT, being longer than 8 and sometimes even 10 minutes.8,11 Sleep onset characteristics at the MSLT were recently studied in 44 patients with narcolepsy and 16 patients with idiopathic hypersomnia. Sleep latency at MSLT was
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Figure 86-1 Idiopathic hypersomnia. This 22-year-old female patient (S. Am.) has idiopathic hypersomnia with excessive daytime sleepiness, prolonged nonrefreshing sleep, and sleep drunkenness. Epworth Sleepiness Scale score is 18/24. She has frequent hallucinations (while falling asleep or on awakening) but no sleep paralysis or cataplexy. Her body-mass index (BMI) is 21. Her family history is positive for excessive daytime sleepiness. Polysomnography (figure) shows sleep efficiency is 98%, sleep latency to NREM 2 sleep is 10 minutes, slow-wave sleep is 22% of sleep period time. She has no snoring, no apnea, and no periodic limbs movement in sleep. The multiple sleep latency test (MSLT) shows a mean sleep latency of 4 minutes and no sleep-onset REM periods (SOREMPs). Actigraphy shows mean time “asleep” (rest or sleep) over 43% of the recording time. Hypocretin-1 in cerebrospinal fluid is normal. HLA DQB1*0602 is positive. Psychiatric assessment is normal. No improvement with modafinil up to 300 mg/ day and reboxetin up to 8 mg/day. MT, movement time; REM, rapid eye movement.
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18-Sep 19-Sep 20-Sep 21-Sep 22-Sep 23-Sep 24-Sep 25-Sep 26-Sep 27-Sep 28-Sep 29-Sep 30-Sep 01-Oct 02-Oct 03-Oct 04-Oct 05-Oct Figure 86-2 Idiopathic hypersomnia. This 32-year-old male patient (S. No.) has idiopathic hypersomnia with excessive daytime sleepiness, prolonged nonrefreshing sleep up to 13 to 18 hours, and sleep drunkenness. Epworth Sleepiness Scale score is 19/24. He has occasional cataplexy-like episodes with both positive and negative emotions, sleep paralysis, and hallucinations. He has migrainous headaches. His body-mass index (BMI) is 27. He has no family history for excessive daytime sleepiness. Polysomnography ad libitum over16 hours shows sleep efficiency of 92%, sleep latency to NREM 2 sleep of 22 minutes, and slow-wave sleep 6% of sleep period time. He has no snoring, no apnea, and no periodic limb movements in sleep. The multiple sleep latency test (MSLT) shows a mean sleep latency of 4.3 minutes and no sleep-onset REM periods (SOREMPs). The maintenance of wakefulness test (MWT) shows mean sleep latency of 4.3 minutes and no SOREMPs. Two-week actigraphy shows mean time “asleep” (rest or sleep) over 48% of the recording time. Hypocretin-1 in cerebrospinal fluid is normal. HLA DQB1*0602 is negative. Psychiatric assessment is normal. No improvement after modafinil, methylphenidate, or melatonin.
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Figure 86-3 Idiopathic hypersomnia. Prolonged (32 hours) polysomnographic recordings in a 26-year-old woman with idiopathic hypersomnia with long sleep time (top 3 panels) and in a 28-year-old control (bottom three panels). An increase in total sleep time and level of slow-wave activity (SWA) and sleep spindle activity, with a slow exponential decay of SWA during the first night is seen in idiopathic hypersomnia. In this patient, a longer duration of the nap during the day with an increase in SWA around 3 PM was also observed.
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assessed both as the time elapsed to the occurrence of a single epoch of sleep stage 1 NREM and of unequivocal sleep (three sleep stage 1 NREM epochs or any other sleep stage epoch, sustained sleep latency). Idiopathic hypersomnia patients showed significantly (P < .0001) longer sustained sleep latency than sleep latency (8 ± 2 versus 6 ± 1 minute, respectively) compared with narcolepsy patients (4 ± 3 versus 4 ± 3 min).44a Other Polysomnographic Protocols Because of the limitations of the polysomnography MSLT procedure, a prolonged (up to 24 to 32 hours) continuous PSG on an ad libitum sleep–wake protocol was proposed as a diagnostic tool for idiopathic hypersomnia.9 This protocol allows the documentation of a major sleep episode (more than 10 hours) and of daytime sleep episodes of more than 1 hour (see Figs. 86-2 and 86-3). Spontaneous sleep periods of up to 19 hours have been previously reported in that condition, with normal MSLT latency.45 In a series of 11 patients, a mean total sleep time of 699 ± 130 minutes at night was observed.46 Several 24-hour recordings have even been suggested to ensure that the patient is saturated with sleep.40,47 These protocols, however, have several drawbacks. First, standardization and validation, especially regarding the level of physical and social activity allowed during the recording, is still lacking: Does the patient remain in bed during the full recording or is the patient allowed to perform some physical activity and at which degree? Should these prolonged polysomnograms be performed in an ambulatory setting or only in a laboratory setting? Second, prolonged sleep times are not specific for idiopathic hypersomnia and have been seen also in patients with hypersomnia related to neurologic disorders and rarely in depressed patients with excessive daytime sleepiness.48-51 Third, standard MSLT for the exclusion of narcolepsy without cataplexy still needs to be performed separately. Fourth, prolonged polysomnographic recordings add considerable cost to the diagnostic workup. Other Findings Instead of an additional 24-hour polysomnography, ambulatory actigraphy monitoring over several days can also demonstrate the prolonged sleep episodes characteristic of idiopathic hypersomnia (see Fig. 86-2).13,15 In addition, actigraphy is helpful to rule out BIISS (see later) and other circadian disorders that can lead to excessive daytime sleepiness. However, actigraphy protocols have not been standardized or validated in idiopathic hypersomnia, and the differentiation between sleep and rest while awake (clinophilia) may be difficult. Brain magnetic resonance imaging (MRI), HLA typing, and assessment of CSF hypocretin-1 levels are not useful in the diagnosis of idiopathic hypersomnia (see earlier), but they may be considered to rule out other causes of excessive daytime sleepiness.
DIFFERENTIAL DIAGNOSIS Narcolepsy with or without Cataplexy Narcolepsy is a common differential diagnostic consideration, but it is not the most difficult, as demonstrated also
by large comparative studies.8,11,12 The presence of excessive daytime sleepiness with clear-cut (definite) cataplexy, two or more sleep-onset REM periods on the MSLT and low or undetectable CSF hypocretin-1 levels are diagnostic for narcolepsy. Conversely, long sleep times, sleep drunkenness, long unrefreshing naps, high sleep efficiency, and high amounts of slow-wave sleep on polysomnography and absence of SOREMPs during MSLT suggest the diagnosis of idiopathic hypersomnia. Some patients fulfilling the current international criteria for idiopathic hypersomnia report a variable excessive daytime sleepiness associated with irresistible sleep episodes, as well as short and refreshing naps. On the other hand, a few patients with narcolepsy with cataplexy present with nonimperative excessive daytime sleepiness, prolonged naps, and prolonged nocturnal sleep.8,36,52 The narcoleptic syndrome can, in addition, initially manifest as excessive daytime sleepiness without or with mild or rare cataplectic episodes, and the positive diagnosis may be in doubt for months or even years. The term narcolepsy without cataplexy is used for this situation. Unfortunately, CSF hypocretin-1 levels have been found to be normal in most patients with either monosymptomatic narcolepsy or idiopathic hypersomnia.15,27,28 Sleep-Disordered Breathing Syndromes Idiopathic hypersomnia should be distinguished from sleep-disordered breathing syndromes, including the upper airway resistance syndrome.53 Clinically, both men and women complain of isolated excessive daytime sleepiness and snoring. Examinations of these subjects often reveal a triangular face or a steep mandibular plane, a highly arched palate, a class II malocclusion, and, at times, retroposition of the mandible. Patients may present a normal weight. Cephalometric radiographs have indicated the presence of a small space behind the base of the tongue (posterior airway space), often near the location of the hyoid bone. On polysomnography they have repetitive short (transient) alpha electroencephalographic arousals that last 3 to 14 seconds and regularly interrupted the abnormally high inspiratory efforts.53 Diagnosis is evoked by these repetitive transient arousals, an increase in snoring just before the arousal, and an increase in inspiratory time and a decrease in expiratory time, as determined with the use of well-calibrated sensors. Significant changes in Sao2 are typically lacking, and the respiratory disturbance index is low (less than 5). If upper airway resistance syndrome is suspected, esophageal pressure monitoring or nasal pressure cannula should be included in the sleep study. In patients with isolated snoring and idiopathic hypersomnia, a trial of continuous positive airway pressure may be warranted. Lack of improvement would support the latter diagnosis.8,44 Behaviorally Induced Insufficient Sleep Syndrome, Chronic Sleep Insufficiency, and Long Sleepers A careful history is needed to differentiate patients with idiopathic hypersomnia from those with BIISS (chronic insufficient nocturnal sleep) who present with excessive daytime sleepiness.54,55 Typically, patients show on ques-
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Figure 86-4 Hypersomnia associated with chronic sleep insufficiency. This 22-year-old male patient (D. Kr.) has sleep insufficiency (excessive daytime sleepiness, sleep drunkenness). Epworth Sleepiness Scale (ESS) score is initially 20/24. He has occasional sleep paralysis on awakening, no cataplexy, and no hallucinations. His body-mass index (BMI) is 24. He has no family history for excessive daytime sleepiness. Sleep deficiency is initially denied. The differential diagnosis of hypersomnia associated with psychiatric disorder is also discussed. On polysomnography, sleep efficiency is 90%, sleep latency to NREM 2 sleep is 12 minutes, and slowwave sleep is 7% of sleep period time. He has no snoring, no apnea, and no periodic limb movements in sleep. The multiple sleep latency test (MSLT) shows a mean sleep latency of 6 minutes, and 3 sleep-onset REM periods (SOREMPs). Two weeks of actigraphy during working days (figure) shows irregular sleep–wake rhythms and mean time “asleep” (rest or sleep) over 35% of the recording time. Hypocretin-1 in cerebrospinal fluid is normal. HLA DQB1*0602 is positive. Psychiatric assessment is normal. After sleep extension of more than 1 hr/day (documented by actigraphy, right inside), there is complete subjective resolution of the excessive daytime sleepiness and normalization of the ESS (4/24). The MSLT now shows a mean sleep latency of 5 minutes and an absence of SOREMPs.
tionnaires a difference of 2 to 3 hours between sleep times on weekdays and weekends. Polysomnographic and MSLT findings may be similar to those of patients with idiopathic hypersomnia. An actigraphic recording is often necessary to rule out BIISS because history may be misleading or inconclusive. Particularly difficult is the recognition of (relative) sleep insufficiency in long sleepers. It is possible that besides long sleepers, also other persons are more prone to develop hypersomnia in association with sleep insufficiency (Fig. 86-4). Some authors have suggested the possibility that idiopathic hypersomnia represents an extreme form of a long sleeper status.33 However, patients with absolute or relative sleep insufficiency, but usually not those with idiopathic hypersomnia, exhibit a subjective and objective improvement of excessive daytime sleepiness with prolongation of sleep times or when allowed to sleep ad libitum. Hypersomnia Associated with Psychiatric Disorders Hypersomnia associated with psychiatric disorders (atypical depression, bipolar depression, dysthymia or neurotic depression, neurotic hypersomnia) is not always easy to differentiate from idiopathic hypersomnia. These conditions can share the following symptoms: nonimperative excessive daytime sleepiness, long nonrefreshing naps, long sleep times, sleep drunkenness or sleep inertia, and depressed mood. The term atypical or vegetative depression has been used for the association of a major depression with these symptoms. Particularly difficult is the differential diagnosis between idiopathic hypersomnia and lesssevere forms of depression (dysthymia, previously called neurotic depression). Polysomnographic findings may be very similar (Fig. 86-5), although patients with hypersomnia associated with psychiatric disorders are generally found to have higher amounts of NREM sleep stage 1 and lower amounts of
slow-wave sleep.56 In patients with hypersomnia associated with psychiatric disorders, the MSLT typically shows normal mean sleep latencies. In addition, these patients might spend a large amount of time in bed and acknowledge “resting” more than “sleeping” (clinophilia). Patients with hypersomnia associated with psychiatric disorders can exhibit mean times “asleep” of up to 50% to 60% of the entire actigraphy recording times.15 Finally, exacerbation of excessive daytime sleepiness in winter months, obesity, and improvement of excessive daytime sleepiness with antidepressants are other typical features of “atypical depression.” Hypersomnia associated with psychiatric disorders may, however, be also accompanied by abnormal MSLT findings (in 36% of cases in one series57) (see Fig. 86-5) and, conversely, patients with idiopathic hypersomnia can exhibit normal MSLT findings.10,15,58 In unclear cases, formal psychiatric assessment is needed. Treatment with activating antidepressants (selective serotonin reuptake inhibitors [SSRIs], monoamine oxidase [MAO] inhibitors, noradrenaline reuptake inhibitors [NARIs]) rather than stimulants may be considered in patients in whom a psychiatric disorder as cause of excessive daytime sleepiness cannot be ruled out with certainty. Chronic Fatigue Syndrome Chronic fatigue syndrome is characterized by persistent or relapsing fatigue that does not resolve with sleep or rest. One of the clinical difficulties is that chronic fatigue syndrome is a poorly defined diagnosis, and patients often fail to differentiate fatigue and desire for sleep, on one hand, from excessive daytime sleepiness and need for sleep. The clinical presentation of chronic fatigue is similar to that seen in patients with hypersomnia associated with psychiatric disorders. In addition to fatigue, patients complain of cognitive difficulties, poor mood, anxiety, fever, myalgias, and other symptoms. Polysomnography may show decreased sleep efficiency and recurrent alpha intrusions,
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17-Dec 18-Dec 19-Dec 20-Dec 21-Dec 22-Dec 23-Dec 24-Dec 25-Dec 26-Dec 27-Dec 28-Dec 29-Dec 30-Dec 31-Dec 01-Jan 02-Jan 03-Jan 04-Jan Figure 86-5 Hypersomnia associated with psychiatric disorder. This 32-year-old female patient (S. He.) has hypersomnia (excessive daytime sleepiness, prolonged nonrefreshing sleep, mild sleep drunkenness). Epworth Sleepiness Scale (ESS) score is 11/24. She has occasional hallucinations on awakening, no cataplexy, and no sleep paralysis. Her mood is mildly depressed. Her body-mass index (BMI) is 27. She has a positive family history for excessive daytime sleepiness and depression. Polysomnography (above) shows sleep efficiency of 97%, sleep latency to NREM 2 sleep of 10 minutes, and slow-wave sleep 22% of sleep period time. She has no snoring, no apnea, and no periodic limb movement in sleep. The multiple sleep latency test (MSLT) shows a mean sleep latency of 7 minutes, and no sleep-onset REM periods (SOREMPs). The maintenance of wakefulness test (MWT) shows mean sleep latency of 10 minutes and no SOREMPs. Actigraphy (below) shows mean time “asleep” (rest or sleep) over 38% of the recording time. Hypocretin-1 in cerebrospinal fluid is normal. HLA DQB1*0602 is negative. Psychiatric assessment shows depression. This patient had complete subjective resolution of the excessive daytime sleepiness with citalopram 40 mg/day within 1 month, normalization of the ESS (2/24), and weight loss of 4 kg.
unlike in idiopathic hypersomnia. The MSLT is typically normal. A few patients with chronic fatigue syndrome are given a specific sleep diagnosis (sleep apnea syndrome, restless legs syndrome, PLMS) after polysomnographic investigation.59 Restless Legs Syndrome and SleepRelated Movement Disorders Sleep-related movement disorders include several conditions such as restless legs syndrome and periodic limb movement (PLM) disorder. Patients or bed partners might complain of movements before or during sleep. Nocturnal sleep disturbances or complaints of fatigue are often reported in these conditions. Restless legs syndrome can be associated with excessive daytime sleepiness.60
A clinical interview should address symptoms such as nocturnal agitation and discomfort of the extremities during periods of inactivity that are relieved with movement. The polysomnographic recording shows objective periodic, highly stereotyped PLMs, exceeding more than 10 to 15 per hour in adults. PLM disorder must be interpreted in the context of a patient’s related complaint, with an important overlap between symptomatic and asymptomatic patients according to the index of PLMS. Circadian Disorders Rarely, excessive daytime sleepiness during the morning hours in patients with a delayed sleep phase syndrome and excessive daytime sleepiness during the afternoon hours in patients with advanced sleep phase syndrome leads to
questions regarding the diagnosis, but an appropriate sleep history, sleep logs covering 15 days, and, if needed, actigraphy indicate a normal total sleep time but abnormal sleep-onset and wakeup times. Hypersomnia and Neurologic or Medical Disorders A medical condition can produce hypersomnia and mimic idiopathic hypersomnia with excessive daytime sleepiness, automatic behavior, prolonged sleep episodes, and sleep drunkenness. excessive daytime sleepiness is usually associated with other manifestations of the underlying condition. Rarely, hypersomnia, excessive daytime sleepiness, or fatigue is the only or main symptom. Several neurologic disorders can cause hypersomnia or excessive daytime sleepiness, with large variability in terms of severity and clinical presentation.61-63 Brain tumors, encephalitis, or stroke and other lesions in the thalamus, hypothalamus, or brainstem can cause hypersomnia that can mimic clinical symptoms of idiopathic hypersomnia with long sleep time but also typically with alteration in sleep continuity.64 Neurodegenerative conditions such as Alzheimer’s disease, Parkinson’s disease, or multiple system atrophy are also associated with excessive daytime sleepiness and hypersomnia.65 Although intrinsic hypersomnia exists in those neurologic disorders, other possible causes of excessive daytime sleepiness, such as sleep-disordered breathing, drugs, and PLMs, need to be excluded. Several genetic disorders (Norrie disease, NiemannPick type C, Prader-Willi syndrome, myotonic dystrophy) may be associated with central hypersomnia but also with sleep-related breathing disorders that lead to excessive daytime sleepiness. Hypersomnia and excessive daytime sleepiness are occasionally observed in diabetes, hepatic encephalopathy, hypothyroidism, and acromegaly. Sleep-related breathing and PLM disorder, may be involved. Hypophysial insufficiency and obesity without sleep-disordered breathing can be associated with apathy, excessive daytime sleepiness or hypersomnia.66,67 Encephalopathies secondary to liver insufficiency, uremia, and hypercapnia can lead to somnolence and excessive daytime sleepiness. Posttraumatic hypersomnia is another etiology of neurologic hypersomnia. Abnormal sleepiness may be observed within 6 to 18 months following head trauma.68 Clinical symptoms may be similar to those of idiopathic hypersomnia, with long sleep time but poor sleep efficiency and frequent association with headaches, memory loss, and lack of concentration. Posttrauma complaints of excessive daytime sleepiness have been associated with variable degrees of impaired daytime functioning. After an acute viral infection (mononucleosis infectiosa, pneumonia) patients can develop a (postviral) syndrome of excessive daytime sleepiness with features similar to those of chronic fatigue and idiopathic hypersomnia.69 In some of these patients an encephalitic process or elevated levels of inflammatory cytokines might play a role.70,71 Human African trypanosomiasis, which is caused by the transmission of trypanosomes by tsetse flies, is a common
CHAPTER 86 • Idiopathic Hypersomnia 977
cause of severe hypersomnia in Western Africa (Trypanosoma brucei ganbiense) and Eastern Africa (Trypanosoma brucei rhodesiense). After an extensive immune reaction during the initial stage, severe impairment of sleep and wake follows, and the disorder at this point is referred to as sleeping sickness. The possibility of human African trypanosomiasis needs to be assessed in persons with excessive daytime sleepiness who have traveled in or migrate from Africa. Periodic Hypersomnias Periodic and recurrent hypersomnias, including the Kleine-Levin syndrome and the recurrent hypersomnia associated with the menstrual cycle, occasionally alternating with episodes of hyposomnia, are usually easy to differentiate from idiopathic hypersomnia by history only.72-76 Drugs and Substance Abuse Medications including beta-blockers, other antihypertensive agents, dopaminergic agents, antidepressants, opioid substances, and, over time, even stimulants can lead to fatigue, excessive daytime sleepiness, and hypersomnia.77
TREATMENT The underlying causes of idiopathic hypersomnia are unknown and therefore only the symptoms can be treated. Prolongation of sleep times has been suggested by Roth but has proved to be generally of no help.8 In fact, restriction of time in bed might be advantageous. Behavioral approaches and sleep hygiene must be recommended but might have little positive impact alone. Daytime naps are long and most commonly nonrefreshing. The pharmacologic options for idiopathic hypersomnia have mirrored the development of treatments for excessive daytime sleepiness in narcolepsy. Treatment response is, however, less common and robust than in narcolepsy, particularly in the polysymptomatic form of idiopathic hypersomnia.8 The list of medications that have been prescribed for patients is extensive, including tricyclic antidepressants, MAO inhibitors, SSRIs, clonidine, levodopa (isolated or in combination), bromocriptine, selegiline, and amantadine. Eventually, only about 50% of patients report significant improvement, most commonly with modafinil or amphetamines.8,11 Modafinil is considered by most experts to be the firstline treatment for idiopathic hypersomnia. The dose of modafinil is typically started at 100 mg and gradually increased to effectiveness to a maximum of 400 mg. The most common side effect is headache, and this negative effect may be eliminated by progressively increasing the dose over time. A positive effect has also been observed in children.78 Treatment with activating antidepressants (SSRIs and MAO inhibitors) rather than stimulants may be first considered in patients in whom a psychiatric or depressive disorder cannot be ruled out with certainty. Fantini and Montplaisir have reported improvement in half of their 10 patients, in whom treatment with melatonin (2 mg slow release at bedtime) was attempted.44 One of the authors could not confirm this observation (CB, unpublished observation).
978 PART II / Section 11 • Neurologic Disorders
CLINICAL COURSE AND PREVENTION The overall psychosocial handicap of patients with idiopathic hypersomnia has been found to be similar to that of narcoleptic patients.41 At times, the severity of the impairment can place lives in jeopardy (persons with idiopathic hypersomnia have sustained third-degree burns during episodes of automatic behavior or have turned on gas furnaces or stoves without lighting them, leading in one case to a severe explosion). In idiopathic hypersomnia, symptoms are generally stable and long lasting; spontaneous improvement in excessive daytime sleepiness may be observed, however, in up to one quarter of patients.8,11,12 No prevention is possible in this disorder. PITFALLS Because idiopathic hypersomnia is rare and essentially a diagnosis of exclusion, the main pitfall is making an accurate diagnosis. The terms idiopathic hypersomnia and hypersomnia of unknown origin should not be used as synonyms. Different research groups have historically used different diagnostic criteria, which makes comparisons difficult. This is particularly true of case series that did not exclude mild forms of sleep-disordered breathing, behaviorally induced insufficient sleep syndrome, and hypersomnia associated with psychiatric disorders. Careful history, sleep questionnaire or actigraphy (or both), full physical examination, overnight polysomnogram, and MSLT are essential for diagnosis and, more importantly, to rule out other causes of excessive daytime sleepiness. Demonstration of increased sleep times by prolonged polysomnographic recordings or actigraphy, formal psychiatric testing, CSF hypocretin-1 measurements, and brain MRI may be necessary to confirm the diagnosis and rule out other causes of excessive daytime sleepiness in unclear cases. Treatment with stimulants is not always satisfactory. The main controversies relate to the clinical overlap between idiopathic hypersomnia and hypersomnia associated with psychiatric disorders, narcolepsy without cataplexy, and behaviorally induced insufficient sleep syndrome; the diagnostic uncertainty in idiopathic hypersomnia without long sleep time); and the pathophysiology of idiopathic hypersomnia (homeostatic or circadian sleep disorder, primary disorder of arousal, deficient monoaminergic transmission). ❖ Clinical Pearl The clinician should consider idiopathic hypersomnia in the differential diagnosis of patients with excessive daytime sleepiness, prolonged nonrefreshing sleep, and great difficulty waking up either in the morning or at the end of a nap.
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2. Roth B. Narkolepsie und Hypersomnie. In: Roth B, editor. Narkolepsie und Hypersomnie. Berlin: VEB Verlag; 1962. 3. Roth B, Nevsìmalovà S, Rechtschaffen A. Hypersomnia with “sleep drunkenness.” Arch Gen Psychiatry 1972;26:456-462. 4. Roth B. Narcolepsy and hypersomnia: review and classification of 642 personally observed cases. Archiv Suisses Neurologie Neurochir Psychiatr 1976;119:31-41. 5. Roth B. Narcolepsy and hypersomnia. Basel: Karger Libri; 1980. 6. Dement W, Rechtschaffen A, Gulevich G. The nature of the narcoleptic sleep attack. Neurology 1966;16:18-33. 7. Berti Ceroni G, Coccagna G, Gambi D, Lugaresi E. Considerazioni clinico-poligrafiche sulla narcolessia essenziale “a sonno lento.” Sistema Nervoso 1967;2:81-89. 8. Bassetti C, Aldrich M. Idiopathic hypersomnia. A study of 42 patients. Brain 1997;120:1423-1435. 9. Billiard M, Dauvilliers Y. Idiopathic hypersomnia. Sleep Med Rev 2001;5:351-360. 10. van den Hoed J, Kraemer H, Guilleminault C, et al. Disorders of excessive daytime somnolence: polygraphic and clinical data for 100 patients. Sleep 1981;4:23-37. 11. Anderson KN, Pilsworth S, Sharples LD, et al. Idiopathic hypersomnia: a study of 77 cases. Sleep 2007;30:1274-1281. 12. Bruck D, Parkes JD. A comparison of idiopathic hypersomnia and narcolepsy-cataplexy using self report measures and sleep diary data. J Neurol Neurosurg Psychiatry 1996;60:576-578. 13. Nevsimalova S. Differential diagnosis of narcolepsy and other hypersomnias. Vigilia-Sueno 1998;10:S85-S96. 14. Nevsimalova-Bruhova S, Roth B. Heredofamilial aspects of narcolepsy and hypersomnia. Schweiz Arch Neurol Neurochir Psychiatr 1972;110:45-54. 15. Bassetti C, Gugger M, Bischof M, et al. The narcoleptic borderland: a multimodal diagnostic approach including cerebrospinal fluid levels of hypocretin-1 (orexin A). Sleep Med 2003;4:7-12. 16. Poirier G, Montplaisir J, Décary F, et al. HLA antigens in narcolepsy and idiopathic central nervous system hypersomnolence. Sleep 1986;9:153-158. 17. Billiard M. Idiopathic hypersomnia. Neurol Clin 1996;14:573582. 18. Honda Y, Honda M. Idiopathic hypersomnia. Review of literature and clinical experience on 16 Japanese cases. Nippon Rinsho 1998;56:371-375. 18a. Tanaka S, Honda M. IgG abnormality in narcolepsy and idiopathic hypersomnia. PLoS one 2010 (Epub ahead of print). 19. Montplaisir J, de Champlain J, Young SN, et al. Narcolepsy and idiopathic hypersomnia: biogenic amines and related compounds in CSF. Neurology 1982;32:1299-1302. 20. Faull KF, Guilleminault C, Berger PA, Barchas JD. Cerebrospinal fluid monoamine metabolites in narcolepsy and hypersomnia. Ann Neurol 1983;13:258-263. 21. Faull KF, Thiemann S, King RJ, Guilleminault C. Monoamine interactions in narcolepsy and hyperosmnia: a preliminary report. Sleep 1986;9:246-249. 22. Faull KF, Thiemann S, King RJ, Guilleminault C. Monoamine interactions in narcolepsy and hypersomnia: reanalysis. Sleep 1989;12: 185-186. 23. Petitjean F, Jouvet M. Hypersomnie et augmentation de l’acide 5-hydroxy-indolacétique cérébral par lésion isthmique chez le chat. C R Soc Biol 1970;164:2288-2293. 24. Kanbayashi T, Kodama T, Kondo H, et al. CSF histamine contents in narcolepsy, idiopathic hypersomnia and obstructive sleep apnea. Sleep 2009;32:181-187. 25. Bassetti CL. Cerebrospinal fluid histamine levels are decreased in patients with narcolepsy and excessive daytime sleepiness of other origin. J Sleep Res. 2010. In press. 26. Bassetti CL, Khatami R, Poryazova R, Buck F. Idiopathic hypersomnia: a dopaminergic disorder? Sleep. 2009;32(Suppl 1):A248-A249. 27. Mignot E, Lammers GJ, Ripley B, et al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of narcolepsy and other hypersomnias. Arch Neurol 2002;59:1553-1562. 28. Dauvilliers Y, Baumann CR, Maly FE, et al. CSF hypocretin-1 levels in narcolepsy, Kleine-Levin syndrome, other hypersomnias and neurological conditions. J Neuro Neurosurg Psychiatry 2003;74. 29. Heier MS, Evvsiukova T, Vilming S, et al. CSF hypocretin-1 levels and clinical profiles in narcolepsy and idiopathic CNS hypersomnia in Norway. Sleep 2007;30:969-973.
30. Kanbayashi T, Inoue Y, Chiba S, et al. CSF hypocretin-1 (orexin-A) concentrations in narcolepsy with and without cataplexy and idiopathic hypersomnia. J Sleep Res 2002;11:91-93. 31. Ebrahim IO, Sharief KK, De Lacy S, et al. Hypocretin (orexin) deficiency in narcolepsy and primary hypersomnia. J Neurol Neurosurg Psychiatry 2003;74:127-130. 32. Sforza E, Gaudreau H, Petit D, Montplaisir J. Homeostatic sleep regulation in patients with idiopathic hypersomnia. Clin Neurophysiol 2000;111:277-282. 33. Billiard M, Rondouin G, Espa F, et al. Physiopathologie de l’hypersomnie idiopathique. Rev Neurol 2001;157:5S101-5S106. 34. Nevsimalova S, Blazejova K, Illnerova H, et al. A contribution to pathophysiology of idiopathic hypersomnia. Suppl Clin Neurophysiol 2000;53:366-370. 35. Sangal RB, Sangal J. P300 latency: abnormal in sleep apnea with somnolence and idiopathic hypersomnia but normal in narcolepsy. Clin Electroenceph 1995;26:146-154. 35a. Vernet C, Leu-Semenescu S, Buzare MA, Arnulf I. Subjective symptoms in idiopathic hypersomnia: beyond excessive sleepiness. J Sleep Res 2010 (Epub ahead of print). 36. Aldrich M. The clinical spectrum of narcolepsy and idiopathic hypersomnia. Neurology 1996;46:393-401. 37. Roth B, Nevsimalova S. Depression in narcolepsy and hypersomnia. Schweiz Arch Neurol Neurochir Psychiatr 1975;116:291-300. 38. Roth B. Idiopathic hypersomnia: a study of 187 personally observed cases. Int J Neurol 1981;15:108-118. 39. Schneider-Helmert D, Schenker J, Gnirss F. Deficient blood pressure regulation in a case of hypersomnia with sleep drunkenness. Electroencephalogr Clin Neurophysiol 1980;48:230-232. 40. Baker TL, Guilleminault C, Nino-Murcia G, Dement WC. Comparative polysomnographic study of narcolepsy and idiopathic central nervous system hypersomnia. Sleep 1986;9:232-242. 41. Broughton R, Nevsimalova S, Roth B. The socio-economic effects of idiopathic hypersomnia—comparison with controls and with compound narcoleptics. In: Popoviciu L, Asgian B, Badiu G, editors. Sleep 1978. Basel: Karger; 1980. p. 229-233. 42. Bove A, Culebras A, Moore JT, Westlake RE. Relationship between sleep spindles and hypersomnia. Sleep 1994;17:449-455. 43. Nicolas A, Lespérance P, Montplaisir J. Is excessive daytime sleepiness with periodic leg movements during sleep a specific diagnostic category. Eur Neurol 1998;40:22-26. 44. Montplaisir J, Fantini L. Idiopathic hypersomnia: a diagnostic dilemma. Sleep Med Rev 2001;5:361-362. 44a. Pizza F, Vandi S, Detto S, et al. Different sleep onset criteria at the multiple sleep latency text (MSLT): an additional marker to differentiate central nervous system (CNS) hypersomnias. J Sleep Res 2010 (Epub ahead of print). 45. Voderholzer U, Backhaus J, Hornyak M, et al. A 19-h spontaneous sleep period in idiopathic central nervous system hypersomnia. J Sleep Res 1998;19:219-223. 46. Billiard M, Merle C, Carlander B, et al. Idiopathic hypersomnia. Psychiatry Clin Neurosci 1998;52:125-129. 47. Montplaisir J, Billiard M, Takahashi S, et al. Twenty-four-hour recording in REM-narcoleptics with special reference to nocturnal sleep disruption. Bio Psychiatry 1978;13:73-89. 48. Hawkins DR, Taub JM, Van de Castle L. Extended sleep (hypersomnia) in young depressed patients. Am J Psychiatry 1985;142: 905-910. 49. Bassetti C, Mathis J, Gugger M, et al. Hypersomnia following thalamic stroke. Ann Neurol 1996;39:471-480. 50. Ulivelli M, Rossi S, Lombardi C, et al. Polysomnographic characterization of pergolide-induced sleep attacks in idiopathic PD. Neurology 2002;58:462-465. 51. Hermann DM, Siccoli M, Brugger P, et al. Evolution of neurological, neuropsychological and sleep–wake disturbances after paramedian thalamic stroke. Stroke 2008;39:62-68.
CHAPTER 86 • Idiopathic Hypersomnia 979 52. Sturzenegger C, Bassetti C. The clinical spectrum of narcolepsy with cataplexy: a reappraisal. J Sleep Res 2004;13:395-406. 53. Guilleminault C, Stoohs R, Clerk A, et al. A cause of excessive daytime sleepiness: the upper airway resistance syndrome. Chest 1993;104:781-787. 54. Roehrs T, Zorick F, Sicklesteel J, et al. Excessive daytime sleepiness associated with insufficient sleep. Sleep 1983;6:319-325. 55. Roehrs TA, Roth A. Chronic insufficient sleep and its recovery. Sleep Med 2003;4:5-6. 56. Dolenc C, Besset A, Billiard M. Hypersomnia in association with dysthymia in comparison with idiopathic hypersomnia and normal controls. Pflugers Arch 1996;431:R303-R304. 57. Billiard M, Dolenc C, Aldaz C, et al. Hypersomnia associated with mood disorders:a new perspective. J Psychosom Res 1994;38(Suppl 1):41-47. 58. Nofzinger EA, Thase ME, Reynolds CF, et al. Hypersomnia in bipolar depression: a comparison with narcolepsy using the multiple sleep latency test. Am J Psychiatry 1991;148:1177-1181. 59. Buchwald D, Pascualy R, Bombardier C, Kith P. Sleep disorders in patients with chronic fatigue. Clin Infect Dis 1994;18:S68-S72. 60. Bassetti C, Mauerhofer D, Mathis J, et al. Restless legs syndrome: a clinical study of 55 patients. Eur Neurol 2001;45:67-74. 61. Lhermitte J, Tournay A. Rapport sur le sommeil normal et pathologique. Rev Neurol. 1927:751-823. 62. Castaigne P, Escourolle R. Etude topographique des lésions anatomiques dans les hypersomnies. Rev Neurol 1967;116:547-584. 63. Autret A, Lucas B, Mondon K, et al. Sleep and brain lesions: a critical review of the literature and additional new cases. Neurophysiol Clin 2001;31:356-375. 64. Bassetti CL, Valko P. Poststroke hypersomnia. Sleep Med Clin 2006;1:139-155. 65. Arnulf I. Excessive daytime sleepiness in parkinsonism. Sleep Med Rev 2005;9:185-200. 66. Vgontzas A, Bixler A, Tan TL, et al. Obesity without sleep apnea is associated with daytime sleepiness. Arch Neurol 1998;158:13331337. 67. Aldrich MS, Naylor MW. Narcolepsy associated with lesions of the diencephalon. Neurology 1989;39:1505-1508. 68. Baumann CR, Werth E, Stocker R, et al. Sleep–wake disturbances 6 months after traumatic brain injury. Brain 2007;130:1873-1883. 69. Guilleminault C, Mondini C. Mononucleosis and chronic daytime sleepiness. A longterm follow-up study. Arch Intern Med 1986;146: 1333-1335. 70. Merriam AE. Kleine-Levin syndrome following acute viral encephalitis. Bio Psychiatry 1986;21:1301-1304. 71. Vgontzas A, Papanicolaou DA, Bixler EO, et al. Elevation of plasma cytokines in disorders of excessive daytime sleepiness: role of sleep disturbance and obesity. J Clin Endocrinol Metab 1997;82: 1313-1316. 72. Kleine W. Periodische Schlafsucht. Monatsch Psychiatri Neurol 1925;57:285-320. 73. Levin M. Narcolepsy (Gélineau syndrome) and other varieties of morbid somnolence. Arch Neurol Psychiatry 1929;22:1172-1200. 74. Critchley M, Hoffmann HL. The syndrome of periodic somnolence and morbid hunger (Kleine-Levin). Br Med J 1942;1:137-139. 75. Critchley M. Periodic hypersomnia and megaphagia in adolescent males. Brain 1962;85:627-656. 76. Arnulf I, Zeitzer JM, File J, et al. Kleine-Levin syndrome: a systematic review of 186 cases in the literature. Brain 2005;128: 2763-2776. 77. Pack A. Risk factors for excessive daytime sleepiness in older adults. Ann Neurol 2006;59:893-904. 78. Ivanenko A, Tauman R, Gozal D. Modafinil in the treatment of excessive daytime sleepiness in children. Sleep Med 2003;4: 579-582.
Parkinsonism
Claudia Trenkwalder and Isabelle Arnulf Abstract Altered sleep and vigilance are among the most frequent nonmotor symptoms in parkinsonism. As many as 60% patients with Parkinson’s disease (PD) suffer from insomnia, 15% to 59% from rapid eye movement (REM) sleep behavior disorder (RBD), and 30% from excessive daytime sleepiness. These frequencies are even higher in atypical parkinsonism. Insomnia in parkinsonism is mainly a distressing difficulty in maintaining sleep, promoted by motor disability, painful dystonia, restless legs syndrome, dysuria, anxiety, and depressed mood. Improving the motor control continuously during the night with levodopa, transdermal or long-acting dopamine agonists, or bilateral subthalamus stimulation can improve sleep continuity, as does the specific treatment of dysuria, anxiety, and depression. RBD is violent, enacted dreaming that exposes the patients or their bed partners to nighttime injuries. It is probably caused by lesions in the REM sleep atonia system. Recent longitudinal studies indicate that RBD, when it affects middleaged patients, might precede parkinsonism (or dementia of Lewy body type) for several years. In this case, it is often associated with early markers of neurodegenerative diseases, including olfactory, cognitive, and autonomic disturbances, decreased dopaminergic transmission in functional imaging,
Parkinsonism is a common and disabling condition that affects 1% to 2% of adults older than 65 years. During the last several decades, there have been major advances in optimizing the treatment of motor symptoms, at least in idiopathic Parkinson’s disease (PD), whereas falls and dementia (which determine the prognosis of the disease) still remain difficult to treat. The interest for sleep disorders in this already complex picture has increased within the movement-disorders community. For decades, abnormal sleep in parkinsonian patients was mostly considered a collateral damage until key observations were made since the 1990s.
DEFINITION Parkinsonism Parkinsonism (or parkinsonian syndrome, or Parkinson syndrome) is defined by the association of slow movements (bradykinesia) with either muscle rigidity (hypertonia), 4 to 6 Hz resting tremor, or postural instability.1 The main cause of parkinsonism is idiopathic Parkinson’s disease (PD), a neurodegenerative disorder with a progressive (but not exclusive) loss of dopaminergic neurons. PD is characterized by asymmetrical parkinsonism, progressive worsening, and important initial benefit from levodopa. When PD is fully developed, the clinical picture is unmistakable.2 PD is primarily a disease of the elderly. Its prevalence increases with age from about 0.9 % among persons 65 to 980
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and slowed electroencephalographic (EEG) rhythms. Movements that seem almost impossible can be restored for short moments during RBD in some PD patients. That is different from the sleep benefit, a motor improvement after a night’s sleep and before drug intake reported by 33% to 55% of patients. PD patients with RBD are less likely to be tremorpredominant and are more exposed to hallucinations and cognitive impairment than patients without RBD. When violent, RBD can be treated with clonazepam and melatonin. Daytime sleepiness and a narcolepsy-like phenotype (irruptions of REM sleep episodes during daytime) is also part of PD. In addition, the use of dopamine agonists exposes patients to more frequent sleep attacks, especially when driving, suggesting an interaction of drug and disease. Patients with multiple system atrophy are disposed to develop a progressive, lifethreatening laryngeal obstruction (stridor) during sleep that should be rapidly treated with positive airway pressure. The disruption of the normal sleep and wakefulness in patients with parkinsonism may be caused by neurodegenerative damage in the brain area responsible for sleep and arousal regulation; by behavioral, respiratory, and motor system phenomena accompanying the disease; and by deleterious effects of medications. All of these effects on sleep have implications for treatment planning.
69 years old to 5% among persons 80 to 84 years old, with a slight male preponderance.3 Only a small percentage of patients, mostly with the genetic forms, develop parkinsonism before the age of 45 years. Major therapeutic advances have been accomplished in PD during the last decades, including fine dopamine substitution and functional neurosurgery. After several years of honeymoon on dopaminergic treatment, most patients develop motor complications, including dyskinesia (abnormal involuntary movements) at the peak of effect of levodopa and painful dystonia (often confused with cramps) at the beginning or the end of effect of levodopa, or early in the morning. Patients use dopaminergic substitutive treatment on daily schedules that becomes stricter and more frequent as the disease progresses. Currently, it is common to treat patients with a 10-year duration with 20 tablets per day, including small doses of levodopa every 3 hours, dopamine agonists every 5 hours, and various pills to prevent the side effects (nausea, orthostatic hypotension, hallucinations) of these treatments. The improvements brought by dopamine substitution can also unmask the nondopaminergic and nonmotor symptoms (mood, cognitive, psychiatric, sleep, and vegetative disturbances) that are not alleviated or are poorly alleviated by these treatments. The most important of these dopamine-unresponsive symptoms are falls (with the risk of fractures) and dementia (which is the major motive for placement in an institution). Sleep disturbances are common—and newly recognized—nonmotor symptoms. They include insomnia,
abnormal movements during sleep (periodic leg movements [PLMs], rapid eye movement [REM] sleep behavior disorder), and excessive daytime sleepiness. The mechanisms of the sleep disturbances are not fully known, but they include a clear interaction between drug and disease. A long interview, followed by sleep monitoring and video monitoring during night and day, are useful tools to understand and adequately treat these patients. Atypical Parkinsonism It is important to differentiate PD from atypical parkinsonism, because treatment and prognosis are different. Indeed, 5% to 10% patients have atypical parkinsonism (or Parkinson plus syndromes) characterized by lesions in other systems, poor levodopa benefit, and worse prognosis. Sleep problems are more common and more severe in atypical parkinsonism than in PD. A specific sleep-associated respiratory symptom, stridor, predisposes some patients with atypical parkinsonism to die during the night and must be looked for. Atypical parkinsonism is a spectrum of disorders, listed here by decreasing incidence: progressive supranuclear palsy (PSP; Steele-Richardson-Olszewski syndrome) associates parkinsonism, abnormal eye movements with limitation of up and down gaze, swallowing problems, dysarthria, cognitive impairment and early falls.4 Multiple system atrophy (MSA) contains the former striatonigral atrophy, Shy-Drager syndrome, and olivopontocerebellar syndrome and associates parkinsonism and cerebellar or autonomic dysfunctions, such as urinary incontinence, erectile dysfunction or orthostatic hypotension, with a fairly intact cognition.5 Exceptional diseases include Guadeloupean parkinsonism,6 Parkinson-dementia complex of Guam, and Parkinson-hypoventilation syndrome.7 Dementia with Lewy bodies is the second most common cause of dementia after Alzheimer’s disease. These patients develop a prominent initial cognitive impairment (mostly affecting visuospatial performance), early hallucinations, and parkinsonism (often sensitive to levodopa), that fluctuates over days or weeks.8 Mild parkinsonian symptoms can also be observed in patients with Huntington’s disease and spinocerebellar ataxia. All these neurodegenerative disorders are also classified according to the mechanism of neuronal loss (Table 87-1), whether it is associated with a deposit of alpha-synuclein in Lewy bodies, a hallmark of synucleopathies (PD, MSA, dementia with Lewy bodies), or of tau protein, a hallmark of tauopathies (PSP, Alzheimer’s disease, Guadeloupean parkinsonism, Parkinsondementia complex of Guam), or secondary to a polyglutamine disease (Huntington’s disease, spinocerebellar ataxia). Although the major emphasis in this chapter is on Parkinson’s disease, much of the discussion also applies to the other degenerative disorders associated with parkinsonism.
HISTORICAL ASPECTS The sleep-related clinical features of PD were described by James Parkinson in 1817 in Essay on the Shaking Palsy. In addition to his description of daytime symptoms, Parkinson noted that “sleep becomes much disturbed” and that the terminal stage of the disease is associated with
CHAPTER 87 • Parkinsonism 981
Table 87-1 Prevalence of REM Sleep Disorders in Neurodegenerative Diseases PREVALENCE (%) DISEASE
RBD
RWA
Synucleopathies Parkinson’s disease
15-6023,24,119
Multiple system atrophy
90120
Dementia with Lewy bodies
8651
Tauopathies Progressive supranuclear palsy
10-11
0-3349-51
Alzheimer’s disease
7
29121
Corticobasal degeneration
Case reports51
Frontotemporal dementia
None
Pallidopontonigral degeneration
077
Guadeloupean parkinsonism
78
077
26
Genetic Diseases Huntington’s disease
12122
Spinocerebellar ataxia type 3
56123
Parkin mutation
60124
RBD, REM sleep behavior disorder; RWA, REM sleep without atonia.
“constant sleepiness, with slight delirium, and other marks of extreme exhaustion.”9 Charcot, in the 19th century, described the impact of severe rigidity and bradykinesia on sleep: This need of change of position is principally exhibited at night in bed. … Half an hour, a quarter of an hour, has scarcely elapsed until they require to be turned again, and if … [this is not] gratified they give vent to moans, which … testify to the intense uneasiness they experience.10 The first polysomnographic (PSG) recordings of parkinsonian patients were performed in 1950s and 1960s.
CLINICAL FEATURES In clinical practice, the patients are referred for three main complaints, including insomnia; abnormal, violent movements when asleep; and daytime sleepiness. These symptoms can arise alone or in association. Insomnia The history of the sleep complaint in PD should include all the features the physician would obtain from any patient with a sleep complaint. It must also include disease-specific questions on nocturnal akinesia, daytime fatigue in relation to medication intake, and psychiatric symptoms. A careful description from the bed partner is essential to determine the presence and frequency of movements during sleep (and their timing), arousals and awakenings, and periods of daytime sleepiness. In PD, most patients report two to five long awakenings during the night (twice more than controls),11 lasting 30% to 40% of the night.12,13 Compared to controls and to patients with diabetes mellitus, there
982 PART II / Section 11 • Neurologic Disorders
were no differences between groups regarding difficulty falling asleep, but frequent (38.9%) or early (23.4%) awakenings were twice as common in PD patients than in other groups, and they were felt as more distressing.14 In patients with moderate to severe PD, special attention should be paid on sensory and motor symptoms during the night. Sensory discomfort during the night is common in PD patients. It includes various types of nonsystematized body pain, restless legs syndrome (RLS) in 12% to 21% patients15,16 (which can be difficult to distinguish from leg pain, because the urge to move is common in PD), and painful dystonia. The dystonia includes the classic early morning dystonia, a long-lasting, postural contraction of the toes in flexion or extension (sometimes with internal rotation of the ankle) that occurs during the second part of the night, is painful, and makes walking difficult. Severe dystonia of the leg, neck, and back muscles can occur only at night, when dopamine levels are low. Abnormal motor phenomena include, in addition to dystonia, severe nighttime bradykinesia. Bradykinetic patients have difficulty turning in bed, readjusting blankets or pillows, sitting, standing up, and walking to the toilet.17 A simple urine voiding can take 20 minutes instead of 5 minutes and be incomplete, with a further need to pass urine in the night. All these symptoms can curtail sleep by one third, if not more, with mostly long intranight awakenings. The difficulty with moving during the night can further increase the anxiety levels. Eventually, a deleterious effect on sleep of dopamine agonists (which have been considered stimulants for a long time), when given at bedtime, can be observed.18 At the extreme of this spectrum, some patients use supraoptimal doses of levodopa and dopamine agonists day and night, and they stay awake and hyperactive at night; hypersexuality and addictive behavior, including using computers and gambling, can occur. This condition is now identified as the dopamine dysregulation syndrome and affects up to 11% patients with PD.19 Two scales, the PD Sleep Scale and the Scales for Outcomes in Parkinson’s Disease—Sleep (SCOPA-Sleep) can be helpful for research purposes on sleep quality in PD.20,21 A checklist of useful questions when investigating a sleep complaint in a PD patient is displayed in Table 87-2. Abnormal Movements during Sleep and REM Sleep Behavior Disorder When a patient is referred for sudden jerks during the night, the clinical diagnosis should establish whether these movements are stereotyped and periodic, suggesting periodic leg movements during sleep (PLMS), or nonstereotyped, suggesting REM sleep behavior disorder (RBD). In addition, various types of myoclonia can occur in PD, including the violent dystonic myoclonia (looking like a transient strong exacerbation of the rest tremor) at the beginning or the end of action of levodopa. Violent dystonic myoclonia occurs during wakefulness but sometimes occurs during the night. REM sleep behavior disorder is dream-enacting activity, such as laughing, talking, swearing, crying, shouting, kicking, slapping, boxing, or fighting invisible enemies during sleep.22 This condition can be violent enough to disrupt sleep and injure the patient or bed partner, although
this is mostly rare. It does not induce daytime sleepiness. In addition to fully expressed complex actions, most patients also have abrupt movements and jerks such as simple aborted proximal or distal movements of the limbs (“looking like a flipper-ball,” reported one spouse). REM sleep behavior disorder occurs with variable within-subject and within-night frequency. One third of PD patients have at least one episode per week that is remembered by either themselves or their bed partners or caregivers.23,24 Typical activities during RBD include talking, laughing, yelling, gesturing, punching, and kicking, all conditions that may be disturbing and dangerous in a couple bed (Videos 87-1 and 87-2). Compared to patients with idiopathic RBD, who are usually selectively referred for violence, RBD is less common and less violent in parkinsonism when sleep is systematically investigated.25 Indeed, we also observed quiet activities including drinking soup, singing a song, cutting beans, and giving a lecture, which were mentioned incidentally by the bed partner as not disturbing.23,26 Arm and leg movements, speeches, laughter, and tears are common, but standing up, walking, and using appropriately the objects in the vicinity is exceptional in PD patients with RBD,24 although it is common in sleepwalking.22 The eyes are usually closed. Rare PD patients with overlap between sleepwalking and RBD have been reported.27 The movements during RBD are purposeful, nonstereotyped, and complex, but they can also consist of short and abrupt jerks. In addition to enacted dreams, RBD patients experience abnormal dreaming phenomena. Compared to dreams of matched controls, patients’ dreams contain more aggressive content (the dreamer being an aggressor, despite normal and even decreased levels of daytime aggressiveness), more animals, and less sex.28 There is often a sharp contrast between the placid personality of the PD patients during daytime and their aggressiveness during RBD. A new area of research pertains to the disappearance of parkinsonism during an RBD episode. In a large series, spouses of PD patients report that their husbands have unusually strong and rapid movements during RBD, with a loud voice, as if they were transiently cured from PD.23 Movements are faster, stronger, and smoother. Speech is more intelligible, louder, and better articulated, and facial expression is normal (with no more parkinsonian amimia). This clinical improvement has been confirmed on sleep and video monitoring, performed after a 12-hour withdrawal of dopaminergic drugs. During the RBD, there is no bradykinesia, tremor, or dystonia. Movements are surprisingly fast, ample, coordinated, and symmetrical (asymmetry is a feature of PD). In two incidental case reports, patients with PSP had totally lost the ability to speak during the daytime but still spoke while asleep during RBD (Video 87-3).29,30 Analyzing the quality of movements during RBD and finding the cause of this spontaneous improvement could help in treating the patients and provide a window into motor control during sleep. Schenck and coworkers first discovered that RBD, which is violent enacting of dreams, may be an early manifestation of parkinsonism or dementia with Lewy bodies.31 Whether RBD is a red flag for developing other
Table 87-2 Nocturnal Sleep Problems in Parkinson’s Disease PROBLEM
SUGGESTS
PROPOSED MANAGEMENT
Frequent (≥2) Micturitions at Night Normal volumes
Sleep apnea syndrome
Check for sleep apnea and treat appropriately
Small volumes, poor stream
Prostatism
Refer to urologist
Small volumes, good stream
Parkinsonismassociated dysuria
Try intranasal desmopressin in the evening Have a bottle for collecting urine in the bedside table
Difficulty Initiating Sleep Early in the evening
Lights-off too early (patient going to bed when fatigued but not necessarily sleepy)
Switch off lights later
Anxiety, or behavioral insomnia
Sleep hygiene Treat anxiety Evening melatonin (0.5-2 mg) Zolpidem, zopiclone
With restlessness
Restless legs syndrome
Check for low ferritin Remove antidepressant drugs If the diagnosis is uncertain, consider polysomnography with leg monitoring Try gabapentin (200-1000 mg per night) Try opiates such as tramadol (50-100 mg) if patient is not confused
Late in the night
Altered circadian cycle?
Sleep hygiene Decrease levodopa or dopamine agonists in the evening Melatonin in late afternoon
Late in night, hyperactive, hypomanic
Assess for dopamine dysregulation syndrome
Remove dopamine agonists Keep on levodopa monotherapy Close neuropsychological follow-up
Difficulty Resuming Sleep With cramps, muscle pain, slowness
Nocturnal akinesia
Try immediate-release levodopa with a glass of water during awakening Try long-acting dopamine agonists
With restlessness
Restless legs syndrome
Check for low ferritin Remove antidepressant drugs If the diagnosis is uncertain, consider polysomnography with leg monitoring Try gabapentin Try opiates such as tramadol if patient is not confused
With anxiety
Anxiety disorder
Try evening antvidepressants such as mianserin (5-30 mg) or amitriptyline (5 to 30 mg)
With low mood
Depressive disorder
Treat the depression
Nightmares and Agitation Confused at night when awake
Presence of hallucination, confusion?
Remove or reduce the evening dose of dopamine agonist and the antidepressant Assess for sleep apnea Try antipsychotics such as quetiapine or clozapine
Kicks, shouts, slaps
REM sleep behavior disorder
Secure the bed environment Remove the antidepressant Assess likelihood of sleep apnea and consider performing video PSG before treating Try clonazepam (0.5-2 mg) in the evening Try melatonin (3-12 mg) in the evening
Sleep attack
Check for possible inducing drugs (dopamine agonist), and remove or change them Warn patient not to drive
Daytime Sleepiness Falls asleep unexpectedly Falls asleep more often than before
Explore level of sleepiness; consider the Epworth sleepiness score Consider polysomnography and MSLT Ask about associated hallucinations Treat sleep apnea if severe Decrease or stop the dopamine agonist during daytime, and other sedative drugs Try modafinil (200-400 mg per day) or methylphenidate (10-40 mg per day) Consider sodium oxybate (9 g per night) in severe cases
MSLT, multiple sleep latency test; PSG, polysomnography.
984 PART II / Section 11 • Neurologic Disorders
disturbances in PD has been investigated. The incidence of RBD is 15% to 60% in PD as against almost 100% in multiple system atrophy and dementia with Lewy bodies. This suggests that more-extensive brain lesions predispose to greater risk of RBD. Following this idea, several teams examined the question of whether patients with PD plus RBD would be more cognitively impaired than those without RBD. In a small group of PD patients without dementia, patients with RBD had lower electroencephalographic (EEG) frequencies than patients without RBD, suggesting either bottom-up consequences of the brainstem lesions causing RBD or early loss of cortical neurons in RBD patients.32 In 110 patients with PD, the subgroup with clinical RBD had altered executive functioning, compared to the group without RBD or hallucinations. This cognitive decline was more marked (with additional impairment of memory and logical abilities) in the presence of hallucinations.33 In 34 nondemented patients with PD for a mean 5 years, the 18 patients with polygraphically confirmed RBD showed lower performance on episodic verbal memory, executive functioning, and visuospatial and visuoperceptual processing than the 16 patients without RBD.34 In a larger group of 65 patients with PD (13 of them having dementia), including patients with and without clinical RBD, 77% of patients had clinical RBD in the group with dementia versus 27% in the group without dementia.35 With respect to the onset of parkinsonism, RBD patients were demented earlier than the non-RBD patients. REM sleep behavior disorder also exposes PD patients to a 2.7-fold higher risk of hallucinations.36 It is tempting to bring together RBD and hallucinations as manifestations of a common dysfunction of REM sleep systems. We indeed have found that the hallucinations coincided with abnormal REM sleep irruptions during daytime, as awake dreams, in 10 PD patients with severe hallucinations and RBD.37 Daytime Sleepiness Frucht and colleagues noted that some patients with PD experienced sleep attacks (or sudden onsets of sleep) when treated with dopamine agonists.38 Due to the high risk of accident in sleepy drivers, the level of daytime sleepiness must be regularly checked in PD patients, especially when the dopaminergic treatment is changed. This is particularly true in young patients who have new-onset PD and receive high doses of dopamine agonists. Daytime sleepiness in PD can be self-reported, but it is better reported by the caregiver, because some patients are unaware of being abnormally sleepy.39 Napping after lunch is common in PD patients, and it is often perceived as beneficial. The Epworth Sleepiness Scale score has been well validated in PD,40 with an abnormal threshold above 10, but it is poorly predictive of sleep attacks.41 Some authors have added specific questions on the ability to fall asleep when driving, eating, working, or performing a routine activity at home,41 which better predict the risk of driving accident. Questioning patients who have daytime sleepiness about hallucinations, and vice versa, is useful. These two symptoms are often associated, but they are underreported because many patients are afraid of being considered insane.
Stridor Stridor corresponds to a partial obstruction of the larynx, resulting in a harsh, high-pitched inspiratory noise. Unlike in obstructive sleep apnea (collapse of the pharynx), which does not expose the patient to immediate vital risk, stridor is a life-threatening condition (Video 87-4). The larynx obstruction usually begins during the night and is observed in 42% of unselected patients with MSA.42 It can be recognized quite easily by mimicking it to the caregiver, or by an audio recording made during the night, but it is not detected on the usual apnea-monitoring devices. Nighttime stridor is alleviated by the application of nasal continuous positive airway pressure,43 which can avoid tracheotomy and provides a long-term benefit on quality of sleep and median survival time. Sleep Benefit In PD, a specific, positive restoration of fluent mobility can occur on awakening from sleep and before taking medication and is named sleep benefit. Based on questionnaires, the frequency of this phenomenon varies from 10% to 20% to 55% of cases.44,45 The restored mobility lasts a mean of 84 minutes, and patients may be able to skip their first dose of levodopa.44 When examining 10 patients with sleep benefit on awakening after a PSG, the motor benefit is small and unrelated to the sleep structure, levodopa serum levels, or sleep chronotype.46
EPIDEMIOLOGY Insomnia Sleep problems, and especially insomnia, are common in all forms of parkinsonism. A community-based survey determined that 60.3% of PD patients had sleep problems, significantly more than in patients with diabetes mellitus (45%), or in aged controls (33%).14 These percentages increase to 76% of PD patients who claim having “broken sleep” in hospital samples and 18% complaining of a poor sleep.17 As many as 52.5% of patients with multiple system atrophy complain of sleep fragmentation, compared to 38.7% of PD patients.47 But the most severe and specific insomnia is observed in patients with PSP.48-50 REM Sleep Behavior Disorder REM sleep behavior disorder affects 30% to 90% patients with synucleinopathies but is rare in tauopathies.51 The prevalence of RBD in the various diseases comorbid with parkinsonism is shown in Table 87-1. Patients with PD are more agitated during the night than patients with Alzheimer’s disease. In an interview of 108 caregivers of 60 patients with Alzheimer’s disease and 48 patients with PD, PD patients were reported to exhibit twice as much disruptive behavior at night (mostly combativeness, incoherent speech, and hallucinations) than patients with Alzheimer’s disease.52 Most,24,25 but not all,23 series of RBD patients with parkinsonism contain more men than women, a ratio that is more consistently observed in idiopathic RBD.53 Patients with the tremor-predominant form of PD (usually a more benign form of the disease) have RBD less often than those with the bradykinetichypertonia form.54,55
Excessive Daytime Sleepiness Excessive daytime sleepiness affects on average one third of patients with PD. Case-controlled epidemiologic studies performed in various countries consistently found higher sleepiness scores and higher percentages (16% to 74%) of abnormal somnolence in PD patients than in age- and sexmatched controls.11,56-58 The incidence of sleepiness was 6% per year in a prospective series.59 Sleepiness can precede the onset of PD; sleepy adults in a large Asian longitudinal study developed PD later in life 3.3 times more often than nonsleepy adults.60 The most worrying aspect of sleepiness in PD is sleep attacks, or sudden onsets of sleep without prodrome, that have first been described in patients using the new nonergot dopamine-agonist drugs pramipexole and ropinirole.38 Examples of sleep attacks include patients falling asleep during stimulating life conditions, such as eating a meal (the head drooping in the plate), walking, attending work, carrying a child on an escalator, and, the most dangerous situation, while driving a car. The percentage of PD patients having experienced sleep attacks varies from 1% to 14%,41,61 and 1% to 4% PD patients report having experienced sleep attacks while driving.
PATHOGENESIS The disruption of the normal sleep and wakefulness in patients with parkinsonism may be caused by neurodegenerative damage in brain areas responsible for regulation of sleep and arousal; by behavioral, respiratory, and motor system phenomena accompanying the disease; and by deleterious effects of medications that can induce nightmares, nocturnal movements, insomnia, or sleepiness. These three elements contribute to various degrees to the clinical symptoms. There is, for example, much more evidence that neuronal loss causes RBD than causes insomnia. Insomnia Insomnia is a nonspecific symptom that does not necessarily result from a selective lesion in any sleep system, except in PSP, where brainstem cholinergic lesions can encompass the REM sleep executive systems.62 General factors, such as aging, anxiety, and depression, can account for some nocturnal sleep disruption in PD. Poor sleep quality correlates with depression and anxiety scores,63 but motor phenomena and disability at night are the major causes of trouble in maintaining sleep.64 The frequency of insomnia increases with advanced motor stages of PD and a need for a higher daily dose of dopaminergic therapy,12,13 an indicator of dopamine denervation. Slow movements, nocturnal akinesia with difficulties turning in bed and adjusting blankets, pain, cramps, nocturnal and early morning dystonia (a clawlike contraction of the toes), and frequent need to pass urine are reported by patients with advanced PD as main causes of their insomnia.17 The difficulty moving during the night can further increase the anxiety levels, and depression, present in one third of patients with PD, also affects sleep, although to a lesser degree than do motor problems. This can lead to early awakenings, as in patients with major depression. Older patients with on-off phenomena and those with
CHAPTER 87 • Parkinsonism 985
hallucinations are particularly likely to have severe sleep disruption.65 In patients with advanced PD, the alleviation of nocturnal bradykinesia and painful dystonia using subthalamic nucleus stimulation at night result in major decrease of time awake at night66 and improvement of subjective sleep quality.67 Restless legs syndrome, a common cause of insomnia in the general population, has a 15% to 20.8% prevalence in PD.15 Except in patients with a family history of RLS, they seem to reflect a secondary phenomenon. There is no evidence that RLS symptoms early in life predispose to the subsequent development of PD.15,68 In clinical practice, RLS may be difficult to distinguish from leg pains, which are common in patients with PD, and from the urge to move, which is common in patients with motor fluctuations. PD patients with RLS have lower ferritin levels than those without.15 There is still a controversy as to whether the circadian system is affected in PD, especially in patients displaying nighttime insomnia and daytime sleepiness. The nocturnal profile of body core temperature is similar in patients with PD and in controls, but the nocturnal temperature fall is blunted in patients with MSA.69 Eventually, a deleterious effect on sleep of dopaminergic agents (which have been considered stimulants), when given at bedtime, can be observed.18 REM Sleep Behavior Disorder The exact cause of RBD in parkinsonism is mostly unknown, but a nondopaminergic lesion of the system controlling atonia during REM sleep is highly suspected.70 Animal models of RBD have been obtained by lesioning the locus coeruleus perialpha (pons) in the cat. This area is distinct from the true noradrenergic locus coeruleus. The animals displayed complex types of behavior including grooming, leaping, being on watch, and hunting invisible prey during REM sleep.71 Muscle atonia is imperfect in rat after lesion of the sublaterodorsalis nucleus.72,73 The equivalent of these nuclei in humans is the subcoeruleus nucleus in the pons. This nucleus, studied in two PD patients with RBD and hallucinations, contained Lewy bodies.37 The subcoeruleus nucleus is also damaged in MSA.74 Lewy bodies (containing alpha-synuclein deposits), the histologic hallmark of PD, are detected in the brains of about 10% of clinically normal people older than 60 years. When Lewy bodies are found in normal persons, the process is sometimes referred to as incidental Lewy body disease. The subcoeruleus–coeruleus complex is affected in incidental Lewy body disease.75 It is proposed that alpha-synucleinopathy initially affects the medulla oblongata and then progresses to more rostral brain areas in a hierarchical sequence (Braak hypothesis).76 In this model, the subcoeruleus nucleus, which is located in the pons, should be affected earlier than the substantia nigra, located in the mesencephalon. Hence the idea that presymptomatic RBD would follow this rule. However, only one third of patients with PD develop RBD before the onset of parkinsonism, and RBD prevalence is not 100%, even in patients with advanced PD, suggesting that this bottom-up rate of progression is not an exclusive rule. Other nuclei, such as the substantia nigra or the pedunculopontine nucleus, do not seem to be implicated in the
986 PART II / Section 11 • Neurologic Disorders
mechanism of RBD. The absence of RBD in four cases with severe lesions of the substantia nigra suggests that a lesion of the substantia nigra is not sufficient to elicit RBD,77 even though this area can be damaged in idiopathic RBD78 and even though muscle activity during REM sleep correlates with reduction of striatal dopamine transporters.79 The cholinergic nuclei located in the pedunculopontine tegmentum have also been suspected to contribute to muscle atonia during REM sleep,80 but they are similarly damaged in patients with and without RBD.81 In murine models, it seems that the phasic and tonic REM sleep muscle activities are controlled by different mechanisms.82 These elements could provide a basis for the clinical observation that REM sleep without atonia can coexist with no activity in some patients, whereas other patients have a perfect chin muscle atonia coexisting with prominent phasic limb activity. In addition, RBD can be triggered or exacerbated pharmacologically, especially by the use of antidepressants such as selective serotonin reuptake inhibitors,83 which are currently used in treating depressive symptoms in parkinsonism. In contrast, there is no evidence that levodopa or dopamine agonists can trigger RBD or elicit REM sleep without atonia, although phasic activity during RBD can increase after the introduction of levodopa.84 In atypical parkinsonism, the lesions are usually more extensive than in PD, complicating the clinicopathologic correlations. As shown in Table 87-1, the synucleinopathies are more often associated with RBD than the tauopathies and polyglutamine diseases, suggesting that the neurons responsible for muscle atonia in REM sleep are more vulnerable to alpha-synuclein deposits than to other mechanisms of damage. Excessive Daytime Sleepiness The mechanisms of sleepiness and sleep attacks in PD can include a complex drug-and-disease interaction. Most arousal systems (Table 87-3) are affected by neuronal loss and Lewy bodies in PD brains, including the norepinephrine neurons in the locus coeruleus,85 the serotonin neurons in the raphe,85 the cholinergic neuron in the basal forebrain,85 and the hypocretin (orexin) neurons (also affected in primary narcolepsy) in the hypothalamus.86,87 In contrast, the wake-active dopamine neurons in the ventral periaqueductal gray matter and the histamine neurons in the hypothalamus are intact in PD brains.88,89 In MSA, there is also a marked decrease of hypocretin neurons.90 Half of patients with MSA complain of daytime sleepi-
ness,47 and about one third of MSA patients show the narcolepsy-like phenotype.57 In PD, sleepiness may be more common in patients with advanced disease.56 Sleep deprivation, a condition observed when PD patients are kept awake at night by restless legs, disabling motor disability, or painful cramps, is a classic cause of somnolence. In large groups of PD patients however, longer sleep time at night is associated with more severe daytime sleepiness,91-93 an association suggesting central hypersomnia. Similarly, sleep apnea (observed in 20% to 30% of PD patients) (Video 87-5), periodic leg movement during sleep, and sleep fragmentation do not correlate with the severity of daytime sleepiness,91-93 suggesting they do not contribute much to the mechanisms of sleepiness (although this assertion could be wrong in individual cases). The use of dopamine agonists exposes PD patients to a twofold to threefold higher risk of sleep attacks38,41,56,61 and points toward the sedative role of dopamine agonists in some PD patients. The risk of sleep attacks is similar using ergot agonists (bromocriptine, pergolide) or nonergot agonists (pramipexole, ropinirole). The risk increases with higher daily dosage and decreases with drug withdrawal. In contrast, levodopa is more rarely sedative.91 Why drugs that are supposed to stimulate the alerting brain system (and do so when given at bedtime)18 are, on the contrary, sedative is as yet unknown. This effect cannot be explained, at these high doses, by the biphasic effect (presynaptic sedative effect at low dose, postsynaptic alerting effect at high dose) of dopamine agonist that has been described in animals.94 The sedation observed in selective PD patients suggests a genetic vulnerability to this side effect of dopamine agonists, although sleepiness does not correlate with genetic variants of the enzyme responsible for dopamine catabolism.95
DIAGNOSIS As with other diseases, the clinical interview is key for diagnosing the causes of sleep complaints in patients with parkinsonism (see Table 87-2). However, in parkinsonism, the information provided by video PSG is so important and useful that the threshold for ordering this test should be very low. Most complaints of excessive daytime sleepiness need to be explored by night and day sleep monitoring. Sleep monitoring may be less useful in patients suffering only from insomnia. The recording of a patient with parkinsonism in a sleep unit can be difficult when the
Table 87-3 Neuronal Loss in Arousal Systems in Brains of Patients with Parkinson’s Disease NUCLEUS
MAIN NEUROTRANSMITTER
NEURONAL LOSS IN PARKINSONIAN BRAIN (%)
Locus coeruleus
Noradrenaline
40-50125
Median raphe
Serotonin
20-40125
Ventral periaqueductal gray matter
Dopamine
989
Pedunculopontine nucleus
Acetylcholine
57125
Tuberomammillary nucleus
Histamine
Unchanged enzymatic activity88
Lateral hypothalamus
Orexin (hypocretin)
23-6286,87
Basal forebrain
Acetylcholine
32-93125
team is not used to monitoring disabled, anxious patients, who might need to be given drugs every 3 hours, to be helped regularly during the night, to receive massage when they have violent cramps or dystonia, and to be reassured when they are confused or experience hallucinations. There is no specific recommendation on monitoring sleep over 1 or 2 nights. The minimal montage should include the usual sleep montage (EEG, electrooculogram [EOG], chin electromyogram [EMG]), electrocardiogram (ECG), nasal pressure, thorax and abdomen efforts, oxygen saturation, and leg EMG. Audio monitoring should also be performed because stridor may be mistaken for snoring if nobody hears the raw sound, and synchronized infrared video or upper limb EMG (hand muscles rather than shoulder or arm muscles)96 should be performed when RBD is suspected. Sleep scoring may be particularly difficult and time-consuming in patients with parkinsonism. Video PSG is helpful for recognizing and scoring sleep and sleep problems in patients with parkinsonism, because EEG features of sleep can change, RBD may be confused with waking activities, and stridor needs to be identified. For example, the number of sleep spindles during non-REM (NREM) sleep is reduced,97 and EEG alpha activity may be prominent during REM sleep98,99 and can even contaminate all sleep stages in PD, giving the false picture of complete wakefulness throughout the night. In patients suffering dementia with Lewy bodies or PSP, the alpha background rhythm during wakefulness may turn to a slow, regular rhythm closer to 5 to 7.5 Hz, with a further left switch of all frequencies during NREM sleep toward slow-wave activity, so that an awake patient with open eyes can have a concomitant EEG suggesting full-blown stage 4 sleep. Sequences of slow or rapid eye movements may be observed during NREM sleep.14 Chin muscle tone may be enhanced during REM sleep, a feature commonly associated with clinical RBD. Increased amount of stage 1 sleep and reduced amount of stages 3 and 4 sleep and REM sleep are also common, and the duration of REM periods may be reduced, although in milder cases sleep architecture may be normal.100 Untreated PD patients show a significant decrease of stages 3 and 4 sleep and increased periodic limb movements.101 The most consistent abnormality in PD sleep architecture is sleep fragmentation, which is, however, different from the multiple arousals observed in sleep apnea. Here, PSG studies have demonstrated increased sleep latency and frequent awakenings, with as much as 30% to 40% of the night spent awake. In contrast to the quiescence of sleep in normal persons, increased muscle tone and abnormal simple and complex movements are common and complicate the scoring of PSGs in PD patients. Tremor, which is present as a 4- to 6-Hz regular artifact at the level of the chin or the legs during wakefulness (Fig. 87-1), disappears with the onset of stage 1 sleep, in some cases before alpha EEG activity is entirely gone.34,35,102 It can persist as a polygraphic finding rather than a clinical movement, in stage 1 and with awakenings, arousals, and body movements.103 Patterns of simple motor activity during sleep include repeated blinking at the onset of sleep, rapid eye movements during NREM sleep, blepharospasm at the onset of REM sleep, and prolonged tonic muscle activity of limb extensor or
CHAPTER 87 • Parkinsonism 987
032 A 097 B
030 A 097 B
031 A 096 B
032 A 096 B
Figure 87-1 Polysomnography of a patient with Parkinson’s disease and nocturnal rest tremor of the right leg between wakefulness and stage 1 sleep. The regular unilateral rest tremor is interrupted by bilateral motor activity. Channels (from top) are 1-2, eye movements; 3-6, EEG; 7, chin EMG; 8, ECG; 9, additional EEG; 10-12, respiratory recording with thoracic and abdominal belts; 13, no recording; 14, EMG of right anterior tibialis muscle; 15, EMG of left anterior tibialis muscle.
028 A 094 B
028 A 095 B
030 A 095 B
026 A 094 B
Figure 87-2 Polysomnography recordings of a Parkinson’s disease patient with REM sleep behavior disorder. The chin EMG shows a highly elevated muscle tone: Multiple motor activities occur in the recording, and typical muscle twitches appear in the EMG channels of both legs. Channels (from top) are: 1-2, eye movements showing a typical REM sleep pattern; 3-6, EEG; 7, chin EMG with increased muscle tone; 8, ECG; 9-17, further EEG channels, showing muscle artifacts of eye movements; 18-20, respiratory recording with thoracic and abdominal belts; 21, no recording; 22-23, EMG of right and left anterior tibialis muscle.
flexor muscles during NREM sleep.98 An example of sleep recordings during an RBD episode is shown in Figure 87-2. Once the EEG and the video are analyzed and nighttime sleep and multiple sleep latency tests are analyzed, the hypnogram generally shows severely fragmented sleep. The first part of the sleep report should include a description of the EEG aspect, and especially the frequency of the alpha background rhythm, because slow (e.g., 6.5 to
988 PART II / Section 11 • Neurologic Disorders
A 1 R 2 3 4
A
11 PM
01 AM
03 AM
05 AM
07 AM
09 AM
11 AM
01 PM
03 PM
Hallucination A 1 R 2 3 4
B
11 PM
01 AM
03 AM
05 AM
07 AM
11 AM
Levodopa
A 1 R 2 3 4
C
09 AM
11 PM
01 AM
03 AM
Major akinesia
05 AM
07 AM
01 PM
03 PM
Levodopa
09 AM
11 AM
01 PM
03 PM
09 AM
11 AM
01 PM
03 PM
Foot dystonia
A 1 R 2 3 4
D
11 PM
01 AM
03 AM
05 AM
07 AM
Figure 87-3 Twenty-four-hour sleep histograms. A, A healthy 60-year-old woman with normal sleep. B, A 54-year-old woman with Parkinson’s disease (PD) treated with levodopa 300 mg/day and bromocriptine 30 mg/day, reporting frequent nighttime awakenings, daytime sleepiness, and hallucinations (indicated by the arrow); she saw a stranger in the room, here synchronous with daytime abnormal irruption of REM sleep (narcolepsy-like phenotype). C, An 80-year-old man with mild PD, complaining of falling asleep 2 to 3 hours after each levodopa dose (arrow), who displayed severe hypersomnia. D, A 72-year-old man with advanced PD and on–off motor fluctuations. After a midnight awakening (arrow), he developed a severe bradykinesia with an axial painful dystonia that prevented him to resume sleep. Later, at 4:30 AM, he had a foot dystonia (early morning dystonia). All these motor phenomena lengthened his time awake. The x axis displays the time of night and day (clock hours), the y axis displays the stages of sleep and wakefulness, with awakening (A), NREM sleep stage 1 (1), stage 2 (2), stage 3 (3), and stage 4 (4), and REM sleep (R).
7.8 Hz) rhythms have been associated with RBD and possibly cortex damage. The presence of abnormal sleep stages, including eye movements during NREM sleep and REM sleep without atonia, should also be specified. Examples of hypnograms obtained in PD patients are shown in Figure 87-3. As for the MSLT, in a series of 54 PD patients, more than half of patients would fall asleep within a mean of 5 minutes, a sign of pathologic sleepiness.74 Moreover, 41% of sleepy patients had at least two sleep-onset REM periods, an abnormal pattern mostly observed in primary narcolepsy.74,104 The narcolepsy-like pattern of sleepiness (multiple sleep-onset REM periods) is observed in 15% of unselected PD patients76 and in some patients with MSA and dementia with Lewy bodies,30 but not in patients with PSP.19 In PD patients with severe hallucinations, there are
also abnormal irruptions of REM sleep episodes during daytime, which are temporally associated during nighttime and daytime with these visual hallucinations, as the hypnagogic hallucinations are in primary narcolepsy.14,105 In another group of PD patients, the hallucinations temporally occur after REM sleep during the night and during wakefulness or stage 1 sleep during daytime.106 Sleep attacks can also consist, as in primary narcolepsy, of sudden, irresistible onsets of stage 2 sleep.107
TREATMENT The management of sleep disorders in parkinsonism depends on the causes identified by interview and monitoring. A list of usual problems and corresponding experience-based management is given in Table 87-2.
Insomnia The comfort of the PD patient during the night can be improved by using sheets that do not slip, silk pajamas without buttons, levodopa tablets and a bottle of water on the bed table, and transitory blockade of nighttime polyuria with an evening intranasal dose of desmopressin. In advanced stages of the disease, the patient’s spouse should be encouraged to sleep in a different bed or room; inadequate rest for the spouse or other caregiver can make the patient’s sleep disturbance intolerable and lead to institutionalization. Although insomnia is common in PD, treatments have been poorly studied in this situation. The treatment of PD insomnia is therefore not codified and is based more on experience than on evidence. Two goals are to improve sleep continuity (and in this case, the sleeping patient will not need any nocturnal dopamine treatment) and to reduce movements and muscle tone during the night. Single, small, unblinded trials of zolpidem, clozapine, quietapine, and sodium oxybate have shown a benefit on sleep in PD patients. Hypnotics and small doses of sedative antidepressants are often used in PD patients in clinical practice provided these drugs do not worsen a preexisting RLS, RBD, hallucinations, or daytime sleepiness. In patients with depression, most antidepressants can worsen preexisting RLS, PLMS, and RBD; however, bupropion could be an appropriate first-line treatment, but it has not been studied in any trial in PD patients. When disturbing hallucinations are present, patients can benefit from the combined antihallucination and sedative effects of a small evening dose of an atypical neuroleptic such as clozapine (with appropriate checks of leukocyte count), or quetiapine. When severe daytime sleepiness is associated with nighttime insomnia, sodium oxybate may be considered. Re-establishing continuous dopaminergic stimulation during day and night can be a strategy to improve nighttime motor disability. A careful report of the time of the symptoms, in correlation with time of drug intake, can help to identify a nighttime gap in dopaminergic stimulation. The benefit of dopaminergic agents in the evening and night has to be weighted against their alerting effect. As an example, pergolide 1 mg in the evening worsened sleep efficiency and fragmentation in patients with repeated nocturnal awakenings caused by PD symptoms.47 In contrast, the use of transdermal rotigotine (up to 16 mg in 24 hours) during day and night improved most aspects of sleep and night quality in patients with advanced PD, compared to placebo, but it was not superior to oral pramipexole three times a day (up to 4.5 mg per day).108 One group had a good experience with open-label trials of cabergoline (1-6 mg per day),109 but ergotic dopamine agonists have now been abandoned because of their risk of valvular heart disease. The use of levodopa 200 mg in the evening improves subjective sleep quality, and decreases nighttime movements.110 Sustained-release forms of levodopa in the evening have not been contrasted with normal-release forms of levodopa. They do not change subjective sleep (general quality, sleep onset latency, total sleep time, number of awakenings) but have a mild effect on nocturnal akinesia in small unblinded trials. We have had good results with rapid-release (dispersible) forms of levodopa soluble in water during the night.
CHAPTER 87 • Parkinsonism 989
Subthalamic nucleus stimulation consistently improves sleep duration, reduces nocturnal awakenings, and reduces early morning dystonia in patients with advanced PD.42,43,111 This benefit might result from the specific effect of stimulation on a single dopaminergic loop, and oral or transdermal dopaminergic therapy may in addition stimulate arousal systems.112 The treatment of nocturnal RLS in PD may be complex, apart from iron supplementation in iron deficiency, evening use of gabapentin and derivatives, and, more rarely, use of opiates in patients who are not demented and not hallucinating.79 No guideline is available for this purpose. The emergence of RLS (and PLMS) during subthalamic stimulation suggests that they are not controlled by basal ganglia.42,113 RLS might correspond to a deficit of dopamine stimulation at night (and would benefit from an evening additional dose of dopamine agonist) or to an excess of dopamine stimulation during the day with rebound restless legs during the night, a condition termed augmentation. These patients can benefit from decreasing the daily dopamine dose. The occurrence of RLS years after (and not before) the onset of parkinsonism supports this last hypothesis. REM Sleep Behavior Disorder RBD patients may secure their bed environment and partner, perhaps by placing a pillow between the patient and the partner, by using twin beds, or by placing the mattress directly on the floor. It can also help to use a wall light instead of bed lamp and night table, which patients can hurt themselves on. In severe cases, reducing or withdrawing antidepressants alleviates RBD. No randomized, double blind, placebo-controlled study has been reported for any drug treatment for RBD. Clonazepam (0.5-2 mg before bedtime) is, however, highly effective and well tolerated in most cases (provided it does not worsen a preexisting severe sleep apnea syndrome).61,114 Melatonin (3-12 mg), also effective on RBD, partially restores normal muscle tone during REM sleep.115 Dopaminergic agents do not change the RBD expression in patients with symptomatic RBD.23,116 Similarly, deep brain stimulation does not change the motor activity during REM sleep.42,43 Excessive Daytime Sleepiness Finding and treating the cause of daytime sleepiness in PD requires a careful interview about nocturnal disturbances, hallucinations, recent changes in dopaminergic and psychotropic treatment, and usually nighttime sleep monitoring, if possible, followed by a multiple sleep latency test. These tests can identify treatable severe sleep apneas or a central disorder of arousal. If efforts to reduce any sedative drug (clonazepam, other benzodiazepines, dopamine agonists, sedative antidepressants, opioids, atypical neuroleptics) are without effect or worsen the motor symptoms, the solution could be to add a psychostimulant during the daytime. Modafinil, a drug routinely used in primary narcolepsy and sleepiness of various causes, is well tolerated in PD patients,117 and it has interesting neuroprotective effects in animal models of dopamine depletion.118 The alerting effect is limited, however; less than one third of patients respond.117 Methylphenidate has been occasionally used, and anti-H3 anti-
990 PART II / Section 11 • Neurologic Disorders
histamines are in development in this indication. Stimulants should be used with caution in cognitively impaired patients (PD patients with dementia, patients with Lewy body dementia, PSP patients), because confusion and violent actions can occur. ❖ Clinical Pearl The clinician should take a careful history of the various sleep problems of a patient with parkinsonism and try to distinguish nighttime bradykinesia, off-dystonia, tremor, PLMS, respiratory disturbances, insomnia, RBD, or psychosis from medication-associated factors and their contribution to the sleep problem. Specific interventions might then be required to increase quality of sleep and reduce daytime sleepiness, thus enhancing quality of life in PD. Nocturnal stridor is a life-threatening symptom in MSA that can benefit from continuous positive airway pressure.
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Chapter
Sleep and Stroke
88
Claudio L. Bassetti Abstract
Sleep disorders and stroke are among the most common neurologic problems and can occur together by chance alone. In addition, each condition can cause the other or can arise from similar predisposing factors. Clinicians who treat patients
Since the 1990s the link between sleep and stroke has received increasing attention. This is mainly due to a better recognition of the strong link between sleep- disordered breathing (SDB) and cardiovascular and cerebrovascular diseases, the high incidence of sleep–wake disturbances in stroke victims, and the impact that SDB, sleep–wake disturbances, and their treatment have on the risk and outcome of stroke.
STROKE Stroke is defined as a focal neurologic deficit of acute onset and vascular origin. Stroke has an incidence of 2 or 3 per 1000 per year and is the most common neurologic disease to warrant hospitalization. Transient ischemic attacks (TIAs), in which neurologic deficits resolve within 1 hour, account for about 20% of acute cerebrovascular deficits and intracerebral hemorrhage for about 15%. The remaining 65% are ischemic strokes. Risk factors for stroke include atrial fibrillation, age older than 65 years, arterial hypertension, heart diseases, asymptomatic carotid stenosis, history of TIA, alcohol abuse, smoking, diabetes mellitus, and hypercholesterolemia. However, these factors explain only about 50% of the cardiovascular disease risk. Inflammatory changes, infection, homocysteine, and SDB represent new risk factors for stroke.1 According to the criteria of the TOAST study (Trial Of Acute Stroke Treatment), the etiology of stroke can be grouped into five categories: macroangiopathy (large-vessel disease), microangiopathy (small-vessel disease), cardioembolism, other etiologies (e.g., dissection, hypercoagulable states, vasculitis), and unknown origin.2 Primary prevention of stroke includes treatment of risk factors (including hypertension and hypercholesterolemia), regular physical exercise, reduction of body mass index to less than 25, anticoagulation for atrial fibrillation, and endarterectomy in patients with 70% or more carotid stenosis.3,5 Treatment of acute stroke includes admitting patients to a stroke unit, recognizing medical complications early, and prescribing agents that inhibit platelet aggregation.3 Fibrinolytic agents are effective in the first 4.5 hours after ischemic stroke.4 Surgery may be considered in patients with accessible (e.g., cerebellar) hemorrhages. After stroke, prevention of further events includes antiaggregants, antihypertension medications, statins, treatment of risk factors, and—in selected patients—anticoagulation and endarterectomy.3
with sleep disorders or stroke should be aware of this potential comorbidity and its clinical implications. Diagnosis and treatment of sleep-disordered breathing and sleep–wake disturbances in patients with stroke have an impact on the risk of stroke as well as on its short- and long-term evolution.
HISTORY Changes in sleep and breathing were reported in stroke patients from the beginning of the 19th century. In 1818 John Cheyne described periodic breathing in a patient with cardiac disease and “apoplexy.”6 Hughlings Jackson recognized that Cheyne-Stokes respiration often accompanies bilateral hemispheric stroke. Symptoms of obstructive sleep apnea (OSA) were recognized in a patient with intracerebral hemorrhage by Broadbent in 1877.7 Charles Beevor described the loss of voluntary respiratory control in a patient with pseudobulbar palsy (cited in Oppenheim’s book8). Although central apnea in the course of progressive paralysis was described already by Weir Mitchell in 1890,9 failure of automatic respiration during sleep (later called “Ondine’s curse”) after brainstem stroke was first reported by Ratto in 1955.9 Hypersomnia following stroke was mentioned by MacNish in 1830,10 but it was only at the beginning of the 20th century that thalamic and mesencephalic stroke, in particular, were implicated.11,12 In 1883 Charcot reported that a patient lost dream recall after a presumed parietooccipital stroke.13 Lhermitte joined the term peduncular hallucinosis in 1922 to describe vivid, colorful, and dreamlike hallucinations following midbrain stroke.14 A first report on sleep electroencephalographic (EEG) changes following stroke appeared in 1948.15
SLEEP-DISORDERED BREATHING AND STROKE Epidemiology Sleep-Disordered Breathing as Risk Factor for Stroke Habitual snoring—that is, snoring occurring always or almost always—affects 4% to 24% of the adult population, with a maximum prevalence around the age of 50 to 60 years, and is strongly associated with OSA.16 Five casecontrol and three cohort studies have shown that habitual snoring represents an independent risk factor for stroke, with a pooled risk of about 1.5.17 Longitudinal and population studies have suggested a direct link between polysomnographically proven SDB and stroke. In a study of 1022 patients admitted to a single sleep center and followed up over up to 6 years, Yaggi and colleagues found that OSA is associated with an increased risk for stroke and death, even after adjusting for 993
994 PART II / Section 11 • Neurologic Disorders
cardiovascular risk factors, such as arterial hypertension, diabetes mellitus, atrial fibrillation, hyperlipidemia. and smoking status, with an hazard ratio (HR) of 2.0 (95% confidence interval [CI], 1.12 to 3.48). The risk was even higher (HR, 3.3; 95% CI, 1.74 to 6.26) in patients with severe OSA (apnea–hypopnea index [AHI] > 36/hr).18 In a single-center study of 1387 male patients with OSA, 377 simple snorers, and 264 controls, matched for age and body mass index (BMI), Marin and coworkers found, after a mean follow-up period of 10 years, a significantly higher incidence of fatal and nonfatal cardiovascular events (e.g., stroke, myocardial infarction, coronary artery bypass graft surgery, percutaneous transluminal coronary angiography) in patients with severe OSA (AHI > 30/hr) as compared to patients with mild to moderate OSA, patients with OSA of any severity treated with continuous positive airway pressure (CPAP), simple snorers, and controls.19 Multivariate statistics, adjusting for potential confounders (hypertension, diabetes, cardiovascular disease, lipid disorders, smoking status) showed that untreated severe OSA increased the risk of fatal and nonfatal cardiovascular events compared with healthy participants. In a cross-sectional analysis of 1475 subjects, Arzt and colleagues showed that those with an AHI of at least 20/ hr have an odds ratio (OR) of 4.3 (95% CI, 1.32 to 15.24) compared to those with an AHI less than 5/hr, even after adjustment for known risk factors.20 In an elderly population of 394 noninstitutionalized stroke-free subjects (>70 years), Munoz’s group showed after a follow-up of 6 years that persons with severe SDB (AHI > 30/hr) have an increased risk for stroke with a hazard ratio of 2.5 (95% CI, 1.04 to 6.01) even when data are adjusted for sex.21 A link between SDB and silent stroke or white matter disease on magnetic resonance imaging (MRI) has also been examined.22-25 In a study of 50 OSA patients, Minoguchi and colleagues found an increased risk for silent brain infarction (as detected by MRI) for those with an AHI of at least 30 when compared with weight-matched patients with mild or no OSA.25 Sleep-Disordered Breathing in Stroke Patients More than 20 studies (Table 88-1) on almost 2000 patients have shown, despite different diagnostic approaches (polysomnography or respirography), that at least 50% of stroke patients exhibit SDB, as defined by an AHI of 10/hr or more.26-49 Few studies suggested a higher incidence of SDB depending upon type (hemorrhagic versus ischemic), presumed etiology (macroangiopathy versus other origins), and severity or clinical characteristics (facial or bulbar involvement, recurrent versus first-ever event) of stroke. In seven studies, the prevalence of SDB was found to be similar also in patients with TIAs and ischemic stroke (see Table 88-1).26,27,31,38,44,51a,51b In a 2010 metaanalysis of 29 articles (2343 ischemic or hemorrhagic stroke and TIA patients), the frequency of SDB with AHI > 5 was 72% and with AHI > 20 was 38%. Only 7% of the SDB was primarily central apnea. There was no significant difference in SDB prevalence by event type, timing after stroke, or type of monitoring. Males had a higher percentage of SDB (AHI > 10) than females (65% compared to 48%, P = 0.001). Patients with recurrent
strokes had a higher percentage of SDB (AHI > 10) than initial strokes (74% compared to 57%, P = 0.013). Patients with unknown etiology of stroke had a higher and cardioembolic etiology a lower percentage of SDB than patients with other etiologies.51c From the acute to the subacute phase of stroke, SDB improves.31,35-37,43 Nevertheless, a significant percentage of patients (up to 50%) exhibit an AHI of at least 10/hr months to years after the acute event (see Table 88-1). Central events improve more than obstructive events. One study suggested a better improvement of SDB in hemorrhagic strokes as compared to ischemic strokes.37 Clinical Features Symptoms Sleep-disordered breathing can manifest with a variety of symptoms and signs that are sometimes attributed to the underlying brain damage. Nighttime symptoms of SDB include difficulties falling asleep (sleep-onset insomnia, see later); respiratory noises (snoring, stridor); irregular or periodic respiration, apneas; disrupted sleep with increased motor activity and frequent awakenings; sudden awakenings with or without choking sensations, shortness of breath, palpitations, and panic attacks; orthopnea; and increased sweating. In patients with severe hypoventilation, arousal responses can be suppressed by increasing sleep debt and can lead to death during sleep. Daytime symptoms of SDB include headaches, fatigue and excessive daytime sleepiness, concentration and memory difficulties, irritability, and depression. Some patients also exhibit breathing irregularities during wakefulness including dyspnea, apneas, inspiratory breath holding (apneustic breathing), irregular breathing, rapid shallow breathing (hyperpnea and central hyperventilation), hiccup, and other breathing abnormalities. Breathing Disturbances during Sleep The most common form of SDB in stroke patients is OSA (Fig. 88-1). Severe OSA (with AHI 20 to 30) is found in 20% to 30% of patients. Occasionally, patients present with both OSA and Cheyne-Stokes breathing, with predominance of the first in rapid eye movement (REM) sleep and of the latter in light non-REM (NREM) sleep.26 Cheyne-Stokes breathing is a type of periodic breathing in which central apneas and hypopneas are separated by a crescendo–decrescendo respiratory pattern (Fig. 88-2). Central periodic breathing can be defined as three or more cycles of regular crescendo–decrescendo breathing associated with a reduction of at least 50% in nasal airflow and effort lasting at least 10 seconds. In the first few days after stroke, Cheyne-Stokes breathing and central periodic breathing during at least 10% of recording time is present in 10% to 40% of patients31,33,48,52,53 Central hypoventilation, failure of automatic breathing (Ondine’s curse) and other neurogenic breathing disturbances are less common and usually associated with brainstem strokes. Breathing Disturbances while Awake Breathing abnormalities occurring during wakefulness following hemispheric strokes have not been well studied. Such abnormalities can include selective impairment of
PATIENTS
128 patients (71 men) with acute stroke (80 patients) or TIA
24 patients (13 men) with acute ischemic or hemorrhagic stroke
47 patients with subacute stroke admitted to a rehabilitation unit
147 patients with subacute first-ever stroke (95 men) admitted to a rehabilitation unit
161 patients with acute first-ever (ischemic or hemorrhagic) stroke or TIA (82 men) 86 subjects reexamined subacutely
50 patients with acute ischemic stroke (30 men)
120 patients with acute ischemic stroke (50 men)
51 patients with acute ischemic stroke (28 men) 20 patients not receiving CPAP reexamined subacutely
68 patients with acute stroke 50 reexamined subacutely
106 patients with acute ischemic and hemorrhagic stroke (70 men) 51 reexamined subacutely
39 patients with subacute stroke (16 with hemorrhage) admitted to a rehabilitation unit
86 patients with TIA (49 men)
STUDY
Bassetti et al. (1996, 1999)
Dyken et al. (1996)
Good et al. (1996)
Wessendorf et al. (2000)
Parra et al. (2000)
Iranzo et al. (2002)
Turkington et al. (2002)
Hui et al. (2002)
Harbison et al. (2002)
Szücs et al. (2002)
Disler et al. (2002)
McArdle et al. (2003)
Table 88-1 Sleep-Disordered Breathing after Stroke
SDB: 29 No SDB: 27 27 ± 4
SDB: 26 ± 3 No SDB: 26 ± 4
24 ± 4
24 ± 4
25 ± 5
NA
NA
27 ± 5
72 ± 9
67 ± 9
79 ± 10
64 ± 13
73 ± 11
67 ± 14
65 ± 15 65 ± 11
Men: 28 ± 1 Women: 33 ± 2
65 ± 10
61 ± 10
29 ± 2
59 ± 15
Continued
AHI ≥ 15/hr in 50% of patients Mean AHI (21 ± 17/hr) similar to age- and sex-matched controls Oxygen desaturations more frequent in patients (12/hr vs. 6/hr)
AHI > 15/hr in 50% of patients studied by respirography 2 mo after stroke
ODI ≥ 10/hr in 70% of patients with ischemic stroke and in 64% of patients with hemorrhagic stroke studied by respirography. After 3 mo significant improvement only in patients with hemorrhagic stroke.
AHI ≥ 10/hr in 94% (≥30/hr in 46%) of patients studied by respirography within the first 2 wk after stroke (mean interval, 10 day) AHI higher in patients with lacunar stroke AHI reduction from the acute to the subacute phase: 31 ± 17 vs 24 ± 16, 6-9 wk after stroke (mean interval, 45 d)
AHI ≥ 10/hr in 67% (≥20/hr in 49%) of patients studied within the first 4 days after stroke, compared with 24% in controls AHI reduction from the acute to the subacute phase: 32 ± 17 vs 23 ± 19, 1 mo after stroke
RDI ≥ 10/hr in 61% (≥15/hr in 45%) of patients studied by respirography within 24 hr after stroke RDI higher in supine sleeping position RDI predicted by BMI, neck circumference, and limb weakness
AHI ≥ 10/hr in 62% studied by PSG 12 ± 5 hr after stroke Increased probability of sleep-related stroke onset in SDB subjects SDB associated with early neurologic worsening, not with functional outcome at 6 mo
AHI ≥ 10/hr in 71% (≥30/hr in 28%) of patients studied by respirography 48-72 hr after stroke AHI ≥ 10 in 62% (≥30/hr in 20%) of patients 3 mo after stroke AHI and central apnea index lower in subacute phase: 17 ± 14 vs. 22 ± 17/hr and 3 ± 8 vs. 6 ± 10/hr, respectively CSB in 26% of patients (7% in the subacute phase)
AHI ≥ 10/hr in 44% (≥20/hr in 22%) of patients studied by PSG 46 ± 20 day after stroke.
ODI > 10 in 32% of patients studied by oximetry
AHI ≥ 10/hr in 77% of men and 64% of women studied by PSG 2-5 wk after stroke, as compared with 23% and 14% of age-matched controls.
AHI ≥ 10/hr in 62% of patients studied by PSG 1-71 day after stroke or TIA (mean interval of 9 day), as compared with 12% in 19 age- and sex-matched controls AHI predicted by age, BMI, snoring history, diabetes mellitus, severity of stroke
BODY MASS INDEX (KG/M2) FREQUENCY AND CHARACTERISTICS OF SDB
AGE (YR)
CHAPTER 88 • Sleep and Stroke 995
214 patients with acute ischemic stroke (142 men)
93 patients with subacute (ischemic and hemorrhagic) stroke
90 patients (70 men) with chronic (ischemic and hemorrhagic) stroke
152 patients (103 men) with acute ischemic stroke 33 reexamined after 6 mo
70 patients (60 men) with acute ischemic stroke and TIA
55 patients (32 male) with acute stroke
30 patients (20 men) with ischemic stroke
60 patients (41 men) with acute ischemic stroke
74 patients (49 men) with first-ever acute ischemic stroke
166 patients (98 men) with subacute ischemic stroke
61 patients with acute ischemic stroke and 13 patients with TIA
Dziewas et al. (2005, 2007)
Nopmaneejumruslers et al. (2005)
Cadhilac et al. (2005)
Bassetti et al. (2006)
Wierzbicka et al. (2006), Rola et al. (2007)
Broadley et al. (2007)
Brown et al. (2008)
Yan-Fang et al. (2007)
Siccoli et al. (2008)
Martinez-Garcia et al. (2009)
Byung-Euk et al. (2010)
25 ± 3
28 ± 4
NA 24 ± 3
58 ± 9
63 ± 13
73 ± 11 63 ± 10
67
NA
AHI ≥ 10/hr in 53% of patients studied by respirography 2 day after stroke
27 ± 4
71
AHI ≥ 5/hr in 65% of stroke patients and 67% of TIA patients studied by respirography within 7 day after stroke AHI predicted by NIH Stroke Scale score on admission and at discharge
Stroke: 29 ± 4 TIA: 29 ± 5
66 ± 11
AHI ≥ 10 in 69% of TIA patients and 51% of stroke patients studied within 48 hr of cerebrovascular event
AHI ≥ 10 in 81% (≥20 in 58%) of patients studied by respirography 58 ± 2 days after stroke
Central AHI ≥ 10 in 41% of patients studied by respirography 45 ± 26 hr after stroke. CSB predicted by age, stroke severity and topography, cardiac function (ECG, ejection fraction).
AHI ≥ 15 in 50% of patients studied by PSG 6 ± 3 day (1-13 day) after stroke Barthel index at 3 mo predicted by Scandinavian Stroke Scale score and AHI
AHI ≥ 5/hr in 73% of patients studied within 7 day after stroke Patients with higher NIH Stroke Scale score spent more time in a supine sleeping position, suggesting that supine sleeping might contribute to elevated AHI in the acute stroke phase
AHI ≥ 10/hr in 58% (≥20 in 31%, ≥30 in 17%) of patients studied by respirography 3 ± 2 day after stroke AHI predicted by age, diabetes mellitus, and nighttime onset of stroke Reduction of AHI from the acute to the subacute phase (32 ± 11 vs. 16 ± 11)
28 ± 3
56 ± 13
AHI ≥ 10/hr in 81% of patients studied by respirography 3 yr after stroke AHI predicted by type and severity (at 1 mo) of stroke
Central AHI ≥ 10/hr (CSB) in 19% of patients studied by PSG 44 ± 3 day after stroke CSB predicted by reduced nocturnal transcutaneous PCO2 and left ventricular ejection fraction
—
No CSB: 28 ± 1 CSB: 27 ± 1
66 ± 1 (no CSB) 71 ± 3 (CSB)
AHI ≥ 10/hr in 51% of patients studied by respirography within 72 hr after admission Higher AHI (27 ± 21 vs. 15 ± 15/hr) in patients with recurrent strokes Atherosclerotic internal carotid artery plaques more frequent in patients with AHI ≥ 10/hr (51%) vs. patients with AHI < 10/hr (33%)
64 ± 15
No SDB: 25 ± 3 SDB: 27 ± 4
BODY MASS INDEX (KG/M2) FREQUENCY AND CHARACTERISTICS OF SDB
65 ± 13
AGE (YR)
Note: With the exception of Dyken’s paper, only studies with more than 30 patients are presented. AHI, apnea–hypopnea index; BMI, body-mass index; CPAP, continuous positive airway pressure; CSB, Cheyne-Stokes breathing; ECG, electrocardiogram; NA, not available; NIH, National Institutes of Health; ODI, oxygen desaturation index; PSG, polysomnography; RDI, respiratory distress index; SDB, sleep-disordered breathing; TIA, transient ischemic attack.
PATIENTS
STUDY
Table 88-1 Sleep-Disordered Breathing after Stroke—cont’d
996 PART II / Section 11 • Neurologic Disorders
CHAPTER 88 • Sleep and Stroke 997
Figure 88-1 Obstructive sleep apnea in acute ischemic stroke. This 70-year-old man (HRS) has left middle cerebral artery stroke, carotid artery occlusion, and atrial fibrillation. He has habitual snoring but no excessive daytime sleepiness on history. Aphasia and severe hemiparesis are clinically apparent. National Institutes of Health (NIH) stroke score is16, and there are no signs of heart failure. Polysomnography 2 days after stroke onset shows an apnea–hypopnea index (AHI) of 79 (33 obstructive, 42 mixed) and minimal oxygen desaturation of 85%. The AHI is normalized (<5/hr) with continuous positive airway pressure (CPAP). (MRI pictures courtesy of Prof. A. Valavanis, Institute of Neuroradiology, University Hospital, Zürich, Switzerland.)
Figure 88-2 Central sleep apnea in acute ischemic stroke. This 63-year-old man (PD) had a left subcortical stroke of unknown origin, with arterial hypertension and habitual snoring but no excessive daytime sleepiness on history. He had clinically mild hemiparesis, with a National Institutes of Health (NIH) Stroke Score of 8 and no signs of heart failure (cardiac ejection fraction, 55%). Polysomnography the first night after stroke onset showed an apnea–hypopnea index (AHI) of 53 (mainly central). The patient spontaneously improved after 1 week (AHI, 16). (MRI pictures courtesy of Prof. G. Schroth, Institute of Neuroradiology, University Hospital, Bern, Switzerland.)
998 PART II / Section 11 • Neurologic Disorders
behavioral or volitional respiratory control with preservation of metabolic control mechanisms. Strokes in the frontal cortex, basal ganglia, or capsula interna can cause respiratory apraxia, with impairment of voluntary modulation of breathing amplitude and frequency, leaving patients unable to take a deep breath or hold the breath.54,55 Several abnormal patterns of breathing, though uncommon, can occur after brainstem stroke, especially during sleep or with decreased levels of consciousness. Sustained respiratory rates above 25 to 30/min in the absence of hypoxemia (neurogenic hyperventilation) were originally described in six comatose patients with ventrotegmental pontine strokes,56 but these rates were subsequently attributed to stimulation of lung and chest wall afferent reflexes due to pulmonary congestion.57 Neurogenic hyperventilation after stroke usually indicates a poor prognosis.58,59 Inspiratory breath-holding (apneustic breathing), originally described in two patients with bilateral ventrotegmental mediocaudal (infratrigeminal) pontine stroke,60 is rare and usually secondary to basilar artery occlusion. Erratic variations in breathing frequency and amplitude (ataxic or Biot’s breathing), and failure of automatic breathing (central sleep apnea or Ondine’s curse), usually imply a lateral medullary stroke, often bilateral.61-64 Damage to the medullary reticular formation and nucleus ambiguus may be sufficient to cause a loss of automatic breathing, and a lesion that also includes the nucleus tractus solitarius is necessary to cause failure of both automatic and voluntary respiration.63 Volitional breathing can be impaired by brainstem strokes involving corticobulbar and corticospinal pathways at pontine and medullary levels.55 Repetitive yawning can accompany hypersomnia (e.g., in patients with thalamic stroke) and can also occur as a release phenomenon after extensive corticospinal lesions (e.g., in patients with a locked-in syndrome.65 Spinal cord stroke can impair both automatic and voluntary breathing control.54,66 The topography and extent of the lesion can determine respiratory effects. Anterior spinal artery strokes can affect reticulospinal pathways, located anteriorly in the lateral columns of the first three cervical segments, which are crucial for automatic breathing.66 In contrast, posterior spinal artery strokes can damage corticospinal pathways in the dorsolateral spinal cord and impair voluntary control of breathing.67 Strokes that extend up to the C1 level usually cause severe respiratory insufficiency and necessitate ventilatory support. Pathophysiology Sleep-Disordered Breathing as a Risk Factor for Stroke Several studies have suggested a variety of physiologic mechanisms by which obstructive sleep-disordered breathing could predispose to stroke. Chronically, SDB and even habitual snoring are associated with hypertension, which in turn is an important risk factor for stroke. Findings from the Wisconsin Sleep Cohort have shown that an AHI greater than 15 is independently associated with a threefold increased risk of developing new hypertension within a 4-year period.68 Furthermore, SDB is associated with coronary heart disease, myocardial infarction, heart failure, and atrial fibrillation, all of which can cause stroke.69-71 The consequences of nocturnal respiratory events include
intermittent hypoxemia, hypercapnia, sleep fragmentation (occasionally with loss of slow-wave and REM sleep), intrathoracic or intracranial pressure changes, and sympathetic activation. A series of hemodynamic (e.g. blood pressure swings), neural (e.g. sympathetic hyperactivity), metabolic (e.g. insulin resistance), and inflammatory or oxidative changes (e.g., increased levels of C-reactive protein, tumor necrosis factor [TNF]-α, interleukin [IL]-6, adhesion molecules) result, contributing to diabetes, increased platelet aggregation, decreased fibrinolysis, endothelial damage, and atherogenesis.69,72,73 Patients with acute stroke also show an increase in some of the molecular markers and consequences of SDB such as elevated levels of fibrinogen and C-reactive protein.74,75 The observation of an increase in the intima-media thickness of the common carotid artery documented by ultrasound techniques in SDB patients as compared with controls matched for age and vascular risk factors gives further support for an increased (chronic) atherogenesis in SDB.76,77 Acutely, apneas and hypopneas during sleep are accompanied by decreased cardiac output, cardiac arrhythmias, systemic hypotension or hypertension, vasodilation due to hypoxia and hypercapnia, and increased intracranial pressure.78 These factors lead to an overall 15% to 20% (in single studies, up to 50%) reduction in cerebral blood flow velocities during respiratory events79-82 (Fig. 88-3). Type, duration, and timing of respiratory events affect hemodynamic consequences. Obstructive apneas of long duration and those that occur during REM sleep may be particularly detrimental.81,83,84 Large fluctuations in cerebral blood velocities (and flow) may be particularly detrimental because patients with SDB have been shown to have a diminished vasodilator reserve.82 Cheyne-Stokes respiration and central apneas also can alter cerebral blood flow.81,85,86 Paradoxical embolization resulting from rightto-left shunting in patients with patent foramen ovale during long apneas is another potential mechanism of stroke.87,88 In view of these observations, it is not surprising that SDB has been associated with the onset of cerebrovascular events at night.32,43 A direct link between SDB and nocturnal cerebrovascular ischemic events has been suggested for retinal infarcts of embolic origin and in single patients with TIA or minor stroke.89-91 A pathogenic role of SDB in vascular disease is further suggested from studies of continuous positive airway pressure (CPAP) treatment. A few studies have shown favorable, although modest, effects of CPAP on mean arterial pressure (MAP).92 Pepperell and coworkers reported that therapeutic CPAP reduced MAP by 2.5 mm Hg, whereas subtherapeutic CPAP levels increased blood pressure by 0.8 mm Hg. Such an effect can lead to a reduction in stroke risk of about 20%.93 Treatment with CPAP can also reverse the detrimental hemodynamic, neural, and molecular effects of SDB-influenced surrogate markers of vascular disease such as factor VII clotting activity, fibrinogen levels, and platelet activation or aggregation.25,72,73,94 Sleep-Disordered Breathing as a Consequence of Stroke Although patients at risk for cerebrovascular disease often have SDB before they experience a stroke, some develop the sleep disorder as a consequence of stroke. The
FV (cm/sec)
CHAPTER 88 • Sleep and Stroke 999
150 100 50
BP (mm Hg)
MFV (cm/se)
0 150 100 50 0 180 133 86.6
PCO2 (mm Hg)
40 80 53.3 26.6 0
Figure 88-3 Cerebral blood flow velocity and obstructive sleep apnea. Flow velocity (FV) and mean flow velocity (MFV) in the right middle cerebral artery, peripheral blood pressure (BP), and end-expiratory PCO2 in a patient with obstructive sleep apnea. Intervals with low end-expiratory PCO2 show apneic episodes. (From Hajak G, Klingelhöfer J, Schulz-Varszegi M, et al. Sleep apnea syndrome and cerebral hemodynamics. Chest 1996;110:670-679.)
observation that recovery from stroke may be accompanied by improvement of SDB gives support to the assumption that SDB is aggravated or even appears de novo after stroke (see earlier). A disturbed coordination of upper airway, intercostal, and diaphragmatic muscles due to brainstem or hemispheric lesions (bulbar and pseudobulbar palsies) might favor the appearance of OSA.95,96 In patients with rostrolateral medullary lesions and SDB, a reduced ventilatory sensitivity to inhaled CO2 can play a role.97 Other factors, including hypoxemia due to aspiration or respiratory infections, reduction of voluntary chest movements on the paralyzed side, supine position, and sleep fragmentation secondary to stroke or stroke complications, can also be involved.45,98 The presence of Cheyne-Stokes breathing has been attributed to CO2-hypersensitivity induced by bilateral supratentorial lesions.99 The presence of bilateral or severe strokes, heart failure, and a decreased level of consci ousness, traditionally described in stroke patients with Cheyne-Stokes breathing, is not always necessary.41,48,52,100 Conversely, the damage of specific brain areas (e.g., those belonging to the autonomic network) may play a so-far neglected role, particularly in the acute phase of stroke.48,53 Patients with brainstem stroke can also develop CheyneStokes breathing.52,101-103 Clinical Significance SDB in patients with cerebrovascular disorders has detrimental effects at different levels. Acutely, SDB detected the first night after brain infarction was found to be associated with early neurologic worsening, longer hospitalization, and higher daytime and nighttime blood pressure levels.32,48,104 Preliminary observations suggest that the acute evolution of stroke, as assessable by magnetic resonance imaging (diffusion and perfusion studies) might also be negatively affected by OSA.105
Chronically, habitual snoring and SDB also affect outcome of stroke. Snoring was found to adversely affects prognosis in stroke survivors.106 Dyken and colleagues reported a 4-year mortality of 21% in stroke patients with SDB.29 Three large subsequent studies confirmed the negative effect of SDB on long-term risk of stroke.43,107,108 Parra’s group reported in 161 patients followed over 23 months that mortality (8%/year) was independently determined by age, initial AHI, coronary heart disease, and involvement of the middle cerebral artery.107 Similarly, Bassetti and colleagues found in 152 patients followed over 60 months that mortality (3%/year) was associated with a higher AHI in the acute phase. Conversely, the incidence of new vascular events (4%/year) was similar in patients with and without SDB.43 In a series of 151 patients observed over 10 years, Sahlin and coworkers found that obstructive—but not central—sleep apnea was a predictor of mortality.108 Several studies have suggested a negative impact on functional outcome. Good and colleagues found a poorer functional outcome in patients with stroke and nocturnal oxygen desaturations.28 Kaneko’s group showed that OSA is significantly and independently related to functional impairment and length of hospitalization in 61 patients admitted to a stroke rehabilitation unit.109 Turkington and colleagues found a relationship between SDB (AHI > 10 found within 24 hours of stroke onset) and functional outcome (as assessed by the Barthel index) and mortality at 6 months in a series of 120 patients.110 In a study of 60 patients, Yan-Fang and Yu-Fing reported a poorer functional outcome (as estimated by the Barthel Index) at 6 months in patients with an AHI greater than 15.47 Diagnosis Based on its impact on stroke outcome and treatability, SDB should be assessed by history and nocturnal recordings (respirography) in all patients with TIA and stroke.
1000 PART II / Section 11 • Neurologic Disorders
The suspicion should be particularly high in obese men with history of habitual snoring, witnessed apneas, hypertension, diabetes mellitus, and sleep-onset stroke.27,32,43 Stroke topography and etiology and history of excessive daytime sleepiness are, conversely, poor predictors of SDB in stroke victims. Respirography is sufficiently accurate to diagnose SDB and estimate its severity even in the acute setting.43 Full polysomnography is needed only in a minority of patients. The optimal timing of sleep studies after stroke or TIA is unknown. Although studies within days of a stroke might be less representative of the baseline condition attained several weeks to months after the ischemic event, treatment of SDB soon after stroke could potentially minimize further damage to injured neural tissue and improve outcome.105 Brown and coworkers estimated that screening and treatment of SDB in stroke patients are cost-effective.111 Treatment As a consequence of brain vulnerability to hypoxia and cardiovascular instability, SDB might impede recovery of ischemic but not yet irreversibly damaged brain tissue. Furthermore, SDB can predispose to serious complications, such as aspiration or respiratory arrest, and contribute to short-term and long-term morbidity and mortality of stroke patients (see earlier). Treatment of SDB in stroke patients represents a clinical, technical, and logistical challenge. Treatment strategies should always include prevention and early treatment of secondary complications (e.g., aspiration, respiratory infections, pain) and a cautious use or avoidance of alcohol and sedative-hypnotic drugs, which can all negatively affect breathing control during sleep. Patient positioning in the acute phase can influence oxygen saturation as well.45,98 Continuous positive airway pressure is the treatment of choice for OSA. Automatic CPAP systems can be used for simultaneous detection of upper airway obstructions and treatment, which is made possible by automatic titration of CPAP pressure.34 The compliance for autotitrating continuous positive airway pressure in the first 3 months after TIA was found to be acceptable (≥4 hours per night for ≥75% of nights) in 12 of 30 patients with SDB.51b Compliance is influenced by the spontaneous improvement of SDB after the acute phase (see earlier) and by the absence of excessive daytime sleepiness in most patients with stroke and SDB. In addition, compliance can be expected to be a problem also in stroke patients with dementia, delirium, aphasia, anosognosia, and pseudobulbar or bulbar palsy. Treatment of SDB in stroke patients was assessed in 10 studies and almost 600 patients (Table 88-2). Wessendorf and colleagues reported a 70% CPAP compliance in 105 stroke patients admitted in a rehabilitation unit. Poor compliance was associated with aphasia and severe stroke. CPAP use led to an improvement of subjective well-being and nighttime blood pressure values in a group of 41 and 16 patients, respectively.30 Sandberg’s group reported a reduction in depressive symptoms after one month of CPAP and poor compliance in patients with delirium and cognitive deficits. No improvement was conversely found
on neurologic recovery, as assessed by the Barthel index.112 Disler and colleagues reported good compliance in five consecutive patients with stroke and SDB treated in a rehabilitation unit.34 Later studies found a generally lower CPAP compliance (about 50% in the acute phase and 30% in the chronic phase; range, 12% to 82%) in stroke patients with SDB. Hui and coworkers found that only 4 (12%) out of 34 patients continued CPAP over more than 3 months.35 Martinez-Garcia and colleagues reported in a series of 51 patients a compliance of 29% over the first month.50 In that study, CPAP use led to a significant, fivefold decrease in vascular events. Bassetti’s group reported that only 8 (22%) out of 36 patients discharged from acute hospital with CPAP continued this treatment on a long-term base (60 months).43 No predictors of long-term compliance could be found. Palombini and colleagues found a compliance of only 22% over the first 2 months after stroke.113 Hsu and coworkers randomized 30 patients with stroke and AHI of 30 to CPAP or no treatment.114 Only 7 (47%) of 15 patients kept CPAP for more than 4 weeks and the average use of CPAP was only 1.4 hours per night. Martinez and colleagues reported a reduction of 5-year mortality in 28 stroke patients with mild to moderate SDB (AHI = 20) who were treated with CPAP as compared to 68 patients with SDB who did not tolerate treatment.49 In this study, the long-term CPAP compliance was 30%. The choice of the headgear may have had an influence on the acceptance of CPAP.115 In patients with central apneas and Cheyne-Stokes breathing improvements of breathing disturbances may be achieved with oxygen.102 A method of ventilatory support called adaptive servo-ventilation may also be considered. Wessendorf’s group found that adaptive servoventilation prevented central apneas in stroke patients with heart failure more efficiently than CPAP or oxygen.116 Tracheostomy and mechanical ventilation might become necessary in patients with central hypoventilation. Control of central apneas and ataxic breathing usually requires assisted ventilation. Hiccup can be treated with neuroleptics or with baclofen.117
SLEEP–WAKE DISTURBANCES Epidemiology Sleep–wake disturbances are found in 20% to 50% of stroke patients. Presentations include increased sleep needs (hypersomnia), excessive daytime sleepiness, fatigue, and insomnia. Not uncommonly, after a stroke, patients report a combination of these symptoms. In a series of 285 consecutive patients we found that 21 months after stroke 27% of patients slept at least 10 hours per day (hypersomnia), 28% had an Epworth Sleepiness Scale score of at least 10 (excessive daytime sleepiness), and 46% had a fatigue severity scale score of at least 3 (fatigue) (unpublished observation). Other studies have similarly suggested a high frequency (30% to 70% of patients) of poststroke fatigue.118,119 In a series of 277 consecutive patients evaluated 3 months after stroke, insomnia was reported by 57% of patients. In 18% of the 277 patients, insomnia appeared de novo after stroke.120
CHAPTER 88 • Sleep and Stroke 1001
Table 88-2 Effect of Continuous Positive Airway Pressure after Stroke STUDY
PATIENTS
AGE (YR)
BMI
FINDINGS
Wessendorf et al. (2001)
105 stroke patients (ischemic and hemorrhagic), RDI ≥15/hr (80 men, 25 women) Patients recruited in a rehabilitation unit 60 day after stroke and followed up over 10 day
61 ± 19
27 ± 4
70% of patients tolerated CPAP (mean CPAP pressure: 9 ± 2 cm H2O) CPAP reduced respiratory events by 82% and increased minimal SaO2 from 76 ± 10 to 89 ± 45% Poor CPAP compliance associated with low Barthel index and aphasia Subjective well-being significantly improved in compliant patients In 16 patients on CPAP, mean nocturnal blood pressure decreased by 8 ± 7 mm Hg
Sandberg et al. 2002
63 patients with ischemic stroke with RDI ≥ 15/hr Patients recruited in a rehabilitation unit 2-4 wk after stroke and followed up over 28 day
No CPAP: 77 ± 8 CPAP: 78 ± 6
No CPAP: 25 ± 5 CPAP: 24 ± 4
Randomized trial, CPAP used by 27/30 patients for 4 wk Compared to control group, depressive symptoms (MADRS total score) improved in patients randomized to nCPAP treatment (P =.004) No significant treatment effect was found with regard to delirium, MMSE or Barthel ADL index Delirium and low cognitive level (MMSE score) explained poor compliance with nCPAP
Hui et al. (2002)
34 patients with ischemic stroke with an AHI ≥ 10/hr Patients recruited 4 day after stroke Follow-up over 3 mo
64 ± 13
24 ± 4
CPAP titration successfully performed in 47% of patients (mean CPAP pressure, 11 ± 1 cm H2O) Only 12% of patients had long-term compliance (average CPAP use, 2.5 ± 0.6 hr/night) 100% were snorers and 75% suffered from daytime sleepiness
Martinez-Garcia et al. (2005)
51 patients with ischemic stroke with an AHI ≥ 20/hr, recruited 2 mo after stroke and followed up over 18 mo
73 ± 9
27 ± 4
15/51 patients (29%) tolerated CPAP and continued therapy over at least 1 mo (mean CPAP pressure, 8 ± 4 cm H2O; mean CPAP use, 6.4 ± 2.2 hr/night) CPAP reduced AHI from 41 ± 14 to 4 ± 3/hr Incidence of new vascular events (stroke, angina, MI) significantly lower in compliant patients (7% vs. 36%)
Hsu et al. (2006)
30 patients with stroke with AHI ≥ 30/hr, for which 658 patients had to be screened Randomization to CPAP over 8 weeks or no treatment Treatment initiated 21-25 day after stroke Patients followed up over up to 6 mo Patients balanced for NIHSS and ESS
No CPAP: mean 73 CPAP: mean 74
No CPAP: mean 25 CPAP: mean 27
Randomized trial Poor objective CPAP, averaging 1.4 hr/night Study ended early because of poor recruitment CPAP treatment resulted in no significant improvements in neurologic outcome, anxiety, depression, or quality of life No significant difference in 24-hr daytime and nighttime systolic BP, diastolic BP, and MAP between groups Only 7/15 patients (47%) used CPAP >4 wk Treatment discontinued in 8 patients because of problems with mask or machine, strokerelated confusional states, or upper airway symptoms CPAP use positively correlated with higher Barthel index and better language capabilities Continued
1002 PART II / Section 11 • Neurologic Disorders Table 88-2 Effect of Continuous Positive Airway Pressure after Stroke—cont’d STUDY
PATIENTS
AGE (YR)
BMI
FINDINGS
Bassetti et al. (2006)
70 acute ischemic stroke patients with AHI > 15/hr or AHI > 10/hr plus EDS Patients recruited within 1 wk after stroke and followed up over up to 5 yr
56 ± 13
26 ± 4
CPAP treatment successfully initiated in 69% of patients, with compliance until patient discharge in 51% and long-term compliance in 15% CPAP users did not differ from nonusers with respect to age, gender, BMI, history of hypertension, diabetes, or coronary disease No difference in EDS, initial NIHSS and initial AHI
Palombini and Guilleminault (2006)
32 patients with stroke evaluated for CPAP study. 11 patients refused to participate, 21 patients assessed by respirography. 14 patients with AHI ≥ 10/hr enrolled during acute hospital stay Patients followed up over 8 wk
62 ± 13
23 ± 3
12/14 patients agreed to initiate CPAP at home (mean pressure 8 ± 4 cm H2O); 7 (50%) continued CPAP over the whole observation period Treatment stopped because of problems with cognition and orientation, inability to apply headgear, mask, and hose, and to readjust equipment
Broadley et al. (2007)
16 stroke patients with AHI ≥ 15/hr enrolled during first week after stroke and followed up over 6 wk
71
27 ± 4
13/16 patients agreed to initiate CPAP therapy, which was tolerated by 8 patients
Scala et al. (2009)
12 patients (4 men, 8 women) recruited within 48 hr after stroke and studied over a single night
75 ± 5
27 ± 5
CPAP acceptance was 84%: 42% using CPAP > 6 hr, 42% 1-3 hr per night (mean 5.2 ± 4.0 hr)
Martinez-Garcia et al. (2009)
166 patients with ischemic stroke, 96 of them with AHI ≥ 20/hr were offered CPAP Patients recruited 2 mo after stroke and followed up over 5 yr
No CPAP: mean 76 CPAP: mean71
No CPAP: mean 28 CPAP: mean 27
Prospective observations study 28/96 patients with AHI ≥ 20 and long-term CPAP treatment had lower mortality (50%) vs. patients with AHI ≥ 20 and no CPAP (68%)
Bravata et al. (2010)
30 patients with acute TIA
Auto-CPAP use over 90 days after acute event was acceptable (≥4 hours per night for ≥75% of nights) in 40% of patients
ADL, activities of daily living; AHI, apnea–hypopnea index; BMI, body-mass index; BP, blood pressure; CPAP, continuous positive airway pressure; EDS, excessive daytime sleepiness; ESS, Epworth Sleepiness Scale; MADRS, Montgomery-Åsberg Depression Rating Scale; MAP, mean arterial blood pressure; MI, myocardial infarction; MMSE, Mini Mental State Exam; nCPAP, nasal continuous positive airway pressure; NIHSS, National Institutes of Health Sleepiness Scale; RDI, respiratory distress index.
Sleep-related movement disorders and parasomnias are less often observed after stroke. In a series of 137 patients assessed 1 month after stroke, restless legs symptom (RLS) symptoms were found de novo in 12% of patients.121 Other sleep–wake disturbances following stroke include an abnormal transition from wake to sleep and vice versa, with confusion between dream and reality (oneiric state), dream changes, and an altered perception of time (Zeitgefühl).122,123
Clinical Features Hypersomnia and Excessive Daytime Sleepiness Hypersomnia is defined clinically as a reduced latency to sleep, increased sleep, or excessive daytime sleepiness. In patients with strokes that affect activating arousal pathways or the paramedian thalamus, hypersomnia can alternate with insomnia (see earlier). Façon and coworkers described, for example, a 78-year-old patient with a tegmental mesencephalic infarct in whom severe, persistent hypersomnia
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was accompanied by an inversion of the sleep–wake cycle with nocturnal agitation.124 Poststroke hypersomnia, with or without excessive daytime sleepiness, is usually observed in association with thalamic (Fig. 88-4), mesencephalic, or upper pontine strokes. Less commonly, strokes in the caudate, striatum, lower pons (Fig. 88-5), medial medulla, and cerebral hemispheres (with or without mass effect) (Fig. 88-6) may be complicated by hypersomnia.125 In deep (subcortical) hemispheric and thalamic stroke, hypersomnia may correspond to presleep behavior, during which patients yawn, stretch, close their eyes, curl up, and assume a normal sleeping posture, while complaining of a constant sleep urge.126 Some of these patients are able to control this behavior when stimulated or given explicit, active tasks to perform. This presleep behavior may be compulsive in that removing the patient from bed can result in repeated attempts to lie down and adopt a sleeping posture. However, during what appear to be daytime sleep periods, relatively quick responses to questions or requests suggest wakefulness. For this peculiar dissociation between lack of autoactivation in the presence of preserved
A
heteroactivation, Laplane suggested the term athymormia, or “pure psychic akinesia.”127 In some patients, hypersomnia evolves to extreme apathy, with lack of spontaneity and initiative, slowness, poverty of movement, and catalepsy, a condition for which the term akinetic mutism was coined.128 Akinetic mutism, and a less severe form, usually referred to as abulia, can persist despite normalization of vigilance or even after appearance of insomnia. In some of these patients, the eventual diagnosis is poststroke fatigue (see later) or poststroke depression. Narcolepsy-like phenotypes have rarely been seen following stroke, even in the absence of human leukocyte antigen (HLA) positivity and cerebrospinal fluid (CSF) hypocretin-1 deficiency.129-131 Hypersomnia with hyperphagia (Kleine-Levin–like syndrome) was reported after multiple cerebral strokes.132 Fatigue A continuum exists of hypersomnia, depression, and fatigue, which is defined as a feeling of physical tiredness, exhaustion with lack of energy accompanied by a strong
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Figure 88-4 Hypersomnia after bilateral paramedian thalamic stroke. This 65-year-old male patient (KM) had initial coma, followed by severe hypersomnia (A), vertical gaze palsy (B), amnesia, and disturbed time perception (Zeitgefühl). Brain MRI shows a bilateral paramedian thalamic stroke (C, D). Polysomnography performed 12 days after stroke onset demonstrates (E) a drastic reduction of sleep spindles and (F) loss of spindle peak (12-14 Hz activity) on spectral analysis (as compared to normal control [G]). A severe central apnea (apnea–hypopnea index, 54/hr) was observed in the acute phase (in the absence of any signs of cardiac dysfunction) but not on follow-up few months later. Actigraphy performed within the first month after stroke shows time “asleep” (rest or sleep) during 61% of the recording time (2 weeks) (H). One year after stroke, the patient still reports increased sleep needs (15 hours per day), apathy (athymormia) and attentional and memory deficits. Modafinil at a dose of 200 mg per day improved his hypersomnia. (MRI pictures courtesy of Prof. A. Valavanis, Institute of Neuroradiology, University Hospital, Zürich, Switzerland.) (From Bassetti CL, Hermann DM. Sleep and stroke. In: Vinken PJ, Bruyn GW. Handbook of clinical neurology. Sleep disorders. New York: Elsevier; 2010. In press.) Continued
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desire for sleep, with usually normal or (paradoxically decreased) sleep propensity. Fatigue may be more common in brainstem strokes.133 The Epworth Sleepiness Scale is a useful tool to differentiate fatigue from excessive daytime sleepiness.134 Insomnia Insomnia is defined by a difficulty in initiating or maintaining sleep, early awakenings, and insufficient sleep quality. Particularly in patients with subcortical (Fig. 88-7), thalamic, thalamomesencephalic, and large tegmental pontine stroke, insomnia may be accompanied by an inversion of the sleep–wake cycle, with insomnia and agitation during the night and hypersomnia during the day.135-138 In the literature, reports of stroke patients with welldocumented (primary) neurogenic insomnia are rare. Van Bogaert and colleagues reported, for example, a patient with pontomesencephalic stroke who presented an almost complete insomnia over more than two months.135 Freemon and coworkers reported a patient with locked-in syndrome due to pontomesencephalic stroke who presented with polysomnographically confirmed insomnia, which was almost complete for more than 1 month.139 Another patient reported by Girard and colleagues with locked-in syndrome due to bilateral basal pontine stroke with extension
to the pontine tegmentum experienced nearly complete, polysomnographically proved insomnia over as long as 6 months.136 Sleep-Related Movement Disorders and Parasomnias REM sleep behavior disorder (RBD) has been reported to occur after strokes in the tegmentum of the pons.140,141 Restless legs syndrome has been observed de novo after stroke.142-145 In a recent series of 137 patients with stroke, RLS was found mainly after pontine, thalamic, basal ganglia, and corona radiata strokes.121 Most commonly RLS was bilateral, appeared within 1 week after stroke, and was accompanied by periodic limb movements (PLMs) in sleep. After stroke, PLMs can increase (and even appear de novo) and lead to insomnia (Fig. 88-8). PLMs can also decrease after unilateral hemispheric stroke and can persist after spinal stroke.146,147 A reduction in physiologic NREM sleep myoclonus has been described in the hemiplegic limbs of a few stroke patients.148 Hallucinations and Altered Dreaming Only few papers have reported on poststroke dream characteristics.149 Patients with strokes in the pontomesencephalic or mesencephalic tegmentum and in the paramedian
CHAPTER 88 • Sleep and Stroke 1005
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Figure 88-5 Hypersomnia or excessive daytime sleepiness after pontomedullary stroke. This 39-year old male patient (UM) had pontomedullary ischemia following subarachnoid hemorrhage and embolization of a giant aneurysm of the basilar artery. This resulted in clinical brainstem syndrome with singultus, left IX, X, XII palsy, dysarthria, gait ataxia, and mild left hemiparesis. Sleep symptoms were postintervention severe excessive daytime sleepiness (EDS; Epworth Sleepiness Score: 23/24) and increased sleep needs (12-14 hours/day). Polysomnography showed sleep efficiency 97%, slow-wave sleep 8% of total sleep time, no sleep apnea, and no periodic limb movements in sleep. The multiple sleep latency test showed mean sleep latency 1 minute and no sleep-onset REM periods. Actigraphy showed time “asleep” (rest or sleep) during 43% of the recording time (2 weeks). Cerebrospinal fluid levels of hypocretin-1 were normal. The patient does not wish any treatment for his EDS and hypersomnia. (MRI pictures courtesy of Prof. A. Valavanis, Institute of Neuroradiology, University Hospital, Zürich, Switzerland.)
thalamus can experience peduncular hallucinosis of Lhermitte, characterized by complex, often colorful, dreamlike visual hallucinations, particularly in the evening and at sleep onset (Fig. 88-9).14,150-152 Peduncular hallucinosis might represent a release of REM sleep mentation. It can be associated with insomnia and resolves spontaneously in most cases.
Figure 88-6 Hypersomnia and sleep architecture changes after middle cerebral artery stroke. This 39-year old female patient (FF) had aphasia, right hemiparesis, depressed mood, and crying spells. National Institutes of Health (NIH) Stroke Score was 16. The patient’s sleep needs increased in the first 1 to 2 weeks after the stroke (12 hours/day as compared to 7 hours/ day before stroke), followed by mild excessive daytime sleepiness (Epworth Sleepiness Score, 12). At 12 months, the patient reported a decrease in sleep needs to 10 hours per 24 hours. Repeated polysomnographic recordings (day 2, day 8, and 70 days after stroke) demonstrate a progressive recovery of spindling activity (coherent activity around 12 Hz) over both the affected (left) and the nonaffected (right) hemisphere. (MRI pictures courtesy of Prof. G. Schroth, Institute of Neuroradiology, University Hospital, Bern, Switzerland.)
The Charles Bonnet syndrome generally involves lesscomplex visual hallucinations that also occur in the setting of diminished arousal.153 These hallucinations, “release phenomena” after stroke that involves vision or visual field abnormalities, may be limited to a hemianopic field.154,155 Cessation or reduction of dreaming occurs in the Charcot-Wilbrand syndrome and is occasionally limited to alteration of the visual component of the dream (as in the original patient described by Charcot).13,156 This syndrome can occur in patients with parietooccipital, occipital, or deep frontal strokes, and the lesions are often bilateral.149,157-161 Patients often, but not invariably, show deficient revisualization (referred to as visual irreminiscence), topographical amnesia, and prosopagnosia. Conversely, REM sleep characteristics may be normal.162 Severe insomnia and loss of dreaming has been reported following lateral medullary stroke.138 Focal (temporal) seizures secondary to stroke can lead to the syndrome of dream–reality confusion or to recurrent
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Figure 88-7 Insomnia after subcortical stroke. This 68-year-old female patient (MZ) had left subcortical hemispheric stroke (corona radiata), with clinically mild right hemisyndrome, National Institutes of Health (NIH) Stroke Score of 6. In the first poststroke week, she had almost complete insomnia and excessive daytime sleepiness (EDS). Two weeks later, she showed recovery from EDS and improvement in insomnia, with 2 to 3 hours of sleep per night. Sleep–wake functions normalized after 4 weeks. (MRI pictures courtesy of Prof. G. Schroth, Institute of Neuroradiology, University Hospital, Bern, Switzerland.)
nightmares, which may be more common with right-sided lesions and can be controlled with antiepileptics.163 An increased frequency or vividness of dreaming can occur following stroke, particularly after thalamic, parietal, and occipital stroke.157 A few patients with severe motor deficits report the persistence of normal motor functions during dreams for up to several years after stroke. Waking up in the morning is a source of great distress in these patients. In other patients, motor handicap may, conversely, be apparent in incorporated in dreams within a few days from stroke onset. Pathophysiology In patients with stroke, sleep–wake disturbances are often of multifactorial origin. In addition to brain damage per se, environmental factors including noise, light, and intensive medical monitoring can contribute to the development of sleep–wake disturbances. Furthermore, SDB, cardiorespiratory disorders, seizures, infections, fever, and drugs can aggravate sleep fragmentation and result in sleep disturbances. Anxiety, depression, and psychological stress (difficulties in coping with stroke in general) often accompany and complicate stroke and can further contribute to sleep–wake disturbances. The importance of these factors is well illustrated by the high occurrence rate of sleep– wake disturbances among intensive care unit (ICU) patients who do not have brain damage.164,165 Hypersomnia and Excessive Daytime Sleepiness A decreased arousal due to lesions involving the ascending arousal pathways is most commonly responsible for poststroke hypersomnia.125 The most severe and persisting forms of dearousal are seen in patients with bilateral lesions of the thalamus, subthalamic or hypothalamic area, tegmental midbrain, and upper pons, where fibers of the ascending arousal pathways are bundled and can be severely
injured even by single small lesions. Such strokes can cause initial coma or, conversely, manic delirium, hyperalertness, and insomnia before hypersomnia evolves. At the thalamomesencephalic level, the dorsomedial nucleus, intralaminar nuclei, centromedian nucleus, and cephalic portions of the ascending reticular activating system are usually involved. Mental arousal seems to be affected more severely by medial lesions, and motor arousal is impaired more strongly by lateral lesions.166,167 Other areas in which stroke can occasionally produce hypersomnia include the caudate, striatum, tegmental pons, median regions of the medulla, and cerebral hemispheres. Hypersomnia after hemispheric stroke usually implicates large lesions, on the left more than on the right and anteriorly more than posteriorly.129,168-170 In large hemispheric strokes, dearousal results from disruption of the upper brainstem secondary to vertical (transtentorial) or horizontal displacement of the brain due to brain edema.171 The occurrence of sleep–wake disturbances following cortical and striatal strokes without mass effect supports the assumption that the role of these structures is in maintenance of arousal and more generally in sleep– wake regulation.172-174 Hypersomnia with increased sleep per 24 hours (active hypersomnia) has occasionally been documented polysomnographically in patients with thalamic, mesencephalic, and pontine stroke.175-177 In a 23-year-old patient with bilateral diencephalic stroke following surgical removal of a craniopharyngeoma. CSF hypocretin-1 levels were low, suggesting a link between poststroke hypersomnia and a deficient hypocretin neurotransmission.178 In two patients with hypersomnia following thalamic and pontine stroke, respectively, we found normal CSF hypocretin-1 levels (see Fig. 88-5).125 Fatigue Fatigue may develop following stroke in association with sleep–wake disturbances (hypersomnia, excessive daytime sleepiness and insomnia), mood and emotional changes, neurologic deficits, and neuropsychological sequelae. Poststroke fatigue is often multifactorial in origin. An overlap exists between poststroke fatigue and poststroke depression. Psychological stress with inadequate coping with stroke consequences in general probably plays an important role, as suggested by the absence of a correlation between poststroke fatigue and stroke size and site and by a high incidence of fatigue following myocardial infarction (without brain damage).179 A dysfunction of arousal and attentional circuits, as suggested also for some forms of poststroke hypersomnia (see earlier), has been postulated also for poststroke fatigue.133 Insomnia Mild to moderate insomnia is a common, usually nonspecific, and multifactorial complication of acute stroke. Recurrent arousals, sleep discontinuity, and sleep deprivation can result from preexisting disorders (e.g., heart failure, pulmonary disease), SDB, medications, infections and fever, inactivity, environmental disturbances (e.g., on ICU), stress, and depression. Psychotropic agents, anxiety, dementia, preexisting insomnia, and stroke severity were found to be risk factors for poststroke insomnia.120
CHAPTER 88 • Sleep and Stroke 1007
A
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C Figure 88-8 Insomnia and left-sided periodic limb movements after right paramedian pontine stroke. This 60-year-old patient (WE) had unilateral lacunar stroke in the right paramedian pons (A and B). He developed acutely severe insomnia, with involuntary, jerky, and tremor-like movements of the left leg and arm appearing periodically at sleep onset and during sleep (periodic limb movements, LM, C). The patient denied restless legs symptoms. (MRI pictures courtesy of Prof. A. Valavanis, Institute of Neuroradiology, University Hospital, Zürich, Switzerland.)
Insomnia may also be related to brain damage per se, a situation for which the term agrypnia has been suggested.180,181 Lesions in the dorsal or tegmental brainstem areas, in the paramedian or lateral thalamus, and subcortically (see Fig. 88-7) have been found to cause poststroke insomnia.14,135,136,138,139,181 The observation in some of these patients of rapid transitions from insomnia to hypersomnia emphasizes the dual role of such brain areas as thalamus, basal forebrain and pontomesencephalic and pontomedullary junction in sleep–wake regulation.182,183 Sleep-Related Movement Disorders and Parasomnias The appearance of RBD after pontine tegmental stroke is consistent with the central role of this brain region in the regulation of REM atonia.184 The de novo onset of restless
legs syndrome after subcortical and brainstem strokes emphasizes the contribution of a dysfunction of the corticospinal system in the pathophysiology of this disorder.121 Clinical Significance The presence of sleep–wake disturbances after stroke are associated with cognitive and psychiatric (depression, anxiety) disturbances.119,120,177,185,186 More recently it was shown that in patients with stroke, sleep between rehabilitation sessions can positively influence motor recovery and learning.187,188 Sleep deprivation and sleep disturbance have been shown experimentally to aggravate the outcome in a rat model of stroke.189 Sleep-enhancing drugs (sodium oxybate) were, on the other hand, shown to accelerate motor recovery in a mouse model of stroke.189a
1008 PART II / Section 11 • Neurologic Disorders
changes in sleep–wake rhythms and sleep or rest needs following stroke (see Figs. 88-4 and 88-5).125,177
Figure 88-9 Dreamlike hallucinations after unilateral paramedian thalamic stroke. This 62-year-old patient (PV) had left paramedian thalamic stroke and presented clinically with confusional state, abulia, anomia, and moderate to severe amnesia in the absence of major sleep–wake disturbances. In the first few days after hospital admission, the patient had recurrent episodes of visual and acoustic hallucinations in form of human figures (mostly relatives, partial insight) seen on the right side of the visual field, which the patient describes as dreamlike. At 7 months after stroke, the patient had persistent memory problems and reported almost daily episodes of psychic hallucinations (“sensed presence”) and a disturbed time perception (Zeitgefühl). (MRI pictures courtesy of Prof. A. Valavanis, Institute of Neuroradiology, University Hospital, Zürich, Switzerland)
In the general population, both hypersomnia and insomnia have been linked with increased mortality.190 One study has shown that insomnia with objective short sleep duration is associated with an increased risk for hypertension.191 Fatigue at 2 years after stroke has been found to predict institutionalization and mortality.192 Whether sleep–wake disturbances directly influence stroke recovery and mortality remains unknown. The presence of restless legs syndrome after stroke has also been linked with a poorer outcome.192a Diagnosis The recognition and diagnosis of poststroke sleep–wake disturbances occurs primarily on clinical grounds. Validated questionnaires such as the Epworth Sleepiness Scale and the Fatigue Severity Scale can help in recognizing poststroke sleepiness and fatigue.193 In stroke patients, the correlation between sleep–wake disturbances and sleep EEG is complex.172,194 In patients with poststroke hypersomnia, sleep EEG can reveal both a reduction and, less commonly, an increase of NREM or REM sleep. In hypersomnia following thalamic infarcts, sleeplike behavior may be accompanied by a variety of EEG patterns, including diffuse low-voltage alpha-beta activity, NREM stage 1 sleep, slow-wave activity, and REM sleep.166,176,177,194,195 Multiple sleep latency tests and other vigilance tests can be used to document excessive daytime sleepiness (see Fig. 88-5). They may become inadequate in patients with thalamocortical lesions.177 Actigraphy is helpful to estimate
Treatment Hypersomnia and Excessive Daytime Sleepiness Treatment of poststroke hypersomnia is often ineffective. In individual patients, some improvement is seen in thalamic and mesencephalic stroke with amphetamines, modafinil, methylphenidate, and dopaminergic agents.125 In patients with paramedian thalamic stroke, treatment with 20 to 40 mg of bromocriptine can improve apathy and presleep behavior.126 Improvement of alertness with 20 mg of methylphenidate and 200 mg of modafinil has been reported in patients with bilateral mesodiencephalic paramedian infarct.125,176 Treatment of an associated depression with stimulating antidepressants can also improve poststroke hypersomnia. It is noteworthy that a favorable influence on early poststroke rehabilitation was reported for both methylphenidate (5 to 30 mg/day in a 3-week trial) and levodopa (100 mg/day in a 3-week trial), an effect that may at least in part be related to improved arousal in these patients.196,197 Fatigue Activating antidepressants and amantidine can be tried for poststroke fatigue.198 A study reported no effect of fluoxetine.199 Modafinil was shown to improve fatigue after brainstem/diencephalic but not cortical stroke.199a Insomnia Treatment of poststroke insomnia should include placement of patients in private rooms at night, protection from nocturnal noise and light, increased mobilization with exposure to light during the day, and, if necessary, temporary use of hypnotics that are relatively free of cognitive side effects, such as benzodiazepine-like substances (zolpidem, zopiclone) and benzodiazepines. These substances can enhance not only sedation and neuropsychological deficits in stroke patients, and they can also lead to the reemergence of other neurologic symptoms and should therefore be used with caution.200 In a small randomized, double-blind trial of 12 patients with poststroke insomnia, zopiclone (3.75 to 7.5 mg) was as effective as lorazepam (0.5 to 1.0 mg).201 In a study of 51 stroke patients, 60 mg/ day of mianserin led to a better improvement of insomnia complaints than placebo, even in patients without associated depression.202 Sleep-Related Movement Disorders and Parasomnias Clonazepam 0.5 to 2.0 mg taken 1 to 2 hours before bedtime is the treatment of first choice in REM sleep behavior disorder. Ropirinol (0.125 to 1 mg/day) and pramipexol (0.125 to 0.5 mg/day) usually improve restless legs syndrome in stroke patients.121 Sleep Architecture Changes Abnormalities in sleep macro- and microstructure are common after acute stroke but result only in part from acute brain damage. Changes in sleep architecture depend upon patient and health characteristics present before the stroke (e.g., age, respiratory disturbances), topography and
CHAPTER 88 • Sleep and Stroke 1009
In animal models as well as in patients with stroke, changes in sleep behavior and sleep EEG depend upon stroke topography, and the correlation between the two is sometimes poor.203,204 In patients with diffuse cortical, thalamic, or pontine stroke, for example, sleep–wake physiologic cyclicity in eyelid tone, respiration, temperature, and motor activity can occur despite prominent EEG abnormalities.177
L EOG-A2 R EOG-A1 Chin EMG F4-C4 C4-A2 P4-02 T4-T6
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A L EOG-A2 R EOG-A1 Chin EMG F4-C4 C4-A2 P4-02 T4-T6 F3-C3
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B Figure 88-10 Sleep spindles and sawtooth waves after severe middle cerebral artery stroke. This 58-year-old man had a moderately severe left middle cerebral artery stroke (Scandinavian Stroke Score, 33/58). Polysomnography 9 days after stroke showed mild obstructive sleep apnea (apnea–hypopnea index,16). A, In NREM sleep, spindling decreased ipsilaterally, with three spindles per hour recorded at C3 and 172 per hour at C4. B, In REM sleep, sawtooth waves were symmetrical. EMG, electromyogram; EOG, electrooculogram.
extent of the lesion, associated complications of stroke (e.g., SDB, fever, infections, cardiovascular disturbances, depression, anxiety), drug treatment, and time after stroke onset. Even patients without brain damage who are admitted to an intensive care unit after acute myocardial infarction can have a decreased total sleep time, sleep efficiency, REM sleep, and slow-wave sleep.164 Some changes in sleep architecture are more specifically related to brain damage (see later). Examples are persistent alteration of spindling and slow-wave sleep in supratentorial stroke and persistent REM sleep abnormalities in infratentorial stroke.
Supratentorial Strokes Reductions in NREM sleep, total sleep time, and sleep efficiency can follow acute supratentorial stroke.172,205-210 Reduction of spindling can be observed in thalamic and cortical or subcortical stroke (Fig. 88-10, see Fig. 88-4).186,211-214 In unilateral thalamic strokes, sleep spindles may be preserved.177,186,208,215 Rarely, spindling and slowwave sleep increase in the acute stage of large middle cerebral artery stroke.207,213,216 In some such cases, the increase in scored slow-wave sleep can reflect a generalized increase in delta activity during both sleep and wakefulness.209,217 Changes in sleep spindle and slow-wave activity do not always coincide. Transient reductions in REM sleep can occur in the first days after supratentorial stroke.208,213 Changes in REM sleep can persist after large hemispheric strokes with poor outcome.207,210 Sawtooth waves can be decreased bilaterally in large hemispheric strokes, especially those that involve the right side.208,218 Changes in sleep architecture after hemispheric stroke often do not have high localizing value.208 Some reports have suggested, however, that right-sided strokes can preferentially decrease REM sleep and REM density and that left-sided strokes can selectively reduce NREM stage 4 sleep.206,219 Cortical blindness has been associated with a reduction of rapid eye movements.220 Spindling and, to a lesser degree, slow-wave activity and K complexes appear to be often (but not invariably) reduced in paramedian thalamic stroke.177,186,215 In severe hypersomnia following paramedian thalamic strokes, prolonged polygraphic recordings can demonstrate an almost continuous state of light NREM stage 1 sleep, perhaps reflecting inability to make the transition from wake to sleep or to produce full wakefulness.177 In these patients, REM sleep can occur at night and during the day despite the absence of slow-wave sleep.177 Like the EEG of wakefulness, the sleep EEG undergoes a reorganization after acute damage, but data on this subject are scarce.221 Hachinski’s group reported that during clinical recovery from a large left hemispheric stroke, one patient had progressive deterioration of the sleep EEG on the right side.213 In patients with paramedian thalamic stroke, recovery from hypersomnia can occur despite the persistence of significant NREM sleep changes.177,186,195 In hemispheric stroke, conversely, sleep EEG changes (over the healthy hemisphere) usually recover over time, even in patients with severe strokes (more than 50 mL in volume).172 Infratentorial Strokes Bilateral paramedian infarcts in the pontine tegmentum or large bilateral infarcts in the ventrotegmental pons can lead to reduction in NREM and, especially, REM
1010 PART II / Section 11 • Neurologic Disorders
sleep.175,222-227 Normal sleep EEG features such as sleep spindles, K complexes, and vertex waves may be completely lost.223,228 Patients usually present clinically with crossed or bilateral sensorimotor deficits, oculomotor disturbances, and, at least initially, disturbances of consciousness. In rare instances, the only focal finding in a patient with severe sleep EEG changes may be a horizontal gaze palsy.229 Patients with abnormal sleep architecture might complain of insomnia, but isolated REM sleep loss can persist for years without cognitive or behavioral consequences.225,230 Bilateral infarction near, but not in, the pontine tegmentum, or infarction of this area only on one side, usually does not alter sleep architecture. Reported examples have included patients with bilateral pontomedullary junction infarcts, bilateral ventral pontine infarcts with locked-in syndrome, and unilateral pontine tegmental infarcts.228 However, exceptions have also been described: A patient with a hematoma in the left pontine tegmentum had an ipsilateral abnormal EEG during REM sleep (despite normal rapid eye movements and muscle atonia),231 and a patient with a hematoma in the right pontine tegmentum had increased NREM stages 1 and 2 sleep and increased total sleep time accompanying clinical hypersomnia.175 Occasionally, NREM or REM sleep may be altered selectively. Strokes that affect the pontomesencephalic junction tegmentum and the raphe nucleus can lead to a moderate to marked decrease in total sleep time with reduction in NREM sleep but no major changes in REM sleep.139,177 Infarctions of the paramedian thalamus and of the lower pons have been associated with absence of slowwave sleep but preservation of REM sleep and appearance of REM at sleep onset.177,224 In contrast, infarction in the lower pons can cause an almost completely selective decrease in REM sleep.228 Increased REM sleep has been noted in one patient who had an infarct in the mesencephalic tegmentum and in another with an infarct in the pontomedullary junction.232 Increased NREM and (to a lesser extent) REM sleep have been reported in patients with mesencephalic stroke.226 Clinical Significance Based in theoretical considerations, it is reasonable to postulate a correlation (if not even some overlap) between the neuronal synchrony necessary to generate normal EEG activity and underlying normal cognitive functions. The existence of a such a direct relationship has never been proved in stroke patients. Nevertheless, wake and sleep EEG changes after stroke have been linked with stroke severity and with clinical and cognitive outcome.172,177,186,208,210,212,213,218,233,234 Low sleep efficiency, decreased spindles, K complexes, slow-wave sleep, and REM sleep predict poor outcome when found after hemispheric strokes.
CIRCADIAN ASPECTS AND DISTURBANCES Ischemic stroke, like myocardial infarction and sudden death, occurs most often in the morning hours, particularly after awakening, between 6 am and noon. A meta-analysis of 31 publications reporting the circadian timing of 11,816
strokes found a 49% increase in stroke of all types (ischemic stroke, hemorrhagic stroke, TIA) between 6 am and noon.235 Lago and colleagues found a higher incidence of strokes on awakening in thrombotic (29%) and lacunar (28%) stroke than in embolic stroke (19%).236 There was no difference in circadian rhythm between first and recurrent stroke. Possible explanations for this pattern have focused on circadian or postural changes in platelet aggregation, thrombolysis, blood pressure, heart rate, and catecholamine levels that occur after awakening and resumption of physical and mental activities.237 In addition, the most prolonged REM sleep period, during which autonomic system instability are known to occur,83,238,239 occurs close to awakening. The highest incidence in the early hours of the morning can be overestimated because of patients who awaken with stroke. Treatment with aspirin does not modify the circadian pattern of stroke onset.240,241 Whereas intracerebral and subarachnoid hemorrhages rarely occur at night, 20% to 40% of ischemic strokes occur at night.242 This suggests that sleep represents a vulnerable phase for a subset of patients with cerebrovascular disease. Sleep-onset stroke should prompt the association with sleep-disordered breathing (see earlier). Acute brain infarction—particularly when the right hemisphere and the insula are affected—can disturb normal circadian variation in autonomic functions (e.g., heart rate, blood pressure, temperature control) and breathing and contribute to increased poststroke cardiovascular morbidity.48,243-247,249 Acute stroke also can alter other circadian functions such as sleep-related secretion of growth hormone and melatonin.216,248 Actigraphy in a few patients with acute stroke and multiinfarct dementia has demonstrated disruption, shortening, lengthening, or shifting of sleep–wake cycles.125 In patients who awaken from coma caused by large hemispheric or brainstem strokes, a polyphasic sleep–wake rhythm often precedes the reappearance of a monophasic rhythm.166 Alteration of circadian variation in core temperature was documented in a patient with a focal (neoplastic) lesion of the ventral hypothalamus, but never following acute stroke.250 However, hyperthermia—which, in some cases, implies diencephalic dysfunction—correlates with stroke severity and represents a bad prognostic sign after acute stroke.251 REFERENCES 1. Diaz J, Sempere AP. Cerebral ischemia: new risk factors. Cerebrovasc Dis 2004;17:43-50. 2. Adams HP, Bendixen BH, Kappelle LJ. Classification of subtype of acute ischemic stroke: definitions for use in a multicenter clinical trial. Stroke 1993;24:35-41. 3. The European Stroke Organisation (ESO) Executive Committee and the ESO writing Committee. Guidelines for management of ischaemic stroke and transient ischaemic attack 2008. Cerebrovasc Dis 2008;25:457-507. 4. Hacke W, Kaste M, Bluhmki E, et al. Thrombolysis with alteplase 3 to 4.5 hours after acute ischemic stroke. N Engl J Med 2009;359: 1317-1329. 5. Sacco RL, Adamas R, Albers GW, et al. Guidelines for prevention of stroke in patients with ischemic stroke or transient ischemic attack. Stroke 2006;37:577-617. 6. Cheyne J. A case of apoplexy in which the fleshy part of the heart was converted into fat. Dublin Hop Rep 1818;2:216-218.
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192. Glader EL, Stegmayr B, Asplund K. Poststroke fatigue: a 2-year follow-up study of stroke patients in Sweden. Stroke 2002;33: 1327-1333. 192a. Medeiros CA, de Bruin PF, Paiva TR, et al. Clinical outcome after acute ischaemic stroke: the influence of restless legs syndrome. Eur J Neurol 2010 (Epub ahead of print). 193. Valko PP, Bassetti CL, Bloch K, et al. Validation of the Fatigue Severity Scale in a Swiss cohort. Sleep 2008;31:1601-1607. 194. Bassetti C, Aldrich M. Idiopathic hypersomnia. A study of 42 patients. Brain 1997;120:1423-1435. 195. Guilleminault C, Quera-Salva MA, Goldberg MP. Pseudo-hypersomnia and pre-sleep behaviour with bilateral paramedian thalamic lesions. Brain 1993;116:1549-1563. 196. Grade C, Redford B, Chrostowski J, et al. Methylphenidate in early poststroke recovery. A double-blind, placebo controlled study. Arch Phys Med Rehab 1998;79:1047-1050. 197. Scheidtmann K, Fries W, Muller F, Koenig E. Effect of levodopa in combination with physiotherapy on functional recovery after stroke: a prospective, randomized, double-blind study. Lancet 2001;358:787-790. 198. De Groot MH, Philipps SJ, Eskes GA. Fatigue associated with stroke and other neurologic conditions: implications for stroke rehabilitation. Arch Phys Med Rehab 2003;84:1714-1720. 199. Choi-Kwon S, Choi J, Kwon SU, et al. Fluoxetine is not effective in the treatment of post-stroke fatigue: a double-blind, placebocontrolled study. Cerebrovasc Dis 2007;23:103-108. 199a. Brioschi A, Gramigna S, Werth E, et al. Effect of modafinil on subjective fatigue in multiple sclerosis and stroke patients. Eur Neurol 2009;62:243-249. 200. Goldstein LB. Common drugs may influence motor recovery. The Sygen in Acute Stroke Study Investigators. Neurology 1995; 45:865-871. 201. Li Pi Shan RS, Ashworth NL. Comparison of lorazepam and zopiclone for insomnia in patients with stroke and brain injury: a randomized, cross-over, double blind trial. Am J Phys Med Rehab 2004;83:421-427. 202. Palomäki H, Berg AT, Meririnne E, et al. Complaints of poststroke insomnia and its treatment with mianserin. Cerebrovasc Dis 2003;15:56-62. 203. Feldman SM, Waller HJ. Dissociation of electrocortical activation and behavioural arousal. Nature 1962;4861:1320-1322. 204. Baumann CR, Kilic E, Petit B, et al. Sleep EEG changes after middle cerebral artery infarcts in mice: different effects of striatal and cortical lesions. Sleep 2006;29:1339-1344. 205. Sumra RS, Pathak SN, Singh N, Singh B. Polygraphic sleep studies in cerebrovascular accidents. Neurol India 1972;20:1-7. 206. Körner E, Flooh E, Reinhart B, et al. Sleep alterations in ischemic stroke. Eur Neurol 1986;25:104-110. 207. Giubilei F, Iannilli M, Vitale A, et al. Sleep patterns in acute ischemic stroke. Acta Neurol Scand 1992;86:567-571. 208. Bassetti C, Aldrich MS. Sleep electroencephalogram changes in acute hemispheric stroke. Sleep Med 2001;2:185-194. 209. Müller C, Achermann P, Bischof M, et al. Visual and spectral analysis of sleep EEG in acute hemispheric stroke. Eur Neurol 2002; 48:164-171. 210. Terzoudi A, Vorvolakos T, Heliopoulos I, et al. Sleep architecture in stroke and relation to outcome. Eur Neurol 2009;61: 16-22. 211. Greenberg R. Cerebral cortex lesions: the dream process and sleep spindles. Cortex 1966;2:357-366. 212. Hachinski V, Mamelak M, Norris JW. Prognostic value of sleep morphology in cerebral infarction. Amsterdam: Excerpta Medica; 1979. 213. Hachinski V, Mamelak M, Norris JW. Clinical recovery and sleep architecture degradation. Can J Neurol Sci 1990;17: 332-335. 214. Gottselig J, Bassetti C, Achermann P. Power and coherence of sleep spindle activity following hemispheric stroke. Brain 2002;125: 373-385. 215. Santamaria J, Pujol M, Orteu N, et al. Unilateral thalamic stroke does not decrease ipsilateral sleep spindles. Sleep 2000;23: 333-339. 216. Culebras A, Miller M. Absence of sleep-related elevation of growth hormone level in patients with stroke. Arch Neurol 1983;40: 283-286.
217. Yokohama E, Nagata K, Hirata Y, et al. Correlation of EEG activities between slow-wave sleep and wakefulness in patients with supratentorial stroke. Brain Topogr 1996;8:269-273. 218. Ron S, Algom D, Hary D, Cohen M. Time-related changes in the distribution of sleep stages in brain injured patients. Electroencephalogr Clin Neurophysiol 1980;48:432-441. 219. Ribeiro Pinto L, Baptistas Silva A, Tufik S. Rapid eye movements density in patients with stroke (abstract). Sleep Res 1994;076. 220. Appenzeller O, Fischer AP. Disturbances of rapid eye movements during sleep in patients with lesions of the nervous system. Electroencephalogr Clin Neurophysiol 1968;25:29-35. 221. Hirose G, Saeki M, Kosoegawa H, et al. Delta waves in the EEGs of patients with intracerebral hemorrhage. Arch Neurol 1981;38: 170-175. 222. Cummings JL, Greenberg R. Sleep patterns in the “locked-in” syndrome. Electroencephalogr Clin Neurophysiol 1977;43: 270-271. 223. Autret A, Laffont F, De Toffol B, Cathala HP. A syndrome of REM and non-REM sleep reduction and lateral gaze paresis after medial tegmental pontine stroke. Arch Neurol 1988;45:1236-1242. 224. Tamura K, Karacan I, Williams RL, Meyer JS. Disturbances of the sleep–waking cycle in patients with vascular brain stem lesions. Clin Electroencephalogr 1983;14:35-46. 225. Gironell A, de la Calzada MD, Sagales T, Barraquer-Bordas L. Absence of REM sleep and altered non-REM sleep caused by a hematoma in the pontine tegmentum. J Neurol Neurosurg Psychaitry 1995;59:195-196. 226. Beck U, Kendel K. Polygraphische Nachtsschlafuntersuchugnen bei Patienten mit Hirnstammläsionen. Arch Psychiat Nervenkr 1971;214:331-346. 227. Landau ME, Maldonado JY, Jabbari B. The effects of isolated brainstem lesions on human REM sleep. Sleep Med 2005;6:37-40. 228. Markand ON, Dyken ML. Sleep abnormalities in patients with brainstem lesions. Neurology 1976;26:769-776. 229. Vallderiola F, Santamaria J, Graus F, Tolosa E. Absence of REM sleep, altered NREM sleep and supranuclear horizontal gaze palsy caused by a lesion of the pontine tegmentum. Sleep 1993;16: 184-188. 230. Lavie P, Pratt H, Scharf B, et al. Localized pontine lesion: nearly total absence of REM sleep. Neurology 1984;34:118-120. 231. Kushida CA, Rye DB, Nummy D. Cortical asymmetry of REM sleep EEG following unilateral pontine hemorrhage. Neurology 1991;41:598-601. 232. Popoviciu L, Asgian B, Corfarici D, et al. Anatomoclinical and polygraphic features in cerebrovascular diseases with disturbances of vigilance. In: Tirgu-Mures L, Popoviciu L, Asgia B, et al, editors. Sleep 1978: Fourth European Congress on Sleep Research. New York: Karger; 1980. p. 165-169. 233. Hachinski V, Mamelak M, Norris JW. Sleep morphology and prognosis in acute cerebrovascular lesions. Amsterdam: Excerpta Medica; 1977.
CHAPTER 88 • Sleep and Stroke 1015 234. Siccoli MM, Rölli-Baumeler N, Achermann P, Bassetti CL. Correlations between sleep and cognitive functions after hemispheric ischaemic stroke. Eur J Neurol 2008;15(6):565-572. 235. Elliott WJ. Circadian variation in the timing of stroke onset: a meta-analysis. Stroke 1998;29:992-996. 236. Lago A, Geffner D, Tembl J, et al. Circadian variation in acute ischemic stroke. A hospital-based study. Stroke 1998;29:1873-1875. 237. Krantz DS, Kop WJ, Gabbay FH, et al. Circadian variation of ambulatory myocardial infarction. Triggering by daily activities and evidence for an endogenous circadian component. Circulation 1996;93:1364-1371. 238. Verrier RL, Muller JE, Hobson JA. Sleep, dreams, and sudden death: the case for sleep as an autonomic stress test for the heart. Cardiovasc Res 1996;31:181-211. 239. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995;96:1897-1904. 240. Marsh EE, Biller J, Adams HP, et al. Circadian variation in onset of acute ischemic stroke. Arch Neurol 1990;47:1178-1180. 241. Bassetti C, Aldrich M. Night time versus daytime transient ischemic attack and ischemic stroke: a prospective study of 110 patients. J Neurol Neurosurg Psychiatry 1999;67:463-467. 242. Wroe SJ, Sandercock P, Bamford J, et al. Diurnal variation in incidence of stroke: Oxfordshire community stroke project. BMJ 1992;304:155-157. 243. Sander D, Klingelhöfer J. Stroke-associated pathological sympathetic activation related to size of infarction and extent of insular damage. Cerebrovasc Dis 1995;5:381-385. 244. Yoon BW, Morillo CA, Cechetto DF, Hachinski V. Cerebral hemispheric lateralization in cardiac autonomic control. Arch Neurol 1997;54:741-744. 245. Korpelainen JT, Sotaniemi KA, Huikuri HV, Myllylä VV. Circadian rhythm of heart rate variability is reversibly abolished in ischemic stroke. Stroke 1997;28:2150-2154. 246. Dawson SL, Evans SN, Manktelow BN, et al. Diurnal blood pressure change varies with stroke subtype in the acute phase. Stroke 1998;29:1519-1524. 247. Dawson SL, Mantelow BN, Robinson TG, et al. Which parameters of beat-to-beat blood pressure and variability best predict early outcome after acute ischemic stroke? Stroke 2000;31:463-468. 248. Beloosesky Y, Grinblat J, Laudon M, et al. Melatonin rhythms in stroke patients. Neurosci Lett 2002;319:103-106. 249. Jain S, Namboodri KKN, Kumari S, Prabhakar S. Loss of circadian rhythm of blood pressure following acute stroke. BMC Neurol 2004;4:1-6. 250. Schwartz WJ, Busis NA, Hedley-Whyte ET. A discrete lesion of ventral hypothalamus and optic chiasm that disturbed the daily temperature rhythm. J Neurol 1986;233:1-4. 251. Reith J, Jorgensen HS, Pedersen PM, et al. Body temperature in acute stroke: relations to stroke severity, infarct size, mortality, and outcome. Lancet 1996;347:422-425.
Sleep and Neuromuscular Diseases Michelle T. Cao, Charles F.P. George, and Christian Guilleminault Abstract Neuromuscular disorders consist of central and peripheral neurologic disorders with impairment of the motor system. The disability of patients with a neuromuscular disorder worsens during sleep, and the abnormal sleep and secondary impairment of daytime function further degrade quality of life. Nocturnal sleep disruptions may be the result of pain and discomfort related to weakness, rigidity, or spasticity that limit movement and posture. Sleep disruptions may also be related to autonomic dysfunction (often seen in these patients), poor sphincter control, problems with clearance of secretions, and
Neuromuscular disorders are diseases caused by impairment of the motor unit comprising the lower motor neuron, nerve root, peripheral nerve, myoneural junction, and muscle. Any classification of neuromuscular disease may be somewhat arbitrary, and the astute clinician must keep in mind that the pathologic process can involve several segments of the nervous system and muscle. For example, myopathies lead to progressive peripheral motor and sensory impairment along with autonomic dysfunction. Disorders such as amyotrophic lateral sclerosis (ALS) or Creutzfeldt-Jacob disease can progress rapidly toward death, whereas certain chronic polyneuropathies such as Charcot-Marie-Tooth or autonomic syndromes such as familial dysautonomia can have a slower evolution. Patients with neuromuscular syndromes are at risk for sleep-related problems. (Video 89-1) Weakness, rigidity, and spasticity limit movements and posture changes during sleep, leading to discomfort, pain, and disrupted sleep. Difficulty with maintaining positions of comfort can lead to cramping, abnormal uncontrolled movements, and weakness, which also contribute to poor sleep. Abnormal sphincter control can induce urinary and fecal disturbances in the form of nocturia, incomplete emptying or incontinence, constipation, or painful defecation. The sleeprelated changes in respiration put the patient with a neuromuscular disorder at a specific ventilatory risk by impairing ventilation. Chronic respiratory muscle failure usually develops slowly over years. It can initially manifest with disordered breathing during sleep, followed by progression to nocturnal hypoventilation then to diurnal hypoventilation, cor pulmonale, and eventual respiratory failure and end-stage disease. Because of its slow progression, ventilatory failure in some disorders can go undetected for some time and contribute to increased mortality. Limited attention is often paid to the impact of sleeprelated issues in this population, particularly because most clinics see a limited number of patients with neuromuscular disorders. Even in a specialized neuromuscular clinic, less than 2% of patients are asked about their sleep-related problems or have been given a prior sleep evaluation.1 1016
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abnormal movements and actions during sleep. Most importantly, sleep-related hypoventilation can occur in all patients, and overlooking this can lead to death. Daytime evaluation can determine the severity of the disability but might not identify the presence and severity of an associated sleeprelated disorder. Nonspecific symptoms of daytime fatigue and sleepiness indicate poor sleep in these patients. Polysomnography is the only test that can objectively identify and evaluate the severity of sleep-related disorders. By recognizing and treating sleep-related problems, improved survival and better quality of life can be achieved in this group of patients.
Moreover, the common problems (i.e., spasticity, sphincter dysfunction, pain, abnormal movement, confusional arousal) leading to sleep fragmentation, insomnia, parasomnias, daytime tiredness, and sleepiness are rarely dealt with by the sleep specialist. Thus, a multidisciplinary approach to treatment is mandatory in neuromuscular disorders.
EPIDEMIOLOGY AND GENETICS Each neuromuscular syndrome has its own epidemiology and etiology. For example, ALS affects 0.005% of the U.S. population, and multiple sclerosis (MS), a neurodegenerative disorder, affects 0.11%. However, there are no cumulative prevalence data that include all neuromuscular disorders. Many neurologic disorders such as maltase deficiency myopathy, myotonic dystrophy, Rett syndrome, or familial dysautonomia have a clear genetic origin. Other disorders are secondary to infectious, vascular, malignant, or degenerative diseases, and the presence or absence of a genetic component has not been demonstrated. Despite the number of reports of abnormal sleep and breathing in patients with neuromuscular diseases, and the number of studies dealing with the treatment of the concomitant respiratory insufficiency,2-5 there are few large studies that examine the prevalence of sleep-disordered breathing in these patients. One study from New Mexico1 attempted to gather information from its entire clinic population of more than 300 patients. (The clinic provided free care including neurologic, orthopedic, and physical therapy services, and such access ensured that virtually all patients with neuromuscular disease from the state would be referred.) Although complete data were available for only 60 patients (20% of the clinic population), the researchers demonstrated that sleep and breathing abnormalities are or may be present in more than 40% of patients who are routinely followed at the neuromuscular disorders clinic.1 Such a high prevalence should not be surprising given the vulnerability of such patients to sleep-related reductions in muscle tone and overall ventilation.
PATHOPHYSIOLOGY The diaphragm is the major muscle of respiration during wake and sleep. During non–rapid eye movement (NREM) sleep, there is an overall reduction in ventilation that is related to sleep state changes in the chemical control of breathing and in response to an increased impedance of the respiratory system. However, rib cage activity is maintained, albeit reduced, as is diaphragmatic activity. The importance of the diaphragm is particularly evident during rapid eye movement (REM) sleep. During REM sleep, there is postsynaptic inhibition of somatic motor neurons, which causes further reduction or even complete loss of tone in rib cage and other accessory muscles of respiration but leaves the diaphragm relatively unaffected. Thus, the diaphragm is the main muscle of respiration during REM sleep, and any process affecting the diaphragm, whether a myopathy or a process involving its innervation, can be expected to cause significant changes in breathing and oxygenation during this stage of sleep. In patients with bilateral diaphragmatic paralysis, marked oxygen desaturation can occur during REM sleep.6-8 The REM sleep–related inhibition of intercostal and accessory muscles leads to profound hypoventilation during this sleep stage, because patients with diaphragmatic paralysis are completely dependent on intercostal and accessory muscles for breathing. This suppression of accessory respiratory muscle tone is a normal process of REM sleep and is seen in normal subjects and in patients with lung disease.9-11 Depending on the type of neuromuscular disorder, breathing abnormalities during sleep may be present as central apneas, obstructive apneas, or periods of prolonged hypoventilation. Sleep disruption with frequent arousals may be seen in patients with neuromuscular disorders as a result of discomfort in the recumbent position, secretion clearance, sphincter control problems, or increase in upper airway resistance from muscle weakness and craniofacial changes due to the long-standing muscle weakness. Periods of hypoventilation can contribute to frequent arousals, reduced sleep time, and sleep deprivation through both ventilatory and arousal responses to changes in oxygen saturation and carbon dioxide levels. Although these changes may be protective to overall ventilation in the short term, over time ventilatory responses to changes in oxygen and carbon dioxide levels become blunted. This blunting process leads to further worsening of hypoventilation, eventually occurring during both wakefulness and sleep. CLINICAL FEATURES Features Common to Most Neuromuscular Disorders Nonspecific complaints such as increased tiredness, daytime fatigue, or disrupted nocturnal sleep can be the initial manifestations of a slowly evolving neuromuscular disease of adult onset.1 Such nonspecific complaints may also be the sole indication of a slow progression of a neuromuscular disorder during sleep. The presence of a neuromuscular condition may bias the clinician toward believing that complaints of tiredness or daytime fatigue are simply part of the neurologic problem itself, and the
CHAPTER 89 • Sleep and Neuromuscular Diseases 1017
impaired sleep mechanisms and sleep-related disturbances may be ignored. Problems with clearance, such as managing saliva or gastric contents, can lead to significant drooling, esophageal reflux, or pulmonary congestion from aspiration or retained secretions. Impairment of cough mechanisms can further impair the ability of the lungs to clear secretions. Autonomic dysfunction may be present in the form of abnormal sensitivity to temperature or to pressure, with discomfort related to the use of sheets and blankets. Cerebral lesions can lead to complex regional pain syndrome, with a prominence in the evening and early part of the night. The disease can affect patients psychologically, and their disability can lead to anxiety, depression, and secondary sleep-onset insomnia, as can be seen with many other chronic illnesses. Pharmacologic agents that are prescribed in the evening might have alerting effects, whereas others used in the morning might lead to daytime sleepiness. In all, patients with chronic evolving neuromuscular disorders have many factors that can disrupt sleep and worsen daytime functioning and quality of life. The addition of sleeprelated problems complicates the already existing neurologic issues. Specific Neuromuscular Disorders Neurodegenerative Diseases Neurodegenerative diseases are a group of heterogeneous diseases of the central nervous system for which no causal agent has been identified. These include both somatic and autonomic disorders, both of which have direct and indirect effects on sleep. Somatic diseases involve the cortex, such as Alzheimer’s disease and MS; the basal ganglia (including basal ganglia plus syndromes) such as Parkinson’s disease, progressive supranuclear palsy, Huntington’s chorea, torsion dystonia, or Tourette’s syndrome; the cerebellum (including cerebellum plus syndromes) such as spinocerebellar ataxias; or motor neurons, such as ALS or motor neuron disease. Autonomic degenerative processes can cause multiple-system atrophy or the Shy-Drager syndrome (see Video 87-5). Sleep disturbances such as insomnia, hypersomnia, circadian rhythm disturbances, parasomnias, and sleep-disordered breathing may be seen in neurodegenerative disorders. Because these illnesses are more common in older adults, the sleep changes occurring with normal aging should also be considered. Still, some of the changes in sleep can be related to environmental factors (e.g., living in nursing home) or mood disorders. (The behavior changes associated with the disappearance of physiologic active muscle atonia normally seen during REM sleep secondary to neurodegenerative disorders leading to REM behavior disorder are not reviewed in this chapter.) Although ALS has not been shown to directly affect the sleep-regulating areas of the brain, it is likely that the indirect effects of the disease cause sleep disruption. Periodic limb movements associated with arousals and sleepdisordered breathing contribute to the sleep disruption in some patients with ALS. Sleep-disordered breathing is reported to be present in 17% to 76% of patients with ALS.12 ALS patients with normal respiratory function, normal phrenic motor responses, and preserved motor
1018 PART II / Section 11 • Neurologic Disorders
units on needle electromyography of the diaphragm can have sleep-disordered breathing with periodic mild oxygen desaturation independent of sleep stage (REM and NREM).13 However, respiratory-related sleep disruption is generally not significant until phrenic nerves are involved and the diaphragm becomes paralyzed. Once there is involvement of phrenic nerves, severe hypoventilation and oxygen desaturation occur during REM sleep. Almost invariably, these patients ultimately need some form of ventilatory support. Some ALS patients without any respiratory disturbance or periodic limb movements still have sleep fragmentation, independent of age. This suggests that other factors contribute to disturbed sleep, such as anxiety, depression, pain, choking, excessive secretions, fasciculations and cramps, and the inability to find a comfortable position or turn oneself freely in bed. Orthopnea, a common complaint in ALS, can also contribute to sleep disruption.14,15 Spinal Cord Disease Poliovirus infection targets the nervous system in several ways, producing meningitis and affecting cranial motor nuclei and spinal cord anterior horn cells, causing acute paresis. As a result, there are many possible effects on respiration. Abnormalities in central regulation of breathing in patients with acute and convalescent poliomyelitis were described in 1958 by Plum and Swanson.16 Subsequently, central, mixed, and obstructive events have been noted.17 Sleep and breathing abnormalities are seen not only in patients who are on respiratory assistance (rocking beds) during sleep but also before ventilatory assistance is initiated.18 Sleep abnormalities include decreased sleep efficiency, increased arousal frequency, and varying degrees of apnea and hypopnea. After treatment of sleep and breathing abnormalities, many symptoms often attributed to the postpolio syndrome improve. Although not all symptoms can be explained, daytime symptoms may be explained by poor sleep quality and abnormal respiration during sleep. Poliomyelitis can alter central and peripheral respiratory functions decades after the acute infection, a condition known as postpolio syndrome.19 Muscle atrophy and immobility lead to kyphoscoliosis and potentially morerestricted ventilation. The anatomic deformities resulting from poliomyelitis can cause chronic pain and consequent sleep abnormalities. Also, bulbar involvement can affect upper-airway muscles. Sleep-disordered breathing is reported to be present in 31% of patients with postpolio syndrome.12 Prolongation of REM latency can result from prolonged recruitment time for damaged neurons in the pontine tegmentum.20 Whether postpolio syndrome has caused fatigue and weakness or these are results of disturbed sleep and thus are potentially treatable can be investigated by sleep studies. Inherited metabolic diseases such as subacute necrotizing encephalomyelopathy (Leigh’s disease) typically appear in childhood and may be associated with respiratory disturbance. Rarely, this disease first appears in adulthood, with automatic respiratory failure during sleep.21 Syringomyelia can be associated with central, mixed, and obstructive apneic events. The involvement of the bulbar and high cervical neurons is responsible for the development of
hypoventilation and central sleep apnea.22-24 The syndrome can be associated with other malformations of the base of skull or high cervical junction (platybasia, Chiari malformations25) that may also give a variable type of sleepdisordered breathing. Polyneuropathies The most common polyneuropathy associated with sleepdisordered breathing is Charcot-Marie-Tooth syndrome, also called hereditary motor and sensory neuropathy.26 This is characterized by chronic degeneration of peripheral nerves and roots, resulting in distal muscle atrophy that begins at the feet and legs and later involves the hands. Sleep-disordered breathing can occur in these patients as result of a pharyngeal neuropathy leading to upper airway obstruction (obstructive apnea, upper airway resistance syndrome)27 or with diaphragmatic dysfunction.28 Autonomic neuropathy, particularly when secondary to type 1 diabetes, may be associated with impaired chemosensitivity to carbon dioxide, although the effects on sleep and breathing are not consistent.29 Neuromuscular Junction Impairments Myasthenia gravis is a disorder of the neuromuscular junction characterized by weakness and fatigability of skeletal muscles. Sleep breathing abnormalities can occur as a result of diaphragmatic weakness. Risk factors for the development of sleep-related ventilatory problems in myasthenia gravis patients include age, restrictive pulmonary syndrome, diaphragmatic weakness, and daytime alveolar hypoventilation.30 Younger patients with a shorter duration of illness are least likely to experience any sleeprelated hypoventilation or oxygen desaturation,31 whereas older patients with moderately increased body mass index, abnormal total lung capacity, and abnormal daytime blood gases are most likely to develop hypopneas or apneas, particularly during REM sleep.32 Sleep apnea is diagnosed in 60% of patients with myasthenia gravis even when the disease is in a clinically stable stage.12,33 A prospective study by Nicolle and colleagues found that obstructive sleep apnea was the predominant abnormality occurring in 36% of myasthenia gravis patients and had significant associations with older age, male gender, elevated body mass index, and corticosteroid use.34 Other neuromuscular disorders that can disturb normal sleep include congenital myasthenic syndromes,35 botulism, hypermagnesemia, and tick paralysis. A careful history is extremely helpful in making the diagnosis in these circumstances. Dyspnea that worsens with activity, morning headache, paroxysmal nocturnal dyspnea, fragmented sleep, and daytime somnolence are among the symptoms that suggest the presence of sleep-disordered breathing in these syndromes. Muscular Diseases M YOTONIC D YSTROPHY Myotonic dystrophy is an autosomal dominant inherited illness; patients present with myotonia and nonmuscular dystrophy. In this illness, there is consistent involvement of facial, masseter, levator palpebrae, sternocleidomastoid, forearm, hand, and pretibial muscles; myotonic dystrophy is, in a sense, a distal myopathy. However, pharyngeal and
laryngeal muscles can also be involved, as well as respiratory muscles, particularly the diaphragm. Central abnormalities also occur in myotonic dystrophy, causing excessive sleepiness via different mechanisms.36-39 For example, damage in dorsomedial nuclei of the thalamus can lead to a medial thalamic syndrome characterized by apathy, memory loss, and mental deterioration. Loss of 5-hydroxytryptamine (serotonin) neuronal cell bodies of the dorsal raphe nucleus and the superior central nucleus,39 as well as dysfunction of the hypothalamic hypocretin system,40 can result in hypersomnia and abnormal results on a multiple sleep latency test (reflecting sleep-onset REM periods) in these patients.37,40 Excessive daytime sleepiness has been found to be common in myotonic dystrophy, being reported in 33.1% to 77% of patients in several studies.41 Involvement of the respiratory muscles can predispose to breathing and oxygenation changes during sleep. There has been ample evidence for the occurrence of periods of alveolar hypoventilation, predominantly in REM sleep,42-44 obstructive apneas,45 and central apneas.46 However, the development of sleep breathing abnormalities in myotonic dystrophy is not simply caused by muscle weakness. When sleep and breathing in patients with myotonic dystrophy are compared with those in patients with nonmyotonic respiratory muscle weakness and in control subjects, periods of hypoventilation and apneas (central and obstructive) occurred in those with myotonic dystrophy and at higher incidences than in nonmyotonic patients who had the same degree of muscle weakness (measured by maximal inspiratory and expiratory pressures).47 This finding adds further evidence that respiratory muscle weakness alone does not account for abnormal breathing in patients with myotonic dystrophy. As a result of muscle weakness, development of craniofacial structures in patients with myotonic dystrophy is impaired. They experience more vertical facial growth than normal subjects, and they have more narrowed maxillary arches and deeper palatal depths. These craniofacial changes can contribute to the development of obstructive sleep apnea. Observations of decreased ventilatory response to hypoxic and hypercapnic stimuli43,48-51 and extreme sensitivity to sedative drugs have suggested a central origin of the breathing impairments in myotonic dystrophy. Whereas increase in ventilation as a result of increased arterial carbon dioxide is a standard technique for assessing control of respiration, in patients with myotonic dystrophy the respiratory muscles must transduce the chemical stimulus. When these muscles are abnormal, as in myotonic dystrophy, it may be difficult to interpret a reduced ventilatory response. That is, chemoreceptor activity and efferent signaling to muscles may be intact, but weak or inefficient respiratory muscles might not permit a normal ventilatory response to a hypoxic stimulus. Measurement of the mouth pressure developed at the beginning of a transiently occluded breath (occlusion pressure, P0.1) can also be used as a measure of respiratory center output.52 In patients with myotonic dystrophy, P0.1 may be as high as or higher than that of control subjects at rest and during stimulated breathing, although overall ventilation is lower.49,53 The finding of a high transdiaphragmatic pressure (Pdi), despite overall lower ventilation,
CHAPTER 89 • Sleep and Neuromuscular Diseases 1019
suggests that increased impedance of the respiratory system accounts for incomplete transformation into ventilation of normal or increased respiratory center output. Magnetic stimulation of the cortex, in conjunction with phrenic nerve recordings, can be used to test the corticospinal tract to phrenic motor neuron pathways and is a reliable method for diagnosing and monitoring patients with impaired central respiratory drive.54 The use of transcortical and cervical magnetic stimulation demonstrates that more than 20% of patients with myotonic dystrophy have impaired central respiratory drive.55 The finding of neuronal loss in the dorsal central, ventral central, and subtrigeminal medullary nuclei in patients with myotonic dystrophy who exhibit alveolar hypoventilation56 and the severe neuronal loss and gliosis in the tegmentum of the brainstem57 also support a central abnormality. O THER M YOPATHIES Abnormalities in sleep and breathing have been reported in isolated series of patients with various neuromuscular disorders, such as congenital myopathies (nemaline or congenital fiber–type disproportion myopathy58-60) or metabolic myopathies (mitochondrial myopathy [KearnsSayre syndrome]61-63 and acid maltase deficiency).64-66 In all of these cases, there are various alterations in control of breathing and breathing pattern changes, including hypoventilation, obstruction, and central apnea. Severe central sleep apnea and marked oxygen desaturation, particularly during REM sleep, resulting in hypoxia-induced nocturnal seizures, pulmonary hypertension, excessive daytime sleepiness, heart failure, and morning headaches, may be seen in patients with congenital muscular dystrophy,67 and obstructive sleep apnea has also been described in Thomsen’s disease (myotonia congenita).68 Myopathies such as Duchenne’s muscular dystrophy (DMD) can cause restrictive lung disease and chest wall deformities.69 These changes also contribute to ventilatory impairment, fragmented sleep, frequent arousals and sleep stage changes, hypercapnia and hypoxemia (more profound during REM sleep),70,71 development of deformities, chronic pain, and discomfort. There is a bimodal presentation of sleep-disordered breathing in children with DMD, where obstructive sleep apnea is more common in younger children in the first decade of life.72 In younger children with DMD, obstructive sleep apnea was amenable to adenotonsillectomy, whereas in older children who had already developed hypoventilation, obstructive sleep apnea was managed with noninvasive ventilation. A special case is maltase deficiency myopathy, in which the rapid and significant diaphragmatic impairment that occurs long before the wasting of other skeletal muscles explains the severity of the sleep-disordered breathing.73 In fact, the breathing problem during sleep and the secondary daytime tiredness may be presenting symptoms of the myopathy.74 Although the disease progresses rapidly, the diaphragmatic impairment, with clear evidence of sleep-disordered breathing, remains as a major component of the syndrome. Facioscapulohumeral muscular dystrophy is an autosomal dominant disease and the third most common form of muscular dystrophy, after DMD and myotonic dystrophy. Marca and colleagues evaluated 46 patients with facioscapu-
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lohumeral muscular dystrophy and found that impaired sleep quality was directly correlated to the severity of the disease. Twenty-seven patients also presented with snoring and 12 reported respiratory pauses during sleep.75
DIAGNOSTIC EVALUATION The clinician who evaluates a patient with a neuromuscular disorder has to consider the type of neurologic disorder and the degree of disability seen during wakefulness. During neurologic assessment, the degree of sensory and motor impairment and the resulting disability, the associated autonomic defects, the intensity of pain and discomfort, and the impact of the illness on the patient’s mood must be assessed. Understanding the patient’s interaction with society and family is an important factor for subsequent treatment decisions. A detailed sleep history is required to outline the severity and type of sleep-related problem(s). For instance, the degree and type of nocturnal disruption, sleep-onset insomnia, awakening difficulties, presence or absence of abnormal behavior during sleep (including confusional arousal), nonrestorative sleep, fatigue, and daytime sleepiness are helpful in the assessment of a sleep-related disorder. General assessment should also determine the degree of pain and discomfort (particularly in the supine position and during sleep), the presence or absence of sphincter problems and urinary or digestive dysfunction during wake and sleep, and any evidence of autonomic dysfunction already present during wakefulness and suspected during sleep (e.g., orthostatic hypotension, dizziness, lightheadedness when standing up just after awakening, cold hands and feet that worsen during the nocturnal period, appearance of skin mottling when supine). The degree of mood impairment caused by illness or sleep disruption should also be characterized. A number of additional diagnostic tests can supplement the evaluation of sleep in the patient with neuromuscular disease. These include a disability index scale,1 a sleep disorder questionnaire, and a sleep log or actigraphy (helpful for investigating daily rhythms and sleep–wake disturbances during a 24-hour period). The severe respiratory insufficiency questionnaire, a multidimensional health-related quality-of-life instrument, may be used for patients who have neuromuscular disorders who are on assisted ventilation.76 Routine measures of pulmonary function (spirometry, lung volumes, diffusing capacity) and gas exchange (Pao2 and Paco2) should be performed in all patients at initial presentation. Static lung volume measurements, both upright and after 15 minutes supine, often demonstrate significant changes caused by respiratory muscle weakness, particularly diaphragmatic weakness. A forced expiratory volume in 1 second (FEV1) or forced vital capacity (FVC) less than 40% of the predicted value, a Paco2 greater than 45 mm Hg, and a base excess of 4 mmol/L or greater can indicate that there is a risk for sleep-related hypoventilation; it has been suggested that when these abnormalities are present, polysomnography should be performed.77-79 Supine inspiratory vital capacity less than 40%, 25%, and 12% will likely result in hypoventilation during REM sleep, full night, and daytime, respectively.77
Overnight polysomnography is the key to a definitive evaluation of sleep and breathing in this patient population. Although it can be done in many settings, including at home, in-laboratory evaluation allows additional measures such as video monitoring to document any behavioral changes (e.g., the presence of confusional arousal), parasomnias including REM sleep behavior disorder, or anoxic seizures. More importantly, measurement of transcutaneous or end-tidal CO2 allows continuous tracking of overall ventilation during sleep and can provide a guide for nocturnal ventilatory assistance.
TREATMENT The greatest advances in the medical treatment of neuromuscular disorders have been for sleep-related abnormalities.80 The goal is restoration of normal sleep architecture, with subsequent improvement of sleep, daytime function, and quality of life. Simple measures such as bedding are often overlooked. Many types of beds and mattresses are available with specifications allowing ease of positional changes, avoidance of skin lesions at pressure points, and segmental inflation or deflation (e.g., air mattresses), thus decreasing the consequences of autonomic dysfunction, cramps, spastic contraction, and rigidity. Great efforts should be made to decrease pain and discomfort of any type. Treatment of abnormal behavior and confusional arousals may require sedatives such as benzodiazepines, but such therapy should be considered after careful evaluation of ventilatory function and risk during sleep so as not to worsen the sleep disorder. Judicious use of pharmacologic agents in the morning, such as modafinil, a wake-promoting drug, 100 to 200 mg, can provide daytime alertness without nocturnal sleep disruption. Prior reports on patients with myotonic muscular dystrophy and ALS have shown beneficial effects of modafinil in improving daytime fatigue.81-84 Modafinil has also been shown to be effective in relieving daytime sleepiness and fatigue in neurodegenerative disorders such as MS and Parkinson’s disease.85-90 Modafinil significantly improves daytime wakefulness and fatigue in narcoleptic patients as assessed by the SF-36 and the profile of mood states (POMS) questionnaire.91 This has led to studies evaluating the clinical efficacy of modafinil for daytime fatigue and sleepiness in MS patients, showing conflicting results. Two pilot studies showed that modafinil (200 mg/ day) significantly improved fatigue and sleepiness based on Fatigue Severity Scale (FSS) and Epworth Sleepiness Scale (ESS) scores, and it is well tolerated in patients with MS.89,90 Another study comparing modafinil (400 mg/day) to placebo showed that there was no significant improvement in fatigue based on the Modified Fatigue Impact Scale (MFIS) in MS patients.92 This discrepancy may be related to the dosing schedule (taken in morning versus twice a day) and dose-related effect (400 mg versus 200 mg). There have been two case reports of modafinil improving nocturnal enuresis in two patients with MS who were on the medication for daytime fatigue.93 Treatment of abnormal breathing during sleep should be based on polysomnographic findings and should be adjusted with regular follow-up polysomnographic studies. Various therapies can improve nocturnal hypoventilation
or offset the attendant oxygen desaturation. Supplemental oxygen has been used to alleviate the REM sleep–related oxygen desaturation in patients with DMD; however, little improvement in sleep ensues.94 Because most of the hypoventilation occurs during REM sleep, pharmacologic manipulation of REM sleep by the use of tricyclic antidepressants is a theoretical option and has been attempted with protriptyline. In a small study of patients with DMD, marked improvement in the nocturnal oxygen saturation profile was seen.95 Similar results with protriptyline were seen in patients with restrictive lung disease96; however, anticholinergic side effects limit the widespread use of such therapy. Inspiratory muscle training has demonstrated improved waking respiratory failure in one patient with acid maltase deficiency.65 This patient had abnormal sleep architecture that was unchanged by the muscle training, but there was major improvement in the nocturnal oxygen saturation. Muscle weakness can lead to nocturnal hypoventilation and worsening of oxygenation. Repeated nocturnal asphyxia can lead to increased muscle weakness, which begets further oxygen desaturation, and reversal of the hypoxemia can arrest the muscle weakness. Such a case has been reported where nocturnal ventilation ablated nocturnal hypoxemia in a patient with acid maltase deficiency, and muscle weakness did not progress over an 8-year period.97 Mechanical ventilation has been a mainstay in supporting ventilation since the days of the poliomyelitis epidemics. Rocking beds, negative-pressure tank ventilators, positive-pressure ventilation via tracheostomy, and cuirass ventilation were long-term options in the past, and some patients are still successfully managed with these forms of therapy.2-4 All of these options are cumbersome, severely limit the mobility of patients, and in the case of tracheostomy can have unwanted complications. Therefore, other forms of assisted ventilation have been developed including phrenic nerve pacing, nasal continuous positive airway pressure (CPAP), and noninvasive positive pressure ventilation (NPPV), including bilevel positive airway pressure (BiPAP). In contrast to CPAP (in which delivered airway pressure is constant), the BiPAP system allows delivery of different positive pressures on inspiration and expiration. By adjusting the inspiratory pressure to be higher than the expiratory pressure, the BiPAP system emulates a conventional positive-pressure ventilatory device and may be used as a means of enhancing ventilation. The new-generation NPPV (derived from the BiPAP concept) is equipped with variable-flow pressure-cycled devices and attempt to self-adjust pressures during the night based on specific algorithms. These devices have not been tested enough to show superiority over the ordinary BiPAP systems. However, they are equipped with a function known as rise time and an expanded range of pressures. The rise time (the speed at which airflow is delivered from expiration to inspiration in tenths of a second) is an important component in patient’s comfort and compliance. The rise time is adjusted based on the severity of thoracic muscle weakness, lung inflation capabilities, amount of secretion accumulated in the airway, and other parameters. This adjustment may be critical because the patient might
CHAPTER 89 • Sleep and Neuromuscular Diseases 1021
not tolerate bilevel equipment if the rise time is inadequate for the situation.98,99 In endotracheally intubated patients or those with a tracheostomy, the differential between expiratory and inspiratory positive airway pressure can be wide. However, unlike an endotracheal or tracheostomy tube, the upper airway is not rigid, and as a result there is variability in airway dilator contraction during inspiration due to several factors, including the degree of local muscle impairment, sleep stage, sleep state, neck position, and narrowing due to anatomic factors (e.g., deviated septum, enlargement of nasal turbinates, presence of adenoids and tonsils). Any of these factors creates turbulence, a phenomenon seen in a circular tube as defined by laws of physics. If the pressure differential becomes wide in the presence of nonlinear flow (turbulence), there will be a greater tendency for upper airway obstruction that translates into flow limitation (visible when studying nasal flow during polysomnography).99 In our practice we keep a maximum differential of 6 cm H2O to avoid iatrogenic induction of variable abnormal upper airway resistance as described earlier. Besides determining appropriate inspiratory and expiratory pressures during overnight polysomnography, the need for a backup respiratory rate may also be assessed. If a backup rate is determined to be helpful, it is commonly set around 10 to 12 breaths per minute, but it will need to be adjusted with time based on the severity and evolution of the syndrome. Bilevel therapy is an effective treatment for a number of neuromuscular diseases,5 and in early stages of the disease it may be as effective as an invasive conventional ventilator. Low-flow oxygen can be bled into the nasal mask during nocturnal sleep to maintain adequate oxygenation. Because the bilevel system acts as a noninvasive ventilator and supports ventilation, it also treats CO2 retention, which is commonly seen in this group of patients in later stages of the disease. In the last 2 decades, NPPV has proved to have a significant positive impact on the natural course of the disease. In neuromuscular diseases, NPPV has been shown to improve quality of life and increase survival.100-107 In postpolio syndrome, the median improvement in life expectancy is more than 20 years. In spinal muscular dystrophy types 2 and 3, DMD, and acid maltase deficiency, the median improvement in life expectancy is 10 years. In myotonic dystrophy, the median improvement in life expectancy is 4 years, and in ALS it is 1 year. Compared to ventilation via tracheostomy, NPPV via nasal interfaces and portable ventilators is becoming the preferred means of assisting ventilation because it simplifies administration of care, is more comfortable for patients, and reduces costs.108,109 Nasal ventilation has been used predominantly nocturnally for patients with postpolio syndrome and other neuromuscular disorders,5,110-117 and it has even been used almost continuously in patients with severe postpolio respiratory insufficiency.114 As the postpolio syndrome and the late sequelae of tuberculosis are disappearing in many parts of the world, ALS has become the most common neuromuscular disorder for which NPPV is used.118 Bourke and colleagues performed a randomized study of 41 ALS patients with orthopnea, maximum inspiratory pressure
1022 PART II / Section 11 • Neurologic Disorders
less than 60% of predicted, or symptomatic daytime hypercapnia compared to controls and found significant improvements in quality of life, sleep-related symptoms, and survival in those without severe bulbar dysfunction with the use of NPPV.101 These improvements were greater than those achievable with any currently available pharmacotherapy. Therefore, a trial of NPPV in ALS patients is warranted even in those with severe bulbar dysfunction for palliative reasons. Regarding the use of NPPV, the choice of setting can influence sleep architecture and quality in patients with various neuromuscular diseases. Tailoring the setting (an option available depending on which portable ventilator is used) to the individual patient’s respiratory effort rather than the usual clinical parameters is associated with even better nighttime gas exchange, percentage of REM sleep, and sleep quality.119 Various modalities of noninvasive nocturnal ventilation have been developed particularly for use in patients with obesity hypoventilation and cardiac failure (i.e., average volume-assured pressure support and adaptive servo ventilation, respectively).120,121 Average volumeassured pressure support (AVAPS) is a modality that automatically adjusts the pressure support level of a patient to provide a consistent tidal volume with each breath. In this setting, it potentially can be an ideal mode for patients who have neuromuscular disease and who are unable to maintain adequate tidal volume during sleep. In almost every case, not only are the nocturnal ventilation and gas exchange abnormalities normalized, but daytime respiratory failure and excessive daytime sleepiness are improved as well. The use of noninvasive positivepressure ventilation allows patients to return to work and even travel, something previously not possible when they were constrained by reliance on a rocking bed or the complications of tracheostomy for nocturnal ventilatory support.16
DECISION TO ASSIST NOCTURNAL VENTILATION When patients present with disrupted sleep, snoring, excessive daytime sleepiness, and unexplained development of peripheral edema or polycythemia, sleep studies will characterize the breathing disorder, and the decision to assist ventilation is an easy one. For patients with obstructive sleep apnea, nasal CPAP or BiPAP is the preferred treatment; patients with predominantly hypoventilation or central apnea and severe oxygen desaturation should be managed with BiPAP (with or without backup respiratory rate and with or without addition of low-flow oxygen bled into the mask), or noninvasive ventilatory support with portable volume ventilators via nasal or oral interfaces. Nocturnal NPPV should be started when nocturnal hypoventilation is present. Clinical symptoms and physiologic markers of hypoventilation are helpful in assessing disease severity and will assist in the decision to initiate nocturnal NPPV. The course of neuromuscular disease follows a two-step process, with the initial onset of nocturnal hypoventilation that is reversible during wakefulness, followed eventually by development of diurnal hypoventilation with associated clinical symptoms. The
development of daytime hypoventilation is a serious progression that can lead to acute respiratory failure in certain clinical settings. Continuous monitoring of arterial carbon dioxide by end-tidal CO2 or transcutaneous CO2 during an overnight sleep study is necessary for documenting nocturnal hypoventilation. This process may be more severe during REM sleep or might occur exclusively during REM sleep. Arterial blood gas and serum chemistry can document daytime hypoventilation with elevated arterial CO2 (Paco2), associated low arterial oxygen (Pao2), relatively normal pH, and high serum bicarbonate. There are no consensus data; however, in neuromuscular patients many clinicians consider starting NPPV with an arterial Pco2 greater than 45 mm Hg and an arterial Po2 less than 70 mm Hg.122 An isolated change in nocturnal oxygen saturation (Sao2) alone is insufficient for deciding whether the patient needs ventilatory assistance. However, sustained nocturnal oxygen desaturation can suggest the presence of nocturnal hypoventilation. In summary, there is long-standing consensus123 on the management of severe progressive neuromuscular disorders in which respiratory failure plays a significant part of the natural history of the disease. The positive impact of noninvasive ventilatory support in patients with neuromuscular disease has become more clear in the last 2 decades.124,125 The most effective time to introduce noninvasive ventilation is when sleep-disordered breathing develops. The clinician must remember that other systems are severely affected as well (e.g., in ALS). Issues such as quality of life must be taken into account. Without specific guidance from the literature, each patient must be assessed in detail, and the clinician must bear in mind that nocturnal (and later, 24-hour) ventilation will treat only one (albeit important) aspect of the disorder. ❖ Clinical Pearl Sleep is a state of vulnerability for patients with neuromuscular disorders, as normal REM sleep-related changes in ventilation are magnified as a result of muscle weakness. Sleep disturbances, in addition to sleep-disordered breathing, may also be related to spasticity, poor secretion clearance, sphincter dysfunction, inability to turn, pain, and any associated or secondary autonomic dysfunction. All of these factors impair sleep and worsen daytime disability. Noninvasive ventilation is a significant contribution to neuromuscular disease patients by allowing them to live near-normal life expectancy, decreases morbidity and improves mortality. The most effective time to introduce noninvasive ventilation is when sleep-disordered breathing develops.
REFERENCES 1. Labanowski M, Schmidt-Nowara W, Guilleminault C. Sleep and neuromuscular disease: frequency of sleep-disordered breathing in a neuromuscular disease clinic population. Neurology 1996;47: 1173-1180. 2. Howard RS, Wiles CM, Hirsch NP, et al. Respiratory involvement in primary muscle disorders: assessment and management. Q J Med 1993;86:175-189.
CHAPTER 89 • Sleep and Neuromuscular Diseases 1023 3. Arens R, Muzumdar H. Sleep, sleep disordered breathing, and nocturnalhypoventilation in children with neuromuscular diseases. Paediatr Respir Rev 2010 Mar;11(1):24-30. 4. Iber C, Davies SF, Mahowald MW. Nocturnal rocking bed therapy: improvement in sleep fragmentation in patients with respiratory muscle weakness. Sleep 1989;12:405-412. 5. Guilleminault C, Philip P, Robinson A. Sleep and neuromuscular disease: bilevel positive airway pressure by nasal mask as a treatment for sleep disordered breathing in patients with neuromuscular disease. J Neurol Neurosurg Psychiatry 1998;65:225-232. 6. Newsom-Davis J, Goldman M, Loh L, et al. Diaphragm function and alveolar hypoventilation. Q J Med 1975;45:87-100. 7. Kreitzer SM, Feldman NT, Saunders NA, et al. Bilateral diaphragmatic paralysis with hypercapnic respiratory failure. Am J Med 1978;65:89-95. 8. Skatrud J, Iber C, McHugh W, et al. Determinants of hypoventilation during wakefulness and sleep in diaphragmatic paralysis. Am Rev Respir Dis 1980;121:587-593. 9. Muller NL, Francis DW, Gurwitz D, et al. Mechanisms of hemoglobin desaturation during REM sleep in normal subjects and in patients with cystic fibrosis. Am Rev Respir Dis 1980;121:463469. 10. Johnson MW, Remmers JE. Accessory muscle activity during sleep in chronic obstructive pulmonary disease. J Appl Physiol 1984; 57:1011-1017. 11. Millman BP, Knight H, Kline LR, et al. Changes in compartmental ventilation in association with eye movements during REM sleep. J Appl Physiol 1988;65:1196-1202. 12. Atalaia A, Carvalho MD, Evangelista T, et al. Sleep characteristics of amyotrophic lateral sclerosis in patients with preserved diaphragmatic function. Amyotroph Lateral Scler 2007;8:101105. 13. Ferguson KA, Strong MJ, Ahmad D, et al. Sleep-disordered breathing in amyotrophic lateral sclerosis. Chest 1996;110:664-669. 14. David WS, Bundlie SR, Mahdavi Z. Polysomnographic studies in amyotrophic lateral sclerosis. J Neurol Sci 1997;152(Suppl. 1):S29S35. 15. Plum F, Swanson AG. Abnormalities in central regulation of respiration in acute and convalescent poliomyelitis. Arch Neurol Psychiatry 1958;80:267-285. 16. Guilleminault C, Motta J. Sleep apnea syndrome as a long-term sequelae of poliomyelitis. In: Guilleminault C, Dement WC, editors. Sleep apnea syndrome. New York: Alan R Liss; 1978. p. 309-315. 17. Steljes DG, Kryger MH, Kirk BW, et al. Sleep in postpolio syndrome. Chest 1990;98:133-140. 18. Burk JB, James AC. Characteristics and management of postpolio syndrome. JAMA 2000;284:412-414. 19. Siegel H, McCutchen C, Dalakas MC, et al. Physiologic events initiating REM sleep in patients with the postpolio syndrome. Neurology 1999;52:516-522. 20. Cummiskey J, Guilleminault C, Davis R, et al. Automatic respiratory failure: sleep studies and Leigh’s disease. Neurology 1987; 37:1876-1878. 21. Chokroverty S. Sleep-disordered breathing in neuromuscular disorders: a condition in search of recognition. Muscle Nerve 2001;24:451-455. 22. Kimura K, Tachibana N, Kimura J, et al. Sleep-disordered breathing at an early stage of amyotrophic lateral sclerosis. J Neurol Sci 1999;164:37-43. 23. Daube JR. Electrodiagnostic studies in amyotrophic lateral sclerosis and other motor neuron disorders. Muscle Nerve 2000;23: 1488-1502. 24. Lam B, Ryan CF. Arnold-Chiari malformation presenting as sleep apnea syndrome. Sleep Med 2000;1:139-144. 25. Stojkovic T, de Seze J, Dubourg O, et al. Autonomic and respiratory dysfunction in Charcot-Marie-Tooth disease due to Thr124Met mutation in the myelin protein zero gene. Clin Neurophysiol 2003;114:1609-1614. 26. Dematteis M, Pepin JL, Jeanmart M, et al. Charcot-Marie-Tooth disease and sleep apnoea syndrome: a family study. Lancet 2001; 357:267-272. 27. Chan CK, Mohsenin V, Loke J, et al. Diaphragmatic dysfunction in siblings with hereditary motor and sensory neuropathy (CharcotMarie-Tooth disease). Chest 1987;91:567-570.
28. Tantucci C, Bottini P, Fiorani C, et al. Cerebrovascular reactivity and hypercapnic respiratory drive in diabetic autonomic neuropathy. J Appl Physiol 2001;90:889-896. 29. Gajdos P, Quera Salva MA. Respiratory disorders during sleep and myasthenia. Rev Neurol (Paris) 2001;157:S145-147. 30. Manni R, Piccolo G, Sartori I, et al. Breathing during sleep in myasthenia gravis. Ital J Neurol Sci 1995;16:589-594. 31. Quera-Salva MA, Guilleminault C, Chevret S, et al. Breathing disorders during sleep in myasthenia gravis. Ann Neurol 1992; 31:86-92. 32. Oztura I, Guilleminault C. Neuromuscular disorders and sleep. Curr Neurol Neurosci Rep 2005;5:147-152. 33. Amino A, Shiozawa Z, Nagasaka T, et al. Sleep apnoea in well controlled myasthenia gravis and the effect of thymectomy. J Neurol 1998;245:77-80. 34. Nicolle MW, Rask S, Koopman WJ, et al. Sleep apnea in patients with myasthenia gravis. Neurology 2006;67:140-142. 35. Iannaccone ST, Mills JK, Harris KM, et al. Congenital myasthenic syndrome with sleep hypoventilation. Muscle Nerve 2000;23: 1129-1132. 36. Phillips MF, Steer HM, Soldan JR, et al. Daytime somnolence in myotonic dystrophy. J Neurol 1999;246:275-282. 37. Gibbs JW 3rd, Ciafaloni E, Radtke RA. Excessive daytime somnolence and increased rapid eye movement pressure in myotonic dystrophy. Sleep 2002;25:672-675. 38. Bourke SC, Gibson GJ. Sleep and breathing in neuromuscular disease. Eur Respir J 2002;19:1194-1201. 39. Ono S, Takahashi K, Jinnai K, et al. Loss of serotonin- containing neurons in the raphe of patients with myotonic dystrophy: a quantitative immunohistochemical study and relation to hypersomnia. Neurology 1998;50:535-538. 40. Martinez-Rodriguez JE, Lin L, Iranzo A, et al. Decreased hypocretin-1 (orexin-A) levels in the cerebrospinal fluid of patients with myotonic dystrophy and excessive daytime sleepiness. Sleep 2003; 26:287-290. 41. Laberge L, Begin P, Montplaisir J, et al. Sleep complaints in patients with myotonic dystrophy. J Sleep Res 2004;13:95-100. 42. Kilburn KH, Eagan JT, Sieker HO, et al. Cardiopulmonary insufficiency in myotonic and progressive muscular dystrophy. N Engl J Med 1954;261:1089-1096. 43. Coccagna G, Mantovani M, Parchi C, et al. Alveolar hypoventilation and hypersomnia in myotonic dystrophy. J Neurol Neurosurg Psychiatry 1975;38:977-984. 44. Coccagna G, Martinelli P, Lugaresi E. Sleep and alveolar hypoventilation in myotonic dystrophy. Acta Neurol Belg 1982;82: 185-194. 45. Guilleminault C, Cummiskey J, Motta J, et al. Respiratory and hypodynamics study during wakefulness and sleep in myotonic dystrophy. Sleep 1978;1:19-31. 46. Cirignotta F, Mondini S, Zucconi M, et al. Sleep related breathing impairments in myotonic dystrophy. J Neurol 1987;235: 80-85. 47. Gilmartin JJ, Cooper BG, Griffiths CJ, et al. Breathing during sleep in patients with myotonic dystrophy and non-myotonic respiratory muscle weakness. Q J Med 1991;78:21-31. 48. Serisier DE, Mastaglia FL, Gibson GJ. Respiratory muscle function and ventilatory control. I, in patients with motor neurone disease. II, in patients with myotonic dystrophy. Q J Med 1982;51: 205-226. 49. Begin R, Bureau MA, Lupien L, et al. Pathogenesis of respiratory insufficiency in myotonic dystrophy. Am Rev Respir Dis 1982;125:312-318. 50. Carroll JE, Zwillich LW, Weil JV. Ventilatory response in myotonic dystrophy. Neurology 1977;27:1125-1128. 51. Gillam PMS, Heaf PJD, Kaufman L, et al. Respiration in dystrophic myotonia. Thorax 1964;19:112-120. 52. Whitelaw WA, Derenne JP, Milic-Emili J. Occlusion pressure as a measure of the respiratory centre output in conscious man. Respir Physiol 1975;23:181-199. 53. Begin P, Mathieu J, Almirall J, et al. Relationship between chronic hypercapnia and inspiratory-muscle weakness in myotonic dystrophy. Am J Respir Crit Care Med 1997;156:133-139. 54. Zifko UA, Hahn AF, Remtulla H, et al. Central and peripheral respiratory electrophysiological studies in myotonic dystrophy. Brain 1996;119:1911-1922.
1024 PART II / Section 11 • Neurologic Disorders 55. Zifko U, Remtulla H, Power K, et al. Transcortical and cervical magnetic stimulation with recording of the diaphragm. Muscle Nerve 1996;19:614-620. 56. Ono SF, Kanda F, Takahashi K, et al. Neuronal loss in the medullary reticular formation in myotonic dystrophy: a clinicopathological study. Neurology 1996;46:A171. 57. Ono S, Kurisaki H, Sakuma A, et al. Myotonic dystrophy with alveolar hypoventilation and hypersomnia: a clinicopathological study. J Neurol Sci 1995;128:225-231. 58. Riley DJ, Santiago RV, Daniele RP, et al. Blunted respiratory drive in congenital myopathy. Am J Med 1977;63:459-466. 59. Maayan C, Springer C, Armen Y, et al. Nemaline myopathy as a cause of sleep hypoventilation. Pediatrics 1986;77:390-395. 60. Wilson DO, Sanders MH, Dauber JH. Abnormal ventilatory chemosensitivity and congenital myopathy. Arch Intern Med 1987; 147:1773-1777. 61. Carroll JE, Zwillich C, Weil JV, et al. Depressed ventilatory response in oculocraniosomatic neuromuscular disease. Neurology 1976;26:140-146. 62. Weng TR, Schultz GE, Chang HC, et al. Pulmonary function and ventilatory response to chemical stimuli in familial myopathy. Chest 1985;88:488-495. 63. Kotagal S, Archer CR, Walsh JK, et al. Hypersomnia, bithalamic lesions, and altered sleep architecture in Kearns-Sayre syndrome. Neurology 1985;35:574-577. 64. Bellamy D, Newsom-Davis JM, Mickey BP, et al. A case of primary alveolar hypoventilation associated with mild proximal myopathy. Am Rev Respir Dis 1975;112:867-873. 65. Martin RJ, Sufit RI, Ringel SP, et al. Respiratory improvement by muscle training in adult-onset acid maltase deficiency. Muscle Nerve 1983;6:201-203. 66. Margolis ML, Howlett P, Goldberg R, et al. Obstructive sleep apnea syndrome in acid maltase deficiency. Chest 1994;105: 947-949. 67. Kryger MH, Steljes DG, Yee WC, et al. Central sleep apnea in congenital muscular dystrophy. J Neurol Neurosurg Psychiatry 1991;54:710-712. 68. Striano S, Meo R, Bilo L, et al. Sleep apnea syndrome in Thomsen’s disease: a case report. Electroencephalogr Clin Neurophysiol 1983;56:323-325. 69. Gozal D. Pulmonary manifestations of neuromuscular disease with special reference to Duchenne muscular dystrophy and spinal muscular atrophy. Pediatr Pulmonol 2000;29:141-150. 70. American Thoracic Society/European Respiratory Society. ATS/ ERS statement on respiratory muscle testing. Am J Respir Crit Care Med 2002;166:518-624. 71. Phillips MF, Smith PE, Carroll N, et al. Nocturnal oxygenation and prognosis in Duchenne muscular dystrophy. Am J Respir Crit Care Med 1999;160:198-202. 72. Suresh S, Wales P, Dakin C, et al. Sleep-related breathing disorder in Duchenne muscular dystrophy: disease spectrum in the paediatric population. J Paediatr Child Health 2005;41: 500-503. 73. Mellies U, Ragette R, Schwake C, et al. Sleep-disordered breathing and respiratory failure in acid maltase deficiency. Neurology 2001;57:1290-1295. 74. Guilleminault C, Stoohs RA, Querra-Salva MA. Sleep related obstructive and nonobstructive apneas in neurologic disorders. Neurology 1992;42:S53-S60. 75. Marca GD, Frusciante R, Vollono C, et al. Sleep quality in facioscapulohumereral muscular dystrophy. J Neurol Sci 2007; 263:49-53. 76. Richman DP, Agius MA. Treatment of autoimmune myasthenia gravis. Neurology 2003;61:1652-1661. 77. Hukins CA, Hillman DR. Daytime predictors of sleep hypoventilation in Duchenne muscular dystrophy. Am J Respir Crit Care Med 2000;161:166-170. 78. Ragette R, Mellies U, Schwake C, et al. Patterns and predictors of sleep disordered breathing in primary myopathies. Thorax 2002;57:724-728. 79. Mellies U, Ragette R, Schwake C, et al. Daytime predictors of sleep disordered breathing in children and adolescents with neuromuscular disorders. Neuromuscul Disord 2003;13:123-128. 80. Bourke SC, Gibson GJ. Sleep and breathing in neuromuscular disease. Eur Respir J 2002;19:1194-1201.
81. MacDonald JR, Hill JD, Tarnopolsky MA. Modafinil reduces excessive somnolence and enhances mood in patients with myotonic dystrophy. Neurology 2002;59:1876-1880. 82. Damian MS, Gerlach A, Schmidt F, et al. Modafinil for excessive daytime sleepiness in myotonic dystrophy. Neurology 2001;56: 794-796. 83. Talbot K, Stradling J, Crosby J, et al. Reduction in excess daytime sleepiness by modafinil in patients with myotonic dystrophy. Neuromuscul Disord 2003;13:357-364. 84. Carter GT, Weiss MD, Lou JS, et al. Modafinil in amyotrophic lateral sclerosis: an open label pilot study. Am J Hosp Palliat Med 2005;22:55-59. 85. Adler CH, Caviness JN, Hentz JG, et al. Randomized trial of modafinil for treating subjective daytime sleepiness in patients with Parkinson’s disease. Mov Disord 2003;18:287-293. 86. Nieves AV, Lang AE. Treatment of excessive daytime sleepiness in patients with Parkinson’s disease with modafinil. Clin Neuropharmacol 2002;25:111-114. 87. Happe S, Pirker W, Sauter C, et al. Successful treatment of excessive daytime sleepiness in Parkinson’s disease with modafinil. J Neurol 2001;248:632-634. 88. Hogl B, Saletu M, Brandauer E, et al. Modafinil for the treatment of daytime sleepiness in Parkinson’s disease: a double-blind, randomized, cross-over, placebo-controlled polygraphic trial. Sleep 2002;25:905-909. 89. Zifko UA, Rupp M, Schwarz S, et al. Modafinil in treatment of fatigue in multiple sclerosis. Results of an open-label study. J Neurol 2002;249:983-987. 90. Rammohan KW, Rosenberg JH, Lynn DJ, et al. Efficacy and safety of modafinil (Provigil) for the treatment of fatigue in multiple sclerosis: a two centre phase 2 study. J Neurol Neurosurg Psychiatry 2002;72:179-183. 91. Feldman NT, Schwartz JRL, Harsh J. Effect of Provigil (modafinil) on the quality of life and mood of patients who previously received unsatisfactory treatment with dextroamphetamine, methylphenidate, or pemoline for excessive daytime sleepiness associated with narcolepsy [abstract]. Sleep 2000;23(Suppl. 2):A307. 92. Stankoff B, Waubant E, Confavreux C, et al. Modafinil for fatigue in MS: a randomized placebo-controlled double-blind study. Neurology 2005;64:1139-1143. 93. Carrieri PB, de Leva MF, Carrieri M, et al. Modafinil improves primary nocturnal enuresis in multiple sclerosis. Eur J Neurol 2007;14:e1. 94. Smith PE, Edwards RH, Calverley PM. Oxygen treatment of sleep hypoxemia in Duchenne muscular dystrophy. Thorax 1989;44: 997-1001. 95. Smith PE, Edwards RH, Calverley PM. Protriptyline treatment of sleep hypoxemia in Duchenne muscular dystrophy. Thorax 1989;44:1002-1005. 96. Simons AK, Parker RA, Branthwaite MA. Effects of protriptyline on sleep related disturbance of breathing in restrictive chest wall disease. Thorax 1986;41:586-590. 97. Olsen LG, Hensley MJ, Saunders NA, et al. Sleep breathing and lung disease. In: Saunders NA, Sullivan CE, editors. Sleep and breathing. New York: Marcel Dekker; 1984. p. 517-558. 98. Cao M, Guilleminault C. Pediatric sleep disorders: how can sleep medicine make a difference. Sleep Med Rev 2009;13(2):107-110. 99. Alves R, Resende M, Skomro R, et al. Sleep and neuromuscular disorders in children. Sleep Med Rev 2009;13(2):133-148. 100. Pinto AC, Avangelista T, Carvalho M, et al. Respiratory assistance with a non-invasive ventilator (BiPAP) in MND/ALS patients: survival rates in a controlled trial. J Neurol Sci 1995;129(Suppl.): 19-26. 101. Bourke SC, Tomlinson M, Williams TL, et al. Effects of noninvasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol 2006;5:140-147. 102. Abboussouan LS, Khan SU, Meeker DP, et al. Effect of noninvasive positive-pressure ventilation on survival in amyotrophic lateral sclerosis. Ann Intern Med 1997;127:450-453. 103. Kleopa KA, Sherman M, Neal B, et al. BiPAP improves survival and rate of pulmonary function decline in patients with ALS. J Neurol Sci 1999;164:82-88. 104. Nugent AM, Smith IE, Shneerson JM. Domiciliary-assisted ventilation in patients with myotonic dystrophy. Chest 2002;121:459-464.
105. Gonzalez C, Ferris G, Diaz J, et al. Kyphoscoliotic ventilatory insufficiency: effects of long-term intermittent positive-pressure ventilation. Chest 2003;124:857-862. 106. Farrero E, Prats E, Povedano M, et al. Survival in amyotrophic lateral sclerosis with home mechanical ventilation: the impact of systematic respiratory assessment and bulbar involvement. Chest 2005;127:2132-2138. 107. Young HK, Lowe A, Fitzgerald DA, et al. Outcome of noninvasive ventilation in children with neuromuscular disease. Neurology 2007;68:198-201. 108. Bach JR. A comparison of long-term ventilatory support alternatives from the perspective of the patient and care giver. Chest 1993;104:1702-1706. 109. Bach JR, Intintola P, Alba AS, et al. The ventilator-assisted individual: cost analysis of institutionalization vs rehabilitation and in-home management. Chest 1992;101:26-30. 110. Kerby GR, Mayer LS, Pingleton SK. Nocturnal positive pressure ventilation via nasal mask. Am Rev Respir Dis 1987;135:738-740. 111. Segall D. Noninvasive nasal mask-assisted ventilation in respiratory failure of Duchenne muscular dystrophy. Chest 1988;93:1298-1300. 112. Ellis ER, Grunstein RR, Chan S, et al. Noninvasive ventilatory support during sleep improves respiratory failure in kyphoscoliosis. Chest 1988;94:811-815. 113. Rodenstein DO, Stanescu DC, Delguste P, et al. Adaptation to intermittent positive pressure ventilation applied through the nose during day and night. Eur Respir J 1989;2:473-478. 114. Bach JR, Alba AS, Shin D. Management alternatives for post-polio respiratory insufficiency: assisted ventilation by nasal or oral-nasal interface. Am J Phys Med Rehabil 1989;68:264-271. 115. Heckmatt JZ, Loh L, Dubowitz V. Night-time nasal ventilation in neuromuscular disease. Lancet 1990;335:579-581.
CHAPTER 89 • Sleep and Neuromuscular Diseases 1025 116. Barbe F, Quera-Salva MA, de Lattre J, et al. Long-term effects of nasal intermittent positive pressure ventilation on pulmonary function and sleep architecture in patients with neuromuscular diseases. Chest 1996;110:1179-1183. 117. Bonekat HW. Noninvasive ventilation in neuromuscular disease. Crit Care Clin 1998;14:775-797. 118. Laub M, Midgren B. Survival of patients on home mechanical ventilation: a nationwide prospective study. Respir Med 2007;101: 1074-1078. 119. Fanfulla F, Delmastro M, Berardinelli A, et al. Effects of different ventilator settings on sleep and inspiratory effort in patients with neuromuscular disease. Am J Respir Crit Care Med 2005;172: 619-624. 120. Ambrogio C, Lowman X, Kuo M, et al. Sleep and non-invasive ventilation in patients with chronic respiratory insufficiency. Intensive Care Med 2008;35:306-313. 121. Storre JH, Seuthe B, Fiechter R, et al. Average volume-assured pressure support in obesity hypoventilation: a randomized crossover trial. Chest 2006;130(3):815-821. 122. Shneerson JM, Simonds AK. Noninvasive ventilation for chest wall and neuromuscular disorders. Eur Respir J 2002;20:480-487. 123. Goldberg A (conference facilitator). Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD, and nocturnal hypoventilation: a consensus conference report. Chest 1999;116:521-534. 124. Simonds AK. Recent advances in respiratory care for neuromuscular disorders. Chest 2006;130:1879-1886. 125. Arens R, Muzumdar H. Sleep, sleep disordered breathing, and nocturnal hypoventilation in children with neuromuscular diseases. Paediatr Respir Rev 2010;11:24-30.
Restless Legs Syndrome and Periodic Limb Movements during Sleep
Jacques Montplaisir, Richard P. Allen, Arthur Walters, Luigi Ferini-Strambi Abstract The restless legs syndrome (RLS) is a neurologic condition characterized by an urge to move, usually associated with paresthesia, that occurs or worsens at rest and is relieved by activity. One of the central characteristics of RLS is the worsening of symptoms in the evening and during the night. Several studies have shown that the severity of leg discomfort follow a circadian rhythm, with the maximum occurring after midnight. The symptoms of RLS have a major impact on nocturnal sleep and daytime functioning. A majority of patients report difficulty falling asleep or waking up shortly after sleep onset with unpleasant leg sensations. They also often experience excessive daytime fatigue and somnolence, probably as a consequence of disrupted nocturnal sleep. Although RLS is usually thought to be a condition of adulthood, it is often reported in children, in whom it could be misdiagnosed as growing pains or attention-deficit/hyperactivity disorder. RLS
DESCRIPTION AND EPIDEMIOLOGY Sensory and Motor Manifestations The restless legs syndrome (RLS) has been described for centuries but only in 1945 was it singled out as a distinct clinical entity and named by the Swedish neurologist Carl Ekbom.1 Patients with RLS report an urge to move associated with dysesthesia when they are at rest.2 Patients use different terms to describe the dysesthesia. Some only say that the sensations are uncomfortable and unpleasant, and others use specific terms such as creepy-crawly, jittery, internal itch, or shocklike feelings; up to 50% of RLS patients describe their sensations as painful. Some people, however, describe only an urge to move, and they are unaware of a sensory component. Symptoms are usually felt over large areas of the thighs or calves (or both) and are usually experienced as coming from deep within the legs rather than as superficial. Although it is called restless legs syndrome, the disorder can also involve the arms and other body parts. Michaud and colleagues3 showed that almost 50% of RLS patients have symptoms in the arms. Symptoms in the legs usually precede involvement of the arms by several years. Arm paresthesias have been associated with a higher severity of the disorder. The involvement of the arms without any involvement in the legs rarely occurs. The second clinical characteristic of RLS is that the urge to move or the unpleasant leg sensation begins or worsens during periods of rest or inactivity such as lying down or sitting (Videos 90-1 to 90-3).2 Typically, patients describe exacerbation of symptoms in situations such as watching television, driving or flying long distances, or attending meetings. Symptoms also worsen in association with a decrease in central nervous system (CNS) activity that leads to a decrease in alertness. 1026
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has been related to several other medical conditions, especially uremia, anemia, and neuropathies. Several epidemiologic studies have shown that the prevalence of RLS symptoms in the white population is probably around 10% and that approximately 3% can be considered RLS sufferers with moderate to severe symptoms associated with significant impact on daytime functioning. There is substantial evidence for a genetic contribution to RLS. There are major controversies regarding the localization of the neural substrate involved in the pathophysiology of RLS. There is increasing evidence for the presence of brain iron deficiency in patients with RLS. As far as treatment is concerned, four categories of medication are commonly prescribed to treat RLS: dopaminergic agents, opioids, anticonvulsants, and benzodiazepines. Because they are more effective and produce fewer adverse effects, dopaminergic agonists are now considered the firstline treatment.
The urge to move and the unpleasant leg sensations are relieved by activity.2 Patients use different motor strategies to relieve the discomfort. When symptoms occur, they move their legs vigorously, flexing, stretching, or crossing them one over the other. In severe cases, they might walk around for hours in the evening or during the night to relieve the discomfort. The relief is generally described as beginning immediately or soon after the activity begins and this relief usually persists as long as the activity continues. In a majority of patients the relief is complete but patients with severe RLS report that movements do not completely suppress the sensations. When the RLS is so severe that relief with movement does not occur, patients recall that earlier in the course of their disease they were able to obtain relief with movements. In severe cases, symptoms can recur rapidly after the cessation of walking or activity, whereas patients with less-severe symptoms can remain symptom-free for 30 to 60 minutes. One of the central characteristics of RLS is the worsening of symptoms in the evening or during the night.2 Several factors can contribute to the worsening of RLS symptoms at that time. One factor is the increase of sleepiness in the evening compared to the daytime. Another contributing factor is the decrease of motor activity in the evening compared to the daytime.3 A third factor could be that the worsening of symptoms is the manifestation of an intrinsic circadian rhythm in RLS symptoms. Three studies used modified constant routine protocols to investigate the circadian pattern in the occurrence of RLS symptoms.4-6 These studies showed that the severity of leg discomfort followed a circadian rhythm, with a maximum occurring after midnight. The circadian rhythm of RLS symptoms was significantly correlated with that of subjective vigilance, core body temperature, and salivary melatonin secretion. Among these variables, the changes in melatonin
CHAPTER 90 • Restless Legs Syndrome and Periodic Limb Movements during Sleep 1027
secretion were the only ones that preceded the increase in sensory or motor symptoms of RLS and might therefore have a causal relationship with the expression of RLS symptoms.
starts during pregnancy it eventually becomes persistent later in life. Positive family history is common in women who develop RLS during pregnancy, which suggests that pregnancy facilitates the expression of RLS rather than causes it.
Nocturnal Sleep and Daytime Vigilance A majority of RLS patients complain of poor sleep. In a study of 133 patients, a large majority of RLS patients (84.7%) often experienced difficulty falling asleep at night because of RLS, and 86% reported that symptoms woke them up frequently during the night.7 Ninety-four percent reported at least one of these two manifestations. Sleep laboratory investigations showed that as a group, RLS patients have severe nocturnal sleep disruption compared to normal controls, including longer sleep latency, reduced sleep efficiency, and total sleep time. A great majority of patients with RLS also experience stereotyped repetitive movements once asleep, a condition known as periodic limb movements during sleep (PLMS). Some patients (46.2% of men and 22.2% of women) also report excessive daytime fatigue or somnolence,7 probably as a consequence of disrupted nocturnal sleep. On the other hand, it is surprising to find a large number of patients who do not experience fatigue and are fully alert during the day in spite of severe and chronic sleep deprivation. One study has suggested that RLS patients have an increased level of hypocretin in the CNS, which would counteract the effects of poor sleep and sleep deprivation.8
Epidemiology Lavigne and Montplaisir14 reported, in a population-based survey of 2019 Canadians, that 15% of subjects reported delayed sleep onset with “restlessness in legs” and 10% reported “unpleasant leg sensations” on awakening from sleep. The percentages were substantially greater for the Francophone than the Anglophone Canadians, suggesting a genetic effect. More recently, several large epidemiologic surveys estimated that the true prevalence of RLS is approximately 5% to 10%, making it the most common movement disorder and among the most common sleeprelated disorders.15 RLS increases in prevalence with age. Most studies also showed9,16 notable gender differences, the prevalence for women being approximately twice that for men. An RLS screening questionnaire was completed by 23,052 patients from the United States, France, Germany, Spain and the United Kingdom,17 and 2223 (9.6%) reported weekly RLS symptoms. An RLS sufferer subgroup (3.4%) likely requiring treatment was defined as subjects reporting symptoms that occurred at least twice weekly and that had appreciable negative impact on their quality of life.
Burden of the Illness The effect of RLS on quality of life depends on its severity. One population-based study showed that for subjects with moderate to severe RLS, the SF-36 dimensions of vitality, role physical, pain, physical functioning, and general health were markedly reduced compared to population norms. Also reduced but to a smaller degree were the remaining dimensions of social functioning, role emotional, and mental health.9 The moderate to severe RLS symptoms are associated with disruption in quality of life that is at least as great as the disruption caused by other chronic medical conditions such as diabetes mellitus, depression, osteoarthritis, or hypertension.9 RLS patients also show disruption of cognitive function involving mostly prefrontal cognitive tasks that are known to be sensitive to sleep loss.10
DIAGNOSIS Clinical Diagnosis The diagnosis of RLS is based on the clinical evaluation of the patient. In 1995, a consensus emerged from a large international RLS study group (IRLSSG) about the four essential criteria for the diagnosis of RLS. These criteria were revised at a National Institutes of Health RLS workshop. The final formulation of the new RLS diagnostic criteria is published in Sleep Medicine.2 These criteria are listed in Box 90-1. In addition to these essential criteria, there are supportive clinical features that are not essential but can help resolve diagnostic uncertainty. The features include a positive family history of RLS and a positive therapeutic response to dopaminergic medications.
Clinical Course RLS is thought to be a condition of middle-aged persons, but there is increasing evidence that RLS might start at an earlier age. Familial cases of RLS have an earlier age of onset, typically before the age of 30 years.11,12 Earlyonset RLS was also associated with increased severity of RLS.13 The intensity of sensory and motor symptoms varies greatly from one case to another; it also fluctuates throughout a patient’s lifetime. Sudden remissions, lasting for months or even years, are as difficult to explain as are relapses, which appear without any apparent reason. In severe cases, symptoms are present every night, and in most patients, symptom severity increases with advancing age. In women, RLS often appears for the first time during pregnancy.13 In some cases, RLS is present only during pregnancy, but in some cases where RLS originally
Sleep Laboratory Diagnosis Originally called “nocturnal myoclonus,” periodic limb movements (PLMs) are best described as rhythmic extensions of the big toe and dorsiflexions of the ankle, with occasional flexions of the knee and hip. Methods for recording and scoring PLMS were summarized by Coleman18 and recently revised by a joint task force of the World Association of Sleep Medicine and the International RLS Study Group (IRLSSG).19 According to standard criteria, PLMs are scored only if they are part of a series of four or more consecutive movements lasting 0.5 to 10 seconds with an intermovement interval of 5 to 90 seconds and amplitude greater than 8 mV above the baseline electromyograph (EMG) signal. A PLMS index (number of PLMs per hour of sleep) greater than 5 for the entire night of sleep was considered pathologic18 and can
1028 PART II / Section 11 • Neurologic Disorders Box 90-1 Diagnostic Criteria Established by the International Restless Legs Syndrome Study Group Essential Features • An urge to move the legs, usually accompanied by or caused by uncomfortable and unpleasant sensations in the legs. Sometimes the urge to move is present without the uncomfortable sensation, and sometimes the arms or other body parts are involved in addition to the legs. • The urge to move or unpleasant sensations begin or worsen during periods of rest or inactivity such as lying down or sitting. • The urge to move or unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues. • The urge to move or unpleasant sensations are worse in evening or night than during the day, or they only occur in the evening or night. When symptoms are very severe, the worsening at night might not be noticeable but must have been previously present. Nonessential but Common Features • Family history: The prevalence of RLS among firstdegree relatives of people with RLS is three to five times greater than in people without RLS. • Response to dopaminergic therapy • Periodic leg movements during sleep (PLMS) or during wakefulness (PLMW). • Natural clinical course: may begin at any age, but most severely affected patients are middle-aged or older. The course is usually progressive, but a static course or remission can occur. • Sleep disturbance • Medical evaluation and physical examination: No abnormalities in the primary form, but in the secondary form, signs of a peripheral neuropathy or radiculopathy may be present. Iron status should be evaluated because decreased iron stores are a significant potential risk factor that can be treated. RLS, restless legs syndrome.
still be used for younger persons, but an index greater than 15 is now often used as a cutoff for older subjects. The number of PLMs varies from night to night, especially in persons with less-severe sleep complaints. PLMs cluster into episodes, each of which lasts several minutes or even hours. In general, these episodes are more numerous in the first half of the night, but they can also recur throughout the entire sleep period. Diagnostic polysomnography always includes central electroencephalography (EEG), electrooculography (EOG), submental EMG, and bilateral EMG of the anterior tibialis muscles. The electrographic picture of a single movement can vary from one sustained contraction to a polyclonic burst with a frequency of approximately 5 Hz. In RLS patients, approximately one third of all PLMS are associated with EEG signs of arousal.20 Movements can be seen on video (Videos 90-4 to 90-10). Regardless of the presence of EEG arousals, almost every PLM is associated with a tachycardia (decreased of R-R intervals for 5 to 10 beats) followed by a bradycardia.20
In addition, continuous monitoring of systolic and diastolic blood pressure reveals significant increases in association with PLMS (on average, 22 mm Hg and 11 mm Hg) (Fig. 90-1).21 These changes were greater in older patients and when PLMs were associated with microarousals. Because RLS patients can have several hundred PLMs every night, PLMS-related blood pressure fluctuations could contribute to the increased risk of cardiovascular diseases in RLS, as reported in two large epidemiologic studies, the Wisconsin Sleep Cohort22 and the Sleep Heart Health Study.23 PLMs were first polygraphically documented in RLS.24 However, PLMs also occur in a wide range of sleep disorders, including narcolepsy, REM sleep behavior disorder, obstructive sleep apnea syndrome (OSAS), insomnia, and hypersomnia. PLMs were also reported in subjects without any sleep complaint, and although they are rare in young persons, they are relatively common in the elderly.25 PLMS in patients who complain of primary sleep-onset or sleep-maintenance insomnia or of primary hypersomnia are called periodic limb movement disorder (PLMD). The basic assumption is that PLMs are responsible for nonrestorative sleep and daytime somnolence reported by these patients. Although some studies have suggested that PLMs may be associated with sleep–wake complaints, most authors have concluded that PLMs have little impact on nocturnal sleep or daytime vigilance.26-29 The same conclusion arises when one considers not only PLMs alone but also PLMs associated with arousals. Although there are major controversies with regard to the functional significance of PLMs, their quantification is a commonly used sleep laboratory diagnostic procedure for RLS. In a recent study of 100 RLS patients and 50 normal controls,30 84% of patients showed a PLMS index greater than 5 and 70% showed an index greater than 10 compared to 36% and 18%, respectively, for the controls. Suggested Immobilization Test A test called the suggested immobilization test (SIT) was designed to quantify both sensory and motor manifestations of RLS in wakefulness.30 During the test, patients remain in bed, reclined at 45-degree angle with their legs outstretched and eyes open. They are instructed to avoid moving voluntarily for the entire duration of the test, which is designed to last an hour and takes place in the evening before bedtime at night (Video 90-12). Surface EMGs from the right and left anterior tibialis are used to quantify leg movements. In addition, every 5 minutes during the test, the patient has to estimate the level of leg discomfort on a scale of 100. Twelve values are obtained (every 5 min for 60 min). The mean leg discomfort score (MDS) represents the average value of these 12 measures. An MDS of 11 has been found to discriminate RLS patients from controls with a sensitivity of 82% and a specificity of 84%. The SIT-PLM index was found less sensitive than the MDS and showed test-to-test variability when the SIT was repeated.31 Severity Assessments The IRLSSG has developed a 10-point scale to measure RLS severity (Box 90-2). This scale has been validated32 by comparing it with independent clinician ratings in a large
CHAPTER 90 • Restless Legs Syndrome and Periodic Limb Movements during Sleep 1029
EEG
ECG
LAT
RAT
BP
Figure 90-1 Polysomnogram of a patient with restless legs syndrome and periodic limb movements in sleep. The figure shows the periodicity of leg movements and reveals significant increases in blood pressure associated with every periodic limb movement. BP, blood pressure; ECG, electrocardiogram; EEG, left central electroencephalogram; LAT, left anterior tibialis electromyogram; RAT, right anterior tibialis electromyogram.
multicenter study. This scale is now largely used in clinical trials to assess the outcome of pharmacologic treatments. Other clinical scales have been used such as the Johns Hopkins RLS Severity scale, which focuses on the usual time at which the symptoms start to occur. It is assumed that the time of onset of symptoms indicates the length of time in a day for which the patient is likely to have RLS symptoms.15 This scale was found to correlate with both PLMS and sleep efficiency. PLMS and PLMW have also been shown to be correlated with subjective RLS severity.15
RESTLESS LEGS SYNDROME IN CHILDHOOD Diagnostic Criteria Although RLS and PLMS are generally thought to be conditions of adulthood, they have been reported in children (Video 90-11).33-35 Special criteria for the diagnosis of RLS were established for children at a National Institutes of Health consensus conference on RLS.2 For a diagnosis of definite RLS, children must meet all four of the diagnostic criteria established for adults and either the child must be able to describe the leg discomfort in his or her own words, or the child must have two of the three following features: sleep disturbance for age, a PLMS index greater than 5/hour of sleep, or a biological parent or sibling with definite RLS. As in adults with RLS, children with RLS respond to dopaminergic therapy, but controlled studies are lacking.35 Prevalence In one of the early studies of the prevalence of RLS in childhood, consistent leg restlessness was found in 6.1% of 1353 children aged 11 to 13 years over a 3-year period.36 Retrospective studies of RLS symptoms in two separate
series of adults found that 12% to 20% recalled symptom onset before the age of 10 years and 38.3% to 45% before the age of 20 years.7,37 In the vast majority of childhood cases, symptoms are mild and medical attention is not usually sought. A recent large epidemiological study of 10,523 families in the United States. and Great Britain (the Peds REST study) found 1.9% of 8- to 11-year-olds and 2% of 12- to 17-year-olds met criteria for RLS. Moderately or severely distressing RLS symptoms occurred at least twice per week in 0.5% and 1% of these age groups, respectively.38 A close connection was found between growing pains and RLS. The prevalence of children who had growing pains of any frequency was 80.6% in RLS subjects versus 63.2% in non-RLS subjects in the Peds REST study (P < .001).38 Relationship to Attention-Deficit/ Hyperactivity Disorder Much recent literature has focused upon the possible relationship among RLS, PLMS, and ADHD. A large metaanalysis of several studies has confirmed the intimate relationship between PLMS and ADHD.39 In two different series, 26% to 64% of children with ADHD had a PLMS index greater than 5 per hour of sleep.40,41 In these series, children with both ADHD and a PLMS index greater than 5 per hour of sleep had increased incidence of both personal and family history of RLS.40,41 Not only do children with ADHD have more PLMS and RLS,42 but children with PLMS have more ADHD. Approximately 44% of children with PLMS have been found to have symptoms of ADHD.43 These data suggest a possible genetic link between RLS or PLMS and ADHD. A link between ADHD and RLS or PLMS is further suggested by data implying that dopaminergic agents improve not only the RLS or PLMS symptoms but also the ADHD symptoms in children with both RLS and
1030 PART II / Section 11 • Neurologic Disorders Box 90-2 International Restless Legs Syndrome Study Group Rating Scale 1. Overall, how would you rate the RLS discomfort in your legs or arms? Very severe, 4; Severe, 3; Moderate, 2; Mild, 1; None, 0 2. Overall, how would you rate the need to move around because of your RLS symptoms? Very severe, 4; Severe, 3; Moderate, 2; Mild, 1; None, 0 3. Overall, how much relief of your RLS arm or leg discomfort do you get from moving around? No relief, 4; Slight relief, 3; Moderate relief, 2; Complete or almost complete relief, 1; No RLS symptoms, 0 4. Overall, how severe is your sleep disturbance from your RLS symptoms? Very severe, 4; Severe, 3; Moderate, 2; Mild, 1; None, 0 5. How severe is your tiredness or sleepiness from your RLS symptoms Very severe, 4; Severe, 3; Moderate, 2; Mild, 1; None, 0 6. Overall, how severe is your RLS as a whole? Very severe, 4; Severe, 3; Moderate, 2; Mild, 1; None, 0 7. How often do you get RLS symptoms? Very often, 4; Often, 3; Sometimes, 2; Occasionally, 1; Never, 0 8. When you have RLS symptoms, how severe are they on an average day? Very severe, 4; Severe, 3; Moderate, 2; Mild, 1; None, 0 9. Overall, how severe is the impact of your RLS symptoms on your ability to carry out your daily affairs, for example carrying out a satisfactory family, home, social, school or work life? Very severe, 4; Severe, 3; Moderate, 2; Mild, 1; None, 0 10. How severe is your mood disturbance from your RLS symptoms—for example angry, depressed, sad, anxious or irritable? Very severe, 4; Severe, 3; Moderate, 2; Mild, 1; None, 0 In the full version of the scale, each of the choices for question 7 has an operational definition.
PLMS.44 ADHD itself has now been independently linked to iron deficiency because patients with ADHD have statistically significantly lower serum ferritin levels than controls.45 ADHD is also responsive to iron therapy.46 These data further tighten the link between RLS and ADHD.
SECONDARY RESTLESS LEGS SYNDROME RLS and PLMS have been related to several other medical conditions but in only a few cases was the association with RLS well documented. Uremia RLS is often associated with uremia, and 15% to 40% of patients under hemodialysis do actually complain of RLS symptoms. Several factors can predispose uremic patients
to develop RLS, including anemia and peripheral neuropathy. The presence of RLS relates to increased mortality rate in patients with end-stage renal disease.47 Symptoms of RLS were found to resolve after successful kidney transplantation.48 Neuropathies There is some evidence suggesting an association between RLS and peripheral neuropathy, but the extent of this association remains a controversial issue. In 1996, Ondo and Jankovic49 performed EMG and nerve conduction velocities in 41 RLS patients, 15 of which were abnormal. Of the 15 neuropathic RLS patients, only seven showed clinical signs of neuropathy. One argument in favor of a causal relationship is the lower prevalence of family history of RLS among those with neuropathic RLS compared to nonneuropathic RLS. Another study,50 in which a thorough neurologic examination was performed, found polyneuropathy in 8 out of 22 (36%) RLS patients. The neuropathic patients in this study had an older age of onset and reported sensory symptoms usually involving pain. In a third study, axonal atrophy was found by sural nerve biopsy performed in eight RLS patients.51 All these studies suggest that in a significant number of RLS patients, neuropathy may be involved. On the other hand, RLS was found in only 5.2% of 144 patients with a clinical diagnosis of polyneuropathy,52 a prevalence not higher than the prevalence found in the general population. Anemia RLS has been reported in association with iron deficiency anemia and folic acid deficiency anemia. Iron status has been extensively studied and evidence has been found that iron deficiency in the CNS may be involved in primary RLS, even in patients without anemia. Others RLS is common in Crohn’s disease and celiac disease.52a,52b RLS was found in 31% of 135 consecutive patients with fibromyalgia53 and in 30% of 70 patients with rheumatoid arthritis.54 RLS has also been reported anecdotally in association with a wide variety of other medical conditions including diabetes, hypothyroidism and hyperthyroidism, chronic lung disease, leukemia, Isaac’s syndrome, stiff-man syndrome, Huntington’s chorea, and amyotrophic lateral sclerosis. Considering the high prevalence of RLS and PLMS in the general population, these associations found in a limited number of patients should be interpreted with caution. Several substances or medications can induce or worsen RLS or PLMS. These include tricyclic or other antidepressants, lithium carbonate, dopamine D2 receptorblocking agents, such as classic neuroleptics, and centrally active antihistamines and alcohol.
MEDICAL INVESTIGATION RLS and PLMS should be differentiated from other state-dependent sensorimotor disorders, such as positional discomfort, hypnic myoclonus, painful legs and moving toes syndrome, nocturnal leg cramps, neurolepticinduced akathisia, and vascular or neurogenic intermittent
CHAPTER 90 • Restless Legs Syndrome and Periodic Limb Movements during Sleep 1031
claudication. Whenever the diagnosis is doubtful, a PSG recording should be performed. Two consecutive nights of PSG are recommended. Because the PLMS index shows night-to-night variability, caution should be taken in drawing conclusions from single-night studies. Because a significant number of RLS patients have peripheral neuropathy,49,50 a careful clinical examination of sensory and motor functions should be performed. EMG and nerveconduction studies should be done if the examination suggests a peripheral neuropathy or radiculopathy. Given the aforementioned associations between anemia or iron deficiency, iron status should be studied in every patient. Iron deficiency cannot be determined by history and can occur with normal hemoglobin. Because iron deficiency is usually treatable and because when present it exacerbates or even causes RLS, standard serum tests for ferritin, total iron-binding capacity, and percent saturation should be considered essential to the medical evaluation of RLS. When these levels are abnormal, further medical evaluation is recommended to determine any possible cause, usually involving blood loss. For example, RLS was found much more commonly in blood donors than in the general population, especially for women donors55 and repeat blood donors.56,56a The diet can also be accountable and should be inquired about. In a study on strict vegetarians and vegans, 40% of women younger than 50 years were found to be iron deficient.57
ETIOLOGY AND PHYSIOPATHOLOGY Genetics There is substantial evidence for a genetic contribution to RLS. Familial aggregation has been well documented with more than 50% of idiopathic cases reporting a positive family history of RLS.1,2,7,11,37,57a In most pedigrees, it segregates in an autosomal dominant fashion, with a high penetrance rate (90% to 100%).11 Seven loci for RLS on chromosomes 12q, 14q, 9p, 2q, 20p, 19p, and 16p (RLS1-RLS7) have been mapped in RLS families (for review, see references 58 and 59) supporting the view that RLS is a genetically heterogeneous complex trait. Genetic heterogeneity was somewhat predictable given the high prevalence of the disease and the reported variability in clinical presentation. Association studies have also looked at candidate genes for RLS. Genes related to dopaminergic transmission (D1 to D5 receptors, tyrosine hydroxylase, dopamine-b-hydroxylase) were first investigated, but no association was found.60 However, there was some evidence for a genetic association between the high-activity allele of monoamine oxidase A and a greater risk of being affected with RLS in women.61 A genome-wide association study of RLS identified common variants in three genomic regions: MEIS1, BTBD9, and MAP2K5 on chromosomes 2p, 6p, and 15q, respectively. Each genetic variant was associated with more than 50% increase in risk for RLS, with the combined allelic variants conferring more than half of the risk.62 MEIS1 has been implicated in limb development, raising the possibility that RLS has components of a developmental disorder. A genome-wide significant association with a common variant in an intron of BTBD9 on chromosome
6p was found independently in the Icelandic population.63 An association between this variant and PLMS without RLS (and the absence of such an association for RLS without PLMS) suggests that it is a genetic determinant of PLMS. These authors found an inverse correlation of the variant with iron stores, which is consistent with the suspected involvement of iron depletion in RLS and PLMS. Neural Substrates There are major controversies with regard to the localization of the neural structures involved in the physiopathology of RLS. There is some evidence of a peripheral origin of RLS. Nerve-conduction abnormalities and small neuropathy were found in a subset of RLS patients, but these abnormal findings were noted in a small subset of patients with secondary RLS, more often in sporadic RLS than in familial RLS and more often in late-onset rather than early-onset RLS. There is most likely a major contribution of the spinal cord to RLS. PLM during sleep and wakefulness were also found in several persons with a spinal cord lesion and even in cases of complete spinal cord transection.64,65 A facilitation of the late component of the flexion reflex indicating a hyperexcitability of motor neurons was found in this condition.66 The late components shared several features with PLMS. This spinal cord generator may be facilitated by the suppression or the decrease of supraspinal inhibitory inputs. On the other hand, an additional long latency component of the blink reflex has been reported in some patients with PLMS.67 This symptom, although not found in every patient, could indicate that PLMS is operative at the pontine level or more rostrally. A study using magnetic resonance imaging (MRI) found no anatomic lesion in patients with RLS.68 However, functional MRI showed that leg-related sensory complaints in RLS were associated with thalamic and cerebellar activation, and periodic leg movements in wakefulness were more closely associated with pontine and red nucleus activation. In neither case was any cortical activation found. The study of 18 patients by transcranial magnetic stimulation also supports a subcortical origin of RLS.69 Neurotransmitter Dysfunctions The therapeutic effects of l-dopa and dopamine agonists on RLS and PLMS support the hypothesis that central dopamine may be involved in the pathophysiology of these conditions. Dopamine antagonists generally make RLS symptoms worse, and in one study they precipitated an increase in PLMW in all but one of the patients evaluated.70 Brain-imaging studies have been inconsistent. Two positron emission tomography (PET) studies with adequate sample sizes showed different results: small but significant decreased striatal binding for raclopride71 and small but statistically significant increased striatal binding for raclopride.72 No differences were found between daytime and nighttime binding, suggesting that variations in D2-receptor availability do not account for the pronounced diurnal nature of the RLS symptoms. Two of three single-photon emission computed tomography (SPECT) studies comparing patients with RLS with age-matched control
1032 PART II / Section 11 • Neurologic Disorders
subjects failed to find a significant difference,73,74 whereas one study (the only one performed in early evening) reported less binding to D2 receptors for the patients with RLS.75 These studies also looked at binding for the dopamine transporter and failed to find any significant difference between patients with RLS and control subjects. In contrast, two 6-[18F] fluoro-l-dopa PET studies reported small decreases in binding for patients with RLS.71,76 There have been two cerebrospinal fluid (CSF) studies on series of patients with RLS compared with control subjects; both failed to find any significant difference for either homovanillic acid or biopterin that was unrelated to age.77,78 A more-recent report, however, notes that in two different studies with CSF obtained at different times of the day (10 pm and 10 am), there were significant increases in 3-ortho-methyldopa that in one of the samples correlated with increased CSF homovanillic acid.79 This suggests a possible increase in dopaminergic activity. Overall, aside from the remarkable pharmacologic response to dopaminergic medications and the one CSF finding regarding 3-ortho-methyldopa increases, there is scant consistent evidence supporting any significant dopaminergic abnormality in RLS. The positive pharmacologic response to opioid treatment in RLS and the reversal of that treatment with the opiate receptor blocker naloxone has also been used as an argument in favor of the hypothesis of an endogenous opiate system dysfunction in RLS and PLMS.80 However, pharmacologic data suggest that the effect of l-dopa is not secondary to the action of dopamine on the opioid system, but rather the reverse. An opiate receptor PET scan study showed no difference in postsynaptic opiate receptor binding between RLS patients and controls, but there was an inverse correlation between the degree of opiate receptor binding and the severity of RLS.81 A preliminary autopsy study showed decreased levels of the endogenous opioids beta endorphin and met-enkephalin in RLS patients compared to controls.82 Hypocretin (orexin) has been reported to be increased in the CSF of early-onset RLS patients.83 Hypocretin arousal is largely mediated by histamine, and it was found that RLS symptoms can be severely exacerbated by antihistamines,84 suggesting a histaminergic abnormality that might be related to increased hypocretin. Iron Ekbom was among the first to note that RLS commonly occurs with iron-deficiency anemia.85 In addition to irondeficiency anemia, end-stage renal disease, pregnancy, low-density lipoprotein apheresis, and gastric surgery have been clearly established as causes of secondary RLS. All of these conditions involve iron deficiency. Treatment of iron-deficiency anemia can completely resolve all RLS symptoms for some patients.86-88 One study showed no significant differences in serum ferritin or iron, but the CSF ferritin was reduced and transferrin was increased, consistent with a CNS iron deficiency occurring despite apparently normal peripheral iron status.89 MRI and ultrasound studies of regional brain iron content have consistently shown reduced brain iron, particularly in the substantia nigra for subjects with RLS
compared with age-matched control subjects.90-92 Autopsy analyses of substantia nigra tissue from patients with RLS compared with age-matched control subjects have revealed a complex pattern of iron-related abnormalities.93 These data suggest that RLS involves an iron deficiency in the substantia nigra that may be associated with an abnormality in the regulation of the transferrin receptor. These findings, combined with the success of intravenous iron treatments, support the putative concept that a brain iron deficiency causes RLS in many patients. Of interest is the role of iron in dopaminergic transmission in the CNS. Iron deficiency is associated with increased extracellular dopamine, decreased dopamine transporter, and decreased D2 and D1 receptors in the striatum of rats. Thus abnormalities in iron metabolism or environmental factors producing brain iron deficiency may be a primary cause of RLS symptoms or they may be factors contributing to the development of RLS.
TREATMENT Nonpharmacologic It is important to inform patients to maintain good sleep hygiene to prevent the development of psychophysiologic insomnia, which is frequently encountered in RLS. Patients should also refrain from drinking alcohol in the evening because it aggravates symptoms in most patients. Some patients report that they alter their sleep patterns to accommodate their RLS.94 Pharmacologic Four categories of medications are commonly prescribed to treat RLS: dopaminergic agents, opioids, anticonvulsants, and benzodiazepines. Dopaminergic Medications L EVODOPA Several open-label and placebo-controlled studies documented the short-term efficacy and long-term benefit of levodopa, given with a dopa-decarboxylase inhibitor, either benserazide or carbidopa, in idiopathic RLS and RLS associated with uremia. Several adverse effects were reported in patients treated with levodopa, including nausea, vomiting, tachycardia, orthostatic hypotension, hallucinations, insomnia, daytime fatigue, and daytime sleepiness. Two adverse effects were more specifically studied in RLS patients treated with levodopa: morning rebound and RLS augmentation. Morning rebound is characterized by the presence of RLS symptoms occurring de novo as a consequence of evening or nighttime treatment. Augmentation95 is characterized by an earlier onset of symptoms by at least 4 hours or by an earlier onset between 2 and 4 hours plus at least one of the following compared to symptom status before treatment: shorter latency to symptoms when at rest, extension of symptoms to other body parts, greater intensity of symptoms, and shorter duration of relief from treatment. One group96 found augmentation in 29 of 36 (81%) patients treated with levodopa. Increased severity of RLS and higher dosage of levodopa were associated with higher risk of developing augmentation. Another recent study97 showed augmentation in 36 of 60 (60%)
CHAPTER 90 • Restless Legs Syndrome and Periodic Limb Movements during Sleep 1033
patients treated for 6 months with levodopa (median daily dose of 300 mg; range, 50 to 500 mg). Mild augmentation may be treated by earlier administration of the drug, but in severe cases the medication should be discontinued. D OPAMINE A GONISTS Because they are more effective and produce fewer adverse effects (especially augmentation), dopamine agonists are now considered the first-line treatment for RLS. Several agonists have been studied in RLS. Pergolide, a D2 receptor agonist, was found effective in short-term and longterm follow-up studies.98,99 In 28 patients treated for 416 days with pergolide, persistent efficacy was noted in 79% of patients, but adverse effects were noted in 71%, including augmentation in 27% of patients.99 Cabergoline, a long-acting D2 receptor agonist, was also used successfully to treat RLS.100 Like pergolide, cabergoline is an ergolinederivative drug; agonists of this class are associated with common adverse effects, especially nausea and orthostatic hypotension. Retroperitoneal and pleuropulmonary fibrosis are well known but rare complications of the treatment with ergolinic dopamine agonists. Some authors have shown that pergolide and cabergoline have a similar risk of inducing fibrotic changes in cardiac valve leaflets.101 Two non–ergoline-derivative agonists, pramipexole and ropinirole, were extensively studied for the treatment of RLS. Pramipexole, a full agonist with high affinity for the D3-receptor subtype, was found very effective in treating RLS and in suppressing PLMS in two double-blind, placebo-controlled studies.102,103 Several long-term follow-up studies of patients treated with pramipexole have shown sustained efficacy of pramipexole in more than 80% of patients.104-106 Augmentation was found in up to 32% of patients on long-term treatment with pramipexole.105 Ropinirole, a dopaminergic agonist with a pharmacologic profile similar to that of pramipexole, was also found effective to treat RLS in placebo-controlled studies.107,108 A long-term open-label study showed that ropinirole maintained the therapeutic efficacy in 82% of RLS patients.109 Like pramipexole, ropinirole is well tolerated and rarely requires the adjunctive use of domperidone. In RLS patients, sleepiness might be seen during treatment with dopamine agonists, but it is much less problematic than in Parkinson’s disease, and no cases of sudden onset of sleep have been reported.110 An exploratory survey study revealed that a small percentage of RLS patients treated with dopaminergic medications noted increased urges and time spent gambling and increased sexual desire,111 a side-effect of dopaminergic medications previously reported in Parkinson’s disease. A new dopamine agonist, rotigotine, has been studied in RLS.112 Transdermal 24-hour delivery of low-dose rotigotine may be used to relieve the nighttime and daytime symptoms of RLS. Skin reactions, mostly mild or moderate, are seen at the application site of the patch in about one third of patients. Opioids The therapeutic effects of opioids have been noted by Ekbom1 and were confirmed in several open-label and controlled clinical trials.94,113-115 A persistent effect of opioids was found in a long-term follow-up studies.114,115
Opioids are often prescribed for severe cases, especially in patients unresponsive to other treatments. Opioids are also very useful during withdrawal from dopaminergic agents in patients who have developed severe augmentation. Although there is little evidence of tolerance or addiction to opioids in the RLS literature, the data are sparse, and therefore prescription of opioids should be restricted to patients without a previous history of substance abuse. Opioids should also be used cautiously in patients who snore and are at risk for having sleep apnea syndrome. Anticonvulsants Studies of anticonvulsants have focused on gabapentin. Several open-label trials and one placebo-controlled study116 showed subjective improvements with gabapentin at doses of 300 to 2400 mg a day. Gabapentin is considered more potent and produces fewer adverse effects than dopaminergic agonists, except for mild daytime somnolence. In mild cases or in patients who have developed adverse effects with dopaminergic medications, gabapentin is a valuable alternative. Because gabapentin is a common treatment for peripheral neuropathy and pain, it has been also recommended for the treatment of neuropathic RLS and in general for patients who use pain as a descriptor for their leg sensations. Benzodiazepines Several studies showed that benzodiazepines, including clonazepam, nitrazepam, lorazepam, and temazepam improve the quality of sleep and reduce PLMS or PLMS associated with arousals in patients with RLS and in patients with both insomnia and PLMS. However, the therapeutic effects of benzodiazepines on subjective ratings of RLS symptoms were either modest or not significant. Therefore benzodiazepines are mostly used to improve sleep continuity in patients with RLS. Because dopaminergic agents often have a stimulating effect and worsen insomnia, benzodiazepines are often used as an adjunctive treatment. Other Treatments When the patient’s ferritin level is less than 45 to 50 µg/L, then oral iron treatment is indicated usually as supplemental treatment. Oral iron treatment can be ferrous sulfate 325 mg, or its equivalent, with vitamin C 100 to 200 mg taken twice a day, preferably on an empty stomach, depending on how well the iron is tolerated. A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose (1000 mg/day) failed to demonstrate significant improvement in RLS reported in prior open-label studies with intravenous iron dextran.117 However, the dextran maintains high peripheral iron availability much longer than does the sucrose. Optimal parental iron therapy is unclear.56a,118,119 Clinical Management In summary, dopamine agonists are now considered the treatment of choice for RLS. Because of their side-effect profile, nonergoline derivatives—pramipexole and ropinirole—are preferred. One advantage of pramipexole is its longer duration of action. In several patients, RLS occurs sporadically, with spontaneous remission lasting weeks or even months. Therefore, the physician should use
1034 PART II / Section 11 • Neurologic Disorders Table 90-1 Management of Restless Legs Syndrome AGENT AND DOSAGE
SIDE EFFECTS
COUNTERMEASURES
Nausea and orthostatic hypotension
Slowly increase dosage or use domperidone if available (10-30 mg)
Insomnia
Use a small dose of benzodiazepines in association with DA agonists
Daytime fatigue and somnolence
Reduce dosage or discontinue DA agonists and use levodopa (if severe and persistent)
Step 1: Dopamine Agonists Pramipexole, 0.125-1.0 mg* Ropinirole, 0.5-4.0 mg*
Compulsive or impulsive behavior
Decreased dose or discontinue DA agonists
Tolerance
Drug holiday for 2 wk, then return to lower dosage
Augmentation
Use small extra dose during daytime or discontinue DA agonists (if severe and persistent)
Same as for DA agonists
See countermeasures for DA agonists
Morning rebound or augmentation of RLS in early evening
Use small extra dose of levodopa during daytime or reduce dosage or combine levodopa with DA agonists or benzodiazepines or discontinue levodopa (if severe and persistent)
Step 2: Dopamine Precursors Levodopa/benserazide or levodopa/carbidopa (regular or slow release), 100/25 or 200/50 mg
Step 3: Benzodiazepines Clonazepam, 0.5-2.0 mg* Temazepam, 15-30 mg* Nitrazepam, 5-10 mg*
Daytime somnolence
Reduce dosage
Tolerance
Drug holiday for 2 wk then return to lower dosage
Constipation
Symptomatic treatment
Dependency
Drug holiday or withdrawal
Daytime fatigue and somnolence
Reduce dosage
Step 4: Opiates Oxycodone, 5 mg† Propoxyphene, 200 mg* Codeine, 15-60 mg* STEP 5: Antiepileptic drugs Gabapentin, 100-400 mg
*One hour before onset of symptoms in the evening or at bedtime if symptoms are not present in the evening † At bedtime and repeated once during the night. DA, dopamine; RLS, restless legs syndrome.
pharmacologic treatments on an irregular basis or consider a drug holiday when appropriate. Continuous pharmacologic treatment should be considered if patients complain of RLS occurring at least three nights per week. All medications treat RLS symptoms and do not influence the course of the illness. Therefore, the clinician should carefully assess the therapeutic benefit versus the severity of adverse effects. A therapeutic flowchart appears in Table 90-1. Each drug is presented with its commonly used therapeutic dosage, its most common side effects, and the appropriate countermeasures to adopt. Higher doses may be administered in severe cases, but when a higher dosage is required, the clinician should carefully assess for the presence of augmentation. If augmentation develops, a different medication should be used. If augmentation occurs with levodopa, patients should be treated with dopaminergic agonists. If it occurs in the course of treatment with agonists, opioids are generally the best alternative treatment. Because of its particular 24-hour transdermal delivery, rotigotine may also be considered in patients who develop augmentation.
❖ Clinical Pearl The clinician should keep in mind that RLS is a common and underdiagnosed condition with a strong genetic component. RLS is showing a good therapeutic response to dopaminergic agonists.
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77. Earley CJ, Hyland K, Allen RP. CSF dopamine, serotonin, and biopterin metabolites in patients with restless legs syndrome. Mov Disord 2001;16(1):144-149. 78. Stiasny-Kolster K, Moller JC, Zschocke J, et al. Normal dopaminergic and serotonergic metabolites in cerebrospinal fluid and blood of restless legs syndrome patients. Mov Disord 2004;19(2): 192-196. 79. Allen RP, Connor JR, Hyland K, Earley CJ. Abnormally increased CSF 3-Ortho-methyldopa (3-OMD) in untreated restless legs syndrome (RLS) patients indicates more severe disease and possibly abnormally increased dopamine synthesis. Sleep Med 2009;10(1): 123-128. 80. Montplaisir J, Lorrain D, Godbout R. Restless legs syndrome and periodic leg movements in sleep: the primary role of dopaminergic mechanism. Eur Neurol 1991;31:41-43. 81. Von Spiczak S, Whone AL, Hammers A, et al. The role of opioids in restless legs syndrome: an 11C diprenorphine PET study. Brain 2005;128:906-917. 82. Walters AS, Ondo WG, Le W. Endogenous opioid levels are decreased in thalamus of restless legs syndrome patients compared to controls: a post-mortem study. Sleep 2008;31(Abs Suppl): A266. 83. Allen RP, Mignot E, Ripley B, et al. Increased CSF hypocretin-1 (orexin-A) in restless legs syndrome. Neurology 2002;59(4): 639-641. 84. Allen RP, Lesage S, Earley CJ. Antihistamines and benzodiazepines exacerbate daytime restless legs syndrome (RLS) symptoms (abstract). Sleep 2005;28:A279. 85. Ekbom KA. Restless legs syndrome. Neurology 1960;10:868-873. 86. Nordlander NB. Therapy in restless legs. Acta Med Scand 1953;145:453-457. 87. Earley CJ, Heckler D, Horská A, et al. The treatment of restless legs syndrome with intravenous iron dextran. Sleep Med 2004; 5(3):231-235. 88. Kryger MH, Otake K, Foerster J. Low body stores of iron on restless legs syndrome: a correctable cause of insomnia in adolescents and teenagers. Sleep Med 2002;3(2):127-132. 89. Earley CJ, Connor JR, Beard JL, et al. Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology 2000;54(8):1698-1700. 90. Allen RP, Barker PB, Wehrl F, et al. MRI measurement of brain iron in patients with restless legs syndrome. Neurology 2001;56(2):263-265. 91. Godau J, Schweitzer KJ, Liepelt I, et al. Substantia nigra hypoechogenicity: definition and findings in restless legs syndrome. Mov Disord 2007;22(2):187-192. 92. Schmidauer C, Sojer M, Seppi K, et al. Transcranial ultrasound shows nigral hypoechogenicity in restless legs syndrome. Ann Neurol 2005;58(4):630-634. 93. Connor JR, Boyer PJ, Menzies SL, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 2003;61:304-309. 94. Hening W, Allen R, Earley C, et al. The treatment of restless legs syndrome and periodic limb movement disorder. Sleep 1999;22:970-999. 95. Early CJ, Allen RP. Pergolide and carbidopa/levodopa treatment of the restless legs syndrome and periodic leg movements in sleep in a consecutive series of patients. Sleep 1996;19:801-810. 96. Garcia-Borreguero D, Allen RP, Kohnen R, et al. Diagnosic standards for dopaminergic augmentation of restless legs syndrome: report from World Association of Sleep Medicine—International Restless Legs Syndrome Study Group consensus conference at the Max Planck Institute. Sleep Med 2007;8:520-530. 97. Garcia-Borreguero D, Kohnen R, Hogl B, et al. Validation of the Augmentation Severity Rating Scale (ASRS): a multicentric, prospective study with levo-dopa in RLS. Sleep Med 2007;8:455-463. 98. Wetter TC, Stiasny K, Winkelmann J, et al. A randomized controlled study of pergolide in patients with restless legs syndrome. Neurology 1999;52:944-950. 99. Stiasny K, Wetter TC, Winkelmann J, et al. Long-term effects of pergolide in the treatment of restless legs syndrome. Neurology 2001;56(10):1399-1402. 100. Stiasny K, Robbecke J, Schuler P, et al. Treatment of idiopathic restless legs syndrome (RLS) with the D2-agonist cabergoline—an open clinical trial. Sleep 2000;23(3):349-354.
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101. Antonini A, Poewe W. Fibrotic heart-valve reactions to dopamineagonist treatment in Parkinson’s disease. Lancet Neurol 2007;6: 826-829. 102. Montplaisir J, Nicolas A, Denesle R, Gomez-Mancilla B. RLS improved by pramipexole: a double-blind randomized trial. Neurology 1999;52(5):938-943. 103. Oertel WH, Stiasny-Kolster K, Bergtholdt B, et al. Efficacy of pramipexole in RLS: a six-week, multicenter, randomized, doubleblind study. Mov Disord 2007;22:213-219. 104. Silber MH, Girish M, Izurieta R. Pramipexole in the management of restless legs syndrome: an extended study. Sleep 2003;26(7): 819-821. 105. Winkelman JW, Johnston L. Augmentation and tolerance with long-term pramipexole treatment of restless legs syndrome. Sleep Med 2004;5:9-14. 106. Montplaisir J, Fantini ML, Desautels A, et al. Long-term treatment with pramipexole in restless legs syndrome. Eur J Neurol 2006;13:1306-1311. 107. Trenkwalder C, Garcia-Borreguero D, Montagna P, et al. Therapy with ropinirole, efficacy and tolerability in RLS-1 Study Group. Ropinirole in the treatment of RLS: results from the TREAT RLS-1 study, a 12-week, randomized, placebo controlled study in 10 European countries. J Neurol Neurosurg Psychiatry 2004; 75:92-97. 108. Montplaisir J, Karrasch J, Haan J, Volc D. Ropinirole is effective in the long-term management of restless legs syndrome: a randomized controlled trial. Mov Disord 2006;21:1627-1635. 109. Garcia-Borreguero D, Grunstein R, Sridhar G, et al. A 52-week open-label study of the long-term safety of ropinirole in patients with restless legs syndrome. Sleep Med 2007;8:742-752.
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Alzheimer’s Disease and Other Dementias
Dominique Petit, Jacques Montplaisir, and Bradley F. Boeve Abstract Sleep anomalies are found in a variety of conditions causing dementia. Specific features of the sleep and electroencephalographic impairments vary in some respects, but a common pattern emerges. Sleep is usually more fragmented, both from more awakenings and from a longer duration of time awake; slow-wave sleep is decreased; spindles and K-complexes are less well formed or less numerous, so sleep stages are more difficult to distinguish; and rapid eye movement (REM) sleep may be reduced. Quantitative analyses show a slowing of the electroencephalogram (EEG) during wakefulness and, in
ALZHEIMER’S DISEASE Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by progressive decline in memory and other cognitive domains. It is considered the primary cause of irreversible dementia in old age. Diagnostic criteria, first established by the National Institute of Neurological and Communicative Disorders and Stroke—Alzheimer’s Disease and Related Disorders Association Work Group, were revised1 in light of the discovery of new markers, brain imaging findings, and cerebrospinal fluid analyses of amyloid B and tau proteins. Accumulation of abnormal tau proteins brings dysfunction and neuronal death. Highly affected structures include: entorhinal cortex, hippocampus, amygdala, nucleus basalis of Meynert, suprachiasmatic nucleus (SCN), intralaminar nuclei of the thalamus, locus coeruleus, raphe nuclei, central autonomic regulators, and the cortex (sparing the primary cortical areas for a long time). Pathologically, findings include neurofibrillary tangles, neuritic plaques, and neuronal loss. Sleep Problems The prevalence of sleep disturbance in AD has been estimated to be around 25% in mild to moderate cases and around 50% in moderate to severe cases. These sleep problems can take many forms: napping excessively during the daytime and having difficulty falling asleep at night, frequent nocturnal awakenings, and waking up to start the day too early. These sleep problems are of consequence because daytime sleepiness, for instance, was found to be associated with greater functional impairments in AD independently of level of cognitive impairment.2 Perhaps the most noticeable sleep problem of patients with AD is the sundowning phenomenon, a delirium-like state characterized by nocturnal agitation or wandering. This phenomenon can be explained, at least in part, by an alteration in the biological clock: the SCN of the hypothalamus. The secretion rhythm of many hormones is affected in the elderly but it is even more apparent in AD patients.3 In addition, there is an earlier timing of the biological clock as evidenced by two common markers, core body temperature and plasma melatonin.3 1038
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Alzheimer’s disease, during REM sleep. These impairments typically worsen with the progression of the disease. Demented patients are also more likely to present with periodic limb movements in sleep and respiratory disturbances. This chapter gives an overview of sleep disturbances, characteristics of sleep architecture and microstructure, and quantitative analyses of wakefulness and sleep EEG in a variety of conditions associated with dementia: Alzheimer’s disease, progressive supranuclear palsy, Parkinson’s disease, dementia with Lewy bodies, vascular dementia, Huntington’s disease, CreutzfeldtJakob disease, and frontotemporal dementia.
Since the turn of the century, a series of pathophysiology findings has shed some light on the circadian rhythm disorder of AD patients. A disrupted melatonin production and rhythm was found,4 even in the early preclinical stages of AD.5 This might be caused by a dysfunction in the sympathetic regulation by the SCN of the pineal melatonin synthesis.4 The SCN itself would be under the modulatory influence of the nucleus basalis of Meynert, which degenerates early in AD. It was proposed that sundowning would be the result of the neocortex being slowly turned off to sleep (due to the defective nucleus basalis) when an arousal signal is still being processed.6 Circadian rhythm disturbances are known to be associated with a variety of medical conditions: cardiovascular problems, the metabolic syndrome, physical disabilities, respiratory symptoms, decreased immune system functioning, and mood and cognitive impairment. Obstructive sleep apnea syndrome (OSAS) has been reported to occur with a greater prevalence in AD patients than in the general population.7 A relationship between AD and apolipoprotein ε (APOE), a lipoprotein made in the liver and brain and involved in cholesterol transport and deposition, were first noted in the early 1990s.8 It was shown that the risk of developing AD was associated with the APOE4 allele. An association has been found between the APOE4 allele and OSAS.9 Finally, the presence of rapid eye movement (REM) sleep behavior disorder (RBD) has been shown in one case of AD with mixed Alzheimer’s and Lewy body dementia (DLB) pathology confirmed on autopsy10 and in one out of 15 consecutive patients with AD.11 The latter study also showed that three more patients with AD presented with REM sleep without atonia. Polysomnography Findings In addition to the presence of sleep problems, sleep architecture is modified in patients with AD. Certain sleep changes seem to be an exaggeration of changes that normally appear with aging. Specifically, patients with AD show an increased number and duration of awakenings and, as a result, an increased percentage of stage 1 sleep. Compared to elderly controls, they also show a reduced
percentage of slow-wave sleep (SWS).12 This is the most consistently reported change in patients with mild to moderate AD. All the prior sleep disturbances worsen with increasing severity of AD.12 Another change in sleep architecture that suggests accelerated aging in AD is a loss of the specific electroencephalographic (EEG) features of stage 2 sleep. Sleep spindles and K-complexes become poorly formed, of lower amplitude, of different frequency, of shorter duration, and much less numerous.13,14 With advancing severity of the disease, due to the absence of these characteristic EEG features, it becomes progressively more difficult to separate stage 2 from stage 1 sleep. The proportion of indeterminate non-REM (NREM) sleep increases even further with the disappearance of the true delta waves of SWS. Conversely, other sleep changes observed in AD do not suggest accelerated aging. Of particular interest is the percentage of REM sleep that remains stable in normal aging but that was reduced in AD patients compared to controls, and this as a result of a decrease in mean REM sleep episode duration.13 Other REM sleep variables, such as REM density, number of REM sleep episodes, and REM sleep latency, are usually unchanged,13,15 as are muscle atonia and phasic electromyographic activity in REM sleep.13 In other words, variables pertaining to the initiation of REM sleep and to its characteristic features were unaffected in mild AD. This is probably because these variables are under the control of the mesopontine cholinergic populations, structures that are relatively spared in mild AD. The lower REM sleep percentage, however, could be due to degeneration of the cholinergic nucleus basalis of Meynert. This nucleus normally exerts an inhibitory influence on the nucleus reticularis of the thalamus,16 the rhythm generator responsible for NREM sleep. Quantitative Electroencephalography in Alzheimer’s Disease Wakefulness Electroencephalogram In AD, waking EEG activity is characterized by more slowing of the dominant occipital rhythm than is found in nondemented old people. There is also an increase in theta and delta activity compared to age-matched controls. Several studies attempted to correlate quantitative waking EEG with clinical severity of AD with variable results. Some demonstrated that relative theta power separated all 4 stages of dementia: none, mild, moderate, and severe dementia. Some reported that decreases of relative power in alpha and beta bands and increases of power in the delta band were correlated with severity of AD. REM Sleep Electroencephalogram EEG slowing was found to be more marked during REM sleep than during wakefulness in AD patients.17,18 Moreover, there was a distinctive topographical pattern of REM sleep EEG slowing in AD patients that parallels findings from neuroradiologic19 and neuropathologic20 studies—a pattern not observed for the waking EEG.21 Indeed, REM sleep EEG slowing was greater in the temporoparietal and frontal regions.18 The quantitative EEG derived from REM sleep (but not from wakefulness) was also correlated with a screening assessment of cognitive functioning in AD (the Mini-Mental State Examination)22 and with a measure
CHAPTER 91 • Alzheimer’s Disease and Other Dementias 1039
of interhemispheric asymmetry of regional cerebral blood flow.23 REM sleep EEG is superior to wakefulness EEG probably because the cholinergic basal forebrain, which degenerates early in AD, is likely more crucial for EEG activation during REM sleep than during wakefulness. EEG activation during wakefulness is the result of many convergent neuronal and neurotransmitter systems, many of which are not active during REM sleep. The importance of the cholinergic system to cortical activation in REM sleep may also be due to an enhanced activity in the cholinergic system during that state.24 NREM Sleep Electroencephalogram The presence of increased EEG delta activity over the entire sleep–wake spectrum makes it difficult to distinguish, especially in NREM sleep, the pathologic from the normal physiologic delta waves. Despite the increases observed in delta activity, patients with AD had elicited K-complexes less often in response to auditory stimulation than age-matched controls and produced K-complexes of lower amplitude.25 Therefore, patients with AD have an impaired ability to generate normal physiologic delta activity during NREM sleep. In these patients, the probability of eliciting a K-complex was also correlated negatively with dementia.25
PROGRESSIVE SUPRANUCLEAR PALSY Progressive supranuclear palsy (PSP), also called SteeleRichardson-Olszewski syndrome, is characterized by progressive axial rigidity, postural instability, and supranuclear gaze palsy. The dementia that often evolves in PSP primarily reflects dysfunction in the frontosubcortical neural networks.26 Because the sleep characteristics of PSP are discussed in Chapter 87, only the aspects related to the dementia are reviewed here. Excessive daytime somnolence is a common occurrence in PSP. Hypocretin 1 (orexin A) levels were found to be low in PSP, and these levels were inversely correlated with the duration of PSP morbidity.27 Perhaps even more striking is the absence or drastic reduction in REM sleep in PSP patients, especially with the progression of the disease.28,29 A reduction in REM sleep has been generally correlated with a decline in cognitive functioning. Despite this reduction in REM sleep, studies have reported some cases of RBD and REM sleep without atonia in patients with PSP.30,31 RBD is, however, much more prevalent (78%) in a Guadeloupean form of PSP probably due to ingestion of sour sop, a tropical fruit containing mitochondrial poisons.32 Cognitive decline is, in turn, reflected by a slowing of the EEG. One study has quantitatively assessed the EEG from both REM sleep and wakefulness in patients with PSP.28 For the REM sleep EEG, there were no significant between-group differences for any of the 16 regions studied. During wakefulness, a slowing of the EEG was found mainly for the frontal regions, compared to control subjects. The frontal EEG slowing during wakefulness is consistent with the results of numerous neuropsychological studies that show deficits to be related to frontal lobe
1040 PART II / Section 11 • Neurologic Disorders
functions. The fact that no EEG slowing was found in REM sleep suggests that the slowing observed for wakefulness was not likely due to a cholinergic deficit. This is consistent with findings that normal neocortical and hippocampal choline acetyltransferase activity was found in some patients with PSP.33 Dopamine levels are, however, severely reduced in the caudate, putamen, and substantia nigra in PSP patients.33 A frontal deafferentation from the striatopallidal complex is thought to be responsible for the impairment because there are extensive fiber connections between these nuclei and the prefrontal region. Indeed, the positive correlations between degree of impairment on frontal tasks and EEG slowing observed in our PSP patients suggest that both impairments could be at least partially the result of a dopaminergic deficiency.28
PARKINSON’S DISEASE PD is a progressive neurologic disorder characterized by rigidity, resting tremor, bradykinesia, and an impairment of postural reflexes and gait and caused in part by the degeneration of the dopaminergic cells in the substantia nigra. The sleep modifications experienced by patients with PD are discussed in Chapter 87; therefore, only information relevant to dementia associated with PD is reviewed here. The incidence of overt dementia in PD is relatively high; in a population-based study of dementia in Parkinson’s disease, approximately 80% of nondemented PD patients developed dementia within 8 years.34 Risk factors include advanced age at onset of symptoms, severe motor symptoms (particularly bradykinesia), levodopa-related confusion or hallucinations, presence of speech and axial involvement, presence of depression, and atypical neurologic features, such as modest response to dopaminergic agents or early autonomic dysfunction.35 Demented patients with PD often experience hallucinations. One study found that patients with REM sleep anomalies have more hallucinations than patients without such anomalies.36 It was proposed that sleep reduction, particularly REM sleep reduction, would trigger hallucinations by enabling the emergence of REM sleep during wakefulness. Hallucinations have been significantly correlated with the presence of RBD independently of age, gender, disease duration, or Unified Parkinson’s Disease Rating Scale score but related to the amount of dopaminergic medication.37 There is growing evidence that RBD is an early manifestation of a neurodegenerative disorder, particularly one of the synucleinopathies (e.g., DLB, PD, and multiple system atrophy).38,39 The occurrence of RBD in PD was estimated at 15% with a structured questionnaire40 but at 33% using polysomnographic recordings41; only half of these had been detected at the clinical interview. The phenomenon of REM sleep without atonia would explain the reduction in REM sleep reported in patients with PD when the sleep staging has been performed according to the standard criteria.42 Previous studies had shown that approximately a third of patients with PD presented with EEG slowing regardless of the presence of dementia.37 Even when only nondemented patients with PD were studied, a slowing of the EEG in the temporo-occipital and the frontal regions has been found in some patients.43 It was demonstrated that
only patients with PD who also had RBD had a slowing of the EEG and of the dominant occipital frequency.44 A higher theta power was found during wakefulness in frontal, temporal, parietal, and occipital regions in patients with PD and RBD compared with patients who had PD without RBD and control subjects. The EEG slowing found only in patients with PD and RBD might not be related to an evolutional stage of PD but rather to the presence of RBD itself. In support of this hypothesis, a higher theta power in the frontal, temporal, and occipital region during wakefulness has also been observed in patients who have idiopathic RBD without PD.45 Similarly, patients with PD and concomitant RBD showed a significantly poorer performance on standardized tests measuring episodic verbal memory, executive functions, and visuospatial and visuoperceptual processing compared to both patients with PD without RBD and control subjects.46 Interestingly, patients with idiopathic RBD had a lower performance (compared to control subjects) on the same neuropsychological tests (executive functions and verbal memory)47 than did the patients with PD and RBD. The association of RBD with dementia in PD was more directly demonstrated by one study.48 Of the 65 patients with PD who completed the study, 24 met the clinical diagnosis of RBD. The incidence of RBD was significantly higher in the demented PD group compared to the nondemented PD group (77% versus 27%). Patients who had PD but not RBD had a lower incidence of dementia (7.3%) compared to patients with PD and RBD (42%). The topography of EEG slowing observed in PD with RBD is similar to that of the hypoperfusion and hypometabolism seen in DLB,49,50 the profile of cognitive impairments noted in PD with RBD resembles that of DLB,51 and many RBD patients later develop DLB.52,53 Thus there is reason to believe that the presence of RBD in patients with PD may be an early sign of an evolution toward dementia. Some evidence suggests that cortical Lewy body–type degeneration is the main source of dementia in PD. One study reported diffuse cortical Lewy bodies only in demented patients with PD, whereas nondemented patients had only brainstem Lewy bodies.54 Two other studies have suggested that α-synuclein–positive cortical (especially frontal) Lewy bodies were associated with cognitive impairment, independent of or more specifically than an AD-type pathologic process.55,56 More studies are necessary to determine the pathologic and neurochemical underpinnings of dementia in PD.
DEMENTIA WITH LEWY BODIES Dementia with Lewy bodies represents the second most common neurodegenerative cause of dementia in old age. Until recently, it was a much underdiagnosed form of dementia. The core clinical features of DLB are progressive cognitive decline, spontaneous parkinsonism, recurrent visual hallucinations, and fluctuating cognition and vigilance.57 Autonomic dysfunction is often present.57 It is pathologically characterized by the presence of Lewy bodies in limbic or neocortical structures, or both. Three subtypes of DLB have been put forward: a brainstem subtype, a limbic subtype, and a diffuse neortical subtype.57
A questionnaire study showed that patients with DLB had more overall sleep disturbances, more movement disorders while asleep, and more daytime sleepiness than patients with AD.58 Based on results from the Epworth Sleepiness Scale, 50% of patients with DLB experience excessive daytime sleepiness.59 However, normal hypocretin-1 levels were found in the cerebrospinal fluid of patients with DLB and daytime sleepiness, suggesting that sleepiness in DLB is not related primarily to a dysfunction of hypocretin neurotransmission.27,60 A polysomnographic study61 found that 73% of patients with DLB had a sleep efficiency less than 80%. High proportions of these patients also had pathologic indexes of respiratory disturbances (88%) or periodic leg movements during sleep (PLMS) with arousal (74%).61 A number of studies or review papers have reported that RBD is a common finding in patients with DLB.52,53 Twelve of 15 patients with RBD and a neurodegenerative disease had limbic or neocortical Lewy body disease at autopsy (the other three had multiple system atrophy), which indicates a synucleinopathy.62 It had even been suggested that the inclusion of RBD in the list of core criteria for DLB would improve the sensitivity and specificity of the diagnosis.51,53,62 RBD now figures as a suggestive feature for the diagnosis of DLB in the third report of the DLB consortium57; these criteria have just been validated.63 As in PD, restless legs syndrome (RLS) and PLMS are also common in DLB and can play a part in sleep-onset insomnia and nocturnal arousals or awakenings, respectively.64 A few quantitative EEG studies have reported a slowing of the awake EEG in DLB, expressed as a loss of the alpha rhythm during wakefulness combined with a slowing of both dominant and nondominant rhythms,65 or expressed as an increase in theta activity,66,67 which correlates with the degree of dementia.66 Frontal intermittent rhythmic delta activity has also been reported.67 Fluctuating cognition, one of the core features of DLB, was shown to be reflected in cortical activation by the variability of the mean EEG power in DLB patients compared to both AD patients and elderly control subjects.68
VASCULAR DEMENTIA The term vascular dementia covers a range of problems of various etiologies and includes the entities known as multiinfarct dementia (MID) and Binswanger’s disease. The most studied form of vascular dementia in sleep medicine is probably MID. An actigraphy study found that patients with MID had a significantly greater disruption of sleep– wake cycles associated with poor sleep quality than AD patients.69 There was no correlation, however, between the degree of sleep disruption and the severity of intellectual deterioration. It was reported that sleep apnea syndrome was more strongly associated with MID than with AD.70 Spectral analysis of the waking EEG of patients with MID revealed a lower dominant occipital frequency,71,72 a higher theta and slow alpha power, a lower high alpha power, and more numerous delta waves than that in control subjects.71 In addition, in patients with MID, the alpha waves had migrated to more-anterior regions. There was
CHAPTER 91 • Alzheimer’s Disease and Other Dementias 1041
no gender difference in the quantitative EEG of patients with MID.71,72 Larger EEG source fluctuations were found in vascular dementia compared to AD patients and controls; the authors reported that this might reflect the patients’ decreased vigilance control and therefore account for their increased fluctuations in cognition.73
HUNTINGTON’S DISEASE Huntington’s disease (HD) is an autosomal dominant hereditary condition associated with atrophy of basal ganglia structures, especially the caudate nucleus, and characterized by choreic movements and progressive dementia associated with psychotic features. A CAG trinucleotide repeat in the IT15 gene located on the short arm of chromosome 4 is the cause of this condition.74 Patients with HD have a disrupted night–day activity pattern. Transgenic mice carrying the HD mutation showed a disruption of night–day activity, which worsened as the degeneration progressed but also showed a marked reduction in the expression of mPer2 and disrupted expression of mBmal1 in the SCN, the motor cortex, and the striatum.75 Ubiquitin-proteasome dysfunction has been suggested to be part of the pathogenesis of HD,76 and such inclusions have been also found in the SCN of the transgenic mice.77 Daily treatment with alprazolam in these mice reversed the dysregulated expression of Per2 and also Prok2, an output factor of the SCN that controls behavioral rhythms, and also markedly improved cognitive performance in a visual discrimination task.78 Restoring circadian rhythms might thus slow cognitive decline that is such a devastating feature of HD. A disturbed sleep architecture has also been reported in patients with Huntington’s disease. Specifically, they showed a longer sleep latency, a lower sleep efficiency, frequent nocturnal awakenings, and less SWS than agematched control subjects.79,80 A PSG study on a large number of patients with HD and control subjects replicated most of these findings except for sleep latency, which was unchanged, and REM sleep latency, which was found to be longer instead of shorter.81 REM sleep duration decreased with disease severity, and it was already significantly reduced in presymptomatic carriers of the defective gene. Three out of 25 patients with HD had RBD. Finally, patients with HD did not have more daytime sleepiness but had more PLMS than controls. Contrary to patients with other neurodegenerative diseases, patients with Huntington’s disease showed a higher density of sleep spindles compared to healthy control subjects.80,82 The sleep disturbances (less SWS and more time spent awake) correlated with the degree of atrophy of the caudate nucleus and the severity of clinical symptoms.80 In fact, a study found sleep disturbances only in moderate to severe cases of Huntington’s disease and none in mild cases.79 However, no correlation was found between the length of the CAG repeat and sleep disturbances.81 Finally, no difference was found on sleep respiratory variables between patients with HD and healthy control subjects.81 On visual inspection, the waking EEG exhibits a gradual slowing and a diminution of amplitude as the disease progresses. A quantitative analysis of the waking EEG in
1042 PART II / Section 11 • Neurologic Disorders
Huntington’s disease revealed increased theta and de creased alpha activity in HD compared to controls; patients with HD were similar to patients with AD.83
CREUTZFELDT-JAKOB DISEASE CJD is a prion-related transmissible spongiform encephalopathy causing extensive neuronal degeneration and pathologic changes, especially in the cortex, and resulting in myoclonic jerks, rapidly evolving dementia, and other signs of central nervous system dysfunctions and leading to death. It develops between the 5th and the 7th decades of life. The mean survival duration is 4 to 8 months84 although 5% to 10% of patients have a clinical course that spans 2 years or more. Two large-sample studies85,86 reported that half of the patients were experiencing sleep disturbances, mostly insomnia. In 15% of these patients, sleep disturbances were a prodromal or presenting symptom. Polysomnographic studies of CJD reveal disorganized sleep patterns with sudden jumps from one sleep stage to the next, very few sleep spindles and K-complexes in stage 2 sleep (which is otherwise normal but difficult to distinguish from stage 3), an absence of stage 4, and a lower percentage of REM sleep, with lower REM density.87,88 Episodes of nocturnal oneiric, sometimes aggressive behavior with dream–reality confusion have been reported in some patients.85,87 Sleep apneas, central or obstructive, also seem prevalent in this condition. The hallmark awake EEG observation in patients with CJD is the presence of periodic sharp wave complexes within a background of generalized slow but low-voltage EEG, suggesting diffuse cerebral pathology.84 Periodic sharp-wave complexes are either simple sharp waves (biphasic or triphasic waves) or complexes with mixed spikes or slow waves. Periodic sharp-wave complexes have been added to the diagnostic criteria for probable CJD89 because they are present in about two thirds of patients and show a high specificity (occurring in only 9% of patients with another neurodegenerative disorder).90 Sleep EEG studies also report the presence of periodic sharp wave complexes as early as 1 to 3 months after the onset of symptoms.91,92 Cyclic changes with periodic complex phases alternating with semirhythmic theta-delta activities have been described.91,92 FRONTOTEMPORAL DEMENTIA Frontotemporal dementia (FTD) is a category of disorders that includes Pick’s disease and corticobasal degeneration. It is a progressive, degenerative condition characterized by a loss of executive and language abilities and a number of noncognitive symptoms, such as loss of insight, overactivity, lack of social awareness, disinhibition, and lack of personal hygiene. Approximately 5% to 15% of patients with dementia have a disorder within the FTD spectrum. It is thought to be underdiagnosed because, in part, of its similarities with AD, especially later in the progression of the disease. However, unlike AD, FTD initially manifests with progressive aphasia and personality changes whereas memory remains relatively intact. Structural and functional brain imaging shows atrophy, reduced cerebral
blood flow, or diminished glucose metabolism in frontal and anterior temporal areas. As in AD, FTD is generally accompanied by a disturbance of the activity rhythm and of the sleep–wake rhythm. However, these disturbances manifest differently in the two conditions, supporting the notion that central changes, rather than environmental factors only (such as institutionalization), cause the rhythm disturbances. In FTD, the activity rhythm is highly fragmented and phase-advanced despite a normal core temperature phase.93 Electroencephalographic slowing during wakefulness is observed in patients with FTD. One study94 found an increased theta power, and another95 reported an increase in both delta and theta power more prominently in anterior regions in a majority of patients. However, 31% had normal EEGs and most patients had a preserved dominant occipital frequency.95 It was found that EEG measures of functional connectivity were normal in patients with mild to moderate FTD.96
TREATMENT OF SLEEP DISORDERS IN PATIENTS WITH DEMENTIA One useful approach to address sleep disorders in the demented patient involves considering symptoms within four major categories: insomnia or fragmented sleep, excessive daytime sleepiness, alteration in the sleep–wake circadian rhythm, and excessive motor activity during the night, including RBD, PLMS, and nocturnal agitation or wandering.97 In addition, one should keep in mind that some of these disturbances could be due to RLS, OSAS, malnutrition, infections, medication effects (and often polypharmacy), depression, bladder catheterization, fecal impactions, or disturbing environmental factors. Management requires the identification and treatment of the underlying medical or psychiatric disorder. For each of these four categories of sleep disorders, we review the appropriate pharmacologic and nonpharmacologic treatment strategies. A summary of selected medication with suggested dosage and titration schedule also appears in Table 91-1. Insomnia Insomnia that is comorbid with other sleep disturbances is a common occurrence in patients with dementia (for review, also see reference 98). These patients are often unable to explain why they are not able to sleep through the night, so caregivers and physicians should carefully investigate the possible sources of the insomnia. Evaluating pain, concomitant medical conditions, and medication effects is essential in order to treat the patient successfully. For example, both untreated depression and some antidepressant medications (fluoxetine and bupropion) can lead to insomnia. The cholinesterase inhibitors, which have been shown to improve cognitive and noncognitive symptoms in patients with AD, can also cause insomnia. This problem usually can be avoided if the medication is administered no later than the evening meal, although in some patients the medication must be given no later than lunchtime. Melatonin was not found effective in treating insomnia in patients with AD in a multicenter, placebo-controlled trial.99
CHAPTER 91 • Alzheimer’s Disease and Other Dementias 1043
Table 91-1 Sleep Disorders and Disturbances in Dementia: Selected Medications with Suggested Dosing Schedules* INITIAL MEDICATION
DOSE
SUGGESTED TITRATING SCHEDULE
TYPICAL THERAPEUTIC RANGE
Insomnia Trazodone
25 mg qhs
Increase in 25-mg increments q 3-5 d
50-200 mg/night
Chloral hydrate
500 mg qhs
Increase in 500-mg increments q5-7d
500-1500 mg/night
Melatonin
3 mg qhs
3-6 mg nightly
3-12 mg/night
Quetiapine
25 mg qhs
Increase in 25-mg increments q3d
25-100 mg night
Zolpidem
5 mg qhs
Increase to 10 mg qhs if necessary
5-10 mg/night
Restless Legs Syndrome, Periodic Limb Movements in Sleep Carbidopa/levodopa
25/100 or1 tab qhs
Increase to 2 tabs 1 week later if necessary
1-2 tabs qhs
Pramipexole
0.125 mg qhs
Increase in 0.125-mg increments q2-3d
0.25-0.75 mg/night
Gabapentin
100 mg qhs
Increase in 100-mg increments q2-3d
300-1800 mg/night
Excessive Daytime Somnolence Methylphenidate
2.5 mg qAM
Increase in 2.5-5 mg increments q3-5d in bid dosing (AM and noon)
5 mg qAM to 30 mg bid
Modafinil
100 mg qAM
Increase in 100-mg increments q5-7d in bid dosing (AM and noon)
100 mg qam to 400 mg/day (400 mg qAM or 200 mg bid)
Amphetamine/ dextroamphetamine
5 mg qAM
Increase in 5-mg increments q7d in qd-bid dosing (AM and noon)
5 mg qAM to 20 mg bid
REM Sleep Behavior Disorder Clonazepam
0.25 mg qhs
Increase in 0.25-mg increments q7d
0.25-0.75 mg/night
Melatonin
3 mg
3-6 mg/night
3-12 mg/night
Psychotic Features, Behavior Dyscontrol, Nocturnal Agitation, Nocturnal Wandering Donepezil
5 mg qAM
Increase to 10 mg qAM 4 wk later
5-10 mg qAM
Rivastigmine†
1.5 mg bid
Increase in 1.5-mg increments q4w in bid dosing (AM and hs)
3-6 mg bid
Galantamine†
4 mg bid
Increase in 4-mg increments q4wk in bid dosing (AM and hs)
4-12 mg bid
Risperidone
0.5 mg qhs
Increase in 0.5-mg increments q7d in bid dosing (AM and hs)
0.5 mg qhs to 1.5 mg bid
Olanzapine
5 mg qhs
Increase in 5-mg increments q7d in bid dosing (AM and hs)
5 mg qhs to 10 mg bid
Clozapine‡
12.5 mg qhs
Increase in 12.5-mg increments q2-3d
12.5-50 mg qhs
Quetiapine
25 mg qhs
Increase in 25-mg increments q3d
25-100 mg qhs
Valproic acid‡
125 mg qhs
Increase in 125mg increments q 3-7d in bid to tid dosing
250 mg qhs to 500 mg tid
Carbamazepine‡
100 mg qhs
Increase in 100-mg increments q3-7d in bid to tid dosing
200 mg qhs to 200 mg tid
*Disclaimer: The choice of which agents to use and which dosing schedules to recommend must be individualized. It is the responsibility of the clinician to consider potential side effects, drug interactions, allergic response, life-threatening reactions (e.g., leukopenia with clozapine), dosing changes due to renal or hepatic dysfunction, etc., before administering any drug to any patient, including those listed above. Drs. Petit, Montplaisir, Boeve, their respective institutions, and Elsevier, will not be held responsible for any adverse reactions of any kind to any patient regarding the content of this information. † If insomnia is problematic, the second dose should be given no later than the evening meal. ‡ Requires periodic laboratory monitoring; refer to the manufacturer’s instructions for laboratory monitoring. Adapted from Boeve B, Silber M, Ferman T. Current management of sleep disturbances in dementia. Curr Neurol Neurosci Rep 2002;2:169-177.
Simple but effective interventions should probably be tried first, such as instituting proper sleep hygiene (e.g., regular schedule, bedtime routine, white noise), limiting caffeine and alcohol intake, and increasing exercise during the day. Before prescribing medication to treat insomnia, the clinician should keep in mind that many such agents
(especially benzodiazepines) can exacerbate cognitive deficits and OSAS and can induce daytime sleepiness. It has been shown that use of sedative-hypnotics (and also antipsychotics) is associated with longer hospital stays in the acute-care setting.100 If no cause is found for the insomnia, trazodone or chloral hydrate may be considered.
1044 PART II / Section 11 • Neurologic Disorders
Restless Legs Syndrome In some cases, insomnia can result from untreated RLS. The exact prevalence of RLS in dementias is not known, but it is a common condition in patients with AD, PD, DLB, FTD, and vascular dementia. Several medications, especially dopamine agonists, have been proved efficacious and well tolerated in nondemented persons with RLS (for review, see Chapter 90). However, to our knowledge, no study has assessed the efficacy and safety of these agents in demented patients. In some patients, dopaminergic agents can cause insomnia due to their stimulating effects or can trigger or exacerbate psychosis. Excessive Daytime Sleepiness Excessive sleepiness during the day has been reported mainly in PD. Daytime sleepiness would not result from poor sleep or from dopaminergic therapy but would be part of PD itself.101 Personal experience has taught us that somnolence, not resulting from another primary sleep problem, can also affect patients with AD, DLB, and FTD. In such cases, methylphenidate (at a low dose) or modafinil can be effective in improving alertness without producing undesirable effects. Obstructive Sleep Apnea Syndrome Hypersomnolence can also result from OSAS, a condition often associated with degenerative disorders, especially AD. The relationship between sleep apnea syndrome and dementia is complex. On one hand, it is known that sleep apneas, if left untreated for many years, will induce cognitive deficits, some of which are reversible with continuous positive airway pressure (CPAP) therapy. There have been severe cases of patients with OSAS in whom dementia had been diagnosed and whose dementia subsided with CPAP therapy. One study showed that long-term CPAP treatment succeeded in slowing the cognitive deterioration, and improving sleep and mood in patients with AD and OSAS.101a However, our clinical experience indicates that a small percentage of patients with a dementing illness significantly improve functionally and on psychometric testing with CPAP therapy, that a significant proportion of patients tolerate CPAP and use it nightly, and that even spouses enjoy a more consolidated sleep when their bed partners with dementia are on CPAP therapy. Disorder of the Sleep–Wake Circadian Rhythm Several studies have demonstrated a disorder of the sleep– wake rhythm in patients with dementia, especially in AD and FTD. In fact, insomnia and excessive daytime somnolence can be the manifestation of a primary disorder of the circadian rhythm. It has been proposed that degenerative changes in the biological clock, the SCN of the hypothalamus and in the pineal gland, resulting in reduced melatonin production, are responsible for the disorganization and flattening of the circadian rhythms.3,5 Melatonin can be helpful for sleep–wake cycle disturbances in patients with dementia; it improves sleep, reduces sundowning, and slows down the progression of dementia in AD.102,103 Bright-light therapy administered in the evening was also found effective to alleviate sleep-wake cycle disturbances
in patients with dementia and to consolidate their nighttime sleep.104-106 In some patients, regular daylight exposure is also effective for day–night reversal problems. Excessive Motor Activity during the Night REM Sleep Behavior Disorder REM sleep behavior disorder is prevalent in various degenerative conditions, especially in the synucleinopathies compared to AD, FTD, and PSP. There is a high interpatient variability in the severity of RBD, but the symptoms generally tend to decrease with the progression of the degenerative disease. It is important to differentiate RDB from nocturnal wandering by taking a careful history. When diagnosis is uncertain and the potential for injury is present, a polysomnographic and video recording is justified. The first step in the management of RBD is to ensure the safety of the patient, which means removing potentially dangerous objects from the bedroom, perhaps placing a soft mattress on the floor next to the bed, and so forth. Clonazepam, which is the treatment of choice for RBD in nondemented persons, can potentially worsen some aspects of dementia and can aggravate OSAS. Before prescribing this agent, it is essential to ensure that the patient does not experience OSAS or that CPAP therapy is effective in the apneic patient. Clinical experience shows us that clonazepam is well tolerated and produces few or no cognitive side effects in the vast majority of patients with dementia and concomitant RBD. Melatonin has also been shown to be effective in alleviating RBD symptoms.107,108 If depression is also present, treatments other than nefazodone should be considered because this drug increases REM sleep, contrary to most other antidepressants, and can therefore potentiate RBD. Periodic Limb Movements during Sleep The prevalence of PLMS in dementia has not been estimated exactly. However, it is known to be elevated, especially in the synucleinopathies. Without a polysomnographic recording, the severity and clinical significance of PLMS for a given patient are difficult to assess. If they are bothersome to the patient or cause daytime sleepiness as a result of sleep fragmentation, treatment with dopaminergic agonists can be considered. Dopaminergic agents should be used cautiously, if at all, in patients with psychotic features. Nocturnal Agitation and Wandering One of the heavier burdens on families of elderly demented patients and the primary cause of institutionalization is the lack of sleep due to nocturnal agitation or nocturnal wandering. Nocturnal agitation could be the result of discomfort (constipation, full bladder, clothing, heat, cold), pain (pressure sores, infection), or environmental interruptions (staff noise, light); hence, verifying the potential sources of discomfort and pain is crucial. As for insomnia management, eliminating alcohol and restricting caffeine intake to the morning can help in alleviating nocturnal agitation. Also, behavioral techniques should be tried before resorting to medication. However, if necessary, medication is atypical neuroleptics (respiridone, olanzapine, clozapine, quetiapine), antiepileptics (carbamazepine,
CHAPTER 91 • Alzheimer’s Disease and Other Dementias 1045
valproic acid), benzodiazepines (clonazepam, lorazepam), or trazodone or chloral hydrate can be effective in treating nocturnal agitation (see Table 91-1 for dosages and titration schedules). Cholinesterase inhibitors can significantly ameliorate hallucinations for patients who are frightened or really bothered by them. In these cases, medications with hallucinatory side effects (levodopa, dopamine agonists, anticholinergics, amantadine, selegiline) should be decreased or eliminated.
CONCLUSIONS Sleep and EEG are customarily impaired in diseases associated with dementia. Although a common general pattern of sleep impairment can be observed in dementia, the study of sleep variables and that of the spectral composition of the EEG in different states can provide valuable tools in establishing a diagnosis and in the evaluation of pharmacologic treatment. ❖ Clinical Pearls The clinician should keep in mind that when managing sleep disturbances in patients with dementia, careful assessment of the underlying causes is essential. Nonpharmacologic treatments, along with ensuring that the basic sleep hygiene rules are followed, should be undertaken before considering medication. One should also keep in mind, before prescribing medication to demented patients, that many agents can exacerbate cognitive deficits and OSAS.
Acknowledgments Dr. Montplaisir is supported by grants from the Canadian Institutes of Health Research. Dr. Boeve is supported by the Alzheimer’s Association and by grants AG06786, AG15866, AG16574, and AG17216 from the National Institute on Aging. REFERENCES 1. Dubois B, Feldman HH, Jacova C, et al. Research criteria for the diagnosis of Alzheimer’s disease: revising the NINCDS-ADRDA criteria. Lancet Neurol 2007;6:734-746. 2. Lee JH, Bliwise DL, Ansari FP, et al. Daytime sleepiness and functional impairment in Alzheimer disease. Am J Geriatr Psychiatry 2007;15:620-626. 3. Ferrari E, Arcaini A, Gornati R, et al. Pineal and pituitary-adrenocortical function in physiological aging and in senile dementia. Exp Gerontol 2000;35:1239-1250. 4. Wu YH, Swaab DF. The human pineal gland and melatonin in aging and Alzheimer’s disease. J Pineal Res 2005;38:145-152. 5. Wu YH, Fischer DF, Kalsbeek A, et al. Pineal clock gene oscillation is disturbed in Alzheimer’s disease, due to functional disconnection from the “master clock.” FASEB J 2006;20:1874-1876. 6. Klaffke S, Staedt J. Sundowning and circadian rhythm disorders in dementia. Acta Neurol Belg 2006;106:168-175. 7. Bliwise DL. Sleep apnea, APOE4 and Alzheimer’s disease: 20 years and counting? J Psychosom Res 2002;53:539-546. 8. Strittmatter WJ, Saunders AM, Schmechel D, et al. Apolipoprotein E: high-avidity binding to β-amyloid and increased frequency of type 4 allele in late-onset familial Alzheimer disease. Proc Natl Acad Sci U S A 1993;90:1977-1981.
9. Kadotani H, Kadotani T, Young T, et al. Association between apolipoprotein E 4 and sleep-disordered breathing in adults. JAMA 2001;285:2888-2890. 10. Schenck CH, Garcia-Rill E, Skinner RD, et al. A case of REM sleep behavior disorder with autopsy-confirmed Alzheimer’s disease: postmortem brain stem histochemical analyses. Biol Psychiatry 1996;40:422-425. 11. Gagnon JF, Petit D, Fantini ML, et al. REM sleep behavior disorder and REM sleep without atonia in probable Alzheimer disease. Sleep. 2006;29:1321-1325. 12. Prinz PN, Vitaliano PP, Vitiello MV, et al. Sleep, EEG and mental function changes in senile dementia of the Alzheimer’s type. Neurobiol Aging 1982;3:361-370. 13. Montplaisir J, Petit D, Lorrain D, et al. Sleep in Alzheimer’s disease: further considerations on the role of brainstem and forebrain cholinergic populations in sleep-wake mechanisms. Sleep 1995;18:145-148. 14. Ktonas PY, Golemati S, Xanthopoulos P, et al. Potential dementia biomarkers based on the time-varying microstructure of sleep EEG spindles. Conf Proc IEEE Eng Med Biol Soc 2007;2464-2467. 15. Vitiello MV, Bokan JA, Kukull WA, et al. Rapid eye movement sleep measures of Alzheimer’s-type dementia patients and optimally healthy aged individuals. Biol Psychiatr 1984;19:721-734. 16. Buzsaki G, Bickford RG, Ponomareff G, et al. Nucleus basalis and thalamic control of neocortical activity in the freely moving rat. J Neurosci 1988;8:4007-4026. 17. Petit D, Montplaisir J, Lorrain D, et al. Spectral analysis of the rapid eye movement sleep electroencephalogram in right and left temporal regions: a biological marker of Alzheimer’s disease. Ann Neurol 1992;32:172-176. 18. Hassania F, Petit D, Nielsen T, et al. Quantitative EEG and statistical mapping of wakefulness and REM sleep in the evaluation of mild to moderate Alzheimer’s disease. Eur Neurol 1997;37: 219-224. 19. O’Brien JT, Eagger S, Syed GMS, et al. A study of regional cerebral blood flow and cognitive performance in Alzheimer’s disease. J Neurol Neurosurg Psychiatr 1992;55:1182-1187. 20. Brun A, Englund E. Brain changes in dementia of Alzheimer’s type relevant to new imaging diagnostic methods. Progr Neuropsychopharmacol Biol Psychiatr 1986;10:297-308. 21. Petit D, Lorrain D, Gauthier S, et al. Regional spectral analysis of the REM sleep EEG in mild to moderate Alzheimer’s disease. Neurobiol Aging 1993;14:141-145. 22. Folstein M, Folstein S, McHugh P. “Mini-mental state.” A practical method for grading the cognitive state of patients for the clinician. J Psychiatr Res 1975;12:189-198. 23. Montplaisir J, Petit D, McNamara D, et al. Comparisons between SPECT and quantitative EEG measures of cortical impairment in mild to moderate Alzheimer’s disease. Eur Neurol 1996;36: 197-200. 24. Kodama T, Takahashi Y, Honda Y. Enhancement of acetylcholine release during paradoxical sleep in the dorsal tegmental field of the cat brain stem. Neurosci Lett 1990;114:277-282. 25. Crowley K, Sullivan EV, Adalsteinsson E, et al. Differentiating pathologic delta from healthy physiologic delta in patients with Alzheimer disease. Sleep 2005;28:865-870. 26. Litvan I, Agid Y, Calne D, et al. Clinical research criteria for the diagnosis of progressive supranuclear palsy (Steele-RichardsonOlszewski syndrome): report of the NINDS-SPSP International Workshop. Neurology 1996;47:1-9. 27. Yasui K, Inoue Y, Kanbayashi T, et al. CSF orexin levels of Parkinson’s disease, dementia with Lewy bodies, progressive supranuclear palsy and corticobasal degeneration. J Neurol Sci 2006;250: 120-123. 28. Montplaisir J, Petit D, Décary A, et al. Sleep and quantitative EEG in patients with progressive supranuclear palsy. Neurology 1997;49: 999-1003. 29. Aldrich MS, Foster NL, White RF, et al. Sleep abnormalities in progressive supranuclear palsy. Neurology 1989;25:577-581. 30. Arnulf I, Merino-Andreu M, Bloch F, et al. REM sleep behavior disorder and REM sleep without atonia in patients with progressive supranuclear palsy. Sleep 2005;28:349-354. 31. Diederich NJ, Leurgans S, Fan W, et al. Visual hallucinations and symptoms of REM sleep behavior disorder in Parkinsonian tauopathies. Int J Geriatr Psychiatry 2008;23:598-603.
1046 PART II / Section 11 • Neurologic Disorders 32. Cochen De Cock VC, Lannuzel A, Verhaeghe S, et al. REM sleep behavior disorder in patients with guadeloupean parkinsonism, a tauopathy. Sleep 2007;30:1026-1032. 33. Kish SJ, Chang LJ, Mirchandani L, et al. Progressive supranuclear palsy: relationship between extrapyramidal disturbances, dementia, and brain neurotransmitter markers. Ann Neurol 1985;18: 530-536. 34. Aarsland D, Andersen K, Larsen JP, et al. Prevalence and characteristics of dementia in Parkinson disease: an 8-year prospective study. Arch Neurol 2003;60:387-392. 35. Emre M. Dementia associated with Parkinson’s disease. Lancet 2003;2:229-237. 36. Comella CL, Ristanovic R, Goetz CG. Parkinson’s disease patients with and without REM behavior disorder (RBD): a polysomnographic and clinical comparison. Neurology 1993;43(Suppl. 2): A301. 37. Onofrj M, Thomas A, D’Andreamatteo G, et al. Incidence of RBD and hallucination in patients affected by Parkinson’s disease: 8-year follow-up. Neurol Sci 2002;23:S91-S94. 38. Boeve B, Silber M, Ferman T, et al. Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy. Mov Disord 2001;16:622-630. 39. Boeve B, Silber M, Ferman T, et al. REM sleep behavior disorder in Parkinson’s disease, dementia with lewy bodies, and multiple system atrophy. In: Bedard M, Agid Y, Chouinard S, et al, editors. Mental and behavioral dysfunction in movement disorders. Totowa, NJ: Humana Press; 2003. p. 383-397. 40. Comella CL, Nardine TM, Diederich NJ, et al. Sleep-related violence, injury, and REM sleep behavior disorder in Parkinson’s disease. Neurology 1998;51:526-529. 41. Gagnon JF, Bédard MA, Fantini ML, et al. REM sleep behavior disorder and REM sleep without atonia in Parkinson’s disease. Neurology 2002;59:585-589. 42. Rechtschaffen A, Kales A, editors. A manual of standardized terminology, techniques, and scoring system for sleep states of human subjects. Washington, DC: US Government Printing Office; 1968. US Public Health Service Publications No. 204. 43. Soikkeli R, Partanen J, Soininen H, et al. Slowing of EEG in Parkinson’s disease. Electroencephalogr Clin Neurophysiol 1991;79: 159-165. 44. Gagnon JF, Fantini ML, Bédard A, et al. Association between waking EEG slowing and REM sleep behavior disorder in PD without dementia. Neurology 2004;62:401-406. 45. Fantini ML, Gagnon J-F, Petit D, et al. Slowing of EEG in idiopathic REM sleep behavior disorder. Ann Neurol 2003;53: 774-780. 46. Vendette M, Gagnon JF, Décary A, et al. REM sleep behavior disorder predicts cognitive impairment in Parkinson disease without dementia. Neurology 2007;69:1843-1849. 47. Massicotte-Marquez J, Décary A, Gagnon JF, et al. Executive dysfunction and memory impairment in idiopathic REM sleep behaviour disorder. Neurology. 2008;70:1250-1257. 48. Marion MH, Qurashi M, Marshall G, Foster O. Is REM sleep Behaviour disorder (RBD) a risk factor of dementia in idiopathic Parkinson’s disease? J Neurol 2008;255:192-196. 49. Lobotesis K, Fenwick JD, Phipps A, et al. Occipital hypoperfusion on SPECT in dementia with Lewy bodies but not AD. Neurology 2001;56:643-649. 50. Minoshima S, Foster NL, Sima AA, et al. Alzheimer’s disease versus dementia with Lewy bodies: cerebral metabolic distinction with autopsy confirmation. Ann Neurol 2001;50:358-365. 51. Ferman TJ, Boeve BF, Smith GE, et al. Dementia with Lewy bodies may present as dementia and REM sleep behavior disorder without parkinsonism or hallucinations. J Int Neuropsychol Soc 2002;8: 907-914. 52. Boeve BF, Silber MH, Ferman TJ, et al. REM sleep behavior disorder and degenerative dementia: an association likely reflecting Lewy body disease. Neurology 1998;51:363-370. 53. Turner RS. Idiopathic rapid eye movement sleep behavior disorder is a harbinger of dementia with Lewy bodies. J Geriatr Psychiatr Neurol 2002;15:195-199. 54. Kosaka K, Tsuchiya K, Yoshimura M. Lewy body disease with and without dementia: a clinicopathological study of 35 cases. Clin Neuropathol 1988;7:299-305. 55. Mattila PM, Rinne JO, Helenius H, et al. Alpha-synuclein-immunoreactive cortical Lewy bodies are associated with cognitive
impairment in Parkinson’s disease. Acta Neuropathol 2000; 100:285-290. 56. Hurtig HI, Trojanowski JQ, Galvin J, et al. Alpha-synuclein cortical Lewy bodies correlate with dementia in Parkinson’s disease. Neurology 2000;54:1916-1921. 57. McKeith IG, Dickson DW, Lowe J, et al. Diagnosis and management of dementia with Lewy bodies: third report of the DLB consortium. Neurology 2005;65:1863-1872. 58. Grace JB, Walker MP, McKeith IG. A comparison of sleep profiles in patients with dementia with Lewy bodies and Alzheimer’s disease. Int J Geriatr Psychiatr 2000;15:1028-1033. 59. Boddy F, Rowan EN, Lett D, et al. Subjectively reported sleep quality and excessive daytime somnolence in Parkinson’s disease with and without dementia, dementia with Lewy bodies and Alzheimer’s disease. Int J Geriatr Psychiatry 2007;22:529-535. 60. Baumann CR, Dauvilliers Y, Mignot E, Bassetti CL. Normal CSF hypocretin-1 (orexin A) levels in dementia with Lewy bodies associated with excessive daytime sleepiness. Eur Neurol 2004;52:73-76. 61. Boeve BF, Ferman TJ, Silber MH, et al. Sleep disturbances in dementia with Lewy bodies involve more than REM sleep behavior disorder. Neurology 2003;60:A79. 62. Boeve BF, Silber MH, Parisi JE, et al. Synucleinopathy pathology and REM sleep behavior disorder plus dementia or parkinsonism. Neurology 2003;61:40-45. 63. Fujishiro H, Ferman TJ, Boeve BF, et al. Validation of the neuropathologic criteria of the third consortium for dementia with Lewy bodies for prospectively diagnosed cases. J Neuropathol Exp Neurol 2008;67:649-656. 64. Boeve BF, Silber MH, Ferman TJ. Current management of sleep disturbances in dementia. Curr Neurol Neurosci Rep 2002;2: 169-177. 65. Briel RC, McKeith IG, Barker WA, et al. EEG findings in dementia with Lewy bodies and Alzheimer’s disease. J Neurol Neurosurg Psychiatr 1999;66:401-403. 66. Barber PA, Varma AR, Lloyd JJ, et al. The electroencephalogram in dementia with Lewy bodies. Acta Neurol Scand 2000;101: 53-56. 67. Calzetti S, Bortone E, Negrotti A, et al. Frontal intermittent rhythmic delta activity (FIRDA) in patients with dementia with Lewy bodies: a diagnostic tool? Neurol Sci 2002;23:S65-S66. 68. Walker MP, Ayre GA, Cummings JL, et al. Quantifying fluctuation in dementia with Lewy bodies, Alzheimer’s disease, and vascular dementia. Neurology 2000;54:1616-1624. 69. Aharon-Peretz J, Masiah A, Pillar T, et al. Sleep–wake cycles in multi-infarct dementia and dementia of the Alzheimer type. Neurology 1991;41:1616-1619. 70. Erkinjuntti T, Partinen M, Sulkava R, et al. Sleep apnea in multiinfarct dementia and Alzheimer’s disease. Sleep 1987;10:419-425. 71. Sato K, Kamiya S, Okawa M, et al. On the EEG component waves of multi-infarct dementia seniles. Int J Neurosci 1996;86:95-109. 72. Signorino M, Pucci E, Belardinelli N, et al. EEG spectral analysis in vascular and Alzheimer dementia. Electroencephalogr Clin Neurophysiol 1995;94:313-332. 73. Tsuno N, Shigeta M, Hyoki K, et al. Fluctuations of source locations of EEG activity during transition from alertness to sleep in Alzheimer’s disease and vascular dementia. Neuropsychobiology 2004;50:267-272. 74. The Huntington’s Disease Collaborative Research Group. A novel gene containing a trinucleotide repeat that is expanded and unstable on Huntington’s disease chromosomes. Cell 1993;72:971-983. 75. Morton AJ, Wood NI, Hastings MH, et al. Disintegration of the sleep–wake cycle and circadian timing in Huntington’s disease. J Neurosci 2005;25:157-163. 76. Zoghbi HY, Orr HT. Glutamine repeats and neurodegeneration. Annu Rev Neurosci 2000;23:217-247. 77. Obrietan K, Hoyt KR. CRE-mediated transcription is increased in Huntington’s disease transgenic mice. J Neurosci 2004;24: 791-796. 78. Pallier PN, Maywood ES, Zheng Z, et al. Pharmacological imposition of sleep slows cognitive decline and reverses dysregulation of circadian gene expression in a transgenic mouse model of Huntington’s disease. J Neurosci 2007;27:7869-7878. 79. Hansotia P, Wall R, Berendes J. Sleep disturbances and severity of Huntington’s disease. Neurology 1985;35:1672-1674. 80. Wiegand M, Moller AA, Lauer CJ, et al. Nocturnal sleep in Huntington’s disease. J Neurol 1991;238:203-208.
CHAPTER 91 • Alzheimer’s Disease and Other Dementias 1047 81. Arnulf I, Nielsen J, Lohmann E, et al. Rapid eye movement sleep disturbances in Huntington disease. Arch Neurol 2008;65: 482-488. 82. Emser W, Brenner M, Stober T, et al. Changes in nocturnal sleep in Huntington’s and Parkinson’s disease. J Neurol 1988;235: 177-179. 83. Streletz LJ, Reyes PF, Zalewska M, et al. Computer analysis of EEG activity in dementia of the Alzheimer’s type and Huntington’s disease. Neurobiol Aging 1990;11:15-20. 84. Wieser HG, Schindler K, Zumsteg D. EEG in Creutzfeldt-Jakob disease. Clin Neurophysiol. 2006;117:935-951. 85. Wall CA, Rummans TA, Aksamit AJ, et al. Psychiatric manifestations of Creutzfeldt-Jakob disease: a 25-year analysis. J Neuropsychiatry Clin Neurosci 2005;17:489-495. 86. Meissner B, Körtner K, Bartl M, et al. Sporadic Creutzfeldt-Jakob disease: magnetic resonance imaging and clinical findings. Neurology 2004;63:450-456. 87. Landolt HP, Glatzel M, Blättler T, et al. Sleep–wake disturbances in sporadic Creutzfeldt-Jakob disease. Neurology 2006;66: 1418-1424. 88. Donnet A, Famarier G, Gambarelli D, et al. Sleep electroencephalogram at the early stage of Creutzfeldt-Jakob disease. Clin Electroencephalogr 1992;23:118-125. 89. World Health Organisation. Consensus on criteria for diagnosis of sporadic CJD. Wkly Epidemiol Rec 1998;73:361-365. 90. Steinhoff BJ, Zerr I, Glatting M, et al. Diagnostic value of periodic complexes in Creutzfeldt-Jakob disease. Ann Neurol 2004;56: 702-708. 91. Calleja J, Carpizo R, Berciano J, et al. Serial waking–sleep EEGs and evolution of somatosensory potentials in CreutzfeldtJakob disease. Electroencephalogr Clin Neurophysiol 1985;60: 504-508. 92. Terzano MG, Parrino L, Pietrini V, et al. Precocious loss of physiological sleep in a case of Creutzfeldt Jakob disease: a serial polygraphic study. Sleep 1995;18:849-858. 93. Harper DG, Stopa EG, McKee AC, et al. Differential circadian rhythm disturbances in men with Alzheimer disease and frontotemporal degeneration. Arch Gen Psychiatry 2001;58:353-360. 94. Besthorn C, Sattel H, Hentschel F, et al. Quantitative EEG in frontal lobe dementia. J Neural Transm 1996;47:169-181. 95. Yener GG, Leuchter AF, Jenden D, et al. Quantitative EEG in frontotemporal dementia. Clin Electroencephalogr 1996;27:61-68.
96. Pijnenburg YA, Strijers RL, Made YV, et al. Investigation of restingstate EEG functional connectivity in frontotemporal lobar degeneration. Clin Neurophysiol. 2008;119:1732-1738. 97. Boeve BF. Update on the diagnosis and management of sleep disturbances in dementia. Sleep Med Clin 2008;3:347-360. 98. Dauvilliers Y. Insomnia in patients with neurodegenerative conditions. Sleep Med 2007;8:S27-S34. 99. Singer C, Tractenberg RE, Kaye J, et al. A multicenter, placebocontrolled trial of melatonin for sleep disturbance in Alzheimer’s disease. Sleep 2003;26:893-901. 100. Ray WA, Federspeil CF, Schaffner W. A study of antipsychotic drug use in nursing homes: epidemiologic evidence suggesting misuse. Am J Public Health 1980;70:485-491. 101. Arnulf I, Konofal E, Merino-Andreu M, et al. Parkinson’s disease and sleepiness: an integral part of PD. Neurology 2002;58: 1019-1024. 101a. Cooke JR, Ayalon L, Palmer BW, et al. Sustained use of CPAP slows deterioration of cognition, sleep, and mood in patients with Alzheimer’s disease and obstructive sleep apnea: a preliminary study. J Clin Sleep Med 2009;5:305-309. 102. Srinivasan V, Pandi-Perumal SR, Cardinali DP, et al. Melatonin in Alzheimer’s disease and other neurodegenerative disorders. Behav Brain Functions 2006;2:15-37. 103. Wang JZ, Wang ZF. Role of melatonin in Alzheimer-like neurodegeneration. Acta Pharmacol Sin 2006;27:41-49. 104. Lyketsos CG, Lindell Veiel L, Baker A, et al. A randomized controlled trial of bright light therapy for agitated behaviors in dementia patients residing in long-term care. Intl J Geriatr Psychiatry 1999;14:520-525. 105. Van Someren E, Kessler A, Mirmiran M, et al. Indirect bright light improves circadian rest-activity rhythm disturbances in demented patients. Biol Psychiatry 1997;41:955-963. 106. Ancoli-Israel S, Gehrman P, Martin JL, et al. Increased light exposure consolidates sleep and strengthens circadian rhythms in severe Alzheimer’s disease patients. Behav Sleep Med 2003;1:22-36. 107. Kunz D, Mahlberg R. A two-part, double-blind, placebo-controlled trial of exogenous melatonin in REM sleep behaviour disorder. J Sleep Res 2010. In press. 108. Aurora RN, Zak RS, Maganti RK, et al. Standards of Practice Committee; American Academy of Sleep Medicine. Best practice guide for the treatment of REM sleep behavior disorder (RBD). J Clin Sleep Med 2010;6:85-95.
Epilepsy, Sleep, and Sleep Disorders Margaret Shouse and Mark W. Mahowald Abstract Epilepsy is the third most common neurologic disorder after stroke and Alzheimer’s disease in the United States. Sleep, sleep disorders, and epilepsy are commonly associated. It is well known that sleep and sleep deprivation increase the inci dence of parasomnias and seizure activity. Conversely, seizure disorders can affect the wake–sleep cycle. Sleep disorders— including parasomnias—can mimic, cause, or even be trig gered by epileptic phenomena, and vice versa. A high index of suspicion and a full awareness of the broad spectrum of sleep and epileptic phenomena is instrumental to an accurate diagnosis.1 Epilepsy refers to a host of seizure disorders characterized by uncontrolled abnormal brain electrical discharges associ ated with undesirable motor, verbal, or experiential phe nomena.2,3 These phenomena often occur during sleep.4 Electroclinical events include interictal discharges (IIDs), which are electrographically but not clinically evident, and ictal events, which are usually electrographically and clinically evident. There are many ways of classifying seizure disorders.2 In spite of considerable diversity in etiologies and in specific ictal or IID characteristics, epileptic seizure manifestations tend to be highly state dependent. Non–rapid eye movement (NREM) sleep is associated with increased incidence and spread of IIDs; clinical accompaniment is most often associated with localization-related epilepsies originating in temporal and frontal lobes.4-6 Rapid eye movement (REM) sleep is a relatively antiepileptic state in that spread of IID is anatomically local ized, and clinically evident seizures are usually suppressed.5,7,8
HISTORICAL ASPECTS In 1965, Gastaut and Broughton14 reported the clinical and polygraphic characteristics of sleep-related episodic phenomena in human patients. They outlined major symptoms of two major parasomnias, sleepwalking and sleep terrors. Both occur during NREM sleep, usually when the patient emerges from stage 4 NREM sleep. Prior to this study,14 these parasomnias were associated with seizure disorders. In 1968, Broughton15 questioned the pathophysiologic mechanisms underlying these paroxysmal (sudden) nocturnal events. Although parasomnias and seizure disorders exhibit common features such as abrupt onset, confusion, disorientation, and retrograde amnesia, Broughton proposed that most if not all of these episodes could be related to a disorder of arousal rather than to epilepsy. After Broughton’s pioneering work, the concept of an arousal disorder generating parasomnias was accepted, but subsequent studies also suggest that arousal disorders can provoke, represent, or be caused by seizure disorders. Certain predisposing factors in NREM sleep seem to increase IID and ictal epileptic events.4,5 The incidence of arousal-related paroxysms, such as sleep spindles, K-complexes, bursts of slow waves, and ponto-geniculo-occipital (PGO) spikes, is closely associated with the occurrence of 1048
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Arousal from NREM or REM sleep can also provoke or mimic seizures or parasomnias.9 The facilitation of sleep upon partial seizures depends in part on the location of the epileptic focus.10 The likelihood that the same basic brain circuitry generates both NREM sleep oscillations and electrical seizures with spike–wave complexes explains the close relationship between seizures and sleep.11 With the advent of neurophysiologic monitoring techniques, it has become obvious that state determination is a very complex and dynamic phenomenon involving multiple neural networks, neurotransmitters, neuropeptides, and neurohor mones, as well as a myriad of sleep-promoting substances. Given these complexities, it has become clear that determining state may be inexact, with components of two or all three states occurring simultaneously or oscillating rapidly. This concept of state dissociation in animals and humans has been extensively reviewed.12 These mixed or rapidly oscillating states result in fascinat ing and perplexing clinical phenomena that can easily be confused with epileptic events; conversely, these sleep disor ders may be perfectly imitated by epileptic events. Further more, other primary sleep disorders can trigger seizures, and conversely, seizures can trigger abnormal sleep phenomena. Clinically there is substantial overlap among epileptic, sleep, and psychiatric phenomena (Box 92-1). There are five primary determinants of the quality of night time sleep and of daytime alertness: homeostatic (duration of prior wakefulness), circadian (biological clock influence), age, drugs, and central nervous system (CNS) pathology.13 These factors determine the overall sleep–wake pattern and also play an integral role in epileptic events.
generalized or focal spikes, epileptiform spike-and-wave, and polyspike-and-wave in human and animal epilepsy.16,17 There is also a statistical relationship between the cyclic alternating pattern (CAP) of fluctuating cortical excitability with both epilepsy and sleep disorders.18,19
EPIDEMIOLOGY There are no definitive epidemiologic studies on the coincidence of parasomnias and seizure disorders, although available studies suggest that nocturnal seizures rarely represent parasomnias.14,15,20 Symptoms of parasomnias—such as nightmares, sleep terrors, violent behavior during sleep, sleepwalking, and REM sleep behavior disorder (RBD)— resemble seizure disorders (notably partial complex seizures), thus warranting comments on reports of incidence, etiology, and clinical course. The incidence of epilepsy has been studied most often in industrialized countries where overall population percentages are similar; available studies conducted in developing countries indicate a higher prevalence than in industrialized countries. The following statistics reflect well-conducted epidemiologic studies in the United States.21 The number of patients in the United States with
CHAPTER 92 • Epilepsy, Sleep, and Sleep Disorders 1049
Box 92-1 Overlap between Sleep and Epileptic Phenomena Sleep Disorder Normal Sleep Phenomena Sleep starts (hypnic jerks) Nightmares Hypersomnia Sleep deprivation Idiopathic central nervous system hypersomnia Narcolepsy • Cataplexy • Sleep paralysis • Hypnagogic hallucinations • Automatic behavior Recurrent hypersomnia • Kleine-Levin • Menstruation-related Sleep apnea that triggers seizures Insomnia Medical Psychiatric Psychological Constitutional Parasomnias Disorders of arousal • Confusional arousals • Sleepwalking • Sleep terrors • Sleepeating REM sleep behavior disorder Dreams, nightmares Enuresis Rhythmic movement disorder Periodic limb movement disorder
Posttraumatic stress disorder Cardiopulmonary disorders • Cardiac arrhythmias • Respiratory dyskinesias Gastrointestinal: paroxysmal choking Panic disorder Psychogenic dissociative disorders Seizures Normal Sleep Phenomena Seizures manifesting as sleep-onset sensorimotor phenomena or nightmares Hypersomnia Hypersomnia as a manifestation of having frequent nocturnal seizures resulting in recurrent arousals or hypersomnia as an accompaniment of epilepsy • Akinetic • Fugue states • Partial complex seizures • Subclinical status • Poriomania Recurrent seizures resulting in prolonged periods of “sleepiness” Seizures resulting in apnea Insomnia Seizures whose arousals
sole
manifestation
is
recurrent
Parasomnias Mesial, frontal, temporal lobe seizures manifesting with complex, bizarre behavior, hypnogenic (nocturnal) paroxysmal dystonia, or autonomic (diencephalic) seizures
Modified from Mahowald MW, Schenck CH: Sleep disorders. In: Engel J Jr, Pedley TA, editors: Epilepsy: a comprehensive textbook. Philadelphia: Lippincott-Raven; 1997. p. 2705-2715 (with permission).
a diagnosis of epilepsy is about 2.5 million, and the cumulative lifetime incidence ranges from 1.3% to 3.1% of the population by the age of 80 years. Epilepsy is the third most common neurologic disorder after stroke and Alzheimer’s disease in the United States. Epilepsies may be categorized as generalized (40%), localization related (57%), or unclassified (3%). Localization-related epilepsies may be further subclassified as partial complex (36%), simple partial (14%), and partial unknown (7%). Localization-related epilepsies, particularly partial complex seizure disorders with tonic-clonic convulsions, are the prototypical pure sleep epilepsies; nearly 60% of these patients exhibit convulsions only during sleep.22,23 Most of these nocturnal seizure disorders are attributed to temporal or frontal lobe foci.6 Onset can occur at any time, although the average peak age at onset is in adolescence.22 Electroclinical symptoms tend to persist, and over time ictal events or IID events, or both, are likely to disperse across the sleep–wake cycle.21-23 Age at onset of parasomnias such as sleepwalking and sleep terrors is believed to be in childhood. The earlier age at onset of some parasomnias can provide one criterion for differential diagnosis from some nocturnal seizure disorders; however, many epilepsies—such as partial
complex seizure disorders—do not remit spontaneously.21-24 Hereditary factors can be more prevalent in some parasomnias than in partial complex seizure disorders. Still, the most definitive criterion for differential diagnosis is polygraphic evidence of epileptic seizure discharge, and this may be difficult to obtain from surface recordings of patients with deep temporal or frontal lobe foci.25 It is likely that the rarity of nocturnal seizures manifesting as other parasomnias is more apparent than real, the correct diagnosis having been overlooked for lack of consideration.
PATHOGENESIS The hypothalamic and brainstem generators of sleep and arousal have diffuse ascending and descending projections26 that give rise to a number of distinguishing physiologic characteristics called components. Components can be tonic or phasic. Tonic components are sustained background activity, such as degree of electroencephalographic (EEG) synchronization and muscle tone. Phasic components include periodic transients, such as sleep spindles, K-complexes, and muscle twitches. The association of these tonic and phasic events is important to the integrity
1050 PART II / Section 11 • Neurologic Disorders
of sleep states. Dissociation or abnormality of these components likely contributes to a variety of sleep, arousal, and seizure disorders as well as their interaction. Direct experimental evidence using dissociative manipulations is best documented with respect to spread of EEG and clinically evident seizures that can coexist with or masquerade as parasomnias.27 Two state-specific components affecting epilepsy are the degree to which cellular discharge patterns are synchronized and alterations in antigravity muscle tone.5 NREM sleep and drowsiness differ from alert waking and REM sleep in that EEG activity is synchronized and postural muscle tone is diminished. REM sleep differs from NREM sleep in that EEG activity is desynchronized, and it differs from waking and NREM sleep in that postural muscle tone is absent. REM sleep has sometimes been called “paradoxical sleep”28 because it is characterized by a “highly active brain in a paralyzed body.”29 During NREM sleep, virtually every cell in the brain discharges synchronously, and the discharge can even reach paroxysmal levels similar to those in epileptic states.30 This occurs to a lesser extent in drowsiness. Lasting oscillations of rhythmic burst–pause firing patterns result in concerted synaptic actions. Synchronous synaptic effects, whether excitatory or inhibitory, are likely to augment the magnitude and propagation of postsynaptic responses, including epileptic discharges. During REM sleep and alert waking, cells discharge asynchronously.31 The divergent synaptic signals associated with asynchronous discharge patterns are less likely to augment the magnitude or propagation of epileptic EEG discharges. Skeletal muscle tone also varies by sleep or waking state. Antigravity muscle tone is preserved in NREM sleep and waking,29,32 thus permitting seizure-associated and conceivably parasomnia-associated movement. Profound lower motor neuron inhibition occurs in REM sleep,29,33 creating virtual paralysis (but sparing the diaphragm to permit continued respiration). Disruption of this important component of REM sleep might underlie RBD and can influence clinically evident motor seizures. These different EEG and skeletal motor components can be experimentally dissociated, as depicted in Figure 92-1.7 Figure 92-1A shows normal feline REM sleep. Figure 92-1B shows that NREM sleeplike EEG synchrony during REM sleep can be induced by systemic administration of atropine. Although it is not shown in the figure, atropine also synchronizes the waking EEG. EEG-synchronizing effects are presumably achieved by blocking acetylcholine (ACh) release from cells in the nucleus basalis of the forebrain and pedunculopontine-peribrachial nuclei of the brainstem, because these are the critical generators of the asynchronous EEG discharges that occur in waking and to a greater extent in REM sleep.26,34 Figure 92-1C shows selective loss of postural muscle tone induced by a lesion in the pontine generators of REM sleep atonia.31 Neural generators are thought to be cholinoceptive and glutaminergic cells in the brainstem atonia regions,31,35 which hyperpolarize lower motor neurons.33 Dissociating these EEG and motor components significantly and differentially influences electrographic and clinical seizure manifestations, as illustrated in Figure 92-2. Figure 92-2A shows the distribution of penicillin-
induced spike–wave complexes during intact NREM and REM sleep states. Figure 92-2B shows the effects of atropine administration. The REM sleep EEG is synchronized, and the spike–wave discharge rate is comparable with that in NREM sleep. Although it is not shown in the figure, atropine similarly synchronizes the waking EEG in conjunction with an increase in spike–wave discharge rate. Unlike waking and NREM sleep, there is no clinical manifestation during REM sleep, presumably because of the skeletal motor paralysis unique to that state. Figure 92-2C shows that a pontine lesion eliminates REM sleep atonia so that a clinically evident myoclonic seizure occurs in REM sleep. These results are supported by other experimental and clinical findings indicating that substrates of state-specific components rather than integrity of the state per se can be salient determinants of seizure propagation. Agents that synchronize the EEG, such as cholinergic or noradrenergic antagonists, have proconvulsant effects.36-38 Conversely, agents that desynchronize the EEG discourage epileptic EEG discharge propagation. Examples are cholinergic and noradrenergic agonists39-42 as well as beta-carbolines such as abecarnil,43 which act on central benzodiazepine receptors. Finally, pharmacologic manipulations that induce atonia, such as carbachol infusion into the brainstem, also block clinical motor accompaniment.41 Consistent observations have been reported in experimental models of primary generalized epilepsy, such as electroconvulsive shock, penicillin epilepsy, and photosensitive epilepsy7,37,39; in animal models of localization-related epilepsies, such as limbic system kindling and the cortical alumina cream preparation41,44; and in the clinical literature on symptomatic generalized epilepsies such as West’s syndrome.40 Collectively, the findings confirm that cellular discharge patterns and alterations in tone affect electrographic and clinically evident seizure manifestations in diverse epileptic syndromes, including those that mimic parasomnias. There is growing evidence that glial cells play a role in epilepsy.45,46
CLINICAL FEATURES This section discusses various areas of overlap and confusion between sleep disorders and seizures. These areas include normal events, hypersomnia, insomnia, and parasomnias (see Box 92-1). Normal Sleep Phenomena Sleep Starts Many healthy people experience sleep starts (hypnic jerks) during the transition from waking to sleep. The most common is the motor sleep start, a sudden jerk of all or part of the body, occasionally awakening the victim or bed partner.47,48 Variations include the visual (flashes of light, fragmentary visual hallucinations), auditory (loud bangs, snapping noises), and somesthetic (pain, floating, something flowing through the body) sleep starts, which occur without the body jerk.49-51 Sleep starts represent a normal (although not understood) physiologic event, and they should not be confused with seizures or other neurologic conditions. It is likely that the exploding head syndrome, characterized by a sensation of a loud sound like an explo-
CHAPTER 92 • Epilepsy, Sleep, and Sleep Disorders 1051
Normal REM Sleep Motor cortex VL Thalamus EOG LGN
A
EMG
REM Sleep without EEG Desynchrony: Systemic Atropine Motor cortex
VL Thalamus EOG LGN
B
EMG
REM Sleep without Atonia Motor cortex VL Thalamus EOG LGN
C
EMG 2 sec
100µV
Figure 92-1 A, The top tracing shows normal REM sleep, evidenced by EEG desynchronization and atonia with periodic bursts of phasic events, including REMs and ponto-geniculo-occipital (PGO) spikes. B, The middle tracing shows that systemic atropine selectively abolishes EEG desynchronization. Instead, there is a NREM sleeplike EEG with synchronized background and sleep spindles. However, atonia is intact, as are eye movements and PGO spikes. Clustering of PGOs is diminished as customarily reported. C, The bottom tracing shows that a pontine lesion selectively eliminates atonia. Note presence of tonic electromyographic (EMG) activity in the bottom channel of this tracing. (From Shouse MN, Siegel JM, Wu FM, et al: Mechanisms of seizure suppression during rapid-eye-movement (REM) sleep in cats. Brain Res 1989;505:271-282.)
1052 PART II / Section 11 • Neurologic Disorders
Penicillin Trial During Normal Sleep SWS
REM Sleep
EEG EOG
A
LGN EMG SWS
Penicillin Trial after Atropine REM Sleep without EEG Desynchrony
EEG EOG
B
LGN EMG SWS
Penicillin Trial after Pontine Lesion REM Sleep without Atonia
EEG EOG LGN
C
EMG 2 sec
100 µV
Figure 92-2 Systemic penicillin epilepsy during slow wave sleep (SWS), the equivalent of NREM sleep in humans (left), and REM sleep (right) before (A) and after (B and C) dissociation of REM-sleep components. Spike–wave paroxysms are visible in the EEG tracing, and myoclonic seizures were associated with electromyographic (EMG) discharges in this cat, as long as lower motor neuron activity is present. (From Shouse MN, Siegel JM, Wu FM, et al: Mechanisms of seizure suppression during rapid-eye-movement [REM] sleep in cats. Brain Res 1989;505:271-282.)
sion or a sensation of bursting of the head,52 is a variant of a sensory sleep start. Similar phenomena might represent the sole manifestation of a seizure.53 There is a single case report of a brainstem lesion associated with auditory sleep starts.54 Nightmares Nightmares are frightening dreams that usually awaken the sleeper from REM sleep (see Chapter 97). Unlike disorders of arousal such as sleep terrors (see later), nightmares are not usually associated with prominent motor or vocal behavior or autonomic excitation, and the arousal results in immediate full wakefulness, with memory for the dream sequence of events that caused the awakening.55 Seizures can manifest as recurrent dreams, nightmares, or disorders of arousal such as sleepwalking and sleep terrors. The diagnosis of seizure-related dreams and nightmares may be overlooked, because the symptom is misinterpreted as a primary sleep phenomenon.56-59 Autosomal dominant frontal epilepsy can also manifest as recurrent nightmares.60 Hypersomnia Epilepsy The sole manifestation of nocturnal seizures may be simple arousals that may or may not be perceived by the patient. If enough arousals occur, the resulting sleep fragmentation will be apparent, with symptoms of severe excessive daytime sleepiness (Fig. 92-3). These seizure-induced arousals may be associated with very minor motor phenomena.61
Some patients with seizures are hypersomnolent during the day, even after discontinuing antiepileptic medication. Seizure-free preadolescent children with epilepsy are sleepier than healthy controls. In one study, there was no difference in objective sleepiness in children with epilepsy on or off medication, suggesting that antiepileptic drugs do not necessarily cause the daytime sleepiness.62 Excessive daytime sleepiness in a patient on antiepileptic medications must not summarily be attributed to antiepileptic medication.63-65 Narcolepsy Narcolepsy is a genetically determined disorder characterized by excessive daytime sleepiness, cataplexy (the sudden loss of muscle tone triggered by emotionally laden events), sleep paralysis, hypnagogic hallucinations, and automatic behavior during which prolonged, complex activities may be performed without conscious awareness or recall.66,67 The spell-like nature of some sleep attacks, cataplexy, and sleep paralysis may be mistaken for seizures. Conversely, atonic (epileptic negative myoclonus) or inhibitory seizures may mimic cataplexy,68-74 and the periods of automatic behavior are often misdiagnosed as partial complex seizures, postictal confusion, or priomania.75,76 The incomplete and waxing and waning nature of cataplexy can imitate tonic–clonic seizure activity. Periodic Hypersomnia (Kleine-Levin Syndrome) The Kleine-Levin syndrome is a poorly understood condition characterized by recurrent periods of hypersomnia. The often-cited association with adolescent males and unusual behavior such as hypersexuality and megaphagia
CHAPTER 92 • Epilepsy, Sleep, and Sleep Disorders 1053
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F7-T3
P.B. 2-8-88
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Airflow
off off off LOC-A1 ROC-A1 C3-A2 O2-A1 Chin EMG L Anterior Tibialis R Anterior Tibialis 50 µV
1 sec
Figure 92-3 Polysomnographic tracing of a child with a history of a “well-controlled” seizure disorder who complained of severe excessive daytime sleepiness. Notice the EEG evidence of arousals, which were the sole manifestation of seizure activity. The seizure-induced arousal index was nearly 100 per hour of sleep, clearly explaining the daytime complaint.
have been overrated.77,78 Menstruation-related periodic hypersomnia might represent a variant of the Kleine-Levin syndrome.79 Similar recurrent episodes of hypersomnia may be caused by “ictal sleep” lasting 13 days at 10- to 60-day intervals.80,81 Sleep-Disordered Breathing There is an interesting and important relationship between sleep-disordered breathing and seizures (Video 92-1). Nocturnal seizures, probably triggered by periods of hypoxemia, may be the presenting symptom in some persons with obstructive sleep apnea or sleep-related hypoventilation.82,83 Furthermore, sleep apnea can exacerbate seizures in patients who have epilepsy that is caused by sleep disruption, sleep deprivation, hypoxemia, or decreased cerebral blood flow.84 Obstructive sleep apnea may be associated with seizure occurrence in older adults with epilepsy.85 Identification and treatment of sleep-disordered breathing in persons with seizures can improve seizure control.86,87 Some seizure-like spells associated with sleep apnea are actually caused by episodes of cerebral anoxia.88
Seizures can also cause periods of apnea, often repetitive, and can closely mimic the conditions of obstructive or central sleep apnea.89-92 Figure 92-4 shows repetitive apneas as the sole manifestation of seizures, and Figure 92-5 shows obstructive sleep apnea inducing electrical seizure activity. Insomnia Paroxysmal, otherwise unexplained awakenings may be the sole manifestation of nocturnal seizures and result in the complaint of insomnia.93-98 Some patients with occasional paroxysmal periodic motor attacks during sleep have very frequent (every 20 to 60 seconds) subclinical arousals causing severe sleep fragmentation.99 These paroxysmal arousals may be due to deep epileptic foci.100 The arousal preceding nocturnal seizures may be the initial manifestation of the seizure.101 Animal studies support the concept of frequent arousals as the manifestation of seizures.102 This might explain why many patients with epilepsy report frequent, otherwise unexplained nocturnal awakenings.103
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LOC-A1
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ROC-A1 C3-A2 C4-A1 O1-A2 Chin EMG L Anterior Tibialis EEG
Respitrace
Airflow (mask) SUM
Chest
1 sec
Abdomen SO2 Figure 92-4 Polysomnographic tracing of a 56-year-old man with a long-standing history of well-controlled generalized seizures who developed severe progressive excessive daytime sleepiness. The polysomnogram (PSG) revealed 22 central apneas per hour as the sole manifestation of seizures. Aggressive medical management was unsuccessful. There was marked improvement in his excessive daytime sleepiness following a right frontal lobectomy. (From Mahowald MW, Schenck CH. Sleep disorders. In: Engel J Jr, Pedley TA editors: Epilepsy: a comprehensive textbook. Philadelphia: Lippincott-Raven; 1997, pp. 2705-2715.)
Parasomnias Disorders of Arousal Disorders of arousal are the most common and impressive of the NREM sleep parasomnias, and they may readily be confused with epileptic phenomena (see Chapter 94). These occur on a continuum ranging from confusional arousals to sleepwalking to sleep terrors. Disorders of arousal may be difficult to differentiate from nocturnal seizures, and vice versa.104,105 Preservation of consciousness during seizures can lead to their being confused with disorders of arousal or psychogenic conditions.106 Crying (dacrystic) or laughing (gelastic) seizures may be misinterpreted as confusional arousals or sleep terrors.107,108 Both disorders of arousal and seizures may be related to the menstrual cycle.109-111 Arousals of any sort may serve to trigger a disorder of arousal. Therefore, any underlying condition resulting in arousal can cause a disorder of arousal, including sleep apnea, gastroesophageal reflux, or seizures. Thus the clinical event of a sleepwalking or sleep terror episode may, in fact, represent an epiphenomenon of a completely different underlying sleep disorder.20 It is common clinical experience to see an improvement in disorders of arousal following effective treatment of obstructive sleep apnea. Conversely, effective treatment of obstructive sleep apnea with nasal continuous positive airway pressure (CPAP) can result in disorders of arousal, presumably associated with deep NREM-sleep rebound.112,113 It must be remembered that sleep terrors and seizures can coexist in the same person.27
REM Sleep Behavior Disorder REM sleep behavior disorder is a condition in which the usual atonia of REM sleep is absent, hypothetically allowing patients to act out their dreams, often with violent or injurious results (see Chapter 95). RBD is typically a disorder of older men and is often misdiagnosed as a nocturnal seizure or psychogenic event. RBD is readily diagnosable by formal sleep studies, which reveal the absence of somatic muscle atonia of REM sleep. RBD responds very well to clonazepam.114,115 Just as RBD can masquerade as nocturnal seizures, the converse is also true.116 Dream and Nightmare Disturbances Dreams (particularly recurrent dreams) or nightmares as the primary manifestation of nocturnal seizures have been well documented. Recurrent dreams as the manifestation of seizures have been well described.57 Enuresis Enuresis was formerly classified as a disorder of arousal, implying a relationship with NREM or slow-wave sleep.15 However, enuresis can occur during either NREM or REM sleep.117,118 Enuresis may be the sole manifestation of nocturnal seizures.20 Rhythmic Movement Disorder Rhythmic movement disorder refers to a number of actions characterized by stereotyped movements (rhythmic oscillation of the head or limbs, head banging, or body rocking during sleep) seen most often in childhood and rarely in
CHAPTER 92 • Epilepsy, Sleep, and Sleep Disorders 1055
964
965
LOC-A1 ROC-A1 C3-A2 Chin EMG L-R Anterior Tibialis EEG F7-T3 T3-T5 T5-O1 F8-T4 T4-T6 T6-O2 F3-P3 F4-P4
Respitrace
Airflow
1 sec
Chest Abdomen
Tachygraph SO2 Figure 92-5 Polysomnographic tracing showing electrical seizure activity beginning during an episode of obstructive sleep apnea.
adults. Rhythmic movement disorder can occur during any stage of sleep, may be familial, and is not usually associated with underlying psychiatric or psychological conditions.119-121 Rarely, rhythmic movement disorder is the sole manifestation of a seizure.20 Periodic Limb Movement Disorder Periodic limb movement disorder (PLMD) is a diagnosis determined by polysomnography. It is characterized by periodic (every 20 to 30 seconds) dorsiflexion of the great toe or foot or flexion of the entire leg. These movements are not perceived by the patient, and they may be asymptomatic or associated with the complaint of either excessive daytime sleepiness or insomnia.122,123 When prominent, these movements may be confused with myoclonic seizure activity or can actually represent epileptic phenomena.124 Propriospinal myoclonus (Video 92-2). May also be confused with periodic limb movement disorder, and the patient can present with the complaint of insomnia or sleep-related movements that are bothersome to the bed partner.125,126 Periodic limb movement disorder may be particularly dramatic in patients with underlying renal failure.127,128
Posttraumatic Stress Disorder Posttraumatic stress disorder (PTSD) is often associated with subjective sleep complaints including nightmares and sleep terror–like experiences.129 It may be confused with nocturnal panic or seizures manifesting solely as arousals with fearful affect. Seizures The behavior associated with nocturnal seizures is often bizarre (Videos 92-3 and 92-4). The seizures thus can masquerade as primary sleep parasomnias, secondary sleep parasomnias, or psychiatric conditions.130 The following seizure types are particularly likely to result in diagnostic dilemmas. Classified Seizures Classified seizures often occur during sleep.2 In many people with epilepsy, seizures occur exclusively during sleep, increasing the likelihood of a misdiagnosis of a primary sleep disorder. A conservative estimate is that 10% of patients with epilepsy display seizures exclusively during sleep.131 One type of seizure that typically occurs predominantly in the sleep period is benign childhood epilepsy with centrotemporal spikes (BECT), also known as benign
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LOC-A1
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439
1 2 3 4 5
Submental EMG L-R Anterior Tibialis FP1-F7 F7-T3
6 7 8 9 10
T3-T5 11 T5-O1 12 FP2-F8 13 F8-T4
14
T4-T6 T6-O1 9 Figure 92-6 Polysomnographic study showing the prominent state-dependent nature of left-sided centromidtemporal spikes, present almost exclusively during NREM sleep.
Rolandic epilepsy. This form of epilepsy is characterized by unilateral somatosensory onset of paresthesias of the tongue, lips, gums, and cheek, with tonic or tonic–clonic movement of the face, lips, tongue, and pharyngeal muscles, and is associated with drooling. The electrical EEG spike discharges are typically activated by sleep (Fig. 92-6).132 Unusual Behavioral Seizures Seizures of frontal lobe origin can manifest as bizarre behavior such as running, loud vocalization, or cursing (Videos 92-5 to 92-7). The extraordinary behavior and the tendency for the behavior to occur during sleep and to cluster in time promote misdiagnosis (often as a disorder of arousal, RBD, or psychogenic spells).130,133-138 Autosomal dominant nocturnal frontal lobe epilepsy (ADNFE) can manifest with predominantly or exclusively sleep-related motor behavior,137,139 as can supplementary sensorimotor seizures.140 In retrospect, it is probable that many reported unusual nocturnal seizures were due to ADNFE. This condition is characterized by a wide variety of seizure manifestations, previously termed “episodic nocturnal wanderings,” and “hypnogenic (nocturnal) paroxysmal dystonia.” The seizures often involve hyperkinetic
thrashing activity with dystonic posturing, often with vocalization. In addition to the behavioral events, patients with ADNFE can experience innumerable brief arousals from sleep, the sole manifestation of the seizure. The attacks are usually brief and without aura or postictal confusion. The EEG is often obliterated by movement artifact, which makes video-EEG monitoring mandatory.141,142 ADNFE often responds to carbamazepine.60 There is evidence that ADNFE represents a channelopathy.143-145 Similar clinical events can also arise in the temporal region.146,147 Nocturnal frontal lobe epilepsy may be particularly difficult to differentiate from disorders of arousal.105,148,149 Episodic nocturnal wanderings are a manifestation of ADNFE. These wanderings, which respond to anticonvulsants, may be indistinguishable by history from sleepwalking and sleep terrors. The patients ambulate, vocalize, and display violent behavior during sleep. Not all exhibit waking EEG abnormalities. There is growing evidence that many of these cases represent epileptic phenomena and are actually ambulatory automatisms.150 Nocturnal paroxysmal dystonia (NPD) is another manifestation of ADNFE. It is characterized by predominantly
or exclusively nocturnal episodes of coarse, occasionally violent, movements of the limbs associated with tonic spasms, often occurring multiple times nightly. Vocalization or laughter can occur. EEGs between events are normal; during events, EEGs display movement artifact, often without clear evidence of electrical seizure activity.151,152 The cyclic alternating pattern of cortical excitability may play a modulatory role in this condition.19 It is clear that NPD is a seizure disorder.153 NPD may be unilateral,154 and there can be a family history.155 Nocturnal and diurnal paroxysmal dystonia may exist in the same patient, as can reflex and hypnogenic paroxysmal dystonia. There is considerable overlap among the different clinical categories of paroxysmal dyskinesias.156 NPD may be posttraumatic157 and can coexist with panic disorder.158 Carbamazepine is often very effective in eliminating these spells. Vigilance level–dependent tonic seizures159 and familial paroxysmal hypnogenic dystonia155 likely represent variants of this condition. Pure tonic seizures also likely represent a manifestation of ADNFE with arousal (or paroxysmal polyspike activity with arousal). They appear as insomnia or hypersomnia due to seizure-induced arousals or sleep fragmentation. An interesting subtype of hypnic tonic postural seizures has been described in 10 children, many with a positive family history.160 This may be a benign epilepsy syndrome similar to benign childhood epilepsy with centrotemporal spikes,161 childhood epilepsy with occipital paroxysms,162,163 and primary reading epilepsy.160 Autonomic or diencephalic seizures are thought to be rare and could occur with such manifestations as intermittent or paroxysmal apnea,91,164 stridor,165 vomiting,166 coughing,167 laryngospasm,168,169 chest pain and arrhythmias,170-173 paroxysmal flushing, and localized hyperhidrosis.174,175 Isolated autonomic symptoms are a well-documented manifestation of seizures and are probably much more common than generally suspected. These simple autonomic seizures are easily confused with other primary or secondary sleep parasomnias or are misattributed to disorders of other organ systems.176 Electrical Status Epilepticus of Sleep Electrical status epilepticus of sleep (ESES) may be detected during a polysomnogram (PSG) performed for other reasons and is characterized by continuous spike and wave activity during NREM sleep.177 ESES is seen in children who may have a history of seizures or neurologic dysfunction. The prognosis is variable, because ESES can be asymptomatic.178 ESES may share some features with the Landau-Kleffner syndrome.179 Cardiopulmonary Manifestations Cardiac Arrhythmias Cardiac arrhythmias, including asystole, may be a manifestation of seizures masquerading as nocturnal cardiac abnormalities.180,181 Conversely, primary cardiac events (e.g., prolonged QT interval) can manifest as seizures.182 Seizures can manifest as syncope,183 or vice versa.184 Respiratory Dyskinesias Peculiar respiratory irregularities can occur or persist during the sleep period. Examples include segmental
CHAPTER 92 • Epilepsy, Sleep, and Sleep Disorders 1057
myoclonus (such as palatal myoclonus185 or diaphragmatic flutter186) and paroxysmal dystonia.187 Respiratory dyskinesias may also be the manifestation of neuroleptic-induced dyskinesias, which do not always persist during sleep.188 These dyskinesias should be differentiated from unusual nocturnal seizures that manifest with primarily or exclusively respiratory symptoms.89 Gastrointestinal Manifestations The sole manifestation of nocturnal seizures may be paroxysmal choking.189
Case Study A girl who was 3 years and 9 months old and who had tuberous sclerosis was referred for evaluation of progressively severe nocturnal choking and gagging episodes that began at 11 2 years of age. There was a remote history of diurnal spells, felt to be seizures, that resolved spontaneously. Aggressive treatment for gastroesophageal reflux had been ineffective. Her father, a nurse anesthetist, was so concerned that she might die during one of these spells that he slept in the same bed with her and kept an intubation tray at her bedside. A sleep study was requested to evaluate for sleepdisordered breathing, because a tonsillectomy and adenoidectomy were being considered as treatment for these nocturnal choking spells. Because of the possibility of nocturnal seizures, a full-seizure montage was employed. Numerous paroxysmal gen eralized bursts of electrical seizure activity, occasion ally associated with coughing or gagging sounds, were present (Fig. 92-7). Carbamazepine adminis tered at bedtime resulted in immediate cessation of the nocturnal gagging episodes.
Nocturnal Panic Attacks Nocturnal panic attacks can occur in patients with diurnal panic or, rarely, can precede the appearance of diurnal panic. In some cases, panic attacks are exclusively nocturnal.190 The striking similarity of the symptoms of dream anxiety attack, sleep terrors, nocturnal seizures, and nighttime panic urges extreme caution in diagnosis. Obstructive sleep apnea can also cause symptoms of nocturnal panic attacks.191 The common association of the affect of fear as an accompaniment of nocturnal seizures intensifies their confusion with nocturnal panic attack. It must be remembered that seizures and panic can coexist.192 Psychogenic Dissociative States Complex and potentially injurious behavior, occasionally confined to the sleep period, may be the manifestation of a psychogenic dissociative state (Video 92-8). A history of childhood physical or sexual abuse, or both, is virtually always present but may be difficult to elicit. In this condition, unlike other parasomnias or nocturnal seizures, during EEG monitoring the complex behavior is seen to arise from clear EEG-determined wakefulness.193 Pseudoseizures can also arise from apparent sleep.193
1058 PART II / Section 11 • Neurologic Disorders Cursor: 01:57:47, Epoch 384-Awake
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FP1-F3 500 µV F3-C3 250 µV C3-P3 250 µV P3-O1 250 µV FP2-F4 250 µV F4-C4 250 µV C4-P4 250 µV P4-O2 250 µV FP1-F7 500 µV F7-T3 250 µV T3-T5 250 µV T5-O1 250 µV FP2-F8 250 µV F8-T4 250 µV T4-T6 250 µV T6-O2 250 µV FZ-CZ 250 µV ECG 1 mV Airflow 256000V
Figure 92-7 Polysomnographic study with a full-seizure montage showing generalized paroxysmal rhythmic activity representing electrical seizure activity. This activity was occasionally associated with coughing or gagging and was followed by an arousal.
DIAGNOSTIC EVALUATION Clinical differentiation between sleep disorders and epileptic events can be difficult, if not impossible, because primary or secondary sleep phenomena can perfectly mimic epileptic phenomena and vice versa. Both epileptic and sleep phenomena should be considered in any case of recurrent, stereotyped, and inappropriate unusual sleeprelated events. The decision to investigate unusual nocturnal events depends upon the clinical situation. The most common condition is the disorder of arousal, which is very common (and normal) in the general population. Simple sleepwalking or sleep terrors can readily be diagnosed clinically. Indications for formal evaluation include behavior that is potentially injurious or violent, that causes disruption for other household members, that results in excessive daytime sleepiness, or that displays unusual clinical features.194 Clinical differentiation between sleep disorders and epileptic phenomena may be most difficult, and misdiagnosis in both directions is common, particularly in the absence of a history of diurnal spells. Waking and sleep-deprived EEGs might not reveal the diagnosis,195,196 necessitating all-night polysomnographic study using a full seizure montage and continuous video recording.197 Even with video recording, interobserver reliability may be poor.198 A number of clinical criteria have been developed to differentiate among the various conditions resulting in complex behaviors arising from the sleep period, but none
is failsafe.149,199-202 Abbreviated EEG montages are inadequate in the differentiation of seizures and nonepileptic events arising from sleep during polysomnography.203 Exclusively nocturnal seizures may be uncommon, but they are routinely misdiagnosed and should never be overlooked as the possible etiology in any sleep-related behavior that is recurrent, stereotyped, or inappropriate, regardless of the specific nature of that behavior. Ambulatory EEG monitoring has led to the misdiagnosis of functional psychiatric disease in a number of our patients who were subsequently demonstrated to have bona fide nocturnal seizures. Erroneous psychogenic branding is reinforced by the bizarre nature of the spells and by the fact that environmental clues may play a role in the context of psychomotor seizures.204 Tassinari has proposed that one explanation for the similarity of motor activities associated with nocturnal seizures and disorders of arousal is that both are due to release of activities generated by central pattern generators triggered by different phenomena.205 Misdiagnosis is common even following formal and appropriate PSG evaluation. Reasons for misdiagnosis include:206 • Obscuration of the scalp EEG by movement artifact. • Absence of scalp-EEG manifestation of the seizure activity. • EEG seizure manifestation appearing to be an arousal pattern. • Absence of EEG or clinical postictal period.
Extensive polysomnographic monitoring employing a full-scalp EEG montage is mandatory. Because the clinical events may be infrequent, multiple studies may be necessary to capture an event. Continuous audiovisual monitoring and recording are indicated, and detailed technician observations are invaluable. The difficulties in evaluating unusual sleep-related events emphasize the necessity of extensive, in-person laboratory monitoring with interpretation of all data (clinical, EEG, sleep, video, and technologist-provided information) by personnel experienced in both sleep medicine and epileptology.
TREATMENT Effective treatment is available for almost all parasomnias, regardless of cause, and is predicated upon an accurate diagnosis. If seizures are responsible for the sleep–wake complaint, treatment is similar to that for other seizure disorders.207 Surgical treatment may be effective in drugresistant nocturnal frontal lobe epilepsy.208 If a primary sleep disorder (such as narcolepsy, sleep apnea, or other parasomnia) is identified, therapy is dictated by the specific diagnosis. Vagal nerve stimulation for treatment of seizures has been reported to improve daytime alertness209; however, vagal nerve stimulation can induce sleep apnea, worsening daytime sleepiness.210 CLINICAL COURSE Few longitudinal studies of nocturnal seizures are available. In some patients the seizures remit spontaneously, and in some patients the seizures become diurnal.211 PITFALLS AND CONTROVERSIES Nocturnal seizures are undoubtedly much more common than generally believed. Underdiagnosis is due to the lack of clinical suspicion. The etiologies of many nocturnal paroxysmal events are not clearly defined. Differential diagnosis of epileptic versus nonepileptic manifestations depends primarily on the use of extracranial recordings, although intracranial EEG recordings are sometimes necessary. Specifically, epileptic seizures originating from mesioorbitofrontal sites often cannot be recorded extracranially, and attacks of uncertain etiology such as sleepwalking, screaming, and complex automatisms may be inaccurately diagnosed as parasomnias. Some evidence also suggests that short-lasting paroxysmal dystonia attacks represent sleep-related frontal lobe seizures.212 In other cases, parasomnias coexist with limbic epilepsy without an apparent common etiology. The interface between sleep disorders and epileptic phenomena is vast and compelling, because sleep affects seizures and seizures affect sleep. The myriad of sleep and epileptic phenomena may perfectly counterfeit one another. A high index of suspicion and a full awareness of the broad spectrum of both sleep and epileptic phenomena is instrumental to an accurate diagnosis. A thorough clinical and laboratory evaluation of unusual phenomena that could be either sleep-related or seizure-related usually leads to a specific diagnosis, with important and effective therapeutic implications. Continued close collaboration
CHAPTER 92 • Epilepsy, Sleep, and Sleep Disorders 1059
between clinicians and basic science sleep and epilepsy researchers will undoubtedly lead to important advances in the understanding of both sleep and epilepsy, with vital clinical diagnostic and therapeutic implications. Acknowledgments We thank our technical and nursing staff, and we thank Paul R. Farber for computer processing and expertise. This work was supported by the Minnesota Regional Sleep Disorders Center and the Hennepin County Medical Center.
❖ Clinical Pearl Nocturnal seizures are routinely misdiagnosed, usually as psychiatric problems or disorders of arousal. Any behavior or experience that is recurrent, stereotyped, and inappropriate may be due to seizures regardless of the nature of the behavior or experience.
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154. Oguni M, Oguni H, Kozasa M, et al. A case with nocturnal paroxysmal unilateral dystonia and interictal right frontal epileptic EEG focus: a lateralized variant of nocturnal paroxysmal dystonia? Brain Dev 1992;14:412-416. 155. Lee BI, Lesser RP, Pippenger CE, et al. Familial paroxysmal hypnogenic dystonia. Neurology 1985;35:1357-1360. 156. Demirkiran M, Jankovic J. Paroxysmal dyskinesias: clinical features and classification. Ann Neurol 1995;38:571-579. 157. Biary N, Singh B, Bahou Y, et al. Posttraumatic paroxysmal nocturnal hemidystonia. Mov Disord 1994;9:98-99. 158. Stoudemire A, Ninan PT, Wooten V. Hypnogenic paroxysmal dystonia with panic attacks responsive to drug therapy. Psychosomatics 1987;28:280-281. 159. Rajna P, Kundra O, Halasz P. Vigilance level–dependent tonic seizures—epilepsy or sleep disorder? A case report. Epilepsia 1983; 24:725-733. 160. Vigevano F, Fusco L. Hypnic tonic postural seizures in healthy children provide evidence for a partial epileptic syndrome of frontal lobe origin. Epilepsia 1993;39:110-119. 161. Holmes GL. Rolandic epilepsy: clinical and electroencephalographic features. In: Degen R, Dreifuss FE, editors. Benign localized and generalized epilepsies of early childhood. Amsterdam: Elsevier Science; 1992. p. 29-43. 162. Panayiotopoulos CP. Benign nocturnal childhood occipital epilepsy: a new syndrome with nocturnal seizures, tonic deviation of the eyes, and vomiting. J Child Neurol 1989;4:43-48. 163. Panayiotopoulos CP. Benign childhood epilepsy with occipital paroxysms. In: Andermann F, Beaumanoir A, Mira L, et al, editors. Occipital seizures and epilepsy in children. London: John Libbey; 1993, p. 151-164. 164. Sanmarti FX, Estivill E, Campistol J, et al. [Episodes of apnea in an infant: unusual forms of epileptic seizures]. Rev Electroencephalogr Neurophysiol Clin 1985;14:269-275. 165. Maytal J, Resnick TH. Stridor presenting as the sole manifestation of seizures. Ann Neurol 1985;18:414-415. 166. Panayiotopoulos CP, Panayiotopoulos CP. Autonomic seizures and autonomic status epilepticus peculiar to childhood: diagnosis and management. Epilepsy Behav 2004;5:286-295. 167. Winans HM. Epileptic equivalents, a cause for somatic symptoms. Am J Med 1949;7:150-152. 168. Ravindran M. Temporal lobe seizure presenting as “laryngospasm.” Clin Electroencephalogr 1981;12:139-140. 169. Amir J, Ashkenazi S, Schonfeld T, et al. Laryngospasm as a single manifestation of epilepsy. Arch Dis Child 1983;58:151-153. 170. Devinsky O, Eherenberg B, Barthlen GM, et al. Epilepsy and sleep apnea syndrome. Neurology 1994;44:2060-2064. 171. Kiok MC, Terrence CF, Fromm GH, Lavine S. Sinus arrest in epilepsy. Neurology 1986;36:115-116. 172. Gilchrist JM. Arrhythmogenic seizures: diagnosis by simultaneous EEG/ECG recording. Neurology 1985;35:1503-1506. 173. Hockman CH, Mauch HP, Hoff EC. ECG changes resulting from cerebral stimulation. II. A spectrum of ventricular arrhythmias of sympathetic origin. Am Heart J 1966;71:695-700. 174. Metz SA, Halter JB, Porte DJ, Robertson RP. Autonomic epilepsy: clonidine blockade of paroxysmal catecholamine release and flushing. Ann Intern Med 1978;88:189-193. 175. Kuritzky A, Hering R, Goldhammer G, Bechar M. Clonidine treatment in paroxysmal localized hyperhidrosis. Arch Neurol 1984;41:1210-1211. 176. Liporace JD, Sperling MR. Simple autonomic seizures. In: Engel J Jr, Pedley TA, editors. Epilepsy: a comprehensive textbook, vol. 2. Philadelphia: Lippincott Williams & Wilkins; 2008. p. 549-555. 177. Kobayashi K, Nishibayashi N, Ohtsuka Y, et al. Epilepsy with electrical status epilepticus during slow sleep and secondary bilateral synchrony. Epilepsia 1994;35:1097-1103. 178. Veggiotti P, Termine C, Granocchio E, et al. Long-term neuropsychological follow-up and nosological considerations in five patients with continuous spikes and waves during slow sleep. Epileptic Disord 2002;4:243-249. 179. Maquet P, Hirsch E, Metz-Lutz MN, et al. Regional cerebral glucose metabolism in children with deterioration of one or more cognitive functions and continuous spike-and-wave discharges during sleep. Brain 1995;118:1497-1520. 180. Weinstein MD, Albertario C. Cardiac asystole and bradycardia as a manifestation of left temporal lobe complex partial seizure. Ann Intern Med 2000;132:165-166.
181. Schuele SU, Bermeo AC, Alexopoulos AV, et al. Videoelectrographic and clinical features in patients with ictal asystole. Neurology 2007;69:434-441. 182. Pacia SV, Devinsky O, Luciano DJ, Vazquez B. The prolonged QT syndrome presenting as epilepsy: a report of two cases and literature review. Neurology 1994;44:1408-1410. 183. Reeves AL, Nollet KE, Klass DW, et al. The ictal bradycardia syndrome. Epilepsia 1996;37:983-987. 184. Bergey GK, Krumholz A, Fleming CP. Complex partial seizure provocation by vasovagal syncope: video-EEG and intracranial electrode documentation. Epilepsia 1997;38:118-121. 185. Lapresle J. Palatal myoclonus. Adv Neurol 1986;43:265-273. 186. Iliceto G, Thompson BL, Day JC, et al. Diaphragmatic flutter, the moving umbilicus syndrome, and “belly dancer’s” dyskinesia. Mov Disord 1990;1:15-22. 187. Sethi KD, Hess DC, Huffnagle VH, Adams RJ. Acetazolamide treatment of paroxysmal dystonia in central demyelinating disease. Neurology 1992;42:919-921. 188. Wilcox PG, Bassett A, Jones B, Fleetham JA. Respiratory dysrhythmias in a patient with tardive dyskinesias. Chest 1994; 105:203-207. 189. Brown LW, Fry JM. Paroxysmal nocturnal choking: a newly described manifestation of sleep-related epilepsy. Sleep Res 1988;17:153. 190. Rosenfeld DS, Furman Y. Pure sleep panic: two case reports and a review of the literature. Sleep 1994;17:462-465. 191. Edlund MJ, McNamara ME, Millman RP. Sleep apnea and panic attacks. Compr Psychiatry 1991;32:130-132. 192. McNamara ME. Absence seizures associated with panic attacks initially misdiagnosed as temporal lobe epilepsy: the importance of prolonged EEG monitoring in diagnosis. J Psychiatry Neurosci 1993;18:46-48. 193. Schenck CS, Milner DM, Hurwitz TD, et al. Dissociative disorders presenting as somnambulism: polysomnographic, video, and clinical documentation (8 cases). Dissociation 1989;4:194-204. 194. Mahowald MW, Rosen GM. Parasomnias in children. Pediatrician 1990;17:21-31. 195. Passouant P. Historical views on sleep and epilepsy. In: Sterman MB, Shouse MN, Passouant P, editors. Sleep and epilepsy. New York: Academic Press; 1982. p. 1-6. 196. Billiard M, Echenne B, Besset A, et al. All-night polygraphic recordings in the child with suspected epileptic seizures, in spite of normal routine and post-sleep deprivation EEGs. Electroencephalogr Clin Neurophysiol 1981;11:450-460. 197. Aldrich MS, Jahnke B. Diagnostic value of video-EEG polysomnography. Neurology 1991;41:1060-1066.
CHAPTER 92 • Epilepsy, Sleep, and Sleep Disorders 1063 198. Vignatelli L, Bisulli F, Provini F, et al. Interobserver reliability of video recording in the diagnosis of nocturnal frontal lobe seizures. Epilepsia 2007;48:1506-1511. 199. Derry CP, Davey M, Johns M, et al. Distinguishing sleep disorders from seizures. Diagnosing bumps in the night. Arch Neurol 2006; 63:705-709. 200. Tinuper P, Provini F, Bisulli F, et al. Movement disorders in sleep: guidelines for differentiating epileptic from non-epileptic motor phenomena arising from sleep. Sleep Med Rev 2007;11:255-267. 201. Manni R, Terzaghi M, Repetto A. The FLEP scale in diagnosing nocturnal frontal lobe epilepsy, NREM and REM parasomnias: data from a tertiary sleep and epilepsy unit. Epilepsia (Series 4) 2008;1581-1585. 202. Montagna P, Provini F, Bisulli F, Tinuper P. Nocturnal epileptic seizures versus the arousal parasomnias. Somnologie 2008;12: 25-37. 203. Foldvary-Schaefer N, De Ocampo J, Mascha E, et al. Accuracy of seizure detection using abbreviated EEG during polysomnography. J Clin Neurophysiol 2006;23:68-71. 204. Forster FM, Liske E. Role of environmental clues in temporal lobe epilepsy. Neurology 1963;13:301-305. 205. Tassinari CA, Rubboli G, Gardella E, et al. Central pattern generators for a common semiology in fronto-limbic seizures and in parasomnias. A neuroethologic approach. Neurol Sci 2005;26: S225-S232. 206. Mahowald MW, Schenck CH. Parasomnia purgatory—the epileptic/non-epileptic interface. In: Rowan AJ, Gates JR, editors. Nonepileptic seizures, 2nd ed. Boston: Butterworth-Heinemann; 2000. p. 71-94. 207. Dreifuss FE, Porter RJ. Choice of antiepileptic drugs. In: Engel J Jr, Pedley TA, editors. Epilepsy: a comprehensive textbook. Philadelphia: Lippincott-Raven; 1997. p. 1233-1236. 208. Nobili L, Francione S, Mai R, et al. Surgical treatment of drug-resistant nocturnal frontal lobe epilepsy. Brain 2007;130:561573. 209. Rizzo P, Beelke M, De Carli F, et al. Chronic vagus nerve stimulation improves alertness and reduced rapid eye movement sleep in patients affected by refractory epilepsy. Sleep 2003;26:607-611. 210. Holmes MD, Chang M, Kapur V. Sleep apnea and excessive daytime somnolence induced by vagal nerve stimulation. Neurology 2003;61:1126-1129. 211. Park SA, Lee BI, Park SC, et al. Clinical courses of pure sleep epilepsies. Seizure 1998;7:369-377. 212. Montagna P. Nocturnal paroxysmal dystonia and nocturnal wandering. Neurology 1992;42(Suppl 6):61-67.
Other Neurologic Disorders Antonio Culebras Abstract Sleep is a function of the brain, and brain alterations affect sleep either by defect or excess. Most neurologic conditions that extensively injure brain function, as well as some lesions in strategic locations such as the brainstem, diencephalon, or thalamus, cause sleep abnormalities. There are numerous examples of acute brain injuries causing abrupt changes in sleep patterns or pathologic alterations in sleep. Stroke, head trauma, diffuse encephalopathies, and the encephalitides are just a few examples of such alterations. Chronic diseases with structural alterations of the brain, such as multiple sclerosis or the neurodegenerative disorders, alter sleep; other chronic neurologic disorders not associated with structural brain alterations, such as headache syndromes, show a peculiar but well-established association with sleep anomalies. The clinical study of neurologic disorders and resulting sleep alterations opens up an opportunity to better comprehend sleep and to participate in the alleviation and management of the primary neurologic disorder and of its associated sleep problems.
HEADACHE There is an intimate relationship between some headache syndromes and sleep.1 Practitioners and patients have been aware of the peculiar effect of sleep on terminating attacks of headache,2 and patients have many times complained of being awakened at night or of waking up in the morning with a headache. The discovery of stage-specific headaches and the intriguing linkage between rapid eye movement (REM) sleep and acute headache attacks3 pointed to the influence that circadian sleep rhythms can have on the advent of headaches. In addition, several well-defined sleep disorders are commonly associated with headaches. These include sleep apnea syndrome and headache on awakening, sleep phase–related headache, and parasomnias and headache. Epidemiologic studies conducted in headache clinics have noted that 17% of the total headache group reports headaches at night or in the early morning before the final awakening period.4 Up to 55% of patients in the headache subgroup had a specific sleep disorder identified by polysomnographic monitoring in a sleep center. The International Classification of Sleep Disorders, 2nd edition,5 recognizes the following headache disorders in association with sleep: classic migraine, migraine with aura, common migraine, migraine without aura, hemiplegic migraine, cluster headache, chronic paroxysmal hemicrania, and hypnic headache. The diagnostic criteria require that the patient complain of headache during sleep or upon awakening from sleep. 1064
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Sleep can terminate attacks of headache and sleep can trigger or promote headaches. Stage-specific headaches include migraine, cluster headache, chronic paroxysmal hemicrania, and hypnic headache. Stage-specific headaches and the linkage between rapid eye movement (REM) sleep and acute headache attacks point to the influence of circadian sleep rhythms on headaches. Some well-defined sleep disorders are commonly associated with headaches, including sleep apnea, sleep phase–related disorders, and parasomnias. Neurologic conditions with extensive brain damage such as multiple sclerosis, traumatic brain injury, infectious or demyelinating encephalitides, and hereditary neurodegenerative disorders can extensively alter sleep–wake schedules and sleep stages. In some instances, specific sleep disorders, such as narcolepsy in patients with plaques of multiple sclerosis in the hypothalamus or REM sleep behavior disorder in neuro degenerative disorders, afford the opportunity to confirm hypotheses of sleep dysfunction. Clinicians should also keep in mind that upper cervical cord lesions may be associated with obstructive sleep apnea syndrome, and brain tumors may be associated with a variety of sleep disorders.
Stage-Specific Headaches Migraine Headaches Migraine headaches can occur during the night in association with stages 3 and 4 sleep or REM sleep. Fiftyfour percent (64% women, 35% men) of patients with narcolepsy report migraine with the full complement of the International Headache Society criteria.6 Sleeprelated migraine attacks are characterized by unilateral throbbing head pain in association with nausea, vomiting, scotomata, visual field defects, photophobia, paresthesias, and even hemiparesis and aphasia. Not all symptoms may be present given the idiosyncratic nature of migraine headaches. Attacks can last for hours to several days. Migraine attacks in children younger than 8 years often resolve after an interval of sleep.7 Children with migraine can have an increased incidence of disturbed sleep and parasomnias8 such as somnambulism, night terrors, and enuresis.9 Prolonged deep sleep is a risk factor for the provocation of sleep terrors and somnambulism, as well as for triggering migraine attacks in susceptible patients at any age.10 Although migraine headaches may be provoked by sleep, the most common association is the onset of sleep following a migraine attack. The therapeutic effect of sleep11 in some attacks of migraine may be related to serotonin metabolism, but proof is lacking. The trigeminovascular system, which promotes vasodilation and release of calcitonin gene–related peptide and substance P,12 has been implicated in the mechanism of migraines because calcitonin
gene-related peptide is elevated in the jugular venous blood of migraineurs during the attack.13 Serotonin (5-HT) is released from platelets during migraine headaches, and 5-hydroxyindoleacetic acid, the main metabolite of serotonin, is excreted in excess in the urine following a migraine attack.14 Sumatriptan (an agonist of the 5-HT1 receptor found in cerebral arteries, where it has an inhibitory effect) aborts the migraine headache. Methysergide (antagonist of the 5-HT2 receptor found mainly in temporal arteries, where it has an excitatory effect) also terminates migraines. Abnormal patterns of hypothalamic hormone secretion such as decreased nocturnal prolactin peak, increased cortisol concentrations, a delayed nocturnal melatonin peak, and lower melatonin concentrations have been reported in patients with chronic migraine.15 Proper sleep hygiene is paramount to help prevent sleep-related migraine headaches. Bruni and coworkers16 evaluated the effect of modifying bad sleep habits in 70 migraineurs with poor sleep hygiene. Mean duration and frequency of migraine attacks were significantly reduced when proper sleep hygiene was maintained. Daily administration of preventive therapy should be considered when migraine attacks occur more than twice a month or when they are prolonged and refractory to acute therapy. In women, attacks might cease after menopause. Cluster Headaches Cluster headaches occur in 0.4% of men and 0.8% of women.17 They are characterized by severe unilateral, periorbital, malar, and temporal pain with lacrimation, rhinorrhea, nasal engorgement, forehead perspiration, and flushing of the malar area. Attacks are of abrupt onset and termination, generally last 2 hours or less, and recur several times during the 24-hour period, sometimes at the same time each day. Seventy-five percent of cluster headaches occur predominantly at night between 9 pm and 10 am.18 Cluster headaches have been linked with REM stage and with sleeping late in the morning, a situation that promotes REM sleep, a possible triggering factor. Spontaneous remissions lasting several months are the norm. Chronic Paroxysmal Hemicrania Chronic paroxysmal hemicrania is characterized by attacks of severe pain associated with conjunctival hyperemia, rhinorrhea, and, more rarely, Horner’s syndrome. Attacks may appear predominantly at night, usually waking the patient at the same hour, sometimes in close linkage with REM sleep, leading to the term REM-sleep locked headache. Chronic paroxysmal hemicrania is considered a variant of cluster headache that features more frequent attacks of pain of shorter duration. It responds quasi-specifically to the therapeutic administration of indomethacin. Hypnic Headache Hypnic headache is an idiopathic headache disorder of rare occurrence, observed in older age groups. The mean age of onset is 63 years, with a range of 36 to 83 years.19 The alternative names—clockwise headache and alarm headache—also attest to its regularity and exclusive occurrence at night. Although it is relatively well known among specialists, this headache syndrome has not yet
CHAPTER 93 • Other Neurologic Disorders 1065
been included in the classification of the International Headache Society. Unlike cluster headache and chronic paroxysmal hemicrania, hypnic headache occurs in a diffuse localization in two thirds of patients. Its intensity varies widely, and only one third of patients complain of severe pain. The pain usually lasts longer than 1 hour, and generally there is only one attack per night, although more than one attack in a night has also been described. The majority of patients experience the attack during the middle third of the night and report regularity in its occurrence. Less than 10% of patients have associated autonomic symptoms such as lacrimation, nasal congestion, or rhinorrhea, and these are usually mild when they occur. Results of laboratory tests including magnetic resonance imaging (MRI) of the head, EEG, and Doppler ultrasound have been invariably normal. Polysomnography has shown occurrence of headache attacks during REM and non-REM sleep.20 The appearance of attacks at the same time during the night has led others to suggest a chronobiological disorder. The differential diagnosis of hypnic headache, cluster headache, chronic paroxysmal hemicrania, and even nocturnal migraine may be difficult at times. The following characteristics should help to make a diagnosis of hypnic headache: older age group, punctuality of attack occurrence, mild or no autonomic symptoms, diffuse location, duration of 1 hour to a maximum of 2 hours, tendency to appear in relation to dreams, and no symptoms characteristic of migraine such as photophobia, phonophobia, or nausea. Prophylaxis of hypnic headache has been successful with lithium carbonate, flunarizine, indomethacin, and caffeine. The attack itself responds best to the administration of aspirin. Hemicrania Horologica Hemicrania horologica, or clocklike hemicrania,21 is a very rare disorder, with headaches lasting 15 minutes, They occur with clocklike precision every 60 minutes, day and night. Hemicrania horologica differs from chronic paroxysmal hemicrania in the lack of autonomic signs, the clocklike regularity over 24 hours, and the response to nonsteroidal antiinflammatory drugs or indomethacin. Unlike with hypnic headache, attacks also occur during the day. Exploding Head Syndrome The exploding head syndrome, originally called “snapping of the brain,”22 is characterized by abrupt flashing lights and noises perceived inside the head during the night.23 The attacks last only seconds and terrify patients despite the absence of pain. The episodes have been shown by polysomnography to appear during any stage of sleep.24 Generally the exploding head syndrome occurs in persons older than 50 years. Headache on Awakening Headache on awakening occurs in half of the patients with sleep apnea syndrome. In at least one study the frequency of headaches was not related to the severity of the syndrome.25 The headache is generally diffuse and of mild to moderate intensity, with a tendency to disappear as the patient becomes increasingly active. Successful
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treatment of sleep apnea syndrome is associated with significant improvement of the headache in 30% of patients.26 Prolonged afternoon naps may also be followed by headache. Headaches on awakening in patients with sleep apnea syndrome have been associated with a variety of mechanisms including hypoxemia, hypercapnia, altered cerebral blood flow, and depression. Headaches on awakening may occur with other disorders. These are common in children with brain tumors, but they appear in only 5% of adults with brain tumors. They may also appear in relation to bruxism, systemic hypertension, depression, muscle contraction, alcohol intoxication, and sinus inflammation. Bruxism, or clenching and grinding of teeth, is a parasomnia that occurs predominantly in stages 1 and 2 NREM sleep and sometimes in REM sleep, occasionally leading to headache on awakening. The prevalence is 8% in the adult population27 and somewhat higher in children.28 It has been related to psychophysiologic stress and iatrogenic interventions, but it may be idiopathic. Both phasic and tonic oromandibular muscle contraction have been observed in bruxism. Frequent grinding causes abnormal wear of the teeth and occasional fractures of teeth or of tooth restorations; temporomandibular joint disorder and jaw pain are not uncommon when the disorder is chronic and severe. Headaches are presumably caused by temporomandibular joint stress and muscle contraction. Patients with many nocturnal events and associated arousals may complain of fatigue and sleepiness during the ensuing day. Masseter muscle hypertrophy may be observed in patients with chronic sleep bruxism, although daytime bruxism may cause hypertrophy too. Insomnia and Headache Insomnia and headache are not uncommonly comorbid conditions. In the postconcussion syndrome, insomnia and headache are prominent symptoms. On the other hand, insomnia and daytime fatigue are commonly reported by patients with chronic headache. Chronic headache sufferers feel more tired (especially the women) and do not sleep as well at night (especially the men).29 Fibromyal gia occurs in 35.6% of patients with chronic migraine, also known as transformed migraine; this group of patients has a higher incidence of insomnia.30 Headaches in Children Chronic headaches in children are often associated with sleep alterations. Common sleep disorders are decreased duration of sleep at night, poor sleep hygiene, increased number of nocturnal awakenings, somnambulism, somniloquy, enuresis, and snoring.31 In a study of the prevalence of sleep disorders in children with headaches, the authors32 found that children with headaches have a significantly higher prevalence of excessive daytime sleepiness, narcolepsy, and insomnia compared with children without headaches (P < 0.005). The study contradicts previous work stating that children with headaches have a higher prevalence of sleep apnea, restlessness, and parasomnias, an association that may be more specific for genuine migraines and not for headaches in general. The authors conclude that pediatricians should inquire about
daytime sleepiness, narcolepsy, and insomnia in children with headaches. Drugs and Headache A variety of drugs used for treatment of sleep disorders can cause headache as a prominent adverse event. Modafinil improves wakefulness in patients with excessive sleepiness associated with shift work sleep disorder, obstructive sleep apnea, or narcolepsy. Safety and tolerability data from six randomized, double-blind, placebo-controlled studies using modafinil evaluated 1529 outpatients receiving modafinil 200, 300, or 400 mg or placebo once daily for up to 12 weeks. Overall modafinil was well tolerated versus placebo, but headache occurred in 34% vs. 23%, respectively.33 Headache has also been cited as a common adverse effect in patients taking ramelteon for treatment of insomnia.34 Headache is the most common side effect reported by patients taking melatonin.35 Common side effects of amphetamines during long-term treatment in patients with narcolepsy include headache along with irritability, bad temper, and profuse sweating.36 Differential Diagnosis and Diagnostic Workup Nocturnal migraine, cluster headache, nocturnal paroxysmal hemicrania, and hypnic headache need to be differentiated from other acute severe headaches, such as those associated with intracranial brain tumors, ruptured aneurysm, and meningitis. Patients with intracranial tumors who are awakened at night by headache report improvement on getting out of bed. Headaches on awakening, as observed in sleep apnea patients, are also seen in patients with severe hypertension, depression, intracranial tumor, muscle-contraction headache, alcohol intoxication, and craniofacial sinus disease. Hypnic headache differs from migraine headache, cluster headache, and chronic paroxysmal hemicrania because the pain is commonly diffuse or bilateral and patients are older. Autonomic symptoms are more prominent in cluster headache and chronic paroxysmal hemicrania. Causes for concern are first or worst-ever headache, associated neurologic symptoms or signs, progressive worsening of headache over days or weeks, intractable nausea or vomiting, fever, lethargy, confusion, and stiff neck. Patients who exhibit causes for concern should have neurologic consultation, neuroimaging studies, and lumbar puncture. Nocturnal polysomnography is indicated for the study of patients suspected of having sleep apnea syndrome or recurrent parasomnias. Videotaping should always be included in the polysomnographic study of parasomnias. Patients with migraine, cluster headache, and hypnic headache can wake up with an acute attack more often during REM sleep than during other stages of sleep, and those with cluster headache and chronic paroxysmal hemicrania can suffer the attack at the same time of the night every night. Attacks of chronic paroxysmal hemicrania may be so closely linked to REM sleep that they have been termed REM-sleep locked. Polysomnography has been recommended in patients complaining of early morning and nocturnal headaches.37 In a study of 25 patients with headache, Paiva and coworkers found 21
patients with disturbed sleep, and in 13 patients the clinical diagnosis had to be reassessed after polysomnography due to the finding of obstructive sleep apnea, periodic limb movements in sleep (PLMS), alpha-delta sleep, and insomnia.
MANAGEMENT Preventive treatment of migraine, cluster headaches, and chronic paroxysmal hemicrania includes good sleep hygiene, with avoidance of precipitating factors such as sleep deprivation, excessive sleep, stress, trauma, and ingestion of certain idiosyncratic foods including alcohol. Pharmacologic prevention of migraine includes administration of beta-blockers, flunarizine, valproic acid, topiramate, calcium channel blockers, serotonin receptor antagonists (methysergide, only for use in periods not to exceed 4 weeks), and 5-HT2 antagonists (cyproheptadine and methylergonovine). Prevention may also be achieved with antidepressants that interact with serotoninergic receptors such as tricyclic antidepressants, monoamine oxidase (MAO) inhibitors, and selective serotonin reuptake inhibitors (fluoxetine and sertraline); anticonvulsants, particularly in children with abnormal EEG; and nonsteroidal antiinflammatory agents.38 Migraine attacks may be aborted with administration of sumatriptan, a 5-HT1 selective agonist, given via subcutaneous injection (6 mg, may repeat after 1 hour; limit is two injections in 24 hours). Other abortive medications include ergotamine derivatives, acetaminophen, corticosteroids, and nonsteroidal antiinflammatory derivatives. Symptomatic treatment for migraine attacks includes nonsteroidal antiinflammatory derivatives, mixed barbiturate and analgesics, antiemetics (promethazine, 50 mg), and, if pain is severe, meperidine (50 mg) or codeine sulfate (30 mg). Cluster headaches may be prevented with ergotamine derivatives at bedtime (1 to 3 mg sublingual), amitriptyline (150 mg daily), methysergide (6 to 8 mg daily), prednisone (40 mg daily), and lithium carbonate (initial dose 250 mg). Acute attacks are terminated with inhalation of oxygen. Chronic paroxysmal hemicrania responds specifically to indomethacin (50 mg at bedtime or 25 mg 3 times a day). Morning headaches related to sleep apnea syndrome generally disappear with successful management of the sleep apnea. Hypnic headaches have responded to any of the following regimens at bedtime: coffee; ergotamine tartrate, 0.6 mg; phenobarbital, 40 mg, with belladonna, 0.2 mg; atenolol, 25 mg; aspirin, 325 mg, with caffeine, 40 mg; indomethacin, 25 mg; and flunarizine, 5 mg. Successful prophylaxis with lithium carbonate has also been reported. Reassurance and administration of clomipramine are curative in most instances of exploding head syndrome. Bruxism is treated with stress management, a mouth guard, or an intraoral occlusal splint.39 For shortterm management, diazepam (5 mg) given at bedtime will reduce teeth-grinding. The manifestations of postconcussion syndrome respond in many instances to the administration of tricyclic antidepressants. Drug-related headaches tend to be benign and respond to conventional analgesics or disappear gradually with continued use of the drug. These headaches generally disappear with discontinuation of the drug.
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HEAD TRAUMA Severe head trauma, whether open or closed, is characterized by loss of consciousness. Structural lesions ensue following traumatic brain injury (TBI); some lesions appear weeks or even months after the event. It is estimated that 500,000 people are hospitalized annually in the United States as a result of head trauma, and 90,000 become permanently disabled, with major medical and social consequences.40 Severe head trauma disrupts brain functions, including the sleep–wake schedule. Mild head trauma is even more prevalent, affecting close to 1.5 million persons annually,41 but its sequelae are less predictable and not so well known. When evaluating a patient with a disturbance of the sleep–wake schedule following TBI, it is important to determine whether the sleep alteration preceded the injury or appeared following the event. Sleep Disruption and Recovery TBI can cause diffuse or localized brain lesions as well as increased intracranial pressure during the acute stage. Sleep studies of patients with TBI have not used uniform measures, and the results have been diverse. The emerging pattern is of major disruption of sleep stages in cases of severe brain injury. Sleep spindles tend to disappear when the lesions are acute and severe,42 showing a high correlation with the Glasgow outcome scores; recovery of sleep spindles suggests improvement of brain function. In patients with traumatic coma, the occurrence of EEG patterns resembling sleep carries a favorable prognosis. Individual sleep stages are generally less distinct during the acute phase. In the initial phase of recovery while the patient emerges from the coma, hypersomnia is common, with poor recollection of dreams. As the rehabilitation progresses, the organization of sleep stages tends to become normalized. Weeks to months following recovery of consciousness, sleep stages 3 and 4 and REM sleep are decreased along with total sleep time.43 The early appearance of sleep–wake cycling indicates a better prognosis. Sleep fragmentation and decreased sleep quality have been reported44 following minor head injury without loss of consciousness. Surveys performed after mild head injury indicate that insomnia predominates over hypersomnia.45 The prevalence of sleep–wake cycle disturbance in patients with closed head injury has been estimated at 68% in a survey conducted in an inpatient specialized brain injury rehabilitation unit.46 Clinical Manifestations Sleep–wake disturbances, particularly excessive daytime sleepiness, fatigue, and hypersomnia, are common after TBI and significantly impair quality of life. In almost one out of two patients, posttraumatic sleep–wake disorders appear to be directly related to the TBI. An involvement of the hypocretin system in the pathophysiology of posttraumatic sleep–wake disorders appears possible. In one study,47 low levels of hypocretin-1 in cerebrospinal fluid (CSF) were found in 4 of 21 patients 6 months after TBI, as compared to 25 of 27 patients in the first days after TBI.
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Sleep-Disordered Breathing Sleep-disordered breathing (SDB) may be caused by injuries of the brain or cervical cord, and they may be worsened by accompanying injuries in other organs, most prominently the upper airway. In a study of 22 patients with stable spinal cord injury, Short and colleagues found 10 patients with sleep-disordered breathing.48 The con dition has also been observed in studies of patients with posttraumatic quadriplegia.49,50 Aggravation of sleepdisordered breathing can occur with the administration of sedatives or hypnotics commonly administered to these patients. Posttraumatic Hypersomnia Posttraumatic hypersomnia is a common occurrence following significant brain injury. It may appear in patients recovering from posttraumatic coma or in patients whose head trauma was deemed relatively benign and not associated with loss of consciousness. The medicolegal implications are important because patients might lose their jobs or at the very least complain of deterioration in the quality of life. In Guilleminault’s study of 184 patients with posttraumatic hypersomnia, 103 were involved in litigation.51 The author divided patients into two groups: group A with premorbid sleep disorder and group B without preceding sleep alteration. Group B was further subdivided into three categories: (1) normal polysomnography with abnormal results on the multiple sleep latency test (MSLT) and an average sleep latency between 6 and 10 minutes; (2) coma, with TBI and hydrocephalus; and (3) coma with or without neurologic sequelae followed by a syndrome of subwakefulness independent of depression. In Guilleminault’s experience, response to treatment is poor in subgroups 1 and 2, whereas patients in subgroup 3 might respond to treatment with amphetamines. Common complaints of patients with posttraumatic hypersomnolence are, in addition to daytime sleepiness, difficulty performing, inability to work, memory difficulties, speech difficulties, poor concentration, and depressive affect. These patients might complain also of headaches, restless sleep, heavy snoring, leg and body jerks during sleep, night terrors, night sweats, nightmares, and seizures during sleep. Posttraumatic Narcolepsy Posttraumatic narcolepsy has been reported in a few cases. Narcolepsy may have preceded the head trauma,52 or the head injury may have served as a triggering factor to unmask premorbid narcolepsy.53 In light of new knowledge about the etiology of narcolepsy, it is conceivable that severe head trauma can affect the hypothalamic system significantly enough to alter the neurotransmitter hypocretin, either transiently or permanently. It is known that following significant TBI there is a decrease in CSF hypocretin levels, perhaps nonspecifically, as a result of hemodynamic changes.54 Narcolepsy with cataplexy developed in a man with acromegaly 2 weeks following irradiation of the pituitary gland. Because the patient had normal CSF concentrations of hypocretin, the authors suggested that the damage was inflicted to hypocretin receptors rather than to secretors
of the neurotransmitter.55 These observations suggest that symptomatic narcolepsy may be caused by physical damage to the hypocretin system, and it is only a matter of time before posttraumatic hypocretin insufficiency with hypersomnia is reported.56 Posttraumatic Kleine-Levin syndrome responsive to lithium administration has been reported in two cases.57 Circadian Rhythm Disorders Circadian rhythm disorders have been described following TBI. Reversal of the circadian rhythm58 and resetting of the biological clock in comatose patients following TBI have also been reported.59 Posttraumatic psychiatric and behavioral disorders can lead to sleep–wake alterations, although the premorbid condition needs to be factored in. Insomnia Insomnia is a common complaint following TBI, with a reported prevalence of 30% to 70%.60,61 Most studies of insomnia in patients with TBI are based upon subjective questionnaires. Comorbid factors that can promote insomnia such as pain, anxiety, depression, medications, or adverse sleep environment are present in many TBI patients during the period of rehabilitation.62 Because persistent insomnia affects 30% of the adult population, it is unclear in many cases of TBI if insomnia represents a preexisting condition aggravated by the traumatic occurrence and comorbidities. Once the factors contributing to insomnia are identified in a given case, specific effective behavioral or pharmacologic therapies, or both, may be undertaken.63 Dreaming Disorders Dreaming can disappear following TBI, perhaps related to impairment of visual memory.64 Paradoxically, studies performed in patients following TBI have found no correlation between amount of REM sleep and loss of dreaming.65 Hallucinations in the recovery phase of TBI might reflect the recovery of REM sleep and breakthrough of REM sleep into wakefulness, as a dissociated state.66
MULTIPLE SCLEROSIS Epidemiology The association between multiple sclerosis and sleep disorders is more common than expected by chance. Reports published in the first half of the 20th century cite cases of multiple sclerosis associated with sleep attacks termed narcolepsy.67-69 Subsequently, cases of narcolepsy with cataplexy in multiple sclerosis, familial or not, were reported.70,71 Later reports pointed out that sleep disturbance is relatively common in multiple sclerosis and that a multifactorial etiology that ranges from depression to lesion site72,73 should be considered. There is coincidence of genetic susceptibility between multiple sclerosis and narcolepsy. The susceptibility to multiple sclerosis is coded by genes within or close to the human leukocyte antigen (HLA) DR-DQ subregion.74 On the other hand, patients with narcolepsy exhibit the highest known association between the HLA DR2 and DQw1 antigens and a disease entity. This has led some
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authors to postulate a common immunogenetic etiology.75 Others have postulated that the HLA Dw2 haplotype in patients with multiple sclerosis and narcolepsy extends to the DRB5 locus.76 Some studies report hypersomnia in certain multiple sclerosis patients. These patients have lesions seen on MRI that suggest plaques in the hypothalamus, as well as undetectable levels of hypocretin in spinal fluid.77 Restless legs syndrome (RLS) is significantly associated with multiple sclerosis, especially in patients with severe pyramidal and sensory disability. The results of a multicenter study involving 861 patients with multiple sclerosis78 strengthen the idea that the inflammatory damage correlated with multiple sclerosis can induce a secondary form of RLS. In this study, the prevalence of RLS was 19% in multiple sclerosis compared to 4.2% in control subjects. RLS in patients with multiple sclerosis has a significant impact on sleep quality; therefore, it should be searched for, particularly in the presence of insomnia unresponsive to treatment with common hypnotic drugs.
methasone85 or prednisolone therapy.86 Dopaminergic agonists may be useful for control of RLS and PLMS. Sleep paralysis in a 40-year-old woman with remitting progressive multiple sclerosis disappeared with weak electromagnetic field treatments delivered extracerebrally once or twice a week over a period of 3 weeks.87 Using this treatment in patients with multiple sclerosis, the same author88 reported restoration of dream recall in four patients, attenuation of suicidal behavior in three additional patients (attributed to improved mental depression),89 and resolution of partial cataplexy in another patient with chronic progressive multiple sclerosis.90
Clinical Manifestations Chronic fatigue is common in multiple sclerosis and can confound the interpretation of sleep disturbances. Patients report difficulty falling asleep, restless sleep, nonrestorative sleep, and early morning awakenings more often than control subjects.79 A variety of underlying physical and emotional factors (bladder problems, spasticity, muscle spasms, periodic leg movements, depression, and anxiety) that converge to disturb nocturnal sleep should be considered. Excessive daytime somnolence may be secondary to nocturnal disruption, which is likely amenable to proper management (see Video 89-1). In a study of 28 consecutive patients with multiple sclerosis, 54% reported sleep-related problems,80 including difficulty initiating or maintaining sleep, frequent awakenings due to leg spasms, habitual snoring, and nocturia. Sleep apnea syndrome occurred in two patients, and three showed episodes of nocturnal desaturation. MRI of the brain was abnormal in 20 of 22 cases studied. Polysomnographic studies of patients with definite multiple sclerosis have shown significantly reduced sleep efficiency and more awakenings during sleep, suggesting a multifactorial etiology of the sleep disorder. In a polysomnographic study of 25 patients with definite multiple sclerosis, sleep efficiency was significantly reduced and awakenings were increased.81 Periodic leg movements were found in 36% of patients compared with 8% of controls. Central sleep apneas were found in two patients. MRI of the brain showed a greater load of lesions in the cerebellum and brainstem in patients with periodic leg movements.
Clinical Manifestations Neurodegenerative disorders may have predominantly cerebellar dysfunction, as in some forms of olivopontocerebellar degeneration, extrapyramidal manifestations as in the synucleinopathies, or a combination of cerebellar and sensorimotor signs as in the spinocerebellar atrophies. Patients with neurodegenerative disorders have many sleep-related complaints including insomnia, hypersomnia, circadian dysrhythmia, abnormal movements, and abnormal behavior in sleep. They are also at risk for the development of sleep apnea syndrome and PLMS. Excessive daytime somnolence secondary to fragmentation of nocturnal sleep caused by sleep apnea, PLMS, or other factors is a common complaint.
Management Fatigue is the most pervasive symptom in multiple sclerosis. Amantadine and modafinil have been suggested for alleviating chronic fatigue in these patients.82,83 Modafinil was assessed in a single-blind study involving 72 patients with multiple sclerosis.84 The results suggested that 200 mg/day of modafinil significantly improved fatigue and was well tolerated.84 Some authors have reported a regression of symptoms of sleep disturbance with dexa-
HEREDITARY NEURODEGENERATIVE AND METABOLIC DISORDERS The occurrence of sleep disorders in this large group of neurologic conditions is limited to case reports and very short series of patients. The list continues to expand with the addition of new reports from the literature.
Diagnosis The sleep evaluation of patients with a neurodegenerative disorder should include overnight polysomnography followed by MSLT. The objectives are to assess the presence of sleep apnea syndrome, PLMS, and REM sleep without atonia and to measure excessive daytime somnolence. In some cases, the MSLT shows REM sleep in daytime naps with short-onset REM sleep latencies suggestive of narcolepsy. In special circumstances of suspected abnormal motor activity, video recording of nocturnal sleep is desirable. Actigraphy has been used in some laboratories to document motor activity during sleep and waking that may unveil a circadian dysrhythmia. Treatment Management of sleep disorders in patients with neurodegenerative disorders follows the general guidelines. Sedatives and hypnotics should be administered with caution to this group of patients to avoid aggravation of muscle weakness or gait ataxia, not only during daytime hours but also during nocturnal awakenings with ambulation in the dark. Illustrative Neurodegenerative Disorders Machado-Joseph Disease Machado-Joseph disease91 is a type 3 spinocerebellar ataxia. Increased prevalence of RLS and PLMS has also
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been reported in this condition. The clinical evaluation of patients with spinocerebellar ataxia type 3 should pursue possible presence of sleep apnea syndrome and PLMS. REM sleep behavior disorder (RBD), a condition also prevalent in the synucleinopathies has been reported in association with Machado-Joseph disease and may be related to striatal monoaminergic deficit.92,93 Vocal cord abductor paralysis and stridor have also been described in Machado-Joseph disease.94 Charcot-Marie-Tooth Disease Charcot-Marie-Tooth (CMT) disease is a hereditary motor and sensory polyneuropathy characterized by degeneration of peripheral nerves and roots. Patients exhibit distal muscle weakness, atrophy, and sensory impairment. Phrenic neuropathy can cause dysfunction of the diaphragm, leading to chronic hypoventilation, particularly in REM sleep.95 Vocal cord dysfunction, possibly due to laryngeal nerve involvement, is found in association with several CMT types and can often mimic asthma. Patients with CMT disease have a high incidence of significant sleep apnea events whose severity is highly correlated with the severity of peripheral neuropathy. In patients with CMT type 1, a significant correlation between the apnea–hypopnea index and neurologic disability was found in one study of 14 unrelated patients, and body mass index and age were not correlated to apnea–hypopnea index. Researchers have hypothesized that sleep apnea events in CMT disease are the consequence of pharyngeal neuropathy affecting the function of pharyngeal dilator muscles, a phenomenon that increases the collapsibility of the upper airway, leading to recurring obstructive respiratory events.96,97 Bilevel positive airway pressure may be more appropriate than continuous positive airway pressure for treating sleep apnea in the patient with concomitant restrictive pulmonary impairment.98 Niemann-Pick Disease Niemann-Pick disease type C is a rare autosomal-recessive condition characterized by the accumulation of unesterified cholesterol in many tissues and storage of sphingolipids in liver and brain. Adult patients exhibit ataxia, dystonia, dementia, and vertical supranuclear palsy along with hepatosplenomegaly. Some patients report hypersomnia and cataplexy. Recent investigations have shown reduced CSF levels of hypocretin in this condition, which are likely responsible for sleep abnormalities and cataplexy.99 Vancova and coworkers suggest that lipid storage abnormalities in Niemann-Pick disease might affect hypocretin-containing cells. Cataplexy attacks respond to the administration of tricyclic antidepressants.
ACUTE ENCEPHALITIDES Sleeping Sickness Sleeping sickness is a meningoencephalitis caused by the protozoan Trypanosoma brucei. The parasite is transmitted to humans by the sting of the tsetse fly in Africa, where 20,000 new cases are reported each year. Sleeping sickness begins with a phase of systemic disease, after which the parasite invades the CNS with manifestations of insomnia
and daytime hypersomnia, followed by psychomotor retardation. The disease then progresses to extrapyramidal manifestations, ataxia, gait disorder, seizures, coma, and death. Polysomnography reveals sleep-onset REM periods shortly after CNS invasion by trypanosomes, then highamplitude slow waves suggesting a diffuse encephalopathy, with preservation of REM-sleep parameters until the final phases of the disease.100,101 CSF analysis has shown increases in cell count, high protein content, and increased immunoglobulin M (IgM) levels.102 Neuropathologic studies have shown demyelinating lesions in cerebral hemispheres and brainstem.103 Acute Disseminated Encephalomyelitis Acute disseminated encephalomyelitis is an acute inflammatory demyelinating disease of the CNS following viral illness or vaccination. The disorder is probably mediated by immunologic mechanisms. There is a report of hypersomnia in a 5-year-old girl with acute disseminated encephalomyelitis.104 The CT of her head showed hypodensity lesions involving basal ganglia as well as posterior hypothalamus and brainstem. Following treatment with intravenous dexamethasone, hypersomnia improved and the lesions disappeared. Total sleep time and slow-wave sleep were increased, and REM stage was within the normal range in the polysomnographic study during the hypersomnic state. Hypocretin levels in CSF were not assayed. There are published case reports of severe sleep alterations including REM sleep behavior disorder, hypersomnia, and insomnia associated with limbic encephalitis that were in some instances reversed with immunotherapy and steroid administration.105,106 Transient obstructive sleep apnea has been described in association with presumed viral encephalopathy.107 Paradoxical respiratory efforts during sleep along with frequent episodes of tachybradycardia and asystole led to suspicion of obstructive sleep apnea syndrome, which was documented with portable polysomnography. All apnea events and cardiovascular concomitants resolved with continuous positive airway pressure (CPAP) applications. This case illustrates the occurrence of sleep-related transient respiratory obstructions in diffuse acute encephalopathy that, if undetected, can lead to serious cardiovascular consequences. Similar alterations can occur in acute encephalopathies of different etiologies. Sedating medications commonly administered to patients in the critical care setting can aggravate the sleep apnea syndrome. Encephalitis Lethargica Encephalitis lethargica of von Economo has virtually disappeared. Its peak incidence spanned several decades in the early part of the 20th century.108 The clinical and neuropathologic study of this form of encephalitis brought to light the correlation between hypothalamic lesions and sleep disorders and contributed to understanding of the links between basal ganglia lesions and extrapyramidal movement disorders.109 The most common forms in the context of an acute febrile encephalitis were lethargic and ophthalmoplegic followed by hyperkinetic.110 The postencephalitic syndrome with prominent parkinsonian features was diagnosed on average 2 years after the episode of acute
Figure 93-1 CT scan of the head of a 55-year-old man complaining of headaches and excessive daytime somnolence that was initially diagnosed as sleep apnea syndrome. The large cystic mass compressing the diencephalon and floor of the third ventricle was found at operation to be a craniopharyngioma. (Reprinted with permission from Culebras A. Clinical handbook of sleep disorders. Boston: Butterworth-Heinemann; 1996.)
encephalitis lethargica, although it often appeared immediately afterward.108
BRAIN TUMORS Brain tumors can disrupt sleep–wake cycles by virtue of their location or indirectly by causing intracranial hypertension or hydrocephalus, or both. Symptomatic narcolepsy has been reported in association with craniopharyngioma compressing the floor of the third ventricle (Fig. 93-1).111 Symptomatic narcolepsy has also been reported in gliomas and colloid cysts of the third ventricle, as well as in pituitary adenomas and midbrain gliomas.112 Lower brainstem tumors have been associated with severe hypoventilation and respiratory failure during sleep (Ondine’s curse) requiring tracheotomy. Increased intracranial hypertension and obstructive hydrocephalus have been associated with subalertness and lethargy. Sleepiness following hypothalamic injury in the course of resection of an astrocytoma has been reported in association with a low concentration of hypocretin in CSF.113 Fatigue and drowsiness are prominent symptoms in patients with systemic cancer and brain metastases.114 SPINAL CORD DISEASE Pathophysiology Sleep-related ventilatory function depends on the integrity of the spinal cord. In patients with spinal cord lesions, sleep disturbances related to respiratory dysfunction are common. The phrenic nerve controls diaphragmatic motor function. It originates in the phrenic nucleus, which forms
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the ventral medial cell column of the cervical ventral gray horn, extending from C3 to the caudal part of C5. The descending respiratory pathway is formed by crossed fibers situated deep in the anterior white column in the vicinity of the anterior horn projecting mainly from the ventral respiratory group in the medulla. High cervical lesions and phrenic nerve damage cause unilateral or bilateral paralysis of the diaphragm, depending on the extent of the cervical cord lesion or on whether one or both phrenic nerves are involved. The intercostal muscles receive their innervation via descending pathways located dorsal to diaphragmatic pathways in the vicinity of the lateral spinothalamic tract. Voluntary respiration is mediated by fibers in the lateral pyramidal tract, whereas involuntary automatic respiration is mediated by reticulospinal fibers emerging from the brainstem respiratory centers. Spinal motor nuclei situated in segments T1 to T11 give origin to intercostal nerves that innervate intercostal muscles. Accessory respiratory muscles receive innervation from cranial nerve XI and nerves C1 to C8. Upper airway muscles involved in nasal, pharyngeal, and laryngeal dilation are innervated by cranial nerves V (tensor veli palatini muscles), VII (levator alae nasi muscles), X (cricothyroid and thyroarytenoid muscles), XII (genioglossus, genihyoid, sternohyoid, and sternothyroid muscles), and C1 to C4 (geniohyoid, sternothyroid, and sternohyoid muscles). These are unaffected by spinal cord lesions below C5, a lesion compatible with a respirator-free life. Lesions of the phrenic and intercostal motor neurons in the spinal cord can occur with spinal cord tumors, spinal trauma, spinal surgery (e.g., cervical cordotomy or anterior spinal surgery), and in demyelinating myelitis. Patients with syringomyelia and syringobulbia (fluid-filled cavities in the spinal cord or brainstem, respectively) with dysphonia and dysphagia are particularly prone to severe respiratory disturbances during sleep (Video 93-1).115 In one study of 22 patients with stable spinal cord lesion above T10,48 45% had some evidence of obstructive sleep apnea syndrome. Cognitive changes in patients with tetraplegia may be related to sleep apnea syndrome.116 Although excessive daytime somnolence secondary to sleep-related respiratory dysfunction is the most common symptom, patients with spinal cord diseases can complain of insomnia as a result of immobility, neck pain, and central pain syndrome. Phrenic nerve damage leads to diaphragmatic paralysis. Unilateral paralysis is asymptomatic, but bilateral paralysis is invariably symptomatic and may be life-threatening. Paresis or weakness with partial diaphragmatic dysfunction can cause sleep-related ventilatory insufficiency. In the supine position, patients complain of profound difficulty breathing because of decreased lung volume and increased respiratory effort as the abdominal contents rise into the thorax. In bilateral severe or acute cases, patients present with nocturnal orthopnea, cyanosis, and fragmented sleep followed by morning headaches, vomiting, and daytime lethargy. Phrenic nerve weakness or paralysis is most prominent in REM sleep when the diaphragm is the only functional respiratory muscle. Upper airway resistance is also higher in REM sleep, contributing to decreased ventilatory efficiency. Patients with weak pharyngeal dilator
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muscles and a weak diaphragm as a result of a diffuse neuromuscular disorder or bilateral phrenic nerve paralysis exhibit the most serious compromise in REM sleep.117 Craniovertebral junction malformation or Chiari malformation in adults, with or without syringomyelia and basilar invagination, produces neuronal dysfunction of the brainstem, cerebellum, cranial nerves, and upper spinal cord (Video 93-2). The incidence of sleep apnea syndrome is significantly higher in patients with craniovertebral junction malformation, especially if basilar invagination is present.118 Obstructive sleep apnea syndrome can appear following anterior cervical spine fusion. Guilleminault and coworkers119 found that placement of anterior cervical plates at the C2 to C4 level reduced the size of the upper airway, causing obstructive sleep apnea syndrome. The condition was controlled with positive airway pressure applications. Restless legs syndrome and PLMS can appear in patients after acute transverse myelitis.120 PLMS has been reported in patients with syringomyelia.121 Treatment Treatment for sleep-related respiratory dysrhythmias in spinal cord diseases should follow the same general principles as those suggested for neuromuscular disorders. Noninvasive ventilation has improved the quality of life and increased survival in many forms of neuromuscular disorder. Patients with significant neuromuscular disorders or high spinal cord disease should be considered candidates for evaluation with polysomnography. In most patients with neuromuscular conditions the most effective time to introduce noninvasive ventilation is when symptomatic sleep-disordered breathing develops.122 A word of caution comes from a study123 showing that obese patients who have spinal cord injury and are taking antispasticity medications might have a higher risk for developing snoring and obstructive sleep apnea. The greatest risk appeared in patients taking diazepam or diazepam and baclofen in combination.
❖ Clinical Pearls Headaches on awakening, as observed in sleep apnea patients, are also seen in patients with severe hypertension, depression, intracranial tumor, muscle-contraction headache, alcohol intoxication, and craniofacial sinus disease. In headache patients, causes for concern are first or worst-ever headache, associated neurologic symptoms or signs, progressive worsening of headache over days or weeks, intractable nausea or vomiting, fever, lethargy, confusion, and stiff neck. Following significant TBI, the early appearance of sleep–wake cycling indicates a better prognosis. The association between multiple sclerosis and sleep disorders is more common than expected by chance. Sleep apnea in patients with Charcot-Marie-Tooth disease may be the consequence of pharyngeal neuropathy affecting the function of pharyngeal dilator muscles.
REFERENCES 1. Culebras A. Headache disorders and sleep. In: Culebras A, editor. Sleep disorders and neurologic diseases. New York: Informa Healthcare USA; 2007. 2. Lance JW, Lambert GA, Goadsby PJ, Duckworth JW. Brainstem influences on the cephalic circulation: experimental data from cat and monkey of relevance to the mechanisms of migraine. Headache 1983;23:258-265. 3. Kayed K, Goadtlibsen OB, Sjaastad O. Chronic paroxysmal hemicrania. IV. “REM sleep locked” nocturnal headache attacks. Sleep 1978;1:91-95. 4. Paiva T, Farinha A, Martins A, et al. Chronic headaches and sleep disorders. Arch Intern Med 1997;157:1701-1705. 5. American Academy of Sleep Medicine. International Classification of Sleep Disorders. Diagnostic and coding manual. 2nd ed. Westchester, Ill: American Academy of Sleep Medicine; 2005. 6. Dahmen N, Querings K, Grun B, Bierbrauer J. Increased frequency of migraine in narcoleptic patients. Neurology 1999;52:12911293. 7. Aaltonen K, Hamalainen ML, Hoppu K. Migraine attacks and sleep in children. Cephalalgia 2000;20:580-584. 8. Bruni O, Fabrizzi P, Ottaviano S. Prevalence of sleep disorders in childhood and adolescence with headache: a case-control study. Cephalalgia 1997;17:492-498. 9. Dexter JD. The relationship between disorders of arousal from sleep and migraine. Headache 1986;26:322. 10. Dalessio DJ. Diagnosing the severe headache. Neurology 1994;44:S6-S12. 11. Dexter JD. Headaches and sleep. Headache 1988;28:671-672. 12. Moskowitz MA, Buzzi MG, Linnik M, Sakas D. Pain mechanisms underlying vascular headaches: progress report. Rev Neurol 1989;145:181-193. 13. Goadsby PJ, Edvinsson L, Ekman R. Vasoactive peptide release in the extracerebral circulation of humans during migraine headache. Ann Neurol 1990;28:183-187. 14. Sicuteri F, Testi A, Anselmi B. Biomedical investigations in headache: increase in hydroxyindoleacetic acid excretion during migraine attacks. Int Arch Allergy 1961;19:55-58. 15. Pérez MF, Sánchez del Río M, Seabra ML, et al. Hypothalamic involvement in chronic migraine. J Neurol Neurosurg Psychiatry 2001a;71:747-751. 16. Bruni O, Galli F, Guidetti V. Sleep hygiene and migraine in children and adolescents. Cephalalgia 1999;19:57-59. 17. Kudrow L. Cluster headache: mechanisms and management. New York: Oxford University Press, 1980. 18. Russell D. Cluster headache: severity and temporal profile of attacks and patient activity prior to and during attacks. Cephalalgia 1981;1:209-219. 19. Evers S, Goadsby PJ. Hypnic headache. Clinical features, pathophysiology, and treatment. Neurology 2003;60:905-909. 20. Liang JF, Fuh JL, Yu HY, et al. Clinical features, polysomnography and outcome in patients with hypnic headache. Cephalalgia 2008;28:209-215. 21. Granella F, D’Andrea G. Hemicrania horologica (“clock-like hemicrania”). Neurology 2003;60:1722-1723. 22. Armstrong-Jones R. Snapping of the brain. Lancet 1920;ii:720. 23. Pearce JMS. Clinical features of the exploding head syndrome. J Neurol Neurosurg Psychiatry 1989;52:907-910. 24. Sachs C, Svanborg E. The exploding head syndrome: polysomnographic recordings and therapeutic suggestions. Sleep 1991;14: 263-266. 25. Aldrich MS, Chauncey JB. Are morning headaches part of obstructive sleep apnea syndrome? Arch Intern Med 1990;150: 1265-1267. 26. Poceta JS, Dalessio DJ. Identification and treatment of sleep apnea in patients with chronic headache. Headache 1995;35:586-589. 27. Lavigne GJ, Montplaisir JY. Restless legs syndrome and sleep bruxism: prevalence and association among Canadians. Sleep 1994;17:739. 28. Laberge L, Tremblay RE, Vitaro F, Montplaisir JY. Development of parasomnias from childhood to early adolescence. Pediatrics 2000;106:67. 29. Spierings EL, van Hoof MJ. Fatigue and sleep in chronic headache sufferers: an age- and sex-controlled questionnaire study. Headache 1997;37:549-552.
CHAPTER 93 • Other Neurologic Disorders 1073 30. Pérez MF, Young WB, Kaup AO, et al. Fibromyalgia is common in patients with transformed migraine. Neurology 2001;57: 1326-1328. 31. Smeyers P. Headaches in childhood: association with sleep disorders and psychological implications. Rev Neurol 1999;28(Suppl. 2):S150-S155. 32. Luc ME, Gupta A, Birnberg JM, Reddick D, Kohrman MH. Characterization of symptoms of sleep disorders in children with headache. Pediatr Neurol 2006;34:7-12. 33. Roth T, Schwartz JR, Hirshkowitz M, et al. Evaluation of the safety of modafinil for treatment of excessive sleepiness. J Clin Sleep Med 2007;3(6):595-602. 34. Erman M, Seiden D, Zammit G, et al. An efficacy, safety, and doseresponse study of ramelteon in patients with chronic primary insomnia. Sleep Med 2006;7:17-24. 35. Buysse DB, Schweitzer PK, Moul DE. Clinical pharmacology of other drugs used as hypnotics. In: Kryger MH, Roth T, Dement W, editors. Principles and practice of sleep medicine. 4th ed. Philadelphia: Saunders; 2005. p. 452-467. 36. Nishino S, Mignot E. Wake-promoting medications: basic mechanisms and pharmacology. In: Kryger MH, Roth T, Dement W, editors. Principles and practice of sleep medicine. 4th ed. Philadelphia: Saunders; 2005. p. 468-483. 37. Paiva T, Batista A, Martins P, Martins A. The relationship between headaches and sleep disturbances. Headache 1995;35:590-596. 38. Baumel B. Migraine: a pharmacologic review with newer options and delivery modalities. Neurology 1994;44:S13-S17. 39. Holmgren K, Sheikholeslam A, Riise C. Effect of full arch maxillary occlusal splint on parafunctional activity during sleep in patients with nocturnal bruxism and signs and symptoms of craniomandibular disorders. J Prosthet Dent 1993;69:293-297. 40. Goldstein M. Traumatic brain injury. Ann Neurol 1990;27:237. 41. Sosin DM, Sniezek JE, Thurman DJ. Incidence of mild and moderate brain injury in the United States. Brain Injury 1996;10: 47-54. 42. Rae-Grant AD, Barbour PJ, Reed J. Development of a novel EEG rating scale for head injury using dichotomous variables. EEG Clin Neurophysiol 1991;79:349-357. 43. Ron S, Algom D, Hary D, Cohen M. Time-related changes in the distribution of sleep stages in brain-injured patients. Electroencephalogr Clin Neurophysiol 1980;48:432-441. 44. Levin HS, Mattis S, Ruff RM, et al. Neurobehavioral outcome following minor head injury: a three center study. J Neurosurg 1987;66:234-243. 45. Segalowitz SJ, Lawson S. Subtle symptoms associated with selfreported mild head injury. J Learn Disabil 1995;28:309-319. 46. Makley MJ, English JB, Drubach DA, et al. Prevalence of sleep disturbance in closed head injury patients in a rehabilitation unit. Neurorehabil Neural Repair 2008;22:341-347. 47. Baumann CR, Werth E, Stocker R, et al. Sleep–wake disturbances 6 months after traumatic brain injury: a prospective study. Brain 2007;130:1873-1883. 48. Short DJ, Stradling JR, Williams SJ. Prevalence of sleep apnea in patients over 40 years of age with spinal cord lesions. J Neurol Neurosurg Psychiatry 1992;55:1032-1036. 49. Cahan C, Gothe B, Decker MJ, et al. Arterial oxygen saturation over time and sleep studies in quadriplegic patients. Paraplegia 1993;31:172-179. 50. Bach JR, Wang TG. Pulmonary function and sleep disordered breathing in patients with traumatic tetraplegia: a longitudinal study. Arch Physical Med Rehabil 1994;75:279-284. 51. Guilleminault C. Post-traumatic hypersomnia. Course 3AS.007. 52nd Annual Meeting of the American Academy of Neurology, San Diego, Calif, 2000. 52. Good JL, Barry E, Fishman PS. Posttraumatic narcolepsy: the complete syndrome with tissue typing. J Neurosurg 1989;71: 765-767. 53. Maccario M, Ruggles KM, Meriwether MW. Post-traumatic narcolepsy. Military Med 1987;152:370-371. 54. Ripley B, Overeem S, Fujiki N, et al. CSF hypocretin/orexin levels in narcolepsy and other neurologic conditions. Neurology 2001; 57:2253-2258. 55. Dempsey OJ, McGeoch P, de Silva RN, et al. Acquired narcolepsy in an acromegalic patient who underwent pituitary irradiation. Neurology 2003;61:537-540.
56. Mignot E, Chen W, Black J. On the value of measuring CSF hypocretin-1 in diagnosing narcolepsy. Sleep 2003;26:646-649. 57. Gill RG, Young JPR, Thomas DJ. Kleine-Levin syndrome: report of two cases with onset of symptoms precipitated by head trauma. Br J Psychiatry 1988;152:410-412. 58. Billiard M, Negri C, Baldy-Moulinier M, et al. Organisations du sommeil chez les sujets attaint d’inconscience post-traumatique chronique. Rev EEG Neurophysiol 1979;9:149-152. 59. Alster J, Pratt H, Feinsod M. Density spectral array, evoked potentials, and temperature rhythms in the evaluation and prognosis of the comatose patient. Brain Injury 1993;7:191-208. 60. Ouellet MC, Beaulieu-Bonneau S, Morin CM. Insomnia in patients with traumatic brain injury: frequency, characteristics, and risk factors. J Head Trauma Rehabil 2006;21:199-212. 61. Fichtenberg NL, Zafontes RD, Putnam S, et al. Insomnia in a post– acute brain injury sample. Brain Injury 2002;16:197-206. 62. Fichtenberg NL, Millis SR, Mann NR, et al. Factors associated with insomnia among post–acute traumatic brain injury survivors. Brain Injury 2000;14:659-667. 63. Thaxton L, Myers MA. Sleep disturbances and their management in patients with brain injury. J Head Trauma Rehabil 2002;17: 335-348. 64. Humphrey ME, Zangwill OL. Cessation of dreaming after brain injury. J Neurol Neurosurg Psychiatry 1951;14:322-325. 65. Prigatano GP, Orr WC, Zeiner HK. Sleep and dreaming disturbances in closed head injury patients. J Neurol Neurosurg Psychiatry 1982;45:78-80. 66. Mahowald MW, Woods SR, Schenck CH. Sleeping dreams, waking hallucinations, and the central nervous system. Dreaming 1998;8: 89-102. 67. Jacobsohn E. Fall von Narcolepsie. Klin Wochenschr 1926;2:2188. 68. Guillain G, Alajouanine T. La somnolence dans la sclérose en plaques. Les episodes aigus ou subaigus de la sclérose en plaques pouvant simuler l’encéphalite léthargique. Ann Med 1928;24: 111-118. 69. Grigioresco D. Contribution a l’étude des troubles du sommeil aux lésions des noyeaux gris centraux dans la sclérose en plaques. Rev Neurol II 1932;27-45. 70. Berg O, Hanley J. Narcolepsy in two cases of multiple sclerosis. Acta Neurol Scand 1963;39:252-257. 71. Ekbom K. Familial multiple sclerosis associated with narcolepsy. Arch Neurol 1966;15:337-344. 72. Leo GJ, Rao M, Bernardin L. Sleep disturbances in multiple sclerosis. Neurology 1991;41:320. 73. Clark CM, Fleming JA, Li D, et al. Sleep disturbance, depression, and lesion site in patients with multiple sclerosis. Arch Neurol 1992;49:641-643. 74. Hillert J, Olerup O. Multiple sclerosis is associated with genes within or close to the HLA-DR-DQ subregion on a normal DR15, DQ6, Dw2 haplotype. Neurology 1993;43:163-168. 75. Younger DS, Pedley TA, Thorpy MJ. Multiple sclerosis and narcolepsy: possible similar genetic susceptibility. Neurology 1991;41: 447-448. 76. Fogdell A, Hillert J, Sachs C, Olerup O. The multiple sclerosis and narcolepsy-associated HLA class II haplotype includes the DRB5*0101 allele. Tissue Antigens 1995;46:333-336. 77. Iseki K, Mezaki T, Oka Y, et al. Hypersomnia in MS. Neurology 2002;59:2006-2007. 78. Italian REMS Study Group, Manconi M, Ferini-Strambi L, et al. Multicenter case-control study on restless legs syndrome in multiple sclerosis: the REMS study. Sleep 2008;31:944-952. 79. Saunders J, Whitham R, Schaumann B. Sleep disturbance, fatigue, and depression in multiple sclerosis. Neurology 1991;41:320. 80. Tachibana N, Howard RS, Hirsch NP, et al. Sleep problems in multiple sclerosis. Eur Neurol 1994;34:320-323. 81. Ferini-Strambi L, Filippi M, Martinelli V, et al. Nocturnal sleep study in multiple sclerosis: correlations with clinical and brain magnetic resonance imaging findings. J Neurol Sci 1994;125(2): 194-197. 82. Zifko UA. Management of fatigue in patients with multiple sclerosis. Drugs 2004;64:1295-1304. 83. Krupp LB, Coyle PK, Doscher C, et al. Fatigue therapy in multiple sclerosis: results of a double-blind, randomized, parallel trial of amantadine, pemoline, and placebo. Neurology 1995;45:19561961.
1074 PART II / Section 11 • Neurologic Disorders 84. Rammohan KW, Rosenberg JH, Lynn DJ, et al. Efficacy and safety of modafinil for the treatment of fatigue in multiple sclerosis: a two centre phase study. J Neurol Neurosurg Psychiatry 2002;72: 179-183. 85. Schluter B, Aguigah G, Andler W. Hypersomnia in multiple sclerosis. Klin Padiatr 1996;208:103-105. 86. Wang CY, Kawashima H, Takami T, et al. A case of multiple sclerosis with initial symptoms of narcolepsy. Brain Dev 1998;30: 300-306. 87. Sandyk R. Resolution of sleep paralysis by weak electromagnetic fields in a patient with multiple sclerosis. Int J Neurosci 1997;90: 145-157. 88. Sandyk R. Weak electromagnetic fields restore dream recall in patients with multiple sclerosis. Int J Neurosci 1995;82:113-125. 89. Sandyk R. Suicidal behavior is attenuated in patients with multiple sclerosis by treatment with electromagnetic fields. Int J Neurosci 1996;87:5-15. 90. Sandyk R. Resolution of partial cataplexy in multiple sclerosis by treatment with weak electromagnetic fields. Int J Neurosci 1996; 84:157-164. 91. Syed BH, Rye DB, Singh G. REM sleep behavior disorder and SCA-3 (Machado-Joseph disease). Neurology 2003;60:148. 92. Gilman S, Koeppe RD, Chervin FB, et al. REM sleep behavior disorder is related to striatal monoaminergic deficit in MSA. Neurology 2003;61:29-34. 93. Friedman JH, Fernandez HH, Sudarsky LR. REM behavior disorder and excessive daytime somnolence in Machado-Joseph disease (SCA-3). Mov Disord 2003;18:1520-1522. 94. Iranzo A, Muñoz E, Santamaría J, et al. REM sleep behavior disorder and vocal cord paralysis in Machado-Joseph disease. Mov Disord 2003;18:1179-1183. 95. Culebras A. Sleep disorders and neuromuscular disorders. In: Culebras A, editor. Sleep disorders and neurologic diseases. New York: Informa Healthcare USA; 2007. 96. Dematteis M, Pépin JL, Jeanmart M, et al. Charcot-Marie-Tooth disease and sleep apnoea syndrome: a family study. Lancet 2001; 357:267-272. 97. Dziewas R, Waldmann N, Böntert M, et al. Increased prevalence of obstructive sleep apnoea in patients with Charcot-Marie-Tooth disease: a case control study. J Neurol Neurosurg Psychiatry 2008 Jul;79(7):829-831. 98. Aboussouan LS, Lewis RA, Shy ME. Disorders of pulmonary function, sleep, and the upper airway in Charcot-Marie-Tooth disease. Lung 2007;185:1-7. 99. Vankova J, Stepanova I, Jech R, et al. Sleep disturbances and hypocretin deficiency in Niemann-Pick disease type C. Sleep 2003;26: 427-430. 100. Schwartz BA, Escande C. Sleeping sickness: sleep study of a case. Electroencephalogr Clin Neurophysiol 1970;29:83. 101. Buguet A, Bisser S, Josenando T, et al. Sleep structure: a new diagnostic tool for stage determination in sleeping sickness. Acta Trop 2005;93:107-117. 102. Whittle HC, Greenwood BM, Bidwell DE, et al. IgM and antibody measurements in the diagnosis and management of Gambian trypanosomiasis. Am J Trop Med Hyg 1977;26:1129-1134. 103. Kristensson K, Bentivoglio M. Pathology of trypanosomiasis. In: Dumas M, Bouteille B, Bughet A, editors. Progress in human African trypanosomiasis, sleeping sickness. Paris: Springer; 1999. p. 157-181
104. Kanbayashi T, Goto A, Hishikawa Y, et al. Hypersomnia due to acute disseminated encephalomyelitis in a 5-year old girl. Sleep Med 2001;2:347-350. 105. Montiel P, Sellal F, Clerc C, et al. Limbic encephalitis with severe sleep disorder associated with voltage-gated potassium channels (VGKCs) antibodies. Rev Neurol (Paris) 2008;164:181-184. 106. Compta Y, Iranzo A, Santamaría J, et al. REM sleep behavior disorder and narcoleptic features in anti-Ma2–associated encephalitis. Sleep 2007;30(6):767-769. 107. Dyken ME, Yamada T, Berger HA. Transient obstructive sleep apnea and asystole in association with presumed viral encephalopathy. Neurology 2003;60:1692-1694. 108. Corral-Corral I, Quereda Rodríguez-Navarro C. Post-encephalitic syndromes in the Spanish medical literature. Rev Neurol 2007; 44:499-506. 109. Ransmayr G. Constantin von Economo’s contribution to the understanding of movement disorders. Mov Disord 2007;22: 469-475. 110. Corral-Corral I, Quereda Rodríguez-Navarro C. How did encephalitis lethargica affect Spain? An analysis of the cases reported between 1918 and 1936. Rev Neurol 2007;44:245-253 111. Culebras A. Sleep disorders associated with psychiatric, medical and neurologic disorders. In: Culebras A, editor. Clinical handbook of sleep disorders. Boston: Butterworth-Heinemann; 1996. p. 233-281. 112. Aldrich MS, Naylor MW. Narcolepsy associated with lesions of the diencephalons. Neurology 1989;39:1505-1508. 113. Arii J, Kanbayashi T, Tanabe Y, et al. A hypersomnolent girl with decreased CSF hypocretin level after removal of a hypothalamic tumor. Neurology 2001;56:1775-1776. 114. Chow E, Fan G, Hadi S, et al. Symptom clusters in cancer patients with brain metastases. Clin Oncol (R Coll Radiol) 2008;20:76-82. 115. Nogués M, Gene R, Benarroch E, et al. Respiratory disturbances during sleep in syringomyelia and syringobulbia. Neurology 1999;52:1777-1783. 116. Sajkov D, Marshall R, Walker P, et al. Sleep apnea related hypoxia is associated with cognitive disturbances in patients with tetraplegia. Spinal Cord 1998;36:231-239. 117. Culebras A. Sleep and neuromuscular disorders. Neurol Clin 1996;14:791-805. 118. Botelho RV, Bittencourt LR, Rotta JM, Tufik S. A prospective controlled study of sleep respiratory events in patients with craniovertebral junction malformation. J Neurosurg 2003;99: 1004-1009. 119. Guilleminault C, Li KK, Philip P, et al. Anterior cervical spine fusion and sleep disordered breathing. Neurology 2003;61:9799. 120. Brown LK, Heffner JE, Obbens EA. Transverse myelitis associated with restless legs syndrome and periodic movements of sleep responsive to an oral dopaminergic agent but not to intrathecal baclofen. Sleep 2000;23:591-594. 121. Nogués M, Cammarota A, Leiguarda R, et al. Periodic limb movements in syringomyelia and syringobulbia. Mov Disord 2000;15: 113-119. 122. Simonds AK. Recent advances in respiratory care for neuromuscular disease. Chest 2006;130(6):1879-1886. 123. Ayas NT, Epstein LJ, Lieberman SL, et al. Predictors of loud snoring in persons with spinal cord injury. J Spinal Cord Med 2001;24:30-34.
Parasomnias
Section
Mark W. Mahowald and Michel A. Cramer Bornemann 94 Non-REM Arousal
Parasomnias 95 REM Sleep Parasomnias 96 Other Parasomnias
97 Idiopathic Nightmares and
Dream Disturbances Associated with Sleep–Wake Transitions
Non-REM Arousal Parasomnias Mark W. Mahowald and Michel A. Cramer Bornemann Abstract Parasomnias are defined as unpleasant or undesirable behavioral or experiential phenomena that occur predominantly or exclusively during the sleep period. These were initially thought to represent a unitary phenomenon, often attributed to psychiatric disease. As more parasomnias are being carefully studied both polygraphically and clinically, it is becoming apparent that parasomnias are not a unitary phenomenon, but rather are due to a large number of completely different conditions, most of which are diagnosable and treatable. Moreover, most, in fact, are not the manifestation of psychiatric disorders and are far more prevalent than previously suspected. The parasomnias may be conveniently categorized as primary parasomnias (disorders of the sleep states per se), and secondary parasomnias (disorders of other organ systems manifest themselves during sleep). The primary sleep parasomnias can be classified according to the sleep state of
There is compelling evidence that extensive reorganization of central nervous system activity occurs as the brain cycles through the three primary states of being: wakefulness, non–rapid eye movement (NREM) sleep, and rapid eye movement (REM) sleep. The concept that certain parts of the nervous system are active in one state but not in the other two is erroneous. Almost all portions of the nervous system are active across all three states of being, but active in a different mode. The reticular response reversal phenomenon, in which excitation of the same anatomic site can have opposite effects on motor activity, depending upon the state (wake or REM) during stimulation is testimony to that fact.2,3 Relevant to many of the parasomnias occurring in humans is the demonstration that the effects of cholinergic drug injection into the pontine reticular formation of cats may have dramatically different effects, depending upon the state of the animal at the time of injection: If the drug is administered during NREM sleep, a state identical to naturally occurring REM sleep is induced; if it is administered during wakefulness, a waking-dissociated state occurs, characterized by EEG desynchronization and muscle atonia in a cat that appeared to be awake and able to track objects in its visual field.4 The concept that
12
98 Disturbed Dreaming as a
Factor in Medical Conditions 99 Sleep Bruxism
Chapter
94
origin: rapid eye movement (REM) sleep, non-REM (NREM) sleep, or miscellaneous (i.e., those not respecting sleep state). The secondary sleep parasomnias can be further classified by the organ system involved1 (see Box 96-1). The focus of this chapter is on the NREM sleep arousal parasomnias, which occur on a broad spectrum and include confusional arousals, sleepwalking, and sleep terrors. The underlying pathophysiology is state dissociation—the brain is partially awake and partially in NREM sleep. The result of this mixed state of being is that the brain is awake enough to perform very complex, and often protracted motor or verbal functions, but it is asleep enough not to have conscious awareness of or responsibility for these actions. These NREM parasomnias are not usually due to underlying serious psychological or psychiatric conditions, and more importantly, they are diagnosable and usually readily treatable.
wake and sleep are all-or-none and therefore mutually exclusive states is erroneous. Sleep is not a global or whole-brain phenomenon.5 Such a waking-dissociated state is likely the basis for many human parasomnias, both REM and NREM parasomnias. A intracerebral neurophysiologic study in a patient with a NREM parasomnia supports this concept.6 Parasomnias are clinical phenomena that appear as the brain becomes reorganized across states; therefore, they are particularly apt to occur during the transition periods from one state to another. In view of the large number of neural networks, neurotransmitters, and other statedetermining substances that must be recruited synchronously for full state declaration and the frequent transitions among states during the wake–sleep cycle, it is surprising that errors in state declaration do not occur more often than they do.7-9 The concept that sleep and wakefulness are not invariably mutually exclusive states and that the various statedetermining variables of wakefulness, NREM sleep, and REM sleep can occur simultaneously or oscillate rapidly is key to the understanding the primary sleep parasomnias. The mixture of wakefulness and NREM sleep would explain confusional arousals (sleep drunkenness), automatic 1075
1076 PART II / Section 12 • Parasomnias
behavior, or microsleeps.9 The tonic and phasic components of REM sleep can become dissociated, intruding or persisting into wakefulness, explaining cataplexy, wakeful dreaming, lucid dreaming, and the persistence of motor activity during REM sleep (REM sleep behavior disorder [RBD]).10
EPIDEMIOLOGY AND RISK FACTORS The disorders of arousal are the most impressive and most common of the NREM sleep parasomnias. These share common features: They tend to arise from slowwave sleep (stages 3 and 4 of NREM sleep), therefore usually occurring in the first third of the sleep cycle (and rarely during naps), and they are common in childhood, usually decreasing in frequency with increasing age.11,12 There is often a family history of disorders of arousal; however, this association has recently been questioned.13 A specific HLA gene (DQB1) appears to confer susceptibility to sleepwalking.14 Importantly, although they most commonly occur during stage N3 sleep (stages 3 and 4 of NREM sleep or slow-wave sleep), disorders of arousal can occur during any stage of NREM sleep, and they can occur late in the sleep period.15 Disorders of arousal may be associated with febrile illness, prior sleep deprivation, physical activity, or emotional stress.16-18 Contrary to popular opinion, alcohol appears not to play a role in triggering disorders of arousal.19 Medication-induced cases have been reported with sedative-hypnotics, neuroleptics, minor tranquilizers, stimulants, and antihistamines, often in combination with each other.17,20-24 There have been numerous reports of extremely complex activities attributed to sedative-hypnotic agents, often resulting in forensic issues. This issue is thoroughly discussed in Chapter 63. In some women, disorders of arousal be exacerbated by pregnancy or menstruation, whereas in others, disorders of arousal may be alleviated by pregnancy, suggesting hormonal influences.25-27 Such precipitants should be thought of as triggering events in susceptible persons, and not causing them. Underlying predisposing, priming, and precipitating factors have been thoroughly reviewed elsewhere.18 Numerous other sleep disorders that result in arousals (obstructive sleep apnea,28 nocturnal seizures, or periodic limb movements) can provoke these disorders. Sleepdisordered breathing has been found to be more prevalent in children and adults with disorders of arousal. One study found that sleep fragmentation induced by sleepdisordered breathing is more common in adults with disorders of arousal than in normal subjects.29,30 The combination of frequent arousals and sleep deprivation seen in these other sleep disorders provide fertile ground for the appearance of disorders of arousal. These represent a sleep disorder within a sleep disorder—the clinical event is a disorder of arousal, but the true culprit is a different, unrelated sleep disorder. This would explain the common clinical experience of improvement of disorders of arousal following identification and treatment of obstructive sleep apnea.31 Conversely, effective treatment of obstructive sleep apnea with nasal CPAP can result in disorders of arousal, presumably associated with deep NREM sleep rebound.32,33
Persistence of these activities beyond childhood or their development in adulthood is often taken as an indication of significant psychopathology.34,35 Numerous studies have dispelled this myth, indicating that significant psychopathology is usually not present in adults with disorders of arousal.36-38 In one study in children, there was an association between disorders of arousal and anxiety.39 These arousals might not be the culmination of ongoing psychologically significant mentation, in that somnambulism can be induced in normal children by standing them up during slow-wave sleep,40,41 and sleep terrors can be precipitously triggered in susceptible persons by sounding a buzzer during slow-wave sleep.11,42 The mechanism of these disorders is not clear, but clearly both genetic43 and environmental factors are operant. It has been suggested that sleep terrors may be the manifestation of anomalous REM sleep mixed with NREM sleep.44
PATHOGENESIS In addition to the phenomenon of state dissociation, in which two states of being overlap or occur simultaneously, there are likely additional underlying physiologic phenomena that contribute to the appearance of complex motor actions during sleep. These include locomotor centers, sleep inertia, and sleep state instability. Locomotor Centers Locomotor centers, present in multiple sites in the central nervous system, may play a role in the disorders of arousal, which represent motor activity that is dissociated from waking consciousness.45 These areas project to the central pattern generator of the spinal cord, which itself is able to produce complex stepping movements in the absence of supraspinal influence.46 This accounts for the fact that decorticate experimental and barnyard animals are capable of performing very complex, integrated motor acts.47 A biological substrate is further supported by the similarity between spontaneously occurring sleep terrors in humans and sham rage induced in animals.48-50 Indeed, human neuropathology can result in similar activities.51-55 Dissociation of the locomotor centers from the parent state of NREM sleep would explain the presence of complex motor behavior seen in disorders of arousal. Spontaneous locomotion following decerebration in cats clearly indicates that such centers, if dysfunctional, release motor activity into the sleeping state.56,57 Single proton emission computed tomography (SPECT) study of a sleepwalker suggested activation of thalamocingulate pathways and persisting deactivation of other thalamocortical arousal systems, resulting in a dissociation between body sleep and mind sleep.58 The concept that the cortex itself can actually be a central pattern generator could explain the expression of previously learned behavior occurring during disorders of arousal.59 Sleep Inertia Sleep inertia (also termed sleep drunkenness) refers to a period of impaired performance and reduced vigilance following awakening from the regular sleep episode or from a nap. This impairment may be severe, last minutes
to hours, and be accompanied by polygraphically recorded microsleep episodes.60-63 Support of a gradual disengagement from sleep to wakefulness comes from neurophysiologic studies in animals64 and cerebral blood flow studies in humans.65-67 The persistent reduction, lasting minutes, of the photomyoclonic response upon awakening from NREM sleep is further confirmation of a less-thanimmediate transition from sleep to wakefulness.68 There appears to be great interindividual variability in the extent and duration of sleep inertia, both following spontaneous awakening after the major sleep period and following naps. Sleep inertia likely plays a role in the susceptibility to disorders of arousal.64 Sleep State Instability The cyclic alternating pattern (CAP) may also play a role in the etiology of disorders of arousal.69 CAP is a physiologic component of NREM sleep and is functionally correlated with long-lasting arousal oscillations. CAP is a measure of NREM instability, with high level of arousal oscillation.70 More sophisticated monitoring techniques, such as topographical EEG mapping, suggest that there may be more delta EEG activity before the onset of sleep terrors.71 There is no difference in the macrostructural sleep parameters between patients with disorders of arousal and controls. However, patients with disorders of arousal have been found to have increases in CAP rate, in number of CAP cycles, and in arousals with EEG synchronization. An increase in sleep instability and in arousal oscillation is a typical microstructural feature of slowwave sleep–related parasomnias and may play a role in triggering abnormal motor episodes during sleep in these patients.72,73 Microarousals preceded by EEG slow-wave synchronization during NREM sleep are more common in patients with sleepwalking and sleep terrors than in controls. This supports the existence of an arousal disorder in these persons.72 Although some have reported hypersynchronous delta activity on polysomnograms (PSGs) of young adults with sleepwalking.74 this has not been the experience of others.75 EEG spectral analysis studies indicate that patients with sleepwalking demonstrate an instability of slow-wave sleep, particularly in the early portion of the sleep period.76 Impairment of efficiency of inhibitory cortical circuits during wakefulness has been reported.77
CLINICAL FEATURES Disorders of arousal occur on a broad spectrum ranging from confusional arousals, through somnambulism (sleep walking), to sleep terrors (also termed pavor nocturnus and erroneously, incubus or succubus) (Videos 94-1 and 94-2). Some take the form of specialized behavior (discussed later) such as sleep-related eating and sleep-related sexual activity without conscious awareness. Confusional Arousals Confusional arousals are often seen in children and are characterized by movements in bed, occasionally thrashing about, or inconsolable crying.78 Sleep drunkenness is probably a variation on this theme.17 The prevalence of confusional arousals in adults is approximately 4%.79
CHAPTER 94 • Non-REM Arousal Parasomnias 1077
Sleepwalking Sleepwalking is prevalent in childhood (1% to 17%), peaking at 11 to 12 years of age, and is far more common in adults (nearly 4%) than generally acknowledged.79-82 Sleepwalking may be either calm or agitated, with varying degrees of complexity and duration. Sleep Terrors Sleep terrors are the most dramatic disorder of arousal. It is commonly initiated by a loud, blood-curdling scream associated with extreme panic, followed by prominent motor activity such as hitting the wall, running around or out of the bedroom, even out of the house—resulting in bodily injury or property damage. A universal feature is inconsolability. Although the victim appears to be awake, he or she usually misperceives the environment, and attempts at consolation are fruitless and might serve only to prolong or even intensify the confusional state. Some degree of perception may be evident, such as running for and opening a door or window. Complete amnesia for the activity is typical, but amnesia may be incomplete.11,12,83 The intense endogenous arousal and exogenous unarousability constitute a curious paradox. As with sleepwalking, sleep terrors are much more prevalent in adults than generally acknowledged (4% to 5%).84 Although usually benign, sleep terrors may be violent, resulting in considerable injury to the victim or others or damage to the environment, occasionally with forensic implications.85,86 Specialized Forms of Disorders of Arousal Sleep-Related Eating Disorder The sleep-related eating disorder, characterized by frequent episodes of nocturnal eating, generally without full conscious awareness, usually not associated with waking eating disorders, likely represents a specialized form of disorder of arousal. This condition often responds to treatment with a combination of dopaminergic and opiate agents or topiramate.87 d-Fenfluramine, which is no longer available, has also been reported to be effective.88 Formal sleep studies are indicated, because sleep-related eating may be the manifestation of other sleep disorders such as restless legs syndrome, periodic limb movements of sleep, or obstructive sleep apnea, all of which predispose to arousal.89-94 Nocturnal binging may be induced by benzodiazepine medication.95 and sleep-related eating has been associated with zolpidem administration and olanzapine.96-98 The sleep-related eating disorder is distinct from the night-eating syndrome characterized by morning anorexia, evening hyperphagia (while awake), and insomnia and associated with hypothalamic-pituitary axis abnormalities.99-101 Sleepsex Inappropriate sexual behavior occurring during the sleep state without conscious awareness, presumably the result of and mixture of wakefulness and sleep, have been reported.102 Such activities can result in feelings of guilt, shame, or depression and can have medicolegal implications.103 (See also Chapter 63.)
1078 PART II / Section 12 • Parasomnias Case Study An 18-year-old white man who resides in a rural Midwestern farming community is academically doing well as a senior in high school. The patient reluctantly presented to the Sleep Center based more upon the persistence of his mother, who has had increasing concerns over her only child’s safety, particularly at night. According to his parents, since childhood their son has had nocturnal activities arising within a few hours after sleep onset. Believing that these activities would resolve as their son grew out of adolescence and into adulthood, the parents were at first not overly concerned and were initially able to easily maintain the safety of their son by remaining vigilant and subtly intervening when necessary. With time these activities have maintained their almost nightly regularity but have developed at times into something more complex, sustained, and violent. Given that their son has grown to be 77 inches tall with a weight of 235 pounds, parental interventions to quell their son’s suddenly eruptive nocturnal activities have become problematic for both parties. The patient states that he has always been completely unaware of these episodes and has no recollection of the events the following morning. Additionally, the parents raise further concern over safety because their son intends to enroll in a college away from home and is looking forward to living in either a dormitory or a high-rise apartment. Without responsible vigilance in college, the parents fear the worst for their son. Of course, the patient, wanting to finally exert his independence, lacked proper insight into understanding the gravity of his situation and clearly had become antagonistic over his parents’ concerns. Given the patient’s continued lack of awareness in these matters, coupled with his sincere denial of any difficulties with either sleep initiation or maintenance, the direct involvement of the patient’s parents was crucial in attaining a comprehensive history as well as a thorough clinical characterization of their son’s activities from sleep. According to his mother, since childhood the patient has had sleep disturbances almost every night. Typically, these episodes occur within the first 2 hours after he has gone to bed, and only rarely do they occur in the latter third of the night. The episodes are characterized by somniloquy, somnambulism, and a general “thrashing around in his bed,” leaving his bedding in complete disarray. Less commonly, the patient abruptly wakes up his household with fits of “screaming and yelling at the top of his lungs.” Despite his parents’ efforts at reassurance and solace, the patient remained unreceptive and inconsolable. In the same way these “night terrors,” as the mother called them, came on, so too would they spontaneously abate. Though the patient’s nocturnal activities were unremitting over recent years, his parents began to discern a trend toward more worrisome physical actions. These particularly “severe” episodes were punctuated by
violent outbursts of punching, hitting, and kicking inflicted upon a foe unseen to the parents in the room. Never at any time were these combative actions directed toward the parents. Many times over recent years the patient was caught attempting to get out through the front door, even though he was visibly asleep. On one occasion the mother caught her son just as he was attempting to leave through an upstairs window, having “already completely kicked out the storm window.” In the last 2 years, it has not been uncommon for the patient to have sustained bruises and superficial cuts to his extremities as a result of these activities arising from sleep. Lastly, the parents note that these “severe” episodes increase in frequency when the patient is staying away from home, such as in a hotel or at summer camp. Aside from a mild form of delayed sleep phase syndrome and consequent volitional sleep deprivation supported by 3 weeks of sleep diaries, the patient has otherwise been absolutely healthy and has not suffered from any medical, neurologic, or mental conditions. The patient does not drink alcohol or partake in illicit drugs. The patient is not taking any prescription medications, including selective serotonin reuptake inhibitors (SSRIs). The patient does not have a history that suggests sleep-disordered breathing or any other primary sleep disorder. Family history is devoid of any nocturnal behavior suggestive of parasomnias. A formal nocturnal polysomnograph (PSG) was undertaken using a full seizure montage. The baseline PSG did not reveal any sleep-disordered breathing, nocturnal myoclonus, or periodic limb movements. Sleep architecture was within normal limits, and the patient attained a sleep efficiency of 96%. Stage REM was attained and observed to have normal atonia. A full seizure montage was employed. There was no electrical or clinical seizure activity. Four discrete episodes of spontaneous NREM-related confusional arousals were observed and were associated with complex motor activity (Fig. 94-1) with overt vocalizations. These confusional arousals were not associated with consequent EEG slowing. As suspected by the clinical history and further supported by the findings on the PSG, a NREM parasomnia was diagnosed. The patient developed a better understanding of his problem after replaying his findings on the PSG video monitor. Management strategies included teaching proper sleep hygiene and minimizing volitional sleep deprivation; refraining from or minimizing alcohol use; discussing techniques to ensure a supportive environment with appropriate responsible vigilance provided by a team of family or friends; lengthy instructional measures to ensure safety, including a strong recommendation for the patient to attain housing on the ground level or basement of his chosen residence; and nightly use of a long-acting sedative hypnotic of the benzodiazepine class.
CHAPTER 94 • Non-REM Arousal Parasomnias 1079
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Figure 94-1 Polysomnographic example of disorder of arousal. This is a 1-minute epoch of a full seizure montage of the patient in the case study. Note the precipitous arousal from slow-wave sleep without anticipatory tachycardia. Although the patient appears to be awake and talking, the EEG shows persistent slowing.
DIAGNOSIS Isolated, often bizarre, sleep-related events may be experienced by perfectly normal people, and most do not warrant further extensive or expensive evaluation. The initial approach to the complaint of unusual sleep-related behavior is to determine whether further evaluation is necessary. The patient should be queried regarding the exact nature of the events. Because many of these episodes may be associated with partial or complete amnesia, additional descriptive information from a bed partner or other observer can prove invaluable. Home videotapes of the clinical event may be quite helpful. In general, indications for formal evaluation of parasomnias include activities that are potentially violent or injurious, are extremely disruptive to other household members, result in the complaint of excessive daytime sleepiness, and are associated with medical, psychiatric, or neurologic symptoms or findings.1 Serious attention should be paid to such parasomnia complaints under these circumstances. Formal PSG studies, appropriately performed, provide direct or indirect diagnostic information in the majority of cases. This is of more than academic interest, because most of these conditions are readily treatable. Emphasis must be placed on the types of studies required; routine PSGs performed for conventional sleep disorders are inadequate. In addition to the physiologic parameters monitored in the standard PSG, there must be an expanded EEG montage and there must be continuous audiovisual monitoring.74,104
Observation by an experienced technologist is invaluable. Multiple night studies may be required to capture an event. Interpretation should be made by a polysomnographer experienced in these disorders. Sleep deprivation prior to formal PSG study can increase the likelihood of capturing an event in the sleep laboratory.105 Unattended studies have no role in the evaluation of parasomnias.106
DIFFERENTIAL DIAGNOSIS Numerous other conditions can perfectly mimic the disorders of arousal. These include obstructive sleep apnea, REM sleep behavior disorder, nocturnal seizures, psychogenic dissociative disorders, and malingering.107-109 NREM parasomnias may be particularly difficult to differentiate from nocturnal epileptic phenomena.110 There may be an association between disorders of arou sal, migraine headache,111 neurofibromatosis type 1,112 or Tourette’s syndrome.113,114 In preverbal children, nocturnal cluster headaches can mimic sleep terrors.115 Obstructive sleep apnea may be associated with and even manifest as disorders of arousal.29,109,116 TREATMENT Given the high prevalence of these disorders in normal persons, formal sleep center evaluation should be confined to cases in which the sleep-related activities are
1080 PART II / Section 12 • Parasomnias
potentially injurious or violent, are extremely bothersome to other household members, result in symptoms of excessive daytime sleepiness, or have unusual clinical characteristics. Treatment is often not necessary. Reassurance of their typically benign nature, lack of psychological significance, and the tendency to diminish over time, is often sufficient. Objective studies documenting efficacy of medication efficacy. Tricyclic antidepressants and benzodiazepines may be effective, and they should be administered if the activity is dangerous to person or property or extremely disruptive to family members.17 Paroxetine and trazodone have been reported effective in isolated cases of disorders of arousal.117,118 Nonpharmacologic treatment such as psychotherapy,42 progressive relaxation,119 or hypnosis120 is recommended for long-term management. Anticipatory awakening has been reported to be effective in treating sleepwalking in children.121 The avoidance of precipitants such as drugs and sleep deprivation is also important. Administration of dopaminergic agents, opiates, or topiramide has been reportedly effective in the sleep-related eating disorder.87,122-124
CLINICAL COURSE AND PREVENTION The natural history of the disorders of arousal is to diminish with increasing age. However, this pattern is hardly universal, and these conditions can persist into, or even begin in, adulthood. Identifiable risk factors in a given patient, such as sleep deprivation or alcohol or medication administration, should be avoided. PITFALLS AND CONTROVERSIES Inasmuch as the disorders of arousal are extremely prevalent in the normal population, the decision to treat with pharmacologic or behavioral therapy may be difficult. Certainly if there is a history of potentially violent or injurious behavior, treatment is warranted. However, our center has seen patients with a history of very benign and infrequent sleepwalking episodes in childhood present with severely injurious sleep-related behavior as adults.86 ❖ Clinical Pearl Disorders of arousal are very common in children and adults, and they are not related to significant underlying psychiatric or psychological problems. The activities may be very complex and protracted. Evaluation and treatment is advised for patients whose activities are potentially violent or are very disturbing to other family members. Because other parasomnias, particularly the REM sleep behavior disorder and nocturnal seizures, can perfectly mimic disorders of arousal, extensive PSG evaluation by clinicians experienced in these disorders is recommended.
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56. Lai YY, Siegel JM. Brainstem-mediated locomotion and myoclonic jerks. I. Neural substrates. Brain Res 1997;745:257-264. 57. Lai YY, Siegel JM. Brainstem-mediated locomotion and myoclonic jerks. II. Pharmacological effects. Brain Res 1997;745:265-270. 58. Bassetti C, Vella S, Donati F, et al. SPECT during sleepwalking. Lancet 2000;356:484-485. 59. Yuste R, MacLean JN, Smith J, et al. The cortex as a central pattern generator. Nat Rev Neurosci 2005;6:477-483. 60. Achermann P, Werth E, Dijk D-J, et al. Time course of sleep inertia after nighttime and daytime sleep episodes. Arch Ital Biol 1995;134:109-119. 61. Dinges DF. Napping patterns and effects in human adults. In: Dinges DF, Broughton RJ, editors. Sleeping and alertness: chronobiological, behavioral, and medical aspects of napping. New York: Raven Press; 1989. p. 171-204. 62. Dinges DF. Are you awake? Cognitive performance and reverie during the hypnopompic state. In: Bootzin RR, Kihlstrom JF, Schacter DL, editors. Sleep and cognition. Washington, DC: American Psychological Association; 1990. p. 159-175. 63. Tassi P, Muzet A. Sleep inertia. Sleep Med Rev 2000;4:341-353. 64. Horner RL, Sanford LD, Pack AI, et al. Activation of a distinct arousal state immediately after spontaneous awakening from sleep. Brain Res 1997;778:127-134. 65. Koboyama T, Hori A, Sato T, et al. Changes in cerebral blood flow velocity in healthy young men during overnight sleep and while awake. EEG Clin Neurophysiol 1997;102:125-131. 66. Balkin TJ, Wesensten NJ, Braun AR, et al. Shaking out the cobwebs: changes in regional cerebral blood flow (rCBF) across the first 20 minutes of wakefulness. Journal of Sleep Res 1998;21:411.A. 67. Balkin TJ, Braun AR, Wesensten NJ, et al. The process of awakening: a PET study of regional brain activity patterns mediating the re-establishment of alertness and consciousness. Brain Res Bull 2002;12:2308-2319. 68. Meier-Ewert K, Broughton RJ. Photomyoclonic response of epileptic and non-epileptic subjects during wakefulness, sleep and arousal. EEG Clin Neurophysiol 1967;23:142-151. 69. Parrino L, Halasz P, Tassinari CA, et al. CAP, epilepsy and motor events during sleep: the unifying role of arousal. Sleep Med Rev 2006;10:267-285. 70. Terzano MG, Parrino L, Spaggiari MC. The cyclic alternating pattern sequences in the dynamic organization of sleep. EEG Clin Neurophysiol 1988;69:437-447. 71. Zadra AL, Nielsen TA. Topographical EEG mapping in a case of recurrent sleep terrors. Dreaming 1998;8:67-74. 72. Halasz P, Ujszaszi J, Gadoros J. Are microarousals preceded by electroencephalographic slow wave synchronization precursors of confusional awakenings? Sleep 1985;8:231-238. 73. Zuccone M, Oldani A, Ferini-Strambi L, et al. Arousal fluctuations in non–rapid eye movement parasomnias: the role of cyclic alternating pattern as a measure of sleep instability. J Clin Neurophysiol 1995;12:147-154. 74. Blatt I, Peled R, Gadoth N, et al. The value of sleep recording in evaluating somnambulism in young adults. EEG Clin Neurophysiol 1991;78:407-412. 75. Schenck CH, Pareja JA, Patterson AL, et al. An analysis of polysomnographic events surrounding 252 slow-wave sleep arousals in 38 adults with injurious sleepwalking and sleep terrors. J Clin Neurophysiol 1998;15:159-166. 76. Bruni O, Ferri R, Novelli L, et al. NREM sleep instability in children with sleep terrors: the role of slow wave activity interruptions. Clin Neurophysiol 2008;119:985-992. 77. Oliviero A, Della Marca G, Tonali PA, et al. Functional involvement of cerebral cortex in adult sleepwalking. J Neurol 2007;254:1066-1072. 78. Rosen G, Mahowald MW, Ferber R. Sleepwalking, confusional arousals, and sleep terrors in the child. In: Ferber R, Kryger M, editors. Principles and practice of sleep medicine in the child. Philadelphia: Saunders; 1995. p. 99-106. 79. Ohayon M, Guilleminault C, Priest RG. Night terrors, sleepwalking, and confusional arousal in the general population: their frequency and relationship to other sleep and mental disorders. J Clin Psychiatry 1999;60:268-276. 80. Hublin C, Kaprio J, Partinen M, et al. Prevalence and genetics of sleepwalking; a population-based twin study. Neurology 1997;48:177-181.
1082 PART II / Section 12 • Parasomnias 81. Klackenberg G. Somnambulism in childhood—prevalence, course and behavior correlates. A prospective longitudinal study (6-16 years). Acta Paediatr Scand 1982;71:495-499. 82. Bixler EO, Kales A, Soldatos CR, et al. Prevalence of sleep disorders in the Los Angeles metropolitan area. Am J Psychiatry 1979;136: 1257-1262. 83. Kahn E, Fisher C, Edwards A. Night terrors and anxiety dreams. In: Ellman SD, Antrobus JS, editors. The mind in sleep psychology and psychophysiology. 2nd ed. New York: John Wiley & Sons; 1991. p. 437-447. 84. Crisp AH. The sleepwalking/night terrors syndrome in adults. Postgrad Med J 1996;72:599-604. 85. Mahowald MW, Bundlie SR, Hurwitz TD, et al. Sleep violence— forensic science implications: polygraphic and video documentation. J Forensic Sci 1990;35:413-432. 86. Mahowald MW, Schenck CH, Goldner M, et al. Parasomnia pseudo-suicide. J Forensic Sci 2003;48:1158-1162. 87. Howell MJ, Schenck CH, Crow SJ. A review of nighttime eating disorders. Sleep Med Rev 2009;13:23-34. 88. Mancini MC, Aloe F. Nocturnal eating syndrome: a case report with therapeutic response to dexfenfluramine. Sao Paulo Med J 1994;112:569-571. 89. Schenck CH, Mahowald MW. Review of nocturnal sleep-related eating disorders. Int J Eat Disord 1994;15:343-356. 90. Schenck CH, Hurwitz TD, O’Connor KA, et al. Additional categories of sleep-related eating disorders and the current status of treatment. Sleep 1993;16:457-466. 91. Schenck CH, Hurwitz TD, Bundlie SR, et al. Sleep-related eating disorders: polysomnographic correlates of a heterogeneous syndrome distinct from daytime eating disorders. Sleep 1991;14: 419-431. 92. Manni R, Ratti MT, Tartara A. Nocturnal eating: prevalence and features in 120 insomniac referrals. Sleep 1997;20:734-738. 93. Winkelman JW. Clinical and polysomnographic features of sleep-related eating disorder. J Clin Psychiatry 1998;59:14-19. 94. Vetrugno R, Manconi M, Ferini-Strambi L, et al. Nocturnal eating: sleep-related eating disorder or night eating syndrome? A videopolysomnographic study. Sleep 2006;29:949-954. 95. Menkes DB. Triazolam-induced nocturnal bingeing with amnesia. Austr N Z J Psychiatry 1992;26:320-321. 96. Paquet V, Strul J, Servais L, et al. Sleep-related eating disorder induced by olanzapine. [case reports letter]. J Clin Psychiatry 2002;63:597. 97. Hwang TJ, Ni HC, Chen HC, et al. Risk predictors for hypnosedative-related complex sleep behaviors: a retrospective, crosssectional pilot study. J Clin Psychiatry 2010 Apr 20. [Epub ahead of print] 98. Najjar M. Zolpidem and amnestic sleep related eating disorder. J Clin Sleep Med 2007;3:637-638. 99. Birketvedt GS, Florholmen J, Sundsfjord J, et al. Behavioral and neuroendocrine characteristics of the night-eating syndrome. J Am Med Assoc 1999;282:657-663. 100. Birketvedt GS, Sundsfjord J, Florholmen JR. Hypothalamicpituitary-adrenal axis in the night eating syndrome. Am J Physiol— Endocrinol Metab 2001;282:657-663. 101. Stunkard A, Allison KC. Two forms of disordered eating in obesity: binge eating and night eating. Int J Obes Relat Metab Disord 2003;27:1-12. 102. Schenck CH, Arnulf I, Mahowald MW. Sleep and sex: what can go wrong? A review of the literature on sleep related disorders and abnormal sexual behaviors and experiences. Sleep 2007;2007: 683-702.
103. Guilleminault C, Moscovitch A, Yuen K, et al. Atypical sexual behavior during sleep. Psychosom Med 2002;64:328-336. 104. Aldrich MS, Jahnke B. Diagnostic value of video-EEG polysomnography. Neurology 1991;41:1060-1066. 105. Zadra A, Pilon M, Montplaisir J. Polysomnographic diagnosis of sleepwalking: effects of sleep deprivation. Ann Neurol 2008;63: 513-519. 106. Mahowald MW, Schenck CH. Parasomnia purgatory—the epileptic/non-epileptic interface. In: Rowan AJ, Gates JR, editors. Non-epileptic seizures. Boston: Butterworth-Heinemann; 1993. p. 123-139. 107. Schenck CH, Mahowald MW. REM parasomnias. Neurol Clin 1996;14:697-720. 108. Mahowald MW, Schenck CH. NREM parasomnias. Neurol Clin 1996;14:675-696. 109. Goodwin JL, Kaemingk KL, Fregosi RF, et al. Parasomnias and sleep disordered breathing in Caucasian and Hispanic children—the Tucson children’s assessment of sleep apnea study. BMC Medicine 2004;2:14. 110. Tinuper P, Provini F, Bisulli F, et al. Movement disorders in sleep: guidelines for differentiating epileptic from non-epileptic motor phenomena arising from sleep. Sleep Med Rev 2007;11:255-267. 111. Casez O, Dananchet Y, Besson G. Migraine and somnambulism. Neurology 2005;65:1334-1335. 112. Johnson H, Wiggs L, Stores G, et al. Psychological disturbance and sleep disorders in children with neurofibromatosis type 1. Dev Med Child Neurol 2005;47:237-242. 113. Barabas G, Matthews WS, Ferrari M. Disorders of arousal in Gilles de la Tourette’s syndrome. Neurology 1984;34:814-817. 114. Wand RR, Matazow GS, Shady GA, et al. Tourette syndrome: associated symptoms and most disabling features. Neurosci Biobehav Rev 1993;17:271-275. 115. Isik U, D’Cruz OF. Cluster headaches simulating parasomnias. Pediatr Neurol 2002;27:227-229. 116. Guillemiault C, Kirisoglu C, Bao G, et al. Adult chronic sleepwalking and its treatment based on polysomnography. Brain 2005;128: 1062-1069. 117. Lillywhite AR, Wilson SJ, Nutt DJ. Successful treatment of night terrors and somnambulism with paroxetine. Br J Psychiatry 1994;164:551-554. 118. Balon R. Sleep terror disorder and insomnia treated with trazodone: a case report. Ann Clin Psychiatry 1994;6:161-163. 119. Kellerman J. Behavioral treatment of night terrors in a child with acute leukemia. J Nerv Ment Dis 1979;167:182-185. 120. Hauri P, Silber MH, Boeve BF. The treatment of parasomnias with hypnosis: a 5-year follow-up study. J Clin Sleep Med 2007;3: 369-373. 121. Tobin JD Jr. Treatment of somnambulism with anticipatory awakening. J Pediatr 1993;122:426-427. 122. Schenck CH, Mahowald MW. Combined bupropion-levodopa therapy of nocturnal sleep-related eating and sleep disruption in two adults with chemical dependency (letter). Sleep 2000;23:587-588. 123. Schenck CH, Mahowald MW. Dopaminergic and opiate therapy of nocturnal sleep-related eating disorder associated with sleepwalking or unassociated with another nocturnal disorder (abstract). Sleep 2002;45:A249. 124. Winkelman JW. Treatment of nocturnal eating syndrome and sleep-related eating disorder with topiramate. Sleep Med 2003;4: 243-246.
REM Sleep Parasomnias Mark W. Mahowald and Carlos H. Schenck Abstract Rapid eye movement (REM) sleep is characterized by numerous physiologic variables that usually occur in concert to produce the fully declared REM sleep. The majority of the REM sleep parasomnias reflect state dissociation, a condition seen when not all of the elements usually comprising REM sleep are present, resulting in fascinating clinical phenomena. The most common and best-studied REM sleep parasomnia is the REM sleep behavior disorder (RBD). In patients with RBD, somatic muscle atonia—one of the defining features of REM sleep—is
REM SLEEP BEHAVIOR DISORDER The discovery of rapid eye movement (REM) sleep in 1953 by Aserinsky and Kleitman expanded the states of mammalian being to three: wakefulness, non-REM (NREM) sleep, and REM sleep. Each of these conditions has its own neuroanatomic, neurophysiologic, neuropharmacologic, and behavioral correlates. Intrusion of components of one state into another can cause severe symptoms in patients. In experiments reported in 1965, bilateral lesions of pontine regions adjacent to the locus coeruleus in cats caused absence of the expected atonia associated with REM sleep, allowing the cats to demonstrate prominent motor activities during REM sleep (oneiric activities).3 This animal model has been important in further studies demonstrating the similarity between the states of wakefulness and REM sleep4 and in studies evaluating the statedependent vulnerability to epileptic activity.5 In the 1970s, scattered reports of dream-enacting behavior involving humans appeared; the polygraphic and behavioral condition was sometimes referred to as “stage 1 REM with tonic electromyogram.”6-9 Recognition of REM sleep behavior disorder (RBD) as a distinct clinical disorder followed the report in 1986 of a series of adults with RBD.10 The cat model has been extended to the rat.11,12 Numerous physiologic phenomena occur during REM sleep13-26 and fall into two categories: tonic (appearing throughout a REM period) and phasic (occurring intermittently during a REM period). Tonic elements include electromyographic (EMG) suppression, low-voltage desynchronized electroencephalogram (EEG), high arousal threshold, hippocampal theta rhythm, elevated brain temperature, poikilothermia, olfactory bulb activity, and penile tumescence. Phasic elements include rapid eye movements (REMs), middle ear muscle activity, tongue movements, somatic muscle twitches of the limbs, variability of autonomic activity (cardiac and respiratory), and pontogeniculo-occipital (PGO) spikes. It is not known whether dreaming occurs tonically or phasically during REM sleep. The synchronizer (pacemaker) for the sleep–wake cycle appears to reside in the suprachiasmatic nucleus of the hypothalamus,27,28 but the generators or executors of the
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absent, permitting the acting out of dream mentation, often with violent or injurious results. RBD is overwhelmingly a disorder affecting older men, many of whom eventually develop neurodegenerative disorders. Increasingly, medications prescribed for psychiatric symptoms (predominantly selective serotonin reuptake inhibitors), are the cause of RBD. The vast majority of patients with RBD respond to clonazepam. Further study of the REM parasomnias will serve to teach us much about sleep and the function of the central nervous system.1,2
various REM phenomena, both tonic and phasic, are located in the pons.17,29,30 The tonic and phasic neurophysiologic processes underlying each state can be variously dissociated and recombined across states.31 For REM sleep, the processes that generally occur in concert may also be seen in dissociated form, both experimentally (e.g., REM sleep–deprived animals with PGO spikes occurring in NREM sleep and wakefulness)32 and in human and animal disease (narcolepsy). In narcolepsy, the best-understood dissociated state, the sleep attacks, hypnagogic hallucinations, sleep paralysis, cataplexy, and automatic behavior each represent the intrusion or persistence of one state of being into another (i.e., cataplexy may be the inappropriate isolated intrusion of REM sleep atonia into wakefulness, usually induced by an emotionally laden event).33,34 RBD likewise represents a dissociated state: REM sleep containing one element of wakefulness—muscle tone. Epidemiology and Risk Factors A recent phone survey of more than 4900 persons between the ages of 15 and 100 years of age indicated an overall prevalence of violent behavior in general during sleep of 2%, one quarter of which were likely due to RBD, giving an overall prevalence of RBD at 0.5%.35 Another survey estimated the prevalence of REM sleep behavior to be 0.38% in elderly persons.36 Increasingly, RBD is becoming associated with underlying neurologic conditions. RBD and Extrapyramidal Disease As more patients with “idiopathic” RBD are carefully followed over time, it is becoming clear that the majority eventually develop neurodegenerative disorders, most notably the synucleinopathies: Parkinson’s disease, multiple system atrophy (MSA; including olivopontocerebellar degeneration and the Shy-Drager syndrome), dementia with Lewy body disease, or pure autonomic failure. RBD may be the first manifestation of these conditions, and it can precede any other manifestation of the underlying neurodegenerative process by more than 10 years.37-47 Combined animal and human studies have identified physiologic and anatomic links between RBD and 1083
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neurodegenerative disorders, leading to the proposal that neurodegeneration can begin in either the rostroventral midbrain or the ventral mesopontine junction and progressively extend to the rostral or caudal part of the brainstem. When the lesion starts in the ventral mesopontine region, RBD develops first, but when the lesion initially involves the rostroventral midbrain, Parkinson’s disease is the initial manifestation.48 Systematic longitudinal study of patients with such neurologic syndromes indicates that RBD and REM sleep without atonia may be far more prevalent than previously suspected. Although the prevalence of RBD in Parkinson’s disease is unknown, subjective reports indicate that 25% of patients with Parkinson’s disease have sleep-related behavior suggesting RBD or they have sleep-related injurious behavior, and polysomnographic studies found RBD in up to 47% of patients with Parkinson’s disease who had sleep complaints.49-52 In one large series of patients with MSA, 90% were found to have REM sleep without atonia and 69% had clinical RBD.53 In another, nearly half had RBD.54 The presence of RBD might differentiate pure autonomic failure from MSA with autonomic failure.55 The finding of incidental Lewy body disease in one patient asymptomatic for Parkinson’s disease suggests that this condition might explain idiopathic RBD in some older patients.56 The presentation of RBD and dementia is suggestive enough of dementia with Lewy body disease that RBD has been proposed as one of the core diagnostic features of dementia with Lewy body disease.57 The link between Parkinson’s disease and RBD (Video 95-1) is supported by the fact that impaired olfactory and color discrimination is common to both.58–59a Also, the possible presence of cognitive deficits and slowing in the waking electroencephalogram in idiopathic RBD share common features with dementia with Lewy body disease.60-62 RBD is also seen in non–synucleinopathy-related Parkinson’s disease, in Guadeloupian parkinsonism, and progressive supranuclear palsy (tauopathies).63-65 The clinical features of RBD are identical in the idiopathic cases and in those with Parkinson’s disease or MSA.66 Interestingly, there is a striking (77%) male predominance in patients with Parkinson’s disease who display RBD.67 To date, no reliable tests have been shown to identify which subgroup of patients with idiopathic RBD is prone to develop Parkinson’s disease.68 The waking motor impairments of Parkinson’s disease can improve or even normalize during REM sleep–related movements in Parkinson’s disease patients with RBD. In a study of 53 patients with Parkinson’s disease and RBD who slept with bed partners, 100% reported improvement of at least one of the following during RBD episodes: faster, stronger, or smoother movements; more intelligible, louder, or better articulated speech; or normalization of facial expression. Furthermore, 38% of bed partners reported that movements were “much better” even in the most disabled Parkinson’s disease patients. The responsible mechanisms for these fascinating observations remain obscure.69 RBD and Narcolepsy RBD might also be yet another manifestation of narcolepsy. It is present in more than half of patients with narcolepsy, it may be an early symptom in childhood
narcolepsy, and it might even be the presenting symptom in narcolepsy.70-74 These patients usually have hypocretin-1 deficiency.72 Tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), and selective serotonin reuptake inhibitors (SSRIs), prescribed to treat cataplexy, can trigger or exacerbate RBD in this population. The demographics (age and sex) of RBD in narcolepsy conform to those of narcolepsy, indicating that RBD in these patients is yet another manifestation of state boundary dyscontrol seen in narcolepsy.75 RBD and Other Conditions Other conditions reported to be associated with RBD include mitochondrial encephalomyopathy, normal pressure hydrocephalus, Tourette’s syndrome, Machado-Joseph disease (spinocerebellar ataxia type 3), cerebellopontine angle tumors, group A xeroderma, multiple sclerosis, ischemic or hemorrhagic cerebrovascular disease, focal brain lesions, autism, Möbius syndrome, voltage-gated potassium channel autoimmunity, and Guillain-Barré syndrome.76-91 Pathogenesis The generalized atonia of REM sleep results from active inhibition of motor activity by pontine centers of the peri– locus coeruleus region, which exert an excitatory influence upon the reticularis magnocellularis nucleus of the medulla via the lateral tegmentoreticular tract. The reticularis magnocellularis nucleus, in turn, hyperpolarizes spinal motor neuron postsynaptic membranes via the ventrolateral reticulospinal tract.92,93 Loss of muscle tone during REM sleep is very complex and has been shown to result from a combination of inactivation of brainstem motor inhibitory systems and inactivation of brainstem facilitative systems.94,95 Normally the atonia of REM sleep is briefly interrupted by excitatory inputs that produce the rapid eye movements and the muscle jerks and twitches characteristic of REM sleep.96-98 REM atonia is thought to be mediated by glycine99 and may be influenced by medullary enkephalinergic neurons.100 The prevailing hypothesis that REM atonia is caused by glycinergic inhibition has been questioned.101 Bilateral pontine tegmental lesions in cats result in persistent absence of REM atonia associated with prominent motor activity during REM sleep.3,15,24,93,102-104 That this represents REM sleep rather than waking activity is supported by the presence of other features typical of REM: loss of thermoregulation, the closed nictitating membrane, miotic pupils (despite signs of autonomic activity), and blunted response to stimuli.22 Cats receiving pontine tegmental lesions exhibit a range of REM sleep activities that can appear as soon as the second day after the lesion has been produced. Loss of REM atonia has been shown to be necessary, but not sufficient, to allow the expression of REM activities. The specific site of a pontine lesion determines whether loss of atonia occurs with simple movements or more complex activities suggesting that the pontine tegmentum is responsible for two separate mechanisms of skeletal motor inhibition during REM sleep: the atonia system and a system that suppresses phasic brainstem motor pattern generators.15 A lesion damaging the atonia mechanism would produce only REM sleep with augmented tone (REM without atonia [RWA]), whereas a lesion affecting both
mechanisms (tonic and phasic), would also release complex activities, with the stereotypical repertoire depending on the precise location of the lesion. Although the classic experimental animal model of RWA involves bilateral perilocus coeruleus lesions,3 it is clear that other regions of the central nervous system can affect muscle tone during REM sleep, including the medulla105 and possibly even the hypothalamus.30 Relevant animal studies have indicated a co-localization of the locomotor and atonia systems operating during REM sleep.106 Given the clear neuroanatomic substrate of a REM behavioral syndrome in cats, experiments of nature could be expected, resulting in an analogous disorder in humans. The pathophysiology of RBD in humans may be presumed to be similar to that postulated for experimental cats,15 namely the loss of REM atonia coupled with enhancement of phasic motor drive. Neuroimaging studies indicate dopaminergic abnormalities in RBD. Single photon emission computed tomography (SPECT) studies have found reduced striatal dopamine transporters,107,108 and decreased striatal dopaminergic innervation has been reported.109 Decreased blood flow in the upper portion of the frontal lobe and pons has been reported,110 as has functional impairment of brainstem neurons.111 Positron-emission tomography (PET) and SPECT studies have revealed decreased nigrostriatal dopaminergic projections in patients with MSA and RBD.112 Decreased blood flow in the upper portion of the frontal lobe and pons has been found in one magnetic resonance imaging (MRI) and SPECT study.110 Impaired cortical activation as determined by electroencephalographic spectral analysis in patients with idiopathic RBD supports the relationship between RBD and neurodegenerative disorders.113 RBD in humans occurs in an acute and a chronic form. Until recently, most reported cases of acute transient RBD fell in the toxic or metabolic category, and the best-studied conditions were the withdrawal states, most commonly involving ethanol.6 Comparable patterns have been described with nitrazepam withdrawal and biperiden intoxication.7,8 Currently, the most common cause of acute RWA and RBD may be iatrogenic. Acute RBD is almost always induced by medications (most commonly tricyclic antidepressants, monoamine oxidase inhibitors (MAOIs), or selective serotonin reuptake inhibitors (SSRIs)) or associated with withdrawal (alcohol, barbiturate, or meprobamate).114,115 Excessive caffeine ingestion has also been implicated,116 as has chocolate ingestion.117 The chronic form is most often either idiopathic or associated with neurologic disorders. Each basic category of neurologic disease (vascular, neoplastic, toxic or metabolic, infectious, degenerative, traumatic, congenital, and idiopathic) could be expected to manifest this disorder. Although RBD has not been reported following infection or trauma, a recent study of persistent hypersomnolence following Epstein-Barr viral infection (infectious mononucleosis and Guillain-Barré syndrome)118 and a case with absent REM sleep as a sequela to a strategically located pontine shrapnel fragment119 indicate that these categories will eventually be implicated. A familial association has been documented120 (Fig. 95-1) and is occasionally sug-
CHAPTER 95 • REM Sleep Parasomnias 1085 12-17-85 716 1)
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Figure 95-1 Abnormal REM sleep polysomnograms of a 10-year-old girl (A) and her 8-year-old brother (B), in which gross body movements accompany bursts of aperiodic chin and limb electromyographic (EMG) twitching (7-11). REM sleep is identified by the presence of rapid eye movements (1-2), an activated EEG (3-6), and a predominantly atonic chin EMG. These two siblings and their father had demonstrated excessive limb jerking during sleep throughout their lives. For the girl, removal of a brainstem astrocytoma was followed by the onset of nightmares and complex, disruptive sleep behavior, which persisted for 1 year, when treatment with clonazepam induced prompt control of both dream and motor problems. A, ear; C, central; E, eye; ECG, electrocardiogram; O, occipital; subscripts 1 and 3, left; subscripts 2 and 4, right.
gested historically during clinical evaluations. Spontaneously occurring idiopathic RBD has been reported in dogs and cats.121,122 The overwhelming male predominance of RBD (not seen in the associated neurodegenerative disorders) raises the intriguing question of hormonal influences, as suggested in male-aggression studies in animals and humans.123125 Another possible explanation for the male predominance is sex differences in brain development and aging.126-128 There is evidence for a sex difference in the effects of sex steroids on the development of the locus coeruleus in rats.129 However, serum sex hormone levels are normal in idiopathic RBD or RBD associated with Parkinson’s disease.130,131 The typically late-age onset of RBD suggests an organic brain factor and may be a manifestation of the reversal or disintegration of ontogeny of state appearance.132 One highly speculative but tantalizing etiologic possibility is that RBD represents a delayed manifestation of REM sleep abnormalities occurring early in development. This explanation invokes the well-documented prolonged effect of
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pharmacologic manipulation upon developing neural tissues.133 In rats, Corner has described an RBD-like polysomnographic (PSG) pattern persisting into adulthood following clomipramine-induced neonatal REM sleep suppression.134 Another is the possible presence of neuronal-specific antibodies as described in neurologic paraneoplastic syndromes and the stiff-man syndrome.135 One study failed to identify anti–locus coeruleus–specific antibodies in patients with RBD.136 As autopsy material becomes available, direct neuropathologic examination could provide important correlative information. The chronic idiopathic category represents patients whose RBD is not associated with psychopathology or detectable neuropathology. Clinical Features The cases reported to date have strikingly similar clinical features.114 The presenting complaint is that of vigorous sleep activities usually accompanying vivid striking dreams (Videos 95-2 and 95-3). These activities can result in repeated injury, including ecchymoses, lacerations, and fractures. Some of the self-protection measures taken by the patients (tethering themselves to the bed, using sleeping bags or pillow barricades, or sleeping on a mattress in an empty room) reveal the recurrent and serious nature of these episodes.137,138 The potential for injury to the patient or the bed partner raises interesting and difficult forensic medicine issues.139 RBD may have serious psychological ramifications for the bed partner: One woman committed suicide because her husband with RBD could not share their bed.140 Chronic RBD is more common in older men and may be preceded by a lengthy prodrome. In some cases there is a familial predisposition. Because effective and safe treatment is available, precise diagnosis is critical. Case Studies The following cases illustrate the idiopathic subtype of RBD and describe the main reason for seeking medical attention. Past history and current neurologic and psychiatric evaluations were unremarkable, apart from the findings reported. All four men were known by day to be calm and friendly people whose nocturnal behavior was completely out of (waking) character. Clonazepam controlled problematic activities and abnormal dreams in each. Figure 95-2 illustrates attempted dream enactments during the REM sleep of the patient described in Case 3.
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Figure 95-2 Polygraphic correlates of nocturnal dream-enacting behavior. REM sleep contains dense, high-voltage REM activity (1-2) and an activated electroencephalogram (3-5, 12-17). The electrocardiogram (11) has a constant rate of 64 per minute, despite vigorous limb movements, a finding that is consistent with REM sleep and inconsistent with a conventional arousal. Chin electromyographic (EMG) tone is augmented with phasic accentuations (6). Arms (7-8) and legs (9-10) show aperiodic bursts of intense EMG twitching, which accompany gross behavior noted by the technician. This sequence culminates in a spontaneous awakening, when the man reports a dream of running down a hill in Duluth, Minnesota, and taking shortcuts through backyards, when he suddenly finds himself on a barge that is rocking back and forth. He feels haunted and desperately holds onto anything to prevent falling into the cargo hold, where there are skeletons. He then awakens. A, ear; C, central; E, eye; F, frontal; O, occipital; T, temporal; subscripts 7, 3, 5, and 1, left; subscripts 8, 4, 6, and 2, right.
Case 1 A 77-year-old minister presented with a 20-year history of frequent somniloquy and aggressive behavior that occurred during “fighting dreams” of defending himself against assaultive children and adults. Although his wife had sustained repeated blows, she remained in bed to protect him from harming himself. Referral was prompted by an injury to his chest from jumping into a table while dreaming. Despite vigorous sleep movements, he generally awakened feeling refreshed. However, fatigue had recently started to interfere with his busy preaching schedule. His wife recalled a memorable night when “he said he was flying above some trees and there was a phone sitting out there on the table and it was ringing, so he
swooped down to answer the phone and, just as he landed, somebody hit him and when he jumped away, he actually bolted out of the bed and was in the hall, just like that.” Medical history was remarkable for coronary artery bypass surgery 3 years previously, which was followed by a pronounced depression of consciousness lasting 4 days and a right-sided hemiplegia that gradually resolved. A mild memory deficit ensued, and his preexisting sleep disturbance intensified. Current neurological examination revealed a memory deficit, mild horizontal nystagmus, modest right-sided cogwheel rigidity, and peripheral neuropathy.
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A 57-year-old retired school principal presented with concern over the possibility of injuring his wife. For 2 years he had inadvertently punched and kicked her during vivid nightmares of protecting himself and family from aggressive people and snakes. Nocturnal arousals were uncommon and he felt refreshed most mornings. He developed an adjustment disorder with depressed mood141 subsequent to a myocardial infarction 1 year previously, but treatment with desipramine and trazodone did not control his problematic sleep movements. The Minnesota Multiphasic Personality Inventory (MMPI) revealed a chronic tendency for somatization. Two brothers reported identical sleep and dream disturbances that had persisted since adolescence. One of them tore the headboard off a bed while dreaming of fighting a bear.
the transition from stage 3-4 to stage 2 sleep with REMs, a vivid dream, and behavioral enactment. This case most likely represents a parasomnia overlap state (discussed later in the section “Variations of REM Sleep Behavior Disorders”). Idiopathic RBD is a chronic progressive disorder, with increasing complexity, intensity, and frequency of expressed behavior. Although irregular jerking of the limbs can occur nightly, the major movement episodes appear intermittently, with a frequency minimum of once in 2 weeks to a maximum of four times nightly on 10 consecutive nights. Observed somniloquy runs the spectrum from short and garbled to long-winded and clearly articulated. Angry speech with shouting, but also laughter, can emerge. One patient appeared to have a dissociated RBD lucid dream state in that he could carry on lengthy and coherent conversations with his wife and family while dreaming and incorporate the conversational material into his dreams. The extended prodrome of prominent limb and body movements during sleep in some patients might reflect a developmental failure to fully establish REM sleep atonia, predisposing them to RBD. Most patients complained of sleep injury but rarely of sleep disruption. They usually did not awaken from their own violent activity but rather from the yelling, often persistent, of their wives. Two conclusions can be drawn. First, chronic RBD is principally a motor disorder and uncommonly also an arousal disorder. Second, the very high arousal threshold constitutes another physiologic marker of REM sleep, which is known to have the highest threshold for arousal compared to wakefulness or NREM sleep.18-20 In addition, the autonomic nervous system was generally not activated during episodes of vigorous REM sleep activities, as indicated by Figure 95-2. However, a few patients described episodes of vivid dreaming with behavioral enactment from which they awakened in a terrified state with full subjective autonomic activation. In RBD patients, arousal from sleep to alertness and orientation is usually rapid and accompanied by complete dream recall (very unlike the confusional arousals observed in the disorders of arousal such as sleepwalking or sleep terrors). After awakening, behavior and social interactions are appropriate, mitigating against a NREM sleep relationship, delirious states, or ictal phenomena, and further supporting a REM sleep phenomenon. The activities, although complex and violent, are of briefer duration than those seen in the disorders of arousal. In some patients, the clinical features contain elements of both RBD and disorders of arousal (see later). Furthermore, appetitive behavior (feeding or sexual) has not been seen as a manifestation of RBD in humans or in the animal model.15
Behavioral Features and their Bases The history of dream-enacting behavior occurring at least 90 minutes after sleep onset and as late as the terminal morning awakening strongly suggests a REM sleep disorder, and in our laboratory nearly all such episodes take place within REM sleep. One rare example of a NREM dream enactment (see Fig. 1 in reference 10) was actually a dissociated state in which an RBD process intruded into
Dream Disorder and Behavior Disorder The Hobson and McCarley activation-synthesis model of dream formation states that during REM sleep, brainstem generators phasically activate motor, perceptual, affective, cognitive, and amnestic circuits whose information flow is synthesized into dreams by the forebrain.142,143 This model would theoretically predict the dream changes observed in patients with RBD. Intensified activity of these generators or biased activation of particular circuits should induce corresponding changes in dream process and content. We
Case 2 A 60-year-old surgeon began to punch and kick his wife and jump out of bed during nightmares of being attacked “by criminals, terrorists, and monsters who always tried to kill me.” Work-related stress was the presumed cause of his sleep disturbance, but the violent behavior intensified despite retirement 3 years later. He sustained several head lacerations and his wife once had a severe headache for 2 days after receiving an accidental blow to the ear. The proper diagnosis was established after 11 years. A prodrome of excessive limb and body jerking during sleep had been present for at least 33 years.
Case 3 A 62-year-old industrial plant manager experienced a progressive disorder of “military nightmares” and combative sleep behavior, which had begun 10 years previously after visiting locations where he had fought in World War II. A psychiatrist diagnosed a posttraumatic stress disorder, but treatment was ineffective, and he continued to scream profanities, throw punches, kick, sit up, and jump out of bed while dreaming of being attacked by enemy soldiers. He broke lamps and once kicked a hole in the wall. One dream-incurred head laceration required 10 sutures. He considered his sleep to be sound and had consistent diurnal alertness. He saw four physicians, including two psychiatrists, for this sleep problem before referral to our center. He had a childhood history of sleepwalking.
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theorize that both these conditions occur to produce RBD. As already proposed for cats with pontine lesions, disinhibition of selective brainstem motor pattern generators accounts for the differential release of stereotypical REM behavior.15 This same process might produce both the behavior and dream disorder of RBD. For example, the generator for violent behavior might become disinhibited and coactivate both a descending output to the spinal motor neurons and an ascending output to forebrain dream-synthesizing centers, thus producing the simultaneous movement and dreaming. These two outputs from the same generator may be isomorphic, so that command for dream action (fictive movements) is equivalent to command for actual movements,144 resulting in acting out of dreams. In our series of patients with RBD, all who acted violently during REM sleep also had violent dreams. In fact, dream recall was most complete following behavioral enactment. The REM sleep activities we observed in our patients corresponded to the reported dream mentation. Most patients repeatedly experienced a typical RBD nightmare, which consisted of being attacked by animals or unfamiliar people, few of whom were bizarre in appearance. Characteristically, the dreamer would either fight back in self-defense or else attempt to flee. Fear, rather than anger, was the usual accompanying emotion reported. An ironic situation was produced by RBD when a dreaming husband would fight to defend his wife from an aggressor while actually striking her in bed. Her yells would then awaken him to the unfortunate reality of his violent oneiric activity. In these patients, medication suppressed both the vigorous sleep activities and the abnormal dreaming, which adds further support to the activation-synthesis model. A singular feature of the dream-enacted episodes in this group of patients is that customary dreams are generally not being played out; rather, distinctly altered, stereotypical, repetitive, and action-packed dreams are put on display. The violence of the sleep-related behavior is often discordant with the waking personality. The increased aggressive dream content experienced by patients with RBD is not associated with increased daytime aggressiveness.145 Diagnosis Routine medical history-taking should include questions that screen for abnormal sleep movements and altered dreams, especially in older adults, in patients of any age who have acute or chronic central nervous system disorders—particularly those who have neurologic conditions that predispose to RBD such as Parkinson’s disease or MSA—or in patients receiving psychoactive medications known to trigger RBD. The diagnosis of RBD may be suspected on clinical grounds; however, our experience has shown that PSG confirmation is mandatory. The complaint of sleep-related injurious or violent activities should be taken very seriously. Reported injuries in our series include lacerations and fractures to the patient and bed partner. RBD has also resulted in subdural hematomas and other serious injuries.146-148 Detailed polysomnographic data in these patients have been reported elsewhere.10,137,149 The overall sleep architecture is usually normal, with the expected cycling of NREM and REM sleep. Most of our subjects had excessive slow-wave sleep for age. Although some of these patients
were initially thought to have a seizure disorder explaining the movements during sleep, neither EEG electrical nor clinical seizure activity has been detected. The conventional scoring parameters of Rechtschaffen and Kales150 must be modified to allow for the persistence of EMG tone during epochs that are otherwise clearly REM sleep. These periods are similar to the “stage 1 REM with tonic EMG” described by the Japanese,9 the “stage 1 REM” seen in delirium tremens,151 and those recorded in the chronic pontine-lesioned cats.3,15,24,93,102-104 There is persistence of muscle tone during REM sleep, and it may be strikingly augmented for prolonged periods, occasionally lasting much of the REM sleep cycle. The onset of a REM sleep period is often marked by a sudden increase in chin EMG activity or prominent twitching in conjunction with REMs. In addition to the intermittent absence of atonia, there are varying amounts of limb twitching (usually far in excess of that observed in normal REM sleep), gross body movements, and complex—often violent—activities that correlate with reported dream mentation. Tachycardia might not accompany these impressive movements. A similar lack of autonomic arousal during REM sleep was observed in a study of delirium tremens.151 This likely represents paresis of the sympathetic nervous system (inactivation of the locus coeruleus) characteristic of REM sleep.152,153 A curious feature of the chin EMG and extremity movements seen during the REM period is the variability of involvement and distribution. The chin EMG may be augmented without body movements, or it may be atonic despite flailing extremities, as shown in Figure 95-3. The arms and legs often move independently, necessitating monitoring of all limbs. Some patients demonstrated persistent (over the span of several years) lateralization of limb EMG activity or also predominant upper or lower extremity movements. Most all patients displayed prominent aperiodic movements of all extremities in every conceivable combination during all stages of NREM sleep. These aperiodic movements are similar but more intense than the fragmentary myoclonus described by Broughton and colleagues in patients with a wide variety of sleep disorders and occasionally as an incidental observation.154,155 Most RBD patients also showed conventional periodic movements of sleep, usually involving the legs, infrequently associated with arousals. Prolonged episodes of aperiodic and periodic movements restricted to the arms were noted occasionally. Figures 95-4 and 95-5 exemplify some of these dissociated wake-REM states. Prominent changes in sleep patterns likely representing variations of RBD have been described in the drug-induced variety of RWA,156,157 narcolepsy,75 and Parkinson’s disease.158,159 Figure 95-6 is a dramatic example of venlafaxine-induced RBD in a 9-year-old boy. Diagnostic Criteria The minimum diagnostic criteria for RBD we have formulated can be satisfied in either of two ways. The diagnosis can be made in patients with a history of problematic sleep behavior that is harmful or potentially harmful, or that disrupts sleep continuity, or that is annoying to the patient or bed partner and that includes excessive augmentation of chin EMG tone or excessive chin or limb EMG twitching,
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Figure 95-3 REM sleep polysomnogram illustrating extensive preservation of submental electromyographic (EMG) atonia (7), despite the emergence of gross arm movements that are noted by the technician and reflected by the prominent twitching in the upper extremity EMGs (8-11). A rapid eye movement (1-2) immediately precedes the onset of complex behavior. A, ear; C, central; ECG, electrocardiogram; LOC, left outer canthus; O, occipital; ROC, right outer canthus; subscripts 1 and 3, left; subscripts 2 and 4, right.
irrespective of chin EMG tone, on polysomnography during REM sleep. In patients with no history of problematic sleep behavior, diagnosis can be made based on excessive augmentation of chin EMG tone or excessive chin or limb EMG twitching irrespective of chin EMG tone on polysomnography during REM sleep and video recording of excessive limb or body jerking, complex movements, or vigorous or violent movements during REM sleep (Video 95-4). A report of dream changes accompanying the sleep activities can buttress the history. The determination of what constitutes excessive EMG augmentation, EMG twitching, or limb jerking requires meticulous execution of standard recording techniques and an experienced polysomnographer. We recommend that any patient with suspected RBD undergo a systematic evaluation consisting of: • Review of sleep and wake complaints (from patient or bed partner) • Neurologic and psychiatric examinations • A sleep laboratory study that includes continuous videotaping of behavior during standard polygraphic monitoring150 of the electrooculogram (EOG), EEG, EMG (chin, bilateral extensor digitorum, and anterior tibialis muscles), electrocardiogram (ECG), and nasal air flow. A certified technician makes written observations of
ongoing activities. The REM density score (REM activity units on a scale of 0 to 8 per minute) is determined by a standard technique160 • Because of the association between RBD and narcolepsy, a multiple sleep latency test161 is routinely administered the day following the overnight sleep study. More extensive neurologic evaluation including multimodal evoked potentials, brain imaging by MRI or computed tomography (CT), or comprehensive neuropsychological testing by methods previously reported149 are indicated only if there is a suggestion of neurologic dysfunction by history or neurologic examination. Differential Diagnosis RBD can masquerade as many other conditions (Box 95-1). Most conditions in this differential diagnosis represented an initial clinical misdiagnosis in our series, leading to inappropriate and ineffective treatment. The differential diagnosis of these disorders has been extensively reviewed elsewhere.162 The disorders of arousal, nocturnal seizures, and rhythmic movement disorder are discussed elsewhere in this volume. It should be remembered that the clinical event (arousal) might not be primary but rather triggered by another, underlying sleep disorder, such as apnea leading to arousal triggering sleep terror. Nocturnal behavior induced by obstructive sleep apnea or
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Figure 95-5 Nocturnal polysomnogram of a dissociated state in a 58-year-old man with multiple sclerosis. A pathologic process usually confined to NREM sleep—periodic leg movements (12)—has intruded into REM sleep, which has typical rapid eye movements (1-2) and a desynchronized electroencephalogram (3-6). Chin electromyographic (EMG) atonia alternates every 3 sec with augmented tone (7). A, ear; C, central; E, eye; ECG, electrocardiogram; O, occipital; subscripts 1 and 3, left; subscripts 2 and 4, right. 150 mV 2 sec
B Figure 95-4 Nocturnal polysomnograms that depict contrasting forms of skeletal muscle activity in a 70-year-old man. Eye tracings, 1-2; electroencephalogram, 3-5; electromyogram (EMG) of chin, arms, and legs, 6-10. A, Lateralized periodic leg movements appear every 20 to 30 seconds throughout a period of stage 2 NREM sleep. B, A different pattern emerges 3 minutes later at the onset of REM sleep, in which both arms have frequent aperiodic movements. REM alpha is present. Chin atonia does not occur in REM sleep but does appear suddenly in NREM sleep just before a leg movement. This man developed a chronic REM sleep behavior disorder at the time of subarachnoid hemorrhage 6 years previously. A, ear; C, central; E, eye; O, occipital; subscripts 1 and 3, left; subscripts 2 and 4, right.
sleep-related seizures can mimic activities of RBD.163-165 Overlap parasomnias are characterized by the clinical history suggestive of sleepwalking or sleep terrors, with PSG features of motor disinhibition during both REM and NREM sleep.166 It is likely that a recent series of somnambulistic-like behavior in elderly subjects found to have PSG features of RBD represents this phenomenon.167 Nocturnal panic disorder is poorly understood and requires more study. It is well established that psychogenic dissociative disorders can arise predominantly or exclusively from the sleep period.168 Finally, our group has seen extremely violent sleep-period behavior that we suspect represents malingering.169 Variations of REM Sleep Behavior Disorders P ARASOMNIA O VERLAP S YNDROME There is a subgroup of parasomnia patients with both clinical and PSG features of both RBD and disorders of
Box 95-1 Differential Diagnosis of REM Sleep Behavior Disorder Disorders of arousal • Primary • Confusional arousals • Sleepwalking • Sleep terrors • Secondary • Obstructive sleep apnea • Periodic limb movement disorder • Gastroesophageal reflux • Nocturnal seizures Parasomnia overlap syndrome Nocturnal seizures Rhythmic movement disorder Posttraumatic stress disorder Nocturnal panic disorder Psychogenic dissociative disorder or conversion hysteria Malingering
arousal (sleepwalking and sleep terrors). These cases demonstrate motor and behavioral dyscontrol extending across NREM and REM sleep and suggest the possibility of a unifying hypothesis for disorders of arousal and RBD: The primary underlying feature is motor disinhibition during sleep. When it is predominantly during NREM sleep, it manifests as disorders of arousal, and when it is predominantly during REM sleep, it manifests as RBD. The parasomnia overlap syndrome occupies an intermediate position, with features of both.166 One AIDS-related case with prominent brainstem involvement has been identified. The abnormal motor and verbal nocturnal activities
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Venlafaxine-induced RBD in 9-y.o. boy Figure 95-6 Polysomnogram of a 9-year-old boy who developed RBD coincident with his being placed on venlafaxine 550 mg daily. Note the prominent tonic and phasic muscle activity of the extremities during REM sleep. A, ear; C, central; ECG, electrocardiogram; LOC, left outer canthus; O, occipital; ROC, right outer canthus; subscripts 1 and 3, left; subscripts 2 and 4, right.
of status dissociatus might respond to treatment with clonazepam.170,171 A GRYPNIA E XCITATA Agrypnia excitata is characterized by generalized overactivity associated with loss of slow-wave sleep, mental oneiricism (inability to initiate and maintain sleep with wakeful dreaming), and marked motor and autonomic sympathetic activation seen in such diverse conditions as delirium tremens, Morvan’s fibrillary chorea, and fatal familial insomnia.172-174 Oneiric dementia is likely a related condition.175 Agrypnia excitata is similar to status dissociatus, which may be the most extreme form of RBD, appearing to represent the complete breakdown of state-determining boundaries. Clinically, patients with status dissociatus, by observation of behavior, appear to be either awake or asleep; however, clinically, their behavioral sleep is very atypical, characterized by frequent muscle twitching, vocalization, and reports of dreamlike mentation upon spontaneous or forced awakening. Polygraphically, there are no features of either conventional REM or NREM sleep; rather, there is the simultaneous mixture of elements of wakefulness, REM sleep, and NREM sleep. “Sleep” may be perceived as normal and restorative by the patient, despite the nearly continuous motor and verbal activities and absence of polysomnographically defined REM or NREM sleep. Conditions associated with status dissociatus include protracted withdrawal from alcohol abuse, narcolepsy, olivopontocerebellar degeneration, and prior openheart surgery. The clinical history alone is insufficient to make the diagnosis, which can be established only with extensive PSG evaluation, including employment of a full seizure montage, respiratory recording, monitoring of all extremities, continuous audiovisual documentation, and detailed observations made by experienced technicians. The physi-
cal and psychological consequences of an erroneous diagnosis are obvious. The impressive response to treatment emphasizes the importance of a definitive diagnosis.137,176 Treatment The acute form is self-limited following discontinuation of the offending medication or completion of withdrawal. About 90% of patients with chronic RBD respond well to clonazepam administered half an hour before sleep time. The dose ranges from 0.5 to 2.0 mg, and there has been little, if any, tendency to develop tolerance, dependence, abuse, or adverse sleep effects despite years of continuous administration and efficacy.137,177 Melatonin at doses up to 12 mg at bedtime or pramipexole may also be effective.178-181 Although tricyclic antidepressants sometimes induce or potentiate RBD, imipramine has been reported effective in three clonazepam-resistant patients.182 Likewise, there are reports of response to an SSRI (paroxetine).183,184 Carbamazepine has been effective in one case.185 Levodopa may be effective, particularly in cases where RBD is the harbinger of Parkinson’s disease.186 There have been anecdotal reports of response to gabapentin, MAOIs, donepezil, and clonidine.187,188 In RBD associated with narcolepsy, the tricyclic antidepressants or MAOIs administered for cataplexy may be continued and clonazepam may be added.75 The treatment of medication-induced or Parkinson’s disease–associated RBD is the same as for idiopathic RBD.38 Pallidotomy has been effective in one case of RBD associated with Parkinson’s disease, whereas chronic bilateral subthalamic stimulation was not.189-191 An isolated episode of RBD has been reported immediately following left subthalamic electrode implantation for the treatment of Parkinson’s disease.192 Underlying obstructive sleep apnea should be ruled out before prescribing clonazepam.193,194 The fact that clonazepam results in striking clinical improvement without discernable effect upon PSG-
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recorded RWA raises the possibility that it acts preferentially upon the locomotor systems, rather than those affecting REM atonia.195 The other essential therapeutic intervention concerns environmental safety. Clonazepam is not failsafe: One patient injured himself during a violent dream 1 year after initiating very satisfactory pharmacotherapy. There was no recurrence during the ensuing 5 months, even though the dose was not increased. Therefore, potentially dangerous objects should be removed from the bedroom, cushions put around the bed, and perhaps the mattress placed on the floor and windows protected. We anticipate some cases in which drug intolerance or ineffectiveness will lead to discontinuation, requiring maximal environmental safety. Clinical Course and Prevention The clinical course depends upon the etiology. Idiopathic RBD is often slowly progressive, as is RBD associated with the synucleinopathies. RDB symptoms may precede other features of synucleinopathies by decades.195a Interestingly, RBD associated with neurodegenerative disorders might remit spontaneously, as the underlying neurodenerative process progresses. Drug-induced RBD will usually improve upon withdrawal of the offending medication. The only known preventable cause of RBD is medicationinduced RBD. Pitfalls and Controversies Numerous parasomnias can perfectly mimic RBD, mandating formal sleep studies to rule out NREM parasomnias, nocturnal seizures, obstructive sleep apnea, psychogenic dissociative disorders, or malingering. Perspectives and Implications A common thread linking RBD and the disorders of arousal is the appearance of motor activity that is dissociated from waking consciousness. In RBD, the motor behavior closely correlates with dream imagery, and in disorders of arousal, it often occurs in the absence of (remembered) mentation. One intriguing explanation for the dissociation of behavior from consciousness has been proposed by Tassinari, who suggests that the activities are generated by locomotor centers released during REM sleep.196 This dissociation of the locomotor centers from the parent state of REM or NREM sleep would explain the presence of complex motor behavior seen in RBD and in disorders of arousal. RBD is an exciting experiment of nature, extending our understanding of state declaration. Its association with narcolepsy and its clinical similarity to status dissociatus and the parasomnia overlap syndrome expand the concept of state boundary dyscontrol. The identification of yet other state declaration errors, and their induction by, or response to, specific pharmacologic agents, promise to unveil much about the neuroanatomy, neurophysiology, neurochemistry, and neuropharmacology of waking and sleep. Such experiments of nature underscore the symbiotic relationship between clinical and basic science medicine.
OTHER REM SLEEP PARASOMNIAS Nightmares and impaired sleep-related penile erections are discussed elsewhere in this volume.
REM Sleep–Related Sinus Arrest REM sleep–related sinus arrest,197 first described by Guilleminault and colleagues in 1984,198 is a cardiac rhythm disorder that affects otherwise healthy young adults of either sex and is characterized by sinus arrest during REM sleep, usually in clusters, with asystoles lasting up to 9 seconds. In one case, vocalizations occurred during periods of REM sleep asystole, with a loud scream and a sensation of being “shocked” (but without chest pain or related symptoms) associated with the longest asystole.199 Periods of asystole do not occur during NREM sleep and are not associated with sleep apnea. Some patients experience faintness, light-headedness, and blurred vision during abrupt awakenings, and syncope can occur during ambulation after an awakening. Also, there may be complaints of vague chest pain or tightness or intermittent palpitations during the daytime. However, daytime ECG (including Holter monitoring) is usually completely normal, and angiography, when performed, is unremarkable. The underlying pathophysiology, therefore, appears to be autonomic dysfunction. The clinical course is unknown. Complications include loss of consciousness and even cardiac arrest from prolonged asystole. This condition must be considered in cases of sudden, unexplained death during sleep. Treatment is usually not indicated, although prophylactic intervention would include a ventricular-inhibited pacemaker with a low rate limit. Sleep-Related Painful Erections Sleep-related painful erection is characterized by penile pain with erections that typically occur during REM sleep.200 Middle-aged or older men are typically affected; they complain of recurrent awakenings with partial or full erections and pain. The cumulative effects of nightly sleep disruption and sleep loss can result in the additional complaints of insomnia, irritability, anxiety, and daytime somnolence. There is usually a history of normal erections during wakefulness. There is little evidence of underlying psychiatric disease, and pathology of the penis is usually not found. Spinal cord pathology has been implicated in one case.201 Although the course is not well known, it appears that this condition can become more severe over time. No systematic studies of treatment efficacy have been performed, but clozapine, propranolol, baclofen, clozapine, or paroxetine may be effective.202-204 ❖ Clinical Pearl REM sleep behavior disorder is the most common of the REM parasomnias and is seen primarily in older men. The presence of RBD in younger persons, particularly younger women, should lead to the suspicion of medication-induced RBD or RBD associated with narcolepsy or a structural central nervous system lesion.
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1096 PART II / Section 12 • Parasomnias 148. Morfis L, Schwartz RS, Cistulli PA. REM sleep behavior disorder; a treatable cause of falls in elderly people. Age Ageing 1997; 26:43-44. 149. Schenck CH, Bundlie SR, Patterson AL, et al. Rapid eye movement sleep behavior disorder. A treatable parasomnia affecting older adults. J Am Med Ass 1987;257:1786-1789. 150. Rechtschaffen A, Kales A. A manual of standardized terminology: techniques and scoring system for sleep stages of human subjects. Los Angeles: UCLA Brain Information Service/Brain Research Institute; 1968. 151. Gross MM, Godenough D, Tobin M, et al. Sleep disturbances and hallucinations in the acute alcoholic psychoses. J Nerv Ment Dis 1966;142:493-514. 152. Morrison AR, Reiner PB. A dissection of paradoxical sleep. In: McGinty DJ, Drucker-Colin R, Morrison A, et al. editors. Brain mechanisms of sleep. New York: Raven Press; 1985. 153. Siegel JM. Mechanisms of sleep control. J Clin Neurophysiol 1990;7:49-65. 154. Broughton R, Tolentino MA. Fragmentary pathological myoclonus in NREM sleep. EEG Clin Neurophysiol 1984;57:303-309. 155. Broughton R, Tolentino MA, Krelina M. Excessive fragmentary myoclonus in NREM sleep: a report of 38 cases. EEG Clin Neurophysiol 1985;61:123-133. 156. Guilleminault C, Raynal D, Takahashi S, et al. Evaluation of short-term and long-term treatment of the narcolepsy syndrome with clomipramine hydrochloride. Acta Neurol Scand 1976;54: 71-87. 157. Besset A. Effect of antidepressants on human sleep. Adv Biosci 1978;21:141-148. 158. Mouret J. Differences in sleep in patients with Parkinson’s disease. EEG Clin Neurophysiol 1975;38:653-657. 159. Askenasy JJM. Sleep patterns in extrapyramidal disorders. Int J Neurol 1981;15:62-76. 160. Taska L, Kupfer D. A system for the quantification of phasic ocular activity during REM sleep. Sleep Watchers 1983;6:15-17. 161. Carskadon MA, Dement WC, Mitler MM, et al. Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness. Sleep 1986;9:519-524. 162. Mahowald MW, Schenck CH. Parasomnia purgatory—the epileptic/non-epileptic interface. In: Rowan AJ, Gates JR, editors. Non-epileptic seizures. Boston: Butterworth-Heinemann; 1993. p. 123-139. 163. Nalamalapu U, Goldberg R, DePhillipo M, et al. Behaviors simulating REM behavior disorder in patients with severe obstructive sleep apnea. Sleep Res 1996;25:311. 164. D’ Cruz OF, Vaughn BV. Nocturnal seizures mimic REM behavior disorder. Am J END Technol 1997;37:258-264. 165. Iranzo A, Santamaria J. Severe obstructive sleep apnea/hypopnea mimicking REM sleep behavior disorder. Sleep 2005;28:203206. 166. Schenck CH, Boyd JL, Mahowald MW. A parasomnia overlap disorder involving sleepwalking, sleep terrors, and REM sleep behavior disorder in 33 polysomnographically confirmed cases. Sleep 1997;20:972-981. 167. Tachibana N, Sugita Y, Terashima K, et al. Polysomnographic characteristics of healthy elderly subjects with somnambulism-like behaviors. Biolo Psychiatry 1991;30:4-14. 168. Schenck CS, Milner DM, Hurwitz TD, et al. Dissociative disorders presenting as somnambulism: polysomnographic, video, and clinical documentation (8 cases). Dissociation 1989;4:194-204. 169. Mahowald MW, Schenck CH, Rosen GR, et al. The role of a sleep disorders center in evaluating sleep violence. Arch Neurol 1992;49:604-607. 170. Mahowald MW, Schenck CH. Status dissociatus—a perspective on states of being. Sleep 1991;14:69-79. 171. Mahowald MW, Schenck CH. Dissociated states of wakefulness and sleep. Neurology 1992;42:44-52. 172. Lugaresi E, Provini F. Agrypnia excitata: clinical features and pathophysiological implications. Sleep Med Rev 2001;5:313-322. 173. Montagna P, Lugaresi E. Agrypnia excitata: a generalized overactivity syndrome and a useful concept in the neurophysiology of sleep. Clin Neurophysiol 2002;113:552-560. 174. Plazzi G, Montagna P, Meletti S, et al. Polysomnographic study of sleeplessness and onericisms in the alcohol withdrawal syndrome. Sleep Med 2002;3:279-282.
175. Cibula JE, Eisenschenk S, Gold M, et al. Progressive dementia and hypersomnolence with dream-enacting behavior. Oneiric dementia. Arch Neurol 2002;59:630-634. 176. Schenck CH, Hurwitz TD, Bundlie SR, et al. Sleep-related injury in 100 adult patients: a polysomnographic and clinical report. Am J Psychiatry 1989;146:1166-1173. 177. Aurora RN, Zak RS, Maganti RK, et al. Standards of Practice Committee; American Academy of Sleep Medicine. Best practice guide for the treatment of REM sleep behavior disorder (RBD). J Clin Sleep Med 2010;6:85-95. 178. Anderson KN, Jamieson S, Graham AJ, et al. REM sleep behaviour disorder treated with melatonin in a patient with Alzheimer’s disease. Clin Neurol Neurosurg 2008;110:492-495. 179. Boeve BF, Silber MH, Ferman JT. Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Med 2003;4:281-284. 180. Fantini ML, Gagno J-F, Filipini D, et al. The effects of pramipexole in REM sleep behavior disorder. Neurology 2003;61:1418-1420. 181. Schmidt MH, Koshal VB, Schmidt HS. Use of pramipexole in REM sleep behavior disorder. Sleep Med 2006;7:418-423. 182. Matsumoto M, Mutoh F, Naoe H, et al. The effects of imipramine on REM sleep behavior disorder in 3 cases. Sleep Res 1991;20A: 351. 183. Takahashi T, Mitsuya H, Murata T, et al. Opposite effect of SSRIs and tandospirone in the treatment of REM sleep behavior disorder. Sleep Med 2008;9:317-319. 184. Yamamoto K, Uchimura N, Habukawa M, et al. Evaluation of the effects of paroxetine in the treatment of REM sleep behavior disorder. Sleep Biol Rhythms 2006;4:190-192. 185. Bamford C. Carbamazepine in REM sleep behavior disorder. Sleep 1993;16:33. 186. Tan A, Salgado M, Fahn S. Rapid eye movement sleep behavior disorder preceding Parkinson’s disease with therapeutic response to levodopa. Mov Disord 1996;11:214-216. 187. Mike ME, Kranz AJ. MAOI suppression of RBD refractory to clonazepam and other agents. Sleep Res 1996;25:63. 188. Ringman JM, Simmons JH. Treatment of REM sleep behavior disorder with donepezil: a report of three cases. Neurology 2000;55:870-871. 189. Rye DB, Dempsay J, Dihenia B, et al. REM-sleep dyscontrol in Parkinson’s disease: case report of effects of elective pallidotomy. Sleep Res 1997;26:591. 190. Iranzo A, Valldeoriola F, Santamaria J, et al. Sleep symptoms and polysomnographic architecture in advanced Parkinson’s disease after chronic bilateral subthalamic stimulation. J Neurol Neurosurg Psychiatry 2002;72:661-664. 191. Arnulf I, Bejjani BP, Garma L, et al. Improvement of sleep architecture in PD with subthalamic stimulation. Neurology 2000; 55:1732-1734. 192. Piette T, Mescola P, Uytdenhoef P, et al. A unique episode of REM sleep behavior disorder triggered during surgery for Parkinson’s disease. J Neurol Sci 2007;253:73-76. 193. Schuld A, Kraus T, Haack M, et al. Obstructive sleep apnea syndrome induced by clonazepam in a narcoleptic patient with REM-sleep-behavior disorder. J Sleep Res 1999;8:321-322. 194. Schenck CH, Bundlie SR, Mahowald MW. Delayed emergence of a parkinsonian disorder in 38% of 29 older men initially diagnosed with idiopathic rapid eye movement sleep behaviour disorder. [erratum appears in Neurology 1996;46(6):1787]. Neurology 1996;46:388-393. 195. Watanabe T, Sugita Y. REM sleep behavior disorder (RBD) and dissociated REM sleep. Nippon RTNSHO (Jpn J Clin Med) 1998;56:433-438. 195a. Claassen DO, Josephs KA, Ahlskog JE, et al. REM sleep behavior disorder preceding other aspects of synucleinopathies by up to half a century. Neurology 2010;75:494-499. 196. Tassinari CA, Rubboli G, Gardella E, et al. Central pattern generators for a common semiology in fronto-limbic seizures and in parasomnias. A neuroethologic approach. Neurol Sci 2005; 26:s225-s232. 197. Diagnostic Classification Steering Committee. International classification of sleep disorders: diagnostic and coding manual. Rochester, Minn: American Academy of Sleep Medicine; 1990. 198. Guilleminault C, Pool P, Motta J, et al. Sinus arrest during REM sleep in young adults. N Engl J Med 1984;311:1106-1110.
199. Rattenborg NC, Lindblom S, Best J, et al. REM sleep-related asystole associated with unusual polysomnographic features: a case history. Sleep Res 1995;24:324. 200. American Academy of Sleep Medicine. International classification of sleep disorders: diagnostic and coding manual. 2 ed. Westchester, Ill: American Academy of Sleep Medicine; 2005. 201. Karsenty G, Werth E, Knapp PA, et al. Sleep-related painful erections. Nat Clin Pract Urol 2005;2:256-260.
CHAPTER 95 • REM Sleep Parasomnias 1097 202. Steiger A, Benkert O. Examination and treatment of sleep-related painful erections—a case report. Arch Sex Behav 1989;18:263267. 203. Ferini-Strambi L, Zucconi M, Castronovo V, et al. Sleep-related painful erections: clinical and polysomnographic findings. Sleep Res 1996;25:241. 204. van Driel MF, Beck JJ, Elzevier HW, et al. The treatment of sleeprelated painful erections. J Sex Med 2008;5:909-918.
Other Parasomnias Mark W. Mahowald Abstract As mentioned in the preceding two chapters, parasomnias may conveniently be divided into two major categories: Primary parasomnias are those due to disorders of sleep per se, and the secondary parasomnias are those that result from dysfunction of other organ systems and that take advantage of the sleeping state to declare themselves. By far, the primary sleep parasomnias are the most common; they are usually the
NORMAL SLEEP PHENOMENA It should be remembered that some normal phenomena arising from REM or NREM sleep may be bothersome enough to a patient to seek medical attention. Sleep Paralysis Sleep paralysis likely represents the persistence of REM sleep atonia into wakefulness and is extremely common in patients who are not narcoleptic, occurring in more than 33% of the general population. It may be familial, and it is more common in the setting of sleep deprivation and being in the supine position. When occurring in isolation, it can lead to erroneous diagnoses such as cardiac disease or seizures or to unwarranted psychiatric diagnoses. Rarely, episodes of periodic paralysis arising from the sleep period may be confused with true sleep paralysis. Management is reassurance that this is a normal phenomenon. Hypnagogic and Hypnopompic Hallucinations Prominent vivid dreamlike mentation can occur at sleep onset, during light NREM sleep, and even during relaxed wakefulness.1 As with sleep paralysis, such sleep onset and sleep offset hallucinatory phenomena are quite common in the nonnarcoleptic population, and they may be combined with sleep paralysis (often referred to as the “old hag” phenomenon).2 As a matter of fact, the original meaning of the word nightmare referred not to the current use of the term (a dream anxiety attack arising from the sleep period) but rather to a combination of sleep paralysis and hypnagogic hallucinations occurring at sleep onset.3 Patients can be reassured that these hallucinations are normal sleep phenomena and not symptoms of psychiatric disease. Sleep Starts (Hypnic Jerks) Sleep starts are experienced by many normal persons during the transition between wake and sleep. The most common is the motor sleep start, a sudden jerk of all or part of the body, occasionally awakening the victim or bed partner. These are so prevalent as to rarely result in neurologic consultation.4 However, variations on this theme can result in neurologic consultation. These include visual (flashes of light, fragmentary visual hallucinations), audi1098
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rapid eye movement (REM) sleep behavior disorder if from REM sleep or disorders of arousal if from non-REM sleep. There remains a large group of other parasomnias, many of which are poorly understood, that can cause impressive and distressing activities arising from the sleep period but that are unrelated to disorders of arousal or REM sleep behavior disorder. This last chapter on parasomnias discusses these lesscommon but fascinating phenomena.
tory (loud bangs, snapping noises) or somesthetic (pain, tingling, floating, something flowing through the body) sleep starts. These sensory phenomena can occur without the body jerk.5 Sleep starts represent a normal (although not understood) physiologic event, and they should not be confused with seizures or other neurologic conditions. Explosive tinnitus, characterized by a loud crashing or banging noise occurring during sleep most likely represents an auditory sleep start.6 It is also likely that the exploding head syndrome (see later discussion) is a variant of a sensory sleep start. Sleep starts may be repetitive, and they should not be confused with epileptic phenomena. Familiarity with nonmotor sleep starts should eliminate unnecessary testing and pharmacologic treatment. There is a single case report of an auditory sleep start associated with insomnia due to a brainstem lesion.7 Management is simply reassurance.
MISCELLANEOUS PRIMARY SLEEP PARASOMNIAS There remain a number of primary sleep phenomena that are poorly understood and appear not to respect sleep stages. (Bruxism is discussed in Chapter 99.) Box 96-1 outlines the various parasomnias. Sleep-Related Expiratory Groaning (Catathrenia) Groaning during sleep has been termed catathrenia (Video 96-1).8 The groans occur intermittently during either REM or NREM sleep and are characterized by prolonged, often very loud, often socially disruptive groaning sounds during expiration. Catathrenia often begins in childhood, but generally it does not come to medical attention until the person plans to sleep in a dormitory environment, such as in college or the military, or when he or she begins to share a bed with another. It is poorly understood, and there is no known effective treatment. Although there have been some reports of a possible relationship with obstructive sleep apnea and response to treatment with nasal continuous positive airway pressure (CPAP), and there have clearly been a number of cases that did not respond to nasal CPAP.9 There is absolutely no evidence that catathrenia is
CHAPTER 96 • Other Parasomnias 1099
Box 96-1 Primary Sleep Parasomnias NREM Sleep Normal: sleep starts • Motor • Sensory (visual, auditory, somesthetic) • Exploding head syndrome • Explosive tinnitus Abnormal: disorders of arousal • Confusional arousals • Sleepwalking • Sleep terrors REM Sleep Normal • Sleep paralysis • Hypnagogic and hypnopompic hallucinations Abnormal • REM sleep behavior disorder • REM-related painful erections • Dream anxiety attacks (nightmares)
• Exploding head syndrome • Hypnic headache Tinnitus Seizures Cardiopulmonary Cardiac arrhythmias Nocturnal angina pectoris Nocturnal asthma Respiratory dyskinesias Sleep hiccup Miscellaneous • Choking • Defibrillator shocks • Coughing Gastrointestinal Gastroesophageal reflux Diffuse esophageal spasm Abnormal swallowing
Miscellaneous Nocturnal groaning (catathrenia) Bruxism Enuresis Rhythmic movement disorder Propriospinal myoclonus Somniloquy (sleeptalking)
Miscellaneous Nocturnal muscle cramps Nocturnal pruritus Trichotillomania Night sweats Nocturnal tongue biting Benign nocturnal alternating hemiplegia of childhood
Secondary Sleep Parasomnias Central Nervous System Headaches • Vascular • Nonvascular
Functional Disorders Nocturnal panic attacks Posttraumatic stress disorder Psychogenic dissociative disorder Malingering, conversion hysteria, Munchausen syndrome, Munchausen syndrome by proxy
related to any underlying psychological or psychiatric problems. Enuresis Enuresis was formerly classified as a disorder of arousal, implying a relationship with slow-wave sleep.10 However, enuresis can occur during either NREM or REM sleep, and the sleep of enuretic children is normal.11 Enuresis is very common in childhood, and it much more prevalent in adolescence and adulthood than generally appreciated (1% to 2% of 18 year-olds and 0.5% of adults).12,13 Many etiologies have been suggested, including genetic,14 behavioral and psychological, bladder size or reactivity abnormalities, lack of vasopressin release during sleep, and delayed development.15 Despite considerable literature, the causes of enuresis remain enigmatic. Local urologic abnormalities account for only 2% to 4% of pediatric cases.16 No specific psychopathology has been identified, and there is overwhelming evidence that enuretic children have no more behavioral or psychological problems than nonenuretic children and that genetic factors are important.17 Formal urologic evaluation is usually not indicated, and simple reassurance and understanding on the part of both
the child and the parents are often sufficient. Conditioning with a bell-and-pad device is effective but may be transient.18 Psychotherapy is generally ineffective and indicated only if obvious psychopathology is present.12 Tricyclic antidepressants (imipramine or desipramine) are effective and may be employed for short-term treatment, but long-term pharmacologic treatment is to be discouraged. Their mechanism of action is not known, but it appears not to involve peripheral anticholinergic effects.19 Desmopressin, an intranasally administered vasopressin analogue, has been reported to be of benefit.20 Enuresis may be the sole manifestation of nocturnal seizures and can accompany obstructive sleep apnea or other primary sleep disorders.21 Formal polysomnographic study with a full seizure montage and enuresis detector is indicated in patients with atypical histories or failure to respond to conventional therapy. Rhythmic Movement Disorder Rhythmic movement disorder (RMD), formerly termed jactatio capitis nocturna, refers to a group of actions characterized by stereotyped movements (rhythmic oscillation of the head or limbs, head-banging or body-rocking during sleep) seen most commonly in childhood (Videos 96-2 and
1100 PART II / Section 12 • Parasomnias
96-3). Its persistence into adulthood is not uncommon. It is familial in some cases. RMD can arise from all stages of sleep, including REM sleep, and it can occur during the transition from wake to sleep.22 Significant injury from repetitive pounding can result.23 The etiology of RMD is unknown, and no systematic studies of pharmacologic or behavioral treatment have been reported, although tricyclic antidepressants and benzodiazepines, particularly clonazepam, may be effective.24 Preliminary data suggest that the use of a waterbed can improve the rhythmic actions,25 as can controlled sleep restriction.26 Hypnosis was effective in a single case.27 Posttraumatic cases involving only the foot have been reported.28 Rarely, RMD is the sole manifestation of a seizure29 or is associated with REM sleep behavior disorder.30 Propriospinal Myoclonus Propriospinal myoclonus is a spinal cord–mediated movement disorder, occasionally associated with acquired spinal cord lesions. It is characterized by repetitive jerks occurring during the transition from wake to sleep.31 Propriospinal myoclonus may be confused with restless legs syndrome or periodic limb movements in sleep, and it can serve to shed light on the pathophysiology of these two disorders.32 It has been described in various neurologic conditions such as restless legs syndrome, paraneoplastic syndromes, and cervical disk herniation, and in extreme cases it can result in life-threatening respiratory compromise.33-36 The movements can appear during relaxation and can result in severe insomnia, particularly at sleep onset.37 Clonazepam or anticonvulsant medications may be effective in alleviating these movements.31 Propriospinal myoclonus may be related to segmental myoclonus, both spinal and palatal.38 Somniloquy (Sleeptalking) Sleeptalking is very common in the general population, might have a genetic component,39 and can occur in either REM or NREM sleep.40 Most cases are not associated with serious psychopathology.41
SECONDARY SLEEP PARASOMNIAS The secondary phenomena are parasomnias representing abnormal or excessive autonomic or physiologic events arising from specific organ systems and occurring preferentially during the sleep period. These can be approached by the offending organ system. Central Nervous System Parasomnias Seizures Nocturnal seizures are an important cause of complex motor actions arising from the sleep period and are discussed in Chapter 92. Headaches V ASCULAR H EADACHES Although some headaches have historically been referred to as “vascular headaches,” there is now overwhelming evidence that the etiology of this headache type is not vascular,
but rather a primary neurologic phenomenon.42 Many headache syndromes are sleep related.43 The headache symptoms of cluster headache, chronic paroxysmal hemicrania, and possibly migraines, in some cases, tend to be related to REM sleep, explaining the common report of sleep-related headaches in these conditions.44 This fact explains the worsening of these symptoms following the discontinuation of REM sleep–suppressing agents (which results in a rebound of REM sleep) such as tricyclic antidepressants, monoamine oxidase inhibitors, clonidine, alcohol, and amphetamines. Circadian rhythm abnormalities can play a role in cluster headache and chronic paroxysmal hemicrania.45,46 Episodic paroxysmal hemicrania might respond to calcium channel blockers or topiramate.47,48 Sleep-disordered breathing can serve as a risk factor for headaches in some persons with cluster headaches.49 N ONVASCULAR H EADACHES Although morning headaches may be more prevalent in persons with sleep complaints in general, headaches are not a reliable marker for sleep-disordered breathing.50 However, in some susceptible persons, obstructive sleep apnea can trigger cluster headaches, which respond to bilevel positive airway pressure (BiPAP).51 Headaches associated with sleep-disordered breathing are more commonly seen in patients with neuromuscular disease who experience REM sleep–related hypoventilation, with hypercapnia-induced migraines arising from the sleep period. Carbon monoxide poisoning must never be overlooked as a cause of morning headaches. E XPLODING H EAD S YNDROME This syndrome is characterized by abrupt arousal, usually occurring in the transition from wake to sleep, with the sensation of a loud sound like an explosion or a sensation of bursting of the head.52 Most reported cases occur in the twilight state of sleep onset, but polysomnographic recording has documented their occurrence during both wakefulness and well-declared REM sleep.53,54 These events might represent a variant of sleep starts55 and are usually benign; however, similar phenomena can represent the sole manifestation of a seizure.56 Clomipramine or nifedipine may be effective, but they are not indicated in most cases due to the benign nature of the condition.57 There is a single case report of exploding head syndrome followed by sleep paralysis as a migraine aura.58 H YPNIC H EADACHE The hypnic headache syndrome has been described in a number of older patients with regular awakenings from sleep at a consistent time of night (usually 4 to 6 hours after sleep onset), occasionally during a dream, with a diffuse headache that generally lasts 30 to 60 minutes and is associated with nausea but no autonomic symptoms. Although only approximately 50 patients with this syndrome have been reported, it is likely more common than previously thought. The headaches are usually generalized, but they may be unilateral59 and may be protracted.60 This condition is felt to be a benign sleep-related headache syndrome affecting the elderly. The few cases studied during sleep suggest it most commonly arises from REM
sleep. It might also represent a circadian rhythm phenomenon and might respond to lithium, indomethacin, prednisone, flunarizine, gabapentin, acetazolamide, or caffeine administered before bedtime.61-63 A detailed neurological history and examination should be performed to rule out focal neurologic conditions such as a posterior fossa meningioma masquerading as hypnic headaches.64 Tinnitus Tinnitus can persist during sleep, resulting in sleep complaints in up to 50% of patients.65 The sleep complaints are not associated with mood or emotional distress.66 Subjective improvement in sleep followed use of an electrical tinnitus suppressor or bedside sound generators.67,68 In another study, nortriptyline decreased depression, functional disability, and loudness of tinnitus, but sleep was not mentioned.69 This condition is poorly understood and requires more systematic study before any conclusions may be reached. Evidence exists that tinnitus may be centrally mediated.70 The term explosive tinnitus most likely refers to an auditory sleep start.6 There is no known predictably effective treatment. Cardiopulmonary Parasomnias Cardiac arrhythmias, nocturnal angina pectoris, and nocturnal asthma are covered elsewhere. (See Chapters 111, 116, 118, and 121.) Respiratory Dyskinesias There are numerous respiratory dyskinesias that occur or persist during the sleep period. These include segmental myoclonus such as palatal myoclonus71,72 or diaphragmatic flutter73 as well as paroxysmal dystonia.74 Respiratory dyskinesias may also be the manifestation of neurolepticinduced dyskinesias, and they might or might not persist during sleep.75 These should be differentiated from unusual nocturnal seizures that manifest with primarily or exclusively respiratory symptoms.76 Effective treatments remain to be identified. Sleep Hiccup Persistent hiccup can continue during all stages of sleep, but its appearance during sleep in persons with chronic hiccup is variable.77 The frequency diminishes during sleep, more so in REM than NREM sleep. Interestingly, sleep hiccups are rarely associated with arousals.78 No treatment studies are available. Miscellaneous Cardiorespiratory Parasomnias Isolated cases of sleep-related dyspnea and choking have been reported. The etiology and treatment are unclear.79 Paroxysmal choking may be the sole manifestation of nocturnal seizures.80 Phantom shocks from implantable cardioverter-defibrillators have been reported. Patients are awakened from a sound sleep with the sensation of having received a defibrillator discharge. These were not associated with dream recall. By observation, there was a motor jolt associated with crying out, as though an actual shock had been administered. Review of the counters indicated that no shock had been delivered. These phantom shocks
CHAPTER 96 • Other Parasomnias 1101
should be verified before medical treatment or device reprogramming is prescribed.81 Intractable cough associated with the supine position, presumably due to position-related collapse of the upper airway, responsive to nasal CPAP has been reported.82,83 Gastrointestinal Parasomnias Numerous gastrointestinal events may result in paroxysmal arousals during sleep, often mimicking disorders of other organ systems. Gastroesophageal reflux disease (GERD) is covered elsewhere in Chapter 127. Diffuse Esophageal Spasm Nocturnal diffuse esophageal spasm simulates nocturnal cardiac disease, occasionally even resulting in arrhythmias.84,85 Diagnosis may be made with esophageal manometric monitoring. Treatment includes administration of anticholinergics, nitrates, or calcium antagonists.86 Abnormal Swallowing Abnormal swallowing during sleep can cause arousals induced by coughing, aspiration, or choking. Polysomnographic studies show brief episodes of coughing and gagging.87 Etiology and treatment are unknown. Miscellaneous Secondary Parasomnias Nocturnal Muscle Cramps The complaint of muscle cramping, often nocturnal, is extremely common but poorly understood. The true incidence and etiology are unknown, and there has been no systematic study of nocturnal muscle cramps. A subjective response to quinine sulfate, magnesium, vitamin E, gabapentin, or verapamil has been reported, as has an isolated case responding to transcutaneous nerve stimulation.88-93 Nocturnal Pruritus Patients with a wide variety of dermatologic disorders associated with pruritus may demonstrate recurrent episodes of scratching during sleep, resulting in sleep disruption.94 These scratching episodes occur during all stages of sleep, being most often in light NREM, intermediate in REM, and least often in slow-wave sleep.95,96 Circadian factors have been suggested.97 The duration of scratching episodes is the same among the sleep stages.98 Anecdotal response to lidocaine patches or mirtazapine have been reported.99,100 Such scratching can interfere with treatment and can play a role in factitious dermatoses.101 Trichotillomania In some persons, trichotillomania (the compulsion to pull out one’s hair) may be confined to sleep.102 Imipramine has been effective in one case.103 Night Sweats Night sweats are very common, but they tend not to be reported to physicians.104 Night sweats (unrelated to infectious, endocrine, or malignant conditions) may be associated with a number of unrelated conditions includ-
1102 PART II / Section 12 • Parasomnias
ing obstructive sleep apnea,105 spinal syringomyelia,106 medications,104 gastroesophageal reflux,107 and autonomic seizures.108 Although night sweats may be associated with other subjective sleep complaints, there is no association with objective evidence of specific sleep disorders.97 Night sweats can also appear around the time of menopause.109 The degree of sweating during sleep may be impressive, necessitating several nightly changes of pajamas and bedding. Benztropine has been reportedly effective in venlafaxine-induced night sweats.110 There is no known effective treatment for idiopathic recurring night sweats. Nocturnal Tongue Biting Tongue biting during sleep has been reported as a manifestation of a number of unrelated conditions, including myoclonic activity, nocturnal seizures, disorders of arousal, and rhythmic movement disorder.111-116 Benign Nocturnal Alternating Hemiplegia of Childhood Benign nocturnal alternating hemiplegia of childhood, a presumably rare condition, is associated with brief periods of hemiplegia arising from the sleep period, rarely occurring during wakefulness. This condition might resolve spontaneously. There is no known treatment. The mechanism is unknown, but there is a high frequency of migraine in relatives. It may be a channelopathy such as hemiplegic migraine or episodic ataxia type 2.117
malingering), unlike other parasomnias, the complex behavior during polysomnographic monitoring is seen to arise from well-developed EEG-determined wakefulness.125 The term pseudoparasomnia has been proposed for this condition.126 Malingering, Conversion Hysteria, or Munchausen’s Syndrome Malingering, conversion hysteria, or Munchausen syndrome can appear to a sleep specialist as sleep-related stridor, asthma, upper airway obstruction, or sleep-related violent behavior in adults,127-132 or as sleep apnea (Munchausen by proxy) in children.133 Cyclic hypersomnia has also been reported as a manifestation of a factitious disorder.134
❖ Clinical Pearl The vast majority of parasomnias are due to either disorders of arousal or the REM sleep behavior disorder. There remain a large number of other parasomnias that may be confused with the more common ones. Careful evaluation by history and polysomnographic study will usually identify the true underlying problem. Undoubtedly, as more patients experiencing unusual phenomena arising from the sleep period are evaluated and studied thoroughly, more fascinating parasomnias will be identified, with important therapeutic implications.
FUNCTIONAL DISORDERS Posttraumatic Stress Disorder Posttraumatic stress disorder is covered in Chapter 53. Nocturnal Panic Attacks Sleep-related panic attacks occur in many (30% to 50%) patients with diurnal panic, and they can precede the appearance of diurnal panic or may be exclusively nocturnal.118 Panic disorder can begin in childhood and adolescence and can masquerade as a wide variety of neurologic syndromes.119 Subjective sleep complaints are common in patients with panic disorder (up to 70%) and include insomnia, nocturnal panic attacks, or fear of going to bed or falling asleep.120 Formal sleep studies may be unremarkable, with no abnormalities of sleep macrostructure or excessive arousability, but suggest that nocturnal panic is a NREM phenomenon.121 It is easy to understand how nocturnal panic and other sleep disorders characterized by precipitous arousals (particularly sleep apnea or gastroesophageal reflux) may be confused.122 The striking similarity of the symptoms of dream anxiety attacks, sleep terrors, nocturnal seizures, sleep apnea, and nighttime panic urges caution in diagnosis. Psychogenic Dissociative States Complex, potentially injurious behavior, occasionally confined to the sleep period, may be the manifestation of a psychogenic dissociative state.123 A history of childhood physical or sexual abuse is virtually always present but may be difficult to elicit.124 In this condition (and
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CHAPTER 96 • Other Parasomnias 1105 132. Goldman J, Muers M. Vocal cord dysfunction and wheezing. Thorax 1991;46:401-404. 133. Skau K, Mouridsen SE. Munchausen syndrome by proxy: a review. Acta Paediatr 1995;84:977-982. 134. Feldman MD, Russell JL. Factitious cyclic hypersomnia: a new variant of factitious disorder. South Med J 1991;84: 1991.
Idiopathic Nightmares and Dream Disturbances Associated with Sleep–Wake Transitions Tore Nielsen and Antonio Zadra Abstract Nightmares and other common disturbances of dreaming involve a perturbation of emotional expression during sleep. Nightmares, the most prevalent dream disturbance, are now recognized as comprising several dysphoric emotions, including especially fear, although some argue that existential (or grief) dreams should be considered a separate entity. A genetic basis for nightmares has been demonstrated and their pathophysiology involves a surprising underactivation of the sympathetic nervous system in many instances. Personality factors, such as nightmare chronicity and distress and coping styles, are mediating determinants of their clinical severity,
Because most common dreaming disturbances (Table 97-1) involve a perturbation of emotional expression during sleep, their study may help clarify the role of emotion in dream formation, dream function, and sleep mechanisms more generally. Physiologic evidence for emotional activity during rapid eye movement (REM) sleep is substantial. Autonomic system variability increases markedly in conjunction with central phasic activation,1 as seen especially in measures of cardiac function,2,3 respiration,4 and skin and muscle sympathetic nerve activity.5 Brain imaging, too, demonstrates increased metabolic activity in limbic and paralimbic regions during REM sleep,6 activity similar to that seen during strong emotion in the waking state.7 These dramatic autonomic fluctuations globally parallel dreamed emotional activity, which is detectable throughout most dreaming when appropriate probes are employed.8 Some studies indicate that most dreamed emotion is negative,9 primarily fearful,8 and may conform to a surgelike structure within REM episodes.10 Many theorists interpret the various forms of phasic activity occurring during sleep as indicating dream-related affective activity.11,12 Waking state emotional and cognitive reactions are also implicated in dream disturbances. For the most common disturbances, such as nightmares, dreamed emotions become unbearably intense, provoking an awakening that can lead to further distress, depressed mood, avoidance and coping behavior, and often even impairment of subsequent sleep. Perturbation of dream-related emotion can thus lead to a cycle of sleep disruption and avoidance, insomnia,13 and psychological distress that often leads the person to seek out professional help.14 However, causal relationships among emotion, dreaming, and other associated symptoms are not well understood. The emotional disruption inherent in nightmare disorder may be limited to sleep-related processes, in which case the dreaming process itself might be considered 1106
Chapter
97
as are drug and alcohol use. Many treatments have been described, with much support for the effectiveness of shortterm cognitive and behavior interventions such as systematic desensitization and imagery rehearsal. Several related dream disturbances occur at the transitions into or out of sleep and involve dysphoric emotions ranging from malaise to fear to frank terror. These disturbances include sleep starts, terrifying hypnagogic hallucinations, sleep paralysis, somniloquy with dream content, false awakenings, and disturbed lucid dreaming. The distinctive nature of these disturbances may be mediated by immediately preceding waking state processes (e.g., consciousness, sensory vividness) that intrude upon or carry over into dreaming.
pathologic in some sense.15 However, the widespread belief that dreaming can serve an emotionally adaptive function (see Chapter 54) also suggests that some dream disturbances are adaptive reactions to more basic pathophysiologic factors rather than pathological per se.16
IDIOPATHIC NIGHTMARES Historical Aspects The Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV)17 criteria for nightmare disorder (Table 97-2) have not changed substantially since the disorder was previously described as “dream anxiety disorder” in the DSM-III-R and “dream anxiety attack” in the DSMIII. The International Classification of Sleep Disorders, 2nd edition (ICSD-II) criteria for nightmares (see Table 97-2) have changed only slightly since the first edition (ICSD). Some new research on the phenomenology of nightmares has prompted a redefinition of the term nightmare in the more recent ICSD-II. The widely accepted definition of a nightmare has long been “a frightening dream that awakens the sleeper,” but researchers have come to reevaluate these defining features. Some18 argue that the “awakening” criterion should indeed designate nightmares but that disturbing dreams that do not awaken (“bad dreams”) should nevertheless be considered clinically significant. Whether or not the person awakens presumably reflects a dream’s emotional severity, but it is not the only index of severity. First, among patients with various psychosomatic disorders, even the most macabre and threatening dreams do not necessarily produce awakenings.19 Second, less than one fourth of patients with chronic nightmares report “always” awakening from their nightmares, and these awakenings do not correlate with either nightmare intensity or psychological distress.13 Third, among subjects with both nightmares and bad dreams, approximately 45% of bad dreams are rated
CHAPTER 97 • Idiopathic Nightmares and Dream Disturbances Associated with Sleep–Wake Transitions 1107
Table 97-1 Sleep Disorders in Which Disturbed Dreaming is Common SLEEP DISORDER
CODE*
STAGE
PREVALENCE
ESSENTIAL FEATURES
Nightmare disorder
307.47-0
REM, 2
Preschoolers: 5%-30% Young adults: 2%-5%
Frightening dreams; awakening
Terrifying hypnagogic hallucinations
307.47-4
Sleep onset
Rare Narcolepsy: 4%-8%
Terrifying dreams similar to those from sleep
Sleep starts
307.47-2
Sleep onset
Lifetime: 60%-70% Extreme form: rare
Sudden brief jerks associated with sensory flash, hypnagogic dream, or feeling of falling
Sleep paralysis
780.56-2
Sleep onset or offset
Isolated, normal persons: 1/lifetime in 40%-50% Familial: rare
Paralysis of voluntary muscles; acute anxiety (with or without dreams) is common
*American Sleep Disorders Association: International classification of sleep disorders, revised: diagnostic and coding manual. Westchester, Ill: American Sleep Disorders Association; 1997.
Table 97-2 Clinical Criteria for Nightmare Disorder DSM-IV DIAGNOSTIC CRITERIA FOR NIGHTMARE DISORDER (307.47)
ICSD-II DIAGNOSTIC CRITERIA FOR NIGHTMARES (307.47-0)
Nature of recalled dream
Repeated awakenings from the major sleep period or naps with detailed recall of extended and extremely frightening dreams, usually involving threats to survival, security, or self-esteem.
Recurrent episodes of awakenings from sleep with recall of intensely disturbing dream mentation, usually involving fear or anxiety but also anger, sadness, disgust, and other dysphoric emotions. Recall of sleep mentation is immediate and clear.
Nature of awakening
On awakening from the frightening dreams, the person rapidly becomes oriented and alert (in contrast to the confusion and disorientation seen in sleep terror disorder and some forms of epilepsy).
Alertness is full immediately on awakening, with little confusion or disorientation.
Nature of distress
The dream experience, or the sleep disturbance resulting from the awakening, causes clinically significant distress or impairment in social, occupational, or other important areas of function.
Associated features include at least one of the following: • Return to sleep after the episodes is typically delayed and not rapid.
Timing
The awakenings generally occur during the second half of the sleep period.
The episodes typically occur in the latter half of the habitual sleep period.
Differential diagnosis
The nightmares do not occur exclusively during the course of another mental disorder (e.g., a delirium, posttraumatic stress disorder) and are not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.
Nightmares are distinguished from several other disorders in a Differential Diagnosis section: seizure disorder, arousal disorders (sleep terrors, confusional arousal), REM sleep behavior disorder, isolated sleep paralysis, nocturnal panic, posttraumatic stress disorder, acute stress disorder.
CRITERIA
on a level of emotional intensity that is equal to or exceeds that of the average nightmare.20 In short, whereas disturbing dreams often can awaken a sleeper, awakenings are not the sole or even the best index of the severity of the disorder. Similarly, researchers have come to define nightmares more inclusively with respect to their emotional tone. This is reflected in the modified ICSD-II definition of nightmares as “disturbing mental experiences” rather than as “frightening dreams” as in the ICSD. Although fear remains the most commonly reported nightmare emotion,20
some argue18 that nightmares can involve any unpleasant emotion. However, distressing dreams related to bereavement are considered by some as constituting a distinct nosologic entity known as existential dreams.21 Prevalence and Frequency Lifetime prevalence for a nightmare experience in the general population is unknown but may well approach 100%. If we consider only dreams of attack and the pursuit theme, which are the most common nightmare themes, the lifetime prevalence varies from 67%22 to 90%.23 Pursuit
Age
0
Boys Girls
yr
10 11 12 13 14 15 16 17 18
*
B
Age
C
*
*
*
.40
*
.30
* *
Males Females
.20
-2 30 9 -3 4 35 -3 9 40 -4 45 4 -4 9 50 -5 4 55 -5 9
5
6
yr 5
o m yr 2
4
yr 5 3
A
2
yr 5
m
m
o
o
0.0
10
.50
-2 4
1.0
*** *** *** ***
25
2.0
15
-1 9
3.0
.60
15
4.0
20
20
Boys Girls
Log (nightmares/mo + 1)
% Often + always
5.0
% Much + very much
1108 PART II / Section 12 • Parasomnias
Age
Figure 97-1 Nightmare prevalence over the lifespan. A, Proportion of preschool children having bad dreams “often” or “always” as reported by parents in a longitudinal study (girls: n = 490-493; boys: n = 468-477).24 No sex difference is apparent at any age. B, Proportion of children and adolescents having nightmares “much” or “very much” in the last month (girls: n = 3372, mean age = 14.1 ± 2.05 years; boys: n = 3355; mean age = 14.0 ± 2.12) (***P < .0001)25; C, log(number of nightmares in a typical month + 1) reported by respondents to an Internet questionnaire (female: n = 19,367, mean age = 24.9 ± 10.14 years; male: n = 4,623; mean age = 25.5 ± 10.81) (*P < .05). (From Nielsen TA, Petit D. Description of parasomnias. In Kushida CA, editor. Handbook of sleep disorders. Oxford: Taylor and Francis; 2008. p. 459-479.)
alone has a lifetime prevalence of 92% among women and 85% among men.23 An ensemble of population studies indicates that the prevalence and frequency of nightmares increases through childhood into adolescence, when a marked gender difference takes hold (Fig. 97-1). Preschoolers report bad dreams surprisingly seldom. From 1.3% to 3.9% of parents report that their children have them “often” or “always” and there is no gender difference at this age (see Fig. 97-1A).24 Subsequently, as shown in a study of 6727 Kuwaiti 10- to 18-year-old children,25 nightmare prevalence increases from ages 10 to 13 years for both boys and girls and thereafter continues to increase for girls but decreases progressively for boys (see Fig. 97-1B). This finding replicates with more precision our finding that boys and girls aged 13 years report bad dreams often with about equal prevalence (boys, 2.5%; girls, 2.7%), whereas at age 16 years prevalence for the same children diverges markedly (boys, 0.4%; girls, 4.9%).26 The gender difference is then maintained into adulthood and old age, even though the prevalence of nightmares decreases steadily over time for both men and women (see Fig. 97-1C).27 This general profile of age and gender differences is consistent with a large corpus of research for young children,28 adolescents,26 young adults,29 middle-aged adults,30 and the general population.31 Slightly different patterns have been reported for some pediatric32 and elementary school33 samples, however. Nightmare prevalence may be elevated in clinical populations. For example, 25% of chronic alcoholics and drug users report nightmares “every few nights” on the Minnesota Multiphasic Inventory (MMPI),34 and 66% of suicide attempters report moderate or severe nightmares.35 However, other findings of elevated prevalence are difficult to assess because a frequency criterion is not specified; for example, approximately 24% of nonpsychotic patients seen in psychiatric emergency services report nightmares, but with an unknown frequency.36 When compared to results from daily home logs, however, retrospective self-reports underestimate current nightmare frequency by a factor of 2.5 in young adults18 to a factor of more than 10 in the healthy elderly.37 In general, a 1-month retrospective estimate is closer to the
estimate provided by daily logs than is a 12-month retrospective estimate and is thus the preferred standard for retrospective assessment. Because nightmare prevalence and frequency are seriously underestimated by retrospective instruments, daily logs are the method of choice. Familial Pattern Twin-based studies have identified persistent genetic effects on the disposition to nightmares in childhood, as reported retrospectively by adults, and in adulthood,30a as well as genetic influences on the co-occurrence of nightmares and some other parasomnias, such as sleeptalking, but not others, such as bruxism.38 In the Finnish twin cohort study, a genetic basis for nightmares was shown in the proportion of phenotypic variance in trait liability for nightmare prevalence attributable to genetic influences at about 45%.30 A second study reports a 51% genetic influence.30a Pathophysiology One laboratory study of nightmares39 indicates moderate arousal—increased heart and respiration rates—during some nightmare episodes, but unexpectedly low arousal in most others. These early findings constitute the principal empirical basis for diagnostic guidelines such as the ICSD and DSM-IV, but there are serious problems with the work, such as the inclusion of psychiatric patients and patients with posttraumatic stress disorder (PTSD) in the study sample. Recordings of heart rate and respiration rate during nightmare and non nightmare REM sleep episodes confirmed a moderate level of sympathetic arousal during nightmares.40 Mean heart rate for nightmare sleep was elevated (by about 6 bpm) for the 3 minutes before awakening. Mean respiration rate was only marginally higher at this time. We have recorded higher absolute and relative alpha power over primarily right posterior sites in the last 2 minutes of nightmare sleep. However, these changes might reflect processes of awakening. The typical sleep of nightmare subjects does not differ dramatically from that of paired controls41; although elevated levels of periodic limb movements in sleep (PLMS) have been observed for both idiopathic and PTSD nightmare sufferers.42 REM sleep measures suggest that night-
Percent skipped REM periods
CHAPTER 97 • Idiopathic Nightmares and Dream Disturbances Associated with Sleep–Wake Transitions 1109
A
70 60 50
*
40 27.3
30 20 9.1
10
0
0 REM1
Mean (SD) %REM
%REM-1st Third
B
19 17 15 13 11 9 7 5 3 1
Nightmare Control
50.0
REM2
%REM-2nd Third
%REM-3rd Third
Nightmare (N = 14) Control (N = 11)
Night 1 Night 3 Night 1 Night 3 Night 1 Night 3
Figure 97-2 Reduced REM propensity among nightmare subjects. A, Elevated number of skipped early REM periods for nightmare subjects on baseline night suggests low REM propensity. Nightmare subjects skipped 7 of 14 expected REM1 periods and 3 of 14 expected REM2 periods; control subjects skipped 1 (*P = .042, Fisher exact test) and 0 (not significant), respectively. B, REM sleep as a percentage of total time asleep (REM%) separated by thirds of the night. Relative to night 1, nightmare subjects showed REM rebound in the first third of night 3 (P = .003) but not the second (P = .128) or third (P = .776) thirds. Control subjects showed REM rebound in the second (P = .018) and third (P = .050) thirds but not the first (P = .275). REM propensity for nightmare subjects is thus low precisely at the time of night when REM sleep is normally most prevalent and most intense (from Nielsen, et al., Sleep Medicine 2010;11:172-179).
mare subjects have abnormally low REM sleep propensity, even during recovery sleep following partial REM sleep deprivation in a 3-night protocol (Fig. 97-2).41 Personality Although many studies report relationships between nightmare frequency and measures of psychopathology,18,26 some do not.43 Several detailed reviews are available.14,44,45 Inconsistent relationships between nightmares and psychopathology likely reflect mediating factors, among which three—nightmare chronicity, nightmare distress, and coping style—are reviewed below. Nightmare Chronicity Adults with a lifelong history of frequent nightmares compose an idiopathic nightmare subgroup with more psychopathologic symptoms than matched controls, such as higher neuroticism and MMPI scores.46 However, Hartmann47 found that no one measure of psychopathology
adequately describes these persons. He proposed48 a general “boundary permeability” personality dimension, correlated with nightmare prevalence,49 which, at one extreme (thin boundaries) characterizes lifelong sufferers who are more open, sensitive, and vulnerable to intrusions than thick-boundary subjects, including a greater sensitivity to events not usually viewed as traumatic.47 Nightmare Distress Nightmare frequency and waking distress over one’s nightmares are only moderately correlated measures in adults50 and largely unrelated in adolescents.51 Subjects might have only few nightmares (e.g., one per month) yet report high levels of associated distress and vice versa. It is nightmare distress, not necessarily nightmare frequency, that is significantly related to psychopathology, especially to measures of anxiety and depression.52 Thus, nightmareinduced distress might simply be an expression of a more general distress style.14 However, even though both state (stress) and trait personality measures correlate with nightmare frequency, trait measures do not account for any variance beyond that accounted for by state measures.53 Nightmare distress should be evaluated during clinical intake because, although it is not among the diagnostic criteria of the DSM-IV or ICSD-II, it is central to defining nightmares as a clinical problem. Coping Style Given the central role of nightmare distress, a person’s ability to cope with stress may be pivotal in whether a clinical problem with nightmares develops. Dysfunctional coping strategies such as dissociation might exacerbate both nightmare distress and chronicity. College students with nightmares report both higher rates of childhood trauma and higher scores on dissociative coping (Dissociative Experiences Scale, DES) than do students without nightmares.54 Adaptive and maladaptive coping strategies may come into play at a very young age because dissociation scores on the Child Dissociative Checklist are associated with nightmares among children as young as 3 to 4 years.55 Effects of Drugs and Alcohol Numerous classes of drugs trigger nightmares and bizarre dreams, including catecholaminergic agents, beta-blockers, some antidepressants, barbiturates, and alcohol. One review56 suggests that the therapies most often associated with nightmares are sedative/hypnotics, beta-blockers, and amphetamines and that REM suppression is a frequent mechanism of action. Among catecholaminergic agents, reserpine, thioridazine, and levodopa are all occasionally associated with vivid dreams and nightmares,57-59 as are beta-blockers such as betaxolol, metropolol, bisoprolol, and propranolol.60-62 Among the antidepressants, bupropion leads to more vivid dreams and nightmares than do other antidepressants.63 The selective serotonin reuptake inhibitors (SSRIs) paroxetine and fluvoxamine suppress dream recall frequency while simultaneously increasing subjective dream intensity and bizarreness, possibly due to serotoninergic REM suppression.64 Bedtime administration of tricyclic and neuroleptic agents leads to a higher recall of frightening dreams than when these are taken in
1110 PART II / Section 12 • Parasomnias Table 97-3 Drugs Reported in Case Studies to Increase Frequency of Nightmares DRUG
FUNCTION
REFERENCE
Betaxolol
Beta-blocker
Mort, 1992126
Carbachol
Cholinergic agent
Mort, 1992126
Donepizil
Cholinesterase inhibitor
Ross and Shua-Haim, 1998127
Erythromycin
Antibiotic
Black and Dawson, 1988133
Fluoxetine
Antidepressant
Lepkifker, Dannon, Iancu, et al, 1995128
Naproxen
Nonsteroidal antiinflammatory
Bakth and Miller, 1991129
Nitrazepam
Benzodiazepine hypnotic
Girwood, 1973132
Thiothixene
Neuroleptic
Solomon, 1983125
Triazolam
Benzodiazepine hypnotic
Forman and Souney, 1989131
Verapamil
Antimigraine agent
Kumar and Hodges, 1988130
two daily doses,65 even though normal dream recall frequency remains the same. Neuroleptics and tricyclics appear to render dream affect more dysphoric rather than to increase dream recall per se. Withdrawal from barbiturates is associated with REM rebound, vivid dreaming, and nightmares.66 A hypothesis has been advanced that barbiturate suppression of REM sleep, much like with alcohol, causes REM sleep rebound after discontinuation of the drug and consequently longer and more vivid dreams.67 In addition, several case studies have alerted physicians to the nightmare-causing effects of specific substances (Table 97-3). Evening, but not morning, doses of the acetylcholinesterase inhibitor donepezil induces nightmares.68 The antimalarial drug mefloquine produces vivid dreams and nightmares.69 Sleep and dream disturbances follow alcohol withdrawal. Alcoholic patients report more vivid dreams and nightmares following withdrawal than they do during ingestion; although these are more frequent in the week following withdrawal, they are still present in subsequent weeks. The nightmares and insomnia of withdrawal can lead to resumed drinking in an attempt to normalize sleep. In fact, 29% of a group of 100 alcoholics reported further drinking to alleviate nightmares.70 This relationship is also of critical importance because of the danger of alcohol self-medication for PTSD71 and other nightmare-producing disorders. Vivid and macabre dreaming may be central to the delirium tremens (DTs) of acute alcohol withdrawal.72 Because alcohol suppresses REM sleep, and because REM percentage (particularly at sleep onset) is extremely elevated in patients with DTs,73 a theory of DT hallucinations emphasizing REM rebound and intrusion of dreaming into wakefulness has been proposed.74 Case studies strongly suggest that hallucinations may seem to continue uninterrupted from an ongoing nightmare.75 DT sleep appears to be a mixture of REM sleep with “stage 1 REM sleep with tonic EMG,” which distinguishes it from the sleep of alcoholics without DTs.76 Some have failed to observe this pattern, however.77 The similarity of sleep patients with DTs to those with REM sleep behavior disorder (RBD) has also been noted.78 Acute withdrawal from cocaine often induces unpleasant dreams.79 Strange dreams, including nightmares, are one of the most consistently reported effects of withdrawal from cannabis; they are persistent, lasting for longer than
45 days after withdrawal.80 In two studies, strange dreams are rated to be “severe” and “moderate” by 20% and 37% of adults and by 8% and 15% of adolescents seeking treatment.81,82 The neuropharmacologic bases of drug-induced or withdrawal-associated disturbed dreaming remain unclear. There may be a balance among various neurotransmitter systems such that nightmares are produced by reduced brain norepinephrine and serotonin or increased dopamine and acetylcholine.47 REM suppression is implicated as a mechanism in the action of many agents (e.g., betablockers), as is dopamine receptor stimulation.56 Dissociation of dream initiation and intensification processes by separate neuromodulatory systems may also be implicated64 (see Chapter 48). Recurrent Dreaming and Nightmares Repetitive dreams, such as posttraumatic nightmares, depict—over numerous, highly similar versions—an unresolved experience, such as a motor vehicle accident or war trauma. These are also referred to as replicative nightmares (see Chapter 53). Recurrent dreams depict conflicts or stressors metaphorically over repeated instances and are also primarily unpleasant in nature.83 The most frequent recurrent dreams of adults are pseudonightmarish: being endangered (e.g., chased, threatened with injury), being alone and trapped (e.g., in an elevator), facing natural forces (e.g., volcanic eruptions), or losing one’s teeth. Dreams with less recurrence—recurrent themes and recurrent contents—extend over long dreams series and are associated with more mild psychopathology, possibly even with attempts at emotional adaption.84 Subjects with recurrent dreams show less successful adaptation on measures of anxiety, depression, personal adjustment, and life-events stress than those without recurrent dreams.85 However, the maintained cessation of recurrent dreaming may reflect an upturn in well-being.86 Case studies have been described in which progressive changes in repetitive dream elements occur as a function of successful psychotherapy.87 Treatment A wide variety of treatments for nightmares has been reported.88,89 Although psychotherapy aimed at resolving conflict has traditionally been the treatment of choice,90 it lacks empirical support. On the other hand, there is much
CHAPTER 97 • Idiopathic Nightmares and Dream Disturbances Associated with Sleep–Wake Transitions 1111
Table 97-4 Treatment Recommendations for Nightmares Level A: Supported by a substantial amount of high-grade evidence and/or based on a consensus of clinical judgment
Image Rehearsal Therapy (IRT)
Level B: Supported by a sparse amount of high-grade evidence or a substantial amount of low-grade data and/or clinical consensus by task force
Systematic Desensitization Progressive Deep Muscle Relaxation training
Level C: Supported by low-grade data without volume to recommend more highly; likely subject to revision with further studies
Lucid Dreaming Therapy Self-Exposure Therapy
Recommendations adapted from Aurora RN, Zak RS, Auerbach SH, et al. AASM Standards of Practice Committee. Best practice guide lines for the treatment of nightmare disorders in adults. J Clin Sleep Med 2010;6:389-401.
support for diverse cognitive behavior interventions that require six or fewer sessions. Systematic desensitization and relaxation techniques, used to countercondition a relaxation response to anxiety-provoking nightmare contents, have been effective in several case studies and in two controlled studies.91 Imagery rehearsal, which teaches patients to change their remembered nightmares and to rehearse new scenarios, has reduced both nightmare distress and frequency.92 The rationale for this approach as well as the major steps covered in therapy have been summarized for clinicians.93 Other treatments with some empirical support are lucid dreaming,94,95 eye movement desensitization and reprocessing,96 and hypnosis.97 Treatment guidelines for nightmares associated with PTSD are reviewed in Box 129-9. Treatment guidelines for nightmare disorder are summarized in Table 97-4.97a
DREAM DISTURBANCES OF THE SLEEP–WAKE TRANSITION Several interrelated dream disturbances occur at the transitions into or out of sleep. These share the attributes of vivid, often intensely real, sensory imagery and disturbing affects such as fear. The distinctive reality quality might stem from an interleaving or boundary dissociation of sleep–wake processes at this time, such as intrusions of real perceptions into sleep or of dreamed objects or characters into wakefulness.98 The nature of the intruding components can determine the distinctiveness of the transition disturbance, including typical or odd combinations such as a frightening hypnagogic image terminating in a sleep start or incomprehensible sleeptalking accompanying sleep paralysis. Sleep Starts Sleep starts, also known as predormital or hypnic myoclonus and hypnagogic or hypnic jerks, are brief phasic contractions of the muscles of the legs, arms, face, or neck that occur at sleep onset. They are often associated with brief,
albeit vivid and forceful, dream events. Perhaps the most common of these events is the illusion of suddenly falling that incites a vigorous, startling jerk. Brief sensory flashes also occur; sometimes they are somatic and somewhat difficult to describe. Complex hypnagogic images can also occur. Mild starts are a normal—even universal—feature of falling asleep, with a prevalence as high as 60% to 70%.99 More-extreme starts can engender difficulties in initiating sleep.100 Sleep starts can bear a striking resemblance to exploding head syndrome101 in that the latter also occurs at sleep onset and produces sudden loud auditory sensations or bright light flashes, or both. Sounds are described variously as thunderclaps, clashes of cymbals, doors slamming, electric shocks, loud snaps, bomblike explosions, and so forth.101 In a sample of 50 patients, 10% reported a concurrent flash of light, 6% reported the curious sensation of stopped breathing and having to make an “uncomfortable gasp” to start again, and 94% reported fear, terror, palpitations, or forceful heartbeats as an aftereffect.101 It is not known whether chronic sleep starts are primarily a disturbance of motor systems, perhaps akin to PLMS, with epiphenomenal imagery, or a disturbance of imagery systems per se, such that gripping images provoke the disruptive reflex activity. EEG events have been noted to accompany sleep starts102; however, more systematic studies of the variety of EEG burst patterns accompanying drowsiness103 are needed. Terrifying Hypnagogic Hallucinations Terrifying hypnagogic hallucinations (THHs) are terrifying dreams similar to those from REM sleep; after a sudden awakening at sleep onset there is prompt recall of frightening content.99 Because they arise from sleep-onset REM (SOREM) episodes, they may be aggravated by factors that predispose to this type of sleep, for example, withdrawal from REM-suppressant medication, chronic sleep deprivation, sleep fragmentation, or narcolepsy. Other sleep and medical disorders can accompany the condition. Content analyses of THHs are lacking, but clinical and anecdotal reports suggest that the themes of attack and aggression also found in REM sleep nightmares are common. THHs are perhaps more anxiety provoking than most nightmares because of a vivid sense of reality related to their close proximity to wakefulness and because of frequently accompanying feelings of paralysis. These features are illustrated in the case example.
Case Study A 36-year-old woman with PTSD had severe THHs. At age 19 years, she was abducted and sexually and physically abused for more than 3 days by motorcycle gang members. She regularly re-experienced these horrors through flashbacks and nightmares, but even worse were the THHs with paralysis occurring as she returned to sleep after a nightmare. She felt as if she were awake, aroused and terrified, yet unable to move; time seemed to pass in slow motion during these “replays.”104
1112 PART II / Section 12 • Parasomnias
The suffering during such episodes is exacerbated by the patient’s simultaneous sense of wakefulness and inability to move or call for help. Further, the intense anxiety associated with recurrent THHs can disrupt sleep onset sufficiently to produce sleep-onset insomnia.99 Prevalence figures for THHs are not available, but an estimate for patients with narcolepsy is 4% to 8%.105 Isolated Sleep Paralysis Isolated sleep paralysis (ISP) consists of episodes of muscle paralysis with clear consciousness that occurs at sleep onset or upon transitions into wakefulness. Physiologic mechanisms of ISP have been studied in some detail,106 but the relationship of ISP to nightmares requires further study. For example, nightmare subjects rate their own home dreams to contain significantly more feelings of inhibition or ineffectuality than do control subjects.41 Patients seldom present for symptoms of ISP alone, but they might when the frequency of their episodes increases, for example, to one per day. Frightening sleep paralysis episodes have also been referred to as sleep paralysis nightmares, and their role in the misdiagnosis of hysteria and allegations of abuse have been described.107 Etiology Although psychopathology does not seem to be a direct cause of ISP,108 associations have been reported between ISP and psychopathologies such as social anxiety,109 panic disorder110 and depression.111 Psychopathologic factors might influence ISP indirectly by their influence on stress and overwork and subsequent disruptive effects on sleep108 or by modulating vigilance levels during sleep disruption.112 Sleep-related life habits are also associated with ISP occurrence in nonnarcoleptic populations,113 for example, poor sleep quality, insufficient sleep, and a proclivity to daytime sleep—all factors that can favor the occurrence of SOREM episodes.113 In fact, ISP episodes have been elicited experimentally by a schedule of sleep interruptions producing SOREM.112 Other mediating factors may be phase advance or rapid resetting of the circadian clock, as is the case with jet lag,114 or sleeping in the supine position.108 However, daytime imaginativeness, as indexed by standardized questionnaires, and vividness of nighttime imagery, as measured by selfreported frequencies of nightmares and sleep terrors and dream vividness, are personality factors most predictive of ISPs in a large college student cohort.108 ISP is typically accompanied by vivid hypnagogic hallucinations. In fact, it is rare to find ISP in the absence of other hallucinatory activity. Only 1.6% (of 387) subjects experienced ISP without other attributes.108 Of six experimentally elicited ISP episodes, all but one included auditory or visual hallucinations and unpleasant emotions.115 Conversely, it is not true that most hypnagogic hallucinations are accompanied by sleep paralysis. Given this association of sleep paralysis with hypnagogic hallucinations, it is unclear whether sleep paralysis is, as some have suggested,116 a type of perception, that is, of ongoing REM sleep muscle atonia. Rather, paralysis sensations may be dreamed, which could account for why the episodes are often reported to be accompanied by odd feelings of oppression, pressure on the chest, or being beaten or choked violently. It could also
explain how paralysis and felt ineffectuality appear routinely and in such variety in normal dreams and nightmares.12 Prevalence Multiple ISP episodes have a low prevalence, occurring “often or always” in 0% to 1% of young adults and “at least sometimes” in 7% to 8% of young adults.105 On the other hand, the ICSD-R99 cites the lifetime prevalence at 40% to 50%, which is somewhat higher than other estimates. We found rates of 25% to 36% among three university student cohorts, which is similar to the 26% reported for 208 Japanese undergraduates,117 the 21% for 1798 Canadian undergraduates,108 and the 34% for 200 sleep-disorder patients. Use on questionnaires of a culturally identifiable term for sleep paralysis, such as kanashibari in Japan, can increase the prevalence estimate by an additional 8%117; the adjusted estimate of 39% corresponds well with estimates from other cultures, such as 37% of 603 Hong Kong undergraduates reporting at least one episode of ghost oppression, the Chinese equivalent of kanashibari.118 One survey of Newfoundland villagers found as many as 62% admitting to old hag attacks.119 Somniloquy with Dream Content Sleeptalking has been observed in all stages of sleep, but especially in non-REM (NREM) stages 2, 3, and 4.120 Arkin120 identified various orders of concordance between sleep-speech and later dream reports. For first-order concordances, sleep-speech exactly matches content in the dream; for example, a subject shouting “No! No!” who dreamed of shouting these words when seeing her baby fall from the bed. For second-order concordances, a conceptual or emotional link between sleep-speech and the dream is preserved; for example, a nightmare patient dreamed repeatedly of trying to yell “Burglars!” but in reality called out “Mama!” Absence of concordance is also seen: One study of 28 chronic sleeptalkers found it in 16.7% of REM, 32.9% of stage 2, and 38.5% of stage 3-4 sleep somniloquy episodes.120 As with sleep paralysis, it remains unknown why imagery and behavior are dissociated in this manner. False Awakening False awakenings are nowhere classified as pathologic, but they can nonetheless produce anxious reactions. Two types of false awakening have been distinguished primarily on the basis of the degree of anxious affect associated.121 Both types usually consist of dream imagery in which the person is (falsely) waking up from sleep or, in variations, from a dream and can engender some confusion while dreaming as to whether one is actually awake or asleep. Both are also often associated with experienced separation from the sleeping body, or out-of-body experience, and of becoming aware of dreaming while dreaming, or lucid dreaming.121 Type 1 awakenings are the more common type and usually depict realistic instances of the person waking up in his or her habitual bed followed by, in many cases, depictions of activities such as dressing, eating breakfast, and setting off for work. Some discrepancy in the imagery might fully awaken the person with the surprising realization that it was just a dream. The dreams are often repetitive, depicting a succession of awakenings or of setting off for work.
CHAPTER 97 • Idiopathic Nightmares and Dream Disturbances Associated with Sleep–Wake Transitions 1113
Type 2 false awakenings are less pleasant than type 1 in that the apparent awakenings in bed are accompanied by a “stressed, electrified, or tense” atmosphere and feelings of “foreboding or expectancy” that may be “apprehensive or oppressively ominous.”121 There may be hallucinations of ominous or anxiety-provoking sounds or strange apparitions of persons or monsters. False awakenings are clearly not always about a person’s own home and bed because instances have been elicited in laboratory subjects that incorporated the laboratory bed and setting.122 Pathologic and Disturbed Lucid Dreaming Lucid dreaming is occasionally associated with disturbed or pathologic reactions. Typically, lucid dreaming is perceptually vivid—the dreamer often feels awake—with a limited capacity to control the unfolding of some dreamed events. It is often spontaneously triggered within a nightmare and can be used in a therapy context to resolve the distressing contents of recurrent nightmares.94 However, some have reported diverse negative reactions associated with lucid dreaming, including a type of burnout resulting from too frequent intentional use of the mental state, mental confusion, and “quasi-psychotic splits with reality” induced by the overlapping of perceptual and dreamlike mentation, and intense fear associated with the loss of control of the vivid dream contents.123 ❖ Clinical Pearl The diagnosis and treatment plan for a great many sleep problems can be enhanced by querying patients during the clinical interview about the nature of their dreams and nightmares and whether they have changed quantitatively or qualitatively since the onset of symptoms. For example, distressing nightmares are often symptomatic of a more general anxiety problem.
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107. Powell RA, Nielsen TA. Was Anna O.’s black snake hallucination a sleep paralysis nightmare? Dreams, memories, and trauma. Psychiatry 1998;61:239-241. 108. Spanos NP, DuBreuil C, McNulty SA, et al. The frequency and correlates of sleep paralysis in a university sample. J Res Pers 1995;29:285-305. 109. Simard V, Nielsen TA. Sensed presence as a possible manifestation of social anxiety. Dreaming 2005;15:245-260. 110. Mellman TA, Aigbogun N, Graves RE, et al. Sleep paralysis and trauma, psychiatric symptoms and disorders in an adult African American population attending primary medical care. Depress Anxiety 2008;25:435-440. 111. Szklo-Coxe M, Young T, Finn L, et al. Depression: relationships to sleep paralysis and other sleep disturbances in a community sample. J Sleep Res 2007;16:297-312. 112. Takeuchi T, Fukuda K, Sasaki Y, et al. Factors related to the occurrence of isolated sleep paralysis elicited during a multi-phasic sleep– wake schedule. Sleep 2002;25:89-96. 113. Takeuchi T, Fukuda K, Yamamoto Y, et al. What kind of sleeprelated life style affects the occurrence of sleep paralysis in normal individuals? Sleep Res 1997;26:518. 114. Snyder S. Isolated sleep paralysis after rapid time zone change (“jet lag”) syndrome. Chronobiology 1983;10:377-379. 115. Takeuchi T, Miyasita A, Sasaki Y, et al. Isolated sleep paralysis elicited by sleep interruption. Sleep 1992;15:217-225. 116. Giaquinto S, Pompeiano O, Somogyi I. Supraspinal inhibitory control of spinal reflexes during natural sleep. Experientia 1963;19:652-653. 117. Fukuda K. One explanatory basis for the discrepancy of reported prevalences of sleep paralysis among healthy respondents. Percept Mot Skills 1993;77:803-807. 118. Wing YK, Lee ST, Chen CN. Sleep paralysis in Chinese: ghost oppression phenomenon in Hong Kong. Sleep 1994;17:609613. 119. Ness RC. The Old Hag phenomenon as sleep paralysis: a biocultural interpretation. Cult Med Psychiat 1978;2:15-39. 120. Arkin AM. Sleep-talking: psychology and psychophysiology. Hillsdale, NJ: Lawrence Erlbaum; 1981. 121. Green C, McCreery C. Lucid dreaming. The paradox of consciousness during sleep. London: Routledge; 1994. 122. Nielsen TA, Montplaisir J. REM sleep hallucinatory episodes induced by somatic stimulation: a phenomenological report. Tenth Congress of the European Sleep Research Society. Strasbourg, France, May 1990. 123. Gackenbach J, Bosveld J. Control your dreams. New York: Harper & Row; 1989.
Disturbed Dreaming as a Factor in Medical Conditions Tore Nielsen Abstract Disturbed dreaming has been identified as a primary or secondary symptom in many medical conditions. The quality of such dreaming can be conveniently classified as varying along a continuum of subjective intensity. At one extreme, dream recall ceases entirely (global cessation of dreaming) or is unusually impoverished in quantity or content (dream impoverishment). Impoverishment affects patients with alexithymia, posttraumatic stress disorder (PTSD), and some brain syndromes. At the other extreme, dreaming is profuse and vivid (excessive dreaming), affecting patients with epic dreaming, some brain lesions, and withdrawal from some medications, or it becomes so intense that it is confused with reality (dream– reality confusion) as is the case with bereavement or the
Beyond common nightmares (see Chapter 97), dreaming disturbances appear as defining or comorbid symptoms of many medical conditions (Table 98-1). In this chapter, these disturbances are classified as falling along a continuum of increasing vividness or intensity, particularly of the apparent reality of the dream experience. At the lower extreme of this continuum, dream recall can cease or the realism of dream content can become impoverished in some respect. At the higher extreme, dream recall can become excessive or dream content unusually vivid and emotional, often being confused with reality or rigidly repetitive in structure. The full range of human emotions, be they dysphoric or euphoric, can appear in disturbed dreams (Fig. 98-1). The intensity dimension of disturbance varies globally in how intensely real the dream experience appears. As described in Chapter 51, reality simulation is widely viewed to be a basic function of the dream-production mechanism, approximating both the process and the contents of typical waking experience. One notable feature of this mechanism is the heightening of perception-like imagery or emotion to the point of equaling or exceeding what is normally perceived or felt during wakefulness. A second notable feature is the increased presence of episodic memory material in dream content. Such material is usually restricted to mere fragments of remembered (episodic) experience (see Chapter 55), but it can become more salient in replay nightmares (see Chapter 53), repetitive dreams, and so forth. Both of these features are likely in play during the most extremely intense dreams, such as those occurring in intensive care unit delirium or dream-reality confusion.
GLOBAL CESSATION OF DREAMING About a third of patients with neurologic illnesses report having ceased dreaming altogether.1 Solms1 and Doricchi2 report that parietal lobe involvement differentiates patients 1116
Chapter
98
postpartum state, intensive care unit (ICU) delirium, limbic lobe damage, and psychotic states. Intense dreaming may become rigidly repetitive (repetitive dream content). Conditions such as rapid eye movement (REM) sleep behavior disorder with or without parkinsonism, epilepsy, PTSD, migraine, and cardiac illness are affected by dream repetition. The intensity dimension of dream disturbance appears to mirror various aberrations of dreaming’s normal capacity to simulate reality. Accordingly, episodic memories, which are normally absent from dream content, appear more frequently in disturbed dreams. Although effective treatments are available for several common dream disturbances, the development of new treatments might benefit from attention to intensified reality simulation and the role of episodic memory activation.
with and without global cessation of dreaming (GCD); 42% of GCD patients have parietal lesions and an additional 7% have lesions in proximity to parietal lobe.1 Frontal lobe lesions characterize some patients (8%) with GCD,1 which is consistent with the reduced dream recall that follows upon frontal lobotomy3 (but see reference 2). An additional 43% of GCD patients have diffuse and nonlocalizable lesions.1 It is noteworthy, however, that few such patients are subjected to rigorous REM sleep awakenings to determine whether the capacity for dream recall under optimal conditions is, in fact, absent. Such studies might reveal that many patients who appear to have GCD instead have dream impoverishment.
IMPOVERISHED DREAMING Dream impoverishment is an attenuation, but not total cessation, in the recall, length, vividness, emotionality, or narrative complexity of dream imagery. Impoverished dreaming has been documented for some types of brain syndromes, for patients with alexithymia, and for patients with posttraumatic stress disorder (PTSD), who also have a high incidence of comorbid alexithymia.4 Impoverished Dreaming in Brain Syndromes In chronic brain syndrome, dream recall from REM sleep deteriorates as the illness progresses from mild (57% recall) to severe (35%) to aged and severe (8%).5 In patients with Korsakoff’s psychosis caused by chronic alcohol abuse, near-normal REM sleep time (29.4%) but poor dream recall (3%) is observed.6 Patients who have permanent amnesia for recent events due to mild encephalitis also have impoverished dreaming; the frequency of their REM awakening reports (28%) is less than normal (75%), and the reported dream content is simple, nonsymbolic and repetitious, stereotyped, and lacking in emotions and day residues.7 Impoverished dream recall has been noted
CHAPTER 98 • Disturbed Dreaming as a Factor in Medical Conditions 1117
Table 98-1 Medical Conditions in which Dreaming is Disturbed DISTURBANCE
CONDITIONS COMMONLY AFFECTED
ESSENTIAL FEATURES
Global cessation of dreaming
Neurologic illness Parietal lobe lesions Frontal lobotomy
Complete loss of dream recall; often sudden onset consequent upon illness or medical procedure
Impoverished dreaming
Brain syndromes Alexithymia PTSD
Reduction in recall, vividness, or complexity of dreaming
Excessive dreaming
Epic dreaming Brain damage Drug withdrawal
Dreaming seems to continue throughout the sleep period; can involve dream vivification or banal or repetitive dream content
Repetitive dream content
RBD/parkinsonism Epilepsy PTSD Migraine Cardiac disease
Frequent recurrence of repetitive or episodic memory content, e.g., features of prior trauma, epileptic aura, or cardiac symptoms
Dream–reality confusion
Bereavement Postpartum state ICU delirium Psychotic and near-psychotic states
Dream vivification; banal episodic content may be confused with actual events
ICU, intensive care unit; PTSD, posttraumatic stress disorder; RBD, REM sleep behavior disorder.
Intensification Positive affect
Dream repetition
Dreamreality confusion
Impoverishment
At
te
nu
at
io
n
Excessive dreaming
Global cessation
Negative affect Figure 98-1 Dream disturbances may be conceptualized as falling along a continuum that captures variations in dreaming’s natural capacity to simulate waking-state experiences of reality (see Chapter 51 for discussion). On the x-axis, disruption of reality simulation during dreaming varies from one extreme of attenuation, associated with cessation and impoverishment of dreaming, to the opposite extreme of intensification (vivification), associated with excessive dreaming, content repetition, and complete confusion of dreaming with reality. On the y-axis, the reality simulation capacity is largely independent of the emotions represented in the dream, which can vary from positive to neutral to negative. However, the intensity of dreamed emotions likely does co-vary with the intensification of reality simulation.
following left8 but not right9 hemispherectomy and supports the more general conclusion10 that left hemisphere processes are more critical for dream generation than are right hemisphere processes. Impoverished Dreaming in Alexithymia Alexithymia refers to a difficulty in verbalizing emotions, literally, to a lack of a lexicon for describing feelings. Early investigations of patients who have psychosomatic disor-
ders linked an alexithymic response style with diminished dream recall11 and an absence of affect in dreams.12 Reduced dream recall among alexithymic patients has since been replicated and linked with the difficulty identifying feelings subscale.13,14,14a One study of subjects with nocturnal asthma15—a population in whom comorbid alexithymia is common—revealed that REM sleep awakenings produced an elevated incidence of impoverished dreaming, especially dreams reported with short sentences and the frequent impression of dreaming but without recall of specific contents. Studies have reported evidence that specific sensory and structural features in dreams are impoverished among alexithymic patients. One study found that alexithymic patients reported colorless dreams16 and a second found that subjects with nonclinical alexithymia had less fantastic dream content than did controls but did not differ on other measures of dream recall and emotion.17 Sleep studies have not yet identified a consistent pattern of changes that might explain dream impoverishment. In one study,18 higher alexithymia scores were associated with more frequent REM episodes, shorter REM latencies, and more stage 1 sleep during and immediately after REM sleep. However, alexithymia was also related to increased NREM stage 1 and decreased NREM stages 3 and 4. In a second study,19 alexithymia scores did not correlate with any polysomnographic variable or with REM density; however, an association with shortened REM latencies was observed. Finally, alexithymia is reliably associated with certain sleep disorders, including chronic insomnia and parasomnias.16 In sum, although converging evidence indicates that dream impoverishment is associated with alexithymia, more research is needed to clarify relationships between alexithymic factors and various attributes of dream recall, content, and emotion and sleep polysomnography. It also bears noting that other patterns of disturbed dreaming characterize some alexithymic patients, such as dreams that are extremely macabre, nightmarish, or lacking in ego and
1118 PART II / Section 12 • Parasomnias
emotional control.20 A similar paradoxical combination of both impoverished and nightmarish dreams is also found among some PTSD patients. Impoverished Dreaming in PTSD In contrast to the high prevalence of nightmares in PTSD (see Chapter 53), one long-term consequence of PTSD appears to be impoverishment of some dreaming attributes (for review see reference 21). Both home and laboratory studies indicate that PTSD patients have lower than normal levels of dream recall and that dreams tend to be brief, to deal with trivial daily events, and to be associated with paradoxically high REM densities.22 One laboratory study of disturbed dreamers found dream recall 42% to 54% of the time compared with 89% to 96% for controls.22 Similarly, a group of 12 “well-adjusted” PTSD patients had a lower dream-recall rate from REM sleep (33.7%) than did 11 less-adjusted (50.5%) and 10 control (80%) subjects.23 Well-adjusted patients reported less complex, less salient dreams; fewer dreams with anxiety, aggression, and conflict; and higher denial of emotions toward their dreams. In contrast, a few studies failed to demonstrate reduced dream recall in PTSD patients24,25 although one has reported that laboratory dream recall is negatively correlated with trauma severity.25 Two, likely interrelated, explanations for these findings have been suggested. First, dream impoverishment in PTSD might reflect an adaptive response or strategy that reduces dream recall and thereby suppresses the occurrence of nightmares.23 Second, mechanisms producing dream impoverishment in alexithymia might also be implicated in PTSD because of its high incidence of comorbidity with alexithymia4; up to 85% of PTSD patients may be alexithymic.26 Hyperarousal and emotional numbing may be common to the etiologies of both conditions. Emotional numbing (considered equivalent to alexithymia in PTSD4) is best predicted by the number of hyperarousal symptoms in PTSD patients.27 PTSD patients might expend so much cognitive, behavioral, and emotional effort on managing hyperarousal and reactivity that they exhaust their emotional resources including, possibly, a depletion of catecholamines.28
EXCESSIVE DREAMING Several conditions are characterized by dreams that are excessively abundant or intense. Epic dreaming refers to complaints of excessive dreaming combined with daytime fatigue.29,30 Patients complain of dreaming all night long about continuous physical activity, often of a banal nature, such as repetitive housework or endless walking through snow or mud. Sensations of acceleration or spinning are also reported. Such dreams occur nightly in 90% of affected patients, and comorbid nightmares are reported by 70%.29 Unlike nightmares, however, epic dreams can lack vivid emotion altogether. The endless dreaming and feelings of fatigue can produce distress, which leads the dreamer to seek medical consultation. No clinical abnormalities have been observed, leaving its etiology and pathophysiology unclear. Cognitive, relaxation, and drug-based treatments and hypnosis have proved ineffective.29 Comparative
studies of epic dreams and nightmares might clarify whether their repetitive motor imagery is a type of nightmare stripped of its emotions. Excessive dreaming characterizes some patients with brain lesions1 and includes increases in both dream frequency and vividness.31 Some patients also report dreaming the same content throughout the night, despite intervening episodes of wakefulness.1,31 Neuropsychological evidence suggests anterior limbic system involvement. Excessive, vivid, and early-onset dreaming can also appear after withdrawal from certain medications such as tricyclic antidepressants32 and short half-life serotonin reuptake inhibitors such as paroxetine or fluvoxamine (see Chapter 48).33
REPETITIVE DREAM CONTENT Dream content repeats itself so often that a repetition dimension of dreaming has been postulated.34 The recurring emotions and themes of nightmares and other typical dreams exemplify this. Here, I consider mainly dreams that occur in conjunction with a medical condition and for which their content, structure, or affective quality has become so highly repetitive that it causes patients distress. Neurobiological and psychological features of the concomitant medical condition are widely thought to shape the repetitive content of such dreams. Assault and Defense Dreams in REM Sleep Behavior Disorder and Parkinsonism REM sleep behavior disorder (RBD) is characterized by sleep-related motor activity that appears to enact the patient’s ongoing dream or nightmare.35,36 Dreamenacting activities were reported by 93%, 87%, 82%, and 64% of patients in four large samples (N = 93, 96, 91, and 52, respectively). Polysomnographic (PSG) evidence suggests that RBD patients do not enact all of their REM dreams, although their partial enactment is suggested by elevated levels of muscle tone (e.g., submentalis37). Patients do not always recall dream content for specific episodes, possibly because most patients are elderly and have reduced dream recall or because some of the dreams lack salience. Nonetheless, a majority of patients report retrospectively that their dreams are more vivid, violent, action-filled, and nightmarish since the onset of their RBD.38 Clonazepam suppresses dream-enacting behavior and the disturbing dreams accompanying them.39 Pramepexole and melatonin have limited effects; melatonin appears to re-establish REM atonia.40 Although a panoply of dream-enacting activities has been reported, associated dream themes are largely repetitive in their structure and emotional content.41,42 This is shown in Table 98-2, which summarizes examples of dreams for which specific enacting activities have been identified by authors. The most common repetitive pattern is that of imminent threat (29/37 or 78.4%), to which patients reacted with vigorous defensive actions (19/29 or 65.5%), attempts to escape (24.1%), or unspecified reactions (10.3%). Most threats (16/29 or 55.2%) were from humans; the rest were from animals (37.9%) or machines (6.9%). Six (6/37 or 16.2%) pleasurable dreams were also
77
Case 1
Mahowald, 2000
N/S
62
—
Husain, 2001103
—
N/S
—
Boeve 2004102
Mahowald, 200041
74
—
M
M
M
N/S
M
—
—
—
—
—
Defend wife from an aggressor
Flying above some trees, he swoops down to answer a ringing phone on a table. As he lands, someone hits him and he jumps away
Pleasurable dream of fishing
Fighting animals in a cave
Being chased by a big black dog
Tried to kick someone high up who had stolen backpacking gear
(same)
“Swimming, floating on my back and then decided … to do … a flip, under the water”
Riding a bicycle, chased by a dog, tried to kick it in the shins
—
“A cat was biting me, and I was squeezing it”
Standing on the wing of an aircraft, hollered and dove off head-first to avoid being struck by the wing of a 2nd aircraft
Wrestling with someone
(same)
M
—
—
Walking down hall of a hospital, thought woman with bottle in hand was about to throw acid at him, went to throw himself through a door
Being chased down a stairway, rounded a corner, tried to pivot around (like around a pole)
70
—
M
M
—
(same)
67
65
—
(same)
—
(same)
M
Trying to hit someone on the other side of a screen door who kept dodging his blows
67
Killing a 6-inch long cockroach
—
—
“Something … was moving and I struck out at it”
Ice skating with his father; his father fell and patient had to jump over him
M
—
“I was arguing and kicking this dog who was growling”
(same)
72
—
M
—
“In a car … started to move backwards … about to go down a ramp. I jumped out of the car to try to stop its movement [by pushing on it]”
Trying to run down the river
75
—
M
—
“I was on a bicycle and turned around; there was a dog. I was angry and scared because I thought he wanted to bite me. I started to chase him away by kicking him”
DREAM CONTENTS
Playing volleyball
65
—
M
—
DIAGNOSIS
(same)
51
—
Schenck, 2005101
M
SEX
(same)
64
AGE (YR)
—
SUBJECT
Fantini, 2009*
STUDY
Table 98-2 Summary of Published Accounts of Dream Enacting in REM Sleep Behavior Disorder
Struck wife in bed Continued
Quickly bolted out of the bed into the hallway
Sat on the edge of his bed as if holding a fishing pole
Passenger on a commercial flight exhibited punching and kicking
Got out of bed and ran into wall, hitting and cutting his eye
Kicked the wall and broke his big toe
Kicking his wife
Grabbed lamp by bed and banged it down on his foot
Fell out of bed and cut head
Squeezed own armpit so tightly it turned black and blue next day
Dove head-first over the end of the bed with blankets and pillows going with him; scraped head and ear against vanity
Had wife in a headlock
Jumped out of bed
Hit his wife with his fist
Jumped out of bed, hitting and cutting cheekbone on nightstand
Kicking legs in the air
Sitting up in bed, pushing out his arms
Stomping feet up and down on the bed
Kicked the poodle off the bed, causing it to yelp
Kicked the wall so hard he put a big hole in it
Jumped out of bed and was pushing against the bed
Kicking his wife, who woke him up
DREAM-ENACTING ACTIVITIES
CHAPTER 98 • Disturbed Dreaming as a Factor in Medical Conditions 1119
104
62
69
Case 1
Case 5
(same)
70
Patient 5
M
M
M
M
M
M
M
—
Shy-Drager syndrome
Treated for diabetes and hypertension
—
Parkinsonism
—
“I was dreaming of being caught and tied up by people who were going to beat me and I was terrified”
I was being beaten by someone I had never seen before and I wanted to get away
Threw something at a bear to stop it from chasing him
To prevent an alligator from getting into his car, he holds its snout with great force
A man had approached him at a party, yanked off his bowtie, threw it in some mud, stamped on it, irritating the patient, who retaliated by throwing punches with his right arm
Being in military combat, enemy soldiers above him, aiming their weapons and shooting through a circle made by his arms and clasped hands down into the ground, he sprang backward rapidly for safety
Chased by a lion and screams for help
Trying to stop his friends from beating their children
Saw Viet Cong soldiers in the trees outside house, then inside house; chased soldier
Someone wanted to shoot him
*Personal communication, 2009 N/S, not stated; PSG, polysomnography; PTSD, posttraumatic stress disorder.
Sforza, 1988112
Culebras, 1989111
69
73
79
45
Fig. 7
Mahowald, 1990110 MB
(same)
—
Chung, 1994109
PTSD
—
M
—
Coy, 1996108
61
—
Standing in a garden, she leaned forward to pat a child on the head
Sforza, 1997107
—
77
—
Morfis, 1997106
F
Surrounded by snakes, had to roll down a slope to escape
M
Defending herself against an enemy
Running for a touchdown, spikes a football in the end zone
DREAM CONTENTS
74
—
Lewy body disease
DIAGNOSIS
Case 2
F
M
SEX
Had won a mahjong game, stood up and walked away from table
72
70
Patient 1
Case 1
AGE (YR)
SUBJECT
(same)
Chiu, 1997105
Boeve, 1998
STUDY
Table 98-2 Summary of Published Accounts of Dream Enacting in REM Sleep Behavior Disorder—cont’d
Moved arms as if to tear someone away, then moved and raised arms and tried to lift legs; after 2 min made sudden body jerks, raised arms in searching and reaching gestures with vocalizations; episode ended in sudden body jerk
Made protective hand and arm movements, leg movements, lifted head and neck with eyes closed as if to avoid or escape something, vocalized, made fearful, pained grimaces
Threw bed covers
Woke up to wife’s shouting and “strongly grabbing her arm”
PSG revealed right arm twitching, chin activation, activation of four limbs, body lifting and repeated punching of the bed rail with the right arm, banging head on bed rail awakened patient
Patient had “flown over my night table about 4 feet and landed on the floor, cutting my left cheek just below the eye and causing a lengthy nosebleed”
Screamed aloud during REM sleep
Flailed arms, screamed, moved vigorously
Loaded a .22-caliber rifle, checked rooms, tripped over furniture and discharged weapon into his own foot
Talking and smiling, reaching for or picking up something, tried to sit up in bed screaming and sending someone away
Standing on the bed, fell to the floor, with laceration to forehead
Lying on floor with bruises and lacerations on head and limbs
Fell to ground and hit her head
Grabbed neck of screaming granddaughter and tried to strangle her
Held wife’s head in headlock, moved legs as if running, exclaimed “I’m gonna make that touchdown!” and attempted to throw wife’s head down toward foot of the bed
DREAM-ENACTING ACTIVITIES
1120 PART II / Section 12 • Parasomnias
CHAPTER 98 • Disturbed Dreaming as a Factor in Medical Conditions 1121
100
.064 .003
RBD Controls
.0001
Percent of dreams
80 .00001 60
40 .002 20
.088
.0001
.088
.077
Sex
Success
0 Animal
Self-neg
Neg-emot
Agg/Fr
Aggressor
Aggress
Friend
Figure 98-2 Dreams reported by 98 patients with REM sleep behavior disorder (RBD) exhibit more aggression and negativity and less prosocial behavior than dreams reported by 69 controls. Of nine content characteristics differentiating groups, RBD patients display more animal characters, self-negativity, negative emotions, aggressive versus friendly interactions, dreamer as aggressor, and dreams with at least one aggression. In contrast, they display fewer dreams with at least one friendly interaction, at least one sexual reference, and at least one success (From Fantini ML, Corona A, Clerici S, et al. Aggressive dream content without daytime aggressiveness in REM sleep behavior disorder. Neurology 2005;65:1010-1015.
Table 98-3 Dream Content Themes in Patients with Parkinson’s Disease RBD (N = 36)
NON-RBD (N = 84)
DREAM CONTENT
N
%
N
%
Chased by person
18
50.0*
7
8.3
22.2
7
8.3
38.9*
0
0.0 1.2
Chased by animal
8
Defense against attack by person
14
Defense against attack by person
4
8.3
1
Aggression by the dreamer
6
16.7*
1
1.2
Adventure or sports
6
16.7
9
10.7
Falling
10
27.8
17
20.2
Lost
8
22.2
15
17.9
Bizarre
3
8.3
5
6.0
Death
5
13.9
7
8.3
Enclosed space
8
22.2
16
19.0
Work related
9
25.0
18
21.4
16
44.4
38
45.2
9
25.0
27
32.1
66.7*
34
40.5
Family or daily activity Past Vivid dreams
24
RBD, REM sleep behavior disorder. *P < .01. From Borek LL, Kohn R, Friedman JH. Phenomenology of dreams in Parkinson’s disease. Mov Dis 2007;22:198-202.
reported. Similar results have been reported for a sample of 37 RBD patients reporting dreams to their physicians43: 89% were aggressive in nature and attacks were by humans for 57% of patients and by animals for 30%. Another study of RBD dream content (Table 98-3) reveals similar fractions (e.g., chase by humans, 50%; chase by animals, 22%).44 Although RBD patients report more dreams with aggressive interactions (especially self as aggressor) than
do controls (Fig. 98-2), they do not have higher scores on a daytime Aggression Questionnaire; in fact, they score lower than controls on physical aggressiveness.45 Dream aggression may be less prevalent for female RBD patients; compared with male RBD patients, their dreams are nonviolent, contain only fear (rather than anger and fear), and do not depict physical confrontation with an assailant.44 Samples of women studied to date are small, however.
1122 PART II / Section 12 • Parasomnias
The repetitive nature of RBD attack and defense dreams remains a source of speculation. One possibility is that the dreams are intensified instances of the most typical dream type, pursuit or assault dreams.46 Such intensification might result from increased levels of motor neuron activity or autonomic dysfunction. A growing literature links RBD with deficits in autonomic function, specifically, diffuse loss of innervation of cardiac sympathetic terminals47 and reduced REM sleep cardiac variability.48 Autonomic dysfunction might also explain patients’ nonaggressive waking dispositions. Another possibility is that a neurodegenerative process underlying many cases of RBD leads to the release of archaic dream patterns such as aggression and animal characters (see Fig. 98-2). It is also unknown how exactly RBD sleep activities reflect their associated dream contents. Reported dreams match activities in general respects (see Table 98-2), but in some cases dreamed and enacted actions differ subtly. For example, Schenck and Mahowald38 report that male patients often dream about repulsing attackers who are threatening their wives only to find on awakening that they themselves are attacking their wives. Such errors resemble cases of somnambulistic violence; for example, a patient dreamed of removing an attackers hands from his wife’s neck while he was in fact throttling her. Analyses of dream contents with video-verified behavioral episodes are clearly needed to clarify this issue. Parkinson’s Disease RBD is known to herald Parkinson’s disease (PD) and other synucleinopathic disorders such as dementia with Lewy bodies (DLB) and multiple system atrophy (MSA) by up to several years.38,49 The presence of RBD among patients with PD is a risk factor for subsequent hallucinations,49 and RBD with hallucinations can presage development of further cognitive impairments.50 Accordingly, vivid dreams, nightmares, dream enactment, and other parasomnias are common among synucleinopathy patients. Because altered dreaming is more prevalent if hallucinations are also part of the clinical portrait, it is possible that dreaming is implicated in the etiology of synucleinopathic hallucinations. Estimates of comorbid hallucination and dreaming in patients with PD is relatively high (e.g., 61.3%, 59%, and 48% in three studies). Laterality of brain dysfunction in PD correlates with both dreaming and hallucinations; patients with right hemisphere dysfunction exhibit both nocturnal hallucinations and more vivid dreaming relative to those with left hemisphere dysfunction.51 That RBD may be associated with development of hallucinations independent of PD severity52 supports the notion that REM mechanisms are implicated in the expression of both dreams and hallucinations. So too does the fact that more REM aberrations (e.g., fragmentation,53 reduced REM percentage54) occur among PD patients with hallucinations than among those without hallucinations. In fact, PD hallucinations and delirium episodes often correspond with brief daytime REM sleep episodes.55 Common treatments for Parkinson’s disease and other synucleinopathies (e.g., levodopa) might account for some alterations in dreaming,52 but the prevalence of altered dreaming after long-term levodopa treatment is only
31%,56 and dosage does not differ between patients who hallucinate and those who do not.57 Dream Repetition in Epilepsy Case studies1,58-60 demonstrate at least two ways episodic memories for seizure activity may be reflected during dreaming. First, epileptogenic features such as auras, phosphenes, or ictal imagery can appear in recurrent nocturnal dreams. Second, recurrent dream themes can appear in close proximity to later seizures. One laboratory study illustrates repetition of dream content that had been present as mental content in epileptic seizures,58 and thus might reflect episodic memories of those seizures. One patient reported in two of three recalled REM sleep dreams (out of 32 REM awakenings) and during seizures telling somebody else he was dying. A second patient reported in two of three recalled REM sleep dreams (six awakenings), in one of two end-of-night dreams (stage not specified), and in her seizures that she was “on a board” going over water and afraid of falling. Repetitive dreams unrelated to seizure content but nonetheless related to the disease have also been discussed.61 However, the existence or importance of such dreams is difficult to discern given the high prevalence of nightmares and nightmarish dreams in the general population46 and the predominance of fear as an ictal emotion.62 Dream repetition might derive from the same discharge pathways active during epileptic seizures; activity in these pathways is stereotyped in expression but changes spontaneously over time.63 Although one review of dream anomalies in epilepsy1 suggests that right hemisphere temporal structures might be a source of such patterning (i.e., right hemisphere involvement in 63% of cases, left hemisphere involvement in 11% of cases, bilateral involvement in 26% of cases), a PSG study of right hemisphere and left hemisphere epilepsy cases64 found few differences in dream content measures. REM sleep anomalies, such as rhythmic temporal epileptiform activity, might also be a source of dream repetition.58 Patients with temporal lobe epilepsy also display other types of dream disturbance. Dream impoverishment is suggested by the fact that laboratory recall is “spotty and confused, short in length and poorly detailed” in some patients.65, p. 370 They also have more unpleasant and higherintensity emotions than do controls,66 a pattern reminiscent of PTSD (see next section). Type of epileptic focus might play a role in such disturbances: Patients with complex partial seizures recall dreams on more days (55%) than do those with generalized seizures (25%), independent of side of epileptic focus, presence of brain lesion, or presence or absence of seizures on the day of recall.67 Medication use is also a potential confounder; medicated patients’ dreams are more vivid than nonmedicated patients’ or controls’ dreams.66 Re-experiencing Dreams in Posttraumatic Stress Disorder A high proportion of PTSD patients report re-experiencing their traumatic events through recurrent nightmares (see Chapter 53). PTSD patients with combat trauma are more likely to state that their nightmares exactly or almost exactly replicate an actual event compared with combat
CHAPTER 98 • Disturbed Dreaming as a Factor in Medical Conditions 1123
veterans who have nightmares but not a diagnosis of PTSD.68 To illustrate, a 45-year-old concentration camp survivor reported the same dream of a traumatic persecution that he had experienced at the age of 6 years (4 decades earlier) regardless of the REM or NREM sleep stage he awoke from.69 This re-experiencing phenomenon is one of the clearest examples of how episodic memories, normally minimized during dreaming, can become hyperactivated. Other aspects of PTSD dreams are treated in more detail in the earlier section “Impoverished Dreaming.” Migraine Dreams Dream repetition is prevalent among headache sufferers, particularly migraineurs. One study70 proposed criteria for defining three highly consistent dream patterns (horrifying nightmares, nostalgic technicolor, waking dreams) that could be useful in diagnosis. Criteria included recurrence, brilliant colors, occurrence at specific times of the patient’s life, particular emotional tones that carry over into waking, and, occasionally, carry-over in the form of hallucinations. Nightmares of terror are by far the most predominant theme (61% of dreams), although other dysphoric themes such as frustration, loss, incest, and outsized creatures also occur. Dreams that precede migraines contain more anger, misfortune, apprehension, and aggressive interactions than do dreams not preceding migraines.71 One source of the repetitive quality of migraine dreams may be similar to the neurophysiological sources suggested earlier for cases of epilepsy, i.e., the neurophysiological activities causing the migraine-related pain and negative emotion may also partially shape the formation of migraine dreams. Prodromal Cardiac Dreams A form of repetition is seen in the recurrent themes of prodromal dreams: dreams that are shaped by ongoing or occult medical conditions. Such dreams can manifest before overt symptoms appear, an occurrence that figured largely in the earliest days of medical science.72 Prodromal dream themes have been proposed for a number of specific illnesses, including gastrointestinal, pulmonary, gynecologic and obstetric, dental, and arthritic.73 In the case of patients with nonacute cardiac conditions, prodromal dreams were identified to accompany heart
function. This appeared as negative relationships between cardiac ejection fraction on the one hand and dreamed death references in men and separation references in women on the other.74 A number of other cardiac-related dream themes have been identified that are direct (e.g., pain or pressure in the arm, heart, chest, or neck), indirect (e.g., clutching or squeezing, references to death, blood, pain), or metaphoric (e.g., explosions) in nature.73 Patients sometimes have “killer dreams” before the occurrence of near-fatal cardiac events, despite the absence of telltale cardiovascular risk factors.75 Some examples appear in Table 98-4. Among men and women who had nightmares very often, the percentages of patients possessing both irregular heart rhythm and spasmodic chest pain were three and seven times higher, respectively, than among those who had nightmares very seldom or never.76
DREAM–REALITY CONFUSIONS As dream imagery grows increasingly vivid and intense, it also appears to more closely approximate real sensorimotor and emotional experience (reality simulation) and confusion between dreaming and reality can result. This intensification is common for nightmares and sleep paralysis attacks. Four other conditions are also characterized by dream–reality confusions. Existential Bereavement Dreams One category of realistic dreams, referred to as existential dreams, often culminate in intensely real endings that can awaken the sleeper.77 The heightened reality quality includes simulation of distressing emotions such as sadness, despair, or guilt; salient bodily feelings such as ineffectuality and paralysis; and failures in attaining goals. Themes often involve separation and loss and the appearance of deceased family figures. These distinguish existential dreams from typical nightmares. Their clinical importance is their appearance during bereavement, which involves a range of distressing emotions other than fear. Existential dreams are common for up to 5 years following a loss, whereas nightmares are more salient immediately after a loss.78 Postpartum Infant Peril Dreams Many new mothers experience vivid dreams of their infants in peril; the realism of these dreams is belied by the fact
Table 98-4 Prodromal Dream Themes in Patients Suffering Serious Cardiac Events CASE
AGE (YR)
SEX
DREAM CONTENT
CARDIAC SYMPTOMS
1
23
M
Dream that he was murdered with his father
Awoke (6 am) with crushing chest pain; cardiac arrest 1 hr later
2
38
M
Dream that he died in a car crash
Awoke (3 am) with severe chest pain and vomiting; presented with acute myocardial infarction 2 hr later
3
42
F
Dreamed that she was running away from the police
Awoke (4 am) with chest pain and shortness of breath; presented with acute myocardial infarction within 1 hr
4
52
M
Nightmare that his son, an illegal immigrant, died walking in the desert
Awoke (3 am) with chest pains; total occlusion of right coronary artery
From Parmar MS, Luque-Coqui AF. Killer dreams. Can J Cardiol 1998;14:1389-1391.
1124 PART II / Section 12 • Parasomnias
that they are often accompanied by behaviors such as searching, calling out, or crying while the woman is asleep.79 A common, highly realistic, theme that we have dubbed the BIB (baby-in-bed) dream type, is that the infant is lost in the bed and the mother, while still asleep, searches frantically for the child while crying, calling out in alarm, or touching her spouse. Peril dreams and sleep behavior are both prevalent and disturbing. Of women able to recall a dream of their infant, 63% report at least one peril dream associated with sleep behavior,79 41% report continuing anxiety after awakening, and 60% report needing to check on their infant. Sleep behaviors are predicted by self-reported sleep disruption and prior psychopathologic factors such as somnambulism, general psychopathology, and attachment disturbance.
average prevalence of 37% (range, 0% to 74%). Disturbed sleep can contribute to ICU dreams and to ICU psychosis more generally.88 Depending on circumstances, such as mechanical ventilation, ICU patients might sleep only a couple of hours a day.89 Their sleep displays extremely poor efficiency, with fragmentation, frequent arousals, prolonged sleep latencies, and a predominance of stages 1 and 2 over stages 3 and 4 or REM sleep.90 Circadian rhythm of melatonin is typically abolished.91 Because stage 1 sleep can account for as much as 40% of total sleep time (versus 5% in controls89), hypnagogic hallucinations may be more salient and enable vivid and frightening sleeponset dreams.92 Guillain-Barré syndrome patients in the ICU who report dreamlike hallucinations also have disrupted sleep with frequent sleep-onset REM periods.93
Intensive Care Unit Dream Delirium Dream intensification is reported by patients recovering from life-threatening conditions in the intensive care unit (ICU). They often report nightmares containing feelings of extreme horror, dread, or impending death and themes depicting their medical afflictions, agonizing treatments, isolation, dependency, and the real possibility of death. Many studies attest to their high prevalence, their alarming nature, and their potentially traumatizing long-term effects. For example, one 6-month follow-up study of 464 Portuguese ICU patients revealed that 51% recalled ICU dreams and nightmares.80 Of these, 14% claimed that the dreams and nightmares continue to disturb daily life 6 months later and they scored lower than normal on a health-related quality-of-life measure. The phenomenon is illustrated by a nightmare from a patient residing in an ICU for 28 days following a peripheral artery bypass graft surgery: “The staff was trying to kill me first in the hospital and ultimately moved me to a basement. … They were extracting my blood by force to sell it. … I was in fear of dying … I pleaded for my life.”81,p. 268 Clearly, such dreams are potentially traumatic—especially if there is persistent confusion of the dreams with reality. One evaluation of traumatic ICU experiences in 80 patients with acute respiratory distress revealed that nightmares are the most commonly remembered trauma (64% patients).82 They are described as “bizarre and extremely terrifying” and far more common than anxiety (41%), pain (40%), or respiratory distress (38%). On follow-up,83 ICU nightmares remain the most prevalent traumatic memory (75%) and predict the future development of PTSD. Length of stay in the ICU is the strongest predictor of ICU nightmares.84,85 Of 127 patients in the ICU for longer than 1 day, 18.1% reported nightmares and 14.2% reported hallucinations; of the 162 staying less than 1 day, the corresponding figures were 2.5% and 0.6%.85 Two thirds of patients premedicated with benzodiazepines later report postoperative dreams, and half of these are nightmares.86 Other contributing factors include pain, anxiety, noise, the inability to lie comfortably in bed, mechanical ventilation, and female gender.84 Vivid ICU dreams are part of the larger constellation of symptoms (e.g., delusions, hallucinations, disorientation, fluctuating consciousness)87 referred to as ICU delirium (ICU psychosis, ICU syndrome) and whose prevalence varies considerably. A review of 26 studies88 found an
Psychotic Dream-Related Aggression An extreme form of dream–reality confusion appears during psychotic episodes or among borderline psychotic patients. In fact, a hallmark of psychotic dreaming is the intensification of dreaming to the point that it is mistaken for reality and, during psychotic episodes, may be lived as a real event.94 Realistic dreams can precede violent psychotic acts, and they occasionally seem to play a causal role. For example, an authoritative dreamed voice might command a crime, or a person might act aggressively in response to being murdered repeatedly in his or her dreams.95,96 There are several reports of violent psychotic acts that follow from such extremely confusional dreams (see reference 97 for review). In one,98 a 53-yr-old “deranged” man attacked 10 young children in a church cafeteria with knives: “In my dreams, I heard a voice saying that my wish will be fulfilled and I will live only if I kill many people”; he told police that he heard the voice when awake as well. Hempel and colleagues96 report five persons with psychotic dream-related aggression; two were charged with homicide and three with violent assaults. All were relatively young (27 to 43 years old), suffered from paranoid psychosis, and typically awakened from their dreams agitated and hostile. Hempel and colleagues propose psychotic dreamrelated aggression (PDRA) as a nosologic category that distinguishes it from somnambulistic violence and other parasomnias.
TREATMENT The emotional—often bizarre—nature of disturbed dreaming in many conditions inclines patients toward reluctance in disclosing their dreams spontaneously to health professionals. It is also, unfortunately, the case that some medical practitioners do not fully appreciate the value of questioning patients about disturbed dreaming. Thus, opportunities for enhancing diagnosis and offering effective treatment may be lost. Additionally, effective patient–physician communication of dream disturbances may be mitigated by psychological, sociologic, and cultural factors. Some patients might have expressive difficulties, such as alexithymia, that hinder self-disclosure. Others might avoid speaking openly about dreams because they consider them to reflect a pathologic state of mind. Yet others may attribute spiritual significance to dreams,
CHAPTER 98 • Disturbed Dreaming as a Factor in Medical Conditions 1125
believing them to originate in the workings of malevolent spirits or other sacred figures. Some patients might thus feel guilt, shame, or embarrassment in revealing dreams with taboo or incriminating contents. Sleep specialists, by the simple fact that they are interested in sleep phenomena, are in a privileged position to help such patients reveal their dream problems and achieve some measure of relief from them. Sensitivity to factors that influence patients’ willingness to self-disclosure—especially within multicultural settings—can facilitate this goal. Successful treatment also depends upon proper identification of factors responsible for disturbing sleep and dreaming. Close scrutiny of medication regimens is vital because many agents are known or strongly suspected to alter the quality of sleep and dreams. Discontinuing or replacing these medications or adjusting their dosage could alleviate symptoms effectively. Similarly, state stress and anxiety are amenable to short-term interventions that can diminish symptoms rapidly. Evaluation of a patient’s sleep hygiene might also reveal behavior that produces sleep fragmentation and deprivation, both of which affect the quality of dreaming (see Chapter 52). Finally, personality variables such as alexithymia or depression are easily assessed and might suggest avenues for therapeutic intervention. Such factors are often amenable to cognitive behavior therapies, which are largely successful in treating nightmares and related dream disturbances. However, new therapies are under development. Their efficacy might benefit by addressing anomalies of the reality-simulation function of dreaming (intensification of perception-like and emotional features, emergence of episodic material in dream content) as these appear in several forms of disturbed dreaming.
❖ Clinical Pearl Assessment of changes in dreaming (including impoverishment or intensification) in a variety of medical conditions can reveal serious comorbid symptoms that can facilitate diagnosis and whose treatment can aid long-term prognosis.
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Sleep Bruxism
Chapter
Gilles Lavigne, Christiane Manzini, and Nelly T. Huynh
Abstract Sleep bruxism, characterized by teeth grinding or jaw clenching, causes tooth destruction, headache, orofacial pain, and jaw dysfunction. In the general population, 8% of adults are conscious of teeth grinding sounds during sleep, as are their sleep partners. The causes of sleep bruxism range from psychosocial factors (e.g., life stress, anxiety) to an excessive sleep arousal response. Clinical recognition is based on a current history of teeth grinding or a stiff or painful jaw upon
The most recent International Classification of Sleep Disorders1 categorizes sleep bruxism as a sleep-related movement disorder and defines it as an oral activity characterized by grinding or clenching of the teeth during sleep. Because it is probable that sleep bruxism differs in terms of etiology from daytime parafunctional jaw muscle activity,2 it should be distinguished from teeth clenching, bracing, or gnashing while awake.3 Teeth grinding and sleep bruxism frequency is reportedly variable over time; some patients go several nights or even weeks without bruxism episodes.2 However, in cases of moderate to severe sleep bruxism, teeth grinding is present every week.4 Patients with sleep bruxism typically experience either phasic (rhythmic) or tonic (sustained) motor activity in jaw muscles (e.g., the masseter and temporalis), with the variable presence of teeth grinding sounds.2,5 The element of sound is the major reason people seek consultation. Teeth-grinding sounds disrupt the bed partner’s sleep. Other reasons for seeking help are related to tooth wear, orofacial pain or temporal area headaches, and tooth hypersensitivity to cold air, beverages, and food. An absence of a medical cause is considered to be primary, or idiopathic sleep bruxism, whereas sleep bruxism associated with a medical condition is the secondary form (Boxes 99-1 and 99-2). The latter is noted after drug intake or withdrawal (e.g., neuroleptics that can induce oral tardive dyskinesia and grinding); this secondary form is classified as iatrogenic. Several orofacial activities are often concomitant: grimacing, chewing automatism, or excessive lip and tongue movements such as thrust or protrusion. In this chapter, the term sleep bruxism is used to denote teeth grinding and oromotor-related activities occurring during sleep, as reported by the bed partner or family, regardless of whether it occurs in the primary or secondary (iatrogenic) form.
ETIOLOGY Throughout the 20th century, support for different theories regarding the etiology of bruxism has swung like a pendulum; theories range from the role of peripheral dental occlusion,6 to a global explanation that includes personality style, the person’s capacity to adapt to life pres1128
99
awakening; tooth wear is often observed but is not a key element in diagnosis, because it can be inaccurate. Final confirmation of current sleep bruxism is made by polygraphic recording of jaw muscle activity, together with, when possible, audio and video signals to rule out common, but nonspecific, orofacial motor manifestations (e.g., myoclonus, tics, swallowing, somniloquy). Techniques for managing sleep bruxism include sleep improvements, relaxation techniques, oral devices (e.g., occlusal bite splint), and medications (e.g., muscle relaxants).
sures presented by the psychosocial environment, and neurochemical and homeostatic sleep maintenance versus arousal mechanisms associated with activity of the autonomic and motor nervous systems.2,6-11
EPIDEMIOLOGY AND RISK FACTORS Most studies and surveys reporting the prevalence (the number of positive cases at a given time) of sleep bruxism are based on self-reports of clenching during the daytime or both clenching and grinding during sleep. As yet, no longitudinal study using biological recordings has been conducted to estimate the fluctuation or persistence of sleep bruxism in a given person with respect to age. Moreover, many patients with sleep bruxism are not aware of grinding if they sleep alone or with a bed partner who sleeps deeply. The overall prevalence of awake clenching is approximately 20% of the adult population, with more women reporting their awareness of clenching than men.12 According to parents’ reports, the incidence of sleep grinding in children younger than 11 years is between 14% and 20%. Concomitant oral activity such as nail biting (onycophagia) is also noted in 9% to 28% of those reporting sleep bruxism, thumb sucking is seen in 21% of children, and snoring is heard in 14%.13,14 In adults, the prevalence of grinding drops with age, from 13% in those 18 to 29 years old to 3% in those 60 years and older, with a mean of 8%.15 No further gender differences have been noted. Caution is necessary in interpreting these numbers, however, because reduced incidence with age can result from inaccurate estimates due to the high prevalence of denture users in the older population (e.g., greater than 40% in some geographic areas). Several concomitant risk factors have been linked to sleep bruxism. Psychological factors such as anxiety, competitiveness, stress, and maladaptive or less-positive coping strategies16 have been associated with sleep bruxism, but some findings remain controversial.17,18 Restless legs syndrome is associated with sleep bruxism, but only in 10% of the RLS population. Survey results show sleep apnea to be a risk factor (significant low odds ratio), a finding to further validate.19,19a Regarding smoking as a risk factor, it remains to be determined whether the variance can be
CHAPTER 99 • Sleep Bruxism 1129
Box 99-1 Types of Bruxism Awake versus Sleep Time Awake Time Tooth clenching or tapping Jaw bracing without tooth contact (grinding is rarely noted during the daytime) Sleep Time Teeth grinding with phasic (rhythmical) or tonic (sustained) or mixed (both types) jaw muscle contractions Primary and Idiopathic versus Secondary and Iatrogenic Forms Primary and Idiopathic No known medical or dental causes Could be associated with exacerbating psychosocial factors in some patients Secondary Associated with a medical or psychiatric condition Could also be iatrogenic; see Box 99-2 Iatrogenic Following drug intake or withdrawal.
explained by the physiologic influences of nicotine or the perception of smoking as an oral habit.20 Another variable is the concomitant finding of orofacial pain or joint sound or lock at the temporomandibular level; patients with sleep bruxism are more at risk for pain and jaw limitation.21,22 For example, we found that half of patients with high incidence of sleep bruxism muscle activity reported mild pain in the morning, which was associated with a lower frequency of sleep bruxism episodes per hour of sleep than in matched controls.22-24 The prevalence of grinding noted in an institutionalized developmentally delayed population is similar to the figure reported in the general population.15,25 A study made of 5- to 18-year-old children with sleep bruxism, as confirmed in sleep laboratory, revealed a higher prevalence of attention behavior and somatic problems.26 Use of several medications or recreational drugs is also a risk factor for sleep bruxism (see Box 99-2).
PATHOPHYSIOLOGY No single mechanism or theory explains the pathophysiology of sleep bruxism.7,23,27 Rather, this motor activity is more likely to be the product of biological and psychosocial influences in a given person (Video 99-1). Bruxism
Box 99-2 Secondary or Iatrogenic Bruxism The following medical conditions and drug chemicals have been associated with or reported in literature with teeth grinding or bruxism-like orofacial motor activities.2,15,19,30,42-44,47,48,56,70-73,86-88,90 Not all associated bruxism is sleep related. Movement Disorders Oral tardive dyskinesia Oromandibular dystonia (Meige’s syndrome) Parkinson’s disease Tics: simple (grunting) and complex (Tourette’syndrome) Huntingdon’s disease Hemifacial spasm Sleep-Related Disorders Sleep fragmentary myoclonus: oromandibular, facial, lingual Sleep-disordered breathing: apnea, snoring Periodic limb movements REM sleep behavior disorder Epilepsy Night terrors Confusional awakening Neurologic or Psychiatric Disorders Cerebellar hemorrhage or infarct Olivopontocerebellar atrophy and Shy-Drager syndrome Coma Neurologic complications related to Whipple’s disease Mental health problems such as dementia, depression, developmental delay Chemical substance and medication related to secondary bruxism Iatrogenic bruxism (e.g., risk of initiation or exac erbation)
Chemical Substances with Abuse Potential Alcohol Nicotine (smoking) Caffeine (?) Cocaine (awake clenching) MDMA (3,4-menthylenedioxymethamphetamine [Ecstasy]) Medications Amphetamine Methylphemidate (Ritalin) for attention-deficit/hyperactivity disorder Antidopaminergic Haloperidol (Haldol) Antipsychotics Haloperidol (Haldol) Lithium (Lithane, etc.) Chlorpromazine (Thorazine) Antidepressants (Selective Serotonin Reuptake Inhibitors) Fluoxetine (Prozac) Sertraline (Zoloft) Citalopram (Celexa) Cardioactives Calcium Blocker Flunarizine (Sibelium, Cinnarizine) Antiarrythmic Flecainide (Tambocor)
1130 PART II / Section 12 • Parasomnias
probably results from a series of influences that do not obey a mechanistic model or the logic of an algorithm. Rhythmical Masticatory Muscle Activity during Sleep in Asymptomatic Sleepers Research involving the recording of masseter electromyographic EMG activity to assess rhythmic masticatory motor activity (RMMA) in the jaw-closer muscles found that about 60% of “normal” sleepers exhibited RMMA (three masseter muscle bursts or contractions within an episode, in the absence of teeth grinding) during sleep.28 In patients with somnambulism and sleep terrors, the term chewing automatism was used to describe the slow rhythmic masticatory activity.29 This term was later used in the identification of the orofacial activities noticed with the rapid eye movement (REM) behavior disorders.30 Phasic oromotor activity is associated with RMMA, and in sleep bruxism it is probably an extreme manifestation of an ongoing or natural activity during sleep. Stress and Psychosocial Influences Bruxism was associated with anxiety and hyperactivity, but strong evidence is absent.27 Rigorous evidence is lacking to support the notion that sleep bruxism is an anxiety-related disorder.17,19 However, patients with sleep bruxism seem to be more task-oriented as a result of their personality and coping style, as opposed to being in a pathologic stress or anxiety-related pattern. Findings in Sleep Studies comparing young, healthy patients who have sleep bruxism and control subjects have shown that the former demonstrate normal sleep organization and macrostructure.5,31-33 Their sleep latency, total sleep time, percentage of time spent in the various sleep stages, and number of awakenings are within normal limits. They also report a normal amount of time spent awake during the sleep period, and they demonstrate sleep efficiency that falls within the usual range of good sleepers (greater than 90%). Thus, they do not complain about sleeping poorly.32 Interestingly, and like episodes of sleep apnea in patients with that disorder, most sleep bruxism episodes (74%) were observed while sleepers were in the supine position.34 Sleep bruxism episodes are most often (greater than 80% of the time) scored in sleep stages 1 and 2,26,32,33,35 although the literature is confusing on this point.36 A high incidence of destructive sleep bruxism, scored from electroencephalographic (EEG) artifacts, was also previously reported in REM sleep36 in patients suffering from depression, and this probably represented secondary sleep bruxism. In sleep bruxism subjects, it was observed that approximately 10% to 25% of sleep bruxism occurred in REM.26,34,35 Most studies support the idea that rather than triggering sleep arousal, sleep bruxism is concomitant or secondary to cyclic alteration in sleep patterns. During sleep, every 20 to 60 seconds, an observable cyclic electroencephalographic-electrocardiographic-electromyographic (EEG-ECG-EMG) activation occurs, called the cyclic alternating pattern (CAP). Interestingly, close to 80% of sleep bruxism episodes have been observed in
association with the CAP, which may act as a resetting mechanism for physiologic functions in relation to sleep environment or endogenous factors.7,9,27,33 The association between sleep bruxism and CAP is supported by findings showing that more than 50% of sleep bruxism episodes occur in clusters (within 100 seconds) and that approximately 15% to 20% occur in the transition from deep sleep (stage 3-4) to REM sleep.33,37 These findings are also consistent with the observation that sleep bruxism is preceded by alpha EEG activity and is associated with a tachycardia.35,38 We have also noticed that RMMA or sleep bruxism episodes occur after physiologic events. In the minutes preceding RMMA or sleep bruxism episodes, there is a slight change in autonomic-cardiac sympathetic (increased) and parasympathetic (decreased) balance; then, at minus 4 seconds, there is a rise in EEG alpha and delta activity, followed by a tachycardia initiated one heartbeat before the onset of jaw-opener muscle activity, associated with a major rise in respiratory amplitude (big breath). About 800 msec later, the jaw-closer muscle contractions start.8,9,27,37,38 These findings support the concept that sleep bruxism is secondary to exaggerated transient motor and autonomic nervous system activation in relation to sleep arousals. Also, young and otherwise healthy patients with sleep bruxism show a normal rate of brief arousals (less than 14 per hour of sleep).35,39 To further explore the mechanism involved in initiating sudden RMMA or sleep bruxism, we developed an experimental model that could trigger arousals during sleep without inducing awakenings. The application of a brief vibrotactile stimulation induced frequent sleep arousals that were followed by RMMA in all patients with sleep bruxism, with teeth-grinding occurring in 86% of trials.40 We therefore suggest that sleep bruxism or teeth grinding is one of the events occurring along the sequence of physiologic activations associated with microarousals (Fig. 99-1).7,9,27,38 The role of cortical EEG activity in the genesis of sleep bruxism has also been studied. There is an increase in alpha and delta activity in the cascade of physiologic activations associated with microarousals.38 EEG K-complexes were not reported to be more frequent in the 60 seconds before sleep bruxism episodes, and, overall, patients with sleep bruxism had 40% fewer K-complex events than matched normals.41 This finding is contrary to previous reports based on studies made in the absence of comparison with normal sleepers. Indirect evidence further suggests that trigeminal motor excitability in patients with self-reported teeth grinding comes mainly under brainstem and not cortical influences.7,9,27 Oromotor Excitability There is little experimental evidence to support a role for the motor system as a primary factor in the genesis of sleep bruxism. At best, some very indirect information from animal physiologic studies may help us understand how the motor system is comodulated during sleep.7 For humans, as for animals, it has been suggested that fluctuations in the activity of the reticular motor area in relation to sleep onset and maintenance could be associated with brief periodic motor excitation.9,27
CHAPTER 99 • Sleep Bruxism 1131 CASCADE IN SB
Physiological activity (% occurence)
Time sequence
Heart
Brain
≈ –60 sec* ↑ Sympathetic tone ↓ Parasympathetic tone ≈ –4 sec ↑ Cortical EEG ↑ Heart rate (≈ 90%) ≈ –1 sec ↑ Breathing ↑ EMG activity
(≈ 80%)
SB onset (time 0)
?: Change in airway patency ?: If jaw protrusion ↑ EMG/RMMA
(100%)
≈ +3 sec
Management strategies A. Behavioral
Jaw opening muscles
Jaw closing muscles
C. Pharmacological ? Benzodiazepine ? Muscle relaxant ? Dopaminergic drugs ? Serotonin-related ? β-Blocker ? Botulinum toxin
?: Saliva Tooth grinding
(≈ 45%)
(≈ 60%) ≈ +5 to 15 sec Swallowing Laryngeal movements *at least 60 sec
Tooth contact
Oropharyngeal muscles
B. Orodental oral splint
Unknown mechanisms
Figure 99-1 Cascade of physiologic events in genesis of sleep bruxism and rhythmic masticatory muscle activity (left) and courses of action for management (right).
Catecholamines and Neurochemistry An early report on Parkinson’s disease linking the use of levodopa (l-dopa) to teeth grinding provided initial support for the suggestion that grinding may be related to dopaminergic brain-related neurotransmitters.2 Teeth grinding, as a manifestation of oromandibular tardive dyskinesia, was also reported for some schizophrenic patients being treated with neuroleptic drugs.42 From these reports, the association of dopamine with sleep bruxism pathophysiology appeared somewhat weak. These patients already had altered nigrostriatal neurons due to disease or to medication. Some evidence further suggests that catecholamines, such as dopamine and norepinephrine, might have a role in sleep bruxism pathophysiology.11,43,44 A controlled polysomnographic study of patients with sleep bruxism with the catecholamine precursor l-dopa revealed a modest reduction in sleep bruxism frequency in comparison to placebo.43 The use of a dopaminergic modest agonist, bromocriptine, in a double-blind control design (using domperidone, a peripheral dopamine blocker, to prevent side effects such as nausea or vomiting) failed to show either a reduction in sleep bruxism motor episodes or a change in dopamine striatal binding.44 The other catecholamine-related medication reported to reduce sleep bruxism and teeth grinding is propranolol, a beta-blocker.45 This medication was also associated with a reduction in daytime teeth grinding in two neuroleptictreated patients presenting with abnormal orofacial movements.46 However, a controlled study of young patients with sleep bruxism revealed that propranolol was not deleterious to their sleep and neither reduced teeth grinding nor influenced the frequency and duration of jaw muscle contraction.47 Also, when interpreting studies using specific pharmacologic agents in sleep bruxism, it should
be noted that other neurotransmitters (e.g., serotonin, cholecystokinin, gamma-aminobutyric acid) and drugs (e.g., selective serotonin reuptake inhibitors, dopamine antagonists, calcium channel inhibitors) exacerbate teeth grinding and rhythmic movement modulation (see Box 99-2).7,9,27,48 Genetics and Familial Predisposition As yet, no genetic markers have been found for transmitting sleep bruxism. It is, however, interesting that between 21% and 50% of patients with sleep bruxism have a firstdegree relative who ground his or her teeth in childhood.13,49 Furthermore, studies of monozygotic and dizygotic twins showed that sleep bruxism was more often observed in monozygotic twins.49,50 A concomitant finding in a recent Finnish study revealed that childhood sleep bruxism persisted in a large number of adults (greater than 86.9%).50 On the other hand, a twin study did not find any genetic correlation with sleep bruxism.51 Thus, the pattern of inheritance for sleep bruxism is unknown, and the role and influences of familial and environmental factors remain to be assessed.27,50 Possible Role of Local Factors It has been suggested that tooth occlusal or morphologic interferences were responsible for teeth grinding. Although this concept of a peripheral cause for sleep bruxism is still reported in the literature, it remains controversial.6,27,52-54 On the basis of noncontrolled evidence, tooth contact is not a dominant activity in a 24-hour cycle; it has been estimated to occur for approximately 17.5 minutes per 24 hours.55 Moreover, during sleep, oromotor muscle activity related to sleep bruxism is present for approximately 8 minutes (about 2% of sleep time) over a 7- to 8-hour sleep period and does not always occur with tooth contact; grinding sounds are reported in approximately 44% of
1132 PART II / Section 12 • Parasomnias
sleep bruxism or RMMA episodes.5,34 The debate over the role of dental occlusion in sleep bruxism is beyond the scope of this chapter; reviews have described peripheral sensory influences on sleep bruxism.52,53 Reduced Salivary Flow, Airway Patency, and Jaw Motor Activity during Sleep Another question is whether the lower salivary flow during sleep increases the risk for tooth wear.56 It appears that no sleep data directly support this premise. The low salivary flow observed during sleep may be related to low swallowing frequency: between 2.1 and 9.1 swallowing movements per hour are observed in sleep, compared with 25 per hour during daytime.57 Based on data retrieved from an analysis of laryngeal swallowing movements observed in controls and in sleep-bruxism subjects, it was hypothesized that RMMA could be associated with an increase in salivary flow during sleep to lubricate the oroesophageal tissues.34,56 Lack of saliva, a natural orodental lubricant, may then cause a dramatic breakdown in the tooth structure of patients with sleep bruxism. Consequently, specific clinical management could be planned for oral dryness in sleep.56 However, it remains to be understood why some frequent teeth grinders show little tooth wear; it may be that a better quality and volume of saliva lubrication or stronger tooth enamel (e.g., density) explains such observations. Sleep breathing disorders (e.g., sleep apnea) have been associated with sleep bruxism.19,19a Results from a large population survey have suggested that self-reports of sleep apnea were two or three times higher in subjects also aware of teeth grinding.19 Because sleep is usually associated with a jaw-opening retrusive position, a tongue muscle relaxation (e.g., genioglossus), and a reduction of airway patency, it remains to be investigated whether RMMA-related sleep arousal assists in the recovery of airway patency or whether this is just a concomitant and typical motor response associated with sleep arousal.7-9,27
CLINICAL FEATURES Clinicians can diagnose sleep bruxism in their patients using the following clinical features as a guide1,2,6,54,58,59: • Teeth grinding or tapping sounds noticed by the patient’s sleep partner or a family member is probably most reliable (Videos 99-2 to 99-4). • The presence of tooth wear (Box 99-3) can be an indication, but it is not accurate in the absence of witnessed grinding or tapping. • Complaints of jaw muscle discomfort, fatigue or stiffness, and occasional headaches (e.g., temporalis muscles) are unspecific symptoms. Other signs and symptoms, all unspecific for sleep bruxism, include tooth sensitivity to hot or cold (one tooth or unspecific several teeth), muscle hypertrophy, temporomandibular joint (TMJ) sound (clicking) or jaw lock (e.g., reduction of opening amplitude)and tongue indentations. Teeth grinding or tapping sounds have to be objectively distinguished from confounding oral sounds during sleep such as snoring, throat grunting, tongue clicking, or TMJ sounds with jaw movements.27,60 The presence of muscle or TMJ tenderness or pain is usually confirmed by digital palpation. Use of a visual analogue scale (e.g., 0 to 100 mm
Box 99-3 Clinical Features of Bruxism Reported by Patients During Sleep Teeth-grinding sounds, usually noticed by another person Possible teeth tapping or oromandibular myoclonus On Awakening during the Night or in the Morning Tooth wear or chipping incisal border Muscle hypertrophy affecting aesthetics Jaw muscle discomfort (fatigue or tension) with or without pain Temporal muscle headache or tenderness Stiff jaw, reduced mobility, difficulty biting food at breakfast Exacerbation by life pressure or stress Teeth hypersensitive to cold food (sometimes to heat), liquid, or air Frequent failure of tooth restorations (e.g., filling, bridge) Observed by Clinicians Tooth wear or fracture, shiny spots on fillings Masseter muscle hypertrophy on voluntary jaw clenching (less important at temporalis level) Muscle (masseter, temporalis, pterygoid, sternocleidomastoid) tenderness or pain upon digital palpation Temporomandibular joint tenderness or pain upon digital palpation Tongue indentation Tense personality or hypervigilant patient (subjective appreciation) Polygraphic observation of jaw muscle activity with audible teeth-grinding sounds Others Exacerbation of periodontal disease (a controversial issue) Reduction in salivary flow, xerostonia Lip and cheek biting Burning tongue with concomitant oral habits
with no pain, and worst pain at either extreme) or a numerical scale (0 to 10) can be used to score the patient’s subjective reports. Close to 50% of patients with sleep bruxism complain of pain on awakening and occasionally during sleep.24,61 By contrast, patients with diurnal clenching mainly report pain toward the end of the afternoon and in the evening.22,23 Tooth wear represents a challenge for the clinical recognition of current sleep bruxism.54,58 Attrition caused by bruxism differs from attrition resulting from dental work (e.g., crown, bridge or denture, tooth equilibration with a dental bur), from trauma (e.g., pipe, sports injury, abrasive dust in the working milieu), or from erosion caused by chemicals (e.g., lemon sucking, gastroesophageal reflux, or vomiting). Tooth wear may be exacerbated by craniodental morphology, which changes with aging. Clinicians need to be aware that observations at the time of examination might have no link with current muscle activity, because teeth grinding frequency fluctuates over time.2,4,54 Wear
can also be localized to one tooth, a few teeth, or a full segment (e.g., the lower incisors).59 The wear pattern can be seen within the normal movement range or in an eccentric jaw position. Finally, although 100% of patients with bruxism show tooth wear, so do 40% of those who are asymptomatic.62 Thus, tooth wear alone cannot be relied on for a definite diagnosis of sleep bruxism, and the other factors mentioned must also be taken into consideration. Tooth sensitivity to temperature stimulations (e.g., cold liquid or air) is also reported after sleep periods with teeth clenching, grinding, or tapping. Another type of tooth substance loss, cervical lesion (a groove in the tooth and gum region), was reported to be three times more prevalent in persons with sleep bruxism.63 However, the cause and effect link remains to be proved. A clinical feature used to recognize sleep bruxism is masseter muscle hypertrophy. This is easily seen when the subject is voluntarily clenching the teeth together: a unilateral or bilateral mass protrudes on the side of the face below the zygomatic arch. This condition needs to be differentiated from swelling resulting from periodontal abscess or the trauma of wisdom tooth extraction, from parotid gland tumor, from blockage of the parotid salivary duct by a calculus, or from sustained contraction of the masseter muscle that constricts the salivary flow. This last problem is named the parotid-masseter syndrome.2
DIAGNOSTIC EVALUATION Clinical Clinical diagnosis of sleep bruxism is based on the patient’s history and orofacial examination. Mostly, the presence of tooth wear can be scored from criteria derived from the literature.6,54,59 To assess tooth wear, dry the tooth with air or cotton and use a dental mirror with a light source. Tooth wear can be monitored over time by taking dental arch impressions and visually analyzing wear patterns using casts or models. For research purposes, scanning electron microscopy or computerized laser analysis could be used. Another technique monitors wear intensity using intraoral appliances, such as the Bruxscore Plate.64 The validity of this measure for assessing sleep bruxism frequency is, however, questionable: Bruxscore Plate data do not correlate strongly with ongoing sleep bruxism muscle activity as monitored with ambulatory EMG units.64 Moreover, the presence of an oral appliance can influence ongoing EMG activity (causing either an increase or a decrease).65 Muscle hypertrophy that is not specific for diagnosing sleep bruxism may be recognized by taking into consideration the patient’s age and dentofacial morphology, having ruled out any unusual condition (see earlier) or swelling caused by infection in the salivary gland. The patient clenches the teeth, which induces a protruding mass at the masseter muscle level (rarely, the temporalis). Using the fingers to palpate the area, a positive score is given if the contracted muscle volume increases at least twofold. For research purposes, sliding rules or ultrasonography measures can also be used, although they have not yet been validated for diagnosing sleep bruxism.66 In addition, we suggest that the following be noted in the patient file (see Box 99-3): location and severity of
CHAPTER 99 • Sleep Bruxism 1133
tooth wear; the presence or absence of masseter muscle hypertrophy; report of sensitive teeth or pain or tenderness in response to digital palpation of muscles and the TMJ; maximum jaw displacement (use the space between both upper and lower central incisors as a reference point); and the presence or absence of joint sounds (e.g., TMJ clicking or grating) using finger palpation. Ambulatory Monitoring and Sleep Laboratory Recording Sleep bruxism motor activity may also be monitored using polygraphy, but this method is recommended only for patients with severe teeth grinding, in the presence of other sleep disorders (e.g., apnea, epilepsy), or for clinical trials.58 First, audio and video home recordings (a home camera with black light in the room) can help to estimate sound frequency and jaw displacement. However, in the absence of polygraphy, it can be very difficult to distinguish the sounds of snoring throat grunting, tooth tapping, TMJ clicking, teeth grinding, and jaw movements such as swallowing, rumination, typical chewing-like movements, smiling, or orofacial myoclonia.60 Second, ambulatory EMG recordings can be used to monitor sleep bruxism at home. Some systems allow only one channel to be used to monitor masseteric EMG (surface) activity during sleep.65,67 Full ambulatory multichannel (EEG, EMG, ECG, respiration, movement, etc.) recorders, with a very good quality EMG signal, are also currently available. Although the use of ambulatory recordings allows patients to be monitored in the home environment, it does have some limitations. In the absence of audio and video recordings, it is difficult to precisely assess the specificity of EMG activity over the large spectrum of orofacial activities that occur during sleep, such as swallowing, coughing, grunting, sighs, yawning, sleep talking, and smiling.27,60,68 Moreover, up to 30% of all orofacial activities scored during sleep (polygraphic and audiovisual recordings) might not be specific to sleep bruxism.32,60 Despite these limitations, ambulatory recordings are a valuable complement to sleep laboratory recordings because they allow low-cost monitoring over several nights in the patient’s natural environment. The suggested sleep bruxism scoring algorithm for ambulatory recordings needs further validation along with laboratory polysomnography (Box 99-4).67,69 Third, in the sleep laboratory (a highly controlled but decidedly less-natural milieu), recording the following biological signals often completes the diagnosis of sleep bruxism (Fig. 99-2)24,32,58: • Two EEG readings (C3A2, O2A1); • Right and left EOG; • EMGs (surface) from both jaw masseter (right and left; in single or jump channel) and temporalis (optional, to improve scoring) muscles for sleep bruxism scoring with chin or suprahyoid muscles for standard sleep hypotonia in REM sleep, and of the anterior tibialis to rule out periodic limb movements in sleep (PLMS); • Nasal air flow, respiratory effort (via chest belt), and microphone recording for sleep apnea and snoring assessments; • Audio and video recordings to identify and quantify jaw and orofacial activities (zoom is on face).
1134 PART II / Section 12 • Parasomnias Box 99-4 Criteria for Diagnosis of Sleep Bruxism by Masseter or Temporal Electromyography Ambulatory Criteria EMG (RMS) level: >10% of maximum (voluntary clench while awake) EMG periodicity: <5 sec between events EMG duration: >3 sec minimum; >0.25 sec to rule out myoclonus Heart rate change: >5% in beats per minute with an EMG event Minimum acquisition: 16.7 Hz or 0.05 sec frequency for EMG or time resolution Sleep Laboratory Criteria Mean SB EMG potentials: >10% or 20% of the maximal clench while awake, masseter muscles SB event episodes types are scored • Phasic (rhythmic): >3 EMG bursts, separated by 2 interburst pauses, in masseter or temporalis muscle, each burst lasting >0.25 sec and <2.0 sec • Tonic (sustained): 1 EMG burst lasting >2.0 sec • Mixed: both phasic and tonic types Minimum acquisition: 128 Hz Diagnostic cut-off criteria • Bruxism events per hour: >4 RMMA for moderate to frequent EMG events or • Bruxism bursts per hour: >2 RMMA for mild frequency EMG events plus • At least one episode of grinding per sleep period Data are expressed in index as • Number of SB events per hour of sleep • Number of SB bursts (contractions) per hour of sleep • Number of SB episodes per night • Duration of SB EMG activity per hour of sleep Ambulatory criteria and sleep laboratory criteria from references 5, 24, 28, 32, 33, 35, 36, and 67-69. EMG, electromyogram; RMMA, rhythmic masticator muscle activity; RMS, root mean square of masseter muscle; SB, sleep bruxism.
LOC–A1
130 µV/cm
EMG–
170 µV/cm
C3–A2
120 µV/cm
MAL
130 µV/cm
MAR
130 µV/cm
TEL
130 µV/cm
TER
130 µV/cm
01: 38: 33
01: 38: 40
01: 38: 50
Figure 99-2 Polygraphic traces of one rhythmic sleep bruxism episode (same subject as in Fig. 99-3). The three upper traces are left eye (EOG = LOC − A1), submental EMG and C3A2 EEG; all show the rhythmic pattern with movement artifacts in both EOG and EEG. The left (L) and right (R) masseter (MA) and temporalis (TE) muscle activity is associated with 11 phasic (rhythmic) bursts. In this patient, the level of muscle activity was elevated and a co-contraction between closer (MA and TE) and submental opener muscles (EMG) is noted. LOC, Left outer canthus.
Chin EMG alone is not very accurate for scoring sleep bruxism. These recordings should be made in a temperaturecontrolled room where light (use black lights for video) and sound are minimal. Before sleep, subjects should swallow, cough, open their jaw vertically and laterally, as well as clench and tap the teeth to help score and assess the EMG signal recognition pattern. All-night data are recorded with a computer at a minimum acquisition speed of 128 Hz32 and are analyzed according to the standard Rechtschaffen and Kales criteria described in Chapter 141. Computer screen segments of 20 or 30 seconds can be used. The EMG sleep bruxism episodes of at least 10% to 20% of the maximum voluntary contraction while awake are scored in parallel with audio and video signals. Three types of sleep bruxism events are identified: phasic, tonic, or mixed, according to criteria derived from the literature (see Box 99-4).5,32,36 If bursts of less than 0.25 second are noticed in the temporalis or masseter muscles, they are scored as twitches or myoclonic events and are distinguished from bruxism.52,68,70,71 We have found that 10% of those in whom sleep bruxism was clinically diagnosed had this activity during sleep. Because repetitive myoclonus can be concomitant with epileptic spikes,70 our patients were recorded for a third night using a full EEG montage. No such neurologic events were found in any of our young and otherwise healthy patients who had oromandibular myoclonus. The frequency of sleep bruxism bursts (single EMG events) is quantified in RMMA episodes per night and per hour of sleep, with or without the presence of grinding sounds or leg movement. Through training, technicians can achieve a strong reliability in scoring the frequencies of events and a moderate capacity to discriminate episode types (e.g., phasic, tonic, or mixed).32 It is strongly suggested that the audiovisual signal be used in parallel with a polygraphic recording to differentiate sleep bruxism episodes occurring with snoring, swallowing, major body movement (e.g., PLMS), somniloquy, and so forth.60 Other Diagnostic Features Using the cutoff criteria described in Box 99-4 to establish a sleep diagnosis, bruxism can be correctly predicted in most patients with sleep bruxism, and asymptomatic status can be confirmed in most controls.24,32 The clinical use of these research cutoffs needs further validation in a larger population. Even when the first night is used mostly for habituation, approximately 10% of subjects with sleep bruxism invited to the sleep laboratory did not have a full first night of sleep (i.e., they had several awakenings with no habituation to sleep laboratory conditions, or they refused to appear for the experimental second night). In a retrospective analysis of patients with sleep bruxism lasting 2 months to 7.5 years (3 to 8 night recordings), we estimated that the time-to-time variability of RMMA or sleep bruxism index per hour of sleep was 25.3%, whereas the variability in the number of episodes of teeth grinding was 53%.4 Other sleep architecture variables, such as sleep duration and efficiency, number of awakenings and arousal movements, and sleep stage distribution, do not usually differ between patients with primary sleep bruxism and asymptomatic controls.5,31-33 However, the most significant sleep-
related variables characterizing sleep bruxism are the following: • Up to three times more EMG bruxism/RMMA episodes occur per hour of sleep.31-33 • Most sleep bruxism episodes can usually be scored in light-sleep stages (60% to 85% in stages 1 and 2) rather than in REM sleep.5,31-33,36 • More sleep bruxism episodes can be noted when subjects sleep on their backs.34,72 In young and otherwise healthy subjects, no obvious differences were noted in the frequency of periodic leg movements during sleep.32,35,73 As described earlier, at the EEG level, most sleep bruxism episodes can be observed in relation to the active phase of the cyclic alternating pattern (CAP),33 and the presence of K-complexes is two to three times less frequent than in matched asymptomatic subjects.41 Some EEG alpha-wave intrusions may also be noted before sleep bruxism episodes, but the specificity of this observation needs further validation in a controlled study.35 Finally, an autonomic response is noticeable with sleep bruxism episodes (as is the case for body movements during sleep), and acceleration in heart rate precedes or is concomitant with sleep bruxism.35,37
TREATMENT/MANAGEMENT As yet, there is no specific cure for bruxism. The clinician’s role is to manage sleep bruxism, with the primary goals of preventing damage to the orofacial structures and reducing sensory complaints. Current interventions are oriented toward behavioral, orodental, and pharmacologic strategies, but controlled studies confirming the efficacy of these strategies are still required6,38,47,48,53,74-76 (see Fig. 99-1). Some of the following recommendations directly address the patient’s awareness of the disorder and management of life stress and anxiety (Box 99-5 and Fig. 99-3). Behavioral Strategies Behavioral strategies should begin with a short and comprehensive explanation of bruxism to the patient, including its definition, causes, and consequences. Next, the clinician should give instructions on sleep hygiene. The psychological and behavioral management strategies for sleep bruxism have been of major interest for years.77 No persistent or clear effects have been obtained with strategies aimed at relaxation and tension reduction or exercise,77,78 but several patients have reported a sensation of well being. One study reported a reduction in both EMG activity and grinding frequency after hypnotherapy.79 However, no control therapy was used. The use of biofeedback is also reported to reduce sleep bruxism EMG activity, but this effect might not last over time without the regular use of the device.77,80 Occlusal Appliances Occlusal appliances such as a mouth guard or stabilization bite splint can protect the orofacial structures from damage. The soft mouth guard is usually recommended for use only on a short-term basis because degradation can occur rapidly. The hard occlusal stabilization splint, covering a full dental arch (Fig. 99-3), is particularly useful (e.g., for protecting teeth) for patients who are frequent and severe
CHAPTER 99 • Sleep Bruxism 1135
Box 99-5 Palliative Management for Sleep Bruxism Behavioral (Modest Evidence)2,6,53, 77-79,80,91 Explanation of causes or exacerbation factors for sleep bruxism Reversing the habit of clenching the teeth or bracing the jaw during daytime in reaction to life pressures (e.g., by abdominal breathing) Lifestyle, sleep hygiene, relaxation, including autohypnosis or winding down before sleep Biofeedback Physical therapy and training (relaxation, breathing) Psychological therapy for managing stress and life pressures Orodental2,6,52,54,74-77,81-83,85,91,92 Mouth guard (soft, short term) for tooth protection (−) Bite splint (hard, need control visits) for tooth protection; risk of aggravating sleep apnea in patients with respiratory disturbance in sleep (+ in short term) Splint with vibration or electrical lip stimulation device; new (+ in short term) Anterior tooth device, e.g., nociceptive trigeminal inhibition (+ in short term) Mandibular advancement appliance (+ in short term) Dental occlusion (controversy exists over tooth equilibration and orthodontic bite corrections) Pharmacologic (Short-Term Use in Clinic for Acute or Severe Condition)2,6,11,27,43-48,74,86-88,93 Sedative and Muscle-Relaxant Properties Diazepam (+/cr) Clonazepam (+) Lorazepam (?) Methocarbamol (+) Cyclobenzaprine (?) Buspirone (+/cr) Serotonin-Related Properties Tryptophan (0) Amitriptyline (0) Venlafaxine (+/cr) Trazodone (?) Dopaminergic-Related Properties Levodopa (+) Bromocriptine (0) Pergolide (+cr) Pramipexole (?) Gamma-hydroxybutyric acid (+/cr) Metoclopramide (+/cr) Cardioactive Propranolol (−) Clonidine (+ but side effects) Other83,87,88,94 Tiagabine (+/cr) Botulinum toxin (?; one controlled study for SB) CPAP (?) Symbols in parentheses following each treatment indicate level of evidence: +, evidence of SB reduction; −, evidence of SB exacerbation; 0, no effect; ?, evidence questionable or unknown; cr, mostly based on case report.
1136 PART II / Section 12 • Parasomnias
the short- and mid-term benefits and the safety of oral devices for managing sleep bruxism alone or in the presence of sleep breathing disorders (e.g., snoring, apnea– hypopnea syndrome). Tooth Equilibration Tooth equilibration, to reduce occlusal interference, has also been suggested as a treatment for sleep bruxism, but the efficacy of such therapy for bruxism is controversial.6,52,53 A
B Figure 99-3 A, An oral appliance (bite splint) made in hard acrylic to protect the upper teeth from wear associated with grinding. B, A similar appliance in the mouth.
grinders or clenchers.6,53 However, not every patient finds relief with these orthopedic treatments. A few experimental control studies using occlusal splint or control devices revealed that the frequency of RMMA, a marker of sleep bruxism, is initially reduced for a period of 7 to 15 days but that RMMA frequency tends to return to baseline level over time.76,81,82 Patient compliance with these oral devices is low over time, and splints are mainly used to prevent tissue damage (e.g., tooth wear or chipping). The use of an oral appliance that pushes the mandible forward to improve breathing during sleep (mandibular advancement appliance), also reduces the frequency of RMMA and sleep bruxism.83,83a It remains possible that the short-term effect of any device or appliance is associated with muscle fibers and spindle adaptation to changes in jaw position or to tongue position and airway patency. Moreover, the use of a maxillary occlusal splint is not recommended in patients with sleep apnea because it can aggravate respiratory disturbances.84 A comparative analysis using the concept of number needed to treat before a clinical benefit can be perceived revealed that occlusal splints and mandibular advancement appliances provide acceptable short-term therapy for protecting teeth from the consequences of sleep bruxism.74 Two Cochrane critical analyses highlighted the need for well-designed randomized, control trials before drawing conclusions about the benefit of oral devices in the management of sleep bruxism.75,85 Relevant outcomes need to be identified using valid scoring methods that assess both
Pharmacologic Management Pharmacologic management is indicated on a short-term basis only (see Box 99-5).48 Clinicians report that centrally acting drugs in the benzodiazepine group and muscle relaxants reduce bruxismrelated motor activity. To our knowledge, only diazepam and methocarbamol have been tested in open study design.2,71 Clonazepan was reported to reduce sleep bruxism in a wide age range of patients.86 However, addiction risk needs to be considered. These medications are usually prescribed at bedtime, and patients must be informed of possible side effects (e.g., not driving in the morning due to potential drowsiness). Antidepressants such as tricyclics have also been used for managing sleep bruxism, but two controlled studies using ambulatory EMG failed to support the efficacy of a small dose of amitriptyline in management of sleep bruxism.48 The use of selective serotonin reuptake inhibitors such as fluoxetine, sertraline, and citalopram has been reported to induce clenching or grinding.48 The use of l-tryptophan (a serotonin precursor) in sleep bruxism management has been reported to have no effect. The use of a weight-control medication related to serotonin, fenfluramine (Ponderal), has been noted to exacerbate grinding. Therefore, caution is suggested before using serotonin-related medication in patients with sleep bruxism. The literature on the safe use of dopamine-related medications is inconclusive.48 Patients with chronic antidopaminergic drug exposure (e.g., haloperidol, a dopaminergic antagonist) exhibited iatrogenic grinding similar to that associated with oral tardive dyskinesia, and a similar effect was seen with l-dopa (a dopaminergic precursor) in a patient already suffering from Parkinson’s disease.46 A randomized experimental trial demonstrated that acutely administered l-dopa modestly reduced bruxism activity in otherwise healthy patients with sleep bruxism, whereas bromocriptine had no effect.43,44 So far, too few studies have been performed on dopaminergic regimens (e.g., ldopa) to consider these in the long-term management of sleep bruxism. It also remains to be demonstrated whether, as in the case of periodic leg movement syndrome (PLMS) (see Chapter 90), a pharmacologic rebound will induce a resurgence of sleep bruxism activity later in the night or during the next day. Another pharmacologic avenue for sleep bruxism management is the use of a beta-adrenergic antagonist, such as propranolol, or clonidine, an alpha agonist. A controlled experimental trial performed in our laboratory with young patients with sleep bruxism, using placebo or long-action propranolol, resulted in no net reduction of sleep bruxism.47 We found that clonidine reduced sleep bruxism by 60%,
CHAPTER 99 • Sleep Bruxism 1137
but severe hypotension was experienced in the morning by 20% of subjects, which limits clinical use.47 Botulinum toxin is reported to reduce the occurrence of RMMA and sleep bruxism.87,88 However, at this time, no controlled studies with polygraphic recordings have demonstrated that botulinum toxin has long-term efficacy and safety for sleep bruxism. Moreover, it has been reported that the botulinum toxin is carried to the central nervous system, and it is not known whether this explains its effects or whether it signifies a potential risk for the patient.89 Further advice could be given for the management of sleep bruxism in patients with secondarily hypersensitive teeth who can use fluoride gel (e.g., Gelkam). Children and Teenagers Sleep bruxism in can be managed in these populations by using behavioral and relaxation methods. The contribution of tonsil and adenoids to sleep bruxism should be excluded.
PITFALLS AND CONTROVERSIES The presence of tooth wear alone is not sufficient to diagnose sleep bruxism, because the tooth wear might have occurred years ago. At a clinical examination, a current report of teeth grinding by the patient’s sleep partner is among the reliable clinical variable indicators of ongoing sleep bruxism. Polysomnographic recording, including EMG of the jaw closing muscles, is not mandatory except if the patient has a concomitant sleep disorder (e.g., apnea, sleep epilepsy, or teeth tapping) or if a clinical trial is planned. In this case, the specificity of polygraphy scoring is greatly improved through the use of audio and video recordings to exclude oral sounds associated with sleep talking, teeth tapping, snoring, TMJ sounds, or grunting. Current studies on the pathophysiology of sleep bruxism suggest that RMMA and teeth grinding are linked to sleep arousals. The role of dental occlusion, (i.e., interferences between tooth microcontacts) and of dopaminergic substances are less significant in the genesis of sleep bruxism than was originally thought. We do not know enough about the role of familial and genetically transmitted factors.
❖ Clinical Pearl In the management of sleep bruxism, the sleep medicine clinician should distinguish primary sleep bruxism from secondary sleep bruxism related to sleep or medical disorders, including arousal-related disorders, sleep apnea, tics such as grunting or teeth tapping, sleep-related epilepsy, and medicationrelated tardive dyskinesia. Dental splints reduce tooth damage and teeth grinding sounds but are not recommended for use by patients with sleep apnea. Medications, such as muscle relaxants and anxiolytics, are indicated for short-term use in more severe cases. In children, cognitive behavior approaches and the use of a soft mouth guard for those with severe grinding is an option, but in the absence of further evidence, clinicians should be prudent and closely monitor the evolution of signs and symptoms, plus controlling for respiratory disturbances.
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52. Kato T, Thie NM, Huynh N, et al. Topical review: sleep bruxism and the role of peripheral sensory influences. J Orofac Pain 2003;17:191-213. 53. Lobbezoo F, van der Zaag J, van Selms MK, et al. Principles for the management of bruxism. J Oral Rehab 2008;35:509-523. 54. Johansson A, Johansson AK, Omar R, et al. Rehabilitation of the worn dentition. J Oral Rehab 2008;35:548-566. 55. Graf H. Bruxism. Dent Clin North Am 1969;13:659-665. 56. Thie NM, Kato T, Bader G, et al. The significance of saliva during sleep and the relevance of oromotor movements. Sleep Med Rev 2002;6:213-227. 57. Lichter I, Muir RC. The pattern of swallowing during sleep. Electro Clin Neurophysiol 1975;38:427-432. 58. Koyano K, Tsukiyama Y, Ichiri R, et al. Assessment of bruxism in the clinic. J Oral Rehab 2008;35:495-508. 59. Tsiggos N, Tortopidis D, Hatzikyriakos A, et al. Association between self-reported bruxism activity and occurrence of dental attrition, abfraction, and occlusal pits on natural teeth. J Prosthet Dent 2008;100(1):41-46. 60. Dutra KMC, Pereira Jr FJ, Rompré PH, et al. Orofacial activities in sleep bruxism patients and in normal subjects: a controlled polygraphic and audio-video study. J Oral Rehabil 2009;36(2):86-92. 61. Rossetti LMN, Pereira de Araujo CDR, Rossetti PHO, et al. Association between rhythmic masticatory muscle activity during sleep and masticatory myofascial pain: a polysomnographic study. J Orofac Pain 2008;22:190-200. 62. Menapace SE, Rinchuse DJ, Zullo T, et al. The dentofacial morphology of bruxers versus non-bruxers. Angle Orthod 1994;64:43-52. 63. Ommerborn MA, Schneider C, Giraki M, et al. In vivo evaluation of noncarious cervical lesions in sleep bruxism subjects. J Prosthet Dent 2007;98:150-158. 64. Pierce CJ, Gale EN. Methodological considerations concerning the use of bruxcore plates to evaluate nocturnal bruxism. J Dent Res 1989;68:1110-1114. 65. Clark GT, Beemsterboer PL, Solberg WK, et al. Nocturnal electromyographic evaluation of myofascial pain dysfunction in patients undergoing occlusal splint therapy. J Am Dent Assoc 1979;99: 607-611. 66. Bakke M, Thomsen CE, Vilmann A, et al. Ultrasonographic assessment of the swelling of the human masseter muscle after static and dynamic activity. Arch Oral Biol 1996;41:133-140. 67. Gallo LM, Lavigne G, Rompré P, et al. Reliability of scoring EMG orofacial events: polysomnography compared with ambulatory recordings. J Sleep Res 1997;6:259-263. 68. Walters AS, Lavigne G, Hening W, et al. The scoring of movements in sleep. J Clin Sleep Med 2007;3:155-167. 69. Ikeda T, Nishigawa K, Kondo K, et al. Criteria for the detection of sleep-associated bruxism in humans. J Orofacial Pain 1996;10: 270-282. 70. Meletti S, Cantalupo G, Volpi L, et al. Rhythmic teeth grinding induced by temporal lobe seizures. Neurol 2004;62:2306-2309. 71. Kato T, Blanchet PJ, Montplaisir JY, et al. Sleep bruxism and other disorders with orofacial activity during sleep. In: Chokroverty S, Hening WA, Walters AS, editors. Sleep and movement disorders. Philadelphia: Butterworth Heinemann; 2003. p. 273-285. 72. Okeson JP, Phillips BA, Berry DTR, et al. Nocturnal bruxing events in healthy geriatric subjects. J Oral Rehab 1990;17:411-418. 73. Okeson JP, Phillips BA, Berry DTR, et al. Nocturnal bruxing events in subjects with sleep-disordered breathing and control subjects. J Craniomand Dis Fac Oral Pain 1991;5:258-264. 74. Huynh NT, Rompré PH, Montplaisir JY, et al. Comparison of various treatments for sleep bruxism using determinants of number needed to treat and effect size. Int J Prosthodont 2006;19:435-441. 75. Macedo CR, Silva AB, Machado MA, et al. Occlusal splints for treating sleep bruxism (tooth grinding). Cochrane Database Syst Rev 2007;(4):CD005514. 76. Harada T, Ichiki R, Tsukiyama Y, et al. The effect of oral splint devices on sleep bruxism: a 6-week observation with an ambulatory electromyographic recording device. J Oral Rehabil 2006;33: 482-488. 77. Pierce CJ, Gale EN. A comparison of different treatments for nocturnal bruxism. J Dent Res 1988;67:597-601. 78. Moss RA, Hammer D, Adams HE, et al. A more efficient biofeedback procedure for the treatment of nocturnal bruxism. J Oral Rehab 1982;9:125-131.
79. Clarke JH, Reynolds PJ. Suggestive hypnotherapy for nocturnal bruxism: a pilot study. Am J Clin Hypnosis 1991;33:248-253. 80. Jadidi F, Castrillon E, Svensson P. Effect of conditioning electrical stimuli on temporalis electromyographic activity during sleep. J Oral Rehabil 2008;35:171-183. 81. Dube C, Rompré PH, Manzini C, et al. Quantitative polygraphic controlled study on efficacy and safety of oral splint devices in toothgrinding subjects. J Dent Res 2004;83:398-403. 82. van der Zaag J, Lobbezoo F, Wicks DJ, et al. Controlled assessment of the efficacy of occlusal stabilization splints on sleep bruxism. J Orofac Pain 2005;19:151-158. 83. Landry ML, Rompré PH, Manzini C, et al. Reduction of sleep bruxism using a mandibular advancement device: an experimental controlled study. Int J Prosthodont 2006;19:549-556. 83a. Landry-Schönbeck A, de Grandmont P, Rompré PH, Lavigne GJ. Effect of an adjustable mandibular advancement appliance on sleep bruxism: a crossover sleep laboratory study. Int J Prosthodont 2009;22:251-259. 84. Gagnon Y, Mayer P, Morisson F, et al. Aggravation of respiratory disturbances by the use of an occlusal splint in apneic patients: a pilot study. Int J Prosto 2004;17(4):447-453. 85. Jagger R. The effectiveness of occlusal splints for sleep bruxism. Evid Based Dent 2008;9:23. 86. Saletu A, Parapatics S, Saletu B, et al. On the pharmacotherapy of sleep bruxism: placebo-controlled polysomnographic and psychometric studies with clonazepam. Neuropsychobiology 2005;51: 214-225.
CHAPTER 99 • Sleep Bruxism 1139 87. Tan E-K, Jankovic J. Treating severe bruxism with botulinum toxin. J Am Dent Assoc 2000;131:211-216. 88. Lee SJ, McCall WD Jr, Kim YK, et al. Effect of Botulin toxin injection on nocturnal bruxism: a randomized controlled trial. Am J Phys Med Rehabil 2010;89:16-23. 89. Filippi GM, Errico P, Santarelli R, et al. Botulinum A toxin effects on rat jaw muscle spindles. Acta Otolaryngol (Stockh) 1993; 113:400-404. 90. Miyamoto K, Ozbek MM, Lowe AA, et al. Mandibular posture during sleep in patients with obstructive sleep apnoea. Arch Oral Biol 1999;44:657-664. 91. Baad-Hansen L, Jadidi F, Castrillon E, et al. Effect of a nociceptive trigeminal inhibitory splint on electromyographic activity in jaw closing muscles during sleep. J Oral Rehabil 2007;34:105-111. 92. Watanabe T, Baba K, Yamagata K, et al. A vibratory stimulationbased inhibition system for nocturnal bruxism: a clinical report. J Prosthet Dent 2001;85:233-235. 93. Van der Zaag J, Lobbezoo F, Van der Avoort PG, et al. Effects of pergolide on severe sleep bruxism in a patient experiencing oral implant failure. J Oral Rehabil 2007;34:317-322. 94. Kast RE. Tiagabine may reduce bruxism and associated temporomandibular joint pain. Anesth Prog 2005;52:102-104.
Sleep Breathing Disorders
Section
13
Mark H. Sanders 100 Central Sleep Apnea
and Periodic Breathing 101 Anatomy and Physiology of Upper Airway Obstruction 102 Snoring 103 Genetics of Obstructive Sleep Apnea 104 Cognition and Performance in Patients with Obstructive Sleep Apnea 105 Clinical Features and Evaluation of Obstructive Sleep Apnea and Upper Airway Resistance Syndrome
106 Medical Therapy for
Obstructive Sleep Apnea 107 Positive Airway Pressure Treatment for Obstructive Sleep Apnea–Hypopnea Syndrome 108 Surgical Management for Obstructive Sleep-Disordered Breathing 109 Oral Appliances for Sleep-Disordered Breathing
Central Sleep Apnea and Periodic Breathing Andrew Wellman and David P. White Abstract Central sleep apnea is a disorder characterized by recurrent episodes of apnea during sleep, resulting from temporary suspension of ventilatory effort. Such apneas generally result from the strong dependence of ventilation during sleep on the metabolic control system and, in particular, arterial PCO2. Examples include central apneas that occur during the transition from wake to sleep, when waking PCO2 may be below sleeping levels and therefore nonstimulatory to ventilatory effort, when the gain of the ventilatory control system is high (Cheyne-Stokes respiration, high-altitude periodic breathing, and possibly idiopathic central sleep apnea), or when PCO2 control mechanisms are defective (hypercapnic respiratory failure and narcotic-induced central apneas). It is also becoming increasingly recognized that central apneas can occur during titration of continuous positive airway pressure (CPAP) in some persons (complex sleep apnea). Regardless of the cause, central apneas often produce arousals from sleep, which can lead to difficulty sustaining sleep and to daytime somnolence. This reflects the symptoms with which these patients may present. The prevalences of
1140
110 Management of
Obstructive Sleep Apnea–Hypopnea Syndrome 111 Sleep in Patients with Asthma and Chronic Obstructive Pulmonary Disease 112 Restrictive Lung Disorders 113 Noninvasive Ventilation to Treat Chronic Ventilatory Failure 114 Obstructive Sleep Apnea and Metabolic Dysfunction 115 Obstructive Sleep Apnea, Obesity, and Bariatric Surgery
Chapter
100
most disorders that are associated with central sleep apnea have been minimally studied, although most are believed to be relatively uncommon. Cheyne-Stokes respiration may be an exception, because a relatively high prevalence has been observed in patients with congestive heart failure. Diagnosis of central sleep apnea generally requires a fullnight polysomnographic evaluation, ideally including measurement of esophageal pressure. However, use of chest and abdominal wall motion as a marker of respiratory effort would be unlikely to lead to an incorrect diagnosis. Treatment of central sleep apnea must be directed, as much as possible, toward the underlying cause. Sleep-onset central apneas do not require treatment unless they are frequent and result in desaturation or repetitive arousals. Cheyne-Stokes respiration is best managed with CPAP alone or in combination with adaptive servoventilation, whereas idiopathic central sleep apnea and high-altitude periodic breathing often respond to oxygen or acetazolamide. Complex sleep apnea often improves over time with consistent CPAP use. Hypercapnic respiratory failure usually requires noninvasive nocturnal ventilation. Thus, the cause of the disordered breathing must be clarified to optimize management.
CHAPTER 100 • Central Sleep Apnea and Periodic Breathing 1141 Central apnea
Obstructive apnea
Airflow Respiratory effort
10 sec
Figure 100-1 The relation between airflow and respiratory effort is demonstrated in both central and obstructive apnea. During a central apnea, there is cessation of airflow for at least 10 seconds with no associated ventilatory effort. An obstructive apnea is defined as a similar cessation of airflow but with continued respiratory effort.
Cessation of breathing during sleep can result from obstruction of the upper airway (obstructive apnea), absence of inspiratory effort (central apnea), or a combination of the two. The term central sleep apnea is used to describe both the pattern of an individual event and the clinical disorder characterized by repeated episodes of apnea during sleep resulting from the temporary suspension of ventilatory effort.1 A central apnea is conventionally defined as a period of at least 10 seconds without airflow due to absence of evident inspiratory effort. This condition differs from the obstructive or mixed apnea by the absence of upper airway obstruction and subsequent inspiratory attempts against the occluded airway (Fig. 100-1). Although this chapter is concerned with central sleep apnea, central and obstructive events are rarely seen in isolation. The vast majority of patients with central apneas also have some obstructive events. This observation suggests that the mechanisms responsible for the different types of apnea must overlap, and research indicates this is likely to be the case. The muscles of the upper airway (the genioglossus and others) behave as ventilatory muscles,2 dilating or stiffening the pharynx on inspiration. If a decrease or loss of activity occurs in both upper airway muscles and the diaphragm,3 one of several consequences seems likely: 1. The decrement in motor tone of the pharyngeal dilator muscles could lead to upper airway occlusion, with subsequent obstructed inspiratory efforts when diaphragmatic inspiratory activity resumes (a mixed apnea). 2. This loss of pharyngeal muscle activity could yield upper airway collapse, but pharyngeal and diaphragmatic muscles resume activation simultaneously, giving the appearance of a central apnea when airway obstruction was actually present during the apnea. 3. If loss of upper airway muscle activity does not lead to pharyngeal obstruction, a pure central apnea will very likely be seen, with no activation of the diaphragm. The propensity of the upper airway to collapse in a given patient may therefore be important in determining whether a central or obstructive apnea results when neural ventilatory “drive” or output to ventilatory muscles decreases during sleep. After tracheostomy for obstructive sleep apnea, periodic fluctuations in ventilation with or without central apnea can persist, but they generally resolve over a period of months.4,5 This can also occur when CPAP is initiated to alleviate upper airway obstruction (complex sleep apnea). In addition, it has been observed that the treatment of
central apneas with either a respiratory stimulant (e.g., acetazolamide6) or diaphragmatic pacing7 can result in obstructive events. Finally, studies report objective evidence of pharyngeal airway narrowing during purely central apneas.8 These observations imply some commonality in the pathophysiology of the various types of apnea, so it is not surprising that central and obstructive apneas are often seen in the same person. Patients with predominantly central sleep apnea constitute less than 10% of persons with sleep apnea in most sleep laboratory populations.1,9-11 As a result, only a small number of studies with more than a few such patients have been reported, which makes knowledge of this disorder scant. Most of this chapter provides a discussion of patients with central sleep apnea who breathe normally during the day; however, any patient with hypoventilation during wakefulness almost certainly has hypoventilation with or without central apneas during sleep. It is important to recognize that a pause in generating inspiratory effort can result from a variety of physiologic or pathophysiologic events. The term central sleep apnea reflects several breathing patterns, all of which include pauses in inspiratory effort; it does not represent a single entity or result from a single cause. Examples include Cheyne-Stokes respiration, high-altitude periodic breathing, and idiopathic central sleep apnea observed at sea level. Each has a different pathogenesis but is manifested by central apneas during sleep. To understand central sleep apnea, the normal mechanisms controlling ventilation during wakefulness and sleep, and the pathologic influences on these mechanisms, must be understood. All possible causes of central apnea must be considered in caring for patients with this disorder.
PATHOPHYSIOLOGY Because central apneas are defined as pauses in breathing due to lack of inspiratory effort, a complete loss of electromyographic activity of the ventilatory muscles during such an apnea would be expected, and this has been demonstrated.3 After the apnea, there is a resumption of normal ventilatory muscle activity. This finding implies that the neuronal output to these muscles ceases during central apnea and returns at the end of the ventilatory pause. Central apneas therefore represent a loss of inspiratory drive. Although the cause of central apnea in many patients remains obscure, investigation into the control of breathing has pointed to a number of possible mechanisms. Control of Breathing Ventilation is controlled by a number of processes that have been generally grouped under three headings.12 The first is the automatic or metabolic control system, consisting of the chemoreceptors (carotid body for hypoxia and carotid body plus medullary chemoreceptors for hypercapnia), vagally mediated intrapulmonary receptors, and various brainstem mechanisms (namely the pre-Bötzinger complex13) that process the information from these peripheral receptors to generate rhythmic breathing. This metabolic system keeps ventilation regular and ensures that the quantity of ventilation occurring at any time is well matched to metabolic requirements. The second
1142 PART II / Section 13 • Sleep Breathing Disorders
system is the behavioral control system. It seems clear that the activities of normal life, such as talking and eating, can influence ventilation and are thought of as behavioral or volitional influences. The origin of this neural input to respiration is probably in the forebrain. The third ventilatory control process in awake humans and animals is the wakefulness stimulus, with increased ventilation being inherent to the waking state.12 Although the mechanisms responsible for this effect of wakefulness on ventilation are poorly defined, it has been proposed that it either results from the influence of the descending arousal systems on respiratory pattern generators in the brainstem or it is a product of tonic input from nonrespiratory sensory mechanisms such as sight or hearing on the respiratory control system.14,15 The important point is that during wakefulness, ventilation is controlled by both the metabolic and the behavioral systems, including this wakefulness stimulus. Ventilation is likely to persist during wakefulness even with the complete absence of metabolic mechanisms. During sleep, particularly non–rapid eye movement (NREM) sleep, breathing is controlled almost solely by the metabolic control system, with ventilation being tightly linked to afferent input from chemoreceptors and vagal intrapulmonary receptors.16 This observation was demonstrated in dogs by blocking the input from each of these receptors and monitoring the change in ventilatory pattern. These interventions produced a marked slowing of ventilatory frequency, with long apneic periods. Apnea can also be produced during sleep (with few to no apneas during wakefulness) by partial destruction of the pre-Bötzinger complex in rats.17 The pre-Bötzinger complex is a major site of respiratory rhythm generation and is modulated by chemoreceptor stimuli. In humans, oxygen administration, which reduces the hypoxic stimulus to breathing, has been shown to decrease ventilation during sleep and to initially prolong apneas in some persons in whom such events were already present. In addition, hypocapnic alkalosis, which reduces the hypercapnic ventilatory drive, has been shown to produce central apneas in otherwise normal men.18,19 This combination of studies indicates the importance of both the hypoxic and the hypercapnic influences on breathing during sleep. The implication is that maintenance of neuronal output to the respiratory muscles during sleep may be critically dependent on incoming stimuli, such as those from chemoreceptors. Considerable investigation has been directed at determining the influence of sleep itself on chemoreceptor activity.20,21 Although this is still controversial, the majority of the available information suggests that ventilatory responses to hypoxia and hypercapnia are reduced somewhat during NREM sleep and fall further during rapid eye movement (REM) sleep.20,21 However, several studies indicate that the decrement during NREM sleep is very likely a product of diminished resistive load compensation (reduced defense of ventilation in the presence of the normal physiologic increase in upper airway resistance associated with NREM sleep) rather than a true loss of chemosensitivity.22 Most investigators believe that chemoresponsiveness is reasonably well maintained during sleep, particularly NREM sleep, and is probably important in maintaining rhythmic ventilation during sleep.
Arterial Carbon Dioxide Tension and Breathing during Sleep In his classic studies, Bülow23 showed that periodic breathing during sleep was related to Pco2 in an important way. He observed that apnea or pronounced reduction of ventilation occurred “only when the preceding Pco2 was relatively low,” suggesting that a reduced Pco2 during sleep can decrease the drive to breathe to the point of apnea. Other studies have confirmed the prominent role played by Pco2 in maintaining rhythmic breathing during sleep. Skatrud and Dempsey18,24 showed that passive positivepressure hyperventilation of sleeping subjects yielded apnea by reducing Pco2 by only 3 to 6 mm Hg below the sleeping value. The actual Pco2 level associated with apnea was often only 1 to 2 mm Hg below the awake value as Pco2 rose from wakefulness to sleep. Each subject had an “apnea threshold,” a Pco2 level below which apnea was commonly seen. It seemed, therefore, that the waking Pco2 level was at or near this apnea threshold, such that waking Pco2 levels may be inadequate to stimulate ventilation during sleep. It was also demonstrated that the periodic breathing during sleep that is often seen with prolonged hypoxia could be abolished by elevating the Pco2 above the predetermined apnea threshold. This finding suggests that the hypocapnia induced by hypoxia, not hypoxia itself, is the pivotal element in this periodic breathing. The authors19 concluded “that effective ventilatory rhythmogenesis in the absence of stimuli associated with wakefulness is critically dependent on chemoreceptor stimulation secondary to Pco2−[H+].” Subsequent studies by this same investigative group suggest that increased tidal volume (mediated by vagal mechanisms) might also be a primary mechanism inhibiting inspiration after a series of large breaths.25 However, the concept of hyperventilation ultimately leading to an inhibition of inspiratory effort as reflected by a central apnea (whether secondary to hypocapnia or vagal mechanisms), remains intact and is likely to be an important one in understanding the pathogenesis of central sleep apnea. Ventilatory Control Stability The mechanisms just described are all seemingly designed to maintain ventilatory stability during wakefulness and sleep, thus avoiding large swings in ventilatory pattern and arterial blood gases. However, abnormalities in the various components of this ventilatory control system can lead to ventilatory instability. This can best be understood by introducing the concept of loop gain, an engineering term that describes the gain of the negative feedback loop that regulates ventilation. Figure 100-2 is a block diagram showing the three major components of this loop: the plant, the circulation delay, and the controller. Plant refers to the lungs, blood, and body tissues where carbon dioxide is stored. Plant gain is the change in alveolar Pco2 for a given change in ventilation. The circulation delay is the time it takes for pulmonary capillary blood to reach the chemoreceptors and is primarily influenced by the cardiac output. The controller represents all the structures responsible for converting chemoreceptor stimuli into ventilation. Controller gain is the change in ventilation for a given change in arterial Pco2.
CHAPTER 100 • Central Sleep Apnea and Periodic Breathing 1143 10
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PaCO2 (mm Hg) Figure 100-2 The chemical control feedback loop for PCO2. A decrease in ventilation [D Ventilation (disturbance)] produces an increase in alveolar PCO2 (ΔPACO2) as a function of the plant gain. The PACO2 signal gets delayed (circulation delay) and mixes with the existing blood in the heart and arteries before changing arterial PCO2 (PaCO2) in the vicinity of the chemoreceptors. This elicits an increase in ventilation [D Ventilation (response)] as a function of the controller gain, or chemoresponsiveness. Loop gain is calculated by dividing the magnitude of the response by the magnitude of the disturbance.
Loop gain, which is the product of the plant and controller gains, is defined as the ventilatory response to a disturbance of ventilation. For example, a reduction in ventilation [D Ventilation (disturbance)], (see Fig. 100-2) produces a change in alveolar Pco2, which, after a delay, produces a change in ventilation [D Ventilation (response)] at the controller. The ratio of the ventilatory response to the ventilatory disturbance is a measure of the stability of the ventilatory control system. A large ratio (high loop gain) indicates an unstable system prone to large swings in blood gases and ventilation. A small ratio, on the other hand, indicates a stable system that exhibits little or no ventilatory fluctuations in response to a disturbance. The dynamic aspects of loop gain that are important to ventilatory control stability are illustrated in Figure 100-3. In this figure, the ventilatory control system is disturbed by reducing ventilation slightly and holding it at a reduced level for several minutes. This produces an increase in the ventilatory drive to breathe. Note that it takes time for ventilatory drive (the response) to reach its final, steady-state value and that the ventilatory response to disturbance ratio is maximal when the response achieves a steady state. Thus, loop gain is not a single number, but rather it is a function of (1) the duration
Figure 100-3 Ventilatory response to disturbance ratio (loop gain) as a function of time. The ventilatory control system is disturbed by reducing ventilation (solid line) from the baseline of 6 L/min to 5 L/min. Therefore, the magnitude of the disturbance (downward arrow) is 1 L/min. This produces an increase in ventilatory drive, which is the ventilation desired by the ventilatory control system in response to the disturbance. Loop gain is calculated by dividing the magnitude of the response (upward arrows) by the magnitude of the disturbance. Note that this ratio depends on the time at which the response is measured. If the response is measured at time 60 seconds, then the loop gain ratio is 1.6. However, if the response is measured at time 120 seconds, then the loop gain ratio is 2.5.
of the disturbance and (2) the time it takes for the response to reach a steady state. In general, a more prolonged disturbance of ventilation means more time for the response to reach a new steady state, and thereby a higher loop gain. This has particular relevance to patients with Cheyne-Stokes respiration and congestive heart failure, in whom the prolonged circulation delay produces a slow cycle frequency (i.e., long apneas and long hyperpneas). Thus, there is more time for blood gases and ventilation to reach a steady state during the apnea and hyperpnea phases. A rapidly responsive ventilatory control system, in which the response achieves a steady state quickly, also tends to yield an elevated loop gain. This is the likely mechanism in high-altitude periodic breathing and hypoxia-induced periodic breathing. In these conditions, the fast-responding peripheral chemoreceptors are accentuated, and thus a near-steady state is more likely to be achieved when the ventilatory control system is disturbed. Sleep-Onset Central Apneas Ventilation is remarkably dependent on the metabolic control system during sleep and the primary stimulus to ventilation during sleep is arterial Pco2. As a consequence, central apneas can occur when the wakefulness drive is lost during the transition from wakefulness to sleep. The mechanism of sleep-onset central apnea is illustrated in Figure 100-4, which shows a plot of the CO2 controller gain during sleep and the metabolic hyperbola. During sleep, the intersection of the two lines marks the steady-state
1144 PART II / Section 13 • Sleep Breathing Disorders 15
0
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Figure 100-4 Mechanism of sleep onset central hypopneas and apneas. A, During sleep in the steady state, ventilation and PCO2 are determined by the intersection of the controller curve with the metabolic hyperbola. During wakefulness, there is an additional (nonmetabolic) drive to breathe, and thus ventilation and PCO2 are to the left of the asleep steady state point. At sleep onset, the wakefulness drive (arrow) is withdrawn and a transient hypopnea occurs until PCO2 rises back to baseline. B, If the wakefulness drive is elevated, and thus the awake ventilation and PCO2 are even further to the left of the asleep steadystate point, a central apnea will occur at sleep onset. A rightward shift in the controller curve (C) or an increase in the controller gain (D) will also predispose to central apneas.
Ventilation (L/min)
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Figure 100-5 Hypoventilation during sleep could be due to a reduction in controller gain without a change in the PCO2-apnea threshold (A), an increase in the apnea threshold without a change in controller gain (B), or a combination of the two. Note that the PCO2 (where the lines cross) is high in both conditions. However, an increase in ventilation is not likely to lower PCO2 below the apnea threshold in A. On the other hand, to the extent that hypoventilation is due to an increase in apnea threshold with a preserved controller gain (B), the likelihood of periodic central apneas increases.
ventilation and Pco2. During wakefulness, however, there is an additional drive to breathe (the wakefulness stimulus), and thus ventilation will be slightly higher (and Pco2 slightly lower) than during sleep. At sleep onset, when the wakefulness drive is withdrawn, central hypopnea or apnea can occur (Fig. 100-4A). A central apnea is likely if there is a large wakefulness drive to breathe (see Fig. 100-4B), if there is a rightward shift in the controller curve (see Fig. 100-4C), or if there is a high controller gain or a flat metabolic hyperbola (see Fig. 100-4D). To the extent that any of these factors are present, an excessive number of central events can occur at the wake-to-sleep transition, producing a pattern indistinguishable from idiopathic central sleep apnea. Likewise, any process that leads to frequent wake– sleep transitions over the course of the night (such as insomnia, obstructive sleep apnea, maladaptation to CPAP, or periodic leg movements) can increase the number of central apneas. It should be clear, however, that nonrepetitive central hypopneas and apneas in the wake-to-sleep transition are probably normal events.
nisms are no longer operative, there may be little residual drive to breathe, and thus significant hypoventilation can occur. Periodic central apneas, however, would be unexpected due to the low loop gain (Fig. 100-5A). This is generally the case in patients with disorders such as central alveolar hypoventilation (Ondine’s curse)26 and the obesity hypoventilation (pickwickian) syndrome.27 If, however, hypercapnia results from a general reduction in the drive to breathe without significant change in the controller gain—namely, a rightward shift in the controller gain line—then cycling central apneas would be expected (see Fig. 100-5B). This is likely to be the case in patients taking opioid medications, in whom central apneas in association with hypoventilation are common.28,29
Hypercapnic Respiratory Failure With loss of wakefulness, ventilation becomes completely dependent on metabolic control mechanisms. In persons with reduced controller gain (i.e., low or absent response to hypoxia or hypercapnia), breathing during wakefulness may be maintained by behavioral or wakeful stimuli. However, during sleep, when these wakefulness mecha-
Idiopathic Central Sleep Apnea By definition, the pathogenesis of idiopathic central sleep apnea is not entirely clear. A handful of studies30-33 have shown that these patients tend to have a high hypercapnic response and low arterial Pco2 levels during wakefulness, suggesting that an elevated loop gain may be responsible for the periodic central apneas. However,
CHAPTER 100 • Central Sleep Apnea and Periodic Breathing 1145
careful examination of the actual ventilatory pattern in this disorder suggests that other mechanisms might be involved as well. A pure cycling of chemoreceptor (Pco2)-mediated respiratory output would yield a gradual waxing and waning of ventilation, with an apnea or hypopnea at the nadir as is seen in Cheyne-Stokes respiration (see later). In idiopathic central sleep apnea, the ventilatory pauses are often terminated with an abrupt, large breath, not with a gradual increment in ventilation. Although the explanation for this has not been fully elucidated, this pattern strongly suggests that the mechanisms involved in respiratory switching (expiration to inspiration) are affected by this disorder.34 The long expiratory pause that characterizes these central apneas seems to be a failure of the expiratoryto-inspiratory switch, which may be influenced by not only the chemoreceptors but other mechanisms as well (lung volume, chest wall mechanoreceptors, blood pressure). How these inputs individually contribute to this cycling ventilatory pattern is unclear. However, the pattern of central sleep apnea clearly suggests a different mechanism from that of Cheyne-Stokes breathing. Cheyne-Stokes Respiration It has long been recognized that congestive heart failure is associated with Cheyne-Stokes respiration during wakefulness and sleep, characterized by a crescendo–decrescendo pattern of tidal volume with a central apnea or hypopnea at the nadir. As stated earlier, this is quite different from the more-abrupt onset and offset of idiopathic central sleep apnea. This breathing pattern is almost entirely a product of ventilatory control system instability (high loop gain) resulting primarily from a prolonged circulation time. As previously discussed (see Ventilatory Control Stability), a prolonged circulation delay means that ventilatory disturbances (e.g., apnea or hyperpnea) go unrecognized, and therefore uncorrected, for a longer time. This leads to greater changes in blood gases and a larger ventilatory response-to-disturbance ratio. A prolonged circulation delay alone, however, is probably not sufficient in most patients to raise the loop gain high enough to produce Cheyne-Stokes respiration. In anesthetized animals, a several-fold increase in circulation time was needed to induce periodic breathing.35 Such an increase is probably greater than what commonly occurs with heart failure. Thus, an elevated controller gain36 or plant gain are probably also necessary. This might explain why the severity of heart failure does not alone account for the presence or absence of Cheyne-Stokes breathing. Cheyne-Stokes respiration has been reported in patients with neurologic disease as well, primarily cerebrovascular disorders37; however, the actual ventilatory pattern in these patients has been less well characterized than in patients with congestive heart failure, and the mechanisms remain less well understood. Neurologic Disorders and Central Sleep Apnea Ventilation during sleep is highly dependent on the metabolic control system, and as a result, any neurologic disorder affecting this system could influence the ventilatory pattern while the person is asleep, possibly leading to central sleep apnea. Various neurologic processes have been implicated in the development of central sleep apnea.
Patients with autonomic dysfunction,38 such as the ShyDrager syndrome, familial dysautonomia, or diabetes mellitus, often have apneas that are generally of central origin, although obstructive events are also reported. These patients have also been noted to have erratic breathing during sleep even when central apneas are not obvious. Because the brainstem is the primary source for generating ventilatory patterns and processing respiratory afferent input from chemoreceptors and intrapulmonary receptors, any disease process affecting this area could influence ventilation during sleep. An example is poliomyelitis, a disease well known to damage medullary neurons.39 In the early stages of the postpolio syndrome, respiration during wakefulness is normal, although short central apneas or mild hypoventilation can occur during sleep. With progression of this process (which can take decades), ventilation during sleep becomes progressively more abnormal, with longer, more frequent apneas and with greater hypoventilation as hypoventilation during wakefulness may become apparent. Finally, some patients actually require ventilatory support during sleep and wakefulness if the disease progresses that far. Other processes, such as tumor,40 infarction,41 hemorrhage, or encephalitis,42 can damage the medullary area, leading to breathing dysrhythmias during sleep, with central apneas being a prominent feature. In addition, if the neural pathways from these medullary respiratory neurons to the motoneurons of the ventilatory muscles are interrupted (without damage to the brainstem itself), the metabolic control of breathing may be affected. This interruption is not an uncommon event after cervical cordotomy,43 and central apnea is described after this procedure. Finally, chronic neuromuscular diseases, such as muscular dystrophy or myasthenia gravis, can lead to waking alveolar hypoventilation, with further hypoventilation during sleep. This is occasionally associated with central apneas, although hypoventilation is the more prominent disorder. In fact, as with most patients with postpolio syndrome, ventilation during sleep in patients with ventilatory muscle disease often deteriorates well before waking ventilation is affected. The treatment of the nocturnal hypoventilation with noninvasive ventilation can delay ventilatory failure during wakefulness. Complex Sleep Apnea The term complex sleep apnea has been used by some to describe patients who initially have obstructive sleep apnea during a diagnostic sleep study but develop more than five central apneas per hour of sleep during administration of therapeutic CPAP. The pathogenesis of this phenomenon is not known, but several hypotheses have been proposed. One is that patients with complex sleep apnea have an elevated loop gain in combination with a narrow upper airway. Thus, when CPAP is applied, it eliminates the upper airway obstruction but does not correct the ventilatory control instability. Hence, cyclic breathing with central apnea persists. However, if the definition of complex sleep apnea requires that disordered breathing be purely obstructive in the absence of CPAP, then a high loop gain is probably not responsible for the central apneas. A high loop gain, particularly one that is high enough to produce repetitive central apneas on CPAP, will almost surely produce some evidence of central, or at least mixed,
1146 PART II / Section 13 • Sleep Breathing Disorders
events during the diagnostic study when there are large disturbances to the ventilatory control system due to arousals and upper airway obstruction. It is also unlikely that CPAP raises the loop gain per se. In addition, the central events occurring on CPAP in these patients are not as strongly periodic as one might expect if a high loop gain were the mechanism. Rather, the events are often aperiodic (or only weakly periodic). Thus, a high loop gain could be responsible for the persistence, but probably not the emergence, of central apneas on CPAP. Another possibility is that activation of the Hering-Bruer reflex by increased lung volume on CPAP produces prolonged expiration to the point of central apnea in some patients. Although this reflex is weak in humans during wakefulness, Hamilton, and colleagues44 showed that it is quite active during sleep and that an increase in lung volume of 1 to 1.5 L (roughly 10 to 15 cm H2O), can prolong expiration by several seconds. This is consistent with the fact that central apneas seem to be more common in patients who are overtitrated, in which the high lung volumes may be eliciting reflex prolongation of expiration. Lastly, central events on CPAP could potentially be due to maladaptation to the device, with frequent arousals causing hyperventilation and sleep-onset central apneas. The extent to which any or all of these mechanisms participate in the pathogenesis of complex sleep apnea awaits further study.
EPIDEMIOLOGY If central sleep apnea as a disorder is to be understood and recognized, it is important to determine how commonly central apneas occur in normal persons. The reported frequency of disordered breathing, and in particular the individual patterns, varies depending on the population studied, the methods used to detect apnea, and the threshold used to define abnormalities.45 Carskadon and Dement46 found that 37.5% of all subjects older than 62 years had apneas or hypopneas, and most of the time, “when determinations were possible, apneas were primarily of central type.” Other studies report an incidence of central sleep apnea of between 12% and 66%,47-50 depending on the population investigated. Lugaresi and colleagues51 stated that “central apneas lasting 5 to 15 seconds may appear during light and REM sleep” in normal subjects. With these limitations in mind, a frequency of more than five central apneas per hour of sleep is generally considered abnormal. Although most research-based studies require a greater frequency of events for inclusion, a report from the American Academy of Sleep Medicine in 2005 defined idiopathic (or primary) central sleep apnea as the presence of five or more central apneas per hour of sleep in patients who are excessively sleepy during the day, have frequent nocturnal arousals or awakenings, or awaken short of breath.52 This same report defined Cheyne-Stokes respiration as at least 10 central apneas and hypopneas per hour, with a crescendo–decrescendo tidal volume pattern, in a patient with a serious medical condition (congestive heart failure, stroke, or kidney failure).52 Thus, a standard now exists for defining these syndromes. In the four studies that specifically considered patients with symptomatic idiopathic central sleep apnea, no con-
sistent epidemiologic trends emerge. Guilleminault’s group,1 White’s group,53 and Bradley’s group30 reported a strong male predominance; Roehrs’s group9 observed central apneas more commonly in women. No explanation can be offered for this discrepancy. All studies, however, noted that this disorder occurred most commonly in middle-aged to older adults, although a few younger patients have been reported. In the case of Cheyne-Stokes respiration, a number of reports suggest that patients with congestive heart failure might have periodic breathing during sleep, particularly in men, persons older than 60 years, and patients with atrial fibrillation.54,55 One study suggests that 45% of patients with congestive heart failure (left ventricular ejection fraction <40%) have more than 20 central apneas plus hypopneas per hour of sleep.56 Thus, Cheyne-Stokes respiration during sleep in patients with congestive heart failure is likely to be quite common. In regard to complex sleep apnea, the prevalence of truly CPAP-emergent central sleep apnea (in which patients with Cheyne-Stokes respiration, heart failure, mixed apneas, or central apneas before CPAP treatment are excluded) is reported to be between 7% and 20% of patients.57-60 A strong male predominance is also suggested in most studies. Lastly, several recent studies indicate that opioid medications, particularly long-acting opioids like methadone, are associated with central apneas. The prevalence of a central apnea index of 5 is between 30% and 75% in patients taking around-the-clock opioids for chronic pain or addiction to narcotics,29,61,62 and the strongest predictor is dose, with the central apnea index increasing as a function of morphine dose equivalent.63
CLINICAL FEATURES AND CONSEQUENCES Idiopathic Central Sleep Apnea The clinical presentation of patients with central sleep apnea varies dramatically depending on the cause of the apnea (Box 100-1). Patients with alveolar hypoventilation (waking hypercapnia) due to a number of possible causes (see “Pathophysiology,” earlier) make up a small percentage of patients with central sleep apnea and generally present with symptoms suggestive of ventilatory failure,30,64 including cor pulmonale, peripheral edema, and polycythemia. Restless sleep and daytime sleepiness are also commonly reported in these patients. On the other hand, nonhypoventilating (normocapnic) patients with idiopathic central sleep apnea have no symptoms of ventilatory failure; these patients have a constellation of symptoms that may be similar to that of patients with obstructive apnea, although differences do exist.1,9,53 On the basis of several studies1,30,53 and personal experience, it seems that persons with idiopathic central sleep apnea less commonly complain of daytime hypersomnolence than do patients with obstructive sleep apnea. As the proportion of obstructive or mixed events increases in these patients (still with predominantly central apnea), hypersomnolence can occur more often. The primary complaint of many patients with idiopathic central sleep apnea tends to be insomnia, restless sleep, or frequent
CHAPTER 100 • Central Sleep Apnea and Periodic Breathing 1147
Box 100-1 Clinical Characteristics of Patients with Sleep Apnea Central Hypercapnic Respiratory failure Cor pulmonale Polycythemia Daytime sleepiness Snoring Nonhypercapnic Daytime sleepiness Insomnia (restless sleep) Mild and intermittent snoring Awakenings (± choking, shortness of breath) Normal body habitus Obstructive Daytime sleepiness Prominent snoring Witnessed apneas/gasping Commonly obese
awakenings during the night. Such awakenings may be accompanied by gasping for air or shortness of breath. These patients also tend to have a normal body habitus, unlike the characteristically obese patient with obstructive apnea. As a result, patients with central sleep apnea as a group may be clinically distinguishable from those with obstructive apnea, although separation of the two disorders by history alone is often difficult (see Box 100-1). The frequency and duration of central apneas required to produce the clinical symptoms described are difficult to determine from the available literature1,9,30,53,65 and can vary considerably across patients.66 In light of absence of evidence, five central events per hour of sleep has been arbitrarily set as the upper limit of normal. Evidence-based data are clearly needed before a meaningful threshold can be chosen. As expected, arterial oxygen desaturation occurs with central apneas. The degree to which the saturation falls during a given apnea is likely to be related to the saturation (or Po2) at the time ventilation ceased, the duration of the apnea, and the lung volume at which the apnea occurred.67 Whether inspiratory effort is occurring (obstructive apnea) or not (central apnea) may also have a minor effect on the rate of desaturation.68 Patients with obstructive apnea generally seem to reach a lower arterial oxygen saturation during an apnea than do patients with central events; this is probably a product of longer apnea duration, reduced lung volume (lower in patients with obstructive apnea due to obesity), and the presence of inspiratory efforts in patients with obstructive apnea. There are only limited studies of the hemodynamic consequences of central apneas. An early study by Schroeder and colleagues69 reported that pulmonary artery pressures increased from 26/16 mm Hg during wakefulness to 41/26 mm Hg during central apneic episodes. A study by Podszus and coworkers70 reported virtually no change in pulmonary artery pressure during central apneas or the central component of mixed apneas despite considerable
arterial oxygen desaturation; however, it seems highly probable that any elevation in pulmonary pressure associated with central apnea will result from hypoxemia and hypercapnia, with the hypoventilating patient with central apnea demonstrating more-severe pressure elevations. There are few data addressing the impact of central apnea on systemic pressures, but Schroeder and colleagues69 reported systemic arterial pressures to increase from 155/84 to 188/117 mm Hg during central apneas in a small number of patients. In addition, White and coworkers71 reported very similar increases in both systemic and pulmonary artery pressures during and after central and obstructive apneas in an anesthetized baboon model. That dysrhythmic breathing can disrupt normal sleep architecture is well known; however, little information is available that specifically addresses central sleep apnea in this role. White and colleagues53 reported an improvement in sleep efficiency and a trend toward more time in deeper (stages 3 and 4) sleep and REM sleep after the treatment of central sleep apnea, which suggests that sleep was disrupted by the apneas. In fact, the six patients reported in that study had a mean of 209 apnea-associated awakenings and arousals during the night before therapy. Roehrs and colleagues9 also found a reduction, compared to what is generally considered to be normal, in the percentage of stage 3 or 4 sleep and an increase in stage 1 or 2 sleep in a group of patients in whom about 50% of apneas were central. The results of these studies suggest that the frequent arousals and awakenings generally associated with the hypercapnia after an apnea can lead to disruption of the normal distribution of sleep stages. Cheyne-Stokes Respiration Considerable data indicate important adverse consequences from Cheyne-Stokes respiration. These studies indicate that the hyperpneic phase of this cycling ventilation leads to frequent arousals and poor sleep quality. Several studies have reported reduced survival rates in persons with left ventricular failure and Cheyne-Stokes respiration72,73 compared with patients with heart failure who breathed rhythmically. At least two studies specifically associated central apneas during sleep with decreased survival rates in these patients.72,73 This may be a product of the increased hypoxia and catecholamines74 found in patients with Cheyne-Stokes respiration. Thus, this nocturnal ventilatory pattern has serious potential health consequences. Complex Sleep Apnea The clinical picture of complex sleep apnea patients is virtually indistinguishable from patients with obstructive sleep apnea (OSA) who do not exhibit central apneas during CPAP administration.58,59 Dernaika and coworkers60 showed that there may be no evidence of occult heart failure in patients who have complex sleep apnea. These authors postulated that in the absence of heart failure, complex sleep apnea is related to frequent arousals on CPAP with subsequent sleep-onset central apnea episodes and that resolution over time was due to acclimatization and thus fewer arousals on CPAP. Two studies suggest that complex sleep apnea may be a transient phenomenon in most patients. Kuzniar and colleagues75 reported that
1148 PART II / Section 13 • Sleep Breathing Disorders
the central events resolved in 7 out of 13 patients who used CPAP for more than 1 month, and Dernaika’s group60 observed that 12 out of 14 patients who had complex sleep apnea had near-complete resolution of central events after 9 weeks of CPAP use. Thus, this disorder may resolve over time in many patients.
DIAGNOSTIC EVALUATION The diagnosis of central sleep apnea generally requires a full-night recording of standard polysomnographic variables with a particular focus on identifying inspiratory effort. To prove that an apnea is indeed central, it must be documented that there is no inspiratory effort throughout the event. This is most effectively and consistently accomplished with an esophageal balloon catheter recording intrathoracic pressure swings that reflect ventilatory effort.76,77 Therefore, in the research setting, esophageal pressure should be measured to definitively document apnea type. Recognizing the patient and laboratory burden associated with use of an esophageal balloon catheter, other strategies have been used. Most evidence suggests that respiratory inductive plethysmography or strain gauges can adequately assess inspiratory effort.76,78 If there is a complete absence of thoracoabdominal motion (respiratory inductive plethysmography [RIP] or strain gauges) throughout an apnea, this strongly suggests the event is central in origin. Although evidence suggests that chest and abdominal wall motion as a measure of effort can overestimate the frequency of central apnea, rarely is the patient misclassified with the use of this methodology.76 A third method of assessing effort would be the use of diaphragmatic electromyography, although this is often difficult to obtain and therefore not always reliable. Classic teaching has suggested that pulse wave artifacts in the oronasal flow signal indicate a patent airway and, therefore, a central apnea. However, a study by Morrell and colleagues79 indicates that this approach is unreliable. Distinguishing central from obstructive hypopneas is extraordinarily difficult and cannot be reliably accomplished with noninvasive monitoring techniques. As a result, central apneas, not hypopneas, must be documented to make a definitive diagnosis of central sleep apnea. TREATMENT Alveolar Hypoventilation and Central Sleep Apnea Because there are few large series of patients with central sleep apnea, investigation into treatment has been somewhat limited. Two general types of therapeutic approaches have emerged depending on the cause of the central apnea. For the hypercapnic patient with alveolar hypoventilation during wakefulness and worsening hypoventilation during sleep with occasional central apneas, nocturnal ventilatory assistance is the most appropriate approach. Originally, such ventilation was accomplished only with tracheostomy with a mechanical ventilator, diaphragmatic pacing, or negative-pressure (cuirass) ventilators.77,80,81 Newer studies indicate that nocturnal ventilatory assistance can be accomplished satisfactorily with a nasal mask and a pressure- or
volume-cycled ventilator,82-84 so the ease of administration has improved substantially, as has patient acceptance. Most patients in whom these techniques have been used have some form of central alveolar hypoventilation or respiratory nerve or muscle disease with severe nocturnal hypoxia and hypercapnia. For patients with central sleep apnea due to opioids, who generally have some degree of hypoventilation and hypoxemia, lowering the opioid dose may be helpful because the effect on central apneas is dose dependent. If the dose cannot be decreased, bilevel positive pressure with a fast back-up rate (12 to 16 breaths per minute)85 or adaptive servoventilation86 may be beneficial, although one study showed little improvement with adaptive servoventilation, probably due to inadequate expiratory positive airway pressure (EPAP) and residual obstructive hypopneas.87 CPAP alone is not helpful in this patient population, because it generally tends to worsen the number of central apneas (for unclear reasons) and does not improve the nocturnal hypoxemia.86,87 Thus, ventilatory assistance is probably necessary, although clinical trials are needed to determine the best treatment approach. Idiopathic Central Sleep Apnea Medication For the patient with insomnia, restless sleep, waking hypersomnolence, and mild to moderate nocturnal hypoxemia secondary to central sleep apnea, a number of therapeutic options are available. First, if no known predisposing abnormality can be found, several pharmacologic approaches can be attempted. Acetazolamide, a carbonic anhydrase inhibitor known to produce a metabolic acidosis and probably a shift in the Pco2 apnea threshold to a lower value, has been used to treat central sleep apnea.53 In a series of six patients, acetazolamide (250 mg four times daily) was shown to reduce central apnea substantially in all participants when used over a short period (1 to 2 weeks). Long-term use of this medication was assessed in only two subjects and was successful in one and unsuccessful in the other. However, a study10 of 14 patients with central apnea suggests that acetazolamide might lead to a more sustained improvement in apnea frequency and symptoms (primarily hypersomnolence). Subsequent discontinuation of acetazolamide did not lead to an immediate return of symptoms or events.11 On the other hand, several studies have reported the development of obstructive apneas after acetazolamide administration in patients previously demonstrated to have central events.6 The explanation for this remains obscure but might relate to the ventilatory-stimulating activity of acetazolamide in a patient with a collapsing airway during sleep. When little ventilatory effort is present, the apneas appear central. However, when drive to the inspiratory chest wall muscles is stimulated, obstructive events develop. Clearly, follow-up sleep studies are necessary in patients being treated with acetazolamide, particularly if symptoms persist. Isolated reports of the use of other medications, such as theophylline, naloxone, and medroxyprogesterone acetate, imply that these drugs have little efficacy in the treatment of central apnea.1 Benzodiazepines, on the other hand, can
CHAPTER 100 • Central Sleep Apnea and Periodic Breathing 1149
significantly reduce the number of central events, particularly when frequent arousals (with subsequent sleep-onset central apneas) are thought to be the primary mechanism.88-90 Clomipramine (a tricyclic antidepressant) was successful in several patients in whom it was tried.1 Theophylline improved apnea in a patient with a damaged brainstem.91 The efficacy and safety of these drugs has not been systematically studied, so firm recommendations regarding their use cannot be made. Positive Airway Pressure, Inhalation of O2 and CO2 CPAP has been shown to be effective therapy for some patients with central sleep apnea.92,93 Pharyngeal airway collapse or closure during sleep may initiate a reflex inhibition of ventilation in some patients and therefore a central apnea. CPAP prevents airway closure, and abolishes such apneas. Similarly, in obese snoring patients with predominantly central apneas, CPAP may be effective therapy. An abstract suggests that CPAP might also be a viable form of therapy in idiopathic central sleep apnea.94 This efficacy was attributed primarily to a CPAP-induced increase in arterial Pco2 such that it was kept above the apnea threshold. Thus, some patients with central apnea might respond to CPAP, although the final role of this modality in central apnea must await further investigation. Some patients may benefit from positive pressure ventilatory assistance, including a timed back-up rate. A number of studies suggest that oxygen may be a useful method of treating central sleep apnea. Martin and coworkers95 observed that central apneas were completely abolished with oxygen administration in two patients during a short-nap study. McNicholas and colleagues96 found a considerable reduction in the number of central apneas present in a patient with central alveolar hypoventilation after oxygen therapy was begun. A study evaluating the effects of low-flow oxygen in nine obese patients with a large component of central apneas reported a considerable reduction in these central events.97 However, the frequency of obstructive apneas was somewhat increased. The mechanism by which oxygen reduces central apnea is probably related to the fact that it decreases controller gain98-105 and thereby stabilizes breathing. Mild increases in inspired carbon dioxide might be effective for this disorder. Xie’s group demonstrated near resolution of central apneas with inhaled CO2 or added dead space in patients with idiopathic central sleep apnea.106 The mechanism is likely due to a widening in the difference between eupneic Pco2 and the apnea threshold, as well as a reduction in plant gain (less change in Pco2 for a given change in ventilation). Larger trials are needed to determine the long-term efficacy and safety of inhaled CO2 for the treatment of this disorder. Choosing Therapy When managing patients with predominantly central sleep apnea, it must be remembered that both central and obstructive apneas are commonly seen in the same person. In these patients, it is often difficult to determine whether the primary cause of the apnea is of central origin or relates to upper airway obstruction, or both. Therefore, in patients who have central apnea with a large component of obstruc-
tive events, treatment of the airway obstruction via one of the currently available methods may have beneficial effects on both types of apnea. Cheyne-Stokes Respiration The treatment of Cheyne-Stokes respiration requires special comment because it has been the subject of a number of studies. First, the heart failure (if present) should be treated as aggressively as possible. Optimal medical treatment, however, abolishes the sleep apnea in only a minority of patients who had originally presented with acute left ventricular failure.107 Second, should this fail, a number of additional options are available. Nocturnal oxygen administration has been shown to reduce apnea frequency and improve symptoms in several studies of congestive heart failure and Cheyne-Stokes respiration.108-110 Several medications have also demonstrated some efficacy; these include theophylline111 and possibly hypnotic agents.88,112 Finally, CPAP has been shown to improve cardiac function in patients with Cheyne-Stokes respiration when used chronically and it has been shown to reduce apnea frequency.113-115 However, the reduction in apneahypopnea index (AHI) is, on average, only about 50%. In patients in whom CPAP is successful at lowering the AHI below 15 events per hour and who adhere to this intervention, one study showed a significant survival benefit.116 There has been an effort to develop positive pressure devices that more specifically address the unstable ventilatory control in these patients. Adaptive servoventilation dampens the fluctuations in breathing by applying supplemental ventilatory support during the apnea–hypopnea phase but only CPAP (or minimal support) during the hyperpnea phase of the periodic breathing cycle. Results so far are encouraging and demonstrate a near-complete resolution of disordered breathing.117,118 However, largescale studies are needed. Complex Sleep Apnea Patients with complex sleep apnea, by definition, do not improve acutely with CPAP, although as mentioned earlier, many such patients improve over time with consistent CPAP use.60 In those who do not improve, the addition of oxygen or CO2 to CPAP or the use of adaptive servoventilation may be effective.117,118
SUMMARY A logical approach to the treatment of central sleep apnea in the symptomatic patient, when it is certain that the apneas are of central origin, is to first rule out treatable causes; these include pharyngeal collapse, congestive heart failure, and, certainly, alveolar hypoventilation. Treatable conditions should be corrected. If no such problem is found, the therapeutic approach must be individualized to the patient. If the patient is obese and snoring or has heart failure, nasal CPAP may be an appropriate first choice. If the patient is hypoxemic during central apneas or the apneas have a clearly periodic nature, then nocturnally administered oxygen may be most appropriate. If none of these conditions exists, then acetazolamide (250 mg four times daily) or possibly hypnotics should be considered.
1150 PART II / Section 13 • Sleep Breathing Disorders ❖ Clinical Pearls Central sleep apnea and periodic breathing occur because the Pco2 during sleep decreases below the apnea threshold. This occurs in the following conditions: • When the ventilatory control system is unstable (high loop gain) such that large fluctuations in ventilation produce periodic hypocapnia and central apnea. • When the awake ventilation lowers Pco2 below the apnea threshold during sleep. • When there is a significant increase in the apnea threshold (rightward shift in the controller curve). The treatment of central sleep apnea must be individualized to the cause of the ventilatory instability. Idiopathic central sleep apnea often responds to oxygen or acetazolamide, whereas Cheyne-Stokes respiration is best treated with positive airway pressure devices. In the obese patient who snores and has substantial central sleep apnea on polysomnography, upper airway obstruction responsive to CPAP is the most likely diagnosis.
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CHAPTER 100 • Central Sleep Apnea and Periodic Breathing 1151 42. White DP, Miller F, Erickson RW. Sleep apnea and nocturnal hypoventilation following western equine encephalitis. Am Rev Respir Dis 1983;127:132-133. 43. Krieger A, Rosomoff H. A respiratory and autonomic dysfunction syndrome following bilateral percutaneous cervical cordotomy. J Neurosurg 1974;39:168-180. 44. Hamilton RD, Winning AJ, Horner RL, et al. The effect of lung inflation on breathing in man during wakefulness and sleep. Respir Physiol 1988;73:145-154. 45. Ancoli-Israel S. Epidemiology of sleep disorders. Clin Geriatr Med 1989;5:347-362. 46. Carskadon MA, Dement WC. Respiration during sleep in the aged human. J Gerontol 1981;36:420-423. 47. Bixler EO, Kales A, Soldatos CR, et al. Sleep apneic activity in a normal population. Res Commun Chem Pathol Pharmacol 1982; 36:141-152. 48. Block AJ, Boysen PG, Wynne JW, et al. Sleep apnea, hypopnea and oxygen desaturation in normal subjects. N Engl J Med 1979; 300:513-517. 49. Block AJ, Wynne JW, Boysen PG. Sleep-disordered breathing and nocturnal oxygen desaturation in postmenopausal women. Am J Med 1980;69:75-79. 50. Webb P. Periodic breathing during sleep. J Appl Physiol 1974; 37:899-903. 51. Lugaresi E, Coccagna G, Cirignotta F, et al. Breathing during sleep in normal and pathological conditions. Adv Exp Med Biol 1978; 99:35-45. 52. American Academy of Sleep Medicine. International classification of sleep disorders. Diagnostic and coding manual, 2nd ed. Westchester, Ill: American Academy of Sleep Medicine; 2005. 53. White DP, Zwillich CW, Pickett CK, et al. central sleep apnea. Improvement with acetazolamide therapy. Arch Intern Med 1982; 142:1816-1819. 54. Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure. Circulation 1998;97: 2154-2159. 55. Sin D, Fitzgerald F, Parker J. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999;160:1101-1106. 56. Javaheri S, Parker TJ, Wexler L, et al. Occult sleep-disordered breathing in stable congestive heart failure [published erratum appears in Ann Intern Med 1995;123(1):77]. Ann Intern Med 1995; 122:487-492. 57. Marrone O, Stallone A, Salvaggio A, et al. Occurrence of breathing disorders during CPAP administration in obstructive sleep apnoea syndrome. Eur Respir J 1991;4:660-666. 58. Morgenthaler TI, Kagramanov V, Hanak V, et al. Complex sleep apnea syndrome: is it a unique clinical syndrome? Sleep 2006;29: 1203-1209. 59. Lehman S, Antic NA, Courtney T, et al. Central sleep apnea on commencement of continuous positive airway pressure in patients with a primary diagnosis of obstructive sleep apnea-hypopnea. J Clin Sleep Med 2007;3:462-466. 60. Javaheri S, Smith J, Chung E. The prevalence and natural history of complex sleep apnea. J Clin Sleep Med 2009;5:205-211. 61. Walker JM, Farney RJ, Rhondeau S, et al. Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing. J Clin Sleep Med 2007;3:455-461. 62. Mogri M, Desai H, Webster L, et al. Hypoxemia in patients on chronic opiate therapy with and without sleep apnea. Sleep Breath 2009;13:49-57. 63. Webster LR, Choi Y, Desai H, et al. Sleep disordered breathing and chronic opioid therapy. Pain Medicine 2008;9:425432. 64. Bradley TD, Phillipson EA. Central sleep apnea. Clin Chest Med 1992;13:492-505. 65. Guilleminault C, Tilkian A, Dement WC. The sleep apnea syndromes. Ann Rev Med 1976;27:465-484. 66. Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163:1925. 67. Findley LJ, Ries AL, Tisi GM, et al. Hypoxemia during apnea in normal subjects: mechanisms and impact of lung volume. J Appl Physiol 1983;55:1777-1783.
68. Fletcher EC, Costarangos C, Miller T. The rate of fall of arterial oxyhemoglobin saturation in obstructive sleep apnea. Chest 1989; 96:717-722. 69. Schroeder JS, Motta J, Guilleminault C. Hemodynamic studies in sleep apnea. In: Guilleminault C, Dement W, editors. Sleep apnea syndromes, New York: Alan R Liss; 1978. p. 177-196. 70. Podszus T, Peter JH, Renke A, et al. Pulmonary artery pressure during central sleep apnea. Sleep Res 1988;17:236. 71. White SG, Fletcher EC, Miller CC 3rd. Acute systemic blood pressure elevation in obstructive and nonobstructive breath hold in primates. J Appl Physiol 1995;79:324-330. 72. Hanley PJ, Zuberi-Khokhar NS. Increased mortality associated with Cheyne-Stokes respiration in patients with congestive heart failure. Am J Resp Crit Care Med 1996;153:272-276. 73. Lanfranchi PA, Braghiroli A, Bosimini E, et al. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation 1999;99:1435-1440. 74. Naughton MT, Benard DC, Liu PP, et al. Effects of nasal CPAP on sympathetic activity in patients with heart failure and central sleep apnea. Am J Respir Crit Care Med 1995;152:473-479. 75. Kuzniar TJ, Pusalavidyasagar S, Gay PC, et al. Natural course of complex sleep apnea—a retrospective study. Sleep Breath 2008;12: 135-139. 76. Boudewyns A, Willemen M, Wagemans M, et al. Assessment of respiratory effort by means of strain gauges and esophageal pressure swings: a comparative study. Sleep 1997;20:168-170. 77. Glenn W, Phelps M, Gersten L, Diaphragm pacing in the management of central alveolar hypoventilation. In: Guilleminault C, Dement W, editors. Sleep apnea syndromes, New York: Alan R Liss; 1978. p. 333-345. 78. Staats BA, Bonekat HW, Harris CD, et al. Chest wall motion in sleep apnea. Am Rev Respir Dis 1984;130:59-63. 79. Morrell MJ, Badr MS, Harms CA, et al. The assessment of upper airway patency during apnea using cardiogenic oscillations in the airflow signal. Sleep 1995;18:651-658. 80. Coleman M, Boros S, Huseby T, et al. Congenital central hypoventilation syndrome. Am Rev Respir Dis 1979;119:901-902. 81. Godfrey C, Man M, Jones R, et al. Primary alveolar hypoventilation managed by negative-pressure ventilators. Chest 1979;76:219221. 82. Guilleminault C, Stoohs R, Schneider H, et al. Central alveolar hypoventilation and sleep. Treatment by intermittent positivepressure ventilation through nasal mask in an adult. Chest 1989; 96:1210-1212. 83. Make BJ, Hill NS, Goldberg AI, et al. Mechanical ventilation beyond the intensive care unit. Report of a consensus conference of the American College of Chest Physicians. Chest 1998;113:289S344S. 84. Shneerson JM, Simonds AK. Noninvasive ventilation for chest wall and neuromuscular disorders. Eur Respir J 2002;20:480-487. 85. Alattar MA, Scharf SM. Opioid-associated central sleep apnea: a case series. Sleep Breath 2009;13(2):201-206 86. Javaheri S, Malik A, Smith J, et al. Adaptive pressure support servoventilation: a novel treatment for sleep apnea associated with use of opioids. J Clin Sleep Med 2008;4:305-310. 87. Farney RJ, Walker JM, Boyle KM, et al. Adaptive servoventilation (ASV) in patients with sleep disordered breathing associated with use of opioids. J Clin Sleep Med 2008;4:311-319. 88. Bonnet MH, Dexter JR, Arand DL. The effect of triazolam on arousal and respiration in central sleep apnea patients. Sleep 1990; 13:31-41. 89. Grimaldi D, Provini F, Vetrugno R, et al. Idiopathic central sleep apnea syndrome treated with zolpidem. Neurol Sci 2008;29:355358. 90. Guilleminault C, Crowe C, Quera-Salva MA, et al. Periodic leg movement, sleep fragmentation and central sleep apnoea in two cases: reduction with clonazepam. Eur Respir J 1988;1:762-765. 91. Raetzo MA, Junod AF, Kryger MH. Effect of aminophylline and relief from hypoxia on central sleep apnea due to medullary damage. Bull Eur Physiopathol Respir 1987;23:171-175. 92. Issa FG, Sullivan CE. Reversal of central sleep apnea using nasal CPAP. Chest 1986;90:165-171. 93. Hoffstein V, Slutsky AS. Central sleep apnea reversed by continuous positive airway pressure. Am Rev Respir Dis 1987;135:12101212.
1152 PART II / Section 13 • Sleep Breathing Disorders 94. Rutherford R, Popkin J, Phillipson EA, et al. Effect of CPAP on Cheyne-Stokes respiration and idiopathic central sleep apnea. Am Rev Respir Dis 1991;143(Suppl.):A197. 95. Martin RJ, Sanders MH, Gray BA, et al. Acute and long-term ventilatory effects of hyperoxia in the adult sleep apnea syndrome. Am Rev Respir Dis 1982;125:175-180. 96. McNicholas WT, Carter JL, Rutherford R, et al. Beneficial effect of oxygen in primary alveolar hypoventilation with central sleep apnea. Am Rev Respir Dis 1982;125:773-775. 97. Gold AR, Bleecker ER, Smith PL. A shift from central and mixed sleep apnea to obstructive sleep apnea resulting from low-flow oxygen. Am Rev Respir Dis 1985;132:220-223. 98. Nielsen M, Smith H. Studies on the regulation of respiration in acute hypoxia. Acta Physiol Scand 1952;24:293-313. 99. Reite M, Jackson D, Cahoon RL, et al. Sleep physiology at high altitude. Electroencephalogr Clin Neurophysiol 1975;38:463-471. 100. Severinghaus JW, Crawford RD. Regulation of respiration. Acta Anaesth Scand Suppl 1978;70:188-191. 101. Cunningham DJC, Robbins PA, Wolff CB. Integration of respiratory responses to changes in alveolar partial pressures of CO2 and O2 and in arterial pH. In: Cherniack NS, Widdicombe JG, editors. Handbook of physiology. The respiratory system. control of breathing. Bethesda, Md: American Physiological Society; 1986. p. 475-528. 102. Bisgard GE, Neubauer JA. Peripheral and central effects of hypoxia. In: Dempsey JA, Pack AI, editors. Regulation of breathing. New York: Marcel Dekker; 1996. p. 617-668. 103. Mohan R, Duffin J. The effect of hypoxia on the ventilatory response to carbon dioxide in man. Respir Physiol 1997;108: 101-115. 104. Duffin J, Mohan RM, Vasiliou P, et al. A model of the chemoreflex control of breathing in humans: model parameters measurement. Respir Physiol 2000;120:13-26. 105. Simakajornboon N, Beckerman RC, Mack C, et al. Effect of supplemental oxygen on sleep architecture and cardiorespiratory events in preterm infants. Pediatrics 2002;110:884-888. 106. Xie A, Rankin F, Rutherford R, et al. Effects of inhaled CO2 and added dead space on idiopathic central sleep apnea. J Appl Physiol 1997;82:918-926. 107. Tremel F, Pepin J, Veale D, et al. High prevalence and persistence of sleep apnoea in patients referred for acute left ventricular failure
and medically treated over 2 months. Eur Heart J 1999;20:12011209. 108. Franklin KA, Eriksson P, Sahlin C, et al. Reversal of central sleep apnea with oxygen. Chest 1997;111:163-169. 109. Hanly PJ, Millar TW, Steljes DG, et al. The effect of oxygen on respiration and sleep in patients with congestive heart failure. Ann Intern Med 1989;111:777-782. 110. Krachman SL, D’Alonzo GE, Berger TJ, Eisen HJ. Comparison of oxygen therapy with nasal continuous positive airway pressure on Cheyne-Stokes respiration during sleep in congestive heart failure. Chest 1999;116:1550-1557. 111. Javaheri S, Parker TJ, Wexler L, et al. Effect of theophylline on sleep-disordered breathing in heart failure. N Engl J Med 1996; 335:562-567. 112. Biberdorf DJ, Steens R, Millar TW, et al. Benzodiazepines in congestive heart failure: effects of temazepam on arousability and Cheyne-Stokes respiration. Sleep 1993;16:529-538. 113. Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005;353:2025-2033. 114. Naughton MT, Liu PP, Bernard DC, et al. Treatment of congestive heart failure and Cheyne-Stokes respiration during sleep by continuous positive airway pressure. Am J Respir Crit Care Med 1995;151:92-97. 115. Sin D, Logan A, Fitzgerald F, et al. Effects of continuous positive airway pressure on cardiovascular outcomes in heart failure patients with and without Cheyne-Stokes respiration. Circulation 2000; 102:61-66. 116. Arzt M, Floras JS, Logan AG, et al. Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation 2007;115: 3140-3142. 117. Morgenthaler TI, Gay PC, Gordon N, et al. Adaptive servoventilation versus noninvasive positive pressure ventilation for central, mixed, and complex sleep apnea syndromes. Sleep 2007;30:468475. 118. Allam JS, Oslon EJ, Gay PC, et al. Efficacy of adaptive servoventilation in treatment of complex and central sleep apnea syndromes. Chest 2007;132:1839-1846.
Anatomy and Physiology of Upper Airway Obstruction
Chapter
101
Richard J. Schwab, John E. Remmers, and Samuel T. Kuna Abstract Patients with obstructive sleep apnea (OSA) develop repetitive pharyngeal airway closure during sleep. Sophisticated physiologic and imaging studies have significantly advanced our understanding of the anatomic risk factors for OSA and illuminated the biomechanical mechanisms by which therapeutic interventions for this disorder such as continuous positive airway pressure, weight loss, oral appliances, and surgery increase upper airway caliber. Pharyngeal airway patency is maintained by a balance of forces between the activity of the upper airway muscles that dilate and stiffen the airway and negative intraluminal pressure. However, this balance can be disturbed by abnormalities in upper airway anatomy and neural control. Patients with OSA have been shown to have a narrowed, more collapsible pharyngeal airway. Sleep-related reduction in upper airway dilating muscle activity can lead to
UPPER AIRWAY FUNCTION The upper airway includes the extrathoracic trachea, larynx, pharynx, and nose. This chapter focuses on the pharynx because it is the site of upper airway narrowing and closure during sleep in patients with obstructive sleep apnea (OSA). The upper airway is a common pathway for digestive, phonatory, and respiratory functions. Deglutition requires the closure of the pharyngeal airway, and phonation requires coordination of the larynx and nasopharynx, valvular structures of the upper airway. As a conduit for airflow, however, pharyngeal patency is critical. With the exception of the upstream and downstream ends of the entire respiratory airway tract (the nares and the small intrapulmonary airways) the pharynx is the only collapsible segment of this anatomically defined system. Normally, the pharynx remains open at all times, except during momentary closures associated with swallowing, regurgitation, eructation, and speech. Pharyngeal patency during wakefulness, with integration and coordination of its various physiologic functions, is in large part attributable to continual neuromuscular control by the central nervous. The sleep state is associated with a decrease in neuromotor output to pharyngeal muscles. When this occurs against the background of anatomic abnormalities of the upper airway, the pharyngeal airway can become severely narrowed or can close. NORMAL UPPER AIRWAY ANATOMY The upper airway has been separated into three regions: the nasopharynx, which includes the posterior margin of the nasal turbinates to the posterior margin of the hard palate; the oropharynx, subdivided into the retropalatal region (the posterior margin of the hard palate to the caudal margin of the soft palate) and the retroglossal region
greater negative intraluminal pharyngeal pressure that further narrows and completely closes the airway. We do not yet fully understand the pathogenesis of OSA, but there are certain fundamental characteristics of airway closure in patients with OSA. Upper airway closure occurs in the oropharynx, usually in the retropalatal region, but it can occur in the retroglossal region or in both regions. There are often multiple sites of pharyngeal airway closure in patients with sleep apnea. Enlargement of the upper airway soft tissues structures are important risk factors for OSA. Pharyngeal airway patency is maintained by a balance between the action of the upper airway dilator muscles and negative intraluminal pressure. Abnormal upper airway anatomy and possibly abnormal neural control during sleep can lead to pharyngeal airway collapse in patients with OSA. This chapter reviews our current understanding of the underlying pathophysiology.
(the caudal margin of the soft palate to the base of the epiglottis); and the hypopharynx, which includes the base of the tongue and epiglottis to the larynx (Fig. 101-1). The majority of patients with OSA manifest upper airway narrowing and closure during sleep in the retropalatal region, the retroglossal region, or both.1,2 In order to evaluate airway closure in patients with OSA it is important to understand how pharyngeal wall structures mediate changes in airway size. The anterior wall of the oropharynx is formed primarily by the soft palate and tongue, and the posterior wall of the oropharynx is composed primarily of the superior, middle, and inferior constrictor muscles. The lateral oropharyngeal walls are formed by several different structures including oropharyngeal muscles (hyoglossus, styloglossus, stylohyoid, stylopharyngeus, palatopharyngeus, palatoglossus, and the superior, middle, and inferior pharyngeal constrictors), lymphoid tissue (palatine tonsils), and adipose tissue (parapharyngeal fat pads). The mandibular rami bound all the structures that form the lateral pharyngeal walls (Figs. 101-2 and 101-3).
STATIC AND DYNAMIC PROPERTIES OF THE NORMAL PHARYNGEAL AIRWAY The mechanical behavior of the pharyngeal airway under passive conditions—that is, in the absence of pharyngeal muscle activity—can be described in terms of the relationship between cross-sectional airway area (A) and transmural pressure (Ptm).3 As depicted in Figure 101-4A, transmural pressure is the difference between intraluminal pressure (PL) and tissue pressure (Pti): Ptm = PL − Pti An increase in transmural pressure, caused either by morepositive intraluminal pressure or more-negative tissue 1153
1154 PART II / Section 13 • Sleep Breathing Disorders Soft palate
A Maxilla
Airway centerline
Mandible
Cervical spine
B
C Tongue D
A
B
Hyoid
Spinal cord
Figure 101-1 A, Midsagittal magnetic resonance image (MRI) in a normal subject highlighting the four upper airway regions: the nasopharynx, which is defined from the nasal turbinates to the hard palate; the retropalatal (RP) oropharynx, extending from the hard palate to the caudal margin of the soft palate; the retroglossal (RG) region from the caudal margin of the soft palate to the base of the epiglottis; and the hypopharynx, which is defined from the base of the tongue to the larynx. B, This diagram demonstrates important midsagittal upper airway, soft tissue, and bone structures.
Airway
Mandible
Box 101-1 Mechanical Influences on the Passive Pharyngeal Airway Static Factors Surface adhesive forces Neck and jaw position Tracheal tug Gravity
Teeth
Tongue
Dynamic Factors Upstream resistance in the nasal airway and pharynx Bernoulli effect Dynamic compliance
Soft palate Parotid
Parapharyngeal fat pad Subcutaneous Spinal fat cord
Pharynageal lateral wall
Figure 101-2 Axial MRI in a normal subject in the retropalatal region. The tongue, soft palate, parapharyngeal fat pads (fat is white on MRI), lateral parapharyngeal walls (muscles between the airway and lateral parapharyngeal fat pads) and mandibular rami can all be visualized on this axial MRI.
pressure, distends and enlarges the airway area. Conversely, a decrease in transmural pressure, caused either by more-negative intraluminal pressure or more-positive tissue pressure, narrows the airway. The mechanical characteristics at a particular region of the passive pharynx are revealed in a plot demonstrating the relation between transmural pressure and intraluminal
cross-sectional area (see Figure 101-4B). This relationship is referred to as the tube law and describes the dependence of cross-sectional area on transmural pressure. The closing pressure (Pclose) is the transmural pressure when cross-sectional airway area reaches zero (i.e., complete obstruction), and the point at which the curve reaches a plateau is the maximum airway area. The slope of the line at any point in the relationship (∆A/∆Ptm) is the effective compliance at that particular transmural pressure. A number of mechanical factors (Box 101-1) influence the upper airway to cause it to be fully open, narrowed, or closed. These factors, classified as static and dynamic, interact with the tube law of the pharynx to determine, at any time, the crosssectional area of the airway. Static Factors Influencing Behavior of the Normal Pharyngeal Airway Surface Adhesive Forces Clinical observations and studies in anesthetized animals indicate that surface adhesive forces between opposed luminal surfaces can contribute to airway patency and closure.4-6 During nasal breathing with the mouth closed, surface adhesive forces help maintain the soft palate in apposition to the base of the tongue and promote contact
CHAPTER 101 • Anatomy and Physiology of Upper Airway Obstruction 1155
Retropalatal axial MR slice
Retroglossal axial MR slice
Midsagittal MR slice
Figure 101-3 Midsagittal MRI in a normal subject depicting the midretropalatal (RP) and midretroglossal (RG) regions.
Pl
Pti
Area
"Tube law"
A
Ptm
Ptm Pclose
Ptm = Pl − Pti
A
Ptm ↑ : Area ↑ ; Ptm ↓ : Area ↓
B
Compliance = dA dPtm
Figure 101-4 A, The concept of transmural pressure (Ptm) and a tube law of the pharynx are schematized. Ptm is defined as intraluminal pressure (P1) minus surrounding tissue pressure (Pti). B, An increase in Ptm results in an increase in the cross-sectional area (A) in accordance with a tube law of the pharynx. The slope of the tube law represents compliance of the pharynx. Pclose, closing pressure; Pti, tissue pressure.
of the tongue with the mucosa of the oral cavity. Mouth opening potentially destabilizes the airway by freeing the mucosal attachments of the tongue and soft palate and allowing these now freely moving structures to relocate posteriorly and compromise the pharyngeal airway. Surface adhesive forces can also make restoration of airway patency more difficult and might explain why the pressure needed to open an already closed airway (opening pressure) is greater than the closing pressure. Although surface adhesive forces are an important determinant of airway patency, reduction in these forces by administering surfactant to the upper airway mucosa results in only a relatively modest reduction in airway collapsibility during sleep.4
Neck and Jaw Position Studies indicate that neck flexion under passive conditions tends to close the airway, and neck extension acts to open it.7 The retropalatal and retroglossal regions of the pharyngeal airway are narrowed as the neck is flexed. Jaw position has also been documented to alter the size of the upper airway. Opening the jaw slightly can actually increase the size of the pharynx by providing more room in the oral cavity for the tongue. This may be particularly important if the tongue is large relative to the oral cavity. However, progressive opening of the jaw leads to posterior movement of the genial tubercle of the mandible: The genial tubercle moves closer to the posterior pharyngeal wall because the mandibular condyle
1156 PART II / Section 13 • Sleep Breathing Disorders
of the temporomandibular joint is considerably rostral to the plane of the mandible (Fig. 101-5). This posterior movement of the genial tubercle of the mandible with mouth opening causes the tongue and hyoid apparatus to move posteriorly, and thereby narrows the pharyngeal airway. Tracheal Tug Increases in lung volume are thought to increase pharyngeal cross-sectional area, reduce closing pressure, and Mandibular condyle
Maxilla
Mental protuberance
Genial tubercle
Hyoid
Sternum Figure 101-5 Jaw opening results in a posterior and caudal displacement of the genial tubercle of the mandible, as well as the floating hyoid bone, through the many hyomandibular attachments. As a result, the anterior pharyngeal wall structures such as the tongue and epiglottis move in a posterior direction, decreasing pharyngeal airway size. Neck flexion would have a similar effect on the hyoid, tongue, and epiglottis even without a change in the relationship between the mandible and the maxilla.
Pharyngeal unfolding
Reduced compliance
stiffen the upper airway.8,9 This action may be exerted through axial forces in the trachea, called tracheal tug. Increasing lung volume causes a caudal displacement of the intrathoracic trachea that, in turn, exerts caudally directed forces on the upper airway. The resulting passive axial tension in the pharyngeal wall tends to open the pharynx. There are at least four mechanisms by which caudal traction on the upper airway may improve airway patency (Fig. 101-6).10 As the upper airway is pulled toward the thorax, folding may be reduced in the walls of both the larynx and oropharynx. Second, stretching should stiffen the upper airway and make it more resistant to collapse. Caudal displacement of fat and other structures surrounding the pharynx can reduce extrinsic compression of the airway. Finally, caudal traction can improve airway patency through its mechanical effect on the hyoid apparatus. Gravity Gravity also has an important influence on pharyngeal airway patency and it is common for patients with OSA to have a higher apnea-hypopnea index in the supine than in the nonsupine position. When the patient is supine, gravity can help to narrow the pharyngeal airway by pulling the tongue and soft palate in a posterior direction.11 Dynamic Properties of the Normal Pharyngeal Airway The upper airway has also been modeled as behaving like a Starling resistor.12 Starling resistor describes a highly collapsible tube having infinite compliance (e.g., more floppy) at one transmural pressure and low compliance (e.g., more stiff) at transmural pressures that are above and below this pressure. The tube is completely closed at one luminal pressure and completely open at a higher luminal pressure. The luminal pressure at which the airway shifts from fully open to fully closed (i.e., the point of infinite compliance) is determined by the extramural pressure and is referred to as the critical pressure (Pcrit).
Pharyngeal decompression
Hyoid retraction
Figure 101-6 Possible mechanisms that can explain how tracheal traction on the upper airway protects upper airway patency (From Van de Graaff WB. Thoracic influence on upper airway patency. J Appl Physiol 1988;65:2124-2131).
CHAPTER 101 • Anatomy and Physiology of Upper Airway Obstruction 1157
Factors Influencing the Dynamic Properties of the Passive Pharyngeal Airway Upstream Resistance within the Nasal Airway Inspiratory airflow through the nose results from a pressure drop between the nares and the nasopharynx, thereby creating a driving pressure. This driving pressure for inspiratory airflow is generated by reduction in nasopharyngeal pressure secondary to active contraction of the diaphragm and other inspiratory pump muscles. The nose has a relatively high resistance and the flow pattern is turbulent, characteristics that are enhanced when the nasal airway is narrowed by such conditions as mucosal congestion, nasal polyps, and turbinate hypertrophy. These factors increase nasal airway resistance during inspiration. This increase is nonlinear relative to inspiratory airflow such that as inspiratory airflow increases, there is disproportionately more negative nasopharyngeal intraluminal pressure generated. Nasopharyngeal pressure is effectively equivalent to the pharyngeal intraluminal pressure if the resistance within the pharynx is relatively low. All other things being equal, increases in nasal resistance produce a more-negative inspiratory swing in pharyngeal intraluminal pressure and consequently, as per the tube law, a reduction of pharyngeal cross-sectional area. The extent to which the lumen narrows depends on regional airway compliance, that is, the relative compliance of each segment. Upstream Resistance within the Pharynx As is the case with nasal resistance, a high resistance within the pharynx is associated with a more-negative intraluminal pressure in more caudal (more downstream) segments during inspiration. In other words, a narrowing at the retropalatal region is associated with a further decline in intraluminal pressure during inspiration at sites caudal to the retropalatal region, thereby increasing the tendency for closure in the retroglossal region and hypopharynx. Bernoulli Effect Two types of physical phenomena promote a reduction in intraluminal pressure as gas flows through a tube: loss of energy by work performed in overcoming flow-resistance aspects of the airway and the Bernoulli effect (the conversion of energy from static to kinetic caused by an increase in the velocity of airflow when cross-sectional airway area decreases). The first phenomenon relates to upstream resistance to airflow. Whenever gas flows through a resistance, potential energy is dissipated in overcoming friction and, consequently, intraluminal pressure decreases. The second phenomenon relates to acceleration of gas as it flows through a narrowed segment of a tube. Both phenomena contribute to decreasing pharyngeal intraluminal pressure during inspiration; therefore, both tend to narrow the pharynx during inspiration. Because pharyngeal pressure must fall below pressure at the airway opening (nares or mouth) to generate inspiratory airflow, nasal or other sites of upstream resistance contribute to the development of negative intraluminal pharyngeal pressure even in the absence of inspiratory flow limitation. However, once inspiratory flow limitation is present, the relatively rigid nasal passage does not contrib-
ute to further pressure drop across the collapsible airway segment. By contrast, progressive narrowing of the upstream pharyngeal segment produces progressively more negative inspiratory intraluminal pressures downstream from the site of narrowing, regardless of inspiratory flow limitation, because of increased viscous energy losses in the narrowed region. If the cross-sectional area of the pharyngeal lumen decreases in some regions, the velocity of airflow is elevated in these regions. This increase in airflow velocity implies an increase in kinetic energy of the airstream and, hence, a decrease in distending pressure. This reduction in distending pressure allows further inspiratory narrowing according to the tube law of the pharynx. Dynamic Compliance During inspiration, the decrease in intraluminal pressure at any point in the upper airway interacts with the dynamic compliance of that segment of the upper airway.13 If intraluminal pressure at the beginning of inspiration is a value that lies on the steep portion of the pressure-area relationship, the upper airway narrows as intraluminal pressure decreases during inspiration. The degree to which pharyngeal cross-sectional area decreases depends on the dynamic compliance of the upper airway. This mechanical property also influences the likelihood of further airway collapse. Specifically, narrowing during inspiration due to a decrease in intraluminal pressure might decrease the area significantly which, in turn, increases the velocity of gas flowing through that segment. This results in further reductions in intraluminal pressure because of the conversion of static to kinetic energy with decreased distending pressure. Such a decline in luminal pressure, in turn, tends to further decrease airway area. This sequence describes dynamic narrowing of the upper airway, which is typically observed under normal conditions if the pharyngeal muscles are hypotonic. In early expiration (positive airway pressure due to chest wall recoil), airway caliber increases, and toward the end of expiration (reduction in positive airway pressure and the upper airway dilator muscles remain inactive), the airway narrows.1 Patients with OSA are at risk for airway closure at the end of expiration and in inspiration. Ventilatory Control Alterations in ventilatory control can also influence the upper airway and promote upper airway obstruction. In humans, arterial oxygen and carbon dioxide levels are tightly controlled by various feedback systems involving chemoreceptors, intrapulmonary receptors, and respiratory muscle afferents. Because ventilatory control is regulated by feedback systems, these systems can become unstable (waxing and waning ventilation). Disturbances in these respiratory feedback systems are generally characterized by an increase in loop gain, which can augment periodicities in breathing patterns and in some persons produces associated periodic upper airway obstruction. (See Chapter 100 for a complete description of loop gain.)
PHARYNGEAL MUSCLES Activation of the Pharyngeal Muscles Many of the 20 or more skeletal muscles surrounding the pharyngeal airway are phasically activated during
1158 PART II / Section 13 • Sleep Breathing Disorders Tensor palatini
Area Active
Levator palatini
Nasopharynx
Passive
Retropalatal oropharynx
Genioglossus
Retroglossal oropharynx
Epiglottis Mental protuberance
A
Hypopharynx
Geniohyoid Hyoid bone
Styloglossus Superior pharyngeal constrictor Digastric
Hyoglossus Genioglossus Mandible Digastric Hyoid bone
B
Thyrohyoid ligament Sternohyoid
Ptm
Pmus
Thyroid cartilage
A
P2
P1
Thyrohyoid
Middle pharyngeal constrictor Inferior pharyngeal constrictor Thyroid cartilage
Figure 101-7 A, Schematic diagram of upper airway anatomy. The tensor palatini moves the soft palate ventrally. The genioglossus acts to displace the tongue ventrally. Coactivation of the muscles in the anterior pharyngeal wall such as the geniohyoid and sternohoid act on the hyoid bone to move it ventrally. B, Schematic diagram of upper airway muscles. Among the many upper airway muscles attaching to the floating hyoid bone are the genioglossus, geniohyoid, hyoglossus, middle pharyngeal constrictor, sternohyoid, and digastric.
inspiration, which helps to dilate the airway and stiffen the airway walls.14,15 As shown in Figure 101-7, the pharyngeal muscles have complex anatomic relationships that help regulate the position of the soft palate, tongue, hyoid apparatus, and posterolateral pharyngeal walls. Contraction of specific muscles within these groups can have antagonistic effects on the pharyngeal airway. For example, contraction of the palatal levator palatini muscle, along with the superior pharyngeal constrictor, closes the retropalatal airway, but contraction of other palatal muscles, the palatopharyngeus and glossopharyngeus, opens the airway in the retropalatal region. Similarly, the extrinsic tongue muscles can have antagonistic effects; namely, the genioglossus and geniohyoid protrude the tongue and the hyoglossus and styloglossus retract it. In addition, pharyngeal muscles can have different effects when activated in concert as opposed to when acti-
Figure 101-8 Airway area under passive conditions (i.e., no muscle activation) can be increased by a rise in transmural pressure (Ptm). Such a change occurs with the application of a positive intraluminal pressure, such as with nasal continuous positive airway pressure (CPAP). Contraction of pharyngeal dilators shifts the passive curve up and to the left. The muscle contraction increases Ptm, and (P2-P1) now represents Pmus (muscle pressure).
vated individually. Co-activation of the hyoid muscles is a particularly good example of this phenomenon (Fig. 101-8; see Fig. 101-7B). The hyoid bone in humans, unlike that in other mammals, does not articulate with any other bony or cartilaginous structure. The position of the hyoid bone is determined by the muscle attachments to this floating bony structure. Muscles inserting on the hyoid include the geniohyoid and genioglossus. Contraction of these muscles pulls the hyoid in a rostral and anterior direction. Strap muscles originating from the sternum (sternohyoid) and thyroid cartilage (thyrohyoid) also insert on the hyoid and pull it in a caudal direction. With simultaneous contraction of all four muscles, the resultant force vector acting on the hyoid is directed caudally and anteriorly. This combined effect moves the anterior pharyngeal wall outward, can stiffen the lateral pharyngeal walls, and promotes upper airway patency. Another example of coactivation of muscles and upper airway patency involves the tongue. Evidence indicates that simultaneous activation of the antagonistic protrudor and retractor tongue muscles, as occurs under hypercapnic and hypoxic conditions, has a synergistic effect in promoting upper airway patency.16 The action of an upper airway muscle depends not only on whether other muscles are simultaneously active but also on its length–tension and force–velocity characteristics at the time of activation. For instance, opening the mouth decreases genioglossus and geniohyoid muscle length, which can affect upper airway caliber. Similarly, neck flexion changes the position of the hyoid bone; altering the anatomic relationships of a variety of muscles acting on this structure and shifting the vector of their forces in a more caudal direction. Other evidence suggests that a particular pharyngeal muscle can have different mechanical effects on the airway depending on the size of the airway at the time of muscle activation.17,18 The ability of a given muscle to produce different mechanical effects
CHAPTER 101 • Anatomy and Physiology of Upper Airway Obstruction 1159
may be due to changes in muscle fiber orientation with concomitant changes in airway size and shape. In addition, the timing of muscle activation relative to the phase of respiration may play a role in determining the mechanical effects of such activation.19 The differing mechanical effects of the pharyngeal muscles, depending on airway conditions at the time of activation, may help explain how pharyngeal muscles can play a role in such disparate functions as respiration, deglutition, and phonation. Rather than a separate set of muscles performing one particular function, activation of a given muscle can have diametrically different mechanical effects on the airway depending on what other muscles are simultaneously active and on the precise anatomic configuration of the muscle at the time of activation. Factors Modulating Pharyngeal Muscle Activation Activation of pharyngeal muscles can alter the mechanical characteristics of the upper airway. The effect of pharyngeal dilator muscle activation on the tube law of the pharynx is shown in Figure 101-8. Under active conditions, the pressure–area relationship is shifted upward and to the left. At any given transmural pressure, muscle activation increases airway area and stiffens the airway, that is, decreases effective compliance. The effect of muscle activation on the tube law is quantified by the term Pmus, the effective pressure exerted by muscle activation, equivalent to the change in transmural pressure required to yield the equivalent change in area on the passive curve (see Fig. 101-8). Under certain conditions, pharyngeal dilator muscles display bursts of inspiratory activity superimposed on tonic activity. Alcohol, sleep deprivation, anesthesia, and sedative-hypnotics suppress respiratory-related pharyngeal muscle activation.20 Additional factors that modulate respiratory-related activity of pharyngeal airway motoneurons include changes in state, proprioceptive feedback, and chemical drive (Fig. 101-9). Changes in State Perhaps the most convincing evidence supporting the overall importance of neuromuscular activity on airway patency is that apneas and hypopneas occur during sleep. That modification of neuromuscular factors (e.g., decrease in genioglossus activity) by sleep is a normal physiologic phenomenon can be inferred from measurements of supraglottic resistance, the airflow resistance extending from the nares to the region above the glottis in normal subjects in whom supraglottic resistance increases fourfold to fivefold with sleep onset (e.g., from 1 to 2 cm H2O/L/sec during wakefulness to 5 to 10 cm H2O/L/sec during sleep).21,22 Supraglottic airway resistance is abnormally high in OSA patients during wakefulness and increases even further with sleep onset. The decrease in upper airway caliber that occurs with sleep onset is explained by a state-dependent reduction in neural output to upper airway muscles, which causes a decrease in Pmus at one or more sites within the pharyngeal airway. EMG recordings of pharyngeal muscles, such as the genioglossus and tensor palatini, confirm this decrease in pharyngeal muscle activity during the transition from wakefulness to sleep.23,24 An even more pronounced reduction in motor output to pharyngeal
Pharyngeal luminal area
0
Airway suction
100%
Proprioceptors
Inspiratory drive
Peripheral chemoreceptors
Dilator muscle tone
Upper airway drive
Central breathing control
Central chemoreceptors
Figure 101-9 Balance of forces that sustain upper airway patency. The two major forces are airway suction pressure and upper airway muscle tone that dilates and stiffens the airway. These in turn are influenced by other factors.
muscles occurs in rapid eye movement (REM) sleep, particularly in phasic REM.25,26 Thus, there is compelling evidence that the neural output to pharyngeal dilator muscles is decreased during sleep. Sensory Modulation of Pharyngeal Muscles Neurosensory feedback from thoracic and upper airway receptors can modulate motor output to pharyngeal muscles.27 During NREM sleep and general anesthesia in animals, withdrawal of vagally mediated phasic volume feedback by tracheal occlusion during inspiration results in an immediate large augmentation in motor output to many upper airway and chest wall inspiratory pump muscles.28-30 Introduction of subatmospheric pressure into an isolated, sealed upper airway in spontaneously breathing tracheostomized animals precipitates neurally mediated muscle activation.31,32 It is believed that upper airway receptors located superficially in the airway wall mediate this reflex activation because it is not present following administration of topical anesthesia.33 The majority of upper airway respiratory-related afferents are located in the upper trachea and larynx and carried in the internal branch of the superior laryngeal nerve. Sensory information from the upper airway is also transmitted in the glossopharyngeal and trigeminal nerves.34 Both intrathoracic and upper airway sensory afferents can also reduce motor output to the thoracic inspiratory muscles, thereby increasing intraluminal pressure below the site of airway obstruction.35 The effects of this reflex on upper airway and respiratory pump muscles could represent a powerful defense mechanism for maintaining upper airway patency during sleep. Presumably, neural reflex activation of pharyngeal muscles by upper airway and thoracic receptors would be initiated by upper airway obstruction and would tend to compensate for airway
1160 PART II / Section 13 • Sleep Breathing Disorders
obstruction by dilating and stiffening the pharynx. However, evidence indicates that these neurally mediated reflexes to protect upper airway patency are blunted in sleeping humans.36 Repetitive mechanical stress on pharyngeal airway structures from recurrent episodes of apnea and snoring on the upper airway appear to have neurosensory consequences. Evidence indicates that there is a sensory-neural abnormality in patients with sleep apnea with impaired upper airway sensation, which is partially reversible with continuous positive airway pressure (CPAP).37-39 In addition, studies have shown the importance of upper airway reflexes that increase upper airway caliber.36 These reflexes are activated by negative inspiratory pressure and may be attenuated by the sensory impairment of the upper airway. Repeated episodes of snoring and vibration at night have also been thought to lead to progressive local neuropathy.40,41 Both the upper airway sensory abnormalities and neuropathy could explain the progressive worsening of sleep apnea over time. Chemical Stimuli Respiratory-related phasic pharyngeal muscle activity, which can be absent during quiet breathing, usually appears under hypercapnic or hypoxic conditions.14 Under conditions of increased chemical drive, the majority of pharyngeal muscles exhibit phasic inspiratory activity that dilates and stiffens the airway. Upper airway and phrenic motor neurons differ in their response to hypocapnia. Upper airway motor neurons appear to have a higher CO2 threshold for activation than respiratory pump muscles. With passive hyperventilation in a tracheotomized, vagotomized, anesthetized animal, phasic upper airway motor neuron activity disappears prior to phrenic activity. When the CO2 level is then allowed to rise, phasic activity first reappears in the phrenic nerve. Transmission of the resulting subatmospheric intrathoracic pressure during inspiration into the pharyngeal airway, in the absence of simultaneous pharyngeal dilator muscle activation, increases the risk of pharyngeal airway narrowing and closure. Thus, cyclic changes in arterial CO2 around the CO2 threshold for activation of upper-airway motor neuron activity could lead to an imbalance of forces acting on the pharyngeal airway and favor closure.
DIFFERENCES IN STATIC UPPER AIRWAY ANATOMY IN PATIENTS WITH SLEEP APNEA Upper Airway Area Most studies have shown that the pharyngeal airway crosssectional area is smaller in patients with OSA compared to normal subjects.42-44 The airway narrowing has been shown to be primarily in the retropalatal region. The reduced size of the pharyngeal airway in patients with OSA compared to normal persons must be secondary to enlargement of the surrounding soft tissues or to reductions or changes to the craniofacial structures. Cephalometric studies have demonstrated reduction in mandibular body length (i.e., retrognathia), inferiorly positioned hyoid bone, and retroposition of the maxilla in patients with OSA compared to
normal subjects.45,46 Reduction in mandibular body length, in particular, has been shown to be an important risk factor for obstructive sleep apnea. In addition to craniofacial differences, enlargement of the upper airway soft tissue structures (tongue, lateral pharyngeal walls, soft palate, parapharyngeal fat pads) has also been demonstrated in patients with OSA compared to normal persons.42,43 Imaging studies with computed tomography (CT) or magnetic resonance imaging (MRI) have demonstrated increases in the cross-sectional area and dimensions of the soft palate, tongue, parapharyngeal fat pads, and lateral pharyngeal walls in patients with OSA.42,47 Figure 101-10A (a mid-sagittal MRI image) demonstrates narrowing of the upper airway and elongation of the soft palate and tongue in an OSA patient compared to a normal subject. Figure 101-10B (an axial MRI in the retropalatal region) demonstrates lateral airway narrowing in an OSA patient compared to a normal subject. A case-control study demonstrated that the volume of the upper airway soft tissue structures (tongue, lateral pharyngeal walls, soft palate, parapharyngeal fat pads) (Fig. 101-11) was significantly greater in OSA patients than normal subjects.42 The volume of the lateral pharyngeal walls, tongue, and total soft tissue surrounding the upper airway remained significantly larger in OSA patients than in normal subjects after adjustments for co-variates including gender, age, ethnicity, craniofacial size, and fat surrounding the upper airway. This study demonstrated that increased volume of the lateral pharyngeal walls, tongue, and total upper airway soft tissue significantly increased the risk (increased odds ratios) for OSA even after adjustment for co-variates.42 There are several possible explanations for the enlargement of the upper airway soft tissue structures in OSA patients including edema, weight gain, muscle injury, gender, and genetic factors. Edema Negative pressure during airway closure or trauma from repeated apneic events can cause edema to the soft tissue structures surrounding the upper airway. This edema could increase the size of these soft tissue structures. The soft palate is especially at risk for developing edema because it can be tugged caudally and traumatized during apneas. Supporting the presence of pharyngeal soft tissue swelling in untreated OSA is the reported reduction in upper airway edema following treatment of these patients with CPAP therapy.48 Quantitative magnetic resonance mapping also suggests that there is more edema in the genioglossus muscles of OSA patients compared to normal subjects.47,49,50 Histologic studies have also shown that patients with OSA have increased edema in the uvula compared to normal subjects.51 Additional support for the presence of upper airway edema is the observation that OSA is commonly associated with conditions that result in fluid overload states such as congestive heart failure52 and kidney failure.53 It has been proposed that increased central venous pressure could increase edema in the upper airway structures.54 In support of this hypothesis, several studies have shown that applying lower body positive pressure with antishock trousers caused a fluid shift from the lower extremities, increasing central venous pressure. This resulted in increased neck
CHAPTER 101 • Anatomy and Physiology of Upper Airway Obstruction 1161 MIDSAGITTAL MRI
A
Normal
Apneic AXIAL MRI
B
Normal
Apneic
Figure 101-10 A, Midsagittal MRI of a normal subject (left) and a patient with sleep apnea (right). The upper airway is smaller and the soft palate is longer in the patient with sleep apnea. The amount of subcutaneous fat (white area at the back of the neck) is greater in the apneic than in the normal subject. B, Axial MRI in the retropalatal region of a normal subject (left) and a patient with sleep apnea (right). The upper airway is smaller (primarily narrowed in the lateral dimension) in the patient with sleep apnea. There is more subcutaneous fat in the patient with sleep apnea.
circumference, pharyngeal airflow resistance, and upper airway collapsibility and reduced upper airway cross-sectional area.55-57b Fat Distribution and Body Weight Obesity is known to be an important risk factor for OSA.58 Although the relationship between obesity and OSA is not well understood, it appears that obesity decreases pharyngeal airway size and increases airway collapsibility. Increased neck size, a better surrogate of upper airway fat distribution than body mass index (BMI), has been demonstrated to be an excellent predictor of OSA.59,60 It is thought that the increased neck size in obese patients with
OSA is related to fat deposition in the neck. Upper airway imaging studies in obese OSA patients have demonstrated increased subcutaneous adipose tissue as well as increased adipose tissue surrounding the airway (primarily enlargement of the lateral parapharyngeal fat pads) (see Figs. 101-2, 101-10B, and 101-11).49 These studies suggest that obesity increases fat deposition in the lateral pharyngeal fat pads, which in turn has been hypothesized to displace the lateral walls and reduce upper airway size. Fat deposition within the tongue or soft palate may also be important in increasing the size of the soft tissue structures and reducing the caliber of the upper airway. Fat has been shown to be deposited in the uvula of patients with
1162 PART II / Section 13 • Sleep Breathing Disorders
Tongue
Parapharyngeal fat pads
Mandible
Soft palate
Normal subject
Tongue
Mandible
Airway
Parapharyngeal fat pads
Patient with sleep apnea
Pharyngeal walls Airway
Soft palate
Pharyngeal walls
Figure 101-11 Volumetric reconstruction of axial MR images in a normal subject and patient with sleep apnea. The mandible is depicted in white, the tongue in red, the soft palate in blue, the lateral parapharyngeal fat pads in yellow, and the lateral-posterior pharyngeal walls in green. The airway is depicted in gray. The normal subject has a larger airway than the patient with sleep apnea. The tongue, soft palate, parapharyngeal fat pads, and lateral pharyngeal walls of the patient with sleep apnea are all larger than in the normal subject.
OSA, supporting the hypothesis that fat deposited outside of the parapharyngeal fat pads may be important in the pathogenesis of OSA.61,62 An autopsy study of tongue volume and percentage of fat content demonstrated that the percentage of fat in the tongue increases with increasing BMI.63 It has also been argued that the total amount of fat surrounding the upper airway may be a more important contributor to OSA than fat localized in a particular anatomic site. Tsuiki and coworkers have hypothesized that increased soft tissue volume, including fat deposition in the space bounded by the mandibular rami, increases tissue pressure that in turn would narrow the airway.64 In addition to direct deposition of fat, weight gain can also alter the muscular tissue surrounding the upper airway because it not only increases the amount of adipose tissue but also increases muscle mass.65,66 Approximately 25% of the increased weight in obese patients is secondary to fatfree tissue.66,67 In support of this, it has been shown there is a larger percentage of muscle in the uvula of patients with OSA compared to normal subjects.68,69 We do not know if this increased muscle mass is a consequence of the apnea itself or is related to obesity. Nonetheless, such data
suggest that weight gain might predispose to OSA by increasing the size of the muscular soft tissue structures (tongue, soft palate, lateral pharyngeal walls) surrounding the upper airway in addition to the direct deposition of fat in the parapharyngeal fat pads. This hypothesis is supported by data in obese nonapneic women that show that weight loss decreases the volume of the lateral pharyngeal walls and parapharyngeal fat pads (Fig. 101-12).70 Other explanations for the relationship between obesity and OSA include changes in upper airway compliance and alterations in the biomechanical relationships of the upper airway muscles.71 Thus although obesity has been shown to be an important risk factor for OSA, the specific effect of weight gain on the upper airway soft tissue structures is not entirely understood. Upper Airway Myopathy It has been hypothesized that patients with OSA have a primary myopathy that contributes to the enlargement of the upper airway soft tissue structures.72 OSA is thought to be associated with changes in the contractile properties of upper airway muscles. Several studies have shown an increase in type II fast-twitch fibers in the genioglossus
A
Pre–weight loss
Pre–weight loss
B
Post–weight loss
Parapharyngeal fat pads
Airway
Post–weight loss
Figure 101-12 A, Axial MRIs of a normal subject, before and after weight loss in the retropalatal region. Airway area and lateral airway dimensions increase with weight loss. The thickness of lateral pharyngeal walls and the size of the parapharyngeal fat pads decrease with weight loss. B, Volumetric reconstructions of the upper airway soft tissues and craniofacial tissue before and after weight loss in a normal subject: soft palate (purple), tongue (orange/rust), lateral pharyngeal walls (green), parapharyngeal fat pads (yellow), and mandible (gray). The size of the upper airway increases with weight loss. The lateral pharyngeal walls and the parapharyngeal fat pads demonstrated the largest reductions in size with weight loss. Mandibular volume did not change with weight loss.
Sex Gender can have an important effect on the size of the upper airway soft tissue structures. Several studies have demonstrated that pharyngeal airway size is smaller in women than in men.68,75 In addition, studies have shown that neck circumference is smaller in women than in men,65 so it has been hypothesized that the size of the upper airway soft tissue structures (tongue, soft palate, lateral pharyngeal walls, lateral parapharyngeal fat pads) are also smaller in women than men. It has been shown that fat distribution is different in women than men.66,67 In men, fat is deposited primarily in the upper body and trunk, whereas in women it is deposited primarily in the lower body and extremities.66,67 These gender-related differences in overall fat distribution suggest that the size of the lateral parapharyngeal fat pads may be greater in men than women. However, two studies have examined gender-related differences in upper airway soft tissue structures in normal subjects with MRI,69,76 and while both showed that the size of the tongue, soft palate, and total soft tissue were greater in normal men than women,69,76 neither found a significant between-gender difference in lateral pharyngeal fat pad size. These data suggest that gender might not have a significant effect on the amount of visceral (parapharygneal fat pads) neck fat but might have an important effect on the size of the other upper airway soft tissue structures. Genetic Factors Genetic factors play an important role in determining the size of the upper airway soft tissue structures (see Chapter 103.) Macroglossia has been shown to be a risk factor for OSA in patients with trisomy 21.77 Family aggregation of craniofacial anatomy (reduction in posterior airway space, increase in mandibular to hyoid distance, inferior hyoid placement) has been shown in patients with OSA.65,78 The data from these studies suggest that elements of craniofacial structure are likely inherited in OSA patients. In addition to craniofacial structures, soft tissue structures are also heritable.79 Using volumetric MRI, and controlling for sex, ethnicity, age, craniofacial size, and visceral neck fat, the lateral pharyngeal walls, soft palate, genioglossus muscle, tongue volume, and total soft tissue volume have been shown to be enlarged in OSA patients and their siblings but not in normal subjects and their siblings. More importantly, the volume of the lateral pharyngeal walls (retropalatal and retroglossal) and tongue, as well as total
pharyngeal soft tissue volume, all demonstrated significant levels of heritability after controlling for confounders. Enlarged retropalatal and retroglossal lateral pharyngeal walls, soft palate, and total soft tissue volume were all independently associated with an increased risk of having a sibling with OSA.79
DYNAMIC PHYSIOLOGIC CHANGES IN UPPER AIRWAY STRUCTURES Although we have gained important insights into the anatomic risk factors for OSA with static studies of the upper airway, examination of the dynamic behavior of the upper airway is also necessary to completely understand the pathogenesis of sleep-disordered breathing. CT, MRI, and nasopharyngoscopy have been used to examine dynamic changes in upper airway caliber and the surrounding soft tissue structures during the respiratory cycle.80,81 Electron beam CT has been used to demonstrate that upper airway size changes during four distinct phases of the respiratory cycle in normal persons and in patients with OSA (Fig. 101-13).80,82 During early inspiration (phase 1; see Fig. 101-13) there is a small increase in upper airway size, but during most of inspiration (phase 2; see Fig. 101-13) upper airway caliber remains relatively constant. The finding that upper airway caliber is relatively constant during inspiration while awake suggests a balance between the action of the upper airway dilator muscles to maintain airway size and the negative intraluminal pressure, which promotes a decrease in airway size. During early expiration, upper airway caliber increases (phase 3; see Fig. 101-13) secondary to positive intraluminal pressure (the upper airway dilator muscles are not
Phases 3 and 4 = Expiration
Upper airway area
muscle of OSA patients.41,73,74 Type II fibers are more likely to fatigue than type I fibers; therefore, the upper airway muscles in patients with OSA would be more susceptible to fatigue than those of normal subjects. The remodeling of the upper airway muscles in patients with OSA may be a primary or secondary phenomenon—that is, a consequence rather than the cause of apneas. Carrera and coworkers74 studied the structure and function of the genioglossus in OSA patients and normal subjects and demonstrated that the myopathy is a secondary phenomenon. These investigators found increased type II fibers in the genioglossus muscle of OSA patients; however, these fiber changes in the genioglossus muscle were reversed with CPAP.
3 4
1
2 Phases 1 and 2 = Inspiration
Tidal volume Figure 101-13 Diagram of the changes in upper airway area as a function of tidal volume during the respiratory cycle. Airway caliber is relatively constant in inspiration (phases 1 and 2), whereas airway size increases in early expiration (phase 3) and decreases in late expiration (phase 4).
CHAPTER 101 • Anatomy and Physiology of Upper Airway Obstruction 1165
phasically active during expiration). Upper airway caliber is largest in early expiration.80,82 At the end of expiration (phase 4; see Fig. 101-13), however, there is a large reduction in upper airway caliber. It has been hypothesized that the end of expiration is a vulnerable time for upper airway narrowing or collapse due to the absence of both phasic upper airway dilator muscle activity (phases 1 and 2, during inspiration) and positive intraluminal pressure (phase 3, early expiration) during this phase of the respiratory cycle. In these investigations, pharyngeal area was smallest at the end of expiration.80,82 The finding that upper airway caliber is smallest at the end of expiration may have important implications with regard to the timing of sleep-induced upper airway closure. Apneas and hypopneas during sleep are thought to occur during inspiration secondary to negative intraluminal pressure generated by chest wall contraction.83 However, studies examining airway resistance have demonstrated that airway closure in patients with OSA can occur during both expiration and inspiration.84,85 Studies using nasopharygoscopy and measurement of closing pressure have also shown that airway closure during sleep occurs during expiration and that subatmospheric intraluminal pressure was not required for pharyngeal closure.86,87 These data indicate that the upper airway is vulnerable to collapse at the end of expiration in addition to collapse during inspiration.
OBSTRUCTION OF THE PHARYNX DURING SLEEP Periodic and Nonperiodic Obstruction of the Pharynx during Sleep A typical polygraphic recording from a patient displaying periodic pharyngeal occlusion during sleep is shown in Figure 101-14A. Periods during which airflow is absent are interspersed with somewhat briefer periods during which airflow is present. During the periods of pharyngeal occlusion, arterial oxygen saturation drops progressively and the magnitude of respiratory fluctuations in the esophageal pressure recording progressively increases. The apneic episodes terminate with an arousal that is associated with a large burst of submental electromyographic (EMG) activity. Sustained nonocclusive narrowing of the pharyngeal lumen can also produce a relatively stable elevation of respiratory resistance associated with sustained arterial oxygen desaturation and repetitive, large inspiratory efforts associated with chin muscle activation (see Fig. 101-14B). As is the case with periodic occlusion, the location of the airway narrowing can be localized to the pharynx by measuring airflow and supraglottic pressure, which can reveal upper airway resistance exceeding 75 cm H2O/L/sec. This tracing also provides insight into a consequence of a collapsible pharyngeal tube (i.e., inspiratory flow limitation). Note that despite a progressively larger driving pressure (as reflected by abnormally negative esophageal pressure) during an inspiratory effort, airflow remains constant, indicating increasing resistance during inspiration, presumably resulting from the progressive reduction of the pharyngeal lumen.
Site and Patterns of Pharyngeal Obstruction The retropalatal region is the most common primary site of airway narrowing or closure during sleep in patients with OSA, although upper airway narrowing can also occur in the retroglossal region.88,89 However, most patients with OSA have more than one site of narrowing. Studies examining state-dependent changes in the upper airway also demonstrate that airway narrowing during sleep occurs in both the lateral and anterior-posterior dimensions (Fig. 101-15).
EFFECT OF TREATMENT OF OBSTRUCTIVE SLEEP ON UPPER AIRWAY CALIBER The following sections review data on the effect of weight loss, CPAP, oral appliances, and surgery on upper airway size and the surrounding soft tissue and craniofacial structure. The purpose of this section is to illustrate how these therapeutic interventions influence upper airway pathophysiology. Other chapters deal specifically with these therapies. Weight Loss Weight loss on the order of 5% to 10% has been shown to improve OSA and decrease the collapsibility of the airway.90-92 However, the mechanism by which weight loss improves OSA, increases the size of the upper airway, and changes the size and configuration of the upper airway soft-tissue structures (soft palate, tongue, parapharyngeal fat pads, lateral pharyngeal walls) is not known. It has been hypothesized that weight loss decreases the volume of the parapharyngeal fat pads, which, in turn, could increase the size of the upper airway. Alternatively, weight loss might decrease the size of the tongue or other upper airway soft tissue structures. Continuous Positive Airway Pressure Although CPAP suppresses upper airway muscle activity, it increases airway caliber by establishing a positive transmural pressure along the entire pharyngeal airway, functioning as a pneumatic splint.93 Initially it was thought that CPAP increased the caliber of the upper airway by anteriorly displacing the tongue and soft palate. However, CT and MRI studies have shown that the dilation of the upper airway with CPAP is greater in the lateral dimension than in anterior-posterior dimension.1,94 Progressive increases in CPAP (up to 15 cm H2O) not only increase airway caliber in the lateral dimension but also significantly increase airway volume (threefold increase) and airway area in the retropalatal and retroglossal regions (Fig. 101-16). Oral Appliances Oral mandibular advancement devices are also used to treat patients with OSA.95 These devices increase the posterior airway space.96 However, the specific biomechanical mechanisms that explain the increase in airway caliber with these devices are not well understood. Furthermore there is no gold standard oral appliance, and the many
1166 PART II / Section 13 • Sleep Breathing Disorders
EEG(C4–A1) EOG EMG(submental) EOG
· V
100% 90% 80% 1L/sec
V
500 cc
SaO2
Peso 10 cm H2O RESPabd MIC 5 sec
A
EEG(C4–A1) EOG EMG(submental) ECG
· V
100% 90% 80% 1L/sec
V
500 cc
SaO2
Peso 10 cm H2O
RESPabd MIC
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5 sec
Figure 101-14 A, A typical tracing derived from a patient with severe obstructive sleep apnea. Bioelectric measurements (top three channels) indicate that the patient is in light sleep between periods of arousals associated with activation of the submental Esophageal electromyogram (EMG). Arterial oxygen saturation (SaO2) decreases periodically and increases after onset of airflow (V). pressure (Peso) and abdominal motion (RESPabd) show continuous respiratory efforts. EEG, electroencephalogram; EKG, electrocardiogram; EOG, electrooculogram; MIC, microphone; V, volume. B, A typical tracing derived from a patient with obstructive sleep hypopnea. A submental electromyogram (EMG) indicates rhythmical bursting of pharyngeal inspiratory muscles. SaO2 reveals stable mild hypoxemia. Airflow demonstrates flow limitation during inspiration. Despite a progressively larger driving pressure during an inspiratory effort (time between dashed vertical lines), flow remains constant, which indicates increasing resistance during inspiration, presumably resulting from progressive narrowing of the pharyngeal lumen. The thickened tracing at this time results from high-frequency oscillation in airflow caused by snoring. EEG, electroencephalogram; EOG, electrooculogram; MIC, microphone; volume; V, airflow. Peso, esophageal pressure; RESPabd, abdominal motion; SaO2, arterial oxygen saturation; V,
commercially available appliances have different mechanisms of action due to their differences in design. It has been hypothesized that mandibular repositioning devices increase airway size more in the retroglossal than in the retropalatal region because these devices advance the man-
dible and pull the tongue forward. However recent studies have shown that mandibular repositioning devices increase airway size in the retropalatal as well as the retroglossal region.97,98 The increase in retropalatal airway area is predominantly in the lateral dimension,98 suggesting that
CHAPTER 101 • Anatomy and Physiology of Upper Airway Obstruction 1167
the mechanism of action of oral appliances may be more complex than simply pulling the tongue and soft palate forward.
Wakefulness
Sleep
Figure 101-15 MRI in the retropalatal region of a normal subject during wakefulness and sleep. Airway area is smaller during sleep in this normal subject. The state-dependent change in airway caliber is a result of decreases in the lateral and anterior–posterior airway dimensions. Thickening of the lateral pharyngeal walls is demonstrated during sleep.
0 cm H2O
5 cm H2O
10 cm H2O
15 cm H2O
Upper Airway Surgery Uvulopalatopharyngoplasty (UPPP) is the most common surgical procedure for patients with OSA.99 During a UPPP the tonsils (if present), uvula, distal margin of the soft palate, and any excessive pharyngeal tissue are removed. The success rate of UPPP partially depends on the site of airway closure.88,100,101 Patients with retropalatal obstruction have better results after UPPP than those with retroglossal obstruction. Unfortunately, the success rate in patients undergoing UPPP surgery is only 50%, which is an unacceptably high failure rate. Morefavorable results with UPPP have been demonstrated if the surgery reduces the critical closing pressure.102 Thus far, the biomechanical changes in the upper airway soft tissue structures that underlie the efficacy, or lack of efficacy, of UPPP have not been identified.1,49,103 Nonetheless, preliminary studies with MRI have demonstrated that in patients who have undergone UPPP, the airway remains small in the nonresected portion of the soft palate, and the airway enlarges in the resected portion of the soft palate (Fig. 101-17).104 Computed tomography studies have also demonstrated increased width of the soft palate after UPPP.105 Persistent upper airway narrowing in the nonresected portion of the soft palate after UPPP might explain why UPPP has not been more successful in treating patients with OSA.1,49,103,104
Nasopharynx Retropalatal Retroglossal Hypopharynx
A
B
CPAP = 0 cm H2O
CPAP = 15 cm H2O
Figure 101-16 A, Volumetric reconstruction of the upper airway with progressively greater continuous positive airway pressure (CPAP) (0 to 15 cm H2O) settings in a normal subject. There are significant increases in upper airway volume in the retropalatal and retroglossal regions with higher levels of CPAP. B, Axial MRI in a normal subject at two levels of CPAP (0 and 15 cm H2O) in the retropalatal region. Airway area is significantly greater at 15 cm H2O. The airway enlargement is predominantly in the lateral dimension. Airway enlargement with CPAP results in thinning of the lateral pharyngeal walls, although the parapharyngeal fat pads are not displaced.
INTERACTION OF ANATOMIC AND NEUROLOGIC FACTORS ON PHARYNGEAL AIRWAY CLOSURE DURING SLEEP: A SCHEMATIC MODEL The overall balance of airway pressure and Pmus generated by upper airway muscles for normal persons and patients with OSA is depicted in Figure 101-18, where a balance beam depicts the counteracting effects of luminal pressure and pharyngeal Pmus, and the angle of equilibrium indicates the pharyngeal luminal area.106 The position of the fulcrum is determined by the mechanical characteristics of the upper airway. In awake normal persons (see Fig. 101-18A), equal values of negative luminal pressure and Pmus result in a widely dilated upper airway because the anatomy of the upper airway favors patency; that is, the fulcrum is to the left of center. In contrast, an anatomic abnormality (increase in the size of the upper airway soft tissue structures or a reduction in the length of the mandible) in patients with OSA moves the pivot position of the balance to the right of center (see Fig. 101-18B). Under these conditions, even in the presence of increased upper airway muscle activity and normal intraluminal airway pressure (as may be present during wakefulness), the pharyngeal airway is still smaller than normal. The effect of sleep on these equilibriums under normal conditions and in obstructive sleep apnea is shown in Figure 101-18C and D. In a normal subject, sleep is associated with a decrease in pharyngeal luminal area because of a sleep-induced
1168 PART II / Section 13 • Sleep Breathing Disorders
of airway occlusion in patients with obstructive sleep apnea, and the latter as the anatomic hypothesis.
A
Pre-UPPP
Post-UPPP
Uvula
B
Pre-UPPP
Post-UPPP
Figure 101-17 A, Midsagittal MRI in a patient with sleep apnea before and after an uvulopalatopharyngoplasty. The uvula is shorter after the uvulopalatopharyngoplasty. However, the airway remains narrow in the region where the soft palate is not resected. B, Axial MRI before and after uvulopalatopharyngoplasty in the region where the uvula was resected. Airway caliber increases substantially after the uvulopalatopharyngoplasty in this region of the airway.
decrease in upper airway muscle activity and a persistence of subatmospheric luminal pressure during inspiration. This means that the upper airway narrows during sleep compared to wakefulness but remains patent. However, patients with OSA develop significant airway narrowing and closure during sleep because the sleep-induced loss of upper airway activity occurs against the background of an anatomic impairment. Although there is no doubt that sleep is associated with a decrease in pharyngeal muscle activity in normal subjects and OSA patients, a fundamental question regarding the pathogenesis of OSA is if the reduced motor output constitutes a key abnormality or if it occurs against the background of an abnormally narrow passive pharynx that constitutes the principal pathogenic alteration. The former can be referred to as the neural hypothesis of the pathogenesis
Neural Hypothesis There is no evidence at present to indicate the existence of a primary neural abnormality in patients with OSA, but this might simply reflect our inability to quantify and compare changes from wakefulness to sleep across populations of OSA patients and normal persons. Genioglossus muscle activity during wakefulness is reported to be greater in patients with OSA than that seen in normal persons.107,108 Such neuromuscular compensation can help preserve airway patency during wakefulness. Loss of pharyngeal muscle activity at sleep onset induces pharyngeal narrowing that becomes more severe as intraluminal pressure falls during inspiration. Whether the level of neuromuscular activation associated with the sleep state in patients with OSA is abnormally reduced or reflects a normal sleeprelated loss of activity remains a question. Evidence suggests, however, that the response of the genioglossus to hypercapnia in normal subjects is attenuated following sleep deprivation.108 A similar reduction in motor output to pharyngeal muscles in patients with OSA resulting from their sleep fragmentation might further reduce pharyngeal muscle activation. In addition, there may be sensorineural abnormalities in the upper airway that propagate sleep apnea.37-41 Anatomic Hypothesis The finding of higher pharyngeal closing pressures in paralyzed, anesthetized patients with OSA compared to normal persons provides strong evidence that independent of neuromuscular factors, structural changes in the upper airway contribute significantly to the pathogenesis of OSA.106 In addition, it has been demonstrated that the volume of the tongue, lateral pharyngeal walls, and total soft tissue were not only larger in OSA patients than in normal persons but also that volumetric enlargement of these structures significantly increased the risk for OSA.42 Thus abnormalities in upper airway anatomy are clearly important in the pathogenesis of OSA.
❖ Clinical Pearl It is important to understand upper airway anatomy and why the upper airway collapses in patients with sleep apnea. Numerous factors including edema, obesity, and genetics can alter upper airway anatomy. There are many anatomic risk factors for sleep apnea including macroglossia, lateral peritonsillar narrowing, elongation of the uvula, narrowing of the hard palate, and retrognathia. These anatomic risk factors need to be sought when patients are being evaluated for sleep apnea. Factors that reduce upper airway muscle tone (alcohol, sedatives, narcotics, hypnotics) also need to be considered in the evaluation of sleep apnea.
CHAPTER 101 • Anatomy and Physiology of Upper Airway Obstruction 1169
Normal
OSA
Pharyngeal luminal area
Pharyngeal luminal area 0
100%
100%
Awake
0
UA muscle activities
Airway pressure
A
UA muscle activities
Normal
B
Airway pressure
Normal
Pharyngeal luminal area
Pharyngeal luminal area 100%
0
100%
Asleep
0
OSA
UA muscle activities
UA muscle activities Normal OSA
C
Airway pressure
Normal
D
Airway pressure
Figure 101-18 Schematic model explaining pharyngeal airway patency, showing upper airway (UA) muscle activities and airway pressure on either side of a fulcrum that represents the intrinsic mechanical properties of the passive upper airway (i.e., upper airway anatomy). The fulcrum of sleep apneic subjects (B and D) is suggested to be to the right side of normal subjects (A and C). OSA, obstructive sleep apnea (From Isono S, Remmers JE, Tanaka A, et al. Anatomy of pharynx in patients with obstructive sleep apnea and in normal subjects. J Appl Physiol 1997;82:1319-1326.)
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CHAPTER 101 • Anatomy and Physiology of Upper Airway Obstruction 1171 68. Brooks LJ, Strohl KP. Size and mechanical properties of the pharynx in healthy men and women. Am Rev Respir Dis 1992; 146(6):1394-1397. 69. Whittle AT, Marshall I, Mortimore IL, et al. Neck soft tissue and fat distribution: comparison between normal men and women by magnetic resonance imaging. Thorax. 1999;54(4):323-328. 70. Welch KC, Foster GD, Ritter CT, et al. A novel volumetric magnetic resonance imaging paradigm to study upper airway anatomy. Sleep 2002;25(5):532-542. 71. Strobel RJ, Rosen RC. Obesity and weight loss in obstructive sleep apnea: a critical review. Sleep 1996;19(2):104-115. 72. Schwab RJ. Imaging for the snoring and sleep apnea patient. Dent Clin North Am 2001;45(4):759-796. 73. Series F, Cote C, Simoneau JA, et al. Physiologic, metabolic, and muscle fiber type characteristics of musculus uvulae in sleep apnea hypopnea syndrome and in snorers. J Clin Invest 1995;95(1): 20-25. 74. Carrera M, Barbe F, Sauleda J, et al. Patients with obstructive sleep apnea exhibit genioglossus dysfunction that is normalized after treatment with continuous positive airway pressure. Am J Respir Crit Care Med 1999;159(6):1960-1966. 75. Brown IG, Zamel N, Hoffstein V. Pharyngeal cross-sectional area in normal men and women. J Appl Physiol 1986;61(3):890-895. 76. Malhotra A, Huang Y, Fogel RB, et al. The male predisposition to pharyngeal collapse: importance of airway length Am J Respir Crit Care Med 2002;166(10):1388-1395. 77. Marcus CL, Keens TG, Bautista DB, et al. Obstructive sleep apnea in children with Down syndrome. Pediatrics 1991;88(1):132-139. 78. Mathur R, Douglas NJ. Family studies in patients with the sleep apnea–hypopnea syndrome. Ann Intern Med 1995;122(3):174178. 79. Schwab RJ, Pasirstein M, Kaplan L, et al. Family aggregation of upper airway soft tissue structures in normal subjects and patients with sleep apnea. Am J Respir Crit Care Med 2006;173(4): 453-463. 80. Schwab RJ, Gefter WB, Hoffman EA, et al. Dynamic upper airway imaging during awake respiration in normal subjects and patients with sleep disordered breathing. Am Rev Respir Dis 1993;148(5): 1385-1400. 81. Morrell MJ, Arabi Y, Zahn B, Badr MS. Progressive retropalatal narrowing preceding obstructive apnea. Am J Respir Crit Care Med 1998;158(6):1974-1981. 82. Schwab RJ, Gefter WB, Pack AI, Hoffman EA. Dynamic imaging of the upper airway during respiration in normal subjects. J Appl Physiol 1993;74(4):1504-1514. 83. Remmers JE, deGroot WJ, Sauerland EK, Anch AM. Pathogenesis of upper airway occlusion during sleep. J Appl Physiol 1978; 44:931-938. 84. Sanders MH, Moore SE. Inspiratory and expiratory partitioning of airway resistance during sleep in patients with sleep apnea. Am Rev Respir Dis 1983;127(5):554-558. 85. Sanders MH, Kern N. Obstructive sleep apnea treated by independently adjusted inspiratory and expiratory positive airway pressures via nasal mask. Physiologic and clinical implications. Chest 1990;98(2):317-324. 86. Schwab RJ, Gupta KB, Gefter WB, et al. Upper airway and soft tissue anatomy in normal subjects and patients with sleep-disordered breathing. Significance of the lateral pharyngeal walls. Am J Respir Crit Care Med 1995;152(5 Pt. 1):1673-1689. 87. Badr MS, Toiber F, Skatrud JB, Dempsey J. Pharyngeal narrowing/ occlusion during central sleep apnea. J Appl Physiol 1995; 78(5):1806-1815. 88. Launois SH, Feroah TR, Campbell WN, et al. Site of pharyngeal narrowing predicts outcome of surgery for obstructive sleep apnea. Am Rev Respir Dis 1993;147:182-189.
89. Morrison DL, Launois SH, Isono S, et al. Pharyngeal narrowing and closing pressures in patients with obstructive sleep apnea. Am Rev Respir Dis 1993;148:606-611. 90. Peppard PE, Young T, Palta M, et al. Longitudinal study of moderate weight change and sleep-disordered breathing. JAMA 2000; 284(23):3015-3021. 91. Newman AB, Foster G, Givelber R, et al. Progression and regression of sleep-disordered breathing with changes in weight: the Sleep Heart Health Study. Arch Intern Med 2005;165(20):2408-2413. 92. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002;165(9):1217-1239. 93. Basner RC. Continuous positive airway pressure for obstructive sleep apnea. N Engl J Med 2007;356(17):1751-1758. 94. Kuna ST, Bedi DG, Ryckman C. Effect of nasal airway positive pressure on upper airway size and configuration. Am Rev Respir Dis 1988;138(4):969-975. 95. Chan AS, Lee RW, Cistulli PA. Dental appliance treatment for obstructive sleep apnea. Chest 2007;132(2):693-699. 96. Kyung SH, Park YC, Pae EK. Obstructive sleep apnea patients with the oral appliance experience pharyngeal size and shape changes in three dimensions. Angle Orthod 2005;75(1):15-22. 97. Liu Y, Zeng X, Fu M, et al. Effects of a mandibular repositioner on obstructive sleep apnea. Am J Orthod Dentofacial Orthop 2000;118(3):248-256. 98. Ryan CF, Love LL, Peat D, et al. Mandibular advancement oral appliance therapy for obstructive sleep apnoea: effect on awake calibre of the velopharynx. Thorax 1999;54(11):972-977. 99. Won CH, Li KK, Guilleminault C. Surgical treatment of obstructive sleep apnea: upper airway and maxillomandibular surgery. Proc Am Thorac Soc 2008;5(2):193-199. 100. Shepard JW Jr, Thawley SE. Evaluation of the upper airway by computerized tomography in patients undergoing uvulopalatopharyngoplasty for obstructive sleep apnea. Am Rev Respir Dis 1989;140(3):711-716. 101. Ryan CF, Lowe AA, Li D, Fleetham JA. Three-dimensional upper airway computed tomography in obstructive sleep apnea. A prospective study in patients treated by uvulopalatopharyngoplasty. Am Rev Respir Dis 1991;144(2):428-432. 102. Schwartz AR, Schubert N, Rothman W, et al. Effect of uvulopalatopharygoplasty on upper airway collapsibility in obstructive sleep apnea. Am Rev Respir Dis 1992;145:527-532. 103. Langin T, Pepin JL, Pendlebury S, et al. Upper airway changes in snorers and mild sleep apnea sufferers after uvulopalatopharyngoplasty (UPPP). Chest 1998;113(6):1595-1603. 104. Welch KC, Goldberg AN, Trudo FJ, et al. Upper airway anatomic changes with magnetic resonance imaging in uvulopatopharyngoplasty patients. Am J Respir Crit Care Med 1997;155:A938. 105. Schmidt-Nowara W, Lowe A, Wiegand L, et al. Oral appliances for the treatment of snoring and obstructive sleep apnea: a review. Sleep 1995;18(6):501-510. 106. Isono S, Remmers JE, Tanaka A, et al. Anatomy of pharynx in patients with obstructive sleep apnea and in normal subjects. J Appl Physiol 1997;82:1319-1326. 107. Mezzanotte WS, Tangel DJ, White DP. Waking genioglossal EMG in sleep apnea patients versus normal controls (a neuromuscular compensatory mechanism). J Clin Invest 1992;89:15711579. 108. Leiter JC, Knuth SL, Bartlett D Jr. The effect of sleep deprivation on activity of the genioglossus muscle. Am Rev Respir Dis 1985;132(6):1242-1245.
Snoring
Christopher Li and Victor Hoffstein
Abstract Snoring is common, occurring in about 40% of the adult population. Snoring occurs when normal physiologic changes in pharyngeal mechanics during sleep become superimposed on underlying pharyngeal abnormalities present during wakefulness. Although snoring is the most common reason for referral to sleep laboratories, its main clinical significance is that it is a marker of obstructive sleep apnea syndrome and upper airways resistance syndrome. To date, there is no convincing evidence of a causal relationship between nonapneic snoring
HISTORICAL PERSPECTIVE Before the 1970s, snoring was thought to be simply an acoustic nuisance. However, with the recognition of obstructive sleep apnea syndrome, snoring began to assume a new importance as the cardinal symptom of this disorder. Investigators began to understand snoring and obstructive sleep apnea as a continuum of sleep-disordered breathing1 and question whether this acoustic nuisance in fact had serious health consequences. As polysomnography became more commonplace, objective evaluation of snoring evolved from a research oddity to an accessible, real-world tool. The 1990s led to the recognition that some nonapneic snorers have frequent respiratory arousals and sleep fragmentation, and the term upper airways resistance syndrome (UARS) was coined to describe these patients (see Chapter 105). In conjunction with increasing scientific evidence regarding the health significance of snoring and public awareness surrounding the importance of sleep disorders, a panoply of treatment options for snoring has become available to patients. Today, snoring remains the most common reason for referral to most sleep laboratories. DEFINITIONS The International Classification of Sleep Disorders defines snoring as a “respiratory sound generated in the upper airway during sleep that typically occurs during inspiration but may also occur in expiration.”2 The manual also lists a number of alternate names for nonapneic snoring, including “primary snoring,” “simple snoring,” “benign snoring,” “habitual snoring,” and “heavy snoring.” PATHOPHYSIOLOGY AND MEASUREMENT OF SNORING Snoring is a sound produced by the vibrating structures of the upper airway. It is not caused by a single, localized abnormality within the airway. Endoscopic and imaging observations of the upper airway in snorers, during natural or induced sleep, demonstrate that any membranous part of the upper airway that lacks cartilaginous support can 1172
Chapter
102 and daytime sleepiness or cardiovascular disease. The best way to treat nonapneic snoring is to modify the risk factors, including obesity and alcohol ingestion; body position training can be beneficial in selected cases. If snoring persists, oral appliances and continuous positive airway pressure are the noninvasive treatments of choice. Nasal lubricants, decongestants, and nasal dilators do not have proven efficacy. Surgical approaches may be warranted in patients whose snoring is problematic and persistent despite noninvasive treatments, but there is a need for better-quality studies using objective measurement of snoring as an endpoint.
vibrate.3 This includes the soft palate, uvula, faucial pillars, pharyngeal walls, and the rest of the upper airway, almost to the level of the vocal cords. This diffuse involvement of the upper airway has made successful treatment of snoring more difficult, as many treatments address only a particular airway segment. Several theoretical models of the human upper airway have been developed (see Chapter 101).4-6 These models include the effects of airway wall compliance, gas density, and airway dimensions on the pressure–flow relationships in the upper airway. They predict that depending on the mechanical properties of the pharynx and the density of gas flowing through it, the walls of the upper airway can be stable (normal breathing), can vibrate or flutter (snoring), or can narrow or collapse completely (obstructive hypopnea or apnea, respectively). Some predictions have been verified experimentally. For example, alcohol ingestion promotes snoring by reducing pharyngeal dilator muscle tone and increasing airway wall compliance, in effect making the pharynx more floppy. On the other hand, breathing a lower-density, helium-containing gas mixture can improve snoring by promoting laminar over turbulent airflow, favorably altering the pressure–flow relationship in the pharynx and thereby reducing vibratory sounds. Spectral analysis of the sound power spectrum can be used to determine the frequency components of snoring sounds. The power spectrum describes how much power is contributed by each constituent frequency component. Because snoring may be generated at several sites along the airway, and sometimes at multiple sites simultaneously, the power spectrum of snoring is wide, encompassing a range of frequencies up to 10,000 Hz. The spectral characteristics of snoring sounds are influenced by the oral or nasal breathing route, sleep stage, whether the sleep is natural or induced, posture, body weight, neck circumference, airway wall mass, and elasticity. The extent to which each factor is responsible for the power spectrum of snoring sound is not known. Although sound recordings have become a routine component of nocturnal polysomnography, there is no standardized technique for recording these signals and
reporting snoring. There is no consensus regarding the choice of instrumentation, where the instrument should be placed, the method of analysis of sound recordings, or the biologic calibration (i.e., validation that the measured sound is what a listener would identify as snoring). Apneas and hypopneas have standardized, objective definitions, and the distribution of such events across stages of sleep and body positions is well delineated in polysomnogram reports; in contrast, snoring is often only commented upon in general terms, rather than measured quantitatively. Methods of measuring snoring vary,7,8 but they generally include one or several of the following parameters: maximum sound intensity, percentage of sleep time spent above a threshold sound level, and number of sound intensity spikes above threshold level. However, these measurements are very specific to an individual laboratory’s configuration and are not standardized. In many laboratories, “measurement” of snoring simply consists of a sleep technologist’s subjective comment. It is therefore not surprising that many patients, particularly those referred only because of their snoring, leave the physician’s office rather disappointed: when they ask about their snoring, all they are told is that they do not have sleep apnea. Until a uniform method for measuring, analyzing, and reporting snoring is developed, a combination of objective sound measurements and subjective assessment with questionnaires, preferably with input from the bed partner, should be used to characterize snoring. In our laboratory, we currently record snoring using a microphone suspended approximately 40 cm above the head. It is connected to a sound meter whose output is analyzed and is a part of the scored polysomnogram report. We report the maximum, mean, and minimum sound intensity, its distribution as a percentage of sleep position, and the histogram of sound intensity duration with respect to sleep time; the ambient noise in our laboratory is 40 dB, and we report percent of total sleep time spent in 5-dB bins starting at 41 dB, with the last bin being 76 to 80 dB.
EPIDEMIOLOGY OF SNORING Snoring is common, but estimates of its prevalence are imprecise and vary widely among studies. The prevalence of snoring ranges from 5% in men and 2% in women9 to 86% in men and 57% in women.10 Although ethnic differences in snoring prevalence undoubtedly exist, most of the variability is very likely a reflection of differences in datacollecting methodology. Snorers rely on a bed partner or family member to describe their snoring. Such reports are inherently subjective and inconsistent. Furthermore, some studies do not even employ bed-partner questionnaires, using only the subject’s impression of his or her own snoring to determine the prevalence of the condition. Night-to-night variability further compounds the difficulty in interpreting reports of snoring. Not surprisingly, therefore, there is commonly a discrepancy between patient reports of snoring and objective snoring recordings. In one study, 15% of self-confessed snorers did not snore at all when studied in the sleep laboratory. On the other hand, 15% of those who reported never snoring actually snored for at least 50% of the night.
CHAPTER 102 • Snoring 1173
The male predominance observed in all prevalence studies of snoring remains unexplained. Possible contributing factors include differences in the perception and reporting of snoring between male and female bed partners,11 hormonal factors influencing upper airway tone, and differences in pharyngeal anatomy and function. The apparent reduction in snoring with age, observed in some studies, may be related to the loss of a bed partner, altered perception of snoring, survival bias, or other methodologic problems.12 A few special conditions appear to be particularly associated with snoring, such as pregnancy,13,14 presence of nasal polyps,15 or nasal obstruction from other causes.16 It is clinically observed that snorers very often have a history of at least one other affected family member. Hence, genetic factors (see Chapter 103) can influence the prevalence of snoring, perhaps through obesity or through inherited oropharyngeal anatomy.
HEALTH EFFECTS OF NONAPNEIC SNORING The most commonly cited adverse health consequences associated with snoring are excessive daytime sleepiness and cardiovascular disease. However, the majority of studies evaluating the health effects of snoring fail to exclude obstructive sleep apnea and UARS with polysomnography. As a result, it is difficult to ascertain how much of the health risk is attributable to the snoring alone. Snoring and Daytime Sleepiness Some of the evidence for a relationship between snoring and daytime sleepiness comes from the Sleep Heart Health Study, a cross-sectional study of 5777 community-dwelling adults. Participants underwent full polysomnography at home. The authors showed a correlation between daytime sleepiness, as measured by the Epworth Sleepiness Scale (ESS), and self-reported snoring; the correlation was independent of the Respiratory Disturbance Index (RDI). The ESS increased progressively (reflecting increasing degrees of perceived sleep propensity during daily activities) with increasing snoring severity across the study population, from 6.4 in nonsnorers to 9.3 in the heaviest snorers.17 A more recent study also described a correlation between objectively quantified snoring and ESS.18 However, the overall correlation was quite weak, as snoring intensity and AHI together only explained 15% of the variance in ESS. Furthermore, the correlation was only present in patients with an AHI of more than 15 events/ hour. This suggests that snoring is not a major cause of sleepiness in patients with mild OSA or nonapneic snoring. Some patients classified in the past as sleepy, nonapneic snorers would probably now be reclassified as having UARS based on the presence of arousals related to respiratory effort (Videos 102-1 to 102-4). Others might now be reclassified as having mild sleep apnea, because of improvements in our ability to detect hypopneas. Clinicians should examine the polysomnogram data carefully for indicative findings. In the sleepy, truly nonapneic snorer without evidence of UARS, we would still hesitate to attribute the somnolence to the snoring alone and would recommend further workup for other causes of sleepiness.
1174 PART II / Section 13 • Sleep Breathing Disorders
Snoring and Cardiovascular Disease Many authors have postulated that there is a relationship between snoring and hypertension. In 1975, Lugaresi and colleagues demonstrated that episodes of snoring were associated with acute, simultaneous increases in blood pressure.19 Many epidemiologic, questionnaire-based studies since then have demonstrated an association between snoring and hypertension. However, without available polysomnographic data it is unclear whether the hypertension is associated with nonapneic snoring, obstructive sleep apnea, or both. Several attempts have been made to clarify this issue. In support of the association between snoring and hypertension is the study of Bixler and colleagues,20 who performed polysomnography in 1741 community dwellers and reported that when compared to nonsnorers, nonapneic snorers had an odds ratio of 1.6 (confidence interval [CI], 1.09 to 2.20) for having hypertension (defined either as taking antihypertensive medication or having elevated blood pressure measured at the time of polysomnography). On the other hand, Stradling and colleagues examined a cohort of snorers from general practice who were unlikely to have significant sleep apnea because they had fewer than two episodes of 4% drops in oxygen saturation per hour of sleep; they found no relationship between snoring and hypertension.21 From the available evidence, it would appear that the association between nonapneic snoring and hypertension is, if anything, modest. Similarly, although epidemiologic studies have demonstrated an association between snoring and cardiovascular disease and stroke, none have convincingly demonstrated that snorers are at risk in the absence of apnea. Marin and colleagues compared long-term cardiovascular outcomes in nonapneic snorers (apnea–hypopnea index [AHI] less than 5 events per hour of sleep), subjects with obstructive sleep apnea, and population-based healthy controls matched for age and body mass index.22 They found that among the nonapneic snorers, there was no increased risk for cardiovascular death and no increase in the rates of nonfatal cardiovascular events. On the other hand, there is intriguing new evidence that snoring may be associated with carotid artery atherosclerosis. In a study of 110 subjects, mainly community volunteers who had nonapneic snoring or mild nonhypoxic obstructive sleep apnea (median AHI 11 events per hour; median 3% oxygen desaturation index 1.5 events per hour, 0% of total sleep time spent with oxygen saturation lower than 91%), the prevalence of carotid atherosclerosis on Doppler ultrasound increased significantly with snoring severity, independent of the AHI.23 This relationship was not seen in the femoral artery, and the authors postulate that transmitted vibrations to the carotid artery might in fact lead to endothelial damage and atherogenesis.
CLINICAL FEATURES AND DIAGNOSTIC ASSESSMENT Clinical History The history is best obtained in the presence of the bed partner. A complete general medical and sleep history
should be taken, but several key components to the snoring history require specific attention. How bad is the snoring? The clinician should determine the loudness and frequency of the snoring, and whether it is positional. The time course of the snoring should be delineated. What was the age of onset of the snoring, and can this be correlated with the development of risk factors, such as weight gain? Is the snoring worsening or has it only become an issue since sleeping with a new bed partner? The history should also explore the effects of the snoring on the bed partner’s sleep, particularly if this is the reason for seeking evaluation. The degree of bed partner distress often affects the patient’s motivation to initiate and comply with therapy. What risk factors for snoring are present? Weight gain should be identified. Alcohol consumption should be quantified, including the usual time of ingestion. Similarly, sedative medication use should be assessed. The clinician should determine if there are symptoms of nasal congestion and discharge or if there is a history of nasal trauma or surgery. A history of recurrent tonsillitis can alert the clinician to hypertrophy of the tonsils. A variety of other medical conditions can also cause oropharyngeal crowding including hypothyroidism, acromegaly, and congenital conditions such as trisomy 21, achondroplasia, and fusion of cervical vertebrae (Klippel-Feil syndrome). Does the patient in fact have obstructive sleep apnea? Much of the clinical assessment of the snorer is directed toward determining the probability of obstructive sleep apnea or UARS. This is discussed in detail in Chapter 105. The clinician should enquire about nighttime symptoms of obstructive sleep apnea such as frequent awakenings, restless sleep, witnessed pauses in breathing, choking and gasping spells, diaphoresis, and nocturia. Daytime symptoms must also be assessed. Patients with obstructive sleep apnea can experience excessive daytime sleepiness, neurocognitive symptoms such as poor concentration and memory, and mood symptoms such as irritability and depression. Daytime sleepiness can be quantified using a standardized tool such as the Epworth Sleepiness Scale (see Chapter 143). Finally, the history should document medical conditions that may be associated with obstructive sleep apnea, such as hypertension and cardiovascular disease. Physical Examination The snoring history defines the problem and helps the clinician estimate the risk of obstructive sleep apnea; physical examination helps to further refine such estimations and identify potential sites for intervention. The general physical examination should include measurement of blood pressure. Obesity may be assessed with the body mass index (BMI); regional obesity more specific to sleep-disordered breathing is documented with the neck circumference. The nose should be inspected for evidence of rhinitis and other causes of obstruction, such as nasal polyps or a deviated nasal septum. The dimensions of the oropharynx should be noted. Is it small and crowded, with a low-lying soft palate? Is there retrognathia or micrognathia? Is there obstruction from hypertrophy of the tonsils?
CHAPTER 102 • Snoring 1175
Is the tongue large? Some physicians report the Mallampati score, a numerical value based on the tongue size and position. The uvula may be inflamed and bulky in snorers, sometimes hardly lifting off the base of the tongue during phonation. Although the ability to predict a patient’s response to treatment (particularly surgery or an oral appliance) based on physical examination of the oropharynx is an attractive one, at present there is no evidence that the presence or absence of specific features improves the success rate of treatment. Clinical and Laboratory Investigations Upper Airway Assessment The upper airway can be assessed during wakefulness using various imaging techniques such as x-ray cephalometry, computed tomography, or magnetic resonance imaging. The results, however, are neither predictive of snoring nor helpful in the selection of surgical candidates, so these techniques are not indicated for the routine assessment of snorers. Only patients who might undergo maxillofacial surgery (a rare occurrence for treatment of nonapneic snoring) require radiographic imaging of the airway. The anatomic structures of the upper airway can be visualized using fiberoptic nasopharyngoscopy, which is usually carried out by an otolaryngologist. Airway pressure measurements, simulated snoring, and Müller’s maneuver may be performed during endoscopic examination, but there is actually little evidence that such maneuvers can accurately determine the site of obstruction or predict surgical success. In fact, even when nasopharyngoscopy is
done during sleep, the findings are a poor predictor of success in palatal surgery for nonapneic snoring.24 Polysomnography Figure 102-1 demonstrates some polysomnographic findings of nonapneic snoring. Snoring was measured in this instance by a snoring microphone, positioned above the patient’s head. Note the snoring in the bottom channel, in the absence of a reduction in flow, oxygen desaturation, or arousal. Polysomnography remains the gold standard for evaluating sleep-disordered breathing, and it is used to differentiate nonapneic snoring from obstructive sleep apnea and UARS. However, polysomnography is relatively labor intensive and costly, and the at-risk population is large. It may be useful to have a protocol to determine which patients require testing. One approach for triaging patients (Fig. 102-2) is to use a clinical prediction rule to ascertain the probability of obstructive sleep apnea. A number of such prediction rules have been developed; here, we discuss use of the adjusted neck circumference (ANC).25 The patient’s neck circumference is measured (in cm) at the level of the cricoid notch in the seated position and adjusted for certain risk factors: hypertension adds 4 cm to the neck circumference, habitual snoring adds 3 cm, and a history of choking or gasping most nights adds 3 cm. An ANC of less than 43 cm confers a low clinical probability of obstructive sleep apnea, an ANC of 43 to 48 cm an intermediate probability, and an ANC greater than 48 cm a high probability. Patients with an intermediate to high probability of obstructive sleep apnea should be evaluated with
EEG C3A2 EEG C4A1 CHIN EMG ECG 95.1 95.1 95.1 95.1 95.1 95.1 95.1 95.1 94.1
94.1 94.1 93.7 93.7 94.1 93.7 94.1 94.1 93.7 93.7 93.7 94.1 94.1 94.1 93.7 94.1 93.7 94.1 93.7 94.1 94.1
% SaO2 FLOW RC ABD SUM SNORE
Figure 102-1 Representative 60-second polysomnogram tracing during stage 3 NREM sleep. Note the snoring in the bottom channel. There is no associated reduction in flow, oxygen desaturation, or arousal to suggest an obstructive event. Upward deflection is inspiration. EEG, electroencephalogram; EMG, electromyogram; ECG, electrocardiogram; % SaO2, oxygen saturation; FLOW, nasal flow; RC, rib cage movement; ABD, abdominal movement; SUM, rib cage + abdominal movement; SNORE, snoring microphone.
1176 PART II / Section 13 • Sleep Breathing Disorders
Non-apneic snoring
Disturbing snoring
Lifestyle modification Weight loss Avoidance of alcohol and sedatives Positional training Ear plugs for partner
Determine adjusted neck circumference (ANC)
ANC < 43 cm
No symptoms of OSA
ANC > 43 cm
Symptoms of OSA
Polysomnography
AHI < 5/hr
No daytime sleepiness
Treat as nonapneic snoring
Daytime sleepiness
Nonrespiratory cause of sleepiness
AHI > 5/hr
Consider treatment for OSA/UARS
UARS
Figure 102-2 Algorithm for investigating snoring. ANC, adjusted neck circumstances AHI, apnea–hypopnea index; OSA, obstructive sleep apnea; UARS, upper airways resistance syndrome.
polysomnography. In patients with a low probability of obstructive sleep apnea, the decision to perform polysomnography depends on the presence of symptoms. Snorers with a history of sleep disruption, unrefreshing sleep, or daytime sleepiness should also have a polysomnogram (see Fig. 102-2). Patients with a low probability of obstructive sleep apnea and no symptoms could be treated without polysomnography, provided they are followed clinically for new-onset symptoms or weight gain. The ANC is derived from a sleep apnea clinical prediction rule, which Flemons and colleagues developed using multiple regression analysis.26 It has been validated in an independent sleep clinic population (published in abstract form),27 but results cannot be extrapolated to a general population. There are potential pitfalls with strict adherence to this approach. For example, a snorer with a small neck circumference but prominent craniofacial abnormalities might elude a diagnosis of obstructive sleep apnea. Some patients are also very poor perceivers of symptoms such as daytime sleepiness, and this could lead to a missed diagnosis of obstructive sleep apnea in a patient with otherwise low probability. Each case needs to be evaluated on its own merits, and the clinical prediction rule should be used as a guide, and not as a substitute, for sound clinical judgment. The vast majority of patients presenting to a sleep clinic with snoring still require some form of testing: Even an otherwise asymptomatic habitual snorer with a neck cir-
Treat nasal congestion (medical) Nasal steroids Nasal dilators Persistent snoring Evaluate for correctable obstruction Tonsillar/adenoidal hypertrophy Obvious nasal obstruction
Oral appliance CPAP Persistent snoring or intolerance of treatment
Surgical assessment Removal of enlarged tonsils/adenoids Correction of nasal obstruction Consider palatal procedure such as RFA Figure 102-3 Algorithm for management of snoring. CPAP, continuous positive airway pressure; OSA, obstructive sleep apnea; RFA, radiofrequency ablation.
cumference of 40 cm (just under 16 inches) will be in the intermediate probability category. This underscores the need for easier and less costly methods of evaluating sleepdisordered breathing. With improvements in portable monitoring technology, unattended home studies—particularly those that allow manual review of raw data—are becoming an increasingly attractive option. We anticipate that in the future, portable monitors will take on a much greater role in evaluating the snoring patient; in fact, in many jurisdictions this is already the case, although standardizing measurement of snoring using unattended portable home monitoring equipment will continue to present a challenge.
TREATMENT Treatment options for nonapneic snoring and sleep apnea are similar. In broad terms, treatment can be divided into nonsurgical and surgical approaches. Nonsurgical treatments can be further subdivided into several categories: lifestyle modification, oral appliances, treatments targeting nasal congestion, and positive pressure therapy. Figure 102-3 contains an algorithm for treatment decisions, beginning with identifying and correcting risk factors and followed by using an oral appliance, using CPAP, and, finally, surgery. This general approach, which favors noninvasive treatments initially, can be applied to obese snorers who do not have an obvious anatomic
abnormality of the upper airway. However, treatment should be individualized on the basis of the clinical circumstances and the patient’s preference. For example, those who have hypertrophied tonsils might be referred early on for surgical assessment. Those who are considering surgery should not expect complete elimination of snoring, and even if snoring is initially improved, there is no guarantee that this favorable result will persist. Lastly, there is no reliable daytime assessment tool—such as Mallampati score, Freidman score,28 or nasopharyngoscopy combined with Müller maneuver—that would allow accurate prediction of postoperative success. Nonsurgical Treatments Lifestyle Modification W EIGHT L OSS Obesity is very common among snorers, and weight loss should be one of the first treatment recommendations, regardless of whether additional treatments are being contemplated. It is clinically observed that weight loss improves and sometimes cures snoring. Improvement with weight loss is almost uniformly demonstrated in studies of sleep apnea patients; for example, in one study of 123 patients (probably a mixed population of patients with sleep apnea and nonapneic snoring) who underwent bariatric surgery, the percentage of self-reported habitual snorers decreased from 82% to 14%, with a mean reduction in BMI from 46 kg/m2 to 35 kg/m2.29 However, this hypothesis remains unconfirmed in nonapneic snorers. It is also difficult to predict the amount of weight loss required to improve snoring in a given patient, but sometimes as little as a few kilograms is sufficient. A VOIDANCE OF A LCOHOL AND S EDATIVES Bed partners of snorers often report that ingesting alcohol before bed worsens snoring. Although moderate alcohol consumption (0.5 g/kg) did not affecct snoring intensity in habitual snorers in one study, other studies have shown that moderate alcohol consumption increases upper airway resistance and collapsibility of the pharynx, reduces nocturnal oxygen saturation, and increases the AHI.30,31 The deleterious effect of alcohol on breathing during sleep is related to the timing of alcohol ingestion, the amount ingested, and the person’s metabolism. The effect may be evident for up to 5 hours after ingestion. Snorers should be advised to avoid drinking alcohol within 2 to 5 hours of going to bed. Similarly, snorers should also avoid sedatives such as benzodiazepines. P OSITIONAL T RAINING Snoring is often worse in the supine position. Bed partners commonly observe that pushing or kicking the snorer to induce a change in position can lead to a temporary improvement in the snoring. This observation was validated in a review of the polysomnograms of 21 nonapneic snorers.32 There was a significant reduction in snoring time and intensity during sleep in the lateral position, as compared to the supine position. Maintaining the lateral position during sleep can be challenging: Even if patients intentionally start the night in the lateral position, many eventually end up supine. A
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number of homemade devices and commercially available products have been developed for the purpose of maintaining the lateral position during sleep. A tennis ball, sewn into a pocket over the back of a tee-shirt has been used, as well as backpacks, vests, and specialized pillows and sleepwear. Such devices have been used to treat positional sleep apnea. Although there are no studies demonstrating efficacy of these devices in nonapneic snorers, it stands to reason that such patients might derive some benefit. Partner Interventions If a tree falls in a forest and no one is around to hear it, does it still make a sound? In some cases, it may be simpler and more effective to have the snorer’s partner simply sleep in a separate room or wear ear plugs. Of course, this approach would not address any potential adverse physiologic effects of the snoring on the snorer. Treating Nasal Congestion P HARMACOLOGIC T REATMENTS Tissue lubricants have sometimes been used to treat snoring. A study using phosphocholinamin in a mixed population of 12 patients with sleep apnea and nonapneic snoring demonstrated a 25% reduction in snoring index (number of snores per hour of sleep), versus a 1% increase in snoring index in the placebo group.33 However, the long-term safety of nightly use of such preparations has not been established, and we do not recommend them. Intranasal corticosteroids are commonly prescribed in an attempt to reduce snoring. One study evaluated 13 patients with obstructive sleep apnea and 10 nonapneic snorers in a randomized, placebo-controlled, crossover study of intranasal fluticasone.34 Fluticasone reduced nasal airway resistance, but there was no change in polysomnographically measured snoring in either the sleep apnea subjects or the nonapneic snorers, compared to placebo. Hence, there is no evidence to support the use of intranasal corticosteroids for the treatment of snoring; however, given the reasonably benign nature of the treatment, a trial of 2 to 4 weeks might be reasonable in patients who also have symptoms of chronic rhinitis. Pseudoephedrine sulfate, a nasal decongestant, has also been put forth as a possible treatment for snoring. It was evaluated together with a prokinetic agent, domperidone, in a study of 30 healthy snorers.35 This placebo-controlled crossover study suggested a reduction in snoring intensity with treatment, based on partner reports. Some patients withdrew from the study because of the development of insomnia and palpitations. Pseudoephedrine should also be avoided in patients with hypertension and ischemic heart disease, and we do not usually suggest long-term treatment of snoring with these medications. N ASAL D ILATORS Two small randomized, controlled crossover trials have employed polysomnography to objectively examine the effects of an external nasal dilator on snoring. Patients had nonapneic snoring or mild obstructive sleep apnea and symptoms of chronic rhinitis or nocturnal nasal obstruction. The dilator consists of an adhesive band, bolstered by two elastic springs. Placed externally over the nose, it
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serves to pull the nares open. The first trial demonstrated that patients with chronic rhinitis experienced a reduction in snoring incidence compared to a placebo dilator, but with no change in snoring intensity.36 The second trial showed no difference in snoring duration or intensity compared to placebo.37 An internal nasal dilator has also been studied in a trial employing polysomnography in 10 patients.38 This device consists of a flexible plastic bar whose ends are placed inside the anterior nares, pushing them open via a springboard action. In this small study, there was a reduction in the incidence of snoring, compared to no treatment. Overall, it appears that nasal dilators may have a modest effect on nonapneic snoring, and given their innocuous nature, a trial of therapy could be of benefit in some patients. Oral Appliances Oral appliances, patented in the late 19th century for treatment of snoring, were at first relatively neglected because of the associated discomfort from wearing the device. More recently, however, there has been considerable progress in design, manufacturing techniques, and the ability to customize the appliance to an individual patient. They have become the treatment of choice in idiopathic nonapneic snorers when lifestyle modification is insufficient.39 A wide variety of appliances are available, but the most commonly used is the mandibular repositioning appliance. This device, usually customized to fit over the teeth, improves upper airway patency by inducing protrusion of the mandible. Oral appliances are covered in detail in Chapter 109. Most studies of oral appliances suggest that snoring is improved with the device. There has been one randomized, crossover, placebo-controlled trial of an oral appliance for the treatment of nonapneic snoring (polysomnography was not done, but all subjects had normal overnight oximetry).40 This study showed statistically significant improvement compared to a placebo device in partner reports of the incidence and loudness of snoring. On a five-point severity scale, snoring incidence went from a mean of 3.72 at baseline to 1.84 after 4 to 6 weeks of oral appliance therapy (versus 3.36 using the placebo device). Loudness of snoring went from a mean of 3.16 at baseline to 1.24 with the oral appliance (versus 2.76 using placebo). When constructed by dentists with specialized expertise, the appliances are relatively comfortable in the majority of patients. In our experience, if patients stop using the appliances, it is generally because of lack of effectiveness, rather than because of side effects. Compliance, defined as nightly or almost nightly use of the appliance, is on the average 62% at 30 months41; it may be as low as 27% and as high as 67% at 10-year follow up.42 Precise strategies regarding selection of candidates for treatment and titration protocols to determine the optimum mandibular protrusion are still under investigation. Continuous Positive Airway Pressure CPAP therapy for obstructive sleep apnea is described in Chapter 107. Studies on CPAP therapy rarely focus on
nonapneic snorers, but it is generally accepted that snoring can be eliminated with CPAP use in most patients. Whether a person with nonapneic snoring will use CPAP therapy, however, is largely a question of motivation. Those with daytime sleepiness (who, arguably, might actually have UARS) can experience symptomatic improvement from CPAP. Those whose partners are very bothered by the snoring might also have sufficient impetus for a trial of CPAP therapy. Surgical Treatments Surgery can seem an attractive option to nonapneic snorers, for several reasons. Many patients find lifestyle modification difficult and slow, and a quick fix may be more desirable. Patients are also often under the impression that surgery is a curative procedure that obviates the need for nightly intrusive interventions. Surgical procedures used for nonapneic snoring parallel those used to treat obstructive sleep apnea—to a point (see Chapter 108). Operations to optimize patency and stability of the nose and oropharynx are common to both conditions, whereas more complicated surgeries such as genioglossal advancement, hyoid myotomy, maxillomandibular osteotomy, and tracheostomy are reserved for patients with obstructive sleep apnea. Overall success rates with surgery are difficult to determine because of the heterogeneity of surgical procedures, and many studies are plagued by methodologic problems such as inconsistent or subjective assessment of endpoints, lack of longer-term follow-up, and selection bias. However, in general terms, the results of surgical treatment for idiopathic snoring (i.e., snoring not associated with discrete upper airway pathology) have been disappointing. Nasal Surgery Nasal obstruction promotes snoring by increasing negative intrathoracic pressure during sleep; this leads to a reduction in the pharyngeal cross-sectional area, pharyngeal collapse, turbulent flow, and vibration of pharyngeal structures. Data from the Wisconsin Sleep Cohort demonstrates a strong association between nocturnal nasal congestion and habitual snoring, with an odds ratio of 3.0.43 Despite this, there is little evidence in the literature to indicate that treating nasal obstruction surgically with septoplasty or turbinate reduction improves the snoring in nonapneic snorers. In what was probably a mixed population of nonapneic snoring and sleep apnea patients (mean apnea–hypopnea index of 13.6 events per hour), one study found no improvement in snoring time or intensity when measured before and after septoplasty with polysomnography, despite demonstrating improvement in nasal resistance.44 Based on the evidence available to date, nasal surgery cannot be generally recommended for treatment of nonapneic snoring. Pharyngeal Surgery A detailed discussion of upper airway surgery for obstructive sleep apnea is provided elsewhere in Chapter 108. In this section we review pharyngeal surgery specifically with respect to patients with nonapneic snoring.
U VULOPALATOPHARYNGOPLASTY Uvulopalatopharyngoplasty (UPPP) was first described in the early 1980s and quickly became the surgical treatment of choice for both sleep apnea patients and nonapneic snorers. A multitude of studies demonstrates impressive short-term improvement in subjective reports of snoring. An early review suggested success rates of up to 90%.45 However, data showing polysomnographically demonstrated improvement in snoring is lacking. One study showed that there was no difference in snoring index before and after surgery in 69 patients with snoring, some of whom had sleep apnea.46 Despite this, 78% of the patients reported reduction in snoring, highlighting the importance of objective testing in the assessment of surgical success rates. Furthermore, longer-term data on subjective snoring (using questionnaires) suggests that the initial improvements reported by patients often do not last. One survey study showed that the subjective success rate for resolution or improvement in snoring with UPPP fell from 76% in the immediate postoperative period to 45% 2 years after surgery. In this study, 61% of patients indicated that they would not have the operation again, although the retrospective nature of this study may certainly have introduced some bias.47 Airway assessment, during wakefulness and even during sleep, is unfortunately a poor predictor of surgical success. In general, younger, less heavy (BMI < 30 kg/m2), nonapneic snorers have a better success rate. The patient should be informed that UPPP might not result in complete abolition of snoring, and in fact there may be no improvement at all. Some patients have an intermediate result, with a reduction in sound intensity or a change in spectral frequency of the sound that is less objectionable to the bed partner. The surgery is generally quite painful, and longterm side effects from UPPP include velopharyngeal insufficiency, dry throat, and difficulty swallowing.48 L ASER- A SSISTED U VULOPLASTY Laser-assisted uvuloplasty (LAUP) was introduced in 1990 as an alternative to UPPP. It is an office procedure done under local anesthesia, which can be performed several times at 1- to 3-week intervals to achieve the desired effect. Less tissue is resected than during UPPP. The efficacy of this procedure for treatment of snoring is not higher than that of UPPP, and the main reason for selecting this procedure is to avoid administering a general anesthetic. In 2001, the Standards of Practice Committee of the American Academy of Sleep Medicine (AASM) published a review of the evidence for LAUP in sleep apnea and snoring.49 They concluded that “the long-term effectiveness of LAUP on treatment of snoring has not been convincingly established.” There are no controlled trials using objective snoring measures as an endpoint. In several case series reports, subjective improvements in snoring measures occurred in 43% to 90% of patients, but there was some recrudescence of snoring with longer follow-up periods. Since the AASM review, a prospective randomized trial has been published. Patients with nonapneic snoring or mild obstructive sleep apnea (AHI < 20) were randomized to either LAUP or a sham surgery followed by oral
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placebo.50 Reassessment 3 months after surgery with both subjective and objective measures of snoring revealed no difference between the groups in either snoring intensity on a visual analogue scale or in snoring index as measured by a laryngeal microphone. Macdonald and colleagues evaluated a number of preoperative measurements in hopes of finding predictors to a response to LAUP51; unfortunately, none of the measured variables of cephalometry, acoustic rhinometry, analysis of snoring sounds, or body mass index was of sufficient predictive value. Based on the available evidence, LAUP cannot be generally recommended as a treatment for snoring. I NJECTION S NOREPLASTY Injection snoreplasty, introduced in 2001, involves injecting a sclerotherapy agent into the submucosa of the soft palate. It can be performed with topical anesthesia on an outpatient basis. This procedure induces scarring and may serve to stiffen and shorten the palate, thereby reducing snoring. Injection snoreplasty using sodium tetradecyl sulfate has been evaluated in a case series of 17 patients and showed some subjective improvement in snoring.52 There was also an objective component to the snoring evaluation, using a portable monitoring device that measures the average loudness of snoring sounds in decibels but also assesses three parameters of palatal snoring (palatal loudness in decibels, proportion of total snoring originating from the soft palate, and palatal flutter frequency in hertz over the recording period). The authors reported statistically significant reductions in palatal flutter and palatal loudness, but there was no significant difference in average loudness of snoring or palatal flutter frequency. It is a bit difficult to judge the clinical significance of these results. Complications from the procedure have included self-limited palatal swelling and mucosal breakdown, as well as transient palatal fistulas. Further studies of this procedure are required. Although the technique has shown some promise, there is insufficient evidence to recommend injection snoreplasty at this time. R ADIOFREQUENCY A BLATION Radiofrequency ablation (RFA) is an outpatient procedure pioneered in 1998 by Powell and colleagues.53 Using a specialized probe, thermal (radiofrequency) energy can be applied to the pharyngeal tissues—the palate, tonsils, uvula, and base of the tongue. The tissues are heated to approximately 80° C, causing volume reduction and stiffening of the pharynx and making the walls less susceptible to vibration and collapse. Only topical anesthetic is required. Most publications on the use of RFA to treat snoring and sleep apnea are case series reports without placebo controls or objective measures of snoring. However, there have been two randomized, placebo-controlled trials of RFA. The first of these examined a population consisting of obstructive sleep apnea patients as well as nonapneic snorers, and it compared RFA to a sham procedure in which the radiofrequency probe was inserted but no energy was applied.54 There was no specific analysis for
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snoring, but the responses to a specific questionnaire,55 which targets symptoms of nocturnal obstruction, showed no difference between the RFA and sham procedure groups. The second study56 also compared RFA to a sham procedure in 23 patients with nonapneic snoring and mild obstructive sleep apnea (AHI < 15 events per hour). Snoring was evaluated by the bed partner using a 10-cm visual analogue scale. There was a reduction in snoring scores in the RFA group from 8.1 to 5.2, and the snoring score in the sham procedure group went from 8.4 to 8.0. The difference between the groups was statistically significant, suggesting that there may in fact be a moderate reduction in partner-reported snoring in this population with RFA. Larger studies using objective measures are needed before firm recommendations can be made, but based on this small study, RFA shows some promise in the treatment of nonapneic snoring. Side effects such as pain, difficulty swallowing, and pharyngeal irritation are generally rated low to moderate; mucosal blanching and erosions occur in 15% to 40%, and palatal fistula and excessive swelling occur in less than 1%. Hemorrhage occurs in 1.6%.57 P ALATAL I MPLANTS These cylindrical implants, measuring 18 mm in length and 1.6 mm in diameter, are made of a braided polyethylene terephthalate. Inserted with a specialized deployment device into the soft palate under local anesthesia, the implants cause an inflammatory reaction and formation of granulomatous tissue; the soft palate is stiffened as a result, in hopes of reducing snoring. The usual procedure is to insert three implants near the midline of the soft palate. Several case series reports describe the use of such palatal implants to treat snoring. One of the earliest studies, of 12 patients (AHI < 15 events per hour), showed a reduction in partner-based visual analogue scores of snoring, from a mean of 79/100 at baseline to 48/100 at 3 months after implantation. The implantation seemed to be associated with fairly mild discomfort, but spontaneous extrusion of the implant occurred in 17% of patients.58 Two subsequent case series reports (one with 3-month follow-up59 and another with 1-year follow up60) also showed improvement in partner-based visual analogue snoring scores, but neither study showed a change in objectively measured snoring. There was no control group in any of these studies. Though not yet done in nonapneic snorers, a randomized, double-blind, placebo-controlled trial of palatal implants has been published in patients with mild to moderate obstructive sleep apnea.61 This trial did not use objective measurement of snoring but demonstrated an improvement in subjective snoring on a visual analogue scale, compared to placebo. However, the study used only patient self-reports as the measurement of snoring. Some aspects of voice might change with implants.62 Overall, it seems that there are minimal side effects from the insertion of palatal implants, but objective improvement in snoring has yet to be demonstrated, and at this time there is insufficient evidence to recommend it.
T ONSILLECTOMY One occasionally comes across the adult snorer with bilateral severe tonsillar hypertrophy. There are no randomized, controlled trials of tonsillectomy in the treatment of nonapneic snoring adults. Case series reports in patients with obstructive sleep apnea suggest improvements in snoring.63 It is our feeling that tonsillectomy may be entertained as a treatment for snoring in selected cases, particularly in the presence of other indications for surgery such as recurrent infections.
CONCLUSION Snoring is a common complaint that brings the patient to a sleep laboratory. It is due to the vibrations of the walls of the upper airway—from the soft palate to below the base of the tongue. It is the most common symptom of obstructive sleep apnea. Although it may be disturbing to the bed partner, there is no convincing evidence that snoring alone, without sleep apnea, is associated with adverse health consequences. Treatment of nonapneic snoring needs to be individualized and generally involves lifestyle modification (weight loss, avoidance of alcohol), sleep position training, oral appliances, and nasal CPAP. Surgery should be reserved for patients in whom these techniques have failed or are not applicable and for patients with definite abnormalities of the upper airway. Because snoring is not localized to a particular airway segment, the patient should be aware that even if the abnormality is corrected, snoring might not be significantly improved.
❖ Clinical Pearl The diffuse involvement of the upper airway has complicated the treatment of patients with nonapneic snoring. Lifestyle modification and oral appliances may be of benefit; CPAP is effective but rarely used in nonapneic snorers. Surgical approaches are largely of unproved efficacy, but they may be considered in those with problematic snoring that persists despite noninvasive treatments.
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9. Janson C, Gislason T, De Backer W, Plaschke P, et al. Daytime sleepiness, snoring, and gastro-oesophageal reflux amongst adults in three European countries. J Intern Med 1995;237:277-285. 10. Norton PG, Dunn EV, Haight JSJ. Snoring in adults: some epidemiological aspects. Can Med Assoc J 1983;128:674-675. 11. Kapsimalis F, Kryger MH. Gender and obstructive sleep apnea syndrome: Part I. Clinical features. Sleep 2002;25:409-416. 12. Wolkove N, Elkholy O, Baltzan M, Palayew M. Sleep and aging: 1. Sleep disorders commonly found in older people. CMAJ 2007; 176:1299-1304. 13. Leung PL, Hui DS, Leung TN, et al. Sleep disturbances in Chinese pregnant women. BJOG 2005;112:1568-1571. 14. Ursavas A, Karadag M, Nalci N, et al. Self-reported snoring, maternal obesity and neck circumference as risk factors for pregnancyinduced hypertension and preeclampsia. Respiration 2008;76: 33-39. 15. Serrano E, Neukirch F, Pribil C, et al. Nasal polyposis in France: impact on sleep and quality of life. J Laryngol Otol 2005;119: 543-549. 16. Kohler M, Bloch KE, Stradling JR. The role of nose in the pathogenesis of obstructive sleep apnea and snoring. Eur Respir J 2007;30:1208-1215. 17. Gottlieb DJ, Yao Q, Redline S, et al. Does snoring predict sleepiness independently of apnea and hypopnea frequency? Am J Respir Crit Care Med 2000;162(4 Pt 1):1512-1517. 18. Nakano H, Furukawa T, Nishima S. Relationship between snoring sound intensity and sleepiness in patients with obstructive sleep apnea. J Clin Sleep Med 2008;4(6):551-556. 19. Lugaresi E, Coccagna G, Farnetti P, et al. Snoring. Electroencephalogr Clin Neurol 1975;39:59-64. 20. Bixler EO, Vgontzas AN, Lin HM, et al. Association of hyper tension and sleep-disordered breathing. Arch Intern Med 2000;160: 2289-2295. 21. Stradling JR, Crosby JH. Relation between systemic hypertension and sleep hypoxaemia or snoring: analysis in 748 men drawn from general practice. BMJ 1990;300(6717):75-78. 22. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea–hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365(9464):1046-1053. 23. Lee SA, Amis TC, Byth K, et al. Heavy snoring as a cause of carotid artery atherosclerosis. Sleep 2008;31(9):1207-1213. 24. El Badawey MR, McKee G, Heggie N, et al. Predictive value of sleep nasendoscopy in the management of habitual snorers. Ann Otol Rhinol Laryngol 2003;112:40-44. 25. Flemons WW. Obstructive sleep apnea. N Engl J Med 2002; 347(7):498-504. 26. Flemons WW, Whitelaw WA, Brant R, Remmers JE. Likelihood ratios for a sleep apnea clinical prediction rule. Am J Respir Crit Care Med 1994;150(5 Pt. 1):1279-1285. 27. Wyckoff CC, O’Donnell AE. Assessing the adjusted neck circumference sleep apnea screening score in patients clinically suspected to be at high risk of obstructive sleep apnea. Chest 2007;132(Suppl. 4):649S 28. Friedman M, Tanyeri H, La Rosa M, et al. Clinical predictors of obstructive sleep apnea. Laryngoscope 1999;109(12):1901-1907. 29. Dixon JB, Schachter LM, O’Brien PE. Sleep disturbance and obesity: changes following surgically induced weight loss. Arch Intern Med 2001;161(1):102-106. 30. Issa FG, Sullivan CE. Alcohol, snoring and sleep apnea. J Neurol Neurosurg Psychiatry 1982;45:353-359. 31. Mitler MM, Dawson A, Henriksen SJ, et al. Bedtime ethanol increases resistance of upper airways and produces sleep apneas in asymptomatic snorers. Alcohol Clin Exp Res 1988;12:801-805. 32. Nakano H, Ikeda T, Hayashi M, et al. Effects of body position on snoring in apneic and nonapneic snorers. Sleep 2003;26:169-172. 33. Hoffstein V, Mateika S, Halko S, Taylor R. Reduction in snoring with phosphocholinamin, a long-acting tissue-lubricating agent. Am J Otolaryngol 1987;8(4):236-240. 34. Kiely JL, Nolan P, McNicholas WT. Intranasal corticosteroid therapy for obstructive sleep apnea in patients with co-existing rhinitis. Thorax 2004;59:50-55. 35. Larrain A, Hudson M, Dominitz JA, Pope CE 2nd. Treatment of severe snoring with a combination of pseudoephedrine sulfate and domperidone. J Clin Sleep Med 2006;2(1):21-25.
CHAPTER 102 • Snoring 1181 36. Pevernagie D, Hamans E, Van Cauwenberge P, Pauwels R. External nasal dilation reduces snoring in chronic rhinitis patients: a randomized controlled trial. Eur Respir J 2000:15(6):996-1000. 37. Djupesland PG, Skatvedt O, Borgersen AK. Dichotomous physiological effects of nocturnal external nasal dilation in heavy snorers: the answer to a rhinologic controversy? Am J Rhinol 2001;15(2): 95-103. 38. Höijer U, Ejnell H, Hedner J, et al. The effects of nasal dilation on snoring and obstructive sleep apnea. Arch Otolaryngol Head Neck Surg 1992;118(3):281-284. 39. John MT. Dentists should participate in the management of patients with obstructive sleep apnea and socially disruptive snoring— findings from a survey of Scottish sleep specialists. J Evid Based Dent Pract 2010;10(2):107-108. 40. Johnston CD, Gleadhill IC, Cinnamond MJ, Peden WM. Oral appliances for the management of severe snoring: a randomized controlled trial. Eur J Orthod 2001;23:127-134. 41. Chan ASL, Lee RWW, Cistulli PA. Dental appliance treatment for obstructive sleep apnea. Chest 2007;132:693-699. 42. Jauhar S, Lyons MF, Banham SW, et al. Ten-year follow-up of mandibular advancement devices for the management of snoring and sleep apnea. J Prosthetic Dentistry 2008;99:314-321. 43. Young T, Finn L, Palta M. Chronic nasal congestion at night is a risk factor for snoring in a population-based cohort study. Arch Intern Med 2001;161:1514-1519. 44. Virkkula P, Bachour A, Hytönen M, et al. Snoring is not relieved by nasal surgery despite improvement in nasal resistance. Chest 2006; 129(1):81-87. 45. Coleman J, Rathfoot C. Oropharyngeal surgery in the management of upper airway obstruction during sleep. Otolaryngol Clin North Am 1999;32:263-276. 46. Miljeteig H, Mateika S, Haight JS, et al. Subjective and objective assessment of uvulopalatopharyngoplasty for treatment of snoring and obstructive sleep apnea. Am J Respir Crit Care Med 1994;150(5 Pt. 1):1286-1290. 47. Hicklin LA, Tostevin P, Dasan S. Retrospective survey of long-term results and patient satisfaction with uvulopalatopharyngoplasty for snoring. J Laryngol Otol 2000;114(9):675-681. 48. Goh YH, Mark I, Fee WE Jr. Quality of life 17 to 20 years after uvulopalatopharyngoplasty. Laryngoscope 2007;117(3):503-506. 49. Littner M, Kushida CA, Hartse K, et al. Practice parameters for the use of laser-assisted uvulopalatoplasty: An update for 2000. Sleep 2001;24:603-608. 50. Larrosa F, Hernandez L, Morello A, et al. Laser-assisted uvulopalatoplasty for snoring: does it meet the expectations? Eur Respir J 2004;24(1):66-70. 51. Macdonald A, Drinnan M, Johnston A, et al. Evaluation of potential predictors of outcome of laser-assisted uvulopalatoplasty for snoring. Otolaryngol Head Neck Surg 2006;134(2):197-203. 52. Brietzke SE, Mair EA. Injection snoreplasty: extended follow-up and new objective data. Otolaryngol Head Neck Surg 2003;128(5): 605-615. 53. Powell NB, Riley RW, Troell RJ, et al. Radiofrequency volumetric tissue reduction of the palate in subjects with sleep-disordered breathing. Chest 1998;113(5):1163-1174. 54. Woodson BT, Steward DL, Weaver EM, Javaheri S. A randomized trial of temperature-controlled radiofrequency, continuous positive airway pressure, and placebo for obstructive sleep apnea syndrome. Otolaryngol Head Neck Surg 2003:128(6):848-861. 55. Piccirillo JF, Gates GA, White DL, et al. Obstructive sleep apnea treatment outcomes pilot study. Otolaryngol Head Neck Surg 1998:118(6):833-844. 56. Stuck BA, Sauter A, Hörmann K, et al. Radiofrequency surgery of the soft palate in the treatment of snoring. A placebo-controlled trial. Sleep 2005;28(7):847-850. 57. Main C, Liu Z, Welch K, et al. Surgical procedures and non-surgical devices for the management of non-apnoeic snoring: a systematic review of clinical effects and associated treatment costs. Health Technol Assess 2009;13(3):1-208. 58. Ho WK, Wei WI, Chung KF. Managing disturbing snoring with palatal implants: a pilot study. Arch Otolaryngol Head Neck Surg 2004:130(6):753-758. 59. Maurer JT, Verse T, Stuck BA, et al. Palatal implants for primary snoring: short-term results of a new minimally invasive surgical technique. Otolaryngol Head Neck Surg 2005;132(1):125-131.
1182 PART II / Section 13 • Sleep Breathing Disorders 60. Maurer JT, Hein G, Verse T, et al. Long-term results of palatal implants for primary snoring. Otolaryngol Head Neck Surg 2005; 133(4):573-578. 61. Friedman M, Schalch P, Lin HC, et al. Palatal implants for the treatment of snoring and obstructive sleep apnea/hypopnea syndrome. Otolaryngol Head Neck Surg 2008;138(2):209-216.
62. Akpinar ME, Kocak I, Gurpinar B, Esen HE. Effects of soft palate implants on acoustic characteristics of voice and articulation. J Voice 2010 Apr 30. [Epub ahead of print] 63. Verse T, Kroker B, Pirsig W, Brosch S. Tonsillectomy as a treatment of obstructive sleep apnea in adults with tonsillar hypertrophy. Laryngoscope 2000;110:1556-1559.
Genetics of Obstructive Sleep Apnea Susan Redline Abstract Patients with obstructive sleep apnea–hypopnea (OSAH) often have relatives—parents, siblings, and children—who have similar symptoms or a diagnosis of OSAH, or both. Related family members with OSAH often share similar anthropomorphic or craniofacial characteristics. In some instances, family resemblances appear strongest for weight and weight distribution (e.g., increased central adiposity); in others, family similarities are noted for jaw size and position (micro- or retrognathia) or face and head shape. These clinical observations are supported by studies demonstrating a familial aggregation of OSAH. Such studies have included reports of families with multiple affected members, twin and cohort studies, assessment of OSAH prevalence among relatives of affected probands, and quantification of the familial aggregation of OSAH by comparing the prevalence OSAH among relatives of affected probands with that in persons without affected relatives. There is clear evidence that a positive family history of OSAH is an important risk factor for an elevated apneahypopnea index (AHI) and associated symptoms such as
DEFINITION OF THE OBSTRUCTIVE SLEEP APNEA–HYPOPNEA PHENOTYPE As is the case with many other complex disorders, there is no standardized phenotypic definition of obstructive sleep apnea–hypopnea (OSAH). Clinically, OSAH is recognized as a syndrome that is defined by the occurrence of repetitive episodes of complete or partial upper airway obstruction during sleep; these episodes usually occur in association with loud snoring and daytime sleepiness. However, operationally, there is much variability in how specific respiratory events are identified, what threshold level for increased numbers of events is considered pathologic, and which other clinical and polysomnographic data are considered necessary for characterizing disease status. Most family and genetic studies of OSAH have used the apnea–hypopnea index (AHI) to define phenotype. The advantages of using the AHI include its relative simplicity, moderate to high night-to-night reproducibility,1 and widespread clinical use. In addition, it is often used clinically to diagnose cases and to justify third-party reimbursement for treatment, and it is often followed as a key outcome in OSAH treatment studies. Because the AHI has been shown to be moderately correlated with other indices of OSAH severity, such as nighttime oxygen desaturation and sleep fragmentation, it may provide information about several correlated traits that are important in disease expression. All genetic studies of OSAH that use the AHI as the outcome variable have demonstrated significant familial aggregation, suggesting that this measure captures useful information for quantifying genetic associations. Combining polysomnographic data with other information, including symptoms, signs, and outcome data, to
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snoring, daytime sleepiness, and apneas. Overall heritability estimates for the AHI are .30 to .40. Approximately 35% of the genetic variance in the AHI may be accounted for by genes that influence obesity (with 65% of the genetic variance likely due to genetic variants in other etiologic pathways). Linkage studies have identified several areas where biologically plausible candidate genes are located, including candidates for the metabolic syndrome, obesity, and sleep–wake control. A number of association studies also provide suggestive evidence for increased susceptibility to OSAH in persons who inherit variants for genes in pathways that might influence body fat distribution, metabolism, craniofacial structure, and ventilatory control. In this chapter, both general and specific approaches for investigating the genetic basis of OSAH are reviewed, and those candidate genes as well as intermediate traits that are likely important in determining the expression and severity of the syndrome are described. The latter knowledge might eventually help elucidate physiologically specific approaches for treating (and possibly preventing) OSAH and its common comorbidities.
derive a multidimensional phenotype is one approach for producing a more comprehensive description. In the Cleveland Family Study, a stronger relationship between familial risk and OSAH was observed when OSAH was defined by an AHI level greater than 15 plus reported daytime sleepiness than when disease was defined by AHI level alone.2 Additional power may be gained in future genetic studies of OSAH that use multidimensional phenotypes. As part of this effort, the polysomnographic variables that best identify specific phenotypes must be clarified. For example, alternatives to the AHI, such as indices of flow limitation during sleep or spectral analysis of sleep architecture, may prove to be superior markers for genetic studies. However, a phenotype must be feasible for use in the large numbers of subjects who are needed for genetic epidemiologic studies of complex traits. The choice of phenotype will be influenced by the cost, degree of invasiveness, and individual burden required for identifying and quantifying the phenotype and for applicability across the spectrum of age and body mass index (BMI), as well as by its accuracy and reliability.
INTERMEDIATE PHENOTYPES OSAH is a complex syndrome that is defined using clinically and physiologically relevant terms; identifying genes that determine intermediate phenotypes that are on a causal pathway leading to OSAH is one way to study it. Such intermediate traits may be more closely associated with specific gene products and may be less influenced by environmental modification than more complex (and downstream) phenotypes. A number of risk factors probably interact to increase propensity for repetitive upper airway collapse that occurs 1183
1184 PART II / Section 13 • Sleep Breathing Disorders
during sleep in patients with OSAH. In a given person, the relevant attributes may be determined by anatomic and neuromuscular factors that influence upper airway size and function. Strong OSAH risk factors are obesity and male gender. Although it has been argued that the genetics of obesity cannot be separated from the genetics of OSAH, careful statistical modeling of AHI and BMI indicates that only about 35% of the genetic variance in AHI is shared with BMI, suggesting that a substantial portion of the genetic basis for OSAH is independent of obesity.3 Other pathoetiologic pathways include those that influence upper airway size, ventilatory control mechanisms, and possibly elements of sleep and circadian rhythm control. Thus, it is useful to consider at least four primary intermediate pathogenic pathways through which genes might act to increase susceptibility to OSAH: obesity and related metabolic syndrome phenotypes, craniofacial and upper airway morphometry, control of ventilation, and control of sleep and circadian rhythm4; these are discussed in more detail later. The limitation of this approach is that the genes so identified might not be sufficient to describe the clinically important phenotype, which might only occur in the context of other genetic and environmental factors. Specifically, susceptibility genes for intermediate traits associated with OSAH might not be equivalent to the susceptibility genes for OSAH.
OBESITY AND BODY FAT DISTRIBUTION Obesity increases risk of OSAH by 2- to 10-fold, with the strongest associations observed in middle-age.5 There are several pathways through which obesity predisposes to OSAH. Fat deposition in the parapharyngeal fat pads may directly narrow the upper airway and predispose it to collapse when neuromuscular activation of upper airway muscles declines with sleep (see Chapter 101). Fat deposition in the thorax and abdomen also increases the work of breathing, which can produce hypoventilation and reduce lung volumes, which in turn reduces parenchymal traction on the trachea, making the airway more collapsible. Reduced lung volumes also can increase propensity for oxygen desaturation to occur, increasing the likelihood that any given reduction in airflow may be classified as a hypopnea and increasing the severity of hypopnea-associated physiologic disturbances. In addition, low lung volumes can reduce oxygen stores and alter loop gain, which, in turn, can influence ventilatory instability. Finally, adipose tissue secretes hormones such as leptin that can influence ventilatory drive (see later). Central body fat distribution appears especially important in the pathogenesis of OSAH. It is unclear whether this is because of the mechanical effects of central fat on lung mechanics and ventilation or upper airway size or because visceral fat is metabolically active. Heritability estimates for obesity-associated phenotypes such as BMI, skinfold thickness, regional body fat distribution, fat mass, and leptin levels range between 40% and 70%, consistent with moderate to strong influences of genetic factors on these traits.6-8 Approximately 7% of cases of early-onset obesity have been estimated to be attributable to the effects of mutations in at least seven
genes influencing the leptin–melanocortin pathways, including melanocortin-4 receptor, leptin, leptin receptor, proopiomelanocortin, and tropomyosin-related kinase-B, which largely influence weight though alterations in appetite regulation.9 Mutations in melanocortin-4 receptor increase risk of severe childhood obesity by approximately 30% and also have been implicated in 0.5% of adult cases of obesity.10 Until recently, the genetic etiology of obesity in the general population was elusive. However, large-scale genome-wide association studies, which examine the variation of frequency of thousands of alleles with disease status in very large samples, have led to the discovery of FTO (fat mass and obesity–associated gene) as an obesitysusceptibility gene.11 These associations, which have been replicated across populations, indicate homozygotes for the risk allele weigh on average 3 to 4 kg more and have a 1.67-fold increased risk of obesity compared with persons without the risk allele. Although the functioning of this gene is not well understood, it is believed that FTO confers a risk of increased obesity risk through regulation of food intake, and possibly via mechanisms that influence stress responses. Other genetic variants, which might individually explain less than 4% of the phenotypic variation, include polymorphisms in genes involved in catecholamine function, mitochondrial respiration, and various pathways involved with insulin sensitivity.8
CRANIOFACIAL MORPHOLOGY Craniofacial morphology, which encompasses both bony and soft tissues, is believed to predispose to OSAH by reducing upper airway patency. Structural features that have been described in patients with OSAH using techniques such as cephalometry include reduction of the anterior-posterior dimension of the cranial base, a reduced nasion-sella-basion angle, reduction of the size of the posterior and superior airway spaces, inferior displacement of the hyoid, elongation of the soft palate, macroglossia, hypertrophy of adenoids and tonsils, increased vertical facial dimension with a disproportionate increase in the lower facial height, and mandibular retrognathia or micrognathia.12-14 (see Chapter 105). A brachycephalic head form, measured by anthropometry, is often found in association with reduced upper airway dimensions. This head form is associated with a small but significant increased risk of OSAH in whites, and it also identifies families at risk for both OSAH and sudden infant death.15 In African Americans, this head form is uncommon and does not appear to increase risk of OSAH. In humans, the genetic basis for craniofacial features is supported by both twin and family studies.16 Over one third of the variability in the volume of soft tissue airway structures including the tongue and lateral pharyngeal walls can be explained by familial factors.17 There are also at least 50 syndromes in which congenital malformations of mandibular and maxillary structure occur, many of which also are associated with respiratory impairment and upper airway obstruction. These include Pierre-Robin syndrome and Treacher Collins syndrome.18,19 Studies of various syndromes and genetic defects suggest potential roles of genes belonging to the fibroblast growth factor
(e.g., FGFR1, FGFR2, FGFR3), transforming growth factor beta (e.g., TGFBR1, TGFBR2), homeobox (e.g., MSX1, MSX2), and sonic hedgehog (e.g., PTCH, SHH) pathways. Other potentially relevant candidate genes are those that have been implicated in craniofacial development, including genes on the endothelin pathway (e.g., ECE1, EDN1, EDNRA),20-22 and TCOF1, the cause of Treacher Collins syndrome.23 Further understanding of homeobox genes and genes controlling growth factors might contribute to our clarifying the origins of craniofacial dysmorphisms found in OSAH. Inherited abnormalities of craniofacial structure appear to explain at least some of the familial aggregation of OSAH. Relatives of OSAH probands have been shown to have decreased total pharyngeal volumes and glottic crosssectional areas, retropositioned maxillas and mandibles, and longer soft palates compared with relatives of controls.24 Relatives of patients with OSAH have been shown by cephalometry to have a more retropositioned mandible and smaller posterior superior airway space compared to normative data.25 In the Cleveland Family Study, both hard tissue (e.g., head form, intermaxillary length) and soft tissue (e.g., soft palate length, tongue volume) factors predicted the AHI level in European Americans. In African Americans, soft tissue factors also predicted AHI levels, but hard tissue anatomic features appeared to be only weakly associated with OSAH.26 These data support the importance of structural features in increasing susceptibility to OSAH, but they also suggest that the anatomic underpinnings and the genes for upper airway anatomy might differ among ethnic groups. Magnetic resonance imaging (MRI) (see Chapter 101) studies have shown that the lateral pharyngeal wall and tongue are larger in OSAH patients compared with matched controls.27 More than one third of the variability in the volume of soft tissue airway structures including the tongue and lateral pharyngeal walls was estimated to be explained by familial factors.17 Although MRI precisely describes anatomic characteristics, its cost limits its utility for large-scale genetic epidemiology studies. An alternative approach is use of acoustic reflectometry, which is a noninvasive technique for assessing airway cross-sectional area as a function of airway distance, and has identified associations of OSAH with mean and minimal airway cross-sectional areas.28-31 The utility of acoustic reflectometry for phenotyping airway risk factors is supported by a study of 568 participants in the Cleveland Family Study. In this sample, the heritability estimate for minimal cross sectional area in both European Americans and African Americans was .37 (P < .05), which increased to .55 once only the highestquality curves were analyzed.32 These estimates were not appreciably changed after considering the influence of BMI, suggesting that between 30% and 55% of the familial similarities in airway dimensions may be explained by genetic factors apart from BMI. Future research needs to assess the ability of such techniques to identify subgroups of persons who inherit polymorphisms associated with genes on craniofacial as compared to other etiological pathways, and further investigation of how anatomic measurements performed awake and in the sitting position predict collapsibility during sleep.
CHAPTER 103 • Genetics of Obstructive Sleep Apnea 1185
VENTILATORY CONTROL PATTERNS Potentially inherited abnormalities of ventilatory control may predispose to obstructive or central sleep apnea by affecting ventilation during sleep and promoting upper airway collapsibility. Ventilatory instability could result from blunted or augmented chemosensitivity, arousability, or load detection. In the presence of a blunted ventilatory drive, neural stimulation of the upper airway dilator muscles can become insufficient to overcome increases in upper airway resistance occurring during sleep and particularly during sleep in the recumbent posture. Conversely, an overly vigorous ventilatory drive can lead to instability of breathing with alternating cycles of hyperventilation and hypoventilation, most commonly recognized as periodic breathing. During the nadir of this cycling, reduction in chemical drive due to hypocapnia can reduce neural output to upper airway muscles to a level below the threshold required to keep the airway open. Mouse models have allowed genes to be identified that influence control of ventilation, including genes that determine respiratory timing, frequency, awake ventilation, chemosensitivity, and load responses. Clear strain differences have been observed for many of these phenotypes, with evidence of quantitative trait loci near plausible candidate genes. Knockout and transgenic mice also have helped identify the role of specific proteins and receptors in ventilatory chemoreception, neuromuscular transmission, and neural integration. Candidate genes identified from such studies include genes that sense hypoxia33-36; genes on the endothelin pathway,37,38 which also are important in craniofacial development; and genes that regulate neural crest migration,38-40 including PHOX2B, mutations of which cause congenital central hypoventilation.41,42 Population variability in the ventilatory neuromuscular responses might also influence propensity for OSAH and might also be inherited. Phenotypes that can both be inherited and influence OSAH propensity include ventilatory responses to the influences of state (sleep– wake), chemical drive (e.g., ventilatory response to hypoxia and hypercapnia), sensitivity of ventilatory load compensation (the degree to which an individual defends the tidal volume or minute ventilation in the presence of an imposed mechanical load to breathing such as an increased resistance or elastance), or arousal may result in different ventilatory responses to sleep-related stresses, shaping both the magnitude of ventilation and ventilatory pattern and the propensity for respiratory oscillations in sleep. The magnitude of ventilatory chemoresponsiveness appears to be subject to major genetic control; heritability estimates for chemoresponsiveness to oxygen saturation levels range from approximately 30% to 75%.43 Ventilatory responses are more strongly correlated between monozygotic than dizygotic twins.44-47 Population differences in ventilatory patterns and hypoxic sensitivity have been identified for populations that have adapted to living at high altitude.48,49 Abnormalities in hypoxic or hypercapnic ventilatory responsiveness have been described in the
1186 PART II / Section 13 • Sleep Breathing Disorders
first-degree relatives of probands with unexplained respiratory failure,50 chronic obstructive pulmonary disease,51,52 and asthma.53 Unfortunately, further identification of the role of ventilatory control as an OSAH intermediate phenotype has been impeded by the overall complexity in measuring relevant ventilatory control abnormalities in humans. Challenges include making measurements during sleep, extrapolating awake responses to the sleep state, use of hypoxic and hypercapnic challenge testing to identify the role of peripheral and central chemoreceptors, respectively, and distinguishing responses that are a primary as compared to an acquired phenotype. An example of an acquired phenotype in this context may be one that results from drugs that alter ventilatory chemosensitivity or conditions in which translation of central nervous system ventilatory drive into the metric of drive, such as ventilation, is impaired by abnormal lung or chest wall function, as can occur in chronic obstructive pulmonary disease and ventilatory muscle weakness. No specific approach for measuring ventilatory control has yet been shown to reliably distinguish OSAH patients from controls. A potential role for inherited impairments of ventilatory control in influencing susceptibility to OSAH has been suggested by several studies of carefully characterized families. These studies have demonstrated blunted hypoxic responses and impairment in load compensation in the families of OSAH patients compared with controls. El Bayadi and colleagues reported the results of anatomic and physiologic studies performed in 10 subjects from three generations of a family with an affected proband with OSAH.54 OSAH was documented in 9 of the 10 family members, all of whom had a body mass index less than 30. Blunted responses to ventilatory challenge tests to progressive hypoxia were demonstrated in all five subjects who underwent ventilatory challenge testing. Cephalometry also showed variable degrees of upper airway anatomic compromise. These findings supported a family basis for OSAH, with evidence that inherited abnormalities in anatomic and physiologic risk factors both contributed to the disease severity. Significantly lower ventilatory responses to hypoxic challenge testing were demonstrated in a study that compared ventilatory control responses in 31 subjects from 12 families with two or more members with OSAH, compared to responses in nine age- and sex-matched controls.55 The selection of subjects from families showing familial aggregation for OSAH might have improved the ability to detect potentially inherited abnormalities in an intermediate phenotype. In another study, differences in responses to inspiratory resistive loading during sleep were examined in 10 apparently healthy (without OSAH) adult offspring of OSAH probands and in 14 control offspring of healthy parents.56 Both groups had similar load responses during wakefulness, but during sleep with inspiratory loading, the offspring of OSAH probands breathed at a lower tidal volume than controls, with development of hypopneas at lower levels of resistance, and were less likely to show EEG arousal with hypopneas than the controls. Similarly, nasal occlusion during sleep was demonstrated to precipitate more hypopneas in the healthy relatives of OSAH probands than controls.57 However, these studies could not
differentiate the extent to which differences in ventilatory patterns between the groups was due to differences in collapsibility versus ventilatory drive. Javaheri and colleagues tested for differences in chemoresponsiveness to progressive hypercapnia and to hypoxia in the healthy relatives of hypercapnic OSAH patients compared to eucapnic OSAH patients.58 Although the chemoresponses among relatives were correlated, the relatives of patients with and without hypercapnia did not differ. Thus, this study did not provide evidence for genetically determined differences in chemoresponsiveness influencing the propensity of hypercapnia in OSAH. The potential impact of deficits in ventilatory control on OSAH susceptibility is likely magnified in persons with anatomically comprised upper airways. With sleep onset, the central inspiratory drive to upper airway motor neurons, a major determinant of airway patency, is reduced or fluctuates.59,60 Any given reduction in central inspiratory drive results in greater increases in upper airway resistance in persons with anatomically compromised airways than in others.61 Conversely, persons with greater degrees of upper airway resistance (due to craniofacial or obesity risk factors) can require a high level of compensatory ventilatory drive to overcome sleep-associated airway collapse, and thus they may be especially vulnerable to the influence of genetically determined ventilatory control deficits. These observations underscore the potential importance of considering the interaction of genetic risk factors that influence more than one etiologic pathway.
CONTROL OF SLEEP AND CIRCADIAN RHYTHM Given the impact of sleep–wake state on respiratory motor neuron activation, insights into the susceptibility of upper airway muscles to collapse during sleep can require delineation of the genetics of sleep–wake control. Remarkable advances in our understanding of narcolepsy have provided important information on genes that might control sleep– wake regulation. Experimental studies in dogs and rodents have implicated deficiencies in the orexins (hypocretins; two polypeptides that are ligands for two G protein– coupled receptors in the brain) in causing the phenotypic abnormalities in sleep regulation that characterize narcolepsy. Abnormalities in orexin genes, or genes coding for their receptors, could be relevant to studies of OSAH because of the potential impact of these neuropeptides on arousal and muscle tone, both of which influence the behavior of respiratory systems, because of the close proximity of these neurons to central respiratory control centers, with potential interactions between arousal and respiratory centers. Orexins have also been shown to play a role in energy homeostasis and the regulation of feeding and projections to areas in the ascending cortical activating system, are involved with regulation of both appetite and sleep–wake states,62,63 as well as ventilatory control.64 Although this pathway has not been well studied in OSAH, orexin A levels are reported to be reduced in OSAH.65 Thus, abnormalities in orexin genes may be relevant to OSAH because of their influence on arousal, muscle tone, ventilatory control, and weight control. Data from the Cleveland
CHAPTER 103 • Genetics of Obstructive Sleep Apnea 1187
Table 103-1 Familial Correlations for Apnea–Hypopnea Index
RELATIONSHIP
PARTIALLY ADJUSTED* FAMILIAL CORRELATION COEFFICIENT
BMI-ADJUSTED† FAMILIAL CORRELATION RELATIONSHIP P VALUE
COEFFICIENT
P VALUE
Parent–offspring
.21
.002
.17
.017
Sib-sib
.21
.003
.18
.008
age , age squared; BMI, body mass index. *Adjusted for age, age2, ethnic group, and gender. † Adjusted for BMI, age, age2, ethnic group, and gender. From Redline S, Tishler PV, Tosteson TD, et al. The familial aggregation of obstructive sleep apnea. Am J Respir Crit Care Med 1995;151:682-687. 2
Family Study indicate that an area on chromosome 6 that houses the orexin-2 receptor is linked with the AHI (see later). In addition to considering the impact of genetic abnormalities on processes that regulate sleep–wake state, it may be useful to consider how respiratory motor neuron control may be influenced by genetic processes that determine circadian clocks, which are known to drive important metabolic and behavioral rhythms. Studies of Drosophila and mouse models have identified a number of genes that influence periodicity and persistence of circadian rhythms,66-69 with evidence that similar mechanisms operate in humans.69,70 The relevance of these findings to OSAH is unclear. However, genetic variations in regulation of sleep–wake rhythm may be factors that influence the expression of OSAH (e.g., ability to compensate or show sleepiness in response to recurrent apneas and sleep disruption).
FAMILIAL AGGREGATION OF OBSTRUCTIVE SLEEP APNEA–HYPOPNEA Significant familial aggregation of AHI, or of symptoms of OSAH, has been observed in studies from the United States, Finland, Denmark, the United Kingdom, Israel, and Iceland.2,24,71-75 Studies have used a variety of designs, including cohorts, small and large pedigrees, twins, and case-control studies; they have included adults and children; and they have employed varying approaches for assessing phenotype. Despite study design and population differences, all studies have consistently shown familial aggregation of the AHI level and symptoms of OSAH in children and adults and in obese and nonobese subjects (Video 103-1). These studies have provided clear evidence that a positive family history of OSAH is an important risk factor for an elevated AHI and for associated symptoms such as snoring, daytime sleepiness, and apneas. However, the estimated magnitude of effects has varied greatly. Several large twin studies have shown that concordance rates for snoring, a cardinal symptom of OSAH, were significantly higher in monozygotic twins than in dizygotic twins.76-78 A study of adult male twins has shown significant genetic correlations for daytime sleepiness as well as snoring, and models were consistent with common genes underlying both symptoms.76 A subsequent report from this cohort showed significant heritability for objectively
measured AHI levels in this twin population.79 A large Danish cohort study showed that the age, BMI, and comorbidity-adjusted risk of snoring was increased threefold when one first-degree relative was a snorer, and it increased fourfold when both parents were snorers.80 The prevalence of objectively measured OSAH among first-degree relatives of OSAH probands has been reported to vary from 22% to 84%.2,24,72,73,75 Among the studies that included controls, the odds ratio (OR), which relates the odds of a person with OSAH in a family with affected relatives to that for someone without an affected relative, has varied from 2 to 46.2,24,72,73,75 Pedigree studies from the United States and Iceland have shown consistent associations; the overall recurrent risk for OSAH in a family member of an affected proband is approximately 2,2,72 which is lower than that reported from case-control studies, which may be subject to biases depending on the appropriateness of the selection of cases and controls. Heritability estimates for the AHI from both pedigree81,82 and twin studies79 are approximately 35% to 40%. Similar parent– offspring (r = .21, P = .002) and sib–sib correlations (r = 0.21, P = .003) have been observed, and they are greater than spouse–spouse correlations.2 OSAH has been described as occurring more commonly as a multiplex (affecting at least two members) than as a simplex (occurring in a single family member) disorder. Further evidence for a genetic basis for OSAH is derived from the observation that the odds of sleep apnea syndrome, defined as AHI greater than 15 and self-reported daytime sleepiness, increases with increasing numbers of affected relatives.2 Table 103-1 shows the odds for sleep apnea syndrome given one, two, or three affected relatives with these findings, as compared with OSAH patients who have no affected relatives, adjusted for age, gender, ethnicity, and BMI. These results support the utility of ascertaining family history as part of the evaluation of the patient for OSAH. Information on snoring, apneas, and sleepiness among first-degree relatives can be used to refine the likelihood of OSAH in any given patient. However, perhaps more importantly, such information can be used to make it easier to diagnose cases by identifying the need for other family members to seek sleep evaluations. Several studies have reported a co-aggregation of OSAH with sudden infant death syndrome (SIDS) or acute life threatening events (ALTEs).72,83,84 Members from families with both OSAH and SIDS cases have been reported to
1188 PART II / Section 13 • Sleep Breathing Disorders
have anatomic features, such as brachycephaly, leading to upper airway narrowing, as well as reduced hypoxic ventilatory responsiveness.84 These observations suggest that the two disorders have a shared genetic predisposition acting via ventilatory control or craniofacial structure pathways. The demonstration of widespread serotoninergic brainstem abnormalities in SIDS victims,85 and the putative role of this pathway in respiratory drive, suggests an interesting biological basis for the potential genetic link between these disorders that might involve ventilatory mechanisms. The relationship between pediatric and adult OSAH is not clearly understood. However, pedigree studies show that the disease is transmitted across generations. The familial aggregation of appropriately age-adjusted AHI values suggests that common risk factors might influence OSAH susceptibility in children and adults. Although hypertrophy of the tonsils is a major risk factor for childhood OSAH, children of OSAH probands more often have residual OSAH after tonsillectomy compared to the offspring of adults without OSAH,86 suggesting the importance of underlying genetic susceptibility as a determinant of treatment response.
GENETIC ANALYSES Segregation Analysis Segregation analysis is an approach whereby statistical models that make alternative assumptions about the underlying mode of inheritance and the impact of environmental factors on a given trait are compared in an attempt to identify the model that best explains the underlying distribution of traits. These analyses are particularly useful in identifying potential patterns of inheritance. In the Tucson Epidemiologic Survey, segregation analyses of self-reported snoring in 584 pedigrees suggested a major gene effect; however, evidence for the connection weakened after adjustments were made for obesity and gender.87 Segregation analysis was applied to a sample of European Americans (177 families, 1202 members) and African Americans (123 families, 709 members) in the Cleveland Family Study. The analyses of AHI were consistent with the segregation of major genetic factors within both sets of families, although the results suggested possible ethnic differences in the mode of inheritance.74 In European Americans, analysis suggested recessive mendelian inheritance of the AHI, which accounted for 21% to 27% of the variance and an additional 8% to 9% of the variation caused by other familial factors, either environmental or polygenic.74 In African Americans, the BMI-adjusted and age-adjusted AHI gave evidence of segregation of a co-dominant gene with an allele frequency of 0.14 that accounted for 35% of the total variance of this trait. Adjustment of the AHI for BMI weakened the findings in the European Americans and strengthened them in the African Americans. These results provide support for an underlying genetic basis for OSAH in African Americans independent of the contribution of BMI. The analyses in European Americans suggested that a major gene for OSAH might be closely related to genes for obesity.
Molecular Genetic Studies The molecular genetics of OSAH has begun to be investigated using candidate gene approaches (association studies) and whole-genome screens. Candidate gene studies compare the frequency of genetic variants thought to relate to disease susceptibility in groups with and without OSAH. Marked advances in technology now permit fairly dense mapping of genetic markers across the genome, with some assays providing coverage of up to one million genetic variants (single nucleotide polymorphisms [SNPs]), providing the opportunity to discover genetic variants for a trait without prior knowledge of candidate genes. Such whole-genome scans can be applied to family members and analyzed with linkage analysis. Linkage analysis quantifies the co-segregation of a disease locus and a marker locus among family members. Typically, the strength of genetic associations is expressed as a LOD score (the log-odds quantifying the probability of receiving alleles at two loci). A LOD score of 3.0 or more usually is considered strong evidence for linkage. Whole-genome scans can also be used to quantify difference in frequencies of genetic variants in unrelated affected or unaffected persons (i.e., genome-wide association). These approaches have yielded novel discoveries of genetic variants that enhance susceptibility to major chronic diseases such as diabetes and inflammatory bowel disease.88 However, such large-scale studies have not yet been systematically performed for OSAH-related traits. A number of plausible candidate genes are found in pathways that influence the intermediate traits of obesity, craniofacial structure, and ventilatory control (Box 103-1). Candidate genes that have been examined in relationship to OSAH in humans include those for apolipoprotein E (APOE), angiotensin converting enzyme (ACE), serotoninergic pathways, and leptin pathways. Apolipoprotein E An allele of the APOE gene (e4) which was previously associated with increased risk for both cardiovascular disease and Alzheimer’s disease, was reported to be associated with OSAH in two cohort studies of predominantly white subjects.89,90 Two other studies, however, did not replicate this finding.91,92 The Cleveland Family Study reported evidence for linkage to AHI near the APOE locus on chromosome 19, using an initial set of genetic markers, with stronger evidence for linkage after inclusion of fine mapping markers.93 However, the APOE genotype did not explain the linkage findings and was not associated with OSAH status. These findings suggested that the susceptibility locus for OSAH is not to APOE but another locus close to it. A candidate gene in this area is hypoxia inducible factor 3, which plays a role in oxygen sensing. Angiotensin II Converting Enzyme Angiotensin II, an important vasoconstrictor, also appears to modulate afferent activity from the carotid body chemoreceptor and thus might influence ventilatory drive.94 Angiotensin II levels are regulated by the actions of ACE, which is encoded by the ACE gene. Several studies of
CHAPTER 103 • Genetics of Obstructive Sleep Apnea 1189
Box 103-1 Candidate Genes* for Intermediate Phenotypes for Obstructive Sleep Apnea Obesity FTO (fat mass and obesity-associated gene) Melanocortin-4 receptor Leptin Proopiomelanocortin Melanocyte-stimulating hormone Neuropeptidase Y Prohormone convertase Neutrophic receptor TrkB Insulin-like growth factor Glucokinase Adenosine deaminase Tumor necrosis factor α Glucose regulatory protein Agouti signaling protein Beta-adrenergic receptor Carboxypeptidase E Insulin signaling protein Resistin Ghrelin Adiponectin Gamma-aminobutyric acid transporter Orexin Ventilatory Control RET protooncogene PHOX2B HOX IIL2 KROX-20 Receptor tyrosine kinase Neurotrophic growth factors • Brain-derived neurotrophic factor • Glia-derived neurotrophic factor • Neurotrophic factor-4 • Platelet-derived growth factor Neuronal synthase Acetylcholine receptor Dopaminergic receptor Substance P Glutamyl transpeptidase Endothelin-1 Endothelin-3 Leptin EN-1 GSH-2 Orexin Craniofacial Structure Class I homeobox genes Growth hormone receptors Growth factor receptors Retinoic acid Endothelin-1 Collagen types I and II Tumor necrosis factor α *Includes related proteins and receptors.
Chinese cohorts have reported an association between polymorphisms in the ACE gene and OSAH, particularly in persons with hypertension type.95-99 Data from the Wisconsin Sleep Cohort and the Cleveland Family Study did not show an association between ACE genotype and OSAH, but they showed variation of hypertension in asso-
ciation with level of OSAH and ACE genotype.100,101 In the Cleveland Family Study, after controlling for co-variates, hypertension risk was reduced in subjects who possessed the ACE deletion (D) polymorphism (OR, 0.63; 95% confidence interval [CI], 0.41-0.96, comparing those with 2 versus 0 D alleles). After stratifying by OSAH severity, the protective effect of the D allele was most evident in those with severe OSAH (OR, 0.47; 95% CI, 0.22-1.00), suggesting that the ACE deletion allele might protect against hypertension in the setting of OSAH. Serotoninergic Pathways Serotonin (5-hydroxytryptanmine [5-HT]) receptors are found in the carotid body and hypoglossal neurons, as well as in the brainstem near ventilatory control centers important for chemoreception. Research on animals suggests that serotoninergic neurotransmission, through peripheral actions at the level of the carotid body or hypoglossal nerve, or centrally, at medullary respiratory control centers, influences a wide range of functions relevant to OSAH, including upper airway reflexes, ventilation, and arousal, as well as sleep–wake cycling. Although the pharmacology is complex, with at least 14 receptor subtypes, there is growing evidence implicating the importance of this pathway in the pathogenesis of SIDS, which, as discussed earlier, might share common genetically determined risk factors with OSAH. Polymorphisms in three genes—SLC6A4 (encoding a serotonin transporter protein that clears serotonin from the synaptic space), HTR2A (encoding the 5-HT2A receptor), and HTR2C (encoding the 5-HT2C receptor)—each have been studied in relationship to OSAH.102-104 A polymorphism in the promoter region of SLC6A4, associated with variations in serotonin reuptake activity, was weakly associated with OSAH among men but not women in a small Turkish study, but this association was not confirmed in a Chinese cohort.102,103 Another polymorphism in SLC6A4, which has unclear functional significance, was weakly associated with OSAH in both studies. A polymorphism for HTR2A was also reported to be associated with OSAH among male, but not female, subjects in a small Turkish cohort,104 but this association was not replicated in a larger Japanese study.105 The latter study also did not identify a role for a polymorphism for HTR2C in OSAH. Leptin Signaling Animal studies suggest that leptin, an adipose-derived circulating hormone that influences appetite regulation and energy expenditure, not only influences body weight but also has important effects on ventilatory drive. Mice homozygous for a knockout mutation in leptin hypoventilate and have a blunted ventilatory response to hypercapnia.106 Leptin replacement improves the ventilatory responses to hypercapnia in both wakefulness and sleep in leptin-deficient mice.107 Leptin’s stimulatory effects on hypercapnic ventilatory response appear to be mediated through melanocortin, which is produced from a precursor polyprotein, proopiomelanocortin. As described earlier, the Cleveland Family Study reported suggestive evidence for linkage to an area on chromosome 2p that houses the proopiomelanocortin locus, an area also
1190 PART II / Section 13 • Sleep Breathing Disorders Table 103-2 Evidence for Linkage for the Apnea Hypopnea Index and Body Mass Index, Cleveland Family Study (European American Subgroup) LOD Score CHR 6 6 10
cM 80.4
AHI
AHI ADJUSTED FOR BMI(5)
BMI
0.6
3.5
162
4.7
0.4
0.7 0.2
118.3
2.7
0.7
0.3
AHI, apnea–hypopnea index; BMI, body mass index; Chr, chromosome; cM, centimorgan. Adapted from Larkin EK, Patel SR, Elston RC, et al. Using linkage analysis to identify quantitative trait loci for sleep apnea in relationship to body mass index. Ann Hum Genet 2008;72(Pt. 6):762-773.
reported by others to be strongly linked to serum leptin levels.108 Thus, hypothalamic and pituitary pathways involved in leptin signaling may be important in influencing ventilatory control as well as obesity phenotypes relevant to OSAH. Linkage Analyses The only whole-genome screens available for OSAHrelated traits have been performed in the Cleveland Family Study.81,82 Preliminary linkage analyses, performed on the most informative subset of the cohort, identified candidate regions on chromosomes 1p, 2p, 12p, and 19p in whites and on 8q in African Americans. Subsequent linkage analyses were performed in 1275 members of 237 families.109 Several areas of significant linkage to AHI were identified (Table 103-2) that were not associated with coincident linkage for BMI. Notably, significant linkage was observed on chromosome 6 for the BMI-adjusted AHI level (LOD score: 3.5). This area houses the orexin 2 receptor. If this analysis is replicated, it would provide important data supporting pleiotropic effects of orexin on numerous phenotypes associated with sleep disorders.
SPECIAL CHALLENGES IN STUDYING THE GENETICS OF OBSTRUCTIVE SLEEP APNEA–HYPOPNEA The AHI has been the most common measure used in genetic studies of OSAH. However, it is not clear that this is the trait that has the highest degree of heritability or whether it provides an index of disease severity that is consistent across the population. As a count, it might not provide maximal information regarding severity of individual events (duration, associated hypoxemia, arousal) and event characteristics (e.g., extent of pleural pressure swings). An overall AHI in an older population might represent somewhat different physiologic perturbations than one derived in a younger population. Genetic determinants also can distinguish persons with a predominance of central events, in whom neural mechanisms might play a potentially greater role than do factors that more directly influence airway collapsibility. More
comprehensive physiologic data might better capture features that define clearer and more-specific phenotypes. The AHI as a trait-defining variable also presents special statistical challenges in genetic studies. Analyses of quantitative trait loci usually provide the greater statistical power in genetic analyses than analyses of binary traits (e.g., present or absent). These analyses are very sensitive to normality assumptions. However, the AHI follows an extremely skewed distribution that even extensive statistical transformations often do not fully normalize. Additionally, these distributions can vary by sex, with different mean values as well as variances for male and female subjects.74 These statistical challenges have required some studies to use specialized statistical transformations applied to each sex separately. Additionally, in the general population, AHI strongly correlates with BMI. Linkage studies suggest there are both common and independent genetic determinants for the AHI and BMI.109 Thus, strategies where the AHI is statistically adjusted for BMI might not be appropriate for identifying genes that causally affect both traits. On the other hand, analyses that do not account for BMI have limited interpretability regarding the specificity for OSAH of any observed genetic associations. Challenges also arise in association studies, where it is necessary to define specific thresholds for classifying disease status. The absolute threshold values that distinguish disease subgroups are very sensitive to the specific application of polysomnographic measurement techniques, and they can also vary according to the age and other characteristics of the population. Because the AHI has a strong age dependency, with marked increases with advancing age and in women after menopause, a single threshold disease-defining value might not be appropriate across the age span.
SUMMARY Despite the challenges in studying an inherently complex trait, there is growing evidence from clinical and epidemiologic studies that genetic factors influence the expression of OSAH. The largest pedigree and twin studies consistently estimate heritability for the AHI to be between 35% and 40%, with recurrent risk factors of approximately 2. Although obesity is the strongest risk factor for OSAH and has a clear genetic basis, causal modeling suggests that only 35% of the genetic variance in the AHI is shared with pathways that determine body weight. Thus, a majority of the genetic variance for the AHI is likely due to the influence of genes that influence other pathways, including those that influence craniofacial structure, ventilatory control, and possibly sleep–wake patterns. Investigating the genetic etiology of OSAH offers a means of better understanding its pathogenesis, with the goal of improving preventive strategies, diagnostic tools, and therapies. Molecular studies of OSAH still lag behind those of other chronic diseases. However, the application of genome-wide association studies to study the genetics of this disorder promise to further elucidate genetic pathways for this disorder, as has been accomplished for other major chronic illnesses.
CHAPTER 103 • Genetics of Obstructive Sleep Apnea 1191
❖ Clinical Pearl A positive family history of OSAH (or of related symptoms) is useful in identifying patients at increased risk for the disorder. Craniofacial abnormalities and obesity can each have a genetic basis and are risk factors for sleep apnea. Clinicians should ask about sleep apnea symptoms in family members. Children who have undergone tonsillectomy for snoring who are the offspring of persons with sleep apnea may be at increased risk for recurrent sleep apnea, and careful monitoring of these children may be indicated.
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68. Gekakis N, Staknis D, Nguyen HB, et al. Role of the CLOCK protein in the mammalian circadian mechanism. Science 1998;280:1564-1568. 69. Bunney WE, Bunney BG. Molecular clock genes in man and lower animals: possible implications for circadian abnormalities in depression. Neuropsychopharmacology 2000;22(4):335-345. 70. Jones CR, Campbell SS, Zone SE, et al. Familial advanced sleepphase syndrome: A short-period circadian rhythm variant in humans. Nature Medicine 1999;5(9):1062-1065. 71. Redline S, Tosteson T, Tishler PV, et al. Studies in the genetics of obstructive sleep apnea. Familial aggregation of symptoms associated with sleep-related breathing disturbances. Am Rev Respir Dis 1992;145(2 Pt. 1):440-444. 72. Gislason T, Johannsson JH, Haraldsson A, et al. Familial predisposition and cosegregation analysis of adult obstructive sleep apnea and the sudden infant death syndrome. Am J Respir Crit Care Med 2002;166(6):833-838. 73. Guilleminault C, Partinen M, Hollman K, et al. Familial aggregates in obstructive sleep apnea syndrome. Chest 1995;107(6): 1545-1551. 74. Buxbaum SG, Elston RC, Tishler PV, Redline S. Genetics of the apnea hypopnea index in caucasians and African Americans: I. Segregation analysis. Genet Epidemiol 2002;22(3):243-253. 75. Pillar G, Lavie P. Assessment of the role of inheritance in sleep apnea syndrome. Am J Respir Crit Care Med 1995;151:688691. 76. Carmelli D, Bliwise DL, Swan GE, Reed T. Genetic factors in selfreported snoring and excessive daytime sleepiness: a twin study. Am J Respir Crit Care Med 2001;164(6):949-952. 77. Ferini-Strambi L, Calori G, Oldani A, et al. Snoring in twins. Respir Med 1995;89(5):337-340. 78. Kaprio J, Koskenvuo M, Partinen M, Telakivi I. A twin study of snoring. Sleep Res 1988;17:365. 79. Carmelli D, Colrain IM, Swan GE, Bliwise DL. Genetic and environmental influences in sleep disordered breathing in older male twins. Sleep 2004;27:917-922. 80. Jennum P, Hein HO, Suadicani P, et al. Snoring, family history, and genetic markers in men: the Copenhagen Male Study. Chest 1995;107:1289-1293. 81. Palmer LJ, Buxbaum SG, Larkin E, et al. A whole-genome scan for obstructive sleep apnea and obesity. Am J Hum Genet 2003;72(2): 340-350. 82. Palmer LJ, Buxbaum SG, Larkin EK, et al. Whole genome scan for obstructive sleep apnea and obesity in African-American families. Am J Respir Crit Care Med 2004;169(12):1314-1321. 83. Guilleminault C, Souquet M, Ariagno RL, et al. Five cases of nearmiss sudden infant death syndrome and development of obstructive sleep apnea syndrome. Pediatrics 1984;73:71-78. 84. Tishler PV, Redline S, Ferrette V, et al. The association of sudden unexpected infant death with obstructive sleep apnea. Am J Respir Critc Care Med 1996;153(6 Pt 1):1857-1863. 85. Paterson DS, Trachtenberg FL, Thompson EG, et al. Multiple serotonergic brainstem abnormalities in sudden infant death syndrome. JAMA 2006: 296: 2124-2132. 86. Morton S, Rosen C, Larkin E, et al. Predictors of sleep-disordered breathing in children with a history of tonsillectomy and/or adenoidectomy. Sleep 2001;24(7):823-829. 87. Holberg CJ, Natrajan S, Cline MG, Quan SF. Familial aggregation and segregation analysis of snoring and symptoms of obstructive sleep apnea. Sleep Breath 2000;4(1):21-30. 88. Wellcome Trust Case Control Consortium. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature 2007;447(7145):661-678. 89. Gottlieb DJ, DeStefano AL, Foley DJ, et al. APOE epsilon4 is associated with obstructive sleep apnea/hypopnea: the Sleep Heart Health Study. Neurology 2004;63(4):664-668. 90. Kadotani H, Kadotani T, Young T, et al. Association between apolipoprotein E epsilon4 and sleep-disordered breathing in adults. JAMA 2001;285(22):2888-2890. 91. Saarelainen S, Lehtimaki T, Kallonen E, et al. No relation between apolipoprotein E alleles and obstructive sleep apnea. Clin Genet 1998;53(2):147-148. 92. Foley DJ, Masaki K, White L, Redline S. Relationship between apolipoprotein E epsilon4 and sleep-disordered breathing at different ages. JAMA 2001;286(12):1447-1448.
93. Larkin EK, Patel SR, Redline S, et al. Apolipoprotein E and obstructive sleep apnea: evaluating whether a candidate gene explains a linkage peak. Genet Epidemiol 2006;30(2):101-110. 94. Allen AM. Angiotensin AT1 receptor–mediated excitation of rat carotid body chemoreceptor afferent activity. J Physiol 1998;510 (Pt. 3):773-781. 95. Xiao Y, Huang X, Qiu C. Angiotension I converting enzyme gene polymorphism in Chinese patients with obstructive sleep apnea syndrome. Zhonghua Jie He He Hu Xi Za Zhi 1998;21(8): 489-491. 96. Xiao Y, Huang X, Qiu C, et al. Angiotensin I-converting enzyme gene polymorphism in Chinese patients with obstructive sleep apnea syndrome. Chin Med J 1999;112(8):701-704. 97. Zhang J, Zhao B, Gesongluobu Sun Y, et al. Angiotensin-converting enzyme gene insertion/deletion (I/D) polymorphism in hypertensive patients with different degrees of obstructive sleep apnea. Hypertens Res 2000;23(5):407-411. 98. Zhang LQ, Yao WZ, He QY, et al. Association of polymorphisms in the angiotensin system genes with obstructive sleep apnea– hypopnea syndrome. Zhonghua Jie He He Hu Xi Za Zhi 2004; 27(8):507-510. 99. Li Y, Zhang W, Wang T, et al. Study on the polymorphism of angiotensin converting enzyme genes and serum angiotensin II level in patients with obstructive sleep apnea hypopnea syndrome accompanied hypertension. Lin Chuang Er Bi Yan Hou Ke Za Zhi 2004;18(8):456-459. 100. Patel SR, Larkin EK, Mignot E, Lin L. The association of angiotensin converting enzyme (ACE) polymorphisms with sleep apnea and hypertension sleep. Sleep 2007;30(4):531-536.
CHAPTER 103 • Genetics of Obstructive Sleep Apnea 1193 101. Lin L, Finn L, Zhang J, et al. Angiotensin-converting enzyme, sleep-disordered breathing, and hypertension. Am J Respir Crit Care Med 2004;170(12):1349-1353. 102. Ylmaz M, Bayazit YA, Ciftci TU, et al. Association of serotonin transporter gene polymorphism with obstructive sleep apnea syndrome. Laryngoscope 2005;115(5):832-836. 103. Yue WH, Liu PZ, Hao W, et al. Association study of sleep apnea syndrome and polymorphisms in the serotonin transporter gene. Zhonghua Yi Xue Yi Chuan Xue Za Zhi 2005;22(5):533-536. 104. Bayazit YA, Yilmaz M, Ciftci T, et al. Association of the −1438G/A polymorphism of the 5-HT2A receptor gene with obstructive sleep apnea syndrome. J Otorhinolaryngol Relat Spec 2006;68(3): 123-128. 105. Sakai K, Takada T, Nakayama H, et al. Serotonin-2A and 2C receptor gene polymorphisms in Japanese patients with obstructive sleep apnea. Intern Med 2005;44(9):928-933. 106. Tankersley C, Kleeberger S, Russ B, et al. Modified control of breathing in genetically obese (ob/ob) mice. J Appl Physiol 1996; 81(2):716-723. 107. O’Donnell CP, Schaub CD, Haines AS, et al. Leptin prevents respiratory depression in obesity. Am J Respir Crit Care Med 1999;159(5 Pt 1):1477-1484. 108. Comuzzie A, Hixson J, Almasy L, et al. A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2. Nat Genet 1997;15:273-276. 109. Larkin EK, Patel SR, Elston RC, et al. Using linkage analysis to identify quantitative trait loci for sleep apnea in relationship to body mass index. Ann Hum Genet 2008;72(Pt. 6):762-773.
Cognition and Performance in Patients with Obstructive Sleep Apnea Terri E. Weaver and Charles F.P. George Abstract Patients with obstructive sleep apnea (OSA) demonstrate variable degrees of cognitive and performance deficits such as difficulties with cognitive processing, sustaining attention, memory, executive functioning, and quality of life, with the deficits in these areas more apparent in those with moresevere disease (higher incidence of abnormal breathing events, greater hypoxemia). The mechanisms leading to such deficits and the relative contribution of sleep disruption, hypoxemia, reduced vigilance, and daytime sleepiness remain unclear. Treatment of OSA with continuous positive airway pressure (CPAP) results in consistent improvement in cognition
Sleep is chronically disturbed in untreated obstructive sleep apnea (OSA). Patients with OSA experience slowed thought processes, forgetfulness, delayed reaction time responses, and inability to concentrate, resulting in impaired daytime functioning. The cognitive and performance deficits experienced by patients with OSA are associated with decreased work performance,1 increased accidents,2 and diminished quality of life.3,4 The threat of impaired performance to the patient as well as the well-being of others presents legal and moral challenges to practitioners. Whether a person should be denied the privilege to operate a motor vehicle or work because of this risk is a matter of professional debate and legislative consideration. This chapter describes the cognitive and performance deficits in patients with OSA, considers the scope of this problem, proposes etiologic mechanisms, presents current methods of assessment, and describes the response to treatment. The legal ramifications of impaired functioning and practitioner liability are also addressed. Because respiratory disturbance index (RDI) and apnea–hypopnea index (AHI) are often used interchangeably in the literature, the term used in the cited literature will be the term applied in the chapter.
EPIDEMIOLOGY Cognitive and performance deficits (defined later) are clearly present in some patients with OSA, but the exact prevalence remains unknown. It has been estimated that approximately 80% of OSA patients complain of both excessive daytime sleepiness and cognitive impairments, and half also report personality changes.5 One in four patients with newly diagnosed OSA have appreciable neuropsychological impairments.6 In research studies examining memory, sustained attention, or executive function, memory impairments can be found in up to 9% of OSA subjects, 2% to 25% have problems with sustained attention, and 15% to 42% demonstrate difficulties with executive functioning.7 Traffic accidents and work-related accidents represent surrogate indicators of neurobehav1194
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and performance, although the magnitude of improvement is variable. The role of CPAP as first-line therapy in mild OSA is currently unknown, and its long-term effectiveness with regard to cognitive and performance deficits needs further study. Practically speaking, health care providers must be aware of the potential for cognitive and performance deficits in OSA patients and routinely ask about performance at work, ability to concentrate and maintain attention, irritability, and difficulties performing everyday tasks. It is the practitioner’s obligation to inform the patient of the risks associated with such deficits and protect the public through appropriate action until the patient is successfully treated.
ioral performance deficits.8 Compared to nonsnoring normal controls, those with OSA are 37 times more likely to complain of sleepiness, 7.5 times more likely to have difficulties with concentration at work, have a ninefold increase in difficulty learning new tasks, and are 20 times more likely to have problems performing monotonous tasks.1 Excessive daytime sleepiness is associated with greater work limitation in terms of difficulties with time management, mental tasks, interpersonal relationships, and work output.8,9 Beyond difficulties with performance, occupational accidents occur in 50% of male OSA patients; the risk of occupational accidents in women with OSA is six times greater than in controls.8,10 Motor vehicle drivers do not always perceive their impairment and continue to drive while sleepy.11 Overall, compared to normal controls, OSA patients are 2 to 13 times more likely to experience an accident.2 Such accidents are more likely to occur in those who manifest greater daytime sleepiness.2,4 However in some studies, OSA has been associated with motor vehicle crashes independent of daytime sleepiness.4 Sleepiness due to work schedules and sleepiness due to OSA are independent risk factors for accidents. For example, in commercial vehicle drivers, where both sleepiness-promoting conditions coexist, those with the highest level of sleepiness have a twofold increase in multiple accidents.12
DEFINITION, ASSESSMENT, AND IMPACT To understand the cognitive and neurobehavioral performance deficits that affect patients with OSA, it is helpful to consider them from a categorical perspective. The effects of sleep loss on performance include changes in cognitive performance, difficulty with working memory, slowing of response or inability to sustain attention across the duration of the task, declines in the best effort or fastest response, lapses (acts of omission), and false responses (acts of commission).13 In OSA, hypoxemia– reoxygenation cycles with attendant biochemical and cellular alterations cause dysfunction of the prefrontal cortex.
CHAPTER 104 • Cognition and Performance in Patients with Obstructive Sleep Apnea 1195
This results in impaired executive function manifesting as false responses (e.g., responding when no stimulus is presented—an example of loss of behavioral inhibition), problems with working memory and contextual memory, problems with cognitive processing (analysis and synthesis) in addition to deficits in the pattern of responses (set shifting), and self-regulation of affect and arousal.14 Box 104-1 presents a description of the performance deficits
and commonly used assessment techniques in OSA patients. Tests that can easily be performed in the clinical setting include the Digit Symbol Substitution Task (90second test) to assess cognitive processing and the Psychomotor Vigilance Task (10-minute task) to evaluate the ability to sustain attention. Summary information regarding the neurobehavioral tests may be found elsewhere.15
Box 104-1 Definition and Assessment of Cognitive and Neurobehavioral Deficits Associated with Obstructive Sleep Apnea Cognitive Processing Behavior Decreased ability to digest information • Slowing on task • Increased errors • Decline in total number correct and/or completed per unit of time Measures Commonly Used to Assess Deficit Self-paced tasks of short duration (1 to 5 min), including arithmetic calculations, communication, or concept attainment • Paced Auditory Serial Addition task (PASAT) • Trailmaking A and B: sequencing numbers (A) or letters and numbers (B) • Category Test: six sets of items organized around different principles with a seventh set comprising previously shown items • Digit Symbol Substitution Test: supplying matching symbol given the corresponding number • Digit Backward: stating verbally provided numbers in reverse order • Letter Cancellation: cancellation of target alphabets from presentation of randomized alphabets Memory Behavior Decreased ability to register, store, retain, and retrieve information Measures Commonly Used to Assess Deficit Short-term memory: timed tasks of up to 10 min that require free recall of words, numbers, paragraphs, or figures • Probed, Recall Memory Task (words) • Digit Span Forward (numbers) • Wechsler Memory Scale Story Task (paragraph) • Rey Auditory-Verbal Learning Test (figure) Long-term memory: presenting the subject with lists of items that are longer than the 7-item memory capacity • California Verbal Learning Test Procedural memory: gradual acquisition and maintenance of motor skills and procedures • Mirror Tracing Task • Rotary Pursuit Task
• Reduction in the fastest optimal response times • Periods of delayed or no response (lapses) • Response to stimuli when none presented (false responses) Measures Commonly Used to Assess Deficit Short-duration tasks (<30 min) • Psychomotor vigilance Task (PVT) • Four Choice Reaction Time Test • Steer Clear • Continuous performance tests Divided Attention Behavior Inability to respond to more than one task or stimuli, such as with driving Measures Commonly Used to Assess Deficit Divided Attention Driving Test (DADT): mimics vigilant-related behavior essential to driving: • Tracking (the ability to stay within the driving lane) • Visual search (looking for and avoiding obstacles, traffic lights, etc.) Executive Functioning Behavior Problems with manipulating and processing information Inadequate planning and execution of plans Disorganization: poor judgment, decision making Inflexible: emotional liability Impulsivity Difficulty maintaining motivation Measures Commonly Used to Assess Deficit Volition component or intentional behavior • Assessed by asking the patients’ preferences, what they like to do, or what makes them angry Planning component • Porteus Maze Test • Tower Tests: Tower of London, Tower of Toronto, Tower of Hanoi • Wisconsin Card Sorting Test Purposive action • Tinkertoy Test Effective performance • Random Generation Task
Sustained Attention or Vigilance Behavior Inability to maintain attention over time. • Slowing of response time (time on task) • Increased errors Adapted from Dinges D. Probing the limits of functional capability: the effects of sleep loss on short-duration tasks. In: Broughton R, Ogilvie R, editors. Sleep, arousal, and performance. Boston: Birkhauser; 1992. p. 177-188.
1196 PART II / Section 13 • Sleep Breathing Disorders 1.5
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Figure 104-1 Summary of mean effect sizes across domains and data sets. Positive values indicate deficits relative to healthy adults, and negative values indicate strengths relative to healthy adults. The data set for moderate intelligence and visual functioning is split into case-controlled and uncontrolled samples for domains where study design (case-controlled versus uncontrolled) moderated the data. ST Mem, short-term memory; LT Mem, long-term memory. (Modified from Beebe DW, Groesz L, Wells C, et al. The neuropsychological effects of obstructive sleep apnea: a meta-analysis of norm-referenced and case-controlled data. Sleep 2003;26:298-307, p. 302.)
The impact of OSA on cognitive processing, memory, sustained attention, executive and motor functioning is summarized in Figure 104-1, which portrays the impact or effect of OSA compared to healthy adults. This difference can be quantified in terms of an effect size: the difference in means between clinical and control group means, divided by the standard deviation. An effect size of 0.2 is considered to be small and clinically nonsignificant, 0.5 is moderate and clinically meaningful, and 0.8 is large.16 Across studies (average AHI = 30 events per hour), the effect size or impact of OSA on memory, executive performance, and attention, weighted for sample size, is 0.5, 0.9 and 1, respectively, indicating that moderate OSA may be associated with moderate to large impairments in neurobehavior.17
COGNITIVE PROCESSING Studies of OSA patients derived from sleep clinic populations show considerable evidence of impaired cognitive processing,4,6,18-20 although the evidence provided by larger population-based studies is less compelling.4 Differences may be due to selection bias of more impaired patients having been referred for clinic evaluation, the tests employed, or the frequent use of snorers as a proxy for polysomnography-documented OSA.4,21 Compared with normal controls (AHI < 5), nonsleepy subjects with milder OSA (AHI 10 to 30) do not have deficits in cognitive processing, suggesting either no deficits or the ability to compensate in less-severe disease.22 On the
other hand, there appear to be robust differences in cognitive processing in sleepy patients with moderate to severe OSA (AHI > 15) compared to normal controls.21 These deficits are likely due to sleepiness, OSA or both. Memory Memory is defined as the ability to register, store, retain, and retrieve information.23 The psychological processes involved in memory include registration, short-term memory, rehearsal, long-term memory, and retrieval.15 Registration, or sensory memory, is the first recognition of a stimulus and serves as evidence of consciousness. Registered information is either processed as short-term memory or quickly decays.15 Short-term, or working, memory involves a limited capacity holding unit for storage of information and operates in conjunction with an executive system to hold and internalize information to direct behavior.15 When these components of memory malfunction, new information is immediately lost and there is a reduction in memory span.15 Repetitive mental processes, or rehearsal, increase the likelihood that the memory trace will endure or be maintained.15 Reduced learning efficiency and loss of new information occurs when there are deficits in rehearsal. Long-term information storage involves the process of consolidation, or the organization of information based on meaning. Neuropsychological deficits resulting from the inability to store information for the long-term result in the inability to learn, retain, or execute skills or functions.15 Retrieval involves recall of information; a deficit in retrieval
CHAPTER 104 • Cognition and Performance in Patients with Obstructive Sleep Apnea 1197
produces difficulty with spontaneous recall.15 Procedural memory is the gradual acquisition and the maintenance of motor skills and procedures.23 Decreased alertness experienced by OSA patients potentially impairs registration and other aspects of memory, but the data remain unclear whether these patients have more difficulty with memory function than normal controls.21,24-26 Differences in study populations such as clinic versus broad population-based samples, level of disease severity, and the use of normal controls versus norm-referenced comparisons, might account for the lack of clarity in the literature regarding this issue. The type of memory assessed (episodic, procedural, short-term, working) might also account for differences among studies.25 Sustained Attention Attention is the composite of different capacities or processes that reflect how stimuli are received and processed.15 It can be sustained (or tonic), as in the case of vigilance, or it can be phasic, in which attention shifts in response to changing stimuli.15 Concentration refers to focused or selective attention to important stimuli while suppressing others.15 Sometimes used interchangeably with concentration, sustained attention is most affected by daytime sleepiness and probably the root cause of a significant source of OSA morbidity and mortality: motor vehicle crashes. With increased time on task, the ability to maintain attention becomes more taxed, producing uneven performance.27 There is a limit to attentional capacity such that engaging in one task requiring controlled attention can interfere with another task requiring the same processing requirements.15 Divided attention is the ability to respond to more than one task or stimulus and is sensitive to situations where there is reduced attentional capacity.15 OSA patients initially perform as well as normal controls during tasks of short duration (e.g., 10 minutes), but performance instability—uneven performance—occurs over the duration of the task with increasing response time, lapses or failure to respond, and responses without prior
stimuli (acts of commission) (Fig. 104-2).27 Deficits in sustained attention are greater in older OSA patients (older than 50 years) compared to younger patients with comparable OSA severity, showing longer reaction time and more lapses in attention in addition to differences compared to the performance of normal controls.28 The magnitude of the impact of OSA on sustained attention tasks ranges from small (effect sizes of 0.2) to very large (effect size of 3.0).3 As with other measures, the magnitude of results in clinic-based (smaller sample size) studies is less but still present when looking at larger community-based samples with lower levels of disease severity.4 To illustrate the effect of OSA on sustained attention using a meaningful example, performance on the psychomotor vigilance task (PVT) was measured in OSA patients and compared with normal controls who ingested alcohol to incrementally raise their blood alcohol level from zero to a mean of 0.80 g/210 L of breath.29 The PVT is a sustained-attention task that measures the speed with which a person responds (presses a button) to a presented stimulus (appearance of lighted numbers). OSA patients generally performed worse than inebriated subjects. For example, the performance of a 47-year-old patient with mild to moderate OSA is comparable to or worse than the performance of a healthy, nonsleepy 27-year-old with a blood-alcohol level above the legal limit in most states in the United States.29 On driving simulators, OSA patients hit more obstacles, have increased error in tracking and visual search, have increased response time to secondary stimuli, and drive out of bounds more times compared to control subjects (Fig. 104-3).30 In a large study of commercial drivers, across levels of disease severity, there were significant differences in lapses on the PVT and in tracking errors on a divided attention driving task.31 Executive Functions In contrast to assessment of cognitive functions in which the person is asked what he or she knows or can do,
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1000
1000
100
100 0
10
20
30
40
Consecutive RTs
50
60
0
10
20
30
40
50
60
Consecutive RTs
Figure 104-2 Comparison of performance of normal controls and sleep apnea patients on the Psychomotor Vigilance Task. Sleep apnea patients demonstrate increased reaction time, indicated by the bars, and lapses in response, indicated by the blank spaces. (From Chugh D, Dinges D. Mechanisms of sleepiness. In: Pack A, editor. Pathogenesis, diagnosis, and treatment of sleep apnea. New York: Marcel Dekker; 2002. p. 273.)
Tracking error (cm)
1198 PART II / Section 13 • Sleep Breathing Disorders 600 500 400 300 200 100 0 Control
Alcohol
OSA
Narcolepsy OSA-Rx
Figure 104-3 Summary of tracking errors in different groups on the Divided Attention Driving Task. OSA, obstructive sleep apnea. (From George CF. Vigilance impairment: assessment by driving simulators. Sleep 2000;23(Suppl. 4):S115-S118, p. S116.)
evaluation of executive functions asks how or whether the person goes about accomplishing a task.15 Executive functions are facilities that produce purposive, independent, or self-serving action and represent frontal lobe functioning.15 There can be considerable loss in cognitive functioning, but if the executive functioning is preserved, the person will be able to be independent and productive.15 However, the reverse is not true, because the loss of executive functions renders the person incapable of performing self-care, working independently, or maintaining normal social relationships even though cognitive functioning remains intact.15 There can also be emotional lability or increased irritability, and impulsivity. Persons with impaired executive function lack motivation, are unable to initiate activity, and have problems with planning and carrying out activities that depict goal-directed behavior.15 The inconsistent finding of the impact of OSA on organization and retrieval aspects of memory, but not long-term storage, may be explained by deficits in executive function.24 Deficiencies in executive functioning in conjunction with difficulties with concentration, sustained attention, cognitive processing, and memory, might contribute to the decrements in functional status that have been reported in OSA patients, although this link has not been systematically studied.3 Although there is some inconsistency within the literature, executive functions may be the performance parameters that are most affected by OSA.14,32 As with other aspects of cognitive function, large effects tend to be found in clinic-based samples,4 and smaller or clinically insignificant findings are found in community-based samples.4 The variability in results can be accounted for both by the heterogeneity of the population studied and the lack of a standardized neuropsychological test battery that includes assessments of different domains of executive function.32 Impairments in executive function identified in the OSA population include problems with verbal fluency, planning, and sequential thinking; slowed information processing; and decreased short-term memory span and constructional ability.3,33
QUALITY OF LIFE Measuring the impact of illness on the patient’s ability to conduct everyday tasks and fulfill roles from the patient’s perspective is a key component in outcome management and the evaluation of treatment efficacy. Quality of life (QOL), health-related quality of life (HRQL), and func-
tional status, although conceptually distinct, have all been used to describe the effect of illness on everyday life.34 Although the term quality of life encompasses such attributes as standard of living, economic status, life satisfaction, quality of housing, health status, and job satisfaction, health-related quality of life comprises only domains considered to be affected by illness. Functional status, a component of quality of life, is multidimensional and defines the ability to carry out activities and tasks necessary to fulfill current life roles. Measures of quality of life are categorized as either generic or disease specific. Generic measures assess a wide variety of activities and domains and are designed to contrast the ability to conduct tasks and roles among heterogeneous populations, enabling crossillness comparisons (Table 104-1).34 Compared to generic measures, disease-specific measures provide greater depth of information regarding the aspects of daily functioning most likely to be affected by the illness or symptom of interest.34 Disease-specific measures that have been designed for use in assessing the impact of OSA include the Functional Outcomes of Sleep Questionnaire (FOSQ), Calgary Sleep Apnea Quality of Life Instrument (SAQLI), and OSA Patient-Oriented Severity Index.34 Because disease-specific measures of quality of life have recently been developed, the majority of research evaluating quality of life in untreated OSA has employed generic measures, such as the Medical Outcomes Study SF-36 (Short Form 36). Large community-acquired samples indicate that OSA affects quality of life with an impact similar to that experienced by persons with other chronic disorders of moderate severity.4 Even patients with mild OSA appear to have difficulties carrying out their daily activities, although whether there is a linear relationship with degree of sleep-disordered breathing is uncertain.4 However, several studies indicate that those with more-severe disease experience the greatest deficits, with an odds ratio of approximately 1.5 times those with less-severe disease.35 One small, limited study showed that the association between AHI and general physical and mental functioning reflected the escalation in AHI from 1 to 15, but no greater deficit was documented beyond that level, suggesting a threshold effect, although the nature and small size of the sample limit interpretation.35a Studies using clinical samples employing norm-referenced data or normal controls for comparison have demonstrated impaired quality of life in OSA patients on both generic and disease-specific measures.34,36 Studies using disease-specific questionnaires demonstrated a greater array of affected tasks and roles than generic measures.34 Patients reported problems in aspects of daily living beyond vigilance-related activities, indicating the pervasive effect of OSA.34 For example, OSA patients had greater deficits than normal controls by up to two standard deviations in all subscales of the FOSQ, reflecting the domains of general productivity, vigilance, activity level, social outcome, and sexual relationships.36 Although several studies have suggested a linear relationship between OSA severity (as measured by AHI) and components of quality of life, prediction of impaired daily functioning is not consistently found.3 For example, a dose-response relationship between scores on the vitality/ energy subscale of the generic SF-36 and OSA severity
CHAPTER 104 • Cognition and Performance in Patients with Obstructive Sleep Apnea 1199
Table 104-1 Comparison of Domains Addressed by Quality-of-Life Instruments Instrument WHOQOLBREF
SICKNESS IMPACT PROFILE
FUNCTIONAL LIMITATIONS PROFILE
MEDICAL OUTCOME STUDY SF-36
NOTTINGHAM HEALTH PROFILE
EUROQOL
Physical functioning
x
x
x
x
x
x
Mental health
x
x
x
x
x
x
x
x
x
x
x
DOMAIN
Psychological distress Psychological well-being
x
Role functioning Social functioning
x
x
x
x
x
x
x
x
Health perceptions
x
Pain
x
x
Vitality
x
x
Mobility and travel
x
x
Sleep
x
x
Cognitive functioning
x
x
Eating
x
x
Recreation and hobbies
x
x
Communication
x
x
x
x
Environment Home management
x x
x
x
WHOQOL, World Health Organization Quality of Life. Data from Weaver TE. Outcome measurement in sleep medicine practice and research. Part 1: assessment of symptoms, subjective and objective daytime sleepiness, health-related quality of life and functional status. Sleep Med Rev 2001;5(2):103-128.
(controlling for age, body mass index [BMI], and other pertinent factors) was documented in one communitybased study, but only when oxyhemoglobin desaturation was included in the definition of disease severity.4 Selfreported sleepiness has been reported to affect quality of life, but the relationship depends on consideration of other critical factors such as chronic illness, BMI, and age.37-39
ETIOLOGY AND MECHANISMS It has been speculated that the cognitive and performance deficits associated with OSA are related to fragmented sleep, nocturnal hypoxemia, or both.14 Although sleep fragmentation and nocturnal hypoxemia have been linked to cognitive and neurobehavioral dysfunction, their relative contributions remain unclear.14 The relationship between the respiratory disturbance index and cognitive and neurobehavior have been either weak or not consistently statistically significant.3,4,40 Available evidence suggests that difficulties with attention and memory are related to excessive daytime sleepiness, and deficits in executive and motor function are attributed to hypoxemia, although hypoxemia can have an effect on all of these functions.19,20,41 The prefrontal model posits that the sleep disruption, intermittent hypoxemia, and hypercarbia experienced by OSA patients alters the normal restorative process that occurs during sleep, generating cellular and biochemical stresses that result in disruption of functional homeosta-
sis and altered neuronal and glial viability within certain brain regions, primarily the prefrontal regions of the brain cortex.14 This model has been proposed as a conceptual framework for the relationship between sleep disruption and nocturnal hypoxemia and primarily frontal deficits (cognitive and neurobehavioral dysfunction) (Fig. 104-4). These physiologic alterations destabilize the executive system, causing behavioral disturbance in inhibition, maintenance of performance, self-regulation of affect and arousal, working memory, analysis and synthesis, and contextual memory.14 Alterations in the executive system can adversely affect cognitive abilities, resulting in maladaptive types of behavior as depicted in Figure 104-4.14 It is important to emphasize that the impairments associated with OSA produce inefficient performance and not the inability to perform.14 When neural systems required for memory or divided attention attempt to perform but are debilitated, other brain systems are recruited in an effort to compensate. However if they too are affected by sleep disruption or hypoxemia, their contributions may be suboptimal. This might account for the increased activation of the prefrontal cortex under conditions of sleep deprivation documented by functional magnetic resonance imaging (fMRI).14 Deficits in performance of OSA patients are explained by impairments of elementary cognitive functions, specifically, sensory transduction, feature integration, or motor preparation and execution, which are required even in simple response-time tasks.41
1200 PART II / Section 13 • Sleep Breathing Disorders OSA AND PREFRONTAL FUNCTIONING Intermittent hypoxia and hypercarbia
Sleep disruption
Disruption of restorative features of sleep
Disruption of cellular or chemical homeostasis
Prefrontal cortical dysfunction Dysfunction of cognitive executive system Behavioral inhibition
Set shifting
Self-regulation of affect and arousal
Working memory
Analysis/ synthesis
Contextual memory
Adverse daytime effects Problems in mentally manipulating information Poor planning and haphazard execution of plans Disorganization Poor judgment, decision making Rigid thinking Difficulty in maintaining attention and motivation Emotional lability (“mood swings”) Overactivity or impulsivity (especially in children)
Figure 104-4 The proposed prefrontal model. In this model, OSA-related sleep disruption and intermittent hypoxemia and hypercarbia alter the efficacy of restorative processes occurring during sleep and disrupt the functional homeostasis and neuronal and glial viability within particular brain regions, particularly the prefrontal regions of the brain cortex. OSA, obstructive sleep apnea. (From Beebe DW, Gozal D. Obstructive sleep apnea and the prefrontal cortex: towards a comprehensive model linking nocturnal upper airway obstruction to daytime cognitive and behavioral deficits. J Sleep Res 2002;11:1-16, p 3.)
Magnetic resonance spectroscopy (MRS) studies have shown evidence of brain damage in patients with OSA correlating with the degree of disease severity as measured by AHI.20,42 Compared to MRS studies of healthy persons, the white matter, but not the cortex, of patients with OSA demonstrated decreases in the N-acetylaspartate/ choline ratio, an indicator of cerebral metabolic injury, as well as other signs of neuronal cellular chemical activity. These functional changes occurred despite no obvious structural abnormality as evidenced by a normal MRI.43,44 Frontal lobe white matter lesions have been associated with impaired executive function.44 Cold challenges showed aberrant responses on fMRI in patients with OSA compared to controls in several cortical areas in addition to other brain areas that may reflect neuronal loss in those sites.20,45 Regional volumetric MRI studies showed diminished gray matter loss, often unilateral, in multiple sites including the frontal and parietal cortex, temporal lobe, anterior cingulate, hippocampus, and cerebellum.46,47 The unilateral loss in adequately perfused areas suggests neural deficits early in the onset of OSA.48 Perturbations in executive function and other cognitive functions associated with the prefrontal cortex may be associated with abnormalities in event-related potentials, indicating dysfunction of this brain region, in patients with OSA.49 Taken together, these findings suggest clear functional abnormalities of wide areas of the brain with less-obvious structural abnormalities.
Figure 104-5 Effects of sleep apnea on brain activation during a working memory task. Pretreatment random effects group activation map of 16 patients with obstructive sleep apnea, contrasted with 10 healthy subjects performing a similar working memory task. Activation in healthy subjects is more extensive, is bilateral, and involves areas well described in the literature: posterior parietal cortex, medial wall in the region of the anterior cingulate cortex, and dorsolateral prefrontal cortex. Sleep apnea patients do not show significant lateral prefrontal activation but do so in left posterior parietal and the medial wall. R, right; L, left. All activations are Bonferroni corrected for multiple comparisons, P < .05. Talairach space z-coordinate is 30. Statistical color scale: red, r = 0.4; yellow, r = 0.8. (From Thomas RJ, Rosen BR, Stern CE, et al. Functional imaging of working memory in obstructive sleep-disordered breathing. J Appl Physiol 2005;98:2226-34, p 2229.)
Functional MRI studies have shown differential brain activation associated with specific cognitive challenges in OSA patients compared to controls.50,51 Working memory speed was decreased compared to normal participants and associated with an absence of dorsolateral prefrontal activation not related to nocturnal hypoxia as illustrated in Figure 104-5. Performance of a verbal learning task was similar between OSA patients and normal controls, despite task-related increases in brain activation in several brain regions (bilateral inferior frontal and middle frontal gyri, cingulate gyrus, and areas at the junction of the inferior parietal and superior temporal lobes, thalamus, and cerebellum).51 This suggests an adaptive, compensatory recruitment response similar to that seen in young adults following total sleep deprivation.51 Collectively, findings from neuroimaging studies support the notion of OSA-associated neurofunctional impairments chiefly in the frontal lobes and hippocampus, which are consistent with models of central nervous system and cognitive dysfunction in OSA implicating the prefrontal cortex.43 They also indicate the presence of subtle cerebral metabolic insults such as neuronal loss, axonal injury, and gliosis, which have been demonstrated in animal models of intermittent hypoxemia.20,52 Studies have
CHAPTER 104 • Cognition and Performance in Patients with Obstructive Sleep Apnea 1201
shown that hypoxemia is linked to attention, executive function, perceptual and organizational or motor speed, memory, and verbal fluency3 as well as a relationship between sleep disruption and executive function. Using factor analysis and by comparing the relative contributions of sleep disturbance, hypoxemia, and sleep quality, others have attempted to more directly isolate the mechanisms operative in producing cognitive and neurobehavioral deficits.40 It was hypothesized that a higher premorbid functional level as demonstrated by the higher intelligence provided a protective effect and compensated for the hypoxic brain damage or daytime sleepiness that may be etiologic factors associated with these deficits. This may be an example of cognitive reserve theory, where high intelligence might have a protective effect against OSArelated cognitive decline. A comparison of cognitive and neurobehavioral functioning in patients with chronic obstructive pulmonary disease, who also suffer from hypoxemia, and OSA patients showed that OSA patients were similarly impaired.6,53 Both types of patients showed problems with cognitive processing and memory, indicating a role for hypoxemia, and sleep apnea patients demonstrated more dysfunction on tests of sustained attention, sensitive to sleepiness.53 Other studies have suggested that sleepiness plays an important role in cognitive and neurobehavioral performance.53 These (and other) findings suggest that the small to moderate deficits in cognitive processing and large impairments in objective sleepiness indicate that sleepiness and decrements in performance share a common biological substrate.54 For example, in rodent models of long-term intermittent hypoxemia, the observed increased sleepiness is related to oxidative injuries to the wake-promoting regions of the forebrain.55
EFFECT OF TREATMENT Continuous positive airway pressure (CPAP) remains the primary treatment for OSA. Evaluating the evidence of the effectiveness of treatment on the cognitive and performance impairments exhibited by OSA patients is challenging because of differences across studies and patients with regard to adherence to and duration of therapy as well as study design issues including sample size, types of control populations, and the nature of placebos when they were employed. Response to treatment may be more clearly demonstrated when comparisons are made only in those who manifest deficits in cognitive processing and performance at baseline and in those more adherent to treatment (e.g., use of CPAP for 6 or more hours per night).56 The majority of controlled clinical trials evaluating the efficacy of CPAP treatment have predominantly involved patients with moderate to severe OSA. In these placebocontrolled studies the superiority of CPAP over placebo has not been demonstrated for cognitive functioning, sustained attention, or executive function.57,58 Despite these lack of changes, there was sufficient evidence of improvements in quality of life with CPAP treatment compared to placebo for the American Academy of Sleep Medicine in practice guidelines to recommend CPAP as a treatment option in this context.59
Few studies have examined the utility of CPAP treatment in patients with mild OSA.57 In patients with mild OSA, when comparing 8 weeks of CPAP treatment to conservative therapy, the only aspect of quality of life showing improvement was an increase in vitality.60 The variable results in these studies might reflect the fact that with milder disease severity there is less cognitive impairment and thus less potential for improvement following therapy.36,61 Improvements in cognitive and neurobehavioral performance might also be a function of baseline level of daytime sleepiness.58 Controlled studies that have examined treatment response in patients without subjective daytime sleepiness, but with mild60 or severe62 OSA have not found CPAP superior to conservative therapy60 or sham CPAP62 when looking at quality of life or cognitive outcomes. Several studies have compared the impact of CPAP treatment to other interventions on cognitive and neurobehavioral outcomes.58 Compared to supplemental oxygen, CPAP treatment of patients with moderate to severe OSA produces equivalent positive benefits for enhanced sustained attention and memory, with greater gains for cognitive processing in mild OSA.7 The effect of positional therapy is not different from CPAP treatment on cognitive performance or general health, but CPAP improved energy levels and positional therapy did not.63 Equivocal or inconsistent results regarding the benefit of oral appliances over CPAP or placebo have been shown for indices of quality of life and neurobehavior.64-66 Although there are a dearth of studies, in general, CPAP remains superior to surgery with respect to the outcomes of quality of life and neurobehavioral performance.67
MEDICAL AND LEGAL ASPECTS OF COGNITIVE AND PERFORMANCE DEFICITS The majority of accidental injuries or death can be explained by human error. Inattention or excessively dividing attention between tasks while driving (e.g., using a mobile telephone) is increasingly recognized as a cause of accidents.68 Functional MRI has provided evidence of reduced cortical activity in brain regions associated with driving, while subjects were listening to someone speaking,69 even though the two tasks (driving and auditory comprehension) draw on different and nonoverlapping cortical areas. These results provide neurobiological evidence for distraction creating inattention to a primary task like driving. Clearly, a motor vehicle operator has an obligation to drive safely in order to avoid foreseeable harm to others. However, the courts often agree that the driver is not criminally negligent when falling asleep while driving unless it appears that he or she continued to drive in reckless disregard of warning symptoms. Table 104-2 illustrates the legal consequence of cases of fall-asleep motor vehicle accidents. A recent and notable exception is in New Jersey, where the state enacted Maggie’s Law. Falling asleep at the wheel and fatigued driving now count as recklessness under the existing vehicular homicide law (NJS 2C:11-5). This legislation is the first bill in the United States to specifically address the issue of driving
1202 PART II / Section 13 • Sleep Breathing Disorders Table 104-2 Case Details of Fall-Asleep Motor Vehicle Accidents OVERNIGHT SLEEP STUDY
MSLT OR MWT
ACCIDENT OUTCOME
LEGAL OUTCOME
REMAINED LICENSED?
OSA and PLMD
With CPAP: AI, 30; AHI, 10; PLMI, 20
MWT20, 4.75 min
2 vehicles, 1 fatality, 2 others injured
No-billed
Yes
OSA and UARS
AI, 41; AHI, 10
MSLT, 9.4 min
2 vehicles, 1 fatality, 2 others injured
No-billed
Yes
CASE
DIAGNOSIS
A
B
C (injured) Sleep deprivation
AHI, 2.4; AHI, 1 MWT40, 40 min
4 vehicles, 5 fatalities, several others
Acquitted
Yes; later withdrawn by RTA and then contested in court
D
OSA
AHI, 30
MWT40, 11 min
6 vehicles, 2 fatalities, 12 others injured
Found guilty, jailed
Yes
E
Idiopathic AHI, 0.4 hypersomnolence
MWT20, 8 min
5 vehicles, 1 fatality, 2 others injured
Pleaded guilty
Yes
F
OSA
AHI, 23
MSLT, 5.5 min
3 vehicles, 2 fatalities
Pleaded guilty, jailed
Yes
G
OSA
AHI, 17
Not 2 vehicles, 1 fatality performed
Found guilty, jailed
Yes; later withdrawn by judge
AHI, apnea–hypopnea index; AI, arousal index; CPAP, continuous positive airway pressure; MSLT, multiple sleep latency test; MWT, maintenance of wakefulness test; MWT20, MWT 20-minute protocol; MWT40, MWT 40-minute protocol; No-billed, not prosecuted; OSA, obstructive sleep apnea; PLMD, periodic limb movement disorder; PLMI, periodic limb movement index; RTA, Roads and Traffic Authority; UARS, upper airway resistance syndrome. Normal values: AHI, 0-5 per hour; AI, 0-10 per hour; MWT20 (sleep onset defined as the first occurrence of one epoch of any stage of sleep in 20-minute protocol), 11-20 minutes; MWT40 (sleep onset defined as three consecutive epochs of stage 1 sleep or any single epoch of another sleep stage in 40-minute protocol), 19-40 minutes; MSLT, 10-20 minutes; PLMI, 0-5 per hour. From Desai AN, Ellis E, Wheatley JR, Grunstein RR. Fatal distraction: a case series of fatal fall-asleep road accidents and their medicolegal outcomes. Med J Aust 2003;178:396-399.
while fatigued, where fatigue is defined as being without sleep for a period in excess of 24 consecutive hours. Other jurisdictions are considering similar legislation. As a result, physicians who believe that a patient is unfit to drive because of sleepiness should inform the patient of this opinion. Those patients who continue to drive and who are believed to be a public health risk should be reported by the physician to the authorities in jurisdictions where they are required to do so. Failure to report such patients can result in personal liability for clinicians. In the 1990s, two Ontario (Canada) Court of Appeal judgments found physicians liable because they had failed to report potentially unfit medical patients to the motor vehicle licensing authorities despite an existing statutory obligation to do so and the patients subsequently had traumatic car accidents.70,71 The courts emphasized the importance of the physicians’ statutory reporting duty to the public. This duty superseded the physicians’ private duty with regard to confidentiality and the dictates of the therapeutic relationship. The courts’ interpretation was a departure from earlier case law. In addition, the courts were unmoved by the physicians’ explanations for their failure to report. It was immaterial that the physicians deemed the medical conditions to be temporary or that they trusted their patients to comply with their medication regimen and instructions against driving. The courts have long recognized civil liability claims and defense for injury caused by loss of consciousness or diminished alertness in transportation-related accidents. Because sleepiness increases periods of inattention, it is not surprising that sleepiness has been linked to accidents on
the road and in occupational settings.72-74 Sleep-related civil liability issues have increased in frequency and complexity, and determining fitness to drive has been problematic for sleep clinicians, particularly in view of the varied laws and jurisdictions. It is therefore important for physicians to fulfill their statutory duties in a diligent yet sensible manner, reporting patients whom they believe have a medical condition that might reasonably make it dangerous to drive, especially where there is a mandatory reporting system. The data for sleep apnea and automobile crashes are numerous and consistent: As a group, OSA patients’ risk of motor vehicle collisions is increased twofold to fourfold (Videos 104-1 and 104-2). Still, not all patients have accidents, and as many as two thirds might never have a collision.75 A means to identify those OSA patients at greatest risk is still not clear based on available literature, and this complicates decision making from a medical and legal perspective. Accordingly, physicians must work to ensure that patients understand the balance between physician’s duty of care to the patient and their statutory duty under the law. They should educate patients about the increased risk of sleepy driving in sleep apnea, pointing out the patient’s civil responsibilities that accompany the privilege of having a driver’s license. Further, by instructing patients in proper sleep hygiene and effective countermeasures to sleepy driving (rest stops, caffeine, napping), physicians begin to modify the risks of drowsy driving. Although it may be argued that mandatory reporting of drivers with sleep apnea will discourage many sleepy drivers from being evaluated for OSA, data supporting this
CHAPTER 104 • Cognition and Performance in Patients with Obstructive Sleep Apnea 1203
argument are lacking. There are data, however, supporting the concept that effective treatment of sleep apnea will reduce collision risk to normal and reduce health care use.75,76 Although mandatory physician reporting of sleep apnea is not uniform in North America or Europe, there are several efforts under way to increase this.77,78 Therefore, where mandatory reporting is in place, treating patients at the same time as notifying the motor vehicle authorities can discharge the clinician’s statutory duty while still maintaining the patient’s ability to drive and earn a living. This strategy assumes appropriate access to care, which regrettably is not yet universal.79 In situations where there is no mandatory reporting, and in cases where ongoing sleepiness is a major concern, physicians must balance the personal risk of litigation for disclosing private medical information without consent against the risk to public safety.
SUMMARY Patients with OSA demonstrate variable degrees of cognitive and performance deficits. Cognitive and performance deficits are more easily identified in those with more-severe disease. Patients with more-severe disease display deficits in cognitive processing, sustained attention, executive functioning, and quality of life, with mixed findings regarding memory. The mechanisms leading to such deficits with respect to the relative contribution of sleep disruption, hypoxemia, and daytime sleepiness are unclear. Although uncontrolled studies present a convincing picture of the positive impact of CPAP therapy, the benefit of this treatment is less persuasive in controlled trials, particularly those employing a sham placebo. The long-term effectiveness of CPAP with regard to reducing cognitive and performance deficits in patients with mild OSA remains undetermined and needs further exploration. Despite the need for more evidence regarding cognitive and performance deficits in community-acquired samples in sham CPAP–controlled studies, there is sufficient documentation to suggest that untreated and nonadherent patients are at risk for traffic- and occupation-related accidents. Legislation such as Maggie’s Law will increase public awareness of the hazard of driving sleepy. However, it is also the duty of the health care provider to assess the patient for cognitive and performance deficits by asking about performance at work, ability to concentrate, ability to maintain attention, irritability, and difficulties performing everyday tasks. It is the practitioner’s obligation to inform the patient of the risks associated with such deficits, protecting the public through appropriate action until the patient is successfully treated. ❖ Clinical Pearl Sleep fragmentation and hypoxemia due to sleep apnea influences cognitive ability and daytime performance. Awareness of these impairments and prompt treatment will reduce burden of illness on the patient and reduce individual and public risk.
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1204 PART II / Section 13 • Sleep Breathing Disorders 26. Daurat A, Foret J, Bret-Dibat JL, et al. Spatial and temporal memories are affected by sleep fragmentation in obstructive sleep apnea syndrome. J Clin Exp Neuropsychol 2007:1-11. 27. Chugh DK, Dinges DF. Mechanisms of sleepiness in obstructive sleep apnea. In: Pack A, editor. Pathogenesis, diagnosis, and treatment of sleep apnea. New York: Marcel Dekker; 2002. p 265-285. 28. Mathieu A, Mazza S, Decary A, et al. Effects of obstructive sleep apnea on cognitive function: a comparison between younger and older OSAS patients. Sleep Med 2008;9:112-120. 29. Powell NB, Riley RW, Schechtman KB, et al. A comparative model: reaction time performance in sleep-disordered breathing versus alcohol-impaired controls. Laryngoscope 1999;109:1648-1654. 30. George CF. Vigilance impairment: assessment by driving simulators. Sleep 2000;23(Suppl. 4):S115-S118. 31. Pack AI, Maislin G, Staley B, et al. Impaired performance in commercial drivers: role of sleep apnea and short sleep duration. Am J Respir Crit Care Med 2006;174:446-454. 32. Saunamaki T, Jehkonen M. A review of executive functions in obstructive sleep apnea syndrome. Acta Neurol Scand 2007; 115:1-11. 33. Verstraeten E, Cluydts R, Pevernagie D, et al. Executive function in sleep apnea: controlling for attentional capacity in assessing executive attention. Sleep 2004;27:685-693. 34. Weaver TE. Outcome measurement in sleep medicine practice and research. Part 1: assessment of symptoms, subjective and objective daytime sleepiness, health-related quality of life and functional status. Sleep Med Rev 2001;5:103-128. 35. Finn L, Young T, Palta M, et al. Sleep-disordered breathing and self-reported general health status in the Wisconsin Sleep Cohort Study. Sleep 1998;21:701-706. 35a. Stepnowsky C, Johnson S, Dimsdale J, Ancoli-Israel S. Sleep apnea and health-related quality of life in African-American elderly. Ann Behav Med 2000;22:116-120. 36. Engleman HM, Kingshott RN, Wraith PK, et al. Randomized placebo-controlled crossover trial of continuous positive airway pressure for mild sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 1999;159:461-467. 37. Baldwin CM, Griffith KA, Nieto FJ, et al. The association of sleepdisordered breathing and sleep symptoms with quality of life in the Sleep Heart Health Study. Sleep 2001;24:96-105. 38. Briones B, Adams N, Strauss M, et al. Relationship between sleepiness and general health status. Sleep 1996;19:583-588. 39. Bennett LS, Barbour C, Langford B, et al. Health status in obstructive sleep apnea: relationship with sleep fragmentation and daytime sleepiness, and effects of continuous positive airway pressure treatment. Am J Respir Crit Care Med 1999;159:1884-1890. 40. Naismith S, Winter V, Gotsopoulos H, et al. Neurobehavioral functioning in obstructive sleep apnea: differential effects of sleep quality, hypoxemia and subjective sleepiness. J Clin Exp Neuropsychol 2004;26:43-54. 41. Lis S, Krieger S, Hennig D, et al. Executive functions and cognitive subprocesses in patients with obstructive sleep apnoea. J Sleep Res 2008;17(3):271-280. 42. Kamba M, Inoue Y, Higami S, et al. Cerebral metabolic impairment in patients with obstructive sleep apnoea: an independent association of obstructive sleep apnoea with white matter change. J Neurol Neurosurg Psychiatry 2001;71:334-339. 43. Zimmerman ME, Aloia MS. A review of neuroimaging in obstructive sleep apnea. J Clin Sleep Med 2006;2:461-471. 44. Alchanatis M, Deligiorgis N, Zias N, et al. Frontal brain lobe impairment in obstructive sleep apnoea: a proton MR spectroscopy study. Eur Respir J 2004;24:980-986. 45. Macey PM, Macey KE, Henderson LA, et al. Functional magnetic resonance imaging responses to expiratory loading in obstructive sleep apnea. Respir Physiol Neurobiol 2003;138:275-290. 46. Macey PM, Henderson LA, Macey KE, et al. Brain morphology associated with obstructive sleep apnea. Am J Respir Crit Care Med 2002;166:1382-1387. 47. Morrell MJ, McRobbie DW, Quest RA, et al. Changes in brain morphology associated with obstructive sleep apnea. Sleep Med 2003;4:451-454. 48. Gale SD, Hopkins RO. Effects of hypoxia on the brain: neuroimaging and neuropsychological findings following carbon monoxide poisoning and obstructive sleep apnea. J Int Neuropsychol Soc 2004;10:60-71.
49. Kotterba S, Rasche K, Widdig W, et al. Neuropsychological investigations and event-related potentials in obstructive sleep apnea syndrome before and during CPAP-therapy. J Neurol Sci 1998;159: 45-50. 50. Thomas RJ, Rosen BR, Stern CE, et al. Functional imaging of working memory in obstructive sleep-disordered breathing. J Appl Physiol 2005;98:2226-2234. 51. Ayalon L, Ancoli-Israel S, Klemfuss Z, et al. Increased brain activation during verbal learning in obstructive sleep apnea. Neuroimage 2006;31:1817-1825. 52. Zhu Y, Fenik P, Zhan G, et al. Selective loss of catecholaminergic wake active neurons in a murine sleep apnea model. J Neurosci 2007;27:10060-10071. 53. Roehrs T, Merrion M, Pedrosi B, et al. Neuropsychological function in obstructive sleep apnea syndrome (OSAS) compared to chronic obstructive pulmonary disease (COPD). Sleep 1995;18:382388. 54. Engleman HM, Kingshott RN, Martin SE, et al. Cognitive function in the sleep apnea/hypopnea syndrome (SAHS). Sleep 2000;23(Suppl 4):S102-S108. 55. Veasey SC, Davis CW, Fenik P, et al. Long-term intermittent hypoxia in mice: protracted hypersomnolence with oxidative injury to sleepwake brain regions. Sleep 2004;27:194-201. 56. Zimmerman ME, Arnedt JT, Stanchina M, et al. Normalization of memory performance and positive airway pressure adherence in memory-impaired patients with obstructive sleep apnea. Chest 2006; 130:1772-1778. 57. Gay P, Weaver T, Loube D, et al. Evaluation of positive airway pressure treatment for sleep related breathing disorders in adults. Sleep 2006;29:381-401. 58. Giles TL, Lasserson TJ, Smith BH, et al. Continuous positive airways pressure for obstructive sleep apnoea in adults. Cochrane Database Syst Rev 2006;(3):CD001106. 59. Kushida CA, Littner MR, Hirshkowitz M, et al. Practice parameters for the use of continuous and bilevel positive airway pressure devices to treat adult patients with sleep-related breathing disorders. Sleep 2006;29:375-380. 60. Redline S, Adams N, Strauss ME, et al. Improvement of mild sleepdisordered breathing with CPAP compared with conservative therapy. Am J Respir Crit Care Med 1998;157:858-865. 61. Barnes M, Houston D, Worsnop CJ, et al. A randomized controlled trial of continuous positive airway pressure in mild obstructive sleep apnea. Am J Respir Crit Care Med 2002;165:773-780. 62. Barbe F, Mayoralas LR, Duran J, et al. Treatment with continuous positive airway pressure is not effective in patients with sleep apnea but no daytime sleepiness. a randomized, controlled trial. Ann Intern Med 2001;134:1015-1023. 63. Jokic R, Klimaszewski A, Crossley M, et al. Positional treatment vs continuous positive airway pressure in patients with positional obstructive sleep apnea syndrome. Chest 1999;115:771-781. 64. Barnes M, McEvoy RD, Banks S, et al. Efficacy of positive airway pressure and oral appliance in mild to moderate obstructive sleep apnea. Am J Respir Crit Care Med 2004;170:656-664. 65. Engleman HM, McDonald JP, Graham D, et al. Randomized crossover trial of two treatments for sleep apnea/hypopnea syndrome: continuous positive airway pressure and mandibular repositioning splint. Am J Respir Crit Care Med 2002;166:855-859. 66. Lim J, Lasserson TJ, Fleetham J, et al. Oral appliances for obstructive sleep apnoea. Cochrane Database Syst Rev 2006/(4):CD004435. 67. Sundaram S, Bridgman SA, Lim J, et al. Surgery for obstructive sleep apnoea. Cochrane Database Syst Rev 2005:CD001004. 68. Administration NHTS. Driver cell phone use in 2006; 2007. 69. Just MA, Keller TA, Cynkar J. A decrease in brain activation associated with driving when listening to someone speak. Brain Res 2008;1205:70-80. 70. Wasserman Sv. 13 CCLT (2d) 267 (GD), [1998] OJ No.2470 (CA). 1992. 71. Foster Tv. OJ No.1413 (CA); 1994. 72. Teran-Santos J, Jimenez-Gomez A, Cordero-Guevara J. The association between sleep apnea and the risk of traffic accidents. Cooperative Group Burgos-Santander. N Engl J Med 1999;340:847851. 73. Lindberg E, Carter N, Gislason T, et al. Role of snoring and daytime sleepiness in occupational accidents. Am J Respir Crit Care Med 2001;164:2031-2035.
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74. George CF, Nickerson PW, Hanly PJ, et al. Sleep apnoea patients have more automobile accidents. Lancet 1987;2:447. 75. George CF. Reduction in motor vehicle collisions following treatment of sleep apnoea with nasal CPAP. Thorax 2001;56:508-512. 76. Hoffman B, Wingenbach DD, Kagey AN, et al. The long-term health plan and disability cost benefit of obstructive sleep apnea treatment in a commercial motor vehicle driver population. J Occup Environ Med 2010;52:473-477. 77. Hartenbaum N, Collop N, Rosen IM, et al. Sleep apnea and commercial motor vehicle operators: statement from the joint Task Force
of the American College of Chest Physicians, American College of Occupational and Environmental Medicine, and the National Sleep Foundation. J Occup Environ Med 2006;48:S4-S37. 78. Alonderis A, Barbe F, Bonsignore M, et al. Medico-legal implications of sleep apnoea syndrome: driving license regulations in Europe. Sleep Med 2008;9:362-375. 79. Flemons WW, Douglas NJ, Kuna ST, et al. Access to diagnosis and treatment of patients with suspected sleep apnea. Am J Respir Crit Care Med 2004;169:668-672.
Clinical Features and Evaluation of Obstructive Sleep Apnea and Upper Airway Resistance Syndrome Michelle T. Cao, Christian Guilleminault, and Clete A. Kushida Abstract Disorders involving disruption of normal breathing during sleep include obstructive sleep apnea and obstructive sleep hypopnea, grouped under the general term obstructive sleep apnea (OSA) and upper airway resistance syndrome (UARS). Obesity and craniofacial dysmorphism are major risk factors for these syndromes. Polysomnography distinguishes UARS from OSA, with the former characterized by the absence of obstructive apneas and hypopneas, an apnea–hypopnea index (AHI) of fewer than 5 events per hour, and an absence of oxygen desaturation less than 92%. Typical daytime symptoms of OSA include excessive daytime sleepiness, afternoon drowsiness, forgetfulness, impaired concentration and attention, personality changes, and morning headaches. UARS patients typically complain of insomnia and daytime fatigue
Obstructive sleep apnea (OSA) syndrome and the related upper airway resistance syndrome (UARS) are becoming increasingly recognized as leading causes of daytime sleepiness. Together they are referred to as sleep-disordered breathing (SDB). When apneas and hypopneas occur with a specified frequency during sleep and in conjunction with symptoms such as daytime somnolence, the term obstructive sleep apnea is applied,1 rather than the older terminology obstructive sleep apnea–hypopnea (OSAH). Obstructive apnea is defined as complete or nearcomplete cessation of airflow for a minimum of 10 seconds; obstructive hypopnea has been defined differently depending on the author and the type of equipment used to monitor nasal airflow. None of the currently available sleep scoring systems have adequately resolved the controversies surrounding the scoring criteria for an obstructive hypopnea. The American Academy of Sleep Medicine guideline1 for scoring an obstructive hypopnea recommends scoring the event based on the system used to monitor airflow at the nose, and this recommendation is based on consensus rather than objective data. The number of abnormal breathing events during nocturnal sleep is presented as apnea–hypopnea index (AHI), reflecting the number of apneas plus hypopneas per hour of sleep. Due to the variability of what is being measured, the term respiratory disturbance index (RDI) sometimes is used interchangeably and incorrectly with AHI; RDI refers to the number of apneas plus hypopneas plus respiratory effort– related arousals (RERAs) per hour of sleep. Obesity and certain craniofacial features are notable predisposing factors for SDB, and a thorough clinical evaluation can point toward the diagnosis. A definitive diagnosis however, requires the integration of clinical evaluation and an overnight sleep study. Obstructive sleep apnea is characterized by episodes of complete or partial upper airway obstruction during sleep. Upper airway obstruction during 1206
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rather than sleepiness, myalgias (similar to those reported by fibromyalgia patients), migrainelike headaches, postural hypotension, and dizziness. Nocturnal signs and symptoms of OSA and UARS include snoring, snorting, observed apneas, awakening with a sensation of choking or gasping, unexplained tachycardia, restless sleep, sweating during sleep, nocturia, bruxism, and nocturnal gastroesophageal reflux. Insomnia, disrupted sleep, sleepwalking, sleep terrors, and confusional arousals are more commonly expressed by UARS patients. The separation of OSA and UARS as two distinct syndromes is controversial. The important issue is to be aware that in the appropriate clinical context, a symptomatic patient who does not fulfill the diagnostic criteria for OSA might have UARS. None of the symptoms are sufficiently specific to be used as a diagnostic modality.
sleep is a polysomnographic finding. In this chapter we review the clinical features, the pathophysiology of OSA and discuss the current understanding regarding UARS.
EPIDEMIOLOGY OSA was first recognized during polysomnographic monitoring in severely obese patients with the pickwickian syndrome.2 Epidemiologic studies in the United States performed in the 1990s based on the general population or community-based cohorts consisting of primarily white persons between 30 and 60 years of age estimated the prevalence of OSA (defined by AHI ≥ 5) to be 24% in men and 9% in women. When complaints of sleepiness were taken into account, 4% of men and 2% of women had OSAS.3-9 More-recent studies after the explosion of the obesity epidemic in industrialized countries have changed these results. The incidence of OSA in whites in countries affected by the obesity epidemic has reached approximately 8%. Studies in other ethnic groups are also available. In Hong Kong the prevalence in the late 1990s was reported to be similar to the one seen in whites (4.1% in middleaged men and 2.1% in women). A study of Chinese subjects in Singapore reported an estimated prevalence of 15%, and the prevalence was reported to be 7.5% in urban middle-aged Indian men, 4.5% in Korean men and 3.2% in middle-aged Korean women, and 8.8% in Malaysian men and 5.1% in Malaysian women.10-12 The prevalence of OSA increases with aging.13,14 Obesity might also contribute the increased prevalence of OSA. In addition, techniques used to calculate prevalence might play a role in discrepancies between studies. The latest study performed on a representative sample of specific districts in the city of Sao Paulo from 2007 to 2008 is the only study in which more than 1100 participants were monitored with actigraphy for 1 week, underwent 1 night
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of polysomnography, answered multiple questionnaires, and had a complete physical evaluation. This Sao Paulo study examined a sample that is similar to residents from the midwestern United States, in particular with obesity, and found a prevalence for OSA to be about 15%.15 The prevalence of OSA is thus variable depending on geographic location, given that age and the degree of obesity also contribute to the prevalence. In addition, truncal or central obesity is associated with an abnormal adipocyte activity, leading to secretion of various peptides that contribute to metabolic abnormalities. Whether obesity is a comorbid condition associated with OSA or is actually the primary problem and OSA is a consequence of the obesity is still in question. Epidemiologic studies so far have not found complete answers to the questions raised regarding the relationship between obesity and OSA.
DEFINITION OF ABNORMAL BREATHING EVENTS An apnea is defined as complete or near cessation of airflow for a minimum of 10 seconds with or without associated oxygen desaturation or sleep fragmentation (arousal defined by electroencephalography [EEG]),16 although they are both usually present. The definition of a hypopnea is still under debate. Thermistors that monitor change in air temperature are considered less sensitive for detecting airflow compared to nasal cannula pressure transducers that measure change in pressure induced by airflow. The nasal cannula pressure transducer is the recommended equipment used to monitor airflow because it is considered a more accurate indicator of change in the nasal flow curve. The nasal cannula pressure transducer permits inference regarding airway resistance through presentation of the inspiratory airflow wave contour.17,18 Normally, in the absence of upper airway narrowing or obstruction, the inspiratory airflow waveform is characterized by a rounded peak contour. In the setting of increased airway resistance, which is usually associated with increased inspiratory effort, there is a plateau or flattening of the peak or an abrupt decrease immediately following an initial peak in the wave contour. The American Academy of Sleep Medicine (AASM) has recommended that a hypopnea be defined by a 30% or greater reduction in the amplitude of the nasal wave contour from baseline and associated with at least 4% oxygen desaturation from the pre-event oxygen saturation, or a 50% or more decrease in the amplitude of the airflow wave contour from baseline in association with at least 3% oxygen desaturation from the pre-event oxygen saturation, or an EEG arousal. When reading the literature, it is important to recognize that even minor differences in event definitions can have a substantial impact on the study data. For example, using the criteria proposed by AASM in 1999 and 2007, a study comparing the scoring criteria of hypopneas with at least 30% decrease in flow amplitude and EEG arousal, or with at least 3% oxygen desaturation in 35 normal-weight 25- to 48-year-old subjects with suspected abnormal breathing during sleep reported that AHI scores could change from 26.9 ± 7.3 to 6.4 ± 3.1 events per hour of sleep when using EEG arousal versus oxygen desaturation criteria, respectively.19
Certain persons with daytime symptoms similar to those endorsed by OSA patients display a pattern indicating increased inspiratory effort, which, in the absence of the currently defined apneas and hypopneas, still leads to sleep disruption (e.g., arousal or awakening).20 It is believed that the sleep disruptions result in significant daytime symptoms such as excessive fatigue or sleepiness. The increase in inspiratory effort can be detected by esophageal manometry (gold standard) or inferred from the signal provided by the nasal cannula pressure transducer17,18 Esophageal pressure (Pes) provides a reflection of intrathoracic pressure fluctuations associated with breathing efforts. The greater the inspiratory effort, the greater the oscillations in Pes. Normally, the most negative Pes value generated during inspiration (measured from the end of expiration to the most negative pressure during inspiration) is 2 to 3 cm H2O in a small woman and 8 to 9 cm H2O in a healthy large man.21 Three patterns of increased inspiratory effort are recognized by Pes measurements. First, Pes crescendo22 reflects progressively more negative breath-by-breath swings in esophageal pressure terminating either with an alpha wave or a mixture of alpha and beta wave EEG arousal, or with a burst of delta wave activation.23 This entity that is formed by the alpha wave or alpha and beta wave bursts is referred to as a respiratory effort–related arousal.1 Second, a pattern of sustained continuous inspiratory effort is a relatively stable but persistent increase in Pes over time (several epochs) terminated with EEG patterns similar to Pes crescendo. Third, the pattern of Pes reversal is an abrupt drop in the esophageal pressure after a sequence of increased inspiratory efforts, independent of the EEG pattern seen (Figs. 105-1, 105-2, and 105-3).21 Historically, OSA has been defined by the AHI (the average number of apneas and hypopneas per hour of sleep). OSA syndrome is diagnosed when the patient has clinical symptoms and the most common is excessive daytime sleepiness in conjunction with an AHI greater than 5 events per hour. With recognition of the other respiratory patterns with increased respiratory effort, a new index was needed. Hence the RDI was introduced. The RDI is the number of apneas plus hypopneas plus RERAs per hour of sleep. Unfortunately, the terms AHI and RDI are used interchangeably in much of the literature, and it is difficult to assess which abnormal breathing events have been scored.
CLINICAL SIGNS AND SYMPTOMS The bed partner of an OSA patient often witnesses snoring (see Chapter 102), nocturnal snorting and gasping, and apneas.24 Nocturnal (sleep-related) symptoms and signs tend to be more specific for OSA than those expressed during diurnal wakefulness such as excessive daytime sleepiness, which is usually the result of abnormal sleep regardless of the cause. The OSA patient might report symptoms of tiredness, fatigue, or drowsiness rather than overt daytime sleepiness. Nighttime Signs and Symptoms Almost all OSA patients and many UARS patients snore. Snoring can be extremely loud and disruptive. A
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96.9 Min 96.7 MIC Cannula Airflow Chest Abdomen Pes 0 cm H2O –10 cm H2O –20 cm H2O Figure 105-1 Example of a snorer with progressive worsening of the “flattening” of the nasal cannula-pressure transducer recording (channel 6 from top). Simultaneously there is a progressive increase in respiratory effort as indicated by the more and more negative peak end inspiratory esophageal pressure (Pes) recording (channel 10 from top). The progressive increase in effort gives a crescendo pattern to the tracing of Pes. At the end of the sequence there is a clear electroencephalogram (EEG) arousal indicated by the changes in EEG frequencies (channel 1 from top). This is associated with a return of respiratory efforts to a less-important amount, translated by a reduction of the negative deflection of Pes (channel 10 from top), called a Pes reversal. The nasal cannula– pressure transducer shows also a disappearance of the reduction in nasal flow (channel 6 from top). Note that the subject snores and has a clear flow of air through the mouth (airflow, channel 7). Normally humans are nose breathers; mouth breathing is abnormal and requires a larger amount of effort than nose breathing. The recording lasts 60 seconds. Note that no oxygen saturation change is seen and SaO2 is greater than 95%. Channel labeling from top to bottom: EEG with monopolar derivation, right eye lead (electrooculogram), chin EMG (electromyogram), microphone to record snoring, nasal cannula to record pressure fluctuations at the nose to reflect airflow, chest movement, abdominal movement, and esophageal pressure.
characteristic pattern in OSA is loud snoring or brief gasps alternating with intervals of silence that terminate with a loud snort or gasp reflecting resumption of breathing.24,25 The complaint of snoring often precedes the complaint of daytime sleepiness, and the intensity increases with weight gain and bedtime alcohol intake. Snoring can be a factor in marital discord; in one study, 46% of patients slept in separate bedrooms from their partners.24 Even though snoring is an important clue, the absence of its report does not exclude the presence of OSA. Pregnancy is associated with an increase in snoring due to the upward displacement of the diaphragm (which reduces lung volume and its stabilizing effect on the upper airway) and nasopharyngeal edema (see Chapter 101). Although up to 30% of pregnant women snore, overt OSA is uncommon. Chronic snoring is seen in 5 to 8% of all pregnant women (including those with preeclampsia). However, the relationship between OSA and preeclampsia is still unclear at this time. To date, despite preliminary data associating the development of early hypertension in
pregnant patients with SDB, no direct linkage has been demonstrated.26-30 Observed apneic episodes are reported by about 75% of bed partners.31 Persistent chest movements can usually be observed during periods of obstructive apneas. Observing apneic periods can cause the bed partner considerable anxiety, and many respond by shaking the patient for fear that breathing might not resume. Apneic episodes are usually terminated by gasps, chokes, snorts, vocalizations, or brief awakenings. Bed partners report a sudden cessation of snoring followed by a loud snort and resumed snoring. Although some patients awaken with a sensation of having stopped breathing, most are unaware of the apneas. A sensation of choking or dyspnea that interrupts sleep is reported by 18% to 31% of patients.24,32,33 On the other hand, particularly in the elderly, there is awareness of frequent unexplained awakenings, and this group tends to complain of insomnia and unrefreshing sleep. About half of OSA patients report restless sleep (tossing and turning) and diaphoresis, usually localized to the neck
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Figure 105-2 Continuous flow limitation indicated by nasal cannula–pressure transducer recording (channel 6 from top) but not reaching the criterion for hypopnea (i.e., decrease of flow by 30% from prior unobstructed recording) and leading to continuous increased effort (indicated by esophageal pressure [Pes] recording) (bottom channel) in an intermittent snorer with complaint of insomnia and fatigue. Note that the Pes reaches 10 cm H2O at peak end inspiration with each breath; there is no crescendo pattern but a continuous maintenance of the same amount of effort during the first part of the segment. When the patient has normal breathing in other parts of the recording, the Pes oscillates to a peak negative inspiratory Pes of −3 to −4 cm H2O. This is the normal respiratory effort during sleep for this subject. Note that there is minimal SaO2 change (1%) in this 60-second segment (channel 5 from top). In the last third of the recording (right) there is a short respiratory noise, not preceded by any prior snoring (microphone channel 4 from top) and an abrupt decrease in effort indicated by a less-negative peak Pes (Pes reversal). The nasal cannula, channel 6 from top, indicates a better nasal flow. Visual scoring of sleep performed at slower speed (30-second epoch) does not show presence of an electroencephalogram (EEG) arousal of 3 seconds or longer, but a high-amplitude slow wave is noted concomitant with the Pes reversal. Channel labeling from top to bottom: EEG with monopolar derivation, right eye lead (electrooculogram), chin EMG (electromyogram), microphone to record snoring, nasal cannula to record pressure fluctuations at the nose to reflect airflow, chest movement, abdominal movement, and esophageal pressure.
and upper chest area (Video 105-1).32,33 These symptoms are probably related to increased breathing effort during periods of upper airway obstruction. Bed partners readily attest to excessive body movements because movements can at times be violent. Bed covers may be noted to be disheveled the morning. During episodes of upper airway obstruction, progressively more vigorous inspiratory efforts lead to more negative intrathoracic pressure swings, with an increase in venous return to the right ventricle. Large negative intrathoracic pressure swings can also adversely affect left ventricular function. These circumstances can increase pulmonary capillary wedge pressure and contribute to the sensation of dyspnea.34 Because nocturnal dyspnea can also occur in patients with congestive heart failure (paroxysmal nocturnal dyspnea) in the absence of SDB, it is important to inquire about other symptoms in order to distinguish heart failure from OSA.35 However, it is not unusual for the two disorders to coexist. In our
experience, nocturnal dyspnea due to OSA usually resolves quickly upon awakening, whereas the paroxysmal nocturnal dyspnea that is characteristic of congestive heart failure takes much longer to resolve. Complaints that suggest nocturnal gastroesophageal reflux and to a lesser degree diurnal gastroesophageal reflux (e.g., heartburn) are often expressed by OSA patients. Vigorous respiratory efforts by the patient during periods of apnea and hypopnea result in greater negative intrathoracic pressure swings during inspiratory efforts while there is relatively increased intraabdominal pressure during expiration (measurements of abdominal muscle activity in have shown that there is an active participation of abdominal muscles during expiration in many OSA subjects). Reflux results when an increased gradient between intra-abdominal and intrathoracic pressures favors the movement of gastric contents cephalad into the esophagus. In our experience and that of others, reflux can lead to laryngospasm.36
1210 PART II / Section 13 • Sleep Breathing Disorders
C3-A2 ROC-A1 Chin EMG MIC 89.1
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Figure 105-3 Example of a continuous sustained effort. This recording is from a man with continuous snoring and absence of apneas. With normal breathing respiratory effort measured by esophageal pressure, recording is a maximum of 9 cm H2O. As can be seen with obstructed breathing, the patient presents a mild change in the nasal cannula–pressure transducer curve (channel 6 from top), but the respiratory effort is greatly increased as demonstrated by the peak end inspiratory pressure (Pes) (channel 10 from top). There is maintenance of the same amount of effort during the entire sequence of increased respiratory effort. The sequence lasted 3 minutes 46 seconds. There is no indication of change of electroencephalogram (EEG) in the 60 seconds presented here and thereafter. The termination of the sequence was indicated by a burst of delta waves. Channel labeling from top to bottom: EEG with monopolar derivation, right eye lead (electrooculogram), chin EMG (electromyogram), microphone to record snoring, nasal cannula to record pressure fluctuations at the nose to reflect airflow, chest movement, abdominal movement, and esophageal pressure.
Untreated reflux can make patients more susceptible to nocturnal aerophagy when treated with nasal continuous positive airway pressure (CPAP).37 Nocturia is relatively common in patients with OSA: 28% of patients report four to seven nightly trips to the bathroom.38 OSA can be an independent cause of frequent urination during sleep in elderly men, and patients might initially consult urologists and attribute their disrupted sleep to repeated nocturia.39 CPAP can significantly decrease the frequency of nocturia and improve quality of life.40 Rarely, an adult patient complains of enuresis. Increased intraabdominal pressure, confusion associated with arousals, and increased secretion of atrial natriuretic peptide40 are proposed contributors to nocturia and enuresis. About 74% of patients with OSA report dry mouth and the desire to drink water either during the night or in the morning.24 On the other hand, about 36% of patients with OSA complain of drooling. These symptoms are useful indicators of evidence for SDB, particularly in premenopausal women, who often have more limited and atypical clinical presentations.41 Dry mouth and drooling are most likely due to mouth breathing during sleep, which is com-
monly seen in patients with OSA. OSA is also commonly associated with nocturnal bruxism.42 Daytime Signs and Symptoms Daytime sleepiness or fatigue is the most common complaint in patients with OSA.24,31,32 The manifestations of sleepiness can have subtle consequences (midafternoon drowsiness during a group meeting or an occasional nap), severe consequences (falling asleep while eating or talking), or catastrophic consequences (falling asleep while driving) (see Video 104-1). In general, it is not normal to feel sleepy immediately after a meal or while watching television. Such drowsiness usually indicates some degree of sleep deprivation or fragmentation, and OSA may be the underlying factor. It is essential to inquire about sleepiness while operating a machine or motor vehicle because of the increased risk of accidents7-9,24,31-33,43-47 and concern regarding bystanders’ safety. In the sleep laboratory, pathologically short sleep latency, objectively assessed by the maintenance of wakefulness test, is associated with impaired driving in a simulator environment.45 Driving tests and simulations have shown that OSA patients might not be aware of their
CHAPTER 105 • Clinical Features and Evaluation of Obstructive Sleep Apnea and Upper Airway Resistance 1211
degree of impairment while driving. Clinical evidence for impaired driving ranges from subtle to dramatic; some drivers recall an occasional honk from the car behind alerting them to the changing of traffic light; others report routinely rolling down the window or drinking coffee to stay awake,45 and others report falling asleep while in motion, resulting in riding on the berm or a crash. Some pathologically sleepy patients deny any problems with driving due to fear of restriction on their license. Studies have shown that there is a correlation between the Maintenance of Wakefulness Test (MWT) and the risk of impaired driving in OSA patients.46,47 However, one of the same studies showed that OSA patients with mildly abnormal results in the MWT had no driving impairment.47 Causes of sleepiness in OSA patients are multifactorial. Nocturnal disruption may be secondary to repetitive abnormal breathing events leading to arousals or complete awakenings in the middle of night or to early morning awakenings, with subsequent complaints of insomnia and reduced total sleep time. Mood disorders that are associated with disturbed nocturnal sleep can coexist with OSA. OSA and obesity often coexist, and whereas the former is associated with increased sleepiness, obesity per se has also been associated with sleepiness. In this regard, obesity may be responsible for the residual sleepiness that has been reported in obese patients who are otherwise appropriately treated for OSA with nasal CPAP.48 In a large survey of clinic patients, Stoohs and colleagues49 found that UARS patients had worse morning performance on the psychomotor vigilance task (PVT) compared to OSA patients who had apneic events that were longer in duration than the flow-limited events leading to sleep disturbance in UARS patients. Obstructive events may terminate with only increased delta on EEG rather than an EEG arousal.23 A study examining noise-induced brainstem activation versus EEG arousal during one nocturnal sleep period during which there were about 200 stimulations showed that the MSLT and PVT were impaired only when EEG arousals were present and not when brainstem activation was induced.50 Studies of sleep restriction lasting 1 week or longer have shown that responses were very different across subjects.51 It is postulated that genetic differences might explain why some subjects are more susceptible to nocturnal sleep disruption and restriction than others. While sleepiness might not be directly perceived by patients, they may complain of “tiredness” or “fatigue.” When asked to rest in a seated position with muscles relaxed to see if the feeling of fatigue could be improved, subjects denied improvement and differentiated between exercise-related fatigue and an overall feeling of fatigue. Subjects also complained that they experienced “lapses” while driving or performing monotonous tasks and reported lack of memory intermittently for a limited time period.45,47 Moreover, rather than, or in addition to sleepiness, patients may report cognitive dysfunction such as concentration, attention, memory, or judgment difficulties affecting their job performance (see Chapter 104). These complaints were most common in premenopausal women with a low AHI (mean, 13 events per hour of sleep) or UARS patients.41 In men performing manual work requiring attention and dexterity, unexplained periods of clumsi-
ness were mentioned in association with concentration difficulties. These issues may be sufficiently substantial that job performance or even the ability to maintain employment is adversely affected. Simple reaction time tests (such as the PVT) are affected, with slowing of response time and increasing frequency of erroneous responses. Neurocognitive functions have been investigated and results have shown that specific tests involving the prefrontal cortex may be affected by OSA, probably as a result of sleepiness. Most patients seem to respond favorably to treatment with nasal CPAP, with return to normal performance. However, some patients still complain of symptoms despite appropriate nasal CPAP use, and these patients need further investigation into the cause of their cognitive dysfunction. As is the case with the individual propensity to daytime sleepiness, it is not clear why some patients are more susceptible to cognitive dysfunction. Genetic influences might play a role; as an example, the APOE4 gene that is associated with neurodegenerative disorders has been clearly identified in OSA patients (see Chapter 103).52 However, the APOe-4 gene may not be directly linked to OSA specifically but may be a gene that favors neurodegenerative disease secondary to several different types of central nervous system insults. It is possible that specific genetic susceptibilities favor persistent neurocognitive dysfunction when exposed to an environmental condition such as OSA. Premenopausal women with a low AHI or UARS might have symptoms similar to attention-deficit/ hyperactivity disorder (ADHD), and may have received a mistaken diagnosis of adult ADHD.41 Personality changes including aggressiveness, irritability, anxiety, or depression may be observed. Treatment with continuous positive airway pressure (CPAP) has been shown to improve symptoms such as depression and fatigue.53,54 In our experience, a third of the patients report decreased libido or impotence that tends to improve with treatment. In addition, about 75% of OSAS patients with erectile dysfunction who have been treated with nasal CPAP report disappearance of difficulties with erection or ejaculation, resulting in significantly improved quality of life.55 Morning or nocturnal headaches are reported in about half of the patients and are often described as dull and generalized.56 Headaches usually last 1 to 2 hours and can prompt the ingestion of analgesics. A study from a clinic specializing in headaches found OSA to be the main cause of nocturnal or morning headaches.56 None of these patients had been previously investigated for OSA. Nocturnal headaches were controlled by OSA treatment.57 It is unlikely that all of these signs and symptoms will be reported by one person. There is a notable lack of specificity for most of these symptoms, and they overlap with other disorders such as depression or hypothyroidism.58 In many patients with depression, the presence of daytime sleepiness should prompt a sleep study to rule out coexisting OSA. With respect to thyroid abnormalities, one study detected hypothyroidism in 3 of 103 patients (2.9%) with OSA versus 1 of 135 control subjects (0.7%),59 and this difference was not significant. The authors concluded that routine thyroid function testing is not indicated in the absence of signs or symptoms of hypothyroidism,
1212 PART II / Section 13 • Sleep Breathing Disorders
although an exception can be made for high-risk groups such as women older than 60 years.
UPPER AIRWAY RESISTANCE SYNDROME There is controversy regarding the classification of UARS separately from OSA, and the current International Classification of Sleep Disorders (2005) classifies UARS under OSA. Considering the multiple definitions regarding what constitutes a hypopnea, this leaves a number of patients with abnormal breathing during sleep who are undiagnosed and untreated. UARS has traditionally been diagnosed when the AHI is fewer than 5 events per hour, and the simultaneously calculated RDI is often, but not necessarily, more than 5 events per hour, the difference due to RERAs being included in the RDI. Hence, RERAs, including the phase A2 of the cyclic alternating pattern scoring system,60 are considered the diagnostic hallmark of UARS.20 The use of the nasal cannula pressure transducer and the esophageal pressure has allowed better recognition of the AASM-defined hypopneas. In light of recent studies showing that UARS has features that differ from OSA61-63 and with the availability of better sensors to monitor nasal flow, establishing the criteria for the diagnosis of UARS has become more significant.17 The definition of UARS has been elaborated upon, with emphasis on the differences among flow limitation, hypopnea, and apnea.64 The lowest oxygen saturation (>92%) during sleep that is acceptable for a diagnosis of UARS is now a part of the definition. The rationale behind these refinements for the definition is that it is important to differentiate what is related to an upper airway problem from SDB, and what is related to abdominal obesity that may be the cause of oxygen desaturation (the chest bellow in particular during physiologic REM sleep atonia is one example). In the latest definition64 an apnea is not seen and oxygen saturation is greater than 92% at termination of an abnormal breathing event. The abnormal breathing event does not meet criteria for a hypopnea, currently defined by AASM with duration of 10 seconds and a drop in amplitude of nasal flow of at least 30%, but it is associated with the presence of well-defined cyclical alternating patterns (CAPs)65 associated with EEG changes or alpha EEG arousal.1 Although symptoms of OSA can overlap with UARS, some important differences have been noted.66 Several studies have indicated that chronic insomnia tends to be much more common in patients with UARS than in those with OSA.41,61,67-69 Many UARS patients report nocturnal awakenings and find that it is difficult to return to sleep. Sleep-onset insomnia and sleep-maintenance insomnia have been reported in UARS. In younger subjects, parasomnias are more commonly reported.70,71 The most common parasomnia is sleepwalking, with or without sleep terrors. Sleep studies performed in persons with UARS and parasomnias show an increase in CAP (phases A2 and A3 CAP rate) indicating NREM sleep instability.71 The treatment of UARS usually eliminates parasomnias and abnormal CAP rates, a response not seen with pharmacologic and psychiatric treatment of the parasomnias in these subjects.70 Patients with UARS are more likely to complain of daytime fatigue rather than sleepiness, with abnormal
ratings in fatigue scales when compared to a normal range in response to the Epworth Sleepiness Scale (ESS).72,73 Postmenopausal women with UARS have higher fatigue scale scores than premenopausal women. Treatment of UARS returns these abnormal scores to normal range.67,74 Referrals for evaluation of abnormal breathing during sleep have also come from Rheumatology Clinics where subjects were seen for chronic fatigue and chronic myalgias. Polysomnography has shown that in these cases the presence of UARS and subsequent treatment is associated with the disappearance of these rheumatologic complaints.74 About half of UARS patients complain of cold hands and feet, usually during teenage years, and about a third have lightheadedness upon standing or bending abruptly. This latter complaint may be related to the observation that systolic blood pressure less than 105 mm Hg and often below 90 mm Hg is more often associated with UARS75 than with OSA, which is commonly associated with hypertension.76 Similarly, autonomic responses to abnormal breathing as seen in UARS, compared to OSA patients, showed a dominance of vagal responses in the UARS abnormal breathing pattern compared to a more dominant sympathetic response in OSA patients.75,77,78 This difference is not surprising because sympathetic activation is commonly secondary to hypoxemia and repetitive arousals, which is much less common in UARS than in OSA. Quantitative EEG analyses have shown that compared to age-matched OSA, UARS patients have different EEG spectra during the night and also a different CAP rate (an abnormal increase in phase A2 CAP rate) at visual scoring, which indicates more sleep disturbances compared to OSA subjects.65,79-81 The cyclic alternating pattern scoring system visually scores an arousal pattern (phase A2) that is not included in the two other international sleep scoring manuals, and computerized EEG analysis is better at detecting EEG frequency changes and arousals compared to visual scoring. Both techniques were concordant in showing a different sleep-disturbance pattern in UARS than in OSA. Studies have compared responses to autonomic stimulation and investigation of sensory inputs from the pharynx during nocturnal sleep in patients with UARS and patients with mild OSA. Investigation of palatal sensory response by the two-point discrimination test showed that responses were similar in UARS subjects and control subjects, and the test was significantly different, with demonstration of sensory impairment in OSA patients.82,83 The patency of the upper airway is related to the balance between negative transpharyngeal pressure during inspiration and a counteracting dilating force due to the contraction of the upper airway dilating muscles as well as mechanical forces associated with diaphragm descent and increasing lung volume.84,85 The reflexes involved in this activity are mediated at least in part through receptors embedded in the pharyngeal mucosa. Signs of local nerve lesions have been demonstrated in the pharyngeal mucosa in patients with OSA. The presence of local polyneuropathy83,86,88 has been well demonstrated using electrophysiology, histology, electron microscopy, histochemistry, and evoked potentials responses. However, a systematic search for local neuro-
CHAPTER 105 • Clinical Features and Evaluation of Obstructive Sleep Apnea and Upper Airway Resistance 1213
logic lesions (local polyneuropathies83,86,88) in the upper airway is not a part of the systematic examination of patients with SDB despite demonstration of their existence and the development of a commercially available air-jet device in Europe to evaluate pharyngeal sensitivity.89 The authors who support a distinction between UARS and OSA base the difference in part on the clinical presentation and in part on the presence or on the decrease or absence of local sensory input due to local nerve lesions.82-83,86-88 Further efforts are required to evaluate them in a systematic fashion because this can have an impact on therapeutic indications, particularly soft palate surgery. Follow-up of untreated UARS patients for about 5 years has shown persistent complaints of insomnia associated with depressive mood and increased use of pharmacologic treatment (hypnotics and antidepressants). Patients with UARS who became overweight during the follow-up period were also subsequently found to have OSA and greater oxygen desaturation on follow-up polysomnography. As further studies are conducted on UARS, its relation to OSA will become clearer. For now it is important to know that the treatment options available to patients with UARS are similar to those for OSA patients, with more patients considering upper airway surgery (nasal surgery, pharyngoplasty with or without adenotonsillectomy) and dental appliances rather than nasal CPAP. Unfortunately, many UARS patients remain untreated and continue to experience worsening symptoms of insomnia, fatigue, and depressed mood.63
RISK FACTORS The presence of certain risk factors can strengthen the clinical suspicion of OSA. The strongest risk factors are obesity and age older than 65 years (Video 105-2). In one study, a body-mass index (BMI) of at least 25 kg/m2 had a sensitivity of 93% and a specificity of 74% for OSA.90 With the obesity epidemic increasing in industrialized countries, there is an ongoing evaluation regarding the association between OSA and android-type obesity (fat deposition predominantly in the neck and abdomen, in contrast to the gynecoid-type obesity with fat deposition in hips and legs). The question that is raised by the coexistence of OSA and obesity confounds assessment of the independent contribution of OSA to many associated health-related conditions. OSA as a comorbid condition of obesity is an important issue to consider because many of the clinical associations seen in overweight subjects who also have OSA could be the direct consequence of the weight problem rather than a result of upper airway narrowing. The association between android-type obesity and OSA leads to male gender being a risk factor for OSA. In community-based studies, the male-to-female ratio for OSA is 2-3 : 1, whereas in clinic-based studies the ratio is increased to 10-90 : 1. The risk for OSA in women increases with obesity and after menopause.91-93 This ratio might not be applicable to UARS patients, in whom, in our experience, the ratio is closer to 1 : 1. Most studies on postmenopausal women treated with hormone replacement therapy have not demonstrated significant improvement in OSA risk compared to those untreated.
A positive family history increases the risk of sleepdisordered breathing by twofold to fourfold.94-95 Firstdegree relatives of OSA patients have a 21% to 84% chance of having SDB compared with 10% to 12% of control subjects.94-95 This genetic predisposition is likely to be expressed through craniofacial anatomy that predisposes subjects to OSA, although the genetic predisposition for obesity has also been considered a potential heritable pathway for OSA (see Chapter 103). The craniofacial features that augment the risk for OSA include a high and narrow hard palate (i.e., abnormal nasomaxillary complex development), an elongated soft palate, a small chin, and an abnormal overjet (i.e., the distance between upper and lower incisors—a dental pattern indicating an abnormal growth pattern of the maxilla or mandible, or both) and can be passed on from parent to child. The anatomic features can become more pronounced as the child grows, especially if the growth period is interrupted by repetitive bouts of allergies, upper respiratory tract infections, and development of mouth breathing. Mouth breathing can contribute to the enlargement of tonsils, which is a common finding in childhood OSA.96 The lack of recognition and treatment for causes of childhood OSA may be the factor behind the clinical complaints of young adults. Several studies have shown that SDB is exacerbated by alcohol ingestion, especially around bedtime.97-98 Alcohol ingestion reduces the activity of the genioglossus muscle and other upper airway dilator muscles, and this can predispose to upper airway collapse and apneas. Additional risk factors include ethnicity (African Americans, Mexican Americans, Pacific Islanders, and East Asians99-102), disorders of craniofacial abnormalities such as Marfan syndrome, Down syndrome (Video 105-3), the Pierre-Robin syndrome, and other congenital craniofacial anomalies.103-104 Isolated studies have implicated tobacco use105 and a low vital capacity on pulmonary function testing as independent risk factors for SDB; however, currently there are insufficient data to include them as part of the accepted risk factors for OSA. Sleep-disordered breathing may be aggravated by certain factors such as sedatives, sleep deprivation, and supine posture.106 Respiratory allergies and nasal congestion can also aggravate snoring and SDB. Lesions caused by sensory impairment to the afferent sensory input (diabetes, chronic uremia, dysautonomia)107-108 can delay compensation to abnormal airway narrowing and can worsen or even lead to OSA. Further studies investigating the role of the autonomic nervous system impairments that are due to specific clinical syndromes are needed to confirm the currently available data in these regards. All of these factors should be identified during the initial clinical evaluation.
CLINICAL EXAMINATION A complete physical examination is required when assessing a patient with suspected OSA and UARS. Patients should be screened for other comorbidities including hypertension and signs of heart failure. Special attention however, must be given to the evaluation of body habitus and the upper airway.
1214 PART II / Section 13 • Sleep Breathing Disorders
Obesity and Neck Circumference Height and weight, BMI, and neck circumference should be determined in every patient. Neck circumference has been reported to correlate better with the presence of obstructive apnea than BMI, and a circumference greater than 40 cm should lead to questions regarding presence of SDB. Katz and colleagues109 reported that the average neck circumference (measured at the superior border of the cricothyroid membrane with the patient in the upright position) was 43.7 ± 4.5 cm (mean ± SD) in patients with OSA and 39.6 ± 4.5 cm (mean ± SD) in patients without OSA (P = .0001). Another study found a correlation between neck circumference and the severity of OSA.110 In their morphometric model of OSA, Kushida and colleagues111 evaluated 423 patients referred to their sleep disorders clinic for suspected sleep-related breathing problems and observed that neck circumference at least 40 cm has a sensitivity of 61% and a specificity of 93% for OSA regardless of the patient’s sex. Upper Airway The purpose of the upper airway examination is to identify structures or abnormalities that potentially can narrow the airway and increase resistance in airflow during sleep, thus reflecting a risk for OSA. Some clinical indices suggesting the presence of OSA include retroposition of the mandible, a cranial base flexure with nasion-sella-basion more acutely flexed than expected, and displacement of the hyoid bone. The upper airway examination can also provide guidance in therapeutic decision making by providing insights into the possible outcome of specific interventions or suggesting benefit from specific combinations of treatment modalities, such as addressing nasal obstruction with septoplasty or radiofrequency treatment of inferior turbinates in a patient who is suboptimally treated with nasal CPAP. The patient should preferably be examined in both the seated and supine positions because the supine position can provide a relatively better reflection of the anatomy during sleep. The presence of retrognathia and dental overjet (a forward extrusion of the upper incisors beyond the lower incisors) should be identified. Analyzing the relative position of teeth on the maxilla and mandible helps classify a subject with a prognathic, orthognathic, or retrognathic mandible. The retrognathic mandible engenders risk of a narrow upper airway behind the base of the tongue. Craniofacial dysmorphism or disproportionate craniofacial anatomy leading to deficient maxilla or mandible (or both) that predisposes a patient to OSA can result from delayed growth of the maxilla or mandible, or both, narrowing the caliber of the upper airway and producing maxillary flattening or retrognathia.111 Dental malocclusion and overlapping teeth are indicators of a small oral cavity leading to tongue malposition, and dislocation of the temporomandibular joint during mouth opening can also contribute to an airway that is predisposed to collapse during sleep. Questions regarding the dental history during teenage years to early 20s and examination of teeth can provide further information. For example in a general population study, OSA has been found to be the most common association with bruxism, and signs of dental clenching and grinding can be noted.
Figure 105-4 Photograph of high arched palate.
The presence of bruxism should alert the clinician to the possibility of undiagnosed OSA. The role of bruxism in OSA is currently the subject of investigation, with the hypothesis that it may be a defense mechanism against repeated occlusion of the upper airway. Extraction of wisdom teeth early in life is usually to address impaction related to a small maxilla or mandible, which is a risk factor for a narrow upper airway. Therefore, a positive history of wisdom teeth removal in earlier years should again alert the clinician to the presence of OSA. The oropharynx should be examined for the presence of an abnormally large tongue or macroglossia, which can narrow the upper airway and predispose to airway obstruction during sleep. A visual estimate of the space between the back of the tongue and the posterior pharyngeal wall should be made because the retroglossal area is a common site of airway obstruction during sleep. The distinction between true macroglossia as opposed to a small oral cavity with relative macroglossia (in reality, a normal tongue size but deceptively large due a small oral cavity) can be difficult. The uvula and soft palate should be assessed for size, length, and height. These soft tissues represent the anterior limit of the upper airway. A small airway diameter increases the suspicion of greater susceptibility to collapse during sleep. The soft palate examination must always be coupled with an evaluation of the hard palate (Fig. 105-4) because the positions of the soft and hard palates are influenced by development of the maxilla early in life, and any abnormality suggests increased risk of oropharyngeal narrowing or collapse during sleep. Edema or erythema of the uvula can indicate repetitive vibratory trauma from chronic snoring. A low-lying redundant soft palate and uvula are commonly seen in patients. Accurate visualization of this area however, can require fiberoptic nasopharyngoscopy. When this procedure is performed in an awake patient, the mechanics of airway obstruction can be completely different from
CHAPTER 105 • Clinical Features and Evaluation of Obstructive Sleep Apnea and Upper Airway Resistance 1215
those during sleep. Nasopharyngoscopy can be performed during the Müller maneuver, in which patients make a sustained inspiratory effort through an occluded mouthpiece with nostrils occluded to achieve a maximum pressure of −25 cm H2O within the upper airway (pressure is measured on the patient’s side of the occluded mouthpiece). This assessment is done to simulate conditions promoting upper airway obstruction during sleep and identifying regions of consequent narrowing or collapse. Fiberoptic examination is useful because it helps to estimate upper airway size in the supine position (in an awake patient) and serves as preoperative assessment for better visualization of potential sites of obstruction before surgical procedures for OSA such as palatopharyngoplasty or maxillomandibular advancement surgery. It is a relatively safe procedure done in the office setting with short-acting nasal local anesthesia. Somnonasopharyngoscopy employs sedation, such as propofol, to induce artificial sleep during endoscopy. Performed with and without simultaneous video recording, this procedure has been reported to be better at localizing regions of collapse in the upper airway. However, this requires specific precautions to ensure patient safety. Additionally, physiologic studies have demonstrated that anesthetics (including local anesthetics) per se, when applied to the upper airway mucosa influence sensory inputs that are involved in maintaining airway patency and timing of upper airway dilators thereby confounding the interpretation of the results. Clinical scores have been useful for standardizing an oropharyngeal clinical evaluation. The most commonly used is the Mallampati scale.112 As initially described, the evaluation is performed by visualizing the oropharynx with the mouth widely open and the tongue protruded. A modified Mallampati technique is performed with the mouth open and without protrusion of the tongue.113 In both cases, the respective positions of the soft palate, the tip of the uvula, the lateral tonsillar pillars, and the tongue are noted. The degree of oropharyngeal crowding is assigned a score between 1 and 4: 1 reflects an unobstructed, wide open oropharynx, with the uvula clearly above the tongue; 2 indicates visible pillars and part of the inferior segment of the uvula; 3 marks a much more limited visualization of the oropharynx, with the base of the uvula barely visible; and 4 indicates a very crowded oropharynx, with only the hard palate visible because the uvula is entirely masked by the tongue. Scores of 3 and 4 have been associated with a difficult intubation and usually imply an abnormally small oropharynx. Tonsils may be graded using the Friedman scale from 0 to 4, with 0 indicating complete absence of the tonsils and 4 indicating kissing tonsils that completely obstruct the oropharynx. It is a common finding to see hypertrophied tonsils in children with OSA. Hypertrophied tonsils are rarely seen in adults. The nose should also be closely examined for collapsibility of nasal valves, size and asymmetry of nares (Fig. 105-5), septal deviation, evidence of trauma, or enlarged inferior nasal turbinates that can lead to nasal obstruction and high nasal resistance to airflow. Although nasal obstruction alone is rarely the primary cause of OSA, it can contribute to increased airway resistance (increased
Figure 105-5 Abnormal nasal anatomy in a patient with upper airway resistance syndrome. Note the deviation of the septum, the asymmetrical size of the nares, and the collapse of the nasal external valves.
nasal airflow resistance plays a major role in mouth breathing in children, with secondary impact on craniofacial growth) and may be a more significant factor in patients with UARS. Kushida and colleagues111 described four measurements that characterize a narrow upper airway: palatal height, maxillary intermolar distance, mandibular intermolar distance, and overjet. Use of scales such as the Mallampati scale112 (developed to assess the likelihood of a difficult airway intubation) has been described to help predict the likelihood of OSA. Whether a scale is being used or not, routine visual examination of the upper airway in patients with and without SDB will quickly familiarize the clinician with the typical appearance of the narrow upper airway (see Fig. 105-4) where a high and narrow hard palate and overjet is seen. Figure 105-5 shows an abnormal nose in a patient with UARS. Gender Despite recognition that OSA is a prevalent disorder, the prevalence specifically in women was for a notable period incompletely examined.22 In the 1980s, rare reports of OSA in women emphasized obesity and that women were much more overweight compared to men for a similar AHI.92 This was later confirmed by the Wisconsin Sleep Cohort study.5 In a case-control study of 334 women between 30 and 60 years of age with SDB, the authors reported a significant difference in the duration of symptoms (mean, 9.7 years) associated with SDB and appropriate referral and diagnosis, compared to 100 men of similar age with SDB.22 This difference between men and women disappeared when BMI was greater than 30 kg/m2. In a large cohort, Young and colleagues6 found that women with an AHI more than 15 events per hour have symptoms similar to those of men with the same degree of apnea severity consisting of snoring, snorting, daytime sleepiness, and breathing pauses.
1216 PART II / Section 13 • Sleep Breathing Disorders
Several authors22,41,114 have indicated that many women have symptoms of UARS and an AHI less than 5. There is a discrepancy between the recognition of SDB in women in the clinical setting versus in large cohorts or the general population. This is most likely due to the lack of recognition of specific symptomatology with which UARS patients present in conjunction with a low AHI, or evidence of increased upper airway resistance with associated arousals on polysomnography, that are not given proper pathologic significance in this context. Women with UARS usually complain of insomnia, fatigue, tiredness, morning headache, muscle pain mimicking fibromyalgia, and anxiety. These nonspecific symptoms are also shared by the functional somatic syndromes.61 When comparing men and women seen for SDB in a clinical setting, Shepertycky and colleagues115 found that women had a significantly higher incidence of depression (odds ratio [OR], 4.6), history of thyroid disease (OR, 5.6), and history of asthma or allergy (OR, 1.9). Guilleminault and colleagues22 noted a significantly greater degree of social isolation and depression in women with SDB; premenopausal women had increased reports of amenorrhea and dysmenorrhea. Thus, women often have a different clinical presentation than men for OSA. Women with SDB generally present with “atypical” symptoms, and therefore a thorough evaluation should be done so as not to miss a diagnosis of SDB. Predictive Value of Clinical Examination Hoffstein and Szalai studied 594 patients referred to their sleep laboratory and reported that clinical impression alone is insufficient to identify patients with OSA.31 Subjective impression had a sensitivity of 60% and a specificity of 63%. The positive predictive value for snoring was 49%, bed partner’s observation of apnea was 56%, and nocturnal choking was 44%. Physical examination of the pharynx revealed that 54% of the patients with OSA (AHI 36 ± 25) had an abnormal pharynx (bulky or long uvula that failed to elevate from the base of the tongue during phonation, large tonsils, or small and narrow pharyngeal orifice). In contrast, 35% of the patients without OSA had an abnormal pharynx. The authors concluded that history and physical examination (including blood pressure and BMI) can predict OSA in only about 50% of patients. Definitive diagnosis of OSA and UARS therefore requires a formal sleep study.
SUMMARY A thorough assessment for signs and symptoms and detailed craniofacial examination followed by a polysomnogram are necessary steps in the evaluation of a patient with SDB. As more physicians become familiar with the clinical presentation of OSA and UARS, diagnosis of these two disorders will increase. Further studies are required to clarify the nature and significance of UARS. As the link between SDB and a variety of medical and psychiatric diseases becomes more certain, referrals to sleep specialists will undoubtedly increase. Furthermore, the public is becoming increasingly more aware of the importance of sleep to a person’s health and social well-being. These are exciting times in the field of sleep medicine, and the role of the sleep specialist is likely to become much more prominent in the future.
❖ Clinical Pearls Clinicians should screen patients for signs and symptoms of SDB, including a bed partner’s report, if available. Confirmation or exclusion of a diagnosis of SDB requires objective assessment of breathing during sleep performed by a polysomnogram. Obesity and certain craniofacial features are notable predisposing factors for SDB, and a thorough clinical evaluation can strongly suggest the diagnosis. Obesity leading to OSA when seen in an overweight subject should be considered a complication of obesity itself and not an incident syndrome of obesity. A positive family history increases the risk of SDB by twofold to fourfold. This genetic predisposition is likely to be expressed through craniofacial anatomy that predisposes to OSA, although the genetic predisposition for obesity has also been considered a potential heritable pathway for OSA. Premenopausal women with normal weight present with atypical symptoms of SDB, and a high clinical suspicion is necessary for diagnosis. This group might present with UARS rather than OSA but can still have associated daytime clinical symptoms, and treatment of the SDB has been shown to improve or alleviate these symptoms.
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1218 PART II / Section 13 • Sleep Breathing Disorders 66. Guilleminault C, Black J, Palombini L, Ohayon M. Clinical investigation of obstructive sleep apnea syndrome and upper airway resistance syndrome patients. Sleep Med 2000;1:51-56. 67. Guilleminault C, Palombini L, Poyares D, Chowdhury S. Chronic insomnia, post-menopausal women and sleep-disordered breathing (SDB). Part 1: Frequency of SDB in a cohort. J Psychosomat Res 2002;53:611-615. 68. Guilleminault C, Palombini L, Poyares D, Chowdhury S. Chronic insomnia, post-menopausal women, and SDB. Part 2: comparison of nondrug treatment trials in normal breathing and UARS postmenopausal women complaining of insomnia. J Psychosomat Res 2002;53:617-623. 69. Guilleminault C, Davis K, Huynh NT. Prospective randomized study of patients with insomnia and mild sleep-disordered breathing. Sleep 2008;31:1527-1534. 70. Guilleminault C, Kirisoglu C, Bao G, Arias V, et al. Adult chronic sleepwalking and its treatment based on polysomnography. Brain 2005;128:1062-1069. 71. Guilleminault C, Kirisoglu C, da Rosa A, Lopes C, et al. Sleepwalking, a disorder of NREM sleep instability. Sleep Med 2006; 7:163-170. 72. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989;46:1121-1123. 73. Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991;14:540-545. 74. Guilleminault C, Poyares D, da Rosa A, Kirisoglu C, et al. Chronic fatigue, unrefreshing sleep and nocturnal polysomnography. Sleep Med 2006;7:513-520. 75. Guilleminault C, Faul JL, Stoohs R. Sleep-disordered breathing and hypotension. Am J Respir Crit Care Med 2001;164: 1242-1247. 76. Peppard PE, Young T, Palta M, Skatrud J, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378-1384. 77. Guilleminault C, Poyares D, Rosa A, Huang YS. Heart rate variability, sympathetic and vagal balance, and EEG arousal in upper airway resistance and mild OSA. Sleep Med 2005;6:451-457. 78. Guilleminault C, Rosa A, Ohayon M, Koester U. Arousal, EEG spectral power and pulse transit time in UARS and mild OSAS subjects. Clin Neurophysiol 2002;113:1598-1606. 79. Guilleminault C, Poyares D. Arousal and upper airway resistance. Sleep Med 2002;3:S15-S20. 80. Guilleminault C, Kim YD, Chowdhuri S, Horita M, et al. Sleep and daytime sleepiness in upper airway resistance syndrome compared to obstructive sleep apnea syndrome. Eur Respir J 2001;17:1-10. 81. Guilleminault C, Lopes MC, Hagen CC, da Rosa A. The cyclic alternating pattern demonstrates increased sleep instability and correlates with fatigue and sleepiness in adults with upper airway resistance syndrome. Sleep 2007;30:641-647. 82. Guilleminault C, Li K, Chen NH, Poyares D. Two-point palatal discrimination in patients with upper airway resistance syndrome, obstructive sleep apnea syndrome, and normal control subjects. Chest 2002;122(3):866-870. 83. Friberg D, Answed T, Borg K, Carlsson-Nordlander B, et al. Histological indications of a progressive snorer disease in upper airway muscle. Am J Respir Crit Care Med 1998;157:586-593. 84. Van De Graaff WB. Thoracic traction on the trachea: mechanisms and magnitude. J Appl Physiol 1991;70:1328-1336. 85. Van De Graaff WB. Thoracic influence on upper airway patency. J Appl Physiol 1988;65: 2124-2131. 86. Friberg D, Gazelius B, Holfelt T, Nordlander B, et al. Abnormal afferent nerve endings in the soft palatal mucosa of sleep apneics and habitual snorers. Regul Pept 1997;71:29-36. 87. Kimoff JR, Sforza E, Champagne V, Ofiara L, et al. Upper airway sensation in snoring and obstructive sleep apnea. Am J Respir Crit Care Med 2001;164:250-255. 88. Affifi L, Guilleminault C, Colrain I. Sleep and respiratory stimulus specific dampening of cortical responsiveness in OSAS. Respir Physiol Neurobiol 2003;136:221-234. 89. Dematteis M, Lévy P, Pépin JL. A simple procedure for measuring pharyngeal sensitivity: a contribution to the diagnosis of sleep apnoea. Thorax 2005;60: 418-426. 90. Grunstein R, Wilcox I, Yang T, Gould Y, et al. Snoring and sleep apnoea in men: association with central obesity and hypertension. Int J Obes 1993;17:533-540.
91. Wilhoit SC, Suratt PM. Obstructive sleep apnea in premenopausal women: a comparison with men and with post-menopausal women. Chest 1987;91:654-658. 92. Guilleminault C, Quera-Salva A, Partinen M, Jamieson A, et al. Women and the obstructive sleep apnea syndrome. Chest 1988; 93:104-109. 93. Richmond RM, Elliot LM, Burns CM, Bearpark HM, et al. The prevalence of obstructive sleep apnoea in an obese female population. Int J Obes 1994;18:173-177. 94. Redline S, Tishler PV, Tosteson TD, Williamson J, et al. The familial aggregates of sleep apnea. Am J Respir Crit Care Med 1995;151:682-687. 95. Guilleminault C, Partinen M, Hollman K, Powell N, et al. Familial aggregates in obstructive sleep apnea syndrome. Chest 1995;107: 1545-1551. 96. Behlfelt K. Enlarged tonsils and the effect of tonsillectomy, characteristics of the dentition and facial skeleton, posture of the head, hyoid bone and tongue, mode of breathing. Swed Dent J 1990; 72(Suppl.):1-35. 97. Krol RC, Knuth SL, Bartlett D Jr. Selective reduction of genioglossal muscle activity by alcohol in normal human subjects. Am Rev Respir Dis 1984;129:247-250. 98. Scrima L, Broudy M, Nay KN, Cohn MA, et al. Increased severity of obstructive sleep apnea after bedtime alcohol ingestion: diagnostic potential and proposed mechanism of action. Sleep 1982;5: 318-328. 99. Redline S, Hans M, Pracharktam N, Tishler PV, Hans MG, et al. Differences in the age distribution and risk factors for sleepdisordered breathing in blacks and whites. Am J Respir Crit Care Med 1994;149:577. 100. Schmid-Nowara WW, Coultas D, Wiggins C, Skipper BE, et al. Snoring in a Hispanic-American population: Risk factors and association with hypertension and other morbidity. Arch Intern Med 1990;150:597-601. 101. Grunstein RR, Lawrence S, Spies JM, et al. Snoring in paradise: the Western Samoa Sleep Survey. Eur Respir J 1989;2(S5):4015. 102. Li KK, Powell NB, Riley RW, Guilleminault C. Obstructive sleep apnea syndrome: a comparison between Far-East Asian and white men. Laryngoscope 2000;110:1689-1693. 103. Cistulli P, Sullivan CE. Sleep apnea in Marfan’s syndrome. Am Rev Respir Dis 1993;147:645-648. 104. Resta O, Barbaro MP, Giliberti T, Caratozzolo G, et al. Sleeprelated breathing disorders in adults with Down syndrome. Down Syndr Res Pract 2003;8:115-119. 105. Wetter D, Young T, Bidwall T, Badr MS, et al. Smoking as a risk factor for sleep disordered breathing. Arch Intern Med 1994;154: 2219-2224. 106. Roth T, Roehrs T, Zorick F, Conway W, et al. Pharmacological effects of sedative-hypnotics, narcotic analgesics, and alcohol during sleep. Med Clin North Am 1985;69:1281-1288. 107. Mondini S, Guilleminault C. Abnormal breathing patterns during sleep in diabetes. Ann Neurol 1985;17:391-395. 108. Resnick HE, Redline S, Shahar E, Gilpin A, et al. Diabetes and sleep disturbances: findings from the Sleep Heart Study. Diabetes Care 2003;26:702-709. 109. Katz I, Stradling J, Slutsky AS, Zamel N, et al. Do patients with obstructive sleep apnea have thick necks? Am Rev Respir Dis 1990;141:1228-1231. 110. Davies RJO, Stradling JR. The relationship between neck circumference, radiographic pharyngeal anatomy, and the obstructive sleep apnoea syndrome. Eur Respir J 1990;3:509-514. 111. Kushida CA, Efron B, Guilleminault C. A predictive morphometric model for the obstructive sleep apnea syndrome. Ann Intern Med 1997;127:581-587. 112. Mallampati SR, Gatt SP, Gugino LD, Desai SP, et al. A clinical sign to predict difficult tracheal intubation: a prospective study. Can Anesth Soc J 1985;32:429-434. 113. Friedman M, Tanyeri H, La Rosa M, Landsberg R, et al. Clinical predictors of obstructive sleep apnea. Laryngoscope 1999;109: 1901-1907. 114. Anttalainen U, Polo O, Saaresranta T. Is ‘MILD’ sleep-disordered breathing in women really mild? Acta Obstet Gynecol Scand 2010;89:605-611. 115. Shepertycky MR, Banno K, Kryger MH. Differences between men and women in the clinical presentation of patients diagnosed with obstructive sleep apnea syndrome. Sleep 2005;28:309-314.
Medical Therapy for Obstructive Sleep Apnea
Charles W. Atwood, Jr., Patrick J. Strollo, Jr., and Rachel Givelber Abstract Positive airway pressure therapy, oral appliances, and surgery are considered the mainstays of sleep apnea therapy for obstructive sleep apnea (OSA), but a variety of medical therapies are occasionally appropriate as part of a primary therapy management strategy for obstructive apneas and hypopneas. In other cases, medical therapy may be a useful adjunct to positive airway pressure therapy in selected cases. Among these medical therapies is weight loss, which may the result of dietary manipulation or surgery. Weight loss can partially ameliorate or even reverse OSA. Alcohol and sedatives can also interact with OSA in a way that can worsen OSA symptoms, and consequently, these patients should refrain from these agents close to bedtime. Several medications are thought to affect OSA. Methylxanthines, progestational agents, selective serotonin reuptake inhibitors, and mixed serotonin receptor antagonists have each been studied with respect to OSA. Although positive studies exist, in aggregate the evidence provides no substan-
The principal therapy for obstructive sleep apnea (OSA) remains positive pressure delivered by a nasal or naso-oral interface (see Chapter 107). Oral appliances can also be useful in selected patients who cannot tolerate positive airway pressure (see Chapter 109). However, other medical options may be important as an adjunct to these treatment options or as a therapeutic intervention alone if the patient cannot accept or tolerate positive airway pressure or oral appliance therapy as a primary treatment. The focus of this chapter is to review these options.
BEHAVIORAL INTERVENTIONS Good medical care requires a comprehensive examination of the patient’s lifestyle and an understanding of how it may predispose to, or interact with, underlying medical problems. This is particularly true in patients with OSA. A number of lifestyle practices place persons at increased risk for OSA or worsen existing OSA. Modification of this behavior can favorably affect risk. These behavioral risks are described next. Multiple interventions may be appropriate in a given patient. Weight Loss A detailed discussion of upper airway physiology in OSA is provided in Chapter 101. To place the importance of weight reduction as a target for intervention in many OSA patients it is important to recognize the pathophysiologic contribution of obesity to this disorder. This issue is discussed in depth in Chapters 101 and 115. The adverse effect of obesity on upper airway function may be mediated through several pathways, one of which is a direct influence on upper airway geometry. Studies in animals have indicated that upper airway resistance is influenced by mass
Chapter
106
tial and consistent results that justify the use of these classes of medications for routine treatment of OSA. Administration of supplemental oxygen therapy has also been used to treat the hypoxemia in OSA. Oxygen therapy has not been proved to improve outcomes in OSA, although treatment of severe hypoxemia that cannot be achieved by interventions that are primarily directed at maintaining upper airway patency is generally considered to be reasonable. Caution is advisable in this circumstance because apneas may be longer during delivery of supplemental oxygen. Perhaps the most common and justifiable use of medication in OSA management is to improve alertness when sleepiness persists despite the successful amelioration of apneas and hypopneas with positive pressure therapy. Amphetamines and methylphenidate may be used for this purpose, but they have common side effects and can lead to dependence. A safer choice for promoting wakefulness in this setting is modafinil or armodafinil. These alertness promoting medications are approved for OSA patients who are adherent to CPAP therapy but still have excessive sleepiness.
loading of the anterior neck, which can simulate the clinical scenario of excessive adipose tissue deposits in this area.1 Further support for a significant pathophysiologic role of cervical obesity is provided by the observation that changes in pressure surrounding the neck are transmitted to the airway lumen and that cyclic pressure fluctuations in the pharyngeal fat pad coincide with intrapharyngeal pressure fluctuations.2,3 These data also support the importance of the observation that OSA patients have thick necks4 and that increased neck circumference is a predictive factor for OSA.5-7 Furthermore, velopharyngeal collapsibility increases with increasing neck circumference, at least in awake OSA patients.8 The presence of intrapharyngeal fat deposition may also be important in the pathophysiology of OSA (see Chapter 101). Several groups of investigators have observed increased intrapharyngeal adipose tissue or increased lateral fat pad size on computed tomography and magnetic resonance imaging of OSA patients.9-12 The significance of a space-occupying intrapharyngeal mass on pharyngeal function has been demonstrated in an animal model with increased upper airway resistance, which is related to the magnitude of inflation of a balloon catheter in the region of the upper airway lateral fat pad.3,13 In summary, upper airway closure during sleep partly depends airway size and shape as well as external tissue pressures from lateral pharyngeal fat pads exerting pressure on the airway lumen. Furthermore, to the extent that upper airway patency is increased by greater lung volume and reduced by decreased lung volume, greater truncal obesity leading to decreased lung volume may be another mechanism contributing to airway closure during sleep. It has been well documented that either medical or surgical weight reduction can have a substantial positive 1219
1220 PART II / Section 13 • Sleep Breathing Disorders
ventilatory control. Several important questions about weight loss and OSA remain unanswered, such as the effectiveness of weight loss in patients with more severe degrees of OSA, the effect of CPAP therapy on weight homeostasis, and the amount of weight loss that should occur before a reevaluation for OSA is recommended. As discussed in detail in Chapter 115, bariatric surgery has gained popularity in the past decade as an alternative to diet and exercise for managing severe obesity. The preponderance of evidence to date suggests that this approach to weight loss brings short-term benefits for many obesityrelated medical problems, including OSA.25,26 The longterm result of gastric bypass surgery on OSA is less clear, but results from one study demonstrated a 75% reduction in the respiratory disturbance index.26 Longer-term data are needed, but the short-term results of gastric-bypass surgery are encouraging.
Mean change in AHI (events/hr)
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−10% to −5% to +5% to +10% to <−5% <+5% <+10% +20% (n = 39) (n = 371) (n = 179) (n = 79) Change in body weight
Figure 106-1 The effect of the change in body weight on the mean change in the apnea–hypopnea index (AHI) over a 4-year period. (Redrawn from Peppard PE, Young T, Palta M, et al: Longitudinal study of moderate weight change and sleepdisordered breathing. JAMA 2000;284:3015-3021.)
impact on this disorder.14-21 In a prospective cohort study examining the association between weight change and the severity of sleep-disordered breathing, Peppard and colleagues demonstrated that a 10% weight loss predicted a 26% reduction in the apnea–hypopnea index (AHI) (Fig. 106-1). Smith and colleagues reported that a relatively modest weight loss provides significant benefit for some persons.22 Tuomilehto and colleagues reported the results of a randomized trial of a very low calorie diet with nutritional support compared to routine lifestyle counseling in patients with mild OSA; the total AHI was 9.3 ± 3.0 in the experimental group and 10.0 ± 3.0 in the control group. Weight loss was 10.7 kg in the experimental group and 2.4 kg in the control group. After 3 months of the weight loss intervention, the AHI in the experimental group was 5.3 and 8.1 in the control group. The 3-month AHI and lifestyle results were sustained over a 12-month period. The authors concluded that this lifestyle intervention was successful in treating mild OSA without resorting to positive airway pressure therapy.23 Although it is clear that there remains a population of nonobese OSA patients and that some patients do not obtain benefit from weight reduction,16,18 obese patients should always be encouraged to lose weight. A multidisciplinary team approach to weight reduction, encompassing modification of lifestyle and diet as well as pharmacologic and surgical options, may optimize clinical results.24 Not only will this have a beneficial impact on overall health, it also has a high likelihood of reducing the severity of upperairway dysfunction during sleep. The nonresponders might be those who have not lost sufficient weight, have coexisting craniofacial abnormalities, or have other operative pathophysiologic mechanisms such as perturbations of
Smoking Cessation Tobacco use is known to have a detrimental effect on sleep. Cigarette users have more difficulty initiating and maintaining sleep and have increased daytime sleepiness.27 Although there are a variety of possible explanations for this, including the impact of nicotine withdrawal, it is conceivable that one mechanism is through an association between smoking and sleep-disordered breathing. Smokers have an odds ratio that is four to five times greater than that of never-smokers for having at least moderate sleepdisordered breathing.28 Cigarette smoking can contribute to upper airway dysfunction during sleep by eliciting mucosal edema and increased upper airway resistance. It is obvious that tobacco use should be discouraged on the basis of its adverse multisystem effects. Early studies of nicotine-containing chewing gum suggested that it may be capable of reducing the AHI.29 However, subsequent studies have demonstrated that there was no clinically significant reduction in incidence of disordered-breathing events after application of transdermal nicotine patches, which have an extended duration of delivery. Apnea duration and snoring intensity was reduced, although the magnitude of the latter impact was insufficient to be therapeutically useful. Adverse effects were observed in conjunction with the transdermal patch including reduced total sleep time, sleep efficiency, and rapid eye movement (REM) sleep.30 Other side effects including gastrointestinal complaints, light-headedness, and tremor were also reported. Cigarette smoking cessation should always be recommended for general health purposes. Cigarette smoking likely contributes to upper airway edema, but the expected impact of smoking cessation on OSA is probably fairly small. To our knowledge there is no compelling evidence that commonly used medications for smoking cessation have more than minimal, if any, affect on upper airway function during sleep. Sleep Hygiene and Sleep Deprivation We live in a sleep-deprived society.31 In addition to the adverse impact of sleep-deprivation on performance, several lines of evidence suggest that absolute sleep deprivation, as well as repetitive sleep disruption, may also predispose to or worsen existing OSA. The effect of sleep
CHAPTER 106 • Medical Therapy for Obstructive Sleep Apnea 1221
deprivation on respiratory control mechanisms is unclear. Some studies have shown a blunted hypoxic and hypercapnic ventilatory chemoresponsiveness during wakefulness32,33 and may prolong apneas and hypopneas with consequently greater oxyhemoglobin desaturation, by depressing the arousal response,34,35 although one morerecent study has not.36 Another investigator has reported that upper airway collapsibility increased after sleep fragmentation but not following short-term sleep deprivation.37 The clinical importance of upper airway vulnerability induced by sleep restriction may be limited, but recommending patients obtain an adequate amount of sleep is a good practice for clinicians to adopt. Body Position A bed partner’s prompting to move to the lateral recumbent position is one of the oldest interventions for snoring and OSA. In many patients, the incidence of sleep-disordered breathing events is substantially greater during sleep in the supine position than in the lateral recumbent position.38-42 Sleeping in the supine position can increase the probability of upper airway occlusion due to the effect of gravity on the tongue, which tends to relapse posteriorly and come into apposition with the posterior pharyngeal wall. If the mass of soft tissue in the anterior cervical region enhances the propensity for upper airway dysfunction,1,4 it is reasonable to speculate that this factor interacts with body position to compromise upper airway patency during sleep. Body position dependency is inversely related to the degree of obesity,38 with a greater likelihood that more obese patients have obstructive sleep apnea–hypopnea (OSAH) regardless of position. One should not assume that a patient with normal body weight has positiondependent OSAH.38 The presence or absence of obesity is not an invariable predictor of supine position–dependent sleep-disordered breathing. It has been suggested that there is no effect of body position specifically during REM sleep.42 Position-related alterations in overall incidence of apnea are present primarily during non-REM (NREM) sleep. There is no body position effect on apnea duration, suggesting that the arousal mechanism is influenced by sleep stage but not by body position. Sleeping with the head and trunk elevated at a 30- to 60-degree angle to the horizontal has a favorable impact on OSA43; upper airway closing pressure (the magnitude of negative pressure when applied to the airway that results in occlusion) is more negative (indicating greater stability) in the 30-degree head-elevated position than in the supine and lateral recumbent positions during NREM sleep.44 Opening pressure (the magnitude of nasal continuous positive airway pressure [CPAP] that eliminates apnea, hypopneas, and oxyhemoglobin desaturation) is less in the head-elevated position than in the supine position but not significantly different from the lateral recumbent position. These data suggest that 30 degrees of head elevation may be more effective in stabilizing the upper airway than sleeping in the lateral recumbent position but that head elevation might not reduce the required magnitude of CPAP relative to lateral recumbency. The data are sufficiently suggestive that body position influences upper airway patency during sleep in some
patients to warrant specific questioning of the patient and bed partner regarding position dependence of sleepdisordered breathing. It is prudent to objectively evaluate sleep and breathing in these different body positions. If there is sufficient control of OSA, as well as maintenance of acceptable oxygenation and sleep continuity, in the lateral recumbent position during REM and NREM sleep, therapeutic management of body position during sleep may be considered. The sleep ball or similar technique to facilitate maintenance of the lateral recumbent position during sleep may be employed. This technique entails sewing a pocket into the back of the patient’s sleeping garment and placing an object such as one or more tennis balls within this pocket. Alternatively, the objects may be placed in a sock, which is safety-pinned to the back of the sleeping garment. Over time, the patient may become trained to sleep in this position, without the need for a physical reminder. The clinician must also recognize the practical issues involved with prescribing a head-elevated position because this can require a wedge on which the patient may sleep (cumbersome with regard to sharing a bed) or a specialized and potentially costly bed. In addition to affecting the incidence of OSA, body position can influence central apnea. We have seen several patients with mixed and central apneas dependent on supine body position. Issa and coworkers45 also remarked on the presence of supine position–dependent central apnea in patients with predominantly obstructive apnea. It has been postulated that occlusion of the upper airway in the supine position is an important element in the pathogenesis of these central apneas. Sanders and colleagues46 suggested that upper airway obstruction during exhalation could result in prolonged, low-level expiratory airflow, which is generally below the threshold for detection by usual recording techniques, thereby simulating true central apnea. Several additional reports, employing video endoscopy, have demonstrated the presence of upper airway occlusion during otherwise central apneas.47,48 Issa’s group45 postulated that supine position–dependent (gravityrelated) apposition of the pharyngeal walls precipitates central apnea via reflex inhibition of ventilation. The tendency for improvement of these central apneas by nasal CPAP45,46,49 or, in some cases, by maintaining the lateral recumbent body position supports a pathophysiologic role of upper airway obstruction in these events. In summary, manipulation of body position to promote sleeping in the lateral recumbent posture or with a 30to 60-degree head elevation can lead to clinically significant improvement of OSAH in a subset of patients. It is important to analyze each patient’s historical and polysomnographic data with this in mind. The potential impact of variation in body position should be considered when critically evaluating published reports describing the effects of other therapeutic interventions for OSAH. The effect of variations in head, neck and shoulder position on upper airway patency during sleep remains to be fully investigated. Alcohol Bed partners and housemates are probably the first to recognize the association between alcohol consumption
1222 PART II / Section 13 • Sleep Breathing Disorders
and upper airway dysfunction during sleep. A discussion of the physiologic effect of alcohol on the upper airway is provided in Chapter 132. It is clear that alcohol evokes obstructive apnea in persons who otherwise only snore and increases the apnea frequency in patients with preexisting OSA.34,50-53 There are limited and conflicting data regarding the contribution of alcohol to the development of upper airway dysfunction in persons who otherwise do not snore or have sleep apnea.51,52 In addition to increasing the frequency of sleep-disordered breathing events, alcohol consumption increases the duration of these events.54,55 Alcohol may also have a particularly adverse impact on daytime alertness in OSAH patients. The hypnotic effect of this agent is enhanced in the presence of underlying sleepiness. Alcohol consumption superimposed on sleepiness, as in sleep deprivation, is associated with worse performance on driving simulator tests compared with sleep deprivation and placebo.56 It would be expected that alcohol would have a greater detrimental impact on daytime alertness in OSA patients who have increased basal sleepiness. The key message is that persons with OSA, treated or untreated, would be best served by abstaining from alcohol. If a patient is unwilling to completely abstain, he or she should limit alcohol intake to a small quantity and should not consume alcohol for a time prior to bedtime that is sufficient to permit the blood alcohol level to fall to nil. A practical rule that we use is to counsel avoidance of alcohol for at least 2 hours before bedtime. There is inconsistency in the literature regarding the impact of alcohol on the magnitude of the positive pressure prescription,57-59 and patients who are unlikely to alter their alcohol consumption should have a therapeutic trial under usual lifestyle conditions. Therapy needs to be proved successful despite the presence of exogenous as well as endogenous influences on the pathophysiologic processes. This includes alcohol consumption as well as other factors, including body position during sleep (some persons may only be able to sleep in the supine position) or unavoidable need for treatment with pharmacologic agents that can adversely effect upper airway stability during sleep (e.g., benzodiazepines). Clinicians should inquire about alcohol use close to bedtime, especially if a decrease in CPAP effectiveness seems to have occurred or if sleep quality has worsened. Sedatives and Hypnotics An overview of the physiologic impact of sedatives and hypnotics on sleep and breathing is provided in Chapter 110. Although the effect of every individual benzodiazepine on breathing during sleep has not been evaluated, flurazepam has been the subject of several investigations. This agent can worsen OSA in some persons who otherwise have mild OSA.60-62 Reports addressing the impact on breathing during sleep in otherwise healthy subjects provide inconsistent results.62,63 A limited number of studies have examined the impact of benzodiazepines other than flurazepam and diazepam. In a group of patients with mild insomnia and sleep apnea (AHI, 8.8 ± 5.3, mean ± SE), 15 to 30 mg of temazepam did not significantly increase the AHI or alter the degree
of oxyhemoglobin desaturation, compared with placebo.64 In a group of patients with mild chronic obstructive pulmonary disease, no significant increase in the group average AHI was observed following 0.25 mg of triazolam.65 Due to the small populations evaluated in published investigations as well as the conflicting results of these studies, the safety of benzodiazepine administration to OSA patients remains uncertain and the issue remains debated.66 Although in usual hypnotic doses, benzodiazepines might not present a substantial risk for evoking OSA in some otherwise normal persons, in view of the inconclusive data regarding the margin of safety, it is prudent to avoid this class of agents in patients who have OSA and those with risk factors for this disorder. Narcotics and Anesthetics There have been anecdotal reports of clinically significant upper airway obstruction developing after administration of intravenous narcotics.67-69 This is discussed in Chapter 132. Normal subjects failed to demonstrate a change in breathing during sleep after oral administration of hydromorphone hydrochloride in 2-mg and 4-mg doses.70 It might not be valid to extrapolate these results to the administration of higher doses of narcotics or give them to patients who have or are at risk for upper airway dysfunction during sleep. It is prudent to withhold, or at least minimize, narcotics given to patients with OSA or those with risk factors for this disorder, depending on the clinical circumstances. In instances when humane medical practice requires analgesia, such as in the postoperative or periprocedure setting, if nonnarcotic or nonventilatory depressant agents cannot provide adequate pain control, and if the risk is deemed clinically acceptable, minimal doses of narcotics should be administered with careful monitoring. Patients who are already using CPAP for OSA should use this therapy in the postoperative and periprocedure periods. They may have increased pressure requirements in the presence of narcotics and following general anesthesia. General anesthesia can also promote upper airway instability by selectively reducing the muscle tone to the upper airway dilator muscles.71 If patients have not previously required CPAP therapy for OSA, empirical use of CPAP can be considered until there is no longer a need for drugs with the potential to affect ventilation or upper airway function. Attention has been paid to the influence of higherpotency narcotics on ventilation during sleep. Several reports have linked opioids to central sleep apnea. On the basis of two relatively small studies, the prevalence of methadone-induced central sleep apnea is about 30%.72,73 Some studies have shown that obstructive sleep apnea is more common in this group.73a Clinicians should be aware of the potential for higher-potency opioids to cause central or obstructive sleep apnea and to consider this in the differential diagnosis of sleep-disordered breathing when evaluating such patients. Barbiturates There have been no systematic assessments of the impact of barbiturates on upper airway function during sleep. Like alcohol, this class of agents selectively reduces the neural
CHAPTER 106 • Medical Therapy for Obstructive Sleep Apnea 1223
output via the hypoglossal nerve, reduces the tone of the upper airway dilator muscles, and predisposes to upper airway occlusion during sleep.74,75 It is prudent to avoid barbiturates in patients who are predisposed to or are known to have sleep-disordered breathing. Other Agents Phosphodiesterase-5 Inhibitors It is not uncommon for erectile dysfunction and OSA to coexist in patients.76 Phosphodiesterase 5 inhibitors such as sildenafil are being used to treat erectile dysfunction and pulmonary hypertension (which also can coexist with OSA). This class of agents inhibits degradation of cyclic guanosine monophosphate (cGMP) and as a consequence they increase nitric oxide (NO) expression. Nitric oxide is associated with smooth muscle relaxation and vasodilation. It can promote nasal congestion and adversely influence hypoxic vasoconstriction in the pulmonary vascular bed and in doing so can increase the propensity for obstructive apneas and hypopneas as well as amplifying the degree of oxyhemoglobin desaturation in conjunction with these events. Along these lines, a double-blind, randomized, controlled study in 14 patients with moderate to severe OSA (AHI, 31.6; 95% confidence interval [CI], 23.6 to 39.5) found that compared with values after placebo, 50 mg of sildenafil before bedtime was associated with increased percentage of the total sleep time during which oxyhemoglobin saturation was less than 90%, a decrease in the mean Sao2, and increased AHI.77 The authors concluded that sleep-disordered breathing should be considered in all patients with erectile dysfunction, and when erectile dysfunction is present, caution should be used when considering prescription of sildenafil. Testosterone Although controversial, there is a body of mostly anecdotal literature suggesting that treatment with testosterone can worsen upper airway function and exacerbate OSA. This topic is discussed in detail in chapter 125. Although more definitive information regarding the relationship between testosterone replacement therapy and OSA is needed, it would seem prudent for clinicians to explore the possibility of OSA in patients before prescribing testosterone and counsel patients who are to receive it about symptoms and signs. A high clinical suspicion for OSA should be maintained in patients receiving this therapy.
ENDOCRINE CONSIDERATIONS Hypothyroidism The physiologic relationship between thyroid function and sleep-disordered breathing is addressed in Chapter 125. Although the magnitude of the clinical association between hypothyroidism and OSA is not clear, there is considerable researech in support of an association between the two conditions.78-81 Thyroid hormone replacement therapy might benefit OSAH patients by reducing the incidence of apnea.80 On the basis of the data suggesting that thyroid hormone replacement improves upper airway function during sleep, clinicians should consider the possibility of hypothyroid-
ism adversely affecting OSAH. Hypothyroid patients (and their bed partners) should be specifically interviewed and examined to detect factors that suggest OSAH is present. Although OSAH may be reduced after initiating thyroid hormone replacement therapy, the degree of improvement may be insufficient to obviate the need for additional treatment.80,82 It is important to repeat an objective assessment of breathing during sleep after restoration of the euthyroid state. Grunstein and colleagues82 made the important observation that thyroid hormone replacement in patients with untreated OSA can precipitate cardiac complications attributable to ischemia in the setting of augmented metabolism and persistent nocturnal hypoxemia. For this reason, as well as the benefit of more-rapid relief of OSA, the authors suggested treatment with nasal CPAP during thyroid replacement. This recommendation could be extrapolated to include successful oral appliance therapy. This strategy appears prudent until objective reassessment is performed when the patient is clinically and chemically euthyroid and further management decisions can be made based on the subsequent reassessment. The utility of screening unselected OSAH patients for hypothyroidism is controversial. Winkelman and coworkers have reported a similar prevalence of chemical hypothyroidism in OSA patients and in persons without OSA.83 These authors concluded that routine screening for thyroid dysfunction is not indicated in OSAH patients unless there are corroborating signs and symptoms. The possibility of concomitant hypothyroidism should be considered in patients who have OSA and are receiving adequate therapy but who continue to report symptoms of fatigue and daytime sleepiness. Estrogen and Progesterone The effect of gender on OSAH has been well defined; the male-to-female ratio is 2 or 3 : 1.84 After menopause, the risk of OSA increases.85,86 The exact mechanism(s) conferring this risk are incompletely understood, but they appear to be in part a function of estrogen and progesterone levels.87 Older reports have demonstrated that hormone replacement therapy (HRT) has a favorable effect on the OSA.85,86 However, the additional risks as defined by the Women’s Health Initiative study likely outweigh the potential benefit. Further research might define subsets of patients and dosing regimens that are safe and effective. It is unlikely that this intervention would be robust enough to preclude the use of positive pressure in severe OSA.87
PHARMACOLOGIC INTERVENTIONS Oxygen Supplemental Oxygen In addition to sleep fragmentation, many of the clinically and physiologically evident consequences of OSA are attributable to nocturnal hypoxemia. Prevention of hypoxemia is a worthwhile therapeutic goal in OSA patients. Several older studies have reported that administration of supplemental oxygen to OSA patients can significantly increase apnea duration with associated hypercapnia and respiratory acidosis.88-90 Martin and colleagues90 observed
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1224 PART II / Section 13 • Sleep Breathing Disorders
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Figure 106-2 Mean percent apnea time for eight patients (closed squares, solid line) and the average nadir of oxyhemoglobin saturation per apnea (open squares, dashed line) for each 7.5-minute interval during the three study conditions (Room air I, Oxygen, Room air II). (Redrawn from Martin RJ, et al: Acute and long-term ventilatory effects of hyperoxia in the adult sleep apnea syndrome. Am Rev Respir Dis 1982;125:175-180.)
an initial prolongation of apnea duration in a group of eucapnic OSAH patients conjunction with significant reduction in the apnea frequency. There was no change in the mean apnea duration after 30 minutes of oxygen administration compared with a period of breathing room air. This resulted in decreased apnea time and maintenance of satisfactory oxyhemoglobin saturation over the study period (Fig. 106-2). The bradycardia that accompanied apnea was eliminated by supplemental oxygen administration. Gold and coworkers91 subsequently reported that supplemental oxygen administration was associated with a statistically, but probably not clinically, significant reduction of apnea frequency, particularly during NREM sleep, as well as improved oxyhemoglobin saturation. Apnea duration increased slightly by an average of 4 to 7 seconds across the study group. There was no improvement in subjective or objective measures of daytime sleepiness during the period of nocturnal oxygen supplementation. The evidence suggests that providing supplemental oxygen during sleep is not sufficiently effective in reducing apnea frequency and increasing daytime alertness to stand alone as therapy for most patients. There may be a population of persons who have no symptoms resulting from sleep fragmentation (hypersomnolence) or who have a minimal frequency of OSA events but who nonetheless experience unacceptable oxyhemoglobin desaturation during sleep. In these patients, increasing nocturnal oxyhemoglobin saturation may be the major, or the only, therapeutic goal.92 The degree and duration of oxyhemoglobin desaturation that is ultimately harmful remains to be determined.93 One study found that desaturations in OSA of 2% to 4% were associated with fasting hyperglycemia, and another found that obstructive hypopneas causing desaturation of 4% or more were associated with cardiovascular disease independent of other risk factors.94,95 Patients with coronary artery disease or cerebrovascular disease (or both) and only a marginally elevated frequency of abnormal breathing events during sleep, with unacceptable oxyhemoglobin desaturation during those events,
might benefit from supplemental oxygen.96,97 Outcome studies are clearly needed to determine at what level of desaturation there is a cost versus benefit justification for providing oxygen therapy. Consideration should be given to performing initial trials of oxygen therapy during attended monitoring. This may be particularly important in patients with concomitant hypercapnia during wakefulness.98 Such monitoring is also necessary to determine the flow of supplemental oxygen required for maintaining acceptable oxyhemoglobin saturation. In addition to providing sole therapy in selected patients with OSA, oxygen may be a useful adjunct to positive airway pressure (CPAP or bilevel positive airway pressure).99 OSA patients who are sufficiently hypoxemic or borderline hypoxemic during wakefulness to warrant supplemental oxygen therapy usually meet the criteria for this therapy during sleep, even if positive airway pressure treatment maintains upper airway patency.100 It should be determined if persistent desaturation on CPAP is related to hypoventilation resulting from the high mechanical impedance to expiration or increased ratio of dead space to tidal volume that may be associated with this modality.101 Bilevel positive pressure can permit sufficient reduction of expiratory pressure to avoid significant hypoventilation and desaturation and obviate the need for supplemental oxygen. Transtracheal Oxygen Delivery Several studies have described the impact of transtracheal oxygen administration to OSA patients.102-104 The data are too limited to provide substantive insight into the clinical utility of this mode of oxygen delivery or to determine if it provides meaningful benefit over less-invasive methods of oxygen delivery. At present, transtracheal oxygen should be considered investigational in the treatment of OSA patients. Nasal Insufflation of Air A small study demonstrated that high flow (20 L/min) humidified air administered through a nasal cannula is capable of decreasing the AHI from 28 ± 5 to 10 ± 3. This trial is thought-provoking, but it had only 11 subjects and must be replicated. If there is supporting evidence from high-quality long-term trials, such a therapy may be promising for some patients.105 Antidepressants Protriptyline In the late 1970s, protriptyline, a nonsedating tricyclic antidepressant, was reported to reduce apnea episodes and increase daytime alertness in patients who had narcolepsy with cataplexy.106 Conceptually, protriptyline can reduce OSAH by reducing the duration of REM sleep107 and by increasing the tone of the upper airway dilator muscles108 with increased hypoglossal and recurrent laryngeal nerve activity. Protriptyline can alter the distribution of obstructive apneas and hypopneas, with a decreased frequency of the former and increased frequency of the latter.109 The clinical significance of converting obstructive apneas to hypopneas is not clear because both can result in arousals, autonomic nervous system activation, and potentially deleterious cardiovascular impact. Although protriptyline
CHAPTER 106 • Medical Therapy for Obstructive Sleep Apnea 1225
administration can result in a statistically significant reduction in sleep-disordered breathing events in study populations, breathing and oxygenation during sleep generally remain abnormal.110 OSA patients receiving protriptyline report subjective improvement in daytime sleepiness despite a persistently elevated arousal frequency.107 This has led to speculation that this agent has specific alerting properties in addition to any effect on breathing. This has clinical relevance in that changes in symptoms after initiating protriptyline therapy cannot be used as a reflection of physiologic changes in breathing during sleep, and objective assessment is required to evaluate therapeutic impact. Protriptyline has a number of side effects, primarily related to its anticholinergic properties, that further limit its utility.107,111 Side effects vary in severity and may limit use. They include dry mouth, urinary hesitancy, constipation, confusion, and ataxia. No significant cardiac dysrhythmias were observed at the dosages employed up to 30 mg daily. Due to its lack of clinically significant therapeutic impact and potentially troublesome side effects, protriptyline is not considered a standard intervention in the treatment of OSAH. Serotonin Uptake Inhibitors Several studies have suggested that serotonin might mediate upper airway dilator muscle and diaphragm activity.110,112 It has been further postulated that the reduction in upper airway dilator muscle tone, particularly during REM sleep, is due to withdrawal of serotonin-related excitatory input to the hypoglossal motor neurons.113 If these postulates are true, it could have substantial implications for the treatment of patients with OSA. Buspirone is a clinically available anxiolytic agent whose mechanism of action is believed to be at least partly mediated through serotonin receptors in the central nervous system.114,115 Several animal studies have suggested that administration of buspirone augments ventilation during wakefulness and sleep and enhances ventilatory responsiveness to carbon dioxide.114,115 In addition, the apneic threshold for carbon dioxide is reduced by an average of 3.7 mm Hg. These data suggests that as a class of agents, serotonin agonists may have a therapeutic role in OSAH. Although buspirone theoretically has characteristics that provide therapeutic benefit in OSA, there are insufficient data on which to base judgments regarding its safety or efficacy. Other serotonin agonists have been evaluated to limited degrees. Following administration of 20 mg/day of fluoxetine, one study found a statistically significant reduction in the apnea plus hypopnea frequency, from 57 ± 9 to 34 ± 6 (mean ± SE), although there was wide intersubject variability and there was no significant impact on the arousal frequency.110 Fluoxetine increased sleep latency independent of its effect on sleep-disordered breathing, and it reduced the percentage of REM sleep. Although these results are disappointing, knowledge regarding the relationship among the serotoninergic system, sleep, breathing is continuing to evolve. There is reason to be hopeful that further knowledge of the relevant receptors will result in more effective interventions.116,117
Mirtazipine Mirtazipine is a mixed serotonin receptor antagonist that also promotes brain serotonin release and has previously been shown to decrease apneas in a rodent model. In a human study, Carley and colleagues administered mirtazipine in a placebo-controlled dose-ranging study (from 4.5 mg to 15 mg) and found significant reduction in sleep apneas. In this study of seven men and five women with newly diagnosed OSA, the reduction in the AHI was approximately 50% of baseline. All 12 subjects showed improvement over placebo. Although it is too early to advocate this medication for routine OSA management, this approach using mixed serotonin receptor agonists deserves further study.118 Stimulants Some OSA patients whose treatment is thought to be adequate to reverse upper airway dysfunction and to maintain acceptable oxyhemoglobin saturation and sleep continuity still complain of disturbing diurnal sleepiness or lack of alertness. There are a number of possible reasons for this, although they are controversial. Mean sleep latency improves during CPAP therapy, but in many cases it does not return to clearly normal values.119 The clinician must consider the possibility of noncompliance with a volitional treatment regimen (e.g. CPAP, oral appliances, body position modification), an inadequate prescription (e.g., CPAP level or mandibular advancement), changing external factors (e.g., weight gain, medications, sleep hygiene, shift work, other medical or psychiatric disorders), or a nonpulmonary sleep–wake disorder, to name a few. Even after these issues have been addressed, some patients remain unacceptably and perhaps dangerously sleepy or inattentive. Animal data have demonstrated that long-term intermittent hypoxia (LTIH) can result in oxidative injury to the sleep–wake regions of the brain.120 After the withdrawal of LTIH, objective sleepiness persisted, supporting the notion that sleepiness associated with sleep apnea might not be completely reversible. Historically, amphetamines have been the class of agents employed as stimulants. Unfortunately, this group of drugs has considerable potential for harmful cardiovascular consequences as well as adverse psychiatric and sleep effects. Modafinil is an agent that is thought to be a central alpha1 agonist with possible dopaminergic properties.121 Limited studies have suggested that modafinil increases daytime alertness and vigilance and memory performance without significant side effects in patients with or without OSAH.121,122 There was no change in the AHI or the nadir of oxyhemoglobin saturation in OSAH patients taking modafinil. Modafinil and its r-isomer armodafinil have been approved by the U.S. Food and Drug Administration for the treatment of residual sleepiness in OSA patients who are adequately treated with positive pressure via a mask. A 4-week randomized, double-blind, placebocontrolled, parallel-group study reported significant improvement in daytime sleepiness with modafinil compared to placebo in OSA patients who were objectively adherent to CPAP therapy.123 There was no decrease in CPAP use in the modafinil versus the placebo group at
1226 PART II / Section 13 • Sleep Breathing Disorders
the 4-week endpoint. In a subsequent 12-week open label study involving 125 patients, improvements in subjective daytime sleepiness and sleep-related functional status were maintained.124 There was a statistically significant decrease in CPAP use from 6.3 ± 1.3 hours per night at baseline to 5.9 ± 1.4 hours per night at the 12-week point, suggesting that modafinil adversely affects adherence to CPAP. Clinicians prescribing modafinil should be aware of this potential and urge their patients to continue CPAP therapy to the greatest possible extent. The most common side effects of modafinil use were headache (28%), anxiety (16%), and nervousness (14%). The potential for addiction to modafinil has been explored using positron emission tomography (PET) imaging techniques. Central nervous system sites known to be associated with addiction were probed with ligands specific for dopamine receptors. Their results demonstrated that modafinil use at common dosages was associated with increased dopamine availability in the central nervous system. This is a pattern similar to that seen in addiction to other substances. Although it is not conclusive evidence for addiction potential, this outcome suggested the possibility that addiction to modafinil, previously thought unlikely, may be possible.125 In 2007, the manufacturer of modafinil received FDA approval for a preparation of modafinil containing only the r-enantiomer, called armodafinil. Armodafinil has a duration of action that is 10% to 15% longer than modafinil’s. At this time, the same clinical indications for use that have applied to modafinil apply to armodafinil. In one study published on armodafinil in OSA, investigators found no negative effect on CPAP use and positive effects on results of the maintenance of wakefulness test and subjective feelings of improved alertness.126 Prescription of stimulants without a diagnostic evaluation risks masking important persistent and significant sleep-related pathology that can negatively affect the quality and duration of the patient’s life, independent of the issue of daytime sleepiness.96,97,127-137 Careful follow-up with objective assessment of adherence to positive pressure therapy should be pursued in patients treated with stimulants.
MECHANICAL THERAPY Continuous positive airway pressure is generally considered the first-line medical intervention for OSA patients. Maintenance of upper airway patency is probably primarily mediated by mechanical splinting, making CPAP a mechanical therapy. Positive-pressure therapy is discussed in depth in Chapter 107. The discussion here focuses on other mechanical therapies. Nasal Dilators Elevated nasal resistance can promote upper airway obstruction during sleep.138,139 Although the therapeutic benefit remains somewhat controversial, snoring and apnea have been reported to improve in about 10% of patients with administration of mucosal vasoconstrictors.140 A variety of devices mechanically dilate the anterior nasal valve to reduce nasal airway resistance and putatively decrease the propensity toward OSA. The use of nasal
dilators in the management of snoring is discussed in Chapter 102. Here we focus on use of nasal dilators as it relates to OSA. In one of the few studies to objectively assess the impact of nasal dilation on sleep, breathing, and oxygenation, Hoijer and colleagues141 assessed the impact of an external nasal dilator in 10 snorers, seven of whom had an apnea index in excess of 5. The average apnea index fell from 18 to 6.4 and the minimum oxyhemoglobin saturation also improved while asleep with the nasal dilator, although the saturation remained severely reduced in persons with more severe baseline desaturation. Neither the hypopnea index nor objectively measured arousal frequency were reported in this study and it is possible that neither the AHI nor the arousal index was favorably affected by the nasal dilator. Only four patients expressed a desire to continue to use the nasal dilator. In contrast, Hoffstein and coworkers142 concluded that dilation of the anterior nasal valve using an external dilator has no impact on sleep-disordered breathing, nadir of desaturation, or mean oxyhemoglobin saturation, although a reduction in snoring intensity was noted. As the authors indicated, their results might have been biased by the absence of a randomized treatment order. Employing an intranasally applied dilator, Scharf and colleagues143 reported that a significant fraction of 20 participants had improved Stanford Sleepiness Scale scores, morning concentration, and subjective quality of sleep, as well as reduced sleepiness on awakening and number of awakenings. However, using a numerical scale, there was no difference in subjective sleep depth, refreshing quality of sleep, morning sleepiness, sleep quality, number of awakenings, and other subjective parameters. The existing literature suggests that these devices might offer some benefit for selected patients, but the literature is too insubstantial to provide guidance on patient selection. Our practice is to consider external nasal dilators for snorers without OSA. Further well-planned and controlled studies of nasal dilators in appropriately selected patients would be helpful in determining the role of these devices in sleep-disordered breathing. Nasopharyngeal Airway Stents The concept of nasopharyngeal intubation to maintain upper airway patency during sleep was originally reported in the literature in the 1970s.144 There have been relatively few reports describing its use.145,146 Nasopharyngeal intubation has limited therapeutic utility. A substantial proportion of patients do not tolerate this intervention, and of those who do, only about two thirds have a clinically significant improvement in sleepdisordered breathing as defined by a reduction in disordered breathing event frequency of 65%, or an apnea index less than 5 and an BiPAP less than 10.146 Some of these patients continued to experience notable oxyhemoglobin desaturation, and there was no major improvement in sleep quality and architecture. Upper Airway Stimulation Phasic activity of the upper airway dilators during inspiration is increased during wakefulness in OSA patients compared with control subjects.147-149 This is consistent with
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ongoing physiologic compensation for compromised upper airway patency. This compensatory augmentation may be diminished during sleep, and, consequently, upper airway dilator muscle tone becomes insufficient to overcome the factors promoting airway occlusion. It is reasonable to speculate that external augmentation of upper airway dilator muscle activity enhances luminal patency during periods when these occlusive forces are operative and natural compensatory mechanisms are reduced. Attempts to stimulate the upper airway dilator muscles using transcutaneous submental or transhyoidal electrodes as well as intraoral electrodes have met with either disappointing results or concern regarding the possible impact of unintentional patient arousal.150-152 In contrast, promising results have been obtained using direct intramuscular genioglossal or hypoglossal stimulation. Unilateral electrical stimulation of the branches of the hypoglossal nerve supplying the genioglossus muscle reduces (i.e., makes more negative) the upper airway critical closing pressure (Pcrit) or increases maximal inspiratory airflow (or both) in feline and canine models.153,154 Schwartz’s group155 applied direct electrical stimulation to the genioglossus muscle in several OSA patients. The electrical stimulus is triggered by the development of negative intrapharyngeal or esophageal pressure consistent with the onset of inspiration. In a small number of patients this reduced the number of inspiratory flow-limited breaths by about 50% and reduced the AHI. Electrical stimulation did not appear to induce arousal because there was no change in the electroencephalogram immediately following the stimulus train compared with the period immediately prior to application of the stimulus, nor was there a difference in the heart rate across the periods before, during, or after stimulation. In a small group of OSA patients with inspiratory airflow limitation, unilateral hypoglossal nerve stimulation employing electrodes applied directly either to the main hypoglossal nerve trunk or specifically to the branches innervating the genioglossus muscle increased maximal inspiratory airflow.156,157 Stimulation significantly improved the AHI and the oxyhemoglobin desaturations (Figs. 106-3 and 106-4). A trend toward deeper stages of NREM sleep was observed. Only three of eight patients remained free from stimulator malfunction at 6 months. The results of hypoglossal nerve stimulation are encouraging but require confirmation in larger studies. The data suggesting that stimulation does not precipitate arousal is of particular importance, but whether this remains the case in patients after the initial treatment period and reduction of sleep drive requires confirmation. The limited available data suggest that electrical stimulation improves, but might not eliminate, OSA. If the impact of this intervention is incomplete, it may be related to the unilateral stimulation technique (one would be reluctant to implant bilateral electrodes due to concern regarding potential bilateral nerve trauma), the importance of other, unstimulated upper airway muscles, or factors related to upper airway lateral wall instability. A durable and reliable system is needed.153 Technical issues related to electrode breakage and malfunction need to be solved before considering hypoglossal nerve stimulation as alternative therapy to positive pressure. Electrical stimulation of the pharyngeal
100 Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8
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Figure 106-3 NREM sleep apnea–hypopnea indexes at baseline versus mean data (months 1, 3, and 6) for the entire night versus mean data (months 1, 3, and 6) for continuous stimulation. (Redrawn from Schwartz AR, Bennett ML, Smith PL, et al: Therapeutic electrical stimulation of the hypoglossal nerve in obstructive sleep apnea. Arch Otolaryngol Head Neck Surg 2001;127:1216-1223.)
dilator muscles is a promising development in the treatment of OSA. Combination Therapy Theoretically, it makes logical sense to combine OSA therapies of different mechanisms to achieve maximum effect in OSA therapy. Genioglossal electrical stimulation and mandibular advancement devices improve sleepdisordered breathing. It is logical to consider them as complementary therapies and combine them. One report studied 14 men, ages 27 to 70 years, in an experimental program of combination therapy.158 The subjects were studied under a short-acting general anesthetic; providing a hypotonic upper airway model for this experimental approach. Change in the Pcrit from baseline was the main outcome. The authors demonstrated that when used separately, both the mandibular advancement splints and the direct genioglossal stimulation were capable of decreasing Pcrit. When these treatments were used together, the Pcrit decreased to a greater degree than when each intervention was used alone. Moreover, the magnitude of the change
1228 PART II / Section 13 • Sleep Breathing Disorders
EOG (µV)
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Figure 106-4 A, Breathing pattern during NREM sleep with hypoglossal stimulation off. B, Breathing pattern during NREM sleep with hypoglossal stimulation on. EOG, electrooculogram; EMG, electromyogram; EEG, C3-A2 electroencephalogram; Pes, esophageal pressure; SaO2, oxyhemoglobin saturation. (Redrawn from Schwartz AR, Bennett ML, Smith PL, et al: Therapeutic electrical stimulation of the hypoglossal nerve in obstructive sleep apnea. Arch Otolaryngol Head Neck Surg 2001;127:1216-1223.)
was slightly more than additive. This physiologic study of combination therapy provides additional basis for upper airway dilator muscle stimulation as a therapy for OSA, but it also needs further study. Cardiac Pacing Atrial overdrive pacing has been examined as a therapy for OSA patients. Based on a report published in 2002 by Garrigue and colleagues, atrial overdrive pacing has been subjected to several clinical trials. Although the initial study by Garrigue demonstrated large decreases in the AHI (from 28 ± 22 to 11 ± 14),159 these findings have not been replicated by other research groups.160,161 At this time, atrial overdrive pacing is not considered a viable therapeutic option. Cardiac Resynchronization Therapy Cardiac resynchronization therapy is a device-based intervention for chronic heart failure based on the observation
of that an increased intraventricular conduction delay results in decreased synchronicity between the right and left ventricles. Biventricular pacing seeks to improve synchronicity and improve overall cardiac performance. Several randomized trials have demonstrated improvement in congestive heart failure in patients undergoing biventricular pacing, and it is plausible that sleep-disordered breathing can improve as well. Although there is a paucity of randomized clinical trial data, what information there is does suggest that patients with sleep-disordered breathing, including those with OSA, show a reduction in apneas and hypopneas after commencing a cardiac resynchronization program.162,163 Some data also suggest that the improvement in AHI is correlated with measures reflecting improved cardiac output.163 At present, cardiac resynchronization therapy cannot be considered adequate therapy for OSA or central sleep apnea. Further study of this promising technique for heart failure management is needed to better understand its effect on outcomes of sleep apnea.
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PITFALLS AND CONTROVERISES The chronic care of the OSA patient often includes medical interventions other than positive pressure via a mask or oral appliance therapy. Behavioral interventions that include avoiding sleep deprivation, improving fitness, quitting smoking, and reducing alcohol consumption should pursued, when appropriate, in all patients. Lifestyle interventions can clearly augment overall management of OSA. Research has demonstrated that adequate treatment with CPAP does not result in weight loss. Specific therapy addressing weight loss must be provided.24 Instituting behavioral change is difficult. Avoiding discussions regarding lifestyle change ensures lack of success. HRT can favorably affect OSAH, although the effect is modest.85 The current evidence indicates that the benefit of chronic HRT for the purpose of improving OSAH is outweighed by the potential risk of other medical complications.164-166 It is unknown whether alternative preparations or dosing regimens favorably modify these significant medical risks. Investigations using a murine model support the notion that residual daytime sleepiness can persist despite adequate control sleep-disordered breathing.120 Stimulants have been shown to improve daytime sleepiness in patients adequately treated with CPAP.122 There may be a temptation to treat sleepiness in OSA patients who do not adequately adhere to or refuse CPAP or bilevel therapy.167,168 The long-term impact on other important physiologic consequences (cardiovascular risk and the metabolic syndrome) of this treatment strategy is unproved, and it can mask a symptom that could motivate the patient to adhere to positive pressure therapy. Acknowledgments The research reported in this chapter is supported in part by National Heart, Lung, and Blood Institute Training Grant T32HL082610. ❖ Clinical Pearl Treatment of OSA is challenging in all age groups, but the treatment of OSA in the elderly presents unique challenges. If the patient is intolerant of positive pressure therapy, treatment options are often limited. Oral appliance therapy may be compromised by the lack an adequate number of teeth or lack of tolerance due to mouth discomfort. One possible approach is to combine oxygen via nasal cannula with elevating the head of the bed.43,44,169 Elevating the head of a hospital bed is usually well tolerated. Oxygen via nasal cannula is often easier to accept than positive pressure via a mask. Objective assessment of the response to therapy is advisable.
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84. Jordan AS, McEvoy RD. Gender differences in sleep apnea: epidemiology, clinical presentation and pathogenic mechanisms. Sleep Med Rev 2003;7:377-389. 85. Bixler EO, Vgontzas AN, Lin HM, et al. Prevalence of sleep-disordered breathing in women: effects of gender. Am J Respir Crit Care Med 2001;163:608-613. 86. Shahar E, Redline S, Young T, et al. Hormone replacement therapy and sleep-disordered breathing. Am J Respir Crit Care Med 2003;167:1186-1192. 87. White D. The hormone replacement dilemma for the pulmonologist. Am J Respir Crit Care Med 2003;167:1165-1166. 88. Motta J, Guilleminault C. Effects of oxygen administration in sleep-induced apneas. In: Guilleminault C, Dement WC, editors. Sleep apnea syndromes. New York: Alan R Liss; 1978. p. 137144. 89. Kimoff RJ, Cheong TH, Olha AE, et al. Mechanisms of apnea termination in obstructive sleep apnea. Role of chemoreceptor and mechanoreceptor stimuli. Am J Respir Crit Care Med 1994; 149:707-714. 90. Martin RJ, Sanders MH, Gray BA, et al. Acute and long-term ventilatory effects of hyperoxia in the adult sleep apnea syndrome. Am Rev Respir Dis 1982;125:175-180. 91. Gold AR, Schwartz AR, Bleecker ER, et al. The effect of chronic nocturnal oxygen administration upon sleep apnea. Am Rev Respir Dis 1986;134:925-929. 92. Strollo PJ Jr. Indications for treatment of obstructive sleep apnea in adults. Clin Chest Med 2003;24:307-313, vii. 93. Sanders MH, Rogers RM. Sleep apnea: when does better become benefit? Chest 1985;88:320-321. 94. Stamatakis K, Sanders M, Caffo B, et al. Fasting glycemia in sleep disordered breathing: lowering the threshold on oxyhemoglobin desaturation. Sleep 2008;31:1018-1024. 95. Punjabi NM, Newman AB, Young TB, et al. Sleep-disordered breathing and cardiovascular disease: an outcome-based definition of hypopneas. Am J Respir Crit Care Med 2008;177:1150-1155. 96. Hanly P, Sasson Z, Zuberi N, et al. ST-segment depression during sleep in obstructive sleep apnea. Am J Cardiol 1993;71: 1341-1345. 97. Franklin KA, Nilsson JB, Sahlin C, et al. Sleep apnoea and nocturnal angina. Lancet 1995;345:1085-1087. 98. Krieger J, Weitzenblum E, Monassier JP, et al. Dangerous hypoxaemia during continuous positive airway pressure treatment of obstructive sleep apnoea. Lancet 1983;2:1429-1430. 99. Sanders MH, Kern N. Obstructive sleep apnea treated by independently adjusted inspiratory and expiratory positive airway pressures via nasal mask. Physiologic and clinical implications. Chest 1990;98:317-324. 100. Piper AJ, Sullivan CE. Effects of short-term NIPPV in the treatment of patients with severe obstructive sleep apnea and hypercapnia. Chest 1994;105:434-440. 101. Martin T, Sanders M, Atwood C. Correlation between changes in Paco2 and CPAP in obstructive sleep apnea (OSA) patients. Am Rev Respir Dis 1993;147:A681. 102. Chauncey JB, Aldrich MS. Preliminary findings in the treatment of obstructive sleep apnea with transtracheal oxygen. Sleep 1990;13: 167-174. 103. Elmer JC, Farney RJ, Walker JM, et al. The comparison of transtracheal oxygen with other therapies for obstructive sleep apnea. Am Rev Respir Dis 1988;137:311A. 104. Farney RJ, Walker JM, Elmer JC, et al. Transtrachal oxygen, nasal CPAP and nasal oxygen in five patients with obstructive sleep apnea. Chest 1992;101:1228-1235. 105. McGinley BM, Patil SP, Kirkness JP, et al. A nasal cannula can be used to treat obstructive sleep apnea. Am J Respir Crit Care Med 2007;176:194-200. 106. Schmidt HS, Clark RW, Hyman PR. Protriptyline: an effective agent in the treatment of the narcolepsy-cataplexy syndrome and hypersomnia. Am J Psychiatr 1977;134:183-185. 107. Brownell LG, West P, Sweatman P, et al. Protriptyline in obstructive sleep apnea. A double blind trial. N Engl J Med 1982; 307:1037-1042. 108. Bonora M, St. John WM, Bledsoe TA. Differential elevation by protriptyline and depression by diazepam of upper airway respiratory muscle activity. Am Rev Respir Dis 1985;131: 41-45. 109. Smith PL, Haponik EF, Allen RP, et al. The effects of protriptyline in sleep-disordered breathing. Am Rev Respir Dis 1983;127:8-13.
110. Hanzel DA, Proia NG, Hudgel DW. Response of obstructive sleep apnea to fluoxetine and protriptyline. Chest 1991;100: 416-421. 111. Conway WA, Zorick F, Piccione P, et al. Protriptyline in the treatment of sleep apnoea. Thorax 1982;37:49-53. 112. Richmonds C, Hudgel DW. Hypoglossal and phrenic motoneuron responses to serotoninergic active agents in rats. Respir Physiol 1996;106:153-160. 113. Veasy SC, Panckeri KA, Hofman EA, et al. The effects of serotonin antagonists in an animal model of sleep-disordered breathing. Am Rev Respir Crit Care Med 1996;153:776-786. 114. Mendelson WB, Martin JV, Rapoport DM. Effects of buspirone on sleep and respiration. Am Rev Respir Dis 1990;141:1527-1530. 115. Garner SJ, Eldridge FL, Wagner PG, et al. Buspirone, an anxiolytic drug that stimulates respiration. Am Rev Respir Dis 1989; 139:946-950. 116. Horner RL. The neuropharmacology of upper airway motor control in the awake and asleep states: implications for obstructive sleep apnoea. Resp Res 2001;2:286-294. 117. Veasey SC. Pharmacotherapies for obstructive sleep apnea: how close are we? Current Opinion in Pulmonary Medicine 2001;7: 399-403. 118. Carley DW, Olopade C, Ruigt G, et al. Effect of mirtazipine in obstructive sleep apnea syndrome. Sleep 2007;30:35-41. 119. Engleman HM, Martin SE, Deary IJ, et al. Effect of continuous positive airway pressure treatment on daytime function in sleep apnoea/hypopnoea syndrome. Lancet 1994;343:572-575. 120. Veasey SC, Davis CW, Fenik P, et al. Long-term intermittent hypoxia in mice: protracted hypersomnolence with oxidative injury to sleep–wake brain regions. Sleep 2004;27:194-201. 121. Lyons TJ, French J. Modafinil: the unique properties of a new stimulant. Aviat Space Environ Med 1991;62:432-435. 122. Arnulf I, Homeyer P, Garma L, et al. Modafinil in obstructive sleep apnea–hypopnea syndrome: a pilot study in 6 patients. Respiration 1997;64:159-161. 123. Pack AI, Black JE, Schwartz JR, et al. Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea. Am J Respir Crit Care Med 2001;164:1675-1681. 124. Schwartz JR, Hirshkowitz M, Erman MK, et al. Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea: a 12-week, open-label study. Chest 2003;124:2192-2199. 125. Volkow ND, Fowler JS, Logan J, et al. Effects of modafinil on dopamine and dopamine transporters in the male human brain: clinical implications. JAMA 2009;301:1148-1154. 126. Hirshkowitz M, Black JE, Wesnes K, et al. Adjunct armodafinil improves wakefulness and memory in obstructive sleep apnea/ hypopnea syndrome. Respir Med 2007;101:616-627. 127. Bradley TD, Rutherford R, Grossman RF, et al. Role of daytime hypoxemia in the pathogenesis of right heart failure in the obstructive sleep apnea syndrome. Am Rev Respir Dis 1985;131:835-839. 128. Buda AJ, Schroeder JS, Guilleminault C. Abnormalities of pulmonary artery wedge pressures in sleep-induced apnea. Int J Cardiol 1981;1:67-74. 129. Findley LJ, Barth JT, Powers DC, et al. Cognitive impairment in patients with obstructive sleep apnea and associated hypoxemia. Chest 1986;90:686-690. 130. Fletcher EC, Lesske J, Quian W, et al. Repetitive, episodic hypoxia causes diurnal elevation of blood pressure in rats. Hypertension 1992;19:555-561. 131. Fletcher EC. The relationship between systemic hypertension and obstructive sleep apnea: facts and theory. Am J Med 1995;98: 118-128. 132. Guilleminault C, Connolly S, Winkle RA. Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol 1983;52:490-494. 133. He J, Kryger MH, Zorick FJ, et al. Mortality and apnea index in obstructive sleep apnea: experience in 385 male patients. Chest 1988;94:9-14. 134. Hla KM, Young TB, Bidwell T, et al. Sleep apnea and hypertension. Ann Int Med 1994;120:382-388. 135. Somers VK, Mark AL, Abboud FM. Potentiation of sympathetic nerve response to hypoxia in borderline hypertensive subjects. Hypertension 1988;11:608-612. 136. Somers VK, Mrk AL, Abboud FM. Sympathetic activation by hypoxia and hypercapnia—implications for sleep apnea. Clin Exp Hypertens 1988;A10(Suppl 1):413-422.
1232 PART II / Section 13 • Sleep Breathing Disorders 137. Zwillich C, Devlin T, White D, et al. Bradycardia during sleep apnea. Characteristics and mechanism. J Clin Invest 1982;69: 1286-1292. 138. Suratt PM, Turner BL, Wilhoit SC. Effect of intranasal obstruction on breathing during sleep. Chest 1986;90:324-329. 139. Lavie P, Fischel N, Zomer J, et al. The effects of partial and complete mechanical occlusion of the nasal passages on sleep architecture and breathing during sleep. Acta Otolaryngol 1983; 95:161-166. 140. Fairbanks DNF, Fairbanks DW. Obstructive sleep apnea: therapeutic alternatives. Am J Otolaryngol 1992;13:265-270. 141. Hoijer U, Ejnell H, Hedner J, et al. The effects of nasal dilation on snoring and obstructive sleep apnea. Arch Otolaryngol Head Neck Surg 1992;118:281-284. 142. Hoffstein V, Mateika S, Metes A. Effect of nasal dilation on snoring and apneas during different stages of sleep. Sleep 1993;16: 360-365. 143. Scharf MB, Brannen DE, McDonnold M. A subjective evaluation of a nasal dilator on sleep and snoring. ENT-Ear Nose Throat J 1994;73:395-401. 144. Kravath RE, Pollack CP, Borowiecki B. Hypoventilation during sleep in children who have lymphoid airway obstruction treated by nasopharyngeal tube and tonsillectomy and adenoidectomy. Pediatrics 1977;59:865-871. 145. Afzelius L-E, Elmqvist D, Hougaard K, et al. Sleep apnea syndrome—an alternative treatment to tracheostomy. Laryngoscope 1981;91:285-291. 146. Nahmias JS, Karetzky MS. Treatment of the obstructive sleep apnea syndrome using a nasopharyngeal tube. Chest 1988;94: 1142-1147. 147. Mezzanotte WS, Tangel DJ, White DP. Influence of sleep onset on upper airway muscle activity in apnea patients versus normal controls. Am J Respir Crit Care Med 1996;153:1880-1887. 148. Mezzanotte WS, Tangel DJ, White DP. Waking genioglossal EMG in sleep apnea patients versus normal controls (a neuromuscular compensatory mechanism). J Clin Invest 1992;89:15711579. 149. Suratt PM, McTier RF, Wilhoit SC. Upper airway muscle activation is augmented in patients with obstructive sleep apnea compared with that in normal subjects. Am Rev Respir Dis 1988;137:889-894. 150. Miki H, Hida W, Chonan T, et al. Effects of electrical stimulation during sleep on upper airway patency in patients with obstructive sleep apnea. Am Rev Respir Dis 1989;140:1285-1289. 151. Edmonds LC, Daniels BK, Stanson AW, et al. The effects of transcutaneous electrical stimulation during wakefulness and sleep in patients with obstructive sleep apnea. Am Rev Respir Dis 1992; 146:1030-1036. 152. Guilleminault C, Powell N, Bowman B, et al. The effect of electrical stimulation on obstructive sleep apnea. Chest 1995;107:67-73.
153. Goding GS, Eisele DW, Testrman R, et al. Relief of upper airway obstruction with hypoglossal nerve stimulation in the canine. Laryngoscope 1998;108:162-169. 154. Schwartz AR, Thut DC, Russ B, et al. Effect of electrical stimulation of the hypoglossal nerve on airflow mechanics in the isolated upper airway. Am Rev Respir Dis 1993;147:1144-1150. 155. Schwartz AR, Eisele DW, Hari A, et al. Electrical stimulation of the lingual musculature in obstructive slep apnea. J Appl Physiol 1996;81:643-652. 156. Schwartz AR, Bennett ML, Smith PL, et al. Therapeutic electrical stimulation of the hypoglossal nerve in obstructive sleep apnea. Arch Otolaryngol Head Neck Surg 2001;127:1216-1223. 157. Eisele DW, Smith PL, Alam DS, et al. Direct hypoglossal nerve stimulation in obstructive sleep apnea. Arch Otolaryngol Head Neck Surg 1997;123:57-61. 158. Oliven R, Tov N, Odeh M, et al. Interacting effects of genioglossus stimulation and mandibular advancement in sleep apnea. J Appl Physiol 2009;106:1668-1673. 159. Garrigue S, Bordier P, Jais P, et al. Benefit of atrial pacing in sleep apnea syndrome. N Engl J Med 2002;346:404-412. 160. Shalaby AA, Atwood CW, Hansen C, et al. Analysis of interaction of acute atrial overdrive pacing with sleep-related breathing disorder. Am J Cardiol 2007;99:573-578. 161. Simantirakis EN, Schiza SE, Chrysostomakis SI, et al. Atrial overdrive pacing for the obstructive sleep apnea–hypopnea syndrome. N Engl J Med 2005;353:2568-2577. 162. Simantirakis EN, Schiza SE, Siafakas NS, et al. Sleep-disordered breathing in heart failure and the effect of cardiac resynchronization therapy. Europace 2008;10:1029-1033. 163. Stanchina ML, Ellison K, Malhotra A, et al. The impact of cardiac resynchronization therapy on obstructive sleep apnea in heart failure patients. Chest 2007;132:433-439. 164. Nelson HD, Humphrey LL, Nygren P, et al. Postmenopausal hormone replacement therapy: scientific review. JAMA 2002;288: 872-881. 165. Nelson HD. Assessing benefits and harms of hormone replacement therapy: clinical applications. JAMA 2002;288:882-884. 166. Miller J, Chan BK, Nelson HD. Postmenopausal estrogen replacement and risk for venous thromboembolism: a systematic review and meta-analysis for the US Preventive Services Task Force. [erratum appears in Ann Intern Med 2003;138(4):360.]. Ann Intern Med 2002;136:680-690. 167. Black J. Pro: Modafinil has a role in management of sleep apnea. Am J Respir Crit Care Med 2003;167:105-106. 168. Pollak CP. Con: modafinil has no role in management of sleep apnea. Am J Respir Crit Care Med 2003;167:106-107. 169. Landsberg R, Friedman M, Ascher-Landsberg J. Treatment of hypoxemia in obstructive sleep apnea. [erratum appears in Am J Rhinol 2002;16(1):67]. Am J Rhinol 2001;15:311-313.
Positive Airway Pressure Treatment for Obstructive Sleep Apnea– Hypopnea Syndrome Peter Buchanan and Ronald Grunstein Abstract Continuous positive airway pressure (CPAP) is the treatment of first choice for obstructive sleep apnea–hypopnea syndrome. CPAP is almost always effective in this setting at an appropriately set pressure. The main limitations to CPAP use
Continuous positive airway pressure (CPAP) is now the established treatment in adults for obstructive sleep apnea– hypopnea (OSAH) syndrome (also regarded as essentially equivalent in this chapter to the terms obstructive sleep apnea [OSA] and OSA syndrome) and for some forms of central apnea. Because of its primacy in the treatment of OSAH, CPAP has also become the appropriate comparator in trials of other non-CPAP treatments of OSAH. Studies have provided information on different aspects of the efficacy, adherence, and use of CPAP therapy. In this chapter, these data are summarized, with an emphasis on the practical use of CPAP therapy in clinical management of patients with OSAH. Nasal CPAP therapy for obstructive sleep apnea in adults was first described in 1981,1 but it was not until about 1985 that it began to be more widely recognized as a clinically realistic form of long-term therapy. Although patients at that time needed to use an adhesive to attach the mask, the prompt relief of sleepiness led to an increasing number of users, and subsequently technical improvements were made in the design of the masks and pressure-delivery systems. Over the past 10 years, the evidence supporting the use of CPAP has improved both in quantity and quality, driven by the demands of government funding authorities and health maintenance organizations and by the availability of industry sponsorship with the increasing commercial success of the CPAP equipment.2 Studies to assess and validate a mechanical device such as CPAP are more difficult to design than the studies required for pharmaceutical registration or approval. Performing truly double-blind, randomized, controlled trials of CPAP treatment or variants is problematic. Sham CPAP by its nature has less efficacy on observable variables such as snoring and apnea, with consequent frustration of efforts to fully blind the study participants. Along similar lines, application of active and sham CPAP are associated with physically perceptible differences, further complicating the blinding process. The most recent phase in CPAP development has been the advent of automatically titrating CPAP devices (autotitrating CPAP), which has major implications for the delivery of health care to patients with sleep apnea and for the traditional relationship between sleep laboratory and patient. CPAP variants that employ expiratory pressure relief have also entered the market. It is important to
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are the patient’s acceptance and tolerance of treatment. Although newer modalities of CPAP, such as autotitrating CPAP, may have a role in selected patients and clinical situations, there need to be ongoing and increased efforts to develop new methods to maximize CPAP use.
ensure that use of all new devices for routine CPAP treatment are driven by evidence, not predominantly by marketing. CPAP is the gold standard of treatment for moderate to severe OSA; it may also be appropriate treatment for mild but symptomatic cases. However, many patients do not use it, or they use it irregularly. Comparative, intentionto-treat trials involving all degrees of severity of OSAH are needed to delineate therapy pathways and should focus on comparative treatments and how to obtain better acceptance of and adherence to treatment. The available data suggest that viable pharmacologic therapy for sleep apnea3-4 will not appear in the near future.
NASAL CONTINUOUS POSITIVE AIRWAY PRESSURE Mode of Action The original experiments with CPAP followed from the concept that closure of the oropharynx in OSAH syndrome results from an imbalance of the forces5 that normally keep the upper airway open (see Chapter 101). In the first description of CPAP use for treatment of OSAH in 1981,1 it was suggested that nasal CPAP acts as a pneumatic splint to prevent collapse of the pharyngeal airway (Fig. 107-1). This notion has been confirmed by a number of studies that either demonstrated the pneumatic splint by endoscopic or other imaging or that showed that CPAP does not increase upper airway muscle activity by reflex mechanisms.6 Detailed magnetic resonance imaging has confirmed that CPAP increases airway volume and airway area and reduces lateral pharyngeal wall thickness and the upper airway edema that result from chronic vibration and occlusion of the airway.7 In addition, recent data support the role of changes in lung volume increments, whether induced by CPAP or manipulated by experimental methodology (head-out rigid shell with adapted vacuum or blower attachment applying extrathoracic negative or positive pressure to the chest), in contributing to improved measured parameters of sleepdisordered breathing.8,9 It is believed that increasing lung volume enhances upper airway size and promotes stability via a caudal traction effect on the upper airway, and conversely, lung volume decrements provide an opposite effect. This lung volume effect can also contribute to the 1233
1234 PART II / Section 13 • Sleep Breathing Disorders SaO2% 100 75 Pn 10 (cm H2O) 0 EMGd
A
B
C
D
IN
EEG
Figure 107-1 Mechanism of upper airway occlusion and its prevention by nasal continuous positive airway pressure (CPAP). When the patient is awake (left), muscle tone prevents collapse of the upper airway during inspiration. During sleep, the tongue and soft palate are sucked against the posterior oropharyngeal wall (middle). CPAP with low pressure provides a pneumatic splint and keeps the upper airway open (right). (Adapted from Sullivan CE, Issa FG, Bethon-Jones M, et al. Reversal of obstructive sleep apnea by continuous positive airway pressure applied through the nares. Lancet 1981;1:862-865.)
Figure 107-3 Polygraphic records demonstrating prevention of central sleep apnea by continuous positive airway pressure (CPAP) applied through the nose. A, Note the presence of central apnea at a nasal CPAP of 2 cm H2O. B, Elevation of nasal CPAP to 6.6 cm H2O changes the apnea from a central to a mixed type. Further increase of nasal CPAP to 10 cm H2O (not shown) leads to a change in the apnea pattern from a mixed to an obstructive apnea. C, Loud, continuous snoring occurs when the nasal CPAP is elevated to 11.5 cm H2O. D, Finally, at a nasal CPAP of 14.5 cm H2O, the patient breathes with an open airway. EEG, electroencephalogram; EMGd, diaphragm electromyogram; IN, inspiration; Pn, nasal pressure; SaO2, arterial oxyhemoglobin saturation (scale, 100% to 75%); time scale is in seconds. Patient is in the supine position. (Adapted from Issa FG, Sullivan CE. Reversal of central sleep apnea using nasal CPAP. Chest 1986;90:165-171.)
Expiratory resistance Nosemask
Airflow
Mouth not obstructed
Figure 107-2 Diagram of method of applying continuous positive airway pressure by nose mask. (From Sullivan CE, Issa FG, Berthon-Jones M, et al. Home treatment of obstructive sleep apnea with continuous positive airway pressure applied through a nosemask. Bull Eur Physiopathol Respir 1984;20:49-54.)
relatively lower level of PAP pressure required in elderly OSA patients.10 For any positive airway pressure (PAP) device, the apparatus providing the pressure at the nasal airway must have the capacity to maintain the prescribed pressure during inspiration (Fig. 107-2). The simplest CPAP systems involve an air blower with sufficient pressure-flow characteristics to provide CPAP via a fixed resistive leak in the system (typically adjacent to the mask). CPAP and Central Apnea Regardless of the mechanism, nasal CPAP has been documented to be effective in eliminating both obstructive and mixed apneas.11 Some central apneas, particularly those observed in patients with predominantly obstructive events, are also eliminated by nasal CPAP (Fig. 107-3).11 Clearly, some central apneas are associated with increased upper airway resistance, and it could be argued that it is
better to consider apnea classification as being CPAP responsive or CPAP nonresponsive. CPAP might also be effective in central apneas associated with cardiac failure on the one hand12,13 but can elicit them in the context of the entity referred to as complex sleep apnea on the other (see later).
PRACTICAL ASPECTS OF TREATMENT Currently, most patients commence CPAP under supervision, usually in a sleep laboratory in a hospital or other facility. The purposes of the supervision are to ensure that the patient is appropriately educated about the therapy, to determine the best estimate of what will be the initially prescribed CPAP pressure, to determine the fit of the interface (mask), and to evaluate immediate acceptance or address problems (e.g., side effects, claustrophobia). Economic pressures within health systems, however, have challenged this approach, which is labor intensive and cost intensive, and caused movement toward less-intensive staffing or even home commencement of CPAP. Regardless of the location or method of CPAP titration, there is a need for proper assessment of the patient before initiating CPAP (to determine, for example, whether the patient has awake respiratory failure or marked hypoxemia in sleep), and this requires specific physician training and experience. There is no evidence for the safety and efficacy of CPAP titration outside of a medically supervised process.14 Current evidence supports the use of trained technologists to provide patient education, technical aspects of titration, and follow-up. However, data from small groups of patients has challenged the notion that close medical supervision is mandatory, and this issue should continue as an ongoing major research focus.15 Dominant determinants of CPAP use include the patient’s understanding of the therapy as well as willingness and ability to overcome practical aspects of using CPAP
CHAPTER 107 • Positive Airway Pressure Treatment for Obstructive Sleep Apnea–Hypopnea Syndrome 1235
Arterial oxygen saturation (%)
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Figure 107-5 Two-minute tracing of rapid eye movement (REM) sleep in a patient exhibiting persisting upper airway flow limitation. The second part of the flow tracing demonstrates chopped-off airflow.
A
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Figure 107-4 All-night recordings of arterial hemoglobin saturation in one of the earliest patients to use home continuous positive airway pressure (CPAP). Top, Control night. Bottom, CPAP trial night. Pink bar, non-rapid eye movement (NREM) sleep; blue bar, rapid eye movement (REM) sleep; open bar, awake. A CPAP of 7 cm H2O was applied at arrow A and continued for the rest of the night. (Adapted from Sullivan CE, Issa FG, Berthon-Jones M, et al. Reversal of obstructive sleep apnea by continuous positive airway pressure applied through the nares. Lancet 1981;1:862-865.)
(self-efficacy), its impact on symptoms, and close professional support, regardless of mask type, CPAP manufacturer, and mode of delivery. The First Night Sleeping with a nasal or other mask or interface and feeling the pressure sensation of CPAP is not necessarily uncomfortable, but it is a novel experience for the patient. Explanations, demonstration videos, and sessions for acclimating to the mask before beginning CPAP are routine in many centers. Education about CPAP reduces the patient’s anxiety and improves acceptance. Current evidence provides support for the benefit of more intensive patient education in CPAP use.14 On the first night of treatment, it is important to ensure that the pressure level that is identified as being most therapeutically effective is sufficient to prevent apnea, hypopnea, and associated oxyhemoglobin desaturation as well as respiratory-related arousals in all sleep stages experienced during the titration and in supine and lateral recumbent postures (Fig. 107-4). Thus, simply preventing apnea and hypopnea is not the endpoint of CPAP titration. It must be ensured that the airflow pressure tracing is normal and not chopped off or flow limited, (Fig. 107-5).2 It is important to correct flow limitation, because it can
indicate residual upper airway obstruction, potentially causing arousal and disrupting sleep.16 Studies have emphasized the importance of proper airflow measurement during CPAP titration using pressure-flow transducers rather than thermistors or other more indirect airflow measures.17 Proper airflow measurement can help determine the optimal pressure level by providing insights regarding the etiology of arousals—for example, whether they are related to respiratory events (respiratory-related arousals) and whether increasing pressure has a beneficial effect on sleep continuity. Although acute (single-night) studies suggest that correcting inspiratory flow limitations may be the preferred endpoint of CPAP titration, long-term data are sparse.18 When the correct pressure level is reached and the airway is optimally open, sleep should no longer be fragmented by repeated arousals, and there may be rebound (increased relative proportions) slow-wave and rapid eye movement (REM) sleep (Fig. 107-6).19 This rebound phase of recovery from severe sleep fragmentation lasts about a week, but the duration and intensity of these rebound sleep episodes decrease quickly after the first night of treatment.19 Other factors such as age and medication use might also be relevant determinants of sleep architectural patterns in such CPAP titration sleep studies. Continued frequent arousals can indicate that a critical level of upper airway resistance persists, especially if the arousals are associated with flow limitation. Persistent snoring is another sign of inadequate CPAP pressure; its specific elimination by titration strategies is supported to some additional degree by preliminary evidence that snoring alone (without the context of defined OHAHS) can contribute to cerebrovascular morbidity.20 Data demonstrate a hysteresis in the relationship between CPAP and upper airway resistance: higher pressures may be required to eliminate inspiratory airflow limitation during upward titration than with downward titration from higher pressures.21 For example, this means that a greater CPAP pressure may be required to render an airway open during the earlier, upward titration stages of a study than is required to maintain airway patency
1236 PART II / Section 13 • Sleep Breathing Disorders B
C
EOG EMG EEG 50 µV P (cm H2O)
10
A
0
3 min Figure 107-6 Recordings demonstrating the swift onset of rapid eye movement (REM) sleep soon after obstructive apnea was prevented by nasal continuous positive airway pressure (CPAP). Note that the onset of each episode of obstructive apnea (left side) is accompanied by fadeout on the electromyogram (EMG). Apneas were prevented when nasal CPAP was increased (arrow A). Note the fadeout of postural EMG activity (arrow B) preceding the changes in electroencephalogram (EEG) and electrooculogram (EOG) characteristic of REM sleep (arrow C). P, nasal airway pressure. (From Sullivan CE, Issa FG, BerthonJones M, et al. Pathophysiology of sleep apnea. In: Saunders NA, Sullivan CE, editors: Sleep and breathing. New York: Marcel Dekker; 1984. p. 299-364.)
later in the study. An up–down titration protocol (wherein the pressure is initially titrated upward to alleviate obstructive sleep-disordered breathing and then reduced to the lowest level at which such improvement is maintained) can thereby enable a somewhat lower recommended set pressure prescription in patients whose pressure requirement is high. Thus, with an up–down titration strategy for fixed-pressure CPAP, patients may start the night at home with the predetermined pressure and prevent obstructive events from developing at a somewhat lower pressure; while patients may receive an advantage from the hystersis gap, this titration method has not been systematically evaluated. Considering the length of time CPAP has been used to treat patients with OSAH, the published data on the variability in CPAP pressure requirement is sparse. Some evidence exists for higher pressure requirements with the supine posture22 and in REM sleep,23 and lower pressure in elderly patients.10 It appears that a pressure level accurately set on one night is generally effective on subsequent nights.24 Early research and clinical experience suggested that this was the case, but the use of autotitrating CPAP technology in the home has provided supporting evidence.25 For patients who report continued daytime sleepiness on home treatment despite an initially favorable CPAP titration and subsequent adequate adherence, it may be appropriate, at least as an initial intervention, to empirically increase CPAP pressure under the presumption that the laboratory study underestimated the pressure requirement. Causes of sleepiness other than OSAH might also need to be considered in this setting. Other factors can have an impact on the therapeutic efficacy of a given CPAP pressure in the home. Weight gain can lead to a need for a higher CPAP setting.26 Heavy (but not moderate) alcohol consumption can affect CPAP pressure, presumably because alcohol depresses upper airway neuromuscular
tone.27 Reasonable advice is to avoid all alcohol within a few hours of sleep, but if alcohol is to be taken within a few hours of sleep, the otherwise healthy patient should restrict consumption to modest levels, such as two standard alcohol drinks for men and one for nonpregnant women. It is also important to warn patients of likely adverse effects on sleep apnea of consuming excessive alcohol in the evening. Nasal congestion or a different posture in the home compared to during the CPAP titration can also lead to different pressure requirements, but this has not been well researched. Treatment of Decompensated Patients with Cardiorespiratory Failure Patients with severe carbon dioxide retention, heart failure, and extreme nocturnal hypoxemia (i.e., an arterial oxyhemoglobin saturation ≤50%) require close supervision when commencing CPAP. Such patients can have confusion at night, from delirium due to their blood gas derangement, that may be exacerbated by someone trying to attach a mask to their face. The nurse or technician attending the study must be aware that the patient might try to pull the mask off repeatedly throughout the night. After the first few nights, these patients typically settle down and sleep with CPAP without the need for intensive nursing. Previously, the therapy choice for these patients with chronic respiratory failure was tracheal intubation or tracheostomy. Intubation may still be an option; however, in trained hands, nasal CPAP or noninvasive ventilation (see Chapter 113) readily controls the breathing disturbance during sleep. Many of these patients have both upperairway obstruction and hypoventilation, and nasal CPAP might not be adequate to normalize gas exchange.28 Increasingly, the clinical approach in these patients is to employ bilevel positive pressure therapy. Autotitrating CPAP approaches are inappropriate in such patients. When possible, hospitalization would be the most reasonable approach in managing patients with severe CO2 retention resulting from a hypoventilation syndrome or chronic lung disease until studies showing the safety of non–hospital-based approaches in these patients are available. Many patients with milder forms of obesity hypoventilation syndrome may be able to be adequately titrated in a supervised laboratory setting with CPAP rather than with more complicated forms of ventilation.29 For patients with mild obesity hypoventilation syndrome this implies a facility to switch to an alternative form of ventilatory support (such as bilevel positive pressure) through the titration night when CPAP is inadequate in this setting (20% of patients in reference 29). CPAP on the Night Sleep Apnea Is Diagnosed? The Split-Night Study It has been suggested that CPAP treatment may be initiated on the same night the diagnosis is established.30,31 However, in these studies, patient selection was not randomized: split-night studies (with the first part of the night used for diagnosis and the second part for treatment) tended to be performed in patients who had more severe disease and had been waiting a shorter time for CPAP titration. Other studies have identified a subset of patients for whom a split-night study provided insufficient time for
CHAPTER 107 • Positive Airway Pressure Treatment for Obstructive Sleep Apnea–Hypopnea Syndrome 1237
CPAP titration to achieve a satisfactory prescription.32 Patients with milder degrees of sleep-disordered breathing (i.e., with an apnea–hypopnea index <20) in whom the titration was initiated later in the night (because prolonged monitoring was required to establish a diagnosis) were more likely to have unsuccessful split-night titrations. The American Academy of Sleep Medicine Positive Airway Pressure Titration Task Force has recognized the advantages and some limitations of split-night studies and has recommended (in a guideline) that such studies follow a titration algorithm similar to that for full-night titration studies.33 Thus, in brief, both full-night and split-night titration studies involve upward titration of CPAP pressure at increments of at least 1 cm of water over periods of at least 5 minutes according to the presence of obstructive breathing events and until a period of at least 30 minutes without such events is observed, to a maximum recommended pressure in adults of 20 cm H2O. Obviously, in a split-night study where the first 2 hours or more is used for diagnostic purposes, there is less time available to complete the titration process. In clinic populations of patients with high prevalence of OSAH symptoms and moderate to severe disease, the cost effectiveness of split-night studies has been demonstrated in modeled analyses.34,35 CPAP titration potentially can be accomplished during the day, but there have been few published studies of this approach.36 In one study, both daytime and nocturnal CPAP titration studies yielded sufficient amounts of REM and non-REM (NREM) sleep to help determine CPAP settings. The diurnal and nocturnal CPAP titrations resulted in comparable therapeutic pressures, resolution of sleep-disordered breathing, and adherence for 1 week. Split-night or day studies can appear attractive from a short-term, cost-saving point of view, but data in larger numbers of unselected patients in different health systems are required before this approach is widely accepted. In the meantime, data support split-night titration approaches in patients who have more severe disease but no significant comorbidities and in whom an accurate diagnosis is likely to be established in the first 2 to 3 hours of the study. It is possible that a combination of split-night diagnosistitration and subsequent home autotitration may be an adequate strategy, but as yet this is speculative. Commencement of CPAP at Home? Theoretically, it may be economically advantageous to start the first night of CPAP application at home and avoid altogether in-laboratory polysomnographic CPAP titration, but outcome studies showing true cost saving are not available. Current reviews and guidelines do not advocate home commencement of CPAP, particularly using autotitrating devices, across the full spectrum of severity of sleep-disordered breathing. It may be a justifiable clinical strategy, however, in patients who have a confirmed diagnosis of symptomatic, moderate to severe OSAH, who have no attendant significant medical or psychiatric comorbidities, who have had appropriate pre-CPAP education, and for whom an appropriate interface (mask) has been selected.37 This approach implies a major change in practice in sleep centers.
A number of studies have shown that an effective CPAP fixed pressure may be derived from data analysis of one or more unattended nights’ recording using autotitrating CPAP; generally, the effective pressure was determined by visual inspection and determination of the 90th percentile pressure from raw airflow data.38-40 One study observed poorer CPAP adherence in patients assessed only with respiratory monitoring,41 but this is not a universal finding.42 Other workers have found reasonable usefulness with unattended in-hospital CPAP titration but not in patients with significant underlying cardiorespiratory disease.43 Studies have shown equivalence of most outcomes up to 6 months after initiation of CPAP whether the set pressure was derived from in-laboratory techician-attended polysomnography (PSG), from unattended autotitrating CPAP for a number of nights with derivation of a set fixed pressure from data analysis of those nights, from autotitrating CPAP as initial and ongoing mode, or from formulaic prescription approaches.40,44-48 Limited advantage for autotitrating CPAP has been seen in a study in which endpoints such as fewer side effects, lower pressures, and patient preference were reported, but without difference in overall compliance or impact on measures of daytime sleepiness or quality of life.49 Importantly, mostly patients in these studies had moderate to severe OSAH, and the studies did not generally include patients with significant comorbidities. In addition, other interventions early in the studies were allowed to facilitate optimal CPAP use. Issues pertaining to the approach that involves an initial night or nights of autotitrating CPAP followed by fixed-pressure CPAP include the number of autotitration nights needed for best determination of effective CPAP set pressure, the percentile choice for effective pressure (90th, 95th, etc.), and device and algorithm specificity. Other studies have suggested that equations can be determined that would allow an empirical pressure level to be set, potentially obviating costs of pressure-determination studies but also potentially preventing the need for any investigation of CPAP efficacy.32 Recent data support this empirical method of CPAP titration instead of laboratory initiation.15,44 Data have also been presented, however, that demonstrate differences between various formulaic pressure level prescriptions and set pressures derived from autotitrating 95th percentile pressure.50 Predicted pressures based on an artificial neural network may be more accurate than regression equations.51 Long-term outcome data for this approach are lacking.
PROBLEMS AND SIDE EFFECTS Side effects reported by the patient are usually, but not exclusively, related to pressure or airflow or the mask–nose interface (Box 107-1). Side effects are important because patients with complaints in this regard use CPAP less often than those without side effects.52 A nonspecific sense of claustrophobia may be reported by patients, but this often involves mask or interface problems, nasal congestion, or exhalation difficulties. Dangerous complications of nasal CPAP therapy (e.g., pulmonary barotrauma, pneumocephalus, increased intraocular pressure, tympanic membrane
1238 PART II / Section 13 • Sleep Breathing Disorders Box 107-1 Side Effects of Nasal Continuous Positive Airway Pressure Nasal Effects Rhinorrhea Nasal congestion Oronasal dryness Epistaxis Mask Effects Skin abrasion or rash Conjunctivitis from air leak Flow-Related Effects Chest discomfort Aerophagia Sinus discomfort Claustrophobia Difficulty exhaling Pneumothorax (very rare) Pneumoencephaly (very rare) Other Problems Noise Partner intolerance Inconvenience
rupture, massive epistaxis, and subcutaneous emphysema after facial trauma) are extremely rare and represent isolated case reports in the literature.53 There are occasional case reports of peripheral edema developing after institution of CPAP.54,55 Mycobacterium gordonae pneumonia was reported in an immunocompromised kidney transplant patient who inadequately cleaned a home CPAP unit used to treat OSAH.56 Irritating side effects such as aerophagia and musculoskeletal chest discomfort (presumably related to increased lung volumes) have also been reported.53 Caution should be used when implementing CPAP therapy after neurosurgery or facial surgery or injury. Nasal Congestion Nasal congestion is a common side effect of CPAP therapy.53 Although most patients experience initial selflimiting nasal congestion, at least 10% complain of persistent nasal stuffiness to some degree after 6 months of therapy.57 There appear to be many reasons for nasal symptoms. CPAP can provoke pressure-sensitive mucosal receptors, leading to vasodilation and mucus production. In some patients, it can unmask allergic rhinitis by restoring the nasal route of breathing after years of mouth breathing. In others, administration of positive airway pressure in the presence of fixed nasal obstruction with polyps or a deviated septum can produce symptoms. Mouth leaks also cause increased nasal resistance, probably by exposing the nasal mucosa to higher flows and reduced relative humidity.58 Treatment of nasal congestion depends on the cause. Mouth leak may be minimized if an incorrectly high CPAP pressure is down-adjusted. Sometimes it is necessary to use a chin strap to minimize mouth leak. These are often
uncomfortable, and acclimation to this accessory is often necessary. Heated, rather than cold, pass-over humidification is best suited to increase the relative humidity and may be used to treat nasal congestion.58,59 Nasal congestion can be treated with antihistamines, topical steroids, or topical saline sprays, and heated humidification of the circuit improves nasal, mouth and throat dryness.60 Intranasal ipratropium bromide can be helpful in abating CPAP-induced rhinorrhea. However, there is no evidence for the routine use of humidification to improve CPAP adherence.61 Nasopharyngoscopy should be performed in patients with persistent symptoms of nasal congestion or those with obvious nasal obstruction, and these patients might require corrective surgery for an obstructive lesion such as a polyp, marked mucosal thickening, or deviated septum. There is some limited evidence of benefit from such intervention in improving CPAP compliance.62-64 Estimating nasal resistance or minimal cross-sectional area before initiating CPAP can identify OSA patients at increased risk of difficulties using CPAP.65 Full-face (oronasal) or oral masks may also be of value in managing patients with nasal side effects.66 Interface Interface technology has improved greatly, and this is important because comfort remains a pivotal influence on CPAP acceptance and adherence (Video 107-1). Poorly fitting interfaces permit air leakage, and the resultant drop in pressure leads to persistent OSAH and sleep fragmentation. Leak may be the source of considerable discomfort; and if it is directed toward the eye it can cause conjunctivitis and other anterior segment problems.67,68 A potential problem with a poorly fitting mask is the development of bruising or even ulceration of the bridge of the nose. Few studies compare different mask and other interface design types despite the ongoing availability of new designs.69 Anecdotally, the newer generation of mask types appears to be associated with fewer fit problems. Nevertheless, certain patients become claustrophobic when using nasal CPAP with any mask. Changing the interface prescription from a nasal mask to the less-confining nasal prongs or pillows can correct that problem. However, nasal prongs can cause irritation in the nares, there may be a relatively low upper limit to the set pressure able to be used effectively with nasal prongs, and long-term use data are needed. It also must be acknowledged that although newer interfaces are constantly being developed, for some patients, particularly those who are younger with mild disease, aesthetic problems with CPAP regardless of interface preclude acceptance of this treatment modality. An infrequent but difficult problem is the patient who has no upper front teeth. The upper teeth provide the rigid structure against which the lower part of a nasal mask can be pulled. If there is no dentition, the mask simply rolls around the top gums into the mouth, with loss of an adequate seal. The problem may be rectified by providing a denture70 or possibly an oronasal mask. Pressure Level and Airflow Although the pressure delivered by the CPAP apparatus is often mentioned as a potential problem, there is no
CHAPTER 107 • Positive Airway Pressure Treatment for Obstructive Sleep Apnea–Hypopnea Syndrome 1239
convincing evidence that it actually impairs adherence (see “Autotitrating CPAP,” later). Some patients complain of initial increased resistance to exhalation or the sensation of too much pressure in the nose. For these patients, a CPAP unit with a ramp feature allows the pressure to increase to the optimal CPAP pressure gradually over a set time interval (usually set up to 30 minutes), allowing an initial lower, more tolerable pressure level during the last vestiges of wakefulness and then with full set pressure applied after sleep onset. No studies have been performed to show that any use of the ramp feature improves acceptance or adherence with CPAP; however, an interesting case of “ramp abuse” has been reported, in which continuous reapplication of the ramp function by the patient led to undertreatment of sleep apnea.71 Alternatively, a bilevel positive pressure system, in which inspiratory positive airway pressure and expiratory positive airway pressure can be adjusted independently, may be used, because this approach lowers mean airway pressure and resistance to expiration. Limited data indicate that routine use of bilevel devices does not affect the number of hours of use of positive pressure in patients with OSAH.72,73 However, in selected patients with poor CPAP adherence, the use of a novel flexible bilevel positive pressure device has been shown to enhance treatment use.74 Bilevel pressure may also be more acceptable to patients with chronic lung or chest wall diseases who also have OSAH, but this has not been studied systematically. Some, but not all, patients with obesity hypoventilation syndrome require bilevel positive pressure to control sleep-disordered breathing.29 A novel type of CPAP with modification of the expiratory pressure-time profile has become available, but there is no evidence of increased patient adherence using this modality.75-77 Patients occasionally find the air generated by the CPAP unit too warm or too cold. If moving the machine from the floor to a bedside table, heating the bedroom, or placing tubing under the blankets does not correct the problem, incorporating a heated humidifier into the circuit can help. If patients prefer a cooler room temperature for sleep with CPAP, addition of a heated breathing tube humidifier may be advantageous to avoid excessive tube condensation.78 Bed partners might also experience cold air on their bodies from the expiratory port of the device. Another complaint, also usually from the bed partner, is that the CPAP machine generates too much noise. Removing the machine from the bedside or placing it in a closet can remedy the problem. Extra tubing may be needed, and it is important to recheck pressures if nonstandard tubing is used. Noise or a changing level of noise may be a problem in some autotitrating CPAP devices because of the nature of their motors. Modern CPAP machines incorporate automatic altitude compensation with the intention that effective pressures are delivered in varying altitude locations. Comparison with Other Treatments Compared with other treatments, one of the great advantages of nasal CPAP is that it is almost immediately and demonstrably effective in relieving OSAH.1,79 Another is that it can be offered on a trial basis and withdrawn if not
tolerated, in contrast to surgical options. This is particularly important in milder cases of OSAH, or where the contribution of OSAH to the patient’s symptomatology is unclear. There is some evidence, however, that CPAP is not a perfect treatment of OSAH, even in adherent patients. One study estimated overall treatment effectiveness of CPAP of approximately 50%.80 In a recent study, the 17% of patients using CPAP but with persistent OSAH manifested a number of factors (mask leak, relatively low nightly use, high body mass index, and high pressure requirement) linked to suboptimal treatment.81 A few studies have attempted to compare CPAP with other treatments for OSAH using formal protocols. The conclusion of most of these studies is that CPAP is the appropriate first-line therapy for patients with moderate to severe sleep apnea.82-84 However, well-designed comparisons of CPAP and dental splints have not been made in this patient group. Other treatment options are described in detail elsewhere in this volume.
ADHERENCE General Issues In terms of mechanical therapies, adherence may be interpreted in different ways (see later). More accurate adherence measurements are possible with modern PAP devices (with data-capturing technology) than with medications. At least 40% to 50% of patients do not use oral medications and inhalers as prescribed.85 In general, the degree of adherence is not associated with age, sex, educational level, economic status, or personality or with the characteristics of a disease, including diagnosis, severity, or frequency of symptoms. In general, physicians cannot predict which of their patients will be adherent.86 Several factors are generally associated with improved adherence.86 These include simplicity of the regimen, family support, the patient’s perception that the disease is serious, a belief that the proposed therapy will be effective, the patient’s understanding of the rationale of treatment, provision of accurate details of the treatment planned, and a close patient-clinician relationship, including close clinician supervision of therapy. Adherence and CPAP In assessing the long-term results of CPAP, a variety of terms have been used to describe the interaction between the patient and CPAP (Table 107-1). The criteria set for the terms can vary: for example, good adherence for one group may be 6 hours of CPAP, 6 nights per week, whereas for others, such criteria may be too strict. Effective adherence measured in average hours of nightly use for one outcome measure may be different from another.87 More recent studies measure CPAP use or adherence using time meters or more sophisticated devices that measure run time and pressure delivery. True efficacy studies have yet to be performed, because they would need to measure total sleep time over a set period and compare this with CPAP use and the actual number of respiratory events not prevented by CPAP. Nevertheless, when looking at all the CPAP use data currently available, adherence with CPAP devices compares favorably with use of medication.
1240 PART II / Section 13 • Sleep Breathing Disorders Table 107-1 Suggested Terminology for Patient Interaction with Continuous Positive Airway Pressure TERM
DEFINITION
Acceptance
Patient meets selection criteria for CPAP treatment and actually proceeds to have CPAP pressure level determined
Prescription
Patient accepts CPAP and commences home treatment
Adherence
Patient is prescribed CPAP and reports continuing use of CPAP
Tolerance
Patient reports ability to use CPAP without side effects (term used interchangeably with adherence)
Use
Patient’s CPAP machine is switched on more than an arbitrary period of time
Compliance
Patient uses CPAP machine and it delivers a preset level (i.e., the mask is likely to be on the patient’s face)
Several factors can affect CPAP adherence, including machine cost, technical advances in equipment, and prescriber motivation. In some countries, machines are provided without direct-to-patient cost, whereas in others, the cost to a patient varies between $1000 and $3000. This can lead to variable prescription and acceptance of the therapy. In addition, there have been rapid changes in CPAP technology. Current machines are quieter, and most now have an optional ramp facility to slowly increase the pressure near sleep onset. In addition, newer machines can offer the option of reduced pressure during a portion of the expiratory phase, although there is no evidence that routine prescription of this modification improves adherence. Also, as previously noted, interface comfort has apparently been improving. Many older CPAP use studies employed equipment that has been replaced by newer devices, and adherence data need to be continually updated to verify whether these technical changes actually influence CPAP use or become, in effect, merely cosmetic marketing ploys. Must patients use CPAP all night every night to receive beneficial therapeutic effects? Average CPAP use of less than 4 hours per night produces a demonstrable reduction in sleepiness.88 Some sleep apnea patients use CPAP for only part of the night because they derive a satisfactory degree of symptomatic benefit from that limited application.83 This may reflect interindividual variation in function with sleep loss or fragmentation.89 Studies have shown that 1 night off CPAP in adherent CPAP users led to a recurrence in daytime sleepiness.90,91 Despite some studies showing apparent benefit from relatively low levels of average nightly use,92,93 data support the contention of a dose-response effect of increasing hours of nightly CPAP use on subjective and objective sleepiness and other functional outcomes.87,94 At this stage, all criteria set in published data for CPAP use or nonuse, or adherence or nonadherence, are essentially arbitrary.88,95 Pending further data, it would seem reasonable for clinicians to recommend maximum nightly use of CPAP by all
patients but accept that patients can derive some benefit from submaximal nightly use. Studies of CPAP Use Patient Acceptance of and Agreement to Prescription of CPAP Limited data are available on patient acceptance of CPAP, because most studies discuss patient data only from the night of CPAP pressure determination or later. Data suggest that 70% of patients offered a CPAP trial night accepted it.84 It is unknown how many people with, for example, moderate to severe obstructive sleep apnea avoid even consulting a physician, or seek referral to surgeons or dentists because they have already decided not to accept the concept of CPAP. Long-Term Use of CPAP Covert objective monitoring of nasal CPAP has demonstrated that adherence is substantially lower than that seen in studies where adherence is reported on the basis of subjective patient data.95 The covert objective monitoring revealed that only 46% of patients used nasal CPAP 4 hours or longer for 70% of the observed nights. Adherence at 1 month predicted adherence at 3 months.95,96 Other studies have generally confirmed this degree and pattern of use.97,98 Follow-up studies of CPAP cohorts are biased by the same factors that affect clinical trials of pharmaceuticals. Patient populations are often highly selected for lack of comorbidity, intellectual capacity, geographic access, and health consciousness— all factors that can affect adherence in the real world. Larger, more open studies from a variety of sleep clinics97 would provide better information on true CPAP adherence. Baseline Indicators That Predict CPAP Use Several studies have confirmed that severity of symptoms has a major impact on continuing use of CPAP—that is, patients with good objective use or reported adherence were sleepier at baseline.53,95,97,99,100 Baseline multiple sleep latency test (MSLT) scores do not appear to predict CPAP adherence. It is controversial whether degree of improvement in MSLT scores can predict adherence.95,99 Sleep fragmentation measured by an electroencephalographic neural network analysis or movement events on video recordings is reasonably correlated with CPAP adherence.101 Improved adherence has also been linked to the higher degree of improvement in sleep efficiency and quality between diagnostic and treatment studies.102 Other factors that may be related to reduced use include previous palatal surgery103 and socioeconomic and ethnic status.104,105 Having a higher pressure level has not had a negative impact on adherence.5,14,15,53 In fact, it may be associated with better adherence, although these data could be confounded by more marked symptoms in patients requiring higher pressures.97 If nasal or other upper airway anatomic pathology is suspected to be impairing CPAP adherence, appropriate assessment and treatment of such might lead to improved use of CPAP (see the earlier discussion of nasal congestion). The patient’s perception of the risk of the illness, perception of treatment benefit, and volition to use the
CHAPTER 107 • Positive Airway Pressure Treatment for Obstructive Sleep Apnea–Hypopnea Syndrome 1241
therapy, formed during the first week of treatment, also affect subsequent adherence,106,107 as does the use of active coping mechanisms to overcome practical obstacles to successful ongoing use of CPAP.108 Motivation Supplied by Clinician Various studies have shown the value of patient education, but it is unclear how much education and support is necessary to improve adherence.14,15,109 There has been a recognition that education, instruction, and support in various forms likely aids CPAP adherence, but there is no clear agreement of how much and in what specific form such additions to the mechanical therapy of CPAP should take.110 A promising form of group cognitive behavior therapy before initiation of CPAP (Video 107-2) has been demonstrated to have positive advantage in a randomized, controlled trial (Fig 107-7).111
AUTOTITRATING CPAP The aims of autotitrating CPAP devices are to detect and prevent, virtually simultaneously, upper airway obstruction using the lowest possible pressure level at any given time during the night.112 If pressure requirements vary with changes in upper airway resistance (due for example to nasal obstruction or use of alcohol or sedatives), then an autotitrating CPAP machine would, in theory, adjust to these changes, unlike a fixed-pressure machine. It was hoped that this would reduce the average overnight pressure level, with consequent improvement of adherence.
1
7 6
0.88
5.9
0.9
5.38
0.8
0.77
0.7 0.6
4 3
0.5 2.97
2.51
2
0.5
0.39
0.4
0.31
0.3 0.15
1
Proportion
Hours
5
0.2 0.1
0
M us ean ag ni e o gh ve tly r 7 CP d A M (ho ays P us ean urs ag n ) e o ig ve htly r2 C 8 P (h da AP ou ys ≥4 Pro rs ho por ) ur tio s/ n ni us gh in ta g t 7 CP ≥4 Pr da AP ho opo ys ur rti s/ on ni gh us t a ing t2 C ≥6 Pr 8 PA da P ho opo ys ur rti s/ on ni gh us t a ing t2 C 8 PA da P ys
0
CBT hours
TAU hours
CBT proportion
TAU proportion
Figure 107-7 Effect of cognitive behavioral therapy (CBT) on continuous positive airway pressure (CPAP) use in a randomized, controlled trial. In this study, 100 patients were randomly assigned to CPAP with treatment as usual (TAU) or CPAP with a CBT intervention, and with measured mask-on time at 7 and 28 days the outcomes of interest. P values are highly significant (<.0005) for all outcomes presented. (Adapted from Richards D, Bartlett DJ, Wong, K et al. Increased adherence to CPAP with a group cognitive behavioral treatment intervention: a randomized trial. Sleep 2007;30(5):635-640.)
An overnight tracing from one such device is shown in Figure 107-8. Economic benefits could also accrue if autotitrating CPAP reduced technician time, eliminated in-laboratory polysomnography for CPAP titration, or reduced clinic visits of patients with CPAP adherence problems. However, a meta-analysis of randomized trials comparing autotitrating CPAP with fixed-pressure CPAP concluded that although notable for heterogeneity of methods and subject inclusion, there were no differences in hours of nightly use, despite a mean decrease in overnight pressure of 2 cm H2O.113 These subjects were mostly men with moderate to severe OSAH, mostly CPAP-naïve, and without significant comorbidities, sleep hypoventilation, or central sleepdisordered breathing. More recent studies have not altered the overall conclusion of the meta-analysis.114 Given the current costs of autotitrating CPAP devices, there is no rationale at this stage for the use of autotitrating CPAP as the standard initial home device replacing the cheaper, fixed-pressure CPAP.113 Based on currently available evidence, the American Academy of Sleep Medicine suggests the long-term use of autotitrating CPAP in self-adjusting mode to treat OSAH as an option only.37 Autotitrating CPAP might have a role in replacing in-laboratory titration of CPAP, but this needs to be further tested in large studies that evaluate cost versus utility, that look at a wide range of unselected patients, and that compare in-laboratory titration with empirical home treatment.39,40,42,113,115 This strategy also remains as an option in current guidelines of the American Academy of Sleep Medicine.37 Autotitrating CPAP is not without potential problems such as overcompensation for mask or mouth leaks, with resultant unnecessarily high pressures (Fig. 107-9). Other potential problems include undertreatment because of slow or inadequate responses to airway obstruction, the presence of central apnea (including central apnea that becomes evident after adequate correction of obstructive events: complex sleep apnea) or hypoventilation (Fig. 107-10). Autotitrating CPAP does not appear to easily correct the flow limitation caused by acute nasal congestion.116 Finally, it is important to recognize that data from studies investigating one type of autotitrating CPAP machine cannot necessarily be extrapolated to other autotitrating devices. Bench testing has demonstrated substantial variation in performance across different manufacturers (and presumably different algorithms).117,118
MANAGEMENT OF CPAP FAILURE Although it is a simple concept that CPAP failure may result from inadequate adherence, or an inadequate treatment response (to adequate adherence), what constitutes CPAP failure in clinical practice is a subjective issue, and practice varies from center to center in the absence of hard data addressing the diverse health consequences of varying degrees of sleep apnea. For instance, CPAP failure has been defined as the “use of CPAP for less than 4 hours per night on 70% of the nights and/or lack of symptomatic improvement.”95 This calculation equates to an average of 2.7 hours of use per night, but it was essentially an arbitrary figure based on the
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Figure 107-8 Autotitrating continuous positive airway pressure (CPAP) tracing of a patient with severe obstructive sleep apnea before (A) and during (B) nasal CPAP treatment. In B, CPAP level varies automatically to prevent flow limitation (denoted by an arbitrary index based on flattening of the shape of the inspiratory flow curve) and apneas.
authors’ expert clinical opinion.95 The existence of a doseresponse relationship between hours of CPAP use and measured benefit, and varying for the measured endpoint, makes the concept of CPAP treatment success or failure more complex. An attempt should be made to identify cause(s) when there is CPAP failure. Some common side effects and
potential solutions have been mentioned. Ear, nose, and throat assessment may be appropriate in looking for any structural reasons to explain CPAP failure. Other considerations include misdiagnosis and coexisting causes of sleepiness.119 In summary, any treatment algorithm for moderate to severe OSAH needs to be individualized in clinical
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CHAPTER 107 • Positive Airway Pressure Treatment for Obstructive Sleep Apnea–Hypopnea Syndrome 1243
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Figure 107-9 Autotitrating continuous positive airway pressure (CPAP) tracing from one device demonstrating persisting apneas with constant increase in pressure in the presence of a mask leak (roughly circled areas). The pressure rises over a 22-minute period from 6 cm to nearly 20 cm, eventually resulting in the patient’s attempting to pull the mask off and a drop in pressure.
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CHAPTER 107 • Positive Airway Pressure Treatment for Obstructive Sleep Apnea–Hypopnea Syndrome 1245
practice. Non-PAP alternatives need to be discussed in selected patients in a timely manner. Appropriate attention to modifiable risk factors and comorbidities should form part of the treatment approach. Positive airway pressure treatment in the form of fixed-pressure CPAP will be the best option for most patients, where this is possible, with careful laboratory-based titration packaged with education and early and ongoing support providing important ancillary elements. Other PAP modalities such as autotitrating CPAP may have a useful role in providing a titration fixed pressure outside the laboratory context or in helping to troubleshoot adaptation difficulties, or it may be a convenient modality in patients in whom significant weight loss is anticipated. Patient preference for autotitrating CPAP likely comes at increased financial cost. There is a limited role for bilevel positive pressure in patients who have failed rigorous attempts to use CPAP effectively.74
COMPLEX SLEEP APNEA Since the first edition of this book it has been reported that central sleep apneas occasionally emerge with CPAP titration of sleep-disordered breathing.120,121,121a,122 This phenomenon has been referred to as complex sleep apnea, although in some reports CPAP treatment failure of varying cause might have been included under that descriptor.123 Complex sleep apnea can occur in patients on opiates.121a Complex ventilatory support (e.g., with adaptive servoventilation) has been proposed as appropriate treatment for such cases of complex sleep apnea that do not respond to CPAP.124 Adaptive servoventilation (ASV) provides both positive airway pressure support to overcome obstructive events during stable breathing when there is adequate respiratory drive and, using an algorithm based on analysis of preceding breathing pattern, introduces a mode of inspiratory and expiratory ventilatory support to maintain a steady minute ventilation when central apneas evolve. Limited data in small numbers of patients suggest although both modes are beneficial in these circumstances, ASV may be superior to bilateral positive pressure support in these patients.125 Others have argued that in most circumstances such central sleep apneas resolve spontaneously with time and continued use of CPAP.126 The reality of the complex sleep apnea phenomenon can only be adequately addressed by an appropriately designed randomized, controlled trial. HEALTH OUTCOMES AND NASAL CPAP Since the turn of the century, a number of randomized, controlled trials have demonstrated that CPAP is effective in improving neurobehavioral outcomes such as daytime sleepiness or improving systemic blood pressure in patients with moderate to severe OSAH.100,127-129 Cardiovascular events may be prevented with effective treatment in middle-aged men with OSAH of varying but usually at least moderate severity.93,130,131 CPAP may improve com orbid depression in OSAH.131a A detailed discussion of neurocognition and performance in OSAH is provided in Chapter 104.
Importantly, from data that have a variety of methodologic limitations but converging implications, motor vehicle crashes are reduced in patients with severe OSAH who use CPAP.132-134 Data also show that health care utilization generally decreases after uptake of CPAP treatment in women and men with moderate or severe OSAH, although in one study in men that advantage was nullified if preexisting ischemic heart disease was present at time of diagnosis of OSAH.135-137 Other data based on assessments using analysis of cost-effectives support the economic advantage of diagnosing and treating OSAH.138,139 The evidence for benefit from treating OSAH is less clear in patients with more severe disease who do not report sleepiness99 and in patients with mild disease,140 and the treatment for the asymptomatic patient with milder disease remains controversial.141-143
CPAP AND HEART FAILURE Sleep apnea is common in patients with cardiac failure (see Chapter 121).144 Use of nasal CPAP for 1 month145 and 3 months146 in patients with OSAH and heart failure leads to improvement in left ventricular function. Additionally CPAP treatment in patients with heart failure and central sleep apnea has been associated with improved mitral regurgitant fraction, improved secretion of atrial natriuretic factor, improved inspiratory muscle strength, reduced left ventricular afterload, increasing Paco2 (toward normal), and decreasing norepinephrine concentrations.147 However, results of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure (CANPAP) trial, although confirming small physiologic changes with active treatment, showed no advantage on survival or heart transplant–free interval in such patients treated with CPAP.13 However, subsequent post hoc subgroup analysis demonstrated improved left ventricular function and transplant-free survival in patients if CPAP effectively suppressed central sleep apnea soon after CPAP initiation.148 ASV is likely preferable in these patients.149,150 Acknowledgments Dr. Grunstein is supported by a Practitioner Fellowship, and Dr. Buchanan and Dr. Grunstein are supported by a Clinical Centre of Research Excellence Grant from the National Health and Medical Research Council of Australia. Thanks to Kate Strang for assistance with Figure 107-7. ❖ Clinical Pearl CPAP is the standard form of treatment for patients with moderate to severe symptomatic OSAH syndrome or forms of central sleep apnea that respond to CPAP. Correction of inspiratory flow limitation appears to be the most practical and effective endpoint for titrating pressure. Severe side effects are rare, but nasal and mask problems can limit adherence. Adherence varies from 40% to 80%, depending on the study, and is probably influenced by the degree to which education and support are provided to the patient. Randomized, controlled studies have provided an evidence-based rationale for CPAP treatment.
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71. Pressman MR, Peterson DD, Meyer TJ, et al. Ramp abuse. A novel form of patient noncompliance to administration of nasal continuous positive airway pressure for treatment of obstructive sleep apnea. Am J Respir Crit Care Med 1995;151:1632-1634. 72. Reeves-Hoche MK, Hudgel DW, Meck R, et al. Continuous versus bilevel positive airway pressure for obstructive sleep apnea. Am J Respir Crit Care Med 1995;151:443-449. 73. Gay P, Weaver T, Loube D, Iber C. Evaluation of positive airway pressure treatment for sleep related breathing disorders in adults. Sleep 2006;29:381-401. 74. Ballard RD, Gay PC, Strollo PJ. Interventions to improve compliance in sleep apnea patients previously non-compliant with continuous positive airway pressure. J Clin Sleep Med 2007;3: 706-712. 75. Gay PC, Herold DL, Olson EJ. A randomized, double-blind clinical trial comparing continuous positive airway pressure with a novel bilevel pressure system for treatment of obstructive sleep apnea syndrome. Sleep 2003;26:864-869. 76. Nilius G, Happel A, Domanski U, Ruhle KH. Pressure-relief continuous positive airway pressure vs constant continuous positive airway pressure: a comparison of efficacy and compliance. Chest 2006;130:1018-1024. 77. Mulgrew AT, Cheema R, Fleetham J, et al. Efficacy and patient satisfaction with autoadjusting CPAP with variable expiratory pressure vs standard CPAP: a two-night randomized crossover trial. Sleep Breath 2007;11:31-37. 78. Nilius G, Domanski U, Franke KJ, Ruhle KH. Impact of a controlled heated breathing tube humidifier on sleep quality during CPAP therapy in a cool sleeping environment. Eur Respir J 2008;31:830-836. 79. Lojander J, Maasilta P, Partinen M, et al. Nasal-CPAP, surgery, and conservative management for treatment of obstructive sleep apnea syndrome. A randomized study. Chest 1996;110:114-119. 80. Grote L, Hedner J, Grunstein R, Kraiczi H. Therapy with nCPAP: incomplete elimination of sleep related breathing disorder. Eur Respir J 2000;16:921-927. 81. Baltzan MA, Kassissia I, Elkholi O, et al. Prevalence of persistent sleep apnea in patients treated with continuous positive airway pressure. Sleep 2006;29:557-563. 82. Grunstein RR, Handelsman DJ, Lawrence SJ, et al. Neuroendocrine dysfunction in sleep apnea: reversal by continuous positive airways pressure therapy. J Clin Endocrinol Metab 1989;68:352358. 83. Hers V, Liistro G, Dury M, et al. Residual effect of nCPAP applied for part of the night in patients with obstructive sleep apnoea. Eur Respir J 1997;10:973-976. 84. Rauscher H, Popp W, Wanke T, Zwick H. Acceptance of CPAP therapy for sleep apnea. Chest 1991;100:1019-1023. 85. Rand CS, Wise RA, Nides M, et al. Metered-dose inhaler adherence in a clinical trial. Am Rev Respir Dis 1992;146:1559-1564. 86. Haynes R, Taylor D, Sackett D. Compliance in health. Baltimore: John Hopkins University Press; 1979. 87. Weaver TE, Maislin G, Dinges DF, et al. Relationship between hours of CPAP use and achieving normal levels of sleepiness and daily functioning. Sleep 2007;30:711-719. 88. Engleman HM, Martin SE, Deary IJ, Douglas NJ. Effect of continuous positive airway pressure treatment on daytime function in sleep apnoea/hypopnoea syndrome. Lancet 1994;343:572-575. 89. Van Dongen HP, Maislin G, Dinges DF. Dealing with interindividual differences in the temporal dynamics of fatigue and performance: importance and techniques. Aviat Space Environ Med 2004;75:A147-A154. 90. Kribbs NB, Pack AI, Kline LR, et al. Effects of one night without nasal CPAP treatment on sleep and sleepiness in patients with obstructive sleep apnea. Am Rev Respir Dis 1993;147:1162-1168. 91. Yang Q, Phillips CL, Melehan KL, et al. Effects of short-term CPAP withdrawal on neurobehavioral performance in patients with obstructive sleep apnea. Sleep 2006;29:545-552. 92. Barnes M, McEvoy RD, Banks S, et al. Efficacy of positive airway pressure and oral appliance in mild to moderate obstructive sleep apnea. Am J Respir Crit Care Med 2004;170:656-664. 93. Campos-Rodriguez F, Pena-Grinan N, Reyes-Nunez N, et al. Mortality in obstructive sleep apnea–hypopnea patients treated with positive airway pressure. Chest 2005;128:624-633.
1248 PART II / Section 13 • Sleep Breathing Disorders 94. Zimmerman ME, Arnedt JT, Stanchina M, et al. Normalization of memory performance and positive airway pressure adherence in memory-impaired patients with obstructive sleep apnea. Chest 2006;130:1772-1778. 95. Kribbs NB, Pack AI, Kline LR, et al. Objective measurement of patterns of nasal CPAP use by patients with obstructive sleep apnea. Am Rev Respir Dis 1993;147:887-895. 96. Weaver TE, Kribbs NB, Pack AI, et al. Night-to-night variability in CPAP use over the first three months of treatment. Sleep 1997;20:278-283. 97. McArdle N, Devereux G, Heidarnejad H, et al. Long-term use of CPAP therapy for sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 1999;159:1108-1114. 98. Budhiraja R, Parthasarathy S, Drake CL, et al. Early CPAP use identifies subsequent adherence to CPAP therapy. Sleep 2007;30: 320-324. 99. Barbe F, Mayoralas LR, Duran J, et al. Treatment with continuous positive airway pressure is not effective in patients with sleep apnea but no daytime sleepiness. a randomized, controlled trial. Ann Intern Med 2001;134:1015-1023. 100. Patel SR, White DP, Malhotra A, et al. Continuous positive airway pressure therapy for treating sleepiness in a diverse population with obstructive sleep apnea: results of a meta-analysis. Arch Intern Med 2003;163:565-571. 101. Bennett LS, Langford BA, Stradling JR, Davies RJ. Sleep fragmentation indices as predictors of daytime sleepiness and nCPAP response in obstructive sleep apnea. Am J Respir Crit Care Med 1998;158:778-786. 102. Drake CL, Day R, Hudgel D, et al. Sleep during titration predicts continuous positive airway pressure compliance. Sleep 2003;26:308311. 103. Han F, Song W, Li J, et al. Influence of UPPP surgery on tolerance to subsequent continuous positive airway pressure in patients with OSAHS. Sleep Breath 2006;10:37-42. 104. Scharf SM, Seiden L, DeMore J, Carter-Pokras O. Racial differences in clinical presentation of patients with sleep-disordered breathing. Sleep Breath 2004;8:173-183. 105. Joo MJ, Herdegen JJ. Sleep apnea in an urban public hospital: assessment of severity and treatment adherence. J Clin Sleep Med 2007;3:285-288. 106. Stepnowsky CJ Jr, Marler MR, Ancoli-Israel S. Determinants of nasal CPAP compliance. Sleep Med 2002;3:239-247. 107. Aloia MS, Arnedt JT, Stepnowsky C, et al. Predicting treatment adherence in obstructive sleep apnea using principles of behavior change. J Clin Sleep Med 2005;1:346-353. 108. Stepnowsky CJ Jr, Bardwell WA, Moore PJ, Ancoli-Israel S, Dimsdale JE. Psychologic correlates of compliance with continuous positive airway pressure. Sleep 2002;25:758-762. 109. Hoy CJ, Vennelle M, Kingshott RN, et al. Can intensive support improve continuous positive airway pressure use in patients with the sleep apnea/hypopnea syndrome? Am J Respir Crit Care Med 1999;159:1096-1100. 110. Haniffa M, Lasserson TJ, Smith I. Interventions to improve compliance with continuous positive airway pressure for obstructive sleep apnoea. Cochrane Database Syst Rev 2004;(4):CD003531. 111. Richards D, Bartlett DJ, Wong K, et al. Increased adherence to CPAP with a group cognitive behavioral treatment intervention: a randomized trial. Sleep 2007;30:635-640. 112. Berthon-Jones M. Feasibility of a self-setting CPAP machine. Sleep 1993;16:S120-S121. 113. Ayas NT, Patel SR, Malhotra A, et al. Auto-titrating versus standard continuous positive airway pressure for the treatment of obstructive sleep apnea: results of a meta-analysis. Sleep 2004;27: 249-253. 114. Damjanovic D, Fluck A, Bremer H, et al. Compliance in sleep apnoea therapy: influence of home care support and pressure mode. Eur Respir J 2009;33:804-811. 115. Kuna ST. Can continuous positive airway pressure be self-titrated? Am J Respir Crit Care Med 2003;167:674-675. 116. Lafond C, Series F. Influence of nasal obstruction on auto-CPAP behaviour during sleep in sleep apnoea/hypopnoea syndrome. Thorax 1998;53:780-783. 117. Rigau J, Montserrat JM, Wohrle H, et al. Bench model to simulate upper airway obstruction for analyzing automatic continuous positive airway pressure devices. Chest 2006;130:350-361.
118. Lofaso F, Desmarais G, Leroux K, et al. Bench evaluation of flow limitation detection by automated continuous positive airway pressure devices. Chest 2006;130:343-349. 119. Stepnowsky CJ Jr, Moore PJ. Nasal CPAP treatment for obstructive sleep apnea: developing a new perspective on dosing strategies and compliance. J Psychosom Res 2003;54:599-605. 120. Fletcher EC. Recurrence of sleep apnea syndrome following tracheostomy. A shift from obstructive to central apnea. Chest 1989;96:205-209. 121. Morgenthaler TI, Kagramanov V, Hanak V, Decker PA. Complex sleep apnea syndrome: is it a unique clinical syndrome? Sleep 2006;29:1203-1209. 121a. Javaheri S, Smith J, Chung E. The prevalence and natural history of complex sleep apnea. Clin Sleep Med 2009;5(3):205-211. 122. Lehman S, Antic NA, Thompson C, et al. Central sleep apnea on commencement of continuous positive airway pressure in patients with a primary diagnosis of obstructive sleep apnea–hypopnea. J Clin Sleep Med 2007;3:462-466. 123. Malhotra A, Bertisch S, Wellman A. Complex sleep apnea: it isn’t really a disease. J Clin Sleep Med 2008;4:406-408. 124. Allam JS, Olson EJ, Gay PC, Morgenthaler TI. Efficacy of adaptive servoventilation in treatment of complex and central sleep apnea syndromes. Chest 2007;132:1839-1846. 125. Morgenthaler TI, Gay PC, Gordon N, Brown LK. Adaptive servoventilation versus noninvasive positive pressure ventilation for central, mixed, and complex sleep apnea syndromes. Sleep 2007;30:468-475. 126. Dernaika T, Tawk M, Nazir S, et al. The significance and outcome of continuous positive airway pressure–related central sleep apnea during split-night sleep studies. Chest 2007;132:81-87. 127. White J, Cates C, Wright J. Continuous positive airways pressure for obstructive sleep apnoea. Cochrane Database Syst Rev 2002;(3):CD001106. 128. Pepperell JC, Ramdassingh-Dow S, Crosthwaite N, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet 2002;359:204-210. 129. Haentjens P, Van Meerhaeghe A, Moscariello A, et al. The impact of continuous positive airway pressure on blood pressure in patients with obstructive sleep apnea syndrome: evidence from a metaanalysis of placebo-controlled randomized trials. Arch Intern Med 2007;167:757-764. 130. Peker Y, Hedner J, Norum J, et al. Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea: a 7-year follow-up. Am J Respir Crit Care Med 2002;166:159165. 131. Marin JM, Carrizo SJ, Vicente E, Agusti AG. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365:1046-1053. 131a. Habukawa M, Uchimura N, Kakuma T, et al. Effect of CPAP treatment on residual depressive symptoms in patients with major depression and coexisting sleep apnea: contribution of daytime sleepiness to residual depressive symptoms. Sleep Med 2010 (Epub ahead of print.) 132. Krieger J, Meslier N, Lebrun T, et al. Accidents in obstructive sleep apnea patients treated with nasal continuous positive airway pressure: a prospective study. The Working Group ANTADIR, Paris and CRESGE, Lille, France. Association Nationale de Traitement a Domicile des Insuffisants Respiratoires. Chest 1997;112:15611566. 133. Barbe F, Sunyer J, de la Pena A, et al. Effect of continuous positive airway pressure on the risk of road accidents in sleep apnea patients. Respiration 2007;74:44-49. 134. George CF. Reduction in motor vehicle collisions following treatment of sleep apnoea with nasal CPAP. Thorax 2001;56:508-512. 135. Albarrak M, Banno K, Sabbagh AA, et al. Utilization of healthcare resources in obstructive sleep apnea syndrome: a 5-year follow-up study in men using CPAP. Sleep 2005;28:1306-1311. 136. Banno K, Manfreda J, Walld R, et al. Healthcare utilization in women with obstructive sleep apnea syndrome 2 years after diagnosis and treatment. Sleep 2006;29:1307-1311. 137. Banno K, Ramsey C, Walld R, Kryger MH. Expenditure on health care in obese women with and without sleep apnea. Sleep 2009;32:247-252.
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138. Mar J, Rueda JR, Duran-Cantolla J, et al. The cost-effectiveness of nCPAP treatment in patients with moderate-to-severe obstructive sleep apnoea. Eur Respir J 2003;21:515-522. 139. Ayas NT, FitzGerald JM, Fleetham JA, et al. Cost-effectiveness of continuous positive airway pressure therapy for moderate to severe obstructive sleep apnea/hypopnea. Arch Intern Med 2006;166:977984. 140. Barnes M, Houston D, Worsnop CJ, et al. A randomized controlled trial of continuous positive airway pressure in mild obstructive sleep apnea. Am J Respir Crit Care Med 2002;165:773-780. 141. Marshall NS, Barnes M, Travier N, et al. Continuous positive airway pressure reduces daytime sleepiness in mild to moderate obstructive sleep apnoea: a meta-analysis. Thorax 2006;61:430-434. 142. Young T, Finn L, Peppard PE, et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 2008;31:1071-1078. 143. Pack AI, Platt AB, Pien GW. Does untreated obstructive sleep apnea lead to death? A commentary on Young et al. Sleep 2008;31:1071-1078 and Marshall et al. Sleep 2008;31:1079-1085. Sleep 2008;31:1067-1068. 144. Javaheri S, Parker TJ, Liming JD, et al. Sleep apnea in 81 ambulatory male patients with stable heart failure. Types and their prevalences, consequences, and presentations. Circulation 1998;97:21542159.
145. Kaneko Y, Floras JS, Usui K, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med 2003;348:1233-1241. 146. Mansfield DR, Gollogly NC, Kaye DM, et al. Controlled trial of continuous positive airway pressure in obstructive sleep apnea and heart failure. Am J Respir Crit Care Med 2004;169:361-366. 147. Bradley TD, Floras JS. Sleep apnea and heart failure: Part II: central sleep apnea. Circulation 2003;107:1822-1826. 148. Arzt M, Floras JS, Logan AG, et al. Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation 2007;115: 3173-3180. 149. Koyama T, Watanabe H, Kobukai Y, et al. Beneficial effects of adaptive servo ventilation in patients with chronic heart failure. Circ J 2010 Jul 29. [Epub ahead of print] 150. Kasai T, Usui Y, Yoshioka T, et al. JASV Investigators. Effect of flow-triggered adaptive servo-ventilation compared with continuous positive airway pressure in patients with chronic heart failure with coexisting obstructive sleep apnea and Cheyne-Stokes respiration. Circ Heart Fail 2010;3:140-148.
Surgical Management for Obstructive Sleep-Disordered Breathing Nelson B. Powell and Robert W. Riley Abstract Obstructive sleep-disordered breathing (OSDB) is defined by total or partial collapse of the upper airway during sleep (obstructive sleep apnea and obstructive sleep hypopnea, respectively). In the presence of specific anatomic features, OSDB is potentially amenable to surgical intervention. Initially, the only treatment available for these patients was a tracheotomy that bypassed the obstruction and resulted in a 100% cure. However, this was not readily accepted by most patients. With increased understanding of OSDB, surgical methods other than tracheotomy were developed to successfully maintain adequate upper airway patency during sleep by making the airway cross-sectionally larger without creating adverse effects.
HISTORICAL PROSPECTIVE In this chapter, obstructive sleep-disordered breathing (OSDB) will be used to collectively refer to snoring, upper airway resistance syndrome (UARS), obstructive sleep apnea (OSA), obstructive sleep hypopnea (OSH) and the combination of the latter two, obstructive sleep apnea–hypopnea (OSAH). These are described in detail in other chapters in this section. The spectrum of OSDB reflects various degrees of the upper airway obstruction occurring episodically during sleep, combined with some yet-unidentified central nervous system abnormality of ventilatory control.1-3 This disordered breathing results in cyclic exposure to hypoxia, sleep fragmentation, altered sleep architecture, and subsequent excessive daytime sleepiness (EDS) as well as other clinically important consequences that are discussed in detail elsewhere in this volume. The pathophysiologic mechanism(s) culminating in upper airway obstruction during sleep are multifactorial, but they generally reflect a disadvantageous influence on the delicate balance of forces that are necessary to maintain upper airway patency in the presence of forces that promote collapse during sleep. Ideally, surgical approaches strive to intervene at the specific anatomic regions that become obstructed during sleep. Medical approaches, including risk modification (manipulation of body position during sleep; avoidance of alcohol and sedating medications), weight loss, and positive airway pressure modalities are usually the first avenues of treatment (see Chapters 106 and 110). Patients who are unable or unwilling to comply with medical management may be candidates for surgery. Patients with the pickwickian syndrome were some of the first to undergo surgery for an anatomic narrowing or blockage of the upper airway during sleep. This early surgical intervention was a tracheotomy, which, although it did not address the anatomic collapse, successfully bypassed the obstruction. 1250
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The three major anatomic regions of potential collapse during sleep in patients with OSDB include the nose, palate, and tongue base. Each region can be surgically reconstructed on its own or in combinations as necessary. Soft tissue can be repositioned or removed, and in some cases the maxilla and mandible may be repositioned forward to expand the posterior airway space. A commitment must be made by the surgeon to clearly advise the patient of all possible treatments, protocols, medical alternatives, and risks. Implementation and completion of the necessary airway reconstruction using an evidence-based Powell-Riley phased surgical protocol is defined throughout this chapter. Completion of this protocol should result in outcomes that are equivalent to those of medical management.
RATIONALE The rationale for surgical intervention is to improve the quality of life, reduce the risk for morbidity, and potentially enhance longevity. Thus, this rationale incorporates the behavioral and pathophysiologic consequences caused by sleep-related upper airway obstructions that are described in detail in Chapter 79. In addition, by virtue of its inherent invasiveness, the potential benefit to risks ratio is a preeminent consideration. INDICATIONS AND CONTRAINDICATIONS The indications and relative contraindications to surgery are listed in Box 108-1 and Box 108-2, respectively. Surgery may be appropriate in patients with an apnea–hypopnea index (AHI; the average number of apneas plus hypopneas per hour of sleep) that is at least 20; an AHI less than 20 in conjunction with severe daytime sleepiness is also an indication for surgery. In addition, a trial of continuous positive airway pressure (CPAP) that alleviates symptoms can provide a further rationale for surgery by linking symptoms to sleep-related upper airway dysfunction. For example, if a patient’s symptoms (such as EDS) do not improve during a CPAP trial despite alleviation of OSDB, it is unlikely that surgery will improve symptoms, and an alternative etiology for them should be sought. PRETREATMENT RECOMMENDATIONS AND CONCERNS Because EDS has numerous other causes, such as narcolepsy, insomnia, and sleep deprivation, the workup should include a complete medical and sleep history, along with a head and neck evaluation, to assess health and detect comorbid medical conditions. Pretreatment evaluation should include full nocturnal polysomnography (PSG) and
CHAPTER 108 • Surgical Management for Obstructive Sleep-Disordered Breathing 1251
Box 108-1 Indications for Surgery in SleepDisordered Breathing Excessive daytime sleepiness Apnea–hypopnea index ≥ 20 Apnea–hypopnea index < 20 with severe excessive daytime sleepiness Lowest sleep-related oxyhemoglobin saturation < 90% Diurnal hypertension or sleep-related arrhythmia or hypertension Esophageal pressure more negative than −10 cm H2O Anatomic airway abnormalities Failure of medical management
Box 108-2 Relative Contraindications for Surgery Morbid obesity Severe pulmonary disease Unstable cardiovascular status Psychological instability Alcohol or drug abuse Older age Unrealistic expectation of outcome
not cardiopulmonary testing, which provides more limited information. A radiographic cephalometric analysis, along with fiberoptic nasopharyngoscopy, is helpful in evaluating soft tissue and skeletal anatomy of the airway. Sleep endoscopy is now being tested in some centers in an attempt to further evaluate the airway in OSDB.4 However, at this time there are no reported clinical outcome studies that support the routine use of this diagnostic method. Rama and colleagues5 evaluated the literature from 1980 to 2002 that reported on a variety of imaging techniques to identify the site(s) of obstruction during sleep, including three-dimensional computed tomography (CT) or magnetic resonance imaging (MRI). They concluded, in part, that identifying “the precise location of the sites of obstruction in patients with OSAH may not be possible using current imaging techniques.” Computational modeling6 and advanced three-dimensional software are now also being investigated. Unfortunately, most of these studies tend to suffer the same confounders because there are at present no known clinical surgical-outcome trials to support correction of the designated site of obstruction as predicted preoperatively. No single test or procedure should be relied on to make a definitive surgical treatment plan. A systematic medical and surgical review should determine the type of sleep disorder, establish parameters of severity, identify comorbidity factors, identify probable sites of upper airway obstruction, decide if treatment is emergent or elective, and assess the risk-to-benefit ratio of surgery. Although the exact etiology of OSDB remains incompletely understood, the areas producing clinical anatomic obstruction are usually well defined.7-10 A major confounder in determining the area of obstruction is that other, less-perceptible regions may be participating in the
obstructive process. In addition, our examinations are performed while the patient is awake. In this regard, when the patient is asleep the airway can change enough to adversely affect the patency of areas in which the possibility of obstruction is less obvious during wakefulness. OSDB can be viewed as a surgically responsive problem caused by the significant contribution from areas of disproportionate anatomy and diffuse upper airway collapse. A systematic approach and application of a surgical protocol will yield improved clinical outcomes for children and adults.
CLINICAL EVALUATION IN ASSESSING SURGICAL CANDIDACY Vital signs, neck circumference, body habitus, and facial skeletal patterns should be documented. A detailed head and neck examination should rule out pathology and then highlight the three major anatomic regions of potential upper airway obstruction: nose, palate, and base of the tongue. The specific nasal anatomic regions of interest include the septum, turbinates, and nasal valve. The nasal valve controls airflow. It is bilateral and in the anterior upper portion of the nose. The palatal region includes the hard and soft palates. The tongue region is the tongue and retrolingual area (the posterior airway space, PAS), which is the space behind the tongue base. Clinical Examinations The nasal examination should be performed while the patient is breathing quietly and also during deep inspiration. This allows assessment of alar support (lower anterior arched part of the bilateral portion of the nose) and nasal valve function during dynamic breathing. Collapse of the ala on deep inspiration is seen in a significant number of subjects with OSDB. Deflection of the nasal septum, enlargement of the turbinates, and webs, polyps, or masses are potentially important in the patient with OSDB. The oral cavity should be examined by assessing dental health, class of occlusion (I, II, or III), oral mucous membranes, and tongue. Issues that mitigate surgical candidacy can include pathology, infection, soft tissues that could not be removed safely, and bony jaw abnormalities. Further examination includes evaluating the length of the soft palate, redundancy of the lateral pharynx, size of the tonsils, and the tongue, vallecula, epiglottis, larynx, and pyriform sinuses. Cephalometric radiographs assist in the overall evaluation of the soft tissue and bony configuration. Other potential upper airway imaging methods include MRI and volumetric CT.11,12 Fujita13 proposed a classification of obstructive regions in the upper airway that is useful in planning therapy and for standardization of scientific reporting (Table 108-1). Fiberoptic Nasopharyngolaryngoscopy Flexible fiberoptic endoscopy provides important information regarding the nasal airway, palate, lateral pharyngeal walls, tongue base, epiglottis, and larynx. This procedure is usually performed while the patient is either supine or sitting. Excessive soft tissues can be evaluated, as can pathologic findings.
1252 PART II / Section 13 • Sleep Breathing Disorders Table 108-1 Fujita Classification of Obstructive Regions
Box 108-3 Philosophy of Surgical Treatment
TYPE
LOCATION
I
Palate (normal base of tongue)
II
Palate and base of tongue
III
Base of tongue (normal palate)
From Fujita S. Pharyngeal surgery for obstructive sleep apnea and snoring. In Fairbanks D, Fujita S, Ikematsu T, et al, editors. Snoring and obstructive sleep apnea. New York: Raven Press; 1987. p. 101-128.
S
SNA SNB PAS PNS-P MP-H
82 80 11 35 15
N
PNS ANS A
P
PAS
Go B MP
H
GN
Figure 108-1 Cephalometric analysis used for evaluation of patients with sleep-disordered breathing. SNA = 82 degrees (SD ± 2), maxilla to cranial base; SNB = 80 degrees (SD ± 2), mandible to cranial base; PAS =11 mm (SD ± 1); PNS-P = 37 mm (SD ± 3), length of soft palate; MP-H =15.4 mm (SD ± 3), distance of hyoid from inferior mandible. MP-H, distance between mandibular plane and hyoid; PAS, posterior airway space; PNS-P, distance between posterior nasal spine and point P; SNA, angle from sella to nasion to point A; SNB, angle from sella to nasion to point B. ANS, anterior spine; GN, lowest point of chin contour; GO, intersection of inferior margin of mandible and posterior margin of mandibular ramus. (From Riley RW, Powell NB, Guilleminault C. Obstructive sleep apnea syndrome: a surgical protocol for dynamic upper airway reconstruction. J Oral Maxillofac Surg 1993;51:742-747.)
Cephalometric Imaging Cephalometric images provide reliable presurgical and postsurgical data on soft tissue and skeletal relationships, length of soft palate, posterior airway space (PAS), and hyoid position (Fig. 108-1). The use of cephalometric radiographs and the anthropomorphic measurements (except the subspinale [SNA] angle and the sella-nasionsupramentale [SNB] angle) seen in Figure 108-1 were first described in 1983 by Riley and coworkers.14 Although easily obtained and relatively inexpensive, cephalometric evaluation is limited in that it is a two-dimensional view and the patient is evaluated while awake and seated, not asleep and recumbent. This technique should not be relied on alone to determine the most appropriate surgical intervention.
Goal: Treat to cure Methods • Careful and systematic plan of management • Obstructions in the entire upper airway are treated (i.e., upper airway reconstruction [UAR]). • Full disclosure of options and risks • Staged surgical management • Follow-up of all treatment interventions
APPROACH TO SURGICAL TREATMENT A systematic approach to the surgical management of patients with OSDB is essential for quality care. A philosophy of treatment is outlined in Box 108-3. Because the potential exists for upper airway narrowing at multiple sites in a given patient, it may be necessary for surgery to address more than one anatomic region. The surgical outcome will be inadequate if the objective is not upper airway reconstruction at all likely sites. Although upper airway anatomic abnormalities of some variety are considered to contribute to most OSDB and to this degree are surgically amenable problems, medical management is usually considered first in formulating the surgical treatment philosophy. Medical management primarily consists of reducing risk factors and using one of several available positive airway pressure therapy modalities to stabilize the upper airway during sleep. Weight loss was recognized more than 30 years ago as an important treatment, and the merit of weight loss in obese patients with OSDB is well documented. Peppard and colleagues15 reported that weight gain in OSDB, even as minor as 10% (relative to stable weight), can result in an approximate increase in a patient’s AHI of 32% (see Chapter 106). Although the ability of patients with OSDB to achieve and maintain adequate weight reduction through dietary means has been limited, a resurgence of interest in obesity with increasing success in therapeutically significant weight reduction through surgery may yield new methods of control (see Chapter 106). Sleep medicine surgeons may be asked to participate in the care of patients who have attempted but failed medical therapy. The phased protocol (see later) has proved, over time, to be effective and safe for controlling upper airway collapse in patients with OSDB. ISSUES IN EVIDENCEBASED MEDICINE Before discussing specific surgical interventions, it is important to discuss evidence-based medicine in the context of surgical, as opposed to medical, research. Clinical practice is ideally directed by high-quality evidence demonstrating safety and outcome efficacy. However, it is important to understand that due to their inherent invasiveness, acquisition of such evidence as reflected by randomized placebo (or sham)-controlled trials (RCTs) is,
CHAPTER 108 • Surgical Management for Obstructive Sleep-Disordered Breathing 1253
in general, ethically and logistically problematic with regard to upper airway and skeletal surgical procedures. The American Medical Association16 reported that surgical placebo controls should be used only when no other trial design will yield the requisite data. Moreover, unlike trials evaluating medical therapy, such trials for sleep-disordered breathing (SDB) surgery are clearly unethical and impractical. Sham surgery (and attendant anesthesia and postoperative analgesia) has inherent and usually unacceptable risks and discomfort to patients with an underlying abnormally collapsible upper airway (some degree of edema is likely even with a sham procedure). Furthermore, even a sham procedure can alter the feasibility of subsequent surgical intervention. Blinding of the patient and investigator to visible evidence of the intervention is impossible, thereby limiting the value of RCT design. The likelihood of recruiting patients who are willing to accept these risks, especially in the context of randomization to a placebo arm, places another fundamental barrier to the conduct of the RCT design in the context of surgical intervention of SDB. Evidence-based medicine has been defined as “integrating individual clinical expertise and the best external evidence.”16 Most surgical results for SDB, such as widening of the upper airway and improved function, may be objectively assessed by, for example, preoperative and postoperative polysomnography, esophageal manometry, and airway imaging including cephalometrics, CT, MRI, three-dimensional volumetric imaging, and direct comparison to preoperative and postoperative management with positive airway pressure. In most cases, this should be sufficient to support efficacy and effectiveness. We believe that although surgical trials are still limited by inability to blind study participants, high-quality evidence can be ethically and feasibility acquired through a design that randomizes patients to an experimental surgical intervention, a current clinical standard surgical intervention for the specific patient group, or the current gold-standard medical treatment. This has been our practice.17,18 Thus, it is important that patients be made aware of the limitations of data available for some procedures and be presented with estimates that are the most accurate available of risks, benefits, and outcomes so that they can make an informed decision.
TWO-PHASED SURGICAL PROTOCOL The Powell-Riley surgical protocol is a two-phase approach that directs surgical treatment toward the specific regions of obstruction during sleep. Its benefits are listed in Box 108-4. Phase I surgical intervention addresses all three levels of airway obstruction and includes nasal reconstruction, uvulopalatopharyngoplasty (UPPP), and a limited mandibular osteotomy with genioglossus advancement– hyoid myotomy and suspension (GAHMS). Radiofrequency (RF) technology using temperature-controlled RF (TCRF) or coblation in combination with GAHMS may be applied in phase I. The specific procedures are described later. The protocol sequence for addressing nasal, oropharyngeal, retropalatal, or lingual obstruction during sleep is presented in Box 108-5. A patient needing intervention at
Box 108-4 Rationales for Powell-Riley Stanford University Phased Surgical Protocol Decreases risk of overoperating Treats conservatively because outcomes are difficult to predict Decreases hospital stay Limits postoperative risk Causes less trauma and pain Better accepted by most patients Improves cure rates in phase II
Box 108-5 Powell-Riley Protocol for Upper Airway Reconstruction Phase I Nasal reconstruction Palate and lateral pharyngeal walls (uvulopalatopharyngoplasty [UPPP] with or without tonsillectomy) Retrolingual (genioglossus advancement—hyoid myotomy and suspension [GAHMS]) Possible use of RF technique Reevaluation at 4 to 6 months (PSG) Phase II* Maxillary and mandibular advancement (MMO) Alternative: surgical or RF tongue reduction *When phase I treatment is insufficient. PSG, polysomnography; RF, radiofrequency.
any of these three anatomic levels should complete phase I surgery, in a sequence that would least jeopardize the upper airway during recovery, before moving on to phase II. This sequence should not interfere with the patient’s ability to use CPAP after surgery. Phase II represents skeletal reconstruction and consists of bimaxillary advancement (BMA), commonly referred to as maxillary and mandibular osteotomy (MMO). Combining phase I and phase II in one surgical procedure is discouraged because of an increased possibility of postoperative edema and upper airway compromise. In addition, phase II might not be necessary. Surgical Expectations All possible medical and surgical options should be reviewed with the patient and the family well in advance, and the rationale for each should be clearly explained. Furthermore, it is mandatory that the patients be medically and psychologically stable and that they wish to undergo the surgical procedure with knowledge of the potential risks, benefits, and likelihoods of success and failure. Surgical outcomes can vary, and it is therefore essential that all patients be reevaluated after each phase is completed. This minimizes the possibility of unnecessary additional surgery and readily identifies those who require further attention. To determine the outcome, each patient who has undergone phase I surgery is reevaluated by PSG and reassessed clinically at 4 to 6 months. Patients who are incompletely treated following phase I surgery become candidates for phase II (MMO). In conjunction with each
1254 PART II / Section 13 • Sleep Breathing Disorders
surgical phase, weight management is encouraged as an essential part of the protocol. Because of concern about postoperative upper airway compromise secondary to surgery, we established a CPAP and surgical strategy19 All patients are encouraged to use CPAP, and those who have an AHI greater than 40 and an oxyhemoglobin desaturation (Sao2) less than 80% are required to use CPAP for at least 2 weeks before surgery, unless they cannot tolerate the device. Patients are also maintained on CPAP immediately after extubation and are encouraged to continue using this therapy during sleep until 2 weeks before the 4- to 6-month postoperative PSG reevaluation. Patients with very severe sleep apnea (AHI > 60, Sao2 < 70%), and significant comorbidities such as severe cardiac sequelae or morbid obesity with body mass index (BMI) of 40 who are intolerant of nasal CPAP should be considered for temporary or permanent tracheotomy. Every treatment protocol has exceptions. In many instances, local resources, experience, and expertise dictate the type of surgical therapy a patient may receive. Some procedures require surgeons with multidisciplinary training, and none may be available in the patient’s community. In such cases, surgical treatment must be left to the choice of the surgeon and the patient. Fortunately, there are a variety of diagnostic and surgical procedures (see later) available that can minimize risks and complications. Powell-Riley Phase I Three regions of the upper airway are evaluated for treatment as directed by the systematic workup. For each region, the most conservative surgery is recommended. Phase I surgery addresses the following susceptible regions: • Nasal: Phase I corrects nasal obstruction depending on the anatomic deformity (septum, turbinates, alar collapse or nasal valve deformities). • Palate and retropalatal (behind soft palate) region: Phase I procedures improve upper airway space (UPPP or the equivalent, with removal of tonsils or adenoids, or both, if these structures are present). • Tongue and retrolingual (behind tongue) region: Phase I procedures may place tension on the tongue to help resist prolapse during sleep, using genioglossus advancement with or without hyoid myotomy and suspension. Tissue-reduction techniques use laser midline glossectomy and lingualplasty, partial glossectomy, or TCRF technology. Before discharge from the hospital, patients undergo monitoring, which includes assessment of at least oxyhemoglobin saturation over 2 nights as well as bedside fiberoptic nasopharyngoscopy while the patient is awake and sitting to evaluate the airway. If significant edema is noted, the patient remains in the hospital until discharge is considered safe. Four to 6 months after phase I (sufficient time for healing, weight stabilization, and neurologic equilibration), the patient undergoes a PSG, as well as a new clinical sleep assessment and clinical examination to assess outcomes.20 Patients who are incompletely treated may be candidates for phase II. Powell-Riley Phase II Phase II reflects skeletal midface advancement, or MMO. Tracheotomy or nasal CPAP may be considered instead
Box 108-6 Criteria for Responders to Powell-Riley Surgical Protocol A surgical responder (or a cure) is identified if items 1 through 4 or items 4 and 5 are accomplished 1. AHI ≤ 20, or AHI is reduced to 50% (or better) of the preoperative AHI if it was ≤20* 2. Oxygen saturation ≥ 90% 3. Normalization of sleep architecture 4. Resolution of excessive daytime sleepiness 5. Response equivalent to positive pressure devices (CPAP or BiPAP) on an attended full-night titration *If the preoperative AHI is <20, the 50% rule is applied. As an example, if the preoperative AHI is 18 (<20), then the postoperative AHI would need to be 9 events per hour of sleep. AHI, apnea–hypopnea index; BiPAP, bilevel positive airway pressure; CPAP, continuous positive airway pressure.
of MMO for control of the tongue base. Other techniques that are used less often but may be considered include midline glossectomy and RF (TCRF or coblation) technology. Defining Clinical Response Early reporting methods defined patients who responded positively to surgery as those who demonstrated a 50% or greater reduction in the number of abnormal breathing events per hour of sleep. However, clinicians and researchers no longer consider such a definition valid. A more stringent surgical goal combines specific PSG parameters with quality-of-life issues, and the outcome should compare favorably with the results of medical management (specifically, positive airway pressure [PAP]). Our criteria for designating a positive surgical responder are presented in Box 108-6. Surgical Techniques Surgical along with other techniques that are employed to provide or facilitate maintenance of a patent upper airway during sleep are listed in Box 108-7. Tracheotomy (Upper Airway Bypass Surgery) R ATIONALE Tracheotomy provides immediate resolution of upper airway obstruction. I NDICATIONS Tracheotomy should be employed when there is an emergent need to establish and ensure a patent airway or where there is neither the specialized equipment nor the surgical expertise to offer an alternative procedure. It may be indicated in selected patients with morbid obesity (BMI, 40 kg/ m2), severe hypoxemia (Sao2 ≤ 70%), serious arrhythmia, or dysrhythmia. It is usually, but not always, poorly tolerated or accepted. In the majority of cases, tracheotomy has taken a second position to CPAP in the treatment of OSDB, especially in light of the successful use of nasal CPAP for severe OSDB.19
CHAPTER 108 • Surgical Management for Obstructive Sleep-Disordered Breathing 1255
Box 108-7 Surgical Techniques
Box 108-9 Uvulopalatopharyngoplasty
Current Techniques Tracheotomy Nasal reconstruction Uvulopalatopharyngoplasty (UPPP) Tongue reduction (surgical) Genioglossus advancement–hyoid myotomy and suspension (GAHMS) Bimaxillary advancement, or maxillary and mandibular osteotomy (MMO)
Rationale Opens the pharyngeal airway Excellent technique for this level
Minimally Invasive Technology Temperature-controlled radiofrequency (turbinates, palate, tongue)
Box 108-8 Nasal Reconstruction Rationale The nasal passage is an integral part of the upper airway. Any obstruction causes increased airway resistance. Rotation of the mandible with mouth breathing and prolapse of tongue into the posterior airway space Indications Deviated septum Enlarged turbinates Collapse of nasal valve or alae External nasal deformities
T ECHNIQUES Temporary or permanent tracheotomy. C LINICAL O UTCOMES In the absence of other confounding conditions (e.g., altered control of breathing physiology), tracheotomy can usually be expected to provide alleviation of OSDB with near 100% certainty. Nasal Reconstruction Rationale A patent nasal airway establishes physiologic breathing and can minimize mouth breathing (Box 108-8). When the mouth is opened, the lower jaw rotates down and back, allowing the tongue to be repositioned into the PAS. In some patients, improvement of the nasal airway (turbinate) can also improve CPAP tolerance or compliance.17 I NDICATIONS Nasal reconstruction is used for symptomatic nasal airway blockage caused by bony, cartilaginous, or hypertrophied tissues that interfere with nasal breathing during sleep. T ECHNIQUES Nasal reconstruction includes septal or bony intranasal reconstruction, alar valve or alar rim reconstruction, and turbinectomy. C LINICAL O UTCOMES The ease and high success rate of nasal reconstruction in improving nasal airway patency makes this procedure a
Indications Long floppy soft palate Enlarged tonsils Redundant lateral pharyngeal wall
very valuable technique for those with nasal obstruction and OSDB. Although it is very unlikely to cure OSDB as a stand-alone procedure, correction of any defects at this level minimizes mouth breathing and can decrease negative-pressure breathing during sleep. Palate in Phase I: Uvulopalatopharyngoplasty R ATIONALE The palatal and lateral pharyngeal tissues have been found to be the most compliant of the upper airway, and documentation of collapse at this level in OSDB is well established (Box 108-9).21 I NDICATIONS Palatal reconstruction can be used to modify a long soft palate, a narrow inlet to the nasopharynx, hypertrophic tonsils, and a redundant lateral pharyngeal mucosa. This level of obstruction is classified as Fujita type I (see Table 108-1).13 T ECHNIQUES Many surgical methods, including traditional UPPP and many variations of it, may be used to modify the pharyngeal region (Fig. 108-2).22 Transpalatal advancements, surgical flaps, lasers, and radiofrequency have also been used.23-26 C LINICAL O UTCOMES Results vary with the experience of the surgeon, the patient’s anatomy, the severity of the OSDB, and the technique selected. The careful removal, shrinking, or repositioning of obstructive soft palate tissues is essential to the improvement of OSDB at this level. The contemporary techniques are excellent in accomplishing this goal. However, these procedures have not maintained widespread popularity over the years because of the pain and discomfort after surgery and because cure rates have been so variable. Although most UPPP techniques do clear the soft palate edges or pharyngeal wall of obstruction, the procedure itself has often been associated with failure, partly because of unrecognized tongue base obstruction. In patients whose site of primary obstruction is only at the soft palate level (Fujita type I), the cure rate can be very favorable. A meta-analysis27 published in 1996 that covered the previous 29 years of surgical therapy found that UPPP had an overall approximate success rate of 40% for correcting OSDB. The most likely cause of a reduced UPPP success (other than poor surgery) is the presence of other regions
1256 PART II / Section 13 • Sleep Breathing Disorders
A
B
C
Figure 108-2 Uvulopalatopharyngoplasty technique. A, Redundant soft palate and tonsillar pillar mucosa are outlined. B, Tonsils, tonsillar pillar mucosa, and posterior soft palate have been excised. The extent of soft palate excision is determined by placing traction on the uvula and noting the position of the mucosal crease. C, Mucosal flaps of the lateral pharyngeal wall and nasal palatal muscle are advanced to the anterior pillar and oral mucosa of the soft palate. The wound is closed with 3-0 Vicryl braided suture. (From Troell RJ, Strom CG. Surgical therapy for snoring. Fed Practitioner 1997;14:29-52.)
in which there was unrecognized obstruction or unaddressed anatomic contributions from tonsils, lateral pharyngeal wall, lingual tonsil, laryngomalacia (floppy epiglottis), skeletal abnormalities, and, most often, the tongue base. UPPP has seldom been credited with curing moderate or severe OSDB. Uvulopalatal Flap: an Alternative Procedure for Palatal Reconstruction R ATIONALE AND I NDICATIONS The rationale and indications for the uvulopalatal flap (UPF) are the same as for UPPP. The UPF is a modification of the UPPP.24 The goal is to reduce the risk of nasopharyngeal incompetence by using a potentially reversible flap that can be taken down in the early postoperative period. Because there are no sutures along the free edge of the palate, there is less postoperative pain. T ECHNIQUE The technique is demonstrated in Figure 108-3. C LINICAL O UTCOMES In a study of 80 patients24 examined in a prospective, nonrandomized, consecutive manner, there were no statistically significant differences between the UPPP group and the UPF group in the preoperative and postoperative variables including BMI, AHI, lowest oxygen desaturation during sleep, and subjective snoring scale. There was much less pain in the UPF group than in the UPPP group. Methods to Treat Base of Tongue Obstruction Obstruction at the tongue base may be bypassed by tracheotomy, or it may be addressed by making more room for the tongue using skeletal advancements (MMO). In addition, the midportion of the tongue base can be reduced in size using RF (TCFR or coblation) techniques. One of the current treatment approaches uses forward repositioning of the genioglossus attachment and hyoid.
Box 108-10 Genioglossus Advancement with Hyoid Myotomy and Suspension Rationale Places genioglossus under tension Fixes major dilators of pharynx Does not gain additional room for tongue Indications Documented base of tongue obstruction Failure of medical management Severe sleep-disordered breathing in patients who, because of the severity of the disorder and their excess weight, are being prepared for maxillary and mandibular osteotomy (MMO) in a stepped sequence using the phased protocol Applied in phase I or II
Mandibular Osteotomy: Genioglossus Advancement–Hyoid Myotomy Suspension The GAHMS procedure includes genioglossus advancement, with or without hyoid myotomy and suspension and is part of the phase I Powell-Riley protocol. The surgery is limited in that the mandible and teeth are not moved, movement is only to the genial tubercle. The advancements place tension on the tongue musculature (genioglossus and geniohyoid) and limit posterior displacement during sleep. No additional room for the tongue is created by this technique. This is in contrast to mandibular advancement or MMO (phase II), which not only places further tension on the genioglossus (after phase I) but also creates more physical space for the tongue. (The hyoid myotomy and suspension are described later). R ATIONALE The GAHMS procedure is used to minimize the posterior displacement of the tongue into the posterior airway space during sleep (Box 108-10). The genioglossus muscle is
CHAPTER 108 • Surgical Management for Obstructive Sleep-Disordered Breathing 1257
A
B
C
Figure 108-3 Reversible uvulopalatal flap (UPF) technique. A, Uvula reflected to identify mucosal crease of muscular sling. B, Knife removes mucosa on proposed flap site. C, Wound is closed with a half-buried suture of 3-0 Vicryl braided suture at the tip of the uvula and simple interrupted sutures along the mucosal closure. (From Troell RJ, Strom CG. Surgical therapy for snoring. Fed Practitioner 1997;14:29-52.)
attached to the lingual surface of the mandible at the geniotubercle and also to the hyoid complex just above the larynx. Movement forward of either or both of these anatomic structures stabilizes the tongue base along with the associated pharyngeal dilatators. Forward movement of the mandible or isolated geniotubercle advancement improves the PAS in most cases, as in the typical jaw thrust used in cardiopulmonary resuscitation to establish an emergency airway. I NDICATIONS Indications for the GAHMS procedure include the general indications for surgery, with additional findings of clinical tongue base obstruction. T ECHNIQUE Detailed knowledge of the preoperative anatomy is essential to the surgeon in planning the procedure. An imaging analysis should include a lateral cephalometric radiograph and a panoramic dental radiograph (Panorex). New imaging using MR or CT computational methods may have a role in evaluating this anatomic region. The panoramic radiograph depicts the course of the inferior alveolar nerve canal and the location of the mental foramen. It further shows the root length of the mandibular canines and central incisor teeth and potential pathologic processes (e.g., periodontal disease, cyst, and tumor). Surgery may be performed under general anesthesia or intravenous sedation. The GAHMS procedure is illustrated in Figure 108-4. H ISTORY AND C LINICAL O UTCOMES Our first attempt to treat OSDB by moving the geniotubercle forward used a horizontal mandibular sliding
A
B Figure 108-4 Mandibular osteotomy with genioglossus advancement (GA) procedure. A rectangular window of symphyseal bone consisting of the geniotubercle is advanced anteriorly, rotated to allow bony overlap, and immobilized with a titanium screw. A, Anterior view. B, Lateral view. (From Fairbanks DNF, Fujita S, editors. Snoring and obstructive sleep apnea, 2nd ed. New York: Raven Press; 1994.)
1258 PART II / Section 13 • Sleep Breathing Disorders
osteotomy. This case was published in 198428 and was evaluated by PSG: AHI was improved from 60 to 45, and the lowest oxyhemoglobin saturation (LSAT) was improved from 66% to 83%. Although the improvement was modest, the technique was insufficient to reduce tongue base obstruction. We subsequently abandoned the technique and in 1986 developed a modified osteotomy for geniotubercle advancement.29,30 In 1993, in 239 patients who completed phase I and underwent preoperative and postoperative PSG, the responder or cure rate ranged from 42% to 77%, depending on the severity of the disorder.31 Overall, the mean responder rate was 61%. To better view the outcomes, the results were stratified by severity (Table 108-2). Outcome results reported by our center and by others vary from a 23% to a 69% response rate. In many cases, techniques were modified and definitions for control were not the same. However, for the most part, the overall outcomes were similar to those achieved at our center. A
summary of peer-reviewed papers on genioglossus advancement with or without hyoid myotomy and suspension is seen in Table 108-3.29-47 Hyoid Myotomy and Suspension R ATIONALE The rationale for including hyoid myotomy and suspension (HMS) in the treatment of base of tongue obstruction is that anatomically the hyoid complex is an integral part of the hypopharynx, both statically and dynamically. Van de Graaff and colleagues48 reported that in dogs, the hyoid complex helps to maintain the upper airway space. Kaya49 and Patton and coworkers50 also independently investigated the hyoid for sleep apnea. Forward movement of the complex improves the PAS. Numerous investigations have supported the concept that surgical intervention at the hyoid level may improve the PAS.51-61
Table 108-2 Phase I Surgical Protocol: Results from 239 Patients DEGREE OF APNEA
RDI
LSAT
TOTAL PATIENTS
PATIENT SUCCESSES
SUCCESS RATE (%)
<20
>85
26
20
77
Moderate
20-40
>80
58
45
78
Moderate to severe
40-60
>70
51
36
71
>60
<70
104
44
42
Mild
Severe
LSAT, lowest oxyhemoglobin saturation; RDI, respiratory disturbance index. From Riley RW, Powell NB, Guilleminault C. Obstructive sleep apnea syndrome: a review of 306 consecutively treated surgical patients. Otolaryngol Head Neck Surg 1993;108:117-125.
Table 108-3 Clinical Outcomes of Genioglossus Advancement AUTHOR (REF)
YEAR
COUNTRY
SUBJECTS (N)
RESPONSE RATE* (%)
Riley et al. (29)
1986
United States
5
77
Riley et al. (30)
1989
United States
55
67
Riley et al. (31)
1993
United States
239
61
Johnson et al. (32)
1994
United States
9
69
Ramirez et al. (33)
1996
United States
12
53
Yoa et al. (34)
1998
United States
23
68
Lee et al. (35)
1999
United States
35
69
Wagner et al. (36)
2000
France
21
25
Bettega et al. (37)
2001
France
44
23
Vilaseca et al. (38)
2002
Spain
20
35
Fibbi (39)
2002
Italy
4
75
Neruntarat (40)
2003
Thailand
31
70
Datillo et al. (41)
2004
United States
42
80
Yin et al. (42)
2005
China
18
83
Yi et al. (43)
2006
China
18
67
Jacobwitz (44)
2006
United States
48
77
Richard et al. (45)
2007
Netherlands
22
45
Foltan et al. (46)
2007
Czech Republic
31
74
Santos Jr et al. (47)
2007
Brazil
10
70
Note: Over 21 years, 19-peer reviewed papers on genioglossus advancement were published from nine countries. The mean of the responder or cure rate of this group is 62.5%. *Response rates varied, in part because the criteria used by the individual investigators to define success varied, and in part because technique variations and deletion of steps were common.
CHAPTER 108 • Surgical Management for Obstructive Sleep-Disordered Breathing 1259
I NDICATIONS HMS is an adjunctive procedure to the genioglossus advancement. Two parameters that need to be considered are the linear distances from the inferior mandibular plane to the hyoid bone (vertical measurement) and the PAS (a horizontal measurement). Distances between the inferior mandibular plane and the hyoid of 15 mm or less suggest a back and downward rotation of the tongue with resultant narrowing of the PAS. The HMS is part of phase I treatment, but it is not always performed concurrently with genioglossus advancement. In patients with severe OSDB (AHI > 40, Sao2 < 80%-85%, BMI > 30), we generally combine the genioglossus advancement only with UPPP. The additional insult to the infrahyoid region when the hyoid myotomy and suspension is included was found to be very difficult for many of these patients to tolerate. When evaluating patients after UPPP and genioglossus advancement, we have also found that the PAS in some patients was sufficiently improved to obviate the need for a hyoid procedure. T ECHNIQUE Although the original description of the hyoid suspension technique involved suspending the hyoid to the anterior mandible with fascia lata,29 the technique has been modified by suspending the hyoid to the thyroid cartilage. This modification was designed to decrease the risk of posterior rotation of the tongue (as described earlier) and to lessen the extent of surgery (i.e., less dissection, no grafting) (Fig. 108-5).51 We now often combine the HMS with ventral and base of tongue TCRF. This approach in some cases decreases the need for phase II intervention, although multiple TCRF treatments are necessary.62 C LINICAL O UTCOMES Fifteen consecutively treated subjects were assessed before and after hyoid myotomy and suspension surgery (isolated hyoid myotomy and suspension to the laryngeal cartilage)
with full PSG and sleepiness evaluations. All patients had previously undergone UPPP plus genioglossus advancement or genioglossus advancement only with incomplete treatment results. Before hyoid surgery, the mean AHI was 46.9 and the LSAT was 81% (BMI, 29.6 kg/m2; mean age, 51.8 years). Postoperatively the mean AHI was 21.3 and the LSAT was 85%. Twelve of 15 (75%) had correction of their EDS and improvement of their SDB. We do not consider this technique a primary therapy, but we do use it as an adjunctive addition to treating tongue base obstruction. Maxillary Mandibular Osteotomy (Powell-Riley Phase II) The first reports of mandibular skeletal surgery for OSDB came from Kuo and colleagues63 in 1979 (N = 3) and Bear and Priest64 in 1980 (N = 1). They reported subjective improvement, but there were no objective PSG data to support outcomes. Powell’s group65 presented a case report of the first objective data (before and attended overnight PSG) on a mandibular advancement for severe OSDB in 1983. R ATIONALE Phase II surgery specifically addresses retrolingual (base of the tongue) obstruction (Box 108-11). Mandibular or MMO advancement helps to clear oropharyngeal and hypopharyngeal obstruction. The converse of mandibular advancement is surgical mandibular retrusion, which is used to correct mandibular prognathism. This procedure has the potential to produce SDB in some patients by narrowing the posterior airway space.66 I NDICATIONS With few exceptions, patients enter phase II surgical management after they have undergone phase I with incomplete alleviation of OSDB due to continued base of tongue obstruction. Some authors have advocated MMO as the first intervention, or only for patients with significant craniofacial disorders (e.g., maxillomandibular deficiency). The use of MMO as the primary surgical treatment modality is generally not advocated by our center because of the acceptable control rates achieved for many patients with the less-invasive phase I surgery.
Box 108-11 Bimaxillary Surgery in Patients with Sleep-Disordered Breathing
Figure 108-5 Modified hyoid myotomy and suspension (HMS) procedure. The hyoid bone is isolated, the inferior body is dissected clean, and the majority of the suprahyoid musculature remains intact. The hyoid is advanced over the thyroid lamina and immobilized with sutures placed through the superior aspect of the thyroid cartilage. (From Riley RW, Powell NB, Guilleminault C. Obstructive sleep apnea and the hyoid: a revised surgical procedure. Otolaryngol Head Neck Surg 1994;111: 717-721.)
Rationale Moves midface forward (palate, maxilla, and mandible) Increases posterior airway space Provides more tension than genioglossus advancement–hyoid myotomy and suspension (GAHMS) Increases room for the tongue Indications Documented base of tongue obstruction Recommended when remaining upper airway has been maximally treated
1260 PART II / Section 13 • Sleep Breathing Disorders
T ECHNIQUE The MMO advancement procedure creates further tension and physical room for the tongue, thus expanding the PAS. Achieving such clearance, especially for long-term improvement, usually necessitates an advancement of the maxilla and mandible of 10 to 20 mm (Figs. 108-6 and 108-7). Movements of less than 10 mm have a higher risk of early partial or total relapse over time. Hence, over the last few years we have become more aggressive, by advancing beyond10 to 15 mm and up to 30 mm in selected cases. Such movements depend on sufficient bone, aesthetic parameters, and occlusal and temporomandibular joint stability. C LINICAL O UTCOMES In 1989, we reported on 25 patients with obesity, mandibular deficiency, and severe OSDB who underwent MMO following failure of other surgical procedures.67 The cure rate for these 25 patients, as well as for a subsequent larger group (n = 91), was greater than 90%.31 Longterm follow-up of a group of our patients who underwent MMO (n = 40) at a mean of 50.7 months (range, 12 to 146 months) showed 36 of 40 (90%) with long-term control.68 In 1990, we reported18 on 30 consecutive patients who underwent soft tissue and MMO surgery. The objective of this investigation was to compare skeletal surgery to CPAP, applying evidence-based medicine. Every patient received two treatments: CPAP and surgery with a comparing of two exposures or therapies. Each patient served as his or her own control. There were no statistical differences
between the CPAP (on the second night of titration) and the postsurgery PSG parameters (6 months after surgery). In addition, postoperatively all subjects’ EDS and snoring improved. This investigation (evidence level 2) supports maxillofacial surgery as an effective treatment to control OSDB and suggests that this surgery is equivalent to nasal CPAP (Fig. 108-8A and B). Preoperative and postoperative overnight attended PSGs and CPAP PSGs were used to evaluate total sleep time (TST), wake after sleep onset (WASO), stages 3 and 4, REM, respiratory disturbance index (RDI), low saturation, and desaturation less than 90%. Key studies by other centers using MMO (bimaxillary surgery) for the treatment of OSDB are combined with some of our reports and are listed in chronological order in Table 108-4.31,37,41,67,69-84, Lye and colleagues84 evaluated quality of life (QOL) in their sleep subjects who underwent MMO surgery using the Functional Outcomes of Sleep Questionnaire (FOSQ). They reported a subjective functional improvement in these MMO patients. Adverse Consequences of Phases I and II As seen at our center, adverse effects associated with the GAHMS, although minimal, can include infection (<2%), need for root canal therapy (<1%), permanent tooth anesthesia (<6%), seroma (<2%), mandibular fracture (0%), and aspiration (0%). MMO can have similar adverse consequences. We have experienced no significant episodes of bleeding or infection. Paresthesias or anesthesia of the lip or chin area seldom lasts more than 6 to 12 months, if either occurs at all. There has been some skeletal relapse, with 15% of the patients developing a malocclusion. The severity is limited but it is not unusual to see minor dental interferences that can require occlusal equilibration or orthodontic follow-up. On very rare occasions, a revision surgical procedure may be necessary.
Pre Bi-Max
Post Bi-Max
PAS Figure 108-6 Maxillomandibular advancement osteotomy (MMO) procedure. Lefort I maxillary osteotomy with rigid plate fixation and a bilateral sagittal split mandibular osteotomy with bicortical screw fixation and titanium plating. The advancement should be at least a minimum of 10 mm and can be as much as 20 to 30 mm in selected cases. A previous genioglossus advancement is shown.
PAS Figure 108-7 This patient has undergone phase I and phase II upper airway reconstruction (UAR). Note the improvement of the posterior airway space (PAS). X-rays show preoperative to postoperative skeletal surgery.
CHAPTER 108 • Surgical Management for Obstructive Sleep-Disordered Breathing 1261
50 45
% Total sleep time
40 35
20.6
30
21.7
25
21.1
19.7
20 15 10 5
humans for treatment of SDB only after an animal (porcine) model study showed efficacy and safety in this delicate tissue.85 The advantages of RF over electrocautery and laser energy surgery reside in its precision in ablating tissues and in the ease of control. All three levels of the upper airway (turbinates, palate, and tongue) may be treated with RF.
TST Pretreatment 367.3 (SD±63.4) CPAP 360.0 (SD±83.2) Surgery 370.0 (SD±52.5)
8.3 8.4
6.6
8.7
2.3
0 Stage 3-4
A
REM CPAP
Pretreatment 100
72.0
90 80
Wake–sleep onset Surgery 275.0
86.0 86.0 61.0
70 60 50 40 30 20 10
9.8 9.6
8.6 8.8
0
B
RDI
Low SaO2
# Oxysen desaturation <90%
Figure 108-8 A, Comparisons of pretreatment and posttreatment nasal continuous positive airway pressure (CPAP) and skeletal surgery polysomnography (PSG) respiratory and sleep parameters. B, Comparisons of pretreatment and posttreatment nasal CPAP and skeletal surgery PSG parameters. SaO2, oxygen desaturation; RDI, respiratory disturbance index; REM, rapid eye movement; SD, standard deviation; TST, total sleep time.
Treatment Alternatives for Tongue Base Obstruction Over the course of the previous 25 years, a number of procedures have been modified or abandoned. For example, previously used treatments such as laser midline glossectomy and lingualplasty or partial glossectomy are now seldom used due to variable results and their inherent invasiveness. Temperature-Controlled Radiofrequency Treatments The advent of RF tissue ablation and subsequent reduction has been studied extensively in many medical and surgical specialties. RF has been employed for precise tissue ablation in conditions affecting vital organs such as the central nervous system, where accurate ablation of the abnormal tissue is mandatory and excess ablation is dangerous. TCRF was applied to the upper airway in
T URBINATES TCRF treatment at the nasal level has shown a positive treatment effect for turbinate hypertrophy, especially in patients who are struggling with this problem during use of CPAP. Powell and coworkers17 reported airway improvement in a prospective, randomized, double-blind, placebocontrolled study on TCRF turbinate reduction and CPAP use. P ALATE TCRF treatment at the palatal level showed positive results when used for simple snoring.86,87 TCRF use in the palate for primary treatment of OSDB is probably limited because of the mass of excess tissue usually encountered. However, Blumen and colleagues88 reported on 29 patients with mild to moderate OSDB who were treated with TCRF for soft palate obstruction. The mean AHI decreased significantly, from 19.1 (range, 10 to 30) to 9.8 events per hour of sleep, with a nonsignificant change in LSAT from 85.3% to 86.4%. EDS, snoring, and PSG results were remarkably improved. T ONGUE TCRF treatment for obstruction at the tongue base level should be done on a case-by-case basis, because the treatment outcomes vary due to the multifactorial findings typical of SDB. A few of these factors include age, health, weight, tongue size, skeletal deficiency, other areas of obstruction, and severity of OSDB. We and others have reported on the application of RF to the tongue, and, although outcomes vary, encouraging results have been noted.89,90,91 We consider tongue base treatment with TCRF to be adjunctive in nature and not usually a primary procedure. Treatment provided as a single high dose can result in increased complications and is less likely to be successful owing to the biophysics of energy delivery. Radiofrequency to the soft tissues of the upper airway in OSDB is a minimally invasive treatment modality. The tongue was the target for its original development as a treatment to shrink the tongue base and open the PAS. However, after 10 years of use and clinical experience, we use it only as an adjunctive measure for tongue reduction. It is excellent for primary turbinate hypertrophy and a reasonable management for snoring of the soft palate. We have not found it acceptable for the treatment of OSDB at the palate level.
AASM SURGICAL PRACTICE PARAMETERS The AASM has proposed practice parameters for the role of surgical treatment of obstructive sleep apnea; these are summarized in Table 108-5.91a,91b
1262 PART II / Section 13 • Sleep Breathing Disorders Table 108-4 Clinical Outcomes of Bimaxillary Advancement* AUTHOR (REF)
YEAR
COUNTRY
SUBJECTS (N)
RESPONDER RATE* (%)
Riley et al. (67)
1989
Waite et al. (69)
1989
United States
25
>90
United States
23
65
Riley et al. (31) Hochban et al. (70)
1993
United States
91
>90
1997
Germany
38
97
Conradt et al. (71)
1997
Germany
15
80
Prinsell (72)
1999
United States
50
100
Lee et al. (73)
1999
United States
3
100
Bettega et al. (37)
2000
France
20
75
Wagner et al. (74)
2000
France
21
70
Li et al. (75)
2000
United States
21
81
Li et al. (76)
2000
United States
19
94
Hendler et al. (77)
2001
United States
40
86
Li et al. (78)
2002
United States
12
100
Goh et al. (79)
2003
Singapore
11
81
Datillo et al. (41)
2004
United States
15
>95
Smatt et al. (80)
2005
France
16
84
Hoekema et al. (81)
2006
Netherlands
4
100
Lu et al. (82)
2007
China
9
100
Kessler et al. (83)
2007
Germany
6
100
Lye et al. (84)
2008
United States
15
86
*There are 20 peer-reviewed papers from the index investigation of Riley et al. in 1989 to 2008 when this procedure was adapted to SDB. Multiple countries participated in these studies with good results. The mean response rate was 88.7%. Three papers used >90% (n = 2) and >95% (n = 1); only the base percentage was used to calculate the mean. Hence, the responder rate over 19 years should be 90% based on these reports. However, cure or responder rates varied, in part because the criteria used to determine success was not uniform among the individual investigators. In addition, variations in surgical technique were common among the studies.
Table 108-5 Summary of Surgical Practice Parameters of AASM of 2010 MANAGEMENT
RECOMMENDATION
Severity of OSA must be documented prior to initiating surgical treatment
Standard
Patient advised about rates of surgical success, the availability, effectiveness, and success rates of other treatments including PAP and oral appliances
Standard
Resolution of clinical signs and symptoms of OSA and normalization of sleep quality, AHI, and gas exchange are desired outcomes
Standard
Postoperatively, after healing there should be follow-up: an objective measure of the severity of SDB and oxygen saturation; assessment for residual symptoms; long term to detect recurrence of OSA
Standard
PROCEDURES
RECOMMENDATIONS
Tracheostomy can be considered when other options do not exist, are refused, and there is clinical urgency
Option
MMA for severe OSA when conventional treatment is not an option*
Option
UPPP for OSA: In severe OSA, PAP treatment to be offered first; for mild to moderate OSA, PAP or oral appliances offered first
Option
Stepwise multiple operations in patients with multiple sites of narrowing in the upper airway, particularly if they have failed UPPP treatment
Option
LAUP is NOT recommended to treat OSA
Standard
RFA can be considered when conventional treatment is not an option*
Option
Palatal implants may be effective in mild to moderate OSA when conventional treatment is not an option*
Option
Note: Recommendations based on whether evidence shows that benefits clearly outweigh harm/burden. Standard, quality of evidence is high; Option, quality of evidence is very low. *Patient can’t or won’t tolerate or adhere to PAP therapy, or in whom oral appliances have been considered and deemed ineffective or undesirable
CHAPTER 108 • Surgical Management for Obstructive Sleep-Disordered Breathing 1263
Box 108-12 Risk Management Protocol 1. Patients with an AHI > 40 and LSAT < 80% begin using nasal CPAP at least 2 weeks before surgery and continue with it postoperatively until polysomnography is performed (at 4 to 6 months) to document outcome. 2. Surgeons are present for anesthetic induction and intubation. For potentially difficult airways, a fiberoptic intubation is performed with the patient awake. 3. Patients are extubated when awake in the operating room immediately after surgery. 4. A patient undergoing multiple procedures (e.g., uvulopalatopharyngoplasty and maxillofacial surgery), or a single procedure when there are significant coexisting medical problems (e.g., hypertension, coronary artery disease), is monitored in the ICU for the first day after surgery and then in the surgical ward. The patient is monitored by oximetry throughout the hospital stay. 5. Patients who previously were prescribed and able to use nasal CPAP must continue to use CPAP during all periods of sleep after surgery. All other patients are maintained on humidified oxygen (35%) via face tent. 6. Analgesia consists of intravenous morphine sulfate or meperidine HCl in the ICU. Intravenous narcotics are administered by a nurse in small, graduated doses while the respiratory rate is monitored. All nurses caring for patients with SDB are educated about the mechanisms of SDB and the use of narcotics in this population. Patient-controlled analgesia (PCA pump) is not recommended. Intramuscular meperidine HCl and oxycodone elixir are used in the surgical ward. Oral hydrocodone or codeine and acetaminophen are used after discharge. 7. Requirements for discharge include adequate oral intake of fluids, satisfactory pain control, stable or resolving surgical edema, and the use of nasal CPAP if the patient can tolerate it. Fiberoptic nasopharyngoscopy is done on each patient at the bedside to assess the status of the airway before discharge. This procedure can reveal significant potential (but asymptomatic at this time) airway compromise that can contribute to airway problems after discharge. AHI, apnea–hypopnea index; CPAP, continuous positive airway pressure; ICU, intensive care unit; LSAT, lowest oxyhemoglobin saturation; SDB, sleep-disordered breathing;
SURGICAL RISK MANAGEMENT FOR OBSTRUCTIVE SLEEPDISORDERED BREATHING Although rare, life-threatening complications have been associated with sleep apnea surgery. Fairbanks,92 on the basis of a national survey, reported 16 fatalities and 7 near fatalities from UPPP in the early postoperative period. Respiratory obstruction, secondary to pharmacologic sedation and surgical edema, was the most commonly cited cause. Several authors have cautioned against the use of narcotics in patients who have OSDB and who undergo upper airway or other surgery.93-96
In an earlier study, we observed that when nasal CPAP was used after surgery, it protected OSDB patients from airway obstruction and hypoxemia and could be used in some cases to avoid tracheotomy.19 Subsequently, we adopted the use of nasal CPAP as a standard whenever possible for all patients undergoing surgery for OSDB, and we developed a risk-management surgical protocol for patients with OSDB. This protocol is frequently updated to provide ongoing improvements in patient safety. An outcomes review of the risk-management protocol was performed on 182 consecutively treated patients with OSDB undergoing 210 surgical procedures in 1995.97 Data examined included the patient’s age, sex, weight (BMI), facial skeletal development, coexisting medical problems, complications with anesthetic induction and extubation, postoperative vital signs, medication requirements for all postoperative days, days in the intensive care unit, and total length of hospital stay. The review concluded that patients undergoing surgical reconstruction of the airway for OSDB often have coexisting medical problems (cardiovascular disease being the most significant) that can complicate therapy. A risk-management protocol is presented in Box 108-12.
❖ Clinical Pearls Sleep-disordered breathing is primarily caused by an anatomic collapse of the upper airway during sleep and hence is a surgical problem. Surgical procedures have been developed over the years to manage and control SDB. Not all of these procedures have equivalent outcomes, but there are combinations that offer the same control of SDB as medical management. Because SDB has multifactorial etiologies and confounds, treatment often involves a combination of medical and surgical management. Both the medical sleep specialist and the sleep surgeon need to be informed in both fields. All patients deserve to be treated by a physician who thoroughly understands all treatment options and can without bias communicate these options to their patients.
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33. Ramirez SG, Loube DI. Inferior sagittal osteotomy with hyoid bone suspension for obese patients with sleep apnea. Arch Otolaryngol Head Neck Surg 1996;122:953. 34. Yoa M, Utley D, Terris D. Cephalometric parameters after multilevel pharyngeal surgery for patients with obstructive sleep apnea. Laryngoscope 1998;108:789-795. 35. Lee N, Givens C, Wilson J, et al. Staged surgical treatment of obstructive sleep apnea syndrome: a review of 35 patients. J Oral Maxillofac Surg 1999;57:382-385. 36. Wagner I, Coiffier T, Sequert C, et al. Surgical treatment of severe sleep apnea syndrome by maxillomandibular advancing or mental transposition. Ann Otolaryngol Chir Cervicofac 2000;117:137146. 37. Bettega G, Pépinl J, Veale D, et al. Obstructive sleep apnea syndrome: fifty-one consecutive patients treated by maxillofacial surgery. Am J Crit Care Med 2000;162:641-649. 38. Vilaseca I, Morello A, Montserrat J, et al. Usefulness of uvulopalatopharyngoplasty with genioglossus and hyoid advancement in the treatment of obstructive sleep apnea. Arch Otolaryngol Head Neck Surg 2002;128:435-440. 39. Fibbi A, Ameli F, Brocchetti F, et al. Combined genioglossus advancement (ACMG): inferior sagittal mandibular osteotomy with genioglossus advancement and stabilization with suture in patients with OSAS. Preliminary clinical results. Acta Otorhinolaryngol Ital 2002;22:153-157. 40. Neruntarat C. Genioglossus advancement and hyoid myotomy under local anesthesia. Otolaryngol Head Neck Surg 2003;129: 85-91. 41. Dattilo DJ, Drooger SA. Outcome assessment of patients undergoing maxillofacial procedures for the treatment of sleep apnea; comparison of subjective and objective results. J Oral Maxillofac Surg 2004; 62:164-168. 42. Yin S, Yi H, Lu W, et al. [Genioglossus advancement and hyoid suspension plus uvulopalatopharyngoplasty for severe OSAHS]. Lin Chuang Er Bi Yan Hou Ke Za Zhi 2005;19:673-677. 43. Yi HL, Yin SK, Lu WY, et al. [Effectiveness of combined surgery for treating obstructive sleep apnea hypopnea syndrome]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi 2006;41:89-94. 44. Jacobwitz O. Palatal and tongue base surgery for surgical treatment of obstructive sleep apnea: a prospective study. Otolaryngol Head Neck Surg 2006;135:258-264. 45. Richard W, Kox D, den Herder C, et al. One stage multilevel surgery (uvulopalatopharyngoplasty, hyoid suspension, radiofrequent ablation of the tongue base with/without genioglossus advancement), in obstructive sleep apnea syndrome. Eur Arch Otorhinolaryngol 2007; 264:439-444. 46. Foltán R, Hoffmannová J, Preti M, et al. Genioglossus advancement and hyoid myotomy in treating obstructive sleep apnea syndrome—a follow-up study. J Craniomaxilllofac Surg 2007;35:246-251. 47. Santo JF Jr, Abrahao M, Gregório LC, et al. Genioplasty for genioglossus muscle advancement in patients with obstructive sleep apnea– hypopnea syndrome and mandibular retrognathia. Rev Bras Otorhinolaringol (Engl Ed) 2007;73:480-486. 48. Van de Graaff W, Gottfried S, Mitra J, et al. Respiratory function of hyoid muscles and hyoid arch. J Appl Physiol 1984;57:197-204. 49. Kaya N. Sectioning the hyoid bone as a therapeutic approach for obstructive sleep apnea. Sleep 1984;7:77-78. 50. Patton TJ, Thawley SE, Water RC, et al. Expansion hyoid plasty: a potential surgical procedure designed for selected patients with obstructive sleep apnea syndrome—experimental canine results. Laryngoscope 1983;93:1387-1396. 51. Riley RW, Powell NB, Guilleminault C. Obstructive sleep apnea and the hyoid: a revised surgical procedure. Otolaryngol Head Neck Surg 1994;111:717-721. 52. Kang Q, Wang X, Wei J, et al. [Central suspension operation of hyoid and lower jaw for OSAS]. Lin Chuang Er Bi Yan Hou Ke Za Zhi 2003;17:541-542. 53. Hörmann K, Baisch A. The hyoid suspension. Laryngoscope 2004;114:1677-1679. 54. den Herder C, van Tinteren H, de Vries N. Hyoidthyroidepexia: a surgical treatment for sleep apnea syndrome. Laryngoscope 2005;115:740-745. 55. Bowden MT, Kezirian EJ, Utley D, et al. Outcomes of hyoid suspension for the treatment of obstructive sleep apnea. Arch Otolaryngol Head Neck Surg 2005;131:440-445.
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56. Stuck BA, Neff W, Hörmann K, et al. Anatomic changes after hyoid suspension for obstructive sleep apnea: an MRI study. Otolaryngol Head Neck Surg 2005;133:397-402. 57. Wang W, Wang Y, Wang X, et al. [Application of hyoid suspension in obstructive sleep apnea-hypopnea syndrome]. Lin Chuang Er Bi Yan Hou Ke Za Zhi 2005;19:978-980. 58. Verse T, Baisch A, Maurer JT, et al. Multilevel surgery for obstructive sleep apnea: short-term results. Otolaryngol Head Neck Surg 2006;134:571-577. 59. Baisch A, Maurer JT, Hörmann K. The effect of hyoid suspension in a multilevel surgery concept for obstructive sleep apnea. Otolaryngol Head Neck Surg 2006;134:856-861. 60. Yuan Y, Pan X, Li X, et al. [Multiple pklane operations in treating severe obstructive sleep apnea-hypopnea syndrome]. Lin Chuang Er Bi Yan Hou Ke Za Zhi 2006;20:502-504. 61. Yin SK, Yi HL, Lu WY, et al. Genioglossus advancement and hyoid suspension plus uvulopalatopharyngoplasty for severe OSAHS. Otolaryngol Head Neck Surg 2007;136:626-631. 62. Riley R, Powell N, Li K, et al. An adjunctive method of radiofrequency volumetric tissue reduction of the tongue for OSAS. Otolaryngol Head Neck Surg 2003;129:37-42. 63. Kuo PC, West RA, Bloomquist DS, et al. The effect of mandibular osteotomy in three patients with hypersomnia and sleep apnea. Oral Surg Oral Med Oral Pathol 1979;48:385-392. 64. Bear SE, Priest JH. Sleep apnea syndrome: correction with surgical advancement of the mandible. J Oral Surg 1980;38:543-549. 65. Powell N, Guilleminault C, Riley R, et al. Mandibular advancement and obstructive sleep apnea syndrome. Bull Eur Physiopathol Respir 1983;19:607-610. 66. Guilleminault C, Riley R, Powell N. Sleep apnea in normal subjects following mandibular osteotomy with retrusion. Chest 1985;88: 776-778. 67. Riley R, Powell N, Guilleminault C. Maxillofacial surgery and obstructive sleep apnea: a review of 80 patients. Otolaryngol Head Neck Surg 1989;101:353-361. 68. Riley R, Powell N, Li K, et al. Surgery and obstructive sleep apnea: long-term clinical outcomes. Otolaryngol Head Neck Surg 2000; 122:415-421. 69. Riley RW, Powell WB, Guilleminault C. Maxillofacial surgery and obstructive sleep apnea: a review of 80 patients. Otolaryngol Head Neck Surg 1989;101:353-361. 70. Hochban W, Conradt R, Brandenburg U, et al. Surgical maxillofacial treatment of obstructive sleep apnea. Plast Reconstr Surg 1997;99: 619-626. 71. Conradt R, Hochban W, Brandenburg U, et al. Long-term follow-up after surgical treatment of obstructive sleep apnea by maxillomandibular advancement. Eur Respir J 1997;10:123-128. 72. Prinsell J. Maxillomandibular advancement surgery in a site-specific treatment approach for obstructive sleep apnea in 50 consecutive patients. Chest 1999;116:1519-1529. 73. Lee N, Givens C, Wilson J, et al. Staged surgical treatment of obstructive sleep apnea syndrome: a review of 35 patients. J Oral Maxillofac Surg 1999;57:382-385. 74. Wagner I, Coiffier T, Sequert C, et al. Surgical treatment of severe sleep apnea syndrome by maxillomandibular advancing or mental transposition. Ann Otolaryngol Chir Cervicofac 2000;117:137146. 75. Li KK, Powell NB, Riley RW, et al. Morbidly obese patients with severe sleep apnea: is airway reconstructive surgery a viable treatment option? Laryngoscope 2000;110:982-987. 76. Li KK, Riley RW, Powell NB, et al. Maxillomandibular advancement for persistent obstructive sleep apnea after phase I surgery in patients without maxillomandibular deficiency. Laryngoscope 2000;110(10 Pt. 1):1684-1688. 77. Hendler BH, Costello BJ, Silverstein K, et al. A protocol for uvulopalatopharyngoplasty, mortised genioplasty, and maxillomandibular advancement in patients with obstructive sleep apnea: an analysis of 40 cases. J Oral Maxillofac Surg 2001;59;892-897.
78. Li KK, Guilleminault C, Riley RW, et al. Obstructive sleep apnea and maxillomandibular advancement: an assessment of airway changes using radiographic and nasopharyngoscopic examinations. J Oral Maxillofac Surg 2002;60:526-530. 79. Goh YH, Lim KA. Modified maxillomandibular advancement for the treatment of obstructive sleep apnea: a preliminary report. Laryngoscope 2003;113:1577-1582. 80. Smatt Y, Ferri J. Retrospective study of 18 patients treated by maxillomandibular advancement with adjunctive procedures for obstructive sleep apnea syndrome. J Craniofac Surg 2005;16:770-777. 81. Hoekema A, de Lange J, Stegenga B, et al. Oral appliances and maxillomandibular advancement surgery: an alternative treatment protocol for the obstructive sleep apnea-hypopnea syndrome. J Oral Maxillofac Surg 2006; 64:886-891. 82. Lu XF, Zhu M, He JD, et al. [Uvulopalatopharyngoplasty and maxillomandibular advancement for obese patients with obstructive sleep apnea hypopnea syndrome: a preliminary report]. Zhonghua Kou Qiang Yi Xue Za Zhi 2007;42:199-202. 83. Kessler P, Ruberg F, Obbarius H, et al. Surgical management of obstructive sleep apnea. Mund Kiefer Gesichtschir 2007;11:81-88. 84. Lye KW, Waite PD, Meara D, et al. Quality of life evaluation of maxillomandibular advancement surgery for treatment of obstructive sleep apnea. J Oral Maxillofac Surg 2008;66:968-972. 85. Powell NB, Riley RW, Troell RJ, et al. Radiofrequency volumetric reduction of the tongue: a porcine pilot study for the treatment of obstructive sleep apnea syndrome. Chest 1997;111:1348-1355. 86. Back L, Tervahartiala P, Piilonen A, et al. Bipolar radiofrequency thermal ablation of the soft palate in habitual snorers without significant desaturations assessed by magnetic resonance imaging. Am J Respir Crit Care Med 2002;166:865-871. 87. Wedman J, Miljeteig H. Treatment of simple snoring using radio waves for ablation of uvula and soft palate: a day-case surgery procedure. Laryngoscope 2002;112:1256-1259. 88. Blumen M, Dahan S, Fleury B, et al. Radiofrequency ablation for the treatment of mild to moderate obstructive sleep apnea. Laryngoscope 2002;112:2086-2092. 89. Powell N, Riley R, Guilleminault C. Radiofrequency tongue base reduction in sleep-disordered breathing: a pilot study. Otolaryngol Head Neck Surg 1999;120:656-664. 90. Woodson B, Nelson L, Mickelson S, et al. A multi-institutional study of radiofrequency volumetric tissue reduction for OSAS. Otolaryngol Head Neck Surg 2001;125:303-311. 91. Farrar J, Ryan J, Oliver E, et al. Radiofrequency ablation for the treatment of obstructive sleep apnea: a meta-analysis. Laryngoscope 2008;118:1878-1883. 91a. Nisha Aurora R, Casey KR, David Kristo D, et al. Practice parameters for the surgical modifications of the upper airway for obstructive sleep apnea in adults. Sleep (in Press); July 2010. 91b. Caples SM, Rowley JA, Prinsell JR, et al. Surgical modifications of the upper airway for obstructive sleep apnea in adults: a systematic review and meta-analysis. Sleep (in press); July 2010. 92. Fairbanks D. Uvulopalatopharyngoplasty complications and avoidance strategies. Otolaryngol Head Neck Surg 1990;102:239-245. 93. Esclamado RM, Glenn MG, McCulloch TM, et al. Perioperative complications and risk factors in the surgical treatment of obstructive sleep apnea syndrome. Laryngoscope 1989;99:1125-1129. 94. Gabrielczyk MR. Acute airway obstruction after uvulopalatopharyngoplasty for obstructive sleep apnea syndrome. Anesthesiology 1988;69:941-943. 95. Kravath RE, Pollak CP, Borowiecki B, et al. Obstructive sleep apnea and death associated with surgical correction of velopharyngeal incompetence. J Pediatr 1980;96:645-648. 96. den Herder C, Schmeck J, Appelboom DJ, et al. Risks of general anaesthesia in people with obstructive sleep apnoea. BMJ 2004;329: 955-959. 97. Riley RW, Powell NB, Guilleminault C, et al. Obstructive sleep apnea surgery: risk management and complications. Otolaryngol Head Neck Surg 1997;117:648-652.
Oral Appliances for SleepDisordered Breathing
Peter A. Cistulli, Kathleen A. Ferguson, and Alan A. Lowe Abstract Oral appliances are an established treatment option for snoring and mild obstructive sleep apnea–hypopnea (OSAH). Oral appliance therapy is a noninvasive, reversible approach to treatment. Oral appliances appear to work by increasing upper airway space, stabilizing the anterior position of the mandible, advancing the tongue or soft palate, or both, and possibly by changing upper airway muscle activity. Randomized, controlled trials of oral appliance therapy have shown a good efficacy in patients with mild to moderate OSAH and in some patients with more severe OSAH. In most of the studies, patients preferred the oral appliance over continuous positive airway pressure (CPAP), although CPAP was more effective in reducing the apnea–hypopnea index (AHI). Most patients report improved sleep quality and excessive daytime sleepiness with oral appliance therapy. Additionally, there is growing evidence of improvements in other important
Oral appliances are an established treatment option for simple snoring and mild obstructive sleep apnea–hypopnea (OSAH). There are two main appliance types in common clinical use: devices that advance only the tongue and those that advance the mandible during sleep. In 2006, the American Academy of Sleep Medicine published updated practice parameters on the use of oral appliance therapy in the treatment of OSAH.1 These guidelines stated that oral appliances are indicated as therapy in patients with simple snoring and mild to moderate OSAH in patients who prefer oral appliances, or those who refuse or have failed CPAP. Oral appliances may also have a role as an alternative therapy for severe OSAH when other therapies have failed. Many prospective studies have been published, including randomized, controlled clinical trials with comparisons with continuous positive airway pressure (CPAP), different oral appliance designs, surgery, and placebo.2-17 With evidence of effectiveness from such studies, there is a growing basis for expanding the indications for oral appliance therapy in the management of OSAH. This chapter provides a review of the mechanism of action, effectiveness, indications and predictors of outcome, side effects, and complications of oral appliance therapy. The role of the physician and dentist is discussed, highlighting the need for an interdisciplinary approach.
TYPES OF APPLIANCES There are two main appliance groups in common clinical use: mandibular repositioning appliances (MRAs) and tongue-repositioning devices. MRAs, also known as mandibular advancement splints (MASs) or mandibular advancement devices (MADs), are the focus of this chapter because they are more widely used in clinical practice and have a greater evidence base. These devices are anchored to part or all of the dental arch so as to induce protrusion 1266
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health outcomes, including neurocognitive function and cardiovascular health. Oral appliance therapy is generally well tolerated, and short-term side effects are usually minor and are related to excessive salivation, jaw and tooth discomfort, and occasionally joint discomfort. These symptoms usually improve over time. Significant temporomandibular joint (TMJ) complications are rare, but long-term occlusal changes are common. With evidence of effectiveness from randomized, controlled trials, it is now reasonable to expand the indications for oral appliance therapy to the treatment of patients with moderate as well as mild OSAH. Oral appliance therapy is a unique opportunity for dentists and physicians to work together to select the ideal patients for this form of treatment. Each plays a crucial role in providing the patient with optimal care. With collaboration and good communication between the dentist and the sleep clinician, many patients with snoring or OSAH can be treated effectively with oral appliances.
of the mandible (Fig. 109-1). Many designs are available, but they generally fall into either one-piece (monobloc) or two-piece (dual-bloc) configurations (Figs. 109-2 to 109-5). They are usually customized to the dentition, although off-the-shelf varieties also exist. Tongue-advancing appliances hold the tongue in a forward position without advancing the mandible. Some tongue-advancing appliances, such as the tongue-retaining device (TRD), hold the tongue forward in a bulb, using suction created by displacement of air when the tongue is advanced into it (Fig. 109-6). TRDs may also be custom made or off the shelf.
MECHANISM OF ACTION Current evidence suggests that the pathogenesis of OSAH reflects reduced upper airway size and altered upper airway dilator muscle activity. Oral appliances can improve upper airway patency during sleep by enlarging the upper airway, by decreasing upper airway collapsibility (e.g., improving upper airway muscle tone), or through both mechanisms.17a The effects of oral appliances on upper airway size vary among studies, and these differences are likely related to variations in imaging techniques used (e.g., cephalometry versus computed tomography [CT]), the study methods (evaluation during wakefulness versus during sleep), the subject’s body position (supine versus upright), the different types of appliances, and the amount of protrusion. However, they are consistent in that most imaging studies suggest that MRAs have a direct effect on position of the mandible and increase upper airway cross-sectional area. Furthermore, such studies have generally observed more-complex changes in airway shape and size than might be initially predicted from simple anterior displacement of the mandible. For example, many studies have identified a predominant change in the lateral dimension, at the level of the velopharynx, highlighting the complex anatomic and functional
CHAPTER 109 • Oral Appliances for Sleep-Disordered Breathing 1267
Figure 109-1 Lateral cephalograms of a patient before treatment (left) and while wearing a Klearway mandibular repositioning appliance (right).
Figure 109-2 The Klearway adjustable oral appliance. (Courtesy of Great Lakes Orthodontics, Ltd, Tonawanda, NY.)
Figure 109-3 An adjustable Herbst appliance. (Courtesy of Great Lakes Orthodontics, Ltd, Tonawanda, NY.)
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Figure 109-6 A tongue-retaining device. (Photograph courtesy of Dr. Alan Lowe, University of British Columbia, Vancouver, British Columbia, Canada.) Figure 109-4 The Monobloc appliance. (Courtesy of Dr. Konrad Bloch, University of Zurich, Switzerland.)
Figure 109-5 The SomnoDent mandibular advancement splint. (Courtesy of SomnoMed Ltd, Crows Nest, Australia)
linkages between segments of the pharynx. The effects on upper airway size are summarized in Table 109-1. Simple anterior movement of the tongue or mandible during wakefulness can increase cross-sectional airway size at all levels in persons with and without OSAH.18 Passive mandibular advancement during general anesthesia (achieved by a jaw thrust maneuver) stabilizes the upper airway by increasing airway cross-sectional area in both the retropalatal and retroglossal area and reducing its collapsibility (i.e., more-negative intraluminal pressure is required to close the upper airway).19 Similarly, mandibular advancement with an MRA reduces closing pressure (e.g., morenegative intraluminal pressure is required to close the upper airway), reflecting decreased upper airway collapsibility.20 Effects of MRAs on upper airway muscle activity have not been well studied. A study using an MRA reported that upper airway muscle tone increased except in the post-
apnea period, when genioglossus tone was lower.21 Another study also found augmentation of genioglossus tone with mandibular advancement during wakefulness in adults without OSAH.22 Although the presence of MRA in the mouth has effects on upper airway tone through stimulation of oral afferent pathways, these effects are insufficient to reduce apnea, and mechanical mandibular advancement is required for the appliance to improve OSAH.7 TRDs appear to affect genioglossus muscle activity in patients with OSAH (either awake or asleep),23,24 but effects of this type of device on other upper airway muscles have not been evaluated. A TRD worn during sleep reduced the apnea–hypopnea index (AHI).24 When the TRD was worn without tongue advancement (no bulb), the AHI decreased and there was increased peak genioglossus activity, measured just before the airway opened at the end of residual obstructive events. The mechanism for this effect and its significance is not certain, but increased genioglossus tone might contribute to upper airway reopening.
CLINICAL OUTCOMES Since the turn of the century there has been a substantial increase in the quantity and quality of research evaluating the efficacy and effectiveness of oral appliance therapy.25,26 The strengths of these newer studies include the use of inactive oral devices or tablets (placebo) as the control treatment, more-stringent definitions of treatment outcome, direct comparisons to CPAP, and an increased focus on health outcomes. A comprehensive review of oral appliance therapy was published in 2006,25 along with updated practice parameters for their use.1 Polysomnographic Variables There is strong evidence from randomized, controlled trials that MRAs are effective in preventing or significantly reducing the number of obstructive breathing events and arousals and in improving arterial oxygen saturation across the full spectrum of OSAH severity. Oral appliances have been associated with a reduction of the AHI to fewer than 5/hr in 36% to 50% of patients,7,27,28 and the proportion of patients achieving an AHI less than 10/hour has ranged from 30% to 70%.25 Using the most liberal definition of success, namely a reduction of more than 50% in AHI, an
CHAPTER 109 • Oral Appliances for Sleep-Disordered Breathing 1269
Table 109-1 Effect of Mandibular Repositioning Appliances on Upper Airway Size IMAGING MODALITY
IMAGE OBTAINED
BODY POSITION
DIMENSION
EFFECT
Lateral cephalometry
Awake
Upright
Posterior airway space
Increased
REFERENCES 75, 91
Awake
Upright
Posterior airway space
Unchanged
92
Awake
Upright
Retropalatal airway space
Increased
93 93, 94
Awake
Upright
Tongue posture
Flattened
Awake
Upright
Oropharynx size
Increased
94
Awake
Upright
Hypopharynx size
Increased
56
Awake
Supine
Velopharynx size
Increased
95
Oropharynx size
Unchanged
Awake
Supine
Sagittal cross-sectional area of the pharynx
Increased
64
Awake
Upright
Mandibular plane to hyoid distance
Decreased
91, 93, 94
Awake
Supine
Mandibular plane to hyoid distance
Decreased
64
Computed tomography
Awake
Supine
Pharyngeal crosssectional airway size
Increased sectional airway size
96
Magnetic resonance imaging
Asleep
Supine
Velopharynx size
Increased
91
Awake
Supine
Oropharynx size
Increased
97
Hypopharynx size
Increased
Velopharynx size
Increased
Videoendoscopy
Awake
Supine
average of 65% of patients achieve this outcome.25 With regard to oxygen saturation parameters, the improvements noted with oral appliances are of a smaller magnitude than the changes in AHI. In general, studies have identified improved minimum oxygen saturation, but rarely to normal levels. Some studies have reported improved sleep architecture, with increases in rapid eye movement (REM) sleep.7 Similarly, reductions in arousal index have been reported.7,27,28 It seems likely that differences in oral appliance designs have an impact on the extent to which these parameters are affected. Although these differences are yet to be fully established, it is thought that minimization of bite opening and impingement on tongue space are important design features. Upper airway resistance syndrome (UARS) is part of the spectrum of sleep-disordered breathing in which subtle degrees of inspiratory flow limitation leads to sleep fragmentation and OSAH symptoms.29,30 The role of oral appliance therapy in this specific subgroup of patients has received little attention. In a prospective trial on 32 patients with UARS, Yoshida found statistically and clinically significant improvements in arousal index (average number of arousals per hour slept), oxygen saturation, sleep efficiency, and subjective and objective sleepiness, suggesting that MRAs may be helpful in the treatment of UARS.31 Efficacy of the TRD has been less well studied than efficacy of the MRA. In 1982, Cartwright and Samelson reported their initial experience with the TRD in 20 patients.32 Among the 14 of the 20 patients who underwent polysomnography before and with the TRD, there was a reduction in AHI of approximately 50%, even though
98
patients wore the TRD only half the night.32 Subsequent uncontrolled studies of the TRD reported a 69% to 80% success rate.33,34 The TRD was found to be more effective in patients who were younger, who were less obese, and those with positional apnea (apnea that is more severe in the supine position).33 A tongue-stabilizing device was assessed in a pilot study of six patients and was found to reduce snoring, but the reduction in AHI was of borderline statistical significance.35 This device is based on the bulb component of the TRD, and because it does not cover the dentition, it is an off-the-shelf product. Snoring Snoring, with or without coexistent OSAH, is prevalent, and oral appliances have a potentially important role in the management of this problem. Uncontrolled studies, using bed-partner reports, suggest that snoring is reduced in the majority of patients.36 Similarly, a placebo-controlled study also reported improvements in subjective snoring.17 Studies using objective measures of snoring frequency and intensity confirm a reduction in both parameters, compared to an inactive oral control device.7,27 Reductions in snoring frequency are of the order of 40% to 60%, and mean snoring intensity reduces by about 3 dB.7,27 This represents a clinically important reduction in noise level and is reflected by the resumption of co-sleeping in a significant percentage of couples after oral appliance treatment.37 Daytime Sleepiness The majority of studies suggest that oral appliance therapy improves subjective daytime sleepiness as measured by
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validated questionnaires such as the Epworth Sleepiness Scale (ESS),38 with evidence from placebo-controlled studies indicating a modest reduction in the ESS score in the order of 2 points.27,39 The effect on objective sleepiness has received limited attention. In one placebo-controlled, study the mean sleep latency on the multiple sleep latency test (MSLT) after 4 weeks of MRA treatment was significantly improved by an average of 1.2 minutes compared with an inactive control oral device.27 Two other randomized, controlled studies evaluated objective sleepiness using the maintenance of wakefulness test (MWT) over treatment periods of 8 to 12 weeks and found no difference in treatment response between CPAP and oral appliance. One study13 showed similar improvement and the other found no change with either treatment.39 In the latter study, Barnes and coworkers did observe improvements in subjective sleepiness despite the lack of improvement in MWT, and poor treatment compliance may have been a factor.39 In summary, successful oral appliance therapy clearly improves subjective sleepiness, although the impact on objective sleepiness is less clear. Nevertheless, the outcomes are similar to those reported for CPAP. Neurocognitive Outcomes Only a few studies have addressed the impact of oral appliance therapy on neuropsychological functioning. Engleman and colleagues compared CPAP to oral appliance intervention in a randomized study and found no significant difference between treatments in effect on cognitive performance.13 A randomized, controlled study using an inactive oral device as a control found that active treatment with the MRA resulted in small to moderately enhanced psychomotor speed but no significant change in other neurocognitive measures.40 In another randomized, controlled study comparing oral appliance, CPAP, and tablet placebo for mild to moderate OSAH, oral appliance therapy improved tension anxiety, divided attention, and executive functioning, but CPAP was superior in improving psychomotor speed and other aspects of mood state.39 These somewhat divergent results highlight the difficulty of directly comparing neurocognitive outcomes between different studies due to differences in methodology and interpretation. Driving performance is an important neurocognitive outcome that may be adversely affected by OSAH. A number of studies have examined the effect of CPAP treatment on driving simulation performance, but there has been little assessment of oral appliances in this regard. A randomized parallel study comparing an oral appliance and CPAP reported similar improvements in driving simulator performance over a period of 2 to 3 months.41 Future studies will need to be carefully designed to overcome the known placebo effect on neurocognitive outcomes associated with OSAH treatments. Collectively, these limited studies indicate a beneficial effect of MRA on selected neurocognitive outcomes, and the magnitude of the effect appears to be similar to that of CPAP. Cardiovascular Outcomes Randomized controlled and uncontrolled studies have identified a modest reduction in blood pressure with oral appliance therapy.39,42-44 In one study, compared with a
placebo oral device, 4 weeks of active MRA treatment produced a mean reduction in awake systolic blood pressure of 3.3 mm Hg and diastolic blood pressure of 3.4 mm Hg.42 In another study, comparing 3-month treatment periods with CPAP, oral appliance, and tablet placebo in patients with mild to moderate OSAH, oral appliance therapy, but not CPAP, was associated with a small reduction in nocturnal diastolic blood pressure (approximately 2 mm Hg).39 More recently, intermediate cardiovascular endpoints have also been explored. A 1-year follow-up study using a Herbst MRA found normalization of endothelial function and markers of oxidative stress, despite incomplete resolution of OSAH,45 calling into question the notion that cardiovascular benefits are only achieved with complete resolution of OSAH. These early data suggest that the control of OSAH by an oral appliance produces a beneficial effect on blood pressure and intermediate cardiovascular endpoints (e.g., endothelial function) similar to that of CPAP. Quality of Life Data regarding the effects of oral appliance therapy on quality of life are somewhat conflicting. A randomized, controlled study found that compared to a tablet placebo, MRA treatment improved quality of life as measured by the Functional Outcomes of Sleep Questionnaire (FOSQ) mean score and social outcome domain, and also by the SF-36 overall health score. The magnitude of improvement was similar to that found with CPAP.39 In contrast, another randomized, controlled study reported that wellbeing as assessed by the SF-36 scores for health transition and mental component were significantly better with CPAP compared to oral appliance therapy.13 In both studies, the assessment included treatment intervals that were shorter than 3 months. In a longer-term study, Walker-Engstrom and colleagues evaluated quality of life in a randomized, controlled trial of an MRA versus uvulopalatopharyngoplasty (UPPP).46,47 After 1 year of follow-up, vitality, contentment, and sleep scores were significantly improved in both groups, but the UPPP group demonstrated significantly greater contentment than the oral appliance group. Further work is required to clarify the impact of long-term oral appliance therapy on quality of life. Comparison of Oral Appliance Designs A number of studies have compared different MRAs or MRA designs. One study evaluated a fixed-position appliance and a modified device in 24 patients with mild OSAH and found that the device that protruded the mandible was more effective in reducing the AHI than the device that minimally opened the vertical dimension without mandibular protrusion.4 Some patients had an increase in AHI using either device. In a randomized, controlled crossover study the AHI was less than 10 in 75% of patients with a monobloc appliance (see Fig. 109-4) and in 67% of patients with the dual-bloc appliance (see Fig. 109-3). Both devices reduced sleepiness and snoring, but patients preferred the monobloc. One randomized crossover study specifically evaluated the effect of vertical opening on the efficacy of a MRA by comparing 4 mm or 14 mm of interincisal opening at the same degree of mandibular advancement.8
CHAPTER 109 • Oral Appliances for Sleep-Disordered Breathing 1271
Both MRAs had similar efficacy in terms of reducing snoring and AHI and improving sleepiness, but there was a trend to more jaw discomfort with the greater (14 mm) incisal opening. Overall, the patients preferred the appliance with less incisal opening for treatment.8 In another randomized crossover study of two distinct MRAs (appliances differed in materials, the amount of vertical opening, and the type of retention) set at approximately 75% of maximum protrusion found that both MRAs improved symptoms including snoring, sleepiness, and sleep quality. The MRA made of hard material with more vertical opening had more side effects and was less effective at improving OSAH.11 In a crossover study comparing two types of MRA with differing coupling mechanisms for 3 months each, similar improvements in AHI and subjective daytime sleepiness were noted.48 Another study evaluated two different amounts of mandibular protrusion, 75% or 50%, with an MRA in 86 men with severe OSAH.15 There were no more side effects with further protrusion. The MRA set at 75% reduced the AHI to less than 10 in 52% of patients, whereas the MRA set at 50% reduced the AHI to less than 10 in 31% of patients. A study comparing the efficacy of an off-the-shelf thermoplastic (boil and bite) MRA versus a custom-made monobloc MRA found the latter to be far superior, suggesting the need for caution in using off-the-shelf thermoplastic devices as a therapeutic option or as a screening tool to find good candidates for MRA therapy.49 In summary, different MRAs have different levels of effectiveness at reducing the AHI. There may be differences in terms of side effects, comfort, and preference. These differences may be related to design features of the appliance such as the amount of vertical opening and the amount of protrusion. Comparison with Nasal CPAP In the first randomized, controlled crossover study of oral appliance therapy, the investigators compared the efficacy, side effects, compliance, and preference between a fixed-position boil-and-bite MRA and CPAP in patients with mild to moderate OSAH (AHI 15 to 40).2 Treatment success (defined as reduction in AHI to 10 events or fewer with relief of symptoms) for the MRA was 48% and for CPAP was 62%. The MRA was well tolerated, with fewer side effects than CPAP, but some patients (24%) were unable or unwilling to use the MRA because of poor retention (ability to keep the oral appliance in place in the oral cavity) or discomfort. The MRA reduced snoring in most patients in reduced daytime sleepiness. Compared with the oral appliance, patients were less satisfied with CPAP. The authors concluded that a simple fixed-position appliance was an effective treatment in some patients with mild to moderate OSAH and was associated with fewer side effects and greater patient satisfaction than CPAP. Since then, there have been a growing number of randomized, controlled trials comparing oral appliances to CPAP.18,39,50-52 These studies vary in their design, inclusion criteria (including severity of OSA), definitions of severity and treatment response, treatment interval, number of dropouts, the MRA’s design, and the measurement tech-
niques used (e.g., portable home monitoring versus inlaboratory polysomnography). Collectively however, they indicate that CPAP is superior in reducing the AHI and improving oxygen saturation, but not arousal index, sleep architecture, or objective sleepiness.53,54 Despite the overall superiority of CPAP over oral appliances, patients in most of the studies preferred the oral appliance, raising important implications for adherence to treatment and effectiveness in the clinical setting. In terms of symptoms, particularly daytime sleepiness (subjective and objective), no substantial differences have been identified between CPAP and oral appliance treatments.53,54 This raises the important possibility that the health effects of both treatments are similar in magnitude, as a result of the superior efficacy of CPAP being offset by its inferior compliance relative to oral appliances. Further research is required to evaluate this possibility. Comparison with Surgical Treatment There is one published randomized study comparing UPPP to an MRA in patients with mild to moderate OSAH.5 The MRA was set at 50% of maximum protrusion and the surgical group had a conventional UPPP. The MRA was more effective at reducing the AHI to less than 10 per hour more often than UPPP (78% of patients with the MRA versus 51% of patients who underwent UPPP). The treatments were equally effective at improving subjective sleepiness. MRA side effects were described as minor and infrequent in a later publication, with no significant occlusal changes.5 Quality-of-life scores measured at 1 year had increased from baseline in both treatment groups.46 Although the MRA reduced the AHI more than UPPP did, there was no difference in vitality and sleep scores between the treatments. Contentment scores were higher in the UPPP group. After 4 years, 10% of patients with UPPP had persistent swallowing complaints, whereas five patients in the MRA group had stopped using the device.47 Some patients in the UPPP group had begun using an MRA because of persisting OSAH. Further well-designed studies are required to clarify the relative efficacy and effectiveness of MRA and surgical interventions.
PREDICTORS OF TREATMENT OUTCOME Although many studies have examined variables that may be associated with treatment outcome, most have been insufficiently powered to find relationships between outcome and these variables. Clinical variables and upper airway characteristics associated with good treatment outcome are summarized in Box 109-1. In general, a younger, thinner patient with positional OSAH (AHI higher when supine) and an overall lower AHI is the preferred candidate for oral appliance therapy. However, more severe OSAH51,55,56 or being overweight10 do not necessarily preclude benefit. One study of 630 patients treated with MRAs found that women had greater success with the device than men.57 They also found that weight gain in treated male patients and nasal obstruction symptoms in female patients decreased treatment success. More recently, attention has
1272 PART II / Section 13 • Sleep Breathing Disorders Box 109-1 Predictors of Treatment Outcome Clinical Variables Younger age10,64,99 Lower body mass index33,99 Smaller neck circumference7 Positional OSA: AHI higher when supine33,57,100 Lower AHI (not a consistent predictor)7,55,57,75,99,101 Increased amount of protrusion by appliance11,15,74,102 Variables from Upper Airway Imaging Smaller or narrow oropharynx64,94,99 Smaller overjet99 Normal mandible length61 Shorter distance from mandibular plane to hyoid92 Shorter soft palate length92 Normal or reduced lower facial height61 Small soft palate and tongue61 Increased retropalatal airway space7 Variables from Respiratory Function Tests Higher nasal resistance59 Reduced midinspiratory flow on flow volume loop58 AHI, apnea–hypopnea index; OSA, obstructive sleep apnea.
focused on physiologic factors, such as nasal resistance and flow volume loops, and these appear to provide some predictive value,58,59 although these assessment techniques require prospective validation. A variety of imaging techniques has been employed to assess the upper airway and the factors associated with treatment response. Upper airway features associated with a good response are summarized in Box 109-1. It has been suggested that a more micrognathic or retrognathic mandible is associated with improved treatment response,60 but other studies have suggested that a normal mandibular length and less overjet is associated with a better outcome.61 A primary oropharyngeal62 or hypopharyngeal63 site of obstruction during sleep may be associated with improved treatment outcome, but patients with velopharyngeal closure may still get a good result.55 Increased hypopharyngeal size and middle airway space (airway width at the tip of the soft palate) with the MRA were associated with a good response in one study of 16 patients using supine cephalography.64 In summary, studies indicate differences in a range of demographic, anatomic, and functional factors between responders and nonresponders. The challenge is to develop prediction models that can be usefully applied to the individual patient in the clinical setting, and further research is required to achieve this goal.
SIDE EFFECTS AND COMPLICATIONS A comprehensive review of oral appliance therapy, including data from controlled and uncontrolled studies with short-term and long-term follow-up, has described in detail the potential side effects and complications of oral appliance therapy.25 Side effects from oral appliance therapy can include excessive salivation, gagging, mucosal
dryness, and discomfort or pain of the tongue, gums, teeth, muscles, and temporomandibular joint (TMJ). There may be problems with retention of the device in the mouth. These side effects vary in incidence and severity. Although many patients report initial discomfort or other problems while acclimating to the oral appliance, in most patients these side effects improve with time. However, dental side effects can result in discontinuation of treatment. Several uncontrolled studies have evaluated the longterm complications of oral appliance therapy.65-69 These studies have focused on the development of changes in occlusion. The types of orthodontic or occlusal change seen include a decrease in overjet and overbite, movement of the incisors, and movement of the first mandibular molars. These changes may be progressive with time,70 and in a small number of patients they can result in discontinuation of treatment.65 More than half the patients in one study were unaware of the occlusal changes that were found on dental examination.65 Some patients can sense a change in the relationship of their upper and lower teeth after removing the MRA in the morning, and in most patients these changes usually resolve after a few minutes. Occasionally, in some patients the opening between the posterior teeth persists throughout the day. Hard acrylic appliances and larger amounts of protrusion were associated with greater changes in occlusion.66 Patients with greater initial overbites appear less likely to have unfavorable changes in occlusion, and indeed they can have favorable changes.70 Overall, there is a degree of occlusal change in patients with long-term use of MRAs, and these changes need to be monitored and addressed when they arise. Usually, the changes are minor and are reversible when treatment is discontinued.71 Rarely, the occlusal changes are permanent.72 Patients need to be informed of the potential for occlusal change when they consider and initiate oral appliance therapy. TMJ problems in patients without preexisting joint problems are very uncommon, and long-term use does not seem to predispose to joint dysfunction.73,74 Occasionally, an oral appliance can worsen apnea severity.3,4,33,55,75 In one trial, 4 of 28 subjects (14%) had an increase in AHI with the appliance.55 The reason for this increase could not be determined from a review of the patients’ data, although weight gain may be one potential explanation. Vigilant clinical follow-up with overnight monitoring to confirm that the oral appliance has improved apnea severity is therefore required given that these appliances are not universally effective and, in some patients, can worsen OSAH.
TREATMENT COMPLIANCE In studies, 76% to 90% of patients have reported regular use (i.e., >5 nights per week) of the MRA.76,77 In two of the studies comparing oral appliances with CPAP, compliance was measured by patients’ reports.2,3 There was no difference in reported nightly use between the treatments (roughly 60% for all treatment arms). Until objective compliance monitors are available for oral appliances, compliance rates will be uncertain given the unreliability of self-report. One study using a built-in compliance
CHAPTER 109 • Oral Appliances for Sleep-Disordered Breathing 1273
monitor embedded in the device found that patients were using the MRA an average of 6.8 hours per night (range, 5.6 to 7.5).78
CLINICAL PROTOCOL FOR ORAL APPLIANCE THERAPY Successful therapy with oral appliances requires that a physician and dentist with training and experience in managing sleep-disordered breathing work together to manage the patient optimally. Guidelines from the American Academy of Sleep Medicine recommend a protocol for the treatment of snoring and OSAH with oral appliances as well as well as defining the roles of the physician and dentist in this regard.1 Pretreatment Assessment Before treating patients with an oral appliance, either for snoring alone or for OSAH, an assessment by a sleep clinician is required. The sleep clinician is responsible for establishing the proper diagnosis and subsequent assessment of the patient’s medical candidacy for oral appliance therapy, largely based on clinical predictors of treatment outcome as outlined earlier, the need for immediate treatment, and the patient’s preference for a particular treatment option. Oral appliances are usually not indicated as first-line therapy for severe OSAH or severe sleepiness or in patients who have very abnormal oxygen levels during sleep. CPAP therapy can be titrated in 1 night, but it can take weeks to months to optimize protrusion of a MRA. This needs to be factored into the treatment choice, particularly for cases requiring prompt treatment. Although studies have assessed overnight titration of an MRA to determine the therapeutic position and efficacy,79-82 the role of this approach in routine care is yet to be proved. Previous UPPP surgery does not contraindicate oral appliance treatment, but problems may be encountered with CPAP treatment in such patients.83,84 There are case reports detailing the successful use of an oral appliance in the treatment of UARS,85,86 with improvements in objective daytime sleepiness.87 In addition, the sleep clinician should undertake a preliminary screen for dental suitability for oral appliance therapy by asking the patient if he or she wears dentures, is missing teeth, or has a history of periodontal disease or temporomandibular joint problems, although none of these conditions is an absolute contraindication to oral appliance therapy. If treatment with an oral appliance is medically appropriate, the clinician provides the dentist with a written referral and a copy of the diagnostic overnight study and clinical reports. Indications and Contraindications The dentist determines whether or not the patient is a good dental candidate for an MRA. The evaluation includes a medical and dental history and a complete intraoral examination. This includes a soft tissue, periodontal, TMJ, and occlusal assessment. The occlusion is assessed and the teeth and restorations are examined. The dentist determines if the patient has sufficient number of healthy teeth (usually eight teeth in the upper and in the lower jaw) for
adequate retention of an MRA. The patient should have the ability to protrude the mandible forward in order to achieve a therapeutic result. Full upper and lower dentures likely preclude the use of an MRA, but some edentulous patients respond well to a TRD. Some partially edentulous patients may benefit from an MRA.87a Dental records are obtained and may include dental radiographs and a panoramic or full-mouth survey. Some practitioners obtain a cephalometric radiograph. The dentist obtains informed consent about the risks and benefits of oral appliance therapy. A discussion about potential long-term side effects and complications should take place as part of the informed consent process. Moderate to severe TMJ problems, bruxism, an inadequate protrusive range, and advanced periodontal disease are all dental relative contraindications to MRA use. Thirty-four of 100 patients consecutively assessed by oral and maxillofacial surgeons had relative or absolute contraindications to therapy, and 16% had dental issues that would require close follow-up.88 Not all TMJ problems are absolute contraindications to MRA therapy—mild problems may be lessened by a forward jaw position. TRDs do not necessarily require teeth, and hence they can have a particular role in edentulous patients. Selecting the Appliance The dentist determines the most appropriate type of appliance to use based on specific clinical features. Information about oral appliances that have received market clearance from the U.S. Food and Drug Administration for treating snoring or OSAH is available at the American Academy of Dental Sleep Medicine and other national and international professional organizations. The appliance may be custom made or off the shelf , may provide partial or full occlusal coverage, may be made of soft or hard materials, and may be rigid or allow jaw movement. Some appliances are made of temperaturesensitive acrylic, becoming pliable in hot water, and when they cool to mouth temperature they firmly grip the teeth and are very retentive. Appliances may be nonadjustable and worn in one position or be partly adjustable (more than one possible preset position). The monobloc type of MRA generally is more rigid and bulky. Dual-bloc MRAs, consisting of upper and lower plates, offer the advantage of a greater degree of mandibular movement (vertical and lateral) and adjustability (advancement), usually permitting attainment of the most comfortable and efficient position of the mandible. It is generally considered that the best retention is achieved with oral appliances that are customized from dental impressions.49 Plaster models are obtained as appropriate for customizing the specific oral appliance. Boil-andbite appliances make use of a thermoplastic (heat-sensitive) material to enable molding and fitting to the patient in the office. Custom appliances may be fabricated by the dentist or by the dental laboratory. The dentist is responsible for teaching the patient how to use the appliance, care for it, and adjust it (if that is a feature of the design) and what side effects and complications to look for. Tongue-repositioning devices, such as the TRD, are often used in patients with large tongues, an inadequate protrusive range, or insufficient teeth to use a MRA. TRDs
1274 PART II / Section 13 • Sleep Breathing Disorders
are custom made or off the shelf. The patient advances the tongue into the bulb while squeezing the bulb to create negative suction. The patient experiments with the amount of forward positioning of the tongue that is required to decrease snoring and symptoms. Denture adhesive powder may be placed into the bulb to enhance retention of the tongue during sleep. Associated dental conditions such as bruxism can influence the choice of appliance design. Bruxism is common in patients with OSAH,89 and patients who experience jaw discomfort after wearing a rigid MRA can benefit from using an appliance that allows lateral and vertical jaw movement. A small amount of movement can improve comfort for patients with bruxism who use a MRA. Titration Protocol The initial position for MRA is usually set between 50% and 75% of maximum mandibular protrusion. Appliances with a single jaw position can usually be remade if the initial position is too far forward and uncomfortable or if it is not forward enough to provide benefit. A typical titration protocol consists of gradual forward adjustments of the MRA to a position associated with a significant reduction in snoring and other symptoms but without significant side effects. Patients vary considerably in the speed of advancement during titration of an MRA and the amount of protrusion they are able to achieve. Gradual forward titration of the mandible by the patient, under the direction of the dental practitioner, without remaking the MRA each time is an advantage of adjustable MRAs. If an optimal position is not obtained (e.g., persistent snoring), the MRA is set at the maximum forward position that does not produce significant side effects. The patient’s compliance should be monitored at each visit. Once a satisfactory improvement in symptoms has taken place, the patient is referred back to the physician for a clinical assessment or repeat overnight assessment. One report has provided some support for a patient self-titration strategy based on symptom control, with additional titration during followup polysomnography if required.90 Posttreatment Assessment Medical follow-up is necessary to evaluate treatment response and to assess for recurrence of OSAH. It is recommended that follow-up overnight studies be performed to objectively verify that the oral appliance is improving apnea, oxygenation, and sleep fragmentation.1 This recommendation is supported by the evidence of a placebo effect with oral appliances7,9 and by evidence that some patients have an increase in AHI with oral appliance treatment.3,4,33,55,75 Long-Term Follow-up Regular follow-up visits are continued as long as the patient is using oral appliance therapy, and the frequency and timing of these depends on the severity of OSAH and other clinical features, such as the adequacy of symptom control, comorbid conditions, weight change, and side effects. Generally, a yearly review is recommended. The dentist monitors use of the device, fit and comfort, effectiveness, symptoms, side effects, complications, and the degree of advancement at follow-up visits. The appliance
might need repairs, modification, further advancement, or even redesign or replacement with a different device if side effects develop or if there is an inadequate subjective or objective improvement.
SUMMARY Oral appliance therapy is a relatively simple and reversible approach to treatment. Patients require alternatives to surgery and CPAP, and the utility of oral appliance therapy is no longer in question. Randomized, controlled clinical trials have shown oral appliances to be an effective treatment option for many patients, particularly in patients with less-severe OSAH. They are indicated in patients who have failed other treatments even if they have severe OSAH. Oral appliances appear to work by increasing airway space, providing a stable anterior position of the mandible, advancing the tongue or soft palate, and possibly by changing upper airway muscle activity. Although MRAs are not as effective as CPAP therapy, they achieve some degree of benefit in most patients to relieve symptoms and apnea, and they are well tolerated by most patients. Most patients report improvements in sleep quality and excessive daytime sleepiness. A significant subgroup of patients (40% to 50%) achieve a complete response to treatment, similar to the response to CPAP treatment. Short-term side effects are usually minor and are related to excessive salivation, jaw and tooth discomfort, and occasionally joint discomfort. These symptoms usually improve over time. Significant TMJ complications are rare, but occlusal changes are more common than previously thought. Oral appliance therapy is a unique opportunity for dentists and physicians with expertise in sleep medicine to work together to select the ideal patients for this form of treatment. Each plays a crucial role in providing the patient with optimal care. With collaboration and good communication between the dentist and the sleep clinician, many patients with snoring or OSAH can be treated effectively with oral appliances. FUTURE DIRECTIONS Studies are needed to compare the effectiveness of different types of appliances and different design features (e.g., the amount of vertical opening). The precise indications, complication rates, and reasons for treatment failure need to be determined for each oral appliance if it is going to be used in clinical practice. Ongoing refinements of appliance design may eventually lead to improved outcomes. Only when the mechanisms of action are fully understood can more effective appliances be developed. Prospective validation studies are required to evaluate predictors of treatment outcome, and more research is needed to determine optimal titration protocols to increase the effectiveness of oral appliances and to decrease the time to effective treatment. On the horizon for the field of oral appliance therapy are the introduction of a compliance monitor that will allow an objective determination of appliance use, and more rapid overnight titration approaches for implementing oral appliance therapy quickly.
CHAPTER 109 • Oral Appliances for Sleep-Disordered Breathing 1275
❖ Clinical Pearl Oral appliances are not as effective as CPAP for treating patients with OSAH. In particular, they work less well in patients with significant hypoxemia or morbid obesity. They are most effective in younger, thinner patients with mild to moderate OSAH. Randomized, controlled clinical trials have indicated that oral appliances may be used as first-line therapy for the treatment of mild to moderate OSAH. However, oral appliances are not the preferred treatment for patients with severe or highly symptomatic OSAH because of the time it can take to achieve the final therapeutic position.
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1276 PART II / Section 13 • Sleep Breathing Disorders 41. Hoekema A, Stegenga B, Bakker M, et al. Simulated driving in obstructive sleep apnoea–hypopnoea; effects of oral appliances and continuous positive airway pressure. Sleep Breath 2007;11:129-138. 42. Gotsopoulos H, Kelly JJ, Cistulli PA. Oral appliance therapy reduces blood pressure in obstructive sleep apnea. A randomized, controlled trial. Sleep 2004;27:934-941. 43. Otsuka R, Ribeiro de Almeida F, Lowe AA, et al. The effect of oral appliance therapy on blood pressure in patients with obstructive sleep apnea. Sleep Breath 2006;10:29-36. 44. Yoshida K. Effect on blood pressure of oral appliance therapy for sleep apnea syndrome. Int J Prosthodont 2006;19:61-66. 45. Itzhaki S, Dorchin H, Clark G, et al. The effects of 1-year treatment with a Herbst mandibular advancement splint on obstructive sleep apnea, oxidative stress, and endothelial function. Chest 2007;131: 740-749. 46. Walker-Engström ML, Wilhelmsson B, Tegelberg Å, et al. Quality of life assessment of treatment with dental appliance or UPPP in patients with mild to moderate obstructive sleep apnoea: a prospective randomized 1-year follow-up study. J Sleep Res 2000;9: 303-308. 47. Walker-Engström ML, Tegelberg Å, Wilhelmsson B, et al. 4-year follow-up of treatment with dental appliance or uvulopalatopharyngoplasty in patients with obstructive sleep apnea: a randomized study. Chest 2002;121:739-746. 48. Gauthier L, Laberge L, Beaudry M, et al. Efficacy of two mandibular advancement appliances in the management of snoring and mildmoderate sleep apnea: a cross-over randomized study. Sleep Med 2009;10(3):329-336. 49. Vanderveken OM, Devolder A, Marklund M, et al. Comparison of a custom-made and a thermoplastic oral appliance for the treatment of mild sleep apnea. Am J Respir Crit Care Med 2008;178: 197-202. 50. Kato J, Isono S, Tanaka A, et al. Dose-dependent effects of mandibular advancement on pharyngeal mechanics and nocturnal oxygenation in patients with sleep-disordered breathing. Chest 2000;117:1065-1072. 51. Barthlen GM, Brown LK, Wiland MR, et al. Comparison of three oral appliances for treatment of severe obstructive sleep apnea syndrome. Sleep Medicine 2000;1:299-305. 52. Tan YK, L’Estrange PR, Luo YM, et al. Mandibular advancement splints and continuous positive airway pressure in patients with obstructive sleep apnoea: a randomized cross-over trial. Eur J Orthod 2002;24:239-249. 53. Hoekema ASB, de Bont LG. Efficacy and co-morbidity of oral appliances in the treatment of obstructive sleep apnea-hypopnea: a systematic review. Crit Rev Oral Biol Med 2004;15:137-155. 54. Lim J, Lasserson TJ, Fleetham J, Wright J. Oral appliances for obstructive sleep apnoea. Cochrane Database Syst Rev 2006;(1): CD004435. 55. Henke KG, Frantz DE, Kuna ST. An oral elastic mandibular advancement device for obstructive sleep apnea. Am J Respir Crit Care Med 2000;161:420-425. 56. Bernhold M, Bondemark L. A magnetic appliance for treatment of snoring patients with and without obstructive sleep apnea. Am J Orthod Dentofacial Orthop 1998;113:144-155. 57. Marklund M, Stenlund H, Franklin KA. Mandibular advancement devices in 630 men and women with obstructive sleep apnea and snoring. Chest 2004;125:1270-1278. 58. Zeng B, Ng AT, Darendeliler MA, et al. Use of flow-volume curves to predict oral appliance treatment outcome in obstructive sleep apnea. Am J Respir Crit Care Med 2007;175:726-730. 59. Zeng B, Ng AT, Qian J, et al. Influence of nasal resistance on oral appliance treatment outcome in obstructive sleep apnea. Sleep 2008;31:543-547. 60. Yoshida K. Prosthetic therapy for sleep apnea syndrome. J Prosthet Dent 1994;72:296-302. 61. L’Estrange PR, Battagel JM, Harkness B, et al. A method of studying adaptive changes of the oropharynx to variation in mandibular position in patients with obstructive sleep apnoea. J Oral Rehabil 1996;23:699-711. 62. Ng AT, Gotsopoulos H, Qian J, Cistulli PA. Oropharyngeal collapse predicts treatment response with oral appliance therapy in obstructive sleep apnea. Sleep 2006;29:666-671. 63. Fransson AM, Isacsson G, Leissner LC, et al. Treatment of snoring and obstructive sleep apnea with a mandibular protruding device: An open-label study. Sleep Breath 2001;5:23-33.
64. Liu Y, Park YC, Lowe AA, et al. Supine cephalometric analyses of an adjustable oral appliance used in the treatment of obstructive sleep apnea. Sleep Breath 2000;4:59-66. 65. Pantin CC, Hillman DR, Tennant M. Dental side effects of an oral device to treat snoring and obstructive sleep apnea. Sleep 1999;22:237-240. 66. Marklund M, Franklin KA, Persson M. Orthodontic side-effects of mandibular advancement devices during treatment of snoring and sleep apnoea. Eur J Orthod 2001;23:135-144. 67. Fritsch KM, Iseli A, Russi EW, et al. Side effects of mandibular advancement devices for sleep apnea treatment. Am J Respir Crit Care Med 2001;164:813-818. 68. Fransson AM, Tegelberg Å, Svenson BA, et al. Influence of mandibular protruding device on airway passages and dentofacial characteristics in obstructive sleep apnea and snoring. Am J Orthod Dentofacial Orthop 2002;122:371-379. 69. Almeida FR, Lowe AA, Otsuka R, et al. Long-term sequelae of oral appliance therapy in obstructive sleep apnea patients: Part 2. Studymodel analysis. Am J Orthod Dentofacial Orthop 2006;129: 205-213. 70. Robertson CJ. Dental and skeletal changes associated with longterm mandibular advancement. Sleep 2001;24:531-537. 71. Hammond RJ, Gotsopoulos H, Shen G, et al. A follow-up study of dental and skeletal changes associated with mandibular advancement splint use in obstructive sleep apnea. Am J Orthod Dentofacial Orthop 2008;132:806-814. 72. Panula K, Keski-Nisula K. Irreversible alteration in occlusion caused by a mandibular advancement appliance: an unexpected complication of sleep apnea treatment. Int J Adult Orthodon Orthognath Surg 2000;15:192-196. 73. Bondemark L, Lindman R. Craniomandibular status and function in patients with habitual snoring and obstructive sleep apnoea after nocturnal treatment with a mandibular advancement splint: a 2-year follow-up. Eur J Orthod 2000;22:53-60. 74. de Almeida FR, Bittencourt LR, de Almeida CI, et al. Effects of mandibular posture on obstructive sleep apnea severity and the temporomandibular joint in patients fitted with an oral appliance. Sleep 2002;25:507-513. 75. Schmidt-Nowara WW, Meade TE, Hays MB. Treatment of snoring and obstructive sleep apnea with a dental orthosis. Chest 1991;99:1378-1385. 76. Yoshida K. Effects of a mandibular advancement device for the treatment of sleep apnea syndrome and snoring on respiratory function and sleep quality. Cranio 2000;18:98-105. 77. Johal A, Battagel JM. An investigation into the changes in airway dimension and the efficacy of mandibular advancement appliances in subjects with obstructive sleep apnoea. Br J Orthod 1999;26: 205-210. 78. Lowe AA, Sjoholm TT. Ryan CF, et al. Treatment, airway and compliance effects of a titratable oral appliance. Sleep 2000;23: S172-S178. 79. Pételle B, Vincent G, Gagnadoux F, et al. One-night mandibular advancement titration for obstructive sleep apnea syndrome: a pilot study. Am J Respir Crit Care Med 2002;165:1150-1153. 80. Raphaelson MA, Alpher EJ. Bakker KW, et al. Oral appliance therapy for obstructive sleep apnea syndrome: progressive mandibular advancement during polysomnography. Cranio 1998;16: 44-50. 81. Tsai WH, Vazquez JC, Oshima T, et al. Remotely controlled mandibular positioner predicts efficacy of oral appliances in sleep apnea. Am J Respir Crit Care Med 2004;170:366-370. 82. Dort LC, Hadjuk E, Remmers JE. Mandibular advancement and obstructive sleep apnoea: a method for determining effective mandibular protrusion. Eur Respir J 2006;27:1003-1009. 83. Mortimore IL, Bradley PA, Murray JA, et al. Uvulopalatopharyngoplasty may compromise nasal CPAP therapy in sleep apnea syndrome. Am J Respir Crit Care Med 1996;154:1759-1762. 84. Millman RP, Rosenberg CL, Carlisle CC, et al. The efficacy of oral appliances in the treatment of persistent sleep apnea after uvulopalatopharyngoplasty. Chest 1998;113:992-996. 85. Loube DI, Andrada T, Shanmagum N, et al. Successful treatment of upper airway resistance syndrome with an oral appliance. Sleep Breath 1998;2:98-101. 86. Guerrero M, Lepler L, Kristo D. The upper airway resistance syndrome masquerading as nocturnal asthma and successfully treated with an oral appliance. Sleep Breath 2001;5:93-96.
CHAPTER 109 • Oral Appliances for Sleep-Disordered Breathing 1277 87. Rose E, Frucht S. Sobanski T, et al. Improvement in daytime sleepiness by the use of an oral appliance in a patient with upper airway resistance syndrome. Sleep Breath 2000;4:85-87. 87a. Giannasi LC, Magini M, Costa MS, Oliveira CS, Oliveira LV. Oral appliance treatment for obstructive sleep apnea in a partly edentulous patient. Am J Orthod Dentofacial Orthop 2010; 137:548-551. 88. Petit FX, Pépin JL, Bettega G, et al. Mandibular advancement devices: rate of contraindications in 100 consecutive obstructive sleep apnea patients. Am J Respir Crit Care Med 2002;166:274-278. 89. Sjöholm TT, Lowe AA, Miyamoto K, et al. Sleep bruxism in patients with sleep-disordered breathing. Arch Oral Biol 2000;45:889-896. 90. Krishnan V, Collop NA, Scherr SC. An evaluation of a titration strategy for prescription of oral appliances for obstructive sleep apnea. Chest 2008;133:1135-1141. 91. Ishida M, Inoue Y, Suto Y, et al. Mechanism of action and therapeutic indication of prosthetic mandibular advancement in obstructive sleep apnea syndrome. Psychiatry Clin Neurosci 1998;52:227-229. 92. Eveloff SE, Rosenberg CL, Carlisle CC, et al. Efficacy of a Herbst mandibular advancement device in obstructive sleep apnea. Am J Respir Crit Care Med 1994;149:905-909. 93. Liu Y, Zeng X, Fu M, et al. Effects of a mandibular repositioner on obstructive sleep apnea. Am J Orthod Dentofacial Orthop 2000;118:248-256. 94. Mayer G, Meier-Ewert K. Cephalometric predictors for orthopaedic mandibular advancement in obstructive sleep apnoea. Eur J Orthod 1995;17:35-43.
95. Tsuiki S, Hiyama S, Ono T, et al. Effects of a titratable oral appliance on supine airway size in awake non-apneic individuals. Sleep 2001;24:554-560. 96. Gale DJ, Sawyer RH, Woodcock A, et al. Do oral appliances enlarge the airway in patients with obstructive sleep apnoea? A prospective computerized tomographic study. Eur J Orthod 2000;22:159-168. 97. Gao XM, Zeng XL, Fu MK, et al. Magnetic resonance imaging of the upper airway in obstructive sleep apnea before and after oral appliance therapy. Chin J Dent Res 1999;2:27-35. 98. Ryan CF, Love LL, Peat D, et al. Mandibular advancement oral appliance therapy for obstructive sleep apnoea: effect on awake calibre of the velopharynx. Thorax 1999;54:972-977. 99. Liu Y, Lowe AA, Fleetham JA, et al. Cephalometric and physiologic predictors of the efficacy of an adjustable oral appliance for treating obstructive sleep apnea. Am J Orthod Dentofacial Orthop 2001;120:639-647. 100. Yoshida K. Influence of sleep posture on response to oral appliance therapy for sleep apnea syndrome. Sleep 2001;24: 538-544. 101. Clark GT, Blumenfeld I, Yoffe N, et al. A crossover study comparing the efficacy of continuous positive airway pressure with anterior mandibular positioning devices on patients with obstructive sleep apnea. Chest 1996;109:1477-1483. 102. Marklund M, Franklin KA, Sahlin C, et al. The effect of a mandibular advancement device on apneas and sleep in patients with obstructive sleep apnea. Chest 1998;113:707-713.
Management of Obstructive Sleep Apnea–Hypopnea Syndrome
Chapter
110
Barbara A. Phillips and Meir H. Kryger Abstract
Sleep-disordered breathing (SDB) exists along a continuum of severity, and the boundaries between pathologic and normal breathing are still not precisely defined. At one end of the spectrum is snoring of varying degrees of intensity; at the other is severe obstructive sleep apnea with profound hypoxemia and sleep disturbance. In between those extremes are varying degrees of inspiratory airflow resistance, including respiratory-effort related arousals (RERAs), hypopneas, and frank apneas. Other respiratory abnormalities that may be caused or exacerbated by sleep include hypoxemia, hypoventilation, and central apneas. The reported prevalence of obstructive sleep apnea–hypopnea (OSAH) is rising, driven by the increasing recognition of persons who have the disorder and by the increasing ubiquity of risk factors, notably obesity and aging, that enhance the risk of SDB. At present, perhaps 5% of the population of the developed world has significant sleep-disordered breathing. Although the prototypical patient with OSAH is a middle-aged, obese man, it is now clear that neither obesity nor male gender is neces-
Sleep-related breathing disorders are common, are present in all age groups, and can result in significant morbidity and mortality. Eighty percent of patients presenting to sleep disorders centers have a manifestation of sleepdisordered breathing as the primary diagnosis. The term sleep-disordered breathing has been used synonymously with the term obstructive sleep apnea (OSA) syndrome, which has been supplanted by the term obstructive sleep apnea–hypopnea (OSAH) syndrome. In this chapter, we use the term sleepdisordered breathing (SDB) to encompass the entire gamut of respiratory abnormalities occurring during sleep. We will apply the term obstructive sleep apnea–hypopnea (OSAH) syndrome in reference to the spectrum of dis orders in the family of obstructive respiratory events, including obstructive sleep apnea (Fig. 110-1). This chapter presents an overview of the identification and management of patients with SDB. Details of diagnosis, clinical features, pathophysiology, and treatment are presented in Chapters 101 to 109.
EPIDEMIOLOGY AND RISK FACTORS Prevalence and Incidence in the General Population The Wisconsin Sleep Cohort Study reported that 4% of men and 2% of women in a middle-aged cohort (ages 30 to 60 years) had obstructive sleep apnea, defined as an apnea–hypopnea index (AHI: the average number of apneas plus hypopneas per hour of sleep) greater than 5, and also daytime hypersomnolence.1 In this cohort, 44% of men and 28% of women were habitual snorers. Since this report in 1993, the general population has become heavier and older. The risk for significant SDB rises both 1278
sary or sufficient to increase the risk of OSAH; increasingly, varying phenotypes of OSAH syndrome, particularly in women, in older persons, and people of color are being described. Tools to monitor breathing during sleep and definitions of SDB events are becoming more precise and standardized, although they remain imperfect. Ongoing development and validation of home (ambulatory) testing and clinical algorithms are increasingly important diagnostic tools because of the notable burden engendered by the large numbers of patients requiring evaluation for SDB as well as the growing recognition of its seriousness. The clinical importance of a disorder may be judged by the prevalence and severity of its outcomes. In this regard, strong associations between OSAH and important sequelae, notably cardiovascular disease, automobile accidents, cognitive impairment, and abnormal endocrine function, have become evident. Continuous positive airway pressure remains the treatment of choice, but behavioral change should be part of the overall management, and oral appliances are now recognized as reasonably effective second-line therapy.
Severe OSA Moderate OSA Mild OSA UARS Chronic, heavy snoring Intermittent snoring Quiet breathing Figure 110-1 The spectrum of sleep-disordered breathing.
body mass index (BMI: weight in kilograms per height in meters squared)2 and with age.3 It is difficult to identify a precise prevalence for sleep apnea for two reasons: Risk factors in the general population are increasing, and the diagnostic criteria continue to evolve as more is learned about physiologic and clinical outcomes. However, the Sleep Heart Health Study (SHHS) reported that 22% of 1824 people had a respiratory disturbance index (RDI) of greater than 15 events per hour. In the context of this particular research study, the RDI was synonymous with the AHI, and the presence or absence of symptoms was not considered in this assessment of prevalence. Most practitioners would consider an RDI greater than 15 to be significant OSAH. However, the
CHAPTER 110 • Management of Obstructive Sleep Apnea–Hypopnea Syndrome 1279
SHHS cohort was not representative of the general population because it was enriched with snorers.4 A National Sleep Foundation Poll5 found that about a third of middleaged adults had signs and symptoms suggesting sleep apnea.5 Certain groups, such as commercial vehicle drivers, have consistently been shown to have a very high prevalence of significant SDB.6,7 The high rates of obesity, male gender, cigarette smoking, and older age in commercial drivers are among the reasons that this particular group is at increased risk for OSAHS. On the basis of an exhaustive review of currently available data, it has been conservatively estimated that 5% of adults have OSAH with sleepiness, and an unknown percentage have SDB without overt sleepiness.8 The Cleveland Family Study of 285 persons without significant sleep apnea at baseline reported that the incidence of developing SDB (as defined by an AHI > 5 events per hour) is about 7% per year, and the incidence of developing an AHI of greater than 15 events per hour is about 2% per year.9 In addition to establishing the first incidence data for SDB, this study confirmed that with aging, male sex and BMI lose importance as risk factors for obstructive sleep apnea.3,9 After menopause, the incidence of SDB rises in women, and the prevalence difference between the sexes essentially vanishes.10 Genetic Influences Sleep-disordered breathing is seen more commonly in patients with a family history of SDB (see Video 103-1). In one study, 41% of the offspring of 45 randomly selected patients with OSAH syndrome had an AHI greater than 5, and 13.3% had an AHI greater than 20.11 Other large family studies have reported a much higher prevalence of OSAH syndrome among offspring of family members with OSAH when compared to the general population (see Chapter 103).8 Ethnicity also appears to play a role in the development of SDB. African Americans, Asians, and Latin Americans are at increased risk for sleep apnea, even controlling for other important risk factors such as BMI.2,8,12,13 Associated Medical Disorders Although it was recognized long ago that heart failure can result in repetitive central apneas (Cheyne-Stokes breathing—see Chapter 100), it is now clear that OSAH can contribute to left ventricular dysfunction and exacerbate congestive heart failure. Thus, SDB should be suspected in all cases of heart failure.14 OSAH also appears to be an independent risk factor for atrial fibrillation15 and stroke.16 Hypothyroidism is more prevalent in those with OSAH than in those without, and it can contribute to the development of SDB by several mechanisms, including obesity, increased tongue size, and reduced ventilatory drive.8,17 Nasal obstruction and rhinitis are also associated with increased snoring and SDB; unfortunately, however, surgery directed exclusively at the nose has a low therapeutic yield.18 Enlarged tonsils and adenoids can cause OSAH, particularly in children. OSAH should be strongly suspected in syndromes that are associated with altered craniofacial morphology, upper airway soft tissue anatomy, and airway caliber such as trisomy 21, achondroplasia, Arnold-Chiari malformation, mucopolysaccharidoses, and
Klippel-Feil, Pierre Robin, Alpert, Treacher Collins, and Marfan syndromes.8 Behavioral Factors Alcohol and sedative medications decrease neuromuscular drive to the upper airway dilator muscles, predisposing to recurrent upper airway collapse.8,19 Tobacco smoke causes an increase in nasal and pharyngeal irritation, resulting in narrowing of the upper airway. OSAH syndrome has been shown to be more prevalent in current smokers than in nonsmokers or ex-smokers.8,20-22
PATHOGENESIS Epidemiologic and genetic studies indicate that the inheritance of OSAHS is likely to be complex, and its development depends on environmental as well as genetic factors (see Chapter 103). Obesity increases the inspiratory work of breathing because the effort of displacing central obesity results in abnormally high levels of negative pressure (suction) against pliable tissues of the posterior pharyngeal space. Suction on the pliable, soft tissues of the upper airway can result in upper airway edema, which is exacerbated by the vibratory trauma of snoring. If there is nasal obstruction (polyps, septal deviation), then increased upstream airway resistance increases the effects of the increased downstream negative pressure (intrathoracic suction). A simple analogy is the collapse of a paper straw that is partially crimped along its length when a very strong suction is applied at one end. For more on the pathophysiology of sleep-disordered breathing, see Chapters 101 and 102. Several studies have also demonstrated that closure or narrowing of the upper airway occurs during inspiration in the breaths before obstructive events.23 CLINICAL FEATURES History Snoring Heavy snoring is the most common symptom in patients with SDB (Box 110-1, Videos 110-1, 110-2, and 110-3).
Box 110-1 Symptoms and Signs of Sleep-Disordered Breathing Symptoms Snoring Witnessed apneas Gasping for breath during sleep Sleepiness Enuresis, nocturia Mood, memory, or learning problems Impotence Recent weight gain Morning headache Dry mouth or dry throat in the morning Signs Obesity Hypertension Crowded oropharynx Retrognathia
1280 PART II / Section 13 • Sleep Breathing Disorders
About 50% of men and 25% of women snore, but somewhat fewer than that have OSAH, so snoring alone is clearly not diagnostic. Snoring accompanied by a bed partner’s reports of observed apnea, snorting, gasping, and choking during sleep is predictive of OSAH.24-26 Witnessed apneas are more predictive of SDB than are patientreported episodes of waking up gasping for breath, which may be a symptom of other diseases such as congestive heart failure, gastroesophageal reflux disease, nocturnal asthma, and panic disorder. Nonetheless, a patient’s complaints of awakening with sensations of gasping or shortness of breath should be explored. Sleepiness Although excessive daytime sleepiness has many possible etiologies, this complaint should increase the suspicion for OSAH syndrome. Subjective sleepiness can be assessed by the Epworth Sleepiness Scale (see Chapter 143, which has been validated in clinical studies and correlates very roughly with objective measures of sleepiness.27 Patients underreport and overreport their sleepiness,28 so querying members of their household is also useful. An Epworth Sleepiness Scale score greater than 10 suggests significant daytime sleepiness, but this is not specific for OSAH syndrome. Sleepiness can be objectively measured with a multiple sleep latency test or with the maintenance of wakefulness test, but these tests are rarely indicated in the routine evaluation of persons with suspected or diagnosed OSAH syndrome. Patients who report falling asleep while driving or performing other safety-sensitive tasks should be evaluated for a variety of sleep disorders, including SDB (see Video 104-1). Because of the threat posed to the patient and others by this symptom, clinicians should have a low threshold for evaluation of patients who report this problem. Other Symptoms Nocturia,29 impotence,30 attention deficits, cognitive impairment (see Chapters 104 and 105), morning headache, dry or sore throat in the morning, and problems with vision31-33 are other symptoms that may be associated with OSAH syndrome. Gender and Symptoms Female patients with OSAH are much more likely than male patients to present with insomnia, and they are less likely to present with a history of observed apnea. Women with OSAH are much more likely than men to have a diagnosed mood disorder and hypothyroidism and are more likely than men to report symptoms of restless legs, nightmares, palpitations, and hallucinations.34 Alcohol and caffeine have been found to be used more by male than by female patients. Physical Findings The physical finding that is most predictive of OSAH syndrome is central obesity. BMI is a convenient but imperfect surrogate for central obesity. A BMI greater than 28 kg/m2 in both men and women reflects a risk factor and should increase the suspicion for OSAH syndrome. Approximately 40% of persons with a BMI greater than 40 and 50% of those with a BMI greater than 50 have significant SDB.2 Premenopausal women with OSAH are
generally much heavier than their male counterparts, and both obesity and sex become less important risk factors for OSAH after age 50 years.8 Measures of central obesity such as neck size are also very useful in predicting the presence of OSAH. Men with a neck circumference greater than 17 inches (43 cm) and women with a neck circumference greater than 16 inches (41 cm) are at particular increased risk for OSAH syndrome confirmed by overnight polysomnography.25,35,36 Nasal obstruction from any cause appears to be a risk factor for SDB, including snoring.37 Several diagnostic schemes are based on intraoral measurements, notably a narrowed posterior oropharynx.26,37,38 Measurement of systemic arterial blood pressure is, of course, a standard part of the physical examination. It is therefore noteworthy that several large epidemiologic studies have demonstrated that OSAHS is a risk factor for hypertension39-41 in a dose-dependent way. Analysis of data obtained from 6132 subjects in the SHHS revealed an odds ratio for hypertension of 1.37 (95% confidence interval [CI], 1.03 to 1.83), comparing the highest category of AHI (>30/hr) with the lowest (<1.5/hr),39 even after adjustment for other factors including age and BMI. In one small study, 83% of patients with drug-resistant hypertension had OSAH.42 Thus, the presence of hypertension, particularly difficult-to-control hypertension, should increase the clinical suspicion for OSAH.
DIAGNOSIS Polysomnography The gold standard for the diagnosis of OSAH remains overnight polysomnography (PSG) (Fig. 110-2). A nocturnal PSG includes recordings of airflow, ventilatory effort, oxygen saturation, and body position, as well as electrocardiography, electromyography, and electroencephalography. In standard, laboratory-based PSG, a technician is present to monitor the patient during the entire study. A single overnight PSG is generally sufficient to diagnose OSAH, but it might not be sufficient to rule it out, particularly if the SDB is caused or exacerbated by factors not present during the study, such as rapid eye movement (REM) sleep, supine sleep, or alcohol ingestion. In many instances, the level of SDB is severe enough that the diagnosis of OSAH can be established early in the study. In this event, a split-night study may be performed, in which the second half of the study is used to titrate treatment (positive airway pressure) for OSAH. Definitions The AHI is the most commonly used criterion to establish the diagnosis of OSAH and to quantify its severity. The AHI is defined as the total number of apneas plus hypopneas divided by the hours of sleep (Box 110-2) in a single night’s study. Obstructive apneas and hypopneas are characterized by an absence or a reduction of airflow, respectively, despite continued inspiratory efforts. Some authors have suggested that the presence of continuous positive airway pressure (CPAP) responsiveness might add additional precision to the diagnosis.43 In central apneas and hypopneas, inspiratory effort is absent or reduced during the period of apnea or reduced airflow.
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CHIN (+1/–1) (250 mV) C3-A2 (125 mV) C4-A1 (125 mV) O2-A1(125 mV) ROC-A1 (125 mV) LOC-A2 (125 mV) ECG (1.25 mV) 23:30:43 23:30:48 23:30:53 23:30:58 23:31:03 23:31:08 23:30:45:5 23:30:50:5 23:30:55:5 23:31:00:5 23:31:05:5 23:31:10:5
100 SaO2 (%) 70 THOR RES (x1)
ABDO RES (x1) Pulse (bpm) CPAP (cm H2O)
120 40 20 2
Airflow (62.5 mV) 23:31:02
23:32:02 23:30:32
23:33:02 23:32:32
23:34:02 23:33:32
23:34:32
Figure 110-2 Polysomnogram from a patient with severe obstructive sleep apnea syndrome. The top seven channels represent about 30 seconds of data and show the electrocardiogram (ECG) and information used to stage sleep. The top channel is chin electromyography. The next three channels are used for electroencephalography (EEG), the next two for eye movements, and the seventh is the ECG. The bottom six channels represent about 5 minutes of data and show the information used to document apnea type. The channels from top to bottom are oxyhemoglobin saturation (SaO2), thoracic movement, abdominal movement, pulse rate, CPAP pressure, and nasal airflow. The 14 apneic episodes in this segment are associated with efforts to breathe, as seen in the chest wall and abdomen channels, but note the intermittent cessation of airflow in the bottom channel. The vertical dark blue line in each segment corresponds to an identical moment in time. Notice that resumption of breathing occurs right after an arousal on EEG (light blue box). Also note the marked variability in pulse rate. CPAP, continuous positive airway pressure.
The American Academy of Sleep Medicine (AASM) has recently published a revised scoring manual for polysomnography.44 In this manual, apnea is defined as a drop in the peak thermal sensor (thermocouple) excursion by >90% of baseline, lasting at least 10 seconds, with at least 90% of the event meeting the amplitudereduction criterion. Apneas are obstructive if there is continued or increased inspiratory effort, and they are central if there is not. The designation of mixed apnea is retained; mixed apnea is described as absent effort at the beginning, with resumption of effort before resumption of airflow. There are now two acceptable definitions of hypopnea according to the revised AASM scoring manual. The “classic” definition of hypopnea, which requires a nasal pressure transducer, is a reduction in nasal pressure excursion by more than 30% of baseline, lasting at least 10 seconds, with a greater than 4% oxyhemoglobin desaturation, with at least 90% of the event meeting the amplitude
reduction criterion. The “new,” alternative definition of hypopnea is a reduction in nasal pressure excursion of at least 50%, lasting at least 10 seconds, with a 3% desaturation or an arousal, with at least 90% of the event meeting the amplitude reduction criterion. It is useful to consider these definitions in light of the Sleep Heart Health Study (SHHS), which is a longitudinal follow-up of more than 6000 persons including in-home PSG.45 In this study, limited to middle-aged and older adults, apneas were identified by absence of airflow for greater than 10 seconds, and hypopneas were defined by a reduction of airflow (to 30% of baseline for apneas and to 70% of baseline for hypopneas) for longer than 10 seconds. In the SHHS, the definitions of apneas and hypopneas require an oxygen desaturation of 4% or more, and they do not include any measure of sleep disturbance or arousal.45-47 These criteria were adopted largely because they are both predictive of cardiovascular sequelae47 and are very reproducible.45,46
1282 PART II / Section 13 • Sleep Breathing Disorders Box 110-2 Definitions
Box 110-3 Obstructive Sleep Apnea, Adult
Apnea A drop in the peak thermal sensor (this would be a thermocouple) excursion by >90% of baseline, lasting at least 10 seconds, with at least 90% of the event meeting the amplitude-reduction criterion. Apneas are obstructive if there is continued or increased inspiratory effort, and they are central if there is no inspiratory effort. The designation of mixed apnea is retained and is described as absent effort at the beginning, with resumption of effort before resumption of airflow.
A, B, and D or C and D satisfy the criteria A. At least one of the following applies: i. The patient complains of unintentional sleep episodes during wakefulness, daytime sleepiness, unrefreshing sleep, fatigue, or insomnia ii. The patient wakes with breath holding, gasping, or choking iii. The bed partner reports loud snoring, breathing interruptions, or both during the patient’s sleep B. Polysomnographic recording shows the following: i. Five or more scoreable respiratory events (i.e., apneas, hypopneas, or RERAs) per hour of sleep ii. Evidence of respiratory effort during all or a portion of each respiratory event (In the case of a RERA, this is best seen with the use of esophageal manometry) OR C. Polysomnographic recording shows the following: i. Fifteen or more scoreable espiratory events (i.e., apneas, hypopneas, or RERAs) per hour of sleep ii. Evidence of respiratory effort during all or a portion of each respiratory event (In the case of a RERA, this is best seen with the use of esophageal manometry) D. The disorder is not better explained by another current sleep disorder, medical or neurological disorder, medication use, or substance use disorder.
Hypopnea A reduction In nasal pressure excursion by >30% of baseline, lasting at least 10 seconds, with a >4% oxyhemoglobin desaturation, with at least 90% of the event meeting the amplitude reduction criterion or A reduction in nasal pressure excursion of at least 50%, lasting at least 10 seconds, with a 3% desaturation or An arousal, with at least 90% of the event meeting the amplitude-reduction criterion Respiratory Effort–Related Arousal A sequence of breaths lasting at least 10 seconds characterized by increasing respiratory effort or flattening of the nasal pressure waveform, leading to an arousal from sleep, when the sequence of breaths does not meet criteria for an apnea or hypopnea Obstructive Sleep Apnea Hypopnea Syndrome Five or more obstructed breathing events per hour of sleep with the appropriate clinical presentation Upper Airway Resistance Syndrome A clinical syndrome of sleepiness resulting from RERAs51 Respiratory Disturbance Index AHI, more or less (may include RERAs) Sleep-Disordered Breathing An ill-defined term used to encompass nonspecified respiratory disturbances during sleep; may include snoring, asymptomatic apneas, and full-blown sleep apnea AHI, apnea–hypopnea index; RERA, respiratory effort–related arousal.
Thus, there is a slight discrepancy between the definition of apnea proposed by the American Academy of Sleep Medicine (AASM),44 which does not require oxygen desaturation, and that used in the SHHS, which does. A careful retrospective analysis of SHHS data has demonstrated that only the only definition of hypopneas that includes at least a 4% oxyhemoglobin desaturation is associated with prevalent cardiovascular disease.48 This is not to say that different desaturation criteria would not be more predictive of other outcomes, such has glucose intolerance.49
Adapted from American Academy of Sleep Medicine. International classification of sleep disorders, 2nd ed. Diagnostic and coding manual. Westchester, Ill: American Academy of Sleep Medicine; 2005.
Diagnostic Criteria Obstructive Sleep Apnea–Hypopnea Syndrome According to the AASM, OSAH syndrome exists when a patient has five or more obstructed breathing events per hour of sleep, with an appropriate clinical presentation (Box 110-3).50 Centers for Medicare and Medicaid Services (CMS) reimburses for CPAP treatment for patients with an AHI greater than 15 or an AHI > 5, with associated hypertension, stroke, sleepiness, ischemic heart disease, or mood disorder (see below, page 1284, Indications).51 Although there is now some consistency in the definitions of SDB, considerable variation continues to exist in recording techniques for measures of airflow and respiratory effort (see Chapter 142).50,52 The innate inaccuracy and variability of current measurement techniques have almost certainly resulted in varying sensitivities for detection of SDB events. Upper Airway Resistance Syndrome The original description of the upper airway resistance syndrome (UARS) emanated from careful study of a small group of persons who had some of the clinical features of OSAH syndrome but negative sleep studies.53 In these patients, increased respiratory effort was identified by esophageal pressure nadirs (measured by esophageal pressure manometry) more negative than one standard deviation below the mean, followed by transient electroencephalography (EEG) arousals. These events were
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termed respiratory effort–related arousals (RERAs), and patients who had five or more such events per hour slept and complaints of sleepiness were deemed to have UARS. Patients with UARS require increased inspiratory effort to generate inspiratory airflow, and this is associated with frequent arousals but without overt apneas (see Videos 102-1 to 102-4). This fragmented sleep is believed to result in increased subjective and objective daytime sleepiness. Much of the current confusion and controversy surrounding UARS probably reflects the lack of standardized definitions and recording techniques. An AASM panel defined a RERA event as “a sequence of breaths characterized by increasing respiratory effort leading to an arousal from sleep, but which does not meet criteria for an apnea or hypopnea.”50 The revised scoring manual also defines RERAs using nasal pressure (they were originally defined using esophageal pressure) as “a sequence of breaths lasting at least 10 seconds characterized by increasing respiratory effort or flattening of the nasal pressure waveform leading to an arousal from sleep when the sequence of breaths does not meet criteria for an apnea or hypopnea.” In other words, both the measurement techniques and the precise definition of RERAs remain somewhat ill-defined. However, a perhaps oversimplified definition of UARS might be five or more RERAs (however defined) per hour of sleep with daytime sleepiness. Techniques that are currently used to detect RERAs in sleep laboratories vary greatly in clinical practice, but few clinical centers actually define and measure UARS as it was originally defined. Because there is no clear standard of diagnosis for this condition, it is probably both underdiagnosed and overdiagnosed (see Chapters 102 and 142). The RDI commonly includes apneas, hypopneas, and RERAs, however they are defined. Although it is possible that the use of the RDI instead of AHI and a wider definition of hypopnea could yield a higher prevalence number for OSAH syndrome, the definition of the disorder should be based on what is associated with adverse health outcomes. An additional issue for clinicians is that the changing definition of hypopnea. The potential replacement of the AHI with the RDI will inevitably lead to increased interrater and laboratory variability. Other Diagnostic Approaches Prediction Formulas and Questionnaires A variety of tools exist to identify persons at risk for OSAH syndrome. Questionnaires generally collect self-reported data from the patient about signs and symptoms, and formulas include physical measures such as blood pressure, BMI, or neck circumference. Because individual features from the history and physical diagnosis are often nondiagnostic, several groups have suggested the use of prediction formulas based on com binations of findings.24-26,36 Among the most useful of such findings are history of witnessed apneas, male sex, BMI, and neck circumference. The Berlin Questionnaire25 focuses on a limited set of known risk factors for OSAH including questions about snoring, daytime sleepiness, and high blood pressure, as well as age, weight, height, sex, and neck circumference (see Chapters 105 and 142).
Specific oropharyngeal measurements are also highly predictive.26,38 Investigators of prediction formulas typically analyze the ability of the proposed formula to predict a given AHI. However, because the AHI does not take into account the degree or duration of oxygen desaturation, sleep disturbance, or cardiac arrhythmias, it is a suboptimal gold standard. A more clinically relevant outcome for prediction formulas might be a positive response to CPAP treatment.43 In general, these formulas perform well when applied to persons with a high likelihood of severe SDB, but this is when such formalized algorithms are least needed by the clinician. Prediction formulas probably have a place in the expedited diagnosis or triage of patients with severe OSAH, particularly in patients with typical presentations, such as sleepy, obese, hypertensive, middleaged men. Home Sleep Testing A MBULATORY M ULTICHANNEL S TUDIES In the spring of 2008, the CMS announced its intent to pay for CPAP treatment on the basis of portable testing (home monitoring) and also announced that continued reimbursement for CPAP after the first 12 weeks of CPAP treatment will be contingent upon demonstration of benefit to the patient. The CMS statement also stipulated that patients should be evaluated by qualified clinicians.51 This decision came after a careful analysis of the available data, including an Agency for Health Quality (AHRQ) report that found that in-laboratory testing does not confer obvious benefit in patient outcomes compared with home testing.54 This national coverage decision (NCD) will be implemented regionally based on local coverage determinations (LCDs), and there is likely to be some regional variation in implementation and a gradual transition. Testing for sleep-disordered breathing is addressed in more detail in Chapter 142. Controversy continues about where sleep studies are best done (Video 110-4) and about the role of screening in general.55,56 Screening has the potential to actually delay diagnosis and to result in false-negative results. In general, screening for OSAH may be useful to screen a person in but not out. Clearly, not all patients will be good candidates for home testing, and the currently proposed reimbursement level for home studies is unlikely to result in a rapid transition from in-laboratory to home testing. Theoretically, home monitoring may result in increased accessibility, enhanced patient convenience, reduced cost, and better sleep in the familiar environment. However, equipment problems cannot be corrected, non-OSAH disorders cannot be detected, and CPAP titrations cannot be performed with home testing. Because autotitrating CPAP performs at least as well as in-laboratory titrated CPAP in patients who have the classic presentation of OSAH syndrome (see later and Chapter 107), the last concern is not particularly valid. The SHHS, using rigid protocols and a centralized PSG reading laboratory, demonstrated that home monitoring can produce reliable data with acceptable rates of data loss.45 The two nonapneic sleep disorders most likely to be identified by laboratory PSG are narcolepsy, which cannot be diagnosed by overnight study alone, and periodic limb movements during sleep. Periodic limb movements are
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extremely common in sleep disorders,57 often unassociated with sleepiness in the nonapneic patient,57 and in some patients may be a marker of SDB.58 A comparison of laboratory PSG and titration with home diagnosis and autotitration found no difference in CPAP compliance between groups, although the home testing group was evaluated more quickly and less expensively.59 Thus, although there are many unresolved issues about the large scale use of home sleep testing in the routine testing for OSAHS, CMS has clearly expanded the options for documenting OSAHS and starting CPAP treatment. At present, home sleep testing is most applicable to confirm the diagnosis of OSAH syndrome in persons with a high likelihood of the disorder.
Box 110-4 Consequences of Untreated Sleep Apnea Impaired cognitive function Impaired quality of life Daytime sleepiness Increased risk of automobile accidents Increased health care costs Hypertension Cardiovascular disease Worsened glucose tolerance Increased mortality rates Impotence
O THER D IAGNOSTIC T OOLS Several other tools have been developed to aid in the evaluation of SDB. Among them are measures of movement such as actigraphy62 and static charge-sensitive bed assessment.63 Also being developed are measures of heart rate variability and pulse pressure, Holter monitoring, and measures of sympathetic nervous system tone.64-66
predictors of progression. Unfortunately, however, the worsening of AHI with a weight gain is greater than the reduction in AHI with a comparable degree of weight loss, and weight gain is much more likely to occur than weight loss in persons with sleep-disordered breathing.81 A report in 1997 estimated that 93% of women and 82% of men with moderate to severe SDB had not received a clinical diagnosis.82 At this point, the need for aggressive diagnosis and treatment of severe, symptomatic SDB is widely recognized. The next frontier is likely to be an understanding of the risks and natural progression associated with milder levels of SDB. This will necessarily involve developing more precise tools and definitions for its identification. At present, even “simple” snoring is associated with some of the risks known to result from unequivocal OSAH syndrome (see Chapter 83).83,84 This is likely to be because the tools that we use to assess breathing disturbances during sleep and their sequelae are very imprecise. Sleep-disordered breathing is a spectrum (Fig. 110-2), and it is not yet clear where to draw the line between normal and pathologic. This likely varies by individual and is influenced by factors such as age and underlying illness. Although some data on cardiovascular morbidity are emerging from the SHHS,46 much more needs to be known about the consequences of “mild” SDB. Because of the burden of illness associated with this disorder, and because the risk of vehicular crashes makes it a public health problem, increasing efforts toward effective diagnosis and cure are appropriate. The National Center for Sleep Disorders Research has published and is continually updating a research blueprint for OSAH syndrome and other sleep disorders.85
CLINICAL COURSE AND PREVENTION Several large studies controlling for obesity and for other confounders have established that SDB is a risk factor for hypertension,39,41,67 car crashes,68,69 neurocognitive dysfunction,70,71 and cardiovascular disease,47,72,73 including strokes and death.16,74 Other likely sequelae include impotence,30 depression,75 glucose intolerance,76,77 reduced quality of life,4,78 and increased health care costs (see Chapters 104 and 105) (Box 110-4).79 Substantial progression of SDB can occur over relatively short time periods.9,80 In the Wisconsin Sleep Cohort, the overall mean AHI increased by 2.6 events per hour of sleep in 8 years. Both snoring and obesity appear to be
TREATMENT Indications The AASM and the CMS have published very similar criteria for treatment of patients with sleep-disordered breathing. CMS reimburses for CPAP treatment for patients with an AHI greater than 15, or with an AHI greater than 5 and concurrent hypertension, stroke, sleepiness, ischemic heart disease, or mood disorders (Box 110-5).51,51a Although there is some debate about whether or not treatment benefits those who have milder degrees of sleep-disordered breathing but who are not sleepy,86 there appears to be a high mortality risk associated with severe sleep-disordered breathing irrespective of sleepiness.46,74,74a,74b
O XIMETRY Because the CMS NCD addressing CPAP treatment of OSAHS covers even the simplest (2-channel) home studies, some regions may stipulate that oximetry is sufficient to diagnose OSAH, so long as one other parameter (typically, heart rate) is also recorded. Oximetry results are the basis for the current definitions of SDB, in that oxygen desaturation of varying degrees are included or required criteria for measures of SDB, notably hypopneas.46,47,50-52 Oximetry has better interrater reliability, and it is a better predictor of the response to CPAP treatment than is the AHI.60,61 In general, patients with significant sleep apnea have a greater fluctuation in oxygen saturation (and heart rate) than do those without. However, thinner, younger patients without lung disease can have significant breathing and sleep disturbance without remarkable oxygen desaturation. Patients with underlying lung disease can have oxygen desaturation without OSA. Thus, oximetry is neither sensitive nor specific for SDB. Several studies have investigated it as a screening or diagnostic tool for OSAH, but their conclusions often conflict. In general, like prediction models, oximetry performs best with more severely affected patients.
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Box 110-5 CMS Indications for CPAP Reimbursement to Patients with Obstructive Sleep Apnea CPAP therapy is covered for adults who have sleepdisordered breathing and the following symptoms or disorders: • AHI >15, or • AHI >5 with any of the following: • Hypertension • Stroke • Sleepiness • Ischemic heart disease • Insomnia • Mood disorders AHI, apnea-hypopnea index; CMS, Centers for Medicare and Medicaid Services; CPAP, continuous positive airway pressure. Information obtained from Centers for Medicare and Medicaid Services.
General Measures Behavior not consistent with health has a major role in causing OSAH, and modifying unhealthful behavior has a major role in treating OSAH. Weight loss can be curative, and even modest weight loss (10%) can relieve mild SDB.70 The relationship among weight, sleep, and appetite is complex, probably mediated in part by leptin, cortisol, insulin, and metabolic rate (see Chapter 86). Patients with newly diagnosed OSAH have a greater increase in weight in the year before diagnosis than do their weight-matched controls, and patients who comply with CPAP treatment tend to gain weight.87,88 All obese patients should be counseled about the potential benefits of weight loss, and those with SDB should be counseled about the potential benefits specifically in this regard. Unfortunately, weight loss through dietary modification takes time, and only a minority of patients can maintain weight loss (bariatric surgery is discussed later). In the long run, simple advice about caloric intake and output may be most effective. The two pharmacologic approaches that are still available in the United States have respectable long-term (2-year) weight loss results of 8% to 10%. One commercially available program (Weight Watchers) has been shown to promote and maintain weight loss more effectively than self-help or other approaches.89,90 Some adults with OSAH have chronic rhinitis. Intra nasal corticosteroid therapy might improve their apnea severity, but not necessarily their snoring or sleep quality,91 so the usefulness of this treatment as sole therapy is not established. Although the data are inconsistent, cigarette smoking has been implicated as a risk factor for snoring and for OSAH, as well as for chronic obstructive pulmonary disease (COPD).4,19 In addition, nicotine disrupts sleep. In general, smokers have more sleep disturbances than nonsmokers.92 Smoking cessation advice should be routine in the management of all patients who smoke. Muscle relaxants, including alcohol and sleeping pills, can make apneas longer by reducing airway tone and by increasing the arousal threshold. Moderate alcohol drink-
ing has been clearly shown to exacerbate OSAH and should be discouraged.93 A subset of patients (usually thinner, older, and with milder disease) have supine position–dependent apnea. In these persons, sleeping on the side can totally eliminate SDB. Unfortunately, the state of the art of position training is still in its infancy. A variety of devices are commercially available, though none has been rigorously tested or Food and Drug Administration (FDA) approved. A tennis ball in a pocket in the back of a T-shirt is often recommended, but it can result in back pain in our experience. Most clinicians are uncomfortable using this technique to treat a condition known to have serious cardiovascular and public health consequences. Continuous Positive Airway Pressure The first line of treatment for OSAH is CPAP (see Chapter 107) (Video 110-5). Typically applied in the range of 5 to 15 cm H2O through a nasal or oronasal mask, CPAP splints open the entire airway (from nares to alveoli), increases functional residual capacity, can increase pharyngeal dilator activity, and reduces afterload on the heart. CPAP is often titrated in a sleep laboratory, with mask fitting and CPAP adjustment done in the second half of the night after the diagnosis of OSAH is established. Diagnosing SDB and titrating CPAP in one night, or splitnight testing, is currently the standard approach. CPAP is begun at 3 to 5 cm H2O, and it is gradually increased until all measures of SDB, including snoring and arousals, are eliminated. CPAP requirements vary across patients and tend to be higher in more-obese patients, during REM sleep, in the supine position, and when alcohol or other muscle relaxants have been consumed. For this reason, achieving a perfect CPAP pressure in a single night’s (or half night’s) titration is more difficult than it sounds. A majority of patients are adequately treated with CPAP pressures between 8 and 12 cm H2O. Autotitrating CPAP machines are now available.94-97 Although the performance algorithms are proprietary and differ among manufacturers, in general these devices infer upper airway narrowing or collapse (e.g., apnea or hypopnea) by real-time assessment of flow or flow profile with detection of reduced patient-generated airflow as well as vibration of upper airway tissues (e.g., snoring). In response to these conditions, the device augments the pressure delivered to the upper airway to restore or optimize upper airway patency and eliminate the vibration (snoring). Autotitrating CPAP machines might not all be equally effective.78 However, most have been validated in studies of small numbers of patients with classic features of OSAH in both laboratory and home studies. Currently, no guidelines exist about how to remedy an inadequate attempt at CPAP titration on a split-night study. Autotitrating CPAP is a cost-effective alternative to laboratory titration for some patients. However, for patients who have severe oxygen desaturation or sleep disruption, have problems with mask leaks or sleep with their mouth open, or have hypoventilation or possible central apnea, laboratory titration with a technician in attendance is recommended. A third approach to establishing CPAP pressure is arbitrary pressure.98 Given that a majority of patients do well
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with CPAP set at 8 to 12 cm H2O, Hukins demonstrated that basing initial CPAP pressures on BMI (8 cm H2O if BMI is <30, 10 cm H2O if BMI is 30 to 35, and 12 cm H2O if BMI is ≥35) results in outcomes comparable to CPAP titrated in the laboratory. Achieving adequate patient compliance with CPAP (somewhat arbitrarily defined as use for 4 or more hours on 5 or more nights a week) remains the most difficult part of chronic CPAP management. Probably only about 50% to 60% of patients comply with CPAP.99-101 Humidification of inspired air (warm better than cold, but cold better than nothing) and education may improve CPAP compliance.102,103 Autotitrating CPAP can also have better rates of compliance and results in reduced mean overnight pressure. Bilevel pressure has not been shown to improve compliance compared with straight CPAP in a head-to-head trial. Mask fit and type, nasal steroids, and decongestants are believed by many clinicians to enhance CPAP use, but there is no convincing evidence that they do so. A Cochrane analysis conducted in 2004 reported, “The effect of AutoCPAP in increasing hours of use in unselected patients starting this treatment remains unclear. The evidence in support of bilevel, self-titration and humidification is lacking and studies are required in these areas. There is some evidence that psychological/educational interventions improve CPAP usage.”104 Although clinicians find CPAP adherence rates disappointing, it is worth remembering that CPAP adherence is actually quite comparable to adherence with other common medical recommendations.105 Complications of CPAP treatment are relatively minor and include epistaxis, ulcer, rashes or irritation on the bridge of the nose, rhinorrhea, chest or sinus discomfort, claustrophobia, nasal congestion, and conjunctivitis. Most of these can be addressed with good mask fit and humidification. CPAP use has been associated with reversal of many of the sequelae of OSAHS, including mortality,74,106 automobile accidents,69,107 hypertension and other cardiovascular diseases,72,73,105,108,109 cognitive impairment,59,110,111 sleepiness,111,112 increased health care costs,79 impaired quality of life,113 depression,75 and impotence.30 Most studies documenting improved outcomes with CPAP have shown benefit with an intention-to-treat model. In other words, if the patient accepts CPAP, benefit occurs even in the absence of well-documented compliance. The healthy adherer effect114 is now recognized as an important variable influencing outcome in treatment trials, and it could certainly be a factor in the positive outcomes seen for those who adhere to CPAP. Randomized, placebocontrolled trials of CPAP benefits are under way, including the Apnea Positive Pressure Long-term Efficacy Study (APPLES) and CPAP Apnea Trial North American Program (CATNAP) trial. Surgery A variety of surgical approaches have been applied to SDB, including tracheostomy, uvulopalatopharyngoplasty (UPPP), laser-assisted uvulopalatopharyngoplasty (LAUP), septoplasty, oromaxillofacial surgery, and radiofrequency volumetric tissue reduction (also known as somnoplasty).
Tonsillectomy appears to be ineffective treatment of OSAHS in adults. Bariatric surgery addresses morbid obesity in patients with OSAH. Chapters 108 and 115 address surgical treatment of OSAH in detail. There is variability in the quality and quantity of clinical trials that have been done to evaluate the various procedures (see below and Chapter 108).114a,114b,114c The definition of success in the surgical literature has typically been a reduction in the AHI or RDI of 50%, irrespective of symptoms or baseline AHI115 Long-term follow-up and measures of effects on automobile accidents, quality of life, blood pressure, cognitive performance, and health care costs are minimal.116,117 Recent parameters for the role of surgery have been developed.117a Uvulopalatopharyngoplasty Of the surgical procedures used to treat OSAH, UPPP is the most commonly performed and best studied. In a meta-analysis of 37 papers including more than 500 patients, Sher noted that the mean decrease in apnea index is 55%, and the mean decrease in RDI is 38%.116 Unfortunately, reducing the RDI by about one third rarely results in a cure. Surgical success is defined in this metaanalysis (as in many papers in the surgical literature) by some ratio of preoperative to postoperative RDI plus a postoperative RDI or apnea index of 10 to 20 events per hour of sleep. Because cardiac and neurocognitive effects can involve RDIs as low as five events per hour of sleep, designating these kinds of responses as a success is questionable.47,118 Even accepting these definitions, UPPP has a success rate of approximately 50%, and it appears to be even less effective in more severely affected, heavier patients.119 In particular, outcomes are poorer for those with a BMI greater than 30 or with a lowest Sao2 less than 88%. Relapse also occurs in as many as half in the fraction who get an initial response, usually (but not always) related to weight gain.116 Complications of UPPP appear to be velopharyngeal insufficiency in up to 2%, postoperative bleeding in about 1%, and nasopharyngeal stenosis (1%), voice change (1%), perioperative upper airway obstruction (0.3%), and death (0.2%). Sher also reported that many papers do not comment on the presence of complications at all. Laser-Assisted Uvulopalatopharyngoplasty LAUP has a surgically defined success rate of 0% to 48% for OSAHS,116 depending on the criteria used. Sher notes that most case series report preoperative and postoperative results in only a fraction of those who had the procedure. In addition, very few long-term results or data about complications are available. Importantly, LAUP has been associated with an acute exacerbation of SDB.120 Because LAUP has typically been done as an outpatient procedure, it could actually pose a risk to patients. At present, many surgeons believe that LAUP is an operation appropriate for snoring only,116 and this type of surgery is now rarely undertaken for treatment of OSAH. Radiofrequency Volumetric Tissue Reduction Radiofrequency volumetric tissue reduction (RFVTR) has been applied to the palate, tongue base, and nasal septum.
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Originally reported as a treatment for SDB,121 this procedure appears to be safer and less painful than LAUP. Follow-up data for RFVTR of both palate and tongue suggest that the initial response is generally not what would be considered a cure by most sleep specialists and that relapse is a significant problem. This procedure is now used primarily for snoring rather than for clinically significant OSAH.116
patients, 16 had decannulation, but five needed CPAP, three had UPPP, two achieved weight loss, and three were lost to follow-up. Immediate complications of tracheostomy included one perioperative myocardial infarction and one tracheal-innominate fistula. Longer-term adverse consequences and lifestyle changes include difficulty speaking and increased risk of infection. Because of its morbidity, tracheostomy is a treatment of last resort.
Palatal Implants The insertion of polyethylene terephthalate (PET) palatal implants has been approved by the FDA as an office-based treatment for the reduction of snoring and for the treatment of mild to moderate obstructive OSAH. Typically, three cylindrical implants made of braided material are inserted under local anesthesia into the upper soft palate to stiffen the tissue and to reduce flutter. Studies of these devices have been small, short-term, and subject to high dropout rates. In one study, the authors paradoxically commented that “polysomnography parameters showed clinically irrelevant changes” about a year after palatal implant surgery, and clearly demonstrated that oxygenation and RDI were statistically and clinically significantly worse!122 Nevertheless, a recent Medical Letter analysis concluded, “Minimally invasive palatal implants for the treatment of snoring and mild-moderate obstructive OSAHS appear to be modestly effective and safe for up to one year in reducing snoring intensity, daytime sleepiness, and the number of apnea/hypopnea events.”123 Based on the available literature, we do not recommend this treatment as first-line therapy in any patient with confirmed sleep apnea and we do not recommend it at all in patients with moderate to severe apnea.
Bariatric Surgery Of the several types of weight-reduction surgeries, gastric bypass done is probably the treatment of choice because it results in greater weight loss and better weight loss maintenance. The laparoscopic approach is associated with fewer complications. Overall, perioperative morbidity and mortality are 10% and less than 1%, respectively. Incisional hernias, wound infections, and vitamin deficiencies can result in the long run. In several studies, gastric bypass surgery appears to be very effective in the treatment of OSAH associated with morbid obesity.126
Oromaxillofacial Surgery Maxillomandibular advancement (MMA) may be of benefit to carefully selected (non-obese) patients who cannot or will not accept CPAP and who are willing to accept the risk of a procedure whose short-term efficacy appears modest and whose long-term efficacy and consequences are incompletely known.124 Combination Surgical Treatment There are a variety of combination surgical procedures, typically including some combination of genioglossal advancement, hyoid myotomy and suspension, UPPP, and RFVTR (see Chapter 108). Studies evaluating these procedures typically include 10 or fewer patients; they often offer a loose definition of success and provide no longterm follow-up. Combination therapy is less likely to be effective when the patient is morbidly obese.124a Tracheostomy Tracheostomy was the first and remains the only approach to very severe OSAH in those who cannot tolerate CPAP or bilevel pressure and face an immediate life-threatening risk. Early resolution of OSAH occurs promptly in 83%, and central apneas slowly resolve in the remainder. Sleepiness resolves in 82% and hypertension resolves in 40% of those who undergo tracheostomy.116 At a mean follow-up of 8 years, tracheostomy was uniformly successful in 79 patients who had severe obstructive OSAH.125 Of those
Oral Appliances Oral appliances are indicated for patients who have mild SDB or are CPAP intolerant. The appliances have beneficial effects on snoring, sleepiness, and mild SDB.127,128 Although CPAP is more effective than oral appliances in alleviating sleep-disordered breathing events, patients who have the opportunity to experience both kinds of treatment consistently prefer the oral appliance over CPAP therapy.127 Oral appliances are more effective than UPPP, another alternative to CPAP, in both the long and the short term.128 Complications of oral appliance therapy include craniofacial and bite changes and exacerbation of temporomandibular joint pain.128a In addition, possibly a third of patients have a contraindication to this therapy, such as insufficient teeth, periodontal problems, or temporomandibular joint disorder (see Chapter 109).129 For these reasons, oral appliance therapy is best undertaken and followed by dentist.
COMMON CLINICAL PROBLEMS ENCOUNTERED IN MANAGING PATIENTS WITH OSAH Negative Sleep Studies When the results of an overnight study are normal, significant SDB is unlikely but cannot be completely excluded. Factors that may contribute to a false-negative sleep study include the following: • Poor-quality sleep during the study, particularly absence of REM sleep • Sleeping on one’s side during the study instead of the usual supine sleeping position; OSAH tends to be most severe in the supine position • Omitting one’s usual alcohol or sedative agent on the night of the study; these agents can exacerbate a tendency to SDB • Insensitive (or, more accurately, overly sensitive) monitors of airflow or respiratory effort, which allow subtle decrements in airflow or marked increases in respiratory effort to go undetected130
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As originally described, UARS occurs in patients who have clinical symptoms that suggest OSAH but no evidence of frank apneas or hypopneas on overnight polysomnography.53 Overreliance on the AHI also probably results in undertreatment of patients who would benefit from CPAP. The AHI does not take into account the duration of SDB events, the degree of oxygen desaturation or sleep disruption, or associated cardiac arrhythmias. A significant number of symptomatic patients would almost certainly benefit from treatment even though they have sleep study findings that do not meet reimbursement criteria for treatment. CPAP Compliance Second to weight loss, CPAP compliance remains the most significant therapeutic challenge, even though some work suggests that the benefits of CPAP are directly related to the average duration of nightly use.72,108,117,131,132 CPAP adherence will likely receive much more attention in the future than it has in the past because of the NCD issued by CMS stipulating that payment for CPAP will continue only for patients who demonstrate “benefit.” CPAP adherence is likely to be one required measure of benefit. Because of this requirement and growing awareness that sleep-disordered breathing is a chronic illness that should be managed as such, it is likely that OSAH educators and other health professionals will be increasingly involved in monitoring and managing these patients, just as they are for patients with chronic illnesses such as diabetes and asthma. Patients who do not accept or comply with CPAP need written and verbal discussion of the risks of untreated OSAH, emphasizing automobile accidents and cardiovascular risk, because these are the best-documented consequences of untreated SDB. For medicolegal purposes, this discussion should be documented in the medical record. Such patients also deserve a frank discussion of alternative treatments, including surgery and oral appliances. They should always have the option of using CPAP even when another treatment was selected first. Documentation should note that the patient was told that neither surgery nor oral appliances have been shown to be as effective as CPAP in alleviating the consequences of OSAH. Driving Risk SDB increases the risk of motor vehicle accidents and CAN specifically increase the risk of accidents associated with property and physical damage133 Clinicians should familiarize themselves with local laws concerning sleepiness and driving. Estimates of increased risk range from 2 to 7 times that in the nonaffected population.134 Identifying those at greatest risk is more art than science; a prior history of automobile accidents or near misses, increased BMI, increased severity of sleep-disordered breathing,133 and an elevated score on the Epworth Sleepiness Scale may help to predict those at greatest risk. Driving simulator data and real-life experience have demonstrated that driving capabilities return quickly (within days) to baseline when patients with OSAH are treated with nasal CPAP.135,136 The prevention of driving accidents in patients with OSAH appears cost effective and might reduce fatalities.137 Both education of the patient with OSAH about sleepy driving and objective documentation of treatment efficacy are
important in reducing the likelihood of accidents (see Video 104-2). Vorona and Ware recommend the following approach to reduce the risk of accidents for patients with SDB134: • Educate patients with OSAHS about the increased risk of sleepy driving. Inform them that sleep-related accidents are disproportionately severe. Provide access to written materials on OSAHS and driving. • Ask patients with OSAHS about a previous history of sleepy driving and any history of motor vehicle accidents. Pay particular attention to patients with a history of previous sleepy accidents and those who drive professionally. • Instruct patients in proper sleep hygiene and encourage them to obtain adequate hours of sleep. • Encourage caffeine and use of rest stops as effective countermeasures to sleepy driving. Napping has also been shown to counteract sleepiness in driving activities. • Order time-of-use meters on CPAP units for objective documentation of patient compliance. • Use PSG to document efficacy of treatment for those undergoing other treatments such as surgery or an oral appliance. • Discourage driving by patients who are not complying with therapy and are believed to be at risk for motor vehicle accidents. Patients continuing to drive and believed to be a public health risk should be reported by the physician to the authorities if state statutes allow. Although some might propose obligatory reporting to the state of all with OSAH, caution is urged as this might reduce the likelihood that patients will seek medical attention.138 Inadequate Response: When to Restudy Repeat testing is usually not routine for several reasons; sleep studies are expensive and inconvenient, and insurance might not cover repeat testing. However, for some patients a repeat test can be very helpful. Among them are patients who have a nondiagnostic first study (see earlier), who are still sleepy despite adequate CPAP therapy, including adequate compliance, those who gain or lose significant amounts of weight, and those who undergo surgery or use an oral appliance to treat their SDB. Patients who remain sleepy on treatment or whose sleepiness and other symptoms recur after an initial good clinical response may benefit from reassessment. The Patient Who Remains Sleepy on CPAP Treatment Sleepiness after initiation of CPAP treatment is common and takes two forms: the patient who has an initial excellent response to treatment and subsequently becomes sleepy again, and the patient who has never had an improvement in sleepiness despite CPAP use. The prevalence of this problem is unknown, but several studies have documented that the mean level of sleepiness does not return to normal in persons treated with CPAP.139,140 Box 110-6 lists the likely causes of sleepiness after CPAP treatment is initiated. The first step in evaluating such patients should probably be to obtain some measure of compliance, typically
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Box 110-6 Potential Causes of Sleepiness despite CPAP Treatment Noncompliance Inadequate total sleep time (e.g., self-imposed sleep restriction) Medication effects A coexisting sleep or medical disorder Depression Permanent brain damage from untreated sleep-disordered breathing CPAP, continuous positive airway pressure.
accomplished by a meter or a card on the CPAP machine. Although minimally acceptable compliance is often suggested to be 4 or 5 hours of CPAP use, optimal CPAP use for individual patients is not known. Evaluating the patient for another sleep disorder, particularly shift work sleep disorder, might clarify the issue. Medications and their effects on nocturnal sleep and daytime alertness should be investigated. Several groups139,141 have investigated the use of modafinil in carefully selected CPAP-compliant patients who remained objectively and subjectively sleepy. There is improvement in some measure of sleepiness with 400 mg of modafinil a day. Whether and when to use this approach for patients with SDB who are still sleepy is likely to remain controversial. Objective measurements of CPAP compliance and of sleepiness would seem to be minimal prerequisites to such treatment. Patients on wake-promoting agents should be counseled that although they might feel less sleepy, this intervention does not treat their OSAH and they must continue to use CPAP. Managing OSAH in Special Patient Groups COPD and OSAH The term overlap syndrome was coined to refer to patients who have both COPD and OSAH (see Chapter 111).142 Data from the SHHS suggest that although there is no association between generally mild COPD and OSAH other than by chance, oxygen desaturation is greater in persons who have both conditions than in those who have either condition alone.143 Continuous positive airway pressure is an effective treatment for the SDB in these patients and can reduce cardiovascular risk. It often appears remarkably effective in reversing the hypoxemia that is associated as well. Unfortunately, CPAP compliance in smokers appears to be lower than in nonsmokers or in those who do not have COPD.99 Some patients with COPD (and other lung diseases) may remain hypoxemic on CPAP pressures that are high enough to eliminate the episodes of apnea and hypopnea. It is possible that bilevel pressure, with or without a set rate, may be of benefit in these situations. Supplemental oxygen can be added to the CPAP circuit to normalize oxygenation. Very little is known about the likelihood of carbon dioxide retention in this situation or its effects. Smoking cessation is imperative for these patients. Not only do ex-smokers appear to have a normalized risk for OSAH compared with active smokers,20 but also smokers
in general sleep more poorly than do nonsmokers.92 Optimal medical management of these patients includes, in addition to CPAP, inhaled bronchodilators and perhaps inhaled antiinflammatory agents to minimize the effects of cough and wheezing on sleep structure. Perioperative Patients The scientific data about optimal perioperative management of patients known or suspected to have SDB are limited. According to a statement by the Clinical Practice Committee of the AASM and a review of the literature,144,145 critical issues in preventing perioperative mishaps in patients with OSAH include having a high degree of clinical suspicion, controlling the airway throughout the perioperative period, using medications very judiciously, and employing appropriate monitoring. Orthopedic patients appear to be at particularly increased risk. The American Society of Anesthesiologists (ASA) has published practice guidelines for the perioperative management of patients with OSAH,146 and untreated OSAH is increasingly recognized as a cause of perioperative complications.147 Oximetry in patients who have clinical features of OSA can identify those at high risk for complications, who can then be treated with arbitrary-pressure CPAP or autotitrating CPAP in the perioperative period. Although the ASA document describes a workable approach to the in-hospital management of patients with suspected or known OSAHS, it does not address management after discharge. Ideally, the patient’s primary care physician, sleep specialist, or consultant will follow up with such patients to be certain that their sleep-disordered breathing is managed as a chronic condition. Further research is clearly needed to define the magnitude of risk and optimal perioperative care. Critically Ill Patients Patients with OSAH have increased health care costs because of cardiovascular risk and other comorbid conditions such as obesity, diabetes, and hypertension.79 It is to be expected, then, that they are often treated in the intensive care unit (ICU). For patients with known OSAH, an attempt to treat with CPAP or bilevel pressure may be of benefit. However, many patients with diagnosed OSAH arrive in the ICU because they have been unwilling or unable to use the CPAP machine. Furthermore, coughing, vomiting, nasogastric tubes, procedures, and patient discomfort can result in intermittent CPAP use. For critically ill patients, intermittent airway patency is a great deal less than optimal. Intubation may be the most definitive and effective initial course for the critically ill patient with OSAH who has respiratory distress. In patients with known OSAH who arrive in the ICU because of inability to use CPAP, tracheostomy is a long-term solution that can prevent another hospitalization. All the caveats of care that are applicable to perioperative patients apply to those in the ICU. Treatment-Emergent Central Apneas or Complex Sleep Apnea Complex sleep apnea is best defined as central apneas and periodic breathing that develop when CPAP is applied to treat patients with OSAH.148,149 his phenomenon appears
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to be more prevalent in older men with congestive heart failure, and its clinical significance is unclear. In our experience, central apneas can emerge when OSAH patients are overtitrated. In most patients, the central apneas resolve over time.150 In a convenience sample of a variety of sleepdisordered breathing syndromes resistant to CPAP, adaptive servoventilation (ASV) appeared to be effective and well tolerated in about half the patients.151 For managing OSAH in the pregnant woman, see Chapter 138. For managing OSAH in the patient with heart failure,152 see Chapter 122.
❖ Clinical Pearl OSAH syndrome is a common condition with significant cardiac, metabolic, and cognitive consequences. Although there is clearly a genetic predisposition, lifestyle factors are important and modifiable risk factors. Witnessed apneas, heavy snoring, daytime sleepiness, obesity, and hypertension are the classic symptoms and signs of sleep-disordered breathing in men; women might present with more subtle findings. CPAP is clearly the most effective treatment, and achieving compliance with this treatment remains an important clinical challenge.
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Sleep in Patients with Asthma and Chronic Obstructive Pulmonary Disease Neil J. Douglas Abstract Nocturnal cough, wheeze, and breathlessness are problems for many asthma patients, and they result from sleep-related nocturnal narrowing of the lower airways, mainly as a result of alteration in neural control of airway caliber during sleep. Usually nocturnal asthma is inconvenient and unpleasant, but occasionally it can be life-threatening. The new development of nocturnal symptoms is an indicator of deteriorating asthma control, and it is an indication for intensifying therapy. Treatment is by optimizing inhaled steroids and beta agonists, often with the addition of long acting inhaled beta agonists. Patients with chronic obstructive pulmonary disease (COPD) exhibit oxyhemoglobin desaturation during sleep, especially
NOCTURNAL ASTHMA Asthma, a disease characterized by variable bronchoconstriction, occurs in about 5% of the population, an incidence that is rising in most countries. The bronchoconstriction is at least initially totally reversible with therapy. Besides spasm of bronchial smooth muscle, other causes of the airflow obstruction are viscous bronchial secretions and inflammation and swelling of the mucosa and submucosa of the lower airways. The airways of asthmatic patients are hyperresponsive. Bronchoconstriction can follow exposure to allergens (pollen, animal dander) or nonallergenic stimuli (e.g., viral infections, low environmental temperature, fumes). In many patients, asthma is worse at night or in the early morning, causing cough, wheeze, or breathlessness. These symptoms reflect overnight bronchoconstriction, which occurs in more than two thirds of asthmatic patients.1 Although the cause of nocturnal bronchospasm remains uncertain, its management is improving with advances in medications. The observation that many asthmatic patients wheeze at night is not new. In 1698, Dr. (later Sir) John Floyer, himself asthmatic, wrote: I have observed the fit always to happen after sleep in the night. … At first waking, about one or two of the clock in the night, the fit of asthma more evidently begins, the breath is very slow … the diaphragm seems stiff and tied. … It is not without much difficulty moved downwards.2 Despite the clarity of this description, more than 2 centuries passed before nocturnal asthma received further attention. The forced expiratory volume in 1 second (FEV1) and peak flow rates fall overnight in patients with asthma,3 the fall being more than 50% in some patients. Patients with such overnight bronchoconstriction have been called morning dippers (Fig. 111-1).4 In asthmatic patients recovering from exacerbations, about one third have bronchoconstriction during the night and another third have 1294
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during rapid eye movement (REM) sleep. This is caused by normal physiologic hypoventilation during REM sleep, which produces greater alveolar hypoventilation in COPD and can have deleterious cardiovascular and hematologic effects. REM hypoxemia in COPD is greatest in patients who are most hypoxemic when awake, and the need for treatment is best predicted by daytime levels of arterial oxygen tension. There is no evidence that overnight polysomnography is helpful in treating such patients, unless there is a clinical suspicion for obstructive sleep apnea–hypopnea syndrome. The treatments of choice are oxygen therapy or oxygen plus nocturnal noninvasive intermittent positive pressure ventilation.
bronchoconstriction before sleep and continue to have it overnight.1 Thus, two thirds of such patients have their lowest flow rates between 10 pm and 8 am, with a mean amplitude of variation of peak flow rates of 29%.1 Circadian Rhythm of Airway Caliber Most normal people also have circadian changes in airway caliber, with mild nocturnal bronchoconstriction.5 The largest series comparing circadian changes in peak flow in healthy subjects and unstable asthmatic patients5 shows that the changes in flow rate are synchronous in asthmatic and normal subjects, whereas the amplitude of peak flow rate changes is far greater in asthmatic patients (50%) than in normal subjects (8%). Thus, nocturnal bronchoconstriction in asthma appears to be an exaggeration of the normal circadian changes in airway caliber. Asthmatic patients are hyperreactive to constrictor stimuli; thus, nocturnal bronchoconstriction in asthmatic patients is probably an expression of hyperresponsiveness to the factors that produce mild nocturnal bronchoconstriction in normal subjects. As with other circadian rhythms, the major synchronizing factor is sleep, although overnight sleep deprivation reduces, but does not abolish, nocturnal airway narrowing (Fig. 111-2).6,7 In asthmatic shift workers, sleep time determines the timing of “nocturnal” airway narrowing,8 and airway caliber changes rapidly invert with inversion of sleep pattern. That some overnight airway narrowing persists even if patients are kept awake all night could be due to a lag between altered sleep times and readjustment of circadian rhythms. Pathogenesis of Nocturnal Airway Narrowing Factors that have been suggested but that seem unlikely primary causes of nocturnal airway narrowing include the sleeping posture, interruption of bronchodilator or other treatment, and allergens in bedding. Posture is not a major
CHAPTER 111 • Sleep in Patients with Asthma and Chronic Obstructive Pulmonary Disease 1295
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Days Figure 111-1 Peak flow rate over a 2-week period in a 62-yearold woman with nonallergic asthma. The flow rate on waking is indicated with a cross. There is marked morning dipping. (From Douglas NJ. Asthma at night. Clin Chest Med 1985;6: 663-674.)
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factor because patients who lie in bed throughout the 24-hour period continue to exhibit overnight bronchoconstriction,3 and lying down does not produce sustained bronchoconstriction.9 Neither is the treatment interval critical, because regular spacing of treatment throughout the 24 hours does not abolish nocturnal bronchospasm,4 and nocturnal wheeze is a presenting complaint of many untreated asthmatic patients. Allergens It is unlikely that allergens in bedding are prime causes of nocturnal asthma, because avoidance of such allergens does not abolish nocturnal airway narrowing.10 In addition, overnight bronchoconstriction occurs in both allergic and nonallergic asthmatic patients1 and in normal subjects.5 Allergic factors can, however, produce nocturnal wheeze; experimental allergen inhalation can cause bronchoconstriction on subsequent nights,11 and scrupulous exclusion of allergens can reduce circadian changes in peak flow rates and the frequency and severity of asthmatic attacks.12 These findings suggest that allergic reactions—and particularly, perhaps, late or delayed allergic reactions—are important in the development of nocturnal wheeze in some patients. There is a close relationship between the extent of nocturnal airway narrowing and the degree of airway twitchiness or bronchial reactivity.13 It seems likely that such allergen exposure increases bronchial reactivity in predisposed patients and thus might result in enhanced nocturnal bronchoconstriction. Airway Cooling Cold, dry air causes bronchoconstriction in asthmatic patients. It had been suggested that nocturnal asthma might be caused either by breathing cooler air at night or by bronchial wall cooling as a result of the overnight decrease in body core temperature. However, overnight bronchoconstriction persists in normal subjects even when temperature and humidity are maintained throughout the 24-hour day at levels present during diurnal wakefulness.14 However, it has been reported that breathing warm, humid
0 10 PM post sleep Sleep night
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Figure 111-2 Peak expiratory flow at night and in the morning on both the asleep and the awake nights. All patients developed bronchoconstriction on both nights, but although the 10 PM peak flow rates were not significantly different, morning peak flow was higher after the awake night. (From Catterall JR, Rhind GB, Stewart IC, et al. Effect of sleep deprivation on overnight bronchoconstriction in nocturnal asthma. Thorax 1986;41: 676-80.)
air (36° C to 37° C, 100% saturation) overnight, compared with breathing room air (23° C, 17% to 24% saturation) overnight, abolished nocturnal bronchoconstriction in six of seven asthmatic patients in whom sleep was not documented.15 Gastroesophageal Reflux There seems to be a high incidence of gastroesophageal reflux (GER) in people with asthma, especially in those with nocturnal wheeze,16 and the GER may be clinically silent. There is no convincing evidence that spontaneous GER causes nocturnal bronchoconstriction.17 Gastric acid suppression with proton pump inhibitors has at best a marginal effect on nocturnal asthma.16,18,19 Mucociliary Clearance Mucociliary clearance is impaired during sleep, and the accumulation of mucus in the airways could contribute to nocturnal airway narrowing. However, this accumulation seems unlikely to be a major factor in nocturnal wheeze, because bronchodilators are rapidly effective. Bronchial Hyperreactivity Bronchial responsiveness to inhaled histamine and allergens increases throughout the night.20 However, the
1296 PART II / Section 13 • Sleep Breathing Disorders
airways are narrower at this time, and thus the increased response could reflect greater initial bronchomotor tone at night rather than any change in mucosal permeability or receptor or neuromuscular function. A skin prick test for allergens and histamine shows marked circadian variation: Maximal effects are in the late evening, and a minimum is reached by early morning.21 Thus, there may be circadian variations in reactivity, although the changes in sensitivity to skin tests are about 8 hours ahead of the circadian changes in airway reactivity. Is Nocturnal Wheeze Related to Sleep Stage? Several groups have recorded electroencephalograms (EEGs) in sleeping asthmatic patients and noted the stage when patients awoke with attacks of asthma. A suggestion that patients awoke more often from REM sleep than would be expected by chance has not been confirmed, asthmatic attacks being randomly distributed throughout the stages of sleep in proportion to the amount of time spent in each sleep stage (Fig. 111-3).22 Esophageal pressure measurements suggest that pulmonary resistance does not differ between sleep stages.7 It thus appears unlikely that there is any difference in the degree of airway narrowing between sleep stages. Breathing Patterns during Sleep Like normal subjects,23 asthmatic patients decrease their ventilation from wakefulness to sleep, ventilation being lower during NREM sleep than during wakefulness, with the lowest levels tending to occur in REM sleep.24 Whether there is any abnormality of breathing pattern during sleep in asthmatic patients is unclear. We found a small, but significant increase in irregular breathing in asthmatic
100 % Sleep time % Asthma attacks 80
patients due almost entirely to more apneas in asthmatic patients,25 but others found no such changes.24 The increased number of apneas that we observed might have been the result of the study’s having been performed in the early summer, when the patients might have had mild rhinitis, which can increase apneas. In addition, the apneas were few and brief and were not associated with significant hypoxemia; thus, their clinical significance is dubious. Lung volume falls during sleep, and this could contribute to increasing resistance to airflow because lower airway caliber drops as lung volume decreases. However, this is not a major cause of sleep-related airway narrowing.26 There is some evidence that smaller airways may be preferentially narrowed at night in nocturnal asthma.27 However, the cause and the significance of this observation are clear. Some nocturnal asthmatic patients who snore or have obstructive sleep apnea develop worsening of their asthma, perhaps as a reflex response to their upper airway vibration. This appears to be a relatively uncommon cause of nocturnal asthma, but it is important that it is recognized, because nasal continuous positive airway pressure (CPAP) therapy may be helpful in such cases (Fig. 111-4).28 Relationship between Nocturnal Asthma and Obesity There has been speculation that asthma is directly related to obesity and thus might be commoner in patients with the obstructive sleep apnea–hypopnea syndrome. However, the evidence of an association between asthma and obesity is still conflicting, with some evidence suggesting the “association” is due to increased awareness of breathlessness in the obese, whereas some studies suggest an increase in airways hyperreactivity in obese subjects.29,30 Further studies are needed to clarify the relationship. Conclusions Nocturnal asthma is largely a sleep-synchronized circadian rhythm in airway caliber. How this results in airway narrowing is discussed later.
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Sleep stages Figure 111-3 Comparison of percentage of night spent in each sleep stage with percentage of asthmatic awakenings from that stage. The asthmatic attack frequency was proportional to the frequency of each sleep stage. (Redrawn from Kales A, Beall GN, Bajor GF, et al. Sleep studies in asthmatic adults: relationship of attacks to sleep stage and time of night. J Allergy 1968;41:164-173.)
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Days Figure 111-4 Peak expiratory flow rate (PEFR), as percentage predicted, at 3 AM in a snoring asthmatic patient measured during a control period, during a period of nocturnal continuous positive airway pressure (CPAP) therapy and during a subsequent period after CPAP withdrawal. The open circle during the CPAP period represents a single night when the CPAP was withdrawn. (Redrawn from Chan CS, Woolcock AJ, Sullivan CE. Nocturnal asthma: role of snoring and obstructive sleep apnea. Am Rev Respir Dis 1988;137:1502-1504.)
CHAPTER 111 • Sleep in Patients with Asthma and Chronic Obstructive Pulmonary Disease 1297
Mechanisms Narrowing Asthmatic Airways at Night Autonomic Function Bronchial (smooth) muscle receives efferent innervation from the parasympathetic system via the vagus nerve, but there is no evidence of direct sympathetic innervation to the muscle in human beings. However, there are sympathetic nerves to the airway, and some probably terminate on the vagal ganglia in the bronchial wall. Circulating (or inhaled) catecholamines probably cause bronchodilation by acting directly on bronchial smooth muscle. There is also a third component of the autonomic nervous system (the nonadrenergic, noncholinergic system), which passes in the vagus nerve and produces bronchodilation. P ARASYMPATHETIC N ERVOUS S YSTEM Parasympathetic tone is increased at night. Studies using cholinergic blockade31,32 indicate that an increase in airway parasympathetic tone contributes significantly to the development of nocturnal asthma.32 However, increased vagal tone does not account for all the nocturnal airway narrowing.32 S YMPATHETIC N ERVOUS S YSTEM There have been no studies of intrinsic sympathetic tone in nocturnal asthma. The bronchodilator response to infused epinephrine is unchanged at night,33 and thus circadian changes in beta-adrenergic receptor sensitivity cannot explain nocturnal asthma. N ONADRENERGIC, N ONCHOLINERGIC N ERVOUS S YSTEM The other autonomic nervous system affecting the airway is the nonadrenergic, noncholinergic bronchodilating system. The precise role of this nervous system and the neurotransmitters involved are still unclear. However, there is some evidence that the activity of this bronchodilating system is impaired in the early morning,34 and this might contribute to tipping the balance of airway caliber toward the development of overnight bronchoconstriction. Circadian Variation of Hormones C ORTISOL Nocturnal breathlessness in asthmatic patients is most marked when the urinary excretion of 17-hydroxycorticosteroid is at its nadir and peak flow rates parallel changes in the levels of circulating steroids.1 This relationship is not causal; overnight falls in peak flow rate remain unchanged if plasma levels of 11-hydroxycorticosteroids are kept constant by infusion of hydrocortisone. In addition, therapy with large doses of steroids does not abolish morning dipping.3 Thus, it seems that circadian changes in circulating cortisol levels are not important in the pathogenesis of nocturnal bronchoconstriction. C ATECHOLAMINES AND O THER M EDIATORS Circulating catecholamine levels show diurnal changes, with a nocturnal nadir. Urinary catecholamine excretion falls to a minimum coincidental with the lowest peak flow
rates in some patients.35 However, catechol infusion does not abolish nocturnal airway narrowing.36 Airway Inflammation Despite considerable interest, there is conflicting evidence whether there are consistent changes in airway inflammatory cell populations or mediators in nocturnal asthma.37-44 Increased inflammatory cells in bronchoalveolar lavage specimens at 4:00 am have been found in some,39,40 but not all37,43,45 studies. Bronchial biopsies at 4:00 am showed no change in cell populations.39,43 Further, there is no evidence of any causal relationship between changes in inflammatory cell numbers and nocturnal airway narrowing.39,43,45 One study has suggested a correlation between the FEV1 at 4:00 am and CD4+ cells in alveolar tissue38 but no causative role has been established. Increases in bronchoalveolar lavage cytokines, eosinophil cationic protein39 and IL-1β44 have been found in some studies. There is no evidence of increased expression of vascular adhesion molecules at 4:00 am in patients with nocturnal asthma.41 Thus, this confusing situation could be summarized by stating that some inconsistent changes in inflammatory markers have been found overnight in the lungs of patients with nocturnal asthma, but their relevance is not yet clear. Similarly, there is no clear link between obesity-related systemic inflammation and inflammation related to either nocturnal asthma or obstructive sleep apnea. Conclusions Airway narrowing at night is a normal physiologic phenomenon, more obvious in asthmatic patients because their airways are already narrower by day. The major cause is a sleep-synchronized circadian rhythm, probably affected largely by changes in the autonomic tone to the airways, with increased parasympathetic bronchoconstrictor tone and decreased nonadrenergic, noncholinergic bronchodilator function in the early morning. Clinical Features of Nocturnal Bronchoconstriction Nocturnal bronchoconstriction and wheezing cause inconvenience and disturbed sleep and probably also hypoxemia and death. Nocturnal symptoms are still being overlooked by patients and physicians46,47 and must be actively sought to minimize the harm caused. Sleep Disturbance The major complaint of patients with nocturnal wheeze is that their sleep is interrupted and that they might feel tired in the daytime (Video 111-1).47,48 This sleep disruption has been confirmed by EEG studies.22,49 The sleep disruption probably impairs daytime cognitive function in patients with nocturnal asthma in comparison with age- and education-matched normal subjects.49 There was no evidence that the observed impairment resulted from drug therapy.49 Indeed, treatment of nocturnal asthma has been reported to improve cognitive function, but this improvement could have been due to increased familiarity with the tests used to assess neurocognition.50 Nevertheless, the potential damage to daytime cognitive function, work, and school performance caused by nocturnal sleep disruption
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Hypoxemia Patients with nocturnal asthma can undoubtedly become hypoxemic during the night, but the hypoxemia is rarely severe; in stable asthmatic patients studied at sea level, the lowest oxygen saturation is usually in the range of 85% to 95%. However, there have been no large studies in unstable patients with nocturnal asthma, and these patients can become more hypoxemic. Nocturnal Asthmatic Attacks Asthmatic patients present with attacks more often by night than by day, both to their family physician and to the emergency department. In addition to the adverse medical impact of these events, this timing significantly impairs the quality of life of all concerned. Death Fortunately, deaths from asthma are uncommon, but there are more deaths from asthma per hour at night than by day.51 When subdivided according to place of death, there was an excess nocturnal rate for the 146 deaths that occurred at home (P < 0.05), and the same trend was seen for the 73 deaths occurring in hospital (0.15 > P > 0.10). The death rate is, of course, higher at night than by day in the general population, but this averages only a 5% increase between midnight and 8 am, in contrast to the 28% increase observed in these asthmatic patients.51 Excess nocturnal mortality could result from many factors, including the inability of hypoxia,52 hypercapnia,53 or increased airflow resistance54 to awaken sleeping subjects rapidly, with resultant delays in taking treatment; reluctance to summon family or medical help at night; and delay in the arrival of medical assistance. Eight of 10 ventilatory arrests in asthmatic patients in the hospital occurred in the early morning,55 suggesting that unavailability of medical assistance is not a major factor. One of the most important causes of nocturnal death seems to be nocturnal bronchospasm. The two asthmatic patients who died at night during a prospective study were both morning dippers,56 which suggests that nocturnal bronchoconstriction can be life threatening. Thus, the morning dip pattern of asthma should be sought and recognized as potentially dangerous when it is marked in patients with unstable asthma. Diagnosis Nocturnal asthma comprises a combination of relevant symptoms—nocturnal wheeze, cough, and breathlessness—associated with a greater than 10% fall in overnight peak flow rate. Peak flow rates should be measured in triplicate, and the highest value taken, at least three times a day for at least 2 weeks. A consistent overnight fall in peak flow rate of greater than 15% is strong evidence of nocturnal asthma. Treatment Nocturnal bronchoconstriction is a sign of inadequately controlled asthma, and the new development of nocturnal wheeze in a patient must be regarded as a dangerous sign requiring monitoring and urgent treatment. Nocturnal
wheeze often responds to increasing conventional daytime maintenance treatment with either prophylactic agents or bronchodilators, and recent evidence indicates that inhaled steroids can help overnight airway narrowing within 12 hours.57 Only when optimal daytime control does not abolish nocturnal symptoms should additional treatment be directed at nocturnal wheeze. Inhalation of bronchodilators immediately before sleep, repeated whenever the patient is awakened by wheeze, is the initial treatment of choice; side effects are few. However, conventional inhaled beta2 agonists last only around 4 hours, and most people sleep for longer than that. Inhaled ipratropium or tiotropium lasts longer, but this increased duration has proved disappointing in clinical practice. In patients for whom these treatments are insufficient, long-acting bronchodilators—either inhaled or oral— should be used. Salmeterol improves symptoms, overnight peak flow rates, and sleep quality58 and also quality of life59 in nocturnal asthma (Fig. 111-5). Formoterol, another long-acting inhaled agent, has been shown to improve overnight lung function.60 In terms of oral bronchodilators, there appears to be little to choose, from the bronchodilation point of view, between oral theophyllines61 and oral beta2 agonists.62 Both can markedly reduce nocturnal symptoms, and the choice will largely be determined by whether the patient develops side effects. These agents can often be taken effectively once a day immediately before going to bed, thus reducing daytime side effects.61 Theophylline absorption tends to be lower at night than in the morning. This is not due to diurnal variations in theophylline absorption or disposition but probably results from differences between nocturnal and morning gastric content, physical activity, and posture.
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underlines the importance of improving therapy in patients with nocturnal asthma.
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Sleep stages Figure 111-5 Mean (standard error [SE]) time spent in each sleep stage by 18 asthmatic patients receiving placebo (green bar) or salmeterol 50 µg (red bar) or 100 µg (yellow bar) twice daily. (Redrawn from Fitzpatrick MF, Mackay T, Driver H, Douglas NJ. Salmeterol in nocturnal asthma: a double blind, placebo controlled trial of a long acting inhaled β2 agonist. BMJ 1990;301:1365-1368.)
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However, it is important to be aware of this difference, because larger dosages can be given at night. Oral theophylline can disturb sleep, as judged by the EEG in patients with nocturnal asthma, despite improving nocturnal symptoms and overnight changes in flow rates.63 However, there was no evidence of sleep disturbance in a medium-term study of normal subjects taking theophylline.64 There have been relatively few studies comparing longacting inhaled beta2 agonists with other agents in the management of nocturnal asthma.65,66 One study showed no major difference in efficacy between salmeterol and oral theophylline, although there were marginal benefits in favor of salmeterol in terms of frequency of arousals from sleep and improved quality of life.65 Another study showed that salmeterol resulted in less deterioration in nighttime lung function and improvement in subjective sleep quality compared with theophylline.66 Salmeterol was superior to oral slow-release terbutaline in terms of the number of nights free of awakenings, morning peak flow rates, and assessment of clinical efficacy.67 Salmeterol 50 µg twice daily was similar in efficacy to fluticasone 250 µg twice daily in improving nocturnal asthma.68 Inhaled long-acting bronchodilators have taken over from oral long-acting bronchodilators, as side effects are fewer.69 However, the U.S. Food and Drug Administration requires that, for safety reasons, long-acting beta agonists be used in combination with inhaled corticosteroids.69a The role of proton pump inhibitors remains unclear.18,16 Their continued widespread use constitutes, at best, a non– evidence-based approach. Patients who do not respond to these measures require oral steroid therapy. A very small minority might need further immunosuppression such as methotrexate, which can improve symptoms and FEV1. In the small minority of asthmatic patients whose nocturnal airway narrowing relates to their snoring or obstructive apneas, weight loss, if appropriate, and CPAP should be tried.28 In my experience and that of others,70 such therapy does not often improve nocturnal asthma. Conclusions Although there have been advances in our understanding of both pathophysiology and therapeutics, overnight wheeze remains a problem for many patients with asthma. Overnight wheeze is caused by a circadian rhythm in airway caliber that is at least partially controlled by neural factors. Long-acting inhaled bronchodilators have simplified the management of these symptoms.
CHRONIC OBSTRUCTIVE PULMONARY DISEASE Chronic obstructive pulmonary disease (COPD) is an umbrella term describing a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases. Patients with COPD become more hypoxemic during sleep than when awake—even more hypoxemic than during exercise.71 They become slightly more hypoxemic as they fall into non-REM (NREM) sleep and much more hypoxemic in REM sleep, when oxygen
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saturation can fall to extremely low levels,72 especially in those whose oxygenation is poorest when awake (Fig. 111-6). This sleep-related hypoxemia affects the cardio vascular and hematologic systems and so is clinically significant. Sleep becomes fragmented (Videos 111-2 to 111-5). Pathogenesis of Hypoxemia during Sleep Many causes of hypoxemia during sleep in COPD have been proposed, including hypoventilation, a decrease in functional residual capacity, and ventilation–perfusion mismatching. Hypoventilation Minute ventilation decreases during all sleep stages compared with wakefulness in normal subjects23 and in patients with COPD.73 The reduction in ventilation from wakefulness to NREM sleep is 20%,73,74 but during REM sleep, there is intermittent marked hypoventilation.23,73 In normal subjects, this hypoventilation is most severe during periods of frequent eye movements,75 when tidal volume falls substantially. The typical REM sleep–related desaturation in COPD is accompanied by hypoventilation and not by apneas (Fig. 111-7).76,77 Breathing pattern during REM sleep is similar in patients with COPD and normal subjects.76 Alveolar ventilation in normal subjects is about 40% lower during bursts of eye movements in REM sleep than during wakefulness. Direct measurements made in patients with COPD sleeping with 4 cm H2O CPAP are compatible with these estimates.73 Because patients with COPD have increased physiologic dead space, the rapid shallow breathing during bursts of eye movements in REM sleep produces an even greater decrease in alveolar ventilation than occurs in normal subjects. This contributes significantly to their REM sleep–related hypoxemia and could account for all the hypoxemia observed in REM sleep in patients with COPD.78
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10 Time (minutes)
Figure 111-7 Tidal volume (VT), O2 saturation, and sleep stage in a patient with chronic obstructive pulmonary disease illustrated in the drop in O2 saturation and irregular hyperventilation during REM sleep. (Redrawn from Fletcher EC, Gray BA, Levin DC. Nonapneic mechanisms of arterial oxygen desaturation during rapid-eye movement sleep. J Appl Physiol 1983;54:632-639.)
Many factors contribute to hypoventilation during sleep. In NREM sleep, ventilation falls in normal subjects despite an increase in respiratory effort as measured by occlusion pressure.79 It is likely that this hypoventilation in NREM sleep is in part due to the increased in upper airway resistance.80 Furthermore, the ventilatory response to added respiratory resistance is impaired during NREM sleep,81 which allows hypoventilation to occur. There is also loss of the wakefulness drive to breathing, which contributes to hypoventilation during NREM sleep52 and an effect from the fall in basal metabolic rate during sleep.82 The marked intermittent hypoventilation during REM sleep seems unlikely to be due to further increases in upper airway resistance because overall airway resistance is no greater in REM sleep than in NREM sleep, at least in normal subjects.80 Furthermore, although few measurements have been made, it appears that the ventilatory response to inspiratory resistance is similar in NREM and REM sleep.81 During REM sleep, there is altered brainstem function, with phasic activity of respiratory neurons and diminution in central respiratory output, which may be a major factor in producing REM sleep–related hypoventilation. During REM sleep, there is also hypotonia of postural muscles, including the intercostal muscles, so that they contribute less to ventilation.83 This further decreases ventilation during REM sleep in hyperinflated patients with COPD, in whom the flattened diaphragm pulls in the flaccid lower chest wall, with resultant highly inefficient ventilation. This might explain why patients with COPD become relatively more hypoxemic during sleep than do patients with pulmonary fibrosis.84 In addition, the postural muscle hypotonia of REM sleep involves not only the intercostal muscles but also the accessory muscles of respiration,85 which may be important
in maintaining adequate ventilation in awake patients with COPD. The hypoventilation of REM sleep is accompanied by a marked diminution of both the hypoxic52 and hypercapnic53 ventilatory responses. The normal defense mechanisms of the body to the resulting hypoxemia and hypercapnia are diminished. Decrease in Functional Residual Capacity Functional residual capacity decreases during REM sleep in normal subjects.80 However, body plethysmographic studies indicate that functional residual capacity does not change during sleep in patients with COPD, although these data were gathered in only five patients.86 Ventilation–Perfusion Mismatching It is inevitable that additional ventilation–perfusion mismatching occurs in patients with COPD during the marked hypoventilation of REM sleep. This is supported by evidence that cardiac output is maintained during these episodes of hypoventilation, which indicates changes in global ventilation–perfusion matching.87 Unfortunately, technology does not allow assessment of the importance of ventilation–perfusion matching relative to the other mechanisms involved. Techniques for quantifying ventilation–perfusion mismatch rely on a steady state of both ventilation and metabolism; certainly, the former does not occur during REM sleep, when ventilation is extremely variable.87 This negates many of the arguments previously advanced for the importance of ventilation–perfusion mismatching. For example, it has been suggested that the greater decrease in alveolar Po2 compared with the rise in arterial Pco2 indicates the importance of ventilation– perfusion changes during REM sleep in patients with COPD. However, because the body stores of carbon
CHAPTER 111 • Sleep in Patients with Asthma and Chronic Obstructive Pulmonary Disease 1301
dioxide are much larger than those of oxygen, the transient episodes of hypoventilation that occur during REM sleep produce much greater decreases in Po2 than rises in Pco2, which is exactly what has been observed.87 COPD Combined with OSAH Syndrome Both COPD and obstructive sleep apnea–hypopnea (OSAH) syndrome are common. These two conditions coexist in some patients, although the prevalence of the OSAH in patients with COPD seems to be no greater than the prevalence of OSAH88,89 in the normal population. In a small minority of patients with COPD, perhaps about 2%,89 nocturnal hypoxemia results from obstructive apneas or hypopneas, in addition to REM sleep–related hypoventilation. Viewed in a different way, one study suggested that 10% of patients with OSAH might have some degree of coexisting COPD.90 In patients with both conditions, the pattern of nocturnal desaturation is different; frequent desaturation results in a broad-band saturation trace rather than the relatively clearly defined spike desaturation typically found in REM sleep (see Fig. 111-6). Hypercapnic patients with COPD may be heavier and have narrower upper airways when awake, predisposing them to OSAH.91 Summary Hypoventilation is the major cause of hypoxemia during REM sleep in patients with COPD. There may be additional contributions from ventilation–perfusion mismatching and a decrease in functional residual capacity. In a small minority of patients with COPD, there may also be coexisting OSAH. Clinical Consequences of Sleep Hypoxemia Hypoxemia during sleep in patients with COPD has significant cardiovascular and neurophysiologic effects, might have hematologic consequences, and might contribute to the incidence of nocturnal death. Cardiac Dysrhythmias Patients with COPD have increased ventricular ectopic beats during sleep. Although in most patients there is no direct relation between ventricular ectopic frequency and oxygen saturation,92 in a minority of the most hypoxic patients a significant relation could be found between ventricular ectopic frequency and nocturnal oxygen saturation. Hemodynamics Pulmonary arterial pressure rises as oxygen saturation falls during REM sleep. Coccagna and Lugaresi93 observed in 12 patients with COPD that mean pulmonary arterial pressure rose from 37 to 55 mm Hg during REM sleep as the average arterial oxygen tension fell from 56 to 43 mm Hg. Boysen and colleagues94 observed an inverse correlation between oxygenation and mean pulmonary arterial pressure, and although individual values varied widely, on average a 1% fall in oxygen saturation led to a rise of 1 mm Hg in mean pulmonary arterial pressure. The clinical significance of these transient episodes of pulmonary arterial pressure elevation is unknown; however, in rats, intermittent hypoxemia induced by breathing 12%
oxygen for as little as 2 hours each day for 4 weeks significantly elevated right ventricular mass, even when individual episodes of hypoxia were as short as 30 minutes.95 It thus seems probable that the intermittent REM sleep hypoxemia in patients with COPD has similar effects on the human myocardium. Polycythemia Intermittent hypoxemia in rats results in an elevation of red cell mass95; the nocturnal desaturation in patients with COPD might also stimulate erythropoiesis. Morning erythropoietin levels are raised in some patients with COPD.96 A study compared red cell mass and pulmonary hemodynamics of 36 patients with COPD who experienced desaturation at night to at least 85% with more than 5 minutes spent below 90% saturation with those of 30 patients who did not so desaturate.97 Those with nocturnal desaturation had significantly higher daytime pulmonary arterial pressures and red cell mass than did the nondesaturators. Although these differences could have resulted from the nocturnal events, the nocturnal desaturators also had significantly poorer daytime oxygenation levels, which could explain the hemodynamic and hematologic differences. Nocturnal erythropoietin rises only in patients with COPD whose oxygen saturations fall below 60% at night.96 This suggests that the relatively minor degree of nocturnal desaturation may be of little hematologic consequence. Sleep Quality Both subjective and objective98 assessments indicate that patients with COPD sleep poorly compared with healthy subjects. Although arousals and sleep fragmentation are common during episodes of desaturation,98 the extent of sleep disruption is at least as great in relatively normoxic patients with COPD. Despite these reports of poor sleep, there is no objective evidence of daytime sleepiness as assessed by the multiple sleep latency test in patients with COPD.99 Consequences of COPD Combined with OSAH Syndrome Patients with both COPD and OSAH are more likely to develop pulmonary hypertension, right-sided heart failure, and carbon dioxide retention than are patients with OSAH alone.100 Indeed, these complications develop earlier in patients with COPD and OSAH than in patients with COPD alone, and many patients who have these complications with both COPD and OSAH have relatively good lung function. This is probably due to their having two causes for nocturnal hypoxemia, resulting in more-severe nocturnal hypoxemia than would have occurred if they had only COPD alone or OSAH alone. Prediction of Nocturnal Oxygenation Oxygenation during wakefulness in patients with COPD is the major predictor of both the mean and lowest levels of oxygenation during sleep and the extent of desaturation during sleep.89,101 Because the hypoxemic complications of pulmonary hypertension and polycythemia relate to the patient’s absolute arterial oxygenation rather than to the
1302 PART II / Section 13 • Sleep Breathing Disorders 100 P < 0.0001 r = 0.75
Lowest SaO2 asleep (%)
80
60
40
20
0 60
70
80
90
100
Mean SaO2 awake (%) Figure 111-8 Relationship between mean oxygen saturation (SaO2) awake and lowest oxygen saturation during sleep in 97 patients with COPD. (Redrawn from Connaughton JJ, Catterall JR, Elton RA, et al. Do sleep studies contribute to the management of patients with severe chronic obstructive pulmonary disease? Am Rev Respir Dis 1988;138:341-345.)
change in saturation, the more important relation is that between absolute levels of nocturnal oxygenation and measurements that can be taken during wakefulness. Several different equations relating these variables have been derived, but their clinical significance is limited because the scatter around the regression lines is wide,89 especially for the more severely hypoxemic patients (Fig. 111-8). Regression relations show that the extent of nocturnal hypoxemia relates not only to daytime oxygenation but also to daytime arterial carbon dioxide tension and to the duration of REM sleep.89 Similarly the predictors of the extent of transcutaneous CO2 rise during sleep were found to be arterial Pco2 awake, amount of REM sleep, and body mass index.102 Clinical Value of Sleep Studies Studying breathing and oxygenation during sleep by either polysomnography or more-limited techniques in patients with COPD could be of clinical relevance by • Detecting unsuspected cases of OSAH • Detecting which patients had clinically important excess nocturnal hypoxemia
• Guiding which patients might benefit from nocturnal oxygen therapy • Determining the optimal inspired oxygen concentration for nocturnal oxygen therapy. The last two roles are discussed in the section “Treatment of Nocturnal Hypoxemia.” There is no evidence that the prevalence of OSAH is increased in patients with COPD.76,88,103 When OSAH syndrome and COPD coexist, the typical symptoms of OSAH are present, and it appears that sleep studies do not yield unsuspected cases of OSAH.89 Thus, all patients with COPD should be questioned about the occurrence of symptoms of OSAH syndrome. If major symptoms are elicited, polysomnography should be performed; oximetry alone studies are difficult to interpret in hypoxemic patients. Oxygenation during sleep can be predicted on the basis of awake arterial blood gas tensions.89 These predictions leave considerable unexplained residual variance, but it is unclear whether this is of clinical significance. Measurement of the extent of nocturnal hypoxemia in such patients has been held to be a useful guide for treatment. To clarify the clinical importance of this variability among patients in the extent of nocturnal hypoxemia, Connaughton and colleagues89 studied the relation between nocturnal oxygen saturation and survival in 97 patients with severe COPD followed up for a median of 70 months. Both the mean nocturnal oxygen saturation and the lowest nocturnal oxygen saturation were significantly related to survival; the lower the nocturnal oxygenation, the worse the prognosis. However, neither nocturnal measure significantly improved the prediction of survival that could be obtained from the easier and cheaper measurements of oxygen saturation or vital capacity when awake.89 These data89 were also analyzed to determine the significance of the scatter around the regression relation between measurements of oxygen saturation and Paco2 when awake and oxygen saturation during sleep. The patients were divided into those who had excess nocturnal hypoxemia, defined as those whose oxygen saturation during sleep was lower than that predicted on the basis of their awake oxygen saturation and arterial Pco2, and those who became less hypoxemic at night than predicted. There was no difference in survival rates at a median of 70 months between those with excess nocturnal hypoxemia and those who became less hypoxemic at night than might be predicted based on the awake oxygenation and Paco2 (Fig. 111-9). Thus, measurement of nocturnal oxygenation does not yield useful prognostic information in addition to that obtained during wakefulness. Another study in a group of patients with daytime arterial oxygen tension 56 to 69 mm Hg found no significant relation between the magnitude of nocturnal hypoxemia and the development of pulmonary hypertension or worsening of arterial blood gas tensions.104 This, again, suggests that the contribution of the additional hypoxemia during sleep to overall daytime pulmonary arterial pressure is relatively small. There is also no evidence that nocturnal desaturators have impaired quality of life or subjective sleep quality.105 There seems to be no clinical advantage, therefore, in performing routine polysomnography in patients with COPD, although undoubtedly there are many research
CHAPTER 111 • Sleep in Patients with Asthma and Chronic Obstructive Pulmonary Disease 1303
proven role for studies of breathing and oxygenation during sleep to aid selection of patients for nocturnal oxygen therapy. Studies in patients with daytime arterial tensions of greater than 55 mm Hg but with nocturnal desaturation reported that nocturnal oxygen therapy did not improve patient survival rates.107 The only patients in whom I suggest that polysomnography be performed in relation to oxygen therapy in COPD are those who develop morning headaches with oxygen therapy, because this can indicate coexisting OSAH syndrome. I do not believe there is any indication or evidence base for oxygen therapy only at night in patients with COPD, whereas there is a strong evidence base for continuous oxygen therapy in patients with daytime hypoxemia.
100 Mean nocturnal oxygen saturation More hypoxic than predicted
Percent surviving
80
P = 0.19
60
Less hypoxic than predicted
40
20
0 0
2
4
6
8
Time after sleep study (yrs) Figure 111-9 Survival curves for patients who are more hypoxic than predicted from their awake oxygen saturation and carbon dioxide level compared with those who are less hypoxic than predicted. There was no significant difference in the survival curves in the two groups. (Redrawn from Connaughton JJ, Catterall JR, Elton RA, et al. Do sleep studies contribute to the management of patients with severe chronic obstructive pulmonary disease? Am Rev Respir Dis 1988;138:341-5.)
areas requiring clarification by this technique. I believe clinical polysomnography is only indicated in patients with COPD if OSAH syndrome is suspected because of symptoms of OSAH syndrome or the development of hypoxemic complications—cor pulmonale and polycythemia—in patients whose daytime arterial oxygen tension is greater than 60 mm Hg. Equally, there is no evidence that recording overnight oxygenation in patients with COPD adds evidence to daytime oxygenation data that either helps their management or the prediction of their prognosis.89,104 Treatment of Nocturnal Hypoxemia Oxygen Therapy Not surprisingly, nocturnal oxygen therapy improves oxygenation during sleep in patients with COPD.72 Some nocturnal desaturation still occurs, particularly during REM sleep, but the hypoxemia is not so profound. A few patients report morning headaches due to carbon dioxide retention as a result of nocturnal oxygen therapy. This may be a particular problem in patients with coexisting OSAH syndrome106 and is as an indication for polysomnography. The patients who become most severely hypoxemic at night are those with the greatest daytime hypoxemia.89 Long-term domiciliary oxygen therapy remains the only treatment shown by controlled clinical trials to prolong life in such patients. Because the period of oxygen administration almost always includes the night, it is possible that some of the benefit of oxygen therapy is due to preventing nocturnal hypoxemia. Long-term domiciliary oxygen therapy is based on data where oxygen treatment depended solely on measurement of arterial blood gas tensions when awake. There is no
Lung Volume Reduction Surgery In patients suitable for lung volume reduction surgery, the procedure can improve objective sleep and nocturnal oxygenation.108 Almitrine The use of the respiratory stimulant almitrine can raise arterial oxygen tension in patients with COPD. In a randomized, double-blind study, 50 mg of almitrine twice daily for 2 weeks improved oxygenation during sleep in patients with COPD.109 The role of almitrine in patients with COPD is limited,110 and the drug is not available in some countries because side effects, especially peripheral neuropathy, have caused it to be withdrawn. Protriptyline Tricyclic agents suppress REM sleep and might thus improve oxygenation. The results of a nonrandomized, nonblinded trial111 suggested that protriptyline might improve daytime arterial oxygen and carbon dioxide tensions in patients with COPD, but side effects were common, causing cessation of therapy within 10 weeks in 4 of 14 patients. I would not advocate the use of protriptyline to improve oxygenation in patients with COPD. Medroxyprogesterone Acetate Despite suggestions that medroxyprogesterone acetate might be beneficial as a respiratory stimulant, in a doubleblind, placebo-controlled trial, Dolly and Block112 found no significant change in the lowest oxygen saturation during sleep in 19 patients with COPD who were taking medroxyprogesterone acetate. In addition, medroxyprogesterone acetate can cause troublesome side effects, including impotence in many patients. The clinical role of the drug in COPD is limited, although there may be some benefit in postmenopausal women.113 Theophylline The use of oral theophylline can improve overnight oxygen saturation and transcutaneous carbon dioxide levels.114 However, the benefits of this bronchodilator are limited and are often outweighed by the side effects. Beta Agonists and Anticholinergic Bronchodilators The use of oral sustained-release salbutamol had no effect on sleep, oxygenation, or morning FEV1 in 14 patients with moderately severe COPD.115 Randomized studies
1304 PART II / Section 13 • Sleep Breathing Disorders
found that the anticholinerigc agents ipratropium bromide116 and tiotropium117 improved oxygenation, and ipratropium also improved sleep quality.116 Intermittent Positive-Pressure Ventilation by Mask Long-term use of nocturnal intermittent positive-pressure ventilation (NIPPV) via a nasal or face mask at home was developed for patients with chest wall or neuromuscular disorders. Some patients with COPD find this technique acceptable, and it has a theoretical advantage over longterm oxygen therapy of reducing, rather than raising, arterial carbon dioxide tension. In patients who can tolerate NIPPV, improvements in arterial blood gas tensions and sleep may be achieved, but nocturnal oxygenation is improved more with nocturnal oxygen therapy than with NIPPV alone.118 Simultaneous nasal NIPPV and nocturnal oxygen therapy produced greater improvements in arterial blood gas tensions and quality of life than did oxygen therapy alone in randomized, controlled trials.119,120 A more detailed review of NIPPV is given in Chapter 113. NIPPV has a role in the treatment of hypoxemic patients with COPD, especially in those who continue to smoke or who have troublesome headaches on long-term oxygen therapy as well as in those with coexisting OSAHS (see next). Treatment of COPD Combined with OSAH Syndrome — the Overlap Syndrome There are remarkably few data indicating how to treat patients who have both COPD and OSAH syndrome (Videos 111-6 and 111-7). A nonrandomized study found that patients with both conditions improved their daytime arterial blood gas tensions (Fig. 111-10) and pulmonary arterial pressures when they were adequately treated for OSAH but not when they received domiciliary oxygen therapy in the absence of adequate therapy for OSAH.121 The overlap syndrome results in increased risk of death and hospitalization and CPAP treatment is associated with improved survival and decreased hospitalizations in these patients.122 Hypnotics in COPD Hypnotics should be used with care in all patients with COPD to avoid inducing respiratory depression. Indeed, the counsel of perfection is that they should never be used, and, if used, in the lowest possible dose. Studies on a selective melatonin MT1/MT2 receptor agonist showed improved sleep duration and quality without impairing gas exchange in patients with mild to moderate and also severe COPD,123 but further data are required before their widespread use could be encouraged.124 Conclusions Patients with COPD become hypoxemic during sleep, particularly during episodes of dense eye movements in REM sleep. The measurement of nocturnal hypoxemia and breathing patterns in individual patients does not provide prognostic information that significantly adds to the simpler measurements of oxygenation and lung function during wakefulness. In a small minority of patients with COPD, OSAH syndrome coexists, and any patient with COPD and a history suggesting OSAH syndrome should
100 Tracheostomy 90
No tracheostomy
80 P < 0.005
70 PO2
NS
60 50 PCO2
NS P < 0.001
40 30 Baseline
Follow up
Figure 111-10 Arterial oxygen (PO2) and carbon dioxide (Pco2) tensions (in mm Hg) in patients with both COPD and sleep apnea at baseline and subsequent follow-up. Open circles indicate those who were treated with tracheostomy, and closed circles indicate those who were treated by other techniques, which largely consisted of long-term oxygen therapy. The P values indicate significant improvements in arterial blood gas tensions in the patients treated with tracheostomy. NS, not significant. (Redrawn from Fletcher EC, Schaaf JW, Miller J, et al. Long-term cardiopulmonary sequelae in patients with sleep apnea and chronic lung disease. Am Rev Respir Dis 1987;135: 525-533.)
undergo full polysomnography. Those found to have OSAH syndrome should be aggressively treated. Domiciliary oxygen therapy is the treatment of choice for patients with COPD who are hypoxemic at day and night, but the role of NIPPV via a nasal mask could grow. REFERENCES 1. Connolly CK. Diurnal rhythms in airway obstruction. Br J Dis Chest 1979;73:357-366. 2. Floyer J. A treatise on the asthma. London, 1698. 3. Clark TJ, Hetzel MR. Diurnal variation of asthma. Br J Dis Chest 1977;71:87-92. 4. Turner-Warwick M. On observing patterns of airflow obstruction in chronic asthma. Br J Dis Chest 1977;71:73-86. 5. Hetzel MR, Clark TJ. Comparison of normal and asthmatic circadian rhythms in peak expiratory flow rate. Thorax 1980;35: 732-738. 6. Catterall JR, Rhind GB, Stewart IC, et al. Effect of sleep deprivation on overnight broncho-constriction in nocturnal asthma. Thorax 1986;41:676-680. 7. Ballard RD, Saathoff MC, Patel DK, et al. Effect of sleep on nocturnal bronchoconstriction and ventilatory patterns in asthmatics. J Appl Physiol 1989;67:243-249. 8. Hetzel MR, Clark TJ. Does sleep cause nocturnal asthma? Thorax 1979;34:749-754. 9. Whyte KF, Douglas NJ. Posture and nocturnal asthma. Thorax 1989;44:579-581. 10. Woodcock A, Forster L, Matthews E, et al. Control of exposure to mite allergen and allergen-impermeable bed covers for adults with asthma. N Engl J Med 2003;349:225-236. 11. Davies RJ, Green M, Schofield NM. Recurrent nocturnal asthma after exposure to grain dust. Am Rev Respir Dis 1976;114: 1011-1019.
CHAPTER 111 • Sleep in Patients with Asthma and Chronic Obstructive Pulmonary Disease 1305 12. Platts-Mills TA, Tovey ER, Mitchell EB, et al. Reduction of bronchial hyperreactivity during prolonged allergen avoidance. Lancet 1982;2:675-678. 13. Ryan G, Latimer KM, Dolovich J, et al. Bronchial responsiveness to histamine: relationship to diurnal variation of peak flow rate, improvement after bronchodilator, and airway calibre. Thorax 1982;37:423-429. 14. Kerr HD. Diurnal variation of respiratory function independent of air quality: experience with an environmentally controlled exposure chamber for human subjects. Arch Environ Health 1973;26: 144-152. 15. Chen WY, Chai H. Airway cooling and nocturnal asthma. Chest 1982;81:675-680. 16. Kiljander TO, Salomaa ER, Hietanen EK, et al. Gastroesophageal reflux in asthmatics: a double-blind, placebo-controlled crossover study with omeprazole. Chest 1999;116:1257-1264. 17. Nagel RA, Brown P, Perks WH, et al. Ambulatory pH monitoring of gastro-oesophageal reflux in “morning dipper” asthmatics. BMJ 1988;297:1371-1373. 18. Kiljander TO, Harding SM, Field SK, et al. Effects of esomeprazole 40 mg twice daily on asthma: a randomized placebo-controlled trial. Am J Respir Crit Care Med 2006;173:1091-1097. 19. Littner MR, Leung FW, Ballard ED, et al. Effects of 24 weeks of lansoprazole therapy on asthma symptoms, exacerbations, quality of life, and pulmonary function in adult asthmatic patients with acid reflux symptoms. Chest 2005;128:1128-1135. 20. Gervais P, Reinberg A, Gervais C, et al. Twenty-four-hour rhythm in the bronchial hyperreactivity to house dust in asthmatics. J Allergy Clin Immunol 1977;59:207-213. 21. Smolensky MH, Reinberg A, Queng JT. The chronobiology and chronopharmacology of allergy. Ann Allergy 1981;47:234-252. 22. Kales A, Beall GN, Bajor GF, et al. Sleep studies in asthmatic adults: relationship of attacks to sleep stage and time of night. J Allergy 1968;41:164-173. 23. Douglas NJ, White DP, Pickett CK, et al. Respiration during sleep in normal man. Thorax 1982;37:840-844. 24. Tabachnik E, Muller NL, Levison H, et al. Chest wall mechanics and pattern of breathing during sleep in asthmatic adolescents. Am Rev Respir Dis 1981;124:269-273. 25. Catterall JR, Douglas NJ, Calverley PM, et al. Irregular breathing and hypoxaemia during sleep in chronic stable asthma. Lancet 1982;1:301-304. 26. Ballard RD, Irvin CG, Martin RJ, et al. Influence of sleep on lung volume in asthmatic patients and normal subjects. J Appl Physiol 1990;68:2034-2041. 27. Kraft M, Pak J, Martin RJ, et al. Distal lung dysfunction at night in nocturnal asthma. Am J Respir Crit Care Med 2001;163: 1551-1556. 28. Chan CS, Woolcock AJ, Sullivan CE. Nocturnal asthma: role of snoring and obstructive sleep apnea. Am Rev Respir Dis 1988; 137:1502-1504. 29. Chinn S. Asthma and obesity: where are we now? Thorax 2003;58:1008-1010. 30. Sulit LG, Storfer-Isser A, Rosen CL, et al. Associations of obesity, sleep-disordered breathing, and wheezing in children. Am J Respir Crit Care Med 2005;171:659-664. 31. Catterall JR, Rhind GB, Whyte KF, et al. Is nocturnal asthma caused by changes in airway cholinergic activity? Thorax 1988;43:720-724. 32. Morrison JF, Pearson SB, Dean HG. Parasympathetic nervous system in nocturnal asthma. Br Med J (Clin Res Ed) 1988; 296:1427-1429. 33. Barnes P, FitzGerald G, Brown M, et al. Nocturnal asthma and changes in circulating epinephrine, histamine, and cortisol. N Engl J Med 1980;303:263-267. 34. Mackay TW, Hulks G, Douglas NJ. Non-adrenergic, noncholinergic function in the human airway. Respir Med 1998;92: 461-466. 35. Soutar CA, Carruthers M, Pickering CA. Nocturnal asthma and urinary adrenaline and noradrenaline excretion. Thorax 1977; 32:677-683. 36. Morrison JF, Teale C, Pearson SB, et al. Adrenaline and nocturnal asthma. BMJ 1990;301:473-476. 37. Jarjour NN, Busse WW, Calhoun WJ. Enhanced production of oxygen radicals in nocturnal asthma. Am Rev Respir Dis 1992; 146:905-911.
38. Kraft M, Martin RJ, Wilson S, et al. Lymphocyte and eosinophil influx into alveolar tissue in nocturnal asthma. Am J Respir Crit Care Med 1999;159:228-234. 39. Mackay TW, Wallace WA, Howie SE, et al. Role of inflammation in nocturnal asthma. Thorax 1994;49:257-262. 40. Martin RJ, Cicutto LC, Smith HR, et al. Airways inflammation in nocturnal asthma. Am Rev Respir Dis 1991;143:351-357. 41. ten Hacken NH, Postma DS, Bosma F, et al. Vascular adhesion molecules in nocturnal asthma: a possible role for VCAM-1 in ongoing airway wall inflammation. Clin Exp Allergy 1998;28: 1518-1525. 42. Kraft M, Striz I, Georges G, et al. Expression of epithelial markers in nocturnal asthma. J Allergy Clin Immunol 1998; 102:376-381. 43. ten Hacken NH, Timens W, Smith M, et al. Increased peak expiratory flow variation in asthma: severe persistent increase but not nocturnal worsening of airway inflammation. Eur Respir J 1998; 12:546-550. 44. Jarjour NN, Busse WW. Cytokines in bronchoalveolar lavage fluid of patients with nocturnal asthma. Am J Respir Crit Care Med 1995;152:1474-1477. 45. Oosterhoff Y, Kauffman HF, Rutgers B, et al. Inflammatory cell number and mediators in bronchoalveolar lavage fluid and peripheral blood in subjects with asthma with increased nocturnal airways narrowing. J Allergy Clin Immunol 1995;96:219-229. 46. Raherison C, Abouelfath A, Le Gros V, et al. Underdiagnosis of nocturnal symptoms in asthma in general practice. J Asthma 2006;43:199-202. 47. Mastronarde JG, Wise RA, Shade DM, et al. Sleep quality in asthma: results of a large prospective clinical trial. J Asthma 2008;45:183-189. 48. Teodorescu M, Consens FB, Bria WF, et al. Correlates of daytime sleepiness in patients with asthma. Sleep Med 2006;7:607-613. 49. Fitzpatrick MF, Engleman H, Whyte KF, et al. Morbidity in nocturnal asthma: sleep quality and daytime cognitive performance. Thorax 1991;46:569-573. 50. Weersink EJ, van Zomeren EH, Koeter GH, et al. Treatment of nocturnal airway obstruction improves daytime cognitive performance in asthmatics. Am J Respir Crit Care Med 1997;156: 1144-1150. 51. Douglas NJ. Asthma at night. Clin Chest Med 1985;6:663-674. 52. Douglas NJ, White DP, Weil JV, et al. Hypoxic ventilatory response decreases during sleep in normal men. Am Rev Respir Dis 1982;125:286-289. 53. Douglas NJ, White DP, Weil JV, et al. Hypercapnic ventilatory response in sleeping adults. Am Rev Respir Dis 1982;126: 758-762. 54. Gugger M, Molloy J, Gould GA, et al. Ventilatory and arousal responses to added inspiratory resistance during sleep. Am Rev Respir Dis 1989;140:1301-1307. 55. Hetzel MR, Clark TJ, Branthwaite MA. Asthma: analysis of sudden deaths and ventilatory arrests in hospital. Br Med J 1977;1: 808-811. 56. Bateman JR, Clarke SW. Sudden death in asthma. Thorax 1979; 34:40-44. 57. Frezza G, Terra-Filho J, Martinez JA, et al. Rapid effect of inhaled steroids on nocturnal worsening of asthma. Thorax 2003; 58:632-633. 58. Fitzpatrick MF, Mackay T, Driver H, et al. Salmeterol in nocturnal asthma: a double blind, placebo controlled trial of a long acting inhaled beta 2 agonist. BMJ 1990;301:1365-1368. 59. Lockey RF, DuBuske LM, Friedman B, et al. Nocturnal asthma: effect of salmeterol on quality of life and clinical outcomes. Chest 1999;115:666-673. 60. Maesen FP, Smeets JJ, Gubbelmans HL, et al. Formoterol in the treatment of nocturnal asthma. Chest 1990;98:866-870. 61. Barnes PJ, Greening AP, Neville L, et al. Single-dose slow-release aminophylline at night prevents nocturnal asthma. Lancet 1982; 1:299-301. 62. Crompton GK, Ayres JG, Basran G, et al. Comparison of oral bambuterol and inhaled salmeterol in patients with symptomatic asthma and using inhaled corticosteroids. Am J Respir Crit Care Med 1999;159:824-828. 63. Rhind GB, Connaughton JJ, McFie J, et al. Sustained release choline theophyllinate in nocturnal asthma. Br Med J (Clin Res Ed) 1985;291:1605-1607.
1306 PART II / Section 13 • Sleep Breathing Disorders 64. Fitzpatrick MF, Engleman HM, Boellert F, et al. Effect of therapeutic theophylline levels on the sleep quality and daytime cognitive performance of normal subjects. Am Rev Respir Dis 1992; 145:1355-1358. 65. Selby C, Engleman HM, Fitzpatrick MF, et al. Inhaled salmeterol or oral theophylline in nocturnal asthma? Am J Respir Crit Care Med 1997;155:104-108. 66. Wiegand L, Mende CN, Zaidel G, et al. Salmeterol vs theophylline: sleep and efficacy outcomes in patients with nocturnal asthma. Chest 1999;115:1525-1532. 67. Brambilla C, Chastang C, Georges D, et al. Salmeterol compared with slow-release terbutaline in nocturnal asthma. A multicenter, randomized, double-blind, double-dummy, sequential clinical trial. French Multicenter Study Group. Allergy 1994;49:421-426. 68. Weersink EJ, Douma RR, Postma DS, et al. Fluticasone propionate, salmeterol xinafoate, and their combination in the treatment of nocturnal asthma. Am J Respir Crit Care Med 1997;155: 1241-1246. 69. Tee AK, Koh MS, Gibson PG, et al. Long-acting beta2-agonists versus theophylline for maintenance treatment of asthma. Cochrane Database Syst Rev 2007;(3)CD001281. 69a. U.S. Food and Drug Administration. Postmarket drug safety information for patients and providers. Available at: http://www.fda.gov/ Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatients andProviders/ucm200776. 70. Lafond C, Series F, Lemiere C. Impact of CPAP on asthmatic patients with obstructive sleep apnoea. Eur Respir J 2007; 29:307-311. 71. Mulloy E, McNicholas WT. Ventilation and gas exchange during sleep and exercise in severe COPD. Chest 1996;109:387-394. 72. Douglas NJ, Calverley PM, Leggett RJ, et al. Transient hypoxaemia during sleep in chronic bronchitis and emphysema. Lancet 1979;1:1-4. 73. Becker HF, Piper AJ, Flynn WE, et al. Breathing during sleep in patients with nocturnal desaturation. Am J Respir Crit Care Med 1999;159:112-118. 74. O’Donoghue FJ, Catcheside PG, Eckert DJ, et al. Changes in respiration in NREM sleep in hypercapnic chronic obstructive pulmonary disease. J Physiol 2004;559:663-673. 75. Gould GA, Gugger M, Molloy J, et al. Breathing pattern and eye movement density during REM sleep in humans. Am Rev Respir Dis 1988;138:874-877. 76. Catterall JR, Douglas NJ, Calverley PM, et al. Transient hypoxemia during sleep in chronic obstructive pulmonary disease is not a sleep apnea syndrome. Am Rev Respir Dis 1983;128:24-29. 77. George CF, West P, Kryger MH. Oxygenation and breathing pattern during phasic and tonic REM in patients with chronic obstructive pulmonary disease. Sleep 1987;10:234-243. 78. Catterall JR, Calverley PM, MacNee W, et al. Mechanism of transient nocturnal hypoxemia in hypoxic chronic bronchitis and emphysema. J Appl Physiol 1985;59:1698-1703. 79. White DP. Occlusion pressure and ventilation during sleep in normal humans. J Appl Physiol 1986;61:1279-1287. 80. Hudgel DW, Martin RJ, Johnson B, et al. Mechanics of the respiratory system and breathing pattern during sleep in normal humans. J Appl Physiol 1984;56:133-137. 81. Wiegand L, Zwillich CW, White DP. Sleep and the ventilatory response to resistive loading in normal men. J Appl Physiol 1988;64:1186-1195. 82. White DP, Weil JV, Zwillich CW. Metabolic rate and breathing during sleep. J Appl Physiol 1985;59:384-391. 83. White JE, Drinnan MJ, Smithson AJ, et al. Respiratory muscle activity during rapid eye movement (REM) sleep in patients with chronic obstructive pulmonary disease. Thorax 1995;50:376-382. 84. Midgren B. Oxygen desaturation during sleep as a function of the underlying respiratory disease. Am Rev Respir Dis 1990; 141:43-46. 85. Johnson MW, Remmers JE. Accessory muscle activity during sleep in chronic obstructive pulmonary disease. J Appl Physiol 1984;57:1011-1017. 86. Ballard RD, Clover CW, Suh BY. Influence of sleep on respiratory function in emphysema. Am J Respir Crit Care Med 1995; 151:945-951. 87. Catterall JR, Calverley PM, MacNee W, et al. Mechanism of transient nocturnal hypoxemia in hypoxic chronic bronchitis and emphysema. J Appl Physiol 1985;59:1698-1703.
88. Sanders MH, Newman AB, Haggerty CL, et al. Sleep and sleepdisordered breathing in adults with predominantly mild obstructive airway disease. Am J Respir Crit Care Med 2003;167:7-14. 89. Connaughton JJ, Catterall JR, Elton RA, et al. Do sleep studies contribute to the management of patients with severe chronic obstructive pulmonary disease? Am Rev Respir Dis 1988;138: 341-344. 90. Chaouat A, Weitzenblum E, Krieger J, et al. Association of chronic obstructive pulmonary disease and sleep apnea syndrome. Am J Respir Crit Care Med 1995;151:82-86. 91. Chan CS, Bye PT, Woolcock AJ, et al. Eucapnia and hypercapnia in patients with chronic airflow limitation. The role of the upper airway. Am Rev Respir Dis 1990;141:861-865. 92. Shepard Jr JW, Garrison MW, Grither DA, et al. Relationship of ventricular ectopy to nocturnal oxygen desaturation in patients with chronic obstructive pulmonary disease. Am J Med 1985;78: 28-34. 93. Coccagna G, Lugaresi E. Arterial blood gases and pulmonary and systemic arterial pressure during sleep in chronic obstructive pulmonary disease. Sleep 1978;1:117-124. 94. Boysen PG, Block AJ, Wynne JW, et al. Nocturnal pulmonary hypertension in patients with chronic obstructive pulmonary disease. Chest 1979;76:536-542. 95. Moore-Gillon JC, Cameron IR. Right ventricular hypertrophy and polycythaemia in rats after intermittent exposure to hypoxia. Clin Sci (Lond) 1985;69:595-599. 96. Fitzpatrick MF, Mackay T, Whyte KF, et al. Nocturnal desaturation and serum erythropoietin: a study in patients with chronic obstructive pulmonary disease and in normal subjects. Clin Sci (Lond) 1993;84:319-324. 97. Fletcher EC, Luckett RA, Miller T, et al. Pulmonary vascular hemodynamics in chronic lung disease patients with and without oxyhemoglobin desaturation during sleep. Chest 1989;95: 757-764. 98. Fleetham J, West P, Mezon B, et al. Sleep, arousals and oxygen desaturation in chronic obstructive pulmonary disease. The effect of oxygen therapy. Am Rev Respir Dis 1982;126:429-433. 99. Orr WC, Shamma-Othman Z, Levin D, et al. Persistent hypoxemia and excessive daytime sleepiness in chronic obstructive pulmonary disease (COPD). Chest 1990;97:583-585. 100. Bradley TD, Rutherford R, Grossman RF, et al. Role of daytime hypoxemia in the pathogenesis of right heart failure in the obstructive sleep apnea syndrome. Am Rev Respir Dis 1985;131: 835-839. 101. Zanchet RC, Viegas CA. Nocturnal desaturation: predictors and the effect on sleep patterns in patients with chronic obstructive pulmonary disease and concomitant mild daytime hypoxemia. J Bras Pneumol 2006;32:207-212. 102. O’Donoghue FJ, Catcheside PG, Ellis EE, et al. Sleep hypoventilation in hypercapnic chronic obstructive pulmonary disease: prevalence and associated factors. Eur Respir J 2003;21:977-984. 103. Weitzenblum E, Chaouat A, Kessler R, et al. Overlap syndrome: obstructive sleep apnea in patients with chronic obstructive pulmonary disease. Proc Am Thorac Soc 2008;5:237-241. 104. Chaouat A, Weitzenblum E, Kessler R, et al. Outcome of COPD patients with mild daytime hypoxaemia with or without sleeprelated oxygen desaturation. Eur Respir J 2001;17:848-855. 105. Lewis CA, Ferguson W, Eaton T, et al. Isolated nocturnal desaturation in COPD: prevalence and impact on quality of life and sleep. Thorax 2009;64:133-138. 106. Goldstein RS, Ramcharan V, Bowes G, et al. Effect of supplemental nocturnal oxygen on gas exchange in patients with severe obstructive lung disease. N Engl J Med 1984;310:425-429. 107. Chaouat A, Weitzenblum E, Kessler R, et al. A randomized trial of nocturnal oxygen therapy in chronic obstructive pulmonary disease patients. Eur Respir J 1999;14:1002-1008. 108. Krachman SL, Chatila W, Martin UJ, et al. Effects of lung volume reduction surgery on sleep quality and nocturnal gas exchange in patients with severe emphysema. Chest 2005;128:3221-3228. 109. Connaughton JJ, Douglas NJ, Morgan AD, et al. Almitrine improves oxygenation when both awake and asleep in patients with hypoxia and carbon dioxide retention caused by chronic bronchitis and emphysema. Am Rev Respir Dis 1985;132:206-210. 110. Saas-Torres J, Domingo C, Moron A, et al. Long-term effects of almitrine bismesylate in COPD patients with chronic hypoxaemia. Respir Med 2003;97:599-605.
CHAPTER 111 • Sleep in Patients with Asthma and Chronic Obstructive Pulmonary Disease 1307
111. Series F, Cormier Y. Effects of protriptyline on diurnal and nocturnal oxygenation in patients with chronic obstructive pulmonary disease. Ann Intern Med 1990;113:507-511. 112. Dolly FR, Block AJ. Medroxyprogesterone acetate and COPD. Effect on breathing and oxygenation in sleeping and awake patients. Chest 1983;84:394-398. 113. Saaresranta T, Aittokallio T, Utriainen K, et al. Medroxyprogesterone improves nocturnal breathing in postmenopausal women with chronic obstructive pulmonary disease. Respir Res 2005;6:28. 114. Mulloy E, McNicholas WT. Theophylline improves gas exchange during rest, exercise, and sleep in severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1993;148:1030-1036. 115. Veale D, Cooper BG, Griffiths CJ, et al. The effect of controlledrelease salbutamol on sleep and nocturnal oxygenation in patients with asthma and chronic obstructive pulmonary disease. Respir Med 1994;88:121-124. 116. Martin RJ, Bartelson BL, Smith P, et al. Effect of ipratropium bromide treatment on oxygen saturation and sleep quality in COPD. Chest 1999;115:1338-1345. 117. McNicholas WT, Calverley PM, Lee A, et al. Long-acting inhaled anticholinergic therapy improves sleeping oxygen saturation in COPD. Eur Respir J 2004;23:825-831. 118. Lin CC. Comparison between nocturnal nasal positive pressure ventilation combined with oxygen therapy and oxygen monotherapy
in patients with severe COPD. Am J Respir Crit Care Med 1996;154:353-358. 119. Clini E, Sturani C, Rossi A, et al. The Italian multicentre study on noninvasive ventilation in chronic obstructive pulmonary disease patients. Eur Respir J 2002;20:529-538. 120. Meecham Jones DJ, Paul EA, Jones PW, et al. Nasal pressure support ventilation plus oxygen compared with oxygen therapy alone in hypercapnic COPD. Am J Respir Crit Care Med 1995;152:538-544. 121. Fletcher EC, Schaaf JW, Miller J, et al. Long-term cardiopulmonary sequelae in patients with sleep apnea and chronic lung disease. Am Rev Respir Dis 1987;135:525-533. 122. Martin JM, Soriano JB, Carrizo SJ, Boldova A, Celli BR. Outcomes in patients with chronic obstructive pulmonary disease and obstructive sleep apnea: the overlap syndrome. Am J Respir Crit Care Med 2010;182:325-331. 123. Kryger M, Wang-Weigand S, Zhang J, et al. Effect of Ramelteon, a selective MT1/MT2-receptor agonist, on respiration during sleep in mild to moderate COPD. Sleep Breath 2008;12: 243-250. 124. Kryger M, Roth T, Wang-Weigand S, Zhang J. The effects of ramelteon on respiration during sleep in subjects with moderate to severe chronic obstructive pulmonary disease. Sleep Breath 2009;13:79-84.
Restrictive Lung Disorders Juan F. Masa and Meir H. Kryger
Abstract Diseases of structures adjacent to the lungs, such as obesity and kyphoscoliosis, lead to extrapulmonary lung restriction and frequently result in breathing problems during sleep and consequent daytime symptoms, as well as significant physiologic perturbations. The most severe cases engender hypoventilation and cardiorespiratory failure. In addition to potentially imposing mechanical limitation on the chest wall, obesity also increases risk for upper airway obstruction and obstructive sleep apnea. Obesity also increases the risk for hypercapnia during wakefulness, known as obesity hypoventilation syndrome. This syndrome is usually treated with continuous positive airway pressure or noninvasive intermittent mechanical ventilation (NIMV), with additional efforts directed toward
Resting lung volume (the volume at the end of a normal exhalation) is determined by the balance between the elasticity and inward recoil of the lung and the outward recoil properties of the chest wall. The former tends to reduce lung volume. Forces that tend to preserve or increase lung volume include the normal, inherent mechanical tendency of the chest wall (considered to consist of three components: the thoracic cage, diaphragm, and abdomen) to recoil outward, as well as tonic inspiratory muscle activity. Restriction of lung expansion may thus be the result of disorders of the lung parenchyma (intrapulmonary restriction) or disorders of structures adjacent to the lungs, such as the skeletal and soft tissue components of the chest wall (extrapulmonary restriction). The physiologic consequences of these two types of restriction are different and result in different effects on respiratory control mechanisms. In general, intrapulmonary restriction is characterized by stimulation of pulmonary vagal receptors, with subsequent tachypnea (e.g., rapid, shallow breathing) and hyperventilation. Patients with extrapulmonary restriction may exhibit blunted ventilatory chemosensitivity and hypoventilation. On the basis of differences during the awake state, one would expect these two groups to behave differently during sleep. Extrapulmonary restriction is most commonly associated with obesity, kyphoscoliosis, neuromuscular diseases, and pregnancy, and intrapulmonary restriction with interstitial lung disease and lung resection. Sleep disorders during pregnancy are reviewed in detail in Chapter 139, and neuromuscular diseases are reviewed in Chapter 88.
OBESITY Definition, Epidemiology, and Risk Factors Obesity is a condition that occurs when body fat exists in excess to the extent that health is impaired.1 The most common clinical measure of obesity in adults and children is the body mass index (BMI).1,2 In adults, the BMI thresholds for overweight and obesity are 25 kg/m2 (Asians, 23) and 30 kg/m2 (Asians, 27), respectively. Children are 1308
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112
weight loss. Kyphoscoliosis, which is associated with reduced chest wall compliance and ventilatory muscle inefficiency resulting in hypoventilation, is usually treated with NIMV. Diffuse pulmonary parenchymal diseases resulting in intrapulmonary lung restriction have many causes, the most common being idiopathic pulmonary fibrosis or cryptogenic fibrosing alveolitis. In these cases, stimulation of pulmonary receptors results in a rapid, shallow breathing pattern and hyperventilation, which also serves to mitigate hypoxemia to varying degrees. Daytime symptoms such as dyspnea predominate, but significant hypoxemia may occur especially during sleep. The most common treatment for sleep hypoxemia in these cases is oxygen therapy. Sleep apnea is uncommon in this group, although its frequency may be higher in those who are also obese.
overweight when their BMI is greater than or equal to the sex- and age-specific 95th percentile.2 In addition, waist circumference can be used to determine central obesity, which appears to be a better predictor of obesity-related diseases.3,4 Thresholds of 102 cm for men and 88 cm for women define central obesity. In the United States, the prevalence of obesity in adults increased from 13% to 32.9% between the 1960s and 2003-2004. In 2003-2004, 66% of adults and 16% of children and adolescents were overweight.5 Similar data were reported for Europe6 and other developed countries. However, more recent U.S. data do not show a statistical difference in prevalence of obesity between the 2003-2004 survey (32.9%) and the 2005-2006 survey (34.2%).7 Numerous studies have shown that obesity increases morbidity and mortality.1,4 Obesity is the second leading preventable cause of disease and death in the United States, surpassed only by tobacco use. Overweight and obesity are associated with significant pathophysiologic alterations and clinically relevant consequences including insulin resistance, type 2 diabetes, dyslipidemia, hypertension, cholelithiasis, certain forms of cancer, steatosis hepatitis, gastroesophageal reflux, obstructive sleep apnea (OSA), degenerative joint disease, gout, lower back pain, and polycystic ovarian syndrome.8 Some of these conditions are components of metabolic syndrome. A significant subset of obese people are considered metabolically healthy: they appear to be protected from obesity-related metabolic abnormalities9 and have a less abnormal inflammation profile.10 Obstructive sleep apnea syndrome (OSAS) has been reported in about 51% of people with obesity11 and in a majority of people with morbid obesity.12 OSAS has been hypothesized to be a predisposing factor for the development of metabolic syndrome.13 Pathogenesis Obese patients have compromised respiratory function while awake and seated. Their ventilatory function may become worse when they assume the supine position, and
it may deteriorate further during sleep. However, the compromise of respiratory function is not the same in all types of obesity.14 Predominantly abdominal adiposity (central obesity) may restrict the descent of the diaphragm and limit lung expansion to a greater degree than adipose tissue mass in other locations. Breathing during Wakefulness Obesity is associated with increased metabolic demands, O2) and carbon reflected by increased oxygen uptake ( V dioxide production ( VCO2). Thus, to sustain normal arterial blood gas tensions (Pao2 and Paco2), these individuals must maintain an elevated level of alveolar ventilation. Moreover, the work required to maintain the augmented ventilation is greater for obese individuals, mainly because of increased stiffness (reduced compliance) and reduced mobility of the thoracic cage. In obese patients, the load on the chest wall caused by adipose tissue reduces the capacity to recoil outward. Thus, resting lung volume (measured as functional residual capacity [FRC]) is reduced in these patients, with consequent reduction of oxygen stores in the lungs. In addition, during expiration, when lung volume falls below a certain level, airways at the lung bases begin to close, reducing ventilation to the alveoli subtended by these airways. Perfusion may continue to these poorly ventilated lung units and result in an imbalance between ventilation and perfu leading to a reduced V ratio and causing Q), Q sion ( V hypoxemia. Breathing in the Supine Position In the supine position, the abdominal hydrostatic force is applied through the diaphragm to the lungs. In addition, the chest wall in obese patients (particularly in central obesity) is stiffer in the supine than in the upright position. Thus, FRC is further lowered in the supine compared with the seated or upright positions, which promotes greater Q and more widespread regional reduction of the V ratio and greater consequent hypoxemia. Moreover, varying degrees of increased upper airway resistance during sleep further increases the work of breathing. This would be the case even in the absence of obstructive apnea, given the normal increase in airway resistance that usually accompanies sleep (see Chapters 23 and 101). Breathing during Sleep Obese patients may present with the following breathing abnormalities during sleep: • Heavy snoring without obstructive upper airway events or hypoxemia. Nocturnal hypoxemia and OSA are frequent in obese patients,11 although some of these individuals (generally those with lesser degrees of overweight or obesity) demonstrate only snoring as a sleep disturbance. • Hypoxemia with no demonstrable obstructive upper airway events. As discussed earlier, obesity-associated respiratory alterations are exacerbated when the patient lies down, especially in the supine position, leading to mismatch and hypoxemia. Moreover, the abnor Q V mal respiratory system mechanics that may accompany obesity, in conjunction with normal sleep physiology such as the tendency for reduced ventilation (relative
CHAPTER 112 • Restrictive Lung Disorders 1309
to wakefulness), hypotonia of the intercostal muscles, and lower lung volume (see Chapter 22), can lead to oxyhemoglobin desaturation and hypercapnia in about 10% of obese subjects even in the absence of OSA.11 Sleep Apnea and Hypoventilation Obesity is the greatest risk factor for developing OSA. Indeed, apneas and hypopneas or respiratory effort–related arousals15 can be observed together or with predominance of one of these events. Although many obese patients develop repetitive sleep obstructive events, some do not. Increased weight alone is not sufficient to cause OSA, and differences in neuromuscular control of upper airway muscles and variations in ventilatory control mechanisms can play a role. In obese individuals, the accumulation of fat in the lateral parts of the pharynx increases the extraluminal pressure and may alter the geometry of the upper airway, predisposing to the collapse.16 The variability in upper airway fat deposition may be related to sex and genetic17 factors. Nocturnal hypoventilation without daytime hypercapnia occurs in 29% of nonselected obese subjects and is frequently associated with OSA.8 Sometimes hypoven tilation is also present during wakefulness, reflecting obesity–hypoventilation syndrome (OHS), which may also be a component of the pickwickian syndrome (see later discussion of obesity–hypoventilation syndrome). OSA is discussed in detail in other chapters of this section. Clinical Features The clinical presentations of people with obesity reflect obesity-related comorbidities that can also affect sleep. For example, they might have diabetes, cardiovascular disease, joint diseases, or sleep breathing disorders. Many patients have combinations of symptoms related to several of these conditions. Diagnosis As previously discussed, the BMI is used to diagnose obesity.1,2 Cutoff points of 25 and 30 kg/m2 in white adults identify overweight and obesity, respectively. Waist circumference, waist-to-hip ratio, and neck circumference are other metrics of adiposity and body fat distribution. Waist circumference is a better predictor of associated cardiometabolic disorders than BMI, and it could be an additional indicator for monitoring changes in obesity (Table 112-1).3 Diagnoses of breathing-related sleep disorders should be confirmed by performing comprehensive polysomnography with or without monitoring of end-tidal or transcutaneous CO2 tension (Pco2tc).18 Less complete polysomnography or a cardiopulmonary sleep study (in hospital or at home) may be considered in selected patients with suspected OSA (see Chapter 105). Treatment Achieving and maintaining normal weight is a challenge, and strategies for treating obesity are beyond the scope of this chapter. Several institutions, medical societies, and national health departments have guidelines for management and prevention of obesity.19,20
1310 PART II / Section 13 • Sleep Breathing Disorders Table 112-1 Parameters of Overweight and Obesity, and Relationship to Disease Risk Disease Risk* Relative to Normal Weight and Waist Circumference†
Underweight
BODY MASS INDEX (KG/M2)
OBESITY CLASS
<18.5
—
MEN: ≤102 CM (40 IN) WOMEN: ≤88 CM (35 IN)
MEN: >102 CM (40 IN) WOMEN: >88 CM (35 IN)
—
—
Normal
18.5-24.9
—
—
—
Overweight
25.0-29.9
—
Increased
High
Obesity Extreme obesity
30.0-34.9
I
High
Very high
35.0-39.9
II
Very high
Very high
40.0+
III
Extremely high
Extremely high
*Disease risk for type 2 diabetes, hypertension, and cardiovascular disease. † Increased waist circumference can also be a marker for increased risk in persons of normal weight.
Dietary weight loss is recommended for overweight and obese patients with OSAS. However, lack of adherence to diet,21 regain of lost weight, and interindividual improvement variability are frequent.22 Large, randomized, placebo-controlled outcome studies are necessary for a full evaluation of the role of weight loss through dieting in OSAS patients. There are no randomized and controlled studies of the efficacy of bariatric surgery in sleep breathing disorders, but information from prospective long-term clinical series is now available. Accordingly, weight loss, secondary to bariatric surgery, leads to improvement in sleep quality and apnea-hypopnea index (AHI).23 Although a 1-year follow-up study showed complete resolution of OSA in only 1 of 24 patients,24 a metaanalysis reported a high resolution rate of sleep apnea (86%).25 Therefore, although more information is necessary, bariatric surgery may play a role in the treatment of morbidly obese patients with OSA, as an adjunct to less invasive and rapidly applicable first-line therapies (see Chapter 111).
OBESITY–HYPOVENTILATION SYNDROME Definition, Epidemiology, and Risk Factors The term obesity–hypoventilation syndrome describes the concurrence of diurnal hypoventilation (Paco2 > 45 mm Hg) and obesity (BMI > 30) when other causes of alveolar hypoventilation, such as severe obstructive or restrictive pulmonary disease, significant kyphoscoliosis, severe hypothyroidism, neuromuscular diseases, or other central hypoventilation syndromes, can be excluded. Although OHS can exist without sleep apnea, approximately 90% of patients with OHS have OSA.26,27 Some confusion exists regarding the term pickwickian syndrome. Although it is a well-characterized entity that entails obesity, hypercapnic respiratory failure, periodic breathing, polycythemia, and cor pulmonale, sometimes it is inaccurately used to mean OHS plus sleep apnea regardless of other components of this syndrome.
The prevalence of OHS is unknown, but it is believed to affect a minority of the obese population. The prevalence of OHS in subjects with suspected sleep apnea varies from 10% to 30%, depending on the study method, BMI score, geographic location (where the patients were selected), and the AHI cutoff point used to diagnose sleep apnea.28 Morbid obesity (BMI > 40) is associated with a higher prevalence of OHS.29 This type of obesity is considered more common in women than in men, and some studies have identified a higher prevalence of OHS in women.30-32 Nevertheless, when several series of patients were examined together,33 OHS was diagnosed more frequently in men (66%). There are no clear risk factors for development of OHS in obese subjects except morbid obesity. Pathogenesis The mechanisms by which diurnal hypoventilation develops in patients with obesity are complex and not fully understood. Abnormal respiratory mechanisms (including respiratory muscle dysfunction), abnormal central responses to hypercapnia and hypoxia, neuro hormonal dysfunction (e.g., leptin resistance), and sleep disordered breathing have all been proposed. Respiratory Mechanics As discussed, the mechanical alterations on the respiratory system produced by obesity can cause respiratory muscle dysfunction34 and daytime hypercapnia. Control of Breathing Diminished responses in both hypercapnia and hypoxia have been observed in patients with OHS,35 but it is not entirely clear if the origin is primary (central) or is secondary to mechanical load. Some studies indicate that there is no genetic predisposition to diminished chemosensitivity,36 and that it can improve with noninvasive intermittent mechanical ventilation (NIMV),35,37 suggesting that a secondary origin is more probable. Because the mechanical alterations caused by obesity do not change with NIMV, the improvement in chemosensitivity would depend on other secondary factors (e.g., reduced buffering and muscle
fatigue). On the other hand, the assessment of central neural drive presents some interpretative difficulties. First, ventilatory pump (e.g., the chest wall, including ventilatory muscles) dysfunction may prevent evaluation of the central neural control of breathing because the dysfunction may impair translation of the central drive to breathe into measured ventilation. Second, the increased buffering capacity to chronic elevation of Paco2 could have a secondary effect on central “real” neural drive. These difficulties contribute to the absence of clear evidence to determine if reduced chemosensitivity has a primary or secondary origin. The hormone leptin, produced by fat cells and thought to reduce appetite, may also act in the nervous system to increase ventilation. Thus hypoleptinemia, or central ner vous system resistance to leptin’s ventilation-promoting effects, may promote daytime hypercapnia. Although leptinemia is elevated in obese subjects and OSA patients, the leptin level is almost twice as high in patients with OHS (obesity and daytime hypercapnia) as in patients with obesity without daytime hypercapnia, when measurements of AHI and obesity are similar.38 On the other hand, leptinemia decreases with NIMV treatment39 in the same way as daytime hypercapnia. Thus, some studies have showed correlation between leptinemia and daytime hypercapnia38,40 and between leptinemia and reduction of hypercapnic ventilatory response.41 Given that leptinemia is very high in patients with OHS and is associated with hypercapnia, the respiratory failure present in patients with OHS may result from leptin resistance in the central nervous system. Sleep When apneic events are present during sleep, they can cause transitory nocturnal hypoventilation (Videos 112-1 and 112-2). Daytime hypercapnia in patients with OSA has been associated with the ratio of event duration to interevent duration, which would indicate that diurnal and nocturnal hypercapnia depends on insufficient recovery from the hypoventilation produced by apneic events, especially during rapid eye movement (REM) sleep.42 Transitory hypercapnia would cause higher daytime serum bicarbonate (which results in increased blood buffering capacity) and consequent blunting of the central CO2 response.28 A similar mechanism can happen when nocturnal hypoventilation (especially during REM sleep) occurs without apneas and hypopneas. As most of the previous mechanisms are interconnected, the combined action of all (or the majority) of them is a more realistic explanation for daytime hypercapnia in patients with OHS (Fig. 112-1). Clinical Features The common clinical features of patients with OHS are obesity, a plethoric complexion, dyspnea, cyanosis, and evidence of right heart failure including peripheral edema.29 Such patients may not complain of dyspnea even when hypoxemia and hypercapnia are present. If OSA is present, other symptoms, such as loud snoring, nocturnal choking episodes with witnessed apneas, excessive daytime sleepiness, morning headaches, and tiredness, can be evidenced.
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Obesity
↑ Mechanical load
↑ Work breathing
Breathing sleep disorders
Leptin resistance
↑ Threshold arousal
Muscle deficiency
REM hypoventilation
Sleep apnea
Sleep hypercapnia Chemoreceptors blunting
↑ Serum bicarbonate
Daytime hypercapnia Figure 112-1 Potential mechanisms explaining how obesity can lead to daytime hypercapnia.
Diagnosis Clinicians should consider OHS in obese patients (BMI > 30) with daytime hypercapnia (Paco2 > 45 mm Hg) without the existence of other diseases that might cause hypercapnia, such as severe obstructive or restrictive pulmonary disease, significant kyphoscoliosis, severe hypothyroidism, neuromuscular diseases, or other central hypoventilation syndromes. Pulmonary function tests can be normal, but more commonly they show a mild to moderate restrictive disorder associated with the mechanical alterations of obesity. Laboratory testing should include thyroid function tests to exclude severe hypothyroidism, and a complete blood count to rule out secondary erythrocytosis. An electrocardiogram and echocardiogram can demonstrate right ventricular hypertrophy, right atrial enlargement, or pulmonary hypertension.26,30 An overnight sleep study may demonstrate a spectrum of findings: episodes of upper airway obstruction, sleep fragmentation, transitory oxygen desaturation and significant hypoventilation (increase in Paco2 of more than 10 mm Hg and oxygen desaturation) during REM sleep.31 In patients without relevant OSA, hypoventilation is the main finding (Fig. 112-2). There are no studies that recommend a limited cardiopulmonary sleep study (portable monitoring), instead of complete polysomnography, for the diagnosis of OSA in OHS. Treatment There are no established guidelines for treatment of OHS. The following paragraphs review the most frequently used therapies. Weight Loss The ideal treatment is weight loss. Return to a normal weight reverses respiratory insufficiency, pulmonary hypertension, and sleep disorders.43 However, it is difficult
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trials that show which of these two treatments is more effective in nonselected patients, or if they are more effective than the ideal treatment, which is weight loss. Neither are there controlled trials that show whether the reper cussions of OHS (arterial and pulmonary hypertension, cardiovascular events, hospital admissions, and mortality) decrease at all with treatment or decrease more with one type of treatment over another.
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Figure 112-2 Transcutaneous PCO2 (PCO2tc), oxygen saturation (SATO2), and hypnogram in a patient with obesity–hypoventi lation syndrome without a significant number of apneas and hypopneas. MT, sleep recording loss resulting from movement; W, awake. (From Masa JF, Celli BR, Riesco JA, et al. Noninvasive positive pressure ventilation and not oxygen may prevent overt ventilatory failure in patients with chest wall diseases. Chest 1997;112:207-213, with permission.)
for these patients to achieve and maintain physiologically meaningful weight loss. Limited data exist about the effect of bariatric surgery in OHS44 and it is an alternative for only a minority of patients because of increased morbidity and mortality.45 Nevertheless, moderate weight loss (10 kg) achieves a decrease in Paco2, although this result has not been demonstrated over the long term.43 Ventilatory Support NIMV consists of the application of intermittent positive pressure ventilation, including fixed bilevel pressure devices, using nasal or naso-oral masks, with the objective of improving alveolar ventilation and letting the ventilatory muscles rest (Video 112-3). Series of cases have shown improvement in clinical markers, arterial blood gases, and sleep disorders with this treatment.32,46,47 In uncontrolled longitudinal studies, decreases in days of hospital admission have been observed.30,47 There are no controlled trials that have evaluated mortality, and decreased mortality is seen only in series of treated patients compared with other studies in which they were not treated.48 One small series of cases reported decreased mortality in treated patients versus patients who refused treatment.27 Although continuous positive airway pressure (CPAP) can correct nocturnal apneic events in patients with OHS, daytime Paco2 does not return to normal in all cases. At present, only one controlled and randomized study has assessed and compared the short-term efficacy of CPAP and NIMV treatments in 36 patients with OHS, selected for their acceptance and favorable response to an initial night of CPAP treatment.49 Clinical, Paco2, and polysomnographic improvements were similar in both groups. However, there are no randomized, controlled
Oxygen Therapy In a group of obese patients with nocturnal hypoventilation (and with normal daytime Paco2), oxygen therapy increased transcutaneous Pco2 during sleep when compared with NIMV.46 However, there are no randomized trials that evaluate the benefits of long-term oxygen therapy in patients with OHS, or oxygen therapy together with weight loss. Furthermore, oxygen treatment has not been compared with CPAP or NIMV in these patients. Although oxygen is frequently added to the circuits in patients in whom NIMV does not entirely resolve hypoxemia, data on the long-term benefits of adding nocturnal oxygen to CPAP or NIMV have not been published. If a trial of oxygen therapy is initiated, close monitoring of Paco2 is mandated to detect worsening of hypercapnia and potential acidosis. Drug Therapy Progesterone increases the chemical drive to breathe without altering lung mechanics. Few patients with classic OHS have been reported as receiving treatment with medroxyprogesterone acetate (MPA).50 Whether MPA is clinically useful in the long term is unclear. MPA might be used for patients with OHS who have an inadequate response to (or are unable to use) CPAP or NIMV, taking into account the secondary effects such as feminization in men and deep vein thrombosis. In summary, on the basis of the present state of knowledge, weight loss, CPAP to initial responders, and NIMV should be considered the most effective OHS treatments.
KYPHOSCOLIOSIS Definition, Epidemiology, and Risk Factors Scoliosis refers to a lateral curvature of the spine, whereas kyphosis refers to anteroposterior curvature of the spine. Kyphoscoliosis, a combination of the two that causes thoracic cage deformity, is usually (in 80% of cases) idiopathic in origin but may be the consequence of many diseases, including paralytic poliomyelitis, neurofibromatosis, Pott’s disease, ankylosing spondylitis, Marfan syndrome, and the mucopolysaccharidoses. Chest wall deformity is more common in females than males. Very severe kyphoscoliosis occurs in about 1 in 10,000 people. Pathogenesis Depending on the cause and degree of spinal curvature, kyphoscoliosis can produce ventilatory failure at ages ranging from adolescence to late adulthood. About 100 degrees of scoliotic curvature is present in patients with
kyphoscoliosis and respiratory failure; in most of the studies reporting on sleep in kyphoscoliosis, the spinal deformity has been of this magnitude.51,52 Respiratory Mechanics During wakefulness, these patients have the rapid, shallow breathing pattern typical of a marked restrictive defect. This pattern is adopted because it is associated with the reduced work of breathing in the context of the stiff chest wall associated with kyphoscoliosis. In addition, the ventilatory muscles, abnormally positioned because of the chest wall deformity, are inefficient. This also promotes the development of a breathing pattern that operates with the greatest efficiency. An important tradeoff is engendered by a rapid, shallow breathing pattern, because it is associated with relatively increased ventilation of the anatomic dead space (the larger, more central airways that do not participate in gas exchange) with a smaller percentage of the inspired tidal volume getting to the alveoli. The deformity also causes an abnormal distribution of inspired air, with Q) consequent atelectasis and ventilation–perfusion ( V mismatching. The small tidal volumes probably also promote airway closure and thus perpetuate the atelectasis and its consequent hypoxemia.Another factor that may play a role is low FRC. Patients with a low FRC have reduced oxygen stores in the lungs. If such a patient becomes apneic, oxygen uptake from the lungs into the pulmonary circulation will continue with abnormally rapid depletion of oxygen stores, thus causing a precipitous drop in alveolar Po2. Compared with obesity, which is also an extrathoracic restrictive disorder, kyphoscoliosis shows a more rapid and shallow pattern of breathing. Control of Breathing Control of ventilation in patients with kyphoscoliosis may be abnormal for two reasons. First, the kyphoscoliosis might be caused by poliomyelitis, in which the defect in the respiratory drive may be secondary to involvement of the respiratory control system in the medulla oblongata, or it may be the result of weakness of the respiratory muscles. Second, the blunting of the drive may be acquired (e.g., related to a substantial mechanical load impairing translation of neural drive into output of the chest wall pump). Respiratory failure may first occur in patients with postpoliomyelitic kyphoscoliosis 20 to 30 years after acute infection and recovery. The ventilatory response to hypercapnia may be markedly reduced. This blunting of the hypercapnic drive may result from mechanical impairment (e.g., chest wall deformity, ventilatory muscle weakness) alone. However, when hypercapnia is present, peak ventilation remains well below the patient’s maximal voluntary ventilation, which suggests a primary defect in the ventilatory drive, although it might also result from ventilatory muscle fatigue or adaptation to minimize the work of breathing. The hypoxic ventilatory drive may also be blunted in some patients. Therefore, although in kyphoscoliosis without other secondary diseases (e.g., poliomyelitis) a primary defect in respiratory center cannot be ruled out, the most probable event is a secondary impairment due to mechanical load.
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Alterations during Sleep During sleep, especially during REM sleep, the physiologic tendency to hypoventilate and the change in mechanical properties, combined with the increased mechanical load produced by kyphoscoliosis (see earlier), cause increases respiratory muscular effort, which might lead to muscle fatigue, leading to hypoventilation and oxygen desaturation and increasing Paco2. These sleep abnormalities can promote or maintain daytime respiratory failure caused by muscle fatigue or blunting of the respiratory center.53 Accordingly, a positive correlation between awake Paco2 and nocturnal increases in Paco2 has been observed in some studies.54 That is, the greater the degree of hypercapnia is during wakefulness, the greater is the increase in Paco2 during sleep. The influence of sleep state on daytime hypoventilation occurs because most kyphoscoliotic patients treated only with nocturnal NIMV normalize their daytime Paco2.47,55 Clinical Features Although hypoventilation during wakefulness is chronic in patients with severe cases of kyphoscoliosis, in less severe cases it appears to be episodically precipitated by infections and, to a lesser extent, by pulmonary emboli or respiratory depressant agents, such as hypnotics or opiates. Patients with chronic hypoventilation show the effects of chronic hypoxemia, including polycythemia, pulmonary hypertension,56 and cor pulmonale. Patients may complain of excessive daytime sleepiness and disrupted nocturnal sleep.51 Some have severe nocturnal or morning headaches, probably caused by CO2 retention during sleep. Both hypercapnia and hypoxia are known to increase cerebral blood flow by vasodilation, which is the likely mechanism by which these headaches occur. Probably the physiologic alterations during sleep precede (and even cause) the awake manifestations, allowing, in theory, a potential preventive treatment with NIMV, especially in symptomatic patients.46,57 Diagnosis Kyphoscoliosis is easily diagnosed by physical examination, and its impact on physiology is documented by testing lung function and arterial blood gases. A Paco2 of greater than 45 mm Hg frequently involves treatment with NIMV (see later). In the most severe cases, sleep symptoms (nocturnal or morning headaches, sleepiness) and cardiorespiratory failure are common. Comprehensive polysomnography is normally indicated when OSA or nocturnal hypoventilation is suspected. Different respiratory patterns have been observed: CheyneStokes respiration (i.e., a periodic breathing pattern with or without apneas; see Chapter 100), central apneas, hypoventilation (primarily during REM sleep),52 and obstructive apneas.51 Apnea duration is substantially greater in REM sleep than in non-REM sleep. Nevertheless, in patients not selected for suspected sleep apnea, the most common clinical finding is a low number of obstructive events.54,55 Common findings include sleep fragmentation,52 desaturation, and Paco2 rise, especially in REM sleep (Fig. 112-3). The lowest oxyhemoglobin saturation (Sao2) during the night is less than 60% in most reported
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Figure 112-3 Transcutaneous PCO2 (PCO2tc), oxygen saturation (SATO2), and hypnogram in a patient with kyphoscoliosis. Left: Before treatment with noninvasive intermittent mechanical ventilation. Right: After treatment. MT, sleep recording loss resulting from movement; W, awake. (From Masa Jiménez JF. Mechanical ventilation at home: current perspectives. Arch Bronconeumol 1994;30:29-39, with permission.)
cases.51,52 Patients with the most severe drops in Sao2 are more likely to develop cor pulmonale.52 Treatment Untreated patients with kyphoscoliosis, respiratory failure, and cor pulmonale have a poor prognosis. Tracheostomy alone, which was used in the past in an attempt to reduce anatomic dead space, is now probably indicated on rare occasions. The use of tracheostomy does not result in consistent improvement in respiratory failure unless it is accompanied by mechanical ventilation58 (see Other Treatments, later). Continuous Positive Airway Pressure Because of the stiffness of the chest wall, continuous pressure alone may, when increasing end-expiratory volume, adversely influence the patient’s ability to breathe in and thus may cause distress or worsen gas exchange. CPAP is therefore not recommended unless that OSAS is documented. Noninvasive Intermittent Mechanical Ventilation NIMV used at home can be expected to be effective, and excellent long-term results have been reported47,55 (see Chapter 114). With such treatment, improvements can be expected in clinical symptoms, quality of life,59 nocturnal hypoventilation, and quality of sleep (see Fig. 112-3), as well as improvement or reversal of the hypercapnic respiratory failure. Other studies have found improvement in muscular performance,55 exercise capacity, and reduction in hospitalization days.47 There is no information about mortality with NIMV treatment, because no controlled and randomized clinical trials have been performed. However, such trials are not considered ethically feasible because of the cumulative favorable clinical and physiologic results reported in clinical series. Today, NIMV is indicated in patients with hypercapnic respiratory failure
or exclusively nocturnal hypoventilation with significant related clinical symptoms.46,57 In the latter case, NIMV could possibly be a preventive treatment. Like patients with severe chronic obstructive pulmonary disease,60 kyphoscoliotic patients who are chronic users of NIMV exhibit clinical and physiologic improvement during exercise.61 Other Treatments Because of the presence of a ventilation–perfusion imbalance caused by mechanical alteration, long-term oxygen therapy was historically considered an alternative to invasive mechanical ventilation. Although oxygen admini stration increases Sao2 during sleep, dyspnea, morning headache, and sleepiness are not always improved.46 Some longitudinal studies have shown better survival with NIMV (or with NIMV plus oxygen) than long-term oxygen therapy alone.62,63 When ventilatory support is not possible with noninvasive modalities, a tracheostomy may become necessary in severe disease. Tracheostomy and appropriate nighttime ventilation have resulted in dramatic improvements in Paco2 and in Pao2 during wakefulness, and in a normalization of hematocrit,59 as well as in better survival than long-term oxygen therapy.62 If invasive or noninvasive ventilator supports are not possible, oxygen is an alternative, although a somewhat unattractive one, because daytime and nocturnal Pco2 can rise. Thus, appropriate monitoring is indicated.
INTERSTITIAL LUNG DISEASE Definition, Epidemiology, and Risk Factors The common factor in this group of diseases reflecting intrathoracic restriction is the accumulation of abnormal cells, tissues, or fluid in the interstitial space of the lung.
This alters the mechanical properties of the lung, making it substantially stiffer and increasing its recoil, which reduces lung volume. Although diffuse interstitial lung disease (ILD) can be caused by over a hundred diseases, the most commonly responsible are idiopathic pulmonary fibrosis (also called cryptogenic fibrosing alveolitis), sarcoidosis, occupational dust exposures, malignancy, and reactions to drugs. Pathogenesis Respiratory Mechanics Patients with ILD have a rapid, shallow breathing pattern thought to be related to stimulation of receptors in the lung by the pathologic process in the lungs resulting in increased vagal afferent activity. The resultant level of ventilation is usually excessive for the level of CO2 production, which causes hypocapnia to occur.64 Alterations during Sleep Breathing frequency tends to remain high, but it may decrease during sleep. Hypoxemia during sleep is common in these patients,65 in particular during REM sleep.66,67 Lung volume is reduced in patients with ILD during wakefulness, and it may be further reduced during REM sleep. Transcutaneous Pco2 can remain at the same levels as during wakefulness,68 or it may increase, as seen in normal subjects.58 Severe hypoventilation does not seem to occur, at least until there is advanced impairment of pulmonary function.58,67 Therefore, hypoxemia may be caused by decreased lung volume during REM sleep and physiologic hypoventilation, because Sao2 and Pao2 during wakefulness are, at least in part, maintained by the hyperventilation. The degree that oxygenation worsens will depend on the starting position over the oxyhemoglobin dissociation curve, resulting in larger swings in Sao2 in response to changes in ventilation than during wakefulness.69 Sleep apnea has been uncommonly reported in patients with ILD.66 However, in a more recent study of patients with cryptogenic fibrosing alveolitis who were selected for the presence of symptoms of OSA, a 61% prevalence rate of OSA was reported.70 In the same study, AHI was correlated with BMI and forced vital capacity (FVC). Obesity is the main risk factor for developing OSA, but low lung volume produces upper airway instability,71 favoring obstructive events during sleep. In a study of patients with sarcoidosis, the prevalence of OSA was 17% as opposed to 3% in the control group.72 It is probable that weight increase caused by corticosteroid treatment plays a role. In other words, ILD is more likely to be associated with OSA in the subgroup of patients who have lower lung volume or obesity (ILD overlap). Clinical Features During wakefulness, patients with ILD have dyspnea, which may become quite severe with exercise. Nonproductive cough is another common symptom. Patients with ILD have symptoms related to sleep alteration. Disrupted sleep can lead to impaired quality of life, mainly associated with hypoxemia (Video 112-4).61,73 Because corticosteroid treatment may lead to obesity, clinicians must be aware of and be prepared to identify
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patients with ILD and OSA, as they may benefit from CPAP treatment. Diagnosis Several methods may be used to determine the physiologic impact of ILD (lung function tests, exercise oximetry) and for diagnosis (chest radiograph, computerized tomography, and lung biopsy). Daytime symptoms, especially dyspnea, can be quite severe, so in general these patients are not referred to a sleep laboratory, and therapy is directed toward attempts to reverse the lung disease and toward the use of oxygen (depending on arterial blood gases, or sometimes exercise oximetry). Nevertheless, it could be appropriate to monitor nocturnal Sao2 in patients without significant awake hypoxemia but with compli cations suggestive of chronic hypoxemia, such as cor pulmonale or polycythemia.74 Polysomnography has documented that patients with ILD have very disrupted sleep, with more arousals, sleepstage changes, sleep fragmentation, and periodic leg movement than normal individuals.66,75 Patients with an Sao2 of less than 90% had more disrupted sleep than did those with an Sao2 of greater than 90%. Sleep stages were also redistributed, with a marked increase in stage 1 and a reduction in REM sleep. Hypoxemia, especially during REM, can provoke arousal and sleep disruption.64 These hypoxemic episodes tend to be brief, so mean sleep Sao2 values may fall only slightly from awake values. Desaturation will decrease as the wakeful baseline Sao2 decreases.67 The maximal drop in Sao2 is similar to that seen during maximal exercise.76 In addition, a subgroup of patients could have ILD overlap and related symptoms of both ILD and OSA.70,72 Nocturnal oximetry can be applied to evaluate the oxygenation level in patients with cor pulmonale or polycythemia without important daytime hypoxemia and to properly adjust the oxygen flow. Polysomnography should be performed when OSA is clinically suspected. Treatment In view of the high drive to breathe and the low incidence of apnea, it is unlikely that nocturnal oxygen therapy would cause either significant apneas or hypoventilation. There are no randomized clinical trials examining the use of oxygen in patients with ILD. In the absence of any literature dealing with indications for nocturnal oxygen therapy in this group, it seems prudent to start with the criteria of the Nocturnal Oxygen Therapy Trial group.77 Supplemental oxygen would thus be used if awake Pao2 is less than 55 mm Hg, or if it is less than 60 mm Hg in the presence of hypoxemic complications (polycythemia or peripheral edema). However, because many of these patients desaturate rapidly with minimal exercise, criteria for home oxygen therapy should be more liberal, and many centers use exercise oximetry as a guide in determining the need for and flow of home oxygen. Some patients may need oxygen therapy only with exercise. Another possible indication for oxygen therapy could be significant desaturation during sleep. As mentioned, nocturnal hypoxemia provokes arousals and sleep fragmentation, and it has been correlated with impairment of quality of life.65 However, oxygen administration improved
1316 PART II / Section 13 • Sleep Breathing Disorders
Sao2 and decreased heart rate and breathing frequency, but it had little effect on sleep efficiency or arousal rate.78 Moreover, nocturnal hypoxemia depends on the level of awake oxygenation,65,67 so for most patients, significant hypoxemia during sleep is an indication for oxygen therapy according to conventional recommendations. Even so, it could be indicated in patients without significant awake hypoxemia (Pao2 > 60) and complications suggesting chronic hypoxemia, such as cor pulmonale or polycythemia. CPAP should be the treatment of choice for symptomatic patients with ILD overlap, but only if testing has confirmed a positive treatment effect. Some of these patients may tolerate bilevel devices better than fixed continuous-pressure devices. ❖ Clinical Pearls Patients with extrapulmonary lung restriction may develop severe hypoventilation during sleep, resulting in cardiorespiratory failure. Treatment with noninvasive mechanical ventilation can result in improved clinical status and even resolution of daytime hypo ventilation. Patients with intrapulmonary restriction generally hyperventilate, and OSA is uncommon unless they have additional risk factors, such as obesity caused by corticosteroid treatment.
REFERENCES 1. World Health Organization: Obesity: preventing and managing the global epidemic—report of a WHO consultation on obesity. Geneva, World Health Organization, 1998. p. 1-276. 2. Kuczmarski RJ, Ogden CL, Grummer-Strawn LM, et al. CDC growth charts: United States. Adv Data 2000;314:1-27. 3. Klein S, Allison DB, Heymsfield SB, et al. Waist circumference and cardiometabolic risk: a consensus statement from shaping America’s health: Association for Weight Management and Obesity Prevention; NAASO, the Obesity Society; the American Society for Nutrition; and the American Diabetes Association. Obesity (Silver Spring) 2007;15(5):1061-1067. 4. Zhang C, Rexrode KM, Van Dam RM, et al. Abdominal obesity and the risk of all-cause, cardiovascular and cancer mortality: sixteen years of follow-up in US women. Circulation 2008 Apr 1;117 (13):1658-1667. 5. Wang Y, Beydoun MA. The obesity epidemic in the United States: gender, age, socio-economic, racial/ethnic, and geographic characteristics: a systematic review and meta-regression analysis. Epidemiol Rev 2007;29:6-28. 6. James PT, Rigby N, Leach R. The obesity epidemic metabolic syndrome and future prevention strategies. Eur J Cardiovasc Prev Rehabil. 2004;11(1):3-8. 7. Overweight and obesity: overweight and obesity trends among adults. Centers for Disease Control and Prevention. Available at: http://www.cdc.gov/nccdphp/dnpa/obesity/trend/index.htm. Accessed September 1, 2008. 8. Haslam DW, James WP. Obesity. Lancet 2005;366:1197-1209. 9. Wildman RP, Muntner P, Reynolds K, et al. The obese without cardiometabolic risk factor clustering and the normal weight with cardiometabolic risk factor clustering: prevalence and correlates of 2 phenotypes among the US population. (NHANES 1999-2004). Arch Intern Med 2008;168(15):1617-1624. 10. Karelis AD, Faraj M, Bastard JP, et al. The metabolically healthy but obese individual presents a favorable inflammation profile. J Clin Endocrinol Metab 2005;90:4145-4150. 11. Resta O, Foschino-Barbaro MP, Legari G, et al. Sleep-related breathing disorders, loud snoring and excessive daytime sleepiness in obese subjects. Int J Obes Relat Metab Disord 2001;25:669-675.
12. Valencia-Flores M, Orea A, Castano VA, et al. Prevalence of sleep apnea and electrocardiographic disturbances in morbidly obese patients. Obes Res 2000;8:262-269. 13. Kono M, Tatsumi K, Saibara T, et al. Obstructive sleep apnea syndrome is associated with some components of metabolic syndrome. Chest 2007;131:1387-1392. 14. Ochs-Balcom HM, Grant BJB, Muti P, et al. Pulmonary function and abdominal adiposity in the general population. Chest 2006; 129:853-862. 15. Exar EN, Collop NA: The upper airway resistance syndrome. Chest 1999;115:1127-1139. 16. Crummy F, Piper AJ, Naughton MT. Obesity and the lung: 2. Obesity and sleep-disordered breathing. Thorax 2008;63(8): 738-746. 17. Lam B, Ip MS, Tench E, et al. Craniofacial profile in Asian and white subjects with obstructive sleep apnoea. Thorax 2005;60(6): 504-510. 18. Iber C, Ancoli-Israel S, Chesson A, Quan SF, for the American Academy of Sleep Medicine. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. Westchester, Ill: American Academy of Sleep Medicine; 2007. 19. National Institutes of Health: Clinical guidelines on the identification, evaluation, and treatment of overweight and obesity in adults. Bethesda, Md: NIH, 1998. Available at: http://www.nhlbi.nih.gov/ guidelines/obesity. Accessed September 1, 2008. 20. Lau DC, Douketis JD, Morrison KM, et al, for Obesity Canada Clinical Practice Guidelines Expert Panel. 2006 Canadian clinical practice guidelines on the management and prevention of obesity in adults and children. CMAJ 2007:176(Suppl. 8):S1-S13. Available at: http:// www.cmaj.ca/cgi/content/full/176/8/S1. 21. Lam B, Sam K, Mok WY, et al. Randomized study of three nonsurgical treatments in mild to moderate obstructive sleep apnea. Thorax 2007;62:354-359. 22. Schwartz AR, Gold AR, Schubert N, et al. Effect of weight loss on upper airway collapsibility in obstructive sleep apnea. Am Rev Resp Dis 1991;144:494-498. 23. Haines KL, Nelson LG, Gonzalez R, et al. Objective evidence that bariatric surgery improves obesity-related obstructive sleep apnea. Surgery 2007;141:354-358. 24. Lettieri CJ, Eliasson AH, Greenburg DL. Persistence of obstructive sleep apnea after surgical weight loss. J Clin Sleep Med 2008;4(4): 333-338. 25. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA 2004;292:1724-1728. 26. Kessler R, Chaovat A, Schinkewitch P, et al. The obesity-hypoventilation syndrome revisited: a prospective study of 34 consecutive case. Chest 2001;120:369-376. 27. Perez del Llano LA, Golpe R, Ortiz Piquer M, et al. Short-term and long-term effects of nasal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome. Chest 2005;128: 587-594. 28. Mokhlesi B, Tulaimat A, Faibursowitsch I, et al. Obesity hypoventilation syndrome: prevalence and predictors in patients with obstructive sleep apnea. Sleep Breath 2007;11:117-124. 29. Mokhlesi B, Kryger MH, Grustein RR. Assessment and management of patients with obesity hypoventilation syndrome. Proc Am Thorac Soc 2008;15:218-225. 30. Berg G, Delaise K, Manfreda J, et al. The use of health-care resources in obesity-hypoventilation syndrome. Chest 2001;120: 377-383. 31. Berger KI, Ayappa I, Chatr-Amontri B, et al. Obesity hypoventilation syndrome as a spectrum of respiratory disturbances during sleep. Chest 2001;120:1231-1238. 32. Masa JF, Celli BR, Riesco JA, et al. The obesity hypoventilation syndrome can be treated with noninvasive mechanical ventilation. Chest 2001;119:1102-1107. 33. Mokhlesi B, Tulaimat A. Recent advances in obesity hypoventilation syndrome. Chest 2007;132:1322-1336. 34. Kress JP, Pohlman AS, Alverdy J, et al. The impact of morbid obesity on oxygen cost of breathing (VO2RESP) at rest. Am J Respir Crit Care Med 1999;160:883-886. 35. Chouri-Pontarollo N, Borel JC, Tamisier R, et al. Impaired objective daytime vigilance in obesity-hypoventilation syndrome: impact of noninvasive ventilation. Chest 2007;131:148-155.
36. Jokic R, Zintel T, Sridhar G, et al. Ventilatory responses to hypercapnia and hypoxia in relatives of patients with the obesity hypoventilation syndrome. Thorax 2000;55:940-945. 37. De Lucas-Ramos P, De Miguel-Diez J, Santacruz-Siminiani A, et al. Benefits at 1 year of nocturnal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome. Respir Med 2004;98:961-967. 38. Phipps PR, Starritt E, Caterson I, et al. Association of serum leptin with hypoventilation in human obesity. Thorax 2002;57:75-76. 39. Yee BJ, Cheung J, Phipps P, et al. Treatment of obesity hypoventilation syndrome and serum leptin. Respiration 2006;73:209-212. 40. Shimura R, Tatsumi K, Nakahara Y, et al. Fat accumulation, leptin, and hypercapnia in obstructive sleep apnea-hypopnea syndrome. Chest 2005;127:543-549. 41. Campo A, Frühbeck G, Zulueta JJ, et al. Hyperleptinaemia, respiratory drive and hypercapnic response in obese patients. Eur Respir J 2007;30:223-231. 42. Ayappa I, Berger KI, Norman RG, et al. Hypercapnia and ventilatory periodicity in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2002;166:1112-1115. 43. Olson AL, Zwillich C. The obesity hypoventilation syndrome. Am J Med 2005;118:948-956. 44. Martí-Valeri C, Sabaté A, Masdevall C, et al. Improvement of associated respiratory problems in morbidly obese patients after open roux-en-y gastric bypass. Obes Surg 2007;17:1102-1110. 45. Surgeman HJ, Fairman RP, Sood RK, et al. Long-term effects of gastric surgery for treating respiratory insufficiency of obesity. Am J Clin Nutr 1992;55:5975-6015. 46. Masa JF, Celli BR, Riesco JA, et al. Noninvasive positive pressure ventilation and not oxygen may prevent overt ventilatory failure in patients with chest wall diseases. Chest 1997;112:207-213. 47. Janssens JP, Derivaz S, Breitenstein E, et al. Changing patterns in long-term non-invasive ventilation: a 7-years prospective study in the Geneva lake area. Chest 2003;123:67-79. 48. Budweiser S, Riedl SG, Jörres RA, et al. Mortality and prognostic factors in patients with obesity-hypoventilation syndrome undergoing non-invasive ventilation. J Intern Med 2007;261:375-383. 49. Piper AJ, Wang D, Yee BJ, et al. Randomized trial of CPAP vs bi-level support in the treatment of obesity hypoventilation syndrome without severe nocturnal desaturation. Thorax 2008;63:395-401. 50. Hudgel DW, Thanakitcharu S. Pharmacologic treatment of sleepdisordered breathing. Am J Respir Crit Care Med 1998;158:691-699. 51. Guilleminault C, Kurland G, Whikle R, et al. Severe kyphoscoliosis, breathing, and sleep: the “Quasimodo” syndrome during sleep. Chest 1981;79:626-630. 52. Mezon BL, West P, Israel J, et al. Sleep breathing abnormalities in kyphoscoliosis. Am Rev Respir Dis 1980;122:617. 53. McNicholas WT. Impact of sleep in respiratory failure. Eur Respir J 1997;10:920-933. 54. Sawika EH, Branthwaite MA. Respiration during sleep in kyphoscoliosis. Thorax 1987;42:801-808. 55. Gonzalez C, Ferris G, Diaz J, et al. Kyphoscoliotic ventilatory insufficiency: effects of long-term intermittent positive-pressure ventilation. Chest 2003;124:857-862. 56. Newman JH. Pulmonary hypertension. Am J Respir Crit Care Med 2005;172:1072-1077. 57. Clinical indications for non-invasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease COPD, and nocturnal hypoventilation—a consensus conference report. Chest 1999;116:521-534. 58. Hoeppner VH, Cockcroft DW, Dorman JA, et al. Night-time ventilation improves respiratory failure in secondary kyphoscoliosis. Am Rev Respir Dis 1984;129:240-243.
CHAPTER 112 • Restrictive Lung Disorders 1317 59. Windisch W, Freidel K, Schucher B, et al. The Severe Respiratory Insufficiency (SRI) Questionnaire: a specific measure of healthrelated quality of life in patients receiving home mechanical ventilation. J Clin Epidemiol 2003;56:752-759. 60. Van’t Hul A, Gosselink R, Hollander P, et al. Acute effects of inspiratory pressure support during exercise in patients with COPD. Eur Respir J 2004;23:34-40. 61. Vila B, Servera E, Marin J, et al. Noninvasive ventilatory assistance during exercise for patients with kyphoscoliosis: a pilot study. Am J Phys Med Rehabil 2007;86:672-677. 62. Chailleux E, Fauroux B, Binet F, et al. Predictors of survival in patients receiving domiciliary oxygen therapy or mechanical ventilation. A 10-year analysis of ANTADIR observatory. Chest 1996; 109:741-749. 63. Gustafson T, Franklin KA, Midgren B, et al. Survival of patients with kyphoscoliosis receiving mechanical ventilation or oxygen at home. Chest 2006;130:1828-1833. 64. Lourenco RV, Turino GM, Davidson LA, et al. The regulation of ventilation in diffuse pulmonary fibrosis. Am J Med 1965;38: 199-216. 65. Clark M, Cooper B, Sigh S, et al. A survey of nocturnal hypoxemia and cryptogenic fibrosing alveolitis. Thorax 2001;56:482-486. 66. Perez-Padilla R, West P, Lertzman M, et al. Breathing during sleep in patients with interstitial lung disease. Am Rev Respir Dis 1985;132:224-229. 67. Tatsumi K, Kimuar H, Kunitomo F, et al. Arterial oxygen desaturation during sleep in interstitial pulmonary disease: correlation with chemical control of breathing during wakefulness. Chest 1989;95:962-967. 68. Shea SA, Winning AJ, McKenzie E, et al. Does the abnormal pattern of breathing in patients with interstitial lung disease persist in deep, non-rapid eye movement sleep? Am Rev Respir Dis 1989; 139:653-658. 69. McNicholas WT. Impact of sleep on ventilation and gas exchange in chronic lung disease. Monaldi Arch Chest Dis 2003;59:212215. 70. Mermigkis C, Chapman J, Polychronopoulus V, et al. Sleep-related breathing disorders in patients with idiopathic pulmonary fibrosis. Lung 2007;185:173-178. 71. Heinzer RC, Stanchina ML, Malhotra A, et al. Lung volume and continuous positive airway pressure requirements in obstructive sleep apnea. Am J Respir Crit Care Med 2005;172:11-117. 72. Turner GA, Lower EE, Corser B, et al. Sleep apnea in sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1997;14:61-64. 73. Mermigkis C, Stagaki E, Amfilochiou A, et al. Sleep quality and associated daytime consequences in patients with idiopathic pulmonary fibrosis. Med Princ Pract 2009;18(1):10-15. 74. Fletcher EC, Luckett RA, Miller T, et al. Pulmonary vascular hemodynamics in chronic lung diseases patients with and without oxyhemoglobin desaturation during sleep. Chest 1989;95:757-766. 75. Prado G, Allen R, Trevisani V, et al. Sleep disruption in systemic sclerosis (scleroderma) patients: clinical and polysomnographic findings. Sleep Med 2002;2:341-345. 76. Midgren B, Hansson L, Eriksson L, et al. Pulmonary vascular hemodynamics in chronic lung diseases patients with and without oxyhemoglobin desaturation during sleep. Thorax 1987;42: 353-356. 77. Nocturnal Oxygen Therapy Trial Group. Continuous or nocturnal oxygen therapy in hypoxemic chronic obstructive lung disease. Ann Intern Med 1980;93:391-398. 78. Vazquez JC, Perez-Padilla R. Effect of oxygen on sleep and breathing in patients with interstitial lung disease at moderate altitude. Respiration 2001;68:584-589.
Noninvasive Ventilation to Treat Chronic Ventilatory Failure Dominique Robert, Patrick Leger, and Mark W. Elliott Abstract Early experience with long-term home mechanical ventilation using either tracheostomy or negative pressure ventilation revealed that even patients with essentially no ventilatory function could be continuously supported, and individuals who retained partial ventilatory function could do well with intermittent (e.g., during sleep) ventilatory assistance. Recognition that noninvasive means of providing ventilatory support (e.g., using noninvasive interfaces such as nasal and oronasal masks and mouthpieces) often obviate or postpone the requirement for tracheostomy has resulted in the availability of this alternative for an increasing number of patients who now benefit from long-term ventilation. Patients with all categories of chronic respiratory diseases and consequent alveolar hypoventilation may benefit from
The first patient populations to receive long-term mechanical ventilation were those with sequelae of poliomyelitis or Duchenne’s muscular dystrophy (DMD). Either noninvasive (negative pressure body ventilators or positive pressure via mouthpiece) or invasive (tracheotomy) ventilation was used.1-3 Early experience revealed that even individuals with essentially no ventilatory function could be continuously supported, and patients who retained partial ventilatory function could be managed successfully with intermittent (e.g., during sleep) ventilatory assistance.2 It is now recognized that intermittent positive pressure ventilation can be delivered comfortably using a noninvasive interface.4 In light of its successful application, use of noninvasive positive pressure ventilation (NPPV) for long-term mechanical ventilation has increased substantially, both in patients with pulmonary restrictive disorders resulting from neuromuscular or chest wall disorders and, to a lesser degree, in patients with lung parenchymal disorders such as chronic obstructive pulmonary disease (COPD), although there are clear differences in practice in different countries.5 This chapter addresses the treatment of patients, other than those with sleep apnea, who require NPPV during sleep to achieve physiologic and clinical improvement while asleep as well as during wakefulness. In addition, we will contrast NPPV and negative pressure modalities.
INDICATIONS FOR NOCTURNAL NPPV Use of NPPV reflects a balance of (1) the disease process and its rate of progression, (2) the disease severity, and (3) the patient’s willingness to undertake this therapy. Diseases The principal diseases that may be successfully addressed using NPPV therapy are shown in Box 113-1. All may 1318
Chapter
113
chronic, noninvasive ventilatory assistance, but those with neuromuscular or chest wall disorders experience the best results and the longest extension of life. Clear evidence of benefit is still lacking for patients with chronic obstructive pulmonary disease. Careful choice and adjustment of masks and ventilator settings are key requisites for clinical success. Volume and pressure preset modes both provide good results, but pressure preset modes, which provide better leak compensation, are better suited for noninvasive ventilation. For some patients, such as those with advanced neuromuscular disorders, who need diurnal as well as nocturnal ventilatory assistance, noninvasive ventilation may be applied during wakefulness using mouthpiece interfaces. Although some patients can be continuously ventilated using noninvasive strategies (using either a mask or a mouthpiece, or both), ventilation via tracheostomy remains a treatment option.
become sufficiently severe to be life-threatening, or to cause alveolar hypoventilation that impairs quality of life. Factors to bear in mind when considering initiating nocturnal NPPV therapy include (1) the relative contributions of chest wall abnormalities, ventilatory muscle weakness, and pulmonary parenchymal pathology to hypoventilation, (2) the natural history of the disease progression (to anticipate the likelihood of evolution from NPPV use exclusively during sleep to requirement of diurnal ventilatory assistance), and (3) the associated comorbidities that may dominate the prognosis. Clinical Severity The presence of clinical symptoms (Box 113-2) or physiologic markers of hypoventilation are useful in identifying disease severity as it relates to deciding when to initiate nocturnal NPPV. The symptoms may be subtle, insidious, and not attributed to nocturnal hypoventilation by patients or nonspecialist health care providers. On close questioning, patients who present with life-threatening ventilatory failure may be found to have exhibited warning symptoms suggestive of nocturnal hypoventilation for some time. Education of patients at risk and those involved in their care is very important; patients should be advised to seek specialist advice if they develop any of the symptoms listed in Box 113-1. Hypoventilation is defined by an abnormally elevated arterial carbon dioxide tension (Paco2) and high serum bicarbonate levels with an associated reduction of arterial oxygen tension (Pao2). There are no validated values at which NPPV is definitely indicated, but many clinicians consider treating patients with nonneuromuscular disorders who have an awake Paco2 of greater than 50 to 55 mm Hg and a Pao2 of less than 65 mm Hg, and patients with a neuromuscular disorder with a Paco2 of greater than 45 mm Hg even with a Pao2 of greater than 65 mm Hg on room air.6 The degrees of severity at which NPPV may be considered are presented in Table 113-1.
CHAPTER 113 • Noninvasive Ventilation to Treat Chronic Ventilatory Failure 1319
Box 113-1 Disorders for Which Benefit May Be Obtained from NPPV Therapy, Grouped by Clinical Category and PFT Profile Extrapulmonary Restrictive Disorders: ↓* VC, ↓* FEV1, ↔* FEV1/VC, ↓ RV, ↓ TLC Chest Wall Disorders Kyphoscoliosis Sequelae of thoracoplasty for tuberculosis Neuromuscular Disorders Spinal muscular atrophy Acid maltase deficit (Duchenne’s muscular dystrophy) Myotonic myopathy Amyotrophic lateral sclerosis Obstructive Lung Diseases: ↔ or ↓ VC, ↓ FEV1, ↓ FEV1/VC, ↑ RV, ↑ TLC Chronic obstructive pulmonary disease Bronchiectasis Cystic fibrosis Abnormal Central Ventilatory Control but Normal Lung Function; Normal PFT Idiopathic hypoventilation Obesity–hypoventilation syndrome *Symbols indicate actual compared with theoretical values: ↓ or ↑, decrease or increase; ↔, normal. FEV1, forced expiratory volume in 1 second; NPPV, noninvasive positive pressure ventilation; PFT, pulmonary function test; RV, residual volume; TLC, total lung capacity; VC, vital capacity.
Box 113-2 Clinical Features of Alveolar Hypoventilation • Shortness of breath during activities of daily living in the absence of paralysis • Orthopnea in patients with disordered diaphragmatic dysfunction* • Poor sleep quality: insomnia, nightmares, frequent arousals* • Nocturnal or early morning headaches* • Daytime fatigue and sleepiness, loss of energy* • Decrease in intellectual performance • Loss of appetite and weight loss • Appearance of recurrent complications: respiratory infections • Cor pulmonale *This symptom indicates an overnight polygraphy or polysomnography when clear diurnal hypoventilation does not exist.
Chronic daytime hypoventilation is an important indicator of a very low respiratory reserve and reflects an unstable state with increased susceptibility to life-threatening acute ventilatory failure that may be triggered by what may otherwise be trivial additional factors. Sleep-related hypoventilation is invariably present and precedes diurnal hypoventilation. Thus, a primary reason for overnight respiratory polygraphy or full polysomnography (PSG), which additionally allows sleep staging in patients with diurnal hypoventilation, is to rule out obstructive apnea, particularly in patients who are obese or have central apnea and chronic heart failure. In patients with mild or moderate underlying disease (e.g., a neuromuscular disorder) but no evidence of hypoventilation or hypercapnia during wakefulness (see Table 113-1), a sleep study is required to rule out sleep apnea and to document nocturnal hypoventilation, which may occur in all sleep stages but in some cases occur exclusively during rapid eye movement (REM) sleep, justifying a trial of NPPV. When full polysomnography is unavailable, an overnight recording of oxygen saturation by pulse oximetry (Spo2) (and, if possible, transcutaneous CO2 tension or end-tidal CO2 tension), as well as ribcage and abdominal excursion, may be useful in detecting hypoventilation-associated reduced ventilatory effort and to rule out upper airway obstruction. However, this strategy has not been subjected to high-quality, systematic study and should not be used to exclude sleep-related alveolar hypoventilation. Pulmonary function tests help define and quantify the ventilatory or respiratory disease and are a very useful guide to the possible presence of sleep-related hypoventilation, but they have poor predictive values in individual patients, for whom management requires expertise in sleep medicine and experience with NPPV. In clinical practice, NPPV is initiated either electively or in the context of acute ventilatory failure. In the latter circumstance, the long-term necessity for NPPV should be reevaluated during follow-up, because the need for NPPV may change as the clinical condition stabilizes.7 Indications for NPPV are listed in Table 113-2. NPPV is indicated in patients with restrictive diseases (including chest wall and neuromuscular disorders but not lung parenchymal disorders such as fibrosis) in the presence of clinical symptoms attributable to either diurnal or nocturnal hypoventilation.6,8 With increasing ventilator dependency, the daily duration of NPPV may be progressively extended from sleep time alone to throughout the 24-hour period.3 Alternatively, a tracheostomy may be performed
Table 113-1 Disease Severity at Which Noninvasive Positive Pressure Ventilation (NPPV) Can Be Considered CLINICAL SIGNS AND SYMPTOMS*
DIURNAL HYPOVENTILATION†
NOCTURNAL HYPOVENTILATION‡
+
Yes
Yes
Severe
+/−
No
Yes
Moderate
+/−
No
Yes
Mild
*See Box 113-1. † PaO2 < 65 mm Hg, and PaCO2 > 50-55 mm Hg. ‡ Proven at least with overnight SpO2, and possibly with CO2 recording (transcutaneous or end-tidal capnography).
SEVERITY
1320 PART II / Section 13 • Sleep Breathing Disorders Table 113-2 Indications for Nocturnal Noninvasive Positive Pressure Ventilation (NPPV) According to Disease and Severity of Hypoventilation
DISEASE OR CONDITION
CLINICAL SIGN* + DIURNAL AND NOCTURNAL HYPOVENTILATION†
CLINICAL SIGN + ONLY NOCTURNAL HYPOVENTILATION‡
NOCTURNAL HYPOVENTILATION ONLY
NEITHER CLINICAL SIGNS NOR HYPOVENTILATION
MAINTENANCE ON NOCTURNAL NPPV (YR) >10-20
Scoliosis
Yes
Yes
Perhaps
No
Tuberculosis
Yes
Yes
No
No
10
Stable or slowly progressive
Yes
Yes
Perhaps
No
10-15
Intermediate progression
Yes
Yes
Yes
No
5
Severe or rapidly progressive
Yes
Yes
Yes
No
0-5
Chronic obstructive pulmonary disease
Perhaps
No
No
No
1-5
Bronchiectasis, cystic fibrosis
Yes
Perhaps
No
No
1-5
Obesity– hypoventilation syndrome
Yes
Yes
Perhaps
No
>10-20
Neuromuscular disease
*Symptoms of chronic ventilatory failure (see Box 113-1). † PaO2 < 65 mm Hg, and PaCO2 > 50-55 mm Hg. ‡ Proven at least with overnight SpO2, and possibly with CO2 recording (transcutaneous or end-tidal capnography).
to facilitate ventilatory assistance.9 On the other hand, for patients with COPD, even with essentially the same symptoms (see Box 113-1), the evidence does not provide unequivocal support for benefit from NPPV. Observational cohorts treated with NPPV plus supplemental O2 did not experience improved survival. This was confirmed by two randomized control trials that did not show substantial benefits, although the studies were underpowered for this endpoint.10,11 One trial provides a possible small positive survival effect but at the cost of worsening quality of life.11a As a result, this question remains open, as parameters other than the survival, such as quality of life or hospitalization days, may have improved. Currently, NPPV may be considered as an option for patients with significant symptoms of hypoventilation or recurrent acute hypoventilation, superimposed on chronic ventilatory failure requiring hospitalization and treatment with NPPV, provided that all aspects of medical therapy, particularly long-term oxygen therapy, have been optimized. In cases of isolated sleep hypoventilation (i.e., in the absence of clinical symptoms during wakefulness and diurnal hypercapnia), NPPV may be indicated for diseases known to rapidly worsen, such as typically amyotrophic lateral sclerosis, but also for primary congenital neuromuscular disorders.8 All at-risk patients must receive regular follow-ups, and both patients and caregivers should be regularly reminded of warning symptoms and signs suggesting impending decompensation. There are limited data regarding the use of NPPV as prophylaxis to prevent acute ventilatory failure or to increase survival in patients who do not have chronic ventilatory failure. However, although frequently criticized
on methodological grounds, one study reported that there was no benefit of such use in patients with muscular dystrophy.12 Patients Needing Continuous NPPV With time, many patients, particularly those with progressive neuromuscular disease, require ventilatory assistance during wakefulness as well as during sleep. At this point, the clinician must reconsider the suitability of NPPV. An interface such as a nasal mask, which functions well during sleep, may be inappropriate during wakefulness. However, a mouthpiece may be a useful interface for intermittent daytime ventilation, and some patients can be ventilated overnight using a mouthpiece held in place with head straps and designed to limit leaks, making it an option for those requiring continuous ventilatory support.13 Another option is to vary the type of interface with the period of use—for example, nasal NPPV at night and NPPV via mouthpiece during the day (Fig. 113-1). This has been reported by different teams in stable but severely impaired neuromuscular patients, such as those with sequelae of poliomyelitis, high-level spinal cord injury, or Duchenne’s muscular dystrophy.14 Nevertheless, some clinicians prefer to create a tracheostomy when the need for ventilatory support approaches 24 hours a day, often because it ensures access to the airway and facilitates secretion removal. Continuation of NPPV assumes that the medical team, patient, family, and caregivers understand assisted cough and secretion removal techniques, especially because secretion clearance may be difficult under the best of circumstances when providing NPPV. There is no clear answer as to whether and beyond what
CHAPTER 113 • Noninvasive Ventilation to Treat Chronic Ventilatory Failure 1321
Neurologic disorders that make it difficult for a patient to apply or adjust the interface increase the complexity of use at home, but success can be achieved by trained caregivers, who have an essential role in providing home care to severely impaired patients. Persistent or repeated difficulties with secretion clearance, resulting in chronically obstructed airways and infection, may be a contraindication to NPPV, but this can often be addressed by coughassisting techniques that can be routinely and efficiently applied by caregivers at home.9,17 Patients with secretion clearance problems caused by airway disease, however, usually have an effective cough in terms of mechanics, but their sputum is excessively viscid, so these devices are not effective.18
Figure 113-1 A patient requiring continuous ventilatory assistance is using only noninvasive ventilation. He uses a nasal mask during sleep and a mouthpiece during the day. The mouthpiece is positioned close to his mouth. He alternates between receiving insufflations from the ventilator (on the back of the wheelchair) and breathing spontaneously.
duration patients who require mechanical ventilatory assistance are better or more safely served by tracheostomy or NPPV. In our experience, patients with DMD who have been using NPPV for 16 to 20 hours per day and subsequently converted to ventilatory assistance via tracheostomy demonstrate weight gain and psychological improvement. This may be because during the daytime, ventilatory assistance that is consistently delivered via the tracheostomy frees the patient from having to repeatedly access a mouthpiece for a few assisted breaths and then release it. The most difficult cases involve patients with motor neuron disease, which usually devastates all muscle function within a few years of diagnosis. NIPPV or tracheostomy, or both, may prolong life despite further muscle loss, leading to a locked-in state or a state of minimal communication in 50% of these patients.15 This debate will probably continue, and, ultimately, the decision to convert to tracheostomy depends on the patient and the family environment and preferences as well as on the philosophy and capabilities of the clinical team. Discussion of such issues should begin early in the disease course, well before a crisis precipitates hasty decisions that are subsequently regretted, and an expert team should be involved for longterm mechanical ventilation. Contraindications There are no absolute contraindications to NPPV other than a patient’s unwillingness to use the equipment (e.g., because of claustrophobia) or a major deformity of the face or upper airway that precludes the use of noninvasive interfaces. Dynamic upper airway dysfunction leading to swallowing difficulties and aspiration (particularly frequent in patients with bulbar amyotrophic lateral sclerosis) makes acceptance of NPPV more difficult and may raise interest in switching to a tracheostomy. Nevertheless, many of these patients can still benefit from NPPV.16
Negative Pressure for Noninvasive Ventilation Negative pressure ventilators function by alternatively applying subatmospheric (negative) and atmospheric (zero) pressures around the thorax and the abdomen. The result is negative intrathoracic pressure that simulates spontaneous inspiration with airflow into the airway and lungs. Three categories of negative pressure ventilators are available.19 With the typical iron lung, the entire body, except the head, is exposed to negative pressure. The chest cuirass (a rigid shell) and wrap-type system (nylon poncho surrounding a semicylindrical tentlike support) are simply enclosures that allow application of negative pressure to the thorax. Because the efficacy in generating tidal volume is related to the degree of body surface area that is exposed to negative pressure, it is greater with the iron lung type than with cuirass or poncho type of negative pressure ventilators. Negative pressure ventilation was successfully and predominantly used for long-term mechanical ventilation until the mid-1980s,3,20,21 but then interest waned, partly because NPPV is more efficacious in patients with altered pulmonary or chest wall mechanics and in those who have comorbid obstructive sleep apnea–hypopnea. In addition, negative pressure ventilation may precipitate upper airway obstruction (i.e., obstructive sleep apnea–hypopnea).22 Furthermore, from a patient-use perspective, negative pressure modalities are cumbersome and relatively impractical.
TECHNICAL CONSIDERATIONS FOR NPPV Interfaces Selecting an appropriate interface and fitting it properly have a significant impact on the quality of ventilation and the patient’s sleep, comfort, tolerance, and compliance with therapy. Table 113-3 summarizes the advantages of, disadvantages of, and indications for a wide variety of interfaces. Nasal Interfaces Many nasal interfaces are commercially available, and they are frequently the first choice offered to the patient. Practical suggestions include (1) follow the manufacturer’s suggestions for proper sizing, using a gauge when supplied; (2) use the smallest mask size that encompasses the nose
1322 PART II / Section 13 • Sleep Breathing Disorders Table 113-3 Interfaces for Noninvasive Positive Pressure Ventilation INTERFACE
ADVANTAGES
DISADVANTAGES
INDICATION
Nasal mask
Allows usual physiologic breathing Natural humidification Patient can speak and expectorate
Damage to nasal bridge Mouth leaks
First choice
Commercially made
Large choice Easy to size
—
More preferred
Custom made
Large contact area with face limits skin damage
Time consuming Risk of nares compression when internal space of the mask is too tight
Less preferred Better for volume-preset than pressure-preset ventilation
Mouthpiece (commercially available lip seal or customized)
Better control of leaks
Patient cannot expectorate or talk Aerophagia Initial hypersalivation Dental pain Orthodontic problem Nasal leaks No physiologic humidification
Nasal obstruction Massive oral air leaks Intermittent daytime ventilation
Oronasal mask (industrial or customized)
Control of oral air leaks
Less choice available for long-term use Difficult to size Claustrophobia Dead space Facial skin necrosis
Nocturnal use Massive air leaks
without pinching the nares; (3) use forehead supports; (4) avoid overtightening head straps to overcome air leaks, and tolerate minimal air leaks; (5) check the skin regularly, and if signs of a pressure sore develop, use mask or skin barriers, or alternate different types of interfaces (e.g., masks versus prongs). Cleaning the mask and skin before a ventilation session increases mask adhesion and limits leaks. Using the correct head gear for the interface and the right size for the patient is essential. Customized, made-to-measure nasal masks are an option for patients who present unusual challenges and have even been used routinely by some teams.4 Usually, such masks are directly molded on the face with formable material, such as silicone paste or thermoplastic, and they then maintain their shape. Making these masks requires skill and regular practice. When tidal-volume preset modes of ventilation are used, custom nasal interfaces have been found to limit leaks and dead space better than commercially available nasal masks.23 Nasal pillows or prongs can be useful when there is abrasion on the nasal bridge or when a nasal mask is considered too obtrusive. Some patients with limited arm movement have also found these interfaces to be easier to put on and remove. Oronasal (Full-Face) Masks When mouth leaks are significant and prevent adequate ventilatory support, a full-face or oronasal mask may be indicated. Oronasal mask ventilation is used extensively during acute ventilatory failure, and some clinicians estimate that as many as 30% to 40% of their patients receiving chronic ventilatory assistance use this type of interface.24 As with nasal masks, proper sizing minimizes
leaks and increases tolerance. Oronasal masks can add significant dead space, and ventilator settings need to be adjusted accordingly. To reduce CO2 rebreathing, the exhalation port has to be positioned properly, and during expiration, flow through the circuit should be maintained at an expiratory positive airway pressure (EPAP) level of at least 4 cm H2O.25,26,28,28a Oronasal interfaces should incorporate a safety valve to permit entrainment of fresh air in case of ventilator failure. The clinician must also consider the risk associated with vomiting and aspiration when the patient uses an oronasal interface. Patients should be counseled regarding this risk and advised to contact their physician if circumstances arise that would predispose to such events. Oral Interfaces Used during Sleep Some clinicians have had success using an oral interface (e.g., a mouthpiece) to apply noninvasive ventilation in patients with postpoliomyelitis.1 The oral interface may be either a commercial or a custom-made model. The main indications for a trial of this interface include unmanageable mouth leaks during nasal ventilation, and nasal obstruction. As with oronasal masks, major drawbacks of this type of interface include swallowing difficulties and potential aspiration risk, particularly in patients with esophageal reflux or vomiting, and the inability to speak. Furthermore, its use may be associated with swallowing difficulties. Clinicians should consider break-away head gear that will permit the patient to expel the mouthpiece, and they should incorporate a safety valve to permit entrainment of fresh air in case of ventilator failure. Since the development of better full-face masks, nocturnal mouthpiece ventilation is rarely used by most teams.
CHAPTER 113 • Noninvasive Ventilation to Treat Chronic Ventilatory Failure 1323
Daytime Use of an Oral Interface An oral interface is primarily used for daytime ventilation and may be an excellent adjunct to nocturnal ventilation for patients who are unable to maintain acceptable diurnal arterial blood gases after nocturnal ventilation alone. For patients with neuromuscular diseases, the mouthpiece can be positioned close to the mouth, where it may be intermittently captured to take a few assisted breaths from the ventilator and then released (see Fig. 113-1). Thus, the patient needing assistance night and day may use a combination of interfaces. Ventilators Ventilators use one of two basic methods to deliver, assist in delivering, or augment tidal volume: volumepreset and pressure-preset (Table 113-4). A volume-preset ventilator always delivers the tidal volume that is set by the clinician, regardless of the patient’s pulmonary system mechanics (compliance, resistance, and active inspiration); however, leaks in the system (e.g., leaks at the skin–mask interface, or mouth leaks when using a nasal interface) reduce the volume received by the patient. On the other hand, with pressure-preset ventilators, changes in pulmonary mechanics directly influence the flow and possibly the delivered tidal volume; within limits, and depending on the type of ventilator, there is some compensation for leaks. With volume-preset delivery, two ventilator modes may be applied: either fully controlled (called control mode), in which the beginning and end of inspiration are uniquely initiated by the ventilator, or partially controlled (called assist-control), in which the patient can initiate (trigger) inspiration or, in the event of failure, the minimal rate set on the ventilator will deliver the breath. In pressure-preset delivery, an additional mode (called spontaneous) is available and is initiated when the end of inspiration occurs at a certain percentage (either determined automatically by the ventilator or set by the physician) of the maximal flow observed at the beginning of inspiration. Compared with conventional ventilators with the classical circuitry, including an expiratory valve, bilevel ventilators are simpler and therefore lend themselves to home
mechanical ventilation.27 These devices provide both inspiratory positive airway pressure and expiratory positive airway pressure (IPAP and EPAP) delivered via a single tubing circuit that incorporates an intentional, calibrated leak located close to the patient. The risk of CO2 rebreathing with such a circuit is decreased by using an EPAP of 2 to 4 cm H2O or more.25,28,28a In bilevel ventilators, the EPAP may be equated with positive end-expiratory pressure (PEEP), as used in more sophisticated critical care ventilators. In general, the modes and settings usually used in the intensive care unit are available for home ventilation. The objective in providing many possible settings is to be able to adapt and optimize patient–machine synchronization. Although this is conceptually attractive, not enough studies have been performed to document or refute the advantages of such complexity in the context of home ventilation.29 Some ventilators may analyze ventilation in real time, keep it in an internal memory, and provide data for future assessment. Few studies have compared volume- and pressure-preset ventilators. The results of short-term investigations show no major differences in the correction of hypoventilation in patients with neuromuscular and chest-wall restrictive disorders or COPD.30-32 These studies suggest that volume-preset ventilators are usually efficient, but that some patients respond better than others. Many clinicians prefer the pressure-preset ventilator for most patients, believing it offers better synchronization and is better able to compensate for leaks. However, clinicians should be flexible and try alternative approaches if problems occur with either type of ventilator. Assisted Coughing Techniques Techniques to assist secretion clearance are intended to mimic the physiologic cough. They provide inspiratory assistance consisting of high inspiratory volume followed by a high expiratory flow (or velocity) that serves to clear the airways. In patients with a neuromuscular disease, inspiration must be mechanically assisted by stacking normal tidal volumes without exhaling between them (thus requiring normal glottis functioning), or by delivering one
Table 113-4 Indications for Volume-Preset and Pressure-Preset Ventilators for Home Mechanical Ventilation VOLUME PRESET
PRESSURE PRESET
Advantages
Tidal volume always delivered Internal batteries provide long-duration electrical autonomy
Comfort Responsive to patient demand PEEP Leak compensation Tidal volume variable
Disadvantages
Decrease of tidal volume in presence of leaks No compensation for leaks Poor response to patient demand Desynchronization
Decrease of tidal volume when resistance increases Failure to maintain pressure and to cycle in presence of massive leaks Variability of FIO2
First choice
For patients with neuromuscular disease (battery needed in case of quite total ventilator dependency or if patient is wheelchair bound)
For patients with COPD, chest wall disease, or tuberculosis
Second choice
When pressure preset is insufficiently efficient or poorly tolerated
When volume preset is insufficiently efficient or poorly tolerated
COPD, chronic obstructive pulmonary disease; FIO2, fraction of inspired O2; PEEP, positive end-expiratory pressure.
1324 PART II / Section 13 • Sleep Breathing Disorders
large tidal volume. Cough assistance techniques should be initiated when expiratory peak flow during cough is below 270 L/min.7 Patients and caregivers must be educated about the techniques. Cough assistance can be provided by using an inflating bag, a ventilator to provide an augmented inspiratory volume (which in turn results in a higher peak cough flow), or an insufflation–exsufflation device. In addition to the high expiratory flow velocity generated by respiratory system recoil after a high-volume inspiration, the effectiveness of the exhalation may be augmented by simultaneously pushing on the upper abdomen and chest wall. Alternatively, when an insufflation– exsufflation device is used, it applies a negative pressure to the airways during exhalation to augment airflow velocity and secretion-clearance capability. When patients are quite totally ventilator dependent and particularly prone to airway plugging and atelectasis, it is recommended to initiate cough assistance techniques very early before clinical obstruction with secretions becomes obvious, or when awake Spo2 is less than 95%.9,17 Initiation and Settings of NPPV NPPV is usually initiated in the hospital, either electively to start ventilation or after a situation requiring acute NPPV. However, a recent randomized controlled study showed that outpatient initiation of home mechanical ventilation was feasible, and that the outcome was equivalent in the outpatient and the inpatient groups.33 The goals of NPPV include patient comfort, synchrony with the ventilator, improvement of sleep, and improvement in arterial blood gases with and without ventilatory assistance. It is good practice to select and adjust the ventilator settings for the first couple of hours while the patient is awake, to ensure physiologic adequacy and patient comfort. One study found that using clinical observation to set the ventilator parameters is as successful as using physiologic measurements, including esophageal pressure.34 Next, the adequacy of ventilatory assistance during sleep (either a nap or nocturnal sleep) should be assessed. Ideally, expiratory tidal volume, airway pressure, and arterial blood gas measurements should be made to confirm delivery of the intended degree of support. However, the invasive nature of and the resources required for frequent arterial blood sampling has led most clinicians to monitor Spo2, transcutaneous CO2 tension (Pco2tc) or end-tidal CO2 tension (Pco2et), and ribcage and abdomen excursion, which, together with sleep staging, permit assessment of efficacy. When resources are not available to perform these detailed recordings, it is recommended that Spo2 and Pco2tc, or at the least Spo2, be recorded. Although there are no clearly established values defining efficient nocturnal ventilation, it is generally acknowledged that, in the context of restrictive diseases, assistance is efficient when an Spo2 of less than 90% occurs less than 5% of the time, and when an improvement of at least 10 mm Hg of Pco2tc (compared with unassisted sleep values) is seen during at least 70% of the night.33 Clearly, this does not hold true for Spo2 if oxygen is added to the ventilator circuit.35 In addition, data related to patient tolerance, comfort, and changes in sleep quality and well-being should be obtained. Reduction of awake Paco2, assessed after 3 hours off the ventilator, of at least 10 mm Hg with
a normal blood bicarbonate level measured in a sample of arterial blood after several nights, confirms the efficacy of NPPV.36 If the results are not satisfactory, alterations must be made to the settings and their effects checked again. In patients with COPD, it is frequently not possible to achieve such improvements. If pressure-preset ventilation is used, 10 cm H2O of inspiratory pressure support (i.e., above the EPAP or PEEP) is a suggested starting point. If necessary, the pressure level is progressively increased to achieve evidence of improvement assessed by clinical symptoms (night comfort, morning rest), overnight Spo2, and awake, unassisted Paco2. Although increased pressures are associated with increased leak, there is still a worthwhile increase in ventilation and reduction in the work of breathing.37 However, inspiratory pressure support higher than 20 cm H2O is rarely necessary in patients with COPD, the addition of positive end-expiratory pressure (PEEP in ventilators with an expiratory valve, or EPAP in bilevel devices) should conceptually improve patient triggering when intrinsic PEEP exists, but there is no long-term study proving its clinical usefulness.38 Depending on the ventilator capabilities and observations of how patient and ventilator interact together, more subtle settings involving triggers, initial flow, and inspiratory time limit (to 1 to 1.5 seconds) could be tried. A backup frequency set close to the spontaneous frequency of the patient during sleep is reasonable to accommodate the inspiratory trigger failure sometime induced by decreased Paco2 under the apnea threshold39 or in the presence of a transient leak that impairs proper cycling to the inspiratory pressure. When using a volume preset ventilator, the initial settings may be established by adjusting the frequency of ventilator-delivered breaths so that it approximates the patient’s spontaneous breathing frequency during sleep, an inspiratory time per total breathing cycle time of between 0.33 and 0.5, and a tidal volume of around 10 mL/kg. Supplemental O2 should be added into the ventilator circuit for patients requiring oxygen while awake because of lung parenchymal disease (e.g., COPD). In the absence of parenchymal disease, it is only after trying to optimize all technical parameters that nocturnal residual desaturation may justify additional O2 bled into the ventilator circuit, provided there is maintenance of an acceptable Paco2 (or an appropriately valid surrogate) during sleep. The minimal O2 supplementation that provides acceptable therapy must be identified by assessing overnight Spo2. Use of Alarms with NPPV Therapy The decision to use alarms to indicate power failure, unacceptable leaks, and patient disconnection during NPPV must depend on the severity of the patient’s physiologic and clinical impairment and consequent risk assessment. Unfortunately, no study of this issue has provided definitive guidance. In general, no particular alarms are mandatory when providing NPPV to patients who retain the capacity to maintain adequate spontaneous ventilation for at least 30 minutes. When ventilator dependency is of a more continuous nature, alarms are theoretically mandatory but require a ventilator that incorporates them in the device or circuit, or for which special adaptation is feasible. Downsides of alarm systems include the
CHAPTER 113 • Noninvasive Ventilation to Treat Chronic Ventilatory Failure 1325
potential for alarms in response to non–life-threatening or minor conditions, which may significantly disturb patients’ and caregivers’ rest and reduce their enthusiasm for adherence to NPPV. Clinicians must weigh issues of security regarding device malfunction, interface leaks, and disconnections in the context of the patient’s clinical condition against the potential disruptive influence of inappropriate alarms. Further study is required to provide guidance in assessing patient risk and defining risk versus benefit in patients across the spectrum of severity of various disorders, as well as to request that industry develop alarms that are specifically suitable for the home NPPV patient. When Should Patients Use NPPV? NPPV is mainly used at night for physiologic and practical reasons, but use should also be encouraged during daytime naps, even in individuals without awake hypoventilation. It has been shown that in the short term, awake ventilatory support provided results that were very similar to 8 consecutive hours during the night; this included similar effects on overnight Spo2.40 Substantial improvements in diurnal arterial blood gas tensions and exercise tolerance have been shown in sham controlled studies of 3 hours of ventilation by day for 5 days a week over 3 weeks.41 Daytime (awake) ventilatory assistance, although less convenient as it encumbers the patient during a considerable part of the day, is an option for individuals who are unable to sleep with a ventilator and are prepared to use it in this way. Follow-Up Clinical follow-up should be conducted and daytime arterial blood gas should be obtained once or twice a year. When possible, recordings during sleep on NPPV, identical to those used when initiating NPPV, are useful. At any time, when there are indications of unsatisfactory results, particularly a recurrence of clinical symptoms or an indication of hypoventilation on the arterial blood gas, inadequate NPPV must be suspected and an objective evaluation during sleep undertaken. At the very least, nocturnal oxim etry must be done. When NPPV is determined to be suboptimal, a change in ventilator modality or setting may be indicated after ensuring that there is no damage to the ventilator tubing, mask, or other part. It is also worth ensuring that the patient has not changed the ventilator settings and that a different machine has not been substituted, as significant changes in performance of machines from the same manufacturer and differences between prescribed and delivered parameters have been reported. Increasing the total duration of NPPV use per day should also be considered, particularly when the underlying disease has progressed. Interfaces should be checked, and changed or adapted as needed.
MANAGEMENT OF COMPLICATIONS DURING NPPV Air Leaks To some degree, leaks are present when using NPPV during sleep in all patients. The major potential adverse effects of such leaks are reduced efficiency of ventilation
and sleep fragmentation.42-44 A variety of measures have been suggested to address problematic mouth leaks, and their effectiveness must be confirmed during a sleep recording. These include using preset pressure ventilation, preventing neck flexion, having the patient assume a semirecumbent position, using a chin-strap or a cervical collar to discourage the mouth from opening and the mandible from falling, decreasing the peak inspiratory pressure, and using a full-face mask. If upper airway obstruction is documented or suspected, judicious addition of PEEP, preferably during polysomnographic recording, may be tried. Nasal Dryness, Congestion, and Rhinitis Nasal dryness, congestion, and rhinitis are addressed in Chapter 107. In our experience, humidification during NPPV is usually not necessary, but for some patients nasal and mouth dryness (usually related to leaks) can increase nasal airway resistances and be a source of discomfort.45 In a study of normal subjects, expired tidal volume fell and nasal resistance increased after 5 minutes of intentional mouth breathing, and this was attenuated by heated humidification.46 Comfort scores were also higher with humidification when there was significant leak. A passover, or heated humidifier, can be use in this situation or for patients with high sputum production (e.g., with bronchiectasis, cystic fibrosis). Heat or moisture exchangers are not very useful in the presence of leaks, as the “dry” flow from the ventilator is higher than the “dampened” flow returning from the patient. Aerophagia Aerophagia, or swallowing air, is frequently reported by patients but is rarely intolerable during NPPV.47 It usually depends on the level of inspiratory pressure and is more commonly seen when using volume or mouthpiece ventilation. The incidence decreases considerably if the peak inspiratory pressure is kept below 25 cm H2O pressure.
OUTCOMES OF NOCTURNAL NPPV Effects of NPPV during Ventilatory Assistance During ventilatory assistance, gas exchange is improved as reflected by increased overnight Spo2 and decreased Pco2tc.32,48-50 Nevertheless, significant episodes of transient hypoventilation may persist and, assuming the ventilator settings are otherwise appropriate, these appear to be related to mouth leaks.42-44 Sleep duration slightly increases during NPPV especially in patients with restrictive disorders.51-56 Among five series studying COPD, three have shown increased and two have shown decreased sleep duration. The two series reporting outcomes in patients with restrictive disorders have shown increases of sleep duration. In patients with COPD and those with a restrictive disorder, sleep efficiency was similar with and without NPPV (70 ± 9% and 73 ± 11%, respectively).10,49,51,57 No significant changes were reported in percentage of non-REM sleep, REM sleep, and arousals in any disease groups.43,48,55,56 Thus, NPPV improves nocturnal hypoventilation, but improvement in sleep quality is inconsistent. A recent study
1326 PART II / Section 13 • Sleep Breathing Disorders
comparing subjective sleep quality in patients with postpoliomyelitis showed than those who had undergone tracheostomy had better results than those who received NPPV.58
2. Resetting of the chemoreceptors. It has been suggested that in response to chronic hypercapnia, the respiratory control centers change their set point, which perpetuates the hypoventilation, rather than trying to generate nonsustainable ventilatory muscle effort.60-62 A study of 20 patients with restrictive chest wall disease reported that an increase in CO2 sensitivity was the predominant mechanism by which noninvasive ventilation improved diurnal blood gas tensions.63 In obesity–hypoventilation syndrome, the mechanism seems more complex because of the coexistence of obstructive apnea and primary hypoventilation.64 3. Decreased ventilatory load. This hypothesis suggests that NPPV is associated with improved respiratory system compliance or stiffness, thereby reducing the ventilatory load and increasing the efficiency of the muscles during spontaneous breathing. Some studies suggest a possible minor role of this mechanism in both restrictive and COPD diseases.65,66 Even if the mechanisms that explain the efficacy of nocturnal assisted ventilation are unknown, it is evident that improvement is more or less related to the normalization, or at least the improvement, of alveolar ventilation during
Effects of NPPV on Daytime Respiratory Function during Spontaneous Breathing This discussion focuses on patients who use nocturnal NPPV but are able to breathe spontaneously (i.e., without ventilatory assistance) for at least 8 hours during the day (Tables 113-5 and 113-6). Although arterial blood gases and pulmonary function tests improve in patients with restrictive disorders, it appears that NPPV is associated with little or no improvement in patients with COPD. Three main hypotheses have been proposed to explain the improvements of diurnal arterial blood gases during spontaneous breathing following initiation of NPPV during sleep in patients with restrictive disorders: 1. Improved respiratory muscle strength. It has been suggested that ventilatory assistance rests the respiratory muscles with consequent reversal of fatigue. However, no study has confirmed this hypothesis.
Table 113-5 Blood Gas Composition of Spontaneous Breathing in Response to Noninvasive Mechanical Ventilation Arterial Blood Gases (mm Hg) PaO2 DISEASE/CONDITION
PATIENTS/STUDIES
BASELINE
PaCO2
CHANGE
BASELINE
CHANGE
Chronic obstructive pulmonary disease
314/16*
56 ± 16
5±5
54 ± 7
−3 ± 4
Scoliosis, tuberculosis
543/16†
54 ± 9
10 ± 5
54 ± 5
−13 ± 10
Neuromuscular disorder
179/14‡
65 ± 7
13 ± 6
57 ± 3
−10 ± 5
Obesity–hypoventilation syndrome
110/1§
58 ± 12
56 ± 8
−14 ± 5
7 ± 11
*Noninvasive positive pressure ventilation (NPPV) references 4, 10, 11, 49, 51, 56, 70, 71, 78-84. † NPPV references 32, 40, 42, 48, 52, 62, 71, 79, 81, 85-88. ‡ NPPV and negative pressure ventilation references 50, 70, 71, 89-95. § NPPV reference 74.
Table 113-6 Responses to Noninvasive Positive Pressure Ventilation: Vital Capacity and Maximal Inspiratory Pressure Vital Capacity (mL or %) DISEASE OR CONDITION
PATIENTS/STUDIES
BASELINE
35/3*
1980 ± 228
Scoliosis, tuberculosis
178/6†
1097 ± 219
Obesity– hypoventilation syndrome
111/1‡
64 ± 16%
Chronic obstructive pulmonary disease
*References 49, 51, 84. † References 40, 42, 85-87, 96. ‡ Reference 74. § References 51, 78, 82, 83. ¶ References 31, 40, 48, 51, 52, 54, 82, 83, 85, 86, 97.
Maximal Inspiratory Pressure (cm H2O) CHANGE 57 ± 143 110 ± 98 15%
PATIENT/STUDY
BASELINE
CHANGE
52/4
§
−48 ± 2
−1 ± 11
112/6¶
−39 ± 6
−14 ± 10
—
—
—
CHAPTER 113 • Noninvasive Ventilation to Treat Chronic Ventilatory Failure 1327
NPPV.49 In general, it is likely that, in addition to reducing the burden of breathing during use in patients with chest wall or neuromuscular diseases, NPPV has a favorable impact on ventilatory mechanics or muscle function during spontaneous breathing, despite intrinsic neuromuscular abnormality. Effects on Hospitalization The home care system in France allows precise tabulation of the days that patients spend in the hospital. Comparison between the year before and the first and second years after beginning nocturnal NPPV reveals a significant reduction in the number of days of hospitalization: 34 days versus 6
during the first year and 5 during the second for patients with scoliosis; 31 days versus 10 and 9 for patients with the sequelae of tuberculosis; and 18 versus 7 and 2 for patients with DMD. In contrast, the number of hospital days for patients with COPD decreased significantly during the first year on NPPV, from 49 days at baseline to 17 and 25 days at 1 and 2 years after NPPV, respectively.4 This reflects a modest long-term effect of NPPV in patients with COPD. In the two control studies on COPD, hospitalizations are not significantly decreased with NPPV.10,11 For patients with bronchiectasis, there was no statistical change in the number of hospital days after initiation of NPPV.4,67
Table 113-7 Long-term Issues for Patients on Noninvasive Positive Pressure Ventilation (NPPV) DISEASE, PRIMARY AUTHOR (REF)
PATIENTS (NO./ AVERAGE AGE)
NPPV CONTINUATION (% AT 5 YR)
NPPV WITHDRAWAL* NO. (%)
TRACHEOSTOMY NO. (%)
DEATHS NO. (%)
Scoliosis Simonds (70) Leger (98) Janssens (71)
47/49
79
1 (2)
NA tech
105/57
73
7 (7)
5 (5)
2 (10)
0 (0)
19/60
71
129/62
NA
Simonds (70)
20/61
94
0 (0)
NA tech
Leger (98)
80/64
68
1 (1)
11(14)
Laub (73)†
NA
NA
7 (9) 15 (14) 3 (16) 34 (26)
Tuberculosis
Janssens (71)
23/75
40
Laub (73)†
98/73
NA
30/51
100
0 (0) NA
1 (5) 17 (21)
1 (4)
11 (48)
NA
47 (48)
Poliomyelitis Simonds (70) Janssens (71) Laub (73)†
12/67
40
141/67
NA
0 (0)
NA tech
0 (0)
1 (8)
NA
NA
0 (0) 5 (42) 39 (29)
Duchenne Muscular Dystrophy Leger (98)
16/21
47
0 (0)
7 (44)
2 (13)
Simonds (72)
23/20
73
0 (0)
NA tech
5 (22)
Chronic Obstructive Pulmonary Disease Simonds (70)
33/57
43
5 (15)
NA tech
Leger (98)
50/63
31
4 (8)1
12 (24)
Sivasothy (24)
26/66
68
0 (0)
—
Janssens (71)
58/63
28
4 (7)
0 (0)
188/65
26
13 (7)
Simonds (70)
13/41
<20
0 (0)
NA tech
Leger (98)
25/55
62
0 (0)
2 (8)
Benhamou (99)
14/64
29
0 (0)
NA tech
10 (71)
Budweiser (97)
6 (19) 15 (30) 6 (23) 23 (40) 84 (45)
Bronchiectasis 7 (54) 6 (24)
Obesity–Hypoventilation Syndrome Budweiser (74)†
126/56
77
21 (17)
0 (0)
16 (13)
Laub (73)†
422/61
75
NA
NA
NA
*Lung transplantations are not included in the withdrawn patients. † Starting with tracheostomy in 6%. NA tech, technique not available in this study.
1328 PART II / Section 13 • Sleep Breathing Disorders
Effect on Quality of Life Staying at home, without the necessity to return to the hospital frequently, is strongly appreciated by patients. Studies examining the effect of NPPV on quality of life have shown different results according to etiology: good in patients with thoracic disorders such as kyphoscoliosis or sequelae of tuberculosis, intermediate in patients with neuromuscular disorders, and little or none in patients with COPD.11,11a,49,67-69
NPPV permits long-term mechanical ventilation to be an acceptable option for patients who would not have been treated if tracheostomy were the only alternative. Thus, nocturnal NPPV represents progress in patient care.
Withdrawal from Therapy or Continuation Interpretation of studies reporting long-term issues with NPPV is confounded by the absence of control groups and of correlation with age. Table 113-7 reviews the results of several series with a 5-year follow-up.4,24,70-73 The causes of discontinuing NPPV include death, need for tracheostomy, and withdrawal (defined as stopping NPPV for reasons other than death, tracheostomy, or lung transplantation). Overall, continued use of NPPV beyond 5 years is greater than 70% for chest wall disorders, around 60% for DMD and late effect of polio, and less than 50% for COPD and bronchiectasis. Differences across studies with regard to continued use of NPPV in patients with sequelae of tuberculosis, poliomyelitis, DMD, and COPD may be related to different medical practices and patient age at which NPPV was initiated. Patients with obesity–hypoventilation syndrome, who usually present with diurnal and nocturnal hypercapnia and in whom there is a high incidence of obstructive sleep apnea, could be treated initially with NPPV with the potential for subsequent conversion to continuous positive airway pressure.74,75
Noninvasive positive pressure ventilation using nasal interfaces and portable ventilators is now the treatment of choice for patients with chronic alveolar hypoventilation due to neuromuscular or chest wall diseases. Many of those patients experience improved blood gases during wakefulness after initiation of ventilatory assistance during sleep. Quality of life and survival are also improved. For obese patients with chronic hypoventilation, the respective roles of continuous and intermittent positive airway pressure are not clear. For patients with alveolar hypoventilation due to underlying COPD, benefit from noninvasive mechanical ventilation has not been documented, and it remains to be shown whether some subgroups might benefit from these techniques.
Survival Survival rates of patients initially treated with NPPV (see Table 113-7) and those initially treated with tracheostomy are in the same range.2 Two factors seem to be related to mortality. The first is the age at which NPPV is started, and the second is the disease, with the worst results in patients with COPD or bronchiectasis. Otherwise, in patients with COPD, two randomized trials comparing NPPV plus O2 to O2 alone did not show a difference in survival.10,11,76 One trial has shown a possible small positive effect on survival. Two observational noncomparative short series that reported positive results raise the questions of possible favorable efficiency in subgroups of patients with COPD who did not tolerate conventional supplemental O2 or who were ventilated with high inspiratory pressure.24,77
CONCLUSION Chronic ventilatory support using NPPV improves and stabilizes the clinical course of many patients with chronic ventilatory failure. The results appear to be better in patients with restrictive disorders than in those with COPD. Among the neuromuscular disorders, results are better in the slowly progressive ones. In restrictive disorders, the benefit of NPPV is reflected by the improvements in survival, blood gas composition, and clinical stability. Because it is noninvasive and relatively simple,
❖ Clinical Pearls
REFERENCES 1. Bach JR, Alba AS, Bohatiuk G, et al. Mouth intermittent positive pressure ventilation in the management of postpolio respiratory insufficiency. Chest 1987;91:859-864. 2. Robert D, Gerard M, Leger P, et al. Permanent mechanical ventilation at home via a tracheotomy in chronic respiratory insufficiency. Rev Fr Mal Respir 1983;11:923-936. 3. Curran FJ, Colbert AP. Ventilator management in Duchenne muscular dystrophy and postpoliomyelitis syndrome: twelve years’ experience. Arch Phys Med Rehabil 1989;70:180-185. 4. Leger P, Bedicam JM, Cornette A, et al. Nasal intermittent positive pressure ventilation. Long-term follow-up in patients with severe chronic respiratory insufficiency. Chest 1994;105:100-105. 5. Lloyd-Owen SJ, Donaldson GC, Ambrosino N, et al. Patterns of home mechanical ventilation use in Europe: results from the Eurovent survey. Eur Respir J 2005;25:1025-1031. 6. Clinical indications for noninvasive positive pressure ventilation in chronic respiratory failure due to restrictive lung disease, COPD, and nocturnal hypoventilation—a consensus conference report. Chest 1999;116:521-534. 7. De Miguel Diez J, De Lucas Ramos P, Perez Parra JJ, et al. Analysis of withdrawal from noninvasive mechanical ventilation in patients with obesity-hypoventilation syndrome. Medium term results. Arch Bronconeumol 2003;39:292-297. 8. Ward S, Chatwin M, Heather S. Randomised controlled trial of noninvasive ventilation (NIV) for nocturnal hypoventilation in neuromuscular and chest wall disease patients with daytime normocapnia. Thorax 2005;60:1019-1024. 9. Finder JD, Birnkrant D, Carl J, et al. Respiratory care of the patient with Duchenne muscular dystrophy: ATS consensus statement. Am J Respir Crit Care Med 2004;170:456-465. 10. Casanova C, Celli BR, Tost L, et al. Long-term controlled trial of nocturnal nasal positive pressure ventilation in patients with severe COPD. Chest 2000;118:1582-1590. 11. Clini E, Sturani C, Rossi A, et al. The Italian multicentre study on noninvasive ventilation in chronic obstructive pulmonary disease patients. Eur Respir J 2002;20:529-538. 11a. McEvoy RD, Pierce RJ, Hillman D, et al. Nocturnal noninvasive nasal ventilation in stable hypercapnic COPD: a randomized controlled trial. Thorax 2009;64:561-566. 12. Raphael JC, Chevret S, Chastang C. Randomised trial of preventive nasal ventilation in Duchenne muscular dystrophy. French Multicentre Cooperative Group on Home Mechanical Ventilation
CHAPTER 113 • Noninvasive Ventilation to Treat Chronic Ventilatory Failure 1329
Assistance in Duchenne de Boulogne Muscular Dystrophy. Lancet 1994;343:1600-1604. 13. Bach JR. Continuous noninvasive ventilation for patients with neuromuscular disease and spinal cord injury. Semin Respir Crit Care Med 2002;23:283-292. 14. Bach JR, Alba AS, Saporito LR. Intermittent positive pressure ventilation via the mouth as an alternative to tracheostomy for 257 ventilators users. Chest 1993;103:174-182. 15. Hayashi H, Oppenheimer E. ALS patients on TPPV Totally lockedin state, neurologic findings and clinical implications. Neurology 2003;61:135-137. 16. Bourke SC, Tomlinson M, Williams TL, et al. Effects of non-invasive ventilation on survival and quality of life in patients with amyotrophic lateral sclerosis: a randomised controlled trial. Lancet Neurol 2006;5:140-147. 17. Bach JR, Ishikawa Y, Kim H. Prevention of pulmonary morbidity for patients with Duchenne muscular dystrophy. Chest 1997;112: 1024-1028. 18. Sivasothy P, Brown L, Smith IE, et al. Effect of manually assisted cough and mechanical insufflation on cough flow of normal subjects, patients with chronic obstructive pulmonary disease (COPD), and patients with respiratory muscle weakness. Thorax 2001;56:438-444. 19. Hill NS. Clinical applications of body ventilators. Chest 1986; 90:897-905. 20. Kinnear W, Petch M, Taylor G. Assisted ventilation using cuirass respirators. Eur Respir J 1988;1:198-203. 21. Shapiro SH, Ernst P, Gray-Donald K, et al. Effect of negative pressure ventilation in severe chronic obstructive pulmonary disease [see comments]. Lancet 1992;340:1425-1429. 22. Levy RD, Cosio MG, Gibbons L, et al. Induction of sleep apnea with negative pressure ventilation in patients with chronic obstructive lung disease. Thorax 1992;47:612-615. 23. Tsuboi T. Noninvasive positive pressure ventilation in patients with COPD. Nippon Rinsho 1999;57:2074-2082. 24. Sivasothy P, Smith IE, Shneerson JM. Mask intermittent positive pressure ventilation in chronic hypercapnic respiratory failure due to chronic obstructive pulmonary disease. Eur Respir J 1998; 11:34-40. 25. Lofaso F, Brochard L, Touchard D, et al. Evaluation of carbon dioxide rebreathing during pressure support ventilation with airway management system (BiPAP) devices. Chest 1995;108:772-778. 26. Schettino GP, Chatmongkolchart S, Hess DR. Position of exhalation port and mask design affect CO2 rebreathing during noninvasive positive pressure ventilation. Crit Care Med 2003;31:2178-2182. 27. Strumpf DA, Carlisle CC, Millman RP, et al. An evaluation of the Respironics BiPAP Bi-Level CPAP device for delivery of assisted ventilation. Respiratory Care 1990;35:415-422. 28. Ferguson GT, Gilmartin M. CO2 rebreathing during BiPAP ventilatory assistance. Am J Respir Crit Care Med 1995;151: 1126-1135. 28a. Szkulmowski Z, Belkhouja K, Le QH, et al. Bilevel positive airway pressure ventilation: factors influencing carbon dioxide rebreathing. Intensive Care Med 2010;36:688-691. 29. Janssens JP, Metzger M, Sforza E. Impact of volume targeting on efficacy of bi-level non-invasive ventilation and sleep in obesityhypoventilation. Respir Med 2009;103:165-172. 30. Meecham Jones DJ, Wedzichia JA. Comparison of pressure and volume preset nasal ventilator systems in stable chronic respiratory failure. Eur Respir J 1993;6:1060-1064. 31. Munoz X, Crespo A, Marti S, et al. Comparative study of two different modes of noninvasive home mechanical ventilation in chronic respiratory failure. Respir Med 2006;100:673-681. 32. Schonhofer B, Sonneborn M, Haidl P, et al. Comparison of two different modes for noninvasive mechanical ventilation in chronic respiratory failure: volume versus pressure controlled device. Eur Respir J 1997;10:184-191. 33. Chatwin M, Nickol AH, Morrell MJ, et al. Randomised trial of inpatient versus outpatient initiation of home mechanical ventilation in patients with nocturnal hypoventilation. Respir Med 2008;102: 1258-1535. 34. Vitacca M, Nava S, Confalonieri M, et al. The appropriate setting of noninvasive pressure support ventilation in stable COPD patients. Chest 2000;118:1286-1293. 35. Fu ES, Downs JB, Schweiger JW, et al. Supplemental oxygen impairs detection of hypoventilation by pulse oximetry. Chest 2004;126: 1552-1558.
36. Domenech-Clar R, Nauffal-Manssur D, Compte-Torrero L, et al. Adaptation and follow-up to noninvasive home mechanical ventilation: ambulatory versus hospital. Respir Med 2008;102(11): 1521-1527. 37. Tuggey JM, Elliott MW. Titration of non-invasive positive pressure ventilation in chronic respiratory failure. Respir Med 2006;100: 1262-1269. 38. Appendini L, Patessio A, Zanaboni S, et al. Physiologic effects of positive end expiratory pressure and mask pressure support during exacerbation of chronic obstructive pulmonary disease. Am J Respir Crit Care Med 1994;149:1069-1076. 39. Johnson KG, Johnson DC. Bilevel positive airway pressure worsens central apneas during sleep. Chest 2005;128:2141-2150. 40. Schonhofer B, Geibel M, Sonneborn M, et al. Daytime mechanical ventilation in chronic respiratory insufficiency. Eur Respir J 1997;10:2840-2846. 41. Diaz GG, Alcaraz AC, Talavera JC, et al. Noninvasive positivepressure ventilation to treat hypercapnic coma secondary to respiratory failure. Chest 2005;127:952-960. 42. Bach JR, Robert D, Leger P. Sleep fragmentation in kyphoscoliotic individuals with alveolar hypoventilation treated by NIPPV. Chest 1995;107:1552-1558. 43. Meyer TJ, Pressman MR, Benditt J, et al. Air leaking through the mouth during nocturnal nasal ventilation: effect on sleep quality. Sleep 1997;20:561-569. 44. Teschler H, Stampa J, Ragette R, et al. Effect of mouth leak on effectiveness of nasal bilevel ventilatory assistance and sleep architecture. Eur Respir J 1999;14:1251-1257. 45. Richards GN, Cistulli PA, Ungar RG, et al. Mouth leak with nasal continuous positive airway pressure increases nasal airway resistance. Am J Respir Crit Care Med 1996;154:182-186. 46. Tuggey JM, Delmastro M, Elliott MW. The effect of mouth leak and humidification during nasal non-invasive ventilation. Respir Med 2007;101:1874-1879. 47. Hill NS. Complications of noninvasive ventilation. Respir Care 2000;45:480-481. 48. Masa JF, Celli BR, Riesco JA, et al. Noninvasive positive pressure ventilation and not oxygen may prevent overt ventilatory failure in patients with chest wall diseases. Chest 1997;112:207-213. 49. Meecham Jones DJ, Paul EA, Jones PW. Nasal pressure support ventilation plus oxygen compared with oxygen therapy alone in hypercapnic COPD. Am J Respir Crit Care Med 1995;152:538-544. 50. Barbé F, Quera-Salva MA, de Lattre J, et al. Long-term effects of nasal intermittent positive-pressure ventilation on pulmonary function and sleep architecture in patients with neuromuscular diseases. Chest 1996;110:1179-1183. 51. Strumpf DA, Millman RP, Carlisle CC, et al. Nocturnal positivepressure ventilation via nasal mask in patients with severe chronic obstructive pulmonary disease. Am Rev Respir Dis 1991;144: 1234-1239. 52. Goldstein RS, De Rosie JA, Avendano MA. Influence of noninvasive positive pressure ventilation on inspiratory muscles. Chest 1991;99: 408-415. 53. Barbe F, Quera-Salva MA, McCann C, et al. Sleep-related respiratory disturbances in patients with Duchenne muscular dystrophy. Eur Respir J 1994;7:1403-1408. 54. Lin CC. Comparison between nocturnal nasal positive pressure ventilation combined with oxygen therapy and oxygen monotherapy in patients with severe COPD. Am J Respir Crit Care Med 1996; 154:353-358. 55. Gozal D. Nocturnal ventilatory support in patients with cystic fibrosis: comparison with supplemental oxygen. Eur Respir J 1997;10: 1999-2003. 56. Krachman SL, Quaranta AJ, Berger TJ. Effects of noninvasive positive pressure ventilation on gas exchange and sleep in COPD patients. Chest 1997;112:623-628. 57. Gay PC, Hubmayr RD, Stroetz RW. Efficacy of nocturnal nasal ventilation in stable, severe chronic obstructive pulmonary disease during a 3-month controlled trial. Mayo Clin Proc 1996;71:533-542. 58. Klang B, Markström A, Sundell K, et al. Hypoventilation does not explain the impaired quality of sleep in postpolio patients ventilated noninvasively vs. invasively. Scand J Caring Sci 2008;22:236240. 59. Kinnear W, Hockley S, Harvey J. The effects of one year of nocturnal cuirass-assisted ventilation in chest wall disease. Eur Respir J 1988;1:204-208.
1330 PART II / Section 13 • Sleep Breathing Disorders 60. Annane D, Chevrolet JC, Chevret S. Nocturnal mechanical ventilation for chronic hypoventilation in patients with neuromuscular and chest wall disorders. Cochrane Database Syst Rev 2000: CD001941. 61. Elliott MW, Mulvey DA, Moxham J, et al. Domiciliary nocturnal nasal intermittent positive pressure ventilation in COPD: mechanisms underlying changes in arterial blood gas tensions. Eur Respir J 1991;4:1044-1052. 62. Hill NS, Eveloff SE, Carlisle C. Efficacy of nocturnal nasal ventilation in patients with restrictive thoracic disease. Am Rev Respir Dis 1992;145:365-371. 63. Nickol AH, Hart N, Hopkinson NS, et al. Mechanisms of improvement of respiratory failure in patients with restrictive thoracic disease treated with non-invasive ventilation. Thorax 2005;60:754760. 64. Chouri-Pontarollo N, Borel JC, Tamisier R, et al. Impaired objective daytime vigilance in obesity-hypoventilation syndrome: impact of noninvasive ventilation. Chest 2007;131:148-155. 65. Bergowsky EH. State of the art: respiratory failure in disorders of the thoracic cage. Am Rev Respir J 1979;119:643-669. 66. Diaz O, Begin P, Andresen M, et al. Physiological and clinical effects of diurnal noninvasive ventilation in hypercapnic COPD. Eur Respir J 2005;26:1016-1023. 67. Domenech-Clar R, Nauffal-Manzur D, Perpina-Tordera M, et al. Home mechanical ventilation for restrictive thoracic diseases: effects on patient quality-of-life and hospitalizations. Respir Med 2003; 97:1320-1327. 68. Windisch W, Freidel K, Schucher B, et al. Evaluation of healthrelated quality of life using the MOS 36-Item Short-Form Health Status Survey in patients receiving noninvasive positive pressure ventilation. Intensive Care Med 2003;29:615-621. 69. Kohler M, Clarenbach CF, Boni L, et al. Quality of life, physical disability, and respiratory impairment in Duchenne muscular dystrophy. Am J Respir Crit Care Med 2005;172:1032-1036. 70. Simonds AK, Elliott MW. Outcome of domiciliary nasal intermittent positive pressure ventilation in restrictive and obstructive disorders. Thorax 1995;50:604-609. 71. Janssens JP, Derivaz S, Breitenstein E, et al. Changing patterns in long-term noninvasive ventilation: a 7-year prospective study in the Geneva Lake area. Chest 2003;123:67-79. 72. Simonds AK, Muntoni F, Heather S. Impact of nasal ventilation on survival in hypercapnic Duchenne muscular dystrophy. Thorax 1998;53:949-952. 73. Laub M, Midgren B. Survival of patients on home mechanical ventilation: a nationwide prospective study. Respir Med 2007;101: 1074-1078. 74. Budweiser S, Riedl SG, Jorres RA, et al. Mortality and prognostic factors in patients with obesity-hypoventilation syndrome undergoing noninvasive ventilation. J Intern Med 2007;261:375-383. 75. Perez de Llano LA, Golpe R, Ortiz Piquer M, et al. Short-term and long-term effects of nasal intermittent positive pressure ventilation in patients with obesity-hypoventilation syndrome. Chest 2005; 128:587-594. 76. Wijkstra PJ, Lacasse Y, Guyatt GH, et al. A meta-analysis of nocturnal noninvasive positive pressure ventilation in patients with stable COPD. Chest 2003;124:337-343. 77. Windisch W, Kostic S, Dreher M, et al. Outcome of patients with stable COPD receiving controlled noninvasive positive pressure ventilation aimed at a maximal reduction of Pa(CO2). Chest 2005; 128:657-662. 78. Lin MC, Huang CC, Lan RS. Home mechanical ventilation: investigation of 34 cases in Taiwan. Chang Keng I Hsueh 1996;19: 42-49.
79. Carroll N, Branthwaite M. Control of nocturnal hypoventilation by nasal intermittent positive ventilation. Thorax 1988;43:349-353. 80. Elliott MW, Simonds AK, Carroll MP, et al. Domiciliary nocturnal nasal intermittent positive pressure ventilation in hypercapnic respiratory failure due to chronic obstructive lung disease: effects on sleep and quality of life. Thorax 1992;47:342-348. 81. Laier-Groeneveld G, Hûttemenn U, Criée CP. Nasal inspiratory positive pressure ventilation. Eur Respir Rev 1992;2:389-397. 82. Renston JP, DiMarco AF, Supinski GS. Respiratory muscle rest using nasal BiPAP ventilation in patients with stable severe COPD. Chest 1994;105:1053-1060. 83. Clini E, Vitacca M, Foglio K, et al. Long-term home care programmes may reduce hospital admissions in COPD with chronic hypercapnia. Eur Respir J 1996;9:1605-1610. 84. Perrin C, El Far Y, Vandenbos F, et al. Domiciliary nasal intermittent positive pressure ventilation in severe COPD: effects on lung function and quality of life. Eur Respir J 1997;10:2835-2839. 85. Ellis ER, Grunstein RR, Chan S, et al. Noninvasive ventilatory support during sleep improves respiratory failure in kyphoscoliosis. Chest 1988;94:811-815. 86. Jackson M, Smith I, King M. Long term non-invasive domiciliary assisted ventilation for respiratory failure following thoracoplasty. Thorax 1994;49:915-919. 87. Leger P, Robert D, Langevin B, et al. Indications of home mechanical ventilation in patients with chest wall deformities due to idiopathic kyphoscoliosis or sequelae of tuberculosis. Eur Respir Rev 1992;2:362-368. 88. Waldhorn RE. Nocturnal nasal intermittent positive pressure ventilation with bi-level positive airway pressure (BiPAP) in respiratory failure. Chest 1992;101:516-521. 89. Curran FJ. Night ventilation by body respirators for patients in chronic respiratory failure due to late stage Duchenne muscular dystrophy. Arch Phys Med Rehabil 1981;62:270-274. 90. Goldstein RS, Molotiu N, Skrastins R, et al. Assisting ventilation in respiratory failure by negative pressure ventilation and by rocking bed. Chest 1987;92:470-474. 91. Heckmatt JZ, Loh L, Dubowitz V. Night-time nasal ventilation in neuromuscular disease. Lancet 1990;335:579-582. 92. Vianello A, Bevilacqua M, Salvador V, et al. Long-term nasal intermittent positive pressure ventilation in advanced Duchenne’s muscular dystrophy. Chest 1994;105:445-448. 93. Sawicka EH, Loh L, Branthwaite MA. Domiciliary ventilatory support: an analysis of outcome. Thorax 1988;43:31-35. 94. Nugent AM, Lyons JD, Gleadhill IC. Home ventilation in Northern Ireland. Ulster Med J 1996;65:47-50. 95. Piper AJ, Sullivan CE. Effects of long term nocturnal nasal ventilation on spontaneous breathing during sleep in neuromuscular and chest wall disorders. Eur Respir J 1996;9:1515-1522. 96. Budweiser S, Murbeth RE, Jorres RA, et al. Predictors of long-term survival in patients with restrictive thoracic disorders and chronic respiratory failure undergoing non-invasive home ventilation. Respirology 2007;12:551-559. 97. Budweiser S, Jorres RA, Riedl T, et al. Predictors of survival in COPD patients with chronic hypercapnic respiratory failure receiving noninvasive home ventilation. Chest 2007;131:1650-1658. 98. Leger P, Petitjean T, Langevin B, et al. Long term effects of nocturnal nasal positive pressure ventilation at home. In: Robert D, editor. Assisted ventilation at home. Paris: Arnette-Blackwell; 1994: 217-232. 99. Benhamou D, Muir JF, Raspaud C, et al. Long-term efficiency of home nasal mask ventilation in patients with diffuse bronchiectasis and severe chronic respiratory failure: a case-control study. Chest 1997;112:1259-1266.
Obstructive Sleep Apnea and Metabolic Dysfunction
Vsevolod Y. Polotsky, Jonathan Jun, and Naresh M. Punjabi Abstract Obstructive sleep apnea (OSA) is a relatively common condition characterized by recurrent collapse of the upper airway during sleep. A growing body of evidence suggests that OSA is associated with insulin resistance, glucose intolerance, type 2 diabetes mellitus, dyslipidemia, and nonalcoholic fatty liver disease independent of the confounding effects of obesity. Experimental and observational data from human studies support the notion that the pathophysiologic consequences of intermittent hypoxemia and recurrent arousals can adversely influence insulin sensitivity and glucose tolerance. Moreover, a number of animal studies have shown that intermittent hypoxia can promote insulin resistance and lead to hepatic
Sleep quantity and quality influence daytime function. Observational and experimental research conducted over the past decade indicates that, in addition to decrements in daytime alertness, sleep restriction can have a negative impact on endocrine function (see Chapter 26), and the effect on glucose homeostasis may increase the risk for type 2 diabetes mellitus.1 Also, substantial evidence implicates obstructive sleep apnea (OSA) as an independent risk factor for other aspects of metabolic dysfunction.2 A plausibly causal association between OSA and altered glucose metabolism has led to an explosion in research of the potential mechanistic pathways. This chapter reviews these potential pathways in OSA, with a particular emphasis on the independent effects of sleep fragmentation and intermittent hypoxemia. Also reviewed are the possible contributions from downstream processes, including altered autonomic activity, changes in corticotropic function, increased oxidative stress, activation of inflammatory pathways, and increased circulating adipokines induced by sleep fragmentation and intermittent hypoxemia of OSA. In addition, the impact of OSA on disorders of lipid metabolism and nonalcoholic fatty liver disease (NAFLD) will be discussed. First, a brief summary of the terminology is provided. Diabetes Mellitus, Glucose Intolerance, and Insulin Resistance The American Diabetes Association consensus guidelines divide diabetes mellitus into four distinct clinical and pathophysiologic types3 and outline the criteria for defining diabetes mellitus and other categories of hyperglycemia (Table 114-1). Type 1 diabetes mellitus results from cell-mediated autoimmune destruction of the pancreatic β cells. It usually occurs in young, nonobese people and accounts for approximately 5% to 10% of those diagnosed with diabetes mellitus. Type 2 diabetes mellitus (formerly known as noninsulin-dependent diabetes mellitus) reflects a state of insulin resistance in peripheral tissues (e.g., skeletal muscle, fat, liver) that is accompanied by an inadequate compensatory increase in insulin secretion. It usually
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114
steatosis and steatohepatitis. Heightened sympathetic nervous system activity, alterations in hypothalamic-pituitary-adrenal function, and systemic inflammation are potential downstream mechanisms linking the pathophysiologic consequences of OSA to metabolic dysfunction. The overall objective of this chapter is to review the available evidence implicating OSA and the associated sleep fragmentation and intermittent hypoxia in the pathogenesis of metabolic abnormalities. In addition, data suggesting that type 2 diabetes mellitus is a risk factor for sleep apnea will be briefly reviewed. Understanding the associations between OSA and metabolic function has implications for practicing clinicians and the research community.
occurs in middle-aged obese adults and accounts for more than 90% to 95% of individuals with diagnosed diabetes mellitus. Gestational diabetes mellitus is the third category of diabetes and is defined as the occurrence of glucose intolerance during pregnancy. Gestational diabetes complicates approximately 4% of the pregnancies in the United States, resulting in 135,000 cases annually. The fourth type of diabetes mellitus includes other secondary types of diabetes mellitus that result from genetic defects of β-cell function and insulin action, other endocrinopathies (e.g., Cushing syndrome), and pancreatic destruction by specific drugs or toxins. In addition to the definitions provided for diabetes mellitus, the American Diabetes Association consensus statement also provides definitions of two prediabetic states: impaired glucose tolerance and impaired fasting glucose. Both of these are known risk factors for type 2 diabetes mellitus and are independently associated with increased risk for cardiovascular disease. Impaired fasting glucose is defined as a fasting glucose level between 100 and 125 mg/dL. Impaired glucose tolerance is defined as a 2-hour postchallenge glucose level between 140 and 200 mg/dL during the oral glucose tolerance test. Studies relating OSA to altered glucose metabolism have examined fasting glucose values and results of the oral glucose tolerance test as the primary outcomes. Several studies have also examined other, more direct measures of insulin sensitivity. The gold standard technique for assessing insulin sensitivity is the hyperinsulinemic euglycemic clamp.4 With this method, exogenous insulin is administered at a rate designed to maintain a stable level of hyperinsulinemia while exogenous glucose is infused to maintain or “clamp” the serum glucose concentration. At steady state, the exogenous glucose infusion rate represents the amount of glucose uptake by the tissues and provides a measure of insulin sensitivity. To maintain euglycemia, insulin-sensitive subjects require high glucose infusion rates, whereas subjects with insulin resistance require low glucose infusion rates. Because the hyperinsulinemic euglycemic clamp method is invasive and time-consuming and 1331
1332 PART II / Section 13 • Sleep Breathing Disorders Table 114-1 Criteria for Diabetes and Prediabetic States CONDITION
TEST PARAMETERS
GLUCOSE LEVEL mg/dL (mmol/l)
Fasting
≥126 mg/dL (≥7.0)
Random
≥200 (≥11.1)
2 hours after glucose load
≥200 (≥11.1)
Impaired fasting glucose
Fasting
100-125 (6.1-6.9)
Impaired glucose tolerance
2 hours after glucose load
140-199 (7.8-11.0)
Diabetes mellitus
imposes a substantial burden on the subject, several alternative and simpler measures of insulin sensitivity have been proposed. These include the insulin suppression test and the intravenous glucose tolerance test, which provide alternative means for assessing insulin sensitivity. Fasting and post–glucose challenge levels of serum insulin are also commonly used, as they are least burdensome and yet provide crude estimates of insulin sensitivity. Finally, the product of fasting insulin (I0) and glucose levels (G0), also known as the homeostasis model assessment (HOMA) index,5 is also a widely used proxy measure of insulin sensitivity, particularly in large epidemiologic studies. Metabolic Syndrome A number of definitions of the metabolic syndrome have been put forth from various international agencies. Although there are subtle differences across the proposed definitions, insulin resistance is common to all and is considered the core defect. According to criteria proposed by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III,6 metabolic syndrome is diagnosed in the presence of three or more of the following: (1) abdominal obesity with waist circumference greater than 40 inches in men and 35 inches in women, (2) serum triglycerides of 150 mg/dL, (3) high-density lipoprotein (HDL) cholesterol less than 40 mg/dL in men and less than 50 mg/dL in women, (4) blood pressure of 130/85 mm Hg, and (5) fasting glucose level of 110 mg/ dL (which has been lowered to 100 mg/dL in recent American Heart Association and National Heart Lung and Blood Institute guidelines7). Proponents of this definition of metabolic syndrome argue that clustering of risk factors is helpful for assessing the risk for type 2 diabetes mellitus and cardiovascular disease.7 However, some argue against the need to define metabolic syndrome, given the limited evidence that cardiovascular disease risk associated with this syndrome is no greater than then risk imparted by its individual components.8 Despite this ongoing controversy, the NCEP definition of the syndrome is used here. Dyslipidemia Lipids circulate in blood in the form of lipoproteins, of which there are five types: chylomicrons, very–low-density lipoproteins (VLDL), intermediate-density lipoprotein (IDL), low-density lipoproteins (LDL), and high-density
lipoproteins. Chylomicrons, the largest of the lipoproteins, are primarily responsible for transporting dietary lipids from the intestine to the liver. VLDL particles, which are produced in the liver, are triglyceride-rich lipoproteins that contain 10% to 15% of the total serum cholesterol. VLDL particles serve as precursors of LDL cholesterol, which constitutes 60% to 70% of the total serum cholesterol. LDL cholesterol is the primary atherogenic lipoprotein associated with an increased risk for cardiovascular disease.6 Triglyceride-rich VLDL can also be atherogenic independently of LDL, especially when serum triglyceride levels exceed 200 mg/dL. In contrast, HDL cholesterol is protective against cardiovascular disease, with low levels increasing the risk for coronary heart disease.6 Atherogenic dyslipidemia can be defined as an LDL cholesterol level of greater than 100 mg/dL, or a triglyceride level of 150 mg/dL, or an HDL cholesterol level of less than 40 mg/dL. Thresholds for abnormal HDL levels in men and women are as follows: less than 40 mg/dL in men and less than 50 mg/dL in women.6 Nonalcoholic Fatty Liver Disease Nonalcoholic fatty liver disease is common in the general population, with prevalence estimates between 17% and 33% and with obesity as a major risk factor.6,9 NAFLD includes a spectrum of abnormalities including hepatic steatosis without inflammation, nonalcoholic steatohepatitis (NASH), and cirrhotic liver disease. NAFLD is an underdiagnosed condition, primarily because serum transaminases are insensitive and nonspecific. Hepatic steatosis can be detected by a computerized tomography or magnetic resonance imaging scan of the abdomen. However, reliable diagnosis and staging of NAFLD is possible only with a liver biopsy. Patients with NAFLD are at higher risk of developing cirrhosis, terminal liver failure, and hepatocellular carcinoma.10 NASH has also been associated with type 2 diabetes mellitus and glucose intolerance, with or without superimposed obesity.
OBSTRUCTIVE SLEEP APNEA AND ALTERED GLUCOSE METABOLISM A number of clinical and epidemiologic studies have identified an independent association between OSA, insulin resistance, glucose intolerance, and type 2 diabetes mellitus. Studies associating OSA to metabolic abnormalities can be categorized into three major groups based on the type of study design. The first group examined the association between symptoms of OSA (e.g., snoring) and glucose homeostasis. These studies have shown that symptoms or signs of OSA such as snoring are associated with a higher incidence of type 2 diabetes mellitus over a 10-year period in men11 and women,12 independent of confounders such as age, body mass index, smoking, physical activity, family history of type 2 diabetes mellitus, and habitual sleep duration. Although these studies provide longitudinal data and suggest a causal effect of OSA, a major deficiency is the lack of polysomnographic data. The second group of studies used polysomnography, and they correlated metrics of OSA severity with abnormalities in glucose homeostasis.2,13,14 In these studies, the apnea–hypopnea index and the degree of sleep-related
CHAPTER 114 • Obstructive Sleep Apnea and Metabolic Dysfunction 1333
hypoxemia have been consistently associated with the degree of insulin resistance, glucose intolerance, and prevalent type 2 diabetes mellitus independent of potentially confounding factors including obesity. Collectively, crosssectional data from several studies that have used polysomnography indicate that the metabolic abnormalities in OSA may be mediated, in part, through intermittent hypoxemia. In fact, results from the Sleep Heart Health Study show that apneas and hypopneas with even mild degrees of oxyhemoglobin desaturation (i.e., 2% and 3%) are associated with fasting hyperglycemia.15 The third group of studies were interventional trials that examined changes that occur in glucose homeostasis after the institution of continuous positive airway pressure (CPAP) to treat OSA.2,13 Relatively few such studies have been conducted over the past decade, and the results have been largely inconclusive. The disagreement over whether CPAP had favorable effects on glucose homeostasis may in part be related to methodological issues, including small study samples, differences in the outcomes assessed, duration of treatment, absence of data on CPAP compliance, and, in some studies, the lack of a control group. Brooks and colleagues16 examined the effect of CPAP treatment for 4 months in 10 severely obese OSA patients with the hyperinsulinemic euglycemic clamp and found significant improvement in insulin sensitivity. Of note, fasting blood glucose and serum insulin levels were not changed by CPAP treatment, which the authors attributed to a masking effect of severe obesity. In one of the largest studies to date documenting a beneficial effect of CPAP, improvements in insulin sensitivity as reflected by the clamp technique were observed within 2 days of starting therapy, with further improvements occurring after 3 months.17 Interestingly, in that study, CPAP treatment for 2 days was associated with improvement in insulin sensitivity only in nonobese individuals, but 3 months of therapy had a beneficial effect in both obese and nonobese subjects. Unfortunately, the study had two major limitations: a greater than 20% attrition at 3 months and the absence of a control group. In another study, CPAP treatment for 83 ± 50 days was found to significantly improve glycemic control, but only in subjects using CPAP for more than 4 hours per night.18 The study was limited by the small number of subjects and the lack of a control group. Of note, several studies failed to find an improvement in insulin resistance with CPAP, but these studies involved a small number of participants.19,20 Taken together, the current body of available studies highlights the need for larger, well-controlled clinical trials with appropriate attention to CPAP compliance to fully investigate the possibility that OSA contributes to glucose dysregulation. The majority of studies have examined the relationship between OSA and steady-state measures of glucose metabolism (e.g., fasting glucose and insulin). Recent data have further demonstrated an association between OSA and impaired glucose and insulin dynamics assessed by frequent sampling of blood glucose and insulin levels throughout the night.21 A decrease in peripheral insulin sensitivity is fed back to the pancreatic β cell, which increases insulin output to maintain normal glucose tolerance.22 A defect in this compensatory response in the face of insulin resistance
is central to the pathogenesis of glucose intolerance and type 2 diabetes mellitus.23 The frequently sampled intravenous glucose tolerance test (FSIVGTT) can be used to model glucose and insulin kinetics and characterize insulin-dependent and insulin-independent mechanisms of glucose disposal (e.g., clearance of the glucose load from the bloodstream).21 In patients with OSA who were free of other medical conditions, the apnea-hypopnea index and the severity of oxyhemoglobin desaturation were negatively correlated the degree of insulin-dependent glucose clearance. A dose–response relationship was observed between the apnea–hypopnea index, the degree of nocturnal hypoxemia, and insulin resistance derived from the FSIVGTT. In addition, glucose effectiveness, which represents the ability of glucose to influence its own clearance independent of an insulin response, was lower in patients with OSA than in control subjects. Finally, despite impaired insulin-dependent and insulin-independent glucose disposal, the expected compensatory increase in pancreatic insulin secretion was absent in the patients with OSA.21 Collectively, these findings suggest OSA may not only diminish insulin sensitivity but also impair insulin secretion and thus increase the risk for type 2 diabetes mellitus. Although much of the foregoing discussion has focused on whether OSA precedes type 2 diabetes and associated abnormalities, it is important to recognize the potential of reverse causation.24-26 Although obesity may explain the high prevalence of OSA in type 2 diabetics, some have suggested that autonomic neuropathy may also increase the predisposition for upper airway collapse during sleep.24-26 Nevertheless, empirical evidence implicating type 2 diabetes as a cause of OSA is, at best, weak. Irrespective of the underlying cause, the possibility of OSA should be considered in patients with type 2 diabetics and diagnostic studies initiated if there is a suggestive clinical history. In the following sections, potential mechanisms through which OSA may lead to metabolic abnormalities, including insulin resistance and dyslipidemia, are considered, with a focus on the effects of sleep fragmentation and intermittent hypoxemia. Physiologic and Biological Mechanisms of Altered Glucose Homeostasis in Patients with OSA Sleep Fragmentation and Glucose Homeostasis Because oxyhemoglobin desaturation (intermittent hypoxemia) and arousal from sleep are inextricably linked in OSA, observational human studies are unable to provide insight regarding potential independent contributions to glucose dysregulation and other metabolic abnormalities. Only by modeling each component, can this issue be assessed. Recently available data suggest that suppression of slow-wave sleep for 3 consecutive nights in lean young healthy volunteers is associated with a decrease in insulin sensitivity and glucose tolerance.27 Furthermore, nonspecific disruption of sleep continuity for 2 nights, with preserved total sleep time (increased stage 1 sleep and decreased slow-wave and REM sleep) in healthy subjects is also associated with a decrease in insulin sensitivity.28 Thus, although the aforementioned studies focused on
1334 PART II / Section 13 • Sleep Breathing Disorders
characterizing short-term metabolic effects of sleep fragmentation or selective sleep stage suppression, the available data certainly implicate sleep fragmentation as an important mediator of metabolic dysfunction. Hypoxemia and Glucose Homeostasis A number of animal and human studies have shown that glucose homeostasis is altered by exposure to sustained or intermittent hypoxia. Indeed, experimentally induced sustained hypoxia increases fasting insulin levels in newborn rats29,30 and calves.31 Exposure to intermittent hypoxia (alternating periods of hypoxia and normoxia) can also diminish insulin sensitivity in lean32 and in genetically obese mice.33 Pancreatic histopathology from mice after short-term (9 hours) intermittent hypoxia demonstrates increased proliferation of the insulin-producing pancreatic β cells,34 perhaps in response to the decrease in insulin sensitivity. Human studies corroborate the notion that hypoxia can adversely affect glucose metabolism. Healthy subjects demonstrate a decrease in insulin sensitivity with sustained hypoxia whether the exposure is for 30 minutes,35 16 hours,36 or 2 days.37 Recent data also show that intermittent hypoxemia for as little as 5 hours in healthy volunteers can diminish insulin sensitivity without an accompanying compensatory increase in insulin secretion.38 Thus, there is mounting evidence implicating intermittent hypoxemia as an important intermediate in the causal pathway between OSA and metabolic dysfunction. The effects of intermittent hypoxia are possibly induced at the level of transcriptional regulation (Fig. 114-1) with an increase in hypoxia-inducible factor-1 (HIF-1).39,40 Consensus is growing in the literature that intermittent hypoxia activates HIF-1 in different organs and tissue (reviewed in reference 41). The lack of HIF-1 activation in HeLa cells and in human aortic endothelial cells in vitro reported by Ryan and colleagues42 and Polotsky and colleagues,42a respectively, is most likely related to the small number of hypoxic cycles in this study. Indeed, Yuan and coworkers39 convincingly showed that robust upregulation of HIF-1 occurs only after 60 cycles. Activation of HIF-1 with intermittent hypoxia may occur either because of hypoxia itself43 or as a result of increased formation of reactive oxygen species.44 HIF-1 is a master regulator of the physiologic responses to hypoxia, including erythropoiesis, angiogenesis, glucose metabolism, and lipid metabolism.43 HIF-1 upregulates sterol regulatory element–binding protein (SREBP)-1,40 which in turn activates genes for lipid biosynthesis.45 SREBP-1 can thus increase accumulation of triglycerides in liver and muscle, with a resulting decrease in insulin sensitivity. SREBP-1 also directly suppresses the transcription of insulin receptor substrate 2, the primary mediator of insulin signaling in the liver.46 In addition to its effects on SREBP-1, HIF-1 increases circulating endothelin-1,47 which can also influence insulin sensitivity. In vitro studies show that endothelin-1 acutely decreases insulin-stimulated glucose uptake,48 stimulates glycogenolysis, causes a dose-dependent increase in hepatic glucose production, and increases plasma glucose levels.49 In humans, endothelin-1 infusion at nonpressor dosages diminishes insulin secretory response to glucose.50 HIF-1 has been implicated in the activation of sympathetic nervous system during intermittent hypoxia, which will be
discussed further.51 Finally, HIF-1 has been implicated in systemic inflammation.41,52 The metabolic significance of HIF-1 is further highlighted by transgenic studies that show that mice with partial deficiency of HIF-1α do not exhibit an increase in serum insulin levels with intermittent hypoxemia.40 Intermittent hypoxia also increases the activity of a major proinflammatory transcription factor, nuclear factor κB (NF-κB).53,54 Although the mechanisms of NF-κB activation with intermittent hypoxia are not well defined, it is likely that enhanced production of reactive oxygen species have an important role. NF-κB may also be induced by HIF-1. In fact, there is an intricate interplay between both transcription factors, which can activate each other.41 Activated NF-κB translocates to the nucleus, where it increases the expression of multiple inflammatory genes for inflammatory cytokines, including tumor necrosis factor (TNF)α, interleukin (IL)-1β, and IL-6.55 TNF-α and IL-6 disrupt insulin signaling pathways and worsen insulin sensitivity. Patients with OSA have elevated circulating levels of TNF-α and IL-6, independent of body weight.53,56 Furthermore, mice exposed to chronic intermittent hypoxia exhibit increased NF-κB activity and TNF-α levels in multiple tissues, including the liver,57,58 which may lead to hepatic insulin resistance. Thus, intermittent hypoxia may lead to insulin resistance via activation of transcription factors HIF-1 and NF-κB in the liver and other insulinsensitive tissues. Other possible mechanisms of metabolic dysfunction with intermittent hypoxia include activation of the sympathetic nervous system and upregulation of counterregulatory hormones (see Fig. 114-1). Sympathetic nervous system activation during intermittent hypoxia may occur because of upregulation of HIF-1 in carotid bodies.51 Sympathetic nervous system activation results in (1) the mobilization of glycogen from muscle, and triglycerides from adipose tissue, (2) decreased glucose uptake by muscle, (3) increased secretion of glucagon, (4) decreased secretion of insulin, and (5) upregulation of gluconeogenesis in the liver. Intermittent hypoxemia in patients with OSA activates the sympathetic nervous system, and this activation is alleviated by CPAP treatment.59,60 In addition to increasing sympathetic activity, intermittent hypoxia could also lead to hypothalamic-pituitary-adrenal axis (HPA) dysfunction, with increasing levels of circulating corticosteroids.2 Steroid hormones impair insulin and glucose regulation through multiple mechanisms, which include an increase in lipolysis, suppression of glycogen synthase in muscle tissue, increase in hepatic glucose output, and inhibition of pancreatic insulin secretion.61 OSA alters the circadian rhythm of corticosteroids, elevating plasma levels of cortisol during sleep.62 Thus, insulin resistance and metabolic dysfunction in patients with OSA could be mediated via activation of the sympathetic nervous system and HPA axes. OSA is associated with high levels of circulating leptin, an adipocyte-produced hormone, which functions as an afferent satiety signal and increases metabolic rate. Leptin deficiency in mice leads to severe obesity and insulin resistance, whereas leptin administration suppresses appetite and increases metabolic rate.63,64 Clinical studies have shown that patients with OSA have significantly higher leptin levels than subjects without sleep apnea.65,66
CHAPTER 114 • Obstructive Sleep Apnea and Metabolic Dysfunction 1335 SLEEP APNEA Intermittent hypoxia Sleep fragmentation Carotid body
Adipose tissue
HIF-1 HPA
Pituitary (ACTH)
Sympathetic NS
Liver
NF-κB HIF-1
Leptin resistance
NF-κB
TNF-α IL-6
HIF-1 SREBP-1
Hepatic steatosis
TNF-α IL-6 NASH
SCD-1
Biosynthesis of CE, TG, and PL VLDL TG, CE
Adrenal (cortisol)
PL Glucose intolerance and insulin resistance Type 2 diabetes
Figure 114-1 Mechanistic links between obstructive sleep apnea and metabolic dysfunction. ACTH, adrenocorticotropic hormone; CE, cholesterol esters; HIF-1, hypoxia-inducible factor-1; HPA, hypothalamic-pituitary-adrenal system; IL-6, interleukin 6; NF-κB, nuclear factor kappa B; PL, phospholipids; SREBP-1, sterol regulatory element-binding protein-1; SCD-1, stearoyl coenzyme A desaturase 1; TG, triglycerides; TNF-α, tumor necrosis factor alpha; VLDL, very–low-density lipoproteins.
Hyperleptinemia correlates with the severity of hypoxemia in patients with OSA, and treatment with CPAP reduces leptin levels.65 Intermittent hypoxia causes an elevation in leptin gene expression and protein level in mice,33 which probably occurs via HIF-1 activation in adipose tissue.40,67 Persistent elevations of leptin lead to a state of leptin resistance,68,69 which then promotes insulin resistance. Collectively, the available data suggest that resistance to leptin may play an important role in development of metabolic abnormalities in OSA. Other adipokines, including adiponectin and resistin, have also been explored,70-75 but their role in the association between OSA and metabolic dysfunction remains to be determined. Finally, insulin resistance in patients with OSA could also be attributed to an elevation in free fatty acid (FFA) levels induced by sympathetic activation. Catecholamines upregulate hormone-sensitive lipase and increase circulating FFA levels. In summary, multiple parallel lines of evidence suggest that intermittent hypoxia in OSA can contribute to metabolic abnormalities through sympathetic nervous system activation, systemic inflammation, dysfunction of the HPA axis, and alteration in adipokine profiles.
OBSTRUCTIVE SLEEP APNEA AND DYSLIPIDEMIA Independent of adiposity, OSA has also been associated with elevated total cholesterol and LDL cholesterol levels.76,77 Elevations in serum lipids are especially pronounced in obese patients with OSA, suggesting a potential interaction between these two conditions.78 Moreover,
recent data suggest that the severity of oxyhemoglobin desaturation in OSA correlates with serum triglyceride and LDL cholesterol levels.79 Interventional studies with CPAP provide additional support for the notion that OSA leads to dyslipidemia, as improvements in total and LDL cholesterol have been observed with CPAP therapy.80-82 With increasing support for an association between OSA and dyslipidemia, a number of studies have also examined the effects of intermittent hypoxia on serum lipids to better define the underlying mechanisms. Exposure to intermittent hypoxia in murine models increases levels of triglycerides, total cholesterol, LDL cholesterol, and VLDL cholesterol.83-85 As observed in the human studies, the degree of dyslipidemia with intermittent hypoxia is correlated with the severity of the exposure.84 Studies using transgenic mice and antisense oligonucleotides technology have led to the hypothesis that intermittent hypoxia induces lipid biosynthesis in the liver because of sequential upregulation of HIF-1, SREBP-1, and stearoyl coenzyme A desaturase (SCD)-1, a key enzyme of lipid biosynthesis and lipoprotein secretion in the liver.79,83,86 Thus, evidence is steadily accumulating implicating OSA and the associated hypoxic stress as independent risk factors for dyslipidemia.
OBSTRUCTIVE SLEEP APNEA AND THE METABOLIC SYNDROME The focus of this chapter thus far has the associations between OSA, glucose homeostasis, and lipid abnormalities. An alternative, but not mutually exclusive, view of the
1336 PART II / Section 13 • Sleep Breathing Disorders
available data is that sleep apnea is yet another component of the metabolic syndrome. Proponents of this perspective argue that common genetic determinants may give rise to pleiotropic effects that include sleep apnea in addition to the components of the metabolic syndrome, including hypertension, central obesity, and dyslipidemia. Such clustering of sleep apnea with other components of the metabolic syndrome was first proposed by Wilcox and colleagues87 and more recently reiterated by others.88,89,89a Even if a common predisposition for and clustering of these conditions is identified, it does not preclude the possibility of causal associations between the individual components of the metabolic syndrome.
associated with NASH and hepatic fibrosis in liver biopsies in several studies,90-92,95 particularly in the bariatric population. Experiments in animal models also show that chronic intermittent hypoxia induces lipid peroxidation, upregulates redox-dependent transcription factor NF-κB, and, in the presence of obesity, increases levels of proinflam matory cytokines including IL-1β, IL-6, macrophage inflammatory protein (MIP)-2, and TNF-α, leading to the development of steatohepatitis and liver fibrosis.57,58 Thus, OSA may accelerate the progression from hepatic steatosis to NASH, but prospective studies in larger patient samples are needed to substantiate this hypothesis and determine whether CPAP therapy is helpful in reversing the cascade.96
OBSTRUCTIVE SLEEP APNEA AND NONALCOHOLIC FATTY LIVER DISEASE Association with Hepatic Steatosis Nonalcoholic fatty liver disease is a common condition that encompasses a spectrum of the disorders including asymptomatic hepatic steatosis, nonalcoholic steatohepatitis, and cirrhotic liver disease. It has been suggested that in addition to abnormalities in glucose and lipid metabolism, OSA could also contribute to the development hepatic steatosis. Indeed, studies in murine models show that chronic intermittent hypoxia can induce hepatic steatosis.58 However, clinical evidence that OSA leads to hepatic steatosis remains controversial. In one study, patients with severe OSA, defined as an apnea–hypopnea index of more than 50 events per hour, had severe hepatic steatosis when compared with patients with an apneahypopnea index of less than 50 events per hour.90 However, several other studies failed to demonstrate such an association.91,92 These differences in overall results may result from the small sample sizes and the differences in study populations.
CONCLUSION The evidence reviewed herein suggests that OSA may contribute to the development of insulin resistance, glucose intolerance, type 2 diabetes, dyslipidemia, and NAFLD. Abnormalities in glucose and lipid metabolism increase the risk for coronary heart disease and type 2 diabetes. Thus, delineating the role of OSA as an independent risk factor for metabolic dysfunction has major implications from clinical and public health perspectives. Clearly, there are major gaps in our knowledge of the associations between OSA and metabolic dysfunction. Further research is needed to provide confirming evidence for a causal link between OSA and the metabolism of glucose and lipids, to delineate the impact of OSA on hepatic and pancreatic β-cell function, and to establish whether treatment of OSA can reverse the associated abnormalities and potentially curtail the associated cardiovascular risk.
Association with Nonalcoholic Steatohepatitis In contrast to the paucity of data addressing the association between OSA and hepatic steatosis, there is good evidence suggesting that OSA may play an important role in the progression from hepatic steatosis to NASH. Clinical studies assessing the relationship between OSA and NASH can be separated in two groups. The first group of studies describes the association between metrics of OSA severity and serum markers of liver injury. OSA has been associated with elevated levels of serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST), which appears to be independently correlated with the nocturnal oxyhemoglobin desaturation.93 Furthermore, treatment with CPAP improves the degree of liver injury independent of any change in adiposity.94 However, it should be noted that liver enzymes are neither sensitive nor specific for the diagnosis of NASH, and a liver biopsy is usually necessary. As hepatic steatosis progresses to NASH, hepatic lobules become infiltrated with a mixed population of inflammatory cells. Inflammation is followed by hepatocyte necrosis, appearance of Mallory bodies, and perisinusoidal fibrosis or cirrhosis. OSA has been independently
❖ Clinical Pearls Obstructive sleep apnea is associated with insulin resistance, glucose intolerance, type 2 diabetes mellitus, dyslipidemia, and nonalcoholic fatty liver disease independent of obesity. Intermittent hypoxemia and recurrent arousals related to apneas and hypopneas may mediate the metabolic disturbance in OSA. Patients with type 2 diabetes mellitus, the metabolic syndrome, and nonalcoholic fatty liver disease should be screened for OSA. Health care providers should be aware of the high prevalence of type 2 diabetes, dyslipidemia, and nonalcoholic fatty disease in patients with OSA, and the potential benefits of CPAP therapy on metabolic function.
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31. Cheng N, Cai W, Jiang M, Wu S. Effect of hypoxia on blood glucose, hormones, and insulin receptor functions in newborn calves. Pediatr Res 1997;41:852-856. 32. Iiyori N, Alonso LC, Li J, et al. Intermittent hypoxia causes insulin resistance in lean mice independent of autonomic activity. Am J Respir Crit Care Med 2007;175:851-857. 33. Polotsky VY, Li J, Punjabi NM, et al. Intermittent hypoxia increases insulin resistance in genetically obese mice. J Physiol 2003;552: 253-264. 34. Yokoe T, Alonso LC, Romano LC, et al. Intermittent hypoxia reverses the diurnal glucose rhythm and causes pancreatic beta-cell replication in mice. J Physiol 2008;586:899-911. 35. Oltmanns KM, Gehring H, Rudolf S, et al. Hypoxia causes glucose intolerance in humans. Am J Respir Crit Care Med 2004;169: 1231-1237. 36. Braun B, Rock PB, Zamudio S, et al. Women at altitude: short-term exposure to hypoxia and/or alpha(1)-adrenergic blockade reduces insulin sensitivity. J Appl Physiol 2001;91:623-631. 37. Larsen JJ, Hansen JM, Olsen NV, et al. The effect of altitude hypoxia on glucose homeostasis in men. J Physiol (Lond) 1997;504 (Pt. 1):241-249. 38. Louis M, Punjabi N. Effects of acute intermittent hypoxia on glucose metabolism in awake healthy volunteers. J Appl Physiol 2009;106(5): 1538-1544. 39. Yuan G, Nanduri J, Bhasker CR, et al. Ca2+/calmodulin kinasedependent activation of hypoxia inducible factor 1 transcriptional activity in cells subjected to intermittent hypoxia. J Biol Chem 2005;280:4321-4328. 40. Li J, Bosch-Marce M, Nanayakkara A, et al. Altered metabolic responses to intermittent hypoxia in mice with partial deficiency of hypoxia-inducible factor-1alpha. Physiol Genomics 2006;25: 450-457. 41. Garvey JF, Taylor CT, McNicholas WT. Cardiovascular disease in obstructive sleep apnoea syndrome: the role of intermittent hypoxia and inflammation. Eur Respir J 2009;33:1195-1205. 42. Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 2005;112:2660-2667. 42a. Polotsky VY, Savransky V, Bevans-Fonti S, et al. Intermittent and sustained hypoxia induce similar gene expression in the human aortic endothelial cells. Physiol Genomics 2010;41:306-314. 43. Semenza GL. HIF-1 and mechanisms of hypoxia sensing. Curr Opin Cell Biol 2001;13:167-171. 44. Goyal P, Weissmann N, Grimminger F, et al. Upregulation of NAD(P)H oxidase 1 in hypoxia activates hypoxia-inducible factor 1 via increase in reactive oxygen species. Free Radic Biol Med 2004;36:1279-1288. 45. Shimomura I, Matsuda M, Hammer RE, et al. Decreased IRS-2 and increased SREBP-1c lead to mixed insulin resistance and sensitivity in livers of lipodystrophic and ob/ob mice. Mol Cell 2000; 6:77-86. 46. Ide T, Shimano H, Yahagi N, et al. SREBPs suppress IRS-2-mediated insulin signaling in the liver. Nat Cell Biol 2004;6:351-357. 47. Yamashita K, Discher DJ, Hu J, et al. Molecular regulation of the endothelin-1 gene by hypoxia. Contributions of hypoxia-inducible factor-1, activator protein-1, GATA-2, AND p300/CBP. J Biol Chem 2001;276:12645-12653. 48. Chou YC, Perng JC, Juan CC, et al. Endothelin-1 inhibits insulinstimulated glucose uptake in isolated rat adipocytes. Biochem Biophys Res Commun 1994;202:688-693. 49. Roden M, Vierhapper H, Liener K, Waldhausl W. Endothelin-1stimulated glucose production in vitro in the isolated perfused rat liver. Metabolism 1992;41:290-295. 50. Teuscher AU, Lerch M, Shaw S, et al. Endothelin-1 infusion inhibits plasma insulin responsiveness in normal men. J Hypertens 1998; 16:1279-1284. 51. Peng YJ, Yuan G, Ramakrishnan D, et al. Heterozygous HIF-1α deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia. J Physiol 2006;577:705-716. 52. Cramer T, Yamanishi Y, Clausen BE, et al. HIF-1alpha is essential for myeloid cell-mediated inflammation. Cell 2003;112:645-657. 53. Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 2005;112:2660-2667.
1338 PART II / Section 13 • Sleep Breathing Disorders 54. Greenberg H, Ye X, Wilson D, et al. Chronic intermittent hypoxia activates nuclear factor-kappaB in cardiovascular tissues in vivo. Biochem Biophys Res Commun 2006;343:591-596. 55. Hayden MS, Ghosh S. Signaling to NF-kappaB. Genes Dev 2004;18:2195-2224. 56. Ryan S, Taylor CT, McNicholas WT. Predictors of elevated nuclear factor-kappaB-dependent genes in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2006;174:824-830. 57. Savransky V, Nanayakkara A, Vivero A, et al. Chronic intermittent hypoxia predisposes to liver injury. Hepatology 2007;45:1007-1013. 58. Savransky V, Bevans S, Nanayakkara A, et al. Chronic intermittent hypoxia causes hepatitis in a mouse model of diet-induced fatty liver. Am J Physiol Gastrointest Liver Physiol 2007;293:G871-G877. 59. Narkiewicz K, van de Borne PJ, Cooley RL, et al. Sympathetic activity in obese subjects with and without obstructive sleep apnea. Circulation 1998;98:772-776. 60. Hedner J, Darpo B, Ejnell H, et al. Reduction in sympathetic activity after long-term CPAP treatment in sleep apnoea: cardiovascular implications. Eur Respir J 1995;8:222-229. 61. Andrews RC, Walker BR. Glucocorticoids and insulin resistance: old hormones, new targets. Clin Sci (Lond) 1999;96:513-523. 62. Parlapiano C, Borgia MC, Minni A, et al. Cortisol circadian rhythm and 24-hour Holter arterial pressure in OSAS patients. Endocr Res 2005;31:371-374. 63. Friedman JM, Halaas JL. Leptin and the regulation of body weight in mammals. Nature 1998;395:763-770. 64. Breslow MJ, Min-Lee K, Brown DR, et al. Effect of leptin deficiency on metabolic rate in ob/ob mice. Am J Physiol 1999;276:E443E449. 65. Chin K, Shimizu K, Nakamura T, et al. Changes in intra-abdominal visceral fat and serum leptin levels in patients with obstructive sleep apnea syndrome following nasal continuous positive airway pressure therapy. Circulation 1999;100:706-712. 66. Ip MS, Lam KS, Ho C, et al. Serum leptin and vascular risk factors in obstructive sleep apnea. Chest 2000;118:580-586. 67. Ambrosini G, Nath AK, Sierra-Honigmann MR, Flores-Riveros J. Transcriptional activation of the human leptin gene in response to hypoxia. Involvement of hypoxia-inducible factor 1. J Biol Chem 2002;277:34601-34609. 68. Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans [see comments]. N Engl J Med 1996;334:292-295. 69. Maffei M, Halaas J, Ravussin E, et al. Leptin levels in human and rodent: measurement of plasma leptin and ob RNA in obese and weight-reduced subjects. Nat Med 1995;1:1155-1161. 70. Masserini B, Morpurgo PS, Donadio F, et al. Reduced levels of adiponectin in sleep apnea syndrome. J Endocrinol Invest 2006;29:700-705. 71. Zhang XL, Yin KS, Wang H, Su S. Serum adiponectin levels in adult male patients with obstructive sleep apnea hypopnea syndrome. Respiration 2006;73:73-77. 72. Zhang XL, Yin KS, Mao H, et al. Serum adiponectin level in patients with obstructive sleep apnea hypopnea syndrome. Chin Med J (Engl) 2004;117:1603-1606. 73. Nakagawa Y, Kishida K, Kihara S, et al. Nocturnal reduction in circulating adiponectin concentrations related to hypoxic stress in severe obstructive sleep apnea-hypopnea syndrome. Am J Physiol Endocrinol Metab 2008;294:E778-E784. 74. Harsch IA, Koebnick C, Wallaschofski H, et al. Resistin levels in patients with obstructive sleep apnoea syndrome—the link to subclinical inflammation? Med Sci Monit 2004;10:CR510-CR515. 75. Magalang UJ, Cruff JP, Rajappan R, et al. Intermittent hypoxia suppresses adiponectin secretion by adipocytes. Exp Clin Endocrinol Diabetes 2009;117:129-134. 76. Newman AB, Nieto FJ, Guidry U, et al. Relation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study. Am J Epidemiol 2001;154:50-59.
77. Redline S, Storfer-Isser A, Rosen CL, et al. Association between metabolic syndrome and sleep-disordered breathing in adolescents. Am J Respir Crit Care Med 2007;176:401-408. 78. Gozal D, Capdevila OS, Kheirandish-Gozal L. Metabolic alterations and systemic inflammation in obstructive sleep apnea among nonobese and obese prepubertal children. Am J Respir Crit Care Med 2008;177:1142-1149. 79. Savransky V, Jun J, Li J, et al. Dyslipidemia and atherosclerosis induced by chronic intermittent hypoxia are attenuated by deficiency of stearoyl coenzyme A desaturase. Circ Res 2008;103:11731180. 80. Chin K, Nakamura T, Shimizu K, et al. Effects of nasal continuous positive airway pressure on soluble cell adhesion molecules in patients with obstructive sleep apnea syndrome. Am J Med 2000;109: 562-567. 81. Robinson GV, Pepperell JC, Segal HC, et al. Circulating cardiovascular risk factors in obstructive sleep apnoea: data from randomised controlled trials. Thorax 2004;59:777-782. 82. Steiropoulos P, Tsara V, Nena E, et al. Effect of continuous positive airway pressure treatment on serum cardiovascular risk factors in patients with obstructive sleep apnea-hypopnea syndrome. Chest 2007;132:843-851. 83. Li J, Thorne LN, Punjabi NM, et al. Intermittent hypoxia induces hyperlipidemia in lean mice. Circ Res 2005;97:698-706. 84. Li J, Savransky V, Nanayakkara A, et al. Hyperlipidemia and lipid peroxidation are dependent on the severity of chronic intermittent hypoxia. J Appl Physiol 2007;102:557-563. 85. Savransky V, Nanayakkara A, Li J, et al. Chronic intermittent hypoxia induces atherosclerosis. Am J Respir Crit Care Med 2007;175:1290-1297. 86. Li J, Nanayakkara A, Jun J, et al. Effect of deficiency in SREBP cleavage-activating protein on lipid metabolism during intermittent hypoxia. Physiol Genomics 2007;31:273-280. 87. Wilcox I, McNamara SG, Collins FL, et al. “Syndrome Z”: the interaction of sleep apnoea, vascular risk factors and heart disease. Thorax 1998;53(Suppl. 3):S25-S28. 88. Coughlin SR, Mawdsley L, Mugarza JA, et al. Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome. Eur Heart J 2004;25:735-741. 89. Vgontzas AN, Bixler EO, Chrousos GP. Sleep apnea is a manifestation of the metabolic syndrome. Sleep Med Rev 2005;9:211224. 89a. Drager LF, Lopes HF, Maki-Nunes C, et al. The impact of obstructive sleep apnea on metabolic and inflammatory markers in consecutive patients with metabolic syndrome. PLoS One 2010; 5:e12065. 90. Tanne F, Gagnadoux F, Chazouilleres O, et al. Chronic liver injury during obstructive sleep apnea. Hepatology 2005;41:12901296. 91. Jouet P, Sabate JM, Maillard D, et al. Relationship between obstructive sleep apnea and liver abnormalities in morbidly obese patients: a prospective study. Obes Surg 2007;17:478-485. 92. Kallwitz ER, Herdegen J, Madura J, et al. Liver enzymes and histology in obese patients with obstructive sleep apnea. J Clin Gastroenterol 2007;41:918-921. 93. Norman D, Bardwell WA, Arosemena F, et al. Serum aminotransferase levels are associated with markers of hypoxia in patients with obstructive sleep apnea. Sleep 2008;31:121-126. 94. Chin K, Nakamura T, Takahashi K, et al. Effects of obstructive sleep apnea syndrome on serum aminotransferase levels in obese patients. Am J Med 2003;114:370-376. 95. Polotsky VY, Patil SP, Savransky V, et al. Obstructive sleep apnea, insulin resistance, and steatohepatitis in severe obesity. Am J Respir Crit Care Med 2009;179:228-234. 96. Shpirer I, Copel L, Broide E, Elizur A. Continuous positive airway pressure improves sleep apnea associated fatty liver. Lung 2010; 188:301-307.
Obstructive Sleep Apnea, Obesity, and Bariatric Surgery Eric J. Olson and Anita P. Courcoulas Abstract Excessive body weight is a growing global health issue. In the United States, two out of three adults weigh more than their ideal body weight. Obesity predicts increased morbidity and mortality. One of the health conditions that adiposity has a significant impact on is obstructive sleep apnea. Inconsistent results from dietary, behavioral, and pharmacologic weight loss therapies has led to increasing interest in bariatric surgery, which encompasses a variety of abdominal opera-
The increasing prevalence of individuals who weigh more than their ideal body weight is a worldwide health concern, with significant medical, psychological, and economic ramifications. In adults, overweight and obesity have been traditionally defined by the body mass index (BMI), which is the quotient of the weight in kilograms divided by the height in meters squared. Table 115-1 depicts the National Heart, Lung, and Blood Institute’s weight classification system for adults who are overweight, defined as a BMI of 25 to 29.9 kg/m2, and obese, defined as a BMI of 30 kg/m2 or more.1 Excess abdominal fat, defined by a waist circumference of greater than 40 inches (>102 cm) in men and greater than 35 inches (>88 cm) in women, is an independent predictor of risk for type 2 diabetes mellitus, dyslipidemia, hypertension, and cardiovascular disease in adults with a BMI between 25 and 34.9 kg/m2.1 Overweight and obesity are a result of a complex interplay of genetic and sociocultural forces that lead to long-term positive energy balance.2 Obesity is associated with myriad complications, including obstructive sleep apnea (OSA). Obesity is one of the most important risk factors for OSA.3 Excessive body weight may increase propensity for upper airway narrowing during sleep by altering the function and the geometry of the pharynx.3 In addition, obesity may alter ventilatory control and respiratory muscle function, leading to obesity hypoventilation syndrome (OHS), which is characterized by the combination of obesity, chronic hypercapnia (in the absence of another identifiable cause), and usually some component of OSA (see Chapter 112).4 Treatment for OSA includes continuous positive airway pressure (CPAP), oral appliances, upper airway surgeries, and risk factors modifications, including weight loss. For patients who are motivated to lose weight, the initial treatments include dietary modifications to reduce energy intake, enhanced physical activity to increase energy expenditure, and behavioral therapies to overcome barriers to compliance.1 Pharmacotherapy may be considered for patients with a BMI of 30 kg/m2 or more, or for those with a BMI of 27 kg/m2 or more and obesity-related disease who fail to achieve their weight loss targets after 6 months of diet and lifestyle changes.1 Surgical therapy for obesity, or bariatric surgery, is indicated for morbidly obese, wellmotivated individuals who have failed other attempts at nonsurgical approaches to weight control. Some bariatric
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tions that restrict caloric intake or absorption, or both. Approximately 200,000 bariatric operations were performed in the United States in 2007. This chapter focuses on bariatric surgery, an appropriate issue for the provider of sleep medicine care given the frequency with which coexistent obesity and sleep-disordered breathing are encountered in routine clinical sleep practice and the important role for the sleep specialist in a comprehensive perioperative bariatric care program.
procedures restrict food intake and others induce malabsorption or maldigestion.5 The number of bariatric procedures being performed has increased dramatically as a result of the rise of severe obesity and refinement of operative techniques. This chapter explores the epidemiology of overweight and obesity, potential mechanisms linking overweight and obesity with OSA, indications for bariatric surgery, technical aspects of common bariatric procedures, perioperative management of OSA, and outcomes of bariatric surgery, including its impact on OSA.
EPIDEMIOLOGY Epidemiology of Overweight and Obesity According to the latest National Health and Nutrition Examination Survey (NHANES), 66.2% of U.S. adults are overweight, 32.9% are obese, and 4.8% have class 3 obesity (see Table 115-1).6 Between 1980 and 2007 the prevalence of obesity doubled (15% to 31%), and the prevalence of class 3 obesity nearly quadrupled (1.4% to 5%).7 Figure 115-1 shows further worsening of the state-specific prevalence of obesity in 2009.8 By 2015, an estimated 75% of United States adults will be overweight or obese, and 41% will be obese.9 Obesity rates are highest amongst nonHispanic black adults, followed by Mexican Americans and then non-Hispanic whites.6 Obesity prevalence is much lower among Asian Americans, and rates in Native Americans are similar to those in non-Hispanic blacks.10 Data from the Framingham Heart Study attributed a reduction in life expectancy of 7.1 years in nonsmoking women and 5.9 years in nonsmoking men at age 40 to obesity,11 with the increased mortality resulting primarily from cardiovascular disease.12 Epidemiologic Association between Overweight/Obesity and OSA Cross-sectional analyses of clinical and population samples have demonstrated notable co-localization of OSA and obesity.3 OSA has been found in 50% to 80% of obese clinical patients,3 and 60% to 90% of adults with OSA may be overweight.13 In the Wisconsin Sleep Cohort, an increase of 1 standard deviation in BMI was associated with a fourfold risk of an apnea–hypopnea index (AHI) of 5 or 1339
1340 PART II / Section 13 • Sleep Breathing Disorders
greater.14 Furthermore, the Sleep Heart Health Study reported a dose-dependent relationship between increasing BMI and OSA, as the prevalence of an AHI of 15 or greater was 10% in the lowest BMI quartile (16 to 24 kg/m2) as opposed to 32% in the highest quartile (32 to 59 kg/m2).15 Longitudinal population and clinical samples also indicate that weight and AHI change congruently. In the Wisconsin Sleep Cohort, each 1% increase (decrease) in weight was associated with a 3% increase (decrease) in AHI, and in individuals with mild obstructive sleep apnea (AHI, 5 to 15) at baseline, a 10% weight gain led to a
Table 115-1 Classification of Overweight and Obesity by Body Mass Index BODY MASS INDEX kg/m2 Underweight Normal Overweight
<18.5 18.5-24.9 25-29.9
Obesity Class 1
30-34.9
Class 2
35-39.9
Class 3 (extreme)
≥40
From North American Association for the Study of Obesity and the National Heart, Lung, and Blood Institute. The practical guide: identification, evaluation, and treatment of overweight and obesity in adults. Bethesda, Md: National Institutes of Health, 2000. NIH publication 00-4084; available at: http://www.cdc.gov/ nccdphp/dnpa/obesity/defining.htm.
sixfold risk for developing moderate to severe OSA (AHI ≥ 15).16 In the Sleep Heart Health Study, parallel changes in weight and AHI were found over 5 years of follow-up, but AHI increased more with weight gain than it decreased with weight loss.17 Men tend to get a greater increase in AHI from weight gain than women,17 whereas BMI has a greater effect on AHI in postmenopausal women than in premenopausal women.3 Increasing age may mute the association of BMI and AHI.15
PATHOGENESIS Mechanism Linking Obesity to OSA Risk Upper airway anatomic and neuromuscular factors may be influenced by parapharyngeal fat accumulation in several ways.18 Obesity may compress upper airway size by the deposition of adipose tissue, especially in the lateral pharyngeal fat pads, intraluminal structures (tongue, soft palate, uvula), and neck.19-23 During wakefulness, increased pharyngeal dilator muscle activity provides compensation, yet the state-dependent attenuation of pharyngeal muscle activity with sleep leaves the upper airway vulnerable to collapse.24 Fat around the upper airway may alter soft tissue properties and thereby heighten the propensity to collapse by increasing upper airway compliance,25,26 or change upper airway geometry3 and thus decrease the ability of pharyngeal muscles to dilate the airway.27 Other purported local mechanistic links include obesity, a chronic inflammatory state itself, directly increasing upper airway tissue inflammation28 or indirectly inducing of upper airway neuropathic damage via diabetes mellitus.29
THE PREVALENCE OF OBESITY (BMI ≥ 30) AMONG U.S. ADULTS, 2009
DC
15%–19% 20%–24% 25%–29% ≥30% Figure 115-1 State-specific prevalence of obesity among adults in the United States, 2009. Only Colorado had an obesity prevalence of less than 20%, whereas nine states (Alabama, Mississippi, and Tennessee) had an obesity prevalence of 30% or greater. (From Centers for Disease Control and Prevention; available at: http://www.cdc.gov/obesity/data/trends.html.)
CHAPTER 115 • Obstructive Sleep Apnea, Obesity, and Bariatric Surgery 1341
The pathogenic importance of abdominal viscera fat accumulation in patients with OSA is highlighted by population surveys reporting a twofold to threefold increase in prevalence of symptomatic OSA in men compared with women,14,30 as men typically have a central distribution of fat involving the neck, trunk, and abdominal viscera, whereas women are more likely to deposit fat in the lower body and extremities. The interaction of hormonal changes and accompanying increases in central fat deposition may contribute to the increased prevalence of OSA in postmenopausal women.3 Central obesity-induced reduction in lung volume31 decreases “tracheal tug,” a caudally directed, pharyngeal stabilizing, lung volume–dependent traction force directed via the trachea.32 The reduction in lung volumes coupled with globally increased oxygen demand may also promote the desaturation that accompanies apneas and hypopneas. There is an evolving discussion regarding the existence of a bidirectional relationship between obesity and OSA. The intermittent hypoxia, sympathetic activation, and sleep fragmentation caused by repetitive apneas and hypopneas produce metabolic alterations that provide biologically plausible means by which OSA may also exacerbate overweight/obesity (see Chapter 114). In summary, the pathogenic interactions between obesity and OSA are complex and not fully explored, leaving the subject open for debate.13
TREATMENT Bariatric Surgery for Medically Complicated Obesity An overall approach to obesity is described in Chapter 112. Bariatric surgery has emerged in the context of the growing prevalence of severe obesity, heightened concern about the associated comorbid medical conditions, and the limited success of traditional weight loss approaches of diet, exercise, and behavior modification. Although the number of bariatric procedures performed is increasing, only 1% of the clinically eligible patients are being treated for medically complicated obesity in this manner.33 Lack of access to bariatric surgery is results from many unstudied factors, including lack of insurance coverage, poor understanding of the procedures and their effects, and cost. Facility costs range from $10,000 to $15,000 per bariatric surgery case.34 Patient Selection Bariatric surgery should be considered as a treatment option for severely obese patients who have instituted but failed an adequate exercise and diet program, and who have a BMI of 40 kg/m2 or more, or a BMI of 35 kg/m2 or more, in conjunction with one or more obesity-related severe comorbid conditions.1 Obesity-associated comorbid conditions include diabetes mellitus, hypertension, dyslipidemia, coronary artery disease, pseudotumor cerebri, OSA, asthma, venous stasis, severe urinary incontinence, debilitating arthritis, gastroesophageal reflux disease, and nonalcoholic fatty liver disease.35 Patients preparing to undergo bariatric surgery must complete nutritional and psychological evaluation screening to rule out untreated depression, substance abuse, or a history of untreated eating disorders. The potential
bariatric patient must demonstrate a complete understanding of the risks and benefits of the operation as a weight loss “tool,” recognize the ongoing necessity to limit portion size and food types, and agree to follow a postoperative vitamin supplementation regimen. Patients should be deemed ineligible for surgery if they cannot understand or will not commit to the dietary changes and lifestyle modifications necessary to complement the procedure. In addition, poor surgical or anesthetic risk status (advanced congestive heart failure or suboptimally controlled angina), very advanced age, reversible endocrine or other disorders that might cause obesity, and active addiction behaviors are contraindications to bariatric surgery. The selection criteria for bariatric surgery are summarized in Table 115-2.35 Patient Assessment for OSA before Bariatric Surgery OSA is common in patients preparing for bariatric surgery. OSA prevalences up to 90% have been reported in patients considered for bariatric surgery,36 yet the true prevalence
Table 115-2 Patient Selection Criteria for Bariatric Surgery FACTOR
CRITERIA
Weight (adults)
BMI ≥ 40 kg/m2 with no comorbidities BMI ≥ 35 kg/m2 with obesityassociated comorbidity
Weight loss history
Failure of previous nonsurgical attempts at weight reduction, including nonprofessional programs (e.g., Weight Watchers)
Commitment
Expectation that patient will adhere to postoperative care Follow-up visits with physician(s) and team members Recommended medical management, including use of dietary supplements Instructions regarding any recommended procedures or tests
Exclusion
Reversible endocrine or other disorders that can cause obesity Current drug or alcohol use Uncontrolled, severe psychiatric illness Lack of comprehension of risks, benefits, expected outcomes, alternatives, and lifestyle changes required with bariatric surgery
From Mechanick JI, Kushner RF, Sugerman HJ, et al. American Association of Clinical Endocrinologists, the Obesity Society, and American Society of Metabolic and Bariatric Surgery medical guidelines for clinical practice for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient. Endocr Pract 2008;14(Suppl 1):1-83, with permission from the American Association of Clinical Endocrinologists.
1342 PART II / Section 13 • Sleep Breathing Disorders
is difficult to know because polysomnography is typically reserved for symptomatic patients in case series. It is important to diagnose OSA before bariatric surgery for a number of reasons. OSA patients may be more difficult to intubate, and the commonly used perioperative drugs have inhibitory influences on central ventilatory drive, protective upper airway reflexes, and arousal mechanisms, which may further jeopardize the already vulnerable airway of the severely obese patient. Postendotracheal intubation upper airway edema, forced supine positioning, and temporary suspension of CPAP because of postoperative circumstances can acutely aggravate the severity of OSA after bariatric surgery. The interaction of obesity-related reduction of pulmonary functional residual capacity with the postoperative milieu may magnify ventilation–perfusion mismatching and thereby worsen gas exchange from untreated sleep-disordered breathing events, which may lead to myocardial ischemia or arrhythmias, altered mental status, unplanned intensive care unit transfers, respiratory arrest, or death.37 Therefore, close collaboration between sleep specialist, anesthesiologist, bariatric surgeon, and bariatric patient is crucial for proper planning to mitigate OSA-related complications perioperatively. The diagnostic features of OSA are discussed in Chapters 57 and 105. No cardinal symptom of OSA, such as snoring or excessive daytime sleepiness, is singularly sufficient to predict OSA or its severity in bariatric candidates. Furthermore, there is not a single best metric of body habitus for predicting OSA.3 Instead, a combination of symptoms and signs is more discriminatory. Prediction formulas for OSA exist, but they have not been prospectively tested in bariatric surgery candidates, although preoperative screening with one model38 has been shown to predict risk for oxygen desaturation after discharge from the postanesthesia care unit (PACU) in a nonbariatric postoperative population.39 The American Academy of Sleep Medicine (AASM) has concluded that no clinical model is recommended for use to predict severity of OSA.40 Given the high prevalence of OSA in severely obese patients, the potential for perioperative complications from unrecognized OSA, and the limited accuracy of clinical impression alone in OSA diagnosis, it has been argued that all bariatric surgery candidates should undergo a sleep study. Maintaining a low threshold for further evaluation of possible OSA certainly seems prudent, and bariatric candidates suspected of having OSA should be evaluated preoperatively by a sleep specialist. Perioperative bariatric surgery clinical practice guidelines published jointly by the American Association of Clinical Endocrinologists, the Obesity Society, and the American Society of Metabolic and Bariatric Surgery35 recommend consideration of OSA as part of a system-oriented approach to medical clearance for surgery, beginning with a history and examination to identify symptoms and signs that are consistent with OSA and proceeding to polysomnography if sleep-disordered breathing is suspected or hypercapnia is discovered. A laboratory-based, technologist-attended polysomnogram remains the diagnostic gold standard for OSA.40 The role for unattended portable cardiorespiratory monitoring for the diagnosis of OSA continues to evolve, but the adult bariatric surgery candidate with a high pretest probability of moderate to severe OSA and without significant comor-
bid cardiopulmonary disease may be a candidate for home sleep diagnostic testing.41 A high index of suspicion should be maintained for OHS, as these patients require more careful presurgical preparation. OHS (as opposed to pure OSA) may be suggested by manifestations such as increased dyspnea, lower extremity edema, higher serum bicarbonate, and lower oxyhemoglobin saturation on pulse oximetry.4 If OHS is suspected, the following tests are recommended: arterial blood gas, pulmonary function tests, chest radiograph, echocardiogram, and thyroid function tests (if not already ordered as part of routine testing of the obese patient). Patients with OHS should be studied with laboratory-based polysomnography, not portable monitoring, because approximately half will require supplemental oxygen in addition to positive airway pressure (PAP) therapy, and many will require bilevel PAP4 (see Chapters 107 and 112). The elective nature of bariatric surgery should allow for follow-up of PAP therapy in the patient with newly diagnosed OSA or OHS before surgery. In many bariatric centers, adherence to PAP for the candidate with OSA is a mandatory prerequisite for surgery, and thus failure to comply with PAP is a deal-breaker. The minimal preoperative PAP trial duration is not known, but because patterns of CPAP use may be established within the first week of therapy,42 close follow-up in the first few weeks to document adherence, address problems, and assess response is advised.43 In the patient with OHS, a repeat measurement of arterial blood gases after 4 weeks of PAP therapy4 may allow discontinuance of supplemental oxygen in the patient responding to PAP or indicate the need for tracheostomy with or without ventilation in the failing patient. Assessment of the Patient with Established OSA before Bariatric Surgery Patients with a known diagnosis of OSA and who are already established on PAP at the time they begin to explore the option of bariatric surgery should be asked preoperatively about compliance, technical difficulties, persistent symptoms despite PAP, and changes in weight since their last sleep evaluation. An affirmative response to any of these questions should prompt referral to a sleep specialist. Follow-up polysomnography is indicated for patients with substantial weight gain (≥10% of body weight) and recurrent OSA symptoms despite PAP adherence.40 Asymptomatic, PAP-adherent patients can proceed to surgery. They should be advised that PAP use will be required postoperatively and that they should bring their equipment to the hospital.44 Those OSA patients treated previously with upper airway surgery who remain symptomatic or who do not have objective evidence of sleepdisordered breathing resolution should be assumed to remain at risk and may benefit from a preoperative evaluation by a sleep specialist before bariatric surgery.45,46 Such patients should be advised that temporary application of PAP may be necessary in the immediate postoperative period if upper airway obstruction occurs. The possibility of temporary PAP after surgery should also be discussed with bariatric candidates who use an oral appliance for OSA, as it may not be feasible to use their dental device immediately postoperatively.
CHAPTER 115 • Obstructive Sleep Apnea, Obesity, and Bariatric Surgery 1343
Common Bariatric Surgical Procedures Bariatric surgery procedures can be grouped into three categories: predominately malabsorptive procedures, predominately restrictive procedures, and procedures with both malabsorptive and restrictive components. All procedures modify the gastrointestinal tract in an effort to reduce nutrient intake or absorption or both. One of the most frequently performed bariatric procedures in the United States is a hybrid procedure of gastric restriction and limited malabsorption known as a Roux-en-Y gastric bypass (RYGB) (Fig. 115-2). A traditional RYGB consists of a small (15-mL) proximal gastric pouch transected along the lesser curvature of the stomach from the larger gastric segment, combined with a modest (60 to 150 cm) intestinal bypass. The Roux-en-Y configuration allows for biliopancreatic secretions and digestive juices to pass via the bile duct into the duodenum and then merge with the alimentary stream passing down from the stomach at the Y-type connection. The lengths of both the Roux and biliopancreatic limbs can be varied to produce more malabsorption, which is associated with greater weight loss in the “superobese” patient (i.e., with a BMI of >50 kg/m2). Today, RYGB is most commonly performed via a minimally invasive laparoscopic, rather than open, approach. Most weight is lost in the first year, with long-term weight loss stabilizing at 2 to 3 years. Typically, 80% of patients experience weight stabilization slightly above weight nadir approximately 3 years after surgery. The remaining patients slowly regain more excess weight over longer-term followup, and they risk becoming surgical failures. Another bariatric procedure that has grown increasingly popular worldwide is the strictly restrictive laparoscopic adjustable gastric banding procedure. The gastric band is an inflatable silicone prosthetic device that is placed around the top portion of the stomach, just below the esophagus (Fig. 115-3). The band is attached to a reservoir, with a port placed under the skin on the abdominal wall, and the inner lining of the band is a balloon that is adjustable by the addition or removal of saline from the reservoir port. Inflation of the band increases the restriction of gastric
outlet size and food flow. Postoperative management for adjustable gastric band patients requires frequent followup visits for band adjustments and strict adherence to dietary guidelines and lifestyle modification to achieve consistent weight loss. The weight loss trajectory after banding procedures is more gradual than weight loss after bypass and continues for a period of 3 years, but the two procedures result in similar long-term weight loss results. The favorable aspects of this procedure are that it is less invasive, requires less operating time, and is both adjustable and removable. The less commonly used biliopancreatic diversion (BPD) and BPD with duodenal switch (BPDDS) are extremely malabsorptive procedures for the treatment of the very “superobese” patients. BPD combines a partial, subtotal gastrectomy and a very long Roux-en-Y anastomosis with a short common channel for nutrient absorption. With this procedure, patients can eat much larger quantities of food and still achieve and maintain weight loss. Disadvantages to the procedure include loose and foul smelling stools, intestinal ulcers, anemia, vitamin and mineral deficiencies, and possible protein-calorie malnutrition. Because of these potential problems, BPD patients require lifelong supplementation and close follow-up. With similar weight loss and complications, the BPDDS is a hybrid operation that combines a gastric sleeve resection (70% greater-curve gastrectomy) with a long intestinal bypass in the Roux-en-Y configuration. In this procedure, ulcer rate is reduced and dumping syndrome (the constellation of nausea, vomiting, abdominal pain or cramping, diarrhea, bloating, fatigue, palpitations, lightheadedness, sweating, and anxiety beginning within 15 to 30 minutes after eating) is eliminated by leaving the first portion of the intestine in the alimentary stream. Both the BPD and BPDDS can also be performed laparoscopically. BPD and BPDDS procedures are clearly the most major and technically difficult procedures performed for weight loss and consequently should be offered only by experienced surgeons and should entail lifelong comprehensive surgical weight loss programs.
Figure 115-2 Roux-en-Y gastric bypass.
Figure 115-3 Gastric band procedure.
1344 PART II / Section 13 • Sleep Breathing Disorders
Despite a substantive body of literature, debate still continues regarding the selection of procedure type for any given patient. Patients are provided with general guidelines about the different mechanisms of action, percent weight loss over time, and morbidity profile between procedures when making a final decision toward surgery. The optimal choice of procedure depends, in part, on the expertise of the surgeon and the institution, patient preference, and risk stratification.35
CLINICAL COURSE Management of OSA Immediately after Bariatric Surgery Many details of optimal care of the bariatric patient with OSA immediately after surgery remain unclear. The following general recommendations are based on experience, consensus expert opinion for generic surgical care published by the AASM45 and the American Society of Anesthesiologists,46 and limited peer-reviewed literature. Airway extubation after bariatric surgery should be performed only when the patient is fully awake and alert and has demonstrated evidence of returned neuromuscular function (as evidenced by sustained head-lift for more than 5 seconds) and adequate vital capacity and peak inspiratory pressure.45 Removal of the endotracheal tube should take place in the operating room, PACU, or special care unit so that airway control can be monitored closely and expertly addressed if lost.45 The patient should be maintained in the semiupright or lateral, not supine, position and should undergo continuous cardiorespiratory monitoring. Immediate application of PAP with or without a nasopharyngeal airway will help prevent upper airway collapse. PACU staff must be capable of monitoring and responding to PAP therapy, including addressing interface leaks and observing diligently for signs of breakthrough upper airway obstruction despite PAP, such as snoring, choking, witnessed apneas, cardiac dysrhythmias, or frequent desaturation. In the first 24 postoperative hours, patients are the most vulnerable with respect to the potential for OSArelated complications,37 although OSA propensity may be increased for at least several days after bariatric surgery because of the aggregate effects of ongoing sleep deprivation, rapid eye movement sleep rebound, and medication synergies.45 Fortunately, the length of hospital stay is usually short (3.5 days and 1.6 days for gastric bypass and restrictive procedures, respectively47). Nevertheless, providers must keep OSA in mind as they consider postoperative analgesia, monitoring, oxygenation, and patient positioning46 for the duration of the hospitalization. Systemic opioids should be used cautiously because of their ability to depress the respiratory drive and cause subsequent oxygen desaturation. The use of patient-controlled analgesia is controversial, although it may be option if it is used without a basal rate and with restricted dosing. Nonsteroidal antiinflammatory agents may help decrease opioid dosing as recovery progresses but should be used cautiously in the postsurgical patient because of the enhanced potential for bleeding complications. Benzodiazepines should be avoided because of their negative effects on the respiratory control and upper airway mus-
culature. Access to PAP should be available at all times44 during recovery, a seemingly obvious recommendation but one that may be overlooked by busy house staff, nurses unfamiliar with PAP, and patients distracted by their debilitation. Properly trained health care staff should be readily available to assist patients in PAP placement, to troubleshoot interface problems, to observe for breakthrough upper airway obstruction, and to reassure patients struggling with PAP. Continuous pulse oximetry monitoring after discharge from the PACU is recommended for as long patients are deemed at increased risk, which may be defined as the duration of intravenous opioid use. Oximetry data should be continuously observed at the bedside in a critical care or stepdown unit, by telemetry on a hospital ward, or by a dedicated, trained observer in the patient’s room. Choosing the optimal monitoring site will depend on the interplay of the severity of underlying OSA or OHS, opioid requirements, and availability of local resources. Incentive spirometry should be encouraged. If desaturations despite PAP are noted, supplemental oxygen should be added while the provider searches for an explanation, such as transient worsening of upper airway obstruction requiring a PAP adjustment, venous thromboembolic event, atelectasis, aspiration, pneumonia, or anastomotic leak. Use of supplemental oxygen without PAP during sleep should be avoided, as this provides no protection against upper airway obstruction and will blunt detection of a disordered-breathing event by oximetry monitoring. Patients should avoid the supine position and instead keep the head of the bed elevated in a semi-Fowler position (to at least 30 degrees) at all times. Venous thromboembolic disease, which can occur after laparoscopic and open procedures, is the most common cause of postoperative mortality,48 so thromboprophylaxis is indicated with low-molecular-weight heparin, low-dose unfractionated heparin three times daily, or fondaparinux, with or without intermittent pneumatic compression stockings.49 In the University HealthSystem Consortium evaluation, a review of the bariatric programs at 29 academic medical centers in the United States, 7.7% of patients undergoing gastric bypass and 1.1% of patients undergoing a restrictive procedure required intensive care unit (ICU) support postoperatively.5 Clinical practice guidelines for bariatric surgery35 conclude that “no consensus exists about which type of patient should be considered for admission to the ICU after bariatric surgery.” It would seem reasonable to consider ICU care for the first 24 to 48 hours for bariatric patients with one or more of the following features: age greater than 50, BMI greater than 60 kg/m2, significant comorbid cardiopulmonary disease, brittle diabetes mellitus, worrisome record of PAP compliance, sluggish emergence from anesthesia, and intraoperative complications. Some patients may not require an ICU stay.49a Prolonged respiratory failure after bariatric surgery is uncommon, occurring in less than 1% of cases.48 Benefits of Bariatric Surgery Postoperative weight loss is typically reported as the mean percentage of excess weight loss, defined by the following formula:
( weight loss ÷ excess weight ) × 100,
CHAPTER 115 • Obstructive Sleep Apnea, Obesity, and Bariatric Surgery 1345
where excess weight equals total preoperative weight minus ideal weight. In a review of 136 studies involving 22,000 bariatric surgery patients, Buchwald and colleagues50 reported that the mean percentage of excess weight loss with bariatric surgery was 61.2%: 47.5% for gastric banding, 68.2% for gastric bypass (principally Roux-en-Y gastric bypass [RYGB]), and 70.1% for BPD and BPDDS.50 The mean decrease in BMI was 14.2 kg/ m2, whereas the mean decrease in absolute weight was 39.7 kg, similar to the 20- to 30-kg weight loss reported in the meta-analysis by Maggard and colleagues.51 Comorbidities correspondingly improved. Diabetes mellitus completely resolved in 76.8%, hyperlipidemia improved in 70%, and hypertension improved or resolved in 78.5%.50 A retrospective cohort study comparing long-term mortality among 7925 patients who underwent gastric bypass and 7925 age-, sex-, and BMI-matched controls demonstrated a 40% reduction in adjusted long-term mortality with bariatric surgery during a mean follow-up of 7.1 years.52 No large randomized trials have compared bariatric surgery with medical management of obesity. The Swedish Obesity Study53 was a large, prospective, nonrandomized, controlled trial that compared 2010 obese subjects treated with bariatric surgery, and 2037 contemporaneously matched obese controls treated conventionally. At 2 years, weight had decreased by 23.4% in the surgery group but had increased by 0.1% in the control group, and after 10 years, the weight had decreased by 16.1% in the surgery group but had increased by 1.6% in controls (P < .001 at both time points). Improvements in diabetes, hypertriglyceridemia, and hypertension were more favorable in the surgery group, and the surgery group had lower 2- and 10-year incident rates of diabetes than controls. Maximal weight losses in the surgical group were observed after 1 to 2 years, and at 10 years the maximal average losses were 32% for gastric bypass, 25% for vertical banded gastroplasty, and 20% for banding.53 Overall mortality was lower in the surgery group.54 Long-Term Impact of Bariatric Surgery on OSA Weight loss induced by bariatric surgery is consistently associated with reductions in AHI.55 Buchwald and coworkers’ meta-analysis50 of selected bariatric surgery outcomes reported that OSA resolved or improved in 83.6%. The weighted mean change in the AHI was 40, with a range of 16 to 52.8. Enthusiasm over these results must be tempered by several methodological concerns. Improvement and resolution with respect to OSA were not explicitly defined. The studies included in the meta-analysis are not entirely specified but a review of studies from the inclusion period (1990 to June 2003) reveals that symptomatic reduction was probably sufficient in some studies to assess OSA response (i.e., postoperative polysomnography was not required in all subjects), the timing of polysomnography after surgery was nonuniform, and the results were most likely variably reported (e.g., only preoperative and postoperative apnea indices were described, not AHIs). Studies published since June 200356-60 corroborate earlier series reporting that surgically induced weight loss is associated with improvement in OSA approximately 1 year or longer after surgery. However, many patients have residual
OSA. Even though bariatric surgery resulted in a mean AHI reduction of 23.4, Lettieri and colleagues60 found that 23 patients (96%) still met criteria for OSA (AHI > 5), 20 (83%) continued to experience transient nocturnal hypoxia (oxyhemoglobin saturation < 90%), and 13 (54%) had persistent sleepiness (Epworth Sleepiness Scale scores, >10) despite an average weight loss of 54 kg at a mean of 418 days postoperatively. In the series of Valencia-Flores,57 15 patients (54%) had a postoperative AHI of greater than 5. A pervasive limitation of these studies is the lack of followup polysomnography in all patients (24% to 60% followup polysomnogram rates), which may introduce selection bias. Health care providers must therefore remain vigilant for persistent OSA with a systematic postoperative followup program, as dramatic changes in weight and symptoms do not guarantee cure of OSA. The optimal timing for postoperative polysomnography is not clear, but it depends, in part, on the patient’s weight loss evolution. The CPAP requirement for residual OSA is likely to fall by at least 2 to 4 cm H2O in the year after surgery.59-61 Autotitrating CPAP after surgery may bridge the patient to their polysomnogram and obviate empiric pressure reductions or serial sleep studies.61 The AASM concluded that bariatric surgery may be adjunctive in the treatment for OSA, but it rates this recommendation as an option, meaning that bariatric surgery is of uncertain clinical use for OSA.62 This designation is based on the lack of data at the Sackett level of evidence I to III, the potential for perioperative complications, and a recognition of the possibility for long-term OSA recurrence without concurrent weight gain.63 Risks and Complications of Bariatric Surgery According to the meta-analysis by Buchwald and colleagues,50 operative mortality, defined as death within the first 30 days, was 0.1% for purely restrictive procedures, 0.5% with gastric bypass, and 1.1% with BPD or BPDDS. Factors that increase risk for mortality include surgical inexperience, greater patient age, BMI of 50 kg/m2 or greater, and comorbidities.5 The University HealthSystem Consortium evaluation, which included 1143 bariatric surgery procedures performed between October 2003 and March 2004, revealed a 30-day mortality rate of 0.4% for gastric bypass procedures (76% performed laparoscopically) and 0% for restrictive procedures (92% performed laparoscopically).47 For gastric bypass procedures, the 30-day readmission rate was 6.6% and the overall complication rate was 16%. For restrictive procedures, the 30-day readmission rate was 4.3% and the overall complication rate was 3.2%.47 Box 115-1 lists the postoperative adverse events from bariatric surgery, which can be grouped as early and late phenomena. A dreaded complication is anastomotic leak. In the University HealthSystem Consortium evaluation,47 the anastomotic leak rate for gastric bypass procedures was 1.6%. The extent to which OSA is linked to complications after bariatric surgery is not fully known. In a review of more than 3000 patients, OSA was found to be an independent predictor for anastomotic leak,64 whereas OSA, hypertension, and surgeon experience were identified as predictors of postoperative complications in a series of
1346 PART II / Section 13 • Sleep Breathing Disorders Box 115-1 Complications of Bariatric Surgery Complications Common to All Bariatric Procedures Early (<30 days) Venous thromboembolic disease Bleeding Anastomotic leaks Wound infections Persistent nausea/vomiting, dehydration Regional abdominal organ trauma Incisional and internal hernias Bowel obstruction Atelectasis Pneumonia Cardiac dysrhythmias Urinary tract infection Death Late (>30 days) Incisional and internal hernias Bowel obstruction from adhesions Nutritional deficiencies Anastomotic strictures and marginal ulcers or erosions Cholelithiasis Anemia Persistence/recurrence of obstructive sleep apnea Need for body contouring Weight regain Procedure-Unique Complications Roux-en-Y Gastric Bypass Dumping syndrome Laparoscopic Adjustable Gastric Banding Band slippage or erosion Port or device malfunction Biliopancreatic Diversion Loose, foul-smelling stools Protein-calorie malnutrition
more than 300 bariatric surgery patients.65 Accordingly, OSA has been linked to increased cost of postoperative care66 and higher risk for prolonged postoperative hospital stay.67 However, other investigators have not identified OSA as an independent predictor of complications after bariatric surgery.68-70 These reports are challenging to interpret and compare because of operative differences and uncertainty over how OSA was managed postoperatively.
PITFALLS AND CONTROVERSY Although a PAP regimen starting before surgery and continued immediately after extubation can markedly reduce the negative effects of sleep-disordered breathing, concerns exist regarding the use of PAP after upper intestinal surgery. Some have avoided application of PAP immediately after surgery because of concern that high levels of positive pressure may inflate the stomach and intestinal loops and increase the risk for anastomotic disruption and leakage. However, in a large prospective series of 1067 bariatric surgery patients, 159 of whom were receiving
CPAP treatment after bariatric surgery for known OSA, there was no increase in anastomotic leak related to CPAP use.71 In another series,72 an increase in number of anastomotic leaks was not reported with empiric bilevel PAP after gastric bypass. Therefore, it appears that PAP immediately after surgery is safe for the bariatric surgery patient with known OSA.
SUMMARY Obesity is a leading cause of preventable disease and death, and its prevalence is increasing. Sixty-six percent of Americans are currently overweight or obese, and the percentage is likely to reach 75% by 2015. Rates of overweight and obesity are higher in Mexican Americans and nonHispanic black Americans than in non-Hispanic whites. Excess weight is the strongest risk factor for OSA because of adverse impacts on upper airway neuromuscular function and anatomy. Bariatric surgery, a variety of procedures that limit food absorption or restrict intake (or both), is indicated for severely obese patients who have instituted but failed an adequate exercise and diet program and who have either a BMI of 40 kg/m2 or more, or a BMI of 35 kg/m2 or more in conjunction with one or more obesity-related severe comorbid conditions. The mean percentage of excess weight loss with bariatric surgery is approximately 60%, and major obesity-related conditions, such as diabetes mellitus and hypertension, consistently improve. Thirty-day mortality of bariatric surgery is less than 1%, and adverse events occur in approximately 20% of cases. ❖ Clinical Pearls The sleep clinician should be mindful that bariatric surgery patients are likely to have OSA, which requires careful consideration during preoperative evaluation as well as in the immediate postoperative and perioperative periods. Bariatric surgery patients should be expected to lose 20 to 50 kg at 1 to 2 years, which contemporary studies indicate should be accompanied by a 50% to 75% reduction in AHI and a drop in PAP levels. Autotitrating CPAP may be a useful management modality as weight falls after surgery. Despite dramatic weight loss, OSA may persist in many patients.
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CHAPTER 115 • Obstructive Sleep Apnea, Obesity, and Bariatric Surgery 1347
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32. Thut DC, Schwartz AR, Roach D, et al. Tracheal and neck position influence upper airway airflow dynamics by altering airway length. J Appl Physiol 1993;75:2084-2090. 33. American Society of Metabolic and Bariatric Surgery. Metabolic and bariatric surgery fact sheet. Available at: http://www.asmbs.org/ Newsite07/media/asmbs_fs_accesstocare.pdf. 34. Livingston EH. Hospital costs associated with bariatric procedures in the United States. Am J Surg 2005;190:816-820. 35. Mechanick JI, Kushner RF, Sugerman HJ, et al. American Association of Clinical Endocrinologists, The Obesity Society, and American Society of Metabolic and Bariatric Surgery medical guidelines for clinical practice for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient. Endocr Pract 2008;14(Suppl 1):1-83. 36. Frey WC, Pilcher J. Obstructive sleep-related breathing disorders in patients evaluated for bariatric surgery. Obes Surg 2003;13: 676-683. 37. Gupta RM, Parvizi J, Hanssen AD, Gay PC. Postoperative complications in patients with obstructive sleep apnea syndrome undergoing hip or knee replacement: a case-control study. Mayo Clin Proc 2001;76:897-905. 38. Flemons WW, Whitelaw WA, Brant R, Remmers JE. Likelihood ratios for a sleep apnea clinical prediction rule. Am J Respir Crit Care Med 1994;150(5):1279-1285. 39. Gali B, Whalen FX Jr, Gay PC, et al. Management plan to reduce risks in perioperative care of patients with presumed obstructive sleep apnea syndrome. J Clin Sleep Med 2007;3:582-588. 40. Kushida CA, Littner MR, Morgenthaler TI, et al. Practice parameters for the indications for polysomnography and related procedures: an update for 2005. Sleep 2005;28:499-521. 41. Collop NA, Anderson WM, Boehlecke B, et al. Clinical guidelines for the use of unattended portable monitors in the diagnosis of obstructive sleep apnea in adult patients. Portable monitoring task force of the American Academy of Sleep Medicine. J Clin Sleep Med 2007;3:737-747. 42. Weaver TE, Kribbs NB, Pack AI, et al. Night-to-night variability in CPAP use over the first three months of treatment. Sleep 1997;20:278-283. 43. Kushida CA, Littner MR, Hirshkowitz M, et al. Practice parameters for the use of continuous and bilevel positive airway pressure devices to treat adult patients with sleep-related breathing disorders. An American Academy of Sleep Medicine report. Sleep 2006;29: 375-380. 44. Hillman DR, Loadsman JA, Platt PR, Eastwood PR. Obstructive sleep apnoea and anesthesia. Sleep Med Rev 2004;8:459-471. 45. Meoli AL, Rosen CL, Kristo D, et al. Upper airway management of the adult patient with obstructive sleep apnea in the perioperative period-avoiding complications. Sleep 2003;26:1060-1065. 46. American Society of Anesthesiologists Task Force on Perioperative Management of Patients with Obstructive Sleep Apnea. Practice guidelines for the perioperative management of patients with obstructive sleep apnea: a report by the American Society of Anesthesiologists Task Force on Perioperative Management of Patients with Obstructive Sleep Apnea. Anesthesiology 2006; 104:1081-1093. 47. Nguyen NT, Silver M, Robinson M, et al. Result of a national audit of bariatric surgery performed at academic centers: a 2004 University HealthSystem Consortium benchmarking project. Arch Surg 2006;141:445-450. 48. Pieracci FM, Barie PS, Pomp A. Critical care of the bariatric patient. Crit Care Med 2006;34:1796-1804. 49. Geerts WH, Bergqvist D, Pineo GF, et al. Prevention of venous thromboembolism. American College of Chest Physicians evidencebased clinical practice guidelines (8th edition). Chest 2008;133: 381S-453S. 49a. Grover BT, Priem DM, Mathiason MA, et al. Intensive care unit stay not required for patients with obstructive sleep apnea after laparoscopic Roux-en-Y gastric bypass. Surg Obes Relat Dis 2010;6: 165-170. 50. Buchwald H, Avidor Y, Braunwald E, et al. Bariatric surgery: a systematic review and meta-analysis. JAMA 2004;292:1724-1737. 51. Maggard MA, Shugarman LR, Suttorp M, et al. Meta-analysis: surgical treatment of obesity. Ann Intern Med 2005;142:547-559. 52. Adams TD, Gress RE, Smith SC, et al. Long-term mortality after gastric bypass surgery. N Engl J Med 2007;357:753-761.
1348 PART II / Section 13 • Sleep Breathing Disorders 53. Sjostrom L, Lindroos A-K, Peltonen M, et al. Lifestyle, diabetes, and cardiovascular risk factors 10 years after bariatric surgery. N Engl J Med 2004;351:2683-2693. 54. Sjostrom L, Narbro K, Sjostrom CD, et al. Effects of bariatric surgery on mortality in Swedish obese subjects. N Engl J Med 2007;357:741-752. 55. Veasey SC, Guilleminault C, Strohl KP, et al. Medical therapy for obstructive sleep apnea: a review by the medical therapy for obstructive sleep apnea task force of the standards of practice committee of the American Academy of Sleep Medicine. Sleep 2006;29: 1036-1044. 56. Guardiano SA, Scott JA, Ware JC, Schechner SA. The long-term results of gastric bypass on indexes of sleep apnea. Chest 2003;124:1615-1619. 57. Valencia-Flores M, Orea A, Herrera M, et al. Effect of bariatric surgery on obstructive sleep apnea and hypopnea syndrome, electrocardiogram, and pulmonary arterial pressure. Obes Surg 2004; 14:755-762. 58. Dixon JB, Schachter LM, O’Brien PE. Polysomnography before and after weight loss in obese patients with severe sleep apnea. Int J Obesity 2005;29:1048-1054. 59. Haines KL, Nelson LG, Gonzalez R, et al. Objective evidence that bariatric surgery improves obesity-related obstructive sleep apnea. Surgery 2007;141:354-358. 60. Lettierri CJ, Eliasson AH, Greenburg DL. Persistence of obstructive sleep apnea after surgical weight loss. J Clin Sleep Med 2008;4: 333-338. 61. Lankford DA, Proctor CD, Richard R. Continuous positive airway pressure (CPAP) changes in bariatric surgery patients undergoing rapid weight loss. Obes Surg 2005;15:336-341. 62. Morgenthaler TI, Kapen S, Lee-Chiong T, et al. Practice parameters for the medical therapy of obstructive sleep apnea. Sleep 2006;29:1031-1035.
63. Pillar G, Peled R, Lavie P. Recurrence of sleep apnea without concomitant weight increase 7.5 years after weight reduction surgery. Chest 1994;106:1702-1704. 64. Fernandez AJ, DeMaria EJ, Tichansky DS, et al. Experience with over 3000 open and laparoscopic bariatric procedures: multivariate analysis of factors related to leak and resultant mortality. Surg Endosc 2004;18:193-197. 65. Perugini RA, Mason R, Czerniach DR, et al. Predictors of complication and sub-optimal weight loss after laparoscopic Roux-en-Y gastric bypass: a series of 188 patients. Arch Surg 2003;138:541-546. 66. Cooney RN, Haluck RS, Ku J, et al. Analysis of cost outliers after gastric bypass surgery: what can we learn? Obes Surg 2003; 13:29-36. 67. Ballantyne GH, Svahn J, Capella RF, et al. Predictors of prolonged hospital stay following open and laparoscopic gastric bypass for morbid obesity: body mass index, length of surgery, sleep apnea, asthma and the metabolic syndrome. Obes Surg 2004;14:1042-1050. 68. O’Rourke RW, Andrus J, Diggs BS, et al. Perioperative morbidity associated with bariatric surgery: an academic center experience. Arch Surg 2006;141:262-268. 69. Fernandez AZ Jr, Demaria EJ, Tichansky DS, et al. Multivariate analysis of risk factors for death following gastric bypass for treatment of morbid obesity. Ann Surg 2004;239:698-702. 70. Campos GM, Ciovica R, Rogers SJ, et al. Spectrum and risk factors of complications after gastric bypass. Arch Surg 2007;142:969-975. 71. Huerta S, DeShields S, Shpiner R, et al. Safety and efficacy of postoperative continuous positive airway pressure to prevent pulmonary complications after Roux-en-Y gastric bypass. J Gastrointest Surg 2002;6:354-358. 72. Joris JL, Sottiaux TM, Chiche JD, et al. Effect of bi-level positive airway pressure (BiPAP) nasal ventilation on the postoperative pulmonary restrictive syndrome in obese patients undergoing gastroplasty. Chest 1997;111:665-670.
Cardiovascular Disorders
Section
Shahrokh Javaheri 116 Sleep and Cardiovascular Disease:
Present and Future 117 Sleep-Related Cardiac Risk 118 Cardiac Arrhythmogenesis during Sleep: Mechanisms, Diagnosis, and Therapy 119 Cardiovascular Effects of Sleep-Related Breathing Disorders
120 Systemic and Pulmonary Hypertension
14
in Obstructive Sleep Apnea 121 Coronary Artery Disease and Obstructive Sleep Apnea 122 Heart Failure
Sleep and Cardiovascular Disease: Present and Future Shahrokh Javaheri Abstract Cardiovascular disorders are very common, affecting 26% of the population. They are associated with excess morbidity and mortality, and huge economic costs. One of the most signifi-
CARDIOVASCULAR DISEASE Cardiovascular disorders have a high prevalence and are associated with excessive morbidity and mortality, and huge economic costs (Table 116-1).1 Each year, the American Heart Association, in conjunction with the Centers for Disease Control and Prevention, the National Institutes of Health, and other government agencies, updates statistics on the morbidity and mortality of cardiovascular disease. According to the 2009 update, approximately 80 million people—38% of the U.S. population—have some form of cardiovascular disease. This has increased from the 2005 edition, when the prevalence was about 23%. Hypertension alone, a disorder that has been proven to be caused by obstructive sleep apnea (see Chapter 120), affects 74 million Americans. Many of these patients are erroneously diagnosed as having essential hypertension. Congestive heart failure and stroke, disorders frequently associated with both central and obstructive sleep apnea, are also highly prevalent, each affecting approximately 6.0 to 6.5 million Americans (see Table 116-1). According to the 2009 update, cardiovascular disorders accounted, in 2005, for approximately 865,000 deaths, which is 35% of all deaths in the United States. When the cases in which cardiovascular disease was a contributing factor to mortality are counted, the mortality was 1.4 million, or 56% of all mortalities. In fact, since 1900, cardiovascular disease has been the number one killer every year except 1918. In 2009, the annual cost of cardiovascular diseases is estimated to be $475 billion (compared with $368 billion
Chapter
116
cant recent developments in the field has been the recognition that sleep disorders such as sleep apnea can cause or worsen cardiovascular disease, and furthermore that cardiovascular disease can cause sleep disorders.
in 2004), and for congestive heart failure, the figure is approximately $37 billion (see Table 116-1). Since polysomnography became a common tool and sleep apnea was recognized as a medical disorder, perhaps the most important development in this field has been the recognition of the association of sleep apnea, both obstructive and central, with cardiovascular disorders (Fig. 116-1, Box 116-1, and Video 116-1).2-7
SLEEP APNEA There has been an explosion of basic science and physiologic studies in both experimental animals and humans, as well as epidemiologic and clinical studies, that support the bidirectional linking of sleep apnea to a variety of cardiovascular disorders (see Fig. 116-1 and Box 116-1) (see Chapters 117 through 122).2-7 Although much more research needs to be done in this area, it is interesting to note that cor pulmonale was recognized as a feature of pickwickian syndrome before it became known that the underlying pathologic process of cor pulmonale is a sleep disorder. Obstructive sleep apnea is associated with a number of biochemical and cellular abnormalities. Obstructive apnea results in neurohormonal activation; release of inflammatory mediators such as cytokines; increased expression of adhesion molecules, resulting in attachment of white blood cells to endothelial cells and their transmigration; and oxidative stress (see Chapter 116). Through increased production of reactive oxygen species,8 a number of transcription factors are activated, increasing the expression of redox-sensitive genes and resulting in the production of 1349
1350 PART II / Section 14 • Cardiovascular Disorders Table 116-1 Prevalence, Mortality, and Economic Burden of Cardiovascular and Cerebrovascular Disorders in the United States POPULATION GROUP
PREVALENCE 2006
MORTALITY 2005
HOSPITAL DISCHARGES 2006
COST 2009
Total
80 Million (36%)
865,000 (39% of all deaths)
7 Million
475 Billion
Women
41 Million (35%)
502,200 (54%)
4 Million
—
Men
39 Million (38%)
390,600 (46%)
3 Million
—
Age ≥ 60 yr
38 Million (47% of 80 million)
—
—
—
Hypertension
74 Million
—
514,000
Coronary heart disease
17 Million
450,000
1.8 Million
165 Billion
Myocardial infarction
8 Million
—
—
—
10 Million
—
—
—
Angina Congestive heart failure
6 Million
Stroke
6.5 Million
59,000* 144,000
73 Billion
1.1 Million
37 Billion
890,000
69 Billion
Numbers are rounded. Data from American Heart Association: Heart disease and stroke statistics—2009 update. Circulation 2009;119: e1-e161. *Total reported mortality, 290,000.
Box 116-1 Potential Cardiovascular and Cerebrovascular Complications of Obstructive Sleep Apnea Primary
Secondary
Sleep apneas and hypopneas
Cardiovascular pathology
Secondary
Primary
Figure 116-1 The relationship between obstructive sleep apnea (a primary sleep disorder), which secondarily could result in cardiovascular diseases, and a primary cardiovascular disease, specifically congestive heart failure, which secondarily could result in sleep-related breathing disorders.
vasoactive and inflammatory proteins. These reactions underlie the pathologic processes involved in endothelial dysfunction syndrome, the underlying pathophysiological mechanism for atherosclerosis, hypertension, stroke, heart failure, and coronary artery disease (Fig. 116-2). Because of the aforementioned abnormalities, and along with cyclic changes in blood pressure resulting in wall stress, changes in coronary and cerebral blood flow, and diminished oxygen delivery, obstructive sleep apnea could play a causative role or contribute to the development of atherosclerosis (see Fig. 116-2). In this context, treatment of obstructive sleep apnea with nasal continuous positive airway pressure (CPAP) devices results in reversal of a number of biochemical abnormalities, indicating a causal relationship (see Chapter 107). Furthermore, a number of studies also demonstrate that in patients with obstructive sleep apnea, treatment with CPAP results in a reduction in systemic and pulmonary hypertension (see Chapter 120).4,9,10 In the previous edition of this book, I expressed
Endothelial dysfunction Hypertension Systemic Pulmonary (cor pulmonale) Heart failure (systolic and/or diastolic) Arrhythmias Coronary artery disease Carotid artery atherosclerosis Stroke; transient ischemic attack Neuropsychological dysfunction Dementia Death (including sudden death)
the hope that long-term treatment of obstructive sleep apnea would be reflected in the prevention of cardiovascular and cerebrovascular diseases. Indeed, studies published since then strongly suggest not only that obstructive sleep apnea is a cause of mortality but also that treatment with CPAP decreases mortality, and this decrease is related primarily to the contribution of cardiovascular disorders. With regard to systemic hypertension, studies show a significant drop in blood pressure with even short-term use of CPAP. The most beneficial therapeutic effects are observed in patients with severe obstructive sleep apnea who are compliant with the CPAP regimen (see Chapter 107).9,10 Importantly, it has been shown that even small reductions in blood pressure over the long term significantly decrease the incidence of cerebrovascular and cardiovascular diseases.11 In prospective studies of 420,000 patients, with a mean follow-up of 10 years, drops in diastolic blood pressure of 5, 7.5, and 10 mm Hg were associated with, respectively, at least 34%, 46%, and 56% less stroke and at least 21%, 29%, and 37% less coronary heart disease.11 Therefore, in patients with obstructive sleep apnea, even a small drop in blood pressure, which could be maintained with long-term use of CPAP, is clinically
CHAPTER 116 • Sleep and Cardiovascular Disease 1351
Primary events
Intermediary mechanisms
Consequences
ygenation/hypocapn ia Reox ia ↓ . rcapn DO e p y h t a 2; ↓ /h Symp etic overactivity a i and m ↑C oxe rtension e p y h l a n r p u i d ↓ d y a n n a BF d l a ↑ wa H n r u t l l te No c Alterations in CBF nsi ↓ and on ↑
Sleep apnea and hypopnea
Adhe sion
Negative swings in intrathoracic pressure
mole
cules Trans cription fa ctors Oxida Pla tive stress tele t agg regatio n/coagulopathy Meta bolic dysregula tion
tion Inflamma tion Inflamma RO S
osis e Thromb tanc resis n i t p Insulin/le
Endothelial dysfunction Systemic HTN Pulmonary HTN Systolic HF Diastolic HF Arrythmias Atherosclerosis CAD TIA Stroke
Cardiovascular mortality
Figure 116-2 The mechanisms by which sleep apnea may result in endothelial dysfunction and cerebrovascular and cardiovascular , oxygen delivery; HF, heart failure; HTN, hypertendisorders. CAD, coronary artery disease; CBF, coronary/cerebral blood flow; DO 2 sion; ROS, reactive oxygen species; TIA, transient ischemic attacks; ↑, increase; ↓, decrease. (From McNicholas WT, Javaheri S. Pathophysiological mechanisms of cardiovascular disease in obstructive sleep apnea. Clin Sleep Med 2007;2(4):539-547.)
meaningful. Furthermore, treatment of obstructive sleep apnea with CPAP may afford additional protection against vascular disorders, because obstructive sleep apnea may contribute to cardiovascular and cerebrovascular disease by a variety of mechanisms in addition to hypertension (see Fig. 116-2).
abnormalities associated with metabolic syndrome. Longitudinal studies should be conducted to determine whether early recognition and treatment of obstructive sleep apnea as a companion of metabolic syndrome will have a preventive effect on cerebrovascular and cardiovascular diseases.
METABOLIC SYNDROME With the emergence of metabolic syndrome (see Chapter 114), a precursor of incident cerebrovascular and cardiovascular diseases, a new epidemic is evolving.12-14 This syndrome, characterized by hypertension, hyperglycemia, insulin resistance, and hypertriglyceridemia, goes handin-hand with obesity. Metabolic syndrome is a proinflammatory and prothrombotic condition with increased serum concentrations of high-sensitivity C-reactive protein, fibrinogen, and von Willebrand’s factor, and increased platelet aggregation. Metabolic syndrome has a high prevalence, affecting 24% of all adults.14 Its prevalence increases with age, reaching approximately 45% in those 60 years or older.14 Because metabolic syndrome is a precursor of cerebrovascular and cardiovascular disorders, its early recognition and targeted therapy have been emphasized by different medical societies.13-15 However, obstructive sleep apnea also accompanies obesity, and it shares a large number of biochemical abnormalities that are markers of metabolic syndrome (see Chapter 114). As an example, through sympathetic stimulation, obstructive sleep apnea contributes to insulin resistance and hypertension. Therefore, metabolic syndrome, obesity, and obstructive sleep apnea together are components of a vicious cycle. In concert with an emphasis on early recognition of metabolic syndrome,13-15 early recognition of obstructive sleep apnea as a comorbid condition also needs to be emphasized, particularly because treatment of obstructive sleep apnea with CPAP has been shown to reverse some of the
SLEEP IN PATIENTS WITH HEART FAILURE Another major development in the field is the rediscovery of central sleep apnea and Cheyne-Stokes breathing in patients with congestive heart failure and systolic dysfunction (see Chapter 122),16 although the discovery of this disorder dates back to John Hunter,17,18 37 years before John Cheyne’s description in 1818. There has been an explosion of physiologic and clinical research studies in this field.19 Many studies show that both central and obstructive sleep apnea are common in patients with congestive heart failure,19 and preliminary studies have shown that treatment of sleep apnea improves mortality in patients with heart failure.20 IMPACT For two major reasons, the recognition of the association of sleep-related breathing disorders and cardiovascular diseases is important. First, as noted previously (see Table 116-1), cardiovascular disorders pose a great burden to patients and society. Second, recent studies show that treatment of obstructive and central sleep apnea results in improvement in the cardiovascular morbidity and probably mortality as well. However, long-term longitudinal studies that are randomized and adequately powered to prove that sleep apnea is a cause of cardiovascular mortality are lacking. Meanwhile, the design of such studies is complicated by a number of factors, such as inclusion and
1352 PART II / Section 14 • Cardiovascular Disorders
exclusion criteria: For example, should the most severe cases—patients with preexisting hypertension or excessive daytime sleepiness—be excluded? Yet such subjects may be the most compliant with CPAP therapy and their response to treatment may have the most favorable impact on mortality, the primary end point of the study. Other factors that complicate a long-term randomized clinical trial of obstructive sleep apnea include cost, compliance with CPAP (particularly when patients do not feel shortterm symptomatic benefit from it), and ethical issues, such as whether to use sham CPAP as a placebo in the control group. Because of the importance of the relationship between sleep-related breathing disorders (both obstructive and central sleep apnea) and cardiovascular disorders, this fifth edition of this book again devotes a series of chapters to cardiovascular diseases and sleep. In Chapters 117 and 118, a number of cardiovascular disorders related to sleep but unrelated to sleep apnea are reviewed. The emphasis in Chapter 117 is on nocturnal myocardial ischemia and infarction, and in Chapter 118, on arrhythmias as they relate to changes in autonomic nervous system and sleep stages. The remaining chapters in the series are devoted to obstructive and central sleep apnea and their relationship to cardiovascular diseases. Much research remains to be done in this field. Some studies have shown that treatment of obstructive sleep apnea reduces some cardiovascular morbidities in OSA patients with cardiovascular disorders, for example hypertension and arrhythmias.21-24 Large future studies will determine impact on cardiovascular mortality. Similarly, prospective therapeutic studies will determine whether treatment of sleep apnea, both central and obstructive, will influence the natural history of left ventricular dysfunction in systolic and diastolic heart failure. There have been no large systematic studies of diastolic heart failure, which is the most common form of left ventricular heart failure in the older population, in whom sleep apnea is also common. Furthermore, there is ample pathophysiologic evidence that the consequences of sleep apnea can cause left ventricular diastolic dysfunction.
❖ Clinical Pearls Cardiovascular disorders are highly prevalent and associated with excess morbidity and mortality and huge economic costs. Sleep-related breathing disorders are common in patients with cardiovascular disorders and may either play a causative role or contribute to the progression of the cardiovascular pathologic process. Observational studies suggest that obstructive sleep apnea is a cause of mortality, and that treatment with CPAP improves survival. Similarly, both central and obstructive sleep apnea may contribute to mortality of patients with systolic heart failure, and effective treatment with CPAP may improve survival.
REFERENCES 1. American Heart Association. Heart disease and stroke statistics—2009 update. Circulation 2009;119:e1-e161. 2. Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378-1384. 3. Nieto FJ, Young TB, Lind BK, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. JAMA 2000;283:1829-1836. 4. Marrone O, Bonsignore MR. Pulmonary hemodynamics in obstructive sleep apnea. Sleep Med Rev 2002;6:175-193. 5. Guilleminault C, Connolly SJ, Winkle RA. Cardiac arrhythmia and conduction disturbances during sleep in 400 patients with sleep apnea syndrome. Am J Cardiol 1983;52:490-494. 6. Koehler U, Fus E, Grimm W, et al. Heart block in patients with obstructive sleep apnoea: pathogenetic factors and effects of treatment. Eur Respir J 1998;11:434-439. 7. Javaheri S. Sleep-related breathing disorders in heart failure. In: Mann DL, editor. Heart failure: a companion to Braunwald’s heart disease. Philadelphia: Saunders; 2004, p. 471-487. 8. Lavie L. Obstructive sleep apnoea syndrome: an oxidative stress disorder. Sleep Med Rev 2003;7:35-51. 9. Becker HF, Jerrentrup A, Ploch T, et al. Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation 2003;107:68-73. 10. Pepperell JC, Randassingh-Dow S, Crosthwaite N, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomized parallel trial. Lancet 2002;359:204-210. 11. MacMahon S, Peto R, Culter J, et al. Epidemiology: blood pressure, stroke, and coronary artery disease: Part 1. Prolonged differences in blood pressures: prospective observational studies corrected for the regression dilution bias. Lancet 1990;335:765-774. 12. Ninomiya JK, L’Italien G, Criqui MH, et al. Association of the metabolic syndrome with history of myocardial infarction and stroke in Third National Health and Nutrition Examination Survey. Circulation 2004;109:42-45. 13. Deedwania PC. Metabolic syndrome and vascular disease: is nature or nurture leading to new epidemic of cardiovascular disease? Circulation 2004;109:2-4. 14. Ford ESF, Giles WH, Dietz WH. Prevalence of the metabolic syndrome among US adults: findings from the Third National Health and Nutrition Examination Survey. JAMA 2002;287:356-359. 15. Grundy SM, Hansen B, Smith SC. Clinical management of metabolic syndrome: report of the American Heart Association/ National Heart, Lung, and Blood Institute/American Diabetes Association conference on scientific issues related to management. Circulation 2004;109:551-556. 16. Cheyne J. A case of apoplexy, in which the fleshy part of the heart was converted into fat. Dublin Hosp Rep Commun 1818;2: 216-223. 17. Ward M. Periodic respiration: a short historical note. Ann R Coll Surg Engl 1973;52:330-334. 18. Allen R, Truk JL, Muricy R. The case books of John Hunter, FRS. New York: Parthenon; 1993. 19. Levy P, Pepin JL, Tamisier R, et al. Prevalence and impact of central sleep apnea in heart failure. Sleep Med Clin 2007;2:615-621. 20. Debacker W, Javaheri S. Treatment of sleep apnea in heart failure. Sleep Med Clin 2007;2:631-638. 21. Lozano L, Tovar JL, Sampol G, et al. Continuous positive airway pressure treatment in sleep apnea patients with resistant hypertension: a randomized, controlled trial. J Hypertens 2010; July. In press. 22. Di Guardo A, Profeta G, Crisafulli C, et al. Obstructive sleep apnoea in patients with obesity and hypertension. Br J Gen Pract 2010;60: 325-328. 23. Abe H, Takahashi M, Yaegashi H, et al. Efficacy of continuous positive airway pressure on arrhythmias in obstructive sleep apnea patients. Heart Vessels 2010;25:63-69. 24. Barbé F, Durán-Cantolla J, Capote F, et al. Long-term effect of continuous positive airway pressure in hypertensive patients with sleep apnea. Am J Respir Crit Care Med 2010;181:718-726.
Sleep-Related Cardiac Risk Richard L. Verrier and Murray A. Mittleman
Abstract The brain, in subserving its need for periodic re-excitation during rapid eye movement (REM) sleep and dreaming, imposes significant demands on the heart by inducing bursts of sympathetic nerve activity, which reaches levels higher than during wakefulness. In patients with cardiac disease, such neural activity may compromise coronary artery blood flow, as metabolic demand outstrips supply, and may trigger sympathetically mediated life-threatening arrhythmias in response to functional myocardial ischemia. An additional challenge is presented by non-REM sleep, when hypotension may lead to malperfusion of the heart and brain as a result of a lowered blood pressure gradient through stenosed vessels. Impairment of ventilation by sleep-related breathing disor-
In healthy individuals, sleep is usually salutary and restorative. Ironically, during sleep in patients with respiratory or heart disease, the brain can precipitate breathing disorders, myocardial ischemia, arrhythmias, and even death. Our observation that 20% of myocardial infarctions (MIs) and 15% of sudden deaths occur during the period from midnight to 6:00 am projects to an estimated 300,000 nocturnal MIs and 48,750 nocturnal sudden deaths annually in the U.S. population.1 The latter figure is equivalent to 87% of the number of U.S. fatalities due to automobile accidents and is more than 2.5 times the number of U.S. deaths resulting from human immunodeficiency virus infection. Thus, sleep is not a fully protected state. Furthermore, the nonuniform distribution of deaths and MIs during the night is consonant with provocation by pathophysiologic triggers. The two main factors implicated in nocturnal cardiac events are sleep state–dependent surges in autonomic activity2 and depression of respiratory control mechanisms,3 which affect a vulnerable cardiac substrate. Precise characterization of their interaction in precipitating nocturnal cardiac events is, however, incomplete. Although sudden death during sleep can be presumed to be painless, in many cases it is premature because it occurs in infants and adolescents and in adults with ischemic heart disease, for whom the median age is 59 years. Populations at risk for nocturnal cardiorespiratory events include several large patient groups (Table 117-1). For example, atrial fibrillation is common in sleep apnea.1a-1f It is an insidious component of the problem of nocturnal risk that many people are unaware of their respiratory or cardiac distress at night and therefore take no corrective action. Thus, sleep presents unique autonomic, hemodynamic, and respiratory challenges to the diseased myocardium that cannot be monitored by daytime diagnostic tests. The importance of nocturnal monitoring of patients with cardiac disease extends beyond identifying sleep state–dependent triggers of cardiac events because nighttime myocardial ischemia, arrhythmias, autonomic activity, and respiratory disturbances carry predictive value for daytime events (Box 117-1).
Chapter
117
ders, including obstructive sleep apnea and central sleep apnea, which afflict millions of Americans, can generate reductions in arterial oxygen saturation and other pathophysiologic sequelae. Obstructive sleep apnea has been strongly implicated, when severe, in the etiology of hypertension, myocardial ischemia, arrhythmias, myocardial infarction, heart failure, and sudden death in individuals with coexisting ischemic heart disease. Similarly, central sleep apnea has been associated with a variety of atrial and ventricular arrhythmias. Atrial fibrillation may be triggered by autonomic or respiratory disturbances during sleep in certain patient populations. Medications that cross the blood–brain barrier may alter sleep structure and provoke nightmares with severe cardiac autonomic discharge.
In this chapter we discuss the pathophysiologic mechanisms responsible for sleep-related cardiac morbidity and mortality. For a review of mechanisms and treatment of nocturnal arrhythmias, see Chapter 118. Effects of sleepdisordered breathing and apnea on the cardiovascular system are discussed in Chapter 119.
AUTONOMIC ACTIVITY AND CIRCULATORY FUNCTION DURING SLEEP The generalized decrease in mean heart rate and arterial blood pressure at the onset of sleep and throughout non– rapid eye movement (NREM) sleep, which occupies 80% of sleep time, has prompted the assumption that sleep is a period of relative autonomic inactivity. NREM sleep, the initial stage, is characterized by marked stability of autonomic regulation with a high degree of parasympathetic neural tone and prominent respiratory sinus arrhythmia.2,4 Baroreceptor gain is high and contributes to the stability of arterial blood pressure and to overall cardiovascular homeostasis.5 Muscle sympathetic nerve activity is stable, falls with the transition from awake to NREM sleep, and decreases progressively with depth of sleep,2,6 reaching half the awake value during stage 4.2 Short-lasting increases in muscle sympathetic nerve activity, heart rate, and arterial blood pressure accompany the appearance of high-amplitude K-complexes during stage 2.2,6 Heart rate accelerations may even precede the electroencephalographic arousals of stage 2 and REM sleep.7 During transitions from NREM to REM sleep, bursts of vagus nerve activity may result in pauses in heart rhythm and frank asystole. Transitions between REM and NREM sleep elicit posture shifts that are associated with varying degrees of autonomic activation and attendant changes in heart rate and arterial blood pressure.8 These shifts in body position increase in frequency as individuals age and sleep becomes fragmented. Autonomic nervous system activity is dramatically altered when REM sleep is initiated (Fig. 117-1). REM 1353
1354 PART II / Section 14 • Cardiovascular Disorders Table 117-1 Patient Groups at Potentially Increased Risk for Nocturnal Cardiac Events INDICATION (U.S. PATIENTS/YR)
POSSIBLE MECHANISM
Angina, myocardial infarction (MI), arrhythmias, ischemia, or cardiac arrest at night; 20% of myocardial infarctions (~300,000 cases/yr) and 15% of sudden deaths (~48,750 cases/yr) occur between midnight and 6:00 AM.
The nocturnal pattern suggests a sleep state–dependent autonomic trigger or respiratory distress.
Unstable angina, Prinzmetal angina
Nondemand ischemia and angina peak between midnight and 6:00 AM
Acute MI (1.5 million)
Disturbances in sleep, respiration, and autonomic balance may be factors in nocturnal arrhythmogenesis. Nocturnal onset of MI is more frequent in older and sicker patients and carries a higher risk of congestive heart failure.
Heart failure (5.3 million)
Sleep-related breathing disorders are pronounced in the setting of heart failure and may contribute to its progression and to mortality risk.
Spousal or family report of highly irregular breathing, excessive snoring, or apnea in patients with coronary disease (5 to 10 million patients with apnea).
Patients with hypertension or atrial or ventricular arrhythmias should be screened for the presence of sleep apnea.
Long QT syndrome
The profound cycle-length changes associated with sleep may trigger pause-dependent torsades de pointes in these patients.
Near-miss or siblings of victims of sudden infant death syndrome (SIDS)
SIDS commonly occurs during sleep with characteristic cardiorespiratory symptoms.
Brugada syndrome in Western populations; Asians with warning signs of sudden unexplained nocturnal death syndrome (SUNDS)
SUNDS is a sleep-related phenomenon in which night terrors may play a role. It is genetically related to the Brugada syndrome.
Atrial fibrillation (2.5 million)
Twenty-nine percent of episodes occur between midnight and 6:00 AM. Respiratory and autonomic mechanisms are suspected.
Patients on cardiac medications (13.5 million patients with cardiovascular disease)
Beta-blockers and calcium channel blockers that cross the blood–brain barrier may increase nighttime risk because poor sleep and violent dreams may be triggered. Medications that increase the QT interval may conduce to pause-dependent torsades de pointes during the profound cycle-length changes of sleep. Because arterial blood pressure is decreased during non–rapid eye movement sleep, additional lowering by antihypertensive agents may introduce a risk of ischemia and infarction due to lowered coronary perfusion.
sleep is marked by profound muscle sympathetic nerve activation, in terms of both frequency and amplitude,2,6 which attains levels significantly higher than in wakefulness.2 Sympathetic nerve activity is concentrated in short, irregular periods that are most striking when accompanied by intense eye movements.2 These bursts trigger intermittent increases in heart rate and arterial blood pressure to levels similar to those in wakefulness, with increased variability.2,6,7 Significant surges and pauses in heart rate during REM sleep have been described in several species, including humans.6,7 Cardiac efferent vagal tone and baroreceptor regulation5 are generally suppressed during REM sleep, and breathing patterns may become highly irregular and may lead, in susceptible individuals, to oxygen desaturation. Thus, while subserving the neurochemical functions of the brain, REM sleep can disrupt cardiorespiratory homeostasis. The brain’s increased excitability during REM sleep can also trigger major surges in sympathetic nerve activity to the skeletal muscular beds, accompanied by muscular twitching,2 which interrupts the generalized skeletal atonia of REM.8 The peripheral autonomic status
characterized by muscle sympathetic nerve recording is compatible with reduced neuronal activity in the brainstem and other regions of the brain and reduced cerebral blood flow during NREM sleep and, during REM sleep, with increased brain activity in several discrete regions to levels higher than waking values.9 The decline in autonomic activity during sleep is also evident in peroneal muscle sympathetic nerve activity2,6 and peripheral levels of epinephrine and norepinephrine, and mirrors the generalized sleep-induced decline in heart rate and arterial blood pressure.10 A nocturnal nadir in plasma catecholamines is evident at 1 hour after sleep onset. Plasma cortisol is also depressed during sleep; increased levels are initiated at 5:00 am. In the absence of readily achieved, direct measures of cardiac-bound nerve activity, analysis of heart rate variability (HRV) has emerged as a widely accepted method for measuring cardiac sympathetic versus parasympathetic neural dominance. High-frequency (HF) HRV is a general indicator of cardiac parasympathetic tone and includes the effects of respiration. The low- to high-frequency
• Because parasympathetic nerve activity is elevated during sleep in healthy individuals, lack of circadian pattern of heart rate variability and baroreflex sensitivity may be readily monitored for increased risk of cardiac events. • Nondemand nocturnal ischemic episodes may disclose a critical underlying coronary lesion, coronary vasospasm, or transient coronary artery stenosis. • In elderly subjects, nighttime multifocal ventricular ectopic activity predicts increased mortality from cardiac causes independent of clinically evident cardiac disease. • Sleep apnea, which may be screened by heart rate variability analysis, conduces to hypertension, ischemia, and atrial and ventricular arrhythmias, and is a risk factor for lethal daytime cardiac events, including myocardial infarction. • Hypertensive patients with less than a 10% nocturnal decline in blood pressure (remaining higher than 101/65 mm Hg) are at increased risk of total and cardiovascular mortality and all cardiovascular endpoints, myocardial ischemia, frequent or complex ventricular arrhythmias, cerebrovascular insult, and increased organ damage, including cardiac hypertrophy. • Elevated nocturnal heart rates are associated with increased mortality.
(LF/HF) ratio is widely accepted as an approximation of cardiac-bound sympathetic nerve activity, as validated by studies involving beta-adrenergic receptor blocking agents. Decreased HRV, indicating a decline in parasympathetic nerve activity, is an established indicator of risk for sudden cardiac death after MI. HRV analysis reveals a generalized increase in vagus nerve activity and a decrease in cardiac sympathetic nerve activity across the sleep period,11,12 probably reflecting the dominance of total sleep time by NREM sleep. HRV studies using 5-minute intervals provide results consistent with muscle nerve recording, indicating increased HF and decreased LF (or parasympathetic nerve dominance) in NREM sleep, but decreased HF and increased LF (or predominant sympathetic nerve activity) in REM sleep and during wakefulness.7 In healthy individuals, the increase in HRV measures of cardiac sympathetic nerve activity at onset of REM sleep is initiated before7,12 the transition from NREM sleep as classically defined from the polysomnographic record. The typical circadian pattern of decreased nocturnal cardiac sympathetic nerve activity as described by heart rate and HRV studies is altered in patients with coronary artery disease,13,14 MI,11,15 and diabetes,16 suggesting either increased nocturnal cardiac sympathetic nerve activity or decreased parasympathetic nerve activity compared with healthy subjects. The HF component has been observed to decrease approximately 10 minutes before onset of nocturnal myocardial ischemia.14 In unmedicated patients with a recent MI, the LF/HF ratio was significantly increased
40
*
30 20 *
10
*
0 Awake 1
2
3
4
REM
250 Burst amplitude (%)
Box 117-1 Predictive Value of Nocturnal Cardiorespiratory Status
Burst frequency (bursts/min)
CHAPTER 117 • Sleep-Related Cardiac Risk 1355
*
200 150 100 50
*
*
3
4
0 Awake 1
2
REM
Figure 117-1 Sympathetic nerve burst frequency and amplitude during wakefulness, non–rapid eye movement (NREM) sleep (eight subjects), and REM sleep (six subjects). Sympathetic nerve activity was significantly lower during stages 3 and 4 (P < .001). During REM sleep, sympathetic nerve activity increased significantly (P < .001). Values are means ± standard error of the mean. (From Somers VK, Dyken ME, Mark AL, et al. Sympathetic nerve activity during sleep in normal subjects. N Engl J Med 1993;328:303-307. Copyright 1993 Massachusetts Medical Society. All rights reserved.)
during both REM and NREM sleep, in contrast to healthy subjects, in whom this ratio during REM sleep is similar to awake levels and higher than during NREM sleep (Fig. 117-2).11 The conclusions were reached that MI decreases the capacity of the vagus nerve to be activated during sleep, resulting in unbridled cardiac sympathetic nerve activity,11 and that loss of rise in the HF component is characteristic of patients after an MI and with residual myocardial ischemia.15 These sleep state–dependent profiles of autonomic activity have significant potential to affect coronary function and cardiac electrical stability in patients with ischemic heart disease.
NOCTURNAL CARDIOVASCULAR EVENTS Nocturnal Myocardial Ischemia and Angina Accurate assessment and treatment of nocturnal angina has been a subject of concern for more than 2 centuries. Heberden in 1768 described angina that “will often oblige [the patients] to rise up out of their bed every night for many months altogether.” John Hunter, the well-known 18th-century surgeon, reported chest pains that “seized
1356 PART II / Section 14 • Cardiovascular Disorders
12 10
Post-MI
8 LF/HF
*
Controls
*
6 4 2 0 Awake
NREM
REM
Figure 117-2 Bar graphs indicating low- to high-frequency (LF/ HF) ratio of heart rate variability during the awake state (left), during non–rapid eye movement (NREM) sleep (middle), and during REM sleep (right) in healthy subjects and in post-myocardial infarction (MI) patients (P < .01 when comparing control subjects and post-MI patients). Values are means ± standard error of the mean. (From Vanoli E, Adamson PB, Ba-Lin, et al. Heart rate variability during specific sleep stages: a comparison of healthy subjects with patients after myocardial infarction. Circulation 1995;91:1918-1922.)
him in his sleep so as to awaken him.”17 As early as 1923, MacWilliam18 postulated that the mechanisms of nocturnal ventricular fibrillation and angina were stimulation of sympathetic nerves and increased arterial blood pressure. He described “reflex excitations, dreams, nightmares, etc., sometimes accompanied by extensive rises of arterial blood pressure (hitherto not recognized), increased heart action, changes in respiration, and various reflex effects” and noted “the suddenness of development of the functional disturbances in arterial blood pressure, heart action, etc., in the dreaming state.” He documented greater stress on the circulatory system during dreaming than during wakefulness, with arterial blood pressures reaching 200 mm Hg. In the middle of the 20th century, the renowned cardiologists Paul Dudley White and Samuel Levine remarked on the frequency of MI and angina in sleep and suggested an association with dreams. Ischemic activity is an important prognostic marker in patients with cardiac disease, and characteristics of both REM and NREM sleep may conduce to nocturnal myocardial ischemia and angina. The few studies in patients with cardiac disease that have used sleep staging have concluded that in the absence of significant depression of left ventricular function, nocturnal ischemic events occur primarily during REM sleep,19,20 which is characterized by increased sympathetic nerve activity, metabolic demands, and heart rate surges. In patients with stable coronary artery disease, myocardial ischemia is largely attributable to bouts of sympathetically mediated surges in heart rate and resultant metabolic demands in flow-limited, stenotic coronary arteries.4,14,20-24 Nowlin and coworkers20 attributed nocturnal angina to heightened blood pressure after performing detailed, multisession polysomnographic analysis of four patients with advanced coronary artery disease and nocturnal angina pectoris. They established that
attacks of nocturnal angina occurred predominantly during REM sleep (32 of 39 recordings) and were associated with heart rate acceleration. Dream content, in patients who could describe it, included awareness of chest pain and involved strenuous physical activity or emotions of fear, anger, or frustration. Nocturnal myocardial ischemia may be generated by mechanisms in addition to sympathetic nerve activity and unsatisfied metabolic demands. This possibility is suggested by the finding that nighttime ischemic events remain, although they are less frequent, in patients receiving beta-adrenergic receptor blockade therapy, the primary therapy that effectively reduces the overall incidence of and suppresses the morning peak in cardiac events by containing sympathetic nerve activity and demand-related myocardial ischemia.24,25 The main factors that may contribute to nondemand-related myocardial ischemia during NREM sleep are decreased coronary perfusion pressure as the result of hypotension4,24-27 and increased coronary vasomotor tone.26 These influences decrease the metabolic threshold for induction of nocturnal myocardial ischemia, which has a nadir between 1:00 am and 3:00 am.21,26,28 During these hours in patients with stable coronary disease, Benhorin and colleagues26 observed that myocardial ischemia can be provoked at heart rates of 83 beats per minute (bpm), in contrast to 96 bpm during midday, and that its incidence was not affected by beta-adrenergic receptor blockade. Patel and colleagues25 noted that nocturnal myocardial ischemia is attended by heart rate elevations of 6 bpm or less in patients with unstable angina receiving beta-adrenergic receptor blocking agents. Mancia4 hypothesized that the hypotension of NREM sleep is a major contributor to nocturnal myocardial ischemia and MI because it “reduces the volume and velocity of blood flow, favoring the development of thrombi and embolic and ischemic phenomena before and after arousal.” It has also been postulated that myocardial ischemia provoked by transient thrombus formation29 is attributable to the nocturnal nadir in endogenous fibrinolytic activity,29 as well as to peaks in serum levels of plasminogen activator inhibitor29 and tissue plasminogen activator antigen, increasing blood viscosity or hypercoagulability at night, and freeradical generation. Nondemand nocturnal myocardial ischemia is prevalent among patients with more severe coronary disease,24,28,30 acute coronary syndromes,15 or diabetes, populations with significant endothelial dysfunction. Indeed, it has been concluded that nondemand nocturnal ischemic episodes disclose a critical underlying coronary lesion, coronary vasospasm, or transient coronary artery stenosis.25 Patel and colleagues25 documented a nocturnal peak in ischemic events in their study of 256 hospitalized patients with the acute coronary syndromes of unstable angina and non– Q-wave MI (Fig. 117-3). Electrocardiograms were recorded within hours after patients’ admission for chest pain to the coronary care unit for new-onset angina, sudden acceleration of previously stable angina, or angina within 1 month of MI. In hospital, they received optimal medical therapy aimed at containing demand-related myocardial ischemia. It is important to note, however, that the peak in out-of-hospital onset of the syndromes followed the usual circadian pattern, as reported by Cannon and
CHAPTER 117 • Sleep-Related Cardiac Risk 1357
25 UA Non-Q
No. of episodes
20 15 10 5 0 0-2
2-4
4-6
6-8
8-10
10-12
12-14
14-16
16-18
18-20
20-22
22-24
Time of day (2-hour blocks)
coworkers31 in the Thrombosis in Myocardial Infarction (TIMI) III Study of 3318 patients. By contrast, in patients with longstanding diabetes or with documented autonomic nervous system dysfunction, there is no nocturnal decrease in myocardial ischemia or onset of acute MI. Demand-related ischemic episodes can be effectively contained by beta-adrenergic receptor blockade,25 but antihypertensive treatment does not reduce the nocturnal incidence of nondemand-related myocardial ischemia.32 The use of vasodilators to treat nondemand episodes resulting from endothelial dysfunction is the subject of debate. The lack of sleep staging and arterial blood pressure monitoring in patients with nocturnal myocardial ischemia leaves unidentified any contribution by autonomic and hemodynamic activity dictated by sleep states. Such monitoring would also disclose the prevalence of the established proischemic influences of nocturnal arousal and rising from bed.13,33 Post-Myocardial Infarction Patients During the first weeks after MI, sleep is significantly disturbed,27,34 and nocturnal oxygen desaturation, especially in patients with impaired left ventricular function, may be generalized or episodic and may directly provoke tachy cardia, ventricular premature beats, and ST-segment changes (Fig. 117-4).34-37 Both the duration and number of nighttime ischemic events are increased, consonant with increased cardiac sympathetic nerve activity25,38 or decreased parasympathetic nerve activity (see Fig. 117-2),11 particularly in patients with residual myocardial ischemia.15 Nocturnal levels of norepinephrine are increased, and nocturnal secretion of melatonin, an endogenous hormone that suppresses sympathetic nerve activity, is impaired.39 These symptoms become normal over time so that within the first 6 months, ventricular tachycardia during sleep is relatively rare.
Oxygen saturation (%)
Figure 117-3 The circadian variation of ischemic activity based on 2-hour time blocks for the in-hospital study population. There is a single peak of ischemic activity at night between 10:00 PM and 8:00 AM, and no morning peak in ischemic activity is apparent. More than 64% of episodes occurred during this period (P < .001 compared with daytime). The circadian distribution of ischemic episodes in unstable angina (UA) and non–Q-wave myocardial infarction (Non-Q) is similar to the overall pattern of ischemic activity. (From Patel DJ, Knight CJ, Holdright DR, et al. Pathophysiology of transient myocardial ischemia in acute coronary syndromes: characterization by continuous ST-segment monitoring. Circulation 1997;95:1185-1192.)
100 80 60 0130
0145
0200
0215
0230
Time
0201 0202 0203 0204 0205 Time Continuous ECG
Figure 117-4 Importance of monitoring nocturnal oxygen saturation in patients who have sustained a myocardial infarction. Nonsustained ventricular tachycardia (bottom) and hypoxemia measured by pulse oximetry (top) occurred simultaneously in a patient on the third night after infarction. The patient died on the following day of cardiogenic shock. ECG, electrocardiogram. (From Galatius-Jensen S, Hansen J, Rasmussen V, et al. Nocturnal hypoxemia after myocardial infarction: association with nocturnal myocardial ischaemia and arrhythmias. Br Heart J 1994;72:23-30.)
The most detailed study to date of sleep in post-MI patients was performed in 1978 by Broughton and Baron,27 who reported on the sleep and cardiovascular condition of 12 patients, aged 33 to 70 years, after severe MI, first during their stay in the intensive care unit and then in the hospital ward. They noted a “marked disturbance of nocturnal sleep patterns … characterized by high amounts of wakefulness, stage 1, and number of awakenings, and REM density and low amounts of REM sleep, shorter
1358 PART II / Section 14 • Cardiovascular Disorders
REM periods with prolonged REM latencies. Sleep efficiency was substantially reduced.”27 All of these sleepquality parameters improved in parallel with time after MI until on day 9 the only remaining abnormal feature was a high content of NREM sleep stages 3 and 4. REM density peaked on postinfarction nights 3 and 4 and NREM sleep on night 4. On subsequent hospital visits after discharge, the patients described terrifying dreams, suggesting that REM suppression was followed by REM rebound more than 2 weeks after the crisis. Importantly, Broughton and Baron observed that NREM sleep provoked nocturnal angina and awakening. They postulated that the hypotension associated with NREM sleep resulted in a diminution in perfusion pressure of the major coronary and collateral vessels supplying the mechanically compromised myocardium. The decreased heart rates typical of NREM sleep, however, were not observed, and heart rates were higher in NREM sleep than in wakefulness on half the nights recorded, indicating enhanced cardiac sympathetic nerve activity even in NREM sleep. In half of the cases, the electrocardiogram amplitude decreased during anginal attacks. In the context of nighttime monitoring, it is of interest to note that T-wave alternans, an electrocardiographic (ECG) phenomenon indicating vulnerability to lethal arrhythmias,40-42 has been recorded in the nighttime electrocardiogram of a patient with left dysfunction enrolled in the ambulatory ECG arm of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) (Fig. 117-5).41
the myocardial oxygen supply–demand relationship or alpha-adrenergically mediated coronary vasoconstriction. Alternatively, in a starkly opposite manner, the hypotension of slow-wave sleep may lead to malperfusion of the myocardium because of reduced coronary perfusion pressure through stenotic vessel segments (Fig. 117-6).44 Several investigators25,45,46 have attributed nocturnal MI and myocardial ischemia to the relative hypotension of NREM sleep, which “reduces the volume and velocity of blood flow, favoring the development of thrombi and embolic and ischemic phenomena before and after arousal.”4 Mancia4 therefore advocated avoiding drugs that enhance the hypotension of NREM sleep and prescribing antihypertensive medications only for daytime therapy. He echoed the argument of Floras,32 who observed that antihypertensive treatment did not reduce the incidence of nocturnal MI and myocardial ischemia. Further evidence of the risk of hypotension-induced infarction has been provided by Kleiman and colleagues,45 who reported that the incidence of subendocardial MI clustered at 2:00 am to 4:00 am, simultaneously with the nadir in arterial blood pressure. Other factors known to contribute to MI are operative during sleep, including increased ventricular diastolic pressures and volumes caused by the fluid shifts resulting from assuming a supine posture, unfavorable alterations in the balance of fibrinolytic and thrombotic factors,29 and chronic or episodic oxygen desaturation.27,34-37 Specific patient groups experience an increased incidence of nighttime MIs, particularly those with poor ventricular function, advanced age, or diabetes.47,48 The risk for development of congestive heart failure is higher for nighttime than daytime MIs,49 potentially because of either the pathologic process or a delay in obtaining high-quality care.
Nocturnal Myocardial Infarction Although only 20% of MIs occur between midnight and 6:00 am, their nonuniform distribution implicates pathophysiologic triggers.1 The dynamic perturbations in autonomic nervous system activity both independent of and in conjunction with apnea43 are likely to constitute important triggers of MI at night. REM-induced surges in sympathetic nerve activity have the potential to provoke tachycardia and hypertension, alterations that carry the potential for inducing MI secondary to coronary artery plaque rupture as well as to inappropriate decreases in
IV
IV
IV
Hypertension Patients whose nighttime arterial blood pressure declines less than 10% from day to night (called “nondippers”) are at increased risk for total and cardiovascular mortality,50 as well as all cardiovascular end points,51 frequent or complex ventricular arrhythmias,52 myocardial ischemia,53
IV
IV
IV
IV
IV
IV
IV
IV
25 m/sec 10 m/mV
75 m/sec 100 m/mV
25 m/sec 10 m/mV 25 m/sec 10 m/mV
03-Jul-2007 04 26 15
62 BPM
Figure 117-5 High-resolution template showing T-wave alternans (65 µV) in precordial lead V3 in superimposed electrocardiographic (ECG) waveforms from a nighttime ambulatory ECG recording of a patient with heart failure and left ventricular dysfunction enrolled in the ambulatory electrocardiographic (AECG) substudy of the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). The associated ECG strip is also provided. (From Stein PK, Sanghavi D, Domitrovich PP, et al. Ambulatory ECG-based T-wave alternans predicts sudden cardiac death in high-risk post-MI patients with left ventricular dysfunction in the EPHESUS Study. J Cardiovasc Electrophysiol 2008;19:1037-1042.)
CHAPTER 117 • Sleep-Related Cardiac Risk 1359
Coronary stenosis
Baseline 300
20 sec
HR (bpm) 0 200 AP (mm Hg) 0 200 CBF (ml/min) 0 +5000
x2
dP/dt (mm Hg/sec) -5000 11.7 PWT (mm) 6.9 15.8 AWT (mm) 7.9 Non-REM sleep
REM sleep
Figure 117-6 Representative tracings for hemodynamic variables at baseline (prior to stenosis) and during non–rapid eye movement (non-REM) (single arrow) and REM sleep (double arrow) in the presence of coronary stenosis. Non-REM sleep initiated a decrease in arterial pressure (AP), resulting in akinesis in the anterior wall (stenotic region). REM sleep induced a rapid increase in heart rate (HR), AP, and dP/dtmax (rate of change of left ventricular pressure). The onset of REM sleep increased coronary blood flow, which returned anterior wall function to the poststenotic condition prior to the onset of non-REM sleep (see expanded tracing in box). AWT, anterior wall thickness; CBF, coronary blood flow; PWT, posterior wall thickness. (From Kim SJ, Kuklov A, Kehoe RF, et al. Sleep-induced hypotension precipitates severe myocardial ischemia. Sleep 2008;31:1215-1220.)
cerebrovascular insult,54 and increased organ damage, including cardiac hypertrophy.55 The absence of a nocturnal decline in blood pressure may be an important marker of complications among patients with type 1 diabetes,56 and it may be reflected in the significant incidence of death at 2:00 am to 4:00 am among hypertensive women reported by Mitler and colleagues (Fig. 117-7).57 Faulty baroreceptor activation may account for the fact that arterial blood pressure during sleep remains significantly elevated in these hypertensive patients, who typically show evidence of central hypersympathetic nerve activity with an increased number of microarousals, a reduced length and depth of NREM sleep, and a shortened REM latency. Blunted endothelium-dependent vasodilation is also implicated. Heart Failure Excess mortality risk attends chronic congestive heart failure, particularly among the 40% to 80% of heart failure patients with either obstructive or central sleep apnea. These sleep-related breathing disorders may contribute to the severity of disease—specifically, to remodeling of cardiac chambers and left ventricular diastolic dysfunction as well as to T-wave alternans, a marker of vulnerability to ventricular arrhythmias and sudden cardiac
death.42,56 In patients with systolic heart failure, central sleep apnea, severe right ventricular systolic dysfunction, and low diastolic blood pressure are associated with increased mortality risks.59 Treatment of apnea with continuous positive airway pressure, medications, or devices frequently lessens heart failure symptoms and mortality risk. Diagnostic and treatment strategies are discussed in Chapter 122. Elderly Patients Elderly individuals’ (particularly women’s) reports of daytime sleepiness, suggesting poor quality of sleep, are associated with mortality, cardiovascular morbidity and mortality, MI, and congestive heart failure.60 Depression, poor health, daytime angina, a limited activity level, and cardiac arrhythmias may accompany disturbed sleep in elderly individuals. Initiating a moderately intense exercise program significantly improves sleep quality61 and autonomic status62 in formerly sedentary older people. Nocturnal myocardial ischemia is not uncommon in older patients with vascular disease who experience regular episodes of oxygen desaturation and increased heart rate. Conflicting evidence has been presented of increased risk for nighttime compared with daytime MI and sudden
1360 PART II / Section 14 • Cardiovascular Disorders
FEMALE DEATHS FROM HYPERTENSIVE DISEASE 10 9
n = 52
Deaths/ 2 hr interval
8 7 6 5 4 3 2 1 0 12 to 2
2 to 4
4 to 6
6 to 8
8 to 10
10 to noon
Noon to 2
2 to 4
4 to 6
6 to 8
8 to 10
10 to 12
Time Figure 117-7 The temporal distribution of female deaths attributed to hypertensive disease peaked at 2:00 AM to 4:00 AM. The temporal concentration was statistically significant (P < .01). Data were derived from a 4600-person (>8%) sample of deaths due to disease in New York City in 1979. (Reprinted from Mitler MM, Hajdukovic RM, Shafor R, et al. When people die: cause of death versus time of death. Am J Med 1987;82:266-274, copyright 1987, with permission from Excerpta Medica, Inc.)
cardiac death in the elderly.46,47,63 Impaired baroreceptor sensitivity,64 a measure of the capacity for reflex vagus nerve activation,5 and increased low-frequency power of HRV65 are evident at night in susceptible elderly patients. Given this autonomic background, it is not surprising that nighttime multifocal activity in elderly patients is a predictor of cardiac mortality.
❖ Clinical Pearls Sleep exerts a major impact on the health of the patient with cardiac disease, through both direct cardiovascular influences and sleep-disordered breathing.66 In a sense, the diseased heart and lungs are unwitting victims of the needs of the sleeping brain, which commands dramatic alterations in autonomic and respiratory activity. A sizeable population experiences cardiac events during sleep, with identifiable high-risk groups (see Table 117-1). Sleep also presents unusual opportunities to monitor the patient with cardiac disease, because there is growing appreciation of the fact that nighttime heart rate, blood pressure, myocardial ischemia, arrhythmias, and respiratory disturbances carry predictive value for daytime events (see Box 117-1). Daytime tests cannot substitute for nighttime monitoring of the patient with cardiac disease, because exercise treadmill testing and daytime ambulatory monitoring cannot replicate the autonomic, hemodynamic, or respiratory challenges that uniquely accompany sleep. Improved identification of the precise triggers of nocturnal cardiac events may be anticipated when technologies are integrated for monitoring sleep state, respiration, oxygen desaturation, and cardiovascular variables.
Acknowledgments The authors thank Sandra Verrier for her editorial contributions. REFERENCES 1. Lavery CE, Mittleman MA, Cohen MC, et al. Nonuniform nighttime distribution of acute cardiac events: a possible effect of sleep states. Circulation 1997;5:3321-3327. 1a. Padeletti M, Vignini S, Ricciardi G, et al. Sleep disordered breathing and arrhythmia burden in pacemaker recipients. Pacing Clin Electrophysiol 2010 Aug 24. [Epub ahead of print] 1b. Matiello M, Nadal M, Tamborero D, et al. Low efficacy of atrial fibrillation ablation in severe obstructive sleep apnoea patients. Europace 2010;12:1084-1089. 1c. Pedrosa RP, Drager LF, Genta PR, et al. Obstructive sleep apnea is common and independently associated with atrial fibrillation in patients with hypertrophic cardiomyopathy. Chest 2010;137:10781084. 1d. Monahan K, Storfer-Isser A, Mehra R, et al. Triggering of nocturnal arrhythmias by sleep-disordered breathing events. J Am Coll Cardiol 2009;54:1797-1804. 1e. Bitter T, Langer C, Vogt J, et al. Sleep-disordered breathing in patients with atrial fibrillation and normal systolic left ventricular function. Dtsch Arztebl Int 2009;106:164-170. 1f. Mehra R, Stone KL, Varosy PD, et al. Nocturnal arrhythmias across a spectrum of obstructive and central sleep-disordered breathing in older men: outcomes of sleep disorders in older men (MrOS sleep) study. Arch Intern Med 2009;169:1147-1155. 2. Somers VK, Dyken ME, Mark AL, et al. Sympathetic nerve activity during sleep in normal subjects. N Engl J Med 1993;328: 303-307. 3. Young T, Palta M, Dempsey J, et al. The occurrence of sleepdisordered breathing among middle-aged adults. N Engl J Med 1993;328:1230-1235. 4. Mancia G. Autonomic modulation of the cardiovascular system during sleep. N Engl J Med 1993;328:347-349. 5. Smyth HS, Sleight P, Pickering GW. Reflex regulation of arterial pressure during sleep in man: a quantitative method of assessing baroreflex sensitivity. Circ Res 1969;24:109-121. 6. Hornyak M, Cejnar M, Elam M, et al. Sympathetic muscle nerve activity during sleep in man. Brain 1991;114:1281-1295.
7. Bonnet MH, Arand DL. Heart rate variability: sleep stage, time of night, and arousal influences. Electroencephalogr Clin Neurophysiol 1997;102:390-396. 8. Hobson JA, Spagna T, Malenka R. Ethology of sleep studied with time-lapse photography: postural immobility and sleep-cycle phase in humans. Science 1979;201:1251-1253. 9. Maquet P, Peters J, Aerts J, et al. Functional neuroanatomy of human rapid-eye-movement sleep and dreaming. Nature 1996; 383:163-166. 10. Dodt C, Breckling U, Derad I, et al. Plasma epinephrine and norepinephrine concentrations of healthy humans associated with nighttime sleep and morning arousal. Hypertension 1997;30:71-76. 11. Vanoli E, Adamson PB, Ba-Lin, et al. Heart rate variability during specific sleep stages: a comparison of healthy subjects with patients after myocardial infarction. Circulation 1995;91:1918-1922. 12. Otzenberger H, Simon C, Gronfier C, et al. Temporal relationship between dynamic heart rate variability and electroencephalographic activity during sleep in man. Neurosci Lett 1997;229:173-176. 13. Huikuri HV, Niemela MJ, Ojala S, et al. Circadian rhythms of frequency domain measures of heart rate variability in healthy subjects and patients with coronary artery disease: effects of arousal and upright posture. Circulation 1994;90:121-126. 14. Vardas PE, Kochiadakis GE, Manios EG, et al. Spectral analysis of heart rate variability before and during episodes of nocturnal ischaemia in patients with extensive coronary artery disease. Eur Heart J 1996;17:388-393. 15. Cerati D, Nador F, Maestri R, et al. Influence of residual ischaemia on heart rate variability after myocardial infarction. Eur Heart J 1997;18:78-83. 16. Aronson D, Weinrauch LA, D’Elia JA, et al. Circadian patterns of heart rate variability, fibrinolytic activity, and hemostatic factors in type I diabetes mellitus with cardiac autonomic neuropathy. Am J Cardiol 1999;84:449-453. 17. Home E. Life of John Hunter. In: Major RH, editor: Classic descriptions of disease. 4th ed. Springfield, Ill: Charles C Thomas; 1955. p. 423. 18. MacWilliam JA. Blood pressure and heart action in sleep and dreams: their relation to haemorrhages, angina, and sudden death. BMJ 1923;22:1196-2000. 19. Kales A, Kales JD. Evaluation, diagnosis, and treatment of clinical conditions related to sleep. JAMA 1970;213:2229-2232. 20. Nowlin JB, Troyer WG Jr, Collins WS, et al. The association of nocturnal angina pectoris with dreaming. Ann Intern Med 1965;63:1040-1046. 21. Quyyumi AA, Wright CA, Mockus LJ, et al. Mechanisms of nocturnal angina pectoris: Importance of increased myocardial oxygen demand in patients with severe coronary artery disease. Lancet 1984;1:1207-1209. 22. Deedwania PC, Nelson JR. Pathophysiology of silent myocardial ischemia during daily life: hemodynamic evaluation by simultaneous electrocardiographic and blood pressure monitoring. Circulation 1990;92:1296-1304. 23. Behar S, Reicher-Reiss H, Goldbourt U, et al. Circadian variation in pain onset in unstable angina pectoris. Am J Cardiol 1991;67: 91-93. 24. Andrews TC, Fenton T, Toyosaki N, et al., for the Angina and Silent Ischemia Study Group (ASIS): subsets of ambulatory myocardial ischemia based on heart rate activity: circadian distribution and response to anti-ischemic medication. Circulation 1993;98:92-100. 25. Patel DJ, Knight CJ, Holdright DR, et al. Pathophysiology of transient myocardial ischemia in acute coronary syndromes: characterization by continuous ST-segment monitoring. Circulation 1997; 95:1185-1192. 26. Benhorin J, Banai S, Moriel M, et al. Circadian variations in ischemic threshold and their relation to the occurrence of ischemic episodes. Circulation 1993;97:808-814. 27. Broughton R, Baron R. Sleep patterns in the intensive care unit and on the ward after acute myocardial infarction. Electroencephalogr Clin Neurophysiol 1978;45:348-360. 28. Figueras J, Cinca J, Balda F, et al. Resting angina with fixed coronary artery stenosis: nocturnal decline in ischemic threshold. Circulation 1986;74:1248-1254. 29. Bridges AB, McLaren M, Scott NA, et al. Circadian variation of tissue plasminogen activator and its inhibitor, von Willebrand factor antigen, and prostacyclin stimulating factor in men with ischemic heart disease. Br Heart J 1993;69:121-124.
CHAPTER 117 • Sleep-Related Cardiac Risk 1361 30. Selwyn AP, Fox K, Eves M, et al. Myocardial ischaemia in patients with frequent angina pectoris. BMJ 1978;2:1594-1596. 31. Cannon CP, McCabe CH, Stone PH, et al. Circadian variation in the onset of unstable angina and non-Q-wave acute myocardial infarction (the TIMI III Registry and TIMI IIIB). Am J Cardiol 1997;79:253-258. 32. Floras JS. Antihypertensive treatment, myocardial infarction, and nocturnal myocardial ischaemia. Lancet 1988;2:994-996. 33. Parker JD, Testa MA, Jimenez AH, et al. Morning increase in ambulatory ischemia in patients with stable coronary artery disease: importance of physical activity and increased cardiac demand. Circulation 1994;99:604-614. 34. Galatius-Jensen S, Hansen J, Rasmussen V, et al. Nocturnal hypoxemia after myocardial infarction: association with nocturnal myocardial ischaemia and arrhythmias. Br Heart J 1994;72:23-30. 35. Spudge DD, Seires SF, Maron BJ, et al. Prevalence of arrhythmias during 24-hour Holter electrocardiographic monitoring and exercise testing in patients with obstructive and nonobstructive hypertrophic cardiomyopathy. Circulation 1979;59:866-875. 36. Javaheri S. Effects of continuous positive airway pressure on sleep apnea and ventricular irritability in patients with heart failure. Circulation 2000;101:392-397. 37. Cripps T, Rocker G, Stradling J. Nocturnal hypoxia and arrhythmias in patients with impaired left ventricular function. Br Heart J 1992;68:382-386. 38. Mickley H, Pless P, Nielsen JR, et al. Circadian variation of transient myocardial ischemia in the early out-of-hospital period after first acute myocardial infarction. Am J Cardiol 1991;67:927-932. 39. Brugger P, Marktl W, Herold M. Impaired nocturnal secretion of melatonin in coronary heart disease. Lancet 1995;345:1408. 40. Verrier RL, Nearing BD, LaRovere MT, et al. Ambulatory ECGbased tracking of T-wave alternans in post-myocardial infarction patients to assess risk of cardiac arrest or arrhythmic death. J Cardiovasc Electrophysiol 2003;14:705-711. 41. Stein PK, Sanghavi D, Domitrovich PP, et al. Ambulatory ECGbased T-wave alternans predicts sudden cardiac death in high-risk post-MI patients with left ventricular dysfunction in the EPHESUS Study. J Cardiovasc Electrophysiol 2008;19:1037-1042. 42. Verrier RL, Kumar K, Nearing BD. Basis for sudden cardiac death prediction by T-wave alternans from an integrative physiology perspective [Invited review]. Heart Rhythm 2009;6(3):416422. 43. Hung J, Whitford EG, Parsons RW, et al. Association of sleep apnoea with myocardial infarction in men. Lancet 1990;336: 261-264. 44. Kim SJ, Kuklov A, Kehoe RF, et al. Sleep-induced hypotension precipitates severe myocardial ischemia. Sleep 2008;31:1215-1220. 45. Kleiman NS, Schechtman KB, Young PM, et al., and the Diltiazem Reinfarction Study Investigators. Lack of diurnal variation in the onset of non-Q-wave infarction. Circulation 1990;91:548-555. 46. Hansen O, Johannsson BW, Gullberg B. Circadian distribution of onset of acute myocardial infarction in subgroups from analysis of 10,791 patients treated in a single center. Am J Cardiol 1992; 69:1003-1008. 47. Hjalmarson A, Gilpin EA, Nicod P, et al. Differing circadian patterns of symptom onset in subgroups of patients with acute myocardial infarction. Circulation 1989;90:267-275. 48. Rana JS, Mukamal KJ, Morgan JP, et al. Circadian variation in the onset of myocardial infarction: effect of duration of diabetes. Diabetes 2003;52:1464-1468. 49. Mukamal KJ, Muller JA, Maclure M, et al. Increased risk of congestive heart failure among infarctions with nighttime onset. Am Heart J 2000;140:439-442. 50. Fagard RH, Celis H, Thijs L, et al. Daytime and nighttime blood pressure as predictors of death and cause-specific cardiovascular events in hypertension. Hypertension 2008;51:55-61. 51. Staessen JA, Thijs L, Fagard R, et al. Predicting cardiovascular risk using conventional vs ambulatory blood pressure in older patients with systolic hypertension. Systolic Hypertension in Europe Trial Investigators. JAMA 1999;282:539-546. 52. Schillaci G, Verdecchia P, Borgioni C, et al. Association between persistent pressure overload and ventricular arrhythmias in essential hypertension. Hypertension 1996;28:284-289. 53. Pierdomenico SD, Bucci A, Costantini F, et al. Circadian blood pressure changes and myocardial ischemia in hypertensive patients with coronary artery disease. J Am Coll Cardiol 1998;31:1627-1634.
1362 PART II / Section 14 • Cardiovascular Disorders 54. Schwartz GL, Bailey KR, Mosley T, et al. Association of ambulatory blood pressure with ischemic brain injury. Hypertension 2007; 49:1228-1234. 55. Verdecchia P, Schillaci G, Guerrieri M, et al. Circadian blood pressure changes and left ventricular hypertrophy in essential hypertension. Circulation 1990;91:523-536. 56. Lurbe E, Redon J, Kesani A, et al. Increase in nocturnal blood pressure and progression to microalbuminuria in type 1 diabetes. N Engl J Med 2002;347:797-805. 57. Mitler MM, Hajdukovic RM, Shafor R, et al. When people die: cause of death versus time of death. Am J Med 1987;82:266-274. 58. Takasugi N, Nishigaki K, Kubota T, et al. Sleep apnoea induces cardiac electrical instability assessed by T-wave alternans in patients with congestive heart failure. Eur J Heart Fail 2009;11:1063-1070. 59. Javaheri S, Shukla R, Zeigler H, et al. Central sleep apnea, right ventricular dysfunction and low diastolic blood pressure are predictors of mortality in systolic heart failure. J Am Coll Cardiol 2007;49: 2028-2034. 60. Newman AB, Spiekerman CF, Enright P, et al. Daytime sleepiness predicts mortality and cardiovascular disease in older adults: the Cardiovascular Health Study Research Group. J Am Geriatr Soc 2000;48:115-123. 61. King AC, Oman RF, Brassington GS, et al. Moderate-intensity exercise and self-rated quality of sleep in older adults: a randomized controlled trial. JAMA 1997;277:32-37.
62. Stein PK, Ehsani AA, Domitrovich PP, et al. Effect of exercise training on heart rate variability in healthy older adults. Am Heart J 1999;138:567-576. 63. Aronow WS, Ahn C. Circadian variation of primary cardiac arrest or sudden cardiac death in patients aged 62 to 100 years (mean 82). Am J Cardiol 1993;71:1455-1456. 64. Parati G, Frattola A, Di Rienzo M, et al. Effects of aging on 24-h dynamic baroreceptor control of heart rate in ambulant subjects. Am J Physiol 1995;268:H1606-H1612. 65. Yamasaki Y, Kodama M, Matsuhisa M, et al. Diurnal heart rate variability in healthy subjects: effects of aging and sex difference. Am J Physiol 1996;271:H303-H310. 66. Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease: an American Heart Association/American College of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council on Cardiovascular Nursing. In Collaboration with the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health). Circulation 2008;118:1080-1111.
Cardiac Arrhythmogenesis during Sleep: Mechanisms, Diagnosis, and Therapy Richard L. Verrier and Mark E. Josephson Abstract The pronounced sleep state–dependent changes in autonomic nervous system activity and respiration can provoke both atrial and ventricular arrhythmias in patients with cardiovascular disease. Mortality is most common during sleep in the distinct syndromes of sudden infant death, sudden unexplained nocturnal death, and the Brugada syndrome, each of which has been linked to genetic abnormalities. Because the etiology of nocturnal arrhythmias is multifactorial, their man-
Cardiac arrhythmias are prevalent in the 13.5 million Americans with heart disease, with potentially severe consequences. Approximately 15% of sudden cardiac deaths, which result from lethal ventricular arrhythmias, occur during sleep, and most atrial arrhythmias in patients younger than 61 years have their onset at nighttime. Sleep apnea profoundly alters autonomic nervous system activity and increases risk of arrhythmia, hypertension, and myocardial infarction. (See Chapter 119.) Lack of streamlined technology for concurrent monitoring of sleep state, electrocardiogram, oxygen saturation, and respiration continues to hamper diagnosis and evaluation of therapy of these arrhythmias. We will review the current state of knowledge regarding epidemiology, risk factors, pathogenesis, and treatment options for each nocturnal arrhythmia type.
VENTRICULAR ARRHYTHMIAS Malignant ventricular arrhythmias are usually suppressed during sleep, as is evidenced by the nocturnal trough in incidence of myocardial infarction, sudden cardiac death, implantable cardioverter–defibrillator discharge, myocardial ischemic events, and arrhythmias in patients with ischemic heart disease.1,2 This decrement coincides with lessened metabolic demands during non–rapid eye movement (NREM) sleep, which occupies approximately 80% of sleep time. However, sleep is not entirely free of risk because the nocturnal incidence of sudden cardiac death, which is attributable to ventricular fibrillation, has been calculated at approximately 15%,3 or 48,750 cases annually in the United States alone. Moreover, the nonuniformity of the nighttime distribution of these events (Fig. 118-1)3 suggests physiologic triggering that may be amenable to monitoring for improved diagnosis and therapy. Surges in cardiac sympathetic nerve activity during REM sleep have been implicated in nocturnal ventricular arrhythmias and myocardial ischemia4-7 (see Chapter 19). The specific mechanisms of REM-induced cardiac events include direct effects on electrophysiologic status or indirect consequences of heart rate and arterial blood pressure accelerations, which may disrupt plaques and lead to intraarterial platelet aggregates, releasing proarrhythmic con-
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agement necessitates a comprehensive approach and consideration of a host of cardiovascular and respiratory factors. Treatment must be tailored to contain neurally induced arrhythmias while avoiding exacerbation of the hypotension of non–rapid eye movement sleep. The proarrhythmic potential of class III antiarrhythmic agents (potassium channel blockers) for patients with significant heart rate pauses and the sleep-disrupting effect of medications must be considered.
stituents such as thromboxane A2.8 Myocardial ischemia or other changes in cardiac substrate and mechanical function resulting from disease,9 infarction,10 or ageing11 can amplify nocturnal electrical instability. Oxygen desaturation may trigger nighttime ventricular tachycardia in patients with cardiac disease in the subacute phase after myocardial infarction10 or in those with heart failure.9 Hypoxemia and tachycardia frequently occur together during sleep after major surgery and may promote myocardial ischemia.12 Frequent or complex arrhythmias are also characteristic of hypertensive patients in whom the typical nocturnal trough in blood pressure is not observed.13 The nocturnal increase in QT-interval dispersion among survivors of sudden cardiac death,14 acute myocardial infarction,15 and heart failure15 provides evidence of their increased vulnerability to cardiac arrhythmias at night. REM-related nocturnal arrhythmogenesis may have a significant affective component. REM sleep dreams, which may be vivid, bizarre, and emotionally intense, commonly generate the emotions of anger and fear. Because these emotions have been linked in wakefulness to the onset of myocardial infarction and sudden death,16 it is reasonable to hypothesize that when these affective states are evoked during dreaming, they may trigger lethal events. This possibility is illustrated by a case report of recurrence of ventricular fibrillation in a 39-year-old man with normal coronary arteries and cardiac function while sleeping. A subsequent sleep study determined that ventricular premature beats were substantially increased during REM and that dreams at the same hour that fibrillation had occurred were emotionally charged.17 In some cases, arrhythmia frequency may be enhanced during NREM sleep, when latent automatic foci are exposed by the generalized reduction in heart rate after withdrawal of overdrive suppression, or when hypotension exacerbates impaired coronary perfusion. Therapy In most cases, an electrically unstable substrate underlies the propensity to develop nocturnal ventricular arrhythmias, and treatment is similar to that for daytime arrhythmias. If surges in sympathetic nerve activity, which typically 1363
1364 PART II / Section 14 • Cardiovascular Disorders
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Figure 118-1 A, Hourly incidence of sudden cardiac death (SCD) onset between midnight and 5:59 AM from 12 studies enrolling 1981 patients. The number of sudden cardiac deaths observed each hour is indicated above each bar. B, Hourly incidence of automatic implantable cardioverter defibrillator (AICD) discharge between midnight and 5:59 AM from seven studies enrolling 1197 patients, who experienced 1200 discharges during the nocturnal period. The number of discharges observed each hour is indicated above each bar. (From Lavery CE, Mittleman MA, Cohen MC, et al. Nonuniform nighttime distribution of acute cardiac events: a possible effect of sleep states. Circulation 1997;5:3321-3327.)
occur during REM sleep and dreaming, are suspected, beta-adrenergic receptor blockade therapy may prove helpful, with careful attention to avoiding medications that disrupt sleep.18 In treating hypertensive patients, it is important to appreciate Mancia’s19 suggestion that pharmacologic therapy that exacerbates the hypotensive effect of NREM sleep may introduce the potential risk of thrombosis and embolism in patients with stenotic lesions in the heart or brain. Floras20 determined that the nocturnal incidence of myocardial infarction was not diminished in patients treated with antihypertensive agents and suggested that the agents induced nocturnal hypotension. Thus, special attention should be given to the hemodynamic effects of antihypertensive drugs and vasodilators to avoid precipitating cardiac events by inducing profound hypotension. The importance of ruling out “white coat” hypertension is underscored because more than 30% of individuals with
elevated blood pressure readings in the physician’s office or hospital prove to be normotensive during daily life as documented by ambulatory blood pressure monitoring.21 Nighttime onset of ventricular arrhythmias may also indicate provocation by disturbed breathing, which can be treated by continuous positive airway pressure.
NOCTURNAL ASYSTOLE AND QT-INTERVAL PROLONGATION Sinus pauses of less than 2 seconds, prolonged atrioventricular (AV) conduction, Wenckebach AV block, and bradycardia are well documented in normal populations during sleep and are attributed to effects of increased parasympathetic activity on AV node conduction.22,23 These asystoles are more frequent in individuals who are young24,25 or physically fit, such as athletes26,27 and heavy laborers.28 More extreme cases were observed by Guilleminault and colleagues,29 who reported periods of sinus arrest of up to 9 seconds during REM sleep in young adults with apparently normal cardiac function. It was concluded that the nocturnal asystoles were the result of exaggerated, if not abnormally elevated, vagal tone, because muscarinic receptor blockers significantly reduced the duration of the nocturnal asystoles but did not prevent them. No further therapeutic intervention was warranted. However, in patients with cardiac disease, especially those taking class III antiarrhythmic drugs (potassium channel–blocking agents), nocturnal asystolic events can set the stage for ventricular arrhythmias. Such prolongation of cycle length can facilitate the development of early afterdepolarizations and the lethal arrhythmia torsades de pointes. In patients with damaged endothelium resulting from coronary atherosclerosis, the acetylcholine released by surges in vagus nerve activity could result in vasoconstriction rather than vasodilation because of impaired release of endothelium-derived relaxing factor.30 Nocturnal heart rate pauses may be particularly arrhythmogenic in subsets of patients with the long QT syndrome, specifically LQT2 and LQT3, who have mutations on the sodium channel, voltage-gated, type V, alpha gene (SCN5A).31 The lethal arrhythmias occur almost exclusively at rest or during sleep, when the QT interval is typically prolonged32 (see Sudden Infant Death Syndrome, later). Therapy Ascertaining whether patients exhibit nocturnal heart rate pauses is important when treating individuals for whom class III antiarrhythmic drugs (potassium channel blockers) are the primary option.
ATRIAL FIBRILLATION In the 2.5 million U.S. patients with atrial fibrillation, which has serious consequences in terms of increased morbidity and mortality,33 it is likely that 10% to 25% of the arrhythmias are facilitated by vagal influences. This has been termed vagally mediated atrial fibrillation. Several investigators have reported nocturnal peaks in onset of paroxysmal atrial fibrillation.34-36 A significant midnight to 2:00 am peak in atrial fibrillation onset and a higher average nocturnal incidence were documented
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Figure 118-2 Hourly total duration of paroxysmal atrial fibrillation in younger (<60 yr; red bars) and older patients (green bars). The single harmonic fit of the data from the younger patients is shown by the unbroken line. The triple harmonic fit in the older patients is shown by the broken line. A prominent monophasic circadian rhythm is present in younger patients, in contrast to a toneless triphasic rhythm in older patients. (From Yamashita T, Murakawa Y, Hayami N, et al. Relation between aging and circadian variation of paroxysmal atrial fibrillation. Am J Cardiol 1998;82:1364-1367.)
CHAPTER 118 • Cardiac Arrhythmogenesis during Sleep 1365
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by Rostagno and colleagues in their review of records from 10 years of responses by mobile coronary care units staffed by cardiologists in Florence, Italy.34 This arrhythmia was also found to exhibit a peak in frequency of onset at midnight in a Japanese population 60 years of age or younger. The maximal duration of the arrhythmia (77 ± 27 minutes per episode) was also greatest between midnight and 6:00 am (Fig. 118-2).35 Other investigators characterized a 4:00 am to 5:00 am peak in onset of paroxysmal atrial fibrillation that was refractory to antiarrhythmic drugs in a 3-month study of 67 patients with implantable cardioverters.36 The 514 recorded episodes with an atrial rate of greater than 220 beats per minute lasted more than 1 minute before termination by pacing or spontaneous reversion. A potential contribution of sympathetic nerve activity is implicated by the timing of these bouts of atrial fibrillation, which occurred during a period of sleep when REM typically emerges. However, the potential of REM sleep to trigger the arrhythmia was not discussed. Records of concurrent monitoring of sleep and nocturnal onset of atrial fibrillation are rare (Fig. 118-3).37 In the case illustrated, disruption of the nocturnal trough in heart rate disclosed sleep-related atrial fibrillation. Available evidence indicates that nocturnal atrial fibrillation is provoked during periods of intense vagus nerve activity, as indicated by heart rate variability studies,38,39 and the presence of bradycardia,40 in individuals with structurally normal hearts. Enhanced adrenergic activity may interact in a complex manner with changes in vagal tone to affect atrial refractoriness and dispersion of repolarization and alter intraatrial conduction, thus increasing the propensity to develop this arrhythmia.33,40 The high level of vagus nerve tone maintained during slow-wave sleep has the capacity to exacerbate atrial fibrillation in patients whose atria are particularly prone to the arrhythmogenic influence of acetylcholine.33
(1 min. HR – 83)
B Figure 118-3 A, Heart rate (HR) trend from an ambulatory electrocardiogram (AECG) showing a normal circadian rhythm with a sleep-induced decrease in heart rate. B, Heart rate trend from an AECG in our patient shows a nocturnal increase in heart rate caused by paroxysmal atrial fibrillation at the onset of sleep and a drop in heart rate after awakening resulting from spontaneous conversion to sinus rhythm. The ECG (below) documents atrial fibrillation during the sleep period. (From Singh J, Mela T, Ruskin J. Images in cardiovascular medicine: sleep [vagal]-induced atrial fibrillation. Circulation 2004;110: e32-e33.)
1366 PART II / Section 14 • Cardiovascular Disorders
Risk of atrial fibrillation is doubled if breathing during sleep is disordered,41 because apnea can provoke nocturnal hypoxemia, sympathetic nerve activity, and hemodynamic stress.42-42d Obstructive apnea–induced surges in blood pressure distend atrial chambers and can activate stretch receptors. Incidence of atrial fibrillation is strongly predicted by nocturnal oxygen desaturation in subjects less than 65 years old and by heart failure in older subjects.43 Therapy Medical therapy is similar to that for patients whose arrhythmias occur during the day, including therapy to control rate or terminate the arrhythmia pharmacologically or with an atrial cardioverter–defibrillator. As nighttime atrial fibrillation is classed as “vagally mediated,” anticholinergic agents such as disopyramide or flecainide are sometimes helpful to prevent recurrences; adrenergic blocking drugs or digitalis sometimes worsen symptoms.44 In addition, individuals with nocturnal onset of atrial fibrillation should be monitored for the presence of sleep-disordered breathing, which can be effectively treated by continuous positive airway pressure. Treatment of the atrial fibrillation alone in a patient with untreated sleep disordered breathing may result in an unfavorable outcome.44a
SUDDEN INFANT DEATH SYNDROME Sudden infant death syndrome (SIDS), the leading cause of mortality in infants between 1 week and 1 year of age, occurs during sleep.45 The syndrome is a diagnosis of exclusion; that is, it includes all causes that remain unexplained after a thorough case investigation, including an autopsy, examination of the death scene, and review of the clinical history. Thus, SIDS, which took a toll of 2234 infants in 2001 in the United States46 or 8.1% of infant deaths, may be attributable to a variety of etiologies that challenge the developing cardiorespiratory system. The fatal event in SIDS victims is characterized by hypotension and bradycardia47 and appears to be attributable to a deficit in the normal reflex coordination of heart rate, arterial blood pressure, and respiration during sleep.48 This failure to respond to cardiorespiratory challenges during sleep may result from a binding deficit in the arcuate nucleus of SIDS infants,48 because muscarinic cholinergic activity in this structure at the ventricular medullary surface is postulated to be involved in cardiorespiratory control. Heart rates in infants who later died of SIDS are generally higher and exhibit a reduced range, suggesting altered autonomic control.49 Autonomic instability has also been documented in NREM sleep in infants with aborted SIDS events.50 Repolarization abnormalities have also been observed. Recent evidence from a 19-year, prospective, multicenter observational study of 34,442 infants determined that significant prolongation (35 msec or more) of the QT interval characterized the 24 (0.07%) infants who died of SIDS within the first year of life.51 These results suggest that some SIDS cases may be attributed to a genetic defect that produces a developmental abnormality in cardiac sympathetic innervation and alters repolarization to increase the risk of ventricular arrhythmia. These repolarization abnormalities typify infants and children with the long QT syndrome genotype linked to chromosome 3 (LQT3). Mutations in the sodium channel gene SCN5A are the most common causes
of long QT syndrome and are responsible for the arrhythmias and reduced heart rates. The genetic locus of the defect and the length of the QT interval are independent predictors of risk.52 T-wave alternans, an electrocardiographic indicator of heightened vulnerability to sudden cardiac death,53 has been reported in infants who became SIDS victims54,55 or who were successfully treated with pacing56 or beta-blockade therapy.57,58 The latter therapy diminished T-wave alternans, indicating antiarrhythmic efficacy. Among environmental influences, the increased risk of SIDS during the winter season is well documented59,60 and is not related to bronchiolitis.61 A genetic susceptibility that may interact with environmental factors has been implicated by a 5.8-fold increase in recurrence of SIDS within families.62 Tishler and colleagues63 reported a significant incidence of deficits in ventilatory responses to hypoxia in families with apnea. Conflicting evidence has been provided regarding the relative increase in risk attributable to prone (face-down) sleeping.64-68 Passive cigarette smoking is a highly significant modifiable risk factor in SIDS. A reduction of 61% in the number of SIDS deaths has been projected if smoking were eliminated from infants’ environments.63-66,69 A dose-dependent effect has been demonstrated.64 Maternal smoking during gestation is also implicated.69-71 Established SIDS risk factors of preterm birth and low birth weight increased risk more than 15-fold among smokers71 but not at all among nonsmokers. Illegal drug use increases risk of SIDS by more than fourfold.69 The mechanisms may include impairment in chemoreceptor responsiveness resulting from decreased sensitivity to carbon dioxide in infants of substance-abusing mothers.72 The increase in SIDS due to passive smoking may be attributable to nicotine’s adverse effect on chemoreceptor activation of respiration,73 dulling the arousal response to hypoxia.74 Nicotine and its metabolites have been found at autopsy in the pericardial fluid of SIDS infants.75,76 Epicardial nicotine is associated with hypopnea77 and affects the sinoatrial node and epicardial neural fibers to induce hypotension and bradycardia,78,79 the documented symptomatology of the final event in SIDS infants.47 Therapy This profile suggests some straightforward opportunities for intervention, including placing infants in a supine (face-up) position for sleeping and avoidance of maternal smoking during gestation and passive smoking during infancy. Theoretically, sodium channel blockade31 or cardiac pacing31,56 might be useful in treating infants diagnosed with the long QT3 syndrome, but prospective studies are required. Beta-blockade is the current treatment of choice.31,57,58 Assessment of vulnerability to arrhythmias by QT-interval prolongation has been suggested in a prospective study,51 and by T-wave alternans in multiple clinical reports based on ambulatory electrocardiographic (AECG) records.54-58
THE BRUGADA SYNDROME AND SUDDEN UNEXPLAINED NOCTURNAL DEATH The striking phenomenon of sudden death during sleep has been reported in Western adults diagnosed with the Brugada syndrome, which strikes men almost exclusively,
and in young, apparently healthy Southeast Asian men with the sudden unexplained nocturnal death syndrome (SUNDS). The latter syndrome is named lai-tai (“sleep death”) in Laos, pokkuri (“sudden and unexpected death”) in Japan, and bangungut (“to rise and moan in sleep”) in the Philippines. These syndromes probably represent the same disorder, which is characterized by right precordial ST segment elevation.80,81 Deaths are due to lethal ventricular arrhythmias. The Brugada syndrome is considered responsible for 4% to 12% of all sudden cardiac deaths and for approximately 20% of deaths in patients with structurally normal hearts.80 The electrocardiographic abnormality is estimated to be present in approximately 5 per 10,000 inhabitants, and, apart from accidents, in geographic regions where it is widespread, this inherited syndrome is the leading cause of death of men younger than 50 years of age. A single sodium channel mutation in the SCN5A gene identified in an eightgeneration kindred with a high incidence of nocturnal sudden cardiac death, QT-interval prolongation, and Brugada-like electrocardiogram characterizes 20% of Brugada patients; other mutations are suspected. Genetic defects in the sodium channel are also associated with progressive conduction system disease attended by bradycardia. A mechanistic link with enhanced presynaptic norepinephrine recycling has been described.82 Presynaptic sympathetic cardiac dysfunction has been hypothesized based on abnormal iodine-123 metaiodobenzylguanidine (123IMIBG) uptake, with bradycardia-dependent QT prolongation, intrinsic sinus node dysfunction, conduction abnormalities, and absence of ventricular ectopy.83 In the United States, 117 SUNDS deaths were registered among male Southeast Asian immigrants or their descendants from 1981 to 1988.84 Autopsies of those who died of SUNDS have established that cardiovascular disease is absent, but, in some instances, that conduction pathways are developmentally abnormal.81 Companions have reported that the immediate symptoms are onset of agonal respirations during sleep along with vocalization; violent motor activity; nonarousability; rapid, irregular deep breathing; perspiration; heart rate surges; and severe autonomic discharge. Several victims revived by vigorous massage reported sensations of airway obstruction, chest discomfort or pressure, and numb and weak limbs. When these symptoms recurred within weeks to months, they culminated in death.85 Three victims who had been resuscitated from ventricular fibrillation then experienced recurring fibrillation in the hospital during sleep accompanied by similar moaning vocalizations. In these three patients, there was no evidence of atherosclerosis or structural abnormalities and no sleep apnea, but creatine kinase levels were markedly elevated and potassium was depressed. Vagal tone is lower in SUNDS survivors than in healthy individuals, particularly at night.86 Cases have also been reported of lethal ventricular arrhythmias during sleep in adults with other variants of long QT syndrome (LQT7 or type 1 Andersen-Tawil syndrome).87 Therapy Development of effective therapy for these syndromes has been particularly challenging. Currently, implantation of cardioverter–defibrillators appears to be the most effective
CHAPTER 118 • Cardiac Arrhythmogenesis during Sleep 1367
approach in patients with Brugada syndrome80 or SUNDS.81
SLEEP-DISRUPTING EFFECTS OF CARDIAC MEDICATIONS Several important medications that are widely prescribed for patients with cardiac disease, including antihypertensive agents and beta-blockers that cross the blood–brain barrier, have the potential to disrupt sleep.18 In particular, the lipophilic beta-blockers (pindolol, propranolol, and metoprolol) increase the total number of awakenings and total wakefulness compared with placebo and with the nonlipophilic atenolol. Penetration of the blood–brain barrier occurs with prolonged therapy, when these distinctions may become less apparent. In addition, pindolol, which has intrinsic sympathomimetic activity, increases REM latency and, as a result, decreases REM sleep time. Sleep disruption may provoke daytime fatigue and lethargy, symptoms widely reported by patients taking beta-blockers, which may prompt discontinuation of the medication or noncompliance. It has been postulated that the mechanism of sleep disruption by beta-blocking agents is their wellknown tendency to deplete endogenous melatonin,88 a key sleep-regulating hormone that modulates sympathetic nerve activity. An additional important side effect of these beta-blockers18 is their potential to provoke nightmares. Despite these effects, it is the lipophilic beta-blockers (propranolol, metoprolol, carvedilol) that have been shown to reduce the risk of sudden cardiac death. Sleep disturbance has also been documented in conjunction with the widely used antiarrhythmic agent amiodarone.89,90 Neurologic side effects were attributed to amiodarone in 20% to 40% of patients. Optimal antiarrhythmic management with this agent to minimize side effects dictates prescription of lower dosages and close patient monitoring and follow-up. ❖ Clinical Pearl
Diagnosing and treating patients with nocturnal arrhythmias have been hampered by a paucity of information about concurrent autonomic nervous system activity, cardiac electrical instability, oxygen desaturation, and breathing disturbances. It is now possible to assess autonomic nervous system activity by AECG monitoring of noninvasive markers such as heart rate variability, a measure of autonomic nervous system tone, and heart rate turbulence, an indicator of baroreceptor function based on the pattern of heart rhythm recovery after a ventricular premature beat.91 Simultaneous measurement of these indicators, along with clinical history and analysis of cardiac electrical instability with QT-interval dispersion14,15 or T-wave alternans,53,92,93 also possible with AECG monitoring, promises to provide valuable information regarding vulnerability to nocturnal arrhythmias and potential provocation by the autonomic nervous system. Concurrent monitoring of oxygen saturation and respiratory patterns will provide essential information. Increased survival from in-hospital nighttime cardiac arrest can be anticipated with improved monitoring.94
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Rep 1996;45:859-863. 46. National Center for Health Statistics. Deaths: final data for 2001. National Vital Statistics Report 2003;52. Available at http://www. cdc.gov/nchs/data/nvsr/nvsr52/nvsr52_03.pdf. 47. Meny RF, Carroll JL, Carbone MT, et al. Cardiorespiratory recordings from infants dying suddenly and unexpectedly at home. Pediatrics 1994;93:43-49. 48. Kinney HC, Filiano JJ, Sleeper LA, et al. Decreased muscarinic receptor binding in the arcuate nucleus in sudden infant death syndrome. Science 1995;269:1446-1450. 49. Schechtman VL, Harper RK, Harper RM. Aberrant temporal patterning of slow-wave sleep in siblings of SIDS victims. Electroencephalogr Clin Neurophysiol 1995;94:95-102. 50. Pincus SM, Cummins TR, Haddad GG. Heart rate control in normal and aborted-SIDS infants. Am J Physiol 1993;264:R638-R646. 51. Schwartz PJ, Stramba-Badiale M, Segantini A, et al. Prolongation of the QT interval and the sudden infant death syndrome. N Engl J Med 1998;338:1709-1714. 52. Priori SG, Schwartz PJ, Napolitano C, et al. Risk stratification in the long-QT syndrome. N Engl J Med 2003;348:1866-1874. 53. Verrier RL, Nearing BD, LaRovere MT, et al. Ambulatory ECGbased tracking of T-wave alternans in post-myocardial infarction patients to assess risk of cardiac arrest or arrhythmic death. J Cardiovasc Electrophysiol 2003;14:705-711. 54. Smith TA, Mason JM, Bell JS, et al. Sleep apnea and QT interval prolongation: a particularly lethal combination. Am Heart J 1979:97:505-507. 55. Weintraub RG, Gow RM, Wilkinson JL. The congenital long QT syndromes in childhood. J Am Coll Cardiol 1990;16:674-680. 56. Tanel RE, Triedman JK, Walsh EP, et al. High-rate atrial pacing as an innovative bridging therapy in a neonate with congenital long QT syndrome. J Cardiovasc Electrophysiol 1997;8:812-817. 57. Mache CJ, Beitzke A, Haidvogl M, et al. Perinatal manifestations of idiopathic long QT syndrome. Pediatr Cardiol 1996;17:118-121. 58. Bosi G, Cappato R, Priori SG, et al. Complex electrocardiographic findings in a neonate with long QT syndrome. Ital Heart J 2002; 3:605-607. 59. Haglund B, Cnattingius S, Otterblad-Olausson P. Sudden infant death syndrome in Sweden, 1983-1990. Season at death, age at death, and maternal smoking. Am J Epidemiol 1995;142:619-624. 60. Douglas AS, Allan TM, Helms PJ. Seasonality and the sudden infant death syndrome during 1987-9 and 1991-3 in Australia and Britain. BMJ 1996;312:1381-1383. 61. Gupta R, Helms PJ, Jolliffe IT, et al. Seasonal variation in sudden infant death syndrome and bronchiolitis: a common mechanism? Am J Respir Crit Care Med 1996;154:431-435. 62. Oyen N, Skjaerven R, Irgens LM. Population-based recurrence risk of sudden infant death syndrome compared with other infant and fetal deaths. Am J Epidemiol 1996;144:300-305. 63. Tishler PV, Redline S, Ferrette V, et al. The association of sudden unexpected infant death with obstructive sleep apnea. Am J Respir Crit Care Med 1996;153:1857-1863. 64. Dwyer T, Ponsonby AL, Blizzard L, et al. The contribution of changes in the prevalence of prone sleeping position to the decline in sudden infant death syndrome in Tasmania. JAMA 1995; 273:783-789. 65. Klonoff-Cohen HS, Edelstein SL. A case-control study of routine and death scene sleep position and sudden infant death syndrome in Southern California. JAMA 1995;273:790-794. 66. Klonoff-Cohen HS, Edelstein SL, Lefkowitz ES, et al. The effect of passive smoking and tobacco exposure through breast milk on sudden infant death syndrome. JAMA 1995;273:795-798. 67. Fleming PJ, Blair PS, Bacon C, et al. Environment of infants during sleep and risk of the sudden infant death syndrome: Results of 19931995 case-control study for confidential inquiry into stillbirths and deaths in infancy. Confidential enquiry into stillbirths and deaths regional coordinators and researchers. BMJ 1996;313:191-195. 68. Brooke H, Gibson A, Tappin D, et al. Case-control study of sudden infant death syndrome in Scotland, 1992-5. BMJ 1997;314:1516-1520. 69. Blair PS, Fleming PJ, Bensley D, et al. Smoking and the sudden infant death syndrome: results from 1993-5 case-control study for confidential inquiry into stillbirths and deaths in infancy. Confidential Enquiry into Stillbirths and Deaths Regional Coordinators and Researchers. BMJ 1996;313:195-198. 70. MacDorman MF, Cnattingius S, Hoffman HJ, et al. Sudden infant death syndrome and smoking in the United States and Sweden. Am
CHAPTER 118 • Cardiac Arrhythmogenesis during Sleep 1369 J Epidemiol 1997;146:249-257. 71. Schellscheidt J, Oyen N, Jorch G. Interactions between maternal smoking and other prenatal risk factors for sudden infant death syndrome (SIDS). Acta Paediatr 1997;96:857-863. 72. Wingkun JG, Knisely JS, Schnoll SH, et al. Decreased carbon dioxide sensitivity in infants of substance-abusing mothers. Pediatrics 1995;95:864-867. 73. Slotkin TA, Lappi SE, McCook EC, et al. Loss of neonatal hypoxia tolerance after prenatal nicotine exposure: implications for sudden infant death syndrome. Brain Res Bull 1995;38:69-75. 74. Cutz E, Ma TK, Perrin DG, et al. Peripheral chemoreceptors in congenital central hypoventilation syndrome. Am J Respir Crit Care Med 1997;155:358-363. 75. Milerad J, Majs J, Gidlund E. Nicotine and cotinine levels in pericardial fluid in victims of SIDS. Acta Pediatr 1994;93:59-62. 76. Rajs J, Rasten-Almqvist P, Falck G, et al. Sudden infant death syndrome: postmortem findings of nicotine and cotinine in pericardial fluid of infants in relation to morphological changes and position at death. Pediatr Pathol Lab Med 1997;17:83-97. 77. Evans RG, Ludbrook J, Michalicek J. Use of nicotine, bradykinin and veratridine to elicit cardiovascular chemoreflexes in unanesthetized rabbits. Clin Exp Pharmacol Physiol 1991;18:245-254. 78. Staszewska-Barczak J. Prostanoids and cardiac reflexes of sympathetic and vagal origin. Am J Cardiol 1983;52:36A-45A. 79. Barber MJ, Mueller TM, Davies BG, et al. Phenol topically applied to canine left ventricular epicardium interrupts sympathetic but not vagal afferents. Circ Res 1984;55:532-544. 80. Antzelevitch C, Brugada P, Borggrefe M, et al. Brugada syndrome: report of the second consensus conference: endorsed by the Heart Rhythm Society and the European Heart Rhythm Association. Circulation 2005;111:659-670. 81. Nademanee K, Veerakul G, Mower M, et al. Defibrillator versus beta-blockers for unexplained death in Thailand (DEBUT): a randomized clinical trial. Circulation 2003;107:2221-2226. 82. Kies P, Wichter T, Schafers M, et al. Abnormal myocardial presynaptic norepinephrine recycling in patients with Brugada syndrome. Circulation 2004;110:3017-3022. 83. Wichter T, Matheja P, Eckardt L, et al. Cardiac autonomic dysfunction in Brugada syndrome. Circulation 2002;105:702-706. 84. National Center for Health Statistics. Update: sudden unexplained death syndrome among Southeast Asian refugees—United States. MMWR Morb Mortal Wkly Rep 1988;37:568-570. 85. Munger RG. Sudden death in sleep of Laotian-Hmong refugees in Thailand: a case-control study. Am J Public Health 1987;77: 1187-1190. 86. Krittayaphong R, Veerakul G, Bhuripanyo K, et al. Heart rate variability in patients with sudden unexpected cardiac arrest in Thailand. Am J Cardiol 2003;91:77-81. 87. Garcia-Touchard A, Somers VK, Kara T, et al. Ventricular ectopy during REM sleep: implications for nocturnal sudden cardiac death. Nature Clin Pract Cardiovasc Med 2007;4:284-288. 88. Garrick NA, Tamarkin L, Taylor PL, et al. Light and propranolol suppress the nocturnal elevation of serotonin in the cerebro spinal fluid of rhesus monkeys. Science 1983;221:474-476. 89. Bucknall CA, Keeton BR, Curry PV, et al. Intravenous and oral amiodarone for arrhythmias in children. Br Heart J 1986;56:278-284. 90. Hilleman D, Miller MA, Parker R, et al. Optimal management of amiodarone therapy: efficacy and side effects. Pharmacotherapy 1998;18:138S-145S. 91. Bauer A, Malik M, Schmidt G, et al. Heart rate turbulence: standards of measurement, physiological interpretation, and clinical use: International Society for Holter and Noninvasive Electrophysiology Consensus. J Am Coll Cardiol 2008;52:1353-1365. 92. Stein PK, Sanghavi D, Domitrovich PP, et al. Ambulatory ECGbased T-wave alternans predicts sudden cardiac death in high-risk post-MI patients with left ventricular dysfunction in the EPHESUS Study. J Cardiovasc Electrophysiol 2008;19:1037-1042. 93. Verrier RL, Kumar K, Nearing BD. Basis for sudden cardiac death prediction by T-wave alternans from an integrative physiology perspective [Invited review]. Heart Rhythm 2009;6:416-422. 94. Peberdy MA, Ornato JP, Larkin GL, et al. Survival from in-hospital cardiac arrest during nights and weekends. JAMA 2008;299:785-792.
Cardiovascular Effects of SleepRelated Breathing Disorders Virend K. Somers and Shahrokh Javaheri Abstract The cycle of apnea and recovery causes hypoxemia/ reoxygenation, hypercapnia/hypocapnia, changes in intrathoracic pressure, and arousals. These consequences of sleep apnea, both obstructive and central apnea, adversely affect
Hemodynamic changes have been most studied in patients with obstructive sleep apnea (OSA), and in these studies, acute apnea-induced hemodynamic changes have been documented. Chronic exposure may also result in left ventricular systolic and diastolic dysfunction, and in increased atrial volume. A limited number of studies have shown that treatment of OSA with nasal continuous positive airway pressure (CPAP) devices or tracheostomy can result in reversal of left ventricular dysfunction and arrhythmias. Whether treatment of sleep apnea reduces cardiovascular events or cardiovascular mortality remains to be demonstrated in randomized control trials. However, several observational studies have reported that treatment of sleep apnea improves survival primarily because cardiovascular events are reduced. Periodic breathing is characterized by cyclic changes in tidal breathing with intervening episodes of obstructive or central apnea or hypopnea. These disordered breathing events result in three basic pathophysiologic consequences: (1) intermittent arterial blood gas abnormalities characterized by hypoxemia/reoxygenation and hypercapnia/ hypocapnia, (2) arousals and a shift to light sleep stages, and (3) large negative swings in intrathoracic pressure (Fig. 119-1).1-3 These pathophysiologic consequences of apnea and hypopnea, both obstructive and central, adversely affect cardiovascular function, acutely and chronically.
ARTERIAL BLOOD GAS ABNORMALITIES AND THEIR CONSEQUENCES Periodic breathing consists of cyclic changes in breathing pattern that include episodes of apnea and hypopnea, resulting in hypoxemia and hypercapnia. After apnea and hypopnea, hyperpnea ensues, resulting in reoxygenation and hypocapnia. These alterations in blood gases affect the cardiovascular system in different ways. Hypoxemia and Reoxygenation Hypoxemia has direct (decreased myocardial oxygen delivery) and indirect (activation of sympathetic nervous system, promotion of endothelial cell dysfunction, and pulmonary arteriolar vasoconstriction) cardiac and vascular effects. Hypoxemia with reoxygenation may be analogous to ischemia with reperfusion, and reoxygenation may cause additional damage through further production of free radical species. Biochemical injury due to hypoxemia– 1370
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119
cardiovascular function. The cardiovascular effects of sleep apnea may be mediated by redox-sensitive gene activation, altered autonomic nervous system activity, oxidative stress, and release of inflammatory mediators. Pathophysiologic consequences of sleep apnea elicit acute and chronic cardiovascular changes.
reoxygenation has considerable relevance to sleep apnea– hypopnea, where intermittent and profound alterations in the partial pressure of oxygen (Po2) may occur hundreds of times during sleep. Direct Effects of Hypoxia on Myocardium Decreased myocardial oxygen delivery may result in an imbalance between myocardial oxygen consumption and demand, resulting in myocardial hypoxia, particularly if there is already coronary artery disease. Potential clinical consequences include nocturnal angina, nocturnal myocardial infarction,4 arrhythmias, and even nocturnal sudden death.5 Hypoxia may also impair myocardial contractility and cause diastolic dysfunction.6 Hypoxemia–Reoxygenation and Coronary Endothelial Dysfunction Coronary vessel endothelial cells play a central role in vasoregulation, coagulation, and inflammation.7 Blood flow and coagulation are modulated by production and release of vasoactive substances that include vasodilators and platelet deaggregators (e.g., nitric oxide, prostacyclin), and vasoconstrictors and platelet aggregators (e.g., endothelin and thromboxane). The balance between vasoregulatory agents is important in modulating coronary blood flow and coagulation status in both health and disease. Through activation of certain transcription factors such as hypoxia-inducible factor-1 and nuclear factor-κB,8,9 hypoxia increases the expression of a number of genes such as those encoding endothelin-1, a potent vasoconstrictor with proinflammatory properties, vascular endothelial growth factor, and platelet-derived growth factor. In contrast, it suppresses the transcriptional rate of endothelial nitric oxide synthase,10 resulting in decreased production of nitric oxide, which is vasodilatory and has antimitogenic properties. Hypoxia also enhances expression of adhesion molecules and promotes leukocyte rolling and endothelial adherence,11 and it is involved in induction of endothelial and myocyte apoptosis.12 Some of the aforementioned adverse effects of sustained hypoxia have also been observed with intermittent hypoxia (i.e., hypoxia–reoxygenation).13-23 In this context, intermittent hypoxia has been proposed to be more deleterious than sustained hypoxia.18,19 Reoxygenation through delivery of oxygen molecules provides a substrate for additional production of oxygen radicals and may contribute to oxidative stress.
CHAPTER 119 • Cardiovascular Effects of Sleep-Related Breathing Disorders 1371
H/R ↑ PCO2
Sleep apnea and hypopnea
Arousals
↓ Ppl
↓ O2 delivery
Organ dysfunction
Endothelial dysfunction syndrome
Vasoconstriction Thrombosis Inflammation
Hypoxic and hypercapnic pulmonary vasoconstriction
↑ RV afterload
Sympathetic activation
↑ SVR/other adverse effects
↑ Transmural P of L and R ventricles, and pulmonary microvascular bed
Changes in R and L ventricular preload and afterload ↑ Lung H2O
Figure 119-1 Pathophysiologic consequences of sleep apnea and hypopnea. Pleural pressure (Ppl) is a surrogate of the pressure surrounding the heart and other vascular structures. H/R, hypoxia-reoxygenation; L, left; P, pressure; R, right; RV, right ventricular; SVR, systemic vascular resistance; ↑, increased; ↓, decreased. (Adapted from Javaheri S. Sleeprelated breathing disorders in heart failure. In: Mann DL, editor. Heart failure: a companion to Braunwald’s heart disease. Philadelphia: Saunders; 2003. p. 478.)
The pathophysiologic consequences of hypoxemia– reoxygenation could lead to vascular inflammation and remodeling, similar to atherosclerosis.7,23 Endothelial dysfunction has been demonstrated in a number of cardio vascular disorders, including hypertension, myocardial infarction, and stroke. Interestingly, these disorders have been also associated with OSA. It is therefore conceivable that endothelial dysfunction caused by sleep-related breathing disorders may contribute to worsening of atherosclerosis, atherothrombosis, and left ventricular dysfunction.1,24 The inflammatory and neurohormonal (see Obstructive Sleep Apnea and Systolic Heart Failure, later) consequences of altered blood gas chemistry have been best studied in patients with OSA, which is associated with increased sympathetic activity, high concentrations of endothelin, adhesion molecules, inflammatory cytokines, activation of white blood cells, oxidative stress, and hypercoagulopathy.1,22,24-39 These biochemical alterations may be reversed with use of nasal CPAP to treat OSA. However, such systematic studies are lacking for central sleep apnea, with the exception of studies showing increased overnight and morning sympathetic activity and increased concentration of endothelin and brain natriuretic peptide in patients with heart failure with central sleep apnea compared with those without central sleep apnea (for details, see Chapter 122).40 Hypoxemia–Hypercapnia and the Autonomic Nervous System Sleep apneas and hypopneas, both obstructive and central (Figs. 119-2 and 119-3), increase sympathetic activity through complex mechanisms. Hypoxemia stimulates the
peripheral arterial chemoreceptors in the carotid bodies, triggering reflex increases in sympathetic activity.41,42 Hypercapnia acts primarily on the central chemoreceptors located in the region of the brainstem, also increasing sympathetic activity. Both hypoxemia and hypercapnia increase ventilation, which, acting via thoracic afferents, buffers the increases in sympathetic drive during hypoxemia, and to a lesser extent during hypercapnia.41,42 Thus, when hypoxemia or hypercapnia occurs during apnea, the absence of ventilatory inhibition results in a potentiation of sympathetic activation and consequent vasoconstriction and blood pressure surges. In this context, and especially when there are potentiated chemoreflex responses to hypoxemia– hypercapnia,43,44 the sympathetic and consequent pressor responses to hypoxemia–hypercapnia, particularly in the absence of inhibitory effects of breathing, are marked. Alveolar Hypoxia–Hypercapnia and Pulmonary Arteriolar Vasoconstriction Alveolar hypoxia, in part through release of endothelin, and hypercapnia cause pulmonary arteriolar vasoconstriction and hypertension, which could adversely affect right ventricular function (see Chapter 120). Hypocapnia Episodes of hyperpnea after apneas and hypopneas result in hypocapnia. Hypocapnia may impair myocardial oxygen delivery and uptake by coronary artery vasoconstriction45 and shifting of the oxygen–hemoglobin dissociation curve to the left. Hypocapnia may also contribute to arrhythmogenesis. Arousals, Shift to Light Sleep Stages, and the Autonomic Nervous System Compared with wakefulness, the balance of activity of sympathetic and parasympathetic nervous system reverses in normal sleep.46,47 Normally, there is a progressive reduction in sympathetic nerve traffic, heart rate, and blood pressure during the deepening stages of non–rapid eye movement (non-REM) sleep, such that sympathetic activity, heart rate, and blood pressure in stage 4 sleep are substantially lower than during supine resting wakefulness.46,47 During phasic REM sleep, there is an abrupt increase in sympathetic activity, resulting in intermittent and brief surges in blood pressure and heart rate. On average, blood pressure and heart rate during REM sleep are similar to levels recorded during wakefulness. Thus, during normal sleep, there is a well-regulated pattern of alteration in autonomic and hemodynamic measures, modulated by changes in sleep stage. These organized responses to normal sleep are disrupted in patients with sleep-related breathing disorders, both obstructive and central sleep apnea. Sleep architecture is dramatically altered in patients with OSA–hypopnea, and also in patients with heart failure and central sleep apnea. There is a shift to light sleep stages. Most important, however, apneas and hypopneas commonly result in arousals that are also associated with an increase in sympathetic activity and a decrease in parasympathetic activity,47,48 and increasing blood pressure and heart rate. In OSA, arousals occur at the end of the apnea and with resumption of breathing. In patients with central
1372 PART II / Section 14 • Cardiovascular Disorders AWAKE
CONTINUOUS POSITIVE AIRWAY PRESSURE THERAPY DURING REM SLEEP
Sympathetic nerve activity
Respiration 150 Blood 100 pressure 50 mm Hg 0
150 100 50 0 10 sec OBSTRUCTIVE SLEEP APNEA (OSA) DURING REM SLEEP
Sympathetic nerve activity
Respiration OSA
OSA
250 200 Blood 150 pressure 100 mm Hg 50 0 Figure 119-2 Recordings of sympathetic nerve activity, intraarterial blood pressure, and breathing in a normotensive patient with obstructive sleep apnea (OSA) during resting normoxic wakefulness (top left). The patient was free of any other overt cardiovascular disease and on no medications. Note the high levels of sympathetic nerve traffic even in the absence of apneic events. During rapid eye movement (REM) sleep (bottom), the repetitive hypoxemia and hypercapnia elicit chemoreflex-mediated sympathetic activation and vasoconstriction. At the end of apneas, with increases in cardiac output and severe vasoconstriction, intraarterial blood pressure can reach levels from 130/60 mm Hg during wakefulness to a peak of 220/130 mm Hg during apneas. At the end of apneas, there also is abrupt inhibition of sympathetic traffic because of the increase in blood pressure acting through the baroreflexes and the sympathetic inhibitory effects of the thoracic afferents. After treatment of OSA with continuous positive airway pressure (top right), there is a marked reduction in sympathetic traffic and in blood pressure. (From Somers VK, Dyken ME, Clary MP, et al. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest 1995;96:1897-1904.)
sleep apnea and Hunter-Cheyne-Stokes breathing pattern, arousals occur at the peak of hyperventilation. In addition to arousals, sleep-related breathing disorders may increase sympathetic activity by hypoxemia, hypercapnia, and changes in ventilation, as noted previously. There are multiple adverse cardiac consequences of sympathetic activation. These include increased systemic vascular resistance and left ventricular afterload, venoconstriction with increased right ventricular preload, increased myocardial contractility, hypertrophy, tachycardia, and
arrhythmias. Furthermore, increased myocardial norepinephrine may cause myocyte toxicity and apoptosis.49,50 Central sleep apnea and OSA increase sympathetic activity as measured by either microneurography or blood and urinary norepinephrine levels.51-56 Treatment of obstructive54-56 and central sleep apnea52,57 decreases sympathetic activity, with important implications. First, with regard to central sleep apnea in heart failure, increased sympathetic activity is associated with poor survival; therefore, a reduction in sympathetic activity should have
CHAPTER 119 • Cardiovascular Effects of Sleep-Related Breathing Disorders 1373
Figure 119-3 Recordings of breathing (top), beat-by-beat blood pressure (middle), and muscle sympathetic nerve activity (MSNA) (bottom) in a patient with severe congestive heart failure, during normal breathing on the left and during Cheyne-Stokes breathing on the right. Oxygen saturation was 94% during normal breathing and oscillated between 97% and 90% during Cheyne-Stokes breathing. MSNA total burst amplitude increased from 1533 arbitrary units per minute during normal breathing to 1759 arbitrary units per minute during Cheyne-Stokes breathing. Mean blood pressure was 70 mm Hg during normal breathing and peaked at 82 mm Hg during the hyperventilation that followed central apnea. Patients with heart failure have high levels of sympathetic drive even during normal breathing. During central apneas, there is a modest but significant further increase in sympathetic activity. (From Van de Borne P, Oren R, Abouassaly C, et al. Effect of Cheyne-Stokes respiration on muscle sympathetic nerve activity in severe congestive heart failure secondary to ischemic or idiopathic dilated cardiomyopathy. Am J Cardiol 1998;81:432-436.)
favorable prognostic implications. OSA causes nocturnal increases in sympathetic activity and blood pressure, which carry over into the daytime. OSA is a known cause of hypertension, and in some patients blood pressure decreases relatively quickly with effective treatment of OSA with CPAP (see Chapter 120). In summary, pathophysiologic consequences of sleeprelated breathing disorders, such as increased periods of wakefulness (interruption insomnia), arousals, hypoxemia, and hypercapnia, collectively contribute to increased sympathetic activity. Exaggerated Negative Intrathoracic Pressure and Its Consequences Large negative intrathoracic pressures are generated during episodes of obstructive apnea. In central sleep apnea, relatively large negative pressure deflections occur during hyperpnea, particularly in the face of less compliant (stiff) lungs (due to heart failure). However, pleural pressure changes are usually more pronounced in obstructive than in central sleep apnea. A number of studies have addressed the cardiovascular consequences of both negative and positive pressure deflections affecting right and left ventricular function.58,59 Negative intrathoracic pressure increases the transmural pressure (pressure inside minus pressure outside) (Fig. 119-4) of the intrathoracic vascular structures, including aorta, pulmonary vascular bed, and ventricles. According to Laplace’s law, increased transmural myocardial pressure increases wall tension and myocardial oxygen consumption. Furthermore, negative intrathoracic perivascular pressure could increase extravascular lung water by favoring fluid transudation across the pulmonary microvascular bed and by diminishing lymph outflow from the lung.60 This may account in part for cases of flash pulmonary edema reported in OSA, and sleep apnea may contribute to excess lung water and pulmonary edema in congestive heart failure. In addition, decreased intra thoracic pressure increases venous inflow, resulting in
increased right ventricular diastolic filling, which in turn may decrease left ventricular compliance and volume, a phenomenon called ventricular interdependence. Application of nasal CPAP to treat sleep apnea, both obstructive and central, reduces transmural pressure by two mechanisms. First, and most important, it decreases or eliminates apneas, desaturation, and arousals, which collectively increase sympathetic activity and result in cyclic surges in arterial blood pressure. Second, nasal CPAP not only attenuates steep surges in intrathoracic pressure, it actually increases the pleural pressure, thus decreasing transmural pressures across intrathoracic structures (see Fig. 119-4).
ACUTE HEMODYNAMIC EFFECTS OF SLEEP APNEA The circulatory responses to individual apneas and hypopneas are governed by the interaction of stresses and physiologic consequences described previously.61,62 Hemodynamic changes are related to development of hypoxemia, hypercapnia, presence or absence of breathing, changes in intrathoracic pressure, and the consequent mechanical effects. Hemodynamic changes have been best studied in human OSA.61,63,64 The evolution of a cycle of apnea and recovery is complex and represents an unsteady hemodynamic state. For these reasons, hemodynamic changes occur during the course of an apnea, and these changes are different from those occurring during the immediate or late postapneic periods. During recovery, arousals and ventilation further affect hemodynamics. Cyclic changes in heart rate and systemic and pulmonary arterial blood pressure paralleling periodic breathing occur commonly.61,63-66 In some patients, there is a very clear and progressive bradycardia toward the end of apnea, with abrupt development of tachycardia with resumption of breathing, because of the vagolytic effects of lung inflation and arousals. This manifests as a pattern of repetitive bradycardias or tachycardias during sleep, which may be evident on Holter monitoring and
1374 PART II / Section 14 • Cardiovascular Disorders
Pr LV Tm
100 – (0.0) = 100
+10
–40
0.0
0.0
140 – (0.0) = 140
100
100
140
100
Ppl
Ppl
Ppl
Ppl
100
100
140
100
CPAP
UAO
Hypertension
Normal
100 – (–40) = 140
100 – (+10) = 90
Figure 119-4 Transmural (Tm) pressure (Pr) of the left ventricle (LV) during systole. Because of an obstructive apnea (UAO, upper airway occlusion), a negative pleural pressure (Ppl) of −40 mm Hg is generated. This increases left ventricular transmural pressure from 100 to 140 mm Hg, which is equivalent to an increase in systolic aortic blood pressure from 100 to 140 mm Hg. Note the reduction in left ventricular transmural pressure with application of nasal continuous positive airway pressure (CPAP). (Adapted from Javaheri S. Sleep-related breathing disorders in heart failure. In: Mann DL, editor. Heart failure: a companion to Braunwald’s heart disease. Philadelphia: Saunders; 2003. p. 480.)
may signify the presence of OSA. In experimental sleep apnea, decreases in heart rate are more severe during central than obstructive apnea, reflecting lack of activation of thoracic afferents.62 The bradycardias may be especially severe,65,66 and they are elicited because of activation of the diving reflex by the combination of hypoxemia and apnea. Episodes of up to 10 seconds or more of sinus arrest may occur because of the chemoreflex-mediated vagal activation. The consequent absence of perfusion, because of asystole, may have implications for patients with preexisting severe cerebral or cardiac ischemia. At the termination of obstructive apneas, there are surges in blood pressure. This cyclic change in blood pressure is one of the most consistent hemodynamic findings in patients with OSA. Multiple mechanisms are involved. During apnea, the increased hypoxemia and hypercapnia, acting through the chemoreflexes, progressively elicit sympathetic activation and vasoconstriction.53 With resumption of breathing, because of the inspiratory increase in right ventricular filling, stroke volume may increase. Vagolytic effects of inspiration result in tachycardia. The increased stroke volume and heart rate result in an increased cardiac output entering a vasoconstricted peripheral circulation, with consequent acute increases in blood pressure.53 However, just after termination of an obstructive apnea, there is abrupt inhibition of sympathetic activity to the peripheral blood vessels, in part because the deep breathing inhibits sympathetic activity through thoracic afferents, and in part because of baroreflex inhibition of sympathetic activity secondary to the postapneic blood pressure surge. Nevertheless, despite the interruption in sympathetic nerve traffic, vasoconstriction persists for several seconds after termination of the sympathetic nerve discharge because of the kinetics of norepinephrine uptake, release, and washout at the neurovascular junction. Another consistent finding is a mild reduction in stroke volume during obstructive apnea, which has been documented using noninvasive techniques for measuring beatto-beat cardiac output.61 This probably results from a decrease in left ventricular preload and an increase in afterload. Changes in stroke volume after termination of the apnea depend on where in the recovery cycle it is being measured.61
Obstructive Sleep Apnea, Left Ventricular Dysfunction, and Heart Failure The relationship between central sleep apnea and heart failure is discussed in Chapter 122. In this section, we review OSA as a cause of heart failure. Obstructive Sleep Apnea and Systolic Heart Failure In a canine model mimicking severe OSA,67 within a 1- to 3-month period of exposure to apneas during sleep, left ventricular systolic dysfunction developed. Left ventricular ejection fraction, measured during the daytime, decreased significantly because of an increase in left ventricular systolic volume. In humans, there are two kinds of studies relating left ventricular systolic dysfunction and OSA—first, studies in which patients with OSA have been assessed for the presence of left ventricular dysfunction,68-71 and second, studies in patients with established left ventricular systolic dysfunction who have been assessed to determine the prevalence of OSA.72,73 In some studies,74-76 changes in left ventricular ejection fraction in response to treatment for OSA have been also described. Results of studies assessing left ventricular systolic function in OSA patients are conflicting.68-70 However, in the two studies69,70 in which technetium-99m was used to assess left ventricular systolic function, OSA was associated with left ventricular systolic dysfunction. Use of radionuclide ventriculography to assess left ventricular function is important because in obese subjects, echocardiography, which has been used in some studies, may be associated with technical difficulties. Alchanatis and colleagues69 studied 29 patients with severe OSA (apnea–hypopnea index [AHI] greater than 15/ hr; mean AHI, 54/hr; lowest arterial oxygen saturation, 62%) and 12 control subjects (AHI, 9/hr; lowest saturation, 92%). The subjects were without known cardiovascular disease. The mean left ventricular ejection fraction was significantly lower in patients with OSA compared with the control group (53% versus 61%; P < .003). Six months after treatment with CPAP, left ventricular ejection fraction increased significantly to 56% (P < .001). Left ventricular diastolic dysfunction also improved significantly (see later). In a large study70 of 169 patients with OSA (AHI greater than 10/hr; mean AHI, 47/hr), 13 subjects (8%) had left
CHAPTER 119 • Cardiovascular Effects of Sleep-Related Breathing Disorders 1375
Table 119-1 Effects of PAP Therapy on Left Venticular Ejection Fraction in Patients with Obstructive Sleep Apnea and Systolic Heart Failure VARIABLE
KANEKO OPEN
MANSFIELD OPEN
EGEA DB
SMITH DB
KHAYAT OPEN
KHAYAT OPEN
n
12
19
20
23
11
13
AHI (n/h)
40
25
44
36
30
34
LVEF (%)
25
35
29
30
29
26
Increase in LVEF (%)
9*
5*
2.2*
0.0
0.5
8.5*
Duration
4 wk
3 mo
3 mo
6 wk
3 mo
3 mo
PAP titration Compliance (hr)
CPAP yes 6.2
CPAP yes 5.6
CPAP yes NR
Auto CPAP 3.5
CPAP yes 3.6
Bilevel yes 4.5
*Indicates a statistically significant change. Data from Kaneko Y, Flores JS, Usui K, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. N Engl J Med 003;348:1233-1241; Mansfield DR, Gollogly, NC, Kaye DM, et al. Controlled trial of continuous positive airway pressure in obstructive sleep apnea in heart failure. Am J Respir Crit Care Med 2004;169:361-366; Egea, CJ, Aizpuru F, Pinto JA, et al. Cardiac function after CPAP therapy in patients with chronic heart failure and sleep apnea: a multicenter study. Sleep Medicine 2008;9:660-666; Schmidt LA, Vennelle M., Gardner RS, et al. Autotitrating continuous positive airway pressure therapy in patients with chronic heart failure and obstructive sleep apnea: a randomized placebo controlled trial. Eur Heart J 2007;28:1221-1227; Khayat RN, Abraham WT, Patt B, et al. Cardiac effects of continuous and bilevel crowded airway pressure for patients with heart failure and obstructive sleep apnea: a pilot study. Chest 2008;134:1162-1168. AHI, apnea-hypopnea index; CPAP, continuous positive airway pressure; DB, double blind; NR, not reported; PAP, positive airway pressure.
ventricular systolic dysfunction (range, 32% to 50%). Left ventricular systolic dysfunction was not the result of ischemic disease as evidenced by echocardiography and dipyridamole stress testing. In seven patients who were treated for OSA (six with CPAP and one with upper airway surgery), 1 year after therapy, mean left ventricular ejection increased significantly from 44% to 63%.70 In the cross-sectional analysis of more than 6000 patients enrolled in the Sleep Health Heart Study,71 the presence of OSA increased the likelihood of having a history of heart failure by an odds ratio of 2.5. Furthermore, there was a significant dose-dependent correlation between AHI and the prevalence of heart failure. In studies of patients with established left ventricular systolic dysfunction undergoing polysomnography (re viewed in Chapter 122), the prevalence of OSA, defined as an AHI of at least 15/hour, ranged from 5% to 32%. This wide range is not particularly surprising. The prevalence depends on a number of factors, including the number of obese patients with heart failure enrolled in each study and the different polysomnographic criteria used by various investigators for diagnosis of OSA. In a prospective study72 of 81 patients with known systolic dysfunction and in whom no question was asked regarding snoring or other symptoms associated with OSA, 11% had OSA with a mean AHI of 36/hour and a lowest arterial oxygen saturation of 72%. In a retrospective study73 of 450 patients with systolic dysfunction who were referred for a sleep study because of loud snoring and other symptoms of sleep apnea, 32% had OSA. From the aforementioned studies, however, it cannot be determined whether OSA preceded heart failure. Yet, as is discussed later, treatment of OSA with nasal CPAP increases left ventricular ejection fraction, indicating that OSA contributes to worsening of left ventricular systolic dysfunction. The mechanisms by which OSA may impair left ventricular systolic function are multiple. Hypoxemia plays a critical role, both by impairing myocardial contractility and through a host of neurohormonal mechanisms. In
addition, increases in left ventricular wall stress and transmural pressure occur because of additive effects of the excess negative juxtacardiac pressure (during obstructive apneas) and development of hypertension. The effects of positive airway pressure therapy on left ventricular ejection fraction in patients with OSA and systolic heart failure has been reported in five randomized clinical trials, two of which have been double blind (Table 119-1). In three of the studies in which CPAP was used, including the only two double-blind randomized clinical trials, the rise in left ventricular fraction was minimal or not at all. It should be noted, however, that in at least two of these studies compliance with CPAP was also limited. In the two open studies in which compliance hours with CPAP were more than those in the double-blind studies, ejection fraction increased between 5% and 9%. In one open randomized clinical trial of CPAP versus abilevel device, the ejection fraction increased significantly only with bilevel therapy. Obstructive Sleep Apnea and Diastolic Heart Failure Isolated left ventricular diastolic heart failure with relative preservation of left ventricular systolic function is the most common form of heart failure in elderly subjects. The pathophysiologic consequences of this form of heart failure relate to a hypertrophied, noncompliant left ventricle, shifting the pressure–volume curve upward and to the left. Therefore, for a given left ventricular volume, left ventricular end-diastolic pressure increases, resulting in elevated left atrial and pulmonary capillary pressure, and pulmonary congestion and edema. As noted previously, hemodynamic studies63,64 of patients with OSA have documented that pulmonary capillary pressure increases during the course of an obstructive apnea, indicating development of diastolic dysfunction. During obstructive apnea, left ventricular transmural wall tension increases because of an increase in aortic blood pressure and a simultaneous decrease in juxtacardiac pressure.
1376 PART II / Section 14 • Cardiovascular Disorders
Arrhythmias in Obstructive Sleep Apnea Obstructive Sleep Apnea Predisposing to an Arrhythmogenic Substrate Repetitive nocturnal apneas elicit severe derangements in cardiovascular homeostasis. Hypoxemia, hypercapnia, acidosis, adrenergic activation, increased afterload, and rapid fluctuations in cardiac wall stress would reasonably be expected to be conducive to tachycardia–brachycardia oscillations and atrial and ventricular arrhythmias (Figs. 119-5 and 119-6). A variety of atrioventricular arrhythmias, including complete heart block and ventricular asystole during sleep, have been observed in patients with OSA84-86 and have been eliminated by either tracheostomy or use of nasal CPAP.84,85 Profound OSA-induced arrhythmias can occur in the absence of any major structural abnormalities in the conduction system.86a Although the normal heart would be less likely to manifest malignant arrhythmias in the setting of severe obstruc-
BP (mm Hg) CVP (mm Hg)
250 125
10 5 0
0
ECG
SNA RESP Apnea
10 sec
Figure 119-5 Recordings of intraarterial blood pressure (BP), central venous pressure (CVP), electrocardiogram (ECG), sympathetic nerve activity (SNA), and respiratory patterns (RESP) in a healthy subject during voluntary end-expiratory apnea. During apnea, there is a progressive increase in the RR interval on the ECG with eventual sinus pause and atrioventricular block. Accompanying this is increased sympathetic activity. The simultaneous sympathetic activation to peripheral blood vessels and vagal activation of the heart is characteristic of the diving reflex. Note the rapid increase in heart rate and sympathetic inhibition during resumption of breathing. This occurs in part because thoracic afferents activated by inspiration inhibit both sympathetic traffic and vagal cardiac drive. (From Somers VK, Dyken ME, Mark AL, Abboud FM. Parasympathetic hyperresponsiveness and brady arrhythmias during apnea in hypertension. Clin Auton Res 1992;2:171-176.)
ECG RESP 200 BP (mm Hg)
Furthermore, hypoxemia may impair left ventricular relaxation, further impairing diastolic function.77 Repeated exposure to nocturnal hypertension and hypoxemia, and consequent development of OSA-induced systemic hypertension and increased left ventricular mass, may also contribute to left ventricular diastolic dysfunction. Most studies show that OSA is associated with an increase in left ventricular mass,78-81 and suggest that the OSA-related cardiac structural changes may resolve with CPAP treatment.80 An early study78 reported that OSA may cause left ventricular hypertrophy even in the absence of daytime systemic hypertension. This finding was later supported by another study79 comparing patients with OSA (AHI greater than 20/hr) with those without OSA (AHI less than 20/hr). In the largest study,81 consisting of 2058 Sleep Heart Health Study participants, left ventricular mass was associated with both apnea–hypopnea and hypoxemia indices after adjustment for age, sex, ethnicity, study site, body mass index, smoking, systolic blood pressure, antihypertensive medication use, diabetes mellitus, myocardial infarction, and alcohol consumption. Although there are some data regarding the prevalence of sleep apnea in patients with systolic heart failure,72,73,82 the prevalence and the impact of OSA in diastolic heart failure need to be determined. In one study,83 approximately half of 20 patients with diastolic heart failure had sleep apnea. As noted earlier, isolated diastolic heart failure is highly prevalent in elderly subjects. Furthermore, elderly subjects have a high prevalence of OSA. It is speculated that OSA could be the cause of diastolic heart failure, or the presence of OSA could contribute to the worsening of left ventricular diastolic dysfunction. In this regard, a preliminary study reported that treatment of OSA improves left ventricular diastolic dysfunction,69 an observation confirmed by the only randomized, placebo (sham CPAP)-controlled trial80 showing that after 12 weeks on effective CPAP therapy, there was a significant increase in E/A ratio (the ratio of early to late diastolic filling), and a significant decrease in isovolumic relaxation and mitral deceleration. These observations are similar to the improvement seen in systolic function when patients with heart failure and OSA are treated with CPAP (see Table 119-1).74-76
100 0
10 sec
Figure 119-6 A patient with sleep apnea manifesting prolonged and profound bradyarrhythmias with absence of either atrial or ventricular contraction. The beat-by-beat blood pressure (BP) recording confirms the absence of any perfusion during the bradycardia. ECG, electrocardiogram; RESP, respiratory pattern. (From Somers VK, Dyken ME, Mark AL, Abboud FM. Parasympathetic hyperresponsiveness and brady arrhythmias during apnea in hypertension. Clin Auton Res 1992;2:171176.)
tive apnea, the ischemic, hypertrophied, or failing heart may be more susceptible.87 Nevertheless, activation of the diving reflex66,88 during apneas can often elicit severe bradyarrhythmias, even in the setting of a normal myocardium and normal cardiac electrophysiologic function. Tachycardia–Bradycardia Oscillations Patients undergoing Holter monitoring may be noted to have repetitive cyclic episodes of tachycardias and bradycardias during the night.89,90 These cyclic fluctuations may be attributable to obstructive apneas, although this cannot be confirmed because standard Holter monitoring does not incorporate simultaneous measurements of either breathing pattern or oxygen saturation.
CHAPTER 119 • Cardiovascular Effects of Sleep-Related Breathing Disorders 1377
These oscillations in cardiac rate are for the most part explained by changes in cardiac autonomic drive related to breathing pattern. During the course of apnea, incremental hypoxemia elicits the diving reflex so that bradycardia becomes progressively more marked. With termination of apnea, hyperpnea occurs with consequent activation of thoracic afferents, which is vagolytic.91 Thus, with resumption of breathing, abrupt lung inflation interrupts vagal drive to the heart, resulting in rapid-onset tachycardia. Furthermore, increased cardiac-bound sympathetic drive and withdrawal of parasympathetic activity because of arousals should also contribute to the tachycardia seen with termination of obstructive apnea. It is interesting that tachycardia persists even though blood pressure increases strikingly with termination of apnea. The vagolytic effects of inspiration and the arousal-associated changes in the autonomic nervous system not only interrupt the chemoreflex-mediated cardiac vagal drive but also blunt the expected cardiac vagal drive that would occur secondary to baroreflex activation by the postapneic surge in blood pressure. Because of the repetitive nature of nocturnal apneas, Holter or other electrocardiographic monitoring at night manifests as a tachycardia–bradycardia pattern. This cardiac rate oscillation is less apparent in patients with autonomic dysfunction, such as patients with long-standing diabetes, or cardiac transplant recipients with denervated hearts. Although the changes in cardiac rate are predominantly reflex-mediated, breathing-related changes in cardiac filling, as well as rapid changes in cardiac transmural pressures resulting from the Müller maneuver, also modulate heart rate by variations in stretch of cardiac conduction tissue. Bradyarrhythmias The primary response to hypoxia is bradycardia.88 When hypoxia is accompanied by the action of breathing, the bradycardic response is masked because of inhibition of cardiac vagal drive by ventilation.66 The sympathetic response to hypoxemia, although evident to some extent during breathing, is also attenuated by ventilation and is therefore potentiated during apnea.92,93 Patients with OSA may be particularly susceptible to hypoxia-induced bradyarrhythmias because their peripheral chemoreflex is heightened, so that even during voluntary apneas, hypoxemia elicits greater bradycardia than is seen in closely matched control subjects.94 The arterial baroreflexes serve as an important buffer to diminish chemoreflex gain.95 Impaired baroreflex sensitivity, such as is seen in hypertension96 and heart failure,97 may be associated with further increased chemoreflex drive. Thus, patients with hypertension or heart failure who have OSA may manifest even greater sympathetic, and perhaps bradycardic, responses to obstructive apneas. Profound bradyarrhythmias may have important consequences, particularly in patients with underlying cardiovascular disease. As an example, in the absence of recognition of OSA as a potential cause of the bradyarrhythmia, patients may receive pacemaker implantation, even though their cardiac conduction system may be completely normal and the bradyarrhythmias could be abolished by effective treatment with CPAP.83,84,98 Second, prolonged episodes of asystole result in absence of perfusion (see Fig. 119-6). Absence of perfusion in the setting of apnea-induced hypoxemia, occurring repetitively
through the night, may have important implications for ischemic damage to end organs in which there may already be preexisting circulatory compromise. Ventricular Arrhythmias There is an extensive literature on sleep apnea inducing nocturnal angina and cardiac ischemia evidenced by STsegment depression.99,100 Thus, there is a potential con tribution of OSA to ventricular arrhythmias through ventricular ectopy during profound bradycardia, as well as polymorphic ventricular tachycardia due to cardiac hypoxia/ischemia. These episodes occur primarily with severe desaturation,83,84 are more common in patients with coronary heart disease,86 and are virtually eliminated with treatment.83,84,98 The prevalence of these arrhythmias is low in patients without premorbid cardiorespiratory disease or severe desaturation.101 Atrial Fibrillation In patients cardioverted for atrial fibrillation, those with polysomnographically proven OSA who were not receiving effective CPAP treatment had a 12-month recurrence rate of 82%, compared with a 42% recurrence rate in patients with OSA receiving effective CPAP.102 In patients cardioverted for atrial fibrillation in whom no sleep study had been done, the recurrence rate was 53%. This risk for recurrence in the patients with atrial fibrillation without a previous sleep study suggests that undiagnosed OSA may be present in a large proportion of patients with atrial fibrillation. In addition, among the untreated patients with OSA, those experiencing a recurrence of atrial fibrillation had more severe nocturnal hypoxemia than those without a recurrence. Furthermore, the increased recurrence in patients with untreated OSA could not be explained by factors such as antiarrhythmic medication, body mass index, hypertension, cardiac function, or atrial size. Mooe and colleagues103 observed that after coronary artery bypass surgery, patients with OSA were more likely to experience postoperative atrial fibrillation. However, it is not clear whether this was explained by other variables in the patients with OSA. In a recent longitudinal study of several thousand patients, those with OSA had an increased risk of developing new-onset atrial fibrillation as compared with those who did not have OSA. This risk was evident in patients aged 65 or younger, and it was especially marked in those with more severe nocturnal hypoxemia.104 There are many reasons why OSA may be conducive to atrial fibrillation. Hypoxemia, pressor surges, and sympathetic activation are all potential mechanisms leading to atrial fibrillation. High levels of C-reactive protein may also independently predict the development of atrial fibrillation.105 Patients with OSA may have increased levels of C-reactive protein.106-108a Furthermore, abrupt and dramatic changes in intrathoracic negative pressures may especially affect the atria, with their relatively thin walls compared with the ventricles. Increased pressure gradients with consequent increased atrial wall stretch, occurring repetitively through the night, may be expected to induce mechanical and electrical changes that are also conducive to atrial fibrillation.109-111 Indeed, about 50% of patients presenting for cardioversion have a high risk for sleep
1378 PART II / Section 14 • Cardiovascular Disorders
apnea, compared with 30% of patients from a general cardiology clinic.112
SUMMARY Sleep-related breathing disorders affect cardiovascular function in a variety of ways. OSA and central sleep apnea act through multiple mechanisms to elicit acute circulatory responses, which have implications for the development of chronic vascular and cardiac dysfunction. The acute responses to apnea are mediated in large part by the effects of apnea on blood gas chemistry, which exerts important cardiovascular effects directly on the myocardium and blood vessels, and also acts through reflex mechanisms. Acute neural, circulatory, endothelial, inflammatory, and other responses to repetitive nocturnal hypoxemia and hypercapnia may act to induce long-term damage to the myocardium and to the coronary and other vascular beds. With the development of functional and structural cardiovascular disease, the consequences of acute apneas are magnified. For example, severe hypoxemia in the setting of sleep apnea is more easily tolerated by an overtly healthy cardiovascular system compared with one where myocardial ischemia or left ventricular dysfunction is present, with consequent diminished cardiovascular reserve. Small, short-term studies have suggested that effective prevention of recurrent apneas may favorably affect surrogates of cardiovascular disease outcome, such as sympathetic activity, blood pressure, and left ventricular ejection fraction. ❖ Clinical Pearls Apnea and recovery cycles result in three basic abnormalities: alterations in blood gases, arousals, and changes in intrathoracic pressure. Hypoxemia–reoxygenation has deleterious effects on the cardiovascular system. This activates redoxsensitive genes, resulting in synthesis of vasoconstrictor and inflammatory mediators; increases sympathetic activity; and causes oxidative stress. These alterations have been best studied in patients with OSA. Untreated OSA may increase the risk of recurrence of atrial fibrillation after cardioversion. Sleep apnea can induce severe bradyarrhythmias, including prolonged periods of asystole and heart block, even in the setting of a normal myocardium and cardiac electrophysiologic function. OSA should be considered in patients who have ST-segment depression or angina occurring primarily at night. Heart failure may be significantly linked to the presence of either central sleep apnea or OSA.
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Systemic and Pulmonary Hypertension in Obstructive Sleep Apnea Terry Young, F. Javier Nieto, and Shahrokh Javaheri Abstract Findings from investigations based on diverse populations and different study designs have consistently supported a role for obstructive sleep apnea (OSA) in systemic and pulmonary hypertension. Both cross-sectional and prospective populationbased epidemiology studies have shown that persons with polysomnographically indicated OSA (15 or more apnea or hypopnea events per hour of sleep) have 2 to 3 times greater odds of having systemic hypertension or of developing new systemic hypertension than persons who do not have OSA. The associations are only partly explained by confounding factors such as increased body mass index (BMI), sex, or age. Some studies suggest that the strength of the link between OSA and hypertension varies by age, BMI, and sex, but nonetheless, the link between OSA and hypertension is consistently found across subgroups, including children and different ethnic groups. A dose-dependent association for OSA and hypertension is seen in the mild to moderate OSA range, but the
Although the clinical association between hypertension and obstructive sleep apnea (OSA) has long been reported1-3 in sleep medicine, the potential importance of OSA in patients with elevated blood pressure and cardiovascular disease is gaining recognition beyond the field of sleep research. In the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, OSA is recognized as an identifiable cause of hypertension.4 Similarly, the World Health Organization has recognized OSA as a cause of secondary pulmonary arterial hypertension.5 Increasing evidence that OSA has a causal role in the development of hypertension has been discussed in two recent task force statements.6,7 Although an accurate estimate of the fraction of systemic hypertension that can be causally attributed to OSA is lacking and data on OSA and pulmonary hypertension are sparse, it is clear that clinical recognition of the high prevalence of systemic and pulmonary hypertension in people with OSA,8,9 as well as the high occurrence of OSA in hypertensive patients,10-12 is imperative. The aim of this chapter is to present the epidemiologic data in support of a role of OSA in systemic and pulmonary hypertension and to describe the clinical issues in identification and treatment of patients with OSA and hypertension.
SYSTEMIC HYPERTENSION Epidemiologic Evidence for a Role of OSA in Systemic Hypertension The early observations of hypertension in patients with sleep apnea stimulated several cross-sectional clinic- and community-based studies that attempted to determine whether there was an association between OSA and hypertension that was not explained by excess body weight or other factors common to both OSA and hypertension (see Chapter 61).9 Results were mixed, but many of the studies
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association appears to plateau with more severe OSA. The associations are seen during both sleep and wake. Pulmonary hypertension, ranging from mild to severe, is prevalent in patients with OSA. Mild pulmonary arterial hypertension (PAH) may occur in patients with OSA without daytime hypoxemia or chronic obstructive pulmonary disease, but these comorbidities are more common in patients with severe OSA. Although definitive randomized clinical trials have not been completed, most studies of both systemic and pulmonary arterial blood pressures before and after continuous positive airway pressure (CPAP) have shown decreases in blood pressure. Intervention trials have generally shown modest reductions in systemic blood pressure with CPAP use (2 to 10 mm Hg), and the largest effects are seen in effectively treated patients with severe OSA. Importantly, such small changes in blood pressure, if maintained, have the potential of significantly decreasing the population incidence of cerebrovascular and cardiovascular disease.
had some methodological shortcomings, such as inadequate sample size, flawed comparison groups, measurement error, or limited statistical analysis.13,14 Since then, findings from both population and clinical studies have shed important new light on this association. Reports from several well-designed epidemiology studies, summarized in Table 120-1, have consistently shown that significant associations of polysomnographically determined OSA and hypertension, defined by blood pressure thresholds or use of antihypertensive medication, remain after adjustment for potential confounding factors.15-17 The strongest epidemiologic evidence for a causal association comes from longitudinal analyses of data from the ongoing Wisconsin Sleep Cohort Study of middle-aged state employees, reported by Peppard and colleagues.18,19 The incidence of new hypertension, defined as systolic blood pressure at least 140 mm Hg, diastolic blood pressure at least 90 mm Hg, or use of antihypertensive medication at follow-up, was significantly dependent on baseline level of OSA. The 4-year hypertension incidence increased from 10% in those with no sleep-disordered breathing at baseline, to 32% for those with moderate sleep-disordered breathing at baseline. After considering confounding factors, the probability of developing new hypertension over 4 years was twofold greater for those with an apnea–hypopnea index (AHI) of 5 to 15, and threefold greater for those with an AHI of greater than 15 at baseline, compared with participants without OSA at baseline (i.e., AHI < 1). Cross-sectional analyses of baseline data from three other population cohorts (Southern Pennsylvania,20 Spain,21 and the U.S. multicenter Sleep Heart Health Study22) using measurements, definitions, and statistical adjustment models similar to those used in the Wisconsin Sleep Cohort, have also shown OSA to be a statistically 1381
1382 PART II / Section 14 • Cardiovascular Disorders Table 120-1 Association of Polysomnographically Determined Sleep-Disordered Breathing and Hypertension in Four Population Studies Odds Ratio* for Hypertension† (95% CI) AHI CATEGORY PARTICIPANTS (N)
STUDY DESIGN 1. Wisconsin Sleep Cohort Study, state employees, ages 30 to 65 years,16 prospective, 4-8 years follow-up
<1.0‡
1 TO 4.9
5 TO 14.9
15 TO 30
≥30
709
1.0
1.2 (1.1-1.8)
2.0 (1.3-3.2)
2.9 (1.5-5.6)
—
a. Cross-sectional22
6132
1.0
1.1 (0.9-1.3)
1.2 (1.0-1.4)
1.3 (1.9-1.6)
1.4 (1.0-1.8)
b. Prospective, 2- and 5-year follow-up23
2470
—
1.0
0.9 (0.7-1.2)
1.1 (0.8-1.5)
1.5 (0.9-2.5)
1741
1.0
—
2.3§ (1.4-3.6)
6.9§ (2.0-26.4)
—
552
1.0
2.5 (1.1-5.8)
1.3 (0.5-4.1)
2.3 (0.9-5.7)
—
18
2. Sleep Heart Health Study,22,23 multicenter, ages 40-97 years
3. Southern Pennsylvania,20 population sample via random-digit dialing, ages 20-100 years, cross-sectional 4. Vitoria-Gasteiz, Spain,21 random census sample, ages 30-70 years, cross-sectional
*Odds ratios are all adjusted for age, sex, body mass index (BMI), neck circumference, alcohol intake, and cigarette smoking. Additional adjustments are made for baseline hypertension and waist circumference in the Wisconsin study, for ethnicity and waist-to-hip ratio in the Sleep Heart Health Study, and for ethnicity, menopause, and hormone replacement therapy in the Southern Pennsylvania study. † Defined by systolic blood pressure ≥140 mm Hg, diastolic blood pressure ≥90 mm Hg, or use of antihypertensive medication. ‡ Reference category for odds ratio. § Estimated at the mean age and BMI of the sample. AHI, apnea-hypopnea index; CI, confidence interval.
significant risk factor for hypertension (Fig. 120-1, and see Table 120-1). More recent prospective data from the Sleep Heart Health Study provides less conclusive results.23 Follow-up blood pressure measurements at 2- and 5-year intervals in participants free of hypertension at the baseline examination (blood pressure below 140/90 and no antihypertension treatment, n = 2470) were compared for baseline AHI categories with cutpoints at 5, 15, and 30. After controlling for age, sex, race, and length of follow-up, the odds ratios (OR) of newly developed hypertension were 1.1, 1.5, and 2.2, for AHI categories of 5 to 15, 15 to 30, and greater than 30 versus an AHI of less than 5, respectively. The latter two were statistically significant. However, after BMI was accounted for, the ORs were attenuated, as shown in Table 120-1. In subgroup analyses, the association appeared to be stronger and statistically significant among women and among participants below median BMI, with demographics- and BMI-adjusted ORs for AHI ≥ 30 versus AHI < 5 of 2.3 (95% confidence interval [CI], 1.1 to 4.8) and 2.7 (95% CI, 1.2 to 5.9), respectively; there appeared to be no differences in the strength of the association according to age and baseline sleepiness. Among the possible reasons that could explain the weaker results in the Sleep Heart Health Study compared with previous studies are the older age of this cohort and the fact that the reference category used in this study
(AHI 0 to 4.9) might have included subjects with mild OSA. (This is in contrast to the baseline cross-sectional analysis in this cohort22 and the prospective analysis from the Wisconsin cohort,18 which used AHI less than 1.5 or AHI equal to 0 as reference categories, respectively.) Nevertheless, although weaker and not as conclusive, these results indicate a modest association and show confidence intervals that are compatible with those found in the other cohorts. Collectively, the relationship between OSA and hypertension has been assessed with state-of-the-art measurements in more than 9,000 men and women from the general population, and results have been consistent. Confidence in the validity of the findings is increased as a result of the care taken by investigators to evaluate the effects of methodological limitations.18,24 If the epidemiology findings do reflect a causal relationship, as is suggested by most of the population-based data, a harder look must be taken at the importance of preventing OSA, or at treating even mild OSA, discussed more fully below. The population studies suggest that there is a dose– response association between OSA and hypertension up to a moderate level of OSA severity. It is possible that such a threshold exists, but methodological limitations may account for this. This feature may reflect a survival bias against persons with high-severity OSA and cardiovascular
CHAPTER 120 • Systemic and Pulmonary Hypertension in Obstructive Sleep Apnea 1383
Mean systolic BP (mm Hg)
130
120
110
Presleep
Sleep
Postsleep
100 –10 –9
–8
–7
–6
–5
–4
–3
–2
A
–1
0
1
2
3
4
5
6
7
0
1
2
3
4
3
4
Hour relative to bedtime
Mean diastolic BP (mm Hg)
85
75
65
Presleep
Sleep
Postsleep
55 –10 –9
B
–8
–7
–6
–5
–4
–3
–2
–1
0
1
2
3
4
5
6
7
0
1
2
Hour relative to bedtime
Figure 120-1 Ambulatory blood pressure (BP) during presleep, sleep, and postsleep by apnea–hypopnea index (AHI) category (Wisconsin Sleep Cohort Study). Triangles: AHI, <5; number of participants, 537. Squares: AHI, ≥5, number of participants, 231. A, Systolic blood pressure. B, Diastolic blood pressure. Mean blood pressure values are adjusted for age, sex, and body mass index.
1384 PART II / Section 14 • Cardiovascular Disorders
disease, greater measurement error at higher AHI levels, or study power limitations from the relatively small number of persons with very severe OSA in the general population. A threshold for hypertension in patients with OSA may also exist because the presence of pathophysiologic consequences of severe OSA, such as nocturia and heart failure, could lessen hypertension. In regard to heart failure, severe OSA has been associated with left ventricular systolic dysfunction25; in the Sleep Health Heart Study, there was a dose-dependent relation between AHI and prevalence of heart failure.26 If left ventricular systolic dysfunction occurs as OSA becomes more severe, adequate left ventricular stroke volume may not be maintained to sustain a high blood pressure. Furthermore, biologically, the mechanisms mediating hypertension in OSA may be threshold dependent and become saturated at a certain level of AHI. In this regard, in a two-arm study27 of therapeutic and subtherapeutic continuous positive airway pressure (CPAP) in OSA, there were no changes in systemic arterial blood pressure from baseline in the subtherapeutic CPAP trial arm despite a decrease in average AHI from 65 to 33 events per hour. These results are consistent with a threshold effect for AHI in mediating existing systemic hypertension, although conclusive evidence for or against a stronger risk of developing new hypertension with severe OSA requires further longitudinal data. OSA and Hypertension in Population Subgroups Determining the association of OSA with hypertension by subgroups (e.g., sex, age, ethnicity, body habitus) will increase understanding of physiologic mechanisms and may help target health care to appropriate subgroups. Most population cohort studies have reported a lack of sex differences in the association of OSA and hypertension This message is particularly important because of past underdiagnosis and undertreatment of OSA in women; less-aggressive evaluation and treatment of OSA in women may lead to a survival disadvantage for them.28 Few studies have included sufficient population diversity to determine if the association of OSA and hypertension varies by ethnicity. Recent population studies of OSA and hypertension in older adults have expanded the focus beyond OSA in middle age. Cross-sectional regression analyses of two large cohort studies with age ranges that include sufficient older people have suggested a negative interaction between age and AHI with respect to hypertension. Bixler and coworkers found that ORs for hypertension exponentially decreased as age increased when patients with an AHI of 30 or greater were compared with those with an AHI of 0, and there was essentially no risk of hypertension associated with OSA for those 70 years and older.20 Similar findings were reported by the Sleep Heart Health Study: after stratifying their sample with a cutoff age of 65 years, the OR for hypertension with an AHI of greater than 30 versus an AHI of less than 1.5 was lower and not statistically significant for ages 65 years and older (OR = 1.23), compared with ages 40 to 65 years (OR = 1.64).22 Further analysis of the Sleep Heart Health Study data revealed that OSA was not associated with isolated systolic
hypertension, the most common form of hypertension in older people.29 In contrast, cross-sectional analysis of the Bay Area Sleep Cohort of 129 older adults found a significant association between frequent (10 or more) apnea and hypopnea events during rapid eye movement sleep and diastolic blood pressure greater than 90 mm Hg.30 This study of adults with a mean age of 72 years also linked occult sleepdisordered breathing to markers of cardiovascular disease. The authors concluded that a role of OSA in cardiovascular disease in older adults should not be ruled out. Although it is possible that OSA outcomes differ in older versus younger people, methodological difficulties arising from high comorbidity and survival bias are inherent in studying health effects of OSA in older populations and could cause a spurious age effect. Clinical practice should not be influenced by the notion that health risks of OSA in older people are lower, until there are conclusive data. The prevalence of overweight, a strong risk factor for both OSA and hypertension, is increasing worldwide. Most studies, using multiple regression, have demonstrated that OSA and obesity are independent factors in the development of hypertension.6 However, understanding of specific mechanisms as well as precise effect sizes are limited by many analytic issues, including the relevant measure of body habitus to use, how the variables should be modeled in analyses (e.g., linear or quadratic terms), and the time course for OSA to have an effect on blood pressure. Adjusting for a marker of obesity (e.g., BMI) in multiple regression analysis of the relationship between OSA and hypertension is justified under the assumption that obesity is a confounder (i.e., obesity is a risk factor for both OSA and hypertension); however, if the relationship between OSA and obesity is bidirectional (e.g., if metabolic changes associated with OSA lead to an increase in body weight), adjustment for obesity in regression models of OSA and hypertension may be biased, leading to an underestimation of the role of OSA. Furthermore, the interaction of obesity and OSA with respect to the development of hypertension is not clear. That is, does the strength of the OSA–hypertension association differ by BMI? Findings from two of the large cohort studies have indicated that OSA is more strongly predictive of hypertension in leaner than in obese individuals: BMI was a significant modifier of the OSA– hypertension association in studies by Young and coworkers31 and Bixler and coworkers.20 The OR for hypertension and OSA increased in magnitude with decreasing BMI, indicating that in leaner people, those with OSA compared with those without may be at particularly high risk for hypertension. This finding has clinical implications, particularly in primary care, where sleep apnea is not likely to be suspected in nonobese patients, even in the presence of symptoms. OSA and Diurnal Blood Pressure Hypertension defined by chronic elevated daytime blood pressure is generally considered to be the outcome of interest, but it is not clear what specific features of elevated blood pressure are important. OSA-related nocturnal perturbations include repeated spiking of pressures that exceed hypertension cutpoints (blood pressure load) and elevated
CHAPTER 120 • Systemic and Pulmonary Hypertension in Obstructive Sleep Apnea 1385
average nighttime blood pressure, as well as a carryover effect resulting in elevated daytime blood pressure.6 Early studies of hemodynamics in patients with OSA involved invasive blood pressure monitoring; more recent studies of circadian patterns of blood pressure rely on ambulatory monitors that sample blood pressure at 15- to 30-minute intervals with arm-cuff inflation-based methods. Most studies with ambulatory blood pressure monitoring have been conducted on patients with sleep apnea. A Marburg study of 93 OSA patients32 showed the number of oxygen desaturation events per hour of presumed sleep was linearly related to both daytime and nighttime systolic and diastolic blood pressure, and it was related more strongly to nighttime pressures. In Great Britain, Davies and colleagues33 performed ambulatory blood pressure studies on 45 pairs of sleep apnea patients and community controls matched to the patients on age, BMI, and treated hypertension. Sleep apnea patients had significantly higher diastolic pressures during the day and night, higher systolic pressures during the night, and a notably smaller nocturnal dip. Data from population studies with polysomnography (PSG) and nocturnal blood pressure measures are sparse. In a preliminary study of 147 Wisconsin Sleep Cohort Study subjects,34 OSA was consistently associated with elevated blood pressure measured by 24-hour ambulatory monitoring. Average systolic and diastolic blood pressures during wake and sleep, and systolic blood pressure load during wake and sleep, were all statistically significantly higher in the participants with AHI greater than 5. Findings from an update with a much larger cohort sample (N = 768) are shown in Figure 120-2. Blood pressures,
2
Changes in BP (mm Hg)
0
P = .01
P = .004
P = .005
–2 –4 –6 –8 –10 –12 MABP
Systolic BP
Diastolic BP
Therapeutic CPAP Subtherapeutic CPAP Figure 120-2 Treatment with therapeutic continuous positive airway pressure (CPAP) decreased systemic blood pressure, whereas use of subtherapeutic CPAP failed to decrease blood pressure. MABP, mean arterial blood pressure. (From Becker HF, Jerrentrup A, Ploch T, et al: Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation 2003;107:68-73.)
adjusted for confounding factors, were higher at every hour before, during, and after sleep for those with an AHI of greater than 5 versus an AHI of less than 5. Nocturnal blood pressure relative to daytime pressure has been of special interest, as studies have shown that the lack of the normal nighttime decline (nondipping) in blood pressure, usually considered to be a nighttime drop of at least 10% of the daytime pressure, is related to adverse cardiovascular outcomes independent of hypertension.35 Findings from relatively small clinic-based samples do suggest that patients with OSA have a smaller nocturnal decline in blood pressure.32,33,35-40 Recently, prospective data from the population-based Wisconsin Sleep Cohort study strengthen the evidence that acute effects of apnea and hypopnea episodes lead to a less favorable nighttime pattern of blood pressures.41 Baseline and 7-year follow-up data from laboratory PSG and ambulatory blood pressure on a subsample of 328 participants in the Wisconsin Sleep Cohort Study, free of nondipping at baseline, were analyzed. There was a dose–response increase in the odds of developing a pattern of nondipping in systolic blood pressure: compared with subjects with an AHI of less than 5 at baseline, ORs, adjusted for confounding factors, were 3.1 (95% CI, 1.3 to 7.7) and 4.4 (95% CI, 1.2 to 16) for an AHI of 5 to 14 and for an AHI of 15 or greater, respectively. Collectively, the ambulatory blood pressure studies do support an association between OSA and elevated blood pressure during both the nighttime and the daytime, and some studies suggest that the effect is greater during nighttime. These findings are particularly important because elevated ambulatory blood pressure has been shown to predict cardiovascular events independently of officemeasured blood pressure and other cardiovascular risk factors.42 Blood Pressure Changes in Patients with OSA after CPAP Treatment Studies of the effect of CPAP on blood pressure have evolved from clinical observations of treated patients, to sophisticated, randomized, double-blind trials, with shamCPAP as the control condition and objectively measured compliance. Results from these studies are important, even though they do not necessarily directly address the basic question of whether OSA caused hypertension to begin with, as the effect of OSA on vasculature hemodynamics might be different at different stages in the natural history of a chronic condition such as hypertension. However, clinical trial results generally show that successful treatment of OSA in patients who are also hypertensive tends to result in lower blood pressure levels. These results, along with both animal and human epidemiologic (particularly longitudinal) studies showing OSA as a cause of hypertension, coupled with biological plausibility studies defining mechanisms linking OSA to hypertension and the reversal of such mechanisms with CPAP, support the hypothesis of a contribution of OSA to elevated blood pressure. However, as briefly reviewed in the following paragraphs, the results of these studies are not uniformly consistent, probably as a result of the differences in study design, patient populations, treatment regimens, and compliance from study to study.
1386 PART II / Section 14 • Cardiovascular Disorders
A significant lowering of blood pressure with CPAP was reported by Pepperell and coworkers43 in a study of 118 patients with OSA and an average oxygen desaturation index (ODI) of 37 per hour, randomized to CPAP or subtherapeutic CPAP (pressure of about 1 cm H2O) for 4 weeks. Ambulatory blood pressure data showed mean blood pressure drops of 2.4 mm Hg during sleep and 3.4 mm Hg during wake in the CPAP group, and an increase of 0.8 mm Hg for the control group. The largest CPAP effect was seen in patients with the most severe OSA (ODI > 33/hr, decrease in blood pressure of 5.1 mm Hg). Furthermore, in patients who used therapeutic CPAP for an average of longer than 5 hours per night, mean blood pressure fell by about 5 mm Hg, compared with no change in blood pressure in those who used CPAP for less than 5 hours. As discussed later, the small changes in blood pressure, when they persisted for the long term, have important implications in preventing cerebrovascular and cardiovascular incidents. The largest effect of CPAP was reported by Becker and colleagues27 in a double-blind 9-week trial, completed by 32 of 60 eligible sleep clinic patients. Full-night PSG, continuous noninvasive blood pressure monitoring (Portapress, FMS, Amsterdam), and a relatively long-term follow-up provided the most detailed look at the effects of CPAP on OSA and 24-hour blood pressure profile. There were no changes in medications or body weight during the 9-week trial. Compliance with CPAP was monitored, and it averaged about 5.5 hours per night in both groups. In analyses restricted to the treatment compliers, AHI decreased from 63 to 3 per hour in the therapeutic CPAP group (average level, 9.1 cm H2O), compared with a decrease of 65 to 33 per hour in the subtherapeutic CPAP group (average level, 3 to 4 cm H2O). In the therapeutic CPAP group, there was a decrease of approximately 10 mm Hg in systolic and diastolic blood pressure, during both day and night. Even though the subtherapeutic group had a 50% reduction in AHI, there was no change in blood pressure. Even though the interpretation of these results is limited by the violation of the intention-to-treat principle, the findings from this study suggest the benefits of effective treatment of OSA for hypertension management. In another study, Coughlin and coworkers used a randomized crossover design to assess the blood pressurelowering effect of 6 weeks of CPAP in 34 previously untreated patients with OSA.44 Compared with sham CPAP, therapeutic CPAP reduced mean waking systolic and diastolic blood pressures by 6.7 and 4.9 mm Hg, respectively. Interestingly, the effect was even stronger in the most compliant group of patients (systolic and diastolic differences of 8.5 and 6.7, respectively), whereas little or no change was observed in a number of metabolic parameters (glucose, lipids, insulin resistance). In another randomized study that used ambulatory blood pressure measurements in patients with OSA,45 a 12-week CPAP regimen resulted in a reduction in 24-hour mean and diastolic blood pressures by 3.8 and 3.5 mm Hg, respectively. In this study, the Epworth Sleepiness Scale score varied from 3 to 18, with 66% of the patients scoring below 10. With a different study design, Hla and coworkers46 investigated the effect of 3 weeks of CPAP on blood pres-
sure in hypertensive subjects with and without OSA to control for effects that CPAP might have on blood pressure independent of an effect from elimination of apnea and hypopnea events. Newly diagnosed, unmedicated hypertensive men from primary care settings were assessed for OSA by laboratory PSG to identify 14 men with an AHI of greater than 5 (mean AHI, 25) and 10 men with an AHI of less than 5 (mean AHI, 1). The OSA group received therapeutic CPAP, and the non-OSA group received CPAP at a pressure of 5 cm H2O for 3 weeks. Ambulatory blood pressure monitoring indicated that nocturnal blood pressure in the OSA group dropped significantly with CPAP (−10.3 mm Hg systolic, −4.5 mm Hg diastolic) but was essentially unchanged with CPAP in the non-OSA group. There was a greater but statistically nonsignificant difference in blood pressure drop in the OSA versus non-OSA group in daytime blood pressure (−2.4 mm Hg systolic, −0.6 mm Hg diastolic). Other randomized trials, however, have shown minimal or nonsignificant effects of CPAP in blood pressure.47-52 A potentially important limitation of some of these studies is that many of the patients included in the trial were not hypertensive, and thus there might be limited room for a lowering of blood pressuring effect, as well as limited compliance with the treatment. Furthermore, some of these studies had limited statistical power because of their small sample size, which could explain the lack of statistically significant results. In a meta-analysis of 16 trials conducted between 1996 and 2006 and including a total of 818 patients,53 a small but statistically significant mean net change in systolic (−2.5 mm Hg [95% CI, −4.3 to −0.6]) and diastolic (−1.8 mm Hg [95% CI, −3.0 to −0.6]) was observed. Net reductions in blood pressure were not statistically different between daytime and nighttime. A meta-analysis by Bazzano and colleagues had some limitations that might limit its generalizability (e.g., most studies included predominantly or exclusively obese middle-aged men, some studies were not blinded, and compliance was often limited). Furthermore, the duration of CPAP treatment in all these studies was relatively short, ranging from 2 to 24 weeks53; longer treatment may be associated with different effects on systemic blood pressure. In an observational longer-term prospective study that followed 55 patients (35 of whom were men) with both OSA and hypertension for 2 years,54 a significant decrease was shown only for diastolic blood pressure (−2.2 mm Hg [95% CI, −4.2 to −0.1) but not in systolic or 24-hour mean arterial blood pressure. Subgroup analyses, however, showed that 24-hour mean blood pressure did decrease significantly in patients with incompletely controlled hypertension at entry (−4.4 mm Hg, P = .01) as well as in those with high CPAP compliance (−5.3 mm Hg, P = .01). The predictors of change in blood pressure associated with CPAP treatment in patients with OSA were examined in an observational prospective study that recruited 86 patients treated for daytime sleepiness with CPAP.55 After 6 months, the average fall in 24-hour mean blood pressure was 4.9 mm Hg (95% CI, −7.1 to −2.1); the main predictors of blood pressure fall were the change in level of self-reported sleepiness and baseline BMI. Improvement in vascular function may help explain the putative improvement in blood pressure associated with
CHAPTER 120 • Systemic and Pulmonary Hypertension in Obstructive Sleep Apnea 1387
CPAP treatment. OSA may increase sympathetic activity (see Chapter 119), which is reversed by therapy with CPAP. Other mechanisms may also be involved. In a randomized controlled trial including 29 patients with OSA associated with desaturation, in comparison with placebo, 6 weeks of CPAP was associated with an improved forearm blood flow in response to both endothelial and non– endothelium-dependent stimuli.56 Previous non–placebocontrolled studies have also demonstrated an association between CPAP and either biochemical markers of vascular function57 or forearm flow-mediated dilation measures.51 Clinical Relevance of the Role of OSA in Hypertension In contrast to the state of evidence 10 years ago, findings in support of a role for OSA in the development of hypertension are now difficult to dismiss as spurious.56a-56c Translating these findings to clinical settings, however, poses new challenges. These findings, as well as new guidelines on hypertension detection and treatment, support casefinding for OSA in patients with hypertension in primary care settings, but what is the next step? Although diagnosis and treatment of a patient with hypertension and symptomatic OSA are priorities, a critical and much-debated question is the course of action that should be taken if a hypertensive patient has mild OSA without daytime symptoms of sleepiness. Is treatment of mild, asymptomatic OSA without complaints of sleepiness warranted on the basis of potential cardiovascular consequences? Arguments against treatment point to the lack of conclusive data. Based on the average effect of CPAP on change in blood pressure, the predicted effect on an individual is likely to be too small to be of clinical significance and thus would not warrant replacing antihypertensive drugs for controlling blood pressure.58 In addition, data showing that CPAP does not improve daytime functioning, including cognitive function and objective sleepiness in patients without subjective sleepiness, leads to skepticism that such patients would be compliant with CPAP use.47 On the other hand, there are arguments for considering CPAP treatment in nonsleepy patients with mild, asymptomatic OSA and coexisting hypertension.59,60 Worsening of mild sleep apnea over time is likely, and cardiovascular consequences that might be attributable to severe OSA could be prevented.60 Some data suggest that CPAP treatment for patients with OSA and drug-resistant hypertension may be of benefit in lowering blood pressure.61 Furthermore, little is known about the interaction of OSA and hypertension in cardiovascular morbidity and mortality. Given the acute negative cardiovascular effects of apnea and hypopnea events, it is plausible that OSA worsens existing hypertension and speeds progression to cardiovascular disease and mortality. It is possible that eliminating the disordered breathing would improve overall cardiovascular prognosis. Two recent follow-up mortality studies of population-based cohorts showed that OSA at baseline, adjusted for age, sex, BMI, and other potential confounding factors, predicted premature death.62,63 Marshall and coauthors62 measured OSA status with a four-channel recorder of snoring, breathing, and oximetry in a cohort of 380 men and women from Buss-
leton, Australia. Based on 14 years of mortality follow-up, the hazard ratio for all-cause mortality associated with 15 or more, versus less than 5, respiratory events at baseline was 6.2 (95% CI, 2.0 to 19.4). Young and colleagues63 analyzed the 18-year mortality rates of participants in the Wisconsin Sleep Cohort who had been studied with inlaboratory PSG at baseline. There was a linear increase in all-cause and cardiovascular deaths with increased AHI at baseline. However, after adjustment, only severe OSA at an AHI of greater than 30 remained statistically significant. The adjusted hazard ratio for all-cause mortality was 3.0 (95% CI, 1.4 to 6.3). The potential role of hypertension or cardiovascular disease diagnosed at baseline in explaining the OSA–mortality link was explored with multiple regression modeling. These conditions accounted for approximately 30% of the mortality risk in patients with OSA: After accounting for hypertension at baseline, the hazard ratio for mortality with OSA dropped from 3 to 2.7. Interestingly, when participants who reported use of CPAP at least 4 nights per week (n = 126) were excluded from the analysis, the hazard ratio for both all-cause and cardiovascular mortality increased; in “untreated” OSA, the hazard ratio increased to 3.8 (95% CI, 1.6 to 9.0) for all-cause mortality and to 5.2 (95% CI, 1.4 to 19) for cardiovascular deaths. Because this was not an intervention study, use of CPAP was individually determined and thus not unbiased. It is not clear what role CPAP had in lowered mortality. CPAP use may have been a marker for good compliance with all medical therapy or a healthier lifestyle in general. In spite of the inability to infer a protective role for CPAP against death, particularly against cardiovascular mortality, these data do support the hypothesis that untreated OSA confers a risk of cardiovascular morbidity. Primary health care providers increasingly recognize markers for OSA, such as snoring, and are becoming more aware of the OSA–hypertension association. Consequently, referrals of patients with mild, asymptomatic OSA for sleep evaluations will very likely increase, heightening the dilemma of whom to treat in the face of limited medical resources. Further understanding of the costs and benefits of OSA treatment in preventing the incidence and progression of hypertension and other cardiovascular diseases is needed before this problem can be satisfactorily addressed. Meanwhile, clinicians providing care for OSA patients using CPAP should underscore the importance of full compliance as well as adequate control of disordered breathing events with CPAP, as evidenced by studies showing the importance of these two variables to lowering high blood pressure.27,43 Long-term small changes in blood pressure have major preventive effects. In prospective studies of 420,000 persons, a decrease of 5 mm Hg in diastolic blood pressure lessened the incidence of stroke and coronary heart disease by approximately 34% and 21%, respectively, and there was a dose-dependent reduction in blood pressure and incident cardiovascular diseases.64 Therefore, in patients with OSA, long-term compliance with CPAP may be effective in preventing adverse cerebrovascular and cardiovascular diseases. The ultimate lowering effect of CPAP on hypertension requires long-term systematic studies. Long-standing
1388 PART II / Section 14 • Cardiovascular Disorders
hypertension is associated with vascular remodeling, which may not be reversible with short-term CPAP therapy.
PULMONARY HYPERTENSION Obstructive Sleep Apnea as a Cause of Pulmonary Hypertension In 1998, the second World Health Organization (WHO) conference on pulmonary arterial hypertension5 recognized sleep-disordered breathing as a secondary cause of pulmonary hypertension (PH). The classification of PH has been revised by a more recent WHO conference.65 There are five classes consisting of various causes of PH. The first class, pulmonary arterial hypertension, includes idiopathic pulmonary arterial hypertension. The second class is pulmonary venous hypertension, which is most commonly due to left ventricular diastolic dysfunction. PH secondary to obstructive sleep apnea falls into the third category, which also includes chronic obstructive pulmonary disease (COPD), interstitial lung disease, and PH in high altitude. The basic pathophysiologic mechanism underlying PH in this group of disorders is hypoxemia. It is difficult to estimate the prevalence of clinically significant PH, defined as PH that contributes to symptoms such as exercise intolerance, and the prognosis for patients with OSA. The gold standard for diagnosis of PH is right heart catheterization. The WHO defines the presence of PH as resting mean pulmonary artery pressure 25 mm Hg or greater with a normal wedge pressure of less than 15 mm Hg. These cutoff points are primarily used for defining idiopathic pulmonary arterial hypertension. Investigators in the field of sleep apnea have used a mean pulmonary artery pressure of 20 mm Hg or greater, a threshold that is lower than that defined for pulmonary arterial hypertension. However, a resting mean pulmonary artery pressure of 20 mm Hg or greater is generally considered abnormal. Also, a mean pulmonary artery pressure exceeding 30 mm Hg with exercise is abnormal. In patients with OSA, the prevalence of PH varies considerably, from 15% to 70%.66-74 This variation in part depends on inclusion in studies of patients with COPD, which contributes to increased frequency, prevalence, and severity of PH in OSA. Meanwhile, in patients with OSA without comorbid disorders, PH is usually mild, although it could also be severe in advanced OSA, resulting in cor pulmonale, a feature of pickwickian syndrome (hyper capnic OSA syndrome). An early study1 of 12 patients with OSA who had undergone right heart catheterization showed cyclic changes in pulmonary artery pressure coinciding with episodes of OSA. A marked degree of hypoxemia and hypercapnia was associated with these hemodynamic abnormalities. In some of these patients, systolic pulmonary artery pressure exceeded 60 mm Hg. During wakefulness, four patients had mild PH, and mean pressure ranged from 20 to 22 mm Hg. One of these four patients had an elevated pulmonary capillary wedge pressure of 16 mm Hg. With exercise, most of the patients developed PH with a mean pulmonary artery pressure of about 30 mm Hg. In some of these patients, the wedge pressure increased with exercise, unmasking left ventricular diastolic dysfunction. This study indicated that OSA impaired the physiologic pro-
cesses that normally operate to enable pulmonary circulation and left ventricular function to maintain pulmonary artery pressure close to normal in the face of increases in cardiac output. Since the study of Tilkian and colleagues,1 many studies have demonstrated that PH is relatively common in patients with OSA. Box 120-1 summarizes four studies in which full-night PSG and right heart catheterization, the gold standard for diagnosis of OSA and PH, were performed. In a French study68 involving 220 consecutive patients with an AHI of greater than 20, 37 patients (17%) had a resting mean pulmonary artery pressure of at least 20 mm Hg (range, 20 to 44 mm Hg), and in 17 patients (8%) the mean pressure was 25 mm Hg or greater. Patients with PH had more severe OSA, a higher Paco2, a higher BMI, and a lower Pao2 than patients without PH. Furthermore, patients with PH had higher prevalence of both obstructive and restrictive pulmonary defects. Paco2 and forced expiratory volume in 1 second (FEV1) were the two major predictors of PH. When PH was defined as a mean pressure of 30 mm Hg with exercise, virtually all patients
Box 120-1 Pulmonary Hypertension (PH) in Patients with Obstructive Sleep Apnea (OSA) Chaouat A, Weitzenblum E, Krieger J, et al. (Reference 68) 220 consecutive French patients with AHI > 20/hr 17% had mean PAP > 20 mm Hg 8% had mean PAP ≥ 25 mm Hg Patients with PH had more severe OSA, higher Paco2 and BMI, lower Pao2, and a more obstructive and restrictive defect Paco2 and FEV1 were independent predictors of PAH Laks L, Lehrhaft B, Grunstein RR, et al. (Reference 69) 100 consecutive Australian patients with AHI > 20/hr 42% had mean PAP > 20 mm Hg; range, 20 to 52 mm Hg Paco2, Pao2, and FEV1 accounted for 33% of the variability in PH Six patients with PAH had normal Pao2 Sanner BM, Doberauer C, Konermann M, et al. (Reference 70) 92 consecutive German patients with OSA and AHI > 10/hr; range, 10 to 100/hr COPD was an exclusion criterion 20% had mild PH; range, 20 to 25 mm Hg Eight patients had increased PCWP; all had systemic hypertension PCWP and time spent at <90% saturation were independent predictors of PAH Bady E, Achkar A, Pascal S, et al. (Reference 71) 44 patients with OSA and AHI > 5/hr COPD was an exclusion criterion 27% had PH with mean pressure ≥ 28.5 mm Hg 18% had mean PAP ≥ 25 mm Hg AHI, apnea–hypopnea index; BMI, body mass index; COPD, chronic obstructive pulmonary disease; FEV1, forced expiratory volume in 1 second; PAH, pulmonary arterial hypertension; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure.
CHAPTER 120 • Systemic and Pulmonary Hypertension in Obstructive Sleep Apnea 1389
met this criterion; in 23 patients (62%), the mean pressure exceeded 40 mm Hg. In an Australian study69 of 100 consecutive patients with an AHI of 20 or more, 42% had PH, with the mean pulmonary artery pressure ranging from about 20 to 52 mm Hg. In several of these patients, the mean pressure was more than 25 mm Hg. In this study, Paco2, Pao2, and FEV1 accounted for about 33% of variability in pulmonary artery pressure. Six patients with PH had normal Pao2. In a German study70 of 92 consecutive patients with an AHI of greater than 10 and with COPD as an exclusion criterion, 20% had mild PH with a mean pulmonary artery pressure of 20 to 25 mm Hg. Eight patients had increased pulmonary capillary wedge pressure, and all of these patients had systemic hypertension that was presumably causing left ventricular diastolic dysfunction. Pulmonary capillary wedge pressure and time spent with a saturation of below 90% were the independent variables predicting PH. The presence of PH in patients with OSA but without COPD was also confirmed in another French study (see Box 120-1).71 In this study, however, COPD was defined by an FEV1 of less than 70% predicted and a ratio of FEV1 to forced vital capacity (FVC) of less than 60% predicted. The study involved 44 patients, 12 of whom (27%) had precapillary PH. The authors reported that mean pulmonary artery pressure was positively correlated with BMI and negatively correlated with Pao2. Patients with PH had significantly lower values for FVC and FEV1. The mechanisms by which BMI positively correlated with PH could have been multifactorial and related to restrictive lung defect and hypoxemia. In conclusion, mild PH is common in patients with OSA and may occur in the absence of COPD and daytime hypoxemia. However, severe OSA, severe hypoxemia, and obstructive or restrictive lung defects are more commonly associated with PH and contribute to its severity. In addition, as noted, PH either becomes manifest or is augmented by exercise and can cause dyspnea and exercise intolerance.72 Mechanisms of Pulmonary Hypertension in Patients with OSA Multiple mechanisms mediate nocturnal rises in pulmonary artery pressure. These include alterations in blood gases, cardiac output, lung volume, intrathoracic pressure, compliance of pulmonary circulation, and left ventricular diastolic dysfunction. Diurnal PH in patients with OSA could be precapillary, capillary, or postcapillary, depending in part on comorbid disorders that may contribute to the development of PH (Box 120-2). Postcapillary PH (pulmonary venous hypertension) results primarily from left ventricular hypertrophy and diastolic dysfunction caused by diurnal systemic hypertension. However, left ventricular hypertrophy could be present in patients with OSA even in the absence of daytime systemic hypertension,75 presumably because of cyclic changes in systemic artery blood pressure and hypoxemia74 during sleep. In the presence of a hypertrophied, noncompliant left ventricle, end-diastolic pressure increases, resulting in an increase in pulmonary capillary and pulmonary artery systolic and diastolic pressures (post-
Box 120-2 Mechanisms of Pulmonary Hypertension in Obstructive Sleep Apnea Precapillary Pulmonary Hypertension Hypoxemia Hypercapnia Endothelial dysfunction or remodeling* Changes in intrathoracic pressure Postcapillary Pulmonary Hypertension Left ventricular hypertrophy and diastolic dysfunction *See Tilkian AG, Guilleminault C, Schroeder JS, et al. Hemodynamics in sleep-induced apnea: studies during wakefulness and sleep. Ann Intern Med 1976;85:714-719.
capillary PH). Left ventricular diastolic dysfunction may become unmasked when cardiac output increases. This may account for the high prevalence of PH with exercise in patients with OSA. Loss of vascular surface area, as may occur in patients with COPD, is an important cause of capillary PH, and it may significantly contribute to PH in patients with OSA. Several studies67-69 have shown that COPD and a low FEV1 are predictors of PH in patients with OSA. COPD could also contribute to PH by way of arteriolar vasoconstriction due to hypoxemia and hypercapnia resulting in precapillary PH (see next paragraph). An important mechanism mediating PH in patients with OSA is the presence of factors that cause constriction of pulmonary arterioles, leading to precapillary PH. The best-known stimulus is alveolar hypoxia, and it is not surprising that hypoxemia is an independent predictor of PH in OSA (see Box 120-1). However, hypercapnia could also increase pulmonary arterial blood pressure. The molecular mechanisms of PH in general are complex and multifactorial. Both acquired and genetic factors are involved. Disordered endothelial cell function, in part caused by hypoxia (and reoxygenation) and manifested biochemically by an imbalance between concentrations of local vasodilators (e.g., nitric oxide and prostacyclins) and vasoconstrictors (e.g., endothelin-1, thromboxane, serotonin), as occurs in endothelial dysfunction syndrome, appears to mediate the development of PH.76,77 It is also conceivable that if OSA is long-standing, pulmonary vascular remodeling similar to that in COPD could occur, as a number of mediators such as vascular endothelial growth factor are proliferative and angiogenic. Even though cyclic PH occurs regularly with episodes of apnea during sleep, it is not clear why only some patients with OSA develop diurnal PH. The same is true for systemic hypertension. Genetic predisposition, however, may confer an increased risk for the occurrence of PH in some patients. In familial inherited PH, mutations in the gene for bone morphogenetic protein receptor type 2 (BMPR2) have been reported.8 Furthermore, aberrant production of angiopoietin-1 has been reported in a variety of disorders with acquired PH,78 including thromboembolic disease, scleroderma, and mitral regurgitation. The expression of angiopoietin-1 messenger RNA and the protein itself were unregulated in the lungs of these patients, and it correlated directly with the severity of the disease. Angiopoietin-1 is
1390 PART II / Section 14 • Cardiovascular Disorders
an angiogenic factor that recruits smooth muscle cells to the endothelial vascular network during the embryogenic stage. However, after development is completed, angiopoietin-1 is expressed only minimally in normal human lung. In contrast, in patients with the various forms of acquired PH, the level of angiopoietin-1 is increased.78 Although the mechanisms leading to upregulation of angiopoietin-1 are unclear, it is conceivable that its upregulation could also contribute to PH in some patients with OSA. In summary, the consequence of OSA on pulmonary circulation may vary from those of cyclic nocturnal PH, which occurs in virtually all patients, to daytime PH, right ventricular dysfunction, and eventually cor pulmonale, a feature of pickwickian syndrome. However, even in the absence of cor pulmonale, which is the manifestation of long-standing severe PH, presence of PH increases right ventricular afterload and myocardial oxygen consumption. If PH develops as a result of increases in cardiac output, for example with exercise, it may cause dyspnea and exercise intolerance. Changes in Pulmonary Artery Pressure after CPAP Treatment of OSA Because mechanisms of PH in OSA are multifactorial (see Box 120-2), the behavioral response of pulmonary circulation to therapy for OSA probably depends on several factors. For example, if loss of vascular surface area due to the presence of COPD or other comorbid pulmonary disorders is contributing to PH in OSA, this component is irreversible.79 Similarly, if remodeling of the pulmonary vascular bed has occurred, long-standing effective therapy is necessary to effect any reversal (reverse remodeling). Therefore, if CPAP is used to treat OSA, long-term compliance with therapy is critical and needs to be confirmed by covert monitoring. Large, long-term systematic studies considering these important factors are necessary to determine the effects of treatment of OSA on pulmonary circulation. Lack of such considerations may lead to serious underestimation of effects. Effective treatment of OSA improves PH. Both Fletcher and colleagues79 and Motta and coworkers80 have reported that with tracheostomy, PH is virtually eliminated. Alchanatis and colleagues81 used Doppler echocardiography to estimate pulmonary artery pressure before and after 6 months of effective treatment with CPAP in 29 patients with OSA and without COPD. In six patients who had mild PH, the mean pulmonary artery pressure decreased significantly, from about 26 to 20 mm Hg, 6 months after treatment with CPAP. In the study by Sforza and colleagues,82 eight patients had mild PH (mean ± SEM = 23 ± 1 mm Hg). After treatment with CPAP for a year, the mean pulmonary artery pressure was 21 (±1) mm Hg. For such a small change to be statistically significant, a large sample of patients is imperative. Sajkov’s group,83 using Doppler echocardiography, studied pulmonary hemodynamics in 20 patients with OSA (average AHI, 49 or greater) before and 4 months after treatment with CPAP. In this study, CPAP compliance was objectively monitored, and the average was 5 hours per night. Patients had normal lung function. Five patients who had mild PH (range, 20 to 32 mm Hg) showed the most dramatic decrease in the pulmonary artery pressure,
all decreasing to less than 20 mm Hg after 4 months of effective treatment with CPAP. In a subject who was not compliant with CPAP, there was no change in pulmonary artery pressure. Although this was a single observation, this finding and those reported for systemic hypertension strongly indicate that effective use of CPAP is necessary to lower systemic and pulmonary artery pressures. There is only one randomized clinical trial regarding therapy of pulmonary hypertension in patients with OSA. Arias and colleagues84 randomized 23 middle-aged patients with severe OSA (AHI, 44/hr or greater) to either sham CPAP or CPAP therapy. In this crossover trial, after 12 weeks of CPAP therapy, pulmonary artery systolic pressure decreased significantly from a mean of about 30 to 24 mm Hg. The reduction was greatest (8.5 mm Hg) in patients with pulmonary hypertension defined as pulmonary artery systolic pressure of 30 or more determined by echocardiography. ❖ Clinical Pearls Epidemiologic studies support a causal role of OSA in systemic hypertension independent of BMI, measures of fat distribution, age, sex, and other possible confounding factors. Randomized double-blind placebo (sham CPAP)controlled trials of patients with hypertension demonstrate that effective treatment of OSA with CPAP lowers blood pressure. A decrease in blood pressure is most pronounced in those with the most severe OSA and who are the most compliant. Even small decrements in blood pressure, maintained for the long term, have been shown to significantly lessen the incidence of cerebrovascular and cardiovascular diseases. Thus, the potential lowering of blood pressure from CPAP treatment holds promise for decreasing cerebrovascular or cardiovascular disease. However, adequate control of OSA and compliance with CPAP, particularly in patients with severe OSA, are critical. Several observational studies show that OSA is a cause of mortality, particularly when severe. Treatment with CPAP improves mortality. Obstructive sleep apnea is a cause of secondary pulmonary hypertension, and this has been recognized by international health organizations. PH is usually mild, although it could be severe, particularly in the presence of comorbid disorders such as COPD. Treatment of OSA with CPAP may improve PH.
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1392 PART II / Section 14 • Cardiovascular Disorders 51. Ip M, Tse H, Lam B, et al. Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med 2004; 169:348-353. 52. Arias MA, Garcia-Rio F, Fernandez AA, et al. Obstructive sleep apnea affects left ventricular diastolic function. Circulation 2005; 112:375-383. 53. Bazzano LA, Khan Z, Reyonlds K, He J. Effect of nocturnal nasal continuous positive airway pressure on blood pressure in obstructive sleep apnea. Hypertension 2007;50(2):417-423. 54. Campos-Rodriguez F, Perez-Ronchel J, Grilo-Reina A, et al. Longterm effect of continuous positive airway pressure on BP in patients with hypertension and sleep apnea. Chest 2007;132:1847-1852. 55. Robinson GV, Langford BA, Smith DM, Stradling JR. Predictors of blood pressure fall with continuous positive airway pressure (CPAP) treatment of obstructive sleep apnoea (OSA). Thorax 2008;63: 855-859. 56. Cross MD, Mills NL, Al-Abri M, et al. Continuous positive airway pressure improves vascular function in obstructive sleep apnoea/ hypopnoea syndrome: a randomised controlled trial. J Am Col Cardiol 2004;43:5S-12S. 56a. Jaimchariyatam N, Rodriguez CL, Budur K. Does CPAP treatment in mild obstructive sleep apnea affect blood pressure? Sleep Med 2010 Aug 16. [Epub ahead of print] 56b. Calhoun DA, Harding SM. Sleep and hypertension. Chest 2010; 138:434-443. 56c. Aihara K, Chin K, Oga T, Takahashi KI, et al. Long-term nasal continuous positive airway pressure treatment lowers blood pressure in patients with obstructive sleep apnea regardless of age. Hypertens Res 2010 Jul 29. [Epub ahead of print] 57. Ogha E, Tomita T, Wada H, et al. Effects of obstructive sleep apnea on circulating I-CAM-1, IL-6, and MCP1. J Appl Physiol 2003;94:179-184 58. Montserrat JM, Barbe F, Rodenstein DO. Should all sleep apnoea patients be treated? Sleep Med Rev 2002;6:7-14. 59. Levy P, Pepin JL, McNicholas WT. Should all sleep apnoea patients be treated? Yes. Sleep Med Rev 2002;6:17-26. 60. Pack AI, Maislin G. Who should get treated for sleep apnea? Ann Intern Med 2001;134:1065-1067. 61. Logan AG, Tkacova R, Perlikowski SM, et al. Refractory hypertension and sleep apnoea: effect of CPAP on blood pressure and baroreflex. Eur Respir J 2003;21:241-247. 62. Marshall NS, Wong KK, Liu PY, et al. Sleep apnea as an independent risk factor for all-cause mortality: the Busselton Health Study. Sleep 2008;31:1079-1085. 63. Young T, Finn L, Peppard P, et al. Sleep disordered Breathing and mortality: eighteen-year follow-up of the Wisconsin Sleep Cohort. Sleep 2008;31:1071-1078. 64. MacMahon S, Peto R, Cutler J, et al. Epidemiology: blood pressure, stroke, and coronary heart disease; Part 1, prolonged difference in blood pressure: prospective observational studies corrected for the regression dilution bias. Lancet 1990;335:765-774. 65. Simonneau G, Galie N, Rubin LJ, et al. Clinical classification of pulmonary hypertension. J Am Col Cardiol 2004;43:5S-12S. 66. Atwood CW Jr, McCrory D, Garcia JGN, et al. Pulmonary artery hypertension and sleep-disordered breathing. Chest 2004;126: 72S-77S.
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Coronary Artery Disease and Obstructive Sleep Apnea Jan Hedner, Karl A. Franklin, and Yüksel Peker
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Abstract Recurrent apneas during sleep lead to a sequence of events that, independently or in concert with other recognized risk factors, are likely to have harmful effects on vascular structure and function. The epidemiologic support for a causal relationship between obstructive sleep apnea (OSA) and coronary artery disease (CAD) is rapidly increasing but is not yet fully confirmed. This relationship is stronger in clinical cohorts than in the general population, which suggests that comorbid OSA in obese, hypertensive, smoking, and hyperlipidemic subjects may provide an additive or synergistic risk factor for development of CAD. OSA-related phenomena including hypoxemia, reoxygenation, and recurrent vascular wall stress may induce CAD, and the events may by themselves aggravate already-existing compromised coronary artery flow reserve.
Epidemiologic data suggest that obstructive sleep apnea (OSA) is overrepresented in patients with coronary artery disease (CAD). On the other hand, evidence suggests that the clinical course of CAD is initiated or accelerated by the presence of the breathing disorder. A rapidly evolving field of experimental data demonstrates that OSA, by phenomena such as hypoxemia and reoxygenation, may trigger a sequence of events involved in the development of atherosclerotic disease. Development of vascular disease and CAD is influenced by a number of genotypic and phenotypic risk factors, several of which have been associated with OSA. Sleep apneic events induce a state of increased cardiac oxygen demand but are also often associated with low oxygen reserve because of lack of ventilation. Nocturnal angina can therefore be triggered by sleep apneas in patients with CAD. There is growing evidence that elimination of sleep apnea can benefit patients with OSA at risk of CAD in the immediate and long term. Other data suggest that treatment of OSA may improve prognosis in patients undergoing coronary revascularization. This chapter reviews the evidence of an association between these two conditions.
EPIDEMIOLOGY The risk of experiencing angina pectoris or an acute coronary syndrome such as unstable angina, acute myocardial infarction (MI), or sudden cardiac death has long been known to be increased during the late hours of sleep or in the hours after awakening.1 This association may be explained by occurrence of OSA. A retrospective analysis showed an overrepresentation of peak time in sudden death from the cardiac causes during the sleeping hours in patients with OSA, which contrasted with a nadir in sudden death from cardiac causes in subjects without OSA and in the general population.2 A small prospective study addressing the time of onset of myocardial infarction showed a higher likelihood of having OSA in those with an onset of
Patients with CAD, including nocturnal angina, should therefore be considered for sleep recording, because elimination of apneas by nasal continuous positive airway pressure during sleep has been shown to reduce angina attacks and nocturnal myocardial ischemia. The long-term tentative causal association between OSA and CAD is supported by experimental data suggesting endothelial dysfunction, acceleration of vascular inflammation, and development of atherosclerotic disease as a result of the breathing disorder. Increased recognition of the adverse impact of OSA on vascular disease may open a perspective of new primary and secondary prevention models for CAD that involve identification and elimination of the OSA.
myocardial infarction during midnight hours.3 Besides this evidence of an immediate detrimental effect of apneas in patients with existing CAD, there is rapidly growing epidemiologic support for a causal relationship between OSA and CAD development. However, this association is yet not fully confirmed. In general, there is a stronger relationship between OSA and CAD in clinical cohorts than in the general population because clinical cohort studies are particularly influenced by comorbidity and confounding factors, including obesity, hypertension, smoking, and hyperlipidemia. This circumstance may also suggest that OSA constitutes an additive or synergistic risk factor for development of CAD. Prevalence of OSA and CAD in the General Population Snoring, a common symptom of OSA, is associated with up to a fivefold risk increase for MI.4,5 It has been claimed that snoring is a relatively insensitive measure of sleepdisordered breathing. However, the strength of these data is that snoring is an accessible symptom in large-scale studies, permitting appropriate adjustment for confounding risk factors. Snoring per se is a hard-to-quantify and observer-dependent phenomenon, but intrathoracic pressure changes typical of snoring may play an important role in the pathogenesis of CAD. This speculation is supported by a smaller-scale community study of 441 subjects,6 with sleep recordings showing an increased prevalence of CAD in nonapneic snorers (12%) compared with nonsnorers (7%), and there was a further increase (20%) in apneic snorers. The largest study to date addressing OSA and CAD is the Sleep Heart Health Study.7 The investigators performed a cross-sectional analysis of 6132 subjects undergoing unattended polysomnography. There was a modest risk increase (peaking at an odds ratio [OR] of 1.27) for self-reported CAD when the highest and lowest apnea– hypopnea index (AHI) quartiles were compared. The weak association in this prevalence study may be explained by a 1393
1394 PART II / Section 14 • Cardiovascular Disorders
proportionally high age and a low median AHI in the investigated population. Prevalence of CAD in Patients with OSA Clinical studies of CAD in sleep clinic cohorts generally involve patients with OSA and with daytime symptoms. Consequently, compared with studies in the general population, these studies selectively deal with symptomatic patients, those likely to suffer from more severe sleep apnea, and potentially also patients with more obesity and other cardiovascular comorbidities. Available data in this area are to a large extent based on uncontrolled studies. For example, in a sleep clinic cohort of 386 subjects,8 CAD was present in almost one fourth of subjects with OSA, and the percentage of patients with CAD was high among those with moderate to severe OSA. Simultaneous polysomnography and electrocardiographic recordings demonstrated that episodes of nocturnal ischemia were more common in patients with OSA who also had CAD, and mainly so during rapid eye movement (REM) sleep, during episodes of high apnea activity, and during sustained hypoxemia.9 Moreover, ST-segment depression on electrocardiography was not uncommon during sleep in patients with OSA but without a history of CAD, and these changes were eliminated by continuous positive airway pressure (CPAP).10 Studies using invasive measures, including angiography, verified CAD in more than 20% of investigated subjects with OSA,11 and an even higher prevalence (68%) was reported in a slightly larger study of unselected patients with OSA.12 Collectively these data suggest a proportionally high prevalence of CAD in sleep clinic cohorts. Prevalence of OSA in CAD Sleep-disordered breathing appears to be common in patients with CAD.13a An early small study13 demonstrated OSA or central sleep apnea with Cheyne-Stokes respiration in more than 75% of subjects with CAD. A subsequent Australian case-control study that investigated middle-aged male survivors of acute MI and age-matched controls14 provided the first clinic-based epidemiologic evidence of an increased prevalence of OSA in patients with CAD. OSA (AHI ≥ 5) was found in approximately one third of the patients compared with only 4% of controls and constituted an independent predictor of MI after adjustment for traditional risk factors. A larger case-control study15 provided a similar OSA prevalence (approximately 30%), whereas the prevalence in the control group was 20%. In this population, an AHI of 20 was associated with a history of MI (odds ratio, 2.0). Finally, in a tightly matched Swedish case-control study of 62 patients, OSA provided an independent odds ratio of 3.1 for CAD.16 There are also data that suggest that the OSA and CAD association may also be influenced by sex and age. In patients with angiographically verified CAD, an AHI of greater than 10 was almost twice as common in men17 but three times more common in women18 younger than 70 years, compared with age-matched controls. An uncontrolled follow-up study found OSA (AHI > 10) in 57% of 89 subjects with acute coronary syndrome undergoing percutaneous coronary intervention (PCI).19 A similar
high prevalence of OSA (66%) was reported in another investigation.20 The possibility that OSA may trigger episodes of nocturnal angina in patients with disabling CAD was addressed in an interventional study.21 OSA was found in 9 of 10 investigated patients with CAD who had nocturnal angina, and episodes of ischemia were reversed after elimination of the apneic events with CPAP treatment. A subsequent larger cross-sectional study found signs of silent nocturnal myocardial ischemia in 31% of 226 patients with CAD22 but failed to demonstrate a general and immediate temporal relationship between OSA and episodes of myocardial ischemia. However, a direct association could be documented in a small subgroup of patients, and, in general, episodes of silent ischemia appeared to be more frequent in those with more severe OSA. A retrospective evaluation of more than 200 patients undergoing electron-beam computer tomography within 3 years of an overnight sleep recording addressed the occurrence of subclinical coronary artery calcification.23 With multivariate adjustment, the OR for coronary artery calcification was 3.3 in the most severe AHI quartile (mean, 63.4 events/hr). The impact of OSA on the prognosis of CAD has been addressed in several studies. In a study of patients with CAD who were undergoing elective PCI, concomitant OSA was significantly related with increased late lumen loss and restenosis after an average follow-up time of 7 months.24 In another study,19 the incidence of adverse cardiac events (cardiac death, reinfarction, and target vessel revascularization) was reported to be almost 24% among patients with OSA, compared with 5% among those without OSA during a 6-month follow-up. Moreover, patients with CAD who had concomitant OSA were found to have an increased risk of cardiovascular mortality over a 5-year period.25,26 However, another study demonstrated no impact of OSA on readmission rate of PCI-treated patients with CAD who had concomitant OSA during a 6-month follow-up period20 and no significant difference regarding the 10-year survival rate for patients with CAD and with OSA compared with those without OSA at baseline.27,28 The incidence of stroke was also increased in patients with CAD who had concomitant OSA (and an AHI of at least 5 events/hr).28 Stroke occurred in 18% of patients with CAD and sleep apnea, compared with 5% of those without sleep apnea, during 10 years of follow-up after a coronary angiography was performed. After adjustments for confounders, including hypertension and atrial fibrillation, the patients with sleep apnea had an adjusted hazard of 2.9 (95% confidence interval [CI], 1.4 to 6.1) for a stroke.28 Hence, OSA is common in patients with MI, but their mean AHI is relatively low in most published reports (Table 121-1).9,13,16-20,29-32 Moreover, the prevalence of OSA is higher in patients with MI than in those with angina pectoris. This finding may be explained by the occurrence of Cheyne-Stokes respiration as a result of reduced ejection fraction.22 Nocturnal angina may be associated with severe OSA in patients with CAD. Available studies of the OSA prevalence in the CAD populations (see Table 121-1) include 776 patients, and more than 40% of those had an AHI exceeding 10. Moreover, the majority of the available data suggests that concomitant
CHAPTER 121 • Coronary Artery Disease and Obstructive Sleep Apnea 1395
Table 121-1 Prevalence of Sleep Apnea in Patients with Coronary Artery Disease FIRST AUTHOR REF (YEAR)
PATIENTS (NO.)
SEX
PATIENTS WITH AHI ≥ 10 (%)
CONTROLLED
De Olazabal 13 (1982)
17
Male
76
No
Andreas 29 (1996)
50
Male, female
50
No
Mooe 17 (1996)
142
Male
37
Yes
Mooe 18 (1996)
102
Female
30
Yes
Koehler 9 (1996)
74
Male
35
No
Peker 16 (1999)
62
Male, female
31
Yes
Moruzzi 30 (1999)
22
Male, female
9
No
Sanner 31 (2001)
49
Male, female
27
No
Mehra 20 (2006)
104
Male, female
66
No
Takama 32 (2007)
65
Male, female
45
No
Yumino 19 (2007)
89
Male, female
57
No
—
42
—
Total or mean
776
OSA provides a worsening of long-term outcome in patients with CAD. Incidence of CAD in Longitudinal Studies The incidence of CAD has been investigated in three large studies with focus on snoring habits. In a Finnish cohort of 4388 men aged 40 to 69 years, snoring provided a 1.9fold increased risk of CAD during a 3-year follow-up.4 The association was somewhat weakened after CAD risk-factor adjustment. A subsequent smaller prospective study33 in 400 subjects suggested that snoring worsened the prognosis of patients with already-known risk factors for cardiovascular disease but did not constitute an independent or predictive risk factor in itself. A large Danish prospective investigation on self-reported snoring habits in middleaged men34 failed to identify an increased incidence of CAD, although a trend was seen in the younger half of the cohort. These data are supported by a well-controlled 4-year prospective Spanish study,35 which showed a tripled risk for acute MI in snorers compared with nonsnorers. Self- or relative-reported heavy snoring has also been identified as a risk factor for case fatality and poor short-term prognosis after MI in a follow-up study.36 Moreover, a large followup study37 showed an almost tripled risk of cardiovascular death when the symptom of daytime sleepiness was added to snoring. The association was stronger in men younger than 60 years. As mentioned, it is likely that snoring provides only a nonspecific measure of OSA. These studies are likely to contain a variable contribution of patients with OSA, and it remains unknown if any specific aspect of snoring, such as profound negative intrathoracic pressures, may be involved in CAD development. Incident CAD data from the longitudinal analysis of the Sleep Heart Health Study has yet not been published. A smaller, retrospective sleep laboratory cohort study reported incident CAD in almost a quarter of untreated patients with OSA during a 7-year follow-up period.38 The corresponding numbers in treated sleep apnea patients and nonapneic snorers were 4% and 6%, respec-
tively. Moreover, more than 50% of a normotensive cohort not treated for OSA developed at least one cardiovascular disease during the 7-year follow-up (Fig. 121-1). New cases of patients with CAD were also found among those maintaining normotension.39 These findings suggest that development of CAD may be in part independent of diurnal systemic hypertension induced by OSA. A larger observational study of a sleep laboratory cohort, containing close to 1300 subjects with OSA, with a mean follow-up of 10 years, found a three to four times higher incidence of fatal and nonfatal cardiovascular events in patients with severe OSA compared with simple snorers.40 Multivariate analysis showed that the risk of fatal cardiovascular events was significantly increased in severe untreated patients with OSA (OR, 3.17; 95% CI, 1.12 to 7.51) compared with healthy controls. Similarly, the 18-year follow-up study of the population-based Wisconsin Sleep Cohort sample reported an adjusted hazard ratio of 5.2 (95% CI, 1.4 to 19.2) for cardiovascular mortality in severe (AHI > 30) patients with OSA and not using CPAP, versus those without OSA.41 Impact of Elimination of OSA on CAD Continuous positive airway pressure is the first-line treatment for reduction of daytime sleepiness and quality of life improvement in patients with OSA.42 A retrospective analysis of 55 patients with OSA and with concomitant CAD over an average follow-up time of 7.3 years showed a significantly lower occurrence of the composite endpoint of cardiovascular death, acute coronary syndrome, hospitalization for cardiac failure, or need for revascularization in those successfully treated with CPAP.43 In another followup study over 7.5 years, deaths from cardiovascular disease were reported to be less common in patients with OSA and treated with CPAP compared with those without treatment.44 Moreover, a review of 371 revascularized patients with OSA with concomitant CAD suggested a significantly lower cardiac death rate (3%) among 175 patients treated with CPAP, compared with 10% among 196 untreated patients during a follow-up period of 5 years.45 In the investigation of the sleep clinic cohort
1396 PART II / Section 14 • Cardiovascular Disorders 60 Incompletely treated OSA (n = 37) Efficiently treated OSA (n = 15) Non-OSA (n = 123)
50
%
40 30 20 10 0 Cardiovascular disease
Hypertension
Coronary artery disease
Cardiovascular event
Figure 121-1 Incidence of cardiovascular disease during a 7-year follow-up in middle-aged men otherwise healthy at baseline. The fraction of individuals with incidence of cardiovascular disease, hypertension, coronary artery disease (CAD), and cardiovascular event (stroke, myocardial infarction [MI], or cardiovascular death) is shown. Depicted are data from patients without OSA (non-OSA) as well as from those incompletely or efficiently treated for their sleep and breathing disorder. (Reprinted from Peker Y, Hedner J, Norum J, et al. Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea: a seven-year follow-up. Am J Respir Crit Care 2002;166:159-165.)
(mentioned earlier),40 treatment with CPAP significantly reduced cardiovascular risk in patients with severe OSA. Plenty of evidence suggests that CPAP treatment reduces the number of ischemic events in patients with nocturnal angina and concomitant OSA in the short term.21 However, some patients with CAD and with OSA may not experience daytime sleepiness (i.e., they are asymptomatic), and less is known regarding the adherence to CPAP therapy in these patients. However, a study of a sleep clinic cohort with concomitant CAD suggested a comparable compliance between sleepy and nonsleepy patients.46 Randomized clinical outcome trials are needed in this area. An ongoing study47 investigating the combined rate of cardiovascular mortality, stroke, MI, and the need for a new revascularization over a 3-year period in revascularized patients with CAD and with concomitant OSA may add further insights.
PATHOGENESIS Obstructive sleep apnea is associated with considerable immediate hemodynamic change (see Chapter 119). During the cycle of the apneic event, there is increased work of breathing, considerable negative intrathoracic pressure, recurrent hypoxia and reoxygenation, and fluctuating autonomic activity (see Chapter 119). Heart rate and blood pressure also fluctuate considerably through the cycle, but the absolute contribution of each of these changes to development of cardiovascular disease is unknown. Increased oxygen demand and reduced oxygen supply (i.e., hypoxemia) after sleep-disordered breathing may trigger an attack of angina pectoris in patients with CAD, who already have reduced coronary flow reserve.21 Nocturnal oxygen desaturations have been related to the severity of coronary atherosclerosis in patients with CAD48 and may be an important contributor to coronary restenosis in patients with CAD who are treated with PCI.49 Another study reported signs of apnea-induced ischemia
predominantly during REM sleep,9 a finding that may be explained by the often more prolonged and severe apneic events that commonly occur in this sleep stage. OSA is also associated with long-term alteration of cardiac structure, hemodynamic reflex function, and vascular structure or function. The disorder leads to immediate and sustained sympathetic activation.50 Baroreceptor and chemoreceptor responsiveness is altered,51 and vascular reactivity in terms of responsiveness to hypoxemia or vasoconstrictors appears to be elevated.52 A series of studies demonstrated that vascular endothelial function, expressed in terms of nitric oxide vascular dilating capacity, appears to be reduced in OSA.53 Changes are specific to OSA in the sense that they are reversed by CPAP (see Chapter 119).54-57 The mechanisms responsible for endothelial cell damage and dysfunction are not entirely understood. However, investigations have shown that oxidative stress, potentially as a result of periodic hypoxia and reperfusion, is enhanced in patients with OSA.55 Oxidative stress results in compromised nitric oxide bioavailability and leads to an activation of redox-sensitive gene expression. Ensuing steps in this chain of events include increased expression of adhesion molecules by an activated endothelium and leukocytes, which finally leads to acceleration of vascular inflammatory cascades and a promotion of atherogenesis and vascular dysfunction. This hypothesis (see Chapter 117)58 is supported by data from patients with OSA demonstrating increased free radical production,55 increased plasma-lipid peroxidation, increased adenosine and uric acid levels,58 and increased levels of redox-sensitive gene expression products including vascular endothelial growth factor59 and inflammatory cytokines.60 Interestingly, there was an improvement of endothelial function in patients with OSA following inhibition of xanthine oxidase by allopurinol61 or supplemental vitamin C.62 Moreover, circulating levels of adhesion molecules63 as well as adhesion molecule–dependent monocyte-to-endothelial-cell avidity appear to be increased in
CHAPTER 121 • Coronary Artery Disease and Obstructive Sleep Apnea 1397
OSA.64 Finally, sleep apnea appears to provide an additive stimulus for adhesion molecule expression in patients with CAD.65 Increased levels of circulating markers of inflammation including tumor necrosis factor (TNF)-α66 and C-reactive protein67 have been inconsistently found to be increased in OSA. It may be that determinants of these markers are, besides OSA, also influenced by multiple circumstances including comorbid risk factors for cardiovascular disease, lifestyle, environmental factors, and genetics. In fact, a study suggested an aggregation of premature CAD and related mortality in patients with OSA compared with controls.68 The tentative association between OSA and CAD is therefore supported by experimental data suggesting endothelial dysfunction, acceleration of vascular inflammation, and development of atherosclerotic disease as a result of the breathing disorder. Atherosclerotic plaque formation may jeopardize coronary flow reserve and generate symptoms of nocturnal angina during periods of increased flow demand. Such episodes occur repeatedly in sleep apnea, and they are associated with hypoxemia that further enhances the vulnerability for ischemia. On the other hand, the majority of heart attacks (i.e., acute MI, sudden cardiac death) stem from sudden rupture of less-obtrusive plaques, which triggers thrombus formation in coronary vessels.69 As earlier mentioned, it is suggested that sleepdisordered breathing influences the circadian acute coronary event distribution. OSA may lead to a disproportionate number of events that occur during or soon after the sleeping period. Although there is scientific support for a considerable impact of OSA on vascular structure and function, it is likely that development of CAD and other forms of vascular disease is determined by multiple genotypic and phenotypic factors. The absolute role of OSA in this concerted influence should evidently be better clarified. However, with the increasing recognition of OSA as an independent, additive, or even synergistic risk factor for CAD, we are facing a need for early identification of high-risk persons and a consensus on well-defined treatment strategies in such patients.
CLINICAL COURSE AND PREVENTION Early recognition and treatment of OSA may be beneficial in terms of CAD prevention. A retrospective analysis of a sleep laboratory cohort followed over 7 years found a reduction (relative risk, 0.29; CI, 0.10 to 0.82) of incident CAD in effectively treated OSA compared with ineffectively treated or untreated patients.38 On the other hand, in a group of patients with CAD followed for 5 years, mortality was higher in those with comorbid OSA (38%) than in those with no OSA (9%).25 Although the higher mortality was in part explained by the presence of other traditional risk factors, there was an independent influence by the breathing disorder. Another study followed 408 patients with stable angina and angiographically verified CAD during 5 years after sleep apnea recordings. The risk for a cerebrovascular event, including stroke and transient ischemic attack, was tripled in patients with CAD and concomitant OSA.26,28
Patients with CAD and nocturnal angina should be considered for sleep recording, because nasal CPAP reduces angina attacks and nocturnal myocardial ischemia.21 In the study of 10 severely disabled patients with a history of frequent nocturnal angina, 9 had sleep apnea.21 Treatment with CPAP reduced episodes of nocturnal ischemia. There is no evidence to suggest that medication used for treatment of CAD affects the severity of the breathing disorder. A double-blind crossover study of nitrates in patients with OSA with or without CAD found lower oxygen saturation during apnea-associated ischemic episodes than during ischemia not associated with apnea (77.3% versus 93.1%), and nitrate administration did not reduce the number of ischemic episodes associated with apnea.70 ❖ Clinical Pearls Recurrent apneas during sleep lead to a sequence of events that independently or in concert with other recognized risk factors are likely to have harmful effects on vascular structure and function. Not only may phenomena such as hypoxemia, reoxygenation, and recurrent vascular wall stress induce CAD but also the events themselves may aggravate already-existing compromised coronary artery flow reserve. The adverse health effects of OSA in terms of CAD development, progression, and proneness to complications are likely to depend on genotypic and phenotypic factors. Markers or predictors for identification of high-risk persons in this context are still lacking. Approximately a third of patients with CAD have OSA defined according to conventional criteria. A large fraction of these patients do not exhibit daytime sleepiness. Additional data on compliance with CPAP treatment, especially for nonsleepy patients with OSA and CAD, is needed. OSA identifies patients at risk for CAD and may represent a highly prevalent and modifiable risk factor. Recognition of the adverse impact of OSA on vascular disease will open a perspective of new primary and secondary prevention models for CAD that involve identifying and eliminating the sleep and breathing disorder.
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1398 PART II / Section 14 • Cardiovascular Disorders 7. Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163:19-25. 8. Maekawa M, Shiomi T, Usui K, et al. Prevalence of ischemic heart disease among patients with sleep apnea syndrome. Psychiatry Clin Neurosci 1998;52:219-220. 9. Koehler U, Dubler H, Glaremin T, et al. Nocturnal myocardial ischemia and cardiac arrhythmia in patients with sleep apnea with and without coronary heart disease. Klin Wochenschr 1991;69: 474-482. 10. Hanly P, Sasson Z, Zuberi N, et al. ST-segment depression during sleep in obstructive sleep apnea. Am J Card 1993;71:1341-1345. 11. Akasaka K, Akiba Y, Ishii Y, et al. Association between sleep apnea syndrome and coronary artery disease. Nippon Kyobu Shikkan Gakkai Zasshi 1997;35:16-21. 12. Bauer T, Ewig S, Schafer H, et al. Heart rate variability in patients with sleep-related breathing disorders. Cardiology 1996;87:492-496. 13. De Olazabel JR, Miller MJ, Cook WR, et al. Disordered breathing and hypoxia during sleep in coronary artery disease. Chest 1982;82:548-552. 13a. Prinz C, Bitter T, Piper C, Horstkotte D, Faber L, Oldenburg O. Sleep apnea is common in patients with coronary artery disease. Wien Med Wochenschr 2010;160:349-355. 14. Hung J, Whitford EG, Parsons RW, et al. Association of sleep apnoea with myocardial infarction in men. Lancet 1990;336: 261-264. 15. Schafer H, Koehler U, Ewig S, et al. Obstructive sleep apnea as a risk marker in coronary artery disease. Cardiology 1999;92:79-84. 16. Peker Y, Kraiczi H, Hedner J, et al. An independent association between obstructive sleep apnoea and coronary artery disease. Eur Respir J 1999;14:179-184. 17. Mooe T, Rabben T, Wiklund U, et al. Sleep-disordered breathing in men with coronary artery disease. Chest 1996;109:659-663. 18. Mooe T, Rabben T, Wiklund U, et al. Sleep-disordered breathing in women: occurrence and association with coronary artery disease. Am J Med 1996;101:251-256. 19. Yumino D, Tsurumi Y, Takagi A, et al. Impact of obstructive sleep apnea on clinical and angiographic outcomes following percutaneous coronary intervention in patients with acute coronary syndrome. Am J Cardiol 2007;99:26-30. 20. Mehra R, Principe-Rodriguez K, Kircher HL, et al. Sleep apnea in acute coronary syndrome: high prevalence but low impact on 6-month outcome. Sleep Med 2006;7:521-528. 21. Franklin KA, Nilsson JB, Sahlin C, et al. Sleep apnea and nocturnal angina. Lancet 1995;345:1085-1087. 22. Mooe T, Franklin KA, Wiklund U, et al. Sleep-disordered breathing in patients with coronary artery disease. Chest 2000;117:1597-1602. 23. Sorajja D, Gami AS, Somers VK, et al. Independent association between obstructive sleep apnea and subclinical coronary artery disease. Chest 2008;133:927-933. 24. Steiner S, Schueller PO, Hennersdorf MG, et al. Impact of obstructive sleep apnea on the occurrence of restenosis after elective percutaneous coronary intervention in ischemic heart disease. Respir Res 2008 June 3;9:50 (Epub ahead of print). 25. Peker Y, Hedner J, Kraiczi H, et al. Respiratory disturbance index: an independent predictor of mortality in coronary artery disease. Am J Respir Crit Care Med 2000;162:81-86. 26. Mooe T, Franklin KA, Holmström K, et al. Sleep-disordered breathing and coronary artery disease: long-term prognosis. Am J Respir Crit Care Med 2001;164:1910-1913. 27. Hagenah GC, Gueven E, Andreas S. Influence of obstructive sleep apnea in coronary artery disease: a 10-year follow-up. Respir Med 2006;100:180-182. 28. Valham F, Mooe T, Rabben T, et al. Increased risk of stroke in patients with coronary artery disease and sleep apnea: a 10-year follow-up. Circulation 2008;118:955-960. 29. Andreas S, Schulz R, Werner GS, et al. Prevalence of obstructive sleep apnoea in patients with coronary artery disease. Coron Artery Dis 1996;7:541-545. 30. Moruzzi P, Sarzi-Braga S, Rossi M, et al. Sleep apnoea in ischaemic heart disease: differences between acute and chronic coronary syndromes. Heart 1999;82:343-347. 31. Sanner BM, Konermann M, Doberauer C, et al. Sleep-disordered breathing in patients referred for angina evaluation-association with left ventricular dysfunction. Clin Cardiol 2001;24:146-150.
32. Takama N, Kurabayashi M. Possibility of close relationship between sleep disorder breathing and acute coronary syndrome. J Cardiol 2007;49:171-177. 33. Zaninelli A, Fariello R, Boni E, et al. Snoring and risk of cardiovascular disease. Int J Cardiol 1991;32:347-352. 34. Jennum P, Hein HO, Suadicani P, et al. Risk of ischemic heart disease in self-reported snorers. A prospective study of 2,937 men aged 54 to 74 years: the Copenhagen male study. Chest 1995;108: 138-142. 35. Zamarron C, Gude F, Otero Otero Y, et al. Snoring and myocardial infarction: a 4-year follow-up study. Respir Med 1999;93:108-112. 36. Janszky I, Ljung R, Rohani M, et al. Heavy snoring is a risk factor for case fatality and poor short-term prognosis after a first acute myocardial infarction. Sleep 2008;31:801-807. 37. Lindberg E, Janson C, Svärdsudd K, et al. Increased mortality among sleepy snorers: a prospective population based study. Thorax 1998;53:631-637. 38. Peker Y, Carlson J, Hedner J. Increased incidence of coronary artery disease in sleep apnoea: a long-term follow-up. Eur Respir J 2006; 28:596-602.28. 39. Peker Y, Hedner J, Norum J, et al. Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea: a seven-year follow-up. Am J Respir Crit Care 2002;166:159-165. 40. Marin JM, Carrizo SJ, Vicente E, et al. Long-term cardiovascular outcome in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365:1046-1053. 41. Young T, Finn L, Peppard PE, et al. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep 2008;31:1071-1078. 42. Basner RC. Continuous positive airway pressure for obstructive sleep apnea. N Engl J Med 2007;356:1751-1758. 43. Milleron O, Pilliére R, Foucher A, et al. Benefits of obstructive sleep apnoea treatment in coronary artery disease: a long-term follow-up study. Eur Heart J 2004;25:728-734. 44. Doherty LS, Kiely JL, Swan V, et al. Long-term effects of nasal continuous positive airway pressure therapy on cardiovascular outcomes in sleep apnea syndrome. Chest 2005;127:2076-2084. 45. Cassar A, Morgenthaler TI, Lennon RJ, et al. Treatment of obstructive sleep apnea is associated with decreased cardiac death after percutaneous coronary intervention. J Am Coll Cardiol 2007;50: 1310-1314. 46. Sampol G, Rodés G, Romero O, et al. Adherence to nCPAP in patients with coronary disease and sleep apnea without sleepiness. Respir Med 2007;101:461-466. 47. Peker Y, Glantz H, Thunstrom E, et al. Rationale and design of the Randomized Intervention with CPAP in Coronary Artery Disease and Sleep Apnoea—RICCADSA trial. Scand Cardiovasc J 2009;43: 24-31. 48. Hayashi M, Fujimoto K, Urushibata K, et al. Nocturnal oxygen desaturation correlates with the severity of coronary atherosclerosis in coronary artery disease. Chest 2003;124:936-941. 49. Hayashi M, Fujimoto K, Urushibata K, et al. Nocturnal oxygen desaturation as a predictive risk factor for coronary restenosis after coronary intervention. Circ J 2005;69:1320-1326. 50. Hedner J, Ejnell H, Sellgren J, et al. Is high and fluctuating muscle nerve sympathetic activity in the sleep apnoea syndrome of pathogenetic importance for the development of hypertension? J Hypertension 1988;6(Suppl. 4):529-531. 51. Parati G, Di Rienzo M, Bonsignore MR, et al. Autonomic cardiac regulation in obstructive sleep apnea syndrome: evidence from spontaneous baroreflex analysis during sleep. J Hypertension 1997;15 (12 Pt. 2):1621-1626. 52. Kraiczi H, Hedner J, Peker Y, et al. Increased vasoconstrictor sensitivity in obstructive sleep apnea. J Appl Physiol 2000;89:493498. 53. Carlson JT, Rangemark C, Hedner JA. Attenuated endotheliumdependent vascular relaxation in patients with sleep apnoea. J Hypertension 1996;14:577-584 54. Narkiewicz K, Somers VK. Sympathetic nerve activity in obstructive sleep apnoea. Acta Physiol Scand 2003;177:385-390. 55. Schulz R, Mahmoudi S, Hattar K, et al. Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea. Impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med 2000;162:566-570.
CHAPTER 121 • Coronary Artery Disease and Obstructive Sleep Apnea 1399
56. Noda A, Nakata S, Koike Y, et al. Continuous positive airway pressure improves daytime baroreflex sensitivity and nitric oxide production in patients with moderate to severe obstructive sleep apnea syndrome. Hypertens Res 2007;30:669-676. 57. Ip MS, Tse HF, Lam B, et al. Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med 2004;169:348-353. 58. Lavie L. Obstructive sleep apnoea syndrome-an oxidative stress disorder. Sleep Med Rev 2003;7:35-51. 59. Lavie L, Kraiczi H, Hefetz A, et al. Plasma vascular endothelial growth factor in sleep apnea syndrome: effects of nasal continuous positive air pressure treatment. Am J Respir Crit Care Med 2002; 165:1624-1628. 60. Yokoe T, Minoguchi K, Matsuo H, et al. Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation 2003;107:1129-1134. 61. El Solh AA, Saliba R, Bosinski T, et al. Allopurinol improves endothelial function in sleep apnoea: a randomised controlled study. Eur Respir J 2006;27:997-1002. 62. Grebe M, Eisele HJ, Weissmann N, et al. Antioxidant vitamin C improves endothelial function in obstructive sleep apnea. Am J Respir Crit Care Med 2006;173:897-901.
63. Ohga E, Tomita T, Wada H, et al. Effects of obstructive sleep apnea on circulating ICAM-1, IL-8, and MCP-1. J Appl Physiol 2003; 94:179-184. 64. Dyugovskaya L, Lavie P, Lavie L. Phenotypic and functional characterization of blood γδ T cells in sleep apnea. Am J Respir Crit Care Med 2003;168:242-249. 65. El-Solh AA, Mador MJ, Sikka P, et al. Adhesion molecules in patients with coronary artery disease and moderate-to-severe obstructive sleep apnea. Chest 2002;121:1541-1547. 66. Kataoka T, Enomoto F, Kim R, et al. The effect of surgical treatment of obstructive sleep apnea syndrome on the plasma TNF-alpha levels. Tohoku J Exp Med 2004;204:267-272. 67. Shamsuzzaman AS, Winnicki M, Lanfranchi P, et al. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation 2002;105:2462-2464. 68. Gami AS, Rader S, Svatikova A, et al. Familial premature coronary artery disease mortality and obstructive sleep apnea. Chest 2007; 131:118-121. 69. Libby P. Atherosclerosis: the new view. Sci Am 2002;286:46-55. 70. Schafer H, Koehler U, Ploch T, et al. Sleep-related myocardial ischemia and sleep structure in patients with obstructive sleep apnea and coronary heart disease. Chest 1997;111:387-393.
Heart Failure Shahrokh Javaheri
Abstract Heart failure is a common disorder that has a significant economic impact and is associated with excess morbidity and mortality. Because of increased average life spans and improved therapy for hypertension and ischemic coronary artery disease, the incidence and prevalence of heart failure remain high. One factor that may contribute to the progressively declining course of heart failure is the occurrence of periodic breathing, with repetitive episodes of apnea, hypopnea, and
Heart failure has been known for more than 2 centuries to be associated with abnormal breathing patterns, and John Cheyne and William Stokes have been credited for its description—hence the eponym Cheyne-Stokes breathing.1,2 However, 37 years earlier, John Hunter,3,4 a British physician, was the first to describe this breathing pattern, which is characterized by gradual crescendo– decrescendo changes in tidal volume, commonly with an intervening central apnea (Fig. 122-1).5-9 We therefore refer to this pattern as Hunter-Cheyne-Stokes breathing. Periodic breathing is a pattern of breathing characterized by cyclic fluctuations in the amplitude of tidal volume.10 It consists of recurring cycles of apnea or hypopnea, or both, followed by hyperpnea. The apneas and hypopneas may be obstructive (i.e., the result of upper airway occlusion) or central.10 Obstructive sleep apnea–hypopnea is the most common form of periodic breathing in persons without heart failure. However, in patients with heart failure, both obstructive and central periodic breathing occur, although central sleep apnea– hypopnea is predominant. Hunter-Cheyne-Stokes breathing (HCSB) is a form of periodic breathing with central sleep apnea that occurs in patients with systolic heart failure and has a long cycle time.11 The latter is an important feature of HCSB breathing and reflects the prolonged circulation time that is a pathologic feature of systolic heart failure. HCSB is a subjective description and is not readily quantifiable. For these reasons, the term central sleep apnea is preferable, and it also avoids misrepresentation, as credit for the discovery of breathing pattern has not been given to the original discoverer. Central sleep apnea observed in awake patients with heart failure has been considered a rare entity and potentially an indicator of a terminal prognosis. However, like obstructive apnea, central apnea occurs primarily during sleep, and polysomnographic studies have reported a high prevalence of this disorder in ambulatory patients with stable heart failure.8,9,12-14 1400
Chapter
122 hyperpnea. Episodes of apnea, hypopnea, and the following hyperpnea collectively cause hypoxemia and reoxygenation, hypercapnia and hypocapnia, changes in intrathoracic pressure, and sleep disruption and arousals. These pathophysiologic consequences of sleep-related breathing disorders have deleterious effects on the cardiovascular system, and they may be most pronounced in the setting of established heart failure and coronary artery disease. Diagnosis and treatment of sleep-related breathing disorders may therefore improve morbidity and mortality rates for patients with heart failure.
EPIDEMIOLOGY OF HEART FAILURE AND SLEEP-RELATED BREATHING DISORDERS Heart Failure Heart failure is approaching epidemic proportions and has become a major public health problem.15 It is estimated that it may contribute directly or indirectly to 266,400 deaths each year. The death rate increases progressively with advanced symptomatology, approaching 30% to 40% annually in patients with heart failure in New York Heart Association class IV. It is the largest single Medicare expenditure because it is the leading cause of hospitalization for patients older than age 65 years. Not surprisingly, therefore, the economic impact of heart failure is also huge, with an estimated cost of $29 billion in 2004 and $37 billion in 2009 (see Chapter 116, Table 116-1).15 Left ventricular myocardial failure is the most common cause of heart failure in adults, and it could be predominantly diastolic or manifested by combined systolic and diastolic dysfunction. The underlying pathology in diastolic heart failure is a stiff, noncompliant left ventricle with preserved systolic function. The principal hallmark of diastolic dysfunction, therefore, is an elevation in left ventricular end-diastolic pressure and consequently in pulmonary capillary pressure, resulting in pulmonary congestion, pulmonary edema, and shortness of breath (backward failure). In contrast, the hallmark of left ventricular systolic dysfunction is a depressed ejection fraction, which is commonly associated with an increase in left ventricular enddiastolic and systolic volumes. The symptoms, which result from both diminished cardiac output and the concomitant diastolic dysfunction, include fatigue, shortness of breath, and exercise intolerance. It is estimated that 1.5% to 2% of the U.S. population has heart failure.15 Heart failure is a disorder of elderly persons, and its prevalence increases to approximately 6% to 10% in those older than 65 years. Furthermore, it is estimated that 20 million people may have asymptomatic
CHAPTER 122 • Heart Failure 1401
LEOG REOG C3A2 O1A2 Chin LEMG ECG *FLOW *CHEST *ABDO SAO2 STAGE
95 97 96 93 90 90 93 97 97 94 91 90 92 96 98 95 93 90 90 95 98 97 93 90 90 94 97 97 94 91 90 92 96 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 S2 60"
120"
180"
240"
300
Figure 122-1 A 10-minute epoch of a patient with systolic heart failure and Hunter-Cheyne Stokes breathing. Note recurrent hypoxia/reoxygenation as a result of central sleep apnea. (Reproduced from Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010.)
Table 122-1 Prevalence of Sleep Apnea in Recent Studies of Systolic Heart Failure COUNTRY OF STUDY, YEAR (REF)
PATIENTS (N)
AHI ≥10/HR (%)
AHI ≥15/HR (%)
CSA (%)
OSA (%)
PATIENTS ON BETA-BLOCKERS (%)
United States, 2006 (16)
100
—
49
37
12
10
United States, 2008 (28)*
108
—
61
31
30
82
Canada, 2007 (23)
287
—
47
21
26
80
China, 2007 (25)
126
71
—
46
25
80
55
—
53
38
15
78
Germany, 2007 (27)*
700
52
33
19
85
85
Germany, 2007 (29)*
203
71
28
43
90
90
Germany, 2007 (26)*
102
54
37
17
80
80
United Kingdom, 2007 (24)
*In these studies, brain waves were not recorded. AHI, apnea–hypopnea index (the threshold used to define the presence of the disorder in each study); CSA, central sleep apnea; OSA, obstructive sleep apnea. From Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010.
cardiac dysfunction, and with time, these persons are likely to become symptomatic. Because of the increased average life span and improved therapy for ischemic coronary artery disease and hypertension, which are risk factors for heart failure, it is predicted that incidence and prevalence of heart failure will continue to rise in the 21st century. Sleep Apnea in Systolic Heart Failure The prevalence of sleep-related breathing disorders has been systematically studied in patients with systolic heart failure.5 Polysomnographic studies6-14,16-25 and studies using respiratory channels26-29 show a high prevalence of sleep apnea in this population. Most recent large studies of con-
secutive patients with systolic heart failure are depicted in Table 122-1. High prevalence rates have been reported in patients who have systolic heart failure and are awaiting transplantation,17 those with valve heart disease,18 and those with an implanted cardiac defibrillator.19,20 The most systematic prospective study of systolic heart failure16 involved 100 ambulatory male patients with stable, treated heart failure. Using an apnea-hypopnea index (AHI) of 15 events per hour or greater as the threshold, 49 patients (49% of all patients) had moderate to severe sleep apnea–hypopnea, with an average AHI of 44. In comparison, a population study of subjects without heart
1402 PART II / Section 14 • Cardiovascular Disorders
failure30 showed that 9% of working men and women aged 30 to 60 years had an AHI of greater than 15. An AHI of 5 or greater has been used to define the presence of a significant number of disordered-breathing events in obstructive sleep apnea–hypopnea syndrome.23 Therefore, with a much higher prevalence of sleep apnea observed in patients with heart failure than in the general population, systolic heart failure should be the leading risk factor for sleep apnea in the general population. In our studies,9,16 about 10% of the patients were on beta-blockers; however, recent studies continue to show a high prevalence of sleep apnea, both central and obstructive, despite the use of beta-blockers. Table 122-1 shows the prevalences of central and obstructive sleep apnea in the largest recent studies.16,23-29 Combining the results of these recent series, which used an AHI of 15 per hour of sleep as the threshold, 52% of 1250 patients with systolic heart failure have moderate to severe sleep apnea, 31% have central sleep apnea (CSA), and 21% have obstructive sleep apnea (OSA) (Fig. 122-2). However, there has been considerable variation in the prevalence of these two forms of sleep apnea in patients with systolic heart failure (see Table 122-1) which depends on a number of issues. The major reasons are the criteria used to define hypopnea, the accuracy of classification of disordered-breathing events (obstructive versus central, particularly in regard to hypopneas), the criteria used to define predominant obstructive versus central sleep apnea, the number of obese patients with heart failure enrolled, the level of arterial Pco2, and the severity of left ventricular systolic dysfunction. Sleep Apnea in Isolated Diastolic Heart Failure Isolated left ventricular diastolic dysfunction (LVDD) with relative preservation of left ventricular systolic function is the most common form of heart failure in elderly patients. The pathophysiologic consequence of LVDD relates to a hypertrophied, noncompliant left ventricle shifting the pressure volume curve upward and to the left.
PREVALENCE OF SLEEP APNEA IN SHF (n = 1250) 60 50
%
40 30 20 10 0 AHI < 15
AHI ≥ 15
CSA
OSA
Figure 122-2 Prevalence of sleep apnea in systolic heart failure (SHF). The data presented combine a series of world sleep studies (see Table 122-1). AHI, apnea–hypopnea index; CSA, central sleep apnea; OSA, obstructive sleep apnea. (Reproduced from Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010.)
Therefore, for a given left ventricular (LV) volume, LV end-diastolic pressure increases, resulting in elevated left atrial and pulmonary capillary pressures, pulmonary congestion, and edema. Hemodynamic studies show that pulmonary capillary pressure increases during the course of obstructive apnea, indicating the development of LVDD (see Chapter 120). Chronic repetitive exposure to negative swings in intrathoracic pressure, cyclic nocturnal hypertension and hypoxemia, and diurnal systemic hypertension could eventually result in LV hypertrophy and LVDD and failure. Studies30-32 suggest that OSA is associated with an increase in LV mass and that OSA-related cardiac structural changes may resolve with continuous positive airway pressure (CPAP) treatment. In the largest study,32 consisting of 2058 Sleep Heart Health Study participants, LV mass was associated with both apnea–hypopnea and hypoxemia indices after adjustment for age, sex, ethnicity, body mass index, smoking, systolic blood pressure, antihypertensive medication use, diabetes mellitus, prevalent myocardial infarction, and alcohol consumption. Furthermore, studies31,33 suggest that treatment with CPAP results in reversal of diastolic dysfunction.33 This has been confirmed by a randomized placebo (sham CPAP)-controlled trial, showing that after 12 weeks on effective CPAP therapy, there was a significant increase in the early-to-atrial filling velocity (E/A) ratio and a significant decrease in isovolemic relaxation and mitral deceleration time. Overall, little is known about the prevalence of sleeprelated breathing disorders and their impact in patients with isolated diastolic heart failure.34,35 Yet both disorders are prevalent in the older population, and the major consequences of sleep-related breathing disorders such as sympathetic activation, nocturnal hypertension, and hypoxemia could impair LV diastolic function. It is, therefore, conceivable that sleep-related breathing disorders are a cause of diastolic dysfunction or contribute to its progression. Epidemiologic and therapeutic studies are needed to define the relationship of these two disorders, particularly in the older population, and the impact of treatment of sleep apnea on the natural history of isolated diastolic heart failure. Sex and Sleep-Related Breathing Disorders in Systolic Heart Failure In the general population, the prevalence of OSA is significantly higher in men than in women. This also holds true for CSA in systolic heart failure. Combining the results of several studies of patients with systolic heart failure,12-14,17,18 40% of the male patients and 18% of the female patients have CSA (Fig. 122-3). A similar trend was found for OSA. The results of population studies of subjects without heart failure (reviewed by Young and colleagues36) suggest that menopause may be a risk factor for OSA, and that the risk is probably reduced by hormone replacement therapy. In women with congestive heart failure and systolic dysfunction, the risk of CSA was six times higher in those aged 60 years or older than in those younger than 60 years.12 A similar difference was also reported for obstructive sleep apnea–hypopnea before and after age 60 years.12 Thus,
CHAPTER 122 • Heart Failure 1403
P = .0001
40
% of each gender
35
P = .1
30 25
Male OSA: (169/496) CSA: (197/496) Female OSA: (25/96) CSA: (17/96)
20 15 10 5 0 OSA
CSA
Figure 122-3 Prevalence of obstructive sleep apnea (OSA) and central sleep apnea (CSA) in men and women with systolic heart failure. The prevalence of CSA is much lower in women than in men. A similar trend is found in OSA, though it is not statistically significant. (From Javaheri S. Sleep related breathing disorders in heart failure. In: Mann DL, editor. Heart failure: a companion to Braunwald’s heart disease. Philadelphia: Saunders; 2004. pp. 471-487.)
female hormonal status plays a role in the development of sleep-disordered breathing in women with and without heart failure. Progesterone is a known respiratory stimulant, and its effects on the respiratory system may in part explain the lower prevalence of central and obstructive sleep apnea in menstruating women. Progesterone increases ventilation37 and the tone of the dilator muscles of the upper airway.38 Furthermore, premenopausal women have a significantly lower apneic threshold than men.39 This should decrease the probability of developing central apnea during sleep in female subjects (see Mechanisms of Central Sleep Apnea, later).
MECHANISMS OF SLEEP-RELATED BREATHING DISORDERS IN HEART FAILURE Mechanisms of Central Sleep Apnea The mechanisms of periodic breathing and central sleep apnea in heart failure are complex and multifactorial (see Chapter 100).5,40-42 In heart failure, alterations occur in various components of the negative feedback system controlling breathing that increase the likelihood of developing periodic breathing, during both sleep and wakefulness. In addition, there are specific sleep-related mechanisms that explain the genesis of CSA and the reason periodic breathing becomes so prevalent during sleep. Mathematical models of the negative feedback system predict that increased arterial circulation time (which delays the transfer of information regarding changes in Po2 and Pco2 from pulmonary capillary blood to the chemoreceptors), enhanced gain of the chemoreceptors, and
enhanced plant gain (e.g., decreased functional residual capacity) collectively increase the likelihood of periodic breathing.5,40-42 Delay in transfer of information plays a fundamental role in destabilization of a negative feedback system.11,43 It has the potential to convert a negative feedback system to a positive feedback system. In heart failure, arterial circulation time may be increased for a variety of reasons including dilation of cardiac chambers, increased pulmonary blood volume, and decreased cardiac output. However, patients with systolic heart failure invariably have increased circulation time. Therefore, although increased circulation time is necessary to develop periodic breathing, it does not explain why only some heart failure patients have periodic breathing. The second factor that increases the likelihood of occurrence of periodic breathing (and also central apnea during sleep) is the gain of the chemoreceptors.44 In persons with increased sensitivity to CO2 (or hypoxia), the chemoreceptors elicit a large ventilatory response whenever the Pco2 rises (or the Po2 decreases). The consequent intense hyperventilation, by driving the Pco2 below the apneic threshold, results in central apnea. As a result of central apnea, Pco2 rises (and Po2 falls) and the cycles of hyperventilation and hypoventilation (hypopnea) or central apnea are maintained.44 Differences in the gain of the chemoreceptors among patients with heart failure may in part explain why only some patients develop periodic breathing and central sleep apnea. The third factor that may contribute to the development of periodic breathing in heart failure is decreased functional residual capacity, which results in underdamping.5,40-42 This means that for a given change in ventilation (e.g., a pause in breathing), changes in the controlled variables—namely Po2 and Pco2—will be augmented. In turn, the augmented changes in Po2 and Pco2 result in a pronounced compensatory ventilatory response, and overcompensation tends to destabilize breathing. Patients with heart failure may have decreased functional residual capacity for a variety of reasons, including pleural effusion, cardiomegaly, and decreased compliance of the respiratory system. Functional residual capacity may decrease further in the supine position, facilitating development of periodic breathing in this position. The aforementioned mechanisms underlying periodic breathing are present during both sleep and wakefulness. However, in the supine position and during sleep, further changes, such as reduction in functional residual capacity, metabolic rate, and cardiac output, occur that will augment the likelihood of developing periodic breathing beyond that observed during wakefulness. Meanwhile, like obstructive apnea, central apnea usually occurs during sleep or when a subject is dozing. The genesis of CSA during sleep relates specifically to the removal of the nonchemical drive of wakefulness on breathing and to the unmasking of the apneic threshold—the level of Pco2 below which rhythmic breathing ceases.42,45 The difference between two Pco2 set points—the prevailing Pco2 minus the Pco2 at the apneic threshold, referred to as Pco2 reserve—is a critical factor for occurrence of CSA. The smaller this difference, the greater is the likelihood of occurrence of apnea (discussed later).
1404 PART II / Section 14 • Cardiovascular Disorders
Normally, with the onset of sleep, ventilation decreases and Pco2 increases. As long as the prevailing Pco2 is above the apneic threshold, rhythmic breathing continues. However, in some patients with heart failure, the awake prevailing Pco2 does not significantly rise with onset of sleep.46,47 In addition, heart failure patients who develop central apnea have increased CO2 chemosensitivity below eupnea.46 Because of this and the proximity of the prevailing Pco2 to the apneic threshold, the likelihood of developing central apnea increases during sleep. The reason for the lack of the normally observed rise in Pco2 in some patients with heart failure is not clear. It could result from the lack of the normally observed sleepinduced decrease in ventilation. Conceivably, because of increased venous return in the supine position, and in the presence of a stiff left ventricle, pulmonary capillary pressure could rise. This results in an increase in respiratory rate and ventilation, preventing the normally observed rise in Pco2. Several studies48-50 have shown that patients with heart failure and low arterial Pco2 have a high probability of developing central apnea during sleep. Predictive value of a low steady-state arterial Pco2 (<35 mm Hg) is about 80%.50 However, although an awake low arterial Pco2 is highly predictive of CSA, it is not a prerequisite. Many patients with heart failure and central sleep apnea have a normal awake arterial Pco2.50,51 What is important is the proximity of the apneic threshold to the arterial Pco2, and an increased CO2 chemosensitivity below eupnea. Mechanisms of Obstructive Sleep Apnea As noted earlier, obstructive sleep apnea and hypopnea are also common in heart failure. The mechanisms are multifactorial. First, periodic breathing resulting from systolic heart failure predisposes the susceptible subjects to develop upper airway occlusion during the nadir of the ventilatory cycles of periodic breathing.7,52 Second, increased venous congestion and pressure resulting from right heart failure may diminish upper airway size53 and facilitate upper airway occlusion. Venous congestion of the upper airway may be worse in the supine (than in the erect) position, and rostral fluid shift, particularly in the presence of edema in the lower extremities and redistribution of fluid into vascular space, may further compound upper airway patency. Third, patients with heart failure and OSA are commonly obese, and obesity may compromise upper airway patency. In summary, decreased upper airway size resulting from both venous congestion and obesity may predispose patients with heart failure to develop upper airway occlusion during the nadir of the ventilatory cycles of periodic breathing, when the tone of the dilator muscles of the upper airway decreases the most.
PATHOLOGIC CONSEQUENCES AND PROGNOSTIC SIGNIFICANCE OF SLEEP-RELATED BREATHING DISORDERS The cycles of apnea–hypopnea and hyperpnea, both obstructive and central, are associated with three adverse consequences. These include intermittent arterial blood gas abnormalities characterized by hypoxemia–
reoxygenation and hypercapnia–hypocapnia, excessive arousals and shift to light sleep stages, and large negative swings in intrathoracic pressure (for details, see Chapter 119). The pathophysiologic consequences of obstructive and central sleep apneas and hypopneas adversely affect various cardiovascular functions and are potentially most detrimental in the presence of established coronary artery disease and left ventricular systolic and diastolic dysfunction. Effects of OSA on Cardiovascular Function and Mortality In patients with systolic heart failure, the presence of OSA is associated with increased sympathetic activity and reduced left ventricular ejection fraction, which are reversed if sleep apnea is effectively treated with nasal CPAP.54-57 There are four randomized clinical trials55-58 of CPAP therapy for OSA in patients with systolic heart failure. In three of these studies,55-57 left ventricular ejection fraction increased significantly (when compared with the control group), by about 10%, 5%, and 2%. In two57,58 of these four studies, sham CPAP was used in the control group; in one,57 left ventricular ejection fraction increased significantly but slightly (by 2%) and in the other one,58 ejection fraction did not increase. In the latter study, autoCPAP was used and the adherence hours to CPAP was less than in the two previous studies,54,55 which had demonstrated 10% and 5% increases in ejection fraction. The increase in left ventricular ejection fraction is important because it is a predictor of survival in patients with systolic heart failure. In patients with established coronary artery disease, obstructive sleep apnea is an independent prognostic factor for recurrent cardiovascular disorders and survival.59-61 Similarly, in systolic heart failure, two observational studies6,22 suggest that OSA contributes to mortality and that therapy with CPAP improves survival, particularly in those who are most compliant with it (Fig. 122-4).62 This latter observation in patients with heart failure is similar to that in patients with hypertension, as studies indicate that the reduction in blood pressure is most prominent in those who are most adherent to CPAP therapy (see Chapter 120). Effects of CSA on Cardiovascular Function and Mortality Like OSA, CSA is associated with increased sympathetic activity and reduced left ventricular ejection fraction, which was reversed by effective therapy with CPAP63 and oxygen (see later). Several studies,21,63-72 but not all,73,74 have suggested that presence of central sleep apnea decreases survival among patients with systolic heart failure. In one73 of the two studies73,74 noted, there was a tendency for excess mortality in heart failure patients with CSA, although this was not significant, probably because of the small number of patients. We followed 88 heart failure patients with (n = 56) or without (n = 32) CSA with a median follow-up of 51 months.72 After controlling for 24 confounding variables, CSA was associated with excess mortality (hazard ratio, 2.14; P = .02; Fig. 122-5). The average survival of heart failure patients without CSA was 90 months compared
CHAPTER 122 • Heart Failure 1405
CPAP DECREASES BP IN HYPERTENSIVE PATIENTS WITH OSA
A
0
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P = .004
≥3.5 hr/night
ITT
0
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–1
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–2
–4
–3
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CHANGES IN BP IN THERAPEUTIC vs. SHAM CPAP
–8 –10
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–7
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Therap CPAP Subtherap CPAP
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(n = 34)
(n = 23)
Figure 122-4 Changes in hypertension induced by obstructive sleep apnea (OSA). Note the improvement in hypertension in patients who are adherent to therapy, when OSA is effectively treated with continuous positive airway pressure (CPAP). ITT, intention to treat. (A, From Becker HF, Javaheri S. Systemic and pulmonary arterial hypertension in obstructive sleep apnea. In: LeeChiong T, editor; Javaheri S, guest editor. Sleep medicine clinics: sleep and cardiovascular disease. Philadelphia: Saunders;2007, pp. 549-557; B, From Coughlin SR, Mawdsley L, Mugarza JA, et al. Cardiovascular and metabolic effects of CPAP in obese males with OSA. Eur Respir J 2007;29:720-727.)
CSA IS A PREDICTOR OF MORTALITY IN SYSTOLIC HF 100 AHI < 5/hr AHI ≥ 5/hr
90 80
Survival %
70 60 50 40 30 20 Hazard ratio = 2.14 P = .02
10 0 0
10
20
30
40
50
60
70
80
90
100
110
120
130
140
150
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170
Months Figure 122-5 Probability of survival in patients with systolic heart failure (HF) according to the presence or absence of central sleep apnea (CSA). AHI, apnea–hypopnea index. (Reproduced from Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010. Modified from Javaheri S, Shukla R, Zeigler H, Wexler L. Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure. J Am Coll Cardiol 2007;49:2028-2034.)
1406 PART II / Section 14 • Cardiovascular Disorders
with 45 months for those with CSA. That CSA contributes to excess mortality in systolic heart failure is supported by the observation that effective treatment of CSA with CPAP devices improves survival.71
CLINICAL PRESENTATION OF OBSTRUCTIVE AND CENTRAL SLEEP APNEA IN PATIENTS WITH HEART FAILURE Obesity is an important risk factor for development of OSA in patients with heart failure,9,12,16 as it is for patients without heart failure.29 Patients with systolic heart failure and OSA are significantly heavier and snore habitually (Fig. 122-6). They may also have a higher systemic arterial blood pressure than subjects with CSA.9,12 Aside from obesity and habitual snoring, it is often difficult to clinically suspect the presence of sleep apnea in patients with heart failure because (1) the prevalence of sleepiness is similar in heart failure patients with and in those without sleep apnea9,16 (see Fig. 122-6), and (2) the symptoms of heart failure and sleep apnea overlap. The overlapping symptoms of sleep apnea and heart failure include sleeponset and maintenance insomnia, nocturia, waking up with shortness of breath (orthopnea, paroxysmal nocturnal dyspnea, hyperpnea due to periodic breathing), unrefreshed sleep, and daytime fatigue. The overlapping of the symptoms of heart failure and sleep apnea undoubtedly contributes to the underdiagnosis of sleep-related breathing disorders in patients with heart failure. Central sleep apnea in particular is most difficult to diagnose,8 because obesity and habitual snoring, which are the two hallmarks
30
P = .8
20 10 0 Patients (n)
Age (yr)
Ht (in)
BMI Snoring (kg/m2) (%)
EDS (%)
Figure 122-6 Demographics, historical data, and physical examination findings in heart failure patients without sleep apnea, with central sleep apnea (CSA), and with obstructive sleep apnea (OSA). Patients with OSA were more obese and had a higher prevalence of habitual snoring than patients with CSA. There was no difference in prevalence of excessive daytime sleepiness between the patients with heart failure and the patients without sleep apnea. BMI, body mass index; EDS, excessive daytime sleepiness; Ht, height. (Reproduced from Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010. Modified from Javaheri S. Sleep disorders in systolic heart failure: a prospective study of 100 male patients—the final report. Int J Cardiol 2006;106:21-28.)
P = .003
70 60
P = .03
P = .04
P = .002 P = .04
50 40 30 20 10 0 fib <3 PV 0 ≥ C/ 30 hr < CP 1 LT ≥1 /h <1 r ≥1 VT /h r PC <3 O 6≥ 2m 3 m 6 hg ≤2 LV 0 EF >2 ,% 0
40
P = .007
80
A.
P < .001 *o
90
R
60 50
P = .01
100
P = .1
NS
P = .1
70
P = .02 *o
Ia NY nd HA II II C I
Arbitrary units
80
Group I Group II Group III
Indications for Polysomnography in Heart Failure As noted, patients with heart failure and sleep apnea do not generally present with symptoms that distinguish them from heart failure patients without sleep apnea. Furthermore, because heart failure is common, it is not possible to perform sleep studies on all patients with heart failure. However, there are a number of clinical and laboratory findings that, when present in patients with heart failure, should increase clinical suspicion for sleep apnea. These markers are different for obstructive and central sleep apnea. Risk factors for obstructive sleep apnea–hypopnea in patients with heart failure are similar to those in patients without heart failure. They include obesity, increased neck size, habitual snoring, and hypertension. These risk factors and others such as witnessed apnea, waking up unrested, and excessive daytime sleepiness, when present, should increase the level of suspicion for the presence of OSA. Nocturnal angina—substernal chest pain that awakens the patient—should increase suspicion for sleep apnea in the general population and for patients with coronary heart disease and heart failure. Paroxysmal nocturnal dyspnea characteristically awakens the patient with shortness of breath, which is relieved with resumption of an erect position. However, this symptom
% With central sleep apnea
90
of OSA (see Fig. 122-6), are commonly absent in heart failure patients with central sleep apnea.8,9 However, there are some clues that, when present, should increase the probability of the presence of CSA. These include a high-numbered class in the New York Heart Association classification, low left ventricular ejection fraction, and steady-state arterial Pco2, atrial fibrillation, and nocturnal ventricular arrhythmias (Fig. 122-7).9
Figure 122-7 Clinical and laboratory characteristics that are more likely to be associated with central sleep apnea. A. fib, atrial fibrillation; CPLT, couplets; LVEF, left ventricular ejection fraction; NSR, normal sinus rhythm; NYHAC, New York Heart Association Class; PVC, premature ventricular contractions; VT, ventricular tachycardia. (Reproduced from Javaheri S. Sleep disorders in systolic heart failure: a prospective study of 100 male patients—the final report. Int J Cardiol 2006;106:21-28.)
may be a perception of shortness of breath occurring during the hyperpneic phase of periodic breathing, suggesting presence of sleep apnea. Restless sleep, maintenance insomnia, and leg movements may reflect periodic arousals and movements after apneas and hypopneas. Periodic limb movement, however, is also found in patients with systolic heart failure.16,75,76 Patients with heart failure and progressive ventricular systolic or diastolic dysfunction or patients who remain in New York Heart Association classes III or IV despite intensive medical therapy should have a diagnostic sleep study. In patients with a cardioverter or defibrillator, the prevalence of sleep apnea is high,19,20 and it may be associated with increased mortality.19 Such patients should have polysomnography and receive appropriate therapy for sleep apnea. The prevalence of sleep apnea is high in patients awaiting cardiac transplantation.17 The waiting period for transplantation is long, and a large number of patients succumb to the consequences of heart failure while waiting. It is conceivable that survival of these pretransplant patients may improve if their sleep apnea is diagnosed and appropriately treated. If so, the chance of receiving cardiac transplantation may increase. As noted earlier, several studies48-50 have shown that heart failure patients with low arterial Pco2 have a high prevalence of CSA. The predictive value of low Pco2 (<35 mm Hg) is about 80%.50 However, many patients with heart failure have CSA apnea without daytime hypocapnia.50,51 Several studies have shown that heart failure patients with sleep apnea have a higher prevalence of atrioventricular arrhythmias, especially atrial fibrillation9,12,16,77 and nocturnal ventricular arrhythmias.9,16,78 Presence of these arrhythmias should increase suspicion for the presence of CSA. In the presence of the aforementioned risk factors for obstructive and central sleep apnea, polysomnography should be performed for diagnosis and response to therapy. Such an approach has been shown to improve survival.79
TREATMENT OF SLEEP-RELATED BREATHING DISORDERS IN PATIENTS WITH HEART FAILURE The choice of therapy for obstructive or central sleep apnea is based on the type of sleep apnea.80 Treatment for Obstructive Sleep Apnea In general, treatment of obstructive sleep apnea–hypopnea is similar in patients with and without heart failure, although there are some differences (Box 122-1). In the presence of cardiovascular disease, every attempt should be made to treat OSA with positive airway pressure devices. Optimization of Cardiopulmonary Function Optimal treatment of heart failure by improving periodic breathing may decrease the likelihood of developing upper airway occlusion. Upper airway occlusion may occur at the nadir of the ventilatory cycle of periodic breathing,52 and in some patients with heart failure, the first few breaths
CHAPTER 122 • Heart Failure 1407
Box 122-1 Treatment of Obstructive Sleep Apnea in Patents with Heart Failure Optimization of cardiopulmonary function: • To eliminate or improve periodic breathing • To decrease right atrial and central venous pressure upper airway congestion/edema, which may increase upper airway size • To improve functional residual capacity, which may increase upper airway size as lung volume increases Avoidance of benzodiazepines, opioids, alcoholic beverages, and Viagra Weight loss if applicable Nasal positive airway pressure devices: • Continuous positive airway pressure (CPAP) • Bilevel positive airway pressure (see Chapter 107) Oral appliances (see Chapter 109): Supplemental nocturnal nasal oxygen to minimize desaturation and to decrease periodic breathing Upper airway procedures: • Uvulopalatopharyngoplasty (see Chapter 108) • Laser surgery (see Chapter 108) • Radiofrequency volume reduction (see Chapter 108)
after central apneas are obstructed.7 Furthermore, in biventricular heart failure, elevated right atrial and central venous pressure may result in pharyngeal congestion and edema, so using therapeutic measures to decrease venous pressure and upper airway narrowing53 is advisable. Also, optimal treatment of heart failure to increase lung volumes may also increase upper airway size, which is dependent on lung volume. Weight Loss In the general population, weight reduction improves OSA (see Chapter 106). Because many patients with heart failure and OSA are also obese,9,12,16 weight loss should be advised. Avoidance of Alcoholic Beverages, Benzodiazepines, and Phosphodiesterase-5 Inhibitors at Bedtime The use of alcoholic beverages and benzodiazepines may increase the likelihood of upper airway occlusion by promoting the relaxation of the muscles of the upper airway. We also advise patients that phosphodiesterase inhibitors used to treat erectile dysfunction (e.g., sildenafil [Viagra], vardenafil [Levitra], and tadalafil [Cialis]) may worsen obstructive sleep apnea. In a randomized double-blind placebo-controlled study,81 it was shown that 50 mg sildenafil significantly increased the obstructive apnea– hypopnea index and desaturation in a group of patients with OSA. Positive Airway Pressure Devices Positive airway pressure devices are the treatment of choice and have been most successfully used to treat OSA in the general population and in patients with heart failure. Firstnight application of nasal CPAP results in a significant decrease in disordered breathing, arterial oxyhemoglobin desaturation, and arousals.82 Short-term use of CPAP in
1408 PART II / Section 14 • Cardiovascular Disorders
patients with heart failure and OSA improves left ventricular ejection fraction, blood pressure, and ventricular systolic volume,55-57 but adherence to CPAP is a critical factor. For CPAP-noncompliant subjects who complain of a high expiratory pressure, bilevel pressure devices should be tried. As noted earlier, a recent observational study of patients with systolic heart failure has shown that effective treatment of OSA with CPAP improves survival, part icularly in those who are compliant with CPAP (Fig. 122-8).62 Supplemental Nasal Oxygen For subjects with heart failure who cannot tolerate positive air pressure devices, oxygen is an alternative for treating OSA. The rationale for use of nocturnal supplemental nasal oxygen is to improve both hypoxemia and periodic breathing. Minimizing desaturation and hypoxemia– reoxygenation may have important therapeutic implications. Furthermore, as noted earlier, improvement in periodic breathing may decrease in obstructive disorderedbreathing events that occur at the nadir of ventilation. Upper Airway Procedures Upper airway surgical procedures are performed for treatment of obstructive sleep apnea in the general population, but there are no data in patients with heart failure.
Cumulative event-free survival (%)
CUMULATIVE EVENT-FREE SURVIVAL BY COMPLIANCE STATUS 100 N = 32 AHI: 46/hr LVEF: 37%
80 60
N = 33 AHI: 44/hr LVEF: 35%
40 20
N = 23 AHI: 38/hr LVEF: 35%
0 0
12
24
36
48
Oral Appliances Oral appliances are used to treat OSA, particularly in patients who cannot tolerate CPAP (see Chapter 109). Limited data are available in heart failure.83 We speculate that efficacy of these devices in heart failure patients with OSA is similar to that in the general population. After application, a sleep study is recommended to ensure effectiveness. Treatment for Central Sleep Apnea Figure 122-9 shows our approach to treatment of patients with CSA in heart failure. Optimization of Cardiopulmonary Function Intensive therapy of heart failure with diuretics, angiotensin-converting enzyme inhibitors, beta-blockers, and cardiac resynchronized therapy (CRT) can improve periodic breathing.5 Because pulmonary congestion and edema are associated with narrowing of Pco2 reserve,84 reduction in wedge pressure should be associated with widening of Pco2 reserve and improvement in CSA. Furthermore, with therapy, arterial circulation time decreases (as stroke volume increases and cardiopulmonary blood volume decreases) and functional residual capacity may increase (because of a decrease in cardiac size, pleural effusion, and intravascular and extravascular lung water). These changes contribute to the stabilization of breathing. Beta-blockers, by increasing stroke volume and decreasing pulmonary capillary pressure, should be particularly helpful in improving periodic breathing in systolic heart failure. An additional beneficial effect of beta-blockers may relate to their counterbalancing of nocturnal cardiac
Optimize therapy: ACEI; β-blockers; diuretics; digoxin; CRT
SRBD eliminated
Persistent SRBD
Follow-up clinically
Consider treatment
60
Months (6.0 hr/night) (3.5 hr/night) Untreated HR 4.02 (1.33-12.2), P = .014 adherent vs. nonadherent HR 2.03 (1.07-3.68), P = .03 all CPAP treated vs. untreated Figure 122-8 Probability for hospitalization and mortality of heart failure patients with obstructive sleep apnea decrease if they are treated with continuous positive airway pressure (CPAP) and adhere to therapy. AHI, apnea–hypopnea index; HR, hazard ratio; LVEF, left ventricular ejection fraction. (Reproduced from Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010. Modified from Kasai T, Narui K, Dohi P, et al. Prognosis of patients with heart failure and obstructive sleep apnea treated with continuous positive airway pressure. Chest 2008;133:690-696.)
Medications
Nocturnal nasal oxygen
Theophylline
Cardiac transplantation
Acetazolamide
nCPAP
PAP devices
APSSV
Figure 122-9 Treatment of central sleep apnea in patients with systolic heart failure. ACEI, angiotensin-converting enzyme inhibitor; APSSV, adaptive pressure support servoventilation; CRT, cardiac synchronization therapy; nCPAP, nasal continuous positive airway pressure; PAP, positive airway pressure; SRBD, sleep-related breathing disorder. (Adapted from Javaheri S. Sleep-related breathing disorders in heart failure. In: Mann DL, editor. Heart failure: a companion to Braunwald’s heart disease. Philadelphia: Saunders; 2004. p. 482.)
Cardiac Transplantation Preliminary studies (reviewed by Javaheri5) and a study92 of 45 patients with heart failure have shown that after cardiac transplantation, CSA is virtually eliminated. However, with time, a large number of cardiac transplant recipients develop OSA.92 In this study,92 36% had an apnea–hypopnea index of 15 per hour or greater. Obstructive sleep apnea developed in those who had gained the most weight after transplantation, and it was associated with habitual snoring, poor quality of life, and systemic hypertension. Cardiac transplantation was also associated with a high prevalence of restless legs syndrome and periodic limb movements (Fig. 122-10).92 Positive Airway Pressure Devices Several devices, including CPAP, bilevel pressure, and adaptive pressure support servoventilation (APSSV), have been used to treat central sleep apnea in patients with systolic heart failure.92a In contrast to treatment of OSA, where application of nasal CPAP invariably results in virtual elimination of obstructive disordered-breathing events, treatment of CSA in patients with systolic heart failure is difficult, and response to therapy is not uniform. Early studies93 of CPAP to treat central sleep apnea in systolic heart failure showed various results, with a number of trials showing no effects94-96 and others, primarily from Toronto, showing positive effects.63,97 One early trial95 showed worsening of heart failure and death in some patients while on CPAP. In our study,82 first-night CPAP titration was effective in improving CSA in 43% of the patients (57% were considered CPAP nonresponsive). In any case, in spite of the early enthusiasm from Toronto studies, the multicenter Canadian trial failed to confirm the initial observations. In this trial,98 132 patients were randomized to the control group and 128 to the CPAP arm. The baseline features were similar in the two randomized groups. The patients in the therapeutic arm were adapted to CPAP over 1 to 3 nights (without polysomnography), and the maximum
80 70 Percent
60 50 40 30 20 10 0
H sn abi or tua Ex in l ce g sl ssiv ee e pi da ne y ss tim e U nr ef sl res ee h p ed R es sy tle nd ss ro le m gs e W ei gh tg ai n H yp er te ns io n
sympathetic hyperactivity resulting from repetitive arousals and desaturation. The reduction in cardiac sympathetic activity may have contributed to improved survival in trials of beta-blockers in patients with heart failure. One particular side effect of beta-blockers, however, is related to their effect on melatonin. Melatonin, a sleep-promoting chemical, is secreted via the cyclic adenosine monophosphate (cAMP)-mediated beta-adrenergic signal transduction system. Some beta-blockers (exceptions include carvedilol), by inhibiting this process, decrease melatonin secretion85,86 and could potentially contribute to worsening of sleep. Regarding improvement in cardiac function and CSA, a few studies of CRT87-90 showed some improvement in CSA, particularly noticeable in those with CRT-induced hemodynamic improvement. However, CRT devices are ineffective for OSA, although in one study,91 OSA improved, and improvement correlated with a decrease in circulation time. If periodic breathing persists after cardiopulmonary function is optimized, several approaches are possible (see Fig. 122-9).
CHAPTER 122 • Heart Failure 1409
Group 1; No OSA or PLMS (AHI = 6) Group 2; PLMS (AHI = 3) Group 3; OSA (AHI = 50) Figure 122-10 Phenotype of patients after heart transplantation. Group 1 did not have obstructive sleep apnea (OSA) or periodic limb movements during sleep (PLMS), Group 2 had PLMS, and Group 3 had OSA. AHI, apnea–hypopnea index. Weight gain is in kilograms since the transplantation. (Adapted from Javaheri S, Abraham W, Brown C, et al. Prevalence of obstructive sleep apnea and periodic limb movement in 45 subjects with heart transplantation. Eur Heart J 2004;25: 260-266.)
pressure was set at 10 cm H2O or whatever was tolerated. A second polysomnography was performed at 3 months in both groups. There was no significant change in AHI in the control group. In the CPAP arm, the average AHI decreased by 50%, with considerable improvement in desaturation. Furthermore, the average plasma norepinephrine level decreased and left ventricular ejection fraction increased (all statistically significant). These measurements remained unchanged in the control group. However, after an interim analysis was performed, the safety-monitoring committee recommended termination of the study. This was in part related to worsened transplantation-free survival (primarily due to increased number of deaths from progressive heart failure and sudden death) of the CPAP-treated patients compared with the control group (P = .02). Although the survival curves diverged after about 3 years (favoring the CPAP arm), the difference was not statistically significant (P = .06). We speculated that CPAP therapy could have resulted in excess early mortality for several reasons, including the following.99 (1) Those who died were heart failure patients with CSA, whose periodic breathing was CPAP nonresponsive. (2) Those who died were heart failure patients whose ventricular function (according to the FrankStarling curve) was preload dependent. If right and left ventricular function is preload dependent, any reduction in venous return by the increased intrathoracic pressure, with application of CPAP, could decrease right ventricular stroke volume and return to the
1410 PART II / Section 14 • Cardiovascular Disorders
Transplant-free survival (%)
TRANSPLANT-FREE SURVIVAL IN HF PATIENTS ACCORDING TO EFFECT OF CPAP ON CSA 100
CPAP responders* (AHI at 3 months < 15/hr, n = 57)
80
Control (AHI = 38/hr, n = 110)
60 CPAP nonresponders (AHI at 3 months ≥15/hr, n = 43)
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20 *Versus control: HR = 0.36, P = .040 0 0
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48
54
60
Time from enrollment (months) Figure 122-11 Probability of survival in patients with systolic heart failure (HF) comparing continuous positive airway pressure (CPAP) responders to a control group (patients with systolic heart failure and similar apnea–hypopnea index [AHI]) and to CPAP nonresponders. CPAP responders had a significantly increased probability of survival compared with the control group. CPAP nonresponders tended to have a poor survival when compared with the control group, although this was not significant. CSA, central sleep apnea; HR, hazard ratio. (Reproduced from Kryger MH. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010. Modified from Artz M, Floras JS, Logan AG, et al. Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure. Circulation 2007;115:3173-3180.)
left ventricle, decreasing left ventricular stroke volume and causing hypotension, diminished coronary blood flow, myocardial ischemia, and arrhythmias. Any such effect of CPAP on blood pressure is further augmented during sleep when blood pressure normally decreases. The aforementioned assumptions that in the Canadian trial excess cardiovascular death due to CPAP occurred primarily in CPAP nonresponders was confirmed by a posthoc analysis of mortality of patients with CSA (Fig. 122-11).71 In those whose CSA responded to CPAP, transplantation-free survival was significantly improved when compared with the untreated control group. In addition, the mortality of CPAP nonresponders appeared to be the worst, although the number of patients was small for statistical significance. In the Canadian trial98 at 3 months, 43% of heart failure patients with CSA were CPAP nonresponsive, compared with 57% in our study81 of first-night use. Typically, CPAP-responsive patients had less severe central sleep apnea than CPAP-nonresponsive patients. In our study,82 in CPAP-responsive patients, the average AHI decreased from 36 to 40 per hour, with elimination of desaturation. An important observation was that the number of premature ventricular contractions, couplets, and ventricular tachycardias decreased. This effect was presumed to result from decreased sympathetic activity, because arousals
decreased and saturation improved. Heart failure patients with severe CSA (57% of the patients) did not respond to CPAP, and use of CPAP had no significant effect on ventricular irritability. The mechanisms of improvement in CSA in CPAPresponsive patients are multifactorial. One may relate to improvement in pulmonary congestion, which should widen Pco2 reserve. CPAP may improve stroke volume by decreasing left ventricular afterload, which decreases arterial circulation time. CPAP should increase functional residual capacity, which decreases underdamping, and CPAP opens the upper airway, which is a benefit for those patients with CSA in whom upper airway closure occurs. However, as noted earlier, 43% to 57% of heart failure patients with CSA are nonresponsive to CPAP. For these patients, and those who are intolerant to CPAP, we recommend the use of APSSV devices. These devices act like a buffer to maintain relatively stable breathing (buffer PAP). The device provides varying amounts of ventilatory support during different phases of periodic breathing. The support is proportional: It is minimal during the hyperpneic phase of periodic breathing and maximal during periods of diminished breathing. In addition, the device initiates a breath on a timely basis, preventing development of a central apnea. These devices have been used to effectively treat CSA in idiopathic Cheyne-Stokes breathing,100 sleep apnea associated with opioids,101 and CPAP-emergent or persistent CSA.102 In several studies,103-112 these devices have also been used to treat CSA in patients with congestive heart failure, generally with favorable results. In an acute (1-night) study103 in 14 subjects with systolic heart failure and CSA, the APSSV device decreased the AHI more than oxygen, CPAP, and bilevel devices. We optimistically hypothesize that systematic long-term studies with buffer PAP devices will prove effective in treatment of CSA, which should translate to improved survival of patients with heart failure. Meanwhile, these devices are effective in treating both CSA and OSA, and because these two sleep disorders commonly occur together in the same patient, the distinction as to which kind of sleep apnea is predominant becomes academic. In conclusion, APSSV devices are effective in treating sleep apnea in patients with systolic and diastolic heart failure, and we recommend them in first-night CPAP nonresponders.111a,111b Cardiac Pacing In 15 subjects with predominantly mild to moderate central sleep apnea, some of whom had mild left ventricular systolic dysfunction, atrial overdrive pacing improved periodic breathing.112 These subjects had permanent atrial-synchronized ventricular pacemakers placed for symptomatic sinus bradycardia. Atrial overdrive (an average of 72 beats per minute versus spontaneous 57 beats per minute) moderately but significantly decreased the AHI from 28 to 11, improved arterial oxyhemoglobin desaturation, and decreased arousals. The mechanism remains unclear, but it could have been the improved cardiac output. However, if cardiac pacing improves CSA, biventricular pacing113 should be more effective than atrial pacing overdrive.
CHAPTER 122 • Heart Failure 1411
80
Apnea–hypopnea index (n/hr)
70 60
Room air Oxygen Means ± SD
P < .0001
P < .01
P < .001
P < .05 50
P < .01 P = .02
40 30 20 10 0 n=9 Hanly
n=7 n = 11 n=7 n = 22 n = 29 Walsh Staniforth Franklin Andreas Javaheri
Figure 122-12 Effects of supplemental nasal oxygen on apnea–hypopnea index in patients with systolic heart failure.
Medications N ASAL N OCTURNAL O XYGEN Systematic studies in patients with systolic heart failure114-119 have shown that nocturnal therapy with supplemental nasal oxygen improves central sleep apnea (Fig. 122-12). Oxygen therapy may also decrease arousals and improve the hypnogram by shifting sleep structure to deep sleep stages. In addition, randomized placebocontrolled double-blind studies have shown that shortterm (1 to 4 weeks) administration of nocturnal supplemental nasal oxygen improves maximal exercise capacity116 and decreases overnight urinary norepinephrine excretion.117 Three randomized clinical trials of nocturnal nasal oxygen therapy120-122 for 9-, 12-, and 52-week periods, reported that, when compared with the control group, oxygen therapy improved CSA and desaturation and significantly increased left ventricular ejection fraction and quality of life of patients with heart failure. In the oxygentreated group, left ventricular ejection fraction increased 5% (versus 1% in the control group) in the 12-week study,122 and 5.5% (versus 1.3% in the control group) in the 52-week study.121 Supplemental administration of nasal oxygen may decrease periodic breathing by several mechanisms.119 These include an increase in the difference between the prevailing Pco2 and the Pco2 at the apneic threshold; a reduction in the ventilatory response to CO2 and perhaps to hypoxemia; and an increase in body stores (e.g., lung contents) of oxygen, which increases damping. Prospective placebo-controlled long-term studies, however, are necessary to determine if nocturnal oxygen therapy has the potential to decrease mortality of patients with systolic heart failure. T HEOPHYLLINE Open and blind studies7,123 have shown the efficacy of theophylline in the treatment of central sleep apnea in heart failure. In a double-blind randomized placebo-controlled
crossover study of 15 patients with treated, stable systolic heart failure, oral theophylline at therapeutic plasma concentration (11 µg/mL, range 7 to 15 µg/mL) decreased the AHI by about 50% and improved arterial oxyhemoglobin saturation.123 Mechanisms of action of theophylline in improving central apnea remain unclear.123 At therapeutic serum concentrations, theophylline competes with adenosine at some of its receptor sites. In the central nervous system, adenosine is a respiratory depressant and theophylline stimulates respiration by competing with adenosine. Conceivably, therefore, an increase in ventilation by theophylline could decrease central apnea during sleep. Theophylline does not increase ventilatory response to CO2. Potential arrhythmogenic effects and phosphodiesterase inhibition are common concerns with long-term use of theophylline in patients with heart failure. Therefore, further controlled studies are necessary to ensure its safety. If theophylline is used to treat CSA, frequent and careful follow-ups are necessary. A CETAZOLAMIDE By inhibiting carbonic anhydrase in red blood cells, kidney, and choroid plexus, acetazolamide causes acidosis in the blood and cerebrospinal fluid124-126 and stimulates breathing. By doing so, acetazolamide increases the Pco2 reserve, decreasing the likelihood of the development of central apnea during sleep.127 Acetazolamide has been used to treat idiopathic central sleep apnea128-129 and periodic breathing at high altitude. In a double-blind placebo-controlled crossover study130 of 12 patients with heart failure, acetazolamide, administered at about 3 mg/kg one-half hour before bedtime, decreased the central apnea–hypopnea index significantly from about 57/hr (in the placebo arm) to 34/hr. Acetazolamide improved arterial oxyhemoglobin desaturation significantly. Furthermore, patients reported improved subjective perceptions of the following: overall sleep quality, feeling rested on awakening, falling asleep unintentionally during daytime, and fatigue. Acetazolamide, therefore, could have other advantageous effects when used in patients with heart failure and CSA, including acting as a mild diuretic and also normalizing the alkalemia (caused by loop diuretics) commonly present in patients with heart failure. In our patients, arterial blood pH decreased from 7.43 to 7.37.130 B ENZODIAZEPINES Benzodiazepines, by decreasing arousals, may decrease central sleep apnea. However, a placebo-controlled double-blind study131 showed a reduction in arousals but failed to show any improvement in CSA in patients with systolic heart failure. Although benzodiazepines do not increase the number of central apneas, their use may increase the likelihood of developing obstructive apneas in some heart failure patients. I NHALED CO AND A DDITION OF E XTERNAL D EAD S PACE Several studies have shown that low-level inhalation of CO2 and addition of external dead space (by increasing Pco2) improve CSA.132-136 However, studies106,133,134 show that CO2 inhalation increases spontaneous arousals, which 2
1412 PART II / Section 14 • Cardiovascular Disorders
are associated with increased sympathetic and decreased parasympathetic activity. One study106 also showed that addition of dead space was associated with increased arousals. Knowing the adverse cardiovascular effects of increased sympathetic overactivity in heart failure, use of CO2 and external dead space to treat CSA in heart failure should be avoided.
❖ Clinical Pearls Because of the increased average life span and improved therapy of ischemic coronary artery disease and hypertension, the prevalence of heart failure remains high. Periodic breathing is common in heart failure and is characterized by apnea, hypopnea, and hyperpnea, which cause sleep disruption, arousals, hypoxemia/reoxygenation, hypercapnia/hypocapnia, and changes in intrathoracic pressure. Periodic breathing includes both obstructive and central sleep-related breathing disorders. All of these adversely affect sleep and cardiovascular function. Periodic breathing may contribute to the remodeling of left ventricular dysfunction and to the progressively declining course of heart failure. Several studies have demonstrated that both CSA and OSA are associated with increased mortality of patients with heart failure and systolic dysfunction. There are only a few long-term studies on treatment of sleep apnea in systolic heart failure. These show that effective treatment of both CSA and OSA with CPAP improves mortality of patients with heart failure.
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107. Kasai T, Narui K, Dohi T, et al. First experience of using new adaptive servo-ventilation device for Cheyne-Stokes respiration with central sleep apnea among Japanese patients with congestive heart failure. Circ J 2006;70:1148-1154. 108. Fietze I, Blau A, Glos M, et al. Bi-level positive pressure ventilation and adaptive servo ventilation in patients with heart failure and Cheyne-Stokes respiration. Sleep Med 2008;9:652-659. 109. Oldenburg O, Schmidt A, Lamp B, et al. Adaptive servoventilation improved cardiac function in patients with chronic heart failure and Cheyne-Stokes respiration. Eur J Heart Fail 2008;10: 581-586. 110. Arzt M, Wensel R, Montalvan S, et al. Effects of dynamic bilevel positive airway pressure support on central sleep apnea in men with heart failure. Chest 2008;134:61-66. 111. Randerath W, Galetke W, Stieglitz S, et al. Adaptive servoventilation in patients with coexisting obstructive sleep apnoea/ hypopnoea and Cheyne-Stokes respiration. Sleep Med 2008;9: 823-830. 111a. Bitter T, Westerheide N, Faber L, et al. Adaptive servoventilation in diastolic heart failure and Cheyne-Stokes respiration. Eur Respir J 2010;36:385-392. 111b. Westhoff M, Arzt M, Litterst P. [Influence of adaptive servoventilation on B-type natriuretic petide in patients with Cheyne-Stokes respiration and mild to moderate systolic and diastolic heart failure]. Pneumologie 2010;64:467-473. 112. Garrigue S, Bordier P, Jaïs P, et al. Benefit of atrial pacing in sleep apnea syndrome. N Engl Med 2002;346:404-412. 113. Abraham WT, Hayes DL. Cardiac resynchronization therapy for heart failure. Circulation 2004;108:2596-2603. 114. Hanly PF, Millar TW, Steljes DG, et al. The effect of oxygen on respiration and sleep in patients with congestive heart failure. Ann Intern Med 1989;111:777-782. 115. Javaheri S, Ahmed M, Parker TJ, with technical assistance of Brown CR. Effects of nasal O2 on sleep-related disordered breathing in ambulatory patients with stable heart failure. Sleep 1999;22: 1101-1106. 116. Andreas S, Clemens C, Sandholzer H, et al. Improvement of exercise capacity with treatment of Cheyne-Stokes respiration in patients with congestive heart failure. J Am Coll Cardiol 1996;27:1486-1490. 117. Staniforth AD, Kinnear WJ, Starling R, et al. Effect of oxygen on sleep quality, cognitive function and sympathetic activity in patients with chronic heart failure and Cheyne-Stokes respiration. Eur Heart J 1998;19:922-928. 118. Franklin KA, Eriksson P, Sahlin C, et al. Reversal of central sleep apnea with oxygen. Chest 1997;111:163. 119. Javaheri S. Pembrey’s dream: the time has come for a long-term trial of nocturnal supplemental nasal oxygen to treat central sleep apnea in congestive heart failure. Chest 2003;123:322-325. 120. Sasayama S, Izumi T, Seino Y, et al. Effects of nocturnal oxygen therapy on outcome measures in patients with chronic heart failure and Cheyne-Stokes respiration. Circ J 2006;70:1-7. 121. Sasayama S, Izumi T, Matsuzaki M, et al. Improvement of quality of life with nocturnal oxygen therapy in heart failure patients with central sleep apnea. Circ J 2009;73:1255-1262. 122. Toyama T, Seki R, Kasama S, et al. Effectiveness of nocturnal home oxygen therapy to improve exercise capacity, cardiac function and cardiac sympathetic nerve activity in patients with chronic heart failure and central sleep apnea. Circ J 2009;73:299-304. 123. Javaheri S, Parker TJ, Wexler L, et al. Effect of theophylline on sleep-disordered breathing in heart failure. N Engl J Med 1996; 335:562-567. 124. Javaheri S, Kennealy J, Runck CD, et al. Cerebrospinal fluid ions in metabolic acidosis in dogs: effects of acetazolamide. J Appl Physiol 1986;61:633-639. 125. Javaheri S, Weyne J, Demeester G, et al. Effects of acetazolamide on ionic composition of cisternal fluid during acute respiratory acidosis. J Appl Physiol 1984;57:92-97. 126. Javaheri S. Effects of acetazolamide on cerebrospinal fluid ions in metabolic alkalosis in dogs. J Appl Physiol 1987;62:1582-1588. 127. Nakayama H, Smith CA, Rodman JR, et al. Effect of ventilatory drive on CO2 sensitivity below eupnea during sleep. Am J Critical Care Med 2002;165:1251-1259. 128. White DP, Zwillich CW, Pickett CK, et al. Central sleep apnea. Arch Intern Med 1982;142:1816-1819.
129. DeBacker WA, Verbraecken J, Willeman M, et al. Central apnea index decreases after prolonged treatment with acetazolamide. Am J Respir Crit Care Med 1995;151:87-91. 130. Javaheri S. Acetazolamide improves central sleep apnea in heart failure: a double-blind prospective study. Am J Respir Crit Care Med 2006;173:234-237 131. Biberdorf DJ, Steens R, Millar TW, et al. Benzodiazepines in congestive heart failure: effects of temazepam on arousability and Cheyne-Stokes respiration. Sleep 1993;16:529-538. 132. Khayat RN, Xie A, Patel AK, et al. Cardiorespiratory effects of added dead space in patients with heart failure and central sleep apnea. Chest 2003;123:1551-1560.
CHAPTER 122 • Heart Failure 1415 133. Andreas S, Weidel K, Hagenah G, et al. Treatment of CheyneStokes respiration with nasal oxygen and carbon dioxide Eur Respir J 1998;12;414-419. 134. Szollosi I, Jones M, Morrel MJ, et al. Effect of CO2 inhalation on central sleep apnea and arousals from sleep. Respiration 2004; 71:493-498. 135. Steens RD, Millar TW, Xiaoling S, et al. Effect of 3% CO2 on Cheyne-Stokes respiration in congestive heart failure. Sleep 1994;17:61-68. 136. Lorenzo-Filho G, Rankin F, Bies I, et al. Effects of inhaled carbon dioxide and oxygen on Cheyne-Stokes respiration in patients with heart failure. Am J Repir Crit Care Med 1999:159:1490-1498.
Other Medical Disorders Charles F.P. George 123 Sleep and Fatigue in Cancer Patients 124 Fibromyalgia and Chronic Fatigue Syndromes 125 Endocrine Disorders
126 Pain and Sleep 127 Gastrointestinal Disorders 128 Sleep in Chronic Kidney Disease
Sleep and Fatigue in Cancer Patients Sonia Ancoli-Israel and Josée Savard Abstract Fatigue is a major complaint in patients with cancer—before treatment, while undergoing chemotherapy or radiation therapy, and after the completion of therapy. The relationship, if any, between fatigue and the quality or quantity of sleep or between fatigue and the sleep–wake circadian rhythm cycle is unknown. One hypothesis is that some of the cancerrelated fatigue may be related to disturbed sleep or to disturbed sleep–wake rhythms. Different dimensions of fatigue (e.g., physical, attentional/cognitive, emotional/affective) are likely to be associated in some way with disrupted sleep and desynchronized sleep–wake rhythms. In cancer patients, as in other medically ill patients, disturbed sleep may be important not only to the expression of fatigue but to the patients’ quality
Patients with cancer complain of fatigue before treatment, during chemotherapy or radiation therapy, and after the completion of therapy.1 These patients also complain of sleep disruption.2 Both fatigue and poor sleep probably contribute to decreased quality of life.3 There is a growing body of literature on the relationship between fatigue and the quality or quantity of sleep. This chapter will review the evidence on cancer-related sleep disruption and fatigue and their treatment, as well as the possible contribution of poor sleep and desynchronized circadian rhythms to cancer-related fatigue.
EPIDEMIOLOGY Sleep Disruption The prevalence of sleep complaints in cancer patients has been studied primarily in cross-sectional studies using convenience samples with heterogeneous definitions and measures of sleep disturbances. In a large questionnaire study of over 900 patients with different types of cancer, fatigue (44%), leg restlessness (41%), insomnia (31%), and excessive sleepiness (28%) were the most prevalent complaints.4 Another survey showed that 61% of the cancer patients had significant sleep deficits, but there was no difference in sleep complaints between the cancer patients and patients with medical conditions other than cancer.5 Almost half of the group had a poor sleep efficiency 1416
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of life, to their tolerance to treatment, and to the development of mood disorders, particularly clinical depression. Disruptions in circadian rhythms themselves affect sleep quality and disrupt many other physiologic mechanisms that pertain to fatigue. Lack of entrainment to the day–night cycle and not keeping regular hours can lead to feelings of grogginess, similar to the feelings of jet lag. The degree of sleep disruption found in patients with cancer is not trivial. Objectively recorded sleep and biological rhythms have not been well investigated in patients with cancer, but because it appears that most may in fact not be getting a good night’s sleep, the goal of future research should be to better characterize the sleep disruption and to find new treatment approaches to improve sleep in this population.
(defined as the percentage of time spent asleep) below 85%. Those patients receiving radiation or chemotherapy tended to have more sleep disturbances than those not receiving treatment. In addition, sleep problems predicted deficits in quality of life. Prevalence rates of insomnia symptoms have ranged from 30% to 50%.6,7 Only two studies have attempted to distinguish between having subclinical and clinical levels of insomnia in cancer patients. These studies found prevalence rates of insomnia symptoms of 48% in breast cancer survivors and 32% in prostate cancer survivors.8,9 With insomnia syndrome defined as sleep-onset latency or wake after sleep onset greater than 30 minutes, at least 3 nights per week, associated with a sleep efficiency lower than 85% and significant daytime impairments or marked distress, the prevalences were 19% and 18%, respectively.8,9 In 95% of the cases, the insomnia syndrome was chronic (i.e., duration > 6 months). Not much is known about how sleep disturbances vary as a function of cancer sites. In one study, the prevalence of sleep disturbances was greater in breast cancer patients,4 but in another study the prevalence was greater in ovarian cancer patients.10 Moreover, as most studies have been conducted several months or even years after patients completed their cancer treatment, the extent to which insomnia symptoms are exacerbated by cancer treatments is unclear.
Large-scale epidemiologic and longitudinal studies are needed to better depict sleep difficulties in cancer patients, characterize the natural course of sleep disturbances throughout cancer care in terms of incidence and remission, and enable comparison across cancer sites and other cancer characteristics. One ongoing longitudinal study conducted among 998 patients with mixed cancer sites has found that the overall prevalence rates of the insomnia syndrome and of insomnia symptoms (including those with an insomnia syndrome) at baseline (T1—i.e., before or right after the surgery) were 27.2% and 56.4%, and they decreased to 21.3% and 39.5% 2 months later (T2), respectively.11 The prevalence rates of insomnia symptoms were highest in patients with breast cancer and gynecologic cancer and lowest in patients treated for prostate cancer. The incidence of insomnia from T1 to T2 was 19%, and the remission rate was 32.0%. Together, these data indicate that insomnia is already prevalent at the time of cancer diagnosis and surgery. Future analyses will determine the course of insomnia symptoms as adjuvant treatments (e.g., chemotherapy, radiation therapy, hormone therapy) are introduced. Sleep disturbances are also very common in patients with advanced cancer. In a study of patients with metastatic breast cancer, 63% reported sleeping difficulties. Difficulty falling asleep was associated with both depression and pain, whereas increased awakening during the night was associated just with depression.12 In another study of 100 palliative care patients attending a pain and symptom control clinic, 72% reported sleep disturbances (63% reported difficulty staying asleep; 40% reported difficulty falling asleep).13 Difficulty falling asleep was mostly associated with fatigue and anxiety, whereas early awakening was more strongly associated with fatigue. In a prospective study, 25.9% of terminally ill cancer patients reported sleep disturbances at admission to a palliative care unit.14 Another study found that patients with advanced lung cancer reported poorer sleep and more daytime sleepiness than healthy controls, and that sleep disturbances of lung cancer patients were characterized by breathing difficulties, cough, nocturia, and frequent awakenings, all of which may be suggestive of sleep-disordered breathing.15 Finally, a study suggested that poor sleep quality and use of sleep medications were, along with hopelessness and depression, the best predictors of desire for hastened death in 102 terminally ill patients attending a palliative care unit,16 thus emphasizing the importance of offering appropriate sleep management to these patients. A few objective studies of cancer patients, using either polysomnography or actigraphy, have been conducted to characterize the sleep disturbances. When the sleep of patients with breast or lung cancer, patients with insomnia, and volunteers with no sleep problems were compared, the insomnia patients had the shortest total sleep time on polysomnography, but the lung cancer patients had the longest sleep onset latency, the lowest sleep efficiency, and the greatest wake time during the night.17 There were no differences in stress levels or emotional state between the cancer patients and the volunteers. There also was no difference in reported total sleep time between the cancer patients and the volunteers. Interestingly, unlike the insomnia patients, the cancer patients did not underesti-
CHAPTER 123 • Sleep and Fatigue in Cancer Patients 1417
mate total sleep time or overestimate wake time during the night. In the same study, although there was no difference in the amount of sleep-disordered breathing, the cancer patients had a higher prevalence of periodic limb movements in sleep (PLMS) than insomnia patients or healthy volunteers.17 However, more recently, in two small-scale studies (17 and 33 patients), an elevated prevalence of obstructive sleep apnea (OSA), ranging from 12% to 91.7%, was found in patients with head and neck cancer.18 Prospective studies are warranted to investigate to what extent OSA is caused by the cancer itself or by the cancer treatment. Sleep-disordered breathing also appears to be frequent in patients with brain tumors, with tumor removal resulting in a significant decrease in the apnea–hypopnea index.19 An ongoing research study indicates that the prevalence of OSA in women with breast cancer who have completed chemotherapy was 48%, and the prevalence of PLMS was 36%.20 These high prevalence rates of PLMS and OSA may help explain some of the sleep disturbance found in this population. Actigraphy, a noninvasive, continuous, ambulatory measure of circadian rest–activity rhythms, has also been used to characterize the sleep and rhythms of patients with cancer.21-24 Studies comparing cancer patients to healthy controls have consistently shown less contrast between daytime and nighttime activity in cancer patients, a pattern indicative of circadian disruption.21,25 In a study of 85 women with breast cancer, 72-hour actigraphy before the start of chemotherapy demonstrated a mean total sleep time of 6 hours, with only 76% of the night spent asleep. On average, the women napped for about 1 hour a day.23 Fatigue Fatigue is one of the most frequent and disturbing complaints of patients with cancer3,26: more than 75% of patients who undergo chemotherapy or radiation therapy report feeling weak and tired. Cancer-related fatigue has been defined as a “persistent, subjective sense of tiredness related to cancer and cancer treatment that interferes with usual functioning.”27 It is believed to be distinct from general fatigue, as it is unrelated to exertion level and is not relieved by rest or sleep. It has been reported that 76% of patients receiving chemotherapy report fatigue at least a few days each month,28 interfering with daily life, reducing quality of life,3,29 and being one of the key reasons for discontinuing treatment. An increasing number of studies in the past few years have followed cancer patients over time. Overall, these studies suggest that fatigue is highly prevalent before as well as during and after treatment.26,29 In one study, 66% of the women reported at least some fatigue before treatment and 84% reported fatigue during treatment.23 Additionally, the percentage of women reporting extreme fatigue doubled from approximately 5% before treatment, to approximately 10% during treatment. Several studies have suggested that fatigue can continue for months, and even years, after the completion of therapy. A recent systematic review of the literature identified 10 longitudinal studies on cancer-related fatigue and concluded that cancer-related fatigue may persist for up to 5 years after completion of adjuvant treatments.30
1418 PART II / Section 15 • Other Medical Disorders
PATHOGENESIS Pathogenesis of Sleep Disruption Patients with cancer may complain of insomnia, hypersomnia, or both, but the pathogenesis of this sleep disruption can be quite varied. Chemotherapy, radiation therapy, and hormone therapy may all contribute to the problem, but studies looking at their different effects on sleep patterns are lacking. In addition, commonly administered analgesics such as opioids, and antiemetic medications such as corticosteroids, are also known to disrupt sleep.31 The estrogen deficiency induced by chemotherapy and hormone therapy, the abrupt cessation of hormone replacement therapy at cancer diagnosis, or an ovary removal may each trigger or exacerbate preexisting hot flashes. A study using objective measurements of both sleep and hot flashes in breast cancer survivors showed that nocturnal hot flashes were associated with more wake time and more stage changes to lighter sleep.32 The amount of insomnia in cancer patients can be as high as the amount found in depressed patients, so clinicians should not overlook the possibility that poor sleep in cancer patients may indicate some psychological distress. However, there is evidence that, although insomnia and psychological distress are interrelated, there are still a significant proportion of patients who have only insomnia. In one sample of newly diagnosed breast cancer patients, insomnia was the most frequent symptom, reported by 88% of the patients, and was correlated with high levels of distress and anxiety.33 However, contrary to the belief that disturbed sleep before treatment is attributable to the increased stress and anxiety resulting from a recent diagnosis of a life-threatening illness, insomnia and fatigue were rated high even in those patients who rated themselves low on anxiety. Similarly, another study revealed that 46% of prostate cancer survivors with an insomnia syndrome did not have clinical levels of anxiety or depressive symptoms.9 Pain has often been thought to be the cause of sleep disruption, not only in patients with cancer but also in patients with a multitude of other medical conditions.2 It is not yet known whether the pain contributes to poor sleep or whether the pain medications contribute to poor sleep, or both. One hypothesis is that pain may be the initial cause of the frequent awakenings, but psychological distress prevents the patient from falling back to sleep.34 A second hypothesis is that while sleep leads to recovery and repair of tissue and may offer a temporary cessation of the psychological awareness of pain, poor sleep leads to difficulty managing pain.35 In this way, a cycle of pain and poor sleep may become self-perpetuating. In a study examining the relationship between pain and sleep disruption, patients with breast cancer, lung cancer, insomnia (with no cancer) and normal controls were questioned. Although those with breast cancer reported pain before bedtime, neither their poor sleep nor that of the patients with lung cancer was associated with reports of pain.17 Another study conducted in patients with advanced cancer showed significant correlations between pain and poor sleep quality.36 Moreover, those patients with poor quality of life had the most disturbed sleep and the highest levels of pain.
Physiological factors e.g., pain anemia
Psychological factors e.g., depression anxiety
NoFatigue estimate
Social/cultural factors e.g., education socioeconomic status
Chronobiological factors e.g., sleep circadian rhythms
Figure 123-1 Diagrammatic representation of possible factors affecting fatigue. (Reprinted with permission from Ancoli-Israel S, Moore P, Jones V. The relationship between fatigue and sleep in cancer patients: a review. Eur J Cancer Care 2001;10[4]:245255.)
Pathogenesis of Fatigue Fatigue is believed to be caused by multiple factors, including physical (e.g., cachexia, weight loss, and biochemical, hematologic, and endocrine abnormalities) and psychological (e.g., depression) and social factors (Fig. 123-1). Anemia and other biochemical abnormalities are found in cancer patients and cause fatigue, although hemoglobin levels are only moderately related to fatigue and quality of life. One study examining the incremental effect of increasing hemoglobin on quality of life found that improving the anemia improved quality of life only to a point, beyond which there was no further improvement.37 Alternative possible physiologic mechanisms include inflammation (e.g., increased proinflammatory cytokines), serotonin dysregulation, hypothalamic-pituitary-adrenal axis dysfunction (e.g., altered cortisol response), and altered muscle metabolism.38 Among these potential mechanisms, inflammation is probably the one currently receiving the most attention and is believed to be a common pathway through which cancer and its treatment would lead to a variety of behavioral consequences, including improved fatigue and decreased sleep disturbances.38 Several studies have found significant relationships between reports of fatigue and depression,26 but it is unclear to what extent these are etiologically related. Indeed, depression is far less common than fatigue in cancer patients, which suggests that fatigue often occurs independently. Moreover, it has been shown that cancerrelated fatigue is different from fatigue experienced by patients with depression. In addition, there is evidence that sleep disturbance is a significant predictor of fatigue.39 Studies on symptom clusters have revealed that sleep and fatigue are often part of a cluster of three or more symptoms.40 Moreover, most cross-sectional and prospective studies found a strong correlation between self-reported sleep complaints and fatigue. Evidence on the relationship between circadian rhythms and subjective ratings of fatigue have been mixed, with most studies finding a significant relationship.24,41 Daytime inactivity and nighttime restlessness were associated with higher subjective ratings of cancer-related fatigue in one
series of studies.41 Women with breast cancer who were undergoing adjuvant chemotherapy reported more fatigue during treatment, and less fatigue at chemotherapy cycle midpoints, in a “roller coaster” pattern. Activity levels were negatively correlated with reports of fatigue (i.e., those with more fatigue showed less activity). Activity levels were reduced during the three treatment sessions compared with the cycle midpoints, thus showing the reverse rollercoaster pattern, with inversely changing fatigue scores. Patients tended to have more nighttime restlessness at treatment times compared with cycle midpoints when higher activity during the day prevailed and there were fewer nighttime awakenings.41,42 Others24 found that self-reported fatigue was significantly associated with an actigraphy measure of sleep–wake pattern stability (i.e., similarity versus dissimilarity of rest and activity patterns across time, a surrogate measure of circadian rhythm), but not with total sleep time. Moreover, changes in fatigue from the second to the fourth on-study chemotherapy cycles were significantly associated with changes in the consistency of the sleep–wake pattern. On the other hand, a study of breast cancer patients before chemotherapy23 found no significant relationship between any of the rhythm variables or objective sleep variables assessed using a 72-hour actigraphy recording, and subjective reports of fatigue. Another study conducted in breast cancer patients before chemotherapy found that most actigraphy measures of sleep–wake, activity–rest, and circadian rhythms derived from a 48-hour recording were not significantly associated with fatigue.22 Together, these studies suggest that fatigue becomes a significant correlate of circadian rhythms only after chemotherapy has been initiated in breast cancer patients. However, longitudinal studies are needed to verify the extent to which the relationship between circadian rhythms and fatigue varies as a function of cancer treatments. Overall, it seems clear that more research is needed to understand the pathogenesis of cancer-related fatigue.
TREATMENT The complaints of sleep disturbances and fatigue in patients with cancer are often overlooked in clinical practice and, when a treatment is initiated, it is often a pharmacologic one (e.g., sedative-hypnotics for insomnia, psychostimulants for fatigue). While pharmacologic therapy may be appropriate at times, there is accumulating evidence supporting the efficacy of alternative treatments including psychological treatments, activity-based interventions, and bright-light therapy. Sleep Pharmacotherapy Hypnotic medications, particularly benzodiazepines, are by far the most commonly prescribed treatment for sleep disturbances in cancer patients.7 In 2005, the National Institutes of Health (NIH) State of the Science Conference on Insomnia concluded that the newer, shorter acting nonbenzodiazepines were safer and more effective than the older, longer-acting benzodiazepines for the treatment of insomnia.43 More recently, newer agents, such as a melatonin receptor agonist, have also been approved by the
CHAPTER 123 • Sleep and Fatigue in Cancer Patients 1419
U.S. Food and Drug Administration for the treatment of insomnia. Although the efficacy of such medications is well established for primary insomnia, its usefulness has yet to be investigated in patients with comorbid cancer and insomnia. Behavioral Therapy The NIH State-of-the-Science Conference on Insomnia also concluded that cognitive-behavioral therapy (CBT) is the most effective treatment for primary insomnia.43 There is now also accumulating evidence supporting its efficacy for insomnia in cancer survivors.44,45 Overall, these studies have been quite consistent in demonstrating that CBT (combining stimulus control, sleep restriction, cognitive restructuring, and sleep hygiene) results in increased sleep efficiency and reduced total wake time, decreased psychological distress, and improved general quality of life. One study also showed changes in immune functioning46 associated with CBT for insomnia, but the clinical relevance of these changes in terms of cancer prognosis or other health outcomes is unknown. Although replication is needed, it appears that the effects of CBT in improving sleep would be mediated by both nonspecific (i.e., treatment expectancies) and specific (i.e., reduced maladaptive sleep habits and dysfunctional beliefs) factors.47 Some evidence from uncontrolled studies suggests that mindfulness-based stress reduction interventions in cancer patients result in improved daily sleep quality.48 However, as none of these studies selected patients on the basis of a minimal insomnia severity, it is unclear whether this intervention is potent enough to treat syndromal or chronic insomnia. Fatigue Numerous medications have been investigated for the treatment of cancer-related fatigue, including hematopoietics (e.g., epoetin alfa, darbepoetin alfa), psychostimulants (methylphenidate), antidepressants (e.g., bupropion, paroxetine), corticosteroids (e.g., methylprednisolone, prednisone), l-carnitine, and modafinil. A recent literature review concluded that hematopoietics are effective in reducing fatigue in patients with anemia.49 Promising results have been obtained in open-label prospective studies investigating the efficacy of other medication classes, in particular psychostimulants and modafinil. However, data from placebo-controlled trials, which would allow counterbalancing beneficial and adverse effects, are warranted, as many of these drugs have significant side effects.49 Several nonpharmacologic interventions for fatigue have been assessed in cancer patients. A recent review of the literature identified a total of 41 publications, 24 assessing the efficacy of various psychological interventions (e.g., cognitive-behavioral therapy) and 17 reporting on the efficacy of activity-based interventions.50 Overall, the effect size obtained was of a small magnitude across all types of intervention and outcome measures (e.g., fatigue, vigor). When types of intervention were compared, a greater effect size was found for psychological interventions than for activity-based interventions. It is noteworthy, however, that none of these studies used heightened levels of fatigue as an inclusion criterion, thus limiting the power to detect
1420 PART II / Section 15 • Other Medical Disorders
intervention effects. Moreover, no study has yet investigated the potentially superior effect of an approach combining psychological and exercise-based interventions. Not much is known about the possible mechanisms of nonpharmacologic interventions for cancer-related fatigue. Biological, environmental, behavioral, and cognitive factors are all potential candidates.50 For example, an exercise program may be beneficial for a variety of reasons, including the resynchronization of the rest–activity rhythms. A second benefit of outdoor exercises would be the increased exposure to bright light, which may promote greater daytime alertness. Patients who report more fatigue tend to be exposed to less light.51 Although the causality of fatigue and light exposure in breast cancer patients is not confirmed, there may be a negative feedback loop such that less light exposure desynchronizes patients’ circadian rhythms, which then causes or deteriorates to fatigue, and fatigue further leads to less light exposure.51
DIFFERENTIAL DIAGNOSIS: IS IT SLEEPINESS, FATIGUE, OR SOMETHING ELSE? The clinician needs to determine the cause of a patient’s symptoms, recognizing that the words used by the patient to describe the symptoms may be vague. Is the symptom related to sleepiness (the patient may describe unintended episodes of falling asleep in the daytime or have an elevated Epworth Sleepiness Scale score), or to fatigue (complaints of muscular weakness, or lack of energy but not weakness)? Patients may also have symptoms attributable to specific effects of cancer or its treatment. When the patient has complaints in one or more of these realms, they may become very difficult to manage. Sleepiness or Insomnia When daytime sleepiness can be attributed to a specific sleep disorder, treatment should target that sleep disorder. If a patient has restless legs syndrome, the clinician should make sure that the patient does not have iron deficiency, which commonly occurs in patients with gastrointestinal carcinomas. If the patient has developed movement disorders secondary to a chemotherapeutic agent, then a trial of a dopaminergic agent should be initiated. If a patient has developed obstructive sleep apnea—for example, secondary to enlarged lymph nodes in the pharynx, as might occur with lymphoma or with nasopharyngeal carcinoma— then continuous positive airway pressure treatment as well as specific treatment directed at these areas should be initiated. If the patient has developed clinical depression along with insomnia, then concurrent therapy for the mood disorder as well as for the insomnia should be initiated. Fatigue As described earlier, fatigue, weakness, and loss of energy are all hallmarks of cancer. Although the pathophysiology is still poorly understood, the clinician should try to determine if the fatigue is caused in part by a correctable factor such as electrolyte imbalance (this might occur in a patient on chemotherapy with severe nausea or vomiting), an underlying infection, or an undiagnosed metabolic disorder such as thyroid disease or diabetes mellitus. The latter
may develop as a result of some types of therapy, such as large doses of corticosteroids. The fatigue might also be exacerbated by poor sleep, in which case treating the insomnia might result in improvements in the fatigue. Direct Effect of Cancer If the cancer is causing pain that is disturbing sleep, the pain needs to be treated concurrently with the insomnia. Hypoxemia caused by spread of cancer to the lung, or the development of lung fibrosis in response to chemotherapy or radiation therapy, may require treatment, as patients with hypoxemia are known to have disturbed sleep.
PITFALLS AND CONTROVERSIES Although the numbers of research studies in the past few years have increased, there is still much that remains unknown about the cause, consequences, and cures of sleeping difficulties and fatigue in patients with cancer. In particular, more longitudinal studies are needed to characterize the natural course of sleep complaints, circadian rhythms impairments, and fatigue during the cancer trajectory, and to better understand how these disturbances are interrelated. Areas for future research also include a better characterization of those disorders across cancer sites. More research is also warranted on patients with advanced cancer, including clinical studies investigating the efficacy of nonpharmacologic interventions for sleep disturbances and fatigue, as it is unclear whether the same treatment modalities can be offered to these patients. Finally, mechanisms through which these interventions are effective also deserve investigation. ❖ Clinical Pearl Fatigue and sleep disturbances are among the most common and most distressing complaints of patients with cancer. When left untreated, these symptoms can significantly impair patients’ quality of life. Clinicians should screen more routinely for these disturbances and administer evidence-based treatment strategies to help patients coping with them.
Acknowledgements Supported by: NCI CA112035, NIA AG08415, Moores UCSD Cancer Center, the Research Service of the Veterans Affairs San Diego Healthcare System, the Canadian Institutes of Health Research, the Canadian Breast Cancer Research Alliance, and the Fonds de la recherche en santé du Québec. This chapter is dedicated to the memory of Dr. J. Christian Gillin, dear friend and colleague, who died of cancer. He was fatigued but he never let it get to him. He was an inspiration and a role model to us all. REFERENCES 1. Zee PC, Ancoli-Israel S. Workshop Participants. Does effective management of sleep disorders reduce cancer-related fatigue? Drugs 2009;69(Suppl 2):29-41. 2. Fleming L, Gillespie S, Espie CA. The development and impact of insomnia on cancer survivors: a qualitative analysis. Psychooncology In Press 2010.
3. Enderlin CA, Coleman EA, Cole C, et al. Sleep across chemotherapy treatment: a growing concern for women older than 50 with breast cancer. Oncol Nurs Forum 2010;37:461-A3. 4. Davidson JR, MacLean AW, Brundage MD, et al. Sleep disturbance in cancer patients. Soc Sci Med 2002;54:1309-1321. 5. Fortner BV, Stepanski EJ, Wang SC, et al. Sleep and quality of life in breast cancer patients. J Pain Symptom Manage 2002;24:471-480. 6. Fiorentino L, Ancoli-Israel S. Insomnia and its treatment in women with breast cancer. Sleep Med Rev 2006;10:419-429. 7. Savard J, Morin CM. Insomnia in the context of cancer: a review of a neglected problem. J Clin Oncol 2001;19:895-908. 8. Savard J, Simard S, Blanchet J, et al. Prevalence, clinical characteristics, and risk factors for insomnia in the context of breast cancer. Sleep 2001;24:583-590. 9. Savard J, Simard S, Hervouet S, et al. Insomnia in men treated with radical prostatectomy for prostate cancer. Psychooncology 2004;30: 474-484. 10. Portenoy RK, Thaler HT, Kornblith AB, et al. Symptom prevalence, characteristics and distress in a cancer population. Qual Life Res 1994;3:183-189. 11. Savard J, Villa J, Ivers H, et al. Natural course of cancer-related insomnia over a 2-month period. Proceedings of the American Psychosocial Oncology Society, Irvine, Calif, Feb 28-March 2, 2008. 12. Koopman C, Nouriani B, Erickson V, et al. Sleep disturbances in women with metastatic breast cancer. Breast J 2002;8:362-370. 13. Sela RA, Watanabe S, Nekolaichuk CL. Sleep disturbances in palliative cancer patients attending a pain and symptom control clinic. Palliat Support Care 2005;3:23-31. 14. Akechi T, Okuyama T, Akizuki N, et al. Associated and predictive factors of sleep disturbance in advanced cancer patients. Psychooncology 2007;16:888-894. 15. Vena C, Parker K, Allen R, et al. Sleep-wake disturbances and quality of life in patients with advanced lung cancer. Oncol Nurs Forum 2006;33:761-769. 16. Mystakidou K, Parpa E, Tsilika E, et al. The relationship of subjective sleep quality, pain, and quality of life in advanced cancer patients. Sleep 2007;30:737-742. 17. Silberfarb PM, Hauri PJ, Oxman TE, et al. Assessment of sleep in patients with lung cancer and breast cancer. J Clin Oncol 1993; 11:997-1004. 18. Nesse W, Hoekema A, Stegenga B, et al. Prevalence of obstructive sleep apnoea following head and neck cancer treatment: a crosssectional study. Oral Oncol 2006;42:108-114. 19. Pollak L, Shpirer I, Rabey JM, et al. Polysomnography in patients with intracranial tumors before and after operation. Acta Neurol Scand 2004;109:56-60. 20. Cornejo M, Liu L, Trofimenko V, et al. Obstructive sleep apnea in breast cancer patients. Sleep 2008;31:A302. 21. Mormont MC, De Prins J, Levi F. Assessment of activity rhythms by wrist actigraphy: preliminary results in 30 patients with colorectal cancer. Bio Rhythm Res 1995;6:423. 22. Berger AM, Sankaranarayanan J, Watanabe-Galloway S. Current methodological approaches to the study of sleep disturbances and quality of life in adults with cancer: a systematic review. Psychooncology 2007;16:401-420. 23. Ancoli-Israel S, Liu L, Marler M, et al. Fatigue, sleep and circadian rhythms prior to chemotherapy for breast cancer. Support Care Cancer 2006;14:201-209. 24. Roscoe JA, Morrow GR, Hickok JT, et al. Temporal interrelationships among fatigue, circadian rhythm and depression in breast cancer patients undergoing chemotherapy treatment. Support Care Cancer 2002;10:329-336. 25. Pati AK, Parganiha A, Kar A, et al. Alterations of the characteristics of the circadian rest-activity rhythm of cancer in-patients. Chronobiol Int 2007;24:1179-1197. 26. Ryan JL, Carroll JK, Ryan EP, et al. Mechanisms of cancer-related fatigue. Oncologist 2007;12(Suppl 1):22-34. 27. Mock V, Atkinson A, Barsevick A, et al. NCCN practice guidelines for cancer-related fatigue. Oncology (Williston Park) 2000;14: 151-161.
CHAPTER 123 • Sleep and Fatigue in Cancer Patients 1421 28. Curt GA, Breitbart W, Cella D, et al. Impact of cancer-related fatigue on the lives of patients: new findings from the Fatigue Coalition. Oncologist 2000;5:353-360. 29. Visser MRM, Smets EMA. Fatigue, depression and quality of life in cancer patients: how are they related? Support Care Cancer 1998;6:101-108. 30. Minton O, Stone P. How common is fatigue in disease-free breast cancer survivors? A systematic review of the literature. Breast Cancer Res Treat 2007;112:5-13. 31. Moore P, Dimsdale JE. Opioids, sleep, and cancer-related fatigue. Med Hypotheses 2002;58:77-82. 32. Savard J, Davidson JR, Ivers H, et al. The association between nocturnal hot flashes and sleep in breast cancer survivors. J Pain Symptom Manage 2004;27:513-522. 33. Cimprich B. Pretreatment symptom distress in women newly diagnosed with breast cancer. Cancer Nurs 1999;22:185-194. 34. Engstrom CA, Strohl RA, Rose L, et al. Sleep alterations in cancer patients. Cancer Nurs 1999;22:143-148. 35. Lewin DS, Dahl RE. Importance of sleep in the management of pediatric pain. J Dev Behav Pediatr 1999;20:244-252. 36. Mystakidou K, Parpa E, Tsilika E, et al. Depression, hopelessness, and sleep in cancer patients’ desire for death. Int J Psychiatry Med 2007;37:201-211. 37. Crawford J, Cella D, Cleeland CS, et al. Relationship between changes in hemoglobin level and quality of life during chemotherapy in anemic cancer patients receiving epoetin alfa therapy. Cancer 2002;95:888-895. 38. Miller AH, Ancoli-Israel S, Bower JE, et al. Neuroendocrineimmune mechanisms of behavioral comorbidities in patients with cancer. J Clin Oncol 2008;26:971-982. 39. Roscoe JA, Kaufman ME, Matteson-Rusby SE, et al. Cancer-related fatigue and sleep disorders. Oncologist 2007;12(Suppl. 1):35-42. 40. Liu L, Fiorentino L, Natarajan L, et al. Pre-treatment symptom cluster in breast cancer patients is associated with worse sleep, fatigue and depression during chemotherapy. Psychooncology 2009;18(2): 187-194. 41. Berger AM, Farr L. The influence of daytime inactivity and nighttime restlessness on cancer-related fatigue. Oncol Nurs Forum 1999;26:1663-1671. 42. Berger AM. Patterns of fatigue and activity and rest during adjuvant breast cancer chemotherapy. Oncol Nurs Forum 1998;25: 51-62. 43. National Institutes of Health State-of-the-Science Conference Statement on manifestations and management of chronic insomnia in adults, June 13-15, 2005. Sleep 2005;28:1049-1057. 44. Savard J, Simard S, Ivers H, et al. Randomized study on the efficacy of cognitive-behavioral therapy for insomnia secondary to breast cancer, part I: sleep and psychological effects. J Clin Oncol 2005; 23:6083-6096. 45. Espie CA, Fleming L, Cassidy J, et al. Randomized controlled clinical effectiveness trial of cognitive behavior therapy compared with treatment as usual for persistent insomnia in patients with cancer. J Clin Oncol 2008;26:4651-4658. 46. Savard J, Simard S, Ivers H, et al. Randomized study on the efficacy of cognitive-behavioral therapy for insomnia secondary to breast cancer, part II: immunologic effects. J Clin Oncol 2005;23:6097-6106. 47. Tremblay V, Savard J, Ivers H. Predictors of the effect of cognitivebehavioral therapy for chronic insomnia comorbid with breast cancer. J Consult Clin Psychol 2009;77(4):742-750. 48. Carlson LE, Garland SN. Impact of mindfulness-based stress reduction (MBSR) on sleep, mood, stress and fatigue symptoms in cancer outpatients. Int J Behav Med 2005;12:278-285. 49. Carroll JK, Kohli S, Mustian KM, et al. Pharmacologic treatment of cancer-related fatigue. Oncologist 2007;12:43-51. 50. Jacobsen PB, Donovan KA, Vadaparampil ST, et al. Systematic review and meta-analysis of psychological and activity-based interventions for cancer-related fatigue. Health Psychol 2007;26:660-667. 51. Liu L, Marler M, Parker BA, et al. The relationship between fatigue and light exposure during chemotherapy. Support Care Cancer 2005;13:1010-1017.
Fibromyalgia and Chronic Fatigue Syndromes James G. MacFarlane and Harvey Moldofsky Abstract Fibromyalgia syndrome and chronic fatigue syndrome involve complex diagnostic and management challenges. These patients present with persistent tiredness or physical fatigue, accompanied by unrefreshing sleep and generalized muscular pain but in the absence of a specific medical disease or a primary psychiatric disorder. Tiredness is the complaint that commonly brings patients to their physicians. Because various meanings have come to be applied to this symptom, an understanding of what the patient means by “tired” is essential for the physician to determine which investigations could aid in diagnosis and management. A key component of these syndromes is unrefreshing sleep. The first step is to determine the contributing factors. The multiple sleep latency test permits differentiation between tiredness characterized by physical exhaustion and tiredness that results from uncontrollable sleepiness. Overnight polysomnography may be important to rule out comorbid sleep disorders, such as sleep apnea, restless legs syndrome, or periodic leg movements during sleep. The sleep electroen-
Chronic fatigue syndrome (CFS) and fibromyalgia syndrome (FMS) are chronic clinical conditions characterized by a variety of nonspecific somatic complaints. The two most prominent complaints for both are intractable fatigue and unrefreshing sleep. In FMS, prominent diffuse musculoskeletal discomfort is the differentiating symptom. However, in terms of demographics and general clinical features, these two conditions cannot be clearly distinguished. That is, the prevalent symptoms of each disorder are present in the other. Sleep disturbance is the common complaint that has kept these conditions within the purview of sleep disorders medicine. The combination of perceived sleep disturbance and chronic fatigue often prompts referrals to a sleep disorders clinic. It is then up to the sleep disorders specialist to decide whether there is evidence for a primary sleep disorder that could explain the daytime impairment. The subjective experience of feeling tired is most often the focal point of the clinical evaluation. The term is commonly used to describe an unpleasant and ill-defined subjective experience, troublesome enough to bring people to their physicians. What each patient means by this complaint must be defined, because tiredness has several attributions and may imply any of the following descriptive categories: 1. Central fatigue. The person describes mental exhaustion with impairment in concentration or thinking that occurs as the result of intellectually demanding activities. The person may be unmotivated, bored, disinterested, or fed up with a particular task. If the lack of motivation is affecting all aspects of the personality, the complaint of tiredness may be a mask for abulia, which characterizes a negative symptom of chronic schizophrenia, or the presence of a degenerative brain disease (e.g., Alzheimer’s, Huntington’s, or Parkinson’s 1422
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cephalogram (EEG) may reveal nonperiodic arousals in association with movement arousals or sleep fragmentation. Periodic EEG arousals or a continuous alpha EEG arousal pattern may correlate with reports of unrefreshing sleep. Nonspecific treatments include behavioral approaches to improve sleep hygiene, such as aerobic fitness and eating habits that help to regularize potential disturbances in circadian sleep–wake rhythms. Although helpful in initiating and maintaining sleep and thus in reducing daytime tiredness, traditional hypnotic agents do not provide restorative sleep or reduce pain. Tricyclic drugs (e.g., amitriptyline, cyclobenzaprine) may improve sleep quality but do not reduce pain in the long term. Two recently approved medications for the treatment of fibromyalgia are the serotonin and noradrenaline uptake inhibitor medication duloxetine (in the United States only) and the neuromodulatory agent pregabalin. No systematic studies have shown that treating restless legs syndrome, periodic leg movements during sleep, or sleep apnea improves the unrefreshing sleep, fatigue, and pain of patients with fibromyalgia syndrome and chronic fatigue syndrome.
disease). Tiredness is often used in the context of a mood disorder, in which the additional symptoms of sadness, irritability, guilt, and poor self-image may indicate a major depressive disorder. Other psychiatric disorders that have tiredness as a symptom include general anxiety disorder, dysthymic disorder, and somatoform disorder, including neurasthenia. 2. Physical fatigue. A sense of overall physical exhaustion or depletion of energy as the result of physical effort can occur with or without any medical disease. Such chronic diseases as cancer; neuroendocrine, metabolic, infectious, or rheumatic diseases; and chronic painful diseases all have an adverse effect on energy. Various drugs, radiation, and immunosuppressants may induce profound physical exhaustion. On the other hand, where there is no evidence for a primary medical disease or psychiatric disorder and the fatigue is accompanied by unrefreshing sleep, such patients may be diagnosed with CFS or FMS. Physical fatigue may be more specific in conditions of muscular weakness, including neuromotor diseases such as amyotrophic lateral sclerosis, postpolio syndrome, or myasthenia gravis. 3. Sleepiness. The person feels an urge to return to sleep, in the absence of central or physical fatigue. This person may actually avoid the sedentary situations preferred by those with FMS and CFS, because to be inactive is to increase the propensity for falling asleep. Whereas fatigue may be relieved or reduced to some extent by rest or withdrawal from mental activities, sleepiness is relieved only by sleep. The literature provides further semiotic confusion when the word fatigue is used to describe operational impairment in task performance (e.g., driver fatigue) or sleepiness. Because of the language confusion in the medical literature and the various meanings intended by patients,
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the clinician must carefully interpret what each patient means or risk prescribing unnecessary and expensive diagnostic procedures or inappropriate treatments. Other chapters in this volume address the diagnostic features and management of those sleep disorders in which tiredness is a synonym for sleepiness; furthermore, the evaluation of the medical and psychiatric conditions that result in tiredness are outside the scope of this chapter. This chapter will focus on the assessment and management of those chronically tired patients who complain of unrefreshing sleep or chronic mental and physical fatigue in the absence of physical or laboratory evidence for a primary medical disease or behavioral evidence for a primary psychiatric disorder. Often, when generalized and ill-defined musculoskeletal pain and tenderness in specific anatomic regions accompany the fatigue, these people acquire descriptive labels such as chronic fatigue syndrome1 or fibromyalgia syndrome.2
EPIDEMIOLOGY Epidemiologic studies reveal that 23% of the adult population in the United States report having experienced the symptom of persistent fatigue sometime during their life. A cross-national epidemiologic study of primary care physicians shows that unexplained substantial fatigue occurring for more than 1 month affects approximately 8% of patients, with a range from between 12% and 15% in Berlin, Santiago, and Manchester to a low prevalence of between 2% and 4% in Ibadan, Verona, Shanghai, Seattle, and Bangalore. Within these variable prevalence clusters of patients with unexplained fatigue lie smaller groups of overlapping primary diagnoses, which include CFS and FMS. In the United States and Japan, between 0.4% and 1.5% of people are affected with CFS (i.e., these patients complain of persistent fatigue for more than 6 months).3,4 FMS affects approximately 2% of the population (more than 80% of them women), and debilitating fatigue affects between 76% and 81% of these patients.2 Because of the similarities of the symptoms, there is considerable overlap between the diagnoses of CFS and FMS, which are also comorbid with such regional pain syndromes as temporomandibular joint disorder, irritable bowel syndrome, migraine, and tension headaches.5 PATHOGENESIS There are no known specific causes for CFS and FMS. Various hypotheses, including genetic predisposition; infectious agents; neurotransmitter, neuroendocrine, neuroimmune, and autonomic disturbances; and psychological stress factors have been proposed for the etiology of these disorders. The fatigue and bodily hypersensitivity are thought to be the result of disturbances in central nervous system functions. In particular, the myalgia and tender points in specific anatomic regions are associated with unrefreshing sleep. The importance of disturbances in sleep physiology for the symptoms of these patients is demonstrated in human and animal experimental studies. More than 30 years ago, the experimental disruption of slow-wave sleep (SWS) with noise in healthy sleeping subjects induced both musculoskeletal pain and fatigue symp-
toms.1 Subsequently, a variety of studies have confirmed the fundamental observation of the artificial induction of pain and fatigue symptoms by disruption of SWS.6 However various procedural differences may have resulted in some differences among the studies. For example, one study that did not employ an adaptation night failed to show significant differences in tender point threshold after noise-induced sleep disruption. Another study showed altered pain thresholds, but there was no associated increase in alpha sleep activity by electroencephalography (EEG).6,7 It is uncertain whether computer-generated frequency analysis used in this study might have excluded noiseinduced EEG arousals from sleep. Experimental total sleep deprivation or specific deprivation of SWS or rapid eye movement (REM) sleep affects pain measures in normal subjects. For example, 40 hours of total sleep deprivation reduces pain thresholds, which return to baseline values specifically after SWS recovery.3 Studies of the effects of either REM or SWS deprivation followed by a night of recovery show that both conditions reduce pressure-pain tolerance thresholds. An increase in SWS on the recovery night is associated with an increase in the pain tolerance threshold. This research showed that sleep deprivation has a specific effect on inducing a hyperalgesic state but does not alter somatosensory functions. The fragmentation of normal human SWS is shown to interfere with the nervous system’s natural inhibitory response to painful noxious stimuli as well as causing increased sensitivity to various nonpainful stimuli (e.g., bright light, loud sounds, strong odors). These symptoms of hypersensitivity to various perceived noxious stimuli typically occur in patients with FMS. Both animal studies of REM sleep deprivation and the loss of 4 hours of sleep, which interferes with emergence of REM sleep in human subjects, induce a hyperalgesic state on the following day. The 4 hours (as opposed to 8 hours) of sleep over 12 consecutive nights causes a 15% reduction in psychosocial behavior and a 3% increase in generalized body pain, back pain, and stomach pain. There are numerous reports of disordered EEG sleep in patients with FMS. The studies show protracted sleeponset latencies, a reduced sleep efficiency index, a reduction of SWS and REM sleep, increased motor activity during sleep, generalized restlessness,8 and an increase in alpha EEG activity during non-REM sleep. The alpha EEG non-REM sleep anomaly is the most extensively studied correlate of nonrestorative sleep, especially as it applies to CFS and FMS. However, it is not specific to these conditions, and some studies have reported a low sensitivity.3,4,9 Patients with FMS are often found to have fragmented sleep as a result of sleep-related periodic arousal disturbances that occur over the course of the night. These periodic sleep-related disturbances include involuntary periodic limb movements (PLM) or restless legs, sleep apnea, and an underlying periodic arousal disturbance in the sleep EEG. This periodic EEG sleep disorder was initially described as a high rate of periodic K-alpha, and it is now better known as the cyclic alternating pattern (CAP).6 The presence of a high frequency of CAP in EEG sleep, which occurs in sequences of 20 to 40 seconds, may interfere with the typical EEG K-spindle complex that
1424 PART II / Section 15 • Other Medical Disorders
typically occurs in stage 2 non-REM sleep. This sleep finding in FMS may account for the finding of a low frequency of sleep spindles. The high index of periodic arousal disturbance in the sleep EEG is an indicator of sleep instability. It is accompanied by less efficient and unrefreshing sleep and is correlated to the severity of clinical symptoms in patients with FMS. Some FMS and CFS patients claim that their symptoms began after a febrile event, even though no specific infectious agent is identified. Other patients report no specific event that heralded the onset of symptoms. This lack of clear evidence for a specific triggering etiologic agent has led to the hypothesis that there may be a combined genetic and environmental predisposition to these syndromes, involving specific genes that, once activated, effect sleep disturbances that are involved in the evolution of these syndromes. Despite the absence of specific structural pathology, there is evidence for disordered metabolic functions that involve the sleeping/waking brain. These include elevation of cerebral spinal fluid substance P, decrease in growth hormone and its metabolites, and disturbances in the hypothalamic-cortical-adrenal axis.10-15 Furthermore, specific dysfunctions in neurotransmitter functions have been shown to contribute to bodily sensitivity and disordered sleep. For example, inhibition of serotonin (5-HT) synthesis by p-chlorophenylalanine induces insomnia and a hyperalgesic state in animals and humans. The increased levels of substance P that are found in the cerebrospinal fluid of patients with FMS led to experimental studies that demonstrated that substance P operates through a neurokinin (NK) pathway to influence nociception and sleep. Intracerebral ventricular administration of substance P in sufficient quantities that did not induce nociceptive response in mice delayed onset of sleep and provoked awakenings from sleep. An NK-1 receptor antagonist reversed the interfering effect on sleep by substance P. This research demonstrates that the blocking of the substance P–induced insomnia by prior treatment of the mice with NK-1 receptor antagonist provides support to the notion of the arousing effect of substance P on the sleeping/waking brain. Moreover, the research provides an experimental animal model for studying sleep disturbances and musculoskeletal pain in FMS. Some studies in FMS with functional neuroimaging support the hypothesis of central pain augmentation. The most recent study showed that patients with FMS have a decrease in gray-matter volume in the prefrontal cortex, the amygdala, and the anterior cingulate cortex. The duration of pain or functional pain disability did not correlate with gray matter volumes. One possible conclusion is that volume reductions might be a precondition for central sensitization in fibromyalgia.15 Alterations in dopamine metabolism might contribute to the associated changes in gray matter volume and density.16 Increased overnight sympathetic activity as measured electrocardiographically is consistent with the notion of circadian autonomic metabolic dysfunction associated with an arousal disturbance during the sleep of patients with fibromyalgia.17 In addition to the chronobiological physiologic abnormalities, there are diurnal changes in behavior. FMS subjects with light unrefreshing sleep have
diurnal impairment in speed of performance on complex cognitive tasks, which are accompanied by sleepiness, fatigue, and negative mood. Such psychological impairment could account for the functional disabilities that are encountered in a work environment and in social behavior.
CLINICAL FEATURES The clinical criteria for CFS are shown in Box 124-1, and those for FMS are shown in Box 124-2. The American College of Rheumatology criteria emphasize pain and tenderness (Fig. 124-1) for the diagnosis of FMS, but this may actually limit sensitivity and specificity. An evaluation for FMS should investigate complaints of chronic fatigue, unrefreshing sleep, cognitive difficulties, and psychological distress. Whereas fatigue, postexertional malaise, and impairment in cognitive functioning are the focus of attention in patients with CFS, unrefreshing sleep, chronic muscular pain, and tenderness also prevail. These symptoms may follow a viral illness or a physical or psychological traumatic event (e.g., an automobile whiplash injury or a work-related soft tissue injury), or they may appear for
Box 124-1 Criteria for Chronic Fatigue Syndrome (Centers for Disease Control, 1994) A. Fatigue Severe, unexplained fatigue that is not relieved by rest, that can cause disability, and that has an identifiable onset (i.e., not lifelong fatigue). It must be persistent or relapsing fatigue that lasts for at least 6 consecutive months. B. Four or More of the Following Symptoms: Impaired memory or concentration problems Tender cervical or axillary lymph nodes Sore throat Muscle pain Multijoint pain New-onset headaches Unrefreshing sleep Postexertional malaise From Fukuda K, Straus SE, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International Chronic Fatigue Syndrome Study Group. Ann Intern Med 1994;121:953-959.
Box 124-2 Criteria for the Classification of Fibromyalgia Syndrome (American College of Rheumatology, 1990) 1. A history of widespread musculoskeletal pain for at least 3 months. 2. Tenderness found in at least 11 of the 18 anatomic sites with the application of 4-kg pressure by palpation at the bilateral anatomic regions shown in Figure 104-1. From Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990;33:160-172.
CHAPTER 124 • Fibromyalgia and Chronic Fatigue Syndromes 1425
no apparent reason. FMS may occur in the context of potentially disabling arthritic disease (e.g., rheumatoid arthritis) or connective tissue disease (e.g., systemic lupus erythematosus), human immunodeficiency virus infection, or Lyme disease. In patients with either CFS or FMS, the quality of sleep is usually impaired. More than 80% of patients with chronic fatigue describe significant impairment in their sleep quality.18 Patients commonly complain of light or superficial sleep, describing sensitivity to noise or inability to turn off thinking during sleep, so their sleep is unrefreshing. Their mental fatigue results in word lapses, word confusions, and problems in multitasking, so they are slower in performing such tasks. However, they do not make more errors than unaffected individuals.19 Their sensory sensitivities may include lowered tolerance to noise, noxious smells or strong perfumes, and bright light. In addition to external sensory hypersensitivities, they may describe internal sensitivities (e.g., intolerance to certain foods and symptoms of irritable bowel syndrome or irritable bladder). The fatigue that characterizes FMS and CFS shows a diurnal variation that is different from that of the sleepiness. On morning awakening from light and unrefreshing sleep, patients with CFS and FMS rate their pain and fatigue as high. Depending on the severity of the symptoms, they may improve during the interval between 10:00 am and 3:00 pm, but this is followed by a feeling of exhaustion and increased pain during the latter part of the afternoon and evening. Typically, the patients feel no better when they awaken than when they went to sleep, or they have more aching, stiffness, and fatigue in the morning, which is indicative of their sleep being nonrestorative. In contrast, in those medical conditions characterized by muscular weakness, the motor tiredness increases coincident with physical activity over the course of the day, and it improves with rest. The tiredness associated with a major depressive disorder is greater on awakening (when the depression is more severe) than in the evening (when both mood and tiredness improve). In a dysthymic disorder, the tiredness increases progressively over the course of the day. Sleepiness as the result of sleep restriction or disruption leaves the person feeling drowsy in the morning and again in the midafternoon. However, there is reduced late afternoon and early evening sleepiness as a result of circadian variation in alertness. In narcolepsy, the sleepiness is prevalent throughout the day.
DIAGNOSIS Although the diagnoses of CFS and FMS are based on clinical criteria, sleep physiologic analyses may provide an added dimension of understanding and a rationale for treatment. Neuropsychiatric assessment may be required to determine whether there is a brain or peripheral neuromotor disease that could explain the fatigue and weakness, or a whether there is a primary psychiatric disorder (e.g., major depressive disorder, general anxiety disorder, dysthymia, or somatoform pain disorder). Psychosocial concerns, such as current stressors and interpersonal, economic, insurance, and medicolegal problems, need to be assessed as part of the overall management strategy.
Figure 124-1 Anatomic distribution of 18 tender points in fibromyalgia syndrome.
Clinical Assessment Specific enquiry about the quality of sleep (e.g., whether sleep is light and unrefreshing) is essential. Sleep–wake habits can be assessed with the aid of a sleep diary. Attention should be directed to potential agents that could interfere with sleep—for example, excessive use of caffeine, alcohol, nicotine, and certain classes of drugs. Some patients may have loud snoring and interruptions of breathing, which could indicate sleep apnea. Others may describe dysesthesia and uncontrollable leg movements in the evening and restlessness or kicking during sleep, which characterize restless legs syndrome and involuntary PLM disorder.20,21 Tiredness as the result of excessive daytime sleepiness should be differentiated from physical and central fatigue. Routine laboratory tests help to exclude a primary medical disease. The routine use of expensive tests (e.g., imaging studies) is not required. However, patients with FMS or CFS may have a concomitant rheumatic or connective tissue disease that requires careful medical diagnostic appraisal. Furthermore, because unrefreshing sleep, fatigue, and cognitive impairment are often accompanied by anxiety or depression, assessment of psychological disturbances is required as part of an overall plan of management. Sleep–Wake Diary A self-monitored sleep–wake diary helps to clarify behaviors (e.g., excessive use of stimulants, alcohol, sedatives, hypnotics, or consumption of street drugs) that may contribute to the tiredness. This simple, inexpensive tool may save costly and unrewarding investigative procedures. Moreover, the diary can assist in reeducation to correct the faulty habits and poor sleep hygiene that contribute to the complaint of tiredness.
1426 PART II / Section 15 • Other Medical Disorders
Clinical Rating Scales for Various Attributes of Tiredness S ELF- R ATING S CALES Tiredness that is a symptom of depression is included in the Beck Depression Inventory. Fatigue scales that provide information about various aspects of fatigue include the following: 1. The Multidimensional Fatigue Inventory (MFI-20) is a 20-item, five-point Likert scale questionnaire that comprises five subscales, which include general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. 2. The Chalder Fatigue Scale has 11 items; it measures fatigue intensity and separates mental from physical fatigue. 3. The Fatigue Severity scale includes nine items that provide a measure of fatigue severity. This simple scale was originally standardized on patients with fatigue related to multiple sclerosis and systemic lupus erythematosus. The preceding fatigue instruments, however, do not evaluate or exclude sleepiness. Therefore, sleepiness scales, such as the following, are commonly used in sleep research and clinical sleep laboratories. 1. The Stanford Sleepiness Scale measures sleepiness at the time of the test. This instrument was originally developed for narcolepsy and comprises seven categories, ranging from 1, indicating alert and wide awake, to 7, indicating almost asleep. 2. The Epworth Sleepiness Scale, which measures an ongoing tendency for sleepiness, inquires about the chance of dozing in eight different situations. The chance of dozing is ranked from 0, meaning never, to 3, meaning there is a high chance of dozing. These passive situations include sitting and reading or watching television, sitting inactive in a public place (e.g., a theater or a meeting, or as a passenger in a car), lying down to rest in the afternoon, sitting and talking to someone, sitting quietly after lunch without alcohol, and, finally, sitting in a car that is stopped for a few minutes in traffic. The sum of the responses gives a global score from 0 to 24, and higher ratings are related to pathologic sleepiness. Interestingly, the Epworth Sleepiness Scale does not include a question regarding irresistible daytime sleepiness. Q UALITATIVE AND Q UANTITATIVE S ELF-RATING S CALES OF S LEEP In addition to a subscale rating of subjective sleep quality, the Pittsburgh Sleep Quality Index questionnaire provides subscale measures of sleep latency, sleep duration, and habitual sleep efficiency. Some components relate to sleep disturbances, use of sleeping medication, and daytime dysfunction. The sum of the scores for these seven components yields one global score that is a composite of sleep quality and quantity. In the Sleep Assessment Questionnaire (SAQ), a 17-item, four-point Likert scale, nonrestorative sleep is a specific sleep factor. Five other factors are insomnia/hypersomnia, restless leg/motility, sleep schedule, excessive daytime sleeping, and sleep apnea. Importantly, this instrument has been validated against data (e.g., the alpha EEG sleep
disorder in patients with FMS and CFS) obtained from polysomnography (PSG). The SAQ shows favorable sensitivity and specificity as a simple screening instrument for nonrestorative sleep disorders and other sleep pathologies. It has been found to be useful in screening for sleep pathologies in an epidemiologic study of a chronically fatigued population. The Karolinska Sleep Diary consists of seven self-rated items on a five-point Likert scale. It yields two factors: (1) the sleep quality index, which assesses the sleep quality, ease of falling asleep, and maintenance and calmness of sleep, and (2) a second factor that assesses the sufficiency of sleep, the ease of awakening, and achievement of a refreshed feeling. The amount of SWS and degree of sleep efficiency were found to be predictors for the sleep-quality index. Performance Tasks The difficulty with self-rating estimates of fatigue is that they are not necessarily related to the observed behavior. Therefore, performance tasks of vigilance are used, especially if daytime sleepiness (e.g., resulting from sleep deprivation or a primary sleep disorder) is being assessed. This psychomotor vigilance task involves a 10-minute computerized assessment battery that is sensitive to the effects of sleep loss and circadian rhythmicity and is devoid of practice effects.22 Efforts are underway to objectively measure performance in specific tasks (e.g., driving a car or truck). Motor vehicle accidents are a common outcome of driver fatigue, in which there are inattention or lapses in alertness as symptoms of sleepiness. Many of these assessment tools are too cumbersome for routine use in the sleep disorders clinic. The most practical tools are (1) the sleep–wake diary to assess scheduling and behavioral factors that may be compounding existing symptoms, (2) the Beck Depression Inventory to rule out comorbid depression, and (3) the SAQ or other screening questionnaires to rule out comorbid sleep disorders. Polysomnography When the diagnosis is uncertain or a primary sleep disorder is suspected, overnight PSG can provide objective evidence for the unrefreshing sleep and a rationale for treatment of the underlying sleep disorder. These sleep disorders include the alpha EEG sleep disorder, which is often associated with poor quality or light and unrefreshing sleep.23 Initially, this sleep disorder was termed alphadelta sleep, and it was described in a heterogeneous group of psychiatric patients with somatic malaise and fatigue.22 Subsequently, alpha EEG sleep was found in stages 2, 3, and 4 non-REM sleep in adults and children with FMS,1,24-26 and in some patients with CFS or unexplained chronic fatigue. The alpha EEG anomaly is not specific to CFS and FMS. Other disorders in which alpha EEG sleep, nonrestorative sleep, and pain and fatigue symptoms may occur include rheumatoid arthritis27,28 and systemic lupus erythematosus. Furthermore, it may be found in patients with psychophysiologic insomnia and unrefreshing sleep and fatigue,29 in some patients with various primary sleep disorders (e.g., PLM disorder, non–24-hour sleep–wake syndrome, sleep apnea, and narcolepsy), and occasionally
CHAPTER 124 • Fibromyalgia and Chronic Fatigue Syndromes 1427
in unaffected people.30 Studies examining the sensitivity of the alpha EEG intrusion as a marker for FMS and CFS have been equivocal. Also, the relative presence of the alpha EEG anomaly is not always correlated with symptom severity.9 Unfortunately, variations in methodology, including frequency analysis techniques and inclusion and exclusion criteria, hamper valid comparisons between many studies. Still, this common but as yet unexplained EEG finding provides an opportunity for additional research into the mechanisms of disease. More recent studies have attempted to clarify the exact nature of the alpha EEG anomaly and its permutations. Frequency analyses show that there is a progressive decline in the alpha EEG through the night. Detailed EEG frequency analyses differentiate three types of alpha EEG sleep: 1. Tonic alpha EEG sleep occurs throughout sleep stages 2, 3, and 4, where global rating of alpha intrusion is 3 to 5 (i.e., greater than 40% prevalence of the alpha frequency).1 2. Phasic alpha EEG sleep, in which the alpha frequency coincides with stages 3 and 4 sleep (alpha-delta sleep), has maximal frontal alpha power localized symmetrically in the left and right anterior cingulum. 3. Periodic K-alpha and periodic polyphasic EEG burst activity (K-alpha/polyphasic burst variety of cyclical alternating pattern) is recorded when four or more consecutive K-complexes, immediately followed by alpha EEG activity of 0.5- to 5.0-second duration, or four or more polyphasic bursts occur in a sequence of approximately 20- to 40-second intervals. A rapid frequency, with an index of greater than 15 per hour of sleep, is associated with unrefreshing sleep, fatigue, and muscle symptoms.30a (For details, see Technical Considerations and Scoring Criteria Additional, later.) Other sleep disorders, such as restless legs syndrome and sleep-related PLM disorder, occur in about 20% of patients with FMS, and 5% of patients with FMS have significant obstructive sleep apnea. The multiple sleep latency test aids in the differentiation of types of tiredness. For some patients, physical and mental fatigue fails to lead to rapid onset of sleep in daytime naps, whereas others have excessive daytime sleepiness and difficulty remaining alert that interferes with concentration. This test is especially important in those patients who, in addition to having FMS or CFS, have hypersomnolence or even narcolepsy.
TREATMENT There is no satisfactory treatment for improving sleep quality, fatigue, and debilitating somatic symptoms in FMS and CFS. Treatment is either nonspecific (e.g., improving sleep habits and a suitable program of exercise) or it uses medications that aim to relieve symptoms or aspects of the sleep disorder. Nonspecific Treatment Methods Overall sleep hygiene and nonspecific methods provide a suitable background regimen that is helpful for regularizing and facilitating sleep.31 Based on the principle that there is a dysregulation of the sleep and the rhythms of the body, the management involves regularizing the patient’s
behavioral and physiologic functions. The psychological methods for improving circadian sleep–wake behavior are central to any cognitive behavior therapy approach in the management of FMS. Sleep hygiene enables regulation of the circadian rhythm of sleep and wakefulness when the pattern is disorganized because of faulty sleep habits. Two of the most common faulty habits, variable bedtimes and inadequate nocturnal sleep time, result in disorganization of circadian rhythms and sleep deprivation with sleepiness and fatigue. Efforts should be directed to stabilize the regulatory functions of sleep by going to bed and awakening at suitable times to ensure adequate duration of sleep. Establishing a regular daily routine not only includes meeting the sleep requirements of the body but also requires a regular schedule of nutritious meals and a suitable exercise program. A systematic study of the research literature shows that muscle strengthening and aerobic fitness improve the symptoms of FMS.31a This gentle, graded aerobic fitness routine should be performed when there is a window of time of least fatigue and pain, usually between 10 am and 3 pm. Patients who are sensitive should avoid the stimulating effects of caffeine and alcohol. In attending to the sleep environment, the aim is to reduce any psychological or environmental disturbances that are disruptive to sleep. Other behavioral methods, such as hypnosis, biofeedback treatments, and cognitive therapy, which reduce psychological distress, are helpful in modulating symptoms. Hypnotherapy results in improvements in muscle pain, fatigue, and sleep disturbance. Electromyographic biofeedback therapy helps to improve pain, tender points, and stiffness on awakening in the morning. Physical methods, which include massage and acupuncture, provide temporary improvement. Ultrasound and interferential current treatment decrease unrefreshing sleep, fatigue, pain, tender points, and tenderness while increasing SWS and decreasing the percentage of stage 1 sleep. Transcranial direct current stimulation of the primary motor cortex increases sleep efficiency and decreases arousals from sleep in patients with FMS. Furthermore, studies show that a decrease in REM latency and an increase in sleep efficiency are associated with an improvement in fibromyalgia symptoms, once again showing the interrelationship of disturbances in sleep physiology and the waking symptoms of FMS. Specific Treatment Methods Sleep-Promoting Agents Medications intended to improve sleep appear to help some patients but have not been demonstrated to provide lasting benefit for pain. Tricyclic antidepressant agents, which facilitate central nervous system serotonin metabolism, may have favorable effects on sleep for up to 2 or 3 months (e.g., cyclobenzaprine) or 5 months (e.g., amitriptyline).33 However, sleep EEG studies show that neither cyclobenzaprine nor amitriptyline reduces the alpha EEG sleep disorder.9,34 Selective serotonin reuptake inhibitors (e.g., fluoxetine) provide no consistent benefits. Agents that increase SWS and reduce the alpha EEG sleep may benefit both the quality of sleep and the pain and fatigue symptoms of FMS. Traditional sedatives and hypnotic benzodiazepines alone do not provide any specific benefit.
1428 PART II / Section 15 • Other Medical Disorders
Nonbenzodiazepine hypnotic drugs (such as zopiclone35 and zolpidem36) improve subjective sleep and daytime tiredness but do not modify alpha EEG sleep or benefit pain symptoms. Over-the-counter sedatives such as antihistamines and herbal agents (e.g., valerian) have not been systematically assessed. Sleep is facilitated by ltryptophan, but there is no effect on alpha EEG sleep, pain, or mood symptoms in patients with FMS. However, 5-hydroxytryptophan, a direct precursor of brain serotonin, tends to improve pain and sleep quality, but its effect on the sleep physiology of patients with FMS is unknown. Although chlorpromazine has been shown to decrease pain and improve sleep physiology by reducing the alpha EEG sleep and increasing SWS, the risk for long-term adverse effects does not make this a desirable drug. Neuromodulatory Agents N EUROTRANSMITTER M ODULATORY D RUGS Neurotransmitter modulatory agents that have been classified as anticonvulsants (e.g., gabapentin, pregabalin, carbamazepine) have sedative properties and antinociceptive effects but have not been systematically assessed in terms of sleep physiology. Pregabalin, which is an alpha2delta ligand that causes increased cellular expression of calcium channels, reduces the expression of substance P and noradrenaline. Studies show that this drug improves the pain, quality of sleep, and fatigue in patients with FMS, which has led to the its approval in the United States for the treatment of FMS pain. Although such alpha2-delta ligands have not been assessed for their effects on the sleep physiology of patients with FMS, such neuromodulatory agents are being evaluated for nonrestorative sleep. Pregabalin: In a recent multicenter randomized placebocontrolled trial, all pregabalin treatment groups (300, 450, or 600 mg/day; dosed twice daily for 13 weeks) showed statistically significant improvement in assessments of sleep and in patients’ impressions of their global improvement.37 Dizziness and somnolence were the most frequently reported adverse events. Pregabalin should be started at 75 mg orally twice a day, increasing incrementally to 300 mg/day over 7 days; maximum dose is 450 mg/ day. Serotonin-noradrenaline reuptake inhibitors (i.e., duloxetine and milnacipran), which are known to be helpful in improving mood, are shown to benefit pain in animal studies, and possibly sleep. Although these drugs reduce the symptoms of FMS, they have not been specifically studied to determine their effects on EEG sleep arousal patterns in patients with FMS. Both of these medications have been approved for the treatment of FMS in the United States. Milnacipran: The most recent multicenter randomized trial of milnacipran showed it to be well tolerated by the majority of patients during 27 weeks of treatment; nausea and headache were the most common adverse events. Milnacipran at a stable dose of 200 mg/day was effective for the treatment of multiple symptoms of FMS.38 Milnacipran should be given orally, starting at 12.5 mg for 1 day, then 12.5 mg twice a day for 2 days, then 25 mg twice a day for 4 days, then 50 mg twice a day; maximum dose is 200 mg/day.
Duloxetine: In this randomized, controlled, 12-week trial, 520 patients meeting American College of Rheumatology criteria for fibromyalgia were randomly assigned to duloxetine (20 mg/day, 60 mg/day, or 120 mg/day) or placebo, administered once daily, for 6 months (after 3 months, the duloxetine 20-mg/day group was titrated to 60 mg/day). Duloxetine at both 60 and 120 mg/day was an effective and safe treatment for many of the symptoms associated with fibromyalgia in subjects with or without major depressive disorder, particularly for women, who had significant improvement across most outcome measures.39 Duloxetine should be started at 30 mg orally every day for 1 week, then increased in 30-mg increments; patients may respond to 30 mg/day; maximum dose is 120 mg/day. A dopamine agonist, pramipexole is claimed to be helpful for pain, fatigue, and overall function in a subset of patients with FMS, half of whom were also taking narcotics. Further properly controlled studies of dopamine agonists are required, because these agents substantially reduce restless legs syndrome or periodic leg movements during sleep, as do narcotics, so that their effects on sleep and symptoms in patients with FMS need to be determined. A multicenter randomized placebo-controlled trial with sodium oxybate given in a 4.5- or 6-g dose at bedtime was shown to reduce alpha EEG sleep, increase SWS, improve the quality of sleep, and reduce pain and fatigue in patients with FMS.40 Because this drug has been shown to be beneficial for the symptoms of FMS, more research should be done to determine its neurophysiologic mechanisms, how it affects the pain and fatigue of patients with FMS, and its role in the management of related syndromes such as CFS. N EUROENDOCRINE M ODULATORY A GENTS No consistent abnormalities in the secretion of melatonin have been reported in patients with either CFS or FMS, nor has its administration been found to be useful, in controlled studies.11 Furthermore, the use of morning brightlight treatment, which tends to modify the timing of the nocturnal secretion of melatonin and is helpful in seasonal affective disorder, does not benefit sleep, pain, or mood symptoms in patients with FMS.41 On the other hand, growth hormone, which is reduced in patients with FMS, improves its symptoms, but its high cost and the need for daily injections make its use impractical. Management of Primary Sleep Disorders For patients with such primary sleep disorders as restless legs and PLM disorder and sleep apnea, some specific remedial measures have been demonstrated to provide relief, and these should be considered. Unfortunately, as yet there are no systematic studies of their benefits for the pain and fatigue symptoms in patients with CFS and FMS.32 Special Considerations in the Management of Patients with FMS and CFS An important consideration when using any medication for the management of symptoms related to FMS or CFS is that these patients are often exquisitely sensitive to
CHAPTER 124 • Fibromyalgia and Chronic Fatigue Syndromes 1429
pharmacologic agents, and they are prone to report troublesome side effects. However, it is not uncommon for them to derive a therapeutic benefit from a fraction of the recommended adult starting dose, and a minimal dose will minimize side effects. If no symptom improvement occurs with the minimal starting dose, the dose of the drug might be gradually increased to assess benefit, according to the patient’s sensitivity and tolerance. Second, patient compliance can be a problem. A vigorous program of exercise that induces or increases pain and fatigue will reduce patient motivation. Therefore, as with medication, the introduction of any treatment should be supervised and performed gently and gradually in accordance with the acceptance and tolerance of the patient. FM and CFS in Children and Adolescents Although FM and CFS are well defined in adult populations, recognition in the pediatric population has only recently been addressed. The estimated prevalence of juvenile primary fibromyalgia syndrome (JPFS) is similar to that of fibromyalgia in the adult population, ranging from 2% to 15%. Prevalence is higher in girls than in boys and peaks at the time of puberty, but prevalence statistics are probably skewed because many of these children are labeled as having an unexplained medical illness. However, JPFS and CFS are becoming syndromes of pediatric concern. It is not clear whether the increased diagnosis in children reflects an actual increase in incidence, a recent recognition by clinicians that children have these syndromes, or an increased awareness of the diagnotic criteria by pediatricians. As in the adult population, the causes of JPFS and CFS are unknown. However, the characteristic symptoms mimic those of the adult syndromes, including difficulty initiating and maintaining sleep, widespread musculoskeletal discomfort, nonrestorative sleep, and daytime fatigue. Actigraphy and PSG studies in children with CFS showed longer total sleep time, decreased SWS, delayed REM onset latency, increased sleep fragmentation, and lower daytime physiologic activity.42,43 Both syndromes have a major influence on health, physical function, and quality of life for children. The cause of JPFS is probably multifactorial, including genetic and anatomic factors, familial and environmental influences, disordered sleep, and psychological distress. A large-population study in Finland showed that the onset of JPFS was predicted by older age, female sex, and various regional back pain symptoms.43 Unlike in the adult population, specific physical injury was not a significant risk factor. CFS has been more commonly reported in association with an acute infection or a prolonged viral illness. Other risk factors for both syndromes include being highly sedentary or highly active (such as during intense physical training), suggesting that a divergence in either direction from normal levels of activity increases the risk for persistent fatigue.43a Psychological distress, comorbid psychiatric disorder (usually mood), and specific somatic pain symptoms appear to be independent risk factors. Surprisingly, smoking and obesity do not appear to be significant risk factors. Other considerations include the possible role for early-life immune insult, including developmental immunotoxicity.
The diagnosis of JPFS is based on the criteria defined by Wolfe and colleagues2 in 1990, which include generalized musculoskeletal aching and at least 11 of 18 typical tender points. As with adults, there is a significant overlap with CFS. Most studies examining juvenile CFS use the criteria devised by the Center for Disease Control in 1994.43 Typically, children complain of severe physical fatigue or overwhelming exhaustion, but most also have headaches and disrupted nocturnal sleep patterns, with difficulty both initiating and maintaining sleep, and less frequently hypersomnia. Many complain of muscle pain or discomfort and concentration problems. In younger children (<12 years), disability was also high, with low levels of school attendance, high levels of fatigue, anxiety, functional disability, and pain. The clinical pattern seen is virtually identical to that in older children, and most fit even with the strictest adult criteria.42 There is often concordance between children and their mothers with regard to the diagnosis of FM. Sleep complaints and PSG findings are often less prominent in affected children than in their mothers, but there remains a significant correlation between PSG sleep anomalies and pain manifestations in children and their mothers. According to emerging studies, a multidisciplinary treatment may be helpful in treating both CFS and JPFS. Clinical reports indicate that family work focused on engagement and on a rehabilitation program (including graded physical fitness and treatment of psychiatric comorbidity) can help even the more severely impaired children. Other strategies include improved sleep hygiene, and improved sleep consolidation (with pharmacologic and nonpharmacologic interventions). A sustained positive benefit of cognitive behavioral therapy in adolescents has been shown, reflected by significantly less fatigue, significantly less functional impairment, and higher school attendance. Interestingly, higher fatigue severity of the mother predicts poorer treatment outcome in adolescent patients.
PITFALLS AND CONTROVERSIES Despite the existence of clinical criteria for the diagnoses of CFS and FMS, the subjective nature of these nonspecific pain and fatigue disorders may become confounded by the psychological distress. This may be especially apparent in patients who are involved with insurance and medicolegal matters related to disability claims. Their need to provide proof of disability and the symptoms of distress may magnify the sleep, fatigue, and pain symptoms and result in controversy about whether symptoms are indications of medical illnesses or are illness behavior. Also, the symptoms are not specific. Similar symptoms of fatigue, pain, and unrefreshing sleep appear with other diagnostic labels that have emerged in various medical specialties to address unexplained symptoms—for example, Gulf War syndrome, multiple chemical sensitivity syndrome, and sick building syndrome (in the fields of allergy, clinical immunology) and chronic pain in somatoform disorder (in psychiatry). These fatigue, pain, and sleep symptoms also occur with other difficult-to-diagnose illnesses, such as irritable bowel syndrome, temporomandibular joint pain syndrome, interstitial cystitis, migraine, chronic headache, and atypical chest pain.37 Furthermore,
1430 PART II / Section 15 • Other Medical Disorders
FMS is not distinctive: The same symptoms may accompany rheumatic or connective tissue disease (e.g., osteoarthritis, rheumatoid arthritis), systemic lupus erythematosus, Lyme disease, endocrine disorder, and myxedema, and in patients with psychiatric illness such as major depression, general anxiety disorder, and posttraumatic stress disorder.44 Given the lack of specificity of symptoms, it is understandable that abnormalities in sleep physiology (e.g., alpha EEG sleep disorder) also lack diagnostic reliability. Contributing to this are the various techniques used to quantify the EEG frequencies (e.g., computer-based spectral analysis, visual scoring techniques). Furthermore, not all researchers adhere to conventional Rechtschaffen and Kales methodology. Attention has been directed to specific stages of sleep and obtaining consensus on observer rating of transient EEG arousals. Others have been interested in examining periodic or continuous EEG physiologic anomalies within these stages of sleep. Indeed, Rechtschaffen and Kales, in Figure 38 of their sleep scoring manual,44a illustrate an “epoch of unambiguous stage 4” of normal sleep that actually features the alpha-delta EEG sleep anomaly. The clinical observer ratings of MacLean and colleagues45 and the cyclical alternating pattern methodology of Terzano and coworkers46 should help advance the field of enquiry into EEG sleep physiology.
CLINICAL COURSE AND PREVENTION Long-term outcome studies indicate that patients with FMS or CFS rarely return to the premorbid levels of energy. Similarly, the prognosis for these patients remains poor because current treatments are limited and equivocal in efficacy, and symptoms may persist over extended periods of time. Aerobic fitness remains an important
mainstay in the long-term management of FMS, as emphasized in recently published evidence-based clinical practice guidelines.47 There are no known measures to prevent CFS and FMS.
TECHNICAL CONSIDERATIONS AND SCORING CRITERIA Alpha EEG: Recording Techniques and Scoring Rules The quantification of the non-REM alpha EEG has traditionally depended on visual scoring. Records are collected and scored using standard Rechtschaffen and Kales criteria. In addition to the central leads, it is preferable to include occipital (Oz) and frontal (Fz) leads. Sensitivity should be set at 50 µV/cm. Alpha EEG activity is assessed from the EEG channel with the most prominent alpha activity. The alpha frequency (7 to 12 Hz) is identified during non-REM sleep stages 2 and/or 3, and 4, with a minimum peak-to-peak amplitude of 5 µV. This alpha frequency is approximately 2 Hz slower in sleep than in wake, and more prominent in the frontal lobes. Observer ratings may use a single global rating or serial epoch ratings for more detailed analysis. The global ratings for prevalence during non-REM sleep range from 1 (0% to 20%), to 2 (21% to 40%), to 3 (41% to 60%), to 4 (61% to 80%), to 5 (81% to 100%).48 (Fig. 124-2 shows an alpha rating of 1 in stage 2 sleep; Fig. 124-3 shows an alpha rating of 5 in stage 2 sleep.) Periodic EEG Phenomena: Recording Techniques and Scoring Rules Cyclic alternating pattern (CAP) has been traditionally measured using a bipolar 10-lead EEG, but this is not practical for most sleep laboratories. Bipolar montages,
C3-A2
C4-A1
Oz-A2
Fz-A2 RE-A1 LE-A2 EMG Figure 124-2 Example of an alpha rating of 1 in stage 2 sleep.
CHAPTER 124 • Fibromyalgia and Chronic Fatigue Syndromes 1431
C3-A2
C4-A1
Oz-A2 Fz-A2 RE-A1 LE-A2 EMG Figure 124-3 Example of an alpha rating of 5 in stage 2 sleep.
C3-A2 C4-A1 Fz-A1 Oz-A2 LOC-A2 ROC-A1 EMG EKG Figure 124-4 This event is tagged as a K-alpha event.
using C3-A2, C4-A1, plus Oz and Fz referred to A1 or A2, are suboptimal but adequate for detection. Previous CAP studies have described the quantification of CAP in terms of CAP rates. The CAP rate is defined as the temporal sum of all CAP sequences, and it is expressed as a percentage ratio of CAP time to total sleep time. The higher the CAP rate, the poorer is the sleep quality. Unfortunately, this concept deviates from the standard nomenclature of PSG, which generally relies on indices rather than on ratios. Other studies specifically examining the relationship between periodic EEG phenomena during sleep and symptoms of nonrestorative sleep have used an index of greater than 15 per hour of sleep as the cutoff for clinical significance.30a Some studies have described variations in CAP in terms of both amplitude and rate. These events have been described as follows:
1. Periodic K-alpha EEG bursts characterized by a K-complex (i.e., an EEG waveform of approximately 0.5 seconds’ duration, consisting of a well-delineated negative component, followed by a positive deflection), immediately followed by 0.5 to 5.0 seconds of alpha EEG activity. Periodic K-alpha is scored when four or more consecutive K-alpha sequences occur within a periodicity range of 5 to 120 seconds. If a submental electromyogram (EMG) burst immediately follows the K-alpha, this event is tagged as both a K-alpha event and a spontaneous arousal (Fig. 124-4). 2. Periodic polyphasic EEG bursts (PPBs),30a characterized by periodic clusters of high-amplitude delta waves, with overlapping alpha, beta, and occasional theta activity. PPBs usually contain 3 to 12 delta peaks but may contain more than 20 delta peaks. They occur most often in stages 2 and 3. If a submental EMG burst
1432 PART II / Section 15 • Other Medical Disorders
C3-A2 C4-A2 FP1-A2 FP2-A2 F3-A2 F4-A2 P3-A2 P4-A2 F7-A2 F8-A2 T3-A2 T4-A2 T5-A2 T6-A2 FZ-A2 CZ-A2 PZ-A2
Figure 124-5 A 19-lead bipolar montage with an epoch length of 30 seconds. The key features of K-alpha and periodic polyphasic EEG bursts are more easily identified from the frontal leads.
C3-A2 C4-A2 FP1-A2 FP2-A2 F3-A2 F4-A2 P3-A2 P4-A2 F7-A2 F8-A2 T3-A2 T4-A2 T5-A2 T6-A2 FZ-A2 CZ-A2 PZ-A2
Figure 124-6 A 19-lead bipolar montage with an epoch length of 60 seconds.
CHAPTER 124 • Fibromyalgia and Chronic Fatigue Syndromes 1433
immediately follows the PPB, this event is tagged as a PPB and a spontaneous arousal. Figures 124-5 and 124-6 show a 19-lead bipolar montage at 30 seconds and at 60 seconds. The key features of K-alpha and PPBs are more easily identified from the frontal leads. Strict amplitude criteria have yet to be established. Normal phase-A CAP requires a 30% increase over background EEG activity. Abnormal phase-A CAP variants generally show a 100% to 500% increase over background. Other Techniques A preliminary study has used low-resolution electromagnetic tomography (LORETA) to determine cortical spatiotemporal genesis of the abnormal phase-A CAP EEG anomaly in patients with fibromyalgia and nonrestorative sleep. This technique allows determination of current density and source localization across the entire EEG frequency band using a minimum 19-lead bipolar montage. Abnormal increases in current density occurred during phase A of the CAP event and were in the delta, theta, and alpha bands. The current density increase was more than 4000% in some frequency bands, compared with the average 300% increase noted in normal phase-A CAP. Maximal increases for delta and theta occurred in the medial frontal gyrus, and in the middle temporal gyrus for the alpha band. These findings further demonstrate the importance of including frontal EEG measurements (i.e., Fz) as part of the standard PSG montage.
❖ Clinical Pearl An accurate diagnosis of CFS and FMS must begin with a clear definition of the most common symptomatic descriptor, “feeling tired.” Furthermore, this must be differentiated from excessive daytime sleepiness, and comorbid sleep disorders must be ruled out. Because of the multidisciplinary nature of sleep disorders medicine, this differentiation may be possible only in the realm of the sleep disorders clinic. Even though treatment for these syndromes is limited, diagnosis remains essential, as validation for the patient is often the critical first step toward selfmanagement and rehabilitation.
REFERENCES 1. Moldofsky H, Scarisbrick P, England R, et al. Musculoskeletal symptoms and non-REM sleep disturbance in patients with “fibrositis syndrome” and healthy subjects. Psychosomat Med 1975;37: 341-351. 2. Wolfe F, Smythe HA, Yunus MB, et al. American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the Multicenter Criteria Committee. Arthritis Rheum 1990;33: 160-172. 3. Onen SH, Alloui A, Gross A, et al. The effects of total sleep deprivation selective sleep interruption and sleep recovery on pain tolerance thresholds in healthy subjects. J Sleep Res 2001;10:35-42. 4. Drewes AM, Nielsen KD, Taagholt SJ, et al. Sleep intensity in fibromyalgia: focus on the microstructure of the sleep process. Br J Rheumatol 1995;34:629-635. 5. Aaron LA, Burke MM, Buchwald D. Overlapping conditions among patients with chronic fatigue syndrome, fibromyalgia, and temporomandibular disorder. Arch Intern Med 2000;24;160:221-227.
6. Lentz MJ, Landis CA, Rothermel J, et al. Effects of selective slow wave sleep disruption on musculoskeletal pain and fatigue in middle aged women. J Rheumatol 1999;26:1586-1592. 7. Drewes AM, Nielson KD, Arendt-Nielson L, et al. The effect of cutaneous and deep pain on the electroencephalogram during sleep: an experimental study. Sleep 1997;20:632-640. 8. Adler GK, Kinsley BT, Hurwitz S, et al. Reduced hypothalamicpituitary-adrenal and sympathoadrenal responses to hypoglycemia in women with fibromyalgia syndrome. Am J Med 1999;106: 534-543. 9. Carette S, Oakson G, Guimont C, et al. Sleep electroencephalo graphy and the clinical response to amitriptyline in patients with fibromyalgia. Arthritis Rheum 1995;38:1211-1217. 10. Landis CA, Lentz MJ, Rothermel J, et al. Decreased nocturnal levels of prolactin and growth hormone in women with fibromyalgia. J Clin Endocrinol Metab 2001;86:1672-1678. 11. Geenen R, Jacobs JW, Bijlsma JW. Evaluation and management of endocrine dysfunction in fibromyalgia. Rheum Dis Clin North Am 2002;28:389-404. 12. Bennett RM, Clark SC, Campbell SM, et al. Low levels of somatomedin C in patients with the fibromyalgia syndrome: a possible link between sleep and muscle pain. Arthritis Rheum 1992;35: 1113-1116. 13. Paiva ES, Deodhar A, Jones KD, et al. Impaired growth hormone secretion in fibromyalgia patients: evidence for augmented hypothalamic somatostatin. Arthritis Rheum 2002;46:440-450. 14. Demitrack MA, Crofford LJ. Evidence for and pathophysiologic implications of the hypothalamic-pituitary-adrenal axis dysregulation in fibromyalgia and chronic fatigue syndrome. Ann N Y Acad Sci 1998;840:684-697. 15. Burgmer M, Gaubitz M, Konrad C, et al. Decreased gray matter volumes in the cingulo-frontal cortex and the amygdala in patients with fibromyalgia. Psychosom Med 2009;71(5):566-573. 16. Wood PB, Glabus MF, Simpson R, Patterson JC. Changes in gray matter density in fibromyalgia: correlation with dopamine metabolism. J Pain 2009;10(6):609-618. Epub 2009 Apr 23. 17. McMillan DE, Landis CA, Lentz MJ, et al. Heart rate variability during sleep in women with fibromyalgia. Sleep 2004;27:A724. 18. Unger ER, Nisenbaum R, Moldofsky H, et al. Sleep assessment in a population-based study of chronic fatigue syndrome. BMC Neurol 2004;19:4-6. 19. Coté KA, Moldofsky H. Sleep, daytime symptoms, and cognitive performance in patients with fibromyalgia. J Rheumatol 1997;24: 2014-2023. 20. Yunus MB, Aldag JC. Restless legs syndrome and leg cramps in fibromyalgia: controlled study. BMJ 1996;312:1339. 21. Tayag-Kier CE, Keenan GF, Scalzi LV, et al. Sleep and periodic limb movements in sleep in juvenile fibromyalgia. Pediatrics 2000;106:E70. 22. Van Dongen HP, Dinges DF. Investigating the interaction between the homeostatic and circadian processes of sleep-wake regulation for the prediction of waking neurobehavioural performance. J Sleep Res 2003;12:181-187. 23. Benca R, Moldofsky H, Ancoli Israel S. Special considerations in insomnia diagnosis and management: depressed, elderly, and chronic pain populations. J Clin Psychiatry 2004:65(Suppl 8): 26-35. 24. Branco J, Atalaia A, Paiva T. Sleep cycles and alpha-delta sleep in fibromyalgia syndrome. J Rheumatol 1994;21:1113-1117. 25. Drewes AM, Nielsen KD, Taagholt SJ, et al. Sleep intensity in fibromyalgia: focus on the microstructure of the sleep process. Br J Rheumatol 1995;34:629-635. 26. Roizenblatt S, Moldofsky H, Benedito-Silva AA, et al. Alpha sleep characteristics in fibromyalgia. Arthritis Rheum 2001;44: 222-230. 27. Moldofsky H, Lue FA, Smythe HA. Alpha EEG and morning symptoms in rheumatoid arthritis. J Rheumatol 1983;10:373-379. 28. Drewes AM, Svendsen L, Taagholt SJ, et al. Sleep in rheumatoid arthritis: a comparison with healthy subjects and studies of sleep/ wake interactions. Br J Rheumatol 1998;37:71-81. 29. Schneider-Helmert D, Kumar A. Sleep, its subjective perception and daytime performance in insomniacs with a pattern of alpha sleep. Biol Psychiatry 1995;37:99-105. 30. Connemann BJ, Mann K, Pascual-Marki RD, Roschke J. Limbic activity in slow wave sleep in a healthy subject with alpha-delta sleep. Psychiatry Res 2001;107:165-171. 30a. MacFarlane JG, Shahal B, Moldofsky H. Periodic K-alpha sleep
1434 PART II / Section 15 • Other Medical Disorders EEG activity and periodic leg movements during sleep: comparisons of clinical features and sleep parameters. Sleep 1996;19:200-204. 31. Moldofsky H. Management of sleep disorders in fibromyalgia. Rheum Dis Clin North Am 2002;28:353-356. 31a. Häuser W, Klose P, Langhorst J, et al. Efficacy of different types of aerobic exercise in fibrolmyalgia syndrome: a systematic review and meta-analysis of randomised controlled trials. Arthritis Res Ther 2010;12(3):R79. 33. Carette S, Bell MV, Reynolds WJ, et al. Comparison of amitriptyline, cyclobenzaprine and placebo in the treatment of fibromyalgia: a randomized double blind clinical trial. Arthritis Rheum 1994;37:32-40. 34. Reynolds WJ, Moldofsky H, Saskin P, et al. The effects of cyclobenzaprine on sleep physiology and symptoms in patients with fibromyalgia. J Rheumatol 1991;18:452-454. 35. Drewes AM, Andreasen A, Jennum P, et al. Zopiclone in the treatment of sleep abnormalities in fibromyalgia. Scand J Rheumatol 1991;20:288-293. 36. Moldofsky H, Lue FA, Mously C, et al. The effect of zolpidem in patients with fibromyalgia: a dose ranging, double blind, placebo controlled, modified crossover study. J Rheumatol 1996;23: 529-533. 37. Mease PJ, Russell IJ, Arnold LM, et al. A randomized, double-blind, placebo-controlled, phase III trial of pregabalin in the treatment of patients with fibromyalgia. J Rheumatol 2008(35):502-514. 38. Mease PJ, Clauw DJ, Gendreau RM, et al. The efficacy and safety of milnacipran for treatment of fibromyalgia. A randomized, doubleblind, placebo-controlled trial. J Rheumatol 2009;36(2):398-409. 39. Russell IJ, Mease PJ, Smith TR, et al. Efficacy and safety of duloxetine for treatment of fibromyalgia in patients with or without major depressive disorder: results from a 6-month, randomized, doubleblind, placebo-controlled, fixed-dose trial. Pain 2008;136(3): 432-444. 40. Moldofsky H, Inhaber NH, Guinta DR, Alvarez-Horine SB. Effects of sodium oxybate on sleep physiology and sleep/wake related symptoms in patients with fibromyalgia syndrome: a randomized,
placebo-controlled study. J Rheumatol 2010;37(10):1-11. 41. Pearl SJ, Lue F, MacLean AW, et al. The effects of bright light treatment on the symptoms of fibromyalgia. J Rheumatol 1996; 23:896-902. 42. Davies S, Crawley E. Chronic fatigue syndrome in children aged 11 years old and younger. Arch Dis Child 2008;95(5):419-421. 43. Mikkelsson M, El-Metwally A, Kautianen H, et al. Onset, prognosis and risk factors for widespread pain in schoolchildren: a prospective 4-year follow-up study. Pain 2008;138(3):681-687. 43a. Viner RM, Clark C, Taylor SJ, et al. Longitudinal risk factors for persistent fatigue in adolescents. Arch Pediatr Adolesc Med 2008;162(5):469-475. 43b. Fukuda K, Strauss SG, Hickie I, et al. The chronic fatigue syndrome: a comprehensive approach to its definition and study. International chronic fatigue study group. Ann Intern Med 1994; 121:953-959. 44. Yunus MA. Comprehensive medical evaluation of patients with fibromyalgia. Rheum Dis Clin North Am 2003;28:201-217. 44a. Rechtschaffen A, Kales A, editors. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Los Angeles: UCLA Brain Information Service/Brain Research Institute; 1968. 45. MacLean AW, Lue FA, Moldofsky H. The reliability of visual scoring of alpha EEG sleep. Sleep 1995;18:565-569. 46. Terzano MG, Parino L, Sherieri A, et al. Consensus report: atlas, rules, and recording techniques for the scoring of cyclic alternating pattern (CAP) in human sleep. Sleep Med 2002;3: 187-199. 47. Brosseau L, Wells GH, Tugwell P, et al. Ottawa Panel evidencebased clinical practice guidelines for aerobic fitness exercises in the management of fibromyalgia: part 1 and 2. Phys Ther 2008;88(7): 857-886. 48. Silver DS, Wallace DJ. The management of fibromyalgia-associated syndromes. Rheum Dis Clin North Am 2002;28:405-417.
Endocrine Disorders Ronald Grunstein
Abstract Sleep disorders, particularly sleep apnea, are common in many endocrine conditions. Most patients with acromegaly have some degree of sleep apnea, with an unusually high prevalence of central sleep apnea. Androgens appear to exacerbate sleep apnea, and there is some evidence of a protective
There are many diverse associations between human endocrine function and sleep. Importantly, neuroendocrine and metabolic physiology is often influenced by behavioral states of sleep and wakefulness (see Chapter 26). Extensive research in this area has flourished since the development of better assays of endocrine function, paralleling the growth of human sleep research stimulated by the availability of polysomnography. Endocrine rhythms have often been labeled either sleep related (when the predominant change in fluctuation is nocturnal) or circadian (when the rhythm appears to be regulated by an internal clock rather than by periodic changes in the external environment). The predominant influences are intrinsic circadian rhythmicity and sleep, which interact to varying degrees to produce the characteristic 24-hour rhythm of each hormone. On the other hand, aberrations of normal endocrine function may influence sleep or alter state-affected parameters such as breathing or the electroencephalogram (EEG). This chapter concentrates on these changes, limiting discussion to particular endocrine disorders in adults and children.
ACROMEGALY AND OTHER GROWTH HORMONE DISORDERS Acromegaly is a condition of growth hormone (GH) excess in adults, characterized by the insidious development of coarsening of facial features, bony proliferation, and soft tissue swelling. It is usually secondary to a GH-producing pituitary adenoma, which may be either a microadenoma or a macroadenoma. Rarely, the GH excess commences before puberty and closure of the epiphyses, and then the condition is termed gigantism. It occurs with equal frequency in both sexes, with a prevalence of 50 to 70 cases per million. The clinical features may result from the local effects of an expanding pituitary mass in addition to the effects of excess GH secretion, which include disordered somatic cell growth and insulin resistance. The mortality of untreated or partially treated acromegaly is about double the expected rate in healthy subjects matched for age. Upper airway obstruction in acromegaly was first described over 100 years ago.1 Epidemiology and Risk Factors Sleep-disordered breathing is extremely common in patients with acromegaly. Studies have shown that at least 60% of unselected patients with acromegaly have sleep
Chapter
125 effect of female sex steroids on upper airway obstruction during sleep. It is controversial whether hypothyroidism is a risk factor for sleep-related disorders. Finally, sleep apnea is associated with the endocrine disorders that are linked to obesity, such as diabetes. Some evidence supports a role of sleep disorders in the pathogenesis of metabolic disturbances associated with obesity.
apnea (Fig. 125-1).1 Almost all patients with acromegaly in this series were noted to have heavy snoring. A number of prevalence studies using limited nocturnal respiratory monitoring have also shown a very high prevalence of sleep-breathing disorders in acromegaly.2,3 In keeping with typical sleep apnea epidemiology, abnormal breathing during sleep in patients with acromegaly is associated with increasing age. However, obesity has less influence on the prevalence of sleep apnea in acromegaly.1-3 Pathogenesis Although it would appear logical that sleep apnea in acromegaly is secondary to macroglossia causing narrowing the hypopharynx, the exact etiology is unclear.1 Endoscopic studies of the upper airway have indicated little posterior movement of the tongue,2 and other studies using cephalometry have produced divergent findings when examining craniofacial anatomy in patients with acromegaly both with and without sleep apnea.4 Patients with acromegaly have a high rate of central apnea, with up to 34% of the total group of patients having sleep apnea in one study.1,5 A waxing-and-waning central apnea pattern of breathing in studies of static charge– sensitive bed has also been reported as more common in patients with acromegaly as opposed to typical upper airway obstruction.2 The high prevalence of central apnea in patients with acromegaly suggests that abnormalities of central respiratory control are involved. This has been supported by the finding that patients with central sleep apnea had significantly lower awake arterial CO2 levels and increased ventilatory responsiveness in the central group6 than those with obstructive apnea (Fig. 125-2).1,7 Central apnea occurs in association with a wide range of disorders, and many potential mechanisms have been described, including disordered central respiratory control.7 The precise cause in acromegaly is unclear, but hypotheses include alterations in central somatostatin pathways disinhibiting respiratory control.7 Another mechanism may be an effect of GH on central respiratory control, either directly or by altering metabolic rate, that induces central apnea. This is supported by the correlation between GH hypersecretion and the prevalence of central apnea.1,7 Interestingly, apparent central apneas have been observed in Beagles exposed to medroxyprogesterone, which in turn causes GH increases and an acromegaly-like condition.7 1435
1436 PART II / Section 15 • Other Medical Disorders 45 Hosp 1
40
Hosp 2
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35 30 25 20 15 10 5 0 0-4
5-9
10-29
30-50
>50
Events per hour Figure 125-1 Prevalence of sleep apnea in acromegaly in two cohorts in Sydney, Australia. In hospital 1, which has a sleep laboratory, almost all patients with acromegaly have sleep apnea. In hospital 2, a regional endocrine center without sleep investigation facilities, 60% of patients have sleep apnea (defined by a respiratory disturbance index of greater than 5).
Hypercapnic ventilatory response (liters/min/mm Hg)
8
6
4
2
0 Central apnea
Obstructive apnea
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Figure 125-2 Ventilatory responses to hypercapnia in patients with acromegaly. Patients with predominantly central sleep apnea have increased ventilatory responses.
Disease Activity in Acromegaly and Sleep Apnea In view of the morbidity and mortality of acromegaly, it is important to define active and inactive (cured) disease. High circulating levels of insulin-like growth factor (IGF)-1 and GH reflect increased GH production and therefore disease activity. Studies describing “cure” after pituitary surgery often use inadequate criteria of disease inactivity. True cure involves observing a physiologic 24-hour GH secretion, normal IGF-1 levels, and normal GH responses to glucose. Even in patients with acromeg-
aly and normal IGF-1 and GH profiles, GH secretory patterns are still different from those of unaffected individuals. Most studies have documented persisting sleep apnea despite treatment of acromegaly by pituitary surgery. Moreover, no clear correlation has been found between disease activity and sleep apnea severity, and no significant differences in mean GH and IGF-1 levels in patients with and without sleep apnea were observed.1 Using more extensive GH measurements in patients with acromegaly, no significant differences in mean GH and GH pulsatility were found between patients with and without sleep apnea.1 In contrast, others8 have reported lower GH levels in patients with milder sleep apnea. Studies using octreotide, a somatostatin analogue, have shown powerful GH reduction with a parallel decrease in apnea severity.5 However, even in this study, there was no relationship between the decrease in apnea and the decrease in GH levels.5 At present, it is not known what proportion of patients with both sleep apnea and acromegaly will have complete resolution of their sleep apnea after cure of acromegaly. This will require careful prospective studies that accurately monitor true cure of acromegaly. However, it is clear that sleep apnea does occur in cured acromegaly.1,5 The combination of inactive acromegaly and sleep apnea may occur for a number of reasons. First, sleep apnea is a common disorder and may be coincident to acromegaly in patients with other risk factors for sleep apnea. Second, it may take a long time after normalization of GH secretion for the effects of acromegaly to resolve, or there may be permanent effects on upper airway function or sleep-breathing regulation. Although there appears to be no relationship between disease activity and the severity of sleep apnea, patients with central sleep apnea have much higher IGF-1 and fasting GH levels than patients with obstructive apnea.1,5 Morbidity and Mortality of Acromegaly and Sleep Apnea The adverse health risks of both acromegaly and sleep apnea are well established. Both disorders are associated with an increased risk of hypertension. In acromegaly, the blood pressure level is sometimes reduced by successful transsphenoidal surgery. One postulated mechanism for hypertension in acromegaly is sodium and water retention secondary to GH overproduction. Interestingly, more than 50% of patients with both acromegaly and sleep apnea have hypertension,1 but all patients with acromegaly who did not have sleep apnea were normotensive. Patients who were hypertensive had significantly higher respiratory disturbance indices and a greater degree of sleep hypoxemia than those who were normotensive. Mean 24-hour GH and IGF-1 levels and the degree of obesity were not significantly different in those with hypertension compared with those without hypertension. Using multiple regression, both the respiratory disturbance index and age were found to be independent predictors of hypertension.1 Historically there has been an excess of deaths resulting from cardiovascular and respiratory causes, although the exact cause of the respiratory deaths was unclear. As there is no excess of chronic lung disease in patients with acromegaly,
CHAPTER 125 • Endocrine Disorders 1437
it is likely that the observed respiration-related deaths were the result of upper airway obstruction. Does Acromegaly Cause Nonrespiratory Sleep Disorders? Somnolence has long been recognized as part of the clinical spectrum of acromegaly. Early descriptions of sleepiness in patients with acromegaly suggested a link with narcolepsy, but subsequent data support the view that the dominant sleep disorder caused by acromegaly is sleep apnea. A direct effect of increased GH in promoting sleep and sleepiness has been suggested, but, alternatively, sleepiness in the absence of sleep apnea result from the effects of radiotherapy.9 Growth Hormone Deficiency Adults with sleep apnea appear to have relative GH deficiency, which is reversible by nasal continuous positive airway pressure (CPAP) (Fig. 125-3).8,10 This deficiency in untreated patients is probably related to abnormal sleep structure (see Chapter 56) and hypoxemia during sleep. There is no evidence that growth hormone deficiency promotes sleep apnea or other sleep disorders.11
SEX HORMONE DISORDERS Male Hormonal Disorders Over the past 2 decades, a number of reports have described the development of sleep apnea in both sexes after testosterone therapy.12 Testosterone was also reported to exacerbate sleep apnea in a 13-year-old boy, associated with an increase in upper airway collapsibility during sleep.6 An important message from these studies is that patients beginning androgen replacement therapy should be questioned closely for sleep apnea symptoms and monitored during the course of their therapy in case such symptoms develop. The possibility of more extensive use of testosterone therapy in eugonadal men for contraception or for “andropause” will probably bring testosterone-induced
0.8 0.7
IGF–1
0.6 0.5 0.4 0.3 0.2 0.1 0 Baseline CPAP n = 43
Control n = 100
Figure 125-3 Insulin-like growth factor-1 (IGF-1) levels in sleep apnea in 43 men before (green bar) and 3 months after (red bar) nasal continuous positive airway pressure (CPAP) therapy. IGF-1 levels increased to levels similar to those observed in a control group (blue bar) of 100 hospital volunteers (mean age, 40 years).
apnea into clinical practice. Simple, device-based methods of sleep apnea screening may also need to be used in such patients. Larger, definitive placebo-controlled testosterone intervention trials in men with androgen deficiency are required. Testosterone also influences sleep architecture. In a study of pharmacologically induced hypogonadism,13 with and without gonadal steroid replacement, hypogonadal males had reduced 24-hour prolactin levels and a reduced percentage of stage 4 sleep in the hypogonadal state compared with those receiving testosterone replacement. Melatonin secretion is increased in male patients with gonadotropin-releasing hormone (Gn-RH) deficiency and in low-testosterone hypergonadotropic hypogonadal patients.14 However there are no data on the prevalence of sleep disturbance in these patients. The observation of reduced total sleep time without worsening alertness on task with high-dose testosterone therapy is intriguing in this context.12 Data demonstrating lower testosterone levels in those with sleep disturbances and shift-work sleep disorder15 indicate that the topic of sex steroids and sleep is clearly worthy of more extensive research. Low testosterone levels have been reported in men with sleep apnea,8 and this appears to be independent of age, degree of obesity, and presence of awake hypoxemia and hypercapnia. In contrast, a cross-sectional population-based study of elderly men found an association between a range of sleep disturbances and low testosterone that were explained largely by body mass index.16 However, testosterone levels increase with treatment of sleep apnea using nasal CPAP or even successful uvulopalatopharyngoplasty.8 These androgen abnormalities in patients with sleep apnea (decreased sex hormone– binding globulin [SHBG] and free and total testosterone) are qualitatively as well as quantitatively distinct from those reported in aging (increased SHBG, decreased free and total testosterone) and obesity (decreased SHBG and total testosterone, normal free testosterone). Importantly, despite the fall in plasma free and total testosterone levels, there was an increase in basal plasma gonadotropin (luteinizing hormone, follicle-stimulating hormone) levels. These findings, together with the retention of pituitary sensitivity to exogenous Gn-RH in sleep apnea,17 point to a hypothalamic abnormality as the cause of the fall in testosterone levels. This is supported by data indicating impaired luteinizing hormone secretion in patients with sleep apnea and partial correction with 9 months of nasal CPAP treatment.18 The potential causes of this hypothalamic abnormality are essentially similar to those involved in reduced GH secretion. Testosterone levels are significantly reduced by sleep deprivation and fragmentation. Therefore, sleep fragmentation in sleep apnea may lead to disruption of sleep-entrained rhythms in luteinizing hormone and testosterone. Sexual dysfunction reported in patients with sleep apnea may be mediated by the sex hormone changes seen in sleepdisordered breathing. The low testosterone levels may also interact with low IGF-1 levels and impair anabolism. Androgens may exacerbate sleep apnea, and it is possible that the fall in androgen levels may be part of an adaptive homeostatic mechanism to reduce sleep-disordered breathing.19 However, androgen-lowering therapy with
1438 PART II / Section 15 • Other Medical Disorders
the nonsteroidal androgen antagonist flutamide did not alter sleep-disordered breathing or awake ventilatory drive.20 Female Sex Hormones and Sleep Studies on the impact of the menstrual cycle and use of oral contraceptives on sleep parameters are limited by sample size and design. Sleep disruption during pregnancy and after the birth is well recognized, and menopause is associated with insomnia related to several factors including hot flashes, mood disorders, and increased sleepdisordered breathing. Epidemiologic studies have confirmed an increase in the prevalence of sleepdisordered breathing among postmenopausal women.21 Other work has suggested that hormone replacement therapy is associated with a lower risk of sleep apnea in postmenopausal women.22 Experimental studies have also shown that testosterone administration in women increases breathing instability during sleep, a finding that is relevant for sleep apnea considering the increased androgen– estrogen balance postmenopausally.23 However, despite these studies, definitive data showing a benefit for female hormone therapy in women with sleep apnea are lacking, and proper randomized controlled trials are needed. Although progesterone levels fall after menopause and progestogens have been shown to stimulate ventilation during the luteal phase of the menstrual cycle, in pregnancy, in normal male subjects, and in conditions of alveolar hypoventilation, there is no consistent therapeutic effect of progestogens in sleep apnea.24 Similarly, it is unclear whether female hormone therapy is beneficial for disordered breathing during sleep.24,25 Increasing central obesity develops with the estrogen deficiency of menopause. This is likely to be the main factor in the increased prevalence of sleep apnea in the postmenopausal state. Obesity occurs in approximately 50% of hyperandrogenic anovulatory women, some of whom also have non–insulin-dependent diabetes mellitus. This is typically associated with polycystic ovary syndrome (PCOS). Two studies have indicated that PCOS is strongly associated with the presence of sleep apnea, and in turn that sleep apnea in PCOS is strongly associated with the degree of androgen excess and increased central fat.26,27
muscles, and reduced central drive to upper airway muscles.30 Nevertheless, the strength of the association between sleep apnea and hypothyroidism is controversial, with evidence of greater than expected sleep apnea in hypothyroid clinical cohorts but varying views on the prevalence of hypothyroidism in sleep apnea clinics. In a cohort of 50 consecutive referral patients with hypothyroidism, 30% were reported to have some degree of obstructive sleep apnea.31 Several large studies have been completed, with conflicting conclusions on the strength of the association between sleep apnea and hypothyroidism and whether all OSA patients should be screened for this disorder.32 It is likely that the prevalence of hypothyroidism in sleep apnea cohorts is too low, and definitive epidemiologic answers require further case-control studies in larger cohorts. However, in studies examining the economic impact of OSA on health, the relative risk of an added diagnosis of hypothyroidism appears quite small compared with nonapneic controls.33,34 The effect of adequate thyroid hormone replacement on sleep apnea in hypothyroidism has been variable, but generally it has been investigated in small cohorts.30 More recent data in larger numbers suggest that sleep apnea in many patients with hypothyroidism is a secondary phenomenon and may well be reversible.31 This suggests that hypothyroidism induces changes in upper airway mechanics or breathing control that may normalize with thyroxine treatment. Importantly, a number of studies have suggested a link between sleep apnea and cardiovascular complications in the initial stages of thyroid hormone replacement therapy. It is recognized that rapid restoration of the euthyroid state in hypothyroid patients may entail significant cardiovascular morbidity and mortality.30,35 Sleep Quality in Hypothyroidism Sleepiness has long been observed as a symptom in hypothyroidism. Although sleep apnea may be one cause, a primary central effect on sleep is also possible in some patients. Marked reduction in SWS has been seen in patients with hypothyroidism, which is reversible with treatment. In patients with congenital hypothyroidism, increased movement in sleep and reduced REM sleep have been noted.
Prolactinoma Drug-free patients with prolactinoma spend more time in slow-wave sleep (SWS) than the controls, with no differences in REM sleep.28 Patients with prolactinoma report good sleep quality. Sleep apnea is also associated with reduced prolactin secretory pulse frequency.29
Hyperthyroidism and Sleep Patients with thyrotoxicosis often complain of insomnia and impaired mood, but these changes are not obvious in subjects with asymptomatic hyperthyroidism detected on random testing.36 Definitive controlled studies of sleep in hyperthyroid patients are lacking.
THYROID DISORDERS Hypothyroidism and Sleep Apnea Although myxedema coma is now rare, in retrospect many cases probably resulted from severe sleepiness and obtundation secondary to severe sleep apnea, coupled with the hypercapnic respiratory failure of sleep apnea. Several mechanisms have been suggested to explain the association between sleep apnea and hypothyroidism. These include reduced upper airway patency due to myxedematous infiltration of tissues, impaired function of upper airway
DISORDERED CORTICOSTEROID SECRETION AND SLEEP Patients with corticosteroid excess secondary to Cushing’s disease are characterized by truncal obesity, hypertension, and depression. In the only published study, about one third of patients appear to have sleep apnea.37 Patients with Cushing’s disease who do not have sleep apnea exhibit poorer sleep continuity, shortened REM latency, and increased first-REM-period density compared with normal subjects with reduced SWS.38 Interestingly,
CHAPTER 125 • Endocrine Disorders 1439
reduced SWS occurs in patients with Addison’s disease, suggesting that normal cortisol secretion is needed for maintenance of SWS.
1.9 Energy expenditure (kcal/min)
DIABETES AND CENTRAL OBESITY No specific sleep architecture abnormalities are associated with diabetes. Even hypoglycemic episodes during sleep are not apparently associated with EEG evidence of arousal.39 Periodic movements in sleep may be more common in patients with diabetes (see Chapter 90), and sleep may be disrupted in those with painful neuropathy.40 Sleep apnea is common in patients with type 2 diabetes,41 where the fundamental link between diabetes and sleep apnea is through a co-association with central obesity.42 Central obesity is often a more crucial determinant of morbidity and mortality than total adiposity.42 Centrally obese individuals have an increased risk of cardiovascular and cerebrovascular disease, diabetes, hypertension, hyperlipidemia, hyperuricemia, and insulin resistance relative to peripherally obese individuals. This cluster of abnormalities is often labeled metabolic syndrome. Central obesity is the commonest metabolic abnormality in sleep apnea.41,42 The health risks of obesity and sleep apnea are similar, and data are complicated by mutually confounding variables.41,42 Multivariate analyses of data and CPAP intervention studies suggest that both sleep apnea and central obesity are additive in the pathogenesis of certain obesity-related morbidity. However, despite increasing research, several fundamental questions about the links between OSA, central obesity, and diabetes remain unanswered. It is clear that central obesity is a powerful epidemiologic predictor of sleep apnea,41-43 and weight reduction may lead to marked improvement in sleep apnea severity and a parallel improvement in metabolic abnormalities.43 However, the data that address the reverse possibility— that sleep apnea may promote the development of obesity—are more limited.44 Unfortunately, long-term prospective studies are lacking. It has been speculated that chronic intermittent hypoxia and sleep fragmentation over years in patients with sleep apnea can lead to changes in central control of energy regulation, appetite control, feeding, and metabolism, which would promote weight gain and thus worsen sleep apnea further. During sleep, energy expenditure typically falls relative to the awake basal state. In patients with severe sleep apnea, energy expenditure in sleep appears to increase during apneic sleep, and it falls with CPAP therapy (Fig. 125-4).45 This would seem to be paradoxical—such changes in energy expenditure would favor weight loss before CPAP and weight gain after CPAP. However, the 24-hour energy expenditure may be different in patients with untreated sleep apnea when reduced spontaneous physical activity (fidgeting, routine physical activities) due to fatigue and sleepiness produce a net decrease in energy expenditure, despite increased energy expenditure in sleep resulting from respiratory effort and sleep fragmentation. Other intriguing data suggest that patients with sleep apnea may have altered but reversible serotonergic sensitivity in the hypothalamus.44 Another potential factor that may promote obesity is leptin resistance. Leptin is a fat-regulating mediator produced widely in the body, especially by fat cells.
2.0
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6 PM
Time
Figure 125-4 Sleep energy expenditure (SEE) curve for a patient (26 years old; body mass index, 40 kg/m2) with severe obstructive sleep apnea before treatment with nasal continuous positive airway pressure (CPAP) (top curve) and reduction in SEE with CPAP therapy (bottom curve). (Adapted from Stenlöf K, Grunstein RR, Hedner J, et al. Energy expenditure in obstructive sleep apnea: effects of treatment with continuous positive airway pressure. Am J Physiol 1996;271:E1036-E1043.)
Central resistance to leptin is not uncommon in patients with obesity and has been observed in those with sleep apnea. Interestingly, there are parallel findings of a serotonindeficient state in patients with central obesity. A cluster of disorders associated with central obesity, including abnormalities of the hypothalamic-pituitary–end organ axis (low GH and testosterone, high cortisol), a “defeat” reaction to stress with psychosocial disability, and carbohydrate craving promoted by a low serotoninergic state. Specific serotoninergic agonists have been used as treatments for central obesity.43 The observed low testosterone and GH in sleep apnea also occur in patients with central obesity.8,43 In central obesity, recombinant GH appears to reduce central body fat, and restoration of GH secretion during sleep with nasal CPAP in patients with sleep apnea may have similar effects.44 However, if sleep apnea causes central obesity, then it would be expected that treatments that reverse sleep apnea would result in weight loss. Some studies suggest that that nasal CPAP will reduce visceral fat deposits even without change in body mass index in patients with sleep apnea,45,46 but well-powered randomized controlled trials specifically addressing this issue are lacking. Most such trials with CPAP are short-term trials addressing hypertension or neurocognitive variables and do not report significant weight loss with short-term follow-up. Central obesity is associated with hyperinsulinemia and insulin resistance. The exact link between obesity, sleep apnea, and insulin resistance is unclear. Certainly, some data also point to increased insulin levels in patients with sleep apnea independent of weight and central obesity.47 However, the question of whether nasal CPAP even improves insulin resistance or diabetic control in type 2 diabetics is controversial.48 Another direction of research
1440 PART II / Section 15 • Other Medical Disorders
?
Central obesity
Sleep apnea ↓ Insulin sensitivity ? Net effects on energy expenditure
↓ Anabolic hormone secretion
Altered central serotonergic tone Figure 125-5 Factors involved in the relationship between central obesity and sleep apnea. Sleep apnea is linked with reduced insulin sensitivity and secretion of anabolic hormones, which would favor development of central obesity. The observed changes in serotonergic “tone” in sleep apnea would also theoretically promote the obese state. Although treatment of sleep apnea with continuous positive airway pressure reduces energy expenditure, the net effects of sleep apnea on energy expenditure are unknown.
linking OSA with the pathogenesis of the health risks of obesity is work showing an overproduction of certain cytokines and the formation of a proinflammatory state in patients with OSA.49,50 These changes with favor the development of increased vascular risk and insulin resistance and metabolic syndrome. In summary, diabetes and central obesity, in particular, are closely linked to sleep-breathing disorders. The association between sleep apnea and central obesity is outlined in Figure 125-5.
❖ Clinical Pearl It is important to consider the potential development of sleep apnea in any patient who has an endocrine disorder or who receives certain hormonal therapies.
Acknowledgment Studies were supported by a Practitioner Fellowship from the National Health and Medical Research Council of Australia. REFERENCES 1. Grunstein RR, Ho KY, Sullivan CE. Acromegaly and sleep apnea. Ann Intern Med 1991;115:527-532. 2. Pelttari L, Polo O, Rauhala E, et al. Nocturnal breathing abnormalities in acromegaly after adenomectomy. Clin Endocrinol (Oxf) 1995;43:175-182. 3. Rosenow F, Reuter S, Deuss U, et al. Sleep apnoea in treated acromegaly: relative frequency and predisposing factors. Clin Endocrinol (Oxf) 1996;45:563-569. 4. Dostalova S, Sonka K, Smahel Z, et al. Craniofacial abnormalities and their relevance for sleep apnoea syndrome aetiopathogenesis in acromegaly. Eur J Endocrinol 2001;144:491-497. 5. Grunstein RR, Ho KY, Sullivan CE. Effect of octreotide on sleep apnoea in acromegaly. Ann Int Med 1994;121:478-483.
6. Cistulli PA, Grunstein RR, Sullivan CE. Effect of testosterone administration on upper airway collapsibility during sleep. Am J Respir Crit Care Med 1994;149:530-532. 7. Grunstein RR, Ho KY, Berthon-Jones M, et al. Central sleep apnea is associated with increased ventilatory response to carbon dioxide and hypersecretion of growth hormone in patients with acromegaly. Am J Respir Crit Care Med 1994;150:496-502. 8. Grunstein RR, Handelsman DJ, Lawrence S, et al. Neuroendocrine dysfunction in sleep apnea: reversal by nasal continuous positive airway pressure. J Clin Endocrinol Metab 1989;68:352-358. 9. Faithfull S. Patients’ experiences following cranial radiotherapy: a study of the somnolence syndrome. J Adv Nurs 1991;16:939946. 10. Meston N, Davies RJ, Mullins R, et al. Endocrine effects of nasal continuous positive airway pressure in male patients with obstructive sleep apnoea. J Intern Med 2003;254:447-454. 11. Peker Y, Svensson J, Hedner J, et al. Sleep apnoea and quality of life in growth hormone (GH)-deficient adults before and after 6 months of GH replacement therapy. Clin Endocrinol (Oxf) 2006;65: 98-105. 12. Liu PY, Yee B, Wishart SM, et al. The short-term effects of highdose testosterone on sleep, breathing, and function in older men. J Clin Endocrinol Metab 2003;88(8):3605-3613. 13. Leibenluft E, Schmidt PJ, Turner EH, et al. Effects of leuprolideinduced hypogonadism and testosterone replacement on sleep, melatonin, and prolactin secretion in men. J Clin Endocrinol Metab 1997;82:3203-3207. 14. Luboshitzky R, Wagner O, Lavi S, et al. Abnormal melatonin secretion in male patients with hypogonadism. J Mol Neurosci 1996; 7:91-98. 15. Axelsson J, Akerstedt T, Kecklund G, et al. Hormonal changes in satisfied and dissatisfied shift workers across a shift cycle. J Appl Physiol 2003;95:2099-2105. 16. Barrett-Connor E, Dam TT, Stone K, et al. Osteoporotic Fractures in Men Study Group. The association of testosterone levels with overall sleep quality, sleep architecture, and sleep-disordered breathing. J Clin Endocrinol Metab 2008;93:2602-2609. 17. Stewart DA, Grunstein RR, Sullivan CE, et al. Neuroendocrine changes in sleep apnea are not related to a pituitary defect. Sleep Res 1989;18:308. 18. Luboshitzky R, Lavie L, Shen-Orr Z, et al. Pituitary-gonadal function in men with obstructive sleep apnea. The effect of continuous positive airways pressure treatment. Neuroendocrinol Lett 2003; 24(6):463-467. 19. Liu PY, Caterson ID, Grunstein RR, et al. Androgens, obesity, and sleep-disordered breathing in men. Endocrinol Metab Clin North Am 2007;36:349-363. 20. Stewart DA, Grunstein RR, Berthon-Jones M, et al. Androgen blockade does not affect sleep-disordered breathing or chemosensitivity in men with obstructive sleep apnea. Am Rev Respir Dis 1992;146: 1389-1393. 21. Young T, Finn L, Austin D, et al. Menopausal status and sleep-disordered breathing in the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med 2003;167:1181-1185. 22. Shahar E, Redline S, Young T, et al. Hormone replacement therapy and sleep-disordered breathing. Am J Respir Crit Care Med 2003; 167:1186-1192. 23. Zhou XS, Rowley JA, Demirovic F, et al. Effect of testosterone on the apneic threshold in women during NREM sleep. J Appl Physiol 2003;94(1):101-107. 24. Cistulli PA, Barnes DJ, Grunstein RR, et al. Effect of short-term hormone replacement in the treatment of obstructive sleep apnoea in postmenopausal women. Thorax 1994;49:699-702. 25. Saaresranta T, Polo-Kantola P, Virtanen I, et al. Menopausal estrogen therapy predicts better nocturnal oxyhemoglobin saturation. Maturitas 2006;55(3):255-263. 26. Fogel RB, Malhotra A, Pillar G, et al. Increased prevalence of obstructive sleep apnea syndrome in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 2001;86:1175-1180. 27. Vgontzas AN, Legro RS, Bixler EO, et al. Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: role of insulin resistance. J Clin Endocrinol Metab 2001;86: 517-520. 28. Frieboes RM, Murck H, Stalla GK, et al. Enhanced slow wave sleep in patients with prolactinoma. J Clin Endocrinol Metab 1998; 83:2706-2710.
29. Spiegel K, Follenius M, Krieger J, et al. Prolactin secretion during sleep in obstructive sleep apnoea patients. J Sleep Res 1995 ;4(1): 56-62. 30. Grunstein RR, Sullivan CE. Hypothyroidism and sleep apnea. Mechanisms and management. Am J Med 1988;85:775-779. 31. Jha A, Sharma SK, Tandon N, et al. Thyroxine replacement therapy reverses sleep-disordered breathing in patients with primary hypothyroidism. Sleep Med 2006;7:55-61. 32. Sjokdt NM, Aktar R, Easton PA. Screening for hypothyroidism in sleep apnea. Am J Respir Crit Care Med 1999;160:732-735. 33. Shepertycky MR, Banno K, Kryger MH. Differences between men and women in the clinical presentation of patients diagnosed with obstructive sleep apnea syndrome. Sleep 2005;28:309-314. 34. Greenberg-Dotan S, Reuveni H, Simon-Tuval T, et al. Gender differences in morbidity and health care utilization among adult obstructive sleep apnea patients. Sleep 2007;30:1173-1180. 35. Abouganem D, Taylor AL, Donna E, et al. Extreme bradycardia during sleep apnea caused by myxedema. Arch Intern Med 1987;147:1497-1499. 36. Schlote B, Schaaf L, Schmidt R, et al. Mental and physical state in subclinical hyperthyroidism: investigations in a normal working population. Biol Psychiatry 1992;32:48-56. 37. Shipley JE, Schteingart DE, Tandon R, et al. Sleep architecture and sleep apnea in patients with Cushing’s disease. Sleep 1992;15: 514-518. 38. Born J, Fehm HL. Hypothalamus-pituitary-adrenal activity during human sleep: a coordinating role for the limbic hippocampal system. Exp Clin Endocrinol Diabetes 1998;106:153-163. 39. Schultes B, Jauch-Chara K, Gais S, et al. Defective awakening response to nocturnal hypoglycemia in patients with type 1 diabetes mellitus. PLoS Med 2007;4:e69. 40. Backonja M, Beydoun A, Edwards KR, et al. Gabapentin for the symptomatic treatment of painful neuropathy in patients with diabe-
CHAPTER 125 • Endocrine Disorders 1441 tes mellitus: a randomized controlled trial. JAMA 1998;280: 1831-1836. 41. West SD, Nicoll DJ, Stradling JR. Prevalence of obstructive sleep apnoea in men with type 2 diabetes. Thorax 2006;61:945-950. 42. Grunstein RR, Wilcox I, Yang TS, et al. Snoring and sleep apnoea in men: association with central obesity and hypertension. Int J Obesity 1993;17:533-540. 43. Yee BJ, Phillips CL, Banerjee D, et al. The effect of sibutramineassisted weight loss in men with obstructive sleep apnoea. Int J Obes 2007;31:161-168. 44. Yee B, Liu P, Phillips C, et al. Neuroendocrine changes in sleep apnea. Curr Opin Pulm Med 2004;10:475-481. 45. Chin K, Shimizu K, Nakamura T, et al. Changes in intra-abdominal visceral fat and serum leptin levels in patients with obstructive sleep apnea following nasal continuous positive airway pressure. Circulation 1999;100:706-712. 46. Trenell MI, Ward JA, Yee BJ, et al. Influence of constant positive airway pressure therapy on lipid storage, muscle metabolism and insulin action in obese patients with severe obstructive sleep apnoea syndrome. Diabetes Obes Metab 2007;9:679-877. 47. Tasali E, Van Cauter E. Sleep-disordered breathing and the current epidemic of obesity: consequence or contributing factor? Am J Respir Crit Care Med 2002;165:562-563. 48. Steiropoulos P, Papanas N, Nena E, et al. Continuous positive airway pressure treatment in patients with sleep apnoea: does it really improve glucose metabolism? Curr Diabetes Rev 2010;6:156-166. 49. Vgontzas AN, Bixler EO, Chrousos GP, et al. Obesity and sleep disturbances: meaningful sub-typing of obesity. Arch Physiol Biochem 2008;114:224-236. 50. Tsaoussoglou M, Bixler EO, Calhoun S, et al. Sleep-disordered breathing in obese children is associated with prevalent excessive daytime sleepiness, inflammation, and metabolic abnormalities. J Clin Endocrinol Metab 2010;95:143-150.
Pain and Sleep
Chapter
Gilles Lavigne, Michael T. Smith, Ronald Denis, and Marco Zucconi Abstract Pain is an acute or chronic condition associated with a sensory and emotional experience reported to interfere with sleep. The impact of acute pain on sleep (e.g., delay in sleep onset, sleep awakening, poor sleep quality, low restorative effectiveness) is usually short term and reversible. However, the presence of chronic pain can be associated with a vicious-cycle pattern— a day with intense pain followed by a night of poor sleep quality, and a night of poor sleep increasing the reports of pain on the next day. Chronic pain is reported by approximately one out of four adults in the general population, and two thirds of them complain of poor sleep quality. Coexistent conditions such as anxiety, depression, insomnia, apnea, periodic limb movements (PLM) during sleep, aging, and use of some medications are among risk factors for poor sleep in the presence of pain, fibromyalgia, previous traumatic nerve injury, and neuropathic or cancer pain. The interaction between pain and poor sleep could be explained by sleep
A majority (50% to 70%) of patients with chronic pain report poor-quality sleep. This chapter provides a better understanding of the mechanisms associated with poor sleep in the presence of pain, and a guide to sleep management for the pain patient. At present, there are no evidence-based guidelines for such problems. Pain of various origins and causes is associated with poor sleep quality. Pain can cause sleep fragmentation that can give rise to reports of unrefreshing sleep in relation to several clinical pain conditions, including restless legs syndrome or periodic limb movements (PLM) during sleep, headaches with or without apnea, irritable bowel, gastric ulcer, visceral distention (bladder or intestinal), cancer pain, musculo skeletal pain (neck or back pain, limb pain, fibromyalgia), neuropathic pain, dental and orofacial pain, spinal cord damage, sensory dysfunction, and burn or trauma.
PAIN AND SLEEP As defined by the International Association for the Study of Pain,1 pain is an “unpleasant sensory and emotional experience associated with actual or potential tissue damage or described in terms of such damage.” The emotional dimension is concomitant with both acute pain (e.g., postoperative) and chronic pain (e.g., arthritic pain, herpetic neuralgia, diabetic neuropathy). In the presence of acute pain, such as a toothache, relief is predictable with appropriate dental care, and the consequences for quality of life and health are usually short term. When pain becomes chronic—that is, if it lasts more than several weeks or months—the patient may report poor quality of life and poor daytime performance at work or familial tasks. For some patients, day-to-day life with intense pain is so unbearable that a suicide attempt is possible if the distress associated with suffering is not managed.2 The sudden 1442
126
fragmentation (arousal, sleep stage shift), or by lower percentage of slow-wave activity during sleep. Most patients with chronic pain report daytime fatigue and sleepiness, reduced cognitive functioning (e.g., memory), and poorer quality of life. A clinical interview and an actigraphic or a polygraphic recording are needed to rule out poor sleep hygiene, insomnia, PLM during sleep, apnea, and altered circadian rhythm. Cognitive–behavioral management is recognized as potentially useful to treat comorbid insomnia occurring in the context of chronic pain and other primary medical or psychiatric disorders. Medications that improve sleep and reduce pain are indicated, although some may alter sleep quality. The roles of the sleep clinician are to recognize that pain interferes with sleep quality, to educate patients about improving sleep hygiene (i.e., avoiding poor sleep habits), to guide the patient to cognitive–behavioral or physical therapies, and to review and prescribe analgesic and sleep-promoting medications.
reappearance of a pain episode can be a sign of the recurrence of a potentially fatal disease (e.g., cancer pain), with its attendant effects on the patient’s well-being, anxiety, and sleep quality. Interest in the interaction between pain and sleep emerged in the 1960s, with descriptions of the processing of tactile cutaneous sensory inputs at the level of the brainstem mesencephalic–reticular formation and the trigeminal sensory nucleus during wakefulness and sleep.3 Clinical interest began in the late 1960s with a series of publications suggesting that patients with chronic pain could demonstrate disturbed sleep homeostasis. At that time, the emerging concept of electroencephalographic (EEG) instability—referred to as alpha intrusions during non–rapid eye movement (NREM) deep sleep—was associated with somatic pain.4 Clinically, both linear and circular relationships exist between pain and sleep, and pain can precede the poor sleep complaints, or vice versa (Fig. 126-1). With acute pain, the poor sleep complaints usually do not continue after pain resolution. However, the initial linear sequence (i.e., pain precedes poor sleep) can be transformed, in some patients, into a vicious-cycle pattern when pain lasts too long (i.e., a day with intense pain followed by a night with poor sleep quality, and a night with poor sleep followed by a higher degree of pain perception or pain reports on the next day).5 The linear relationship was reported by 53% to 89% of patients with various types of musculoskeletal pain.6,7 The vicious cycle is reported for patients with chronic pain such as fibromyalgia or severe skin burns.8-10 Recent epidemiologic data have shown a reciprocal relationship between sleep duration and frequency of next-day pain in the general population. Specifically, transitioning from a night of relatively normal sleep duration (6 to 9 hours) to a night of less than 6 hours or greater than 9
CHAPTER 126 • Pain and Sleep 1443
Novel PAIN More intense PAIN Altered quality of life
Acute pain
Chronic pain (vicious circle)
Short-term “REVERSIBLE” POOR SLEEP If good sleep or pain management Long-term POOR SLEEP
Stress and anxiety Activation of HPA axis and rise in IL–6 release Figure 126-1 Linear (acute pain) and vicious-cycle (chronic pain) relationships. HPA, hypothalmic-pituitary-adrenal; IL-6, Interleukin-6.
hours was linked to a substantial increase in next-day pain frequency. Pain during the day also predicted alterations in sleep duration at night.11 Pain Pain is a protective response, involving neuronal, glial, and immune cellular activities (e.g., gene expression, ionic channel and receptor activation), to integrated behavior such as the fight-or-flight reaction, with the activation of several limbic structures such as the hypothalamus, amygdala, cingulate, and frontal cortical areas.3,3a,12-14 Chronic pain may also be considered a disorder of the nervous system; when it is persistent, there are reversible or permanent changes associated with neuronal plasticity, or there are modifications at the cellular or network level (both neuronal and glial cells with immune responses). Pain is associated with direct nerve activation (e.g., trigeminal neuralgia), with inflammation (e.g., arthritis), with changes in nerve environment (e.g., neuropathic pain), or with changes at the cortical sensory representation areas (enlargement of the sensory cortical territory, a reverberating loop that potentiates sensory nonpain inputs to a frequency that is interpreted as pain). In summary, with most somatic pain, there is a usual sequence of activation from nociception to pain perception that involves the following: (1) activation of nerve endings, (2) transmission through sensory A delta and C sensory fibers, (3) a first relay at spinal cord neurons, (4) a second relay at thalamic levels and interactions with brainstem cells, (5) cortical neuronal network activation, and (6) the final reaction to pain, such as withdrawal or escape behaviors with or without emotional reactions such as tearing, crying, or anxiety. Visceral pain is different from most somatic pain. In the presence of visceral pain (e.g., irritable bowel syndrome), the patient thinks that the sensation is diffuse and poorly localized. When visceral nociceptors are activated, they tend to react to innocuous and noxious stimuli without discrimination. Thus, the tissue sensory ending and its brain localization become oversolicited (i.e., hypersensitive), which can result in allodynia (i.e., normally non painful stimulation is described by the patient as a pain sensation). Interestingly, pain perception can be attenuated by activation of the brain’s descending influences that are either
localized on specific neurons or diffuse, and the result is a better tolerance of pain. Such mechanisms are linked to the expression of several opioid, serotonin, norepinephrine, and other genes (polymorphism) and proteins acting in the periphery and at the spinal cord or brainstem level. Epidemiology and Risk Factors The costs of pain and of poor sleep are in the billions of dollars in North America, but no specific cost assessment has been done for the cumulative impact of pain and poor sleep together.15 Comorbidities are a dominant feature of the pain and sleep interaction. A survey done in a primary care family practice network revealed that chronic pain, including arthritis and joint pain, was associated with complaints of being sleepy during daytime activities, of symptoms suggestive of restless legs syndrome, and of loud snoring and cessation of breathing during sleep (risk odds ratio [OR], 1.7 to 2.7).16 Clinicians involved in the diagnosis and management of complaints of pain and poor sleep quality appreciate the relevance of the interaction between the two conditions. In a general population survey, it was noted that the frequency of a day’s pain symptoms can be predicted by whether an individual sleeps less than 6 hours or more than 9 hours.11 Short or long sleep duration (either end of a U-shaped distribution) was also reported to be associated with health risks.17 The prevalence of chronic pain in the adult population is estimated to be 11%, but figures as high as 29% have been reported depending on the questions asked to the target population.18 Between 50% and 70% of adults and children with chronic pain reported poor sleep in relation to their pain conditions, which include arthritis, cervical pain, fibromyalgia, orofacial joint and muscle pain (temporomandibular pain), and low back pain.6,7,19-21 Other medical conditions with concomitant pain that are also reported to interfere with sleep quality are headaches, irritable bowel syndrome, spinal cord injury, traumatic brain injury, and metastatic breast cancer.4,22-26 A risk factor that contributes to the perpetuation of poor sleep is chronic pain, with a low OR of approximately 1.5 (i.e., 44% of patients with chronic pain report insomnia, versus 19% of subjects without pain).4 Concomitant conditions such as anxiety, fatigue, mood disturbances, depression, and poor physical fitness also affect the interaction between pain and sleep. Sleep and pain interactions are influenced by multiple factors. To a large extent, the data are derived from surveys (e.g., simple questions or questionnaires on sleep, mood, pain) of general populations or of patient cohorts, in which pain intensity and sleep quality reports are subjective. About 30% of the interactions between pain and sleep (i.e., from poor sleep quality to insomnia) can be explained by the presence of concomitant fatigue, depression or mood alteration, poor physical condition, and anxiety.7,21,22,27,28 A recent comparison between women suffering from fatigue in the presence of osteoarthritis, rheumatoid arthritis, or fibromyalgia revealed that in the women with rheumatoid arthritis or fibromyalgia, there was a relationship between daily pain and fatigue.29 Insomnia complaints also tended to be related to lower scores on physical and emotional pain and to vitality domains when the 36-item Short-Form Health Survey (SF-36) was administered to older patients.30
1444 PART II / Section 15 • Other Medical Disorders
Gender and aging are also concomitant variables. Chronic pain is more frequently reported by women, at approximately double the rate in men. With age, pain becomes more prevalent (e.g., in 25% to 50% of patients older than 55 years) and lasts longer, although older patients seem to cope better with pain and tend to be more stoic.30,31 PLM during sleep and sleep breathing disorders are other important variables to control for when studying the effect of age (see Chapters 90, 100 to 105). We recently observed that patients with chronic widespread pain have four times more PLM per hour of sleep than matched controls, and the presence of sleep breathing conditions (snoring, upper airway resistance, apnea–hypopnea syndrome) was also reported to be a common finding in patients with chronic pain.16,32-34 This suggests that the interaction between aging, pain, and poor sleep complaints depends on several variables.30
PATHOGENESIS The interaction between pain and poor sleep could be partially explained by sleep fragmentation (higher frequency of arousals or sleep stage shifts) and by a lower percentage of slow-wave sleep (SWS) (i.e., stages 3 and 4, or deep or restorative sleep). Indeed, most patients with chronic pain report daytime fatigue and sleepiness, reduced cognitive function (e.g., memory impairment), and poor quality of life. So far, no simple mechanism explains the pathophysiology of the interaction between pain and poor sleep quality, or the presence of the vicious-cycle pattern found in some patients with chronic pain (see Fig. 126-1). Pain perception and modulation are altered in relation to sleep state. In general, sensory information is filtered during sleep, but relevant inputs threatening body homeostasis may trigger a rapid return of consciousness, with the patient reporting pain on awakening. Neurobiological Basis of Sensory-Pain Perception in Sleep Recent animal studies have confirmed that in the presence of brief sensory or pain stimulations during sleep, the spinoreticular and trigeminothalamic tract neurons (part of the ascending sensory and pain pathways) behave as a gated control mechanism to trigger or inhibit an awakening response. Such activity is not homogeneous across sleep stages (quiet NREM or active REM sleep) and seems to depend on brainstem raphe magnus cell activity (serotonergic or not).35,36 Moreover, the latency of the painrelated sensorimotor reflex, the tail flick, allows a sensitive assessment of spinal nociception. Compared with in wakefulness, the reflex latency in cats is increased threefold in NREM and fivefold in REM sleep.37 Based on animal and human findings, it is now accepted that a sleeping brain is not completely isolated from the external milieu, and that neuronal sensorimotor networks related to vigilance and body protection remain active in sleep.35,38 In humans, the perception of pain during sleep depends on the type of sensory stimulation. Differing stimuli—brief sensory nerve, midduration thermal, or long chemical or mechanical stimulations—produce very different outcomes, from spinal reflex to integrated cortical response and autonomic sleep arousal-awakening, all the way up
to conscious awareness of stimulation.39-41 The spinal nociceptive reflex is a short-loop spinal reflex triggered by intense and brief electrical stimulation of the sural nerve area. Compared with wakefulness, the latency of this reflex is longer in deep NREM sleep and REM sleep, with its threshold significantly increased by 60% in NREM and by 200% in REM sleep.39 Laser stimulations in the milliseconds range, sufficient to evoke a brief cortical potential during the waking state, produce an observable cortical response during sleep stage 2 and REM.40 Midduration (6- to 12-second) thermal pain stimulations, causing a pain sensation with an intensity of 6 on a 10-point scale during wakefulness, triggered clear cortical arousals to approximately 50% of stimulations in stage 2 sleep, and responses to only approximately 30% of stimulations in SWS (stages 3 and 4) or REM sleep. These data indicate that the nociceptive temperature threshold is higher in SWS and REM sleep.41 Another pain model infuses hypertonic saline (5%) into muscle to evoke during wakefulness a pain intensity of 3 of 10 for more than 70 seconds. Using this model, where experimental pain mimics a muscle cramp, clear awakening responses are produced with a similar response rate across sleep stages; interestingly, most patients remembered a pain experience during their sleep, in contrast to the thermal stimulation experiments described previously.42,43 Again, available data demonstrating how ongoing sleep is interrupted by clinical pain are very limited. Circadian Variation in Pain Perception In healthy subjects, most studies suggest that pain perception to experimental thermal stimulation, chemical infusion, or mechanical pressure does not show variation over a 24-hour period or between evening and morning measurements when data are controlled for mood state and sex.41,44 However, patients’ self-reports of pain intensity vary with daytime symptoms. For example, patients with arthritis report that pain is worst in the morning with body motion. About 50% to 80% of those with muscle-related pain, including headaches, report higher pain intensity in the afternoon and evening, whereas pain from torticollis is completely relieved by sleep.45,46 Cognitive Impairment, Sleep Deprivation, and Pain Perception Regardless of its cause, sleep fragmentation is associated with a subsequent increase in sleepiness and fatigue and a decrease in cognitive and motor performance. Effects of pain on sleep and cognition may therefore be nonspecific and mediated simply by the degree to which pain causes sleep fragmentation.4,47 Few studies suggest that memory and attention are impaired in patients with chronic musculoskeletal pain and fibromyalgia.48,49 More studies are needed to clarify the cognitive changes associated with chronic pain and poor sleep, taking into consideration the impact of sleep fragmentation and of concomitant anxiety, mood dysfunction, fatigue, and the like. Development or validation of more naturalistic tests related to real-life working or driving performance may provide new information on the cognitive deficit related to the interaction of pain and sleep or secondary to medication prescribed in its management.15,50
Moreover, all sleep stages seem to be necessary for memory consolidation, and a nap of at least 60 to 90 minutes offers similar advantages.51,52 In studying the interaction of pain and sleep, it is important to control for both napping and sleep continuity in assessing poor sleep quality in patients with chronic pain when daytime napping habits are unknown.47 To study the short-term effects on pain sensitivity and clinical pain reports, several studies (using relatively small samples) have disrupted or fragmented sleep, selectively abolished time spent in various sleep stages, curtailed total sleep time, or implemented total sleep deprivation procedures.53 Although the sleep manipulation methods were heterogeneous and the studies varied in the quality of the experimental design and the extent to which confounders were controlled, most reported that sleep loss and disruption produced significant hyperalgesia or induced spontaneous pain reports in healthy subjects. Earlier work suggested that SWS loss versus REM deprivation was differentially hyperalgesic,54,55 but those findings have not always been replicated.56 Data exist that show that thermal pain sensitivity is enhanced by both SWS deprivation and forced awakenings during REM sleep.56,57 Not enough studies have been done using the same sleep disruption techniques or pain testing modalities to clearly specify which type of sleep disruption, and what degree of it, causes which type of alterations in pain sensitivity. Future sleep deprivation studies need to account for the complex interactions between fatigue, cognitive function, Physiological dysregulation, and pain. The mechanisms by which sleep deprivation contributes to pain remain largely unknown; they are most likely multiple and determined by complex interacting factors. A study of 6 days of sleep restriction is associated with elevated neuroimmune markers, including proinflammatory cytokines, specifically interleukin (IL)-6, which are known to sensitize nociceptors.58 In another experiment, 3 nights of sleep continuity disturbance (multiple prolonged forced awakenings) impairs psychophysical measures of endogenous pain inhibition and increases spontaneous clinical pain reports in healthy young women.59 Descending pain inhibitory mechanisms are believed to be mediated in part by opioidergic and serotoninergic pathways in the brainstem, which are in turn regulated by multiple higher cortical structures including the anterior cingulate and regions of the frontal cortex (see Chapter 18). Aging, Pain Perception, and Dysfunctional Endogenous Analgesia With age, pain complaints increase and pain perception is altered but, paradoxically, older patients are reported to cope better with the consequences of chronic pain than middle-aged subjects.60,61 Pain sensitivity is lower and the pain threshold higher probably because of age-related changes in tissues (e.g., reduced thickness, changes in microcirculation). In addition, there is lower cerebral discrimination of sensory information (processing at spinal cord or cortical levels). Despite increases in pain threshold, older adults demonstrate impairments in higher-order pain modulatory capacity (diffuse noxious inhibitory controls [DNIC]).62 The DNIC system is an upper-brain function that reduces pain perception in the whole body
CHAPTER 126 • Pain and Sleep 1445
through the activation of neurochemicals (e.g., opioids) in distant body areas, in a nonselective distribution (i.e., a diffuse general reduction in pain threshold is found). As demonstrated by experimental manipulations, DNIC activation is apparently dysfunctional in patients with fibromyalgia.63 This is further supported by evidence that in the presence of generalized pain, such as in patients with fibromyalgia, an abnormal sensitization (e.g., generalized body pain) and abnormal temporal summation of pain are dominant.64 Recent evidence suggests that the DNIC system is dysfunctional in temporomandibular pain patients with poor sleep.65 Alpha Electroencephalogram Intrusions, Phasic Arousal, and Autonomic Activity Alpha EEG intrusions were found in several sleep studies of patients with fibromyalgia, but more recent controlled and quantitative scoring failed to support the notion that alpha EEG intrusions were pain or fibromyalgia specific.22,66,67 The current trend is to reassess such findings in the setting of mood alterations, psychiatric conditions (e.g., insecure attachment, hypervigilance), and sleep respiratory and movement events (e.g., apnea, PLM), and to reconcile them with the fact that patients with pain have arousals in clusters or in a sequence of phasic events, also termed the cyclic alternating pattern.4,20,68-70 Neurochemistry, HPA Axis, and Genetics in the Interaction between Pain and Sleep There is indirect evidence that pain modulatory systems may be altered in the context of chronic pain and poor sleep. Animal findings suggest that serotoninergic and nonserotoninergic brainstem neurons modify alertness in relation to the raphe magnus “off” cells, which prevent arousal in response to external sensory stimulations such as pain.36 Surprisingly, almost no evidence links the “alertness” or vigilance network (i.e., ascending reticular activating system) to changes in cholinergic, dopaminergic, gamma-aminobutyric acid, or adrenergic neuronal reticular and hypothalamic activity in relation to alterations in sleep homeostasis in the presence of chronic pain.37,71 Although hypothalamic orexinergic system—an important axis of vigilance—was suggested to be involved in pain and headache, the level of information in humans is rather low.72 More specifically, it is unknown whether hypocretin (orexin) gene activity and Clock gene expression are altered in the presence of chronic pain with secondary sleep alterations.73 Special interest has also been devoted to growth hormone because its release is associated with SWS. However, the evidence is limited that supports an alteration in serum levels of insulin-like growth factor (formerly called somatomedin C) in patients with fibromyalgia or other pain.74,75 There is evidence to suggest multiple interactions between pain and sleep in relationship to the arousal parameter hypothalamic-pituitary-adrenal axis (HPA) and the immune system. Prediction of new cases of chronic widespread musculoskeletal pain (OR-3) was possible with the dexamethasone cortisol suppression test and measures of evening and morning salivary cortisol.76 Insomnia, a frequent finding in pain patients,27 was also found to be
1446 PART II / Section 15 • Other Medical Disorders
associated with a rise in HPA, adrenocorticotropic hormone, cortisol secretion, and inflammatory cytokines IL-6 and tumor necrosis factor α.77 Deprivation of sleep in normal subjects also revealed a high correlation between insufficient sleep (4 instead of 8 hours) and pain rating, with a rise in IL-6.58 In the general population, nociception dysregulation is rarely hereditary and was reported to be modulated by genetic polymorphism such as opioid (Oprm gene), catecholamine-O-methyltransferase (COMT), interleukin-related genes (e.g., for IL-1), and others.14 Interestingly, COMT is associated with sleepiness in patients with Parkinson’s disease and narcolepsy.78,79 Some animal findings suggest that morphine dependence is linked to orexin gene expression.80 IL-1 gene expression was also found to interfere with circadian Clock genes in mice.81 Before concluding, however, that such findings can be extrapolated to explain the cause and effect of the circular relationship of pain and sleep, much more integrated research needs to be done.
CLINICAL FEATURES Most of the sleep-related variables described in Box 126-1 are not pain specific because they are also found with sleep disorders such as sleep apnea, PLM, and insomnia. Patients with pain commonly complain, during the day as well as at night, of unrefreshing sleep, fatigue, headache, sleepi-
Box 126-1 Some Sleep-Related Symptoms and Findings in the Presence of Pain* Bedtime Symptoms • Delay in sleep onset • Anxiety, rumination • Intense fatigue and more intense pain Sleep-Time Findings • Lower sleep efficacy (<90%) • Longer percentage sleep time in stage 1 or 2, with less in stages 3 and 4 • Numerous sleep stage shifts (stages 3 and 4 toward stages 2 or 1) • Fragmentation of sleep continuity (increase in number of microarousals, awakenings, sleep-stage shifts, respiratory events, movement intrusions) • Alpha electroencephalographic intrusions in stages 3 and 4 with or without elevated phasic arousals (cyclic alternating pattern) • Absence of reduction in heart rate variability in sleep (cardiac sympathetic overactivation)† • Nightmares, periodic leg movements, apnea, sweating, heart palpitations • Wakefulness during sleep time refer because of pain (e.g., neck, lower back, visceral, tooth) Wake-Time Symptoms • Sensation of unrefreshing sleep, fatigue, headache • Sleepiness while driving • Anxiety and anger over fulfilling daytime requirements at home or work *Most are not pain specific and/or based on low evidence. † Debated.
ness while driving, or anxiety with occasional anger at fulfilling home or work tasks. The reports of more intense pain during the day after a night with poor sleep or the sensation of unrefreshing sleep when the pain was intense during the day or night before are good indicators of a cyclical relationship between pain and sleep quality or efficacy (see Fig. 126-1). Estimating such variables in a clinical setting requires skill and time—for example, is the reported fatigue with the result of intense physical activity or of monotony due to lack of stimulation or motivation? The location of the pain, how long it lasts, and its impact on sleep and daytime function are all related issues.82 Reports of delayed sleep onset (more than 30 minutes) at bedtime often involve anxiety or rumination related to daytime stressful events, intense fatigue that prevents the behavioral relaxation or wind-down process, or persistence of intense pain—all key elements that help in the selection of sleep hygiene advice or choice of treatment (Table 126-1). Complaints of sudden awakenings with pain (e.g., neck, lower back, visceral, tooth) during sleep strongly indicate pain as an intruder. If the patient cannot resume sleep, the pain may be triggering secondary insomnia, and management should be planned accordingly.
DIAGNOSIS Clinical Evaluation When evaluating a patient complaining of both pain and a sleep problem, possible risk factors should be identified first. These include concomitant fatigue, anxiety, mood alteration, pain, alcohol or drug abuse, poor lifestyle, lack of physical activity, long delay in sleep onset or awakening during sleep time, snoring, and poor quality of the sleep environment.82,83 Pain intensity and related emotional feelings can be assessed by several self-report scales. In the investigation of the interaction between pain and sleep, patient diaries are valuable for identifying bad habits and customizing treatment for the patient. Whether completed on paper or hand-held computer, such diaries can highlight pain intensity and interference with sleep and napping, as well as the temporal pattern of sleep time and awakening. Each tool has limitations, and selection depends on the goal— whether evaluating, for example, clinical patients or research subjects, children or adults, or patients on psychoactive medication.22,84,85 For pain assessments, the most frequently used tools are the category scales (no pain, or mild, moderate, or severe pain), visual analogue scales (a 10-cm line, with “no pain” at one extreme and “most intense pain” at the other), and numeric scales (0 for no pain to 10 for maximal pain).84,85 In children, a set of face drawings (smile for no pain, up to tears and sad face for intense pain) is useful. For muscle and joint pain, manual palpation using the fingers or pressure devices can localize tender, pain-related spots. These well-known techniques correlate well with patient verbal pain reports. For assessing nerve damage or neuropathy, many modalities are used, including the brush, pin and needle, von Frey hairs of various sizes, and twopoint touch discrimination, as well as ice, heat, and vibration.86 Pain threshold (the subject detects a sensory stimulus
CHAPTER 126 • Pain and Sleep 1447
Table 126-1 Management Algorithm of Concomitant Pain and Sleep Problems* Step 1 Detection of a primary sleep disorder
Examples: insomnia, sleep-disordered breathing, primary snoring, periodic leg movements during sleep, headache or bruxism, daytime fatigue or sleepiness
Step 2 Sleep hygiene overview
Evaluation of • Sleep environment (e.g., dark, cool, and quiet bedroom) • Wake–sleep cycle (e.g., consistent bedtime and morning awakening) • Lifestyle habits (e.g., intense exercise, smoking, or alcohol at night) • Presence of nonsleeping infant, snoring or tooth-grinding sleep partner
Step 3 Behavioral–cognitive strategies and physical management
• Establish regular routines for evening relaxation, avoid “bringing work home” and intense or troubling evening discussions, develop a short nap schedule, if possible, during daytime (≤20 min) • Moist heat application (10 to 20 min) or ice massages (5 min) • Physical manipulations: massage-fascia therapy, physical therapy (osteopathy, chiropractic); transcutaneous electrical nerve stimulation (TENS)
Step 4 Medical/Surgical interventions†
Short term: • Analgesic either alone or combined with a muscle relaxant in the evening: • Ibuprofen, aspirin, or acetaminophen • Acetaminophen with chlorzoxazone • Methocarbamol with acetaminophen, aspirin, or ibuprofen Mild condition: A. Muscle relaxant/sedative (in evening to reduce morning dizziness): • Low-dose cyclobenzaprine ( 12 or full 10-mg tablet) • Clonazepam (lowest dose available, short term because of risk of dependence) ± analgesic such as acetaminophen, ibuprofen, or aspirin in the evening B. Sleep facilitator: • Benzodiazepine hypnotic (e.g., triazolam, temazepam) • Non-benzodiazepine hypnotic; zopiclone, eszopiclone, zolpidem, zaleplon; latter short acting thus useful in middle of night insomnia, ideal in sleep apnea • Low-dose gabapentin (low dose at bedtime) More severe/persistent cases (physician consult recommended): • Low-dose amitriptyline (lowest dose at first in increasing doses if required in the evening; daytime sedation frequent) or nortriptyline • Trazodone (PRN, low dose) • Nefazodone • Gabapentin, pregabalin, sodium oxybate, pramipexole, or duloxetine • Opiate analgesic: could cause poor sleep quality by reducing slow wave sleep and exacerbate breathing disorder • Anesthetic nerve block, surgery (e.g., ablation, resection) of tissues causing pain • Implantable devices that stimulate structures in brain, spine, peripheral nerves
Other products with unknown efficacy on comorbid pain and sleep conditions
Natural products such as valerian, lavender Glucosamine sulfate for osteoarthritis Muscle relaxants such as carisoprodol or tizanidine Plus: Antihistamines, local anesthetics (lidocaine patches), or topical agents (capsaicin)
*No recognized guidelines are available at this time. The evidence level is low (few blinded, prospective, large, controlled studies) for most treatments because of the paucity of specific pain and sleep studies. † For steps 3 and 4, combined strategies could be considered, but only on a case-by-case basis. Caution for step 4: Because of daytime sleepiness and dizziness with most of these medications, it is recommended that patients avoid driving (e.g., in the morning if residual sleepiness is present) and that they try to avoid use of any potentially hazardous tool or decision-making process. Some medications (e.g., gabapentin, pregalbalin, clonazepam) are popular in the clinic but have not been specifically approved by governing bodies or agencies for pain or sleep management. Modified from Brousseau M, Manzini C, Thie NMR, et al. Understanding and managing the interaction between sleep and pain: an update for the dentist. J Can Dent Assoc 2003;69:440-445.
as being painful 50% of the time) and tolerance (the maximal pain a subject can accept) assessments with electrical, thermal, chemical, or mechanical modalities are excellent research tools but are complicated to use and time consuming in a clinical sleep laboratory.39-43,82 Some of the most common outcome variables in pain and sleep investigations are reflex threshold and latency; changes in rate of sleep arousal and awakening as scored with EEG, electromyography, and electrocardiography; and morning subject reports of being aware of stimulus perception during sleep. Although brain imaging has revealed impor-
tant information regarding pain perception and modulation,38 it is not currently used in assessing clinical pain perception and it is methodologically difficult to perform during sleep. Several other questionnaires have been selected for specific assessments, including (1) for health and mood, the Beck Anxiety-Depression Inventory, the SF-36, the Symptom Checklist-90, the Sickness Impact Scale, and the Impact of Event Scale; (2) for pain, the McGill Pain Questionnaire and the Multidimensional Pain Inventory; and (3) for sleep, the Pittsburgh Sleep Quality Index and
1448 PART II / Section 15 • Other Medical Disorders
a dream inventory.7,21,30,82,87 Future directions include developing scales to assess daytime consequences of poor sleep in relation to pain. Few studies suggested that memory and attention are impaired in patients with chronic musculoskeletal pain and fibromyalgia.48,49 More studies are needed to clarify the cognitive changes associated with chronic pain and poor sleep, taking into consideration factors such as concomitant anxiety and mood dysfunction. Tests related to real-life working or driving performance may provide new information on the cognitive deficits related to the interaction of pain and sleep or secondary to the medication prescribed in the management of pain.15,50 Sleep Recordings Both ambulatory (actigraphy, polygraphy) and sleep laboratory (polygraphy) recordings are useful to assess patients’ circadian rhythm, sleep habits and quality, and physiologic disturbances as related to pain and sleep complaints.82,88 Although data collected with these ambulatory devices should be interpreted with caution, they are powerful population-based tools for longer-term study. The standard polygraphic techniques include EEG, electrocar diographic, electromyographic, and electrooculographic recordings plus video to rule out movement disorders (e.g., PLM during sleep), and respiratory sensors to rule out respiratory disorders (e.g., apnea). Dedicated software allows unbiased, rapid, and powerful quantitative (spectral) analysis of EEG and heart rate variability.89 In the absence of other sleep disorders, the most common sleep abnormalities found in patients with chronic pain are listed in Box 126-1. In more detail, these nonspecific findings are as follows: Lower sleep efficacy (below 90%): In a recent analysis done in our laboratory with healthy subjects matched to patients with a medical and sleep diagnosis of insomnia, PLM during sleep, or chronic widespread musculoskeletal pain (CWP), we noted that the patients with pain had a much lower sleep efficiency than insomniac patients.32 Similar findings are reported for patients with irritable bowel syndrome, fibromyalgia, rheumatoid arthritis, and back pain compared with subjects without pain.19,67 Longer percentage of sleep time in stage 1 or 2, and less in stages 3 and 4: The stage 1 sleep duration is reported to be shorter in patients with fibromyalgia and longer in patients with irritable bowel syndrome than in healthy subjects in some but not all studies. Differences in patient selection and concomitant psychobehavioral changes could account for these findings. Conflicting results for stage 3 and 4 sleep duration may also be seen.19,20,90 Numerous sleep stage shifts (stages 3 and 4 toward stages 2 or 1): Surprisingly, there are very few data on this sleep variable. In a comparative study with healthy subjects and patients with CWP and pain,32 we found no difference. However, there were significantly more shifts reported in patients with fibromyalgia.90 Fragmentation of sleep continuity assessed by an increase in the number of arousals, awakenings, respiratory disturbances, and movement intrusions: This seems to be a stronger group of variables because most studies show an increase in the arousal and awakening index or absolute number, but the lack of standard scoring criteria prevents us from drawing any firm conclusions. For the arousal index, depending on
the scoring criteria selected, an index below 15 events per hour of sleep in young adults and below 30 per hour in older persons is considered acceptable, although the impact of sleep fragmentation needs careful investigation because chronic long-term sleep disruption may alter several physiologic functions.47,91 The presence of respiratory disturbances (e.g., apnea syndrome) in patients with fibromyalgia does not entirely explain the poor sleep, but it remains to be seen whether brief episodes of hypopnea or apnea influence sleep fragmentation in the general pain population. The intrusion of body movement is also frequent in patients with fibromyalgia and rheumatoid arthritis,19 and although the association with PLM is not very clear, significantly more PLM in patients with CWP than in healthy subjects was reporterd (approximately three times more).32,67 Alpha EEG intrusions in stages 3 and 4 sleep, with or without elevated phasic arousal (cyclic alternating pattern): Alpha EEG intrusions were found in several sleep studies in patients with fibromyalgia, but more recent controlled and quantitative scoring failed to support such a strong association.22,67,83 The current trend is to reassess such findings with corrections for mood alterations and sleep respiratory and movement events (e.g., apnea, PLM) and to reconcile them with the fact that patients with pain experience arousals in clusters or in a sequence of phasic events (i.e., cyclic alternating pattern), as described previously (see Pathogenesis, earlier).4,20,68,69 Absence of reduction in heart rate variability in sleep, suggesting cardiac sympathetic overactivation during sleep: Finally, recent observations in patients with fibromyalgia suggest that sleep in these subjects lacked the usual reduction in heart rate variability.92 If these findings can be confirmed in patients with pain without mood alteration or respiratory or motor sleep disorders, it may support patient complaints of poor sleep due to sleep instability associated with maintenance of sympathetic activation and nonrestorative function. The significance of this variable in the interaction of pain and sleep deserves more study, as a high incidence of PLM during sleep in patients with CWP may explain some of the findings.32
TREATMENT/MANAGEMENT No consensus has been reached regarding guidelines or principles in managing the interaction of pain and sleep, as has been done for acute pain and cancer pain.93 Several suggestions have been made in a few reviews.22,94-96 To mitigate the deleterious effects of pain on sleep, most of the management is directed at alleviating nighttime complaints by reducing pain and the related anxiety. The prevention of sleep disturbances (e.g., reduction of noise to prevent excessive sleep fragmentation as indicated by the presence of arousals, awakenings, and stage shifts) may also be as effective as the treatment of nighttime pain for patients with chronic pain. In the absence of comprehensive studies to support one or the other management strategy, targeting either pain relief or sleep quality is appropriate. For most of these patients, the treatment is selected on a subjective basis without instrumental or objective measures of sleep. However, polysomnographic assessment of sleep structure is usually reserved for patients complaining of severe pain, of nighttime disturbances (e.g.,
movement, respiratory perturbation), and of daytime sleepiness or fatigue. As a management algorithm, we suggest the steps outlined in Table 126-1: (1) detection of the pain and sleep condition with differential diagnosis, (2) sleep hygiene instruction, (3) when possible, behavioral– cognitive strategies and physical management, and (4) medications for pain relief and sleep improvement.95 Consumption of analgesics is very frequent in pain patients.15 Prescribing pain medication to avoid daytime sleepiness and to preserve sleep continuity is complex. Although most nonsteroidal antiinflammatory drugs (NSAIDs) have little influence on sleep architecture,32 opioids may reduce the duration of SWS activity and increase the risk of breathing problems.95,97,98 Thus it may be preferable to prescribe opioids for early in the day,99 and for the evening to prescribe NSAIDs and other medication (e.g., trazodone, pregabalin) to preserve good sleep architecture. Patients with pain are prescribed hypnotics, anxiolytics, and antidepressive medications.16 Little is known about the carryover effects of analgesic, hypnotic, and antidepressive medications to daytime functioning (work performance, memory, risk of transportation or work accidents). Furthermore, the increased popularity of complementary medicine (herbal products and devices [e.g., brain stimulation]) should not be ignored; clinicians need to be aware of possible interactions.
CONCLUSION In the presence of poorly managed acute pain, the risk for the development of chronic pain is ever present. However, not every patient is at risk for persistent pain. In the presence of acute pain, most sleep complaints are rapidly reversible when the pain is resolved. Whether chronic pain will ensue depends on a number of factors. These include socioeconomic factors (e.g., secondary benefit, depression, anxiety) and genetic makeup, which might predispose to poor healing and subsequent changes at the sensory nerve or brain hemisphere level, so prompt pain management is beneficial. Emerging data from the burn injury literature suggests that insomnia during acute injury may be a risk factor for the development of chronic pain, independent of the effect of pain and degree of tissue damage. This finding suggests that aggressively treating insomnia during acute pain may have prophylactic benefit, but this hypothesis has yet to be tested.100 The long waiting lists in pain clinics and the lack of efficient medications for some chronic pain (e.g., widespread musculoskeletal or neuropathic pains), coupled with the complexity of the interaction between sleep and pain, all contribute to perpetuating the vicious cycle of pain and poor sleep. Chronic pain tends to interfere with sleep architecture and initiates the cycle of chronic pain, poor sleep, and low quality of life (see Fig. 126-1). The safety and efficacy of most pain and sleep management approaches is unknown. Because the problem of pain is so great, research continues to develop new medical and surgical therapies.100-108 PITFALLS AND CONTROVERSIES For clinicians, the most common pitfall is to focus exclusively on alpha EEG intrusions to explain the influence of
CHAPTER 126 • Pain and Sleep 1449
pain on sleep. Recent evidence suggests that alpha EEG intrusions are nonspecific to pain, and instead represent the sleep fragmentation process consisting of phasic and recurrent arousals during sleep, referred to as the cyclic alternating pattern.20,67-70,83 The influence of other physiologic activities needs to be further investigated in patients with chronic pain and complaints of poor sleep quality and insomnia, and more efficient management strategies need to be developed.32,82 Another pitfall is the potentially harmful influence of some analgesics (e.g., morphine) on sleep architecture (e.g., awakenings, reduction in SWS and REM sleep). This paradoxical effect needs further investigation. Moreover, the carryover of several medications, such as opioid analgesics and antidepressants, on next-day functioning needs to be estimated objectively in relation to cognitive function and vigilance, such as while driving or attending classes. Data also indicate that chronic use of opioids may exacerbate sleep apnea and can cause respiratory complications.97,98 In the absence of evidence-based algorithms or guides in the choice of medication, clinicians must select their management strategy on the basis of minimal risk of inducing adverse effects (e.g., sleep fragmentation or awakening of breathing disorders). ❖ Clinical Pearl In the management of poor sleep complaints associated with pain, the sleep medicine clinician should recognize the presence of concomitant sleep disorders and related causes (e.g., insomnia, sleep apnea, PLM). The influence of acute pain on sleep is usually brief and reversible. In patients reporting chronic pain, sleep can be disturbed to the point that comprehensive management is required, including review of sleep hygiene, cognitive and behavioral approaches, and use of analgesic and hypnotic medications or antidepressant drugs in more persistent cases.
Acknowledgments The sleep and pain studies done by the authors were made possible by the support of the Canadian Institutes of Health Research and the Fonds de Recherche en Santé du Québec for Gilles Lavigne, and from the NIH for Michael Smith. Gilles Lavigne is a Canada Research Chair in pain, sleep, and trauma. We thank Alice Peterson for editing, and Carmen Remo for manuscript preparation. Diana McMillan contributed to the previous edition of this chapter. REFERENCES 1. Merskey H, Bogduk N. Classification of chronic pain. 2nd ed. Seattle, Wash: IASP Press; 1994. 2. Smith MT, Edwards RR, Robinson RC, et al. Suicidal ideation, plans, and attempts in chronic pain patients: factors associated with increased risk. Pain 2004;111:201-208. 3. Julius D, Basbaum AI. Molecular mechanisms of nociception. Nature 2001;413:203-210. 3a. Tracey I, Mantyh PW. The cerebral signature for pain perception and its modulation. Neuron 2007;55:377-391. 4. Moldofsky H. Sleep and pain: clinical review. Sleep Med Rev 2001;5:387-398.
1450 PART II / Section 15 • Other Medical Disorders 5. Liszka-Hackzell JJ, Martin DP. Analysis of nighttime activity and daytime pain in patients with chronic back pain using a self-organizing map neural network. J Clin Monit Comput 2005; 19:411-414. 6. Morin CM, Gibson D, Wade J. Self-reported sleep and mood disturbance in chronic pain patients. Clin J Pain 1998;14:311-314. 7. Riley JL 3rd, Benson MB, Gremillion HA, et al. Sleep disturbances in orofacial pain patients: pain-related or emotional distress? J Craniomandib Pract 2001;19:106-113. 8. Affleck G, Urrows S, Tennen H, et al. Sequential daily relations of sleep, pain intensity, and attention to pain among women with fibromyalgia. Pain 1996;68:363-368. 9. Raymond I, Nielsen TA, Lavigne G, et al. Quality of sleep and its daily relationship to pain intensity in hospitalized adult burn patients. Pain 2001;92:381-388. 10. Nicassio PM, Moxham EG, Schuman CE, et al. The contribution of pain, reported sleep quality, and depressive symptoms to fatigue in fibromyalgia. Pain 2002;100:271-279. 11. Edwards RR, Almeida DM, Klick B, et al. Duration of sleep contributes to next-day pain report in the general population. Pain 2008;137:202-207. 12. Woolf CJ, Salter MW. Neuronal plasticity: increasing the gain in pain. Science 2000;288:1765-1768. 13. Scholz J, Woolf CJ. The neuropathic pain triad: neurons, immune cells and glia. Nat Neurosci 2007;10:1361-1368. 14. Lötsch J, Geisslinger G. Current evidence for a modulation of nociception by human genetic polymorphisms. Pain 2007;132:18-22. 15. Lavigne GJ, Manzini C. Pain and poor sleep their impact on public health. In: Léger D, Pandi-Perumal SR, editors. United Kingdom: Informa Healthcare; 2007. p. 193-208. 16. Alattar M, Harrington JJ, Mitchell CM, et al. Sleep problems in primary care: a north Carolina Family Practice Research Network (NC-FP-RN) Study. J Am Board Fam Med 2007;20:365-374. 17. Bonnet MH, Arand DL. Hyperarousal and insomnia: state of the science. Sleep Med Rev 2010;14:9-15. 18. Boulanger A, Clark AJ, Squire P, et al. Chronic pain in Canada: have we improved our management of chronic noncancer pain? Pain Res Manag 2007;12:39-47. 19. Atkinson JH, Ancoli-lsrael S, Slater MA, et al. Subjective sleep disturbance in chronic back pain. Clin J Pain, 1988;4:225-232. 20. Roizenblatt S, Moldofsky H, Benedito-Silva AA, et al. Alpha sleep characteristics in fibromyalgia. Arthritis Rheum 2001;44:222-230. 21. McCracken LM, Iverson GL. Disrupted sleep patterns and daily functioning in patients with chronic pain. Pain Res Manage 2002;7:75-79. 22. Menefee LA, Cohen MJ, Anderson WR, et al. Sleep disturbance and nonmalignant chronic pain: a comprehensive review of the literature. Pain Med 2000;1:156-172. 23. Widerstrom-Noga EG, Felipe-Cuervo E, Yezierski RP. Chronic Pain after spinal injury: interference with sleep and daily activities. Arch Phys Med Rehabil 2001;82:1571-1577. 24. Rains JC, Penzien DB. Chronic headache and sleep disturbance. Curr Pain Headache Rep 2002;6:498-504. 25. Koopman C, Nouriani B, Erickson V, et al. Sleep disturbances in women with metastatic breast cancer. Breast J 2002;8:362-370. 26. Chaput G, Giguère JF, Chauny JM, et al. Relationship among subjective sleep complaints, headaches, and mood alterations following a mild traumatic brain injury. Sleep Med 2008;10:713-716. 27. Tang NK, Wright KJ, Salkovskis PM. Prevalence and correlates of clinical insomnia co-occurring with chronic back pain. J Sleep Res 2007;16:85-95. 28. Ward TM, Brandt P, Archbold K, et al. Polysomnography and self-reported sleep, pain, fatigue, and anxiety in children with active and inactive juvenile rheumatoid arthritis. J Pediatr Psychol 2008; 33:232-241. 29. Zautra AJ, Fasman R, Parish BP, et al. Daily fatigue in women with osteoarthritis, rheumatoid arthritis, and fibromyalgia. Pain 2007; 128:128-135. 30. Schubert CR, Cruickshanks KJ, Dalton DS, et al. Prevalence of sleep problems and quality of life in an older population. Sleep 2002;25:889-893. 31. Scudds R, Ostbye T. Pain and Pain-related interference with function in older Canadians: the Canadian study of health and aging. Disabil Rehabil 2001;15:654-664. 32. Okura K, Lavigne GJ, Huynh N, et al. Comparison of sleep variables between chronic widespread musculoskeletal pain, insomnia,
periodic leg movements syndrome and control subjects in a clinical sleep medicine practice. Sleep Med 2008;9:352-361. 33. Gold AR, Dipalo F, Gold MS, et al. The symptoms and signs of upper airway resistance syndrome: a link to the functional somatic syndromes. Chest 2003;123:87-95. 34. Wahner-Roedler DL, Olson EJ, Narayanan S, et al. Gender specific differences in a patient population with obstructive sleep apneahypopnea syndrome. Gend Med 2007;4:329-338. 35. Soja PJ. Modulation of prethalamic sensory inflow during sleep versus wakefulness. In: Lavigne GS, Sessle BJ, Choinière M, Soja PJ, editors. Sleep and pain. Seattle: IASP Press; 2007. p. 45-76. 36. Foo H, Mason P. Brainstem modulation of pain during sleep and waking. Sleep Med Rev 2003;7:145-154. 37. Kshatri AM, Baghdoyan HA, Lydic R. Cholinomimetics, but not morphine, increase antinociceptive behavior from pontine reticular regions regulating rapid-eye-movement sleep. Sleep 1998;21: 677-685. 38. Nofzinger EA, Derbyshire SWG. Pain imaging in relation to sleep. In: Lavigne GS, Sessle BJ, Choinière M, Soja PJ, editors. Sleep and pain. Seattle: IASP Press; 2007. p. 153-173. 39. Sandrini G, Milanov I, Rossi B, et al. Effects of sleep on spinal nociceptive reflexes in humans. Sleep 2001;24:13-17. 40. Bastuji H, Perchet C, Legrain V, et al. Laser evoked responses to painful stimulation persist during sleep and predict subsequent arousals. Pain 2008;137:589-599. 41. Lavigne G, Zucconi M, Castronovo C, et al. Sleep arousal response to experimental thermal stimulation during sleep in human subjects free of pain and sleep problems. Pain 2000;84:283-290. 42. Drewes AM, Nielsen KD, Arendt-Nielsen L, et al. The effect of cutaneous and deep pain on the electroencephalogram during sleep: an experimental study. Sleep 1997;20:623-640. 43. Lavigne G, Brousseau M, Kato T, et al. Experimental pain perception remains equally active over all sleep stages. Pain 2004; 110:646-655. 44. Bentley AJ. Pain perception during sleep and circadian influences: The experimental evidence. In: Lavigne GS, Sessle BJ, Choinière M, Soja PJ, editors. Sleep and pain. Seattle: IASP Press; 2007. p. 123-136. 45. Lobbezoo F, Thu Thon M, Rémillard G, et al. Relationship between sleep, neck muscle activity, and pain in cervical dystonia. Can J Neurol Sci 1996;23:285-290. 46. Bruni O, Russo PM, Ferri R, et al. Relationships between headache and sleep in a non-clinical population of children and adolescents. Sleep Med 2008;9:542-548. 47. Bonnet MH, Arand DL. Clinical effects of sleep fragmentation versus sleep deprivation. Sleep Med Rev 2003;7:297-310. 48. Kewman DG, Vaishampayan N, Zald D, et al. Cognitive impairment in musculoskeletal pain patients. Int J Psychiat Med 1991; 21:253-262. 49. Côté KA, Moldofsky H. Sleep, daytime symptoms, and cognitive performance in patients with fibromyalgia. J Rheumatol 1997;24: 2014-2023. 50. George CFP. Driving simulators in clinical practice. Sleep Med Rev 2003;7:311-320. 51. Stickgold R, James L, Hobson JA. Visual discrimination learning requires sleep after training. Nat Neurosci 2000;3:1237-1238. 52. Mednick S, Nakayama K, Stickgold R. Sleep dependent learning: a nap is as good as a night. Nat Neurosci 2003;6:697-698. 53. Kundermann B, Lautenbacher S. Effects of impaired sleep quality and sleep deprivation on diurnal pain perception. In: Lavigne GS, Sessle BJ, Choinière M, Soja PJ, editors. Sleep and pain. Seattle: IASP Press; 2007. p. 137-152. 54. Moldofsky H, Scarisbrick P, England R, et al. Musculoskeletal symptoms and non-REM sleep disturbance in patients with “fibrosis syndrome” and healthy subjects. Psychosom Med 1975;37: 341-351. 55. Lentz MJ, Landis CA, Rothermel J, et al. Effects of selective slow wave sleep disruption on musculoskeletal pain and fatigue in middle aged women. J Rheumatol 1999;26(7):1586-1592. 56. Onen SH, Alloui A, Gross A, et al. The effects of total sleep deprivation, selective sleep interruption and sleep recovery on pain tolerance thresholds in healthy subjects. J Sleep Res 2001;10:35-42. 57. Roehrs T, Hyde M, Blaisdell B, et al. Sleep loss and REM sleep loss are hyperalgesic. Sleep 2006;29:145-151. 58. Haack M, Sanchez E, Mullington JM. Elevated inflammatory markers in response to prolonged sleep restriction are associated
CHAPTER 126 • Pain and Sleep 1451 with increased pain experience in healthy volunteers. Sleep 2007; 30:1145-1152. 59. Smith MT, Edwards RR, McCann UD, et al. The effects of sleep deprivation on pain inhibition and spontaneous pain in women. Sleep 2007;30:494-505. 60. Kaasalainen S, Molloy W. Pain and aging. Geriatrics Today: J Can Geriatr Soc 2001;4:32-37. 61. Riley JL, Wade JB, Robinson ME, et al. The stages of pain processing across the adult lifespan. J Pain 2000;1:162-170. 62. Edwards RR, Fillingim RB. Effects of age on temporal summation and habituation of thermal pain: clinical relevance in healthy older and younger adults. J Pain 2001;2:307-317. 63. Lautenbacher S, Rollman GB. Possible deficiencies of pain modulation in fibromyalgia. Clin J Pain 1997;13:189-196. 64. Staud R, Vierck CJ, Cannon RL, et al. Abnormal sensitization and temporal summation of second pain (wind-up) in patients with fibromyalgia syndrome. Pain 2001;91:165-175. 65. Edwards RR, Grace E, Peterson S, et al. Sleep continuity and architecture: associations with pain-inhibitory process in patients with temporomandibular joint disorder. Eur J Pain 2009;13:10421047. 66. Mahowald ML, Mahowald MW. Nighttime sleep and daytime functioning (sleepiness and fatigue) in less well-defined chronic rheumatic diseases with particular reference to the “alpha-delta NREM sleep anomaly.” Sleep Med 2000;1:195-207. 67. Rains JC, Penzien DB. Sleep and chronic pain challenges to the a-EEG sleep pattern as a pain specific sleep anormaly. J Psychosom Res 2003;54:77-83. 68. Staedt J, Windt H, Hajak G, et al. Cluster arousal analysis in chronic pain-disturbed sleep. J Sleep Res 1993;2:134-137. 69. Rizzi M, Sarzi-Puttini P, Atzeni F, et al. Cyclic alternating pattern: a new marker of sleep alteration in patients with fibromyalgia? J Rheumatol 2004;31:1193-1199. 70. Parrino L, Zucconi M, Terzano GM. Sleep fragmentation and arousal in the pain patient. In: Lavigne GS, Sessle BJ, Choinière M, Soja PJ, editors. Sleep and pain. Seattle: IASP Press; 2007. p. 213-234. 71. Mignot E, Taheri S, Nishino S. Sleeping with the hypothalamus: emerging therapeutic targets for sleep disorders. Nat Neurosci 2002;5(Suppl.):1071-1075. 72. Holland P, Goadsby PJ. The hypothalamic orexinergic system: pain and primary headaches. Headache 2007;47:951-962. 73. Taheri S, Mignot E. The genetics of sleep disorders. Lancet Neurol 2002;1:242-250. 74. Gronfier C, Luthringer R, Follenius M, et al. A quantitative evaluation of the relationships between growth hormone secretion and delta wave electroencephalographic activity during normal sleep and after enrichment in delta waves. Sleep 1996;19:817-824. 75. Van Cauter E, Leproult R, Plat L. Age-related changes in slow wave sleep and REM sleep and relationship with growth hormone and cortisol levels in healthy men. JAMA 2000;287:861-868. 76. McBeth J, Silman AJ, Gupta A, et al. Moderation of psychosocial risk factors through dysfunction on the hypothalamic-pituitaryadrenal stress axis in the onset of chronic widespread musculoskeletal pain: findings of a population-based prospective cohort study. Arthritis Rheum 2007;56(1):360-371. 77. Vgontzas AN, Chrousos GP. Sleep, the hypothalamic-pituitaryadrenal axis, and cytokines: multiple interactions and disturbances in sleep disorders. Endocrinol Metab Clin North Am 2002;31:15-36. 78. Dauvilliers Y, Neidhart E, Lecendreux M, et al. MAO-A and COMT polymorphism and gene effects in narcolepsy. Mol Psychiatry 2001;6:367-372. 79. Rissling I, Frauscher B, Kronenberg F, et al. Daytime sleepiness and the COMT val158met polymorphism in patients with Parkinson disease. Sleep 2006;29:108-111. 80. Georgescu D, Zachariou V, Barrot M, et al. Involvement of the lateral hypothalamic peptide orexin in morphine dependence and withdrawal. J Neurosci 2003;23:3106-3111. 81. Cavadini G, Petrzilka S, Kohler P, et al. TNF-alpha suppresses the expression of clock genes by interfering with E-box-mediated transcription. Proc Natl Acad Sci U S A 2007;104:12843-12848. 82. Lavigne GJ, Khoury S, Laverdure-DuPont D, et al. Tools and methodological issues in the investigation of sleep and pain interactions. In: Lavigne GS, Sessle BJ, Choinière M, Soja PJ, editors. Sleep and pain. Seattle: IASP Press; 2007. p. 235-266. 83. Dauvilliers Y, Carlander B. Sleep and pain interactions in medical disorders: the examples of fibromyalgia and headache. In: Lavigne
GS, Sessle BJ, Choinière M, Soja PJ, editors. Sleep and pain. Seattle: IASP Press; 2007. p. 285-309. 84. Turk DC, Melzack R. Handbook of pain assessment. 2nd ed. 2001, New York: Guilford Press; 2001. 85. McDowell I, Newell C. Measuring health: a guide to rating scales and questionnaires, vol. 8. 2nd ed. New York: Oxford University Press, 1996. 86. Rolke R, Baron R, Maier C, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain 2006;123:231-243. 87. Raymond I, Nielsen TA, Lavigne G, et al. Incorporation of pain in dreams of hospitalized burn victims. Sleep 2002;25:765-770. 88. Smith MT, Buenaver LF. Electroencephalographic correlates of pain and sleep. In: Lavigne GS, Sessle BJ, Choinière M, Soja PJ, editors. Sleep and pain. Seattle: IASP Press; 2007. p. 189-212. 89. Carette S, Oakson G, Guimont C, et al. Sleep electroencephalography and the clinical response to amitriptyline in patients with fibromyalgia. Arthritis Rheum 1995;38:1211-1217. 90. Burns JW, Crofford LJ, Chervin RD. Sleep stage dynamics in fibromyalgia patients and controls. Sleep Med 2008;9(6):689-696. 91. Boselli M, Parrino L, Smerieri A, Terzano MG. Effect of age on EEG arousals in normal sleep. Sleep 1998;21:351-357. 92. Martínez-Lavín M, Hermosillo AG, Rosas M, et al. Circadian studies of autonomic nervous balance in patients with fibromyalgia: a heart rate variability analysis. Arthritis Rheum 1998;41:1966-1971. 93. Miaskowski C, Cleary J, Burney R, et al. Guideline for the management of cancer pain in adults and children. Glenview, Ill: American Pain Society; 2005. p. 166. 94. Cohen MJ, Menefee LA, Doghramji K, et al. Sleep in chronic pain: problems and treatments. Int Rev Psychiat 2000;12:115-126. 95. Beaulieu P, Walczak JS. Pharmacological management of sleep and pain interactions. In: Lavigne GS, Sessle BJ, Choinière M, Soja PJ, editors. Sleep and pain. Seattle: IASP Press; 2007. p. 390-415. 96. Dworkin RH, O’Connor AB, Backonja M, et al. Pharmacologic management of neuropathic pain: evidence-based recommendations. Pain 2007;132:237-251. 97. Walker JM, Farney RJ, Rhondeau SM, et al. Chronic opioid use is a risk factor for the development of central sleep apnea and ataxic breathing. J Clin Sleep Med 2007;3:455-461. 98. Webster LR, Choi Y, Desai H, et al. Sleep-disordered breathing and chronic opioid therapy. Pain Med 2008;9:425-432. 99. Rosenthal M, Moore P, Groves E, et al. Sleep improves when patients with chronic OA pain are managed with morning dosing of once a day extended-release morphine sulfate (AVINZA): findings from a pilot study. J Opioid Manag 2007;3:145-154. 100. Smith MT, Klick B, Kozachik S, et al. Sleep onset insomnia symptoms during hospitalization for major burn injury predict chronic pain. Pain 2008;138:497-506. 101. Moldofsky H, Inhaber NH, Guinta DR, Alvarez-Horine SB. Effects of sodium oxybate on sleep physiology and sleep/wake-related symptoms in patients with fibromyalgia syndrome: a double-blind, randomized, placebo-controlled study. J Rheumatol 2010 Aug 3. [Epub ahead of print] 102. Russell IJ, Perkins AT, Michalek JE; Oxybate SXB-26 Fibromyalgia Syndrome Study Group. Sodium oxybate relieves pain and improves function in fibromyalgia syndrome: a randomized, double-blind, placebo-controlled, multicenter clinical trial. Arthritis Rheum 2009;60:299-309. 103. Wolter T, Knoeller S, Berlis A, Hader C. CT-guided cervical selective nerve root block with a dorsal approach. Am J Neuroradiol 2010 Aug 26. [Epub ahead of print] 104. Barbarisi M, Pace MC, Passavanti MB, et al. Pregabalin and transcutaneous electrical nerve stimulation for postherpetic neuralgia treatment. Clin J Pain 2010;26:567-572. 105. Paemeleire K, Van Buyten JP, Van Buynder M, et al. Phenotype of patients responsive to occipital nerve stimulation for refractory head pain. Cephalalgia 2010;30:662-673. 106. Van Calenbergh F, Gybels J, Van Laere K, et al. Long term clinical outcome of peripheral nerve stimulation in patients with chronic peripheral neuropathic pain. Surg Neurol 2009;72:330-335. 107. Zaghi S, Heine N, Fregni F. Brain stimulation for the treatment of pain: a review of costs, clinical effects, and mechanisms of treatment for three different central neuromodulatory approaches. J Pain Manag 2009;2:339-352. 108. Leone M, Franzini A, Proietti Cecchini A, et al. Deep brain stimulation in trigeminal autonomic cephalalgias. Neurotherapeutics 2010;7:220-228.
Gastrointestinal Disorders William C. Orr
Abstract Alterations in physiologic functioning have been shown to be critically important in the development of a variety of disease states, particularly those related to respiratory disorders such as sleep apnea. It is becoming increasingly clear that alterations in gastrointestinal functioning during sleep also play an important role in the pathophysiology of various gastrointestinal disorders. Alterations in gastrointestinal functioning during sleep often manifest as symptoms—most notably the epigastric pain from duodenal ulcer disease that awakens patients from sleep. Sleep disturbance has also been described as a common occurrence in patients with gastroesophageal reflux disease (GERD) and irritable bowel syndrome (IBS). Although Helicobacter pylori has been shown to be important in the pathogenesis of duodenal ulcer disease, suppression of nocturnal acid secretion remains an important element in
This chapter reviews how sleep alters the manifestation or pathogenesis of gastrointestinal and related disorders. It focuses on adults, and only research that has appeared in peer-reviewed journals is included, unless a specific abstract is mentioned to focus on a particularly interesting or promising area of work.
NOCTURNAL GASTROINTESTINAL SYMPTOMS Among the gastrointestinal symptoms that occur during sleep, perhaps the best example is the epigastric pain that characteristically awakens the patient in the early morning hours. This pattern, which is quite predictable by the patient, can help establish a diagnosis of duodenal ulcer disease. Patients may also have awakenings from sleep with symptoms that are not ostensibly related to gastrointestinal disorders. For example, individuals may complain of sleep disruption caused by chest pain, heartburn, or regurgitation into the throat. Asthmatic patients may be awakened from sleep by the exacerbation of bronchial asthma secondary to gastroesophageal reflux (GER). Respiratory symptoms secondary to GER are common and are often noted secondary to sleep-related GER.1 Other disconcerting symptoms that may occur during sleep include nocturnal diarrhea, fecal incontinence, and chest pain. Although a denial of symptoms thought to be related to gastrointestinal problems such as GER does not necessarily preclude the occurrence of the sleep-related abnormalities, a positive symptom history enhances the probability of the existence of a nocturnal gastrointestinal disorder, as may be the case in patients with functional bowel disorders such as irritable bowel syndrome (IBS) or functional dyspepsia. 1452
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127
healing duodenal ulcers. Alterations in typical responses to contact between acid and mucosa during sleep have also been shown to be important in the development of the esophageal and extraesophageal complications of acid reflux disease. In addition, the patterns of esophageal acid contact during waking and sleeping are quite different and contribute to the development of these complications. Sleep is associated with fewer episodes of acid reflux but with a much more prolonged interval of esophageal acid contact. Suppression of nocturnal acid secretion therefore remains a mainstay in the treatment of GERD. Sleep-related acid reflux also appears to be related to the various respiratory complications of GERD. Although our understanding of the relationship between sleep and altered intestinal motility is evolving, it appears that patients with IBS do manifest alterations in intestinal motility and visceral perception, and these may be related to alterations in autonomic functioning during sleep.
NOCTURNAL ACID SECRETION IN DUODENAL ULCER DISEASE Patients with duodenal ulcer disease maintain a circadian pattern of gastric acid secretion, and the levels of secretion are enhanced.2 Peak acid secretion occurs at approximately midnight, with minimal acid secretion occurring during the day in the absence of food ingestion. There does not appear to be a relationship between sleep stage and gastric acid secretion (see Chapter 27). However, patients with duodenal ulcer disease demonstrate a failure to inhibit acid secretion during the first 2 hours of sleep.3 Bedtime administration of histamine type 2 (H2) receptor antagonists have documented that duodenal ulcers can be healed by suppression of nocturnal acid. It has been shown that duodenal ulcer healing rates were at least as good with a once-a-day, bedtime dose of these potent acid-suppressing compounds as with the more conventional multiple times a day dosing regimens.4 Data on nocturnal dosing of H2 receptor antagonists in more than 12,000 patients with duodenal ulcer disease show that nocturnal dosing has an advantage over multiple daily doses.4 Taken together, these data strongly support the notion that nocturnal acid suppression alone is sufficient to heal a duodenal ulcer. Other studies in patients with refractory duodenal ulcer suggest that nocturnal acid suppression is not only sufficient but necessary for duodenal ulcer healing. Reduction in nocturnal acid secretion through parietal cell vagotomy produced an enhanced healing rate in patients who were unresponsive to conventional cimetidine treatment.5 When treated with conventional H2 blockers, only patients with a substantial suppression of nocturnal acid secretion demonstrated ulcer healing, whereas patients whose ulcer again failed to heal maintained a nocturnal peak in gastric acid secretion.6 Further support for the important role of
GASTROESOPHAGEAL REFLUX DURING SLEEP Gastroesophageal reflux, particularly with its familiar symptom of heartburn, is recognized as a common phenomenon. Most healthy people experience occasional bouts of heartburn, and about 7% of otherwise healthy people experience heartburn nearly every day. Furthermore, the majority of patients with frequent heartburn complain of nighttime GER symptoms, and a substantial proportion (more than 50%) of these patients report that their symptoms disrupt sleep and affect daytime functioning.8,9,9a Many patients who present to a physician with a complaint of heartburn can be readily treated with simple alterations in lifestyle, such as the avoidance of certain provocative foods and the use of antacid therapy, although the data that specifically address these measures in the treatment of sleep-related symptoms are limited.10 The familiarity of this symptom and its rapid response, in most instances, to relatively simple therapeutic measures belie the severity and potential complications of this disease process. Complications of GER appear to be the result of recurrent episodes of sleep-related GER. GER events do occur during sleep, most commonly during brief arousals from sleep.11,12 Reflux events occur much more frequently in patients with diagnosed gastroesophageal reflux disease (GERD), and relatively infrequently in healthy volunteers. Most reflux events occur in stage 2 sleep and in association with polygraphically determined waking after sleep onset (Fig. 127-1). The different patterns of GER associated with waking and sleeping were documented in studies involving 24-hour monitoring of the distal esophageal pH.13 The GER was identified as occurring when the pH fell below 4 for a period of more than 30 seconds, and the termination of the reflux episode was arbitrarily to occur when the pH returned to 4. There are two patterns of reflux. Reflux in the upright position (primarily in daytime) occurs most often postprandially and usually consists of two or three reflux episodes that are rapidly cleared (2 to 3 minutes) (Fig. 127-2). Reflux in the supine or recumbent position (primarily during sleep) is usually associated with sleep and with a more prolonged clearance time (Fig. 127-3). It has been shown that highly significant increases in the
% Reflux events
100 80 60 40 20 0 WASO
Stage 1
Stage 2
SWS
REM
Figure 127-1 Gastroesophageal reflux (GER) noted during sleep stages. (From Penzel T, Becker HR, Brandenburg U, et al. Arousal in patients with gastro-esophageal reflux and sleep apnea. Eur Respir J 1999;14:1266-1270.)
NORMAL POSTPRANDIAL REFLUX (in normal volunteer) 8 6 pH
Therapeutic Considerations The observation that suppression of nocturnal gastric acid secretion is an important element in ulcer pathogenesis and healing does not imply that the numerous other factors implicated in the pathogenesis of duodenal ulcer disease (such as Helicobacter pylori) are not equally important; it simply strongly affirms that nocturnal acid secretion appears to be an important element in ulcer formation. The pathogenesis of duodenal ulcer disease is complex, but ulcer healing will not occur, or will be severely retarded, without effective nocturnal acid suppression.
GER DURING SLEEP
4 2
Meal 0 16:00
Heartburn 17:00
18:00
19:00
Time (PM) Figure 127-2 Pattern of gastroesophageal reflux noted in the upright position during waking. Reflux events are identified when the esophageal pH drops below 4.0.
SLEEP REFLUX SUPINE SLEEP CONDITION 8 6 pH
nocturnal acid secretion in the pathogenesis of duodenal ulcer disease comes from data showing that the maintenance of a modest degree of nocturnal acid suppression effectively prevents the recurrence of duodenal ulcer disease.7
CHAPTER 127 • Gastrointestinal Disorders 1453
4 2 0 0:20
0:40
1:00
1:20
1:40
Figure 127-3 Pattern of gastroesophageal reflux noted during sleep. Reflux is identified when the esophageal pH drops below 4.0.
time of contact between acid and mucosa in patients with esophagitis, and these differences were most impressive when the person was in the recumbent position or asleep (i.e., there was a greater difference between patients and control subjects in the recumbent position as opposed to the upright position).14 Even though acid–mucosa contact time may be equivalent in the upright and recumbent positions, the prolonged acid clearance times associated with sleep appeared to result in greater damage to the
1454 PART II / Section 15 • Other Medical Disorders
Mean percent total time pH < 4
esophageal mucosa.14 The patterns of GER, as determined by 24-hour esophageal pH monitoring, and the endoscopic evaluation of the esophageal mucosa appear to be correlated. Regardless of whether the patient had reflux primarily when upright (waking), primarily when supine (sleep), or at both times equally (e.g., when reflux was evident throughout the 24-hour day), the greater the nocturnal acid exposure, the greater was the severity of esophageal mucosal damage. Additional studies15,16 compared the results of 24-hour esophageal pH monitoring in patients who had either normal findings on endoscopy or erosive esophagitis. The results showed that total acid exposure time and the number of reflux episodes requiring longer than 5 minutes to clear (i.e., to return to pH 4) could be reliably used to discriminate between these two groups of patients. Furthermore, 50% of the patients with reflux symptoms had normal results on 24-hour pH monitoring, and 29% of the patients with erosive esophagitis also had normal pH studies. The most effective variable in distinguishing the two groups of patients was the number of episodes requiring longer than 5 minutes to return to pH 4. These findings have been extended using 24-hour pH monitoring in a group of symptomatic patients with heartburn and normal endoscopic results and a group of patients with severe complications of GER, including erosive esophagitis, stricture, and Barrett’s esophagus.16 The results also showed that the best discriminator between the two groups is the number of episodes of prolonged acid clearance (longer than 5 minutes) in the supine position. These episodes appear to be more likely to occur during sleep, confirming the notion that prolonged acid clearance is an important determinant in the development of esophagitis. State of consciousness, rather than body position, appears to be more important for reflux events.17 The percentage of contact with acid and the number of reflux events were not significantly different between upright and recumbent positions during wakefulness, but both were significantly greater than during the subjectively identified sleeping interval (Fig. 127-4). Reflux events seem to be predomi-
* 12.8
14 12 10
*P < .0001 n = 64
* 8.5
8
* 4.3
6 4 2 0 Upright
Supine-awake
Supine-asleep
Figure 127-4 Esophageal acid contact in the upright, recumbent awake, and recumbent during the sleeping interval noted during 24-hour pH monitoring. (From Dickman R, Shapiro I, Malagon B, et al. Assessment of 24-h oesphageal pH monitoring should be divided to awake and asleep rather than upright and supine time periods. Neurogastroenterol Motil 2007;19:709715.)
nant in the earlier part of the sleeping interval, raising speculation that this may be related to the proximity to the last meal, as food ingestion is a known stimulus for GER. However, the first half of the sleep interval is dominated by slow-wave sleep, and the last half by rapid eye movement (REM) sleep. The effect of these different sleep stages on the occurrence of GER has not yet been elucidated. Sleep disorders are a common occurrence in patients with GERD.18,19 Several studies have elucidated the relationship between sleep, as measured via polysomnography (PSG), sleep-related GER with nighttime heartburn, and sleep disorders. In two studies,18,19 acid suppression in patients with GERD gave similar positive results with regard to improvement in sleep, whether or not there were preexisting sleep complaints. In one study, patients with GERD were studied during sleep via PSG and simultaneous monitoring of esophageal pH before and after treatment with powerful acid suppression via a proton pump inhibitor (PPI) drug.18 Subjective sleep assessments of sleep quality were improved, but the objective PSG measures were not significantly altered. In a similar study, reflux-related sleep arousals and awakenings were significantly reduced with PPI treatment.19 In a select group of patients who demonstrated sleep disturbance on placebo treatment, sleep efficiency was significantly improved with PPI treatment. Nighttime acid exposure was shown to be related to a worse perception of sleep quality, and patients with poorer sleep quality had long reflux events. Similarly, it has been shown that patients with GERD who had nighttime heartburn had elevated acid exposure via 24-hour pH monitoring.19 Another interesting aspect of the relationship between sleep and GERD is the finding that sleep deprivation decreases the threshold for esophageal acid perception in patients with GERD.20 The presence of GERD has been shown to be to be nearly 13% in an unselected group of patients with sleep disorders of unknown etiology.21 The patients identified with GERD also had significantly higher scores on the Epworth Sleepiness Scale than those without GERD. In addition, patients with unrefreshing sleep and no complaints of heartburn had significantly greater acid contact than a group of normal controls without sleep complaints.21 Among both patients and controls, about 25% had a reflux event on at least one of two study nights, but the group with unrefreshed sleep showed a marked elevation in acid contact time, suggesting that sleep-related GER may be much more common than previously thought and may exist in the absence of heartburn complaints.
ESOPHAGEAL ACID CLEARANCE DURING SLEEP Acid clearance during sleep seems to be an important contributing factor in the development of reflux esophagitis. The process of acid clearance takes place in two phases: an initial phase, termed volume clearance, and a second phase, termed acid neutralization. The vast majority of the volume of refluxed material is cleared from the esophagus quite rapidly by the first two or three swallows. A coating of acid remains on the esophageal mucosa, however, that keeps
the esophageal pH well below 4. Subsequent swallows deliver saliva, with its buffering capacity, to the distal esophagus, and the distal esophageal pH returns to its normal level (5.5 to 6.5). When salivation is inhibited by anticholinergic drugs, acid clearance is reduced. Both swallowing frequency and salivation have been shown to be markedly depressed during sleep, indicating a prolongation of acid clearance during sleep.22 Swallowing occurs sporadically during sleep, and there are long periods (>30 minutes) without swallowing. Overall, the rate of swallowing during sleep is approximately six swallows per hour, and the swallows usually occur in association with a movement arousal. The highest frequency of these events occurs in stages 1 and 2 and REM sleep. A marked reduction in swallows associated with esophageal acid infusion during sleep has also been demonstrated.22 Studies incorporating the clearance of infused acid (15.0 mL 0.1 N HCl) during sleep have focused specifically on esophageal acid clearance during sleep. This approach allowed the infusion of acid into the distal esophagus during specific periods of documented sleep (REM versus non-REM), and it allowed the investigators to time the infusions so that the amount of sleep before each infusion could be relatively well controlled. This model also permitted a comparison of acid clearance during waking and during sleep under wellcontrolled conditions. The initial study in this series compared acid clearance during sleep in healthy volunteers and in patients with mild to moderate esophagitis.21a Sleep infusions in both groups were associated with a statistically significant prolongation of acid clearance time. The absolute clearance time (in minutes) was nearly doubled in both groups. Although there was no significant difference between the clearance times in the patients and in the control subjects, this was believed to be a somewhat academic point because, as noted previously, healthy persons rarely have reflux during sleep, whereas it is somewhat more common in patients with esophagitis. In addition, it was clear from the PSG observations that clearance was invariably associated with an arousal from sleep, and if this did not occur, there was a marked prolongation in acid clearance time. These data led to the conclusion that both arousal responses and waking are important elements in the response to an acidic distal esophagus. To evaluate the motor functioning of the esophagus during sleep and the associated arousals from sleep, a subsequent study was performed using a specially designed esophageal probe to monitor not only distal esophageal pH but esophageal peristalsis.22 This study also confirmed the importance of arousal responses in the efficient clearance of acid from the distal esophagus. The test was performed on healthy volunteers who had a negative acid perfusion test; that is, they did not show any sensitivity to acid dripped into the distal esophagus and could not distinguish acid from water in the esophagus. However, the determination of arousal responses to these two different substances infused during sleep revealed that the acid infusions produced a significantly greater number of arousal responses. In addition, an exponential relationship was described between the percentage of waking during the acid clearance interval and the acid clearance time; that is,
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the greater the amount of waking during the acid clearance interval, the faster the clearance time. This finding substantiates those from the previous study of patients with esophagitis. Of note, peristaltic parameters occurring during sleep and during waking did not differ. To test more definitively the hypothesis that complications of GER are associated with prolonged acid clearance, 13 patients with Barrett’s esophagus were studied.22a Barrett’s esophagus is believed to be related to chronic, severe GER, which results in the replacement of normal esophageal squamous epithelium with gastric columnar epithelium. Surprisingly, the patients with Barrett’s esophagus were shown to have significantly faster acid clearance during sleep and waking than the control subjects. However, this can be explained by the fact that the patients with Barrett’s esophagus showed both a higher frequency of arousal responses and a shorter latency to the first swallow than did the control subjects. This highlights the importance of arousal responses in the clearance process. Patients with Barrett’s esophagus cannot be distinguished from controls on the basis of any parameters associated with esophageal motor functioning, such as the amplitude of the peristaltic contraction or the esophageal transit time. However, the number of episodes of spontaneous GER in the group with Barrett’s esophagus was markedly increased compared with that in the control subjects. These data suggest that the severe esophagitis in the patients with Barrett’s esophagus is acquired through repeated episodes of spontaneous GER during sleep, which are associated with an overall increase in the accumulation of acid contact; even though individual events may be cleared faster than in controls, the increased number of events results in more mucosal contact time. Therapeutic Considerations GER appears to be affected by sleeping position; in particular, sleeping in the left lateral position significantly reduces the incidence of GER. The pattern of GER during waking and sleep is important in producing a prolongation of acid clearance,22 and this finding is strengthened by data showing that the back-diffusion of hydrogen ions in the esophagus is directly related to the duration of acid– mucosa contact time (Fig. 127-5).23 Further evidence for the importance of nocturnal GER comes from a clinical study that showed that individuals with symptoms of nocturnal heartburn, as well as dysphagia and chest pain, were much more likely to have demonstrable esophageal disease. Taken together, these results substantiate the traditional clinical approach to persistent reflux, which is that the patient sleep with the head of the bed elevated, despite there being little objective documentation of its therapeutic effect. Subsequent testing using intraesophageal pH monitoring during sleep has confirmed that sleeping with the head of the bed elevated produces a 67% improvement in the acid clearance time, although the frequency of reflux episodes remains unchanged.23a The use of a cholinergic drug (bethanechol) that produces an elevation in lower esophageal sphincter pressure and increases esophageal peristaltic efficiency results in a decrease in both reflux frequency (30%) and acid clearance time (53%).
1456 PART II / Section 15 • Other Medical Disorders
Net NetAcid acidFlux flux (µEq/10 min) Out out of of lumen Lumen
H+ FLUX AND DURATION OF ACID EXPOSURE 80
60
40
20
rR = 93 NAF = 1.25t + 10.8 N=5 15
30
45
60
Time (min) Figure 127-5 Hydrogen ion concentration as a function of the duration of esophageal acid contact. (From Johnson LF, Harmon JW. Experimental esophagitis in a rabbit model: clinical relevance. J Clin Gastroenterol 1986;8(Suppl. 1):26-44.)
Avoidance of late evening meals has also been tested, and results have brought this therapy into question. Reflux events during monitored sleep were not increased by a late evening provocative meal in patients with symptomatic GER disease. However, an over-the-counter dose (75 mg) of ranitidine at bedtime was effective in significantly reducing reflux events during sleep.23b Effective gastric acid suppression can adequately control GER. Powerful acid suppression is the most common treatment for GERD, and long-acting PPIs have been shown to be effective in suppressing GER during both daytime and at night, as well as in providing effective remission of symptoms of nighttime heartburn. No direct comparisons have shown any direct relationship between the suppression of sleep-related acid suppression and a decrease in actual sleep-related GER. The “breakthrough” of acid suppression has been described as a drop in the intragastric pH that occurs during the sleeping interval with PPI treatment. It has been suggested that adding an H2 receptor blocker at bedtime can control this breakthrough, but this has not been demonstrated clinically. Studies have shown that the addition of an H2 blocker at bedtime does not alter the occurrence of nighttime GER. One clinical trial in patients with significant nighttime heartburn and sleep disturbance related to the nighttime heartburn has shown that a PPI given once a day in the morning can significantly reduce both nighttime heartburn events and the associated sleep disturbance.24 Sleep-related GER and heartburn symptoms are both significantly decreased with Nissen fundoplication.25 Subjective and objective sleep measures are also improved after surgery. More specifically, there is a very small but significant increase (approximately 5%) in non-REM sleep, whereas there are more robust improvements in difficulty falling asleep, sleep quality, and daytime sleepiness. There
are data to suggest that the administration of nasal continuous positive airway pressure (CPAP) to patients who are being treated for obstructive sleep apnea (OSA) had the additional therapeutic benefit of reducing GER during sleep and consequent esophageal acid–mucosa contact time.26 Similar improvement was reported in patients with GER without apnea. It appears that CPAP reduces the nadir pressure of the transient relaxations of the lower esophageal sphincter during sleep, and shortens the duration of these relaxations.27 In fact, patients with sleep apnea have a high incidence of GER, although there is little relationship between severity of sleep apnea and GER, or between apneic events and reflux events. Similar results have been reported in other studies, but an overall increase in reflux events and acid clearance time was noted despite the absence of a clear relationship between obstructive apneic events and reflux events.28 It is not clear what the pathogenesis of increased sleep-related GER in patients with OSA is. They clearly share some risk factors, such as obesity, alcohol consumption, and perhaps hiatal hernia, but based on some clinical and physiologic data, obesity alone does not appear to be an adequate explanation for this relationship. On the other hand, another questionnaire study showed a significant reduction in nighttime heartburn symptoms after CPAP treatment, and those with higher CPAP levels had a greater reduction in symptoms of nighttime heartburn.28a Another study that evaluated reflux symptoms (i.e. heartburn, acid regurgitation) in patients with OSA found that there was no difference in reflux symptoms between those with OSA and those designated as “simple snorers.” Furthermore, no relationship was found between the severity of OSA and the reflux symptoms. However, this investigation did not specifically address nighttime GER symptoms.29 An interesting physiologic study addressed the relationship between GER and OSA by identifying individuals with significant OSA and GER, and treating them with acid suppression with a PPI.30 In this study, it was noted that after treatment with the PPI for 1 month, there was a significant reduction in complete obstructive events, although the overall respiratory disturbance index showed only a strong trend toward a reduction after treatment (P < .06). On the basis of these data, it appears that the incidence of nighttime heartburn is elevated in patients with OSA at a rate (62% in one study) that is similar to that in patients with frequent heartburn complaints. Furthermore, the frequency shows a very significant decline with CPAP treatment. This coincides well with other physiologic studies that have shown a significant decline in esophageal–acidmucosa contact time with CPAP treatment. The mechanism by which CPAP reduces esophageal acid contact time remains somewhat controversial, but it appears that effects on the transient relaxations of the lower esophageal sphincter may be playing an important role.27,27a Studies have documented that sedating drugs such as benzodiazepines and alcohol prolong acid clearance during sleep. One study has shown that alcohol consumption approximately 3 hours before sleep resulted in marked prolongation of acid clearance associated with spontaneous episodes of GER.31 The reflux of nonacidic gastric contents is an important issue in patients being treated with acid-suppressing drugs such as H2 receptor blockers and
PPIs. Powerful acid inhibition can result in an increase in sleep-related nonacidic reflux, but arousal responses and proximal migration were similar with both acidic and nonacidic reflux events.32 Arousal responses to GER are an important and common response to sleep-related GER. For example, in a large group of consecutive patients with excessive daytime sleepiness referred for evaluation in a sleep laboratory, patients with reflux symptoms have significantly more arousals from sleep and significantly lower quality-of-life scores than those without reflux symptoms.33 To summarize, these studies on acid clearance during sleep lend increasing support to the idea that sleep time is a time of considerable risk for patients with reflux esophagitis and that intact afferent arousal mechanisms are important in allowing normal acid clearance from the distal esophagus. Furthermore, sedating compounds such as hypnotic drugs and alcohol appear to result in a prolongation of acid clearance time, which might make otherwise benign GER a more clinically significant event. This is especially true with PPI treatment for heartburn, which may result in an increase in nighttime nonacidic GER.
PULMONARY COMPLICATIONS OF SLEEP-RELATED GASTROESOPHAGEAL REFLUX In an epidemiologic study, individuals who reported GER symptoms once or twice a week were significantly more likely to report symptoms of sleep-disordered breathing, and subjects with a combination of asthma and GER had a higher prevalence of nocturnal cough and sleep-related symptoms.34 These results suggest that the occurrence of nocturnal GER is strongly associated with both asthma and respiratory symptoms, as well as symptoms of OSA. In another report from the same data set, symptoms of nocturnal GER were associated with daytime sleepiness with an odds ratio of 2.6, and with daytime tiredness or fatigue with an odds ratio of 4.5.54a Nocturnal wheezing in persons with asthma and chronic nocturnal cough are pulmonary symptoms that have been linked to the occurrence of GER. The GER may be clinically silent, and treatment of the GER may reduce nocturnal asthma symptoms. In fact, a much greater incidence of nocturnal symptoms has been identified in asthmatic patients who were subsequently found to have GER. Results of the studies reviewed strongly suggest that prolonged acid clearance is most likely to occur during sleep. A physiologic study with asthmatic patients who complained of nighttime heartburn concluded that GER duration may determine the severity of nocturnal bronchoconstriction in asthmatic patients with GER.35 In a study that supports the important role of sleep, infraglottic resistance in asthmatic subjects was shown to increase significantly during sleep.36 However, patients with chronic obstructive pulmonary disease failed to show any reflex bronchial constriction to esophageal acid infusion, and their nocturnal and diurnal acid exposure times were completely normal on 24-hour pH monitoring. Thus, with regard to the relationship between pulmonary functioning and reflux during sleep, it appears that there is something unique about the asthmatic patient.
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Only rarely does acute or chronic inflammatory lung disease develop as the direct consequence of GER. Although there are pulmonary symptoms that suggest nocturnal GER in their pathogenesis, daytime symptoms suggesting GER are not as consistently clear. In a study of patients with esophageal pH and symptoms indicative of pulmonary aspiration, only approximately half had significant symptoms of heartburn. The symptoms commonly associated with GER are not necessarily reliable indicators of the physiologic presence of GER, particularly in patients with chronic pulmonary symptoms. A number of parameters of GER are believed to be related to the likelihood of pulmonary aspiration and subsequent damage to the lung parenchyma: two of these are the volume and the pH of the refluxed material. Questions concerning esophageal responsiveness to these critical stimuli during sleep were addressed in a study of healthy, asymptomatic volunteers with a negative acid perfusion test (i.e., no distinction between acid and water infused into the esophagus). Acid provoked a marked increase in arousal responses during sleep. This suggests that esophageal responsiveness is altered during sleep and that the enhanced arousal responses and shortened latency to swallowing were endogenous mechanisms designed to protect the tracheobronchial tree from the aspiration of esophageal contents. Another parameter may be the degree of proximal acid migration in the esophagus. It has been shown in cats that tracheal stimulation with minute amounts of acid produces a markedly greater bronchoconstrictive response than occurs with much larger volumes placed in the distal esophagus.37 These study results are compatible with the notion that responses to a noxious and potentially dangerous stimulus such as acid are altered or amplified under circumstances of increased risk (e.g., a decreased level of consciousness such as the sleeping state). This hypothesis was tested by investigating the effect of parameters that would produce an increased risk of pulmonary aspiration, such as volume and pH. An increasing volume of reflux into the esophagus would be considered a greater risk for pulmonary aspiration, and it would be hypothesized that larger volumes would produce more prompt and vigorous responses. To test this hypothesis, three different volumes of 0.1 N HCl were infused into the distal esophagus during waking and sleep.38 The data revealed that acid clearance was more rapid for the higher volumes; during waking, the latency to the first swallow was not noted to be significantly different, but after acid infusion during sleep, the latency progressively decreased with increasing volume. Similarly, the latency to the arousal from sleep was significantly reduced with increasing volume. In a follow-up study, as a further test of the hypothesis of differential esophageal acid sensitivity during sleep, the effect of different pH levels infused with constant volume was studied.39 Aspiration of fluid into the lungs at a relatively high pH (above 3) does not produce any significant damage to the lungs. However, considerable damage and, in some instances, death can occur with the aspiration of more acidic gastric contents. When acid (0.1 N HCl) is infused into the esophagus at a constant volume (15 mL) but with varying pH (1.2, 3, or 5), esophageal acid sensitivity is enhanced during sleep compared with during the waking
1458 PART II / Section 15 • Other Medical Disorders
state. Arousal latency, for example, was shown to be significantly decreased with an infusion of the lowest pH compared with the highest pH, and the latency to the first swallow was significantly decreased with pH 1.2 compared with 5. No differences were noted with infusions in the waking state. Data from these two experiments are quite consistent with the notion that the esophagus responds differentially during sleep to stimuli that would be considered to produce an increased risk of esophageal injury or pulmonary aspiration. Clearly, GER can occur during waking or sleep; therefore, symptom induction by this mechanism would be expected to occur both during the daytime and at night. In our experience, symptom provocation in most people with esophagitis may take 5 minutes or longer with the acid perfusion test, so one might extrapolate that the esophagus must be perfused for a period of several minutes before symptoms occur. From the results of previous studies, this could most commonly occur with nocturnal GER. The relationship between small airway disease, GER, and symptoms can be difficult to document historically because small airway resistance resulting from bronchial asthma can intensify at night without accompanying symptom exacerbation. It seems clear, however, that regardless of the mechanism, empirical therapy can determine this relationship by resolving pulmonary symptoms through a reduction in nocturnal GER. The physiologic and clinical data noted earlier suggest a relationship between asthmatic symptoms, particularly nocturnal wheezing, and a reflex bronchoconstriction caused by GER. Despite the numerous studies noted, controversy remains, and any explanation of these phenomena must account for some significant negative data. For example, patients with nocturnal wheezing were studied at night with the use of respiratory and PSG monitoring.40 These data showed no relationship between spontaneous GER and pulmonary resistance measures, nor was there any relationship with the exogenous infusion of acid. Similarly, in patients with chronic obstructive pulmonary disease and varying degrees of reversible lung disease, acidification of the distal esophagus did not produce any notable change in respiratory resistance or conductance. Furthermore, these patients did not exhibit any alterations in daytime or nocturnal GER as noted with 24-hour pH monitoring. Further documentation of the relationship between nocturnal pulmonary symptoms and nocturnal aspiration of gastric contents comes from a study that used a scintiscanning technique that involved the instillation of a radionuclide into the stomach before sleep and a lung scan the next morning to identify any radioactivity.41 Positive scans were documented in three of six patients suspected of having nocturnal pulmonary aspiration. In the patients with positive scans, the investigators also documented the presence of prolonged episodes of reflux during sleep. A similar study documented a positive lung scan in 45% of healthy persons who had a radionuclide placed in the posterior pharynx during sleep.41a These data suggest that subtle pulmonary aspiration occurs in healthy persons during sleep. It is interesting (1) that depressed consciousness markedly enhanced the rate of positive lung scans in this study, and (2) that of the healthy persons studied,
those who reported multiple arousals during sleep uniformly had negative scans. These data suggest that arousals from sleep are important elements in the response to acid in the upper airway. Similar techniques have been applied to asthmatic patients with nocturnal wheezing which have not revealed any evidence of pulmonary aspiration, suggesting that either the technique itself may lack adequate sensitivity or that pulmonary aspiration is relatively uncommon in asthmatic persons with nocturnal symptoms. Although the actual aspiration of gastric contents into the lungs may be uncommon, the aspiration of gastric contents may not be necessary to produce symptoms.37 It has been suggested that a reflex gradient exists from the distal esophagus to the posterior pharyngeal airway and results in increasing intensity of reflex bronchoconstriction when acid is introduced in these areas.37 Although some studies have suggested that proximal esophageal acid exposure can produce symptoms such as chronic cough, there are no definitive studies related to the occurrence of these symptoms and their relationship to PSG-monitored sleep and esophageal acid exposure. However, a study has suggested that sleep itself may predispose to the proximal migration of acidic fluid in the distal esophagus.42 In this study, 1 mL of infused volume into the distal esophagus revealed no evidence of proximal migration in the waking state; however, during sleep, 40% of the healthy volunteers studied showed evidence of proximal migration. An increase in the volume to 3 mL led to a substantial increase in the percentage of subjects showing proximal migration (80%).
INTESTINAL MOTILITY DURING SLEEP AND IRRITABLE BOWEL SYNDROME Because of the technological and practical difficulties of monitoring intestinal activity, which typically requires an unpleasant intubation for data acquisition, information on intestinal motility during sleeping and waking is limited in patient populations of interest. However, some data have been appeared in the literature. In one study of patients with IBS, 24-hour ambulatory monitoring of small intestinal motility showed that nocturnal motor patterns could not differentiate the patient group from the control subjects. The notable lack of motility activity during sleep makes differentiation of motor patterns difficult. However, one study showed a marked increase in REM sleep in patients with IBS, which supports speculation that this syndrome is associated with central nervous system abnormalities.43 The observation that REM sleep was enhanced in patients with IBS has prompted a number of investigations into sleep and functional bowel disorders to include IBS and functional dyspepsia. Using subjective reports of sleep quality, it has been documented that the exacerbations of IBS symptoms and poor sleep show a strong correlation. However, subjective studies without physiologic measurement of sleep are limited: the occurrence of waking symptoms may unduly influence the perception of the previous night’s sleep, and without PSG documentation of sleep, this influence cannot be discounted. In a study of nonulcer dyspepsia (characterized by epigastric postpran-
dial bloating, nausea, or early satiety), two thirds of 65 patients with nonulcer dyspepsia complained of general sleep disturbances suggestive of nonrestorative sleep (i.e., numerous awakenings after sleep onset, morning awakenings without feeling rested).44 These were significantly more common than noted in control subjects, and 65% of those complaining of sleep disturbance attributed their sleep problem to their abdominal symptoms. It is of potential importance to note that, as previously mentioned,19 sleep deprivation can alter the visceral pain threshold, and thus fragmented sleep may lower the pain threshold for abdominal pain. Several studies have documented increased sleep complaints in patients with IBS. In all of these studies, full PSG was conducted. One study found no difference in any of the sleep measures reported between patients with IBS and healthy subjects,45 whereas the other did show a significant prolongation of REM sleep.46 However, in another study, investigators noted a number of significant PSG differences in the patients with IBS compared with control groups, including decreased slow-wave sleep, increased arousal responses, and increased waking after sleep onset. Further research with larger sample sizes and stratification by IBS diagnostic subtype may help elucidate and resolve these discrepancies. In a group of patients with sleep complaints, the presence of a sleep disturbance was independently associated with a diagnosis of IBS.47 In an attempt to replicate and extend the original observation of prolonged REM sleep in patients with IBS,43 nine patients with IBS and nine control subjects were studied with full PSG monitoring and with gastric electrical activity monitored by the surface electrogastrogram, the latter measure so that more natural sleep could be obtained.48 In this study, a statistically significant increase in REM sleep was documented in the patients with IBS, but the absolute level of REM sleep was not nearly in the range reported in the previous study.48 In addition, specific electrogastrographic changes were found to be associated with sleep in healthy subjects that were not noted in patients with IBS. Healthy volunteers showed a significant decrease in the spectral amplitude of the electrogastrographic threecycles-per-minute rhythm during non-REM sleep compared with waking. During REM sleep, however, the amplitude was significantly increased to levels approaching those in the waking state. The patients with IBS failed significantly to modulate the amplitude of the dominant frequency of the gastric electrical rhythm during any of these states of consciousness. The lack of modulation of the dominant frequency of the electrogastrographic amplitude during sleep in patients with IBS raises the possibility that other autonomic abnormalities may be unmasked by further study of physiologic functioning during sleep. In a subsequent study, it was noted that patients with IBS who had dyspeptic symptoms in addition to classic symptoms of abdominal pain and cramping did not exhibit the increase in sympathetic dominance in REM sleep that was noted only in the patients with abdominal cramping alone as part of their IBS symptomatology.49 Collectively, these results from various sleep investigations in patients with functional bowel disorders suggest not only that sleep disturbances are noted in this patient population but that the sleep disturbances may contribute to altered gastroin-
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testinal functioning or altered visceral perception These studies confirm the notion that there are central nervous system alterations in patients with functional bowel disorders and that these alterations are perhaps uniquely identified during sleep. Future studies on sleep in patients with functional bowel disorders should provide additional understanding of the pathophysiology of the brain-gut axis and its alterations during sleep. Colonic motility has been monitored for 24 hours in healthy volunteers and in patients with chronic constipation.50 Although there was a decrease in the number and duration of mass movements in the patients with chronic constipation, as well as a circadian pattern of decrease in mass movements during the night, no significant difference was noted between patients and control subjects with regard to the circadian pattern itself. In a similar study, the motor activities of the distal colon, rectum, and anal canal were monitored over a 24-hour interval in patients with slow-transit constipation and compared with healthy controls.51 The patients with slow-transit constipation had impaired responses to feeding as well as reduced colonic contractile activity on awakening from sleep in the morning. Another interesting observation concerning alterations in anorectal functioning during sleep comes from a study monitoring rectal motor activity during sleep in patients who had ileoanal anastomosis.52 The investigators noted that decreases in anal resting pressure coupled with marked minute-to-minute variations in pressure during sleep occurred in both control subjects and patients, and, when these changes were particularly profound, nocturnal fecal incontinence occurred in some patients.
CONCLUSIONS It appears that there is an important relationship between sleep and the development of various acid peptic diseases, such as duodenal ulcer disease and GERD. The pathogenesis and treatment of these disorders relate in large measure to the control of acid secretion during sleep. The suppression of nocturnal acid secretion appears to be an essential element in the healing of duodenal ulcers, and the occurrence of nocturnal GER is an unquestionably important aspect of the development of serious complications of this disorder. Continuous monitoring of the distal esophageal pH to document nocturnal GER is emerging as an important and useful diagnostic tool. The respiratory complications of GER also appear to be associated with sleep-related GER. In addition, prolonged monitoring of small and large bowel motility appears to be a promising tool for further understanding the pathogenesis of various gastrointestinal diseases and how these diseases may be altered by sleep. Functional bowel disorders, as well as GER, appear to be associated with an increased incidence of sleep complaints, and the autonomic dysfunction specifically noted during REM sleep appears to characterize a subset of patients diagnosed with IBS. An awareness of these sleep-related phenomena is an important element in the practice of state-of-the-art gastroenterology, and future research will undoubtedly further substantiate the important role of sleep in the pathogenesis of gastrointestinal disease.
1460 PART II / Section 15 • Other Medical Disorders ❖ Clinical Pearl Sleep-related GER is an important element in the pathogenesis of the complications of GERD and in some respiratory disorders such as bronchial asthma and pulmonary aspiration.
REFERENCES 1. Kasasbeh A, Kasasbeh E, Krishnaswamy G. Potential mechanisms connecting asthma, esophageal reflux, and obesity/sleep apnea— a hypothetical review. Sleep Medicine Reviews 2007;11:47-58. 2. Feldman M, Richardson CT. Total 24-hour gastric acid secretion in patients with duodenal ulcer: comparison with normal subjects and effects of cimetidine and parietal cell vagotomy. Gastroenterology 1986;90:540-544. 3. Orr WC, Hall WH, Stahl ML, et al. Sleep patterns and gastric acid secretion in duodenal ulcer disease. Arch Intern Med 1976; 136:655-660. 4. Howden CW, Jones DB, Hunt RH. Nocturnal doses of H2 receptor antagonists for duodenal ulcer. Lancet 1985;1:647-648. 5. Gledhill T, Buck M, Paul A, et al. Comparison of the effects of proximal gastric vagotomy, cimetidine, and placebo on nocturnal intragastric acidity and acid secretion in patients with cimetidine resistant duodenal ulcer. Br J Surg 1983;70:704-706. 6. Galmiche JP, Tranvouez JL, Denis P, et al. L’enregistrement nocturne du pH gastrique permet-il de prévoir la response thérapeutique des ulc: ageres duodenaux sév; ageres traites par la ranitidine? Gastroenterol Clin Biol 1985;9:583-589. 7. Silvis SE. Final report on the United States multicenter trial comparing ranitidine to cimetidine as maintenance therapy following healing of duodenal ulcer. J Clin Gastroenterol 1985;7:482-487. 8. Shaker R, Castell DO, Schoenfeld PS, et al. Nighttime heartburn is an under-appreciated clinical problem that impacts sleep and daytime function: the results of a Gallup survey conducted on behalf of the American Gastroenterological Association. Am J Gastroenterol 2003;98:1487-1493. 9. Farup C, Kleinman L, Sloan S, et al. The impact of nocturnal symptoms associated with gastroesophageal reflux disease on healthrelated quality of life. Arch Intern Med 2001;151:45-52. 9a. Allen L, Poh CH, Gasiorowska A, et al. Increased oesophageal acid exposure at the beginning of the recumbent period is primarily a recumbent-awake phenomenon. Aliment Pharmacol Ther 2010 Sep;32(6):787-794. 10. Orr WC. Lifestyle measures for the treatment of gastroesophageal reflux disease. In: Bayless TM, Diehl AM, editors. Advanced therapy in gastroenterology and liver disease. Hamilton, Ontario: BC Decker; 2005. 11. Orr WC, Heading R, Johnson LF, et al. Sleep and its relationship to gastro-oesophageal reflux. Aliment Pharmacol Ther 2004;9(Dec 20 Suppl.):39-46. 12. Penzel T, Becker HR, Brandenburg U, et al. Arousal in patients with gastro-esophageal reflux and sleep apnea. Eur Respir J 1999;14: 1266-1270. 13. DeMeester TR, Johnson LF, Guy JJ, et al. Patterns of gastro esophageal reflux in health and disease. Ann Surg 1976;184:459-470. 14. Johnson LF, DeMeester TR, Haggitt RC. Esophageal epithelial response to gastroesophageal reflux: a quantitative study. Am J Dig Dis 1978;23:498-509. 15. Schlesinger PK, Honahue PE, Schmid B, et al. Limitations of 24-hour intraesophageal pH monitoring in the hospital setting. Gastroenterology 1985;89:797-804. 16. Orr WC, Allen ML, Robinson M. The pattern of nocturnal and diurnal esophageal acid exposure in the pathogenesis of erosive mucosal damage. Am J Gastroenterol 1994;89:509-512. 17. Dickman R, Shapiro I, Malagon B, et al. Assessment of 24hr oesophageal pH monitoring should be divided to awake and asleep rather than upright and supine time periods. Neurogastroenterol Motil 2007;19:709-715. 18. Orr W, Goodrich S, Robert J. The effect of acid suppression on sleep patterns and sleep related gastroesophageal reflux. Aliment Pharmacol Ther 2005;21:103-108.
19. Chen CL, Robert JT, Orr WC. Sleep symptoms and gastroesophageal reflux. J Clin Gastroenterol 2008;42:13-17. 20. Schey R, Dickman R, Parthasarathy S, et al. Sleep deprivation is hyperalgesic in patients with gastroesophageal reflux disease. Gastroenterology 2007;133:1787-1795. 21. Guda N, Partington S, Shaw MJ. Unrecognized GERD symptoms are associated with excessive daytime sleepiness in patients undergoing sleep studies. Dig Dis Sci 2007;52:2873-2876. 21a. Orr WC, Robinson MG, Johnson LF. Acid clearing during sleep in patients with esophasitis and controls. Dig Dis Sci 1981;26: 423-427. 22. Orr WC, Johnson LF, Robinson MG. The effect of sleep on swallowing, esophageal peristalsis, and acid clearance. Gastroenterology 1984;86:814-819. 22a. Orr WC, Lackey C, Robinson MG. Esophageal acid clearance during sleep in patients with Barrett’s esophagus. Dig Dis Sci 1988;33:654-659. 23. Johnson LF, Harmon JW. Experimental esophagitis in a rabbit model: clinical relevance. J Clin Gastroenterol 1986;8(Suppl. 1):26-44. 23a. Johnson LF, DeMeester TR. Evaluation of the head of the bed, bethanechol and antacid form tablets on gastroesophageal reflux. Dig Dis Sci 1981:26:673-680. 23b. Orr WC, Harnish MJ. Sleep-related gastroesophageal reflux: provocation with a late evening meal and treatment with acid suppression. Aliment Pharmacol Ther 1998:12;1033-1038. 24. Johnson DA, Orr WC, Crawley JA, et al. Effect of esomeprazole on nighttime heartburn and sleep quality in patients with GERD: randomized placebo-controlled trail. Am J Gasrtoenterol 2005;100: 1914-1922. 25. Guda N, Partington S, Shaw MJ. Unrecognized GERD symptoms are associated with excessive daytime sleepiness in patients undergoing sleep studies. Dig Dis Sci 2007;52:2873-2876. 26. Kerr P, Shoenut P, Millar T, et al. Nasal CPAP reduces gastroesophageal reflux in obstructive sleep apnea syndrome. Chest 1992;101:1539-1544. 27. Shepherd K, Holloway R, Hillman D, Eastwood P. The impact of continuous positive airway pressure on the lower oesophageal sphincter. Am J Physiol (Gastrointest Liver Physiol) 2007;292: G1200-G1205. 27a. Shepherd K, Hillman D, Holloway R, Eastwood P. Mechanisms of nocturnal gastroesophageal reflux events in obstructive sleep apnea. Sleep Breath 2010:14. [Epub ahead of print] 28. Ing AJ, Ngu MC, Breslin AB. Obstructive sleep apnea and gastroesophageal reflux. Am J Med 2000;108(Suppl. 4a):120S-125S. 28a. Green BT, Broughton WA, O’Connor JB. Marked improvement in nocturnal gastroesophageal reflux in a large cohort of patients with obstructive sleep apnea treated with continuous positive airway pressure. Arch Int Med 2003;163:41-45. 29. Valipour A, Makker H, Hardy R, et al. Symptomatic gastro esophageal reflux in subjects with a breathing sleep disorder. Chest 2002; 121:1748-1753. 30. Senior BA, Khan M, Schwimmer C, et al. Gastroesophageal reflux and obstructive sleep apnea. Laryngoscope 2001;111:2144-2146. 31. Vitale GC, Cheadle WG, Patel B, et al. The effect of alcohol on nocturnal gastroesophageal reflux. JAMA 1987;258:2077-2079. 32. Orr WC, Craddock A, Goodrich S. Acidic and non-acidic reflux during sleep under conditions of powerful acid suppression. Chest 2007;131(2):460-465. 33. Orr WC, Goodrich S, Fernstrom P, et al. Occurrence of nighttime gastroesophageal reflux in disturbed and normal sleepers. Clin Gastroenterol Hepatol 2008;10:1099-1104. 34. Gisalson T, Janson C, Vermeire P, et al. Respiratory symptoms and nocturnal gastroesophageal reflux. Chest 2002;121:158-163. 34a. Janson C, Gislason T, De Backer W, et al. Daytime sleepiness, snoring and gastroesophageal reflux amongst young adults in three European countries. J Intern Med 1995:237;277-285. 35. Cuttitta G, Cibella F, Visconti A, et al. Spontaneous gastroesophageal reflux and airway patency during the night in adult asthmatics. Am J Respir Crit Care Med 2000;161:177-181. 36. Ballard RD, Saathoff MC, Patel DK, et al. The effect of sleep on nocturnal bronchoconstriction and ventilatory patterns in asthmatics. J Appl Physiol 1989;67:243-249. 37. Tuchman DN, Boyle JT, Pack AI, et al. Comparison of airway responses following tracheal or esophageal acidification in the cat. Gastroenterology 1984;87:872-881.
38. Orr WC, Robinson MG, Johnson LF. The effect of esophageal acid volume on arousals from sleep and acid clearance. Chest 1991;99: 351-355. 39. Orr WC, Johnson LF. Responses to different levels of esophageal acidification during waking and sleep. Dig Dis Sci 1998;43:241-245. 40. Tan WC, Martin RJ, Pandey R, et al. Effects of spontaneous and simulated gastroesophageal reflux on sleeping asthmatics. Am Rev Respir Dis 1990;141:1394-1399. 41. Chernow B, Johnson LF, Janowitz WR, et al. Pulmonary aspiration as a consequence of gastroesophageal reflux: a diagnostic approach. Dig Dis Sci 1979;24:839-844. 41a. Huxley EJ, Viroslav J, Gray WR, et al. Pharyngeal aspiration in normal adults with depressed consciousness. Am J Med 1978;64: 564-568. 42. Orr WC, Craddock A, Goodrich S. Acidic and non-acidic reflux during sleep under conditions of powerful acid suppression. Chest 2007;13:460-465. 43. Kumar D, Thompson PD, Wingate DL, et al. Abnormal REM sleep in the irritable bowel syndrome. Gastroenterology 1992;103:12-17. 44. Fass R, Fullerton S, Tung S, et al. Sleep disturbances in clinic patients with functional bowel disorders. Am J Gastroenterol 2000;95:1195-2000. 45. Elsenbruch S, Harnish MJ, Orr WC. Subjective and objective sleep quality in irritable bowel syndrome. Am J Gastroenterol 1999;94: 2447-2452.
CHAPTER 127 • Gastrointestinal Disorders 1461 46. Heitkemper M, Charman AB, Shaver J, et al. Self-report and polysomnographic measures of sleep in women with irritable bowel syndrome. Nurs Res 1998;47:270-277. 47. Heitkemper M, Jarrett M, Burr R, et al. Subjective and objective sleep indices in women with irritable bowel syndrome. Neurogastroenterol Mot 2005;17:523-530. 48. Orr WC, Crowell MD, Lin B, et al. Sleep and gastric function in irritable bowel syndrome: derailing the brain-gut axis. Gut 1997;41:390-393. 49. Thompson JJ, Elsenbruch S, Harnish MJ, et al. Autonomic functioning during REM sleep differentiates IBS symptom subgroups. Am J Gastroenterol 2002;97:3147-3153. 50. Bassotti G, Gaburri M, Imbimbo BP, et al. Alimentary tract and pancreas: colonic mass movements in idiopathic chronic constipation. Gut 1988;29:1173-1179. 51. Ferrara A, Pemberton JH, Hanson RB. Motor responses of the sigmoid, rectum and anal canal in health and in patients with slow transit constipation (STC). Gastroenterology 1991;100:A441. 52. Orkin BA, Soper NJ, Kelly KA, et al. Influence of sleep on anal sphincter pressure in health and after ileal pouch-anal anastomosis. Dis Colon Rectum 1992;35:137-144.
Sleep in Chronic Kidney Disease Mark L. Unruh and Mark H. Sanders
Abstract Sleep disturbance has been linked to disability days, use of health care, and quality of life in patients with chronic kidney disease (CKD). Although there are many potential causes of poor sleep in kidney disease patients including depression, insomnia, restless legs, and periodic limb movements, sleep apnea may be the most common. A significant percentage of patients with kidney disease report hypersomnolence, snoring,
Chronic kidney disease (CKD) has been defined by either a chronic decrease in kidney function or other evidence of chronic kidney damage such as proteinuria or cystic disease.1 The prevalence of CKD is increasing,2 and in view of the growing prevalence of the metabolic syndrome, diabetes, and hypertension, this trend is expected to continue.3 As a result, CKD is a burgeoning public health problem that has been strongly linked to an increased risk of sleep disorders. It is estimated that there are 15 million adults in the United States with stage 3 or greater CKD (defined by an estimated glomerular filtration rate [eGFR] <60 mL/min/1.73 m2).2 An additional 10 million have CKD of lesser severity, with an eGFR between 60 and 90 mL/min/1.73 m2 or microalbuminuria, an early indicator of kidney damage, as well as an independent risk factor for cardiovascular events.4,5 This chapter reviews sleep disorders and related symptoms across the spectrum of kidney dysfunction and describes current knowledge regarding prevalence, risk factors, and consequences of sleep disorders among these patients. We focus on sleep issues that are thought to have a particularly high prevalence in CKD, such as excessive daytime sleepiness, insomnia, restless legs, periodic limb movement disorder (PLMD), and sleep apnea. In addition, sleep disorders in the context of dialysis treatment are discussed.
DEFINITION OF TERMS The various terms and treatments used in caring for patients with kidney disease may be unfamiliar to sleep clinicians and researchers. Therefore Box 128-1 provides a descriptive list of the terms and dialysis-management strategies discussed in this chapter for concise, albeit simplistic, descriptive reference. Although thirty times as many CKD patients are not on dialysis compared to those who are receiving dialysis, most of the studies examining sleep and sleep disorders have been performed in the latter population, with far fewer studies of patients with mild to moderate kidney disease and following kidney transplantation. Thus, there is a substantial gap in our knowledge that is relevant to a large population in the community. 1462
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and witnessed apneas. The potential etiologies for sleep apnea in this population include upper airway edema, unstable ventilatory control, and shared risk factors between CKD and sleep apnea, such as older age and diabetes. The best strategy for diagnosing and treating sleep disorders in persons with CKD has not been evidentially defined, and current clinical practice is largely based on data obtained from study samples that have generally excluded such patients.
Kidney Disease The term chronic kidney disease encompasses all degrees of kidney dysfunction.6 At one end of the spectrum is mild kidney disease, which is very common, and although it has been associated with poor outcomes, it may present few bothersome symptoms to patients and is largely underrecognized. At the other end of the CKD spectrum, endstage renal disease (ESRD) is defined as kidney failure for which medical management alone is inadequate and is usually associated with a glomerular filtration rate less than 15 mL/min/1.73 m2. ESRD results in the inability to excrete waste products, control serum electrolytes, handle the daily dietary and metabolic acid load, and maintain fluid balance. The treatment options for ESRD are listed in Box 128-1. Treatment Hemodialysis passes the patient’s blood through a semipermeable membrane by which toxins and fluid are removed by diffusion and convection. Traditionally, patients undergo hemodialysis thrice weekly at a dialysis center during morning, afternoon, or evening shifts. In peritoneal dialysis, a catheter is inserted into the peritoneum through which fluid (dialysate) is infused and then drained after a suitable dwell time. The peritoneal membrane functions as a semipermeable filter facilitating the removal of waste products and fluid. Continuous ambulatory peritoneal dialysis (CAPD) describes the strategy in which the patient or caregiver instills fluid into the abdomen and then drains it after a dwell time of 4 to 6 hours during the day. Instillation and subsequent drainage of fluid after a period of dwell time is termed an exchange. The CAPD patient also usually has a nighttime dwell of peritoneal fluid, and the fluid is drained on awakening. In nocturnal peritoneal dialysis (NPD), the fill and drain exchange process is automated and is performed at night while the patient is asleep. Nocturnal hemodialysis is another contemporary approach whereby ESRD patients undergo hemodialysis 3 to 7 nights a week as well as short daily hemodialysis in which patients do hemodialysis 6 days a week for 2 to 2.5 hours.7 Kidney transplantation and palliative care are additional management strategies.
Chronic kidney disease (CKD): Chronic decrease in kidney function or other evidence of chronic kidney damage such as proteinuria or cystic disease. End-stage renal disease (ESRD): Kidney failure for which medical management alone is inadequate (estimated glomerular filtration rate <15 mL/ min/1.73 m2), requiring dialysis or kidney transplantation to sustain life. Hemodialysis: Conventional hemodialysis. It is performed thrice-weekly for 3 to 4 hours at a dialysis center. Nocturnal hemodialysis (NHD): Hemodialysis conducted overnight, therefore usually outside of a dialysis center and over a longer duration; it provides more clearance than conventional thriceweekly hemodialysis. The frequency of NHD can range from 3 to 7 nights a week. Continuous ambulatory peritoneal dialysis (CAPD): The patient instills fluid into the abdomen and then drains it after a dwell time of 4 to 6 hours throughout the day. The CAPD patient also usually has a nighttime dwell of peritoneal fluid (but no exchanges), and the fluid is drained on awakening. Nocturnal peritoneal dialysis (NPD): Peritoneal dialysis performed overnight by an automated machine that instills and drains (exchanges) fluid from the patient during sleep.
1
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Year 2
Year 3
0
1 0
–1
–1
–2
–2
–3 –4
–3
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–4
A Mean change with 95% CI
Box 128-1 Definitions of Terms and Dialysis Strategies in Chronic Kidney Disease
Mean change with 95% CI
CHAPTER 128 • Sleep in Chronic Kidney Disease 1463
1
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–3 Low flux High flux
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B Figure 128-1 The impact of high-dose and high-flux hemodialysis on sleep quality in a study of 1846 hemodialysis patients. A, There was no significant effect of high-dose hemodialysis; average effect was 1.81 (0.95); P = .06. B, There was a small but significant effect of high-flux hemodialysis on sleep quality; average effect was 2.25; (0.95); P = .02. The adjusted mean changes are denoted by circles and the unadjusted mean changes are denoted by diamonds. The error bars represent the 95% confidence intervals.
EPIDEMIOLOGY Symptoms related to sleep and fatigue are common, persistent, and important to patients with advanced CKD and ESRD.8-15 In a systematic review of 59 studies to estimate the prevalence of symptoms among patients on dialysis, several of the most common and severe were related to sleep and fatigue, with fatigue or tiredness endorsed by an average of 71%, disturbed sleep by 44%, and restless legs by 30%.16 Similar to those on dialysis, patients with advanced CKD have been shown to have a pattern of sleep and fatigue symptoms that are only slightly less severe than persons with ESRD.17 The need to identify and manage patients in this population who have complaints regarding sleep quality is underscored by a high rate of use of hypnotics.12,18 Studies reporting use of hypnotics likely underestimate the prevalence because patients also use diphenhydramine, antidepressants, and opiates to promote sleep. Subjective sleep quality is also clinically meaningful for CKD patients because sleep problems may be an indication to initiate or modify dialysis management. For example, nephrologists increase the dose of dialysis in an effort to mitigate symptoms related to sleep problems. This practice was tested as a prespecified quality-of-life outcome in the Hemodialysis (HEMO) Study, a multicenter study of hemodialysis dose and membrane flux.19 The dose of dialysis reflects the adequacy of small molecule clearance, and high flux increases the clearance of middle molecules such as β2-microglobulin and parathy-
roid hormone. As shown in Figure 128-1, there was no significant effect of high-dose dialysis on sleep quality. High-flux hemodialysis had a small beneficial effect on sleep quality that did not reach significance after accounting for multiple comparisons made by the HEMO Study investigators.19 Despite receiving an adequate dose of hemodialysis, longitudinal analysis of the HEMO Study demonstrated that approximately 30% of study participants experienced a clinically significant decline in sleep quality over the course of 3 years.20 In the CKD and ESRD population, complaints of sleep problems have been linked to disability days, use of health care, and health-related quality of life.21-24 Also, both dialysis and kidney transplant patients with decreased sleep quality have a significantly higher mortality rate than similar patients with good sleep.23,25,26 Attribution of causality is difficult because most information in this regard comes from observational studies, but the poor quality of life and increased risk of death among those with worse sleep quality might reflect acquired sleep disorders, the negative impact of poor sleep quality on mood, or even the treatment of sleep problems. Nonetheless, symptoms related to sleep and fatigue are common and persistent, and patients on dialysis strongly value improvement in these symptoms.27 In a study of 100 hemodialysis patients, 93% would favor more frequent hemodialysis treatments if it improved fatigue, and 57% would do more frequent
1464 PART II / Section 15 • Other Medical Disorders
SUBJECTIVELY AND OBJECTIVELY ASSESSED EXCESSIVE DAYTIME SLEEPINESS IN PATIENTS WITH END-STAGE RENAL DISEASE Excessive daytime sleepiness (EDS) is highly prevalent in patients with ESRD. Assessments using standardized questionnaires demonstrate that 52% to 67% of ESRD patients endorse EDS.28,29 Moreover, EDS has been demonstrated in both hemodialysis and peritoneal dialysis patients using the multiple sleep latency test (MSLT).30-32 The average sleep latency was 6.3 minutes by MSLT among patients undergoing CAPD.30 Hanly and colleagues reported that the subjects with shorter sleep latency had a higher BUN (blood urea nitrogen, reflecting a greater uremic burden) and significantly more-frequent periodic limb movements (PLMs). Although there was a direct association between severity of uremia and sleep latency, there was not a significant improvement in daytime sleepiness after con version from conventional hemodialysis to nocturnal hemodialysis.31 EDS may be objectively demonstrated in ESRD patients thought to be at low risk by history and symptoms for sleep disorders. Parker and coworkers performed MSLT on 46 hemodialysis patients without a history suggestive of sleep disorders and found that 46% had mild to severe sleepiness as defined by a sleep latency of less than 10 minutes. There was also a high prevalence of REM sleep in the naps of these patients, which the investigators felt might reflect either severe sleep disruption or a shift in the timing of REM sleep. Daytime sleepiness can contribute to the poor vocational and rehabilitation potential traditionally associated with ESRD.33 In view of the notably high prevalence of EDS in patients with ESRD and the multiplicity of potential etiologies, a comprehensive history, physical examination, and referral to a sleep specialist may be a first step in the evaluation of daytime sleepiness in patients with CKD. INSOMNIA IN PATIENTS WITH CHRONIC KIDNEY DISEASE Insomnia is common and has substantial health consequences in patients with kidney disease. Insomnia reflects difficulty falling asleep, maintaining sleep, or waking early in the morning, with associated daytime difficulties (see Chapter 78). Although the prevalence of poor sleep quality of patients with CKD has been shown to be high,34,34a the majority of studies have examined patients undergoing dialysis. Insomnia among dialysis patients has been associated with decreased quality of life, and a worsening of insomnia over the first year of dialysis has been associated with an increased mortality risk.23 Up to two thirds of dialysis patients experience insomnia,13-15,35,36 although most of the studies have been limited to examining the prevalence of symptoms of poor sleep
initiation and maintenance. These subjective complaints are consistent with short and fragmented sleep as measured by polysomnography and wrist actigraphy in these patients. A comparison of 46 conventional hemodialysis patients to 137 controls from the Sleep Heart Health Study (SHHS) demonstrated a higher prevalence of short sleep (<5 hours) (odds ratio [OR], 3.27; 95% confidence interval [CI], 1.16 to 9.25) and decreased sleep efficiency (OR, 5.5; 95% CI, 1.5 to 19.6).37 This study also demonstrated a higher subjective burden of insomnia, with hemodialysis patients reporting more difficulty getting back to sleep (OR, 2.25; 95% CI 1.11 to 4.60) and awakening too early (OR, 2.39; 95% CI, 1.01 to 5.66). Wrist actigraphy has revealed notable variability in sleep–wake pattern among patients undergoing hemodialysis as shown in Figure 128-2. In this study, those with early-morning hemodialysis had significantly shorter nocturnal sleep time compared with those who had later hemodialysis shifts when averaged over the course of 2 weeks. In addition, those with increased variability in sleep times were found to have higher levels of daytime sleepiness.38 Because kidney transplantation reduces the need to attend a fixed dialysis schedule, insomnia associated with ESRD can improve after kidney transplantation. Using the Athens Insomnia Scale, the prevalence of chronic insomnia after kidney transplantation was 8% compared to 15% among wait-listed patients on hemodialysis.13 Aside from addressing underlying disorders known to cause insomnia, insomnia treatment among patients with kidney disease is guided by limited evidence. Caution should be exercised with regard to pharmacologic intervention in this population because some hypnotics such as diazepam and some nonhypnotics such as gabapentin used by patients to promote sleep require changes in dosing with underlying renal disease. There are also potential drug-drug interactions in this population in which polypharmacy is common, and there have been only a few small
800 700 Total sleep time (minutes)
treatments to improve sleep.27 This contrasts with 19% of patients who are willing to undergo more frequent dialysis to extend their life up to 3 more years.27 These findings underscore the profound impact of sleep on the experiences of patients with CKD and ESRD.
600 500 400 300 200 100 0 HD
HD
HD
HD
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Days Figure 128-2 Total sleep time (TST) on hemodialysis treatment (HD) and non-HD nights. Diamonds represent subjects with longer TST on post-HD nights. Squares represent subjects with shorter TST on post-HD nights. Triangles represent subjects with a stable sleep pattern on pre- and post-HD nights.
trials of insomnia treatment. A small study of zaleplon in the hemodialysis population showed improved sleep efficacy.39 Twenty-four peritoneal dialysis patients with insomnia without active psychiatric illness were randomized to receive cognitive behavioral therapy (CBT) and counseling regarding good sleep hygiene or just sleep hygiene counseling.40 After 4 weeks, there were substantial improvements in the Pittsburgh Sleep Quality Index (PSQI) and the Fatigue Severity Scale in the CBT group.40 This demonstrates that patients undergoing peritoneal dialysis might benefit from CBT, and the use of this treatment should be considered in light of the potential problems associated with the polypharmacy. One approach to the management of insomnia among patients with CKD consists of providing counseling to optimize sleep hygiene, screening for other sleep disorders such as sleep apnea and restless legs syndrome (RLS), providing a brief trial of cognitive behavioral therapy and hypnotics, and considering an overnight PSG in patients who remain symptomatic. For patients undergoing hemodialysis, it may be reasonable to ask the patient to avoid napping during dialysis sessions and to consider using cool dialysate for hemodialysis. In this regard, ongoing work is examining the influence of dialysate temperature on the circadian rhythm of patients undergoing thrice-weekly hemodialysis. This work is based on the concept that standard hemodialysis disrupts circadian rhythms by delivering a heat load with the combination of volume removal, which increases core temperature, and warm dialysis (37° C), which is usually a higher temperature than the core temperature of the hemodialysis patient at the time of treatment.41 Parker and colleagues demonstrated that patients receiving hemodialysis are subject to a heat load and have proposed that cool dialysate (35° C) hemodialysis might ameliorate the sleep problems in this population.42 Patients using overnight peritoneal dialysis might need to adapt their regimen to avoid frequent alarms and the sensation of nocturnal abdominal discomfort due to the automated filling and draining of dialysate. The use of melatonin in the ESRD population has received only limited evaluation. Studies have demonstrated both increased and depressed daytime melatonin levels among patients undergoing hemodialysis.43,43a Despite these conflicting findings, the use of melatonin for treatment of insomnia in ESRD merits further research44 because investigators have consistently demonstrated attenuation of the nocturnal surge of melatonin among both humans and animal models of ESRD. Pilot testing in ESRD patients demonstrated a substantial beneficial effect of melatonin on sleep in ESRD patients.45
RESTLESS LEGS SYNDROME IN PATIENTS WITH CHRONIC KIDNEY DISEASE Epidemiology End-stage renal disease has been strongly associated with RLS. A comprehensive discussion of RLS and PLMD is provided elsewhere in this volume (see Chapter 90). The majority of investigations examining RLS in CKD patients have been cross-sectional studies of chronic dialysis
CHAPTER 128 • Sleep in Chronic Kidney Disease 1465
patients, thereby limiting our understanding of the natural history of RLS in the broader CKD population as well as how it relates to the progression of kidney disease. A study has outlined the difficulties of using questionnaires to diagnose RLS in the ESRD population, but work operationalizing the International Restless Legs Syndrome Study Group (IRLSSG) definition of RLS has demonstrated a relatively consistent estimate of RLS ranging between 20% and 30%.46 Studies using a clinical assessment have found that approximately 23% to 33% of chronic hemodialysis patients have RLS, and data from our center have also shown a 30% prevalence of RLS among hemodialysis patients using a questionnaire based on IRLSSG criteria.47 Etiology and Risk Factors Although the estimates of RLS among the hemodialysis population range up to 10 times more common than in the general population,48 the etiology and risk factors for RLS in those with ESRD remain unclear. Because uremic RLS is improved with dopamine agonists, opioids, and gabapentin, it seems likely that the pathophysiology is similar to that of idiopathic RLS. It may be that patients with ESRD are primed for RLS by increased neural excitability secondary to uremic neuropathy. Furthermore, patients undergoing hemodialysis are challenged by their treatment regimen, which mandate periods of relative immobility for up to 4 hours thrice weekly, perhaps unmasking subclinical RLS. In the general population, it has been demonstrated that RLS is caused by blockade of the D2 receptor in the diencephalon.49 However, small studies in ESRD have correlated RLS to a number of factors, including iron deficiency, calcium levels, calcium channel blockers, parathyroid hormone levels, hemoglobin, dialysis timing, and dialysis adequacy. Morbidity and Mortality RLS has been associated with substantial morbidity and mortality in the ESRD population. As in the general population, RLS has been associated with poor mental health in patients receiving hemodialysis. Symptoms of restless legs were associated with a lower health-related quality of life (HRQOL) among a nationwide sample of 900 dialysis patients.50 A causal link between insomnia and RLS in the ESRD population has not been established using treatment trials; however, RLS was associated with increased risk of insomnia in a sample of 333 hemodialysis patients.51 RLS has also been associated with shorter survival in hemodialysis patients after controlling for age, sex, and duration of dialysis.50,52 In patients with RLS, the inability to sit still can lead to shortening treatment times or skipping hemodialysis treatments. RLS was associated with hemodialysis nonadherence and it may be that poor adherence to the dialysis prescription, rather than the RLS per se, contributes to the increased mortality risk.52 It has also been demonstrated that RLS and PLMD increase sleep fragmentation, and this fragmented sleep can in turn promote hypertension.53 Lastly, it may be that RLS severity is a marker for inadequate dialysis, inflammation, or PLMs. RLS remains a major diagnostic and therapeutic challenge for those caring for patients undergoing dialysis.
1466 PART II / Section 15 • Other Medical Disorders
Transplant Patients Although kidney transplantation has been associated with a lower prevalence of RLS, RLS remains associated with poor outcomes among kidney transplant recipients. The improvement of RLS has been demonstrated in a small longitudinal study of 11 patients where hemodialysis patients demonstrated a rapid resolution of RLS after kidney transplantation.54 Larger studies using questionnaires have demonstrated prevalence of RLS of approximately 5% among patients with a successful kidney transplant.55 However, this same group has shown that kidney transplant patients with RLS have a higher risk of premature death.26 Therapy The therapy of idiopathic RLS has been outlined in Chapter 90, and the core concepts described in that chapter apply to RLS in the setting of CKD. It should be recognized however, that understanding of the pharmacokinetics in CKD and efficacy of treatments in uremic RLS are limited by a paucity of high-quality evidence. Similar to idiopathic RLS, the treatments for uremic RLS need to be tailored to the severity of symptoms, and the initial approach should be nonpharmacologic. Several specific characteristics of uremic RLS should be considered. First, uremia can attenuate the response of RLS to dopamine. In a study of idiopathic RLS and uremic RLS, those with uremic RLS were less responsive to ldopa. However, other studies have demonstrated clinically significant effects of dopamine agonists on RLS symptoms in those undergoing hemodialysis. The timing and type of dialysis should be individualized to minimize symptoms of restless legs. For example, in our experience, patients who undergo hemodialysis in the evening and who have severe symptoms of restless legs can benefit from a change to the morning shift when symptoms of RLS may be less intense. Likewise, patients using continuous cycler peritoneal dialysis can benefit from a change to CAPD, which is done predominantly during the day. This change permits peritoneal dialysis patients to have more freedom to move in the late evening. Regardless of the type or timing of dialysis treatment, it is important to treat the RLS. The use of intravenous iron in the treatment of RLS among dialysis patients has been studied in a small doubleblinded randomized trial examining short-term changes in RLS symptoms and adverse treatment effects.56 Twentyfive hemodialysis patients with RLS were randomly assigned to receive either iron dextran (11 patients) or normal saline IV (14 patients). A single iron infusion was associated with a significant reduction in symptoms, which lasted only 2 weeks.56 Additional studies are needed to assess the impact of intravenous iron therapy on sleep quality, quality of life, and survival of this at-risk population. An approach to the treatment of RLS among patients with kidney failure has been outlined.57 Patients with complaints consistent with RLS should have a history and physical examination that excludes other etiologies such as peripheral vascular disease and neuropathy. In patients with infrequent RLS, the clinician should focus on nonpharmacologic interventions (e.g., using a bicycle, engag-
ing in distracting activities). If RLS is frequent and affects functioning, pharmacologic treatment can improve quality of life and encourage adherence to dialysis. RLS in ESRD also occurs in the milieu of other potential sleep disorders. If there is no improvement in daytime functioning or symptoms with treatment of RLS, it may be reasonable to reassess the patient closely for other chronic health conditions such as anemia and to have a low threshold for diagnostic polysomnography because there is a high rate of obstructive sleep-related breathing disorders.
PERIODIC LIMB MOVEMENTS IN PATIENTS WITH CHRONIC KIDNEY DISEASE RLS is diagnosed using a validated questionnaire based on standard criteria, but the diagnosis of PLMs requires monitoring of leg movements during sleep. (A complete discussion of PLMs is provided in Chapter 90.) A small study of dialysis patients that unfortunately did not account for comorbidities or RLS58 reported an association among PLMs, increased daytime sleep tendency, and shorter survival.58 In a study that examined both RLS and PLMs in conventional hemodialysis, there was not a substantial difference between those with and without PLMs in the domains of insomnia, daytime sleepiness, depression, and HRQOL.59 Given the small number of patients studied and the conflicting findings, the incidents, correlates, and outcomes associated with PLMs merit further study in the setting of kidney disease. SLEEP-RELATED BREATHING DISORDERS IN PATIENTS WITH CHRONIC KIDNEY DISEASE There is increasing evidence supporting an association between sleep-related breathing disorders (SRBDs) and CKD. In describing studies that have not delineated the type of sleep breathing disorder, this section uses the broad term SRBD and specifies the type or pattern of breathing disorder when permitted by the published data. In studies describing SRBDs, the severity is usually described using the apnea–hypopnea index (AHI), which is the frequency of apneas and hypopneas (average number of apneas + hypopneas per hour of sleep). A descriptive study of 35 patients with advanced CKD (mean creatinine clearance, 27 mL/min/1.73 m2) demonstrated that 50% had an AHI greater than 5, and approximately one third had an AHI greater than 15.60 However, these findings were limited by the lack of a comparison group without kidney disease but similar SRBD risk profile. The association of SRBD seems stronger with more advanced kidney disease, but the causal direction of this relationship is unclear, and there is no evidence of a cutpoint in kidney function where obstructive sleep apnea– hypopnea (OSAH) becomes more prevalent. A large epidemiologic study of elderly men examining the association between kidney function and obstructive SRBD suggested that age and BMI were important modifiers of a relationship between kidney function and SRBD.61 Further, in the same population of elderly men, higher AHI was
associated with higher quartiles of cystatin-C, a novel marker of kidney function that is thought to be less influenced by body mass.62 However, this association between cystatin-C and AHI was attenuated by adjustment for BMI.62 In a large registry study from Japan, the diagnosis of SRBD in a sleep center was associated with a higher rate of CKD compared to the prevalence of CKD in the population estimated from a large screening study of the general population.63 In another large crosssectional study of a health care plan database based in the United States, moderate kidney disease (eGFR < 45 mL/min/1.73 m2) was associated with an SRBD diagnosis using ICD-9 coding for sleep apnea and CPT coding for positive airway pressure devices.64 In this study, the risk for SRBD using administrative coding was approximately 30% higher among those with CKD compared to those without, but there was not a strong dose– response relationship between the severity of kidney dysfunction and sleep apnea. These findings highlight gaps in our understanding of the natural history of SRBD in CKD. The association of OSAH seems stronger with more-advanced kidney disease, but the causal direction of this relationship is unclear,64a and there is no evidence of a cutpoint in kidney function where SRDB becomes more prevalent.
SLEEP-RELATED BREATHING DISORDERS IN PATIENTS WITH END-STAGE RENAL DISEASE Studies estimating the prevalence of SRBD in ESRD with various methods such as sleep questionnaires, limited channel sleep studies, and overnight polysomnography (PSG) have consistently estimated that it is greater than 50%.30,36,65-73 However, most studies of patients with ESRD have been limited by small study samples,67,68,74-76 the use of limited channel sleep monitors,28,76,77 or study samples composed of symptomatic patients.65,68,71 A study examined sleep and SRBD among 46 hemodialysis patients and 137 participants without known kidney disease from the Sleep Heart Health Study matched for age, gender, race, and BMI.78 The study sample was 62.7 ± 10.1 years old, predominantly male (72%) and white (63%), with a BMI of 28 ± 5.3 kg/m2. Hemodialysis patients had a higher frequency of arousals per hour of sleep (25.1 versus 17.1; P < .0001), higher AHI (27.2 versus 15.2; P < .0001), and a greater percentage of total sleep time spent with oxyhemoglobin saturation below 90% (7.2% versus 1.8%; P < .0001). Moreover, the odds of ESRD patients having an AHI greater than 30 was fourfold higher compared to the controls. There remain gaps in our understanding of the relationship of SRBD to the type of dialysis and whether sleep apnea worsens when a patient with CKD starts dialysis. Despite these gaps in our knowledge, it is reasonable for clinicians caring for symptomatic patients with ESRD to have a high index of suspicion for OSAH. Pathophysiology ESRD can specifically contribute to OSAH through several pathways including uremia and volume overload.
CHAPTER 128 • Sleep in Chronic Kidney Disease 1467
Although community-based studies identify obesity, male gender, and increased neck circumference as risk factors for OSAH,79 these risk factors have not been associated with OSAH among patients with ESRD,30,65-67,80 although the samples were small in these studies. In a study of 58 patients with ESRD, those with SRBD (primarily obstructive), were found to have increased ventilatory sensitivity to progressive hypercapnia during wakefulness under both isoxic-hypoxia (Po2, 6.65 kPA) and isoxichyperoxia (Po2, 19.95 kPa) conditions compared to ESRD patients without SRBD.81 Because increased ventilatory chemosensitivity and increased loop gain are associated with ventilatory control instability and implicated in the pathophysiology of SRBD including OSAH and central sleep apnea or periodic breathing, it is plausible that this feature also contributes to the pathogenesis of SRBD in ESRD patients. The increased ventilatory sensitivity to hypercapnia under both isoxic hypoxia and isoxic hypercapnic conditions suggests that both central and peripheral chemoreceptor sensitivities are increased in patients with SRBD and ESRD, potentially leading to destabilization of respiratory control during sleep (see Chapter 100). Altered chemosensitivity during sleep might in part explain the development of OSAH in ESRD, other factors compromising upper airway patency in ESRD—including both extracellular fluid volume overload, which can lead to upper airway edema, and reduced upper airway muscle tone due to uremia82—are also likely contributors. Several mechanistic studies among healthy participants have suggested that fluid overload contributes to an increased propensity of obstructive sleep apnea due to localization of increased fluid in the neck.83 Investigators have demonstrated a narrowing of the airway among patients with ESRD using pharyngometry.84 Other potential contributors to the pathogenesis of OSAH in ESRD patients have also been proposed including upper airway uremic myopathy, neuropathy, uremic toxins, accumulation of cytokines, and increased extracellular fluid volume leading to narrowed upper airway.65,70,85-87 Influence of Breathing Disorders on Outcomes of Disease Obstructive sleep apnea–hypopnea contributes to the morbidity and mortality in the ESRD population. OSAH leads to the poor quality of life of those with ESRD65 by causing EDS and diminished quality of life.28,77,88 In a study examining the relationship between SRBD and HRQOL in ESRD patients, 21 of 31 subjects had an AHI greater than 5, and the median AHI was 13.3.77 Persons without OSAH (AHI < 5) scored more favorably in the SF-36 domains of vitality, social functioning, and mental health and the emotional reactions from the Nottingham Health Profile than those with sleep apnea.77 Both poor social functioning as obtained from the SF-36, and emotional reactions from the NHP were independently associated with the AHI after adjusting for body mass index. Because patients with ESRD have a 10- to 100fold higher risk of cardiovascular death compared to the general population, the role of OSAH as a potential risk factor has been explored.89,90 Chan’s group proposed that increased cardiac and peripheral adrenergic drive might
1468 PART II / Section 15 • Other Medical Disorders
Apnea–hypopnea index (episodes per hour of sleep)
80 70 60 50 40 30
†
20 10
A
0 On NPD
On CAPD P < .001
80 Obstructive apnea index (episodes per hour of sleep)
Treatment Both standard treatment of OSAH and using dialysis to reduce the severity of OSAH have been considered in the treatment of patients with ESRD. There is very limited literature on the efficacy of continuous positive airway pressure (CPAP) in the ESRD population. CPAP was used in a small study of eight patients with some improvement in nocturnal oxygenation and improved daytime alertness.85 CPAP is not widely used among patients with ESRD, and as few as 2% have the diagnosis based on administrative data (United States Renal Data Systems, personal communication). Along these lines, there is a paucity of data describing the effect of CPAP and related treatment outcomes in ESRD patients with SRBD. In light of the possibility that uremia per se contributes to the development of SRBD, some investigators have examined the effects of dialysis on SRBD. The contribution of uremia and volume overload to the pathogenesis of SRBD in ESRD is supported by improvement in SRBD following conversion from conventional thrice-weekly hemodialysis to nocturnal hemodialysis and improvement of SRBD with use of a nocturnal automated peritoneal cycler.70,94,95 In a small study performed at two dialysis centers, Tang and coworkers observed a reduction in the severity of SRBD with the use NPD.94 This study suggested that NPD might benefit patients with kidney failure compared to CAPD (prevalence of sleep apnea, 52% and 91%, respectively; P = .007). Twenty-four incident peritoneal dialysis patients underwent one polysomnogram (PSG) study during NPD while awaiting their turns for CAPD training and a second PSG recording shortly after they were established on a stable program of CAPD. AHI increased from a mean of 3.4 ± 1.34 during NPD to a mean of 14.0 ± 3.46 during CAPD (P < .001). The CAPD patient group also experienced a marked increase in weight (average increase, 2.7 kg), which might in part explain the increase in AHI. Further research demonstrated a marked rise in obstructive apnea (Fig. 128-3) and used volumetric MRI imaging to demonstrate reduced pharyngeal volumes after conversion from NPD to CAPD.95 These findings are consistent with the possibility that differences in fluid overload may have contributed to differences in the severity of OSAH between the two peritoneal dialysis methods in this study. Nocturnal hemodialysis is a novel hemodialysis technique that provides longer and more-frequent hemodi-
90
70 60 50 40 30 20 10 0
B
On NPD
On CAPD P = .03
Central apnea index (episodes per hour of sleep)
help explain why SRBD and nocturnal hypoxemia are associated with left ventricular hypertrophy,91 hypertension,92 and increased cardiovascular events in the ESRD population.90 In addition to the neurohormonal effects of SRBD, Jung and colleagues observed an association between AHI and coronary calcification scores in 26 hemodialysis patients.93 The authors proposed that intermittent cycles of nocturnal hypoxemia and reoxygenation might lead to oxidative stress, which promotes coronary calcification. Hypoxemia can also lead to increased sympathetic activity, vasoconstriction, and cardiac arrhythmia. A study in the hemodialysis population has demonstrated that nocturnal hypoxemia was independently associated with shorter survival.90
C
50 40 30 20 10 0 On NPD
On CAPD
Figure 128-3 Individual changes in overall apnea–hypopnea index (A), obstructive apnea index (B), and central apnea index (C) in 38 subjects during nocturnal peritoneal dialysis (NPD) and after conversion to continuous ambulatory peritoneal dialysis (CAPD).
alysis treatments. It has been shown to reduce SRBD compared to conventional daytime thrice-weekly hemodialysis. Following conversion from conventional thriceweekly dialysis to nocturnal hemodialysis, patients experienced a significant reduction in the severity of sleep apnea (AHI was reduced from 25 ± 25 to 8 ± 8 per
CHAPTER 128 • Sleep in Chronic Kidney Disease 1469
90 Apnea–hypopnea index
80 70 60 50 40 30 20 10 0 2 days after CHD
Day of CHD
On NHD
Off NHD
Figure 128-4 Apnea–hypopnea index in seven patients with a baseline apnea–hypopnea index higher than 15. The mean values are represented by the broken line. Data from the single patient who had Cheyne-Stokes respiration during conventional hemodialysis and persistent obstructive sleep apnea during nocturnal hemodialysis are represented by the black line. CHD, conventional hemodialysis; ND, nocturnal hemodialysis.
hour, P < .05).70 The effect of nocturnal hemodialysis was larger in patients who had a higher AHI on thriceweekly hemodialysis (AHI was reduced from 46 ± 19 to 9 ± 15 per hour, P < .05 (Fig. 128-4). This study also demonstrates that the effects of nocturnal hemodialysis on AHI dissipate with an increase in AHI after one evening off treatment, as shown by the trend toward more apnea the evening following nocturnal hemodialysis treatment, which suggests that it might not be only the timing of the hemodialysis but also the frequency that reduces the AHI. Chan and colleagues studied nine ESRD patients before and after conversion from conventional thriceweekly hemodialysis to nocturnal hemodialysis and 10 control participants without SRBD or known kidney disease.74 Nocturnal hemodialysis decreased the AHI (29.7 ± 9.3 to 8.2 ± 2.0, P = .02) and duration of nocturnal hypoxemia as measured by the percent of total sleep time with an oxygen saturation less than 90% (13.9 ± 5.2 to 2.6 ± 1.9%, P = .02).74 After conversion to nocturnal hemodialysis, heart rate fell and vagal tone increased as measured by high-frequency power using spectral analysis of heart rate variability.74 Although the findings from both the NPD and nocturnal hemodialysis studies are limited by the lack of an adequate control group, small sample size, and potential for selection bias, the results support the need to examine the impact of NPD and nocturnal hemodialysis on sleep apnea in larger randomized, controlled trials. These novel dialysis modalities may also be used in mechanistic studies to better understand the association of OSAH with kidney failure. Kidney Transplantation SRBD can contribute to the high prevalence of sleeprelated complaints in the kidney transplant population. Similar to nocturnal hemodialysis, improved clearance of
uremic toxins after successful kidney transplantation would be expected to alleviate OSAH. The relatively few studies of kidney transplant patients have provided conflicting findings regarding the effect of kidney transplantation on SRBD. In a larger study of kidney transplant recipients, Mallamaci’s group examined SRBD in 163 kidney transplant patients and compared these findings to both Italian and U.S. cohorts with measures of AHI. Their findings suggest that the severity of AHI in the kidney transplant population is no higher in that the prevalence found in matched controls.96 These results suggest that kidney transplantation mitigates the risk of sleep apnea; however, this report was limited by a cross-sectional design and by comparisons to control cohorts that measured AHI with different methods than the kidney transplant population.96 A study of nine hemodialysis patients with mild sleep apnea demonstrated improvement in AHI in eight after kidney transplantation.97 On the other hand, Beecroft and colleagues reported that only 3 of the 11 patients with SRBD improved after kidney transplantation.98 Although the authors found no significant correlation between response and BMI or comorbid conditions, the potential role of the immunosuppressive protocol including prescription of corticosteroids was not investigated.98 Because cardiovascular disease remains the leading cause of mortality in kidney transplant patients and sleep complaints are prevalent in transplant patients, further research is required to determine the extent to which kidney transplantation might improve OSAH. Thus, the available evidence indicates that there is a high prevalence of OSAH in patients with chronic kidney disease. This risk seems to begin with mild kidney disease and extends to patients undergoing conventional hemodialysis and peritoneal dialysis. Studies in the CKD population have been too small to assess the relationship of CKD to other established risk factors. The impact of kidney transplantation on OSAH remains to be defined. The high risk of SRBD in ESRD after accounting for comorbidities supports the position that there are unique factors associated with uremia. Limited data suggest that volume overload and higher chemoreceptor sensitivity predispose ESRD patients to upper airway obstruction during sleep, and further studies exploring these intriguing observations are required.
SUMMARY Sleep is disrupted in patients with kidney disease. This population has been shown to have higher prevalences of SRBD, insomnia, excessive daytime sleepiness, and restless legs syndrome compared to the general population. It remains to be shown whether the sleep disorders are a cause, consequence, or co-traveler with kidney disease. The diagnosis and treatment of sleep disorders in this population offers a tremendous opportunity to improve quality of life and perhaps cardiovascular outcomes. A number of novel therapies for ESRD, such as nocturnal hemodialysis and nocturnal peritoneal dialysis, might offer both treatment and insight for OSAH in the setting of kidney failure.
1470 PART II / Section 15 • Other Medical Disorders ❖ Clinical Pearls Patients with ESRD have been shown to have a high rate of insomnia, sleep apnea, restless legs, and PLMs. Sleep apnea in patients with chronic kidney disease can cause diminished quality of life, daytime symptoms of sleepiness and fatigue, and decreased mood. Sleep apnea in patients who have CKD and are on dialysis may be treated with CPAP or with a change in the type of dialysis. One approach to managing insomnia in ESRD is to optimize sleep hygiene, screen for other sleep disorders, and use a brief trial of cognitive behavior therapy or hypnotics (or both). The treatment of restless legs should be appropriate to the severity of symptoms and should start with eliminating aggravators, including appropriate iron stores and timing of dialysis.
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17. Abdel-Kader K, Unruh ML, Weisbord SD. Symptom burden, depression, and quality of life in chronic and end-stage kidney disease. Clin J Am Soc Nephrol 2009;4:1057-1064. 18. Noda A, Nakai S, Soga T, et al. Factors contributing to sleep disturbance and hypnotic drug use in hemodialysis patients. Intern Med 2006;45:1273-1278. 19. Unruh M, Benz R, Greene T, et al. Effects of hemodialysis dose and membrane flux on health-related quality of life in the HEMO Study. Kidney Int 2004;66:355-366. 20. Unruh ML, Newman AB, Larive B, et al. The influence of age on changes in health-related quality of life over three years in a cohort undergoing hemodialysis. J Am Geriatr Soc J 2008;56: 1608-1617. 21. Hays RD, Kallich JD, Mapes DL, et al. Development of the kidney disease quality of life (KDQOL) instrument. Qua Life Res 1994; 3:329-338. 22. Iliescu EA, Coo H, McMurray MH, et al. Quality of sleep and health-related quality of life in haemodialysis patients. Nephrol Dialy Transplant 2003;18:126-132. 23. Unruh ML, Buysse DJ, Dew MA, et al. Sleep quality and its correlates in the first year of dialysis. Clin J Am Soc Nephrol 2006;1: 802-810. 24. Elder SJ, Pisoni RL, Akizawa T, et al. Sleep quality predicts quality of life and mortality risk in haemodialysis patients: results from the Dialysis Outcomes and Practice Patterns Study (DOPPS). Nephrol Dial Transplant 2008;23:998-1004. 25. Molnar MZ, Novak M, Mucsi I. Sleep disorders and quality of life in renal transplant recipients. Int Urol Nephrol 2009;41: 373-382. 26. Molnar MZ, Szentkiralyi A, Lindner A, et al. Restless legs syndrome and mortality in kidney transplant recipients. Am J Kidney Dis 2007;50:813-820. 27. Ramkumar N, Beddhu S, Eggers P, et al. Patient preferences for in-center intense hemodialysis. Hemodial Int 2005;9:281295. 28. Kuhlmann U, Becker HF, Birkhahn M, et al. Sleep-apnea in patients with end-stage renal disease and objective results. Clin Nephrol 2000;53:460-466. 29. Parker KP, Kutner NG, Bliwise DL, et al. Nocturnal sleep, daytime sleepiness, and quality of life in stable patients on hemodialysis. Health Qual Life Outcomes 2003;1:68. 30. Stepanski E, Faber M, Zorick F, et al. Sleep disorders in patients on continuous ambulatory peritoneal dialysis. J Am Soc Nephrol 1995;6:192-197. 31. Hanly PJ, Gabor JY, Chan C, et al. Daytime sleepiness in patients with CRF: impact of nocturnal hemodialysis. Am J Kidney Dis 2003;41:403-410. 32. Parker KP, Bliwise DL, Bailey JL, et al. Daytime sleepiness in stable hemodialysis patients. Am J Kidney Dis 2003;41:394-402. 33. Kimmel PL, Gavin C, Miller G, et al. Disordered sleep and noncompliance in a patient with end-stage renal disease. Adv Ren Replace Ther 1997;4:55-67. 34. Kurella M, Luan J, Lash JP, et al. Self-assessed sleep quality in chronic kidney disease. Int Urol Nephrol 2005;37:159-165. 34a. Kumar B, Tilea A, Gillespie BW, et al. Significance of self-reported sleep quality (SQ) in chronic kidney disease (CKD): the Renal Research Institute (RRI)-CKD study. Clin Nephrol 2010;73: 104-114. 35. Sabbatini M, Minale B, Crispo A, et al. Insomnia in maintenance haemodialysis patients. Nephrol Dial Transplant 2002;17:852-856. 36. Jurado-Gamez B, Martin-Malo A, Alvarez-Lara MA, et al. Sleep disorders are underdiagnosed in patients on maintenance hemodialysis. Nephron Clin Pract 2007;105:c35-c42. 37. Unruh ML, Redline S, An MW, et al. Subjective and objective sleep quality and aging in the sleep heart health study. J Am Geriatr Soc 2008;56:1218-1227. 38. Barmar B, Dang Q, Isquith D, et al. Comparison of sleep/wake behavior in CKD stages 4 to 5 and hemodialysis populations using wrist actigraphy. Am J Kidney Dis 2009;53:665-672. 39. Sabbatini M, Crispo A, Pisani A, et al. Zaleplon improves sleep quality in maintenance hemodialysis patients. Nephron Clin Prac 2003;94:c99-c103. 40. Chen HY, Chiang CK, Wang HH, et al. Cognitive-behavioral therapy for sleep disturbance in patients undergoing peritoneal dialysis: a pilot randomized controlled trial. Am J Kidney Dis 2008; 52:314-323.
41. Parker KP, Bliwise DL, Rye DB. Hemodialysis disrupts basic sleep regulatory mechanisms: building hypotheses. Nurs Res 2000; 49:327-332. 42. Parker KP, Bailey JL, Rye DB, et al. Lowering dialysate temperature improves sleep and alters nocturnal skin temperature in patients on chronic hemodialysis. J Sleep Res 2007;16:42-50. 43. Karasek M, Szuflet A, Chrzanowski W, et al. Circadian serum melatonin profiles in patients suffering from chronic renal failure. Neuro Endocrinol Lett 2002;23(Suppl. 1):97-102. 43a. Koch BC, van der Putten K, Van Someren EJ, et al. Impairment of endogenous melatonin rhythm is related to the degree of chronic kidney disease (CREAM study). Nephrol Dial Transplant 2010;25: 513-519. 44. Koch BC, Nagtegaal JE, Kerkhof GA, et al. Circadian sleep–wake rhythm disturbances in end-stage renal disease. Nat Rev Nephrol 2009. 45. Koch BC, Hagen EC, Nagtegaal JE, et al. Effects of nocturnal hemodialysis on melatonin rhythm and sleep–wake behavior: an uncontrolled trial. Am J Kidney Dis 2009;53:658-664. 46. Siddiqui S, Kavanagh D, Traynor J, et al. Risk factors for restless legs syndrome in dialysis patients. Nephron Clin Pract 2005; 101:c155-c160. 47. Allen R, Earley C. Validation of a diagnostic questionnaire for RLS. Neurology 2001;56:A4. 48. Cirignotta F, Mondini S, Santoro A, et al. Reliability of a questionnaire screening restless legs syndrome in patients on chronic dialysis. Am J Kidney Dis 2002;40:302-306. 49. Ruottinen HM, Partinen M, Hublin C, et al. An FDOPA PET study in patients with periodic limb movement disorder and restless legs syndrome. Neurology 2000;54:502-504. 50. Unruh ML, Levey AS, D’Ambrosio C, et al. Restless legs symptoms among incident dialysis patients: association with lower quality of life and shorter survival. Am J Kidney Dis 2004;43:900-909. 51. Mucsi I, Molnar MZ, Ambrus C, et al. Restless legs syndrome, insomnia and quality of life in patients on maintenance dialysis. Nephrol Dial Transplant 2005;20:571-577. 52. Winkelman JW, Chertow GM, Lazarus JM. Restless legs syndrome in end-stage renal disease. Am J Kidney Dis 1996;28: 372-378. 53. Lofaso F, Coste A, Gilain L, et al. Sleep fragmentation as a risk factor for hypertension in middle-aged nonapneic snorers. Chest 1996;109:896-900. 54. Winkelmann J, Stautner A, Samtleben W, et al. Long-term course of restless legs syndrome in dialysis patients after kidney transplantation. Mov Disord 2002;17:1072-1076. 55. Molnar MZ, Novak M, Ambrus C, et al. Restless legs syndrome in patients after renal transplantation. Am J Kidney Dis 2005;45: 388-396. 56. Sloand JA, Shelly MA, Feigin A, et al. A double-blind, placebocontrolled trial of intravenous iron dextran therapy in patients with ESRD and restless legs syndrome. Am J Kidney Dis 2004;43: 663-670. 57. Perl J, Unruh ML, Chan CT. Sleep disorders in end-stage renal disease: “Markers of inadequate dialysis”? Kidney Int 2006;70: 1687-1693. 58. Benz RL, Pressman MR, Hovick ET, et al. Potential novel predictors of mortality in end-stage renal disease patients with sleep disorders. Am J Kidney Dis 2000;35:1052-1060. 59. Rijsman RM, de Weerd AW, Stam CJ, et al. Periodic limb movement disorder and restless legs syndrome in dialysis patients. Nephrology (Carlton) 2004;9:353-361. 60. Markou N, Kanakaki M, Myrianthefs P, et al. Sleep-disordered breathing in nondialyzed patients with chronic renal failure. Lung 2006;184:43-49. 61. Canales MT, Lui LY, Taylor BC, et al. Renal function and sleepdisordered breathing in older men. Nephrol Dial Transplant 2008;23:3908-3914. 62. Canales MT, Taylor BC, Ishani A, et al. Reduced renal function and sleep-disordered breathing in community-dwelling elderly men. Sleep Med 2008;9:637-645. 63. Iseki K, Tohyama K, Matsumoto T, et al. High prevalence of chronic kidney disease among patients with sleep related breathing disorder (SRBD). Hypertens Res 2008;31:249-255. 64. Sim JJ, Rasgon SA, Kujubu DA, et al. Sleep apnea in early and advanced chronic kidney disease: Kaiser Permanente Southern California cohort. Chest 2009;135:710-716
CHAPTER 128 • Sleep in Chronic Kidney Disease 1471 64a. Adeseun GA, Rosas SE. The Impact of Obstructive Sleep Apnea on Chronic Kidney Disease. Curr Hypertens Rep 2010 Jul 31. [Epub ahead of print] 65. Kimmel PL, Miller G, Mendelson WB. Sleep apnea syndrome in chronic renal disease. Am J Med 1989;86:308-314. 66. Fletcher EC. Obstructive sleep apnea and the kidney. J Am Soc Nephrol 1993;4:1111-1121. 67. Wadhwa NK, Mendelson WB. A comparison of sleep-disordered respiration in ESRD patients receiving hemodialysis and peritoneal dialysis. Adv Perit Dial 1992;8:195-198. 68. Benz RL, Pressman MR, Hovick ET, et al. A preliminary study of the effects of correction of anemia with recombinant human erythropoietin therapy on sleep, sleep disorders, and daytime sleepiness in hemodialysis patients (The SLEEPO study). Am J Kidney Dis 1999;34:1089-1095. 69. Hallett M, Burden S, Stewart D, et al. Sleep apnea in end-stage renal disease patients on hemodialysis and continuous ambulatory peritoneal dialysis. ASAIO J 1995;41:M435-M441. 70. Hanly PJ, Pierratos A. Improvement of sleep apnea in patients with chronic renal failure who undergo nocturnal hemodialysis. N Engl J Med 2001;344:102-107. 71. Millman RP, Kimmel PL, Shore ET, et al. Sleep apnea in hemodialysis patients: the lack of testosterone effect on its pathogenesis. Nephron 1985;40:407-410. 72. Parker KP, Bliwise DL. Clinical comparison of hemodialysis and sleep apnea patients with excessive daytime sleepiness. ANNA J 1997;24:663-665. 73. Venmans BJ, van Kralingen KW, Chandi DD, et al. Sleep complaints and sleep disordered breathing in hemodialysis patients. Neth J Med 1999;54:207-212. 74. Chan CT, Hanly P, Gabor J, et al. Impact of nocturnal hemodialysis on the variability of heart rate and duration of hypoxemia during sleep. Kidney Int 2004;65:661-665. 75. Mendelson WB, Wadhwa NK, Greenberg HE, et al. Effects of hemodialysis on sleep apnea syndrome in end-stage renal disease. Clin Nephrol 1990;33:247-251. 76. Venmans BJW, van Kralingen KW, Chandi DD, et al. Sleep complaints and sleep disordered breathing in hemodialysis patients. Neth J Med 1999;54:207-212. 77. Sanner BM, Tepel M, Esser M, et al. Sleep-related breathing disorders impair quality of life in haemodialysis recipients. Nephrol Dial Transplant 2002;17:1260-1265. 78. Unruh ML, Sanders MH, Redline S, et al. Sleep apnea in patients on conventional thrice-weekly hemodialysis: comparison with matched controls from the Sleep Heart Health Study. J Am Soc Nephrol 2006;17:3503-3509. 79. Young T, Shahar E, Nieto FJ, et al. Predictors of sleep-disordered breathing in community-dwelling adults: the Sleep Heart Health Study. Arch Intern Med 2002;162:893-900. 80. Zoccali C, Mallamaci F, Tripepi G. Sleep apnea in renal patients. J Am Soc Nephrol 2001;12:2854-2859. 81. Beecroft J, Duffin J, Pierratos A, et al. Enhanced chemo-responsiveness in patients with sleep apnoea and end-stage renal disease. Eur Respir J 2006;28:151-158. 82. Hanly P. Sleep apnea and daytime sleepiness in end-stage renal disease. Semin Dial 2004;17:109-114. 83. Su MC, Chiu KL, Ruttanaumpawan P, et al. Difference in upper airway collapsibility during wakefulness between men and women in response to lower-body positive pressure. Clin Sci (Lond) 2009; 116:713-720. 84. Beecroft JM, Hoffstein V, Pierratos A, et al. Pharyngeal narrowing in end-stage renal disease: implications for obstructive sleep apnoea. Eur Respir J 2007;30:965-971. 85. Pressman MR, Benz RL, Schleifer CR, et al. Sleep disordered breathing in ESRD: acute beneficial effects of treatment with nasal continuous positive airway pressure. Kidney Int 1993;43:1134-1139. 86. Wadhwa NK, Akhtar S. Sleep disorders in dialysis patients. Semin Dial 1998;11:287-297. 87. Kimmel P. Sleep apnea in end-stage renal disease. Semin Dial 1991;4:52-58. 88. Shayamsunder AK, Patel SS, Jain V, et al. Sleepiness, sleeplessness, and pain in end-stage renal disease: distressing symptoms for patients. Semin Dial 2005;18:109-118. 89. Zoccali C, Mallamaci F, Tripepi G. Nocturnal hypoxemia: a neglected cardiovascular risk factor in end-stage renal disease? Blood Purif 2002;20:120-123.
1472 PART II / Section 15 • Other Medical Disorders 90. Zoccali C, Mallamaci F, Tripepi G. Nocturnal hypoxemia predicts incident cardiovascular complications in dialysis patients. J Am Soc Nephrol 2002;13:729-733. 91. Zoccali C, Mallamaci F, Tripepi G, et al. Autonomic neuropathy is linked to nocturnal hypoxaemia and to concentric hypertrophy and remodelling in dialysis patients. Nephrol Dial Transplant 2001; 16:70-77. 92. Zoccali C, Benedetto FA, Tripepi G, et al. Nocturnal hypoxemia, night-day arterial pressure changes and left ventricular geometry in dialysis patients. Kidney Int 1998;53:1078-1084. 93. Jung HH, Han H, Lee JH. Sleep apnea, coronary artery disease, and antioxidant status in hemodialysis patients. Am J Kidney Dis 2005; 45:875-882. 94. Tang SC, Lam B, Ku PP, et al. Alleviation of sleep apnea in patients with chronic renal failure by nocturnal cycler-assisted peritoneal
dialysis compared with conventional continuous ambulatory peritoneal dialysis. J Am Soc Nephrol 2006;17:2607-2616. 95. Tang SC, Lam B, Lai AS, et al. Improvement in sleep apnea during nocturnal peritoneal dialysis is associated with reduced airway congestion and better uremic clearance. Clin J Am Soc Nephrol 2009;4:410-418. 96. Mallamaci F, Leonardis D, Tripepi R, et al. Sleep disordered breathing in renal transplant patients. Am J Transplant 2009;9: 1373-1381. 97. Jurado-Gamez B, Martin-Malo A, Rodriguez-Benot A, et al. Kidney transplantation improves sleep-related breathing in hemodialysis patients. Blood Purif 2008;26:485-490. 98. Beecroft JM, Zaltzman J, Prasad R, et al. Impact of kidney transplantation on sleep apnoea in patients with end-stage renal disease. Nephrol Dial Transplant 2007;22:3028-3033.
Psychiatric Disorders Ruth M. Benca 129 Anxiety Disorders 130 Mood Disorders 131 Schizophrenia 132 Medication and Substance Abuse
Anxiety Disorders
Anxiety disorders are often associated with complaints of disturbed sleep. This chapter provides a review of the diagnostic criteria, sleep features, and treatment of sleep-related problems in patients with panic disorder, generalized anxiety disorder (GAD), social phobia, obsessive–compulsive disorder (OCD), and posttraumatic stress disorder (PTSD). Subjective sleep complaints are most prominent in patients with PTSD,
Anxiety disorders are the most common group of mental disorders, affecting more than 18% of persons in the general population in a 1-year period,1 and even more during a lifetime. The National Comorbidity Survey Replication (NCS-R), a large, cross-national epidemiologic survey conducted in 2001 to 2003, found that 28.8% of adults in the age group 18 years and older had a lifetime anxiety disorder diagnosis.2 Up to one third of the population experiences insomnia at any given time,3-5 and insomnia is often comorbid with mental disorders.3,6 The extant data suggest that although the relationship of anxiety and insomnia is bidirectional, the most typical pattern is for insomnia to begin concurrent with or following the onset of an anxiety disorder.3,7-9 Thus, from an epidemiologic perspective, the onset of an anxiety disorder often heralds the onset of sleep problems, suggesting that a sizable portion of the burden of insomnia in the general population is associated with—and perhaps even etiologically attributable to—anxiety disorders. Anxiety disorders are also commonly seen in patients presenting in primary care settings for general medical care, where complaints of sleep problems are often prominent.10 Sleep disturbances are included among the diagnostic features of posttraumatic stress disorder (PTSD) and generalized anxiety disorder (GAD), two of the six categories for anxiety disorders in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Sleep disturbances are commonly associated with other anxiety disorders, although they are not incorporated into the diagnostic criteria, per se (e.g., panic disorder). Treatments for sleep problems and those targeting worry,
16 Chapter
Holly Ramsawh, Murray B. Stein, and Thomas A. Mellman
Abstract
Section
129
panic disorder, and GAD, and they must be understood in the context of depressive disorders that are commonly comorbid. Abrupt nocturnal awakenings are not uncommonly encountered in anxiety disorders such as panic disorder and PTSD, where they are thought to be related to non–rapid eye movement (NREM) and REM sleep, respectively. Treatments that target sleep can improve outcomes in patients with anxiety disorders.
tension, and other manifestations of anxiety often use similar approaches (e.g., cognitive or behavioral techniques, benzodiazepine medications, relaxation). Thus, from a clinical perspective, it is important to consider the diagnosis and treatment of anxiety disorders when caring for a patient with prominent sleep complaints. The converse is equally true: Attention to sleep problems is integral to the management of patients with anxiety disorders. There are also theoretical links between anxiety and sleep disorders. Sleep is a necessary and restorative state of diminished cortical arousal. Anxiety and fear states manifest with heightened cortical and peripheral arousal. Increased arousal is also implicated when sleep initiation or maintenance are disturbed. Thus, insights into mechanisms regulating arousal would be applicable as well to anxiety and sleep disorders (and their overlapping features). Whereas sleep has been extensively studied in depressive disorders, the polysomnographic (PSG) study of anxiety disorders is less well developed. PSG studies of anxiety disorders provide information regarding measurable objective disturbances in initiating and maintaining sleep and in sleep structure, as well as the presence of a primary sleep pathologic process. Such studies are the primary focus of the material reviewed in this chapter. Sleep disturbance does not seem related to specific phobias, and this subject has been little studied, so it is not included here. In the cases of panic disorder and PTSD, an additional focus relates to the core paroxysmal events that can manifest in relation to sleep (e.g., panic attacks, 1473
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nightmares). This chapter also reviews current pathophysiologic concepts for sleep disturbances in the anxiety disorders, and it reviews the types of treatments (and their outcomes) that target or indirectly influence sleep in these conditions.
PANIC DISORDER Epidemiology and Clinical Features Panic disorder has a 12-month general population prevalence of 2% to 3%, is more common in women than men, and has a typical age of onset in late teens or early twenties (although it can start earlier in life).1,2 Onset is rare in older adulthood.2 The characteristic feature of panic disorder is recurrent unexpected panic attacks (Box 129-1), which are acute episodes of severe anxiety associated with a wide array of somatic symptoms, such as chest pain, tachycardia, shortness of breath, psychosensory disturbances (i.e., changes in sound or light intensity, alterations in the perception of time, derealization), and lightheadedness. Classic panic attacks reach peak severity quickly and last only seconds to minutes in most cases. Panic attacks can occur during sleep; in this chapter, the terms nocturnal panic and sleep panic are synonymous and refer to the same phenomenon. Panic disorder is diagnosed when a person experiences recurrent unexpected panic attacks. Some persons experience infrequent panic attacks for years without conspicuous changes in their health. More often, however, panic attacks are complicated by anticipatory anxiety (i.e., apprehension about future attacks) or worry about possible underlying medical disorders (e.g., heart disease). Such concerns, if lasting for 1 month or longer after the panic
Box 129-1 DSM-IV Criteria for Panic Attack Panic attack is a discrete period of intense fear or discomfort, in which four (or more) of the following symptoms developed abruptly and reached a peak within 10 minutes: • Palpitations, pounding heart, or accelerated heart rate • Sweating • Trembling or shaking • Sensations of shortness of breath or smothering • Feeling of choking • Chest pain or discomfort • Nausea or abdominal distress • Feeling dizzy, unsteady, lightheaded, or faint • Derealization (feelings of unreality) or depersonalization (being detached from oneself) • Fear of losing control or going crazy • Fear of dying • Paresthesias (numbness or tingling sensations) • Chills or hot flashes DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Adapted with permission from the American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Press; 1994. Copyright 1994 American Psychiatric Association.
attack or attacks, justify the diagnosis of panic disorder. Alternatively, behavioral change (e.g., frequent visits to the emergency department; avoidance of places where attacks have occurred in the past) subsequent to the attacks also justifies this diagnosis. Patients also may become frightened of places or situations in which unexpected panic attacks have occurred. Marked distress in—or the actual avoidance of—places (e.g., bridges, tunnels, airplanes) or situations (e.g., driving, shopping, traveling) in which unexpected panic attacks or panic-like symptoms have occurred in the past is referred to as agoraphobia (Box 129-2). Depending on the absence or presence, respectively, of agoraphobia, patients are given a diagnosis of panic disorder without or with agoraphobia (Boxes 129-3 and 129-4). Agoraphobia can also occur independently of panic disorder, although this is thought to be relatively rare. In such circumstances, agoraphobia (i.e., fear and avoidance of particular situations owing to fear of incapacitation or embarrassment) may be a complication of illness (and the repercussions thereof) such as vertigo or other forms of physical incapacity. Sleep Features The extant literature suggests that at least two thirds of patients with panic disorder report moderate to severe
Box 129-2 Criteria for Agoraphobia* Agoraphobia is anxiety about being in places or situations from which escape might be difficult (or embarrassing) or in which help might not be available in the event of having an unexpected or situationally predisposed panic attack or panic-like symptoms. Agoraphobic fears typically involve characteristic clusters of situations that include being outside the home alone, being in a crowd or standing in a line, being on a bridge, and traveling in a bus, train, or automobile. Consider the diagnosis of specific phobia if the avoidance is limited to one or only a few specific situations. Consider social phobia if the avoidance is limited to social situations. The person avoids situations (e.g., travel is restricted) or else endures them with marked distress or with anxiety about having a panic attack or paniclike symptoms or requires the presence of a companion. The anxiety or phobic avoidance is not better accounted for by another mental disorder, such as social phobia (e.g., avoidance is limited to social situations because of fear of embarrassment), specific phobia (e.g., avoidance is limited to a single situation, such as elevators), obsessive–compulsive disorder (e.g., avoidance of dirt in someone with an obsession about contamination), posttraumatic stress disorder (e.g., avoidance of stimuli associated with a severe stressor), or separation anxiety disorder (e.g., avoidance of leaving home or relatives). * Agoraphobia is not a DSM-IV disorder that can be coded. Code the specific disorder in which the agoraphobia occurs (e.g., panic disorder with agoraphobia or agoraphobia without history of panic disorder). DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition.
CHAPTER 129 • Anxiety Disorders 1475
Box 129-3 DSM-IV Criteria for Panic Disorder without Agoraphobia Panic disorder without agoraphobia includes: • Recurrent unexpected panic attacks • At least one of the attacks has been followed by 1 month (or more) of one (or more) of the following: • Persistent concern about having additional attacks • Worry about the implications of the attack or its consequences (e.g., losing control, having a heart attack, “going crazy”) • A significant change in behavior related to the attacks • The absence of agoraphobia The panic attacks are not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hyperthyroidism) The panic attacks are not better accounted for by another mental disorder such as social phobia (e.g., occurring on exposure to feared social situations), specific phobia (e.g., on exposure to a specific phobic situation), obsessive–compulsive disorder (e.g., on exposure to dirt in someone with an obsession about contamination), posttraumatic stress disorder (e.g., in response to stimuli associated with severe stressor), or separation anxiety (e.g., in response to being away from home or close relatives). DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Adapted with permission from the American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Press; 1994. Copyright 1994 American Psychiatric Association.
Box 129-4 DSM-IV Criteria for Panic Disorder with Agoraphobia Panic disorder with agoraphobia: • Meets the criteria for panic disorder • Meets the criteria for agoraphobia DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Adapted with permission from the American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Press; 1994. Copyright 1994 American Psychiatric Association.
sleep difficulties, including difficulty initiating and maintaining sleep, nonrestorative sleep, and nocturnal panic attacks.11-13 Sleep difficulties and sleep deprivation can lead to worsening of anxiety symptoms, including panic attacks, in patients with panic disorder.14 Most PSG studies have found decreased sleep efficiency and sleep duration with panic disorder,15-19 although some studies have not found such disturbances.20 Because panic disorder and major depression are often comorbid, it is possible that comorbid depression may be partially responsible for sleep disturbances in panic disorder; however, some of these studies have excluded subjects with comorbid depression.17,19,20 Of
those excluding comorbid depression, some still found evidence for sleep disturbance in persons with panic disorder.17,19 One type of sleep disturbance reported to occur in panic disorder is isolated sleep paralysis, a transient gross motor paralysis that can occur at sleep onset or offset in persons without narcolepsy. It appears to arise when the involuntary immobility characteristic of rapid eye movement (REM) sleep intrudes into the waking state. In addition to being unable to move during isolated sleep paralysis, some patients report anxiety, chest pressure, and other somatic sensations. Isolated sleep paralysis has been reported in association with panic disorder,21-24 although it can also occur in other anxiety disorders (see also Posttraumatic Stress Disorder, later). A study investigated the prevalence of isolated sleep paralysis in a small, mostly white outpatient sample.25 In this sample, the prevalence of isolated sleep paralysis in subjects with a primary diagnosis of panic disorder (20.8%) did not seem differentially higher than that in sleep paralysis (22.2%) or GAD (15.8%). Because the prevalence of isolated sleep paralysis in persons with panic disorder is reportedly higher in certain ethnic minority groups,22,23 more ethnically diverse clinical samples might yield different findings. Several surveys and studies of populations with panic disorder have documented the occurrence of panic attacks emerging from sleep as a not uncommon feature of the disorder. These episodes are often described as being awakened abruptly from sleep, usually with physical symptoms such as shortness of breath that also characterize the person’s panic attacks in awake states. Sleep panic attack episodes appear to be NREM sleep phenomena that occur at the transition between sleep stages N2 and N3 (non– rapid eye movement [NREM] sleep stages 2 and 3), and thus they are not associated with dream mentation.15,26 Approximately one half of patients with panic disorder report experiencing sleep panic attacks at some point during the course of their illness.11,27 Some studies estimate that up to one third of patients experience recurrent nocturnal panic.11,12,27,28 Although it has been suggested that nocturnal panic may itself be a marker of more-severe panic disorder,27,29 this has not consistently been found across studies.28,30,31 Nocturnal panic appears to be associated with states of diminished arousal such as sleep and relaxation.11,31-33 Although greater motor activity during sleep as evidenced by increased epochs of movement time has been reported with panic disorder, patients might actually move less on the nights when they experience sleep panic attacks,34 leading the authors to suggest that movement during sleep may serve as a temporary protective mechanism against the episodes. Several authors have suggested that the occurrence of panic attacks during NREM sleep implicates a more endogenous, physiologic (rather than cognitive or attributional) explanatory mechanism. Specific mechanisms that have been proposed include sensitivity to subtle increases in blood carbon dioxide levels,35 irregular breathing during slow-wave sleep,36 and abnormalities in autonomic activity.15,16,33 In addition, sodium lactate administered during sleep was found to be associated with increased cardiac and respiratory reactivity in panic disorder patients relative to
1476 PART II / Section 16 • Psychiatric Disorders
controls,37 and pentagastrin administered during sleep resulted in abrupt awakenings accompanied by panic symptoms in patients with panic disorder.38 These findings have been upheld as evidence for a physiologic explanation for nocturnal panic, because during sleep the influence of cognitive factors is purportedly minimal or absent. However, several studies suggest that cognitive factors also play a role. In an investigation employing caffeine administration during sleep, more fully elaborated panic attacks were preceded by a period of lighter sleep before awakening, providing support for a mixture of physiologic and cognitive influences on sleep panic.39 In another study, participants with recurrent nocturnal panic attacks who were primed to expect intense physiologic changes during sleep (as indicated by an auditory signal) were less likely to awaken with panic symptoms than those for whom such a signal was unexpected, highlighting a role for presleep attributions.40 Physiologic differences in those with nocturnal panic have also been found to normalize with cognitive behavior therapy (CBT).41 Based on this evidence, it has been argued that although physiologic differences exist for those with nocturnal panic, they should be seen as a function of panic disorder psychopathology rather than as an explanatory mechanism.33 Treatment The aim of drug treatment is to block panic attacks (waking and nocturnal panic attacks) and to eliminate secondary fears and avoidance activities (e.g., sleep phobias). The removal of exogenous (e.g., caffeine) factors or the correction of maladaptive behavior (e.g., sleep deprivation) that often exacerbate panic disorder should also be an integral part of the drug treatment program. If a thorough medical assessment has not recently been performed, this should be conducted (including, routinely, thyroid-stimulating hormone measurement to rule out most thyroid problems) before proceeding with antipanic treatments. Historically, tricyclic antidepressants (e.g., imipramine) and monoamine oxidase inhibitors (e.g., phenelzine) were mainstays in the treatment of panic disorder. For reasons of tolerability and safety, these have been largely supplanted by the selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine, sertraline, paroxetine, and
controlled-release paroxetine, which are approved by the U.S. Food and Drug Administration (FDA) for this purpose. The SSRIs have been found to be effective in the treatment of panic disorder (with or without agoraphobia). High-potency benzodiazepines (alprazolam, extendedrelease alprazolam, and clonazepam are approved by the FDA for this purpose) have also been widely used to treat panic disorder (with or without agoraphobia). Some medications (e.g., propranolol, buspirone) used often in the management of other forms of anxiety have been shown to be ineffective in the treatment of panic disorder.42,43 Although there has been little pharmacologic research on the treatment of sleep disturbances associated with panic disorder, preliminary observations suggest that sleep panic attacks are responsive to antidepressant antipanic medications.44,45 Research has shown CBT to be at least as beneficial as first-line drug treatments.46 CBT involves challenging irrational thoughts about panic symptoms and their consequences, the elimination of avoidance behavior, and gradual exposure to feared interoceptive sensations and agoraphobic situations. CBT also has the benefit of yielding long-lasting effects.46 It is unclear whether standard CBT for panic disorder is beneficial in improving sleep, although one study suggests that combined pharmacologic treatment and CBT was insufficient in eliminating objective and self-reported sleep disturbances.19 One CBT study included modifications targeted to nocturnal panic, such as psychoeducation about normal physiologic changes during sleep, challenging of catastrophic thoughts about nocturnal panic, interoceptive exposure to relaxation conditions, and sleep hygiene.41 Compared to waitlist controls, participants who received this intervention fared better on measures of physiologic and self-reported anxiety and sleep quality, including nocturnal panic specifically. There is otherwise little information to guide the specific treatment of patients with panic disorder who have nocturnal panic attacks; this remains an area ripe for further research. In the absence of empirical data in this regard, it is recommended that patients with significant sleep disturbance including nocturnal panic attacks be treated with an antipanic agent or with CBT and that they be instructed on the implementation of good sleep hygiene measures (see Chapters 79 and 80).
Case Study: Sleep Panic Ms. R. is a 28-year-old woman with a 2- to 3-month history of onset of episodes during sleep where she awakes abruptly with a feeling of fear and shortness of breath. She is also aware of tachycardia at the time of awakening. She otherwise feels intensely alert, with no sense of confusion and no dream recall on awakening. She and her significant other deny somnambulism. After experiencing an episode, she typically gets out of bed and has great difficulty going back to sleep. She also reports increasing worries and avoidance about going to sleep. The patient reports that she has been experiencing somewhat similar attacks during the daytime on an
occasional basis since the age of 17 years. She reports having experienced these episodes—which feature shortness of breath, tremulousness, tachycardia, and dizziness—several times weekly from 17 to 20 years of age; during this period, she sought care in the emergency department and had multiple medical tests to rule out a seizure disorder or a vestibular disorder. The attacks eventually waned, although she admits to experiencing lesser forms of these attacks once or twice monthly from age 20 years through to the time of her presentation. She states that she had learned that these attacks, although bothersome, were not dangerous, and she was able to function well despite
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their continued occurrence during this period. Because the pattern of attacks has now changed to occur during sleep, she is concerned that her belief about their innocuous nature might be mistaken. She also admits to an increase in work-related stresses concurrent with the onset of the nocturnal attacks. She is not depressed and denies suicidal ideation. She also denies substance abuse or excessive caffeine use. Although Ms. R. was thin and had no obvious physical risk factors for sleep apnea, an ambulatory sleepbreathing evaluation was conducted. That revealed no evidence of obstructive apnea. Thyroid-stimulating hormone level was normal.
GENERALIZED ANXIETY DISORDER Epidemiology and Clinical Features GAD is typified by chronic anxiety and excessive, pervasive worry (Box 129-5). In community surveys, the 12-month prevalence of GAD is approximately 3%,1 with lifetime rates being higher (approximately 6%).2 As is the case for all of the anxiety disorders (with the exception of obsessive–compulsive disorder [OCD]) the prevalence is higher in women than in men, with GAD showing an approximate 2 : 1 female-to-male ratio. The natural course of GAD can be characterized as chronic, with few complete remissions, a waxing and waning course of symptoms, and the substantial depressive comorbidity. GAD, it might be argued, has been poorly named. This has led to a tendency to consider it a generic form of anxiety and to make the diagnosis inappropriately and pervasively. Many anxiety (and depressive) disorders are characterized by chronic anxiety and tension; these features alone are therefore insufficient to make this diagnosis. It is the presence of excessive and uncontrollable worry about multiple factors—such as work, health, and the well-being and safety of family members—that defines GAD. Patients with GAD often present to their primary care practitioner, where somatic complaints (e.g., headache, back or shoulder pain due to chronic muscle tension, chronic gastrointestinal distress) might predominate. Sleep Features Insomnia and GAD are highly overlapping and comorbid disorders. Sleep disturbance, further defined as difficulty initiating or maintaining sleep, or sleep that is restless and unsatisfying, is one of the six features (a minimum of three of which are needed to establish the diagnosis) associated with chronic worry in the DSM-IV criteria for GAD. Three of the other five features—fatigue, irritability, and difficulty concentrating—are also possible consequences of sleep loss. The core cognitive feature of GAD, excessive worry (“apprehensive expectation”), is commonly implicated in the genesis and maintenance of insomnia problems, in that patients often report their worry as most uncontrollable and bothersome at bedtime, interfering with their ability to fall asleep. In a study of comorbid psychiatric disorders in an insomnia sample, GAD was the most commonly diagnosed anxiety disorder.47 Conversely, difficulty sleeping has been reported in 56% to 75% of
In light of the clear history of daytime panic attacks in the past, despite their relative infrequency lately, a probable diagnosis of panic disorder was applied. Ms. R. was given a choice of participating in a course of CBT directed toward the panic disorder or starting on an antianxiety medication that would be intended to block the occurrence of the attacks. Citing time constraints that would make it difficult for her to begin CBT, she opted for treatment with an SSRI, a pharmacologic treatment with a good evidence base for its efficacy in the treatment of panic disorder (although data supporting the efficacy of any treatment specifically for nocturnal panic are sorely lacking).
Box 129-5 DSM-IV Criteria for Generalized Anxiety Disorder Generalized anxiety disorder consists of excessive anxiety and worry (apprehensive expectation) occurring more days than not for at least 6 months about a number of events or activities (such as work or school performance). The person finds it difficult to control the worry. The anxiety and worry are associated with three (or more) of the following six symptoms, with at least some symptoms present for more days than not for the past 6 months. Only one item is required in children: • Restlessness or feeling keyed up or on edge • Being easily fatigued • Difficulty concentrating or mind going blank • Irritability • Muscle tension • Sleep disturbance: difficulty falling or staying asleep; restless, unsatisfying sleep The focus of the anxiety and worry is not confined to features of an axis 1 disorder. The anxiety or worry is not about having a panic attack (as in panic disorder), being embarrassed in public (as in social phobia), being contaminated (as in obsessive–compulsive disorder), gaining weight (as in anorexia nervosa), having multiple physical complaints (as in somatization disorder), or having multiple illness (as in hypochondriasis). The anxiety and worry do not occur exclusively during posttraumatic stress disorder. The anxiety, worry, or physical symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. The disturbance is not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hyperthyroidism) and does not occur exclusively during a mood disorder, psychotic disorder, or pervasive development disorder. DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Adapted with permission from the American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Press; 1994. Copyright 1994 American Psychiatric Association.
1478 PART II / Section 16 • Psychiatric Disorders
persons with generalized anxiety disorder,48,49 although empirical data are largely lacking on the prevalence of sleep disturbance in GAD samples. One difference between GAD and primary insomnia may be the foci of worry at night; in primary insomnia the focus of worry is typically the insomnia itself, whereas in GAD, the worry is focused on areas that are also preoccupations during the day (e.g., career, finances, relationships). The PSG sleep of insomniac patients with GAD has been compared with that of healthy control subjects in a handful of studies, with a synthesis of the findings published.50 In this synthesis, it is concluded that patients with GAD have increased sleep latency, increased wake time after sleep onset, lower sleep efficiency, and reduced total sleep time relative to controls. The sleep architecture findings in GAD are unremarkable, and the conclusion is that GAD is characterized by a nonspecific sleep-onset and sleep-maintenance insomnia that compromises sleep quality. Notably, these studies provide evidence that GAD can be differentiated from major depression: The classic reduction in REM sleep latency seen in endogenous major depression is usually not seen in nondepressed patients with GAD.51-53 However, given that most patients with GAD, particularly those encountered in general medical settings, also suffer from major depression, it should be expected that more classic depression-related sleep problems (e.g., early morning awakening) also will be seen. It is doubtful that differentiation of GAD from other anxiety or depressive disorders can be made on the basis of differences in sleep symptoms or PSG findings. Treatment Treatment for this chronic condition is, not surprisingly, often prolonged (i.e., several years). Benzodiazepines (e.g., alprazolam, clonazepam) are used extensively in the management of GAD. Although tolerance to the hypnotic effects of benzodiazepines is commonly encountered, the available evidence suggests that the antianxiety effects of these compounds persist indefinitely in most cases and are not associated with dosage escalation in the long term.54 In addition, strong evidence from double-blind, placebo-controlled studies indicates that certain classes of antidepressants, such as the SSRIs55 and the dual reuptake inhibitors (also known as norepinephrine and serotonin reuptake inhibitors [NSRIs], e.g., venlafaxine extended-release)56 are efficacious.57 A substantial advantage of antidepressants over benzodiazepines is the fact that the former treat comorbid depression, whereas the latter do not. Tricyclic antidepressants are also effective, although their use has largely been supplanted by that of the SSRIs and NSRIs. There is evidence to suggest that antihistamines may also be helpful for treating core GAD symptoms,58,59 although few studies have been conducted to date. Clinical experience suggests that improvement in insomnia parallels the overall benefits associated with pharmacologic treatment of GAD; however, studies often do not report sleep findings in GAD. One study found that the hypnotic zopiclone was beneficial for both insomnia symptoms and daytime anxiety associated with GAD.60 The novel agents pregabalin and tiagabine that also target benzodiazepine receptors or related gamma-aminobutyric
acid–ergic (GABAergic) neurotransmission have been reported to alleviate sleep disturbances associated with GAD, although neither has FDA approval for GAD or insomnia.61,62 Finally, a double-blind, placebo-controlled study found that combination treatment of GAD and insomnia with escitalopram and eszopiclone was associated with greater improvement in sleep and anxiety symptoms compared with escitalopram and placebo.63 CBT is highly effective in treating GAD,64 and such treatments have also been shown to be effective for insomnia complaints.48 In older adults, where benzodiazepines may be relatively contraindicated because of concerns about adverse effects (e.g., falls leading to fractures), psychosocial treatments may be particularly appealing.65 The potential efficiency of integrated psychotherapeutic interventions that target both excessive generalized worries and worries about sleep warrants further exploration66; however, empirical investigation of such treatment approaches is not yet available.
SOCIAL PHOBIA Epidemiology and Clinical Features The term social anxiety disorder is synonymous with social phobia, and the two terms may be used interchangeably. Social phobia can be described as excessive fear of being judged negatively, embarrassed, or humiliated in one or more social situations (Box 129-6). Anxiety in social situations can take the form of a panic attack, marked by extreme discomfort, physical symptoms such as heart racing, shaking, sweating, blushing, and other symptoms. In other cases, the symptoms are less acute but last longer, especially in anticipation of or before an upcoming social situation (e.g., worrying for days or weeks ahead of time about having to attend a dinner party). Overt signs of discomfort (blushing, tremor in voice, sweating, motor tics) that might be apparent to another person are extremely distressing to the social phobic patient. One of these symptoms (“I sweat too much”; “I have the shakes”) might be the chief and exclusive complaint of the social phobic patient when seeking treatment from his or her family physician. Public speaking may also be endorsed as a prominent source of anxiety, although further inquiry often reveals social fears and avoidance in many more socially routine situations such as speaking to small groups, interacting with authority figures, and relating to peers. In situations where social fears and avoidance are pervasive, a diagnosis of generalized social phobia is applied. Comorbid depressive or substance abuse is more likely to accompany the generalized type of social phobia than the nongeneralized type (e.g., public speaking fears only). Social phobia and the associated avoidance can significantly interfere with daily functioning and reduce quality of life.67 Many patients with social phobia report that they always have been “shy”; onset of the disorder is in early childhood (i.e., it has “always been there”) in approximately half of cases, whereas in the other half it appears to develop de novo in adolescence among those without a background of pathologic shyness. Social phobia affects slightly more
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Box 129-6 DSM-IV Criteria for Social Phobia Social phobia is a marked and persistent fear of one or more social or performance situations in which the person is exposed to unfamiliar people or to possible scrutiny by others. The person fears that he or she will act in a way (or show anxiety symptoms) that will be humiliating or embarrassing. In children, there must be evidence of the capacity for age-appropriate social relationships with familiar people, and the anxiety must occur in peer settings, not just in interactions with adults. Exposure to the feared social situation almost invariably provokes anxiety, which can take the form of a situationally bound or situationally predisposed panic attack. In children, the anxiety may be expressed by crying, tantrums, freezing, or shrinking from social situations with unfamiliar people. The person recognizes that the fear is excessive or unreasonable. In children, this feature may be absent. The feared social or performance situations are avoided or are endured with intense anxiety or distress. The avoidance, anxious anticipation, or distress in the feared social or performance situation interferes
significantly with the person’s normal routine, occupational (or academic) functioning, or social activities or relationships, or there is marked distress about having the phobia. In children younger than 18 years, the duration is at least 6 months. The fear or avoidance is not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition and is not better accounted for by another mental disorder (e.g., panic disorder with or without agoraphobia, separation anxiety disorder, body dysmorphic disorder, pervasive developmental disorder, or schizoid personality disorder). If a general medical condition or another mental disorder is present, the fear of social situations is unrelated to it. For example, the fear is not of stuttering, trembling in Parkinson’s disease, or exhibiting abnormal eating behavior in anorexia nervosa or bulimia nervosa. Specify if the fears include most social situations. Also consider the additional diagnosis of avoidant personality disorder.
DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Adapted with permission from the American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Press; 1994. Copyright 1994 American Psychiatric Association.
women than men, although men more commonly present to mental health treatment settings for its treatment. Sleep Features Complaints of insomnia are not uncommon in patients with social phobia if the clinician specifically elicits them, although it is rare for a patient with social phobia to present with sleep disturbances as his or her chief complaint. Anecdotally, persons with social phobia are somewhat more likely to experience sleep difficulties, particularly increased sleep latency, when experiencing increased anticipatory anxiety in advance of a highly feared social event (e.g., job interview, oral presentation). In one of only two published studies that specifically focus on subjective sleep in patients with social phobia, 60% of participants could be categorized as poor sleepers, as compared to only 7% of healthy controls.68 A morerecent investigation found that 18% of participants with social phobia had moderate to severe insomnia versus only 5% of controls, and an additional 40% had subthreshold insomnia symptoms.69 Further, this study found that the relationship between social phobia and insomnia was partially mediated by depressive symptoms. The results of PSG are largely normal in social phobia, with sleep latency and sleep efficiency being similar in patients with social phobia and in healthy control subjects. REM sleep latency, REM sleep distribution, and REM sleep density are also normal in social phobia.70 Secondary sleep problems can also develop in patients who abuse alcohol. Prominent sleep complaints in social phobia should, in fact, prompt a further exploration as to etiology, including taking a thorough history of substance abuse.
Treatment There is a solid evidence base for the managing social phobia with either pharmacotherapy or CBT. Five classes of medications are effective in the treatment of social phobia: high-potency benzodiazepines (alprazolam, clonazepam), monoamine oxidase inhibitor antidepressants (i.e., phenelzine, tranylcypromine), SSRIs (paroxetine and sertraline have FDA approval for the treatment of social phobia), SNRIs (venlafaxine extended-release has FDA approval for the treatment of social phobia), and, in certain cases, beta-blockers (e.g., atenolol, propranolol).71 Clinical experience suggests that some patients with nongeneralized social phobia (e.g., public speaking or anxiety limited to other performance situations such as playing a musical instrument in public) may respond to beta-blockers on an as-needed basis, whereas the more generalized, pervasive form of social phobia requires regular dosing with either a benzodiazepine or one of the aforementioned antidepressants. Individual and group CBT for social phobia are also effective in the treating social anxiety disorder, and their duration of effects is longer than that for medication treatments.72-74 A combination of psychosocial and drug therapies may be considered to achieve an optimal response, although research demonstrating the utility and cost-effectiveness of such combination approaches is still lacking.75 One potentially efficacious combination treatment is augmentation of CBT with d-cycloserine, which has shown promise.76 The impact of successful social anxiety disorder treatment on sleep symptoms has not been ascertained. For transient insomnia symptoms, a short course of hypnotics may be beneficial.
1480 PART II / Section 16 • Psychiatric Disorders
OBSESSIVE–COMPULSIVE DISORDER Epidemiology and Clinical Features Lifetime prevalence of OCD is approximately 2% to 3%, with the 12-month prevalence in the range of 0.5% to 1.0%. The disorder is approximately equally distributed among men and women in adulthood, although in childhood a predominance of boys is apparent (where it is often comorbid with attention-deficit/hyperactivity disorder). The age of onset is adolescence or early adulthood, although it can begin in childhood, where it often assumes a more malignant course than when it starts later in life. Up to one in five patients with OCD has comorbid tic disorders. The key signs and symptoms of OCD are obsession or compulsions. Obsessions are persistent, intrusive thoughts, images, or impulses recognized by the patient as being irrational or foolish. Common obsessions include the belief that objects are contaminated with germs, which will lead to illness, or doubting whether one has completed a task completely or accurately (e.g., doubting whether one has turned off the stove or locked the door), which will lead to fire, burglary, or other untoward consequences. Most persons with OCD concede that their obsessions make little sense, although the DSM-IV specifier “with poor insight” may be applied for patients who are largely unable to recognize the unreasonableness of their obsessions and compulsions throughout the course of their disorder. Compulsions are repetitive but deliberate actions performed by the patient in response to a particular obsession (Box 129-7). These are distinguished from tics, which are
not purposeful, although they can share with compulsions the ability to suppress them temporarily. The compulsions are performed in a predictable and often ritualized fashion in an attempt to lessen, neutralize, or ward off distressing obsessions. Compulsions only temporarily reduce the obsessions, and soon the afflicted person feels rising anxiety and an increasing urge to repeat the behavior. There may also be mental obsessions, as in counting or repeating words or phrases internally. In the case of contamination obsessions, the corresponding compulsion commonly consists of avoidance of touching “contaminated” surfaces and the need to wash repeatedly if contact is made. Compulsions may have a superstitious quality, in that they are not realistically connected to the obsession they are intended to reduce or prevent (as in a tapping ritual to prevent one’s loved one from being harmed). Sleep Features Neither the core syndromal manifestations nor prominent associated features of OCD include sleep disturbances. An early PSG study did find evidence for impaired sleep maintenance and reduced latency to REM sleep in a group with OCD,77 although two PSG studies failed to replicate these findings and concluded that sleep patterns of patients with OCD are essentially normal.78,79 However, another study with a much larger sample than the earlier investigations found evidence for disturbed sleep continuity, decreased total sleep time, and increased density of first REM sleep episode in subjects with OCD compared with controls.80 Some of these studies included patients with what were considered temporally secondary depressive disorders.78,80 Thus, it can be concluded that some patients with OCD
Box 129-7 DSM-IV Criteria for Obsessive–Compulsive Disorder Obsessive–compulsive disorder includes either obsessions or compulsions: • Obsessions • Recurrent and persistent thoughts, impulses, or images that are experienced, at some time during the disturbance, as intrusive and inappropriate and that cause marked anxiety or distress. • The thoughts, impulses, or images are not simply excessive worries about real-life problems. • The person attempts to ignore or suppress such thoughts, impulses, or images or to neutralize them with some other thought or action. • The person recognizes that the obsessional thoughts, impulses, or images are a product of his or her own mind (not imposed from without as in thought insertion). • Compulsions • Repetitive actions (e.g., hand washing, ordering, checking) or mental acts (e.g., praying, counting, repeating words silently) that the person feels driven to perform in response to an obsession, or according to rules that must be applied rigidly. • The actions or mental acts are aimed at preventing or reducing distress or preventing some dreaded event or situation. However, these actions or mental acts either are not connected in a realistic
way with what they are designed to neutralize or prevent or are clearly excessive. At some point during the course of the disorder, the person has recognized that the obsessions or compulsions are excessive or unreasonable. This does not apply to children. The obsessions or compulsions cause marked distress, are time consuming (take more than 1 hour a day), or significantly interfere with the person’s normal routine, occupational (or academic) functioning, or usual social activities or relationships. If another axis 1 disorder is present, the content of the obsessions or compulsions is not restricted to it (e.g., preoccupation with food in the presence of an eating disorder, hair pulling in the presence of trichotillomania, concern with appearance in the presence of body dysmorphic disorder, preoccupation with drugs in the presence of a substance use disorder, preoccupation with having a serious illness in the presence of hypochondriasis, preoccupation with sexual urges in the presence of a paraphilia, or guilty ruminations in the presence of major depressive disorder). The disturbance is not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.
DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Adapted with permission from the American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Press; 1994. Copyright 1994 American Psychiatric Association.
have problems with sleep, although there does not appear to be a specific sleep architecture profile characteristic of OCD. When a sleep problem is present, it is likely related to comorbid depressive illness or to the obsessions and compulsions themselves (e.g., need to check the alarms and stove repetitively before going to bed). Treatment Treatment is targeted toward managing obsessions or compulsions and treating comorbid depressive symptoms. Pharmacologic treatment for OCD consists of administering antidepressant drugs that block synaptic reuptake of serotonin; these include a tricyclic antidepressant, clomipramine, and the SSRIs (e.g., fluoxetine, fluvoxamine, sertraline, paroxetine). Drug therapy should be continued for several years, and in some cases, indefinitely, because the available data suggest that the patient’s symptoms will return within several months after medications are stopped. Specialized CBT treatments, most notably exposure and response prevention, have been demonstrated to be at least as efficacious as some pharmacologic treatments,81 although the relative dearth of clinicians trained in these methods and the considerable time investment required can make pharmacotherapy a more attractive option. Available data suggest that providing behavior therapy while the patient is taking medication can delay or prevent relapse when medication is discontinued.82 In extreme cases, patients with OCD that is severe, disabling, and refractory to treatment (i.e., unresponsive to several good pharmacotherapy trials and at least one good trial of behavior therapy) may be considered for psychosurgery (i.e., cingulotomy or limbic leukotomy).83 There are few data available on sleep outcomes with either pharmacologic or behavioral treatment of OCD.
POSTTRAUMATIC STRESS DISORDER Epidemiology and Clinical Features Posttraumatic stress disorder is characterized by the recurrent, unwanted re-experiencing of a previous traumatic event. The trauma is one that would be experienced by almost anyone as profoundly disturbing, usually falling into the category of an event that was life-threatening (e.g., violent attack with physical injury, sexual assault, serious motor vehicle collision) or profoundly and abruptly lifealtering (e.g., sudden death of a loved one from accidental or unanticipated medical causes). Traumatic experiences that yield PTSD, such as military combat or domestic violence (i.e., intimate partner abuse), often are repeated episodes and not single events. After exposure to severe traumatic experiences, it is the norm to experience brief (lasting several days) periods of anxiety, recurrent thinking about the event, and insomnia. In cases where these symptoms persist more than a few days and cause functional impairment, accompanied by prominent feelings of unreality or memory problems (i.e., dissociative symptoms), a diagnosis of acute stress disorder may be appropriate. In most such cases, the symptoms wane over the ensuing weeks, but when they do not (which is the pattern in 10% to 30% of cases, depending on the nature and severity of the traumatic event) and the symptoms interfere with functioning or
CHAPTER 129 • Anxiety Disorders 1481
cause great distress, a diagnosis of PTSD may be applied. To qualify for a PTSD diagnosis, characteristic symptoms must be noted in three domains: re-experiencing symptoms (e.g., nightmares or daytime intrusive thoughts or images, including flashbacks), avoidance and numbing symptoms (e.g., avoidance of reminders of the trauma), and hyperarousal symptoms (e.g., insomnia or increased startle response) (Box 129-8). Lifetime prevalence of PTSD is reported to be as high as 7% to 8%, with a 12-month prevalence in the range of 2% to 3%. PTSD is approximately twice as prevalent in women as men in the general population. Common sources of PTSD in men (although increasingly in women) are military combat; in women, intimate partner violence and violent injury (often associated with sexual assault) is a common source. Like many of the other anxiety disorders, PTSD is often encountered comorbid with major depression, both in general population samples and in clinical settings. More than with any of the other anxiety disorders, sleep complaints in almost any context should warrant inclusion of PTSD in the differential diagnosis. Sleep complaints are virtually ubiquitous in patients with PTSD.84 Patients sometimes report not having slept well for decades, with these reports corroborated by their bed partners. Extreme hypervigilance (sometimes bordering on paranoia, but evidently linked to habits learned during combat experiences) may take the form of a combat veteran with PTSD spending several hours each evening “patrolling” the perimeter of his home to ensure that it is protected from intruders. Nightmares, often accompanied by vivid recall upon wakening, are commonplace, as is extreme motor activity, according to companions’ reports. It is not uncommon to encounter patients who have tried numerous over-the-counter and prescription medications to help with their sleep, to no avail. Many patients also have alcohol abuse problems, which can complicate the clinical picture and make determining the nature of the sleep disorder even more difficult. In some cases, other risk factors for disorders of sleep initiation and maintenance— such as obstructive sleep apnea—are present, making an informed evaluation by a sleep expert (with a particular focus on possible sleep-disordered breathing) of considerable value. Sleep Features Subjective sleep complaints in PTSD often include the two sleep symptoms listed in the diagnostic criteria: nightmares (which are viewed as re-experiencing phenomena) and insomnia (i.e., impairment in initiating and maintaining sleep). A survey of male Vietnam War veterans with PTSD confirms that insomnia complaints are very common symptoms of PTSD, although nightmares are more specific to the disorder.85 In a community survey, PTSD was often (in approximately 70% of cases) associated with sleep complaints including insomnia as well as other types of sleep disturbance such as violent or injurious activities during sleep, sleeptalking, or hypnagogic and hypnopompic hallucinations.86 These rates seem very high and need to be replicated, but they do point to the usefulness of a thorough sleep assessment in conjunction with diagnostic assessment of PTSD and other trauma-related disorders. Heightened arousal during sleep has also been reported by patients with PTSD, including excessive motor activity
1482 PART II / Section 16 • Psychiatric Disorders Box 129-8 DSM-IV Criteria for Posttraumatic Stress Disorder In posttraumatic stress disorder, the person has been exposed to a traumatic event in which both of the following were present: • The person experienced, witnessed, or was confronted with an event or events that involved actual or threatened death or serious injury or a threat to the physical integrity of self or others. • The person’s response involved intense fear, helplessness, or horror. In children, this may be expressed instead by disorganized or agitated behavior. The traumatic event is persistently re-experienced in one (or more) of the following ways: • Recurrent and intrusive distressing recollections of the event, including images, thoughts, or perceptions. In young children, repetitive play can occur in which themes or aspects of the trauma are expressed. • Recurrent distressing dreams of the event. Children can have frightening dreams without recognizable content. • Acting or feeling as if the traumatic event were recurring (includes a sense of reliving the experience, illusions, hallucinations, and dissociative flashback episodes, including those that occur on awakening or when intoxicated). • Intense psychological distress at exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event. • Physiologic reactivity on exposure to internal or external cues that symbolize or resemble an aspect of the traumatic event. The person persistently avoids stimuli associated with the trauma and has numbing of general respon-
siveness (not present before the trauma), as indicated by three (or more) of the following: • Efforts to avoid thoughts, feelings, or conversations associated with the trauma • Efforts to avoid activities, places, or people that arouse recollections of the trauma • Inability to recall an important aspect of the trauma • Markedly diminished interest or participation in significant activities • Feeling of detachment or estrangement from others • Restricted range of affect (e.g., unable to have loving feelings) • Sense of foreshortened future (e.g., does not expect to have a career, marriage, children, or a normal life span) The person has persistent symptoms of increased arousal (not present before the trauma), as indicated by two (or more) of the following: • Difficulty falling or staying asleep • Irritability or outbursts of anger • Difficulty concentrating • Hypervigilance • Exaggerated startle response Duration of the symptoms is longer than 1 month. The disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. Specify if the symptoms are acute (duration less than 3 months) or chronic (duration 3 months or longer). Specify if the symptoms have delayed onset (onset at least 6 months after the stressor).
DSM-IV, Diagnostic and Statistical Manual of Mental Disorders, 4th edition. Adapted with permission from the American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Press; 1994. Copyright 1994 American Psychiatric Association.
and awakenings with somatic anxiety symptoms.87 Isolated sleep paralysis is also associated with PTSD, and with trauma exposure even in the absence of PTSD, although its specificity to PTSD relative to other anxiety disorders is unclear (see also Panic Disorder, earlier).24,86,88,89 It has been reported that the severity of sleep complaints mediates the relationship between PTSD and functional disability.90 Findings on objective sleep disturbances in PTSD are inconsistent. Subjective reports of sleep disturbance are often discrepant with the findings of PSG. In early PSG studies of PTSD, mostly featuring male combat veterans during a chronic phase of the disorder, findings are mixed with respect to the presence of impaired sleep initiation and maintenance. Several studies report reduced sleep time or efficiency or increased awakenings in the patients with PTSD,87,91 whereas in other studies measures of sleep maintenance did not differ from that of control subjects.92-94 In the largest PSG study of PTSD conducted to date, investigators conducted sleep studies for 2 consecutive nights with 292 trauma-exposed young adults from the community, 71 of whom had lifetime PTSD.95 On standard measures of sleep disturbance, no differences were detected between subjects with PTSD and controls, irrespective of trauma history or major depression in the
control subjects. The investigators concluded that they found no objective evidence for clinically relevant sleep disturbances in PTSD. This study raises the possibility that the presence of sleep disturbance in PTSD may be a prevailing factor in determining treatment-seeking and disability, so that patient samples are enriched for sleep disturbance. However, the authors of a meta-analysis of 20 PSG studies found that overall, PTSD patients had increased stage 1 sleep, decreased slow-wave sleep, and increased frequency of eye movements during REM sleep periods (REM sleep density).96 Moreover, they found that several moderating variables—age, sex, and comorbid depression and substance use—affected the relationship between PTSD and sleep disturbances. Another factor that can contribute to the lack of significant findings in individual studies, as raised in a review,97 is that some persons with PTSD (and other psychiatric conditions, such as primary insomnia), might sleep better in the laboratory environment due to the perception that it is a “safe” setting, thus making evidence of objective sleep disturbance less discernible. Other sleep disturbances in PTSD include movement abnormalities and sleep-disordered breathing. Self-reports of excessive motor activity have been corroborated by studies documenting frequent periodic limb or gross body
movement during sleep,87,98,99 although one report found reduced movement time during sleep in patients with PTSD compared with controls.100 The latter study also found reduced sleep movement time to be associated with self-report of trauma-related nightmares in the past month.100 Several studies in patients with PTSD have found many patients (including combat veterans as well as civilians with sexual trauma) to have evidence of sleepdisordered breathing.99,101,102 Although not yet widely replicated in other laboratories, the likelihood that PTSD is often associated with sleep-disordered breathing and might, taken a step further, be amenable to treatments that target the breathing abnormality (e.g., continuous positive airway pressure) is a very promising avenue for future research.103 The prominence of nightmares in PTSD (which most typically arise from REM sleep) has focused interest on REM sleep variables. Abnormalities in the timing or amount of REM sleep in PTSD have not been consistently found, but other subtle differences in REM sleep in PTSD are emerging. First, increases in REM sleep density have been reported.96,104 Second, there is evidence for greater REM sleep fragmentation in PTSD. For example, increased frequency of REM sleep to wakefulness87 and REM sleep to stage 1 transitions95 have been reported. Third, abnormalities in REM sleep activity after trauma exposure might predict subsequent development of PTSD. In a study of physically injured subjects who were admitted to hospital and who had at least one night of PSG recording within a month of injury, development of PTSD symptoms was associated with a shorter average duration of REM sleep before a stage change and with more periods of REM sleep.105 More recently, in a subsequent report from a subset of this sample, sympathetic activation indices were higher during the REM sleep of the 9 subjects who were positive for PTSD symptoms, compared with the 10 subjects who were PTSD negative.106 Taken together, these studies strongly suggest that sleep in PTSD is characterized by REM sleep abnormalities. Furthermore, the development of PTSD symptoms after traumatic injury is associated with a more-fragmented pattern of REM sleep and increased sympathetic activation during REM sleep, suggesting that increased noradrenergic activity during REM sleep may contribute to the development of PTSD. These hypotheses deserve to be explored further because they might suggest avenues for pharmacologic intervention to prevent the development of PTSD in persons exposed to traumatic events. Treatment As noted previously, thorough assessment of sleep complaints is integral to the overall management of PTSD. Although the absolute rates of sleep disturbances such as obstructive sleep apnea or parasomnias in patients with PTSD remain to be determined, clinical experience suggests that these are not uncommonly encountered in this clinical population and should be seriously considered in most cases. This might require, in select cases where the suspicion is high, referral to a sleep physician for assessment. Patients with PTSD are also likely to have comorbid mental disorders such as major depression and other anxiety disorders such as panic disorder. Treatment there-
CHAPTER 129 • Anxiety Disorders 1483
fore needs to encompass these clinical entities, as well as comorbid alcohol or other substance abuse or dependence, which are also often encountered in patients with PTSD. There is a strong and growing evidence base for particular pharmacologic and psychological treatments for PTSD. Pharmacologic treatments with support for efficacy in the treatment of PTSD include the SSRIs (sertraline and paroxetine are approved by the FDA for this indication) and, to a lesser extent in terms of strength of evidence, tricyclic antidepressants and monoamine oxidase inhibitors.107 Novel and promising treatments for PTSD that can have a particular beneficial impact on sleep include the alpha1adrenergic receptor antagonist prazosin108-110a and the adjunctive (or monotherapeutic) use of atypical antipsychotics (e.g., olanzapine, risperidone, or quetiapine).111 Early results for the anticonvulsant tiagabine showed promise,112 although findings from a large double-blind study found no differences in PTSD treatment efficacy from placebo.113 More than in any of the other anxiety disorders (with the possible exception of OCD, where behavioral therapy is also very important), the use of evidence-based psychotherapy is critical either as primary or adjunctive treatment for PTSD.114-116 There is accumulating evidence that psychosocial treatments that focus on sleep aspects of PTSD such as nightmares can have strong therapeutic effects across the full spectrum of PTSD symptoms.117,118 Practice guidelines based on evidence are available (Box 129-9).119
PITFALLS AND CONTROVERSIES The anxiety disorders are often, but not always, associated with disturbances in initiating and maintaining sleep. When comorbid conditions such as major depression are present—which is often the case in many of the anxiety disorders—then sleep problems may be accentuated and take on the features of the predominating mood disorder. The common comorbidity of mood and anxiety disorders makes it very difficult, in fact, to paint a particular sleep symptomatic or PSG portrait of the anxiety disorders. Moreover, it could be argued that because comorbid anxiety disorders have been so rarely accounted for in studies of major depression, their presence could contribute to some of the variability in PSG findings seen in major depression. Patients with GAD can have increased sleep latency and significant reductions in total sleep time and sleep efficiency. Clinical experience suggests these disturbances are tightly linked to pathologic worry, and improvement in insomnia closely parallels the successful amelioration of core anxiety symptoms. PTSD and, to a lesser extent, panic disorder are often characterized by recurrent frightening arousals from sleep. Sleep complaints are so prevalent in PTSD that it could be argued that every assessment of sleep disturbance should include the taking of a thorough history of traumatic events. Available evidence suggests that the predominating sleep pathologic process in PTSD relates to REM sleep, whereas that in nocturnal panic relates to NREM sleep. However, reports of high rates of obstructive sleep apnea and parasomnias in PTSD suggest that a more-complex
1484 PART II / Section 16 • Psychiatric Disorders Box 129-9 Treatment Recommendations of PTSD-Associated Nightmares Level A: Supported by a substantial amount of high grade evidence and/or based on a consensus of clinical judgment Level B: Supported by a sparse amount of high grade evidence or a substantial amount of low grade data and/or clinical consensus by task force Level C: Supported by low grade data without volume to recommend more highly and likely subject to revision with further studies
Prazosin Clonidine Venlafaxine is NOT suggested Medications: trazodone, atypical antipsychotic medications, topiramate, low dose cortisol, fluvoxamine, triazolam and nitrazepam, phenelzine, gabapentin, cyproheptadine, and tricyclic antidepressants. Nefazodone is not recommended as first line therapy for nightmare disorder because of the increased risk of hepatotoxicity Behavioral therapies: Exposure, Relaxation, and Rescripting Therapy (ERRT); Sleep Dynamic Therapy; Hypnosis; Eye-Movement Desensitization and Reprocessing (EMDR); and the Testimony Method.
Recommendations adapted from Aurora RN, Zak RS, Auerbach SH, et al. AASM Standards of Practice Committee. Best practice guidelines for the treatment of nightmare disorders in adults. J Clin Sleep Med 2010;6:389-401.
etiology for sleep disturbance might exist in individual patients with this disorder. Reports of a high prevalence of sleep breathing disturbances in PTSD are controversial and remain to be widely replicated and differentiated from a high base rate of sleeprelated breathing disorders that might otherwise be seen in patients with PTSD (e.g., when male combat veterans in their sixth decade, with comorbid obesity and other medical problems, are studied). It has been suggested that PTSD and panic disorder seem to converge on several sleep-related parameters, namely, sleep quality, presence of episodic parasomnias, and movement time, whereas they diverge in the particular phenomenologic nature of episodic parasomnias, namely, nightmares or nocturnal panic attacks.120 As suggested by the authors of that report, further investigations focusing on sleep disturbances in PTSD and panic disorder have the potential to further our understanding of the biology of these disorders. As this research advances, it will be important that sleep studies include representative samples of persons with the disorders of interest, so that our vantage point is not constrained to treatment-seeking patients with the severest disease. Many evidence-based pharmacologic and psychosocial treatments for anxiety disorders seem to improve sleep as part of their spectrum of therapeutic effects. However, sleep outcomes are not often reported in clinical trials, leaving some uncertainty as to a given treatment’s efficacy for sleep disturbances. In some instances, preferred medications with good evidence of efficacy for anxiety disorders (e.g., SSRIs) can actually worsen sleep while they ameliorate daytime and phobic anxiety. What is a clinician to do in such cases? Here, there is little in the way of guidance to be found in the published literature. There seems to be great interindividual variability in the impact of SSRIs on sleep, so that it may make sense to switch to a different SSRI in the hope that sleep problems are ameliorated. But it may also be the case that direct therapeutic benefits on
anxiety are so substantial that the patient (and the clinician) is reluctant to make a switch. In such cases, or when switching between antidepressants does not improve the insomnia, therapeutic trials of adjunctive sleep aids (e.g., benzodiazepines, low-dose atypical antipsychotics) may be considered on an individualized basis. This is an area where further research is sorely needed.
❖ Clinical Pearls Effective treatment of anxiety disorders includes assessing and managing sleep symptoms. Clinical experience suggests that education and encouragement about basic sleep hygiene can be helpful as an adjunct to treatment in nearly all cases. If sleep disturbances persist after the successful treatment of the primary anxiety disorder (and are not an obvious iatrogenic result of treatment), the patient should be reevaluated for other possible medical or sleep disorders. In the case of PTSD, where there is reason to suspect that comorbid medical and sleep disorders (e.g., obstructive sleep apnea) are especially common, a high index of suspicion should be maintained and a thorough medical and sleep evaluation may be considered early in the course of assessment and treatment.
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103. Krakow B, Lowry C, Germain A, et al. A retrospective study on improvements in nightmares and post-traumatic stress disorder following treatment for co-morbid sleep-disordered breathing. J Psychosom Res 2000;49(5):291-298. 104. Mellman TA, Nolan B, Hebding J, et al. A polysomnographic comparison of veterans with combat-related PTSD, depressed men, and non-ill controls. Sleep 1997;20(1):46-51. 105. Mellman TA, Bustamante V, Fins AI, et al. REM sleep and the early development of posttraumatic stress disorder. Am J Psychiatry 2002;159(10):1696-1701. 106. Mellman TA, Knorr BR, Pigeon WR, et al. Heart rate variability during sleep and the early development of posttraumatic stress disorder. Biol Psychiatry 2004;55(9):953-956. 107. Zhang W, Davidson JRT. Post-traumatic stress disorder: an evaluation of existing pharmacotherapies and new strategies. Expert Opin Pharmacother 2007;8(12):1861-1870. 108. Raskind MA, Peskind ER, Kanter ED, et al. Reduction of nightmares and other PTSD symptoms in combat veterans by prazosin: a placebo-controlled study. Am J Psychiatry 2003;160(2): 371-373. 109. Taylor FB, Martin P, Thompson C, et al. Prazosin effects on objective sleep measures and clinical symptoms in civilian trauma posttraumatic stress disorder: a placebo-controlled study. Biol Psychiatry 2008;63(6):629-632. 110. Dierks MR, Jordan JK, Sheehan AH. Prazosin treatment of nightmares related to posttraumatic stress disorder. Ann Pharmacother 2007;41(6):1013-1017. 110a. Byers MG, Allison KM, Wendel CS, Lee JK. Prazosin versus quetiapine for nighttime posttraumatic stress disorder symptoms in veterans: an assessment of long-term comparative effectiveness and safety. J Clin Psychopharmacol 2010;30:225-229.
CHAPTER 129 • Anxiety Disorders 1487 111. Pae CU, Lim HK, Peindl K, et al. The atypical antipsychotics olanzapine and risperidone in the treatment of posttraumatic stress disorder: a meta-analysis of randomized, double-blind, placebocontrolled clinical trials. Int Clin Pharmacol 2008;23(1):1-8. 112. Taylor FB. Tiagabine for posttraumatic stress disorder: a case series of 7 women. J Clin Psychiatry 2003;64(12):1421-1425. 113. Davidson JRT, Brady K, Mellman TA, et al. The efficacy and tolerability of tiagabine in adult patients with post-traumatic stress disorder. J Clin Psychopharmacol 2007;27(1):85-88. 114. Monson CM, Schnurr PP, Resick PA, et al. Cognitive processing therapy for veterans with military-related posttraumatic stress disorder. J Consult Clin Psychol 2006;74(5):898-907. 115. Schnurr PP, Friedman MJ, Engel CC, et al. Cognitive behavioral therapy for posttraumatic stress disorder in women—a randomized controlled trial. JAMA 2007;297(8):820-830. 116. American Psychiatric Association. Practice guideline for the treatment of patients with acute stress disorder and posttraumatic stress disorder. Am J Psychiatry 2004;161(11 Suppl.):3-31. 117. Krakow B, Hollifield M, Johnston L, et al. Imagery rehearsal therapy for chronic nightmares in sexual assault survivors with posttraumatic stress disorder—a randomized controlled trial. JAMA 2001;286(5):537-545. 118. Germain A, Shear MK, Hall M, Buysse DJ. Effects of a brief behavioral treatment for PTSD-related sleep disturbances: a pilot study. Behav Res Ther 2007;45(3):627-632. 119. Aurora RN, Zak RS, Auerbach SH, et al. AASM Standards of Practice Committee. Best practice guidelines for the treatment of nightmare disorders in adults. J Clin Sleep Med 2010;6:389-401. 120. Sheikh JI, Woodward SH, Leskin GA. Sleep in post-traumatic stress disorder and panic: convergence and divergence. Depress Anxiety 2003;18(4):187-197.
Mood Disorders
Michael J. Peterson and Ruth M. Benca
Abstract Mood disorders, including major depressive disorder and bipolar disorder, are commonly associated with sleep disturbance, and sleep problems are part of the diagnostic criteria for these disorders. Although subjective complaints of insomnia are most common, hypersomnia and fatigue are also sometimes reported during periods of depression. Insomnia and hypersomnia are associated with an increased risk for the development or recurrence of mood disorder and increased severity of psychiatric symptoms. Polysomnographic studies of depressed patients have consistently revealed abnormali-
Mood disorders are the second most common category of psychiatric disorders after anxiety disorders,1 and major depression alone affects at least 121 million persons worldwide. Moreover, the associated disability of mood disorders is among the highest reported for any disease: In 2000, bipolar disorder was in the top 10 causes of disability, and depression was the leading cause of disability and the fourth leading contributor to the global burden of disease. By 2020, depression is projected to be the second leading contributor to global burden of disease for all ages and both sexes.2 The impact of mood disorders includes eventual suicide in 15% of those affected, as well as increased morbidity and mortality from other illnesses. Subjective sleep complaints are some of the most consistent symptoms associated with mood disorders. Disruptions of typical sleep patterns (insomnia, hypersomnia, or decreased need for sleep) are a core diagnostic criterion of mood episodes in the DSM-IV-TR3 (Boxes 130-1 and 130-2), reflecting their importance and prevalence in the presentation of these disorders. Sleep has been studied more extensively in patients with depression than with any other psychiatric disorder, and in addition to the subjective reports, there are objective, robust, and relatively specific changes in sleep architecture that can relate to the underlying neurobiology of depression.
CLASSIFICATION AND DIAGNOSIS Mood disorders are subclassified into depressive and bipolar disorders, based on the pattern of depressive and manic episodes.3 Diagnostic criteria for major depressive episodes are listed in Box 130-1 and include the characteristic finding(s) of depressed mood or anhedonia lasting at least 2 weeks. Recurrent major depression includes multiple, distinct major depressive episodes separated by at least 2 months of remission. In contrast, dysthymic disorder includes persistent but less-severe symptoms lasting for at least 2 years. Manic episodes are described in Box 130-2 and are characterized by elevated or irritable mood lasting at least a week or requiring hospitalization. Hypomania has similar 1488
Chapter
130 ties in sleep architecture in comparison to controls, including decreased time in slow-wave sleep, reduced latency to rapid eye movement (REM) sleep onset, and disrupted sleep continuity. These associations provide insight into the neurobiological relationships between mood and sleep. Both subjective and objective sleep abnormalities commonly persist even during periods of clinical remission, making sleep disturbance a chronic problem for many patients with a history of a mood disorder. Depression thus must be assessed in any patient with a sleep complaint, and sleep problems often require specific and potentially ongoing treatment in persons with mood disorders.
but less severe symptoms and may be less persistent. Mixed episodes occur when patients concurrently meet criteria for both manic and major depressive episodes for at least 1 week. Patients who experience one or more manic or mixed episodes have bipolar I disorder, and those with at least one lifetime episode each of major depression and hypomania have bipolar II disorder. Major depressive episodes may be further categorized with one of several specifiers, including melancholic, atypical, or seasonal, each of which is at least partly related to sleep patterns. Melancholic depression includes a loss of pleasure in all, or almost all, activities; a lack of improvement in mood in response to normally pleasurable stimuli; and early morning awakening and diurnal variation in mood, with depression worse in the morning. Interestingly, patients with melancholic depression are more likely to have an improvement of depression with total sleep deprivation. Depression with atypical features includes significant mood reactivity to positive events, and weight gain and hypersomnia during periods of depression. Depressive episodes, in both major depression and bipolar disorder, can have a seasonal pattern, with a typical onset in the fall or winter and remission (or even mania or hypomania, when associated with bipolar disorder) in the spring or summer, suggesting a correlation with diurnal patterns of light exposure (Box 130-3).
EPIDEMIOLOGY AND RISK FACTORS Major depression is a common disorder and is reported to have a lifetime prevalence of 16.2% and a prevalence of 6.6% for the past 12 months in U.S. adults, with an increased risk (odds ratio [OR], 1.7) in women.4 The reason for increased rates of major depressive episodes in women is unclear, but it might include hormonal factors as well as differences in psychosocial stressors, and it is likely that the increased rates of both insomnia and depression in women are related. In contrast to major depression, bipolar I and II disorders each affect about 1% of the population (lifetime) and show no sexual predilection.5 Most bipolar disorder patients have at least
CHAPTER 130 • Mood Disorders 1489
Box 130-1 DSM-IV-TR Criteria for Major Depressive Episode At least five of the following symptoms have been present during the same 2-week period and represent a change from previous functioning; at least one of the symptoms is either depressed mood or loss of interest or pleasure. Do not include symptoms that are clearly the result of a general medical condition or that are mood-incongruent delusions or hallucinations. • Depressed mood most of the day, nearly every day, as indicated by either subjective report (e.g., feels sad or empty) or observation made by others (e.g., appears tearful). In children and adolescents, can be irritable mood. • Markedly diminished interest or pleasure in all, or almost all, activities most of the day, nearly every day as indicated by either subjective account or observation made by others. • Significant weight loss when not dieting or weight gain (e.g., a change of more than 5% of body weight in a month) or decrease or increase in appetite nearly every day. In children, consider failure to make expected weight gains. • Insomnia or hypersomnia nearly every day. • Psychomotor agitation or retardation nearly every day (observable by others, not merely subjective feelings of restlessness or being slowed down). • Fatigue or loss of energy nearly every day.
• Feelings of worthlessness or excessive or inappropriate guilt (which may be delusional) nearly every day (not merely self-reproach or guilt about being sick). • Diminished ability to think or concentrate, or indecisiveness, nearly every day (either by subjective account or as observed by others). • Recurrent thoughts of death (not just fear of dying), recurrent suicidal ideation without a specific plan, or a suicide attempt or a specific plan for committing suicide. The symptoms do not meet criteria for a mixed episode. The symptoms cause clinically significant distress or impairment in social, occupational, or other important areas of functioning. The symptoms are not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition (e.g., hypothyroidism). The symptoms are not better accounted for by bereavement (i.e., after the loss of a loved one). The symptoms persist for longer than 2 months, or the symptoms are characterized by marked functional impairment, morbid preoccupation with worthlessness, suicidal ideation, psychotic symptoms, or psychomotor retardation.
Adapted from the American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed, text revision.
Box 130-2 DSM-IV-TR Criteria for Manic Episode A manic episode is a distinct period of abnormality and persistently elevated, expansive, or irritable mood, lasting at least 1 week (or any duration if hospitalization is necessary). During the period of mood disturbance, three (or more) of the following symptoms have persisted (four if the mood is only irritable) and have been present to a significant degree: • Inflated self-esteem or grandiosity. • Decreased need for sleep (e.g., feels rested after only 3 hours of sleep). • More talkative than usual or pressure to keep talking. • Flight of ideas or subjective experience that thoughts are racing. • Distractibility (i.e., attention too easily drawn to unimportant or irrelevant external stimuli). • Increase in goal-directed activity (socially, at work or school, or sexually) or psychomotor agitation. • Excessive involvement in pleasurable activities that have a high potential for painful consequences (e.g.,
engaging in unrestrained buying sprees, sexual indiscretion, or foolish business investments). The symptoms do not meet criteria for a mixed episode. The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features. The symptoms are not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication, or other treatment) or a general medical condition (e.g., hyperthyroidism). Manic-like episodes that are clearly caused by somatic antidepressant treatment (e.g., medication, electroconvulsive therapy, light therapy) should not count toward a diagnosis of bipolar I disorder.
Adapted from the American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed, text revision.
one other DSM-IV comorbidity (such as substance use or anxiety disorders) and are more likely to have a persistent course and severe impairment.5 Major depression and bipolar disorders have an onset in early adulthood; the median age for major depression is 32 years and for
bipolar disorders 18 to 20 years.5 Major depression and bipolar disorder both usually have recurrent episodes with recovery between episodes. However, increased number and severity of episodes and poorer interepisode recovery can lead to an overall worse prognosis, suggesting that
1490 PART II / Section 16 • Psychiatric Disorders Box 130-3 DSM-IV-TR Criteria for Seasonal Pattern Specifier There has been a regular temporal relationship between the onset of major depressive episodes in bipolar I or bipolar II disorder or recurrent major depressive disorder and a particular time of the year (e.g., regular appearance of the major depressive episode in the fall or winter). Do not include cases in which there is an obvious effect of seasonal-related psychosocial stressors (e.g., regularly being unemployed every winter). Full remissions (or a change from depression to mania or hypomania) also occur at a characteristic time of the year (e.g., depression disappears in the spring). In the last 2 years, two major depressive episodes have occurred that demonstrate the temporal seasonal relationships defined in the first two criteria, and no nonseasonal major depressive episodes have occurred during that same period. Seasonal major depressive episodes (as described above) substantially outnumber the nonseasonal major depressive episodes that might have occurred over the person’s lifetime. Adapted from the American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed, text revision.
chronic treatment may be beneficial for patients with recurrent illness.
PATHOGENESIS Despite the devastating impact of mood disorders, relatively little is known about their etiology or pathophysiology. It has long been hypothesized that deficiencies in central nervous system monoaminergic systems, including noradrenergic, serotoninergic, and dopaminergic neurotransmission, are responsible for depression, and most effective antidepressant treatments, including medications and electroconvulsive therapy, increase intrasynaptic concentrations of monoamines.6,7 Antidepressants can also precipitate mania in susceptible persons, which supports the theory that mania may be related to increased monoaminergic activity. Neural plasticity (via amino acid neurotransmitters, such as glutamate, and brain-derived neurotrophic factor [BDNF] levels) has been shown to play a role in depression.6,7 In addition to the role of neurotransmitter systems in mood pathophysiology, researchers have begun to elucidate the neuroanatomic, endocrine, and genetic factors involved.6,7 Studies of normal sleep and disrupted sleep also demonstrate clearly that most of the systems involved in mood regulation also appear to be involved in the regulation of sleep and wakefulness (see Chapter 7), suggesting that dysfunction in particular brain systems might lead to both mood and sleep abnormalities.
CLINICAL FEATURES Subjective Sleep Complaints Problems with sleep are some of the earliest and most commonly reported symptoms of mood disorders. Specific sleep complaints include difficulty falling asleep, frequent nocturnal awakenings, early morning awakening, nonrestorative sleep, decreased or increased total sleep, and disturbing dreams. Insomnia, hypersomnia, or both are reported by approximately 75% of adults, children, and adolescents with major depression.8,9 Similarly, patients with bipolar disorder also often report insomnia or hypersomnia when they are depressed, but they are more likely to exhibit hypersomnia than unipolar patients.10 Little has been reported about sleep during (hypo)manic episodes, but diagnostic criteria (see Box 130-2) include a decreased need for sleep, usually accompanied by decreased sleep time. Association of Sleep Disturbance and Mood Disorders Sleep problems are extremely common in the general population and are often associated with psychiatric comorbidity. More than 35% of adults report some sleep problem.11 In the general adult population, 14% to 20% of persons with significant complaints of insomnia and about 10% of those with hypersomnia showed evidence of major depression, whereas rates of depression were less than 1% in those without sleep complaints.11,12 Additionally, the degree and duration of insomnia were positively correlated with more severe or recurrent major depression, or both.12 An assessment of the lifetime prevalence of sleep disturbance and psychiatric disorders in young adults also found greatly increased rates of major depression in persons with insomnia (OR, 3.8) in comparison to those with no sleep complaints (2.7%).13 The association between insomnia and depression may be even greater in clinical samples. More than half of patients with insomnia and medical or psychiatric patients evaluated by clinical interview in sleep disorders centers had a sleep disorder associated with mood disorder according to the International Classification of Sleep Disorders diagnosis.14 In children seen in general pediatrics clinics, insomnia and daytime fatigue were strongly correlated with elevated scores on the Child Behavior Checklist, and insomnia was particularly associated with symptoms of depression, anxiety, and attentional problems.15 Predictive Value of Sleep Complaints It has historically been assumed that mood disorders cause changes in sleep patterns. Sleep disturbances, however, can also affect mood disorders, and epidemiologic data support this contention. Insomnia often precedes the onset of a first episode of major depression13 or mania10; in contrast, insomnia was more likely to occur subsequent to the onset of anxiety disorders.13 A similar temporal relationship between onset of insomnia and depression or anxiety has also been shown in adolescents.13 In prospective two-wave longitudinal studies, subjects who reported sleep disturbance at both the initial and 1- to 3-year follow-up interviews were much more likely to have developed new-onset major depression.16,17 The presence
of insomnia or difficulty sleeping at an initial assessment is also associated with a long-term (>30 years) increased relative risk for development of major depression.18 In a meta-analysis of prospective studies on risk factors for depression among community-dwelling elderly persons, 57% of the risk for depression was attributable to insomnia, and insomnia was second only to recent bereavement in predicting depression.19 Women with more disrupted sleep also had more depression both before and after giving birth, and the presence of initial insomnia seemed to be the most relevant screening question for identifying women at risk for postpartum depression.20 Children who reported decreased amounts of sleep21 or insomnia13 were more likely to develop symptoms of depression and reduced self-esteem. In patients who have had a previous episode of depression or mania, sleep changes remain a robust predictor of recurrent mood episodes, and their persistence is associated with a more severe course. Insomnia and fatigue were the most commonly reported symptoms preceding a recurrent major depression.22 In patients with bipolar disorder, an increase or decrease of 3 hours or more of sleep suggested imminent onset of a recurrent mood episode.23 Interepisodic Persistence of Subjective Sleep Disruption Although insomnia can improve with remission from major depression, it also often persists. In fact, insomnia is the most commonly reported residual symptom during remission of major depression24 or bipolar disorder.25 Persistence of sleep disturbances has been shown to predict increased severity and recurrence of major depression.24 Polysomnographic Findings Major depression has been studied polysomnographically more than any other psychiatric disorder, and the majority of patients have shown objective sleep disturbances (reviewed in reference 26). Since at least the late 1960s, sleep electroencephalographic (EEG) changes have been extensively evaluated for their potential as biological markers of mood disorders. Objective sleep abnormalities in depression have been grouped into three general categories: disturbance of sleep continuity, deficits of slowwave sleep (SWS, non–rapid eye movement [NREM] sleep stage 3), and abnormalities of REM sleep.27 Depressed patients showed prolonged sleep latency, increased wakefulness after sleep onset, and early morning awakening, which results in sleep fragmentation and decreased sleep efficiency. Patients with depression have decreased SWS, both as a fraction of total sleep and as SWS minutes. SWS loss is most significant during the first NREM period, but depressed patients appear to have reduced delta (1 to 4.5 Hz) EEG power and slowwave counts throughout the night.28 The distribution of SWS during the night is abnormal, with a decreased ratio of slow-wave activity in the first relative to the second NREM period.29 The most robust finding in depression is a decreased REM sleep latency (time from onset of sleep to onset of REM sleep).26 Other REM sleep abnormalities include a prolonged first REM sleep period and increased REM density. Increased percentage of REM sleep has also been observed. Common sleep
CHAPTER 130 • Mood Disorders 1491
Box 130-4 Sleep Abnormalities in Depression Subjective Complaints Insomnia • Difficulty falling asleep • Increased awakening at night/restless sleep • Early morning awakening • Decreased amounts of sleep Sleep is less deep or refreshing Disturbing dreams Polygraphic Findings Sleep continuity disturbances • Prolonged sleep latency • Increased wake time during sleep • Increased early morning wake time • Decreased total sleep time SWS deficits • Decreased SWS amount • Decreased SWS percentage of total sleep REM sleep abnormalities • Reduced REM sleep latency • Prolongation of the first REM sleep period • Increased REM activity (total number of eye movements during the night) • Increased REM density (REM activity/total REM sleep time) • Increased REM sleep percentage of total sleep REM, rapid eye movement; SWS, slow-wave sleep.
complaints and polysomnographic abnormalities are listed in Box 130-4. Studies of subjects with bipolar disorder during either mania or depression have reported similar findings. During manic episodes, disrupted sleep continuity, shortened REM sleep latency, and increased REM density have been reported.30 Patients with bipolar depression and hypersomnia did not consistently show reduced REM sleep latency, and although they complained of daytime sleepiness, their sleep latency, as measured on the multiple sleep latency test (MSLT), was relatively normal.31 Results from the few studies investigating dysthymia have been variable, but they suggest that some of the characteristic sleep findings of major depression are present but not to the same extent.32 Sleep disturbances in patients with mood disorders are not limited to periods of acute depression or mania: Several studies have reported abnormal sleep parameters in patients during remission and during acute illness. Some sleep abnormalities may be more severe in acute versus remission phases, including increased REM density and reduced sleep efficiency.33 However, reduced REM sleep latency and decreased SWS can persist for prolonged periods in otherwise asymptomatic persons. Thus, sleep disturbances—particularly reduced REM sleep latency and SWS abnormalities—may be trait markers for some patients with mood disorders rather than simply indications of an acute state of illness. The persistence of sleep abnormalities suggests that sleep disturbance might indicate a biological susceptibility for depression and predate the illness, or sleep changes may be caused by depression and persist
1492 PART II / Section 16 • Psychiatric Disorders
much longer than other affective symptoms.27 Additionally, first-degree relatives of subjects with major depression also show reduced REM sleep latency and SWS deficits, whether or not they have a personal history of a mood disorder,34 suggesting that sleep changes in depression include a hereditary component. Advanced Sleep Electroencephalographic Analysis Traditional polysomnography (PSG) studies have recorded from only a few electrodes and relied primarily on sleep architecture—an indirect assessment of brain activity during sleep—as the primary analysis variable. However, technologic improvements in EEG systems and computerized analysis have provided new tools to more directly assess normal and disrupted brain function in mood disorders by analyzing the fundamental oscillations of the sleep EEG. Techniques include quantitative analysis of EEG activity across a broad range of frequencies (power spectral analysis), the automated detection and investigation of specific EEG waveforms such as slow waves, spindles, and REMs, as well as measures of the similarity of EEG oscillations across brain regions over time (synchrony and coherence). One advantage of these approaches is the ability to more completely assess specific EEG frequencies or waveforms, independent of sleep stage (e.g., slow waves can be evaluated in all NREM sleep, not just SWS). Power Spectral Analysis Sleep EEG power spectra (also known as power density) for individual subjects are highly consistent between nights.35 Power spectral analysis has been used to characterize slow wave activity (SWA, 1 to 4.5 Hz EEG power) in control and depressed subjects, which confirmed that SWS reductions in major depression were correlated with decrements in SWA and validated the use of EEG power spectra to quantify sleep slow waves.36 Changes in SWA in response to treatment, like SWS changes, can predict outcomes: depressed subjects who had an acute increase of SWA over the whole night following antidepressant administration were more likely to respond to subsequent treatment.36 Decreased SWA in depressed subjects compared to controls persists from acute depression and remission, and it is more likely a trait marker of major depression.36 Automated Analysis of Slow Waves Manual identification of slow waves is complemented by using automated or semiautomated algorithms, and it has also provided improved sensitivity for detecting slow waves and a more quantifiable measure of slow waves than from sleep staging alone.36 The delta sleep ratio has been defined as the ratio of the average slow (delta) wave counts per minute in the first NREM sleep period to the average counts per minute in the second NREM sleep period.36 In control subjects, this ratio (typically >1.6) reflects the higher density of slow waves in the first NREM sleep period. Depressed subjects tend to have a lower ratio (≤1.10), reflecting this abnormal distribution.36 The delta sleep ratio has been thought to reflect an abnormal homeostatic regulation of SWS in depression (deficient Process
S37). In major depression, REM sleep onset is earlier, and there is less SWS during the first NREM sleep period, which is the opposite of the normal homeostatic pattern. The delta sleep ratio, as with other SWA markers, has been shown to predict treatment response and likelihood of recurrence: Patients with higher delta sleep ratios were more likely to respond to treatments, and those with lower ratios were more likely to experience recurrent depression.38,39 While reduced SWA in the first NREM sleep period has also been found in subjects with schizophrenia, only subjects with depression showed a reduced delta sleep ratio, suggesting that this measure may be more specific for major depression.40 Coherence of Sleep EEG Rhythms Coherence is a measure of the similarity of EEG rhythms at different cortical locations. EEG coherence is thought to reflect the functional relationships among different cortical regions. Decreased coherence may indicate impaired brain connectivity associated with psychiatric disorders including major depression.41 Both intra- and interhemispheric coherence in the delta (0.5 to 4 Hz) and beta (16 to 32 Hz) frequency ranges have been shown to be lower in adolescents and adults with major depression compared to controls, even in the absence of differences in sleep stage amounts.41,42 Reduced coherence also appears to be present in offspring at risk for developing major depression43 and it correlates with risk of recurrence in children and adolescents with major depression,42 suggesting that it may be a biological marker of depression. Mechanisms Associated with Sleep and Mood Disorders The high coincidence and overlapping symptoms of major depression and insomnia suggest common neurobiology. Attempts have been made to explain the mechanisms for sleep changes in mood disorders as well as to correlate them with other biological abnormalities in depression. A number of hypotheses have been advanced and include neurotransmitter imbalance, neuroimaging, dysregulation of the hypothalamic-pituitary-adrenal axis, and genetic polymorphisms. Neurotransmitter Imbalance The monoamine hypothesis suggests that decreased levels of serotonin, norepinephrine, and dopamine result in the symptoms of depression. This model fits with the proposed action of most antidepressant medications and with the characteristic findings of increased REM and decreased SWS during depression. Considerable evidence suggests that REM sleep is promoted by cholinergic activation within the medial pontine reticular formation (mPRF) and is inhibited by aminergic (serotoninergic and noradrenergic) activation (see Chapter 8).44 Thus, short REM sleep latency and elevated REM density in depression could be related to enhanced cholinergic neurotransmission or diminished aminergic neurotransmission, or both. Each of these systems is under strong genetic control and could define an endophenotype of depression.45 Antidepressant medications produce immediate increases in monoamine levels yet have a therapeutic lag of weeks.6 This delay is likely related to secondary neuroplastic
changes that mediate the longer-term effect of antidepressants. The glutamate system is a key neuromodulator related to plasticity, and it is also intimately tied to both sleep and mood regulation.46 Glutamate interacts with cholinergic neurons to increase activity of the reticular system associated with REM sleep onset. During NREM sleep, excitatory glutamate neurotransmission has a prominent role in the thalamocortical generation of sleep EEG oscillations.44 Additionally, sleep has increasingly been shown to be necessary for plastic processes such as learning and memory, and it affects the expression of plasticityrelated genes.47 The intertwined processes of mood, sleep, and plasticity, and their modulation through factors such as glutamate and BDNF, make them appealing targets for future therapies for mood disorders.46 Neuroimaging Neuroimaging has been an invaluable tool for identifying specific brain structures with altered activity or function in mood disorders.48 The same modalities can be applied to healthy and depressed subjects during waking and sleep to identify brain regions involved in regulating sleep and how their activity is altered in depressed patients with sleep disturbances. During normal NREM sleep, metabolic activity is broadly decreased in the frontal, temporal, and parietal cortices compared to waking levels. Subjects with current major depression had a smaller decrease in these cortical regions from waking to sleep, and they had a relative hypoactivity during wakefulness.49 Other brain areas involved in emotional regulation (anterior cingulate cortex, amygdala, parahippocampal cortex, thalamus) also had a smaller difference in metabolic rates between waking and NREM sleep and elevated metabolic rates during sleep in depressed subjects relative to controls (reviewed in reference 48). Altered function in these regions could relate to a failure of arousal mechanisms to decline from waking to sleep, as well as changes in cognition, attention, and emotional regulation in depression.50 Similarly, increased metabolic activity during REM sleep was seen in depressed subjects compared to controls in diffuse cortical and subcortical structures.50 These alterations could also reflect the imbalance of monoaminergic and cholinergic systems in altered mood states, and they could explain the increased REM sleep, decreased REM sleep latency, and decreased SWS in depression. Other imaging studies have focused on changes in brain activity after total or partial sleep deprivation of depressed patients. Around 50% of patients with major depression show a rapid improvement in symptoms after sleep deprivation (discussed later and reviewed in reference 51), further supporting the hypothesis that sleep and mood regulation are controlled by overlapping brain regions: patients who responded to sleep deprivation initially had increased metabolic activity in the amygdala, orbital prefrontal cortex, inferior temporal lobe, and anterior cingulate that normalized after sleep deprivation.52,53 Predeprivation perfusion levels correlating with the reduction of depressive symptoms and single photon emission computed tomography (SPECT) studies suggest that sleep deprivation responders may have a particular deficit in dopaminergic and serotoninergic systems involved with attention, arousal, and mood.52
CHAPTER 130 • Mood Disorders 1493
Dysregulation of the HypothalamicPituitary-Adrenal Axis Many patients with depression show dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, characterized by excessive corticotropin-releasing hormone (CRH) and cortisol secretion; they also show a lack of cortisol suppression in response to challenge with dexamethasone.54 Chronic stress also increases secretion of cortisol, linking life events to mood episodes. It is possible that increased activity of the HPA axis could contribute to sleep changes in depression, because excessive cortisol secretion is associated with depression and with reduced REM sleep latency.55 CRH is known to increase arousal, disrupt sleep, and possibly contribute to reduced REM sleep latency (reviewed in references 55 and 56). Supporting this hypothesis, administration of a CRH receptor antagonist was reported to improve sleep EEG patterns of depressed patients.57 Growth hormone–releasing hormone (GHRH) has a reciprocal relationship with CRH and promotes sleep. GHRH and growth hormone may also be decreased in some patients with depression, further contributing to SWS decrements.56 Genetic Polymorphisms At least 33% of the risk for major depression and 85% of the risk for bipolar disorder can result from genetic factors, and numerous candidate genes have been implicated.58 Additionally, a growing number of genes have a role in mood disorders and in sleep regulation. Both the gene for monoamine oxidase-A (MAO-A) and the serotonin transporter gene promoter (linked polymorphic region [5-HTTLPR]) have been implicated in depression and can correlate with insomnia scores (MAO-A) or treatment response to sleep deprivation (5-HTTLPR).59 Similarly, there are some early associations of clock genes, which regulate circadian rhythms, and disrupted sleep in mood disorders. Multiple reports have now linked a CLOCK gene polymorphism (3111 T/C) to the presence of insomnia or decreased sleep time in depressed and bipolar patients,60 and the genotype might interact with lithium treatment: Lithium appeared to enhance CLOCK activity in the evening and reduced differences between genotype groups.60 Lithium, the prototypical pharmacologic mood stabilizer, has also been shown to inhibit glycogen synthase kinase 3 (gsk3), which is also a circadian regulator that affects the stability of the Rev-erb protein, which in turn regulates the activation of other clock genes.61 This is an intriguing possible link between bipolar disorder and circadian genes, but it has not yet been demonstrated in patients. Primary Sleep Disorders and Mood Disorders There may also be an increased association between primary sleep disorders and mood disorders. Persons with sleep apnea have a 1.8-fold increased risk of developing major depressive disorder and those with depression a 1.6-fold increased risk for obstructive sleep apnea (OSA).62 Similarly, in a longitudinal study, persons with sleep-related breathing disorders showed a severity-related risk of developing depression, with odds ratios from 1.6 (minimal) to 2.6 (moderate or worse sleep-related
1494 PART II / Section 16 • Psychiatric Disorders Box 130-5 Examples of Questions to Elicit Primary Symptoms of Depression Depressed Mood How has your mood been recently? Have you been feeling down, depressed, sad, or blue lately? Has your sleep problem affected your mood? Loss of Interest or Pleasure Has your ability to enjoy things changed? Has your interest in things decreased? Are you less motivated to do things that are normally enjoyable for you?
breathing).62 Depression may also be a modifier of clinical course: In patients with OSA and depression, depression is directly associated with severity of daytime fatigue independent of severity of OSA.63 Other studies have shown that treating OSA results in a sustained improvement in depression, and the degree of improvement in OSA with continuous positive airway pressure (CPAP) also correlated with the improvement in depression.64 The relationship between major depression and restless legs syndrome (RLS) is less well defined. Several studies have shown an inconsistent correlation between the two disorders, even when controlling for the potential exacerbation of RLS by serotoninergic antidepressants.65
TREATMENT Patients with mood disorders often present to primary care physicians or sleep clinics with complaints of insomnia or fatigue, or both. However, because of the strong association between mood disorders and insomnia, any patient presenting with sleep complaints must be screened for depression. Recognition of major depression is important for determining appropriate treatment and must also include a careful assessment of possible suicide risk. In screening patients for depression, it is important for the clinician to establish rapport and create a permissive and supportive atmosphere for the patient to discuss any psychological symptoms. It is often necessary to ask about depressed mood and anhedonia in several ways (Box 130-5 gives examples) before a patient recognizes or admits to these symptoms. Treatment of Sleep Disturbance in Patients with Mood Disorders Mood disorders and the accompanying sleep disturbances may be treated with medication, psychotherapy, or both. Patients with moderate to severe depression usually are treated with medication, either alone or in combination with psychotherapy (Table 130-1; reviewed in reference 66). Treatment with Medication D EPRESSION Selective serotonin reuptake inhibitors (SSRIs) are currently the most widely prescribed class of drugs for depres-
sion in the United States. Along with the serotonin– norepinephrine reuptake inhibitors (SNRIs; desvenlafaxine, duloxetine, and venlafaxine) and newer atypical antidepressants (e.g., bupropion and mirtazapine), they have become first-line agents because of their safety and improved sideeffect profiles in comparison to the tricyclic antidepressants (TCAs) and monoamine oxidase inhibitors (MAOIs). However, SSRIs, SNRIs, and bupropion can cause significant sleep disruption and worsen insomnia in some patients.66 In contrast, trazodone, nefazodone, and mirtazapine are sedating and can improve sleep initiation and maintenance.66 Although use of TCAs and MAOIs has diminished because of the associated side effects and greater potential toxicity, these drugs may be effective in patients who fail to improve with the newer antidepressants. Most TCAs are quite sedating and therefore may be helpful to depressed patients with insomnia; they continue to be used for treatment of migraine headaches and other chronic pain conditions. Low doses of TCAs have commonly been prescribed for insomnia, and a few studies have shown good efficacy and tolerability of low-dose TCAs as hypnotics in the absence of significant depression.67 MAOIs are sometimes used, albeit rarely, in patients who fail to improve with other antidepressants, particularly patients with atypical features (hypersomnia, increased appetite) or a significant comorbid anxiety. The most serious potential side effect of MAOIs is the danger of hypertensive crisis if used in combination with sympathomimetic drugs or with foods containing tyramine. For severely depressed patients, including those with psychotic features or strong suicidal intent or whose depression is resistant to antidepressants alone, additional treatment modalities, including electroconvulsive therapy (ECT), transcranial magnetic stimulation (TMS), or antipsychotic medications, should be considered. Second-generation antipsychotics (SGAs; e.g., risperidone, olanzapine, quetiapine, ziprasidone, or aripiprazole) are used to enhance the antidepressant response to SSRIs or as mood stabilizers in bipolar patients (Table 130-2 and see Chapter 131 for further discussion of antipsychotic medications). Patients with severe fatigue or hypersomnia might also benefit from adjunctive use of stimulant medications, although there is limited evidence that they directly affect mood or treatment course.68 B IPOLAR D ISORDER The standard maintenance treatment for bipolar disorder is a mood stabilizer (see Table 130-2). Lithium carbonate is the gold standard mood stabilizer for treating bipolar patients. The anticonvulsants carbamazepine, oxcarbazepine, sodium valproate, and lamotrigine also have been found to be effective treatments for patients with bipolar disorders; they may be used alone or in combination with lithium. Each of the mood-stabilizing agents has antimanic effects but limited antidepressant effects, with the exception of lithium and lamotrigine, which appear to be effective in treating bipolar depression and prolonging time to recurrence of mood episodes. For mood episodes with psychotic features or as an adjunct treatment, the use of SGAs has become much more widespread. Additionally, some SGAs are also approved monotherapy for bipolar
CHAPTER 130 • Mood Disorders 1495
Table 130-1 Treatment of Major Depression* MEDICATION
USUAL DOSAGE RANGE
PHARMACOLOGIC MECHANISM
SIDE EFFECTS*
EFFECTS ON SLEEP
Inhibit serotonin and norepinephrine reuptake Anticholinergic Antihistaminergic
Anticholinergic effects: blurred vision, dry mouth, urinary retention, orthostatic hypotension, flushing, tachycardia, confusion, others (drugs are listed in decreasing order of severity) Other side effects: liver toxicity, lowering of seizure threshold, sweating, weight gain
Sedation (drugs listed in decreasing order: clomipramine, desipramine and protriptyline may be nonsedating or activating) REM sleep suppression Increased stage 2 sleep
Inhibit monoamine oxidase Increase norepinephrine, serotonin, and dopamine
Hypertensive crisis in combination with tyramine-containing foods or sympathomimetics Anticholinergic effects Dizziness, agitation Liver toxicity Weight gain
Insomnia Potent REM sleep suppression
Gastrointestinal disturbances Sexual dysfunction Anxiety, agitation Possible increased risk for suicide
Insomnia REM sleep suppression Increased eye movements in NREM sleep
Tricyclic Antidepressants (TCAs) Amitriptyline (Elavil) Imipramine (Tofranil) Doxepin (Sinequan) Nortriptyline (Pamelor) Clomipramine (Anafranil) Desipramine (Norpramin) Protriptyline (Vivactil)
50-150 mg 150-300 mg 150-300 mg 50-150 mg 150-250 mg 75-200 mg 20-60 mg
Monoamine Oxidase Inhibitors (MAOIs) Phenelzine (Nardil) Isocarboxazid (Marplan) Tranylcypromine (Parnate) Selegiline transdermal (Emsam)
45-90 mg 10-30 mg 10-30 mg 6-12 mg/ 24-hr patch
Selective Serotonin Reuptake Inhibitors (SSRIs) Fluoxetine (Prozac) Paroxetine (Paxil) Sertraline (Zoloft) Citalopram (Celexa) Escitalopram (Lexapro)
20-60 mg 20-60 mg 50-200 mg 20-60 mg 10-20 mg
Inhibits reuptake of serotonin
Serotonin-Norepinephrine Reuptake Inhibitors (SNRIs) 150-375 mg 50 mg 30-120 mg
Inhibits reuptake of serotonin and norepinephrine
Anxiety Anorexia Hypertension Possible increased risk for suicide
Insomnia
Trazodone (Desyrel)
150-600 mg
Inhibit serotonin reuptake 5-HT2 receptor antagonist
Decreased REM sleep Increased SWS Sedation
Nefazodone (Serzone)
200-300 mg
Inhibit serotonin reuptake 5-HT2 receptor antagonist
Bupropion (Wellbutrin)
150-450 mg
Inhibits norepinephrine and dopamine reuptake
Mirtazapine (Remeron)
15-45 mg
Few anticholinergic effects Priapism Nausea, dizziness, dry mouth Few anticholinergic effects Priapism Nausea, dizziness, dry mouth Gastrointestinal upset Lowering of seizure threshold Anxiety Increased appetite, weight gain Dizziness
Venlafaxine (Effexor) Desvenlafaxine (Pristiq) Duloxetine (Cymbalta)
Other Antidepressants:
Alpha2 adrenergic receptor antagonist 5-HT1a agonist 5-HT2 and 5-HT3 receptor antagonist
No change or increased REM sleep Increased SWS Sedation Insomnia Increased REM sleep Sedation
* In October 2004, the U.S. Food and Drug Administration (FDA) directed manufacturers to add a black box warning to the health professional labeling of all antidepressant medications to describe include warnings about increased risks of suicidal thinking and behavior, known as suicidality, in young adults ages 18 to 24 years during initial treatment (generally the first 1 to 2 months) and emphasize the need for close monitoring of patients starting on these medications. 5-HT, 5-hydroxytryptamine mine; REM, rapid eye movement; SWS, slow-wave sleep.
1496 PART II / Section 16 • Psychiatric Disorders
maintenance treatment and prevention of recurrent mood episodes.
Light therapy and its use in treating depression are reviewed in detail in Chapter 79.
C ONCURRENT T REATMENT OF D EPRESSION AND I NSOMNIA Some depression treatment studies have investigated the efficacy of co-administering antidepressants (SSRIs or TCAs) with hypnotic agents such as eszolpiclone,69 zolpidem70 or lorazapam.71 The results from the limited number of studies suggests that addition of a hypnotic was generally well tolerated, improved insomnia associated with depression, and might improve time to improvement of both insomnia and mood.69 However, hypnotics alone are insufficient treatment for depression and are not a substitute for approved antidepressant treatments. Insomnia that persists in spite of treatment with other antidepressants or mood stabilizers might require additional pharmacotherapy. Trazodone has been shown to have hypnotic effects in patients with insomnia and depression72 and is often combined with other antidepressants to improve sleep.73
Treatment of Mood Disorders with Sleep Deprivation A variety of sleep manipulations, including total and partial sleep deprivation or selective deprivation of REM sleep, have been shown to have rapid antidepressant effects, although they have not come into widespread clinical use.78,79 A single night of total sleep deprivation generally shows antidepressant effects (50% reduction of Hamilton Depression Rating Scale scores); response rates are 30% to 60%, with peak antidepressant effects by the afternoon following a night of total sleep loss.78,79 Patients with a more pronounced diurnal pattern of illness have better responses to sleep deprivation. The major drawback to total sleep deprivation as a therapy for depression, however, has been the immediate reversibility of the antidepressant effects by recovery sleep, including short naps, in at least 50% to 80% of responders, not to mention the problems associated with sleep deprivation itself (e.g., increased sleepiness, limited ability to sustain treatment). Sleep deprivation has been combined with other treatment modalities (including medications (lithium, antidepressants), sleep-phase advance, light therapy, and transcranial magnetic stimulation), with mixed results, as an attempt to combine the rapid response with sustained improvements from other modalities.79 Like total sleep deprivation, partial deprivation can be immediately effective and has comparable response rates in some studies.78,79 The timing of partial sleep deprivation (e.g.—sleep restricted to the first or second half of the night) does not appear to be as critical as the degree of deprivation.79 Chronic REM sleep deprivation also improved depressive symptomatology,78,79 although the response was not as robust, and it was not clear that NREM sleep was not affected. However, unlike total sleep deprivation, the antidepressant effects of chronic REM sleep deprivation took several weeks to appear and were not immediately reversed following recovery sleep. Although the mechanism for the antidepressant effects of sleep deprivation is not known, functional neuroimaging studies suggest that they are correlated with effects on limbic structures. Increased rates of glucose metabolism52 or blood flow53 in the amygdala and cingulate before sleep deprivation have been reported in depressed subjects who respond to sleep deprivation. Normalization of activity after sleep deprivation in these limbic structures was associated with a decrease in depression.52,53 The antidepressant response to sleep deprivation has been correlated with other biological markers in sleep EEG39 and genetic59 studies. Additionally, response to sleep deprivation can serve as a biological marker of a major depression subtype, as well as the basis for designing novel antidepressants.
S LEEP E FFECTS OF P SYCHIATRIC M EDICATIONS Antidepressants have a variety of effects on sleep: more sedating or anticholinergic agents (e.g., trazodone, nefazodone, mirtazapine, and TCAs) can cause hangover effects; conversely, activating antidepressants (e.g., bupropion, SSRIs, and MAOIs) can cause or exacerbate insomnia. SSRIs have been associated with frequent eye movements in NREM sleep, which can persist for prolonged periods following cessation of treatment; the clinical significance of this effect is unknown.74 TCAs and SSRIs have been implicated in precipitating or exacerbating restless legs syndrome and periodic leg movements, and they can exacerbate symptoms of insomnia or daytime fatigue by this mechanism in some patients.75 REM sleep behavior disorder also has been reported following administration of various REM sleep– suppressing antidepressants.74 Despite their increasingly common use, there are few studies investigating objective sleep changes related to the use of SGAs.66 In general, SGAs appear to decrease sleep-onset latency and improve sleep continuity and efficiency, but they also commonly cause weight gain, which can increase the risk of OSA. Lithium can prolong REM sleep latency and suppress REM sleep time, and it can increase SWS in manic patients.76 Nonpharmacologic Treatments Empirically validated psychotherapies (e.g., cognitive behavior therapy [CBT] and interpersonal therapy [IPT]) are efficacious treatments for depression, particularly for patients who do not tolerate the sleep-related side effects of antidepressant medications. Patients with significant insomnia should be instructed in the basic aspects of sleep hygiene; behavioral techniques such as relaxation or stimulus control may be useful for some patients as well (see Chapter 79). For more severe or chronic symptoms, CBT for insomnia is effective in improving sleep disturbances associated with mood disorders.77 For patients with seasonal depression and hypersomnia, bright light therapy has been shown to be effective, either alone or in combination with antidepressant medication.
Sleep Loss and Bipolar Disorder The mood-elevating effects of reduced sleep have been most dramatically demonstrated by reports that sleep deprivation or spontaneous periods of sleeplessness triggered manic episodes in some patients with bipolar depression.23,79 Although it can be difficult to isolate insomnia’s possible role as a prodromal symptom of mania, studies
CHAPTER 130 • Mood Disorders 1497
Table 130-2 Mood Stabilizers MEDICATION
USUAL DOSAGE RANGE
SIDE EFFECTS
EFFECTS ON SLEEP
Lithium carbonate
600-1800 mg/day Plasma level: 0.7-1.2 mEq/L
Increased white blood cell count Polyuria, polydypsia Diabetes insipidus Decreased thyroid function Weight gain Gastrointestinal upset Tremor
Sedation Increased total sleep Can increase slow-wave sleep, decrease REM sleep
Carbamazepine (Tegretol)
800-1200 mg/day Plasma level: 4-12 µg/mL
Sedation
Oxcarbazepine (Trileptal)
1200-2400 mg/day
Sodium valproate (Depakote)
30-60 mg/kg/day Plasma level: 50-100 µg/mL
Lamotrigine (Lamictal)*
100-400 mg/day
Bone marrow suppression (rare) Liver toxicity Rashes Bone marrow suppression (rare) Liver toxicity Rashes Gastrointestinal upset Liver toxicity Tremor Weight gain Rashes Rash Stevens-Johnson syndrome
Weight gain Hyperglycemia, diabetes Hypotension, syncope Extrapyramidal side effects
Sedation Decreased sleep latency Increased sleep continuity
Anticonvulsants
Sedation Mild sedation No significant effects on sleep
Mild sedation Minimal effects on sleep architecture
Second-Generation Antipsychotics† Olanzapine (Zyprexa) Quetiapine (Seroquel) Ziprasidone (Geodon) Risperidone (Risperdal) Aripiprazole (Abilify)
5-20 mg/day 200-800 mg/day 80-160 mg/day 1-6 mg/day 15-30 mg/day
*Not directly antimanic; more useful for bipolar depression but may prevent recurrence of mania. † Refer to Chapter 131 for more details. REM, rapid eye movement.
have used various designs to demonstrate that sleep loss may be a risk factor for mania, independent of prodromal mood symptoms. Interestingly, sleep loss has also been associated, although not as strongly, with bipolar depression.22,23 Sleep loss in bipolar patients is often followed by the onset of mood episodes, either manic or depressive, in the following 24-hour period, and the magnitude of sleep change appears to correlate with the likelihood of a subsequent mood change.23 These findings stress the importance of closely monitoring sleep patterns in patients with bipolar disorder and of aggressively treating the first signs of sleep loss and insomnia. Clinical Application of Sleep Studies Sleep studies have potential utility in psychiatry for diagnosis and for evaluating treatment. Although a specific psychiatric diagnosis cannot be made solely on the basis of standard polysomnographic data, sleep studies can sometimes answer specific questions. Sleep complaints in most patients with mood disorders are usually related to the underlying psychiatric illness; however, diagnostic polysomnography can sometimes be helpful given the risk for primary sleep disorders in psychiatric patients, and vice versa. Furthermore, in patients with mood disorders and significant sleep complaints that do not respond to therapy, it is important to consider the possibility of a concomitant primary sleep disorder, such as OSA, particularly given the
overlap of common symptoms. For example, sleep apnea and periodic limb movements can disrupt nocturnal sleep and lead to insomnia, fatigue, and poor concentration, which are also symptoms of depression. It is also important to consider side effects of psychiatric medications that may be responsible for precipitating or exacerbating sleep disorders. The potential prognostic utility of sleep studies in mood disorders has not yet been fully realized. It is possible that specific sleep abnormalities, such as REM and SWS changes, may be diagnostic or predictive of treatment response. However, these findings have not shown consistency that is adequate to justify widespread implementation.26,36 Alternatively, medication-induced changes in sleep patterns may be correlated with treatment response to antidepressants. The amount of REM sleep suppression during the first night of treatment with tricyclic antidepressants was correlated with eventual antidepressant response in several studies,80,81 although prolongation of REM sleep latency alone was less consistent in predicting treatment response. Sleep variables may also be helpful in identifying persons susceptible to developing affective illnesses or relapses. For instance, a decreased delta sleep ratio has been shown to correlate with an increased risk of relapse and predict treatment outcome.38,82 In interpreting sleep studies in clinical settings, it is important to bear in mind that reduced REM sleep latency
1498 PART II / Section 16 • Psychiatric Disorders
can be present in a variety of conditions other than mood disorders. Short REM sleep latency and decreased SWS have been reported in other conditions, including schizophrenia, borderline personality disorder, eating disorders, and alcoholism.26 Early appearance of REM sleep is also characteristic of narcolepsy. Short REM sleep latency and REM sleep rebound commonly occur in patients who have been withdrawn recently from antidepressant medications, benzodiazepines, or alcohol and in OSA patients during initial CPAP titration.
CLINICAL COURSE AND PREVENTION Mood disorders tend to be remitting and relapsing disorders with long courses, although some patients experience only a single episode. Increasingly, it is recognized that repeated episodes of mood disorders contribute to a poor prognosis, which underscores the importance of early and effective treatment. Patients with multiple episodes of depression probably require chronic treatment to prevent or minimize recurrence. Bipolar disorder is more likely to be recurrent than major depression; at least 90% of bipolar patients have multiple episodes. Additionally, more than 60% of mood episodes in bipolar disorder are more likely to result in severe impairment, compared to about 40% in major depression. Overall, bipolar patients have a worse prognosis than those with major depressive disorder; more than one third have a chronically progressive course. The standard of care for bipolar disorders requires chronic maintenance therapy with a mood stabilizer to minimize relapsing episodes. Following treatment with pharmacotherapy or psychotherapy (or both), about one third of depressed patients recover fully, one third have partial remission, and one third do not respond significantly to treatment. Treatment of depressive episodes reduces episode length, but it should be continued for at least 6 months to a year following remission because the risk of relapse is greater during this period. All patients, including those considered to be in remission, can continue to experience residual symptoms of depression. Sleep disturbance is one of the more common residual symptoms and has been estimated to occur in up to 44% of patients in remission from major depression.83 In addition, insomnia is one of the most predictive symptoms heralding the onset of an episode of mania or depression,10,13 as discussed earlier in this chapter. Thus it is not surprising that patients with mood disorders often suffer from chronic sleep problems. PITFALLS AND CONTROVERSIES Despite the lack of an ideal theory, there is considerable evidence suggesting that sleep is biologically linked to mood disorders. Perhaps the most basic question is whether a causal link exists between sleep and depression, regardless of the specific mechanism involved. For example, does depression cause sleep abnormalities? Alternatively, do the neurobiological mechanisms contributing to abnormal sleep patterns specifically lead to an increased susceptibility to depression? Indirect evidence suggests that changes in sleep herald the onset of mood episodes. On the other
hand, narcoleptic patients with short REM sleep latency are not invariably depressed, and inducing “depressive” sleep patterns in normal persons with cholinergic agents does not cause depression. Although sleep and mood symptoms are highly associated, it has not yet been clearly defined how the course of symptoms may affect outcomes. For example, sleep problems often precede mood episodes, but it is not yet evident if the sleep problem is due to the underlying neurobiology of the mood disorder or if a primary sleep problem is associated with a predisposition for mood problems. Similarly, although some studies have begun to address this issue, the effect of concurrent treatment for sleep problems on the clinical course of mood disorders is not yet fully elucidated. Continued study of sleep in mood disorders and in psychiatric disorders in general will elucidate neurobiological and genetic mechanisms involved in sleep regulation and psychiatric illnesses and can provide novel directions for future neuropharmacologic treatments.84,85
❖ Clinical Pearl Because of the strong association between sleep disturbance and mood disorders, all patients with sleep complaints should be screened for mood disorders, and vice versa. Sleep might not normalize with resolution of mood disorders, and recurrence or worsening of sleep can predict the relapse of mood symptoms. Concurrent and aggressive treatment of sleep problems, in addition to the treatment for mood, is important for improving morbidity and quality of life in our patients.
REFERENCES 1. Kessler RC, Berglund P, Demler O, et al. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62 (6):593-602. 2. World Health Organization. What is depression? Available at: http:// www.who.int/mental_health/management/depression/definition/ en/. Accessed December 7, 2009. 3. American Psychiatric Association. Task Force on DSM-IV. Diagnostic and statistical manual of mental disorders: DSM-IV-TR. 4th ed. Washington, DC: American Psychiatric Association; 2000. 4. Kessler RC, Berglund P, Demler O, et al. The epidemiology of major depressive disorder: results from the National Comorbidity Survey Replication (NCS-R). JAMA 2003;289(23):3095-3105. 5. Merikangas KR, Akiskal HS, Angst J, et al. Lifetime and 12-month prevalence of bipolar spectrum disorder in the National Comorbidity Survey replication. Arch Gen Psychiatry 2007;64(5):543-552. 6. Krishnan V, Nestler EJ. The molecular neurobiology of depression. Nature 2008;455(7215):894-902. 7. Ebmeier KP, Donaghey C, Steele JD. Recent developments and current controversies in depression. Lancet 2006;367(9505):153167. 8. Yates WR, Mitchell J, John Rush A, et al. Clinical features of depression in outpatients with and without co-occurring general medical conditions in STAR*D: confirmatory analysis. Prim Care Companion J Clin Psychiatry 2007;9(1):7-15. 9. Liu X, Buysse DJ, Gentzler AL, et al. Insomnia and hypersomnia associated with depressive phenomenology and comorbidity in childhood depression. Sleep 2007;30(1):83-90.
10. Mitchell PB, Goodwin GM, Johnson GF, Hirschfeld RM. Diagnostic guidelines for bipolar depression: a probabilistic approach. Bipolar Disord 2008;10(1 Pt 2):144-152. 11. Roth T, Jaeger S, Jin R, et al. Sleep problems, comorbid mental disorders, and role functioning in the national comorbidity survey replication. Biol Psychiatry 2006;60(12):1364-1371. 12. Taylor DJ, Lichstein KL, Durrence HH, et al. Epidemiology of insomnia, depression, and anxiety. Sleep 2005;28(11):1457-1464. 13. Johnson EO, Roth T, Breslau N. The association of insomnia with anxiety disorders and depression: exploration of the direction of risk. J Psychiatr Res 2006;40(8):700-708. 14. Buysse DJ, Reynolds CF 3rd, Kupfer DJ, et al. Clinical diagnoses in 216 insomnia patients using the International Classification of Sleep Disorders (ICSD), DSM-IV and ICD-10 categories: a report from the APA/NIMH DSM-IV Field Trial. Sleep 1994;17(7):630-637. 15. Stein MA, Mendelsohn J, Obermeyer WH, et al. Sleep and behavior problems in school-aged children. Pediatrics 2001;107(4):E60. 16. Ford DE, Kamerow DB. Epidemiologic study of sleep disturbances and psychiatric disorders. An opportunity for prevention? JAMA 1989;262(11):1479-1484. 17. Breslau N, Roth T, Rosenthal L, Andreski P. Sleep disturbance and psychiatric disorders: a longitudinal epidemiological study of young adults. Biol Psychiatry 1996;39(6):411-418. 18. Chang PP, Ford DE, Mead LA, et al. Insomnia in young men and subsequent depression. The Johns Hopkins Precursors Study. Am J Epidemiol 1997;146(2):105-114. 19. Cole MG, Dendukuri N. Risk factors for depression among elderly community subjects: a systematic review and meta-analysis. Am J Psychiatry 2003;160(6):1147-1156. 20. Goyal D, Gay CL, Lee KA. Patterns of sleep disruption and depressive symptoms in new mothers. J Perinat Neonatal Nurs 2007; 21(2):123-129. 21. Fredriksen K, Rhodes J, Reddy R, Way N. Sleepless in Chicago: tracking the effects of adolescent sleep loss during the middle school years. Child Dev 2004;75(1):84-95. 22. Perlman CA, Johnson SL, Mellman TA. The prospective impact of sleep duration on depression and mania. Bipolar Disord 2006; 8(3):271-274. 23. Bauer M, Grof P, Rasgon N, et al. Temporal relation between sleep and mood in patients with bipolar disorder. Bipolar Disord 2006; 8(2):160-167. 24. Buysse DJ, Angst J, Gamma A, et al. Prevalence, course, and comorbidity of insomnia and depression in young adults. Sleep 2008; 31(4):473-480. 25. Harvey AG, Schmidt DA, Scarna A, et al. Sleep-related functioning in euthymic patients with bipolar disorder, patients with insomnia, and subjects without sleep problems. Am J Psychiatry 2005;162 (1):50-57. 26. Benca RM, Obermeyer WH, Thisted RA, Gillin JC. Sleep and psychiatric disorders: a meta-analysis. Arch Gen Psychiatry 1992;49: 651-668. 27. Reynolds CF, III, Kupfer DJ. Sleep research in affective illness: state of the art circa 1987. Sleep 1987;10(3):199-215. 28. Borbely AA, Tobler I, Loepfe M, et al. All-night spectral analysis of the sleep EEG in untreated depressives and normal controls. Psychiatry Res 1984;12(1):27-33. 29. Kupfer DJ, Reynolds CF 3rd, Ulrich RF, Grochocinski VJ. Comparison of automated REM and slow-wave sleep analysis in young and middle-aged depressed subjects. Biological Psychiatry 1986; 21:189-200. 30. Hudson JI, Lipinski JF, Keck PE Jr, et al. Polysomnographic characteristics of young manic patients. Comparison with unipolar depressed patients and normal control subjects. Arch Gen Psychiatry 1992;49(5):378-383. 31. Nofzinger EA, Thase ME, Reynolds CF 3rd, et al. Hypersomnia in bipolar depression: a comparison with narcolepsy using the multiple sleep latency test. Am J Psychiatry 1991;148:1177-1181. 32. Akiskal HS, Judd LL, Gillin JC, Lemmi H. Subthreshold depressions: clinical and polysomnographic validation of dysthymic, residual and masked forms. J Affect Disord 1997;45(1-2):53-63. 33. Thase ME, Fasiczka AL, Berman SR, et al. Electroencephalographic sleep profiles before and after cognitive behavior therapy of depression. Arch Gen Psychiatry 1998;55(2):138-144. 34. Giles DE, Kupfer DJ, Rush AJ, Roffwarg HP. Controlled comparison of electrophysiological sleep in families of probands with unipolar depression. Am J Psychiatry 1998;155(2):192-199.
CHAPTER 130 • Mood Disorders 1499 35. Buckelmuller J, Landolt HP, Stassen HH, Achermann P. Trait-like individual differences in the human sleep electroencephalogram. Neuroscience 2006;138(1):351-356. 36. Kupfer DJ. Sleep research in depressive illness: clinical implications —a tasting menu. Biol Psychiatry 1995;38(6):391-403. 37. Borbely AA. The S-deficiency hypothesis of depression and the twoprocess model of sleep regulation. Pharmacopsychiatry 1987;20: 23-29. 38. Jindal RD, Thase ME, Fasiczka AL, et al. Electroencephalographic sleep profiles in single-episode and recurrent unipolar forms of major depression: II. Comparison during remission. Biol Psychiatry 2002;51(3):230-236. 39. Nissen C, Feige B, Konig A, et al. Delta sleep ratio as a predictor of sleep deprivation response in major depression. J Psychiatr Res 2001;35(3):155-163. 40. Hoffmann R, Hendrickse W, Rush AJ, Armitage R. Slow-wave activity during non-REM sleep in men with schizophrenia and major depressive disorders. Psychiatry Res 2000;95(3):215-225. 41. Armitage R. Sleep and circadian rhythms in mood disorders. Acta Psychiatr Scand Suppl 2007;(433):104-115. 42. Armitage R, Hoffmann R, Emslie G, et al. Sleep microarchitecture in childhood and adolescent depression: temporal coherence. Clin EEG Neurosci 2006;37(1):1-9. 43. Morehouse RL, Kusumakar V, Kutcher SP, et al. Temporal coherence in ultradian sleep EEG rhythms in a never-depressed, high-risk cohort of female adolescents. Biol Psychiatry 2002;51(6):446-456. 44. Pace-Schott EF, Hobson JA. The neurobiology of sleep: genetics, cellular physiology and subcortical networks. Nat Rev Neurosci 2002;3(8):591-605. 45. Modell S, Lauer CJ. Rapid eye movement (REM) sleep: an endophenotype for depression. Curr Psychiatry Rep 2007;9(6):480-485. 46. Zarate CA Jr, Singh J, Manji HK. Cellular plasticity cascades: targets for the development of novel therapeutics for bipolar disorder. Biol Psychiatry 2006;59(11):1006-1020. 47. Cirelli C. A molecular window on sleep: changes in gene expression between sleep and wakefulness. Neuroscientist 2005;11 (1):63-74. 48. Davidson RJ, Pizzagalli D, Nitschke JB, Putnam K. Depression: perspectives from affective neuroscience. Annu Rev Psychol 2002; 53:545-574. 49. Nofzinger EA, Buysse DJ, Germain A, et al. Alterations in regional cerebral glucose metabolism across waking and non–rapid eye movement sleep in depression. Arch Gen Psychiatry 2005;62(4):387-396. 50. Nofzinger EA, Buysse DJ, Germain A, et al. Functional neuroimaging evidence for hyperarousal in insomnia. Am J Psychiatry 2004; 161(11):2126-2128. 51. Berger M, van Calker D, Riemann D. Sleep and manipulations of the sleep–wake rhythm in depression. Acta Psychiatr Scand Suppl 2003;(418):83-91. 52. Wu JC, Buchsbaum M, Bunney WE Jr. Clinical neurochemical implications of sleep deprivation’s effects on the anterior cingulate of depressed responders. Neuropsychopharmacology 2001;25(5 Suppl):S74-S78. 53. Clark CP, Brown GG, Frank L, et al. Improved anatomic delineation of the antidepressant response to partial sleep deprivation in medial frontal cortex using perfusion-weighted functional MRI. Psychiatry Res 2006;146(3):213-222. 54. Nestler EJ, Barrot M, DiLeone RJ, et al. Neurobiology of depression. Neuron 2002;34(1):13-25. 55. Buckley TM, Schatzberg AF. On the interactions of the hypothalamic-pituitary-adrenal (HPA) axis and sleep: normal HPA axis activity and circadian rhythm, exemplary sleep disorders. J Clin Endocrinol Metab 2005;90(5):3106-3114. 56. Steiger A. Neurochemical regulation of sleep. J Psychiatr Res 2007;41(7):537-552. 57. Held K, Kunzel H, Ising M, et al. Treatment with the CRH1receptor-antagonist R121919 improves sleep-EEG in patients with depression. J Psychiatr Res 2004;38(2):129-136. 58. Belmaker RH, Agam G. Major depressive disorder. N Engl J Med 2008;358(1):55-68. 59. Benedetti F, Colombo C, Serretti A, et al. Antidepressant effects of light therapy combined with sleep deprivation are influenced by a functional polymorphism within the promoter of the serotonin transporter gene. Biol Psychiatry 2003;54(7):687-692. 60. Benedetti F, Dallaspezia S, Fulgosi MC, et al. Actimetric evidence that CLOCK 3111 T/C SNP influences sleep and activity patterns
1500 PART II / Section 16 • Psychiatric Disorders in patients affected by bipolar depression. Am J Med Genet B Neuropsychiatr Genet 2007;144(5):631-635. 61. Yin L, Wang J, Klein PS, Lazar MA. Nuclear receptor Rev-erbα is a critical lithium-sensitive component of the circadian clock. Science 2006;311(5763):1002-1005. 62. Peppard PE, Szklo-Coxe M, Hla KM, Young T. Longitudinal association of sleep-related breathing disorder and depression. Arch Intern Med 2006;166(16):1709-1715. 63. Bardwell WA, Ancoli-Israel S, Dimsdale JE. Comparison of the effects of depressive symptoms and apnea severity on fatigue in patients with obstructive sleep apnea: a replication study. J Affect Disord 2007;97(1-3):181-186. 64. Wells RD, Freedland KE, Carney RM, et al. Adherence, reports of benefits, and depression among patients treated with continuous positive airway pressure. Psychosom Med 2007;69(5):449-454. 65. Ulfberg J, Bjorvatn B, Leissner L, et al. Comorbidity in restless legs syndrome among a sample of Swedish adults. Sleep Med 2007; 8(7-8):768-772. 66. DeMartinis NA, Winokur A. Effects of psychiatric medications on sleep and sleep disorders. CNS Neurol Disord Drug Targets 2007; 6(1):17-29. 67. Scharf M, Rogowski R, Hull S, et al. Efficacy and safety of doxepin 1 mg, 3 mg, and 6 mg in elderly patients with primary insomnia: a randomized, double-blind, placebo-controlled crossover study. J Clin Psychiatry J Clin Psychiatry 2008;69(10):1557-1564. 68. Candy M, Jones L, Williams R, et al. Psychostimulants for depression. Cochrane Database Syst Rev 2008;(2):CD006722. 69. Krystal A, Fava M, Rubens R, et al. Evaluation of eszopiclone discontinuation after cotherapy with fluoxetine for insomnia with coexisting depression. J Clin Sleep Med 2007;3(1):48-55. 70. Asnis GM, Chakraburtty A, DuBoff EA, et al. Zolpidem for persistent insomnia in SSRI-treated depressed patients. J Clin Psychiatry 1999;60(10):668-676. 71. Buysse DJ, Reynolds CF 3rd, Houck PR, et al. Does lorazepam impair the antidepressant response to nortriptyline and psychotherapy? J Clin Psychiatry 1997;58(10):426-432. 72. Scharf MB, Sachais BA. Sleep laboratory evaluation of the effects and efficacy of trazodone in depressed insomniac patients. J Clin Psychiatry 1990;51(Suppl):13-17.
73. Kaynak H, Kaynak D, Gozukirmizi E, Guilleminault C. The effects of trazodone on sleep in patients treated with stimulant antidepressants. Sleep Med 2004;5(1):15-20. 74. Geyer JD, Carney PR, Dillard SC, et al. Antidepressant medications, neuroleptics, and prominent eye movements during NREM sleep. J Clin Neurophysiol 2009;26(1):39-44. 75. Bakshi R. Fluoxetine and restless legs syndrome. J Neurol Sci 1996;142(1-2):151-152. 76. Billiard M. Lithium carbonate: effects on sleep patterns of normal and depressed subjects and its use in sleep-wake pathology. Pharmacopsychiatry 1987;20(5):195-196. 77. Smith MT, Huang MI, Manber R. Cognitive behavior therapy for chronic insomnia occurring within the context of medical and psychiatric disorders. Clin Psychol Rev 2005;25(5):559-592. 78. Ringel BL, Szuba MP. Potential mechanisms of the sleep therapies for depression. Depress Anxiety 2001;14(1):29-36. 79. Giedke H, Schwarzler F. Therapeutic use of sleep deprivation in depression. Sleep Med Rev 2002;6(5):361-377. 80. Gillin JC, Wyatt RJ, Fram DH, Snyder F. The relationship between changes in REM sleep and clinical improvement in depressed patients treated with amitriptyline. Psychopharmacology 1978;59: 267-272. 81. Kupfer DJ, Spiker DG, Coble PA, et al. Sleep and treatment prediction in endogenous depression. Am J Psychiatry 1981;138: 429-434. 82. Thase ME, Fasiczka AL, Berman SR, et al. Electroencephalographic sleep profiles before and after cognitive behavior therapy of depression. Arch Gen Psychiatry 1998;55(2):138-144. 83. Nierenberg AA, Keefe BR, Leslie VC, et al. Residual symptoms in depressed patients who respond acutely to fluoxetine. J Clin Psychiatry 1999;60(4):221-225. 84. Gass N, Ollila HM, Utge S, et al. Contribution of adenosine related genes to the risk of depression with disturbed sleep. J Affect Disord 2010;126:134-139. 85. Gałecki P, Szemraj J, Bartosz G, et al. Single-nucleotide polymorphisms and mRNA expression for melatonin synthesis rate-limiting enzyme in recurrent depressive disorder. J Pineal Res 2010; 48:311-317.
Schizophrenia
Kathleen L. Benson and Irwin Feinberg
Abstract Schizophrenia is perhaps the most devastating neuropsychiatric illness. Worldwide, its prevalence rate is about 1%. Although its etiology remains unknown, schizophrenia is considered a neurodevelopmental disorder involving the interplay of susceptibility genes and environmental factors. There is a wide range of pathologic findings, but there is no specific or diagnostic laboratory abnormality. Consequently, schizophrenia remains a clinical diagnosis, and its defining symptoms are typically delusions and hallucinations in the absence of extreme emotion. Cognitive impairment or thought disorder is also considered a cardinal symptom. Sleep patterns in schizophrenic patients can be markedly disturbed. In times of severe psychotic agitation, schizophrenic patients often experience a profound insomnia or total sleeplessness. They can also develop sleep–wake reversals, with a preference for sleeping during the day. Severe insomnia is one of the prodromal symptoms associated with psychotic relapse or exacerbation. Clinically stable, medicated patients with schizophrenia can also experience ongoing sleep disturbance, particularly early and middle insomnia. Many polysomnographic abnormalities have been identified, but none are diagnostic of schizophrenia. Such abnormalities include poor sleep
In many ways, the dream experience is similar to psychosis. Hallucinations, perceptual distortions, bizarre thinking, and temporary delusions intermingle with more normal thought and perceptual processes. Consequently, the discovery of REM sleep and its associated dream reports1 not only ushered in the modern era of sleep research but also engendered many of the seminal studies of the sleep of schizophrenics. These studies2-5 explored the hypothesis that the pathogenesis of schizophrenia might rest with REM sleep abnormalities or, more directly, with the intrusion of the dream state into waking. These early polysomnographic (PSG) studies of sleep in schizophrenic patients found no gross abnormalities of REM sleep or any evidence of an intrusion of REM sleep into wakefulness. However, in subsequent years, a large body of research revealed other abnormalities more consistently characteristic of the sleep patterns in schizophrenia. Schizophrenia is associated with immense human and economic cost. It is also associated with severe insomnia, particularly during episodes of psychotic exacerbation. This chapter provides an overview of the clinical features of schizophrenia and associated risk factors and neuropathology. It also describes the sleep abnormalities characteristic of schizophrenia and their neurobiological correlates. Finally, we address the issues surrounding antipsychotic medications and their side effects, particularly those associated with the development of comorbid dyssomnias.
Chapter
131 efficiency, slow-wave sleep deficits, and short rapid eye movement (REM) sleep latencies. The most consistently observed sleep abnormality is early insomnia or difficulty attaining a state of persistent sleep. Although some schizophrenic patients have a full recovery after an initial psychotic episode, the majority require longterm treatment with antipsychotic medications. These agents are classified as first-generation or second-generation antipsychotics. They differ in their receptor binding profiles, clinical efficacy, and range of side effects. Relative to the secondgeneration antipsychotics, first-generation antipsychotics are thought to produce more extrapyramidal side effects and tardive dyskinesia. Several second-generation antipsychotics are associated with significant weight gain and abnormal glucose regulation, including diabetes. Schizophrenic patients also suffer from a range of intrinsic and extrinsic dyssomnias including inadequate sleep hygiene, irregular sleep–wake patterns, parasomnias, obstructive sleep apnea, restless legs syndrome (RLS), and periodic limb movements during sleep (PLMS). The second-generation antipsychotics include agents that can induce or exacerbate sleep-disordered breathing, RLS, or PLMS. Sleep specialists should treat schizophrenic patients who have dyssomnias in the same manner as they do other patients.
EPIDEMIOLOGY AND RISK FACTORS Most studies of schizophrenia suggest a prevalence rate of 5 cases per 1000 people.6 Lifetime prevalence is approximately 1% worldwide.6 Estimated annual new case appearance, or incidence, is 0.35 cases per 1000 population.6 Schizophrenia is equally common in both sexes. Although the age of onset is usually in the second decade of life, the disorder seems to begin earlier in male than in female patients. Although the etiology of schizophrenia remains unknown, several factors are associated with an increased likelihood for developing schizophrenia. First, a genetic predisposition greatly elevates the risk for developing schizophrenia. Family, twin, and adoption studies provide strong evidence that schizophrenia is highly heritable. The prevailing genetic model of the etiology of schizophrenia suggests that multiple combinations of common mutations among candidate genes act together to increase the risk of developing the disease. A single genetic mutation would not be necessary or sufficient for developing schizophrenia.7 Multiple combinations of common susceptibility genes, interacting with one another, suggest that multiple forms of schizophrenia might exist. In contrast, research suggests that highly penetrant, individually rare mutations, even of recent origin, can predispose to schizophrenia. These mutations, which vary from person to person, were largely involved in networks controlling neurodevelopment.8 Because the concordance rate for monozygotic 1501
1502 PART II / Section 16 • Psychiatric Disorders
twins only approaches 50%, genetic makeup alone is not sufficient for the development of schizophrenia, and nongenetic or sporadic forms of the disorder must exist. Among the environmental factors that might play a role in the development of schizophrenia are obstetric complications and viral infection.6 Obstetric complications could include premature birth, low birth weight, trauma, and poor oxygenation. Some hypothesize that schizophrenia is an autoimmune disease potentially triggered by maternal antibodies to viral infection.9 A better understanding of both genetic and environmental risk factors and their interaction should open a window on the etiology and pathophysiology of the disease.
DIAGNOSIS The term schizophrenia derives from Bleuler’s description of the splitting or disintegration of normal thought processes.10 His belief that cognitive impairment or thought disorder is the defining symptom of schizophrenia shaped the course of diagnostic criteria developed during the 20th century. Current criteria for the diagnosis of schizophrenia are defined in the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR; Box 131-1).11 As reviewed by Black and Andreasen,12 schizophrenia is a clinical diagnosis because there are no specific laboratory abnormalities diagnostic of the disorder. It is
also, in large part, a diagnosis of exclusion, eliminating psychotic disturbances attributable to a variety of medical, psychiatric, and substance-abuse disorders. In addition, the number and diversity of symptoms complicates the clinical presentation. To simplify the task of the clinician, characteristic symptoms11 (see Box 131-1) are organized into two main categories, positive and negative symptoms. According to DSM-IV, “positive symptoms appear to reflect an excess or distortion of normal functions, whereas the negative symptoms appear to reflect a diminution or loss of normal functions.” Positive symptoms can be further subdivided into a psychotic dimension that includes hallucinations and delusions and a disorganization dimension that includes disorganized speech and behavior. Negative symptoms include flattening of affect, avolition, and poverty of speech. The second diagnostic criterion11 (see Box 131-1) reflects a marked deterioration in occupational and social functioning. The sleep abnormalities found in schizophrenia lack diagnostic specificity. Consequently, they do not reliably differentiate schizophrenia from other psychiatric disorders. It is unlikely, therefore, that a sleep clinic would be asked to diagnose schizophrenia. However, the sleep clinic could help differentiate schizophrenia from narcolepsy, which can manifest with a strong hallucinatory component.13
Box 131-1 DSM-IV Diagnostic Criteria for Schizophrenia Characteristic Symptoms Two (or more) of the following, each present for a significant portion of time during a 1-month period (or less if successfully treated): • Delusions • Hallucinations • Disorganized speech (e.g., frequent derailment or incoherence) • Grossly disorganized or catatonic behavior • Negative symptoms: affective flattening, alogia, or avolition Only one of these symptoms is required if delusions are bizarre or hallucinations consist of a voice keeping up a running commentary on the person’s behavior or thoughts, or two or more voices conversing with each other.
that meet criteria for active-phase symptoms and may include periods of prodromal or residual symptoms. During these prodromal or residual periods, the signs of the disturbance may be manifested by only negative symptoms or two or more active-phase symptoms presented in an attenuated form (e.g., odd beliefs, unusual perceptual experiences).
Social or Occupational Dysfunction For a significant portion of the time since the onset of the disturbance, one or more major areas of functioning such as work, interpersonal relations, or self-care are markedly below the level achieved before the onset. When the onset is in childhood or adolescence, failure to achieve expected level of interpersonal, academic, or occupational achievement is the criterion.
Substance and General Medical Condition Exclusion The disturbance is not due to the direct physiologic effects of a substance (e.g., a drug of abuse, a medication) or a general medical condition.
Duration Continuous signs of the disturbance persist for at least 6 months. This 6-month period must include at least 1 month of symptoms (or less if successfully treated)
Schizoaffective and Mood Disorder Exclusion Schizoaffective disorder and mood disorder with psychotic features have been ruled out because either no major depressive, manic, or mixed episodes have occurred concurrently with the active-phase symptoms or if mood episodes have occurred during active-phase symptoms, their total duration has been brief relative to the duration of the active and residual periods.
Relationship to a Pervasive Developmental Disorder If there is a history of autistic disorder or another pervasive developmental disorder, the additional diagnosis of schizophrenia is made only if prominent delusions or hallucinations are also present for at least 1 month (or less if successfully treated).
DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision. Adapted from the American Psychiatric Association: Diagnostic and statistical manual of mental disorders, 4th ed. Washington, DC: American Psychiatric Press; 2000. Copyright 2000 American Psychiatric Association.
PATHOGENESIS The etiology of schizophrenia is poorly understood, but accumulating evidence has revealed a wide range of brain abnormalities.6,12 Brain structural abnormalities have been found in postmortem studies and in living subjects by computed tomography (CT) and magnetic resonance imaging (MRI).11,12 Regarding the latter, structural dysmorphologies have included enlarged lateral and third ventricles; loss of total gray matter, frontal, and temporal lobe volume; and a reduction in total brain size. These findings seem to be present at the onset of illness and cannot be attributed to progressive degeneration; however, most findings are nonspecific and are observed in other psychiatric disorders. Functional imaging studies using positron emission tomography (PET) or regional cerebral blood flow have observed decreased metabolism in the frontal cortex (hypofrontality) and left hemisphere dysfunction. Abnormalities of neurotransmitter systems have also been extensively investigated. For many years, the prevailing theory of schizophrenia has centered on the dopamine system. The dopamine (DA) hypothesis of schizophrenia derived from two observations. First, the potency of standard antipsychotic medication correlates with the amount of D2 receptor blockade. Second, drugs such as amphetamines, which enhance DA activity, can cause a psychosis that mimics paranoid schizophrenia and can exacerbate schizophrenic symptoms. The hypothesis holds that psychotic symptoms such as hallucinations and delusions are associated with hyperactivity of the mesolimbic DA system. Serotonin (5-hydroxytrypamine [5-HT]) and norepinephrine have also been associated with the pathophysiology of schizophrenia because the potency of second-generation antipsychotics has been linked to 5-HT and alpha-adrenergic receptor blockade. Finally, the role of the excitatory neurotransmitter glutamate in the pathophysiology of schizophrenia is gaining greater credence in part because several of the recently identified schizophrenia susceptibility genes target glutamatergic transmission.7,8,14 Agonists of metabotropic glutamate receptors (mGluRs) are currently being investigated as treatments for schizophrenia.15 Metabotropic glutamate receptor agonists actually decrease brain excitability. They also have profound effects on the sleep electroencephalogram (EEG), diminishing REM sleep and non-REM (NREM) fast frequencies in the rat.16 Because no discrete pathologic abnormality has emerged as an etiologic factor, schizophrenia may be an abnormality of neuronal connectivity17 or of integrative neuronal circuits.18 Neither of these theories is inconsistent with the broader and prevailing view that schizophrenia is a neurodevelopmental disorder.19,20 Although abnormal events can occur early in development (prenatal or perinatal), maturational abnormalities can appear during the second decade of life21 or even into middle age.22 CLINICAL COURSE AND PREVENTION In the prevailing pathophysiologic model, schizophrenia is viewed as a neurodevelopmental disorder with onset typically (but not always) in late adolescence. The onset may be abrupt or insidious—that is, beginning with a prodro-
CHAPTER 131 • Schizophrenia 1503
mal phase characterized by subtle changes in behavior, mild thought disorder, and social withdrawal. The prodromal phase is followed by an active phase marked by positive psychotic symptoms such as hallucinations and delusions. This phase can wax and wane, but some degree of psychoticism usually persists during the waning or residual phase. Positive symptoms (relapse or acute exacerbation) can recur episodically. Over the course of the illness, positive psychotic symptoms can gradually decline; in contrast, negative symptoms such as affective flattening and avolition tend to increase with the progression of the disease. For about 50% of patients, the onset of the illness is both progressive and insidious; for the remainder, the onset is acute, with little or no prodromal syndrome. Also, for about 50% of patients, the course of the illness is continuous; for others the course is marked by episodic flareups. The likelihood of relapse has been associated with stressful life events, a critical and hostile family environment, and drug abuse. If a positive outcome is defined as the absence of psychotic symptoms and normal levels of social functioning, long-term follow-up studies suggest that 20% to 30% of patients have a full recovery. Another 20% to 30% of patients recover to levels where they can function occupationally and socially, but they have residual symptoms. Approximately 50% continue to show moderate to severe dysfunction requiring numerous outpatient interventions or rehospitalization with each relapse. Approximately one fifth require long-term institutionalization. Although the atypical antipsychotics can lower the number of hospitalizations, antipsychotic treatment does not fundamentally alter these outcomes. A better outcome has been associated with acute onset, episodic course, female sex, and lack of family history of schizophrenia. The course of illness in schizophrenia can include dysphoria or depressive episodes, particularly early in the course. Relative to other major psychiatric disorders, schizophrenic patients tend to marry less, are more likely found in an institutional setting, and have poorer occupational functioning. Schizophrenic patients also have a higher mortality rate owing to suicide as well as physical illness. Schizophrenia is probably the most devastating of all psychiatric illnesses. We can neither cure this disorder nor prevent its occurrence. Most schizophrenics, after an early onset, can anticipate lifelong mental disability as well as social and economic marginalization.
SLEEP-RELATED FEATURES Subjective Sleep Complaints With the onset of psychotic symptoms, and with each subsequent relapse, sleep is usually markedly impaired. The sleep of schizophrenic patients who are in a state of psychotic agitation usually, but not invariably, is manifested by prolonged periods of total sleeplessness. In times of less severe psychotic agitation, sleep is often characterized by a pronounced insomnia—long sleep-onset latencies, reduced total sleep time, and sleep fragmented by bouts of waking. Recurrence or exacerbation of symptoms is often heralded by increasing insomnia. Even among clinically stable, medicated patients with schizophrenia,
1504 PART II / Section 16 • Psychiatric Disorders Table 131-1 Comparison of Sleep Stage Designations CLASSIC TERMINOLOGY
REVISED TERMINOLOGY
Wakefulness
Stage W
Stage 1 sleep
Stage N1 (NREM 1 sleep)
Stage 2 sleep
Stage N2 (NREM 2 sleep)
Stage 3 sleep
Stage N3 (NREM 3 sleep)
Stage 4 sleep
Stage N3
Slow wave sleep
Stage N3
Stage REM sleep
Stage R (REM sleep)
ongoing subjective sleep disturbance is common, particularly early and middle insomnia.23 There may also be a reversal of sleep and wake so that the patient sleeps during the day and remains awake at night. Subjective complaints of poor sleep quality are correlated with sleep–wake reversals.24 Schizophrenic patients also complain of poor sleep quality, including restlessness and agitation, disturbing hypnagogic hallucinations, and nightmares. Subjectively assessed poor sleep quality is predictive of self-assessed poor quality of life and impaired coping skills.25,26 Although there are no systematic studies, anecdotal clinical reports suggest that alcohol and substance abuse can disturb sleep and cause the patient to relapse. Alternatively, use of these drugs may be an attempt to self-medicate and attenuate the psychic misery of this illness. Polysomnographic Features Polysomnographic studies have provided a comprehensive and objective description of the range of dyssomnias found in schizophrenia, and they have been broadly consistent with subjective complaints. However, these PSG studies have, on occasion, produced discrepant findings, owing perhaps to differences in protocol design, composition of control groups, sample size, inclusion criteria (e.g., age, medication status and history, clinical features, and clinical history), as well as algorithms to quantify sleep parameters. In this section, we rely on meta-analyses27,28 and a review29 to summarize the diversity of these findings. The reader should note that sleep stages reported in this chapter are based on the sleep scoring rules and terminology which prevailed before 2007 and which are broadly consistent with those developed by Rechtschaffen and Kales.30 They are designated classic terminology in Table 131-1. In 2007, the American Academy of Sleep Medicine revised the rules and terminology for the scoring of sleep stages.31 An overview of this revision is presented in Chapter 141. Table 131-1 provides a simplified translation of classic to revised terminology. Total Sleep, Sleep Maintenance, and Sleep Continuity Polysomnographic studies have shown that the sleep of schizophrenic patients is characterized by poor sleep efficiency. Often this takes the form of a reduction in total sleep time as well as early, middle, and late insomnia. The most consistently reported abnormality is early insomnia or difficulty reaching a state of persistent sleep. Many of
these empirical studies have evaluated schizophrenic patients who were treated with antipsychotics, suggesting that some degree of residual insomnia is not an uncommon outcome of standard treatment. Note that severe insomnia is one of the prodromal signs of impending psychotic decompensation or relapse subsequent to discontinuing antipsychotic medication.32-34 Abnormalities of REM Time and REM Eye Movements Despite early speculation regarding potential REM sleep abnormalities in schizophrenia, studies comparing schizophrenic patients with healthy control subjects have consistently shown that REM sleep time is not systematically augmented or reduced.27,28 Eye movements during REM sleep have also been studied. Visual scoring of REM sleep eye movements report no difference in density of eye movements between schizophrenic patients and control subjects.35,36 An automated eye-movement detection system37 yielded the same conclusion, but it extended the observation, finding no differences in eye movement density in schizophrenic patients, nonpsychiatric control subjects, and patients with major depressive disorder. REM Sleep Latency Many PSG studies have quantified the latency to the onset of the first REM sleep period.27-29 Several have compared the REM latency of unmedicated schizophrenic patients with that of nonpsychiatric control subjects. Approximately half have reported significant between-group differences, with the schizophrenic patients demonstrating abnormally short REM latency. Even in studies finding no between-group differences, a bimodal distribution of REM latency values in schizophrenic patients has been observed, suggesting that there are subgroups of schizophrenic patients with sleep-onset REM periods.35,38 Short REM latency might represent an active, or primary alteration of REM sleep mechanisms. Alternatively, as suggested by Feinberg and colleagues,39 a slow-wave sleep (SWS) deficit in the first NREM period might permit the passive advance or early onset of the first REM period. Abnormalities of NREM Sleep Slow-wave sleep deficits are often, but not consistently, observed in PSG recordings of schizophrenic patients. In visually scored PSG, SWS is reported as the summation of sleep stages 3 and 4, with stage 4 sleep having the greater incidence of underlying slow wave activity. Documentation of SWS or stage 4 deficits has been reported in many studies of schizophrenic patients.27-29 Although some research has suggested that prior exposure to, or withdrawal from, antipsychotics might explain these inconsistencies,36 SWS deficits have been observed in antipsychotic-naive patients in their first episode of schizophrenia.40 In addition to clinical heterogeneity, another factor might contribute to the inconsistency, notably the insensitivity of visual scoring to the incidence and amplitude of slow- or delta-wave (0 to 3 Hz) EEG that underlies SWS. Sleep-Related Brain Wave Activity Studies41-44 using computer quantification of the sleep EEG (e.g., Fourier analysis, period and amplitude analysis)
have confirmed the degradation of sleep-related delta activity in schizophrenic patients relative to age-matched nonpsychiatric control subjects. Significant decrements in delta amplitude between schizophrenic patients and nonpsychiatric controls have been observed despite comparable amounts of visually scored SWS.45 Laterality of frontal cortex delta counts is reduced in schizophrenic patients relative to healthy controls, suggesting right frontal pathophysiology among the schizophrenic patients.44 In contrast to degradation of delta (0 to 3 Hz) activity, power in the high-frequency beta (20 to 35 Hz) and gamma (35 to 45 Hz) ranges of the sleep EEG may be greater in unmedicated schizophrenic patients relative to healthy controls.46 Also, the number and amplitude of NREM sleep spindles (12 to 15 Hz) may be reduced in medicated schizophrenic patients, a finding that suggests some abnormality in thalamic–reticular and thalamocortical function in schizophrenia.47 Slow-Wave Sleep Homeostasis Deficits of SWS, whether scored visually or quantified by computer algorithm, raise concern about the integrity of homeostatic regulatory mechanisms in schizophrenia. In 1974, Feinberg advanced the homeostatic model of SWS; according to this model, the homeostatic drive builds up during waking and dissipates in SWS across successive NREM cycles.48 In healthy subjects, SWS increases in proportion to the amount and intensity of prior waking, suggesting that the homeostatic or dynamic response might serve a restorative role in the central nervous system. This homeostatic drive is demonstrated by a rebound in SWS or EEG delta activity following the naturalistic probe of total sleep deprivation. Two studies have looked at potential homeostatic dysregulation in schizophrenia. In the first, no homeostatic recovery of visually scored SWS was found after 85 hours of total sleep deprivation.49 More recently, SWS visual scoring and computer analysis of delta activity were examined after 1 night of total sleep deprivation.50 Stage 4 sleep was absent on both baseline and recovery nights, but period and amplitude analysis of EEG delta activity revealed a significant (although modest) recovery night increase in delta incidence and amplitude relative to baseline. Therefore, it would appear that the homeostatic drive in schizophrenia is operative but diminished. In support of this conclusion, it has been shown that on an intranight basis, the time course of delta activity dissipation over all NREM sleep cycles is normal in schizophrenic patients.45 Correlation with Clinical and Neurobiological Measures Many of the sleep abnormalities associated with schizophrenia have been studied in relationship to global symptom severity, the severity of positive and negative symptoms, clinical prognosis, and neurocognitive impairment.29 Brain dysmorphologies have also been studied in relationship to sleep abnormalities in patients with schizophrenia. On a theoretical level, SWS deficits have been associated with microstructure brain abnormalities. Feinberg21 has proposed that schizophrenia is a neurodevelop-
CHAPTER 131 • Schizophrenia 1505
mental disorder arising from a malfunction in the normal maturational process of synaptic elimination during the second decade of life; excess synaptic pruning would result in less capability for synchronous EEG slow-wave activity and a deficit of SWS. Empirically, SWS deficits or a reduction in its stage 4 component have been associated with enlarged ventricular system volume.51,52 A related study using antipsychotic-naive schizophrenic patients did not concur.36 PSG studies have also noted a relationship between brain dysmorphologies in schizophrenia and sleep maintenance abnormalities.36,51,53 These reports of brain dysmorphologies and their relationship to sleep abnormalities in patients with schizophrenia must be viewed with some interpretive restraint. Terms such as “enlargement” and “atrophy” need longitudinal assessment, but all the reported studies employed a cross-sectional design. Volumetric status of the reported brain structures before the point of cross-sectional assessment is only speculative. We must also view with some restraint any contention that sleep abnormalities with a neuroanatomic correlate must have a stable or traitlike presentation over time. First, many of the dyssomnias of schizophrenia do change over time in respond to antipsychotic treatment. Second, consistent with the observation of adult neurogenesis54 in the human brain are demonstrations of longitudinal changes in the brain structure of schizophrenic patients undergoing antipsychotic treatment.55-57 Our understanding of how neurochemical mechanisms might correlate with, or possibly mediate, the sleep abnormalities of schizophrenia is limited to a small number of studies whose findings may be confounded by long-term exposure to antipsychotics. Furthermore, although dopamine and glutamate dysfunction might occupy prominent roles in the pathophysiology of schizophrenia, the relationship of sleep abnormalities in schizophrenia to either of these neurochemical systems has not been directly tested. Limited reports involving four other neurotransmitter systems have been published. Cholinergic supersensitivity has been associated with short REM latencies in patients with schizophrenia.58 Among unmedicated schizophrenic patients, SWS deficits have been linked to a 5-HT dysfunction; this study reported a positive correlation between SWS time and cerebrospinal fluid (CSF) levels of the 5-HT metabolite 5-hydroxyindole acetic acid.59 A separate study reported that increased CSF levels of norepinephrine and its principal metabolite, 3-methoxy4-hydroxyphenylglycol (MHPG), accompanied psychotic decompensation and relapse-related insomnia.32 CSF hypocretin, a wake-promoting neurotransmitter that excites midbrain dopamine neurons, has been correlated with sleep latency, suggesting a relationship between hypocretin and hyperarousal in schizophrenia.60
TREATMENT Treating Schizophrenia with Antipsychotic Agents Consistent with standards of practice, most patients with schizophrenia are treated with one or more of the antipsychotic agents listed in Table 131-2. Antipsychotics differ in their chemical design and have differential effects on
1506 PART II / Section 16 • Psychiatric Disorders Table 131-2 Commonly Used Antipsychotic Medications ANTIPSYCHOTIC MEDICATIONS
USUAL ADULT DAILY MAINTENANCE DOSE (MG)
First-Generation Antipsychotics Chlorpromazine (Thorazine)
50-400
Fluphenazine (Prolixin)
1-15
Haloperidol (Haldol)
1-15
Perphenazine (Trilafon)
8-24
Thioridazine (Mellaril)
50-400
Thiothixene (Narvane)
6-30
Trifluoperazine (Stelazine)
4-30
Second-Generation Antipsychotics Aripiprazole (Abilify)
10-30
Clozapine (Clozaril)
200-600
Olanzapine (Zyprexa) Quetiapine (Seroquel) Paliperidone (Invega) Risperidone (Risperdal) Ziprasidone (Geodon)
5-20 150-750 6-12 2-8 80-160
DA, 5-HT, alpha-adrenergic, cholinergic, and histaminic receptors and their various subtypes.61,62 The receptor binding profiles of these agents are associated with different side effects and clinical outcome. Types of Antipsychotic Agents F IRST- G ENERATION A NTIPSYCHOTICS The therapeutic efficacy of the first generation of antipsychotics is attributed to their ability to block the dopamine D2 postsynaptic receptor, particularly the D2 receptors in the striatum, but the clinical benefits associated with these first-generation antipsychotics have occurred with some cost. Given their signature binding profile, these antipsychotics often result in extrapyramidal side effects (EPS) such as akathisia, dystonia, and parkinsonism. A more damaging side effect associated with D2 receptor blockade is tardive dyskinesia. The traditional antipsychotics are also associated to varying degrees with cholinergic side effects including sedation, changes in blood pressure and myocardial conduction, sexual dysfunction, and weight gain. A rare but potentially fatal side effect associated with hyperthermia is the neuroleptic malignant syndrome. S ECOND- G ENERATION A NTIPSYCHOTICS Several factors played a role in motivating the development of the second-generation antipsychotics. First, up to 30% of patients with chronic schizophrenia have a poor or inadequate response to first-generation antipsychotics. Second, although traditional antipsychotics have demonstrated success in ameliorating positive symptoms, they have been less successful in treating negative symptoms. Third, the side effects associated with traditional antipsychotics, particularly EPS and tardive dyskinesia, were a source of noncompliance and raised difficult management
issues. Clozapine was the first of the second-generation antipsychotics to demonstrate good clinical efficacy with no EPS. The atypical antipsychotics now include six other agents, listed in Table 131-2. Although they demonstrate unique receptor binding profiles, as a group they are characterized by weaker affinity for the D2 receptor (relative to traditional antipsychotics), and strong affinity for 5-HT2 receptors.62 Second-generation antipsychotics are now considered first-line treatment for schizophrenia. Relative to the traditional antipsychotics, they offer better compliance and fewer hospitalizations. However, second-generation antipsychotics are not the panacea once envisioned.63 Only clozapine has clearly demonstrated effectiveness in treatment-refractory schizophrenia and in childhood schizophrenia. None of the atypical antipsychotics has been strongly effective against negative symptoms. Like the traditional antipsychotics, the atypical antipsychotics can have serious side effects. Although the incidence of EPS and tardive dyskinesia remains low with atypical antipsychotics, both EPS and tardive dyskinesia can occur with atypical antipsychotics at higher doses. Clozapine is associated with increased risk of agranulocytosis and of seizures at higher doses. The atypical antipsychotics are associated with increased morbidity owing to weight gain, dyslipidemia, and impaired glucose regulation including type 2 diabetes mellitus. Weight gain may be particularly striking and puts the patient at increased risk of developing sleeprelated breathing disorders and other obesity-related morbidities. The National Institute of Mental Health–sponsored Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study64 compared one first-generation antipsychotic to several second-generation antipsychotics in terms of effectiveness and side effects. This study found no significant difference in efficacy between perphenazine and three atypical antipsychotics (risperidone, quetiapine, and ziprasidone). Olanzapine, which is more effective than perphenazine, was also associated with greater weight gain and metabolic morbidities. The CATIE study underscores the need for more systematic comparisons of first- and second-generation antipsychotics in terms of efficacy, side effects, and expense. Sleep-Promoting Effects of Antipsychotics Broadly speaking, first-generation antipsychotics alter sleep architecture by improving sleep maintenance with augmentations of total sleep time and sleep efficiency and reductions in sleep latency and waking.65-69 With less consistency, the traditional antipsychotics have been associated with increases in REM latency,65-68 REM sleep time,66,67 and REM eye movement density.65,67,69 In one study, chlorpromazine was associated with increased SWS time.65 With regard to the effect of second-generation antipsychotics on sleep patterns in schizophrenic patients, clozapine has been the most widely studied. Clozapine has been shown to have strong consolidating effects on sleep, including increased total sleep time, sleep efficiency, and stage 2 sleep and decreased sleep latency and wake time after sleep onset.69-71 Relative to a medication-free baseline, a significant decline in SWS and stage 4 was observed in
schizophrenic patients treated with clozapine.70 Olanzapine has also been shown to be a sleep-promoting agent with increases in both sleep efficiency and SWS.72,73 Likewise, a significant enhancement of SWS has been noted in schizophrenic patients treated with risperidone.74 Paliperidone’s effects on sleep patterns in patients with schizophrenia revealed increased sleep efficiency, total sleep time, and stage 2 and stage REM minutes as well as decreased sleep latency, waking, and stage 1 minutes.75 PSG evaluations of schizophrenic patients treated with quetiapine, ziprasidone, and aripiprazole have not been undertaken; however, effects of quetiapine and ziprasidone on the sleep of healthy controls include improvements in sleep induction and consolidation.76,77 Treating Comorbid Psychiatric Illness Although monotherapy with second-generation antipsychotics is standard practice, augmentation with additional antipsychotics is not uncommon and can optimize therapeutic response. In addition to antipsychotics, schizophrenic patients may be prescribed other psychoactive agents to treat comorbid psychiatric illness. For example, schizophrenic patients with problems of impulse control and patients with schizoaffective disorder may be prescribed adjunct mood stabilizers such as valproate. It is not uncommon for comorbid depression to be diagnosed in schizophrenic patients, and adjunct antidepressants may be prescribed. Mood stabilizers and antidepressants often demonstrate beneficial effects on sleep. Schizophrenic patients may be enrolled in dual-diagnosis programs to treat comorbid problems of alcohol and substance abuse; by themselves, alcohol and substance abuse can contribute to significant sleep disruption. Treating Sleep Disorders in Patients with Schizophrenia After the symptoms of schizophrenia and other comorbid medical and psychiatric illnesses have been optimally treated, clinicians might need to address a range of residual sleep disorders. These residual sleep disorders can encompass insomnia, hypersomnia, and parasomnias. Insomnia The CATIE study64 reported that rates of residual insomnia in antipsychotic-treated schizophrenic patients ranged from 16% to 30%. It is not uncommon for insomnia to be attributed to poor sleep hygiene, sleep-related movement disorders, and untreated hyperarousal associated with the schizophrenia illness. I NADEQUATE S LEEP H YGIENE Many schizophrenic patients lack daytime structure and prefer to avoid social interactions. Consequently, they can develop bad habits in relation to sleep initiation and sleep maintenance, including sleep reversals and polyphasic sleep patterns with extended periods of daytime napping. Daytime naps affect nocturnal sleep more when the naps are taken later in the day. This situation may be further complicated by excess caffeine intake and the self-prescribed alcohol or psychoactive drugs such as cocaine. Patients with schizophrenia are always good candidates for sleep hygiene counseling.
CHAPTER 131 • Schizophrenia 1507
S LEEP- R ELATED M OVEMENT D ISORDERS Because prevalence studies of sleep disorders in antipsychotic-naive schizophrenic patients are lacking, baseline rates for comorbid sleep disorders in this population have not been established. However, schizophrenic patients do present with insomnia disorders typically seen in the setting of a sleep disorders clinic. Although some sources of insomnia, such as poor sleep hygiene, may be associated with lifestyle habits, others are side effects of treatment, being enhanced by, or induced by, antipsychotic medication. Because RLS and PLMS respond to dopamine agonists, DA deficiency is thought to be central to their pathophysiology.78 Consequently, the D2 receptor blockade of antipsychotic agents might induce RLS and PLMS in antipsychotic-treated schizophrenic patients. Consistent with this hypothesis, the prevalence of RLS in antipsychotic-treated schizophrenic patients has been reported to be more than twice that of healthy controls.79 Although the diagnosis of RLS is made by clinical interview, the diagnosis of PLMS requires overnight PSG; consequently, the prevalence of PLMS in patients with schizophrenia has been less systematically examined. PLMS prevalence rates for schizophrenic patients with a history of treatment with first-generation antipsychotics have been reported to be in the 13% to 14% range.80,81 Certain atypical antipsychotics, such as olanzapine82,83 and risperidone,84 have been associated with the development of RLS and PLMS. Although DA agonists such as ropinirole and pramipexole are firstline treatments for RLS and PLMS, treatment options for schizophrenic patients with RLS or PLMS should be carefully considered. One might first consider a reduction in antipsychotic dose or a change to a different antipsychotic agent. Patients might also be evaluated for possible iron deficiency, a known risk factor for the development of RLS, or use of substances, such as caffeine, that might worsen sleep-related movements. Although agents such as ropinirole and pramipexole are not first-line choices for patients with schizophrenia, such agents might be necessary when their benefits outweigh the risk. Chapter 90 addresses evaluation and treatment options for patients with RLS and/or PLMS. Clinicians should note that akathisia, which is characterized by intense motor restlessness and pacing, is a common side effect of antipsychotic treatment. By itself, akathisia can cause significant sleep disruption. Although RLS might be confused with the restlessness of akathisia, the clinical presentation of RLS is associated with a circadian worsening of symptoms in the evening or at night and symptomatic relief by movement. S CHIZOPHRENIA- R ELATED H YPERAROUSAL Antipsychotic-treated schizophrenic patients may also experience a residual and persistent insomnia directly associated with hyperarousal or an inadequately treated component of their clinical illness. Given sufficient severity, the clinician may opt to treat residual insomnia by changing the antipsychotic agent, changing the dose of the antipsychotic agent, or adding an adjunctive, more-sedating antipsychotic medication. Alternatively, supplemental use of anxiolytics or sedative hypnotics may also be considered,85 but these agents should be prescribed cautiously,
1508 PART II / Section 16 • Psychiatric Disorders
particularly for patients with a sleep-related breathing disorder or a history of alcohol or drug abuse. Use of melatonin as an adjunct treatment for residual insomnia has been the subject of investigational study. Melatonin is the principal hormone produced by the pineal gland. Because disturbed patterns of melatonin secretion have been associated with insomnia, patterns of melatonin secretion have been examined in medication-free schizophrenic patients. In certain studies, the nighttime peak in melatonin secretion was blunted, and normalization of melatonin levels did not occur following clinical improvement with antipsychotic-treatment.86,87 Subsequent studies tested the effect of exogenous melatonin on residual insomnia in antipsychotic-treated schizophrenic patients. Melatonin replacement was associated with improved sleep maintenance measured by actigraphy88 and by self-report.89 Hypersomnia The CATIE study64 also reported rates of antipsychoticrelated somnolence. Rates of somnolence in antipsychotictreated schizophrenic patients ranged from 24% to 31%. Somnolence in antipsychotic-treated schizophrenic patients may be a side effect of antipsychotic treatment, or it may be symptomatic of a sleep disorder such as a sleeprelated breathing disorder enhanced by, or induced by, antipsychotic treatment. S OMNOLENCE AS A S IDE EFFECT OF A NTIPSYCHOTIC M EDICATION Among first-generation antipsychotics, sedation is a side effect associated with high-milligram, low-potency agents such as chlorpromazine. In contrast, the low-milligram, high-potency agents such as haloperidol have lower sedation rates. Among second-generation antipsychotics, clozapine and olanzapine are the most sedating. The remaining atypical agents have lower rates of sedation. Sedation rates also reflect the half-life of the agent as well as dosing levels. Clinicians typically address excessive antipsychotic-related sedation by changing antipsychotic agents or reducing dosage. Investigational studies have examined the effect of modafinil as an adjunct to antipsychotic treatment. Modafinil is a wake-promoting agent whose mechanism of action remains unclear. Its primary FDA-approved target is the excessive daytime sleepiness associated with narcolepsy. However, modafinil may improve excessive daytime sleepiness in a variety of off-label conditions such as antipsychotic-induced daytime somnolence. Case studies90 and an open-label pilot study91 have shown that modafinil can increase wake time, reduce total sleep time, and ameliorate fatigue in antipsychotic-treated schizophrenic patients. However, a randomized, double-blind, placebo-controlled trial of modafinil as an adjunct to antipsychotic treatment reported only a nonsignificant trend toward less nighttime and daytime sleep time.92 Taken together, these studies suggest that modafinil may be beneficial in countering somnolence in some antipsychotictreated schizophrenic patients. However, off-label use of modafinil as an adjunct to antipsychotic treatment in schizophrenia needs further study, particularly because stimulant drugs run the risk of exacerbating psychosis in patients with schizophrenia.93
S OMNOLENCE A SSOCIATED WITH S LEEP- D ISORDERED B REATHING The prevalence of sleep-disordered breathing (SDB), such as obstructive sleep apnea (OSA), in antipsychotic-naive schizophrenic patients has not been established. Antipsychotic-treated schizophrenic patients who have volunteered for research protocols have demonstrated a high prevalence rate for SDB, with reported estimates of 17%,80 19%,94 and 48%.81 These studies varied in terms of sample size, age, sex, type of antipsychotic, and measurement instrument (PSG, oximetry, and ambulatory apnea monitor respectively). In contrast, among schizophrenic patients referred to a sleep clinic for a suspected sleep disorder, more than 46% had a respiratory disturbance index greater than 10 events per hour; the mean respiratory disturbance index was 64.8 events per hour (Video 131-1).95 In this study, the most powerful predictor of OSAS was obesity. Weight gain has long been a reported side effect of antipsychotic treatment, but as discussed previously, weight gain secondary to the use of the atypical antipsychotics has been associated with greater rates of morbid obesity and the development of moderate to severe SDB.96 Daytime somnolence is a relatively common side effect of antipsychotic treatment, but clinicians must consider the possibility of comorbid SDB for schizophrenic patients who have a history of obesity or who have gained weight secondary to antipsychotic treatment. Schizophrenic patients with comorbid SDB can be treated effectively with nasal continuous positive airway pressure and can demonstrate relatively good compliance and significant clinical improvement.97,98 Parasomnias First-generation antipsychotics, particularly in combination with lithium99 can induce somnambulism. Sleepwalking also has been documented in patients treated with second-generation agents such as olanzapine.100 Because sleepwalking is associated with impaired arousal from SWS, patients treated with lithium and olanzapine may develop somnambulism because these agents have been credited with SWS enhancement. It has been reported that clonazepam may be a treatment option for antipsychoticinduced somnambulism101 but with the same caveats as those noted for hypnotic use. Another parasomnia, sleeprelated eating disorder, may be induced by antipsychotics such as haloperidol,102 olanzapine,103 and risperidone.104 Treatment options for sleep-related eating disorders might include topiramate, a selective serotonin reuptake inhibitor, or a sedative agent.
CONTROVERSIES One of the ongoing controversies is the diagnostic specificity of sleep abnormalities. Although a range of abnormalities is observed in schizophrenia, they lack diagnostic specificity. Long sleep-onset latencies and other sleep maintenance abnormalities found in schizophrenia are observed in primary insomnia as well as in psychotic depression. Sleep-onset REM periods and SWS deficits are also observed in depressive illness. A goal less ambitious than establishing diagnostic specificity is to find a brain abnormality that would reliably
CHAPTER 131 • Schizophrenia 1509
characterize a subgroup of patients in a meaningful way. SWS deficits (measured as stage 4 with visual scoring or as delta power or integrated amplitude with computer analysis) could furnish a biological basis for separating subgroups of schizophrenic patients. Although low SWS is not specific to schizophrenia, it is a highly reliable, enduring trait that is consistently found in 40% to 50% of samples and might provide a meaningful phenotype. Despite its reliability, SWS deficits have received attention from only a few schizophrenia researchers. This seems to us a neglected area for research on a critically important psychiatric illness. The synaptic pruning model of schizophrenia noted that it was possible that too few, too many, or the wrong synapses might be pruned during adolescence.21 One testable hypothesis might be that patients characterized by an enduring decrease in SWS would show different trajectories or greater amounts of cortical thinning detectable by structural MRI.105 There are, of course, many other hypotheses that could be advanced. Given the paucity of biological abnormalities in schizophrenia, it is puzzling that so robust and consistent a brain abnormality as low SWS should have been so neglected. Further empirical research might also address the role of SWS deficits in both clinical presentation and outcome. The homeostatic property of SWS suggests some central nervous system restorative function with potential neuropsychiatric consequences; if so, are SWS deficits in schizophrenia associated with greater cognitive impairment and thought disorder, and do schizophrenic patients with less SWS impairment face a better clinical outcome? As a corollary, do antipsychotics that augment SWS produce a greater likelihood of positive clinical outcome? Although insomnia is a defining characteristic of schizophrenia, we do not understand the role that sleep disruption might play in the illness. Is insomnia only a characteristic symptom of schizophrenia, or might ongoing sleep disturbance also affect the course of the illness? Because ongoing sleep disturbance might have a negative impact on clinical outcome, treatment plans for schizophrenic patients should explicitly incorporate strategies to deal aggressively with complaints of poor sleep quality. The restorative effect of antipsychotics on sleep maintenance and structure may contribute to their clinical efficacy and to their tolerance. A positive clinical outcome may require the restoration of sleep’s recuperative powers. Comorbid sleep disorders in schizophrenics should be treated. Untreated sleep disorders can augment the fragility of underlying sleep processes in schizophrenia, with potentially adverse effects on clinical outcome. Research into sleep and circadian mechanisms in these patients may yield novel treatments.106 ❖ Clinical Pearl Schizophrenia is associated with insomnia that is often severe. Because insomnia is a prodromal sign of relapse, outpatient clinics should always query schizophrenic patients about changes in their sleep patterns. This query should also address the possible emergence of sleep disorders associated with antipsychotic treatment.
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53. Keshavan MS, Reynolds CF, Ganguli R, et al. Electroencephalographic sleep and cerebral morphology in functional psychosis: a preliminary study with computed tomography. Psychiatry Res 1991;39:293-301. 54. Gross CG. Neurogenesis in the adult brain: death of a dogma. Neurosci 2000;1:67-73. 55. Corson PW, Nopoulos P, Miller DD, et al. Change in basal ganglia volume over 2 years in patients with schizophrenia. Am J Psychiatry 1999;156:1200-1204. 56. Dazzan P, Morgan KD, Orr K, et al. Different effects of typical and atypical antipsychotics on grey matter in first episode psychosis: the AESOP study. Neuropsychopharmacology 2005;30:765-774. 57. Newton SS, Duman RS. Neurogenic actions of atypical antipsychotic drugs and therapeutic implications. CNS Drugs 2007; 21(9):715-725. 58. Riemann D, Hohagen F, Krieger S, et al. Cholinergic REM induction test: muscarinic supersensitivity underlies polysomnographic findings in both depression and schizophrenia. J Psychiat Res 1994;28(3):195-210. 59. Benson KL, Faull KF, Zarcone VP. Evidence for the role of serotonin in the regulation of slow wave sleep in schizophrenia. Sleep 1991;14:133-139. 60. Nishino S, Ripley B, Mignot E, et al. CSF hypocretin-1 levels in schizophrenia and controls: relationship to sleep architecture. Psychiatry Res 2002;110:1-7. 61. Bymaster FP, Calligaro DO, Falcone JF, et al. Radioreceptor binding profile of the atypical antipsychotic olanzapine. Neuropsychopharmacology 1996;14:87-96. 62. Meltzer HY, Li Z, Kaneda Y, Ichikawa J. Serotonin receptors: their key role in drugs to treat schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry 2003;27:1159-1172. 63. Bridler R, Umbricht D. Atypical antipsychotics in the treatment of schizophrenia. Swiss Med Weekly 2003;133:63-76. 64. Lieberman JA, Stroup TS, McEvoy JP, et al. Effectiveness of antipsychotic drugs in patients with chronic schizophrenia. N Engl J Med 2005;353(12):1209-1223. 65. Kaplan J, Dawson S, Vaughan T, et al. Effect of prolonged chlorpromazine administration on the sleep of chronic schizophrenics. Arch Gen Psychiatry 1974;31:62-66. 66. Nofzinger EA, van Kammen DP, Gilbertson MW, et al. Electroencephalographic sleep in clinically stable schizophrenic patients: twoweeks versus six-weeks neuroleptic free. Biol Psychiatry 1993; 33:829-835. 67. Keshavan MS, Reynolds CF, Miewald JM, et al. A longitudinal study of EEG sleep in schizophrenia. Psychiatry Res 1996;59: 203-211. 68. Maixner S, Tandon R, Eiser A, et al. Effects of antipsychotic treatment on polysomnographic measures in schizophrenia: a replication and extension. Am J Psychiatry 1998;155:1600-1602. 69. Wetter TC, Lauer CJ, Gillich G, et al. The electroencephalographic sleep pattern in schizophrenic patients treated with clozapine or classical antipsychotic drugs. J Psychiatr Res 1996;30:411419. 70. Hinze-Selch D, Mullington J, Orth A, et al. Effects of clozapine on sleep: a longitudinal study. Biol Psychiatry 1997;42:260-266. 71. Lee JH, Woo JI, Meltzer HY. Effects of clozapine on sleep measures and sleep-associated changes in growth hormone and cortisol in patients with schizophrenia. Psychiatry Res 2001;103: 157-166. 72. Salin-Pascual RJ, Herrera-Estrella M, Galicia-Polo L, et al. Olanzapine acute administration in schizophrenic patients increases delta sleep and sleep efficiency. Biol Psychiatry 1999;46:141-143. 73. Müller MJ, Rossbach W, Mann K, et al. Sub chronic effects of olanzapine on sleep EEG in schizophrenic patients with predominantly negative symptoms. Pharmacopsychiatry 2004;37(4):157-162. 74. Yamashita H, Morinobu S, Yamawaki S, et al. Effect of risperidone on sleep in schizophrenia: a comparison with haloperidol. Psychiatry Res 2002;109:137-142. 75. Luthringer R, Staner L, Noel N, et al. A double-blind, placebo controlled, randomized study evaluating the effect of paliperidone extended-release tablets on sleep architecture in patients with schizophrenia. Int Clin Psychopharmacology 2007;22:299-308. 76. Cohrs S, Rodenbeck A, Guan Z, et al. Sleep-promoting properties of quetiapine in healthy subjects. Psychopharmacology 2004;174(3): 421-429.
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Medication and Substance Abuse Timothy Roehrs and Thomas Roth
Abstract Nearly all of the psychoactive drugs with a known abuse liability have profound effects on sleep and wakefulness. Substance abuse is characterized by physiologic dependence (e.g., withdrawal syndrome on drug discontinuation) and behavioral dependence (e.g., repetitive and compulsive drug seeking and consumption), both of which can vary depending on the drug and its duration of use. The neurobiological mechanisms
Substance abuse and dependence is common: 18% of the United States population will experience a substance abuse disorder during their lifetime, and about 20% of patients in general medical practice and 35% of psychiatric patients present with substance abuse disorders. Although the sleep-disorders clinician does not make formal diagnoses, awareness of the criteria for abuse are important for referral decisions. Various legal medications and all illegal drugs acting on the central nervous system (CNS) have a high abuse liability; that is, the likelihood of developing physiologic or behavioral dependence to these substances is heightened. Virtually all drugs with a high abuse liability also have profound effects on sleep and waking; therefore, sleep clinicians should be aware of the potential effects of drug dependence on treatment. This chapter reviews the sleep–wake alterations produced by administration and discontinuation of various drug classes associated with abuse. Also discussed is the way that the state-altering characteristics (i.e., their disruptive effects on sleep or daytime alertness) of these drugs contribute to their dependence liability. Finally, what is known about the neurobiological and behavioral mechanisms that underlie these drugs’ abuse liability and their state-altering effects is discussed.
SUBSTANCE ABUSE AND DEPENDENCE The generally accepted diagnostic classification system for substance-related disorders is the Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). Substance-related disorders are divided into two major classes, substance abuse and substance dependence (Boxes 132-1 and 132-2). Substance abuse is a milder expression of maladaptive substance use and typically occurs earlier in a patient’s substance use history. Substance dependence is characterized by compulsive and repeated substance use despite aversive psychosocial, legal, and medical consequences. An important feature is difficulty controlling and reducing the substance use and repeated relapse episodes after periods of abstinence. 1512
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underlying physiologic and behavioral dependence are known, but the effects of abused drugs on sleep–wake state are not fully known, although they are likely important. Legal and socially acceptable drugs can also be subject to abuse and may be the cause of patients’ sleep or alertness complaints. Some drugs indicated in the treatment of sleep disorders also have abuse liability. For that reason, guidelines are provided for sleep disorders clinicians to help in differentiating drugseeking behavior from therapy-seeking behavior.
Although most of the drugs of abuse disrupt sleep or daytime alertness (or both), such disturbances are not major criteria for substance dependence in DSM-IV. They are only mentioned as possible symptoms in a withdrawal syndrome, which is one of the seven major criteria for substance dependence. DSM-IV provides the option of using a diagnosis of substance-induced sleep disorder when the sleep or daytime alertness disturbance has an intensity or duration beyond that normally expressed during substance intoxication or withdrawal (Box 132-3). As discussed later, the role of disruptions of sleep and daytime alertness in substance dependence is not fully elaborated in DSM-IV. There are two kinds of drug dependence: physiologic and behavioral. Physiologic dependence is a state induced by repeated drug use that results in a withdrawal syndrome when the drug is discontinued or an antagonist is administered. Many legal medications and illegal drugs can produce physiologic dependence, although the syndrome intensity, relation to dose, and necessary duration of use vary among different drugs. The fact that a drug produces physiologic dependence, meaning a withdrawal syndrome appears when the drug is discontinued, does not necessarily imply substance abuse. Physiologic dependence may be a component of behavioral dependence, but it is not a necessary or sufficient condition for it. Behavioral dependence is a pattern of behavior characterized by repetitive and compulsive drug seeking and consumption, despite considerable substance-related problems.
DRUG DEPENDENCE AND SLEEP MEDICINE In the sleep field, rapid eye movement (REM) sleep rebound can indicate a patient’s physiologic dependence on a drug. REM sleep rebound manifests physiologically as reduced REM sleep latency, increased REM sleep time, increased REM density, and subjective reports of nightmares. Most antidepressant medications at therapeutic doses suppress REM sleep, and a REM sleep rebound occurs when the drug is discontinued. Although REM sleep rebound does not lead to resumption of
CHAPTER 132 • Medication and Substance Abuse 1513
Box 132-1 DSM-IV Criteria for Substance Abuse Substance abuse is a maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by one (or more) of the following, occurring within a 12-month period: • Recurrent substance use resulting in a failure to fulfill major role obligations at work, school, or home (e.g., repeated absences or poor work performance related to substance use; substancerelated absences, suspensions, or expulsions from school; neglect of children or household) • Recurrent substance use in situations in which it is physically hazardous (e.g., driving an automobile or operating a machine when impaired by the substance) • Recurrent substance-related legal problems (e.g., arrests for substance-related disorderly conduct) • Continued substance use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of the substance (e.g., arguments with spouse about consequences of intoxication, physical fights) The symptoms have never met the criteria for substance dependence for this class of substance. DSM-IV, Diagnostic and statistical manual of mental disorders, 4th edition. Adapted from American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed, text revision. Washington, DC: American Psychiatric Press; 2000. Copyright 2000 American Psychiatric Association.
antidepressant use, a reduced REM sleep latency (e.g., one sign of REM sleep pressure and an underlying REM sleep disturbance) in abstinent alcoholics predicts alcoholic relapse. This is an example of physiologic dependence that does not necessarily lead to drug dependence or abuse in one case, but does in another. Because virtually all drugs with a high abuse potential have profound effects on sleep and wake, sleep disorders clinicians should assess all the drug-taking behavior of their patients, including: prescribed and over-the-counter drugs, recreational drugs, tobacco and caffeine, health foods, steroids, botanicals, and natural substances. Some drugs of abuse have no legal therapeutic indications (e.g., marijuana, except in several states); others have very narrowly defined therapeutic indications (e.g., amphetamine, methylphenidate), and some have broader therapeutic indications (e.g., benzodiazepine receptor agonists). Some drugs of abuse also have wide use as social drugs (e.g., alcohol and caffeine). The following guidelines are provided for sleep disorders clinicians to help them differentiate drug-seeking behavior from therapy-seeking behavior. In drug-seeking behavior the drug and its effects are the focus of the drug use, and in therapy-seeking the medication’s ability to reverse the signs and symptoms of the disease is the focus of the drug use. This distinction is important because many of the drugs used by sleep disorders clinicians are used chronically, and hence long-term use should be differentiated from abuse. Also, many of these medications have scientifically documented efficacy and are therefore indicated for specific sleep disorders; some of these drugs also are abused and importantly may be the cause of a sleep disorder.
Box 132-2 DSM-IV Criteria for Substance Dependence Substance dependence is a maladaptive pattern of substance use, leading to clinically significant impairment or distress, as manifested by at least three of the following, occurring at any time in the same 12-month period: • Tolerance, as defined by either of the following: • A need for markedly increased amounts of the substance to achieve intoxication or desired effect • Markedly diminished effect with continued use of the same amount of the substance • Withdrawal, as manifested by either of the following: • The characteristic withdrawal syndrome for the substance • The same (or a closely related) substance is taken to relieve or avoid withdrawal symptoms • The substance is often taken in larger amounts or over a longer period than was intended. • There is a persistent desire or unsuccessful efforts to cut down or control substance use. • A great deal of time is spent in activities necessary to obtain the substance (e.g., visiting multiple doctors or driving long distances), use the substance (e.g., chain-smoking), or recover from its effects. • Important social, occupational, or recreational activities are given up or reduced because of substance use. • The substance use is continued despite knowledge of having a persistent or recurrent physical or psychological problem that is likely to have been caused or exacerbated by the substance (e.g., current cocaine use despite recognition of cocaineinduced depression or continued drinking despite recognition that an ulcer was made worse by alcohol consumption). Specify physiologic dependence: Evidence of tolerance or withdrawal is present. Course specifiers: • Early full remission • Early partial remission • Sustained full remission • Sustained partial remission • On agonist therapy • In a controlled environment DSM-IV, Diagnostic and statistical manual of mental disorders, 4th edition. Adapted from American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed, text revision. Washington, DC: American Psychiatric Press; 2000. Copyright 2000 American Psychiatric Association.
UNDERSTANDING SUBSTANCE ABUSE Scientific attempts to understand substance abuse have proceeded at two levels of analysis: behavioral and neurobiological. Interestingly, the scientific evidence at these two levels of analysis has converged. For sleep scientists and clinicians, an obvious question is: How does a drug’s effect on sleep and daytime alertness relate to the behavioral and neurobiological changes that occur in the substance-dependent person?
1514 PART II / Section 16 • Psychiatric Disorders Box 132-3 DSM-IV Diagnostic Criteria for Substance-Induced Sleep Disorder Substance-induced sleep disorder is a prominent disturbance in sleep that is sufficiently severe to warrant independent clinical attention. There is evidence from the history, physical examination, or laboratory findings of either: • The symptoms developed during, or within a month of, substance intoxication or withdrawal. • Medication use is etiologically related to the sleep disturbance. The disturbance is not better accounted for by a sleep disorder that is not substance induced. Evidence that the symptoms are better accounted for by a sleep disorder that is not substance induced might include the following: • The symptoms precede the onset of the substance abuse (or medication use). • The symptoms persist for a substantial period of time (e.g., a month) after cessation of acute withdrawal or severe intoxication or are substantially in excess of what would be expected given the type or amount of substance used or the duration of use. • There is other evidence that suggests the existence of an independent non–substance-induced sleep disorder (e.g., history of recurrent non–substancerelated episodes). The disturbance does not occur exclusively during the course of a delirium. The sleep disturbance causes clinically significant distress or impairment in social, occupational, or other important areas of functioning. Specify subtype: alcohol, amphetamine, caffeine, cocaine, opioids, sedative, hypnotic, anxiolytics, or other. Specify type: • Insomnia type if the predominant sleep disturbance is insomnia • Hypersomnia type if the predominant sleep disturbance is hypersomnia • Parasomnia type if the predominant sleep disturbance is parasomnia • Mixed type if more than one sleep disturbance is present and none predominates Specify if onset is during intoxication or during withdrawal. DSM-IV, Diagnostic and statistical manual of mental disorders, 4th edition. Adapted from American Psychiatric Association. Diagnostic and statistical manual of mental disorders, 4th ed, text revision. Washington, DC: American Psychiatric Press; 2000. Copyright 2000 American Psychiatric Association.
Behavioral Mechanisms Substance use behavior, whether in therapeutic, socially accepted recreational forms or in excessive, socially unacceptable, physically hazardous forms, can be analyzed to determine factors important to the initiation and maintenance of substance abuse. Drug reinforcement is a major factor to be considered in substance-use behavior. Drugs are viewed as reinforcers when they promote and maintain drug-seeking and drug self-administration as a function of
the effects the drug produces, which can include the drug’s pharmacologic and nonpharmacologic effects. Two mechanisms of drug reinforcement are hypothesized. In the first hypothesis, the drug produces an inferred mood-elevating or euphorogenic effect and thus acts as a positive reinforcer. In the second, the drug acts as a negative reinforcer by reversing an inferred aversive state, such as a withdrawal syndrome or excessive sleepiness or fatigue. The two processes, positive and negative drug reinforcement, are not necessarily mutually exclusive and can operate concurrently or at the different stages in a drug-abuse cycle (initiation, maintenance, or relapse). These two reinforcement processes lead to the initiation and maintenance of excessive and hazardous drug use. The state-altering consequences in negative and positive reinforcement can be relevant to the treatment of sleep disorders. The alerting effects of stimulants, for instance, are reinforcing for persons who are sleepy, fatigued, and having difficulty functioning at their desired level. Healthy normal subjects self-administer a stimulant when they are sleepy but not when alert.1 That self-administration does not imply dependence or abuse. However, in substance abuse, sleepiness may be present as part of a withdrawal syndrome due to abstinence following chronic use of a stimulant. It has been hypothesized that continued substance use, difficulty reducing use, or relapse might reflect self-medication to reverse excessive sleepiness caused by abstinence. For example, in amphetamine or cocaine abuse, excessive sleepiness during initial drug abstinence has been consistently reported, and use of the stimulants reverses the sleepiness. More commonly, in chronic caffeine or nicotine dependence, the 8-hour sleep period is functionally an enforced abstinence. The pharmacokinetics of these drugs and the enforced abstinence of the sleep period can result in enhanced sleepiness in the morning, and, in extreme cases, smoking during the night. Caffeine or nicotine taken immediately when arising reverses the sleepy state, which reinforces use of these stimulants. Clinicians can gauge the severity of a nicotine addiction by asking patients when they have their first morning cigarette. During a period of chronic drug use, daytime sleepiness can also result from a drug-induced disturbance of nocturnal sleep. All the stimulants reviewed later disrupt nocturnal sleep, and the degree of disruption depends on dose and proximity of their use to the sleep period. Disrupted and fragmented sleep produces daytime sleepiness. Similar to the reinforcement cycle described earlier, a druginduced sleep disturbance at night could lead to daytime sleepiness, which then enhances the likelihood of selfadministration of the stimulant. This is a common vicious circle seen in heavy coffee drinkers. Daytime sleepiness is not necessarily drug induced. Chronic insufficient sleep in healthy normal persons or disturbed sleep efficiency and circadian dysrhythmia seen in altered work schedules can also cause daytime sleepiness. Night workers and rotating-shift workers have shortened and disturbed sleep when sleeping during the day as well as increased sleepiness when awake at night. Rotating-shift workers and night workers report a disproportionate use of sedating drugs, especially alcohol, to improve sleep and stimulants, especially caffeine, to
improve alertness.2,3 Although healthy normal persons might self-administer a stimulant when experiencing sleepiness, this kind of substance use can increase risks of substance dependence and abuse. Sedative-hypnotics, tetrahydrocannabinol (THC), and alcohol can become reinforcers and lead to substance dependence or abuse through their capacity to induce sleep in persons with insomnia or to reverse a waking hyperaroused state. In one study, persons who had insomnia but no history of alcoholism or drug abuse and healthy normal subjects were given an opportunity to choose between previously experienced color-coded ethanol and placebo beverages at night before sleep. The insomniac subjects chose ethanol, but healthy normal subjects with a similar level of self-reported social drinking chose placebo.4 Interestingly, insomniac subjects showed not only nighttime but also daytime self-administration of benzodiazepine-receptor agonists. However, only insomniac subjects who showed evidence of daytime physiologic hyperarousal self-administered benzodiazepines during the day.5 Whether these drug self-administration patterns reflect drug-seeking or therapy-seeking is considered later. Neurobiological Mechanisms The positive-reinforcement neurobiology of drug selfadministration is generally accepted to involve mesocorticolimbic projections originating in the ventral tegmental area of the rostral reticular activation system and terminating in the nucleus accumbens. Most drugs of abuse interact in some way with this system. This dopamine system is part of a broader dopaminergic system that projects into several forebrain regions and as a whole is considered to have executive and integrative functions.6 The dopaminergic neurons of the ventral tegmental area are modulated by a number of other neurotransmitter systems. It is through this modulation that sleep–wake state and level of sleepiness or alertness during wake could have an impact on a drug’s reinforcing properties. In chronic use, Koob hypothesized that the neurobiological systems involved in acute positive reinforcement adapt by establishing opponent processes.6 These opponent processes neutralize the acute reinforcing effects of the drug and during abstinence are left unopposed. Consequently, they produce the abstinence syndrome, an inverse state to the drug state, which becomes a basis of negative reinforcement (reversal of abstinence symptoms). For example, stimulant abstinence produces sleepiness, which in turn leads to self-administration of stimulant drugs. Koob hypothesized that the opponent processes do not necessarily develop through the same neurobiological system that produces positive reinforcement. Other neurobiological systems, and possibly sleep−wake systems, could be one basis of the opponent processes. Consistent with this model are two important sleep–wake findings: One is the REM sleep suppression and REM sleep rebound associated with administration and discontinuation of most of the drugs with an abuse liability. The other, the persisting disturbance of sleep that is found after weeks of abstinence, suggests that some type of neurobiological adaptation to the chronic drug exposure has occurred within sleep–wake systems.
CHAPTER 132 • Medication and Substance Abuse 1515
SLEEP–WAKE ALTERATIONS AND SPECIFIC SUBSTANCES Alcohol and Alcoholism Alcohol in Healthy Adults Alcohol in large doses is mildly stimulating on the rising phase of the plasma concentration curve and is sedating on the declining side of the curve.7 In lower doses it has few stimulatory effects on the rising phase and is mildly sedating on the declining phase. Studies of alcohol effects on sleep typically administer alcohol 30 to 60 minutes before sleep, which results in peak concentrations occurring before or at bedtime. Doses used in these studies range from 0.16 to 1.0 g/kg, the rough equivalent of one to six standard drinks, producing breath ethanol concentrations (BrEC) up to 0.105% at bedtime.8 One study reported increased sleep time at a low 0.16 g/kg dose but not at higher 0.32 and 0.64 g/kg doses. The sleep-disruptive rebound wakefulness that occurs in the second half of the night with the higher doses of alcohol is likely why improved sleep is seen only at low doses. The typical BrEC at lights out for higher doses is between 0.05% and 0.09%; because ethanol is metabolized at a rate of 0.01% to 0.02% BrEC per hour, it has been completely metabolized within the first 4 to 5 hours of the sleep period. This leads to a rebound wakefulness during the last hours of the sleep period.9 Thus, sleep time for the whole night is not increased at high doses and instead is often decreased. In addition to these effects on sleep induction and maintenance, ethanol affects the normal progression of sleep stages.10 Studies report a dose-dependent suppression of REM sleep and, in some cases, increased slow-wave sleep in the first half of the night (i.e., when ethanol blood levels are present). When first-half REM sleep suppression is observed, a second-half REM sleep rebound is reported as well. As with rebound wakefulness, the second-half REM sleep rebound likely relates to the timing of complete ethanol elimination from the body. Repeated nightly administration of ethanol leads to tolerance to both the sleep induction and sleep stage effects, but interestingly not in the rebound effects. Finally, discontinuation of ethanol is followed by a REM sleep rebound, although the appearance of a REM sleep rebound is likely related to dose, duration of use, basal level of REM sleep, and the extent of prior REM sleep suppression and development of tolerance. The aftereffects of heavy alcohol consumption, commonly referred to as hangover, are typically experienced after peak BrECs of 0.100% and greater.11 Some laboratory studies of heavy drinking, hangover, and next-day cognitive and psychomotor performance have demonstrated impairment in the morning with BrEC zero 14 hours after ethanol ingestion the previous night and approximately 4 hours before going to bed.12 Some studies have related the next-day impairment to the degree of ethanol-related sleep loss and fragmentation during the previous night.13 Even with low alcohol doses and an absence of hangover symptoms, the sleep-disruptive and performance-impairing effects can continue after alcohol is completely metabolized and BrEC is zero. Lateafternoon drinking with BrEC zero at bedtime disrupted
1516 PART II / Section 16 • Psychiatric Disorders
sleep in the second half of the night, and morning or midday drinking continues to impair performance for 2 to 3 hours after BrEC is zero.14,15 Alcohol Effects in Primary Sleep Disorders Approximately 30% of persons with insomnia in the general population report using alcohol to help them sleep, and 67% of those people have reported that the alcohol was effective in inducing sleep.16 The laboratory studies of healthy normal subjects showing sleep-disruptive ethanol effects used higher doses (e.g., BrEC > 0.05% at bedtime) than the doses (e.g., 1 or 2 drinks) used by persons with insomnia. In laboratory studies of persons with primary insomnia, ethanol administered 30 minutes before sleep, which raised BrEC to only 0.04% at bedtime, improved sleep without producing a second-half wakefulness rebound.17 Compared to age-matched subjects who did not have insomnia and who had a similar social drinking history, the insomniac subjects chose to selfadminister alcohol before sleep more often. The risk associated with using alcohol as a sleep aid is that tolerance to its initial beneficial effect develops within 5 nights, and insomniacs increase their self-administered dose to compensate.18 Later, guidelines are offered to help clinicians determine when initial therapy-seeking (e.g., use of alcohol as a sleep aid) has shifted to drug-seeking behavior. Alcohol is a mild respiratory depressant in the wake state; during sleep it exacerbates obstructive sleep apnea (OSA) and can precipitate sleep-disordered breathing in at-risk persons. In one study, patients with moderate OSA, defined as an average respiratory disturbance index (RDI: number of apneas and hypopneas per hour of sleep) of 22, received 300 mL of bourbon 2 hours before bedtime.19 That dose of ethanol increased the RDI to 28. In a different study of patients with a range of sleep-related breathing disorders, an unspecified dose and BrEC of ethanol increased the RDIs of every patient with baseline RDI between 14 and 54.20 The effects of ethanol are also found in other sleep-related respiratory disorders. For example, in several patients with chronic obstructive pulmonary disease (COPD), ethanol worsened the degree of hypoxemia, and in several patients with only a snoring history it induced apnea. That an asymptomatic snorer with no apnea will develop apnea after ethanol was convincingly shown in a later study.21 In another study, ethanol (BrEC = 0.08%) in snoring men increased their RDIs to a pathologic level (RDI >10).22 On the other hand, the findings in asymptomatic persons without risk factors have been inconsistent. The risk of periodic limb movements (PLMs) during sleep was increased in association with self-reported alcohol consumption in a sample of sleep disorders clinic patients.23 However, in an abstinent alcoholic patient population, the rate of PLMs was not different than the general sleep disorders clinic sample rate of PLMs.24 Alcoholism is associated with deficiencies in iron, ferritin, magnesium, and vitamin B12 and with polyneuropathy, all of which are also associated with PLMs and restless legs syndrome (RLS). To the extent that the alcoholic has any of these deficiencies, RLS and PLMs may be precipitated or exacerbated by alcohol.
Sleep of Alcoholics and Alcohol Effects in Alcoholics Patients with alcoholism commonly complain of sleep problems, daytime sleepiness, and parasomnias. During drinking binges, alcoholics report polyphasic sleep patterns with short sleep periods followed by short waking periods that are distributed across the 24-hour day. This type of sleep pattern is seen in organisms without a circadian pacemaker (i.e., a lesioned superchiasmic nucleus [SCN]). It is possible that during these binges the sleep– wake cycles of alcoholics are so chaotic that they are arrhythmic. It would be of interest to see the circadian pattern of temperature, dim light melatonin onset, and other phase markers in this population. Laboratory studies of patients with alcoholism show that sleep latency and total sleep time are disturbed on both drinking and discontinuation nights.25 The prolonged sleep latency in alcoholics when drinking contrasts with the reduced sleep latency that alcohol produces in nonalcoholics and suggests development of tolerance and possible neurobiological changes, as discussed earlier. In addition, as in healthy normal persons, drinking in alcoholics is associated with increased slow-wave sleep and suppression of REM sleep, with rapid development of tolerance to these effects.25 The acute alcohol abstinence phase lasts 1 to 2 weeks, although some of the withdrawal symptoms such as mood instability, disturbed sleep, and craving remain beyond this period. During the acute abstinence phase, slow-wave sleep is reduced, sometimes to minimal levels, and REM sleep continuity is disrupted.26 There are frequent REM sleep episodes and shortened non-REM (NREM)−REM sleep cycles during the acute abstinence. Recovery and Long-term Abstinence Abnormal sleep patterns can persist for up to 3 years in some patients with alcoholism during recovery and abstinence. Sleep remains shortened and REM sleep pressure remains elevated, as evidenced by elevated levels of and shortened latencies to REM sleep.27 Figure 132-1 illustrates the abnormally short sleep and elevated REM sleep percentages of abstinent primary alcoholic patients. Although it is tempting to attribute these sleep abnormalities to the excessive alcohol drinking of the patients, the sleep problems could have preceded the development of the alcoholism or they could be secondary to the development of other medical and psychiatric disorders that develop during the alcoholic drinking phase. Regardless of the cause of the sleep disturbance evident in alcoholism, both objective and subjective measures of sleep taken after the immediate acute abstinence predict the likelihood of relapse during long-term abstinence. Early laboratory studies suggested that low levels of slow-wave sleep predict alcoholism relapse.28 More-recent studies have identified REM sleep disturbances, either elevated REM sleep percentage or shortened REM sleep latency, as predicting relapse.29 That risk was greater than the risk associated with other variables such as age, marital status, employment, duration and severity of alcoholism, hepatic enzymes, and depression ratings.
CHAPTER 132 • Medication and Substance Abuse 1517
ONE YEAR FOLLOW-UP IN SOBER ALCOHOLICS
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Weeks of abstinence Figure 132-1 Polygraphic sleep recordings for REM sleep percentage and total sleep time in nine sober, recovering, primary nondepressed male alcoholic patients for more than 1 year. Note that both measures differ from age-matched healthy control subjects for most of the recovery period. Values for the patients are mean plus or minus standard error of the mean, and for healthy control subjects, mean + 90% confidence interval (CI) (Data adapted from Drummond SPA, Gillin JC, Smith TL, Demodena A. The sleep of abstinent pure primary alcoholic patients: natural course and relationship to relapse. Alcohol Clin Exp Res 1998;22:1796-1802).
Treatment of the Sleep Disturbance of Alcoholism Treatment of sleep disturbance in alcoholic patients is challenging because there are few placebo-controlled studies to guide the clinician. The drug class of choice for insomnia treatment in nonalcoholic patients is the benzodiazepine receptor agonists. However, although these drugs have a relatively low abuse liability in nonalcoholic patients, their risk in outpatient alcoholics after acute inpatient withdrawal is unknown.30 These drugs are effective for the immediate inpatient withdrawal syndrome because they share the same mechanism of action as alcohol itself, promotion of GABA inhibition. A further caution to their outpatient use is that they have a high potential for toxicity and overdose when combined with alcohol, which makes them particularly dangerous for the alcoholic who relapses. Sedating antidepressant medications such as trazodone or doxepin are often used in the United States to treat primary insomnia and insomnia comorbid with depression. Trazodone has been used to treat sleep disturbance in alcoholic patients in open-label, uncontrolled studies.30 In doses of 50 to 300 mg it improved self-report measures of insomnia. Anticonvulsant drugs such as gabapentin have
also been used in uncontrolled studies. Self-reported sleep is improved, and PSG measures showed an increase in total sleep time.30 Currently, the three FDA-approved alcoholism treatments are disulfiram, naltrexone, and acamprosate. Unfortunately, sleep problems have not been major outcome measures in the various clinical trials supporting the efficacy of these drugs as treatments for alcoholism. Cognitive behavior therapy (CBT) for insomnia is an alternative to medication, and several trials in alcoholics with sleep disturbance have been conducted. A randomized, controlled trial of a brief CBT for the insomnia associated with alcoholism studied 60 alcoholics without comorbid depression.31 The CBT, compared to wait-list controls, improved sleep diary measures of sleep quality, sleep efficiency, awakenings, and time to fall asleep. CBT had no impact on drinking relapse rates over the 6-month follow-up period. An open trial of CBT for insomnia in patients with alcoholism similarly found improved sleep but not improved drinking outcomes.31 It is tempting to assume that alcoholism is the sole or primary cause of the alcoholic’s insomnia. However, other primary sleep disorders, and possibly circadian disorders, are present in patients with alcoholism at a higher rate than in nonalcoholics. Furthermore, depression is often present in alcoholism, and the sleep disturbances of depression have been well documented. However, patients with alcoholism often deny their drinking problems and might focus on their sleep problems to avoid confronting their drinking problems. Treating the insomnia alone will not initiate abstinence, and so insomnia treatment must begin with referral to addiction treatment specialists. Additionally, appropriate treatment of the comorbid sleep or psychiatric disorders should be pursued in patients with alcoholism. Stimulants Caffeine Caffeine is not generally considered a drug of abuse by society, and even within the medical community its potential for abuse is not fully appreciated. Laboratory data indicate there are conditions under which caffeine is persistently self-administered and that it does have abuse liability, although its liability is low compared to other recognized drugs of abuse.32 A cup of coffee, a socially acceptable dose of caffeine, contains about 100 mg of caffeine. As might be expected, caffeine in doses of 150 to 400 mg administered immediately before sleep prolongs the onset of sleep and reduces total sleep time in healthy normal subjects.33-38 To compare the disruptive effects of caffeine to the psychomotor stimulants, in one study 300 mg of caffeine reduced sleep efficiency from 89% to 74%, 40 mg of pemoline reduced it to 80%, and 20 mg of methylphenidate reduced it to 61%.35 As to sleep-stage effects, some studies report reductions of stage 3-4 sleep,34,35 but unlike the psychomotor stimulants, stage REM is not affected. Discontinuing the chronic use of caffeine is associated with mood and performance disturbance. A withdrawal syndrome was observed after a double-blind, placebo-controlled cessation of chronic, but moderate (235 mg, or 2 to 3 cups daily on average), caffeine consumption.36 On the second day of caffeine cessation (20 hours after caffeine use), in addition to the ubiquitous headache, reduced vigor
1518 PART II / Section 16 • Psychiatric Disorders
and increases in sleepiness, fatigue, and drowsiness were experienced. For moderate to heavy caffeine users, the 8-hour sleep period is essentially a caffeine discontinuation, and the morning cup of coffee immediately after arising probably restores caffeine levels and alertness. Nicotine That nicotine is a drug of abuse is undisputed, and some have argued that it rivals the abuse liability of cocaine. The development of nicotine delivery systems (i.e., nicotine gum and patches) for use in clinical smoking cessation programs has also facilitated the study of nicotine’s effects on sleep. In healthy normal subjects, transdermal nicotine (7 to 14 mg) produced a dose-dependent increase in wakefulness and a reduction in percentage of REM sleep relative to a placebo patch.39 A study of nonsmoking normal subjects also found that 17.5 mg transdermal nicotine increased wake time and decreased REM sleep percentage.40 In obese nonsmoking patients with sleepdisordered breathing, 15 mg transdermal nicotine reduced both total sleep time and percentage of REM sleep; additionally, it did not improve the sleep-disordered breathing of these patients, which was the study’s primary purpose.41 The discontinuation of nicotine in nicotine-dependent persons is associated with a disturbance of sleep and wakefulness. In an uncontrolled study that compared the sleep of smokers during the week before and the week after cessation of chronic smoking, the number of arousals, awakenings, and sleep stage changes were all increased during the cessation week.42 In a double-blind study using a placebo versus nicotine patch during the discontinuation of the average daily use of 30 cigarettes, the number of arousals was increased relative to the smoking baseline in the placebo group, and in the nicotine (22 mg) patch group, arousals were reduced and stage 3-4 sleep was increased relative to the smoking baseline.43 However, given the pharmacokinetics of nicotine, any smoking baseline is based on the partial discontinuation of nicotine use during the usual 8-hour sleep period. Because the nicotine patch was worn continuously, it is probable that sleep was improved relative to a partial discontinuation (i.e., a smoking baseline). This interpretation is consistent with the several questionnaire studies that find smokers are more likely than nonsmokers to report problems falling asleep and staying asleep.44 Psychomotor Stimulants C OCAINE Cocaine is the CNS stimulant with the greatest abuse liability. Few laboratory studies have examined the effects of cocaine and its discontinuation on sleep and daytime alertness. Clinical assessments have described continued and prolonged wakefulness during “cocaine runs,” days of protracted cocaine use. The cocaine runs are then followed by “crashes,” which are characterized by excessive sleep and sleepiness.45 Several PSG studies of cocaine discontinuation in cocaine-dependent persons have reported elevated sleep time and REM sleep time rebound during the initial abstinence. That disturbance was then followed by a persisting insomnia and REM sleep disturbance for the
3-week duration of the study.46 A laboratory study of cocaine administration and discontinuation found that 600 mg/day intranasal cocaine (insufflated from 7 pm to 9 pm) severely disrupted sleep, delaying its onset at the 11 pm bedtime for up to 3 to 4 hours and suppressing REM sleep.47 During the first two discontinuation days, average daily sleep latency on the multiple sleep latency test (MSLT) was less than 5 minutes (i.e., a pathological level of sleepiness), most probably due to the severe sleep disturbance of the prior 5 days of cocaine self-administration. The MSLT also showed multiple sleep-onset REM periods (SOREMPs), probably resulting from the prior REM sleep suppression during the cocaine-administration nights. Then, even after 14 days of abstinence, a nocturnal sleep and REM sleep disturbance remained, although the MSLTs were free of SOREMPs and the latencies returned to normal levels. Later, we discuss how these state-altering effects may serve to maintain cocaine dependence. A MPHETAMINE Amphetamine is also a drug of abuse. During the 1950s, before its manufacture and distribution became tightly controlled, an epidemic of amphetamine abuse occurred in the United States. Although it is not the drug of choice, it has therapeutic indications for the treatment of narcolepsy and attention-deficit/hyperactivity disorder (ADHD). Few PSG studies of amphetamine administration and discontinuation have been performed. In one of the earliest PSG drug studies conducted, 10 or 15 mg of d-amphetamine doubled sleep latency and suppressed REM sleep in healthy young adults.48 Another study of healthy adults and patients with narcolepsy reported that administration of methamphetamine at 7 am to 8 am reduced sleep efficiency that night (11 pm bedtime) at 10-mg doses in control subjects and at 40- to 60-mg doses in the narcoleptics.49 No REM sleep effects were observed in the normal subjects. However, the narcoleptic subjects received higher doses, and their REM sleep latencies were increased and REM sleep times were reduced. A study of amphetamine-dependent subjects assessed sleep during the drug’s discontinuation.50 On the second night after the last amphetamine dose, REM sleep time rebounded and remained elevated for 3 to 5 nights. This REM-sleep rebound was delayed relative to that associated with cocaine discontinuation, which may be due to the pharmacokinetic differences between the drugs (i.e., the longer half-life of amphetamine). The REM-sleep rebound after amphetamine discontinuation also lasted longer, which may be due to differences in the duration or amount of prior use or the level of REM sleep suppression. Additionally, total sleep times were elevated over the same 3- to 5-day time period, which might indicate recovery sleep resulting from the prior drug-induced sleep loss. Subsequent to the 3- to 5-day period, sleep times became shorter than normal, suggesting continuing insomnia. As in abstinence from cocaine dependence, the continued insomnia in amphetamine abstinence raises questions regarding a stimulant-induced, persisting alteration of CNS sleep– wake mechanisms. The effects of amphetamine discontinuation on daytime levels of sleepiness or alertness have not been studied in
amphetamine-dependent persons. One might predict that amphetamine discontinuation could be associated with increased daytime sleepiness and multiple SOREMPs on the MSLT similar to that reported for the discontinuation of cocaine. M ETHYLPHENIDATE Methlyphenidate has a lower abuse liability than other psychomotor stimulants, although case reports of its abuse have appeared over the years. In terms of therapeutic indications, it is the drug of choice for ADHD and a secondchoice drug for narcolepsy. In healthy normal subjects, 20-mg doses reduced total sleep time, increased the latency to REM sleep, and reduced the time spent in REM sleep, whereas 10 mg only increased REM sleep latency.51 In an earlier study, 5 mg was reported to increase the latency to REM sleep and reduce the percentage of REM sleep without affecting other sleep measures in healthy normal subjects.52 In children with ADHD, studies are inconclusive regarding the effects of daytime doses of methylphenidate on subsequent sleep. Sleep time was shortened in one study53 and increased in another54 study. In a third study, REM sleep was fragmented.54 However, these studies can be questioned for a variety of methodologic and control issues. We are unaware of studies that have documented the discontinuation effects of methylphenidate in dependent persons. Increased daytime sleepiness with multiple SOREMPs might be predicted. The excessive sleepiness following discontinuation of any of these stimulant drugs might have a reinforcing role in the drug’s continued use and abuse, as illustrated by self-administration studies done in healthy normal subjects. Healthy normal subjects, with no current or previous history of substance abuse, were more likely to self-administer methylphenidate (20 mg) when given an opportunity to do so following 4 hours of time in bed than 8 hours of time in bed (80% versus 20%) on the previous night.1 These data are consistent with and extend the cocaine data showing that in sleep-deprived healthy normal subjects, stimulants have performance-enhancing effects and profoundly reinforcing effects for sleepy persons or normal persons experiencing sleep loss. Opioids The opioids are drugs with a high abuse liability. They have disruptive effects on sleep continuity and sleep staging. Heroin (3, 6, and 12 mg/70 kg), administered intramuscularly in a double-blind, placebo-controlled study of abstinent opioid addicts, produced dose-related decreases in total sleep time, stage 3-4, and REM sleep.55 Heroin is metabolized to morphine and, as would be expected, morphine (7.5, 15, and 30 mg/70 kg) also produced a doserelated decrease in sleep time, stage 3-4 and REM sleep in the abstinent opioid addicts.56 Methadone (7.5, 15, and 30 mg/70 kg) also decreased total sleep time and stage 3-4 and REM sleep in abstinent opioid addicts.57 All these drugs also produced increased brief arousals and frequent sleep stage changes (i.e., sleep fragmentation). Several studies have indicated that tolerance to the sleep-disrup-
CHAPTER 132 • Medication and Substance Abuse 1519
tive effects develops within weeks.58 With development of tolerance, the sleep fragmentation is lessened and the REM sleep suppressive effects tend to diminish. The discontinuation of chronic opioid use is associated with sleep disturbance. This disturbance was demonstrated when treatment was discontinued in methadone-maintained heroin addicts in an outpatient research treatment program and their sleep was recorded in the laboratory.59 Sleep latency and latency to REM sleep were prolonged and percentage of stage 3-4 sleep was reduced compared to normal subjects. Interestingly, after a week of buprenorphine 4 mg, a partial mu opioid agonist, the sleep patterns normalized. Opioids also affect other sleep disorders. Although not the first line of treatment, opioids improve RLS. They are also often used in patients who do not respond to dopamine agonists. Given their negative effects on respiratory drive, however, they are contraindicated in sleep apnea. In fact, several case series have reported a high prevalence of central and complex apnea in patients using opiates for chronic pain or in patients on methadone maintenance treatment.60-62 Mixed treatment success with continuous positive airway pressure or adaptive servoventilation has been reported. Sedative-Hypnotics Within society and the medical community, sedative-hypnotics are considered to have a relatively high abuse liability; however, this perception is largely based on the early sedative-hypnotics, barbiturates and ethanol-based drugs (ethchlorvynol, choral hydrate), which clearly produce both physical and behavioral dependence. On the contrary, scientific evidence from epidemiologic and laboratory studies indicates that the abuse liability of modern sedative-hypnotics is relatively low. Modern benzodiazepine receptor agonists are not as likely to lead to abuse as earlier sedative-hypnotics. In the 1980s, daytime self-administration was studied in normal subjects, persons with substance-abuse histories, and patients with anxiety disorders; the results showed a generally low behavioral dependence liability. The benzodiazepine receptor agonists were self-administered by substance abusers at low and declining rates over time63 and were not differentially self-administered relative to placebo by the normal subjects or patients with anxiety disorders.64,65 Research has found that some patients with anxiety disorders self-administered alprazolam at rates greater than placebo.66 Our own studies of presleep triazolam or placebo self-administration in patients with insomnia have found that triazolam and placebo are self-administered at similar rates (67% to 88%) in a single-choice paradigm (i.e., choice of taking the available capsule or not).67-69 However, when forced to choose on a given night between triazolam and placebo, subjects preferred triazolam 80% of the time.69 Most importantly, when given an opportunity in a single-choice paradigm to self-administer multiple capsules on the same night, a 0.27-mg average nightly triazolam dose was self-administered (i.e., one capsule), but the placebo dose was escalated to the threecapsule maximum. Normal volunteers in these studies self-administered capsules at a 20% to 40% nightly rate,
1520 PART II / Section 16 • Psychiatric Disorders
MDMA An amphetamine derivative that has become increasingly popular as a recreational and drug of abuse is 3,4-methylenedioxymethamphetamine (MDMA), or “ecstasy.” This drug has hallucinogenic properties and acts indirectly by stimulating the release of brain monoamines.78 Exposure to MDMA decreases total sleep time, with a decrease in NREM sleep but no significant effects on REM sleep. Within the NREM sleep, persons who use MDMA have less stage 2 sleep, but there are no apparent differences in stage 1 or slow-wave sleep (stages 3 and 4).79 In a placebocontrolled study, acute MDMA use shortened sleep primarily by increasing sleep latency; it also reduced stage 3-4 sleep and suppressed REM sleep.80 The MDMA-reduced sleep time was not associated with increased daytime sleepiness the following day, as seen in a 4-hour sleeprestriction condition (Fig. 132-2). The day after nighttime placebo, average daily sleep latency was increased on the MSLT in MDMA users compared to age-matched controls, and MDMA users had more SOREMPs compared to controls.
Total sleep time (min)
Hallucinogens Tetrahydrocannabinol Tetrahydrocannabinol is one of the principal active ingredients in marijuana. In the United States, marijuana still remains the most frequently abused illicit drug, although its popularity appears to cycle, trending up and down over decades. THC is classified as a mild sedative at low doses and a hallucinogen at high doses. Study of THC’s effects on sleep and wakefulness occurred predominantly during the 1970s. Low doses of THC (4 to 20 mg) had mild suppressive effects on REM sleep in experienced marijuana users and nonusers.70-72 In several of the studies, total sleep time or stage 3-4 sleep was increased,70,72 but it then decreased to baseline levels after a week of repeated nightly use.72 At high doses (50 to 210 mg) in naive or chronic marijuana users, THC again suppressed REM sleep, but effects on total sleep time were not observed73 and stage 3-4 sleep was reduced in one report.74 Some studies report a REM sleep rebound on the THC discontinuation nights70,73 and some report a reduction in sleep time or an increase in sleep latency.71,73 All of these studies have involved presleep laboratory administration of THC. Several studies have also been done in situ or in semicontrolled laboratory situations, with moderate and heavy marijuana users smoking their usual marijuana cigarettes during the day or early evening. Self-reported or raterobserved sleep time was increased in two such studies.75,76 In a PSG study, little or no effect on sleep measures was observed.77 These mild sedative effects have also been observed during daytime studies using performance assessments. In situ assessment of daily activity levels also show reduced activity during moderate or heavy marijuana use.76
500 400
*
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Treatment
18 MSLT mean sleep latency (min)
significantly lower than that of the insomniac subjects. This high self-administration by insomniacs and preference for active drug by some anxiety patients raises questions about distinguishing between therapy-seeking and drug-seeking behavior, an issue discussed later.
Recovery Night
*P < .05 **P < .01
16 14 12 10 8
**
6 4 2 0 Treatment
Recovery Day
Placebo MDMA 2 mg/kg Sleep restrict Figure 132-2 Polygraphic sleep recordings for total sleep time and multiple sleep latency test (MSLT) the following day in moderate MDMA users (N = 7) after placebo, MDMA 2 mg/kg, or a 4-hour restricted time in bed. Mean sleep latency is the latency to the first epoch of sleep. Drug or placebo was administered at 6 PM, and time in bed was 11 PM to 7 AM on drug or placebo nights and 3 AM to 7 AM on sleep-restricted nights. Note the unusually high MSLT after placebo and again after MDMA despite the MDMA-shortened sleep time the previous night. After sleep restriction, the MSLT did decline. (Graphs adapted from Randall S, Johanson CE, Tancer M, Roehrs T. Effects of acute 3,4-methylenedioxymethaphetamine on sleep and daytime sleepiness. Sleep 2009;32(11):1513-1519.)
DRUG SEEKING VERSUS THERAPY SEEKING In drug-seeking behavior, the drug and its effects, typically its euphorogenic effect, is the focus of the drug use, whereas in therapy-seeking behavior, the alleviation of diseaserelated symptoms is the focus of the drug use. In the clinic, drug seeking and therapy seeking can become closely intertwined, and what was once therapy seeking can shift to drug seeking. The challenge to sleep disorders clinicians is to differentiate the two phenomena in making diagnoses and appropriately treating patients. Some of the potentially differentiating and defining characteristics of
CHAPTER 132 • Medication and Substance Abuse 1521
Box 132-4 Characteristics of Drug-Seeking versus Therapy-Seeking Behavior Drug-Seeking Behavior Drug is chosen over other commodities or activities Drug is taken in excessive, nontherapeutic amounts Drug is taken on a chronic basis, leading to tolerance and physical dependence Drug is taken in a nontherapeutic context Therapy-Seeking Behavior Drug has demonstrated efficacy Duration and dose of self-administration is limited to therapeutic effects Patient has signs and symptoms for which drug is indicated Drug is believed to be and is experienced as being efficacious
drug-seeking versus therapy-seeking behavior are presented in Box 132-4. The defining characteristic of drug-seeking is evidence that the drug is taken in excessive amounts, is taken in nontherapeutic contexts, and is preferred over other commodities (e.g., money) and various social and occupational activities. The risk for abuse of a substance is related to the degree to which it is chosen over other commodities or social activities. Supportive of its reinforcing capacity is evidence in the scientific literature that the drug is readily discriminated from placebo by behavioral and subjective assessment. A drug’s reinforcing capacity is evidenced by the ability for patients to discriminate it from placebo by behavioral and subjective assessment. That is, the drug’s subjective effects are the focus of its use. Then, to the degree that the dose is escalated over time, one has evidence of the development of tolerance and possible physical dependence. Therapy-seeking behavior is evident if the drug has demonstrated efficacy for the disorder or condition being treated and if the patient has the signs and symptoms and the appropriate diagnosis for the indicated use of the drug. The pattern of drug taking—its dose and duration of use—is consistent with its therapeutic effects in therapyseeking behavior. Finally, the patient believes that the drug is effective and readily experiences its therapeutic effects. Determining therapy-seeking behavior can be less straightforward in practice, particularly where therapyseeking shifts to drug-seeking behavior. For example, presleep ethanol use might initially be effective in improving sleep in a person with insomnia; however, this use can be concerning given the likelihood of rapid development of tolerance and subsequent escalation of dose. Further, ethanol’s other reinforcing effects (i.e., its euphorogenic effects) may be discovered by the individual, especially as dose is escalated, and its use can then extend beyond the therapeutic context (i.e., before sleep as a hypnotic). A similar shifting pattern can be described for stimulant or opiate use. On the other hand, drug-seeking may be maintained because the drug, in addition to its mood altering and euphorogenic effects, also has therapeutic effects (i.e., the
stimulant effects of cocaine or amphetamine do reverse the excessive sleepiness that is experienced during drug discontinuation). Thus, the dependence is maintained by both its mood-altering effects and its therapeutic effects, which has been termed self medication (i.e., both positive and negative reinforcing effects). Thus, the first cigarette or cup of coffee in the morning is likely reversing drug discontinuation effects after a night of abstinence.
❖ Clinical Pearl In assessing patients with sleep complaints, the sleep clinician must gather information on substance use including prescribed medications, OTC drugs, legal recreational drugs, and illegal recreational drugs, as well as their quantity and pattern of use. When substance abuse is suspected, referral to a substance abuse specialist is desirable. Patients should be followed closely to monitor their appropriate therapeutic use, especially if they are prescribed drugs with a high abuse liability.
Acknowledgment Dr. Roehrs’s work is supported in part by NIDA grant no. ROIDA 17355. REFERENCES 1. Roehrs T, Papineau K, Rosenthal L, Roth T. Sleepiness and the reinforcing and subjective effects of methylphenidate. Exp Clin Psychopharm 1999;7:145-150. 2. Johnson EO, Roehrs T, Roth T, Breslau N. Epidemiology of alcohol and medication as aids to sleep in early adulthood. Sleep 1998;21: 178-186. 3. Johnson E, Roehrs T, Roth T, Breslau N. Epidemiology of medication as aids to alertness in early adulthood. Sleep 1999;22:485-488. 4. Roehrs T, Papineau K, Rosenthal L, Roth T. Ethanol as a hypnotic in insomniacs: self administration and effects on sleep and mood. Neuropsychopharmacololgy 1999;20:279-286. 5. Roehrs T, Bonahoom A, Pedrosi B, et al. Nighttime versus daytime hypnotic self administration. Psychopharmacology (Berl) 2002;161: 137-142. 6. Koob GF, Stinus L, LeMoal M, Bloom FE. Opponent theory of motivation: neurobiological evidence from studies of opiate dependence. Neurosci Biobehav Rev 1989;13:135-150 7. Papineau K, Roehrs T, Petrucelli N, et al. Electrophysiological assessment (the multiple sleep latency test) of the biphasic effects of ethanol in humans. Alcohol Clin Exp Res 1998;22:231-235. 8. Stone BM. Sleep and low doses of alcohol. Electroencep Clin Neurophys 1980;48:706-709. 9. Roehrs T, Roth T. Sleep, sleepiness, sleep disorders and alcohol use and abuse. Sleep Med Rev 2001;5:287-297. 10. Hyde M, Roehrs T, Roth T. Alcohol, alcoholism, and sleep. In: LeeChiong T, editor. Sleep: a comprehensive handbook. Philadelphia: John Wiley & Sons; 2006. p. 867-871. 11. Roehrs T, Roth T. Alcohol, sleep, sleep disorders, and consequent daytime impairment. In: Pandi-Perumal SR, Verster JC, Monti JM, et al. editors. Sleep disorders: diagnosis and therapeutics. Oxford: Taylor and Francis; 2008. p. 480-486. 12. Yesavage JA, Leirer VA. Hangover effects on aircraft pilots 14 hours after alcohol ingestion: a preliminary report. Am J Psychiatry 1986; 143:1546-1550. 13. Roehrs T, Yoon J, Roth T. Nocturnal and next-day effects of ethanol and basal level of sleepiness. Human Psychopharm 1991;6:307-311. 14. Landolt HP, Roth C, Dijk DJ, Borbely AA. Late-afternoon ethanol intake affects nocturnal sleep and sleep EEG in middle-aged men. J Clin Psychopharmacol 1996;16:428-436.
1522 PART II / Section 16 • Psychiatric Disorders 15. Roehrs T, Roth T. Sleep, sleepiness, and alcohol use. Alcohol Res Health 2001;25:101-109. 16. Ancoli-Israel S, Roth T. Characteristics of insomnia in the United States: results of the 1991 National Sleep Foundation Survey. I. Sleep 2000;22:S347-S353. 17. Roehrs T, Papineau K, Rosenthal L, Roth T. Ethanol as a hypnotic in insomniacs: self administration and effects of sleep and mood. Neuropsychopharmacology 1999;20:279-286. 18. Roehrs B, Blaisdell B, Cruz N, Roth T. Tolerance to hypnotic effects of ethanol in insomnias [abstract]. Sleep 2004;27:352. 19. Guilleminault C. Sleep apnea syndromes: impact of sleep and sleep states. Sleep 1980;3:227-234. 20. Issa FG, Sullivan CE. Alcohol, snoring and sleep apneas. J Neurol Neurosurg Psychiatry 1982;45:353-359. 21. Mitler MM, Dawson A, Henriksen SJ, et al. Bedtime ethanol increases resistance of upper airways and produces sleep apneas in asymptomatic snorers. Alcohol Clin Exp Res 1988;12:801-805. 22. Herzog M, Riemann R. Alcohol ingestion influences the nocturnal cardio-respiratory activity in snoring and non-snoring males. Eur Arch Otorhinolarygol 2004;261:459-462. 23. Aldrich MS, Shipley JE. Alcohol use and periodic limb movements of sleep. Alcohol Clin Exp Res 1993;17:192-196. 24. LeBon O, Verbanck P, Hoffmann G, et al. Sleep in detroxified alcoholics: Impairment of most standard sleep parameters and increased risk for sleep apnea, but not for myclonias—a controlled study. J Stud Alcohol 1997;58:30-36. 25. Brower KJ. Alcohol’s effects on sleep in alcoholics. Alcohol Res Health 2001;25:110-125. 26. Hyde M, Roehrs T, Roth T. Alcohol, alcoholism and sleep. In: LeeChiong T, editor. Sleep: a comprehensive handbook. Hoboken, NJ: John Wiley & Sons; 2006. p. 867-871. 27. Drummond SPA, Gillin JC, Smith TL, Demondena A. The sleep of abstinent pure primary alcoholic patients: natural course and relation to relapse. Alcohol Clin Exp Res 1998;22:1796-1802. 28. Allen RP, Wagman AM, Funderburk FR, Well DT. Slow wave sleep: a predictor of individuals differences in response to drinking. Biol Psychiatry 1980;15:345-348. 29. Gillin JC, Smith TL, Irwin M, et al. Increased pressure for rapid eye movement sleep at time of hospital admission predicts relapse in nondepressed patients with primary alcoholism at 3-month followup. Arch Gen Psychiatry 1994;51:189-197. 30. Brower KJ. Insomnia, alcoholism and relapse. Sleep Med Rev 2003;7:523-539. 31. Currie SR, Clark S, Hodgins DC, el-Guebaly N. Randomized controlled trial of brief cognitive-behavioural interventions for insomnia in recovering alcoholics. Addiction 2004;99:1121-1132. 32. Arnedt JT, Conroy D, Rutt J, et al. An open trial of cognitivebehavioral treatment for insomnia comorbid with alcohol dependence. Sleep Med 2007;8:176-180. 33. Griffiths RR, Mumford GF. Caffeine—a drug of abuse. In: Bloom FE, Kupfer DJ, editors. Psychopharmacology: the fourth generation of progress. New York: Raven Press; 1995. p. 1699-1713. 34. Brezinova V. Effect of caffeine on sleep: EEG study in late middle age people. Br J Clin Pharmacol 1974;1:203-208. 35. Karacan I, Thornby JI, Anch M, et al. Dose-related sleep disturbances induced by coffee and caffeine. Clin Pharmacol Ther 1977; 20:682-689. 36. Nicholson AN, Stone BM. Heterocyclic amphetamine derivatives and caffeine on sleep. Br J Clin Pharmacol 1980;9:195-203. 37. Okuma T, Matsuoka H, Matuse Y, Toyomura K. Model insomnia by methylphenidate and caffeine and use in the evaluation of temazepam. Psychpharmacology 1982;76:201-213 38. Bonnet MH, Arand DL. Caffeine use as a model of acute and chronic insomnia. Sleep 1992;15:526-536. 39. Gillin LC, Lardon M, Ruiz C, et al. Dose-dependent effects of transdermal nicotine on early morning awakening and rapid eye movement sleep time in non-smoking normal volunteers. J Clin Psychopharmacol 1994;14:264-267. 40. Salin-Pascual RJ, de la Fuente JR, Galicia-Polo L, Drucker-Colin R. Effects of transdermal nicotine on mood and sleep in nonsmoking major depressed patients. Psychopharmacology 1995;121:476-479. 41. Davila DG, Hurt RD, Offord KP, et al. Acute effects of transdermal nicotine on sleep architecture, snoring, and sleep-disordered breathing in nonsmokers. Am J Respir Crit Care Med 1994;1560: 469-474.
42. Prosise GL, Bonnet MH, Berry RB, Dickel ML. Effects of abstinence from smoking on sleep and daytime sleepiness. Chest 1994;105:1136-1141. 43. Wetter DW, Fiore MC, Baker TB, Young TB. Tobacco withdrawal and nicotine replacement influence objective measures of sleep. J Con Clin Psychol 1995;63:658-667. 44. Phillips BA, Danner FJ. Cigarette smoking and sleep disturbance. Arch Intern Med 1995;155:734-737. 45. Gawin FH, Kleber HD. Abstinence symptomatology and psychiatric diagnosis in cocaine abusers. Gen Psychiatry 1986;43:107-113. 46. Kowatch RA, Schnoll SS, Knisely JS, et al. Electroencephalographic sleep and mood during cocaine withdrawal. J Addict Disord 1992;11:21-45. 47. Johanson CE, Roehrs T, Schuh K, Warbasse L. The effects of cocaine on mood and sleep in cocaine-dependent males. Exp Clin Psychopharm 1999;4:338-346. 48. Rechtschaffen A, Maron L. The effect of amphetamine on the sleep cycle. Electro Clin Neurophysiol 1964;16:438-445. 49. Mitler MM, Hajdukovic R, Erman MK. Treatment of narcolepsy with methamphetamine. Sleep 1993;16:306-317. 50. Watson R, Hartmann E, Schildkraut JJ. Amphetamine withdrawal: affective state, sleep patterns and MHPG excretion. Amer J Psychiat 1972;129:262-269. 51. Nicholson AN, Stone BM. Stimulants and sleep in man. Agressologie 1981;22:73-78. 52. Braekeland F. The effect of methylphenidate on the sleep cycle in man. Psychopharmacologia 1966;10:179-183. 53. Tirosh E, Sadeh A, Munvez R, Lavie P. Effects of methylphenidate on sleep in children with attention-deficit hyperactivity disorder. Am J Dis Child 1993;147:1313-1315. 54. Greenhill L, Puig-Antich J, Goetz R, et al. Sleep architecture and REM sleep measures in prepubertal children with attention deficit disorder with hyperactivity. Sleep 1983;6:91-101. 55. Kay DC, Pickworth WB, Neidert GL. Morphine-like insomnia from heroin in non-dependent human addicts. Br J Clin Pharmacol 1981;11:159-169. 56. Kay DC, Eisenstein RB, Jasinski DR. Morphine effects on human REM state, waking state, and NREM sleep. Psychopharmacologia 1969;14:404-416. 57. Pickworth WB, Neidert GL, Kay DC. Morphine-like arousal by methadone during sleep. Clin Pharmacol Ther 1981;30:796-804. 58. Kay DC. Human sleep during chronic morphine intoxication. Psychopharmacologia 1975;44:117-124. 59. Mello NK, Mendelson JH, Lukas SE, et al. Buprenorphine treatment of opiate and cocaine abuse: clinical and preclinical studies. Harvard Rev Psychiatry 1993;1:168-183. 60. Mogri M, Desai H, Webster L, et al. Hypoxemia in patients on chronic opiate therapy with and without sleep apnea. Sleep Breath 2009;13:49-57. 61. Farney RJ, Walker JM, Boyle KM, et al. Adaptive servoventilation (ASV) in patients with sleep disordered breathing associated with chronic opioid medication for non-malignant pain. J Clin Sleep Med 2008;15:311-319. 62. Javaheri S, Malik A, Smith J, Chung E. Adaptive pressure support servoventilation: a novel treatment for sleep apnea associated with use of opioids. J Clin Sleep Med 2008;15:305-310. 63. Griffiths RR, Weerts EM. Benzodiazepine self-administration in humans and laboratory animals. Implications for problems of longterm use and abuse. Psychopharmacology 1997;134:1-37. 64. deWit H, Pierri J, Johanson CE. Reinforcing and subjective effects of diazepam in nondrug-abusing volunteers. Pharm Biochem Behav 1989;33:205-213. 65. deWit H, Uhlenhuth EH, Hedeker D, et al. Lack of preference for diazepam in anxious volunteers. Arch Gen Psychiatry 1986;43: 533-541. 66. Oswald LM, Roache JD, Rhoades HM. Predictors of individual differences in alprazolam self-medication. Exp Clin Psychopharm 1999;7:379-390 67. Roehrs T, Merlotti L, Zorick F, Roth T. Rebound insomnia and hypnotic self administration. Psychopharmacology 1992;107:480-484. 68. Roehrs T, Pedrosi B, Rosenthal L, et al. Hypnotic self administration and dose escalation. Psychopharmacology 1996;127:150-154. 69. Roehrs T, Pedrosi B, Rosenthal L, et al. Hypnotic self administration: forced-choice versus single-choice. Psychopharmacology 1997; 133:121-126.
70. Pivick RT, Zarcone V, Dement WC, Hollister LE. Delta-9-tetrahydrocannabinol and synhexl: effects on human sleep patterns. Clin Pharmacol Ther 1972;13:426-435. 71. Freemon FR. The effect of delta-9-tetrahydrocannabinol on sleep. Psychopharmacologia 1974;35:39-44. 72. Barratt ES, Beaver W, White R. The effects of marijuana on human sleep patterns. Biol Psychiat 1974;8:47-53. 73. Feinberg I, Jones R, Walker JM, et al. Effects of high dosage delta9-tetrahydrocannabinol on sleep patterns in man. Clin Pharmacol Ther 1976;17:458-466. 74. Tassinari CA, Ambrosetto G, Peraita-Adrados MR, Gastaut H. The neuropsychiatric syndrome of delta-9-tetrahydrocannabinol and cannabis intoxication in naive subjects: a clinical and polygraphic study during wakefulness and sleep. In: Braude MC, Szara S, editors. The pharmacology of marihuana. New York: Raven Press; 1976. pp. 357-382. 75. Babor TF, Mendelson JH, Kuehnle J. Marihuana and human physical activity. Psychopharmacology 1976;50:11-19.
CHAPTER 132 • Medication and Substance Abuse 1523 76. Chait LD. Subjective and behavioral effects of marijuana the morning after smoking. Psychopharmacology 1990;100:328-333. 77. Karacan I, Fernandez-Salas A, Coggins WJ, et al. Sleep electroencephalographic-electrooculographic characteristics of chronic marijuana users: part I. Ann N Y Acad Sci 1977;103:348-374. 78. Schmidt CJ, Levin JA, Lovenberg W. In vitro and in vivo neurochemical effects of methylenedioxymethamphetamine on striatal monoamine systems in the rat brain. Biochem Pharmacol 1987;36: 747-755. 79. Allen RP, McCann UD, Ricaurte GA. Persistent effects of 4-methylenedioxymethamphetamine (MDMA, “ecstasy”) on human sleep. Sleep 1993;16:(6)560-564. 80. Randall S, Johanson CE, Tancer M, Roehrs T. Effects of acute 3, 4-methylenedioxymethaphetamine on sleep and daytime sleepiness. Sleep 2009;32(11):1513-1519.
Sleep Medicine in the Elderly
Section
17
Sonia Ancoli-Israel 133 Medical and Psychiatric Disorders and the Medications Used to Treat Them 134 Obstructive Sleep Apnea in the Elderly 135 Insomnia in Older Adults 136 Sleep in Independently Living and Institutionalized Elderly
Medical and Psychiatric Disorders and the Medications Used to Treat Them Steven R. Barczi and Mihai Teodorescu Abstract Insomnia in later life is prevalent and often multifactorial. It fits the profile of a geriatric syndrome, defined as a multifactorial health condition that occurs when the accumulated effects of impairments in multiple systems lead to an older person’s vulnerability to situational challenges. Comorbid insomnia is the preferred term for insomnia that coexists with medical or psychiatric conditions that can disturb sleep. A previously used term, secondary insomnia, presupposed that the causal relationship between a disease and a sleep change is estab-
The number of older people is steadily rising, and by 2050, 20% of the U.S. population will be aged 65 years and older.1 The prevalence of sleep difficulties increases with age; more than 30% of older people have trouble sleeping.1 Sleep reflects overall health and is susceptible to the influence of many endogenous and exogenous factors. Changes in sleep in older adults appear to be associated with psychosocial and health factors rather than with aging itself.2,3 The 2003 Sleep in America survey reported an inverse proportion between the self-perceived quality of the respondents’ sleep and the number of comorbidities they had.2 In 1999, 65% of aged Medicare beneficiaries had multiple chronic conditions.3 The simultaneous occurrence of several medical conditions in the same person constitutes the concept of multimorbidity. The specific prevalence of individual conditions varies based upon the age group, gender, and population sampled (e.g., community-based versus clinic cohort). The epidemiologic literature supports that the most commonly defined chronic conditions in those 70 years or older include osteoarthritis, hypertension, heart disease, diabetes, obstructive lung disease, and cancer in approximate descending order of incidence from 55% to 10%.4,5 1524
Chapter
133
lished. However, this is not always the case. Historically, treatments have focused on optimizing the health problems associated with the sleep disturbance. This disregards the dynamic relation between illness and insomnia. Management of comorbid insomnia requires a multifaceted approach that addresses the associated medical and psychiatric conditions, optimizes medications, intervenes on concurrent primary sleep disorders, and targets perpetuating factors that can reinforce poor sleep hygiene during or after the initial physiologic insult.
Population-based surveys reported that between 89% and 94% of those older than 65 years take prescription medications; nearly 40% take more than five medications and 12% taking more than 10 medications.6,7 Polypharmacy is often defined as taking more than five medications and increases incrementally in relationship to the number of coexisting age-associated diseases.7 Consequences of polypharmacy include adverse drug effects, drug-drug interactions, and medication cascade effects.7 The cascade effect refers to the use of medications to treat the side effects of other medications. Multiple physicians treating one patient, increasing comorbidities, and an increase in the variety of drugs available contribute to the adverse effects of polypharmacy on the elderly patient. In prior diagnostic criteria for insomnia, the presumption was that insomnia occurring in the context of a primary disorder is caused by that condition and should fluctuate in severity along with changes in the medical disorder. Guidelines for clinical practice suggested that the primary medical illness should be the focus of treatment, because it was assumed that secondary insomnia is untreatable as long as the medical cause persists. In older adults with chronic illnesses, the terms of primary
CHAPTER 133 • Medical and Psychiatric Disorders 1525
Host factors • Age • Neuropsychological phenotype • Sleep and wake hygiene • Activity pattern • Response to stress
Sleep/wake
Environmental factors • Noise • Light • Temperature • Bedroom environment • Disruptive schedules - Medical care - Personal care • Social interaction • Schedule of sleep–wake cycle
Illness • Medical problems • Psychiatric problems • Cognitive problems • Medications • Sleep disorders • Pain • Delirium
Figure 133-1 Sleep and wake symptoms depicted as a syndrome that results from dynamic interactions between the individual state with genetic and phenotypic characteristics, illness, as a function of comorbidities and polypharmacy, and environment, which include modulating nociceptive interactions with disruptors and zeitgeber qualities. This model could further identify predisposing, precipitating, and perpetuating factors, but it underscores the limited ability to establish a clear, consequential relationship in the context of ever-changing interplay of these factors.
insomnia and secondary insomnia are probably not accurate enough to address the complexity of the etiology of insomnia. Sleep difficulties in older persons could be conceptualized as a geriatric syndrome because they are attributable to multiple and interdependent predisposing, precipitating, and perpetuating factors.8 The medical or psychiatric condition can act as a precipitating event and produce symptoms of discomfort and emotional distress that can lead to increased sympathetic drive, activation of the hypothalamic-pituitary-adrenal axis, and ultimately recruitment of neural systems to produce arousal.12,13 Psychological factors of hyperarousal, stress response, predisposing personality traits, and maladaptive attitudes can perpetuate sleep changes seen during illness in later life.9 In many situations, interplay between underlying medical and psychiatric illnesses and their treatments, sleep hygiene, medications, and environment are all contributing to the problem (Fig. 133-1). For these reasons, establishing a clear, consequential relationship becomes a clinical challenge. The 2005 National Institutes of Health State-of-the-Science Conference on Insomnia proposed using the diagnosis of comorbid insomnia when an illness coexists with sleep changes but the dynamics of cause and effect are not proved.10 The precise relationship between an illness and the neurophysiologic, biochemical, and hormonal sequelae that contribute to sleep disruption remains uncertain in most cases of comorbid insomnia.
The approach to the management of comorbid insomnia is evolving. Historically, if a sleep problem was attributed to an associated physical or mental illness, then the primary focus was on optimizing treatment of that underlying health concern. More recently, a series of controlled trials have demonstrated the efficacy of cognitive behavior therapy (CBT) in managing insomnia complaints in a variety of different illnesses. Although more data are needed to determine the most effective approach, there is a growing trend for all comorbid or secondary insomnia to be approached the same as primary insomnia; a multifaceted intervention appears most logical, including optimization of comorbid health issues and treatment of insomnia using CBT or pharmacotherapy, or both.11
PSYCHIATRIC CONDITIONS AND SLEEP IN THE OLDER ADULT Mental health conditions are prevalent in the geriatric population and are often associated with complaints of difficulties with sleep. Indeed, sleep disruption is a part of the diagnostic criteria of many psychiatric disorders. Therefore, to be an independent diagnosis, insomnia has to constitute a distinct complaint and be more prominent than that typically associated with mental disorders.12 Psychiatric and somatic symptoms, as well as the level of physical activity, significantly and independently increase the risk of insomnia in older clinic patients.13 Acutely ill psychiatric patients show reduced sleep efficiency, prolonged sleep latency, decreased total night sleep, and increased arousals.14 Depressive and Bipolar Disorders Depression is associated with sleep disturbances in both the elderly general population15 and in clinical populations, and insomnia in the primary care setting shows a stronger association to depression than any other medical disorder.16 In the geriatric population, sleep difficulties increase the risk for comorbid depression.17,18 Sleep complaints also foreshadow the onset of depression in older adults, and insomnia is a strong risk factor for future depression in elderly patients not currently depressed.19 Insomnia at baseline and 1 year later increased eight times the risk of developing depression20 in one elderly cohort. Objective and subjective sleep findings in depression have different implications and do not always correlate with each other.21,22 Between 63% and 80% of depressed adults and older adults complain of difficulty falling or staying asleep or being tired in the day.23,24 These subjective sleep complaints can persist beyond the resolution of depressive symptoms.25 Prevalence of symptoms is comparable between sexes.26 Objective sleep findings in older adults with depression include prolonged time to sleep onset, decreased sleep efficiency, poor sleep continuity, and increased early morning awakening. Additionally, total sleep time is reduced, with relative increases in stages 1 and 2 sleep and corresponding decreased slow-wave sleep. There is also shortened rapid eye movement (REM) sleep latency, a longer first REM period, and increased total REM sleep and REM density. A distinguishing feature of bipolar affective disorder is a manic episode, which involves a prolonged time of
1526 PART II / Section 17 • Sleep Medicine in the Elderly
increased activity with minimal sleep. Insomnia precedes manic episodes as a first symptom in up to 77% of cases.27 Although first-onset mania can occur in the elderly, alternate etiologies such as medical illness or drug effects should be considered first. Of those with first episode of mania in later life, many have a history of depression.28 Sleep loss can trigger manic episodes, emphasizing a need to clinically monitor sleep changes and address sleep-disrupting factors in an attempt to decrease such exacerbations.27 Bereavement and Grief In bereavement, sleep difficulties are often associated with depressive and physical symptoms. The highest levels of grief are usually found within the first 4 months of bereavement, with recovery periods varying with the stress of the bereavement or coping skills and extending to 2 to 3 years. In a cross-sectional survey of 170 women (mean age, 66 years) at 4 to 60 months (average, 26 months) from the loss event, insomnia was reported by 13% of subjects; other sleep-related symptoms included an irregular sleep pattern, nightmares, and sleeping excessively.41 Sleeping 6.5 to 9 hours per night at baseline predicts better social functioning, better emotional health, and more energy during bereavement in older persons.29 Baseline complicated grief scores of recently widowed elderly persons were significantly associated with sleep difficulties at 18-month follow-up.30 In a study of 28 spousally bereaved older adults assessed at 4 months or later from the loss event, polysomnographic data demonstrated mildly prolonged latency to sleep and REM sleep and mildly reduced sleep time and sleep efficiency. Higher grief tended to be associated with less time spent asleep and reduced alertness at 8 pm.31 Anxiety Disorders Many older adults can have increased anxiety when faced with chronic health conditions, functional limitations, or concerns about issues such as safety or finances. These situations, as well as certain medications used to treat them, can contribute to neurochemical changes or increased adrenergic drive. This is reflected in the findings that even subclinical anxiety symptoms are associated with higher levels of wake after sleep onset as measured by actigraphy and a sleep log.32 Sleep disturbance is a core symptom in the diagnosis of generalized anxiety disorder (GAD) and is endorsed in about two thirds of patients with this diagnosis.33 Objective findings include more awakenings, longer time to fall asleep, decreased sleep efficiency and time, less-consistent findings of more stage 2, and decreased slow-wave sleep (SWS).14,34 About 80% of older adults with GAD also have a depressive disorder, making specific objective sleep findings difficult to interpret. Panic disorder is associated with sleep complaints, including trouble falling sleep, disturbed and restless sleep, and nocturnal panic attacks. Nearly a quarter of patients with panic disorder report either severe sleep restriction (≥5 hours) or increases (≥9 hours) in sleep duration.35 Nocturnal panic attacks occur at least weekly in 18% to 45% of patients with panic disorder.33,36 These attacks are characterized by similar symptom severity and duration of
daytime panic attacks and occur usually in the first few hours of sleep in transition from stage 2 to SWS.37 People with nocturnal panic attacks have higher rates of insomnia and depression than people with panic disorder without nighttime episodes.38,39 Older adults with posttraumatic stress disorder (PTSD) have less re-experiencing of the stressful event but more symptoms of hyperarousal compared with younger people, and the severity seems similar.40 In a meta-analysis of 20 polysomnographic studies, older PTSD patients had less SWS and more REM sleep than age-matched control participants, with possible confounding by the time elapsed since traumatic experiences.41
MEDICAL CONDITIONS AND SLEEP IN THE OLDER ADULT An individual medical illness can have several mechanisms that interfere with sleep and can have different effects on sleep architecture in its acute versus chronic state. The immediate physiologic derangements or distress of an illness can transiently disturb sleep. Chronic pain, cardiovascular disease, pulmonary disease, chronic kidney disease, gastrointestinal conditions, endocrine conditions, and genitourinary conditions have been associated with poor sleep. Sleep disturbance can worsen symptoms in these disorders or even worsen the prognosis. Pain Pain is a common contributor to comorbid insomnia. The relationship between pain and sleep is complex; pain can disrupt sleep, and poor sleep can increase perceived pain intensity.42 In community-dwelling older persons, 25% to 50% are reported to have important pain problems.43 In a population of adults aged 55 to 84 years, 19% reported that pain disrupted their sleep at least a few nights per week, and 12% reported almost nightly sleep fragmentation due to pain.2 In referral populations of patients with chronic pain, prevalence rates of insomnia can range between 50% and 70%.44 Painful conditions are often associated with reduced total sleep time, reduced REM sleep, frequent brief arousals, and increased wake after sleep onset.45,46 Arthritis As a condition producing pain and disability, arthritis increases with advancing age.47 As many as 60% of those with arthritis experience pain during the night, mediating a substantial amount of the relationship between arthritis and sleep problems. Adults who are older than 65 years with knee arthritis have been observed to have problems initiating sleep (31%) and maintaining sleep (81%) and have a tendency to awaken early in the morning (51%).48 Patients with rheumatoid arthritis have a high prevalence of restless legs syndrome (RLS) (25%).49 Persons with selfreported arthritis-related sleep disruption are more likely then those without sleep disturbance to pursue multiple sources of self-care and medical care.50 A recent randomized clinical trial involving older adults with arthritis and comorbid insomnia demonstrated efficacy for cognitive behavior approaches in improving self-reported measures of sleep.51
Gastroesophageal Reflux Disease Symptoms of gastroesophageal reflux disease (GERD) increase with aging, with a prevalence of 10% for daily reflux symptoms for those older than 50 years.52 In population surveys, between 50% and 70% of persons with GERD report nighttime symptoms and reduced sleep quality.53 The relationship between disturbed sleep and GERD is bidirectional: Sleeping increases the likelihood of reflux, and reflux episodes often awaken the patient.54,55 Patients with nighttime acid reflux can underestimate the degree of sleep disruption that occurs when objective measurements of pH and electroencephalogram (EEG) arousal are compared to the patient’s recollection the next morning.55 A pilot study enrolling 16 subjects with chronic insomnia reported silent reflux in 25% of subjects, as evidenced by abnormal 24-hour pH testing. Aggressive treatment of these subjects resulted in normalization of sleep efficiency in three out of four subjects. Reviewing the patient history for nocturnal cough or wheezing as a surrogate for reflux is also important, because not all patients with overnight reflux experience classic chest pain, but their sleep may be disrupted nevertheless. Published evidence demonstrates that acid-suppression therapy reduces nighttime heartburn symptoms, reduces GERD-associated sleep disturbances, and improves subjective sleep quality and next day’s work performance.56 Heart Disease Coronary artery disease and congestive heart failure are a leading cause of morbidity and mortality in older adults. Nocturnal ischemia, nighttime arrhythmias, and sleepdisordered breathing are all linked to altered sleep in underlying heart disease. A well-described circadian pattern of myocardial ischemia or infarction occurs early to midmorning and is ascribed to the catecholamine surge that accompanies awakening and upright status. In a retrospective analysis of 3309 adults presenting with acute coronary syndrome, 26% of the subjects were awakened from sleep,57 and only older age and lower left ventricular ejection fraction were independent predictors of a nocturnal acute coronary syndrome. Coronary artery bypass surgery is associated with protracted sleep disturbance up to 2 years following the procedure.58 The mechanism for this is unclear; occult heart failure, secondary mood issues, or brain microvascular ischemic changes are possibilities. In a cross-sectional study of 223 elderly patients with New York Heart Association (NYHA) classification II to IV, consistent difficulties maintaining sleep were reported by 23% of men and 20% of women, and 25% of the subjects were awake 1 to 3 hours per night.59 The classic sleep maintenance disturbance associated with congestive heart failure (CHF) includes orthopnea, paroxysmal nocturnal dyspnea, nocturia, and sleep-disordered breathing. Comorbid depression was also identified as a factor that increasingly contributes to sleep disturbance in elderly patients with CHF.60 More than 50% of patients with moderate to severe CHF experience periodic breathing in the form of Cheyne-Stokes respiration. This can lead to increased sleep fragmentation and an increase in daytime sleepiness.61,62
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When reviewing risk factors for central sleep apnea (CSA) and obstructive sleep apnea (OSA) in men and women with congestive heart failure, age older than 60 years is an independent predictor for OSA in both sexes and for CSA in women.63 More-severe nighttime periodic breathing occurring in heart failure correlates with worse prognosis and increased cardiac death.62 Chronic Lung Disease Chronic lung disease in the form of chronic obstructive pulmonary disease (COPD) contributes to poor sleep continuity and increased daytime sleepiness.64 Changes reported include increase in sleep-stage changes, decreased total sleep time, and increased number of arousals.65 The sleep disturbance is often related to nocturnal cough, wheezing, and shortness of breath due to worsening of pulmonary mechanics and gas exchange during sleep. Hypoxemia, which is common in COPD during REM sleep, correlates with an increase in arousal and excessive daytime sleepiness. Oxygen therapy often corrects the underlying hypoxemia, but it does not appear to improve sleep quality.65 The use of an ipratropium bromide inhaler improves sleep quality and duration, presumably by improving airflow.66 A small observational study of lung volume reduction surgery in older adults, mean age 63 years, also demonstrates improved polysomnographic sleep quality and nocturnal oxygenation.67 By retrospective analysis, the prevalence of overlap syndrome (coexistent OSA and COPD) was 12% in COPD and 41% in OSA patients in an older Veterans Affairs (VA) population.68 Nocturnal asthma symptoms resulting in nighttime awakenings occur in more than 70% of persons with asthma. Other reported sleep symptoms include difficulties falling asleep, difficulties maintaining sleep, early morning awakenings, and daytime sleepiness. Asthma control correlates with quality of sleep.69 Diabetes and Endocrine Disorders Endocrine disorders such as diabetes and menopause are age-related and have characteristic sleep difficulties. Thirty percent of diabetic patients demonstrate sleep maintenance disturbances, and the severity of disruption correlates with the degree of hyperglycemia.70,71 One third of patients with diabetes have problems with sleep fragmentation, and nocturia, leg cramps, leg pain, and cough are contributing factors. Diabetes appears to lower the percentage of REM sleep and increase the prevalence of periodic breathing.72 Patients with diabetes have an increased prevalence of RLS and periodic limb movements in sleep (PLMS).73 In menopause, an estimated 40% to 50% of women reported sleep difficulties following cessation of menstruation. Although some of this is transient during the time of acute hormonal changes, others have persisting symptoms for years. Hormone replacement therapy has been shown to improve subjective but not objective sleep measures.74 Kidney and Urologic Diseases Sleep disruption is common in urologic and kidney diseases. Benign prostatic hyperplasia (BPH) and prostate
1528 PART II / Section 17 • Sleep Medicine in the Elderly
cancer are typically diseases of aging men, steeply increasing with age. Overactive bladder is characterized by urinary urgency, urinary frequency, nocturia, and sometimes incontinence. It increases markedly with advancing age in both men and women.75 Nocturia is a well-recognized etiology for sleep maintenance disturbance in later life, and nighttime urination is often associated with poor quality of sleep and increased fatigue in the daytime.76 It is reported to be an independent predictor of self-reported insomnia (75% increased risk) and reduced sleep quality (71% increased risk) based on a survey of 1424 elderly persons.77 In a Danish population of 2799 men and women aged 60 to 80 years, prevalence of nocturia (≥1 void) was 75% in women and 78% in men, with no significant difference between genders. The severity of nocturia increased with advancing age. Urinary incontinence, recurrent cystitis, and diabetes mellitus were the strongest associated factors for nocturia of any degree.78 Other etiologies include polyuria, low bladder capacity, sleep apnea, intake of excessive fluid before bedtime, alcohol, caffeine, diuretics, and medical disorders such as hypertension, CHF, and prostatic disease. The nocturnal polyuria syndrome is characterized by an inappropriate nocturnal urine output, often an undetectable plasma antidiuretic hormone (ADH) during the night, and increased thirst, particularly at night79; The 24-hour urine output is normal or only moderately increased. Approximately 40% of community-dwelling older adults report sporadic or chronic urinary incontinence,80 and the most common cause is the overactive bladder syndrome. Urine loss is considered a geriatric syndrome insofar as it leads to a spectrum of physical, psychological, and social consequences that can be detrimental to a person’s function and quality of life. The effects of incontinence on sleep are best studied in the nursing home population, with polysomnographic and actigraphy samples demonstrating sleep disruption with nocturnal wetting episodes. Interestingly 51% of these episodes occurred during or within 60 seconds of an abnormal sleep breathing event.81 In those who are chronically incontinent, the relationship between urine loss and awakening are not as tightly linked.82 Chronic kidney disease and end-stage renal disease have a steady increase in persons older than 60 years, with a striking rise in prevalence beyond age 75 years.83 Overall prevalence of insomnia in hemodialysis patients ranges between 45% and 86%.84 Fifty-seven percent of patients with end-stage renal disease report sleep-maintenance problems, and 55% report early morning awakening. There are marked abnormalities seen in the sleep EEGs of patients with chronic kidney disease, with overall reduction in total sleep time, decreased sleep efficiency due to wake after sleep onset, and reduced total REM.85 This might reflect the impact of uremia and other metabolic derangements on brain function during sleep. Patients on hemodialysis have a 50% to 80% rate of sleep–wake complaints and a higher prevalence of OSA (which improves following dialysis), RLS, periodic limb movements, early insomnia, and excessive daytime sleepiness.86-88 Quality of sleep was associated with hemoglobin level, serum albumin, and depression in 89 hemodialysis patients with a mean age of 60 years.114 In a study involving
hemodialysis patients with a mean age of 65 years, the treatment of anemia of kidney disease with erythropoietin improved sleep quality by polysomnographic and subjective measures.89 This appears to correspond to reduced numbers of periodic limb movements. More than 50% of hemodialysis patients endorse chronic pain, and this is thought to be significantly associated with insomnia and depression in this condition.90 Cancer Cancer is very often a disease of older persons, and 60% of all cancers are diagnosed after age 65 years.91 The prevalence of sleep problems in persons with cancer is difficult to determine because of wide variance based upon type and stage of cancer. Large epidemiologic studies suggest that sleep problems are very common, involving 55% to 87% of patients.92,93 Approximately half of patients report onset within the period 6 months before diagnosis to 18 months after diagnosis.94 In a study of 867 elders (46% women) with newly diagnosed breast, colorectal, lung, or prostate cancer and followed at four points during the year after diagnosis, insomnia remained present in 23.2% of patients 1 year after their cancer diagnosis. The authors reported a lessening of reports of pain, fatigue, and insomnia over time, but a high attrition rate was present.95 Persons with cancer might have a baseline history of insomnia or a primary sleep disorder; or they might have sleep effects from the cancer, its treatment, or the psychological response to the diagnosis.93 Most of the studies reported in the literature report on sleep changes in earlystage cancer.94 Forty-four percent of hospitalized cancer patients are prescribed hypnotic therapy.96 Although limited in number and size, trials using cognitive behavior therapy in cancer patients suggest significant improvement in their sleep.92 Sleep Disorders Sleep disorders in the elderly are covered in other chapters. In sleep clinic populations, 40% to 50% of patients with a sleep-related breathing disorder (SRBD) are noted to have concurrent insomnia symptoms. In a cross-sectional sample of 200 nondepressed, nondemented community-dwelling adults 65 years or older, SRBD was less prevalent in participants with insomnia symptoms than in those without insomnia symptoms, even though these two groups were similar in other SRBD risk factors such as body mass index (BMI) and gender. SRBD was still quite common, affecting nearly one in three older adults with insomnia symptoms. Concomitant insomnia and SRBD was associated with more daytime dysfunction than having insomnia alone.97
EFFECT OF MEDICATIONS ON SLEEP A multitude of prescription and over-the-counter (OTC) medications are associated with direct or indirect effects on overnight sleep quality and quantity as part of their side-effect, drug-drug interactions or drug-disease interactions profile; these are more likely to occur in older adults. These effects can then result in more permanent sleep– wake cycle alterations, leading to comorbid insomnia. Their effects can be broadly categorized as those that
produce drowsiness or daytime somnolence, those that are activating or stimulating to the brain, those that interfere with sleep by indirect mechanisms, those that can directly exacerbate primary sleep disorders, and those that influence sleep architecture via other affects. Many of these drugs can alter patterns of sleep and wakefulness during periods of administration and during periods of withdrawal. It is especially important to avoid using hypnotics or stimulants as agents in the cascade effect (use of medications to treat sleep-related side-effects of other medications) unless all other attempts at medication adjustment have been considered. Medications Associated with Daytime Sleepiness Drowsiness is an extremely common side effect of medications, and more than 584 medications are cited as causing drowsiness in the side effects index of the Physician’s Desk Reference.98 Many medications have the capacity to interfere with acetylcholine or histamine, both of which are regulatory neurotransmitters for wakefulness. Anticholinergic agents are known to have somnogenic effects, waking drowsiness, and negative cognitive, affective, and qualityof-life outcomes in older adults.99 Oxybutynin is the most studied of the anticholinergic agents. Night terrors have been reported with this agent in case reports, in addition to mild sedation. Polysomnographic changes include a decrease in the amount of REM sleep of approximately 15%, increased REM sleep latency, with power reduction in theta, alpha1, alpha2, and beta1 bands.100 Antihistaminergic drugs appear to have variable central nervous system penetration and binding; H1 antagonists such as diphenhydramine have much greater likelihood for sedation and cognitive impairment than do tertiary antihistamines.101 General classes of agents with these effects include antihistamines, antispasmodics, antipsychotics, antiemetics, and antiparkinsonian drugs. Notable specific examples include tricyclic antidepressants such as amitriptyline, doxepin, imipramine, cimetidine, and mirtazapine. Medications can also produce sleepiness via other mechanisms. In persons taking levodopa or dopamine agonists, there is an increased prevalence of excessive daytime sleepiness and sleep attacks.102 Anticonvulsant agents such as gabapentin, lamotrigine, tiagabine, and levetiracetam often produce sleepiness in older adults. Morphine and other opiate analgesics can contribute to daytime somnolence and decreased alertness and can disrupt overnight sleep efficiency and architecture. Medications That Activate the Central Nervous System A large number of medications disturb sleep via excitation or activation of the central nervous system. Sleep quality may be affected if the drug is taken before bedtime or if it has a sustained half-life that extends into the typical sleep period. OTC products for cold and flu contain ephedrine, pseudoephedrine, or other sympathomimetics. OTC analgesics employed for headache therapy contain caffeine. Agents used to manage chronic lung disease such as inhaled and oral beta-agonists, corticosteroids, and theophylline can contribute to sleep disruption.
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Activating antidepressants such as desipramine, bupropion, venlafaxine, reboxetine, and most selective serotonin receptor inhibitors (SSRIs) can sometimes adversely affect sleep initiation and maintenance. The prevalence of insomnia has been reported at 16.4% with sertraline, 15% with fluoxetine, and 14% with paroxetine.103 Even when patients appreciate an improvement in subjective sleep quality with use of SSRIs, objective sleep often worsens.21 Other activating medications such as methylphenidate, selegiline, and modafinil are often seen on geriatric medication lists. Careful evaluation of doses and times of administration for such medications may be considered to avoid interference with the desired sleep period. Medications That Affect Sleep by Worsening other Conditions Medications can sometimes interfere with sleep by worsening an underlying medical or psychiatric condition that then affects sleep. Medications that worsen heart failure such as nonsteroidal antiinflammatory drugs, calcium channel blockers, or sodium-complexed antibiotics have the potential to cause central sleep apnea, nocturia, or other sleep problems seen in this condition. Medications including nitrates and calcium channel blockers can decrease lower esophageal sphincter tone and result in nocturnal gastroesophageal reflux. Amitriptyline and other anticholinergic medications, although potentially helpful with sleep owing to their sedating effects, can also contribute to confusion and urinary retention, with subsequent arousals from delirium or nocturia. Late afternoon or evening diuretic treatment can cause nocturia and sleep fragmentation. Many antipsychotic medications, which are used for various symptoms in the elderly, have the potential to produce parkinsonian features, with commonly associated sleep difficulties. Quetiapine may be one of the least common offenders in this category of medications. Hypoglycemic agents can increase arousals through nocturnal hypoglycemia. Medications That can Exacerbate Primary Sleep Disorders A number of medications have been reported to exacerbate primary sleep disorders. Nocturnal movement disorders such as restless legs syndrome (RLS) and PLMS can worsen in the setting of a number of antidepressant medications. In a study of 274 consecutive patients on antidepressants as compared with 69 controls, those taking selective serotonin reuptake inhibitors (SSRIs) or venlafaxine had an odds ratio greater than 5 for a PLM index greater than 20, and bupropion was similar to controls.104 Tricyclic antidepressants and lithium are also associated with a greater prevalence of nocturnal movement disorders. Caffeine, antihistamines, alcohol, and withdrawal from benzodiazepine can all worsen RLS. Antipsychotic therapies are associated with greater prevalence of PLMS. Opiate analgesics, especially sustained-release or long halflife formulations, may be associated with increased central apneas, sustained hypoxemia, and prolonged duration of abnormal breathing events.105 These changes occur in the context of the well-established acute respiratory depressant effects. Hypnotics such as benzodiazepines can also worsen sleep-disordered breathing by affecting the arousal threshold.
1530 PART II / Section 17 • Sleep Medicine in the Elderly
Medications That Affect Sleep Architecture via Other Mechanisms Certain medications can directly affect the sleep architecture. Beta-blockers are often prescribed in older adults who have hypertension and heart disease. Lipophilic agents such as propanolol and some of the newer-generation beta-blockers have been shown to suppress melatonin, increase sleep fragmentation, and increase nightmares in some people.106 Other agents, such lithium, benzodiazepine receptor agonists, and gamma-hydroxybutyrate, and withdrawal from benzodiazepines are associated with a worsening of disorders of non-REM (NREM) parasomnias. Tricyclic antidepressants, monoamine oxidase inhibitors, venlafaxine, and mirtazapine have all been documented to induce REM sleep behavior disorder, a parasomnia very specific to older adults. Reported effects of donepezil include an increase in REM sleep and a decrease in slow frequencies in REM sleep, decrease in stage 1, and increase in stage 2.107 An increase in REM sleep density, decrease in REM sleep latency, and nightmares have been reported in healthy elderly volunteers.108 Changes observed with galantamine in healthy volunteers include a decrease in REM sleep latency, increase in REM sleep density, and a decrease in slow-wave sleep.109
SUBSTANCE ABUSE IN OLDER ADULTS Community rates of alcohol dependence in the geriatric population are 2% to 3% of men and 1% of women.110 In elderly clinical cohorts, rates are higher (4% to 23%), likely due to the increased comorbid medical disorders that accompany alcohol dependence.111 Many elderly alcoholics are dependent on nicotine (50% to 70%) and some are dependent on prescribed sedatives, anxiolytics, and opioid analgesics (2% to 14%).111 Alcoholics older than 55 years have higher sleep latency, lower sleep efficiency, and lower delta sleep when compared to younger alcoholics and to nonalcoholics of both age groups.112 In abstinent male alcoholics, 75% older than 60 years have sleep-disordered breathing compared with 25% for the age group of 40 to 59 years and 3% for those younger than 40 years.113 Consumption of caffeine is common in the elderly and can contribute to sleep disruption. Because of the greater ratio of adipose tissue to lean body mass in elderly persons, a dose of caffeine expressed as milligrams per kilogram of total body weight can result in higher plasma and tissue concentrations in elderly than in younger persons. Age and plasma caffeine concentrations significantly predict poorer-quality sleep.114 Changes related to caffeine intake include decreased total sleep time, increase in sleep-onset latency, and increased number of awakenings. Adults older than 67 years who are taking caffeine-containing medications report significantly more trouble falling asleep, after controlling for multiple factors.115 Hospital-dwelling elderly patients with a higher serum caffeine concentration reported sleep problems more than those with lower levels.114 Nearly 11% of the population age 65 years and older smokes.116 Elderly smokers endorse more difficulties with sleep onset and staying asleep than nonsmokers. In all age
groups, smokers drink more caffeine and are more likely to be depressed.117 When offered the tools they need, older smokers quit smoking at rates comparable to those of younger smokers.
SPECIAL CONDITIONS Caregiving Up to two thirds of older adult caregivers have some form of sleep disturbance.118 Predisposing factors for changes in the sleep of a caregiver include increasing age, female gender, and caregiver burden.119 Caregiver burden encompasses the spectrum of physical, psychological or emotional, social, and financial problems experienced by the care provider. The caregiver’s situation is analogous to that of a rotating shift worker who must be alert both at night and during the day, often on an inconsistent schedule.118 The combination of depression and high-stress situations (e.g., caring for a spouse or a person with dementia or living with the care recipient) increased the likelihood of sleep problems.120 In addition, by virtue of their age, older caregivers are at risk for developing many of the chronic illnesses that can directly affect sleep, as described in previous chapters. Sleep problems in a caregiver may be precipitated by changes in the nighttime routines of the person for whom they are caring, including agitation, sundowning, wandering, or sleep-disordered breathing. In the case of the vulnerable caregiver, it can be very difficult to fall back asleep after being awakened by a care recipient who needs assistance with toileting, administration of medication, redirection back into bed, orientation, or emotional reassurance, particularly when these nocturnal interactions are prolonged or emotionally charged. Inadequate sleep hygiene can become a perpetuating cause for caregiver-disrupted sleep patterns, as part of an ineffectual attempt to compensate for having their nightly rest disturbed. Caregivers might increase daytime napping, drink coffee or alcohol, or spend longer hours in bed. The decay of available time and opportunity for recreation and social contact can further contribute to the overall deterioration of their sleep–wake routines. In addition, grief and bereavement may be important perpetuating factors in caregivers who continue to have significant ongoing sleep complaints after the death or institutionalization of their loved ones. Caregivers or a spouse of a person with dementia or disability carry an increased risk for sleep problems. In a study of community-dwelling spousal caregivers of patients with Alzheimer’s disease, caregivers objectively slept less than older noncaregivers, and they subjectively reported more sleep problems and functional impairment as a result of poor sleep.121a In a subsequent study, after controlling for a number of cardiovascular risk factors (age, sex, blood pressure, body mass index), increased wake after sleep onset was associated with norepinephrine levels and plasma D-dimer.121a There are also situational needs that the caregiver must respond to, such as nocturnal wandering in a demented spouse. This situation puts the caregiver at risk for long- term partial sleep deprivation that might partially explain why one of the strongest factors in deciding to
institutionalize a spouse or family member with dementia is poor overnight sleep of the affected caregiver.122 Sleep in Hospitalized Older Adults Hospitalization for acute illness is a major risk factor for sleep disturbances in the elderly population. Older adults account for 37% of all discharges and 47% of all inpatient days of care. Overall, older patients report poorer sleep quality, and surgery patients report more sleep disturbances on the first night of hospitalization as compared with medical patients.123 Actigraphic data of first 3 nights in the hospital reported low total sleep times (3 to 4 hours per night) and sleep efficiencies of 39% to 47%, which deteriorated by the third night, as well as 13 to 26 awakenings per night. The average sleep onset occurred nearly 2 hours after bedtime, and the longest uninterrupted sleep interval was just over 2 hours.124 Familiar environmental conditions are modified by acute illness and hospital environment. Medical care is the priority and acts as a powerful zeitgeber.124 Additional factors influencing sleep include type of bedding and light and temperature during the night. Excessive light (>10 lux) is recurrent and can reach an exposure level of 1.5 hours per night. Levels of sound in the hospital rooms were consistently elevated: Median nocturnal sound level was 53 dB and peak sound levels were as high as 110 dB.124 Social routines such as mealtimes and physical activity change according to ward routines, which could be quite dramatically different from home routines and have a dramatic effect on sleep. Anxiety is perhaps the main psychological factor that affects a patient’s sleep in the hospital. Patients describe the ward environment as a “public, complicated, and noisy place” and experience a “lack of peace, comfort, privacy and space.”124a A sense of helplessness can emerge from little ability to control ward routines, daytime inactivity, and unfulfilled requests. Sleep in patients in the intensive care unit (ICU) is characterized by prolonged sleep latencies, sleep fragmentation, predominance of stages 1 and 2 NREM sleep, decreased or absent slow-wave sleep, and decreased or absent REM sleep. Mechanically ventilated patients have highly fragmented sleep, in addition to the effects on sleep from commonly used medications for sedation, such as benzodiazepines and opiates. Major contributing factors in the ICU population are type and severity of underlying illness, the pathophysiology of acute illness or injury, and pain from surgical procedures. Environmental factors contributing to sleep disruption in the ICU include lack of diurnal cues (lighting practices, excessive noise), patient care activities (vital sign measurements, therapeutic interventions, mechanical ventilation), diagnostic procedures (lab draws, radiographs), and medications (sedatives, analgesics).125 The rest–activity rhythms are severely altered in the initial period of acute illness and are progressively restored following clinical improvement.124 Older adults experience significant problems with sleep during hospitalization due to powerful disruptors. Sleep is characterized by delayed onset, decreased total sleep, decreased sleep efficiency, decreased length of sleep periods, and frequent, prolonged periods of wakefulness.
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Palliative Care Patients who are terminally ill often have disrupted sleep, more commonly as a complication of the primary condition, often with multiple etiologies. In a sample of 74 patients (41 women, 33 men), mean age 69 years, 52 (70%) endorsed sleep difficulties.126 Seventy-five percent of these developed insomnia after their condition was diagnosed. Lack of symptom control was the most prevalent cause for insomnia symptoms and was cited by 60% of patients. Pain alone or in combination with another symptom was the most prevalent (48% of patients), followed by urinary frequency and dyspnea. Certain drugs, such as steroids, stimulant antidepressants, bronchodilators, and diuretics, were associated with insomnia in 13% of cases. Fifty percent of patients had “sleep disturbing thoughts” (related to family, diagnosis, and future). Another study of 102 patients (56 women, 46 men, mean age of 63 years) with stage IV cancer reported that poor quality of sleep as assessed by the Pittsburgh Sleep Quality Index (PSQI) correlated to poor quality of life and pain.127 Other conditions leading to disrupted sleep are depression (prevalence up to near 60% in terminal illness cohorts), delirium, respiratory distress, gastrointestinal symptoms, medications, and hospitalization.128 Geriatric Syndromes Falls and gait problems are a common and serious problem facing older adults. About one third of those aged 65 years and older living in the community fall at least once a year. This increases to one in two for those aged 80 years and older.129 Falls are typically the result of multiple interacting etiologies. Older persons who have insomnia and are taking hypnotics have a higher risk for falls, due in part to the adverse effects of benzodiazepines and other hypnotics on balance, cognition, and reaction time; withdrawal of these agents reduces the risk for future falls.130 Evidence highlights that it may be the underlying insomnia with its neurocognitive consequences that predisposes an older person to falls, as in a large nursing home sample.131 In a prospective study of 2978 primarily community-dwelling women 70 years and older, short nighttime sleep duration (5 hours or less per night) and increased sleep fragmentation were associated with increased risk for falls in older women, independent of benzodiazepine use and other risk factors for falls.132 Delirium is a serious acute neuropsychiatric syndrome with core features of inattention and cognitive impairment. Associated features include changes in arousal, altered sleep–wake cycle, and fluctuating changes in mental status. Delirium is common in critically ill and palliative care patients and likely encompasses adverse effects of stressresponses pathways, induced by aberrations in the normally adaptive systemic and central nervous system responses to stressors. Sleep disturbances appear to have a bidirectional relationship with delirium and are part of many delirium assessment instruments, such as the Intensive Care Delirium Screening Checklist. Sleep disturbances are defined as “sleeping less than 4 hours or waking frequently at night, sleeping during most of the day.”133 Sleep–wake cycle disturbances occurred in almost 70% of patients with delirium as compared with 12% of patients
1532 PART II / Section 17 • Sleep Medicine in the Elderly
Optimize environment • Limit noise exposure during sleep • Limit light exposure pre- and during sleep • Limit disruption from medical or personal care • Optimize bedroom factors: bed partner, pets, temperature • Remove inappropriate zeitgebers • Adjust sleep/wake cycle requirements
Sleep hygiene/education • Avoid alcohol • Avoid nicotine • Keep consistent schedules • Limit napping • Avoid presleep exercise, heavy meals • Set realistic expectations • Increase daytime exercise, daylight
Control sleep disorders • Sleep-disordered breathing • Restless legs syndrome • Sleep-related movement disorders • REM sleep behavior disorder • Circadian rhythm disorders
Control comorbidities/optimize medication regimen interfering with sleep • Pain • Medical problems • Psychiatric problems • Avoid medications disruptive of sleep–wake status • Identify and address substance use and abuse • Identify and address stress situations: grief, caregiving • Assess and optimize cognitive status
Pharmacotherapy • Benzodiazepines • Nonbenzodiazepines Exercise caution in: • Nonapproved FDA use for hypnotic indications • Risk of falls • Risk of MVA • Cognitive dysfunction
Cognitive behavioral therapy for insomnia (CBT-I) • Stimulus control • Relaxation • Cognitive therapy • Sleep restriction • Paradoxical intention Exercise caution in: • Acute/unstable illness • Frail individuals • Cognitively impaired individuals • Epilepsy • Bipolar illness
Figure 133-2 Interventions to be considered in comorbid insomnia. A multifactorial targeted intervention appears most appropriate based on the model of comorbid insomnia and current evidence. Considering all potential predisposing, precipitating, and perpetuating factors can increase the effectiveness of the therapeutic act while ensuring optimal control. Interventions should be balanced in regard to potential adverse consequences.
without delirium in a series of 600 consecutive patients admitted to the intensive care unit for more than 24 hours134 and were highly discriminating for the diagnosis of delirium.134 Another study of 100 cases of delirium in a palliative care inpatient service reported sleep disturbances in 97% of patients.135 In a study of 13 patients (6 with delirium and 7 without delirium) employing actigraphy, delirious patients showed fewer nighttime minutes resting, fewer minutes resting over 24 hours, greater mean activity at night, and a smaller amplitude of change in activity from day to night. Rest and activity consolidation were significantly reduced in delirious patients, as was the amplitude of day and night differences in rest and activity.136
SUMMARY As the field of medicine continues to advance, people are living longer with more comorbid medical and psychiatric conditions. This higher burden of illness and the numbers of medications used to treat these conditions plays an important role in the quality and quantity of sleep in older adults. In approaching sleep complaints in geriatric patients, it is essential that practitioners recognize the multidimensional mechanisms by which illness affects sleep. Equally important, a balanced management approach (Fig. 133-2) that includes optimizing the underlying illness, adjusting medications, using cognitive behavior approaches, and using judicious hypnotic therapy seems justified based on the current evidence.
❖ Clinical Pearls Etiology of the sleep complaint(s) is often multifactorial, with contributions from chronic health issues as well as the associated changes in a person’s lifestyle, sleep hygiene, and medication regimens that occur secondary to the medical or psychiatric illness. These health problems rarely exist in isolation and instead often coexist with psychiatric diagnoses, neurologic diseases, and primary sleep pathology. A multifaceted management approach is in order in the case of comorbid insomnia. This includes optimizing the treatment of the underlying illness and the environment, adjusting potentially offending medications, using cognitive behavior approaches, and employing judicious hypnotic therapy based on current evidence. Older adults in special situations (caregiving, hospitalization, institutionalization, end of life, abstinence after alcohol dependence) are a particularly vulnerable population with a high incidence of sleep disturbances, and a heightened awareness and recognition of these situations is necessary. Many drugs can alter patterns of sleep and wakefulness during periods of administration and during periods of withdrawal. It is especially important to avoid using hypnotics or stimulants to treat sleeprelated side effects of other medications unless all other attempts at medication adjustment have been considered.
CHAPTER 133 • Medical and Psychiatric Disorders 1533
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1534 PART II / Section 17 • Sleep Medicine in the Elderly 50. Jordan JM, Bernard SL, Callahan LF, Kincade JE, et al. Selfreported arthritis-related disruptions in sleep and daily life and the use of medical, complementary, and self-care strategies for arthritis: the National Survey of Self-Care and Aging. Arch Fam Med 2000;9:143-149. 51. Rybarczyk B, Stepanski E, Fogg L, Lopez M, et al. A placebocontrolled test of cognitive-behavioral therapy for comorbid insomnia in older adults. J Consult Clin Psychol 2005;73:1164-1174. 52. Bretagne JF, Richard-Molard B, Honnorat C, Caekaert A, et al. [Gastroesophageal reflux in the French general population: national survey of 8000 adults]. Presse Med 2006;35:23-31. 53. Farup C, Kleinman L, Sloan S, Ganoczy D, et al. The impact of nocturnal symptoms associated with gastroesophageal reflux disease on health-related quality of life. Arch Intern Med 2001;161:45-52. 54. Penzel T, Becker HF, Brandenburg U, Labunski T, et al. Arousal in patients with gastro-oesophageal reflux and sleep apnoea. Eur Respir J 1999;14:1266-1270. 55. Orr WC. Sleep and gastroesophageal reflux disease: a wake-up call. Rev Gastroenterol Disord 2004;4(Suppl. 4):S25-S32. 56. Johnson DA, Orr WC, Crawley JA, Traxler B, et al. Effect of esomeprazole on nighttime heartburn and sleep quality in patients with GERD: a randomized, placebo-controlled trial. Am J Gastroenterol 2005;100:1914-1922. 57. Peters RW, Zoble RG, Brooks MM. Onset of acute myocardial infarction during sleep. Clin Cardiol 2002;25:237-241. 58. Chocron S, Tatou E, Schjoth B, Naja G, et al. Perceived health status in patients over 70 before and after open-heart operations. Age Ageing 2000;29:329-334. 59. Brostrom A, Stromberg A, Dahlstrom U, Fridlund B, et al. Sleep difficulties, daytime sleepiness, and health-related quality of life in patients with chronic heart failure. J Cardiovasc Nurs 2004;19: 234-242. 60. Lesman-Leegte I, Jaarsma T, Sanderman R, Linssen G, et al. Depressive symptoms are prominent among elderly hospitalised heart failure patients. Eur J Heart Fail 2006;8:634-640. 61. Ingbir M, Freimark D, Adler Y. [Cheyne-Stokes breathing disorder in patients with congestive heart failure: incidence, pathophysiology, treatment and prognosis]. Harefuah 2001;140:1209-1212, 1227. 62. Lanfranchi PA, Braghiroli A, Bosimini E, Mazzuero G, et al. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation 1999;99:1435-1440. 63. Sin DD, Fitzgerald F, Parker JD, Newton G, et al. Risk factors for central and obstructive sleep apnea in 450 men and women with congestive heart failure. Am J Respir Crit Care Med 1999;160: 1101-1106. 64. Klink M, Quan SF. Prevalence of reported sleep disturbances in a general adult population and their relationship to obstructive airways diseases. Chest 1987;91:540-546. 65. Fleetham J, West P, Mezon B, Conway W, et al. Sleep, arousals, and oxygen desaturation in chronic obstructive pulmonary disease. The effect of oxygen therapy. Am Rev Respir Dis 1982;126: 429-433. 66. Martin RJ, Bartelson BL, Smith P, Hudgel DW, et al. Effect of ipratropium bromide treatment on oxygen saturation and sleep quality in COPD. Chest 1999;115:1338-1345. 67. Krachman SL, Chatila W, Martin UJ, Hugent T, et al. Effects of lung volume reduction surgery on sleep quality and nocturnal gas exchange in patients with severe emphysema. Chest 2005;128: 3221-3228. 68. O’Brien A, Whitman K. Lack of benefit of continuous positive airway pressure on lung function in patients with overlap syndrome. Lung 2005;183:389-404. 69. Krouse HJ, Krouse JH. Diurnal variability of lung function and its association with sleep among patients with asthma. J Asthma 2007;44:759-763. 70. Lamond N, Tiggemann M, Dawson D. Factors predicting sleep disruption in type II diabetes. Sleep 2000;23:415-416. 71. Sridhar GR, Madhu K. Prevalence of sleep disturbances in diabetes mellitus. Diabetes Res Clin Pract 1994;23:183-186. 72. Resnick HE, Redline S, Shahar E, Gilpin A, et al. Diabetes and sleep disturbances: findings from the Sleep Heart Health Study. Diabetes Care 2003;26:702-709. 73. Rijsman RM, de Weerd AW. Secondary periodic limb movement disorder and restless legs syndrome. Sleep Med Rev 1999;3: 147-158.
74. Purdie DW, Empson JA, Crichton C, Macdonald L, et al. Hormone replacement therapy, sleep quality and psychological wellbeing. Br J Obstet Gynaecol 1995;102:735-739. 75. Milsom I, Abrams P, Cardozo L, Roberts RG, et al. How widespread are the symptoms of an overactive bladder and how are they managed? A population-based prevalence study. BJU Int 2001; 87:760-766. 76. Donahue JL, Lowenthal DT. Nocturnal polyuria in the elderly person. Am J Med Sci 1997;314:232-238. 77. Bliwise DL, Foley DJ, Vitiello MV, Ansari FP, et al. Nocturia and disturbed sleep in the elderly. Sleep Med 2009;10:540-548. 78. Bing MH, Moller LA, Jennum P, Mortensen S, et al. Nocturia and associated morbidity in a Danish population of men and women aged 60-80 years. BJU Int 2008;102:808-814. 79. Asplund R, Aberg H. Diurnal variation in the levels of antidiuretic hormone in the elderly. J Intern Med 1991;229:131-134. 80. Chang CH, Gonzalez CM, Lau DT, Sier HC, et al. Urinary incontinence and self-reported health among the U.S. Medicare managed care beneficiaries. J Aging Health 2008;20:405-419. 81. Bliwise DL, Adelman CL, Ouslander JG. Polysomnographic correlates of spontaneous nocturnal wetness episodes in incontinent geriatric patients. Sleep 2004;27:153-157. 82. Ouslander JG, Buxton WG, Al-Samarrai NR, Cruise PA, et al. Nighttime urinary incontinence and sleep disruption among nursing home residents. J Am Geriatr Soc 1998;46:463-466. 83. Stolzmann KL, Camponeschi JL, Remington PL. The increasing incidence of end-stage renal disease in Wisconsin from 1982-2003: an analysis by age, race, and primary diagnosis. WMJ 2005;104: 66-71. 84. Sabbatini M, Minale B, Crispo A, Pisani A, et al. Insomnia in maintenance haemodialysis patients. Nephrol Dial Transplant 2002; 17:852-856. 85. Parker KP, Bliwise DL, Bailey JL, Rye DB, et al. Polysomnographic measures of nocturnal sleep in patients on chronic, intermittent daytime haemodialysis vs those with chronic kidney disease. Nephrol Dial Transplant 2005;20:1422-1428. 86. Williams SW, Tell GS, Zheng B, Shumaker S, et al. Correlates of sleep behavior among hemodialysis patients. The Kidney Outcomes Prediction and Evaluation (KOPE) study. Am J Nephrol 2002; 22:18-28. 87. Parker KP. Sleep disturbances in dialysis patients. Sleep Med Rev 2003;7:131-143. 88. Hanly PJ, Pierratos A. Improvement of sleep apnea in patients with chronic renal failure who undergo nocturnal hemodialysis. N Engl J Med 2001;344:102-107. 89. Benz RL, Pressman MR, Hovick ET, Petcrson DD, et al. A preliminary study of the effects of correction of anemia with recombinant human erythropoietin therapy on sleep, sleep disorders, and daytime sleepiness in hemodialysis patients (The SLEEPO study). Am J Kidney Dis 1999;34:1089-1095. 90. Davison SN, Jhangri GS. The impact of chronic pain on depression, sleep, and the desire to withdraw from dialysis in hemodialysis patients. J Pain Symptom Manage 2005;30:465-473. 91. Ries L, Eisner M, Kosary C. SEER cancer statistics review, 19731999. Bethesda, Md: National Cancer Institute; 2002. 92. Davidson JR, Waisberg JL, Brundage MD, MacLean AW, et al. Nonpharmacologic group treatment of insomnia: a preliminary study with cancer survivors. Psychooncology 2001;10:389-397. 93. Savard J, Morin CM. Insomnia in the context of cancer: a review of a neglected problem. J Clin Oncol 2001;19:895-908. 94. Davidson JR, MacLean AW, Brundage MD, Schulze K, et al. Sleep disturbance in cancer patients. Soc Sci Med 2002;54:1309-1321. 95. Kozachik SL, Bandeen-Roche K. Predictors of patterns of pain, fatigue, and insomnia during the first year after a cancer diagnosis in the elderly. Cancer Nurs 2008;31:334-344. 96. Stiefel FC, Kornblith AB, Holland JC. Changes in the prescription patterns of psychotropic drugs for cancer patients during a 10-year period. Cancer 1990;65:1048-1053. 97. Gooneratne NS, Gehrman PR, Nkwuo JE, Bellamy SL, et al. Consequences of comorbid insomnia symptoms and sleep-related breathing disorder in elderly subjects. Arch Intern Med 2006; 166:1732-1738. 98. Pagel JF. Medications and their effects on sleep. Prim Care 2005;32:491-509. 99. Mintzer J, Burns A. Anticholinergic side-effects of drugs in elderly people. J R Soc Med 2000;93:457-462.
100. Diefenbach K, Arold G, Wollny A, Schwantes U, et al. Effects on sleep of anticholinergics used for overactive bladder treatment in healthy volunteers aged > or =50 years. BJU Int 2005;95: 346-349. 101. Nicholson AN, Stone BM. Antihistamines: impaired performance and the tendency to sleep. Eur J Clin Pharmacol 1986;30: 27-32. 102. Larsen JP, Tandberg E. Sleep disorders in patients with Parkinson’s disease: epidemiology and management. CNS Drugs 2001;15: 267-275. 103. Grimsley SR, Jann MW. Paroxetine, sertraline, and fluvoxamine: new selective serotonin reuptake inhibitors. Clin Pharm 1992;11: 930-957. 104. Yang C, White DP, Winkelman JW. Antidepressants and periodic leg movements of sleep. Biol Psychiatry 2005;58:510-514. 105. Wang D, Teichtahl H, Drummer O, Goodman C, et al. Central sleep apnea in stable methadone maintenance treatment patients. Chest 2005;128:1348-1356. 106. Brzezinski A. Melatonin in humans. N Engl J Med 1997;336: 186-195. 107. Moraes Wdos S, Poyares DR, Guilleminault C, et al. The effect of donepezil on sleep and REM sleep EEG in patients with Alzheimer disease: a double-blind placebo-controlled study. Sleep 2006;29: 199-205. 108. Schredl M, Hornung O, Regen F, Albrecht N, et al. The effect of donepezil on sleep in elderly, healthy persons: a double-blind placebo-controlled study. Pharmacopsychiatry 2006;39:205-208. 109. Riemann D, Gann H, Dressing H, Muller WE, et al. Influence of the cholinesterase inhibitor galanthamine hydrobromide on normal sleep. Psychiatry Res 1994;51:253-267. 110. Grant BF. Prevalence and correlates of alcohol use and DSM-IV alcohol dependence in the United States: results of the National Longitudinal Alcohol Epidemiologic Survey. J Stud Alcohol 1997; 58:464-473. 111. Atkinson R. Substance abuse. In: Coffee C, Cummings J, editors. Textbook of geriatric neuropsychiatry. Washington DC: American Psychiatry Press; 2000. p. 367-400. 112. Brower KJ, Aldrich MS, Hall JM. Polysomnographic and subjective sleep predictors of alcoholic relapse. Alcohol Clin Exp Res 1998;22:1864-1871. 113. Aldrich MS, Shipley JE, Tandon R, Kroll PD, et al. Sleep-disordered breathing in alcoholics: association with age. Alcohol Clin Exp Res 1993;17:1179-1183. 114. Curless R, French JM, James OF, Wynne HA, et al. Is caffeine a factor in subjective insomnia of elderly people? Age Ageing 1993;22:41-45. 115. Brown SL, Salive ME, Pahor M, Foley DJ, et al. Occult caffeine as a source of sleep problems in an older population. J Am Geriatr Soc 1995;43:860-864. 116. LaCroix AZ, Lang J, Scherr P, Wallace RB, et al. Smoking and mortality among older men and women in three communities. N Engl J Med 1991;324:1619-1625. 117. Phillips BA, Danner FJ. Cigarette smoking and sleep disturbance. Arch Intern Med 1995;155:734-737. 118. McCurry SM, Logsdon RG, Teri L, Vitiello MV, et al. Sleep disturbances in caregivers of persons with dementia: contributing factors and treatment implications. Sleep Med Rev 2007;11: 143-153. 119. Happe S, Ludemann P, Berger K. The association between disease severity and sleep-related problems in patients with Parkinson’s disease. Neuropsychobiology 2002;46:90-96.
CHAPTER 133 • Medical and Psychiatric Disorders 1535 120. Kochar J, Fredman L, Stone KL, Cauley JA, et al. Sleep problems in elderly women caregivers depend on the level of depressive symptoms: results of the Caregiver-Study of Osteoporotic Fractures. J Am Geriatr Soc 2007;55:2003-2009. 121. McKibbin CL, Ancoli-Israel S, Dimsdale J, Archulcta C, et al. Sleep in spousal caregivers of people with Alzheimer’s disease. Sleep 2005;28:1245-1250. 121a. Mausbach BT, Ancoli-Israel S, von Kanal R, Patterson TL, et al. Sleep disturbance, norepinephrine, and d-dimer are all related in elderly caregivers of people with Alzheimer’s disease. Sleep 2006; 29:1347-1352. 122. Hope T, Keene J, Gedling K, Fairburn CG, et al. Predictors of institutionalization for people with dementia living at home with a carer. Int J Geriatr Psychiatry 1998;13:682-690. 123. Tranmer JE, Minard J, Fox LA, Rebelo L, et al. The sleep experience of medical and surgical patients. Clin Nurs Res 2003;12: 159-173. 124. Vinzio S, Ruellan A, Perrin AE, Schlienger JL, et al. Actigraphic assessment of the circadian rest–activity rhythm in elderly patients hospitalized in an acute care unit. Psychiatry Clin Neurosci 2003;57:53-58. 124a. Lee CY, Low LP, Twinn S. Older men’s experiences of sleep in the hospital. J Clin Nurs 2007;16:336-343. 125. Friese RS. Sleep and recovery from critical illness and injury: a review of theory, current practice, and future directions. Crit Care Med 2008;36:697-705. 126. Hugel H, Ellershaw JE, Cook L, Skinner J, et al. The prevalence, key causes and management of insomnia in palliative care patients. J Pain Symptom Manage 2004;27:316-321. 127. Mystakidou K, Parpa E, Tsilika E, Pathiaki M, et al. The relationship of subjective sleep quality, pain, and quality of life in advanced cancer patients. Sleep 2007;30:737-742. 128. Hajjar RR. Sleep disturbance in palliative care. Clin Geriatr Med 2008;24:83-91, vii. 129. O’Loughlin JL, Robitaille Y, Boivin JF, Suissa S, et al. Incidence of and risk factors for falls and injurious falls among the communitydwelling elderly. Am J Epidemiol 1993;137:342-354. 130. Campbell AJ, Robertson MC, Gardner MM, Norton RN, et al. Psychotropic medication withdrawal and a home-based exercise program to prevent falls: a randomized, controlled trial. J Am Geriatr Soc 1999;47:850-853. 131. Avidan AY, Fries BE, James ML, Szafara KL, et al. Insomnia and hypnotic use, recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes. J Am Geriatr Soc 2005;53:955-962. 132. Stone KL, Ancoli-Israel S, Blackwell T, Ensrud KE, et al. Actigraphy-measured sleep characteristics and risk of falls in older women. Arch Intern Med 2008;168:1768-1775. 133. Bergeron N, Dubois MJ, Dumont M, Dial S, et al. Intensive Care Delirium Screening Checklist: evaluation of a new screening tool. Intensive Care Med 2001;27:859-864. 134. Marquis F, Ouimet S, Riker R, Cossette M, et al. Individual delirium symptoms: do they matter? Crit Care Med 2007;35: 2533-2537. 135. Meagher DJ, Moran M, Raju B, Gibbons D, et al. Phenomenology of delirium. Assessment of 100 adult cases using standardised measures. Br J Psychiatry 2007;190:135-141. 136. Jacobson SA, Dwyer PC, Machan JT, Carskadon MA, et al. Quantitative analysis of rest–activity patterns in elderly postoperative patients with delirium: support for a theory of pathologic wakefulness. J Clin Sleep Med 2008;4:137-142.
Obstructive Sleep Apnea in the Elderly Barbara A. Phillips
Abstract The prevalence of obstructive sleep apnea increases with age, but the peak prevalence of clinically diagnosed obstructive sleep apnea–hypopnea (OSAH) syndrome is in middle age. Differences in the clinical presentation and manifestations of
More than half of older adults report sleeping difficulty.1-5 Because sleep complaints are so prevalent in older people, clinicians sometimes discount them. However, sleep complaints in the geriatric population correlate with health complaints, depression, and mortality.1-6 This is likely because some sleep symptoms in the elderly result from sleep-disordered breathing, which is both clinically important and treatable. Sleep disorders are thus important in geriatrics.6a-6c Although studies of clinical populations identify peak prevalence of clinically significant sleep-disordered breathing in middle age, population-based studies have shown that sleep-disordered breathing increases with age.7,8 This observation is of particular interest given known decreases in obesity with increasing age.9 One disorder leading both to sleep disturbance and to increased mortality is sleep apnea. Longitudinal and cross-sectional studies have also shown that the prevalence of sleep apnea increases with increasing age.10-14 This chapter focuses on obstructive sleep apnea (OSA) in the older patient. For discussion of central sleep apnea, see Chapters 100, 113, 116, and 122.
EPIDEMIOLOGY AND DEFINITIONS Estimates of the prevalence of OSA in older people depend on how it is defined. For example, there has been considerable variation in the definitions and measurements of respiratory events (such as apneas, hypopneas, and respiratory effort–related arousals [RERAs]) used to identify sleep-disordered breathing. Further, which respiratory events to count toward the threshold used to define sleep apnea has also varied. The apnea–hypopnea index (AHI) typically includes only apneas and hypopneas, but the respiratory disturbance index (RDI) may include other events, such as RERAs. The demarcation between normal and abnormal has also been somewhat fluid. In populationbased studies, about one third of those older than 65 years have AHIs of 5 or more events per hour of sleep,15,16 and about two thirds have RDIs of 10 or more events per hour.16,17 Although measures of sleep-disordered breathing events alone do not establish a diagnosis of OSA, the classically associated symptoms of the disorder (sleepiness, hypertension, cognitive dysfunction) increase in prevalence with aging. Thus, a majority of older persons who meet laboratory-defined criteria for OSA also have a finding that is commonly associated with the syndrome; for this reason, 1536
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obstructive sleep-disordered breathing between older and younger persons likely account for the gap in prevalence and established diagnosis. It is not clear that older adults with OSAH suffer the same consequences as do younger persons. Diagnosis and treatment of OSAH in older patients is similar to that of younger patients.
defining clear-cut criteria for sleep apnea in older persons is difficult. However, the Centers for Medicare and Medicaid Services (CMS), the primary provider of health care coverage for people older than 65 years in the United States, defines OSA as an AHI greater than 15, or an AHI greater than 5 in persons with hypertension, stroke, sleepiness, ischemic heart disease, or mood disorder.18
CLINICAL MANIFESTATIONS AND PRESENTATION Most studies of the clinical presentation and manifestations of OSA have focused on middle-aged subjects. In the older patient with OSA, cognitive impairment is more severe, and erectile dysfunction, cardiac arrhythmias, and heart failure are more common.18a-18d Thus it is becoming increasingly clear that the phenotype of OSA can be quite different between younger and older populations. Perhaps most striking is the change in sex as a risk factor for sleep-disordered breathing in aging. Prospective data from the Wisconsin Sleep Cohort have demonstrated male sex is no longer an important risk factor for OSA after the age of about 50 years,19 confirming work from other studies.8 At least part of the reason for this phenomenon is that the prevalence of OSA rises strikingly for women as they go through menopause, which occurs at about age 50 years.20-23 As a consequence, some investigators have reported a male-to-female ratio of 1 : 1 for older people.19 In addition to the loss of effect of male sex as a risk for OSA with aging, there is reduced importance of obesity as a risk factor. Beginning at about age 60 years, obesity is no longer a statistically significant risk factor for sleep-disordered breathing.19,21 Some data suggest that obesity is a more important risk factor for men than for women, but aging, perhaps specifically achieving menopause, is a more important risk factor for women than for men.19,21,22,24 However, in an 18-year follow-up of 427 communitydwelling elderly persons, Ancoli-Israel and colleagues found that the changes in RDI that occurred were associated only with changes in body mass index (BMI) and were independent of age.25 The authors pointed out that this finding underscores the importance of managing weight for older adults, particularly those with hypertension. Studies of obstructive sleep apnea–hypopnea (OSAH) syndrome in older persons have tended to report milder disease, with lower AHIs, and better-preserved oxygen saturation than that seen in younger adults.10,15,21
CHAPTER 134 • Obstructive Sleep Apnea in the Elderly 1537
In a study of nearly 100 community-dwelling adults aged 62 to 91 years, Endeshaw found that almost one third (equally divided between men and women) had an AHI of 15 or more per hour of sleep and that the traditional risk factors such as snoring, BMI, and neck circumference were not significantly associated with OSAH in this group. Rather, those with an AHI of at least 15 were more likely to report not feeling well rested in the morning, to have higher Epworth sleepiness scores, and to have greater frequency of nocturia.26 This confirms earlier work from the Sleep Heart Health Study, which reported that witnessed apneas are much less often reported in older patients than in younger ones.14 In short, the classic presenting symptoms of OSA are uncommon in older persons, which might account in part for the reduced prevalence of clinical diagnosis of the disorder in this population. Table 134-1 presents an overview of some of the differences in sleep apnea’s presentation and consequences between older and younger patients.
Data specifically focusing on the consequences of OSAH in older persons is scant. Notably, although OSAH increases the risk of death in younger populations, it has not been associated with increased mortality in older groups.29,30 The reasons for this are unknown, but they might include a survivor effect, the generally reduced severity of sleep-disordered breathing in older people, competing causes of mortality, or some combination of these factors. Lavie speculates that the reduced effect of OSAH on mortality in older people is a result of ischemic preconditioning resulting from the nocturnal cycles of hypoxiareoxygenation and points out that in patients with sleep-disordered breathing, there is an association of ischemic preconditioning with increased levels of vascular endothelial growth factor and increased production of reactive oxygen species, heat shock proteins, adenosine, and tumor necrosis factor α (TNF-α).31 However, several manifestations of sleep-disordered breathing appear to be particularly significant in aging populations, including nocturia, cognitive dysfunction, and cardiac disease. OSAH is strongly associated with cardiovascular disease in middle-aged populations, but there is very little evidence about the relationship between sleepdisordered breathing and heart disease in the elderly. The best-proved association and evidence for benefit is with hypertension, and the data are largely derived from middle-aged populations.
PATHOPHYSIOLOGY The pathophysiology of OSA may be different in older persons than in younger persons. Chapter 101 outlines the pathophysiology of OSA in adults. With aging, loss of tissue elasticity can also contribute for airway collapse. For older women, declining levels of sex hormones appear to be partly responsible for increased collapsibility of the posterior oropharynx.27,28 CLINICAL CONSEQUENCES A majority of studies of the consequences of OSAH have been undertaken in clinical samples of middle-aged people.
Nocturia Nocturia is a particularly troublesome symptom of aging, and it appears to be related to the severity of sleepdisordered breathing. Because older persons with significant sleep-disordered breathing might not manifest classic
Table 134-1 Differences between Younger and Older Patients with Obstructive Sleep Apnea–Hypopnea RISK FACTORS
OLDER PATIENTS (>60 yr)
YOUNGER PATIENTS (<60 yr)
Sex
1 : 1
2 : 1 (M : F)
Obesity
Unimportant
Very important
Witnessed apneas
Witnessed apneas rarely reported
Witnessed apneas strongly predictive
Snoring
Infrequently reported
Frequently reported
AHI > 5
30%-40%
9% for women, 24% for men
RDI > 10
62%
10%
Nocturia, impaired cognition, atrial fibrillation
Death, ischemic cardiac disease, hypertension, cerebrovascular disease, depression, metabolic consequences
CPAP pressure
May require lower CPAP pressures
May require higher CPAP pressures
Compliance
No difference in tolerance or adherence
No difference in tolerance or adherence
Demographics
Clinical Features
Prevalence
Consequences Morbidity and mortality
Treatment
AHI, apnea–hypopnea index; CPAP, continuous positive airway pressure; RDI, respiratory disturbance index.
1538 PART II / Section 17 • Sleep Medicine in the Elderly
symptoms of OSAH, the presence of nocturia in the older patient should heighten the clinical suspicion for OSAH. Indeed, nocturnal urination of more than three times per night had a positive and negative predictive values of 0.71 and 0.62 for severe OSA in one study.32 The postulated mechanism of nocturia in OSAH is that the negative intrathoracic pressures resulting from occluded breaths cause distention of the right atrium and ventricle. This right-sided cardiac distention results in release of atrial natriuretic peptide (ANP), which inhibits the secretion of antidiuretic hormone (ADH) and aldosterone and causes diuresis through its effect on glomerular filtration of sodium and water.33 Several studies have demonstrated improvement in nocturia with use of continuous positive airway pressure (CPAP).34-36 CPAP might improve nocturia by allowing the normal nocturnal rise in ADH, resulting in increased resorption of sodium and water from the collecting tubules and production of lower volumes of more-concentrated urine.37 In a retrospective review of 196 patients whose mean age was 49 years, predictors of nocturia included increasing age and diabetes mellitus. Although a complaint of nocturia was equally likely to occur in patients with and without OSAH, frequency of nocturia was significantly related to age, diabetes, and severity of sleep-disordered breathing in patients who had OSAH. Patients with OSAH and nocturia who were treated with CPAP experienced significant reductions in the frequency of nocturnal voiding.38 In a study of 21 women with a mean age of 65 years, the same group of investigators reported that OSAH is present in a majority of women with nocturia and that the presence of diluted nighttime urine in a patient with nocturia is a sensitive marker for OSA.39 Impaired Cognition Impaired cognition, including sleepiness, impaired vigilance, worsened executive function, and dementia, increase in prevalence with aging. Neuropsychological assessment of patients with OSAH demonstrates declines in cognition similar to that of aging. For example, patients with OSAH have sleepiness,40 impaired executive function,41 working memory,42 alertness,43 and attention.44 In general, the association between sleep-disordered breathing and impaired cognition has been best studied in middle-aged persons. Because of the association with aging itself on impaired cognition, the effects, if any, of OSAH on cognitive function in older people are of great importance.18a In a small study of persons older than 55 years who had OSA, Aloia and coworkers found that the degree of sleepdisordered breathing, especially oxygen desaturation, was associated with delayed verbal recall and constructional abilities. After 3 months, those who were compliant with CPAP had greater improvements in attention, psychomotor speed, executive functioning, and nonverbal delayed recall than those who were not compliant.45 Despite the logical notion that cognitive impairment associated with OSAH in older people might be more severe than in younger people because of cumulative effects of age and sleep-disordered breathing, Mathieu’s group were unable to demonstrate any group-by-age interaction for any neuropsychological variable. In a study of
matched older and younger patients with and without OSAH, they found that performance on most tasks deteriorated with advancing age in both controls and OSAH patients without evidence of a compounded effect.46 The mechanism by which sleep-disordered breathing impairs neurocognitive function remains incompletely understood. Some authors have suggested that sleep fragmentation is the primary culprit,47 and others maintain that hypoxemia is the primary cause. It is likely that different functions are affected by hypoxemia than by sleep deprivation, as suggested by Sateia: “Disturbances in general intellectual function and executive function show strongest correlations with measures of hypoxemia. Not unexpectedly, alterations in vigilance, alertness, and, to some extent, memory seem to correlate more with measures of sleep disruption.”48 Information about the effects CPAP treatment on cognition is rare, and data about CPAP’s effects on cognition in older persons is even rarer. In a small group of patients whose mean age was 56 years, CPAP resulted in normalization in attention, visuospatial learning, and motor performances after 15 days, but there was no further improvement after 4 months of treatment. CPAP did not improve performance on tests evaluating executive functions and constructional abilities.49 A meta-analysis of randomized, placebo-controlled, crossover studies of CPAP treatment involving 98 sleep apnea patients demonstrated mostly trends for better performance on CPAP than on placebo.50 In a group of middle-aged subjects with significant OSAH, Zimmerman demonstrated that memory normalized for the group that used CPAP at least 6 hours a night,51 but it did not improve in those who were not adherent to CPAP treatment. In a review of CPAP adherence and benefits for older patients, Weaver and Chasens noted that in general, older adults have increased alertness; improved neurobehavioral outcomes in cognition, memory, and executive function; and decreased sleep disruption.52 They also noted that older patients might require lower CPAP pressures than younger ones, and they tolerate CPAP well, with similar rates of adherence. Thus, although there are differences in the clinical presentation and impact of sleep apnea in the elderly, CPAP treatment is likely to be well tolerated and beneficial in symptomatic patients.53,54 A final concern about cognitive dysfunction and sleepdisordered breathing is that there are likely to be variations in susceptibility. Alchantis and colleagues have proposed that high intelligence can protect against cognitive decline caused by sleep-disordered breathing, perhaps due to increased cognitive reserve.55 One large study reported that severity of SDB was not associated with indices of sleep-related symptoms or sleeprelated quality of life in community-dwelling older women, suggesting that this group may be resistant to OSAH’s adverse effects on cognition.56 Given the facts that improvement in cognition likely depends on CPAP adherence, that there may be gender and intelligence influences on susceptibility to impaired cognition, and that most studies addressing this issue have not included geriatric OSAH patients and objectively measured adherence, firm conclusions about the reversibility
CHAPTER 134 • Obstructive Sleep Apnea in the Elderly 1539
of cognitive deficits in older OSAH patients are impossible to draw at present. With regard specifically to Alzheimer’s disease, the prevalence of OSAH in patients with is higher than in nondemented seniors, and sleep-disordered breathing is believed to contribute to cognitive dysfunction in those with Alzheimer’s disease. A randomized, double-blind, placebo-controlled crossover trial of CPAP in patients with OSA and Alzheimer’s disease demonstrated a significant improvement in cognition following 3 weeks of CPAP.57 In addition to improving cognition, CPAP treatment can improve sleepiness in Alzheimer’s disease patients with OSAH.58
colleagues found that OSA was a risk factor for stroke, controlling for other important variables.71 Treatment did not affect the risk of either stroke or death in this study.
Cardiovascular Disease Sleep-disordered breathing is strongly linked to cardiovascular disease including hypertension, congestive heart failure, stroke, cardiac arrhythmias, ischemic events, and pulmonary artery hypertension.59 Very few studies of the relationship between OSAH and cardiovascular disease are prospective and control for confounding variables such as obesity. Even fewer have been conducted in older adults. However, hypertension, atrial fibrillation, and stroke are particularly relevant comorbidities of OSAH in older patients because of their prevalence and clinical importance in that population. The evidence that sleep-disordered breathing causes hypertension has been established by several studies, including prospective and CPAP sham-controlled trials.6067 In general, CPAP has modest effects on blood pressure in patients with OSAH, but it is most effective in those who have significant hypertension and are most adherent with its use.60,67 Atrial fibrillation is strongly both with aging and with OSA.59,68,68a The Sleep Heart Health Study investigators found that those with severe sleep-disordered breathing had double or quadruple the risk of complex cardiac arrhythmias that those with no sleep-disordered breathing had, controlling for multiple relevant confounders.68 In this study, atrial fibrillation was the arrhythmia most strongly associated with sleep-disordered breathing. Gami and coworkers reported that both obesity and nocturnal oxygen desaturation were independent predictors of incident atrial fibrillation, but only in subjects younger than 65 years.69 In a small, retrospective study of patients with atrial fibrillation, some of whom had treated sleep apnea and some of whom did not, the patients with untreated OSAH had a higher recurrence of atrial fibrillation after cardioversion than did the patients without sleep apnea.70 Treatment with CPAP in the sleep apnea patients was associated with lower recurrence of atrial fibrillation at 1 year of follow-up. This study is particularly relevant to older patients because the mean age of the study population was about 66 years. At present, however, sleep apnea cannot be definitively stated to be a cause of atrial fibrillation. Stroke The prevalence of stroke increases with age. In a 6-year follow-up study of more than a thousand patients whose mean age at enrollment was about 60 years, Yaggi and
Other Effects In middle-aged men, OSAH is associated with increased health care costs, which decrease following treatment.72 CPAP treatment is a cost-effective treatment for severe sleep apnea in middle-aged people.73 Among sleep apnea patients, expenditures for health care in older people are about twice as high as they are for middle-aged patients. After adjusting for age, BMI, and AHI, cardiovascular disease and use of psychoactive drugs were important determinants of health care costs for older sleep apnea patients in one study.74 OSA may mask anemia of aging.74a Sex likely influences the effects of sleep-disordered breathing in older people, just as it does for younger persons. For example, a significant relationship between SDB and hypertension, history of diabetes, and low HDL cholesterol has been reported in women older than 65 years, but these effects were not demonstrable in older men.75
TREATMENT Continuous Positive Airway Pressure As with younger adults, CPAP is the treatment of choice in the older patients. Because most studies of effects of CPAP have been done in clinical (e.g., middle-aged) populations, evidence of the benefits of CPAP for older persons is not robust. Complex sleep apnea appears to be more prevalent in older than in younger people. Complex sleep apnea is characterized as OSA in which central apneas and periodic breathing develop when CPAP is applied.76,77 This phenomenon appears to be more prevalent in older men with congestive heart failure, and its clinical significance is unclear. In many patients, these treatment-emergent central apneas simply resolve over time. In a convenience sample of a variety of sleep-disordered breathing syndromes resistant to CPAP, the mean age of 72 years was much higher than typically observed in clinical populations of sleep apnea patients. In that cohort, adaptive servoventilation (ASV) appeared to be effective and well tolerated in about half.78 Because complex or treatment-emergent central apnea appears to be more prevalent in older persons, formal, in-laboratory titrations may be more important for this group. Compliance with CPAP in older patients may be affected by factors such as cognitive impairment, medical and mood disturbances, nocturia, lack of a supportive partner, and impaired manual dexterity. However, older age per se does not affect adherence to CPAP treatment,52,79 and behavioral interventions can improve CPAP adherence in the elderly.80 The major predictors of CPAP nonadherence in older sleep apnea patients are nocturia, current cigarette smoking, lack of resolution of symptoms, and advanced age at the time of diagnosis.81 Older men with nocturia can find CPAP particularly confining, and they may be particularly likely to have
1540 PART II / Section 17 • Sleep Medicine in the Elderly
difficulty with its use, although CPAP can actually improve nocturia.79 Patients with OSA who have dementia, even including Alzheimer’s disease, have been demonstrated to tolerate CPAP, although depressive symptoms appear to predict worsened adherence in demented seniors with sleep apnea.82 Oral Appliances Oral appliances are effective in treating snoring and mild to moderate OSA.83-86 Although they are not as effective as CPAP, these agents improve sleep-disordered breathing, sleepiness, nocturnal oxygen saturation, and blood pressure. There are two basic types of oral appliances: mandibular repositioners and tongue-retaining devices. Mandibular repositioners pull the mandible (and with it, the tongue) forward. Tongue-retaining devices adhere to the tongue by suction and pull it forward. Because these are not approved by the FDA for treating sleep apnea, they are used much less commonly in clinical practice. See Chapter 109 for a detailed discussion of the use of oral appliances. No studies address the use of these devices specifically in older persons. Common side effects of oral appliances include dry mouth, increased salivation, tooth soreness, and jaw muscle or jaw joint discomfort. Pain is occasionally severe enough that patients discontinue the use of the appliance.86 Bite changes, (e.g., the inability to close on the back teeth) combined with heavy contact of the front teeth upon removal of the appliance in the morning are also reported, but these changes generally resolve when the device is removed. Oral appliances can be made to fit over false teeth, although this is not optimum. The use of oral appliances in edentulous patients may be attempted with a tongueretaining device, but these devices are not FDA approved, and the efficacy of this approach is unknown. Surgery As with younger adults, surgery is not a particularly effective treatment for OSA in older patients, and it can carry an especially increased morbidity in the elderly.87 Pharmacologic Treatment Several medications have been applied to the treatment of SDB. In general, no drug is effective enough to recommend as first-line treatment. Antidepressants, nasal steroids, hormone replacement therapy (HRT), and modafinil have all been studied in younger patients. In the 1980s, protriptyline was demonstrated to show modest efficacy in treating apnea, probably because it reduces REM sleep, when apnea is worst.88 There is some early experimental work with the selective serotonin reuptake inhibitors (SSRIs) in the treatment of sleep apnea, but results have not been promising in humans.89 SSRIs can suppress REM sleep, but not as much as the tricyclic antidepressants. Nasal steroids have been demonstrated to have modest efficacy in the treatment of sleep-disordered breathing.90 In the Sleep Heart Health Study, women who were on HRT were less likely to have sleep apnea, but overall lifestyle and health care are significant confounders in drawing
conclusions about the efficacy of HRT for OSA.91 Although estrogen is an option to consider, it would need to be discussed carefully with the patient because of recognized complications of HRT. Modafinil has been evaluated as an adjunct to CPAP in patients who remain sleepy while being treated with CPAP.92,93 This application is limited to those who are actually using and compliant with CPAP. Body Position The supine sleeping position predisposes to airway collapse and to reduced lung volume, and it has long been known to exacerbate OSA. Indeed, some patients have obstructive events exclusively when sleeping on their backs.94,95 Upper airway size decreases with increasing age in both men and women, and upper airway collapsibility while supine increases with aging.96 In my experience, position-related obstructive apnea is prevalent in older persons. Position therapy has not been well studied for any group of patients, but it shows promise as treatment for the older patient with mild disease.93,97
DRIVING AND THE OLDER PATIENT WITH OSAH Untreated OSAH is a well-established risk for crash in drivers (see Chapter 104) and might be expected to affect older drivers as well. In a review of conditions increasing crash risk in older drivers, Marshall found that several conditions were believed to be associated with increased risk of crash in older persons, including alcohol abuse and dependence, cardiovascular disease, cerebrovascular disease, depression, dementia, diabetes mellitus, epilepsy, use of certain medications, musculoskeletal disorders, schizophrenia, vision disorders, and, finally, OSA. He noted that these “conditions can serve as potential warnings for reduced fitness to drive, but many persons with these medical conditions would still be considered safe to continue driving.”98 SUMMARY Sleep-disordered breathing increases in prevalence with aging, but it can confer a lower risk of mortality. However, the morbidity and impact of SDB in the older patient is significant, and it clearly responds to treatment in adherent patients. Consideration and treatment of sleep apnea in the older population can improve health and quality of life.
❖ Clinical Pearl Older people with OSA present differently than their middle-aged counterparts, and thus their sleep apnea may be overlooked by clinicians. Female gender and obesity are less important risk factors in older people than they are in younger people. Symptoms of sleep apnea change with aging: Whereas the classic symptoms of OSA are witnessed apneas and sleepiness, older patients are more likely to present with nocturia and cognitive dysfunction.
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CHAPTER 134 • Obstructive Sleep Apnea in the Elderly 1541 18d. Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation 2010;122:352360. 19. Tishler PV, Larkin EK, Schluchter MD, et al. Incidence of sleepdisordered breathing in an urban adult population. JAMA 2003; 289:2230-2237. 20. Young T, Finn L, Austin D, et al. Menopausal status and sleep-disordered breathing in the Wisconsin sleep cohort study. Am J Respir Crit Care Med 2003;167:1181-1185. 21. Bixler EO, Vgontzas AN, Lin HM, et al. Prevalence of sleep-disordered breathing in women: effects of gender. Am J Respir Crit Care Med 2001;163(3 Pt. 1):608-613. 22. Dancey DR, Hanly PJ, Soong C, et al. Impact of menopause on the prevalence and severity of sleep apnea. Chest 2001;120:151-155. 23. Resta O, Bonfitto P, Sabato R, et al. Prevalence of obstructive sleep apnoea in a sample of obese women: effect of menopause. Diabetes Nutr Metab 2004;17:296-303. 24. Kirkness JP, Schwartz AR, Schneider H, et al. Contribution of male sex, age, and obesity to mechanical instability of the upper airway during sleep. J Appl Physiol 2008;104:1618-1624. 25. Ancoli-Israel S, Gehrman P, Kripke DF, et al. Long-term follow-up of sleep disordered breathing in older adults. Sleep Med 2001;2: 511-516. 26. Endeshaw Y. Clinical characteristics of obstructive sleep apnea in community-dwelling older adults. J Am Geriatr Soc 2006;54: 1740-1744. 27. Popovic RM, White DP. Upper airway muscle activity in normal women: influence of hormonal status. J Appl Physiol 1998;84: 1055-1062. 28. Malhotra A, Huang Y, Fogel R, et al. Aging influences on pharyngeal anatomy and physiology: the predisposition to pharyngeal collapse. Am J Med 2006;119:72.e9-e14. 29. He J, Kryger MH, Zorick FJ, et al. Mortality and apnea index in obstructive sleep apnea. Experience in 385 male patients. Chest 1988;94:9-14. 30. Lavie P, Lavie L, Herer P. All-cause mortality in males with sleep apnoea syndrome: declining mortality rates with age. Eur Respir J 2005;25:514-520. 31. Lavie L, Lavie P. Ischemic preconditioning as a possible explanation for the age decline relative mortality in sleep apnea. Med Hypotheses 2006;66:1069-1073. 32. Kaynak H, Kaynak D, Oztura I. Does frequency of nocturnal urination reflect the severity of sleep-disordered breathing? J Sleep Res 2004;13:173-176. 33. Umlauf M, Chasens E, Greevy R. et al. Obstructive sleep apnea, nocturia and polyuria in older adults. Sleep 2004;27:139144. 34. Kiely L, Murphy M, McNicholas WT. Subjective efficacy of nasal CPAP therapy in obstructive sleep apnoea syndrome: a prospective controlled study. Eur Respir J 1999;13:1086-1090. 35. Kramer NR, Bonitati AE, Millman RP. Enuresis and obstructive sleep apnea in adults. Chest 1998;114:634-637. 36. Guilleminault C, Lin C, Goncalves M, Ramos E. A prospective study of nocturia and the quality of life in elderly patients with obstructive sleep apnea or sleep onset insomnia. J Psychosomat Res 2004; 56:511-515. 37. Asplund R, Aberg H. Diurnal variation in the levels of antidiuretic hormone in the elderly. J Intern Med 1991;229:131-134. 38. Fitzgerald MP, Mulligan M, Parthasarathy S. Nocturic frequency is related to severity of obstructive sleep apnea, improves with continuous positive airways treatment. Am J Obstet Gynecol 2006;194: 1399-1403. 39. Lowenstein L, Kenton K, Brubaker L, et al. The relationship between obstructive sleep apnea, nocturia, and daytime overactive bladder syndrome in women. Am J Obstet Gynecol 2008;198:598; e1-e5. 40. Guilleminault C, Partinen M, Quera-Salva MA, et al. Determinants of daytime sleepiness in obstructive sleep apnea. Chest 1988;24: 32-37. 41. Naegele B, Thouvard V, Pepin JL, et al. Deficits of cognitive executive functions in patients with sleep apnea syndrome. Sleep 1995; 18:43-52. 42. Thomas RJ, Rosen BR, Stern CE, et al. Functional imaging of working memory in obstructive sleep-disordered breathing. J Apply Physiol 2005;98:2226-2234.
1542 PART II / Section 17 • Sleep Medicine in the Elderly 43. Mazza S, Pepin JL, Naegele B, et al. Most obstructive sleep apnea patients exhibit vigilance and attention deficits on an extended battery of tests. Eur Respir J 2005;25:75-80. 44. Verstraten E, Cluydts R. Executive control of attention in sleep apnea patients: theoretical concepts and methodological considerations. Sleep Med Rev 2004;8:257-267. 45. Aloia MS, Ilniczky N, Di Dio P, et al. Neuropsychological changes and treatment compliance in older adults with sleep apnea. J Psychosom Res 2003;54:71-76. 46. Mathieu A, Mazza S, Decary A, et al. Effects of obstructive sleep apnea on cognitive function: a comparison between younger and older OSAS patients. Sleep Med 2008;9:112-120. 47. Verstraeten E, Cluydts R, Pevernagie D, Hoffmann G. Executive function in sleep apnea: controlling for attentional capacity in assessing executive attention. Sleep 2004;27:685-693. 48. Sateia MJ. Neuropsychological impairment and quality of life in obstructive sleep apnea. Clin Chest Med 2003;24:249-259. 49. Ferini-Strambi L, Baietto C, Di Gioia MR, et al. Cognitive dysfunction in patients with obstructive sleep apnea (OSA): partial reversibility after continuous positive airway pressure (CPAP). Brain Res Bull 2003;61:87-92. 50. Engleman HM, Kingshott RN, Martin SE, Douglas NJ. Cognitive function in the sleep apnea/hypopnea syndrome (SAHS). Sleep 2000;23(Suppl. 4):S102-S108. 51. Zimmerman ME, Arnedt JT, Stanchina M, et al. Normalization of memory performance and positive airway pressure adherence in memory-impaired patients with obstructive sleep apnea. Chest 2006;130:1772-1778. 52. Weaver TE, Chasens ER. Continuous positive airway pressure treatment for sleep apnea in older adults. Sleep Med Rev 2007; 11:99-111. 53. Launois SH, Pepin J, Levy P. Sleep apnea in the elderly: a specific entity? Sleep Med Rev 2007;11:87-97. 54. Ancoli-Israel S. Sleep apnea in older adults—is it real and should age be the determining factor in the treatment decision matrix? Sleep Med Rev 2007;11:83-85. 55. Alchanatis M, Zias N, Deligiorgis N, et al. Sleep apnea–related cognitive deficits and intelligence: an implication of cognitive reserve theory. J Sleep Res 2005;14:69-75. 56. Kezirian EJ, Harrison SL, Ancoli-Israel S, and the Study of Osteoporotic Fractures Research Group. Behavioral correlates of sleepdisordered breathing in older women. Sleep 2007;30:1181-1188. 57. Ancoli-Israel S, Palmer BW, Cooke JR, et al. Effect of treating sleep disordered breathing on cognitive functioning in patients with Alzheimer’s disease: a randomized controlled trial. J Am Geriatr Soc 2008;56:2076-2081. 58. Chong MS, Ayalon L, Marler M, et al. Continuous positive airway pressure reduces subjective daytime sleepiness in patients with mild to moderate Alzheimer’s disease with sleep disordered breathing. J Am Geriatr Soc 2006;54:777-781. 59. Somers VK, White DP, Amin R, and the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology; American Heart Association Stroke Council; American Heart Association Council on Cardiovascular Nursing; American College of Cardiology Foundation. Sleep apnea and cardiovascular disease: an American Heart Association/American College Of Cardiology Foundation Scientific Statement from the American Heart Association Council for High Blood Pressure Research Professional Education Committee, Council on Clinical Cardiology, Stroke Council, and Council On Cardiovascular Nursing. In collaboration with the National Heart, Lung, and Blood Institute National Center on Sleep Disorders Research (National Institutes of Health). Circulation 2008;118: 1080-1111. 60. Lavie P, Herer P, Hoffstein V. Obstructive sleep apnoea syndrome as a risk factor for hypertension: population study. BMJ 2000;320: 479-482. 61. Nieto FJ, Young TB, Lind BK, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study. JAMA 2000;283:1829-1836. 62. Grote L, Ploch T, Heitmann J, et al. Sleep-related breathing disorder is an independent risk factor for systemic hypertension. Am J Respir Crit Care Med 1999;160:1875-1882. 63. Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378-1384.
64. Peker Y, Hedner J, Norum J, et al. Increased incidence of cardiovascular disease in middle-aged men with obstructive sleep apnea. A 7-year follow-up. Am J Respir Crit Care Med 2002;166: 159-165. 65. Logan AG, Perlikowski SM, Mente A, et al. High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens 2001;19:2271-2277. 66. Chobanian AV, Bakris GL, Black HR and the National Heart Lung and Blood Institute Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: National High Blood Pressure Education Program Coordinating Committee. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure: the JNC 7 report. JAMA 2003;289:2560-2572. 67. Alajmi M, Mulgrew AT, Fox J, et al. Impact of continuous positive airway pressure therapy on blood pressure in patients with obstructive sleep apnea hypopnea: a meta-analysis of randomized controlled trials. Lung 2007;185:67-72. 68. Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing. The Sleep Heart Health Study. Am J Respir Crit Care Med 2006;173:910-916. 68a. Mehra R, Stone KL, Varosy PD, et al. Nocturnal Arrhythmias across a spectrum of obstructive and central sleep-disordered breathing in older men: outcomes of sleep disorders in older men (MrOS sleep) study. Arch Intern Med 2009 Jun 22;169(12):1147-1155. 69. Gami AS, Hodge DO, Herges RM, et al. Obstructive sleep apnea, obesity, and the risk of incident atrial fibrillation. J Am Coll Cardiol 2007;49:565-571. 70. Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 2003;27: 2589-2594. 71. Yaggi HK, Concato J, Kernan WN, et al. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005;353: 2034-2041. 72. Albarrak M, Banno K, Sabbagh AA, et al. Utilization of healthcare resources in obstructive sleep apnea syndrome: a 5-year follow-up study in men using CPAP. Sleep 2005;28:1306-1311. 73. Guest JF, Helter MT, Morga A, et al. Cost-effectiveness of using continuous positive airways pressure in the treatment of severe obstructive sleep apnoea/hypopnoea syndrome in the UK. Thorax 2008;63:860-865. 74. Tarasiuk A, Greenberg-Dottan S, et al. The effect of obstructive sleep apnea on morbidity and healthcare utilization of middle-aged and older adults. J Am Geriat Soc 2008;56:247-254. 74a. Khan AM, Ashizawa S, Hlebowicz V, Appel DW. Anemia of aging and obstructive sleep apnea. Sleep Breath 2010 Feb 17. [Epub ahead of print] 75. Newman AB, Nieto FJ, Guidry U, et al. Relation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study. Am J Epidemiol 2001;154:50-59. 76. Pusalavidyasagar SS, Olson EJ, Gay PC, et al. Treatment of complex sleep apnea syndrome: a retrospective comparative review. Sleep Med 2006;7:474-479. 77. Morgenthaler TI, Kagramanov V, Hanak V, et al. Complex sleep apnea syndrome: is it a unique clinical syndrome? Sleep 2006;29: 1203-1209. 78. Allam JS, Olson EJ, Gay PC, Morgenthaler TI. Efficacy of adaptive servoventilation in treatment of complex and central sleep apnea syndromes. Chest 2007;132:1839-1846. 79. Pelletier-Fleury N, Rakotonanahary D, Fleury B. The age and other factors in the evaluation of compliance with nasal continuous positive airway pressure for obstructive sleep apnea syndrome. A Cox’s proportional hazard analysis. Sleep Med 2001;2:225-232. 80. Aloia MS, Di Dio L, Ilniczky N, et al. Improving compliance with nasal CPAP and vigilance in older adults with OAHS. Sleep Breath 2001;5:13-21 81. Russo-Magno P, O’Brien A, Panciera T, et al. Compliance with CPAP therapy in older men with obstructive sleep apnea. J Am Geriatr Soc 2001;49:1205-1211. 82. Ayalon L, Ancoli-Israel S, Stepnowsky C, et al. Adherence to continuous positive airway pressure treatment in patients with Alzheimer’s disease and obstructive sleep apnea. Am J Geriatr Psychiatry 2006;14:176-180. 83. Kushida CA, Morgenthaler TI, Littner MR, et al. Practice parameters for the treatment of snoring and obstructive sleep apnea with oral appliances: an update for 2005. Sleep 2006;29:240-243.
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84. Giles T, Lasserson T, Smith B, et al. Continuous positive airways pressure for obstructive sleep apnoea in adults. Cochrane Database Syst Rev 2006:CD001106. 85. Ferguson KA, Cartwright R, Rogers R, Schmidt-Nowara W. Oral appliances for snoring and obstructive sleep apnea: a review. Sleep 2005;29:244-262. 86. Pantin CC, Hillman DR, Tennant M. Dental side effects of an oral device to treat snoring and obstructive sleep apnea. Sleep 1999;22: 237-240 87. Jones TM, Earis JE, Calverley PM, et al. Snoring surgery: a retrospective review. Laryngoscope 2005;115:2010-2015. 88. Brownell LG, West P, Sweatman P, et al. Protriptyline in obstructive sleep apnea: a double-blind trial. N Engl J Med 1982;307:10371042. 89. Dumont GJ, de Visser SJ, Cohen AF, and the German Association for Applied Human Pharmacology. Biomarkers for the effects of selective serotonin reuptake inhibitors (SSRIs) in healthy subjects. Br J Clin Pharmacol 2005;59:495-510. 90. Kiely JL, Nolan P, McNicholas WT. Intranasal corticosteroid therapy for obstructive sleep apnoea in patients with co-existing rhinitis. Thorax 2004;59:50-55. 91. Shahar E, Redline S, Young T, et al. Hormone replacement therapy and sleep-disordered breathing. Am J Crit Care Med 2003;167: 1186-1192.
92. Schwartz JR, Hirshkowitz M, Erman MK, et al. Modafinil as adjunct therapy for daytime sleepiness in obstructive sleep apnea: a 12-week, open-label study. Chest 2003;124:2192-2199. 93. Morgenthaler TI, Kapen S, Lee-Chiong T, and the Standards of Practice Committee, American Academy of Sleep Medicine. Practice parameters for the medical therapy of obstructive sleep apnea. Sleep 2006;29:1031-1035. 94. Malhotra A, Trinder J, Fogel R, et al. Postural effects on pharyngeal protective reflex mechanisms. Sleep 2004;27:1105-1112. 95. Eckert DJ, Malhotra A. Pathophysiology of adult obstructive sleep apnea. Proc Am Thorac Soc 2008;5:144-153. 96. Martin SE, Mathur R, Marshall I, Douglas NJ. The effect of age, sex, obesity and posture on upper airway size. Eur Respir J 1997;10:2087-2090. 97. Skinner MA, Kingshott RN, Filsell S, Taylor DR. Efficacy of the “tennis ball technique” versus nCPAP in the management of position-dependent obstructive sleep apnoea syndrome. Respirology 2008;13:708-715. 98. Marshall SC. The role of reduced fitness to drive due to medical impairments in explaining crashes involving older drivers. Traffic Inj Prev 2008;9:291-298.
Insomnia in Older Adults Sonia Ancoli-Israel and Tamar Shochat
Abstract Insomnia is a complaint of difficulty initiating or maintaining sleep or of nonrestorative sleep resulting in significant daytime consequences. Chronic insomnia is prevalent in about 10% of the adult population; however, increasing age is a risk factor for the development of insomnia, especially in women. Although late-life insomnia is usually attributed to medical and psychiatric morbidity rather than to age-related changes per se, underlying age-related physiologic changes in sleep–
Insomnia is a complaint of difficulty initiating sleep, difficulty maintaining sleep, or experience of nonrestorative sleep occurring at least three times a week and lasting at least 1 month.1 Typically, insomnia may be a chronic condition lasting for several years. In the elderly population, a chronic insomnia complaint is common, and it is often related to medical or psychiatric comorbidity. Owing to the widespread notion that insomnia is an inevitable consequence of aging, it is often not recognized or properly treated. However, growing evidence suggests that insomnia is not only a symptom consequent to morbidity but also a potential contributor to subsequent morbidity.2 Thus, increasing the awareness of clinicians and older adults regarding the significance of identifying and managing insomnia is imperative for improving sleep and health in this population.
EPIDEMIOLOGY AND RISK FACTORS The prevalence rate of insomnia increases with age, and it has been shown to be higher in women.3 In a sample of more than 5000 adults from the Sleep Heart Health Study (SHHS), older age was significantly related to poor sleep in men, particularly reduction in slow-wave sleep and increased stages 1 and 2, whereas in women, older age was related to subjective sleep complaints.4 It has been suggested that when categorizing studies based on the definition of insomnia used, studies focusing on symptoms of insomnia have shown an increased prevalence with age, and studies focusing on global sleep dissatisfaction and on the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR) diagnosis for insomnia were not age dependant.5 This hypothesis is supported by a study of more than 13,500 participants aged 47 to 69 years, assessing the prevalence of three major insomnia complaints and their correlates.3 Twenty-two percent of the sample complained of difficulty falling asleep, 39% complained of difficulty staying asleep, and 35% complained of nonrestorative sleep. In a multivariate analysis, increasing age was significantly associated only with a complaint of difficulty staying asleep, whereas depression and heart disease were associated with all three complaints. Other factors related to the sleep complaints were medical illnesses, lower socioeconomic status and 1544
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wake regulation—circadian rhythms and sleep homeostasis— have been identified. Other factors associated with insomnia in the elderly include medications or other substances and primary sleep disorders. Key elements in appropriate evaluation and management include considering the type of insomnia complaint and assessing sleep patterns, including daytime napping, daytime consequences, and comorbidity. Behavioral treatment should be considered first, and when necessary, the newer hypnotic medications may be added.
education, and unhealthy behavior such as current or former alcohol use and cigarette smoking. Other studies have also examined insomnia in the elderly population. In a sample of more than 9000 participants aged 65 years and older from the National Institute of Aging’s Established Populations of Epidemiological Studies of the Elderly (EPESE), more than 50% reported at least one sleep complaint, and 35% to 40% reported disorders of initiating or maintaining sleep (or both) on a chronic basis.6 In a 3-year follow-up of this sample, an annual incidence rate of 5% was reported.7 Incidence rates were highest in those with chronic medical conditions such as heart disease, stroke, and diabetes. Remission occurred in nearly half of those with insomnia at baseline, and it was related to improvements in perceived health. Similarly, in a representative sample of general practice patients aged 65 years and older, the annual incidence rate for late-life insomnia was 3.1%.8 Significant and independent risk factors in this sample were depressed mood, poor physical health, and intermediate to low physical activity. Based on the National Sleep Foundation survey from 2003, depression, heart disease, bodily pain, and memory problems were the disorders most commonly associated with insomnia.9 In fact, in studies using rigorous exclusion criteria for comorbidities, prevalence of insomnia is very low in healthy older adults. These findings lend further support to the epidemiologic evidence demonstrating that the bulk of geriatric sleep complaints and disorders is not the result of age per se, but rather co-segregates with medical and psychiatric disorders and related health burdens and even gender.10,10a One problem with insomnia in the elderly is that it is often unrecognized by physicians. In a study of older adults in primary care practices in the midwest United States, 69% of patients endorsed at least one sleep problem, 40% endorsed at least two sleep problems, and 45% endorsed symptoms of insomnia, but these complaints were identified in the medical charts only 19% of the time.11 In this same study, the two questions that best identified those with poor sleep at risk for medical and psychiatric problems were “Do you feel excessively sleepy during the day?” and “Do you have difficulty falling asleep, staying asleep, or being able to sleep?” These two questions would be easy for physicians to integrate into their standard history.
CONSEQUENCES OF INSOMNIA The reason it is so important to identify insomnia in older adults is that poor sleep can result in serious consequences. Studies have assessed the health consequences of insomnia as well as the effect of insomnia on physical functioning and performance. In a study of several thousand older men, lighter and more fragmented sleep were associated with poorer performance, particularly in age-adjusted models. Shorter total sleep time, sleep efficiency below 80%, and more than 90 minutes of wake time were associated with lower grip strength, slower walking speed, inability to stand from a chair without assistance, and inability to complete a narrow walk course.12 Results of multiple surveys have shown that insomnia in adults can result in decreased cognitive performance, such as difficulty sustaining attention, slowed response time, and memory problems. In a controlled laboratory study comparing patients with insomnia and good sleepers, performance impairments such as decreased vigilance, working memory, and motor control, as well as mood disturbances, concentration difficulties, and fatigue were evident in the insomnia group.13 Changes in cognition are of particular concern in the elderly population, where cognitive decline depends on age and may be an early sign of dementia.14 In a 2-year prospective study assessing relationships between snoring, sleep duration, and sleep difficulties with cognitive functioning in elderly women, short sleep duration (≤5 hours) and insomnia complaints were related to lower scores on cognitive tests at baseline but not at 2-year follow-up.15 In a 3-year longitudinal study, chronic insomnia was found to be an independent risk factor for cognitive decline in older men but not in older women,16 suggesting that cognitive decline in insomnia might correlate with sex. Alternatively, daytime sleepiness may be the underlying factor for cognitive decline, rather than insomnia. In a longitudinal study, daytime sleepiness, but not insomnia, was related to incident dementia and cognitive decline in men.17 On the other hand, in the Study of Osteoporotic Fractures (SOF), cognitive decline in close to 3000 elderly women age 70 years and older was associated with poor sleep based on actigraphically measured sleep efficiency of 70% or less, long sleep latency, and increased wake after sleep onset.18 In a study of more than 1000 older men and women, cognitive impairment was associated with short sleep duration of less than 6 hours and daytime nap of longer than 1 hour.19 Additionally, studies on the consequences of insomnia have identified reduced measures of health-related quality of life (HR-QOL), increased psychological distress, lower medical status and increased utilization of health services.20-22 Further consequences are related to reduced professional performances, such as increased absenteeism, decreased work performance, increased risk for road accidents, poor self-esteem, and less job satisfaction.23 Several studies have found that poor sleep is associated with increased risk of falls, even after controlling for relevant factors including benzodiazepine use.24,25 In the SOF study, less than 5 hours of sleep per night and sleep efficiency of 70% or less were independent risk factors for
CHAPTER 135 • Insomnia in Older Adults 1545
falls in elderly women, but use of benzodiazepines did not increase the risk.25 Insomnia also increases the risk of mortality. In a study of older adults followed for close to 5 years, those with initial sleep latencies of longer than 30 minutes or sleep efficiency less than 80% had close to twice the risk for mortality.26 Similar results were found in the SOF study of older women. After adjusting for clinical and demographic factors, subjects who slept less than 5 hours a night and who had a sleep efficiency less than 65% or who napped for more than 2 hours a day had an increased risk of mortality at follow-up.27 For these reasons, it is imperative for physicians to be able to recognize and treat insomnia in older adults.
ETIOLOGY Underlying factors involved in the development of late-life insomnia include age-related changes in homeostatic and circadian sleep–wake regulation, psychiatric and medical comorbidities, medications and other substances, and primary sleep disorders. Evidence for each of these factors is reviewed separately. Age-Related Changes in Sleep Regulation Developmental changes in sleep in the elderly are characterized by advanced sleep phase, including earlier bedtimes and earlier wake times, reduced sleep consolidation, and altered sleep architecture, indicating a transition to lighter sleep. To understand the basis for these changes, it is necessary to understand some of the basic mechanisms of human sleep regulation. Sleep regulation is based on an interaction between the homeostatic pressure for sleep and the output of the circadian pacemaker. Homeostatic sleep pressure reflects the increasing need for sleep that accumulates during the waking hours and dissipates during sleep, as marked by increased EEG slow waves at the beginning of the nocturnal sleep episode, which gradually decrease throughout the night. The endogenous circadian pacemaker located in the suprachiasmatic nucleus (SCN) of the hypothalamus regulates the synchronous timing of several physiologic variables including hormone secretion, core body temperature, and sleep–wake states. Regulation of the timing of sleep and wake states is achieved by promoting a signal of increased wakefulness throughout the day and a signal of increased sleep consolidation throughout the night.28,29 In young adults, daytime wakefulness and nighttime sleep consolidation are high due to both of these bioregulatory mechanisms. However, both homeostatic and circadian mechanisms change with age. Advanced age has been associated with a marked reduction in slow-wave sleep (SWS) and an increase in lighter sleep. This reduction in SWS indicates weaker homeostatic sleep pressure in the elderly.30 Under entrained conditions, timing of the circadian rhythm of core body temperature and habitual wake times are advanced to an earlier hour in the elderly, and the amplitude of the circadian rhythm of core body temperature is decreased, indicating a reduced circadian signal promoting sleep in the early morning hours.31 The circadian signal for wakefulness is also reduced,32 as reflected
1546 PART II / Section 17 • Sleep Medicine in the Elderly
in sleep episodes and reports of sleepiness in the early evening hours. In summary, reductions in both the homeostatic drive for sleep and in the strength of the circadian signal for sleep in the early morning hours and for wakefulness in the early evening hours have been implicated as underlying factors for reduced sleep consolidation, advanced sleep phase, and early-morning awakenings in the elderly. Medical and Psychiatric Comorbidities Many chronic medical conditions and illnesses are known to disrupt sleep. These include arthritis, angina pectoris, congestive heart failure, coronary artery disease, chronic obstructive pulmonary disease, end-stage renal disease, diabetes, asthma, stroke, gastroesophageal reflux disease, dementia and Alzheimer’s disease, Parkinson’s disease, cancer, and menopause. In a study of more than 1000 older adults aged 60 to 101 years, poor health was associated with short sleep duration, long sleep latency (longer than 80 minutes) and going to bed late and waking early.19 In a large survey of older adults, those with heart disease, lung disease, stroke, or depression were more likely to report difficulties with sleep. In addition, the more medical conditions subjects reported, the worse the sleep complaint and the more likely subjects were to rate their sleep as poor.9 In a group of older adults who are likely to have multiple medical or psychiatric conditions, poor sleep is a likely comorbid condition. In a study examining sleep and health in 1500 adults older than 60 years in 11 primary care offices, complaints of poor sleep and excessive daytime sleepiness were significantly associated with both poor physical and poor mental health–related quality of life.11 Other studies have also shown an association between poor mental health, especially depression and anxiety, and late-life insomnia.6,33 Insomnia has also been implicated as a risk factor for heart disease,34 although the mechanism mediating this relationship is yet to be determined. The authors hypothesized that insomnia may be part of a larger syndrome including poor health and depression, or it may be a marker of chronic stress and autonomic dysfunction. Collectively, the evidence indicates that insomnia may be a cause or a consequence of comorbidity. Thus, comorbid insomnia has been suggested as the more appropriate term.35 Such a distinction has important implications not only in determining causal relationships between insomnia and comorbidity but also for considering treatment strategies. Treatment and management should focus not only on comorbid illnesses but also on insomnia as a distinct entity. Medications and Substances Polypharmacy is a serious problem in older adults, and the use of multiple medications also contributes to insomnia. Prescription medications known to be related to insomnia include antidepressants, such as bupropion, selective serotonin reuptake inhibitors (SSRIs), monoamine oxidase inhibitors (MAOs), and tricyclic antidepressants (TCAs) except for amitriptyline and venlafaxine.36 Other medications prescribed for medical conditions that are associated with insomnia include bronchodilators, beta-blockers, central nervous system (CNS) stimulants, gastrointestinal drugs, and cardiovascular drugs. Concomitant use of
several types of medication (polypharmacy) further increases the risk of sleep disturbances in this age group. Adjustment of the timing and dosing and the contraindications between medications in elderly persons can lead to improvements in their sleep.36 Moderate alcohol consumption in elderly persons has been related to sleep disturbances including insomnia and sleep-disordered breathing (SDB).37 Other substances known to be related to insomnia include caffeine and nicotine. Although the effects of these substances are yet to be investigated in the elderly population, it is unlikely that they would not also disrupt sleep in the elderly. Primary Sleep Disorders Insomnia is often related to a primary sleep disorder. Common primary sleep disorders in the elderly include SDB, periodic limb movements in sleep (PLMS), and restless leg syndrome (RLS). Relationships between insomnia and each of these disorders are discussed. In addition, the development of insomnia as a primary sleep disorder is discussed. Sleep-Disordered Breathing Sleep-disordered breathing is a respiratory dysfunction syndrome during sleep, characterized by partial (hypopnea) to complete (apnea) airway collapse causing pauses in breathing that occur repeatedly during the night. These respiratory events reduce blood oxyhemoglobin saturation and terminate in partial arousals. Symptoms of SDB include excessive daytime sleepiness and heavy snoring. The prevalence of SDB is 4% to 9% in men and women,38 and the incidence increases considerably with age to as much as 45% to 62% in older adults.39 Other risk factors include obesity, male sex, and hypertension. Treatment of choice for SDB is positive airway pressure (PAP), a nasal mask attached via a hose that allows the continuous flow of positive air pressure through the nose, thereby eliminating respiratory events and associated outcomes. Insomnia and SDB often appear together in sleep clinic populations.40,41 Other variables associated with the insomnia complaint included female sex, psychiatric diagnosis, chronic pain, and restless legs symptoms. Collectively, these studies suggest that insomnia is highly prevalent in SDB and is associated with poor sleep and psychiatric distress; however, the underlying relationship between these two prevalent sleep disorders is currently unknown. Conversely, SDB may be veiled in older patients with insomnia who had initially been screened by clinical intake and did not have traditional signs and symptoms of SDB.42 In a sample of 80 adults with insomnia aged 59 years and older who had undergone rigorous screening for SDB, 29% had an apnea–hypopneas index (AHI) greater than 15, indicating significant SDB. These findings confirm that clinical interview alone might not suffice for identifying veiled SDB in the older adult population. Periodic Limb Movements in Sleep Periodic limb movements in sleep (PLMS) is a disorder characterized by involuntary leg jerks during sleep appearing in repetitive clustered episodes, often leading to brief awakenings from sleep. PLMS has traditionally been associated with insomnia or excessive daytime sleepiness. A
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PLM index (the number of limb movements per hour of sleep) greater than 5, accompanied by arousals, indicates clinical diagnosis of PLMS. The prevalence of PLMS has been shown to increase with age. Prevalence rates reported in community-dwelling elderly persons for a PLM index greater than five events per hour range between 37% and 66%.43,44 A long-term follow-up study of an elderly sample showed no overall change in PLMS with increasing age.45 Despite its high prevalence, studies on the pathologic significance of PLMS in the elderly have yielded inconsistent results. In two studies on the prevalence and clinical significance of the PLMS in community-dwelling elderly persons, investigators found no relationship between PLMS severity and any measurement of sleep disturbance.46,47 However, in a large study of community-dwelling older women, PLMS accompanied by arousals was related to indicators of disturbed sleep that are associated with insomnia.44
comorbid conditions such as medical or psychiatric illness, medications being taken, poor sleep hygiene, and other sleep disorders. The assessment of insomnia does not necessitate overnight PSG monitoring; however, symptoms and signs of comorbid sleep disorders, especially sleep-disordered breathing, do warrant a PSG study. Based on AASM standard guidelines, actigraphy is indicated in insomnia patients, including the elderly and institutionalized elderly, for the assessment of circadian rhythms and sleep–wake patterns and their disturbances, as well as for monitoring treatment for insomnia and circadian rhythm disturbances.53 Actigraphy is considered a more reliable measurement tool compared to sleep logs (although sleep logs are often used to complement actigraphy) and is particularly useful in populations that might not tolerate PSG, such as the institutionalized elderly.54
Restless Legs Syndrome Restless legs syndrome is a neurologic disorder characterized by dysesthesia in the legs and an irresistible urge to move them in order to relieve the discomfort. Symptoms of RLS increase during the evening and at night, usually when the patient is in a relaxed or restful state, resulting in a sleep disturbance. PLMS is a common finding in 80% of RLS cases and is also implicated as a major cause of sleep disturbance in RLS patients. PLMS and related sleep disturbance can also occur without RLS symptoms.48 Pharmacologic treatment studies for PLMS and RLS have included adults older than 65 years; however, despite the marked prevalence of these disorders in the elderly population, no studies thus far have been dedicated exclusively to older adults. Treatment strategies for both conditions, PLMS and RLS, are similar, and they should be limited to symptomatic persons with comorbid insomnia or daytime sleepiness. In the United States, the only treatments approved by the Food and Drug Administration for the treatment of RLS are the dopamine agonists pramipexole and ropinorole. Other medications are often used off-label, such as levodopa with the dopa decarboxylase inhibitor carbidopa. However, in the elderly these medications can increase daytime sleepiness, and therefore monitoring and follow-up are recommended. Second-line, off-label treatments include sedative-hypnotics, anticonvulsants, opioids, and adrenergic medications.49
TREATMENT The effectiveness of pharmacologic and nonpharmacologic treatments has been demonstrated for late-life insomnia. The evidence for their efficacy as well as specific considerations for their use in the elderly are reviewed in here.
EVALUATION AND DIAGNOSIS Despite its widespread prevalence, insomnia is underrecognized and often inadequately treated in the health care system.11,50 Guidelines for evaluating insomnia in the adult population, based on the Standards of Practice Committee of the American Academy of Sleep Medicine (AASM),51 call for a thorough sleep history and determination of the specific sleep complaint: sleep-onset or sleep-maintenance insomnia. Useful information when taking a sleep history in the elderly includes questions on the timing of bedtime and wake time, number and length of nocturnal awakenings, use of hypnotic medication, daytime sleepiness, the timing and duration of daytime naps, and effects of insomnia on daytime functioning.52 It is essential to identify
Nonpharmacologic Nonpharmacologic treatments for insomnia include cognitive behavioral therapy, and bright-light treatments (Box 135-1). In an update of the AASM practice parameters for psychological and behavioral treatments of insomnia,55 stimulus control, relaxation training, and cognitive behavior therapy (CBT) were recommended treatments for chronic insomnia with a high level of evidence from clinical trials. Treatments reaching moderate levels of evidence for efficacy included sleep-restriction therapy, multicomponent therapy (without cognitive therapy), biofeedback, and paradoxical intention. These treatments have been found to be effective in older adults and in patients who chronically use hypnotics. There was insufficient evidence regarding the efficacy of sleep hygiene, imagery training, and cognitive therapy. Cognitive behavior therapy has proved successful for older adults with primary and comorbid insomnia and for those with dependency on hypnotics. For example, in a clinical ambulatory PSG trial with 6-week and 6-month follow-ups, CBT was compared with zopiclone and placebo in elderly patients with chronic insomnia. For the CBT group, wake time was significantly reduced, and sleep efficiency and SWS were significantly increased at both 6-week and 6-month follow-ups compared to the zopiclone and placebo groups.56 In a sample of patients aged 31 to 92 years who had insomnia and who chronically used hypnotic medication, CBT maintained efficacy at 3-, 6-, and 12-month follow-ups, including improved reported global sleep quality and reduced use of hypnotics.57 Importantly, these improvements were not age dependent, indicating that even older insomnia patients who are chronic hypnotic medication users can benefit from CBT. In another study on late-life insomnia, comparing the effects of CBT with a sedative-hypnotic medication (temazepam) and with both treatments combined (CBT
1548 PART II / Section 17 • Sleep Medicine in the Elderly Box 135-1 Instructions for Nonpharmacologic Therapies for Late-Life Insomnia Stimulus Control The patient is instructed to go to bed only when sleepy. If sleep is not obtained in 20 minutes, the patient leaves the bedroom and returns to bed only when sleepy. This process is repeated as needed until sleep is obtained. Wake time is normal and naps are not allowed. Sleep Restriction Time in bed is restricted to self-estimated total sleep time. Sleep efficiency (ratio between time asleep and time in bed) is assessed weekly. Time in bed may gradually be increased following increases in sleep efficiency. No naps are allowed. Cognitive Behavioral Therapy Dysfunctional beliefs regarding the distinction between normal and abnormal sleep are identified, addressed, and redefined to induce positive changes in sleep-related cognitions and associated behavioral and emotional outcomes. Stimulus control and/or sleep restriction are initiated to deal with maladaptive behaviors. Sleep Hygiene Education Based on sleep history, ineffective habits and behavior related to poor sleep are targeted and clear guidelines for better sleep are provided, such as creating a stable sleep–wake schedule and a sleep-inducing bedroom environment, minimizing napping, avoiding sleep-inhibiting substances and activities at night, including caffeine, nicotine, and alcohol; heavy meals and high fluid intake; worrisome thoughts; and clock watching. Relaxation Training Various relaxation techniques are used, including meditation, muscle relaxation, and biofeedback for reducing somatic and cognitive arousal. Paradoxical Intention The patient is instructed to lie in bed and attempt to remain awake with eyes open for as long as possible. The bedroom should be dark and quiet, and the patient must not engage in other activities other than the continuous endeavor to remain awake. Bright Light Patients are exposed either to a bright-light box or to natural outdoor light in the evening hours.* *Indicated for advanced sleep phase and early morning awakenings.
and temazepam), good short-term efficacy was reported for all three treatments compared to placebo, with a small increased benefit for the combined treatment.58 However, at a 2-year follow-up, sustained long-term gains were achieved only in the CBT groups, especially in the CBTonly group, indicating that CBT alone is superior to combined therapy. Therefore, CBT provides a particularly promising alternative for this age group. In the 2005 NIH State-of-the-Science Conference on Insomnia, CBT was found to be as effective as prescription medications for brief treatment of chronic insomnia, with indications that
beneficial effects of CBT, in contrast to those produced by medications, may last well beyond termination of treatment.35 Evening bright light exposure has been indicated for the treatment of advanced circadian sleep phase syndrome (ASPS) and insomnia characterized by early-morning awakening, both which are common in elderly persons. In one study, 2 evenings of bright-light treatment significantly delayed circadian rhythms of core body temperature and melatonin, and based on actigraphy and sleep diaries collected for 1 month, they reduced night awakenings, increased total sleep time, and tended to delay morning wake times.59 The practical usefulness of bright light treatment in late-life insomnia, however, is still under study. Pharmacologic Hypnotic medication use is highest and most chronic in older adults.60 General guidelines for the use of sedative hypnotics in the elderly include selection of the appropriate drug (short acting versus long acting), considering the type of insomnia complaint (sleep-onset versus sleepmaintenance insomnia), starting with a low dose and increasing as needed, considering drug-drug interactions, and monitoring for adverse effects, particularly residual effects of daytime sleepiness and cognitive performance. It is important to keep in mind that the adverse consequences of sedative hypnotic use can outweigh the benefits, particularly in those with cognitive impairment. Commonly used hypnotic prescription medications for the treatment of insomnia include traditional benzo diazepine sedative hypnotics (temazepam, estazolam, flurazepam, quazepam, triazolam), newer selective nonbenzodiazepine sedative “Z drug” hypnotics (eszopiclone, zaleplon, zolpidem, and zolpidem MR), and the melatonin receptor agonist ramelteon. Sedating antidepressants (e.g., trazodone or doxepin), antipsychotics (e.g., quetiapine) and antihistamines (diphenhydramine) are also used off label, despite limited efficacy data. Self-treatments for insomnia include over-the-counter medications such as herbal or dietary supplements. In the 2005 State-of-the-Science conference on insomnia, the panel concluded that the risks of these off-label drugs outweigh the benefits, and therefore they did not recommend the use of antidepressants, antihistamines, or antipsychotics for the treatment of insomnia.35 The NIH also concluded that the new agents, particularly the Z drugs, are safer and more effective than the older benzodiazepines. All the selective nonbenzodiazepine hypnotics have been investigated in the older population. In a sample of 549 elderly insomnia patients, both zaleplon (5 or 10 mg per night) and zolpidem (5 mg per night) significantly improved sleep parameters.61 Rebound effects were observed following discontinuation for zolpidem but not for zaleplon. In a subsequent open-label trial with follow-up at 6 to 12 months, long-term use of 5 or 10 mg of nightly zaleplon was safe and effective, improved sleep measures were maintained, and there was no rebound insomnia upon discontinuation.62 The efficacy of two doses of eszopiclone (1 or 2 mg/ night) was evaluated in 231 elderly primary insomnia patients for 2 weeks.63 A dose of 1 mg was sufficient to significantly shorten sleep latency, and a dose of 2 mg significantly shortened sleep latency, increased total sleep
CHAPTER 135 • Insomnia in Older Adults 1549
time, reduced wake after sleep onset, and improved sleep quality. Daytime improvements included decreased napping, alertness, and a sense of physical well-being. A 12-month study also showed safety and efficacy in the older adult.63a Ramelteon is a selective agonist for melatonin subtype 1 and 2 receptors. Assessment of the efficacy of ramelteon 8 mg per night with placebo over 5 weeks in 800 older adults with chronic insomnia has demonstrated significantly decreased sleep latency, with no withdrawal or rebound insomnia after discontinuation based on patient reports.64 These findings were supported by a PSG repeated-measures design with two treatment days for each treatment phase (8 mg and placebo) and an intervening washout period.65 PSG results demonstrated reduced latency to persistent sleep, increased total sleep time, and increased sleep efficiency for both doses compared to placebo. No residual effects were found for next day cognitive and psychomotor performance.65
SUMMARY Symptoms of insomnia are highly common in the elderly population and are largely underrecognized and undertreated. Increasing evidence of the significant consequences of insomnia warrants careful assessment and appropriate treatment strategies for this population. Proper treatment of insomnia in this age group is effective and can improve overall physical and mental health, well-being, and quality of life in the elderly patient. Further research is required in selected elderly subjects to understand the mechanisms underlying the development of insomnia and its related comorbidities and consequences and to determine how these processes can be effectively treated or prevented. ❖ Clinical Pearl Insomnia is very common in older adults, but is generally related to medical and psychiatric illness, medication, circadian rhythm changes, and other primary sleep disorders and not to aging per se. Clinicians should routinely screen for problems with sleep and initiate appropriate treatment.
Acknowledgments The work reported in this chapter was supported by NIA AG08415, NCI CA112035, NIH M01 RR00827, and the Research Service of the Veterans Affairs San Diego Healthcare System. REFERENCES 1. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed. text revision. Washington, DC: American Psychiatric Association; 2000. 2. Bloom H, Ahmed I, Alessi CA, et al. Evidence-based recommendations for the assessment and management of sleep disorders in older adults. J Am Geriatr Soc 2009;57(5):761-789. 3. Phillips BA, Mannino DM. Correlates of sleep complaints in adults: the ARIC study. J Clin Sleep Med 2008;1:277-283. 4. Unruh ML, Redline S, An MW, et al. Subjective and objective sleep quality and aging in the sleep heart health study. J Am Geriatr Soc 2008;56:1218-1227. 5. Ohayon MM. Epidemiology of insomnia: what we know and what we still need to learn. Sleep Med Rev 2002;6:97-111.
6. Foley DJ, Monjan AA, Brown SL, et al. Sleep complaints among elderly persons: an epidemiologic study of three communities. Sleep 1995;18:425-432. 7. Foley DJ, Monjan A, Simonsick EM, et al. Incidence and remission of insomnia among elderly adults: an epidemiologic study of 6,800 persons over three years. Sleep 1999;22:S366-S372. 8. Morgan K, Clarke D. Risk factors for late-life insomnia in a representative general practice sample. Br J Gen Pract 1997;47: 166-169. 9. Foley DJ, Ancoli-Israel S, Britz P, Walsh J. Sleep disturbances and chronic disease in older adults: results of the 2003 National Sleep Foundation Sleep in America Survey. J Psychosom Res 2004; 56:497-502. 10. Vitiello MV, Moe KE, Prinz PN. Sleep complaints cosegregate with illness in older adults: clinical research informed by and informing epidemiological studies of sleep. J Psychosom Res 2002;53: 555-559. 10a. Jaussent I, Dauvilliers Y, Ancelin ML, et al. Insomnia symptoms in older adults: associated factors and gender differences. Am J Geriatr Psychiatry 2010 Jun 10. [Epub ahead of print] 11. Reid KJ, Martinovich Z, Finkel S, et al. Sleep: a marker of physical and mental health in the elderly. Am J Geriatr Psychiatry 2006; 14:860-866. 12. Dam TT, Ewing SK, Ancoli-Israel S, et al. Association between sleep and physical function in older men: the Osteoporotic Fractures in Men Sleep Study. J Am Geriatr Soc 2008;56:1665-1673. 13. Varkevisser M, Kerkhof GA. Chronic insomnia and performance in a 24-h constant routine study. J Sleep Res 2005;14:49-59. 14. Chen P, Ratcliff G, Belle SH, et al. Patterns of cognitive decline in presymptomatic Alzheimer disease: a prospective community study. Arch Gen Psychiatry 2001;58:853-858. 15. Tworoger SS, Lee S, Schernhammer ES, et al. The association of self-reported sleep duration, difficulty sleeping, and snoring with cognitive function in older women. Alzheimer Dis Assoc Disord 2006;20:41-48. 16. Cricco M, Simonsick EM, Foley DJ. The impact of insomnia on cognitive functioning in older adults. J Am Geriatr Soc 2001;49: 1185-1189. 17. Foley D, Monjan A, Masaki K, et al. Daytime sleepiness is associated with 3-year incident dementia and cognitive decline in older Japanese-American men. J Am Geriatr Soc 2001;49:1628-1632. 18. Blackwell T, Yaffe K, Ancoli-Israel S, et al. Poor sleep is associated with impaired cognitive function in older women: the Study of Osteoporotic Fractures. J Gerontol Med Sci 2006;61:405-410. 19. Ohayon MM, Vecchierini MF. Normative sleep data, cognitive function and daily living activities in older adults in the community. Sleep 2005;28:981-989. 20. Roth T, Ancoli-Israel S. Daytime consequences and correlates of insomnia in the United States: results of the 1991 National Sleep Foundation Survey. II. Sleep 1999;22:S354-S358. 21. Hatoum HT, Kong SX, Kania CM, et al. Insomnia, health-related quality of life and healthcare resource consumption. A study of managed-care organisation enrollees. Pharmacoeconomics 1998;14: 629-637. 22. Leblanc M, Beaulieu-Bonneau S, Merette C, et al. Psychological and health-related quality of life factors associated with insomnia in a population-based sample. J Psychosom Res 2007;63:157-166. 23. Leger D, Massuel MA, Metlaine A. Professional correlates of insomnia. Sleep 2006;29:171-178. 24. Avidan AY, Fries BE, James MC, et al. Insomnia and hypnotic use, recorded in the minimum data set, as predictors of falls and hip fractures in Michigan nursing homes. J Am Geriatr Soc 2005;53: 955-962. 25. Stone KL, Ancoli-Israel S, Blackwell T, et al. Poor sleep is associated with increased risk of falls in older women. Arch Intern Med 2008;168:1768-1775. 26. Dew MA, Hoch CC, Buysse DJ, et al. Healthy older adults’ sleep predicts all-cause mortality at 4 to 19 years of follow-up. Psychosom Med 2003;65:63-73. 27. Stone KL, Ewing SK, Ancoli-Israel S, et al. Self-reported sleep and nap habits and risk of mortality in a large cohort of older women. J Am Geriatr Soc 2009;57(4):604-611. 28. Dijk DJ, Czeisler CA. Contribution of the circadian pacemaker and the sleep homeostat to sleep propensity, sleep structure, electroencephalographic slow waves, and sleep spindle activity in humans. J Neurosci 1995;15:3526.
1550 PART II / Section 17 • Sleep Medicine in the Elderly 29. Shochat T, Luboshitzky R, Lavie P. Nocturnal melatonin onset is phase locked to the primary sleep gate. Am J Physiol 1997;273: R364-R370. 30. Dijk DJ, Duffy JF, Riel E, et al. Ageing and the circadian and homeostatic regulation of human sleep during forced desynchrony of rest, melatonin and temperature rhythms. J Physiol (London) 1999;516: 611-627. 31. Duffy JF, Dijk DJ, Klerman EB, Czeisler CA. Later endogenous circadian temperature nadir relative to an earlier wake time in older people. Am J Physiol 1998;275:R1478-R1487. 32. Munch M, Knoblauch V, Blatter K, et al. Age-related attenuation of the evening circadian arousal signal in humans. Neurobiol Aging 2005;26:1307-1319. 33. Paudel M, Taylor B, Diem S, et al. Association between depressive symptoms and sleep disturbances among community-dwelling older men. J Am Geriatr Soc 2008;56:1228-1235. 34. Schwartz S, McDowell AW, Anderson W, et al. Insomnia and heart disease: a review of epidemiologic studies. J Psychosomatic Res 1999;47:313-333. 35. National Institutes of Health State-of-the-Science Conference Statement on Manifestations and Management of Chronic Insomnia in Adults, June 13-15, 2005. Sleep 2005;28:1049-1057. 36. Ancoli-Israel S. Insomnia in the elderly: a review for the primary care practitioner. Sleep 2000;23:S23-S30. 37. Dufour MC, Archer L, Gordis E. Alcohol and the elderly. Clin Geriatr Med 1992;8:127-141. 38. Young T, Palta M, Dempsey J, et al. The occurrence of sleep disordered breathing among middle-aged adults. N Engl J Med 1993; 328:1230-1235. 39. Ancoli-Israel S, Kripke DF, Klauber MR, et al. Sleep disordered breathing in community-dwelling elderly. Sleep 1991;14(6): 486-495. 40. Lavie P. Insomnia and sleep-disordered breathing. Sleep Med 2007;8(Suppl. 4):S21-S25. 41. Smith S, Sullivan K, Hopkins W, Douglas J. Frequency of insomnia report in patients with obstructive sleep apnoea hypopnea syndrome (OSAHS). Sleep Med 2004;5:449-456. 42. Lichstein KL, Riedel BW, Lester KW, Aguillard RN. Occult sleep apnea in a recruited sample of older adults with insomnia. J Consult Clin Psychol 1999;67:405-410. 43. Ancoli-Israel S, Kripke DF, Klauber MR, et al. Periodic limb movements in sleep in community-dwelling elderly. Sleep 1991;14(6): 496-500. 44. Claman DM, Redline SS, Blackwell T, et al. Prevalence and correlates of periodic limb movements in older women. J Clin Sleep Med 2006;2:438-445. 45. Gehrman P, Stepnowsky C, Cohen-Zion M, et al. Long-term followup of periodic limb movements in sleep in older adults. Sleep 2002;25:340-346. 46. Dickel MJ, Mosko SS. Morbidity cut-offs for sleep apnea and periodic leg movements in predicting subjective complaints in seniors. Sleep 1990;13(2):155-166. 47. Youngstedt SD, Kripke DF, Klauber MR, et al. Periodic leg movements during sleep and sleep disturbances in elders. J Gerontol 1998;53:M391-M394. 48. Stiasny K, Oertel WH, Trenkwalder C. Clinical symptomatology and treatment of restless legs syndrome and periodic limb movement disorder. Sleep Med Rev 2002;6:253-265. 49. Hening WA, Allen RP, Earley CJ, et al. Restless Legs Syndrome Task Force of the Standards of Practice Committee of the American
Academy of Sleep Medicine. An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep 2004;27:560-583. 50. Shochat T, Umphress J, Israel AG, Ancoli-Israel S. Insomnia in primary care patients. Sleep 1999;22:S359-S365. 51. Chesson AL Jr, Anderson WM, Littner M, et al. Practice parameters for the nonpharmacologic treatment of chronic insomnia. An American Academy of Sleep Medicine report. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep 1999;22:1128-1133. 52. Ancoli-Israel S, Cooke JR. Prevalence and co-morbidity of insomnia and impact on functioning in elderly populations. J Am Geriatr Soc 2005;53:S264-S271. 53. Morgenthaler T, Alessi C, Friedman L, et al. Practice parameters for the use of actigraphy in the assessment of sleep and sleep disorders: an update for 2007. Sleep 2007;30:519-529. 54. Ancoli-Israel S, Cole R, Alessi CA, et al. The role of actigraphy in the study of sleep and circadian rhythms. Sleep 2003;26:342-392. 55. Morgenthaler T, Kramer M, Alessi C, et al. Practice parameters for the psychological and behavioral treatment of insomnia: an update. An American Academy of Sleep Medicine report. Sleep 2006; 29:1415-1419. 56. Sivertsen B, Omvik S, Pallesen S, et al. Cognitive behavioral therapy vs zopiclone for treatment of chronic primary insomnia in older adults: a randomized controlled trial. JAMA 2006;295:2851-2858. 57. Morgan K, Dixon S, Mathers N, et al. Psychological treatment for insomnia in the regulation of long-term hypnotic drug use. Health Technol Assess 2004;8:iii-68. 58. Morin CM, Colecchi C, Stone J, et al. Behavioral and pharmacological therapies for late life insomnia. JAMA 1999;281:991-999. 59. Lack L, Wright H, Kemp K, Gibbon S. The treatment of earlymorning awakening insomnia with 2 evenings of bright light. Sleep 2005;28:616-623. 60. Glass J, Lanctot KL, Herrmann N, et al. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ 2005;331:1169-1176. 61. Ancoli-Israel S, Walsh JK, Mangano RM, Fujimori M, Zaleplon Clinical Study Group. Zaleplon, a novel nonbenzodiazepine hypnotic, effectively treats insomnia in elderly patients without causing rebound effects. Prim Care Companion J Clin Psychiatry 1999;1: 114-120. 62. Ancoli-Israel S, Richardson GS, Mangano R, et al. Long-term use of sedative hypnotics in older patients with insomnia. Sleep Med 2005;6:107-113. 63. Scharf MB, Erman M, Rosenberg R, et al. A 2-week efficacy and safety study of eszopiclone in elderly patients with primary insomnia. Sleep 2005;28:720-727. 63a. Ancoli-Israel S, Krystal AD, McCall WV, et al. A 12-week, randomized, double-blind, placebo-controlled study evaluating the effect of eszopiclone 2 mg on sleep/wake function in older adults with primary and comorbid insomnia. Sleep 2010;33:225-234. 64. Roth T, Seiden D, Sainati S, et al. Effects of ramelteon on patientreported sleep latency in older adults with chronic insomnia. Sleep Med 2006;7:312-318. 65. Roth T, Seiden D, Wang-Weigand S, Zhang J. A 2-night, 3-period, crossover study of ramelteon’s efficacy and safety in older adults with chronic insomnia. Curr Med Res Opin 2007;23:1005-1014.
Sleep in Independently Living and Institutionalized Elderly Donald L. Bliwise Abstract Although not a mainstream source of patients in most sleep clinics, an ever-increasing proportion of the population residing in institutional settings necessitates that sleep medicine specialists be comfortable with and understand issues that affect sleep in those settings. Many patients residing in assisted living facilities or nursing homes meet criteria for dementia, and sleep-related syndromes such as sleep-disordered breathing, nocturnal incontinence, falls, agitation, and wandering are very common comorbidities in those patients. Medication to improve nocturnal sleep or to enhance daytime alertness should be considered, but it must be judiciously
This chapter is organized around common clinical problems commonly seen by the sleep medicine specialist who encounters geriatric patients, including those living independently, but especially those residing in assisted living and nursing homes. For many older persons, loss of cognitive capacities in late life overlay the multiple medical morbidities and syndromes (e.g., nocturia, incontinence, wandering, agitation) that constitute problems with sleep in this population. Treatment considerations must be made viewing the frailty of the patient, evaluating the riskto-benefit ratio, and, ultimately, the cost and feasibility of implementing treatment. Elucidation of central nervous system pathophysiology underlying disturbed sleep in specific dementing conditions is covered in greater detail elsewhere (see Chapter 91). This chapter focuses on issues related to interventions, including their efficacy and rationale.
SLEEP PROBLEMS IN DEMENTED NURSING HOME PATIENTS Clinicians encountering patients with sleep problems in institutional environments face innumerable challenges. Considerable heterogeneity exists in the range of dementing conditions that are present. Patients are most likely to carry a diagnosis of Alzheimer’s disease (AD), but dementia with Lewy bodies (DLB), frontotemporal dementia (FTD), Parkinson’s disease with dementia (PDD), and vascular dementia (VasD) are likely to be present in sizeable proportions of the nursing home population as well (see Chapter 91 for a more-detailed description of these conditions). Many patients are placed in long-term care without the benefit of well-documented neurologic evaluations and neuroimaging, and chart notes are unlikely to contain sufficient detail to ascertain which specific diagnoses may be present in a given patient. With the possible exceptions of DLB (see Nocturnal Wandering, later) and VasD (see Sleep Apnea, later), the specific diagnosis of dementia subtype is unlikely to affect treatment decisions.
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implemented and carefully monitored. Sleep apnea interventions, such as nasal continuous positive airway pressure, can also be considered in some cases, especially in the presence of an engaged caregiver or spouse. Appropriate expectations should be fostered regarding the value of treating sleep apnea in late life. In certain cases, the sleep medicine specialist plays a critical role at the institutional level by educating staff about identifying specific sleep disorders (sleep apnea, restless legs syndrome), relevant sleep pharmacology, and principles of nonpharmacologic management, including optimizing the sleep environment. Treatment of sleep and sleep disorders in nursing home patients can benefit both patients and their caregivers and significantly affect quality of life.
THE NURSING HOME ENVIRONMENT AS A CHALLENGE TO SLEEP INTEGRITY A major challenge to the integrity of sleep–wake in the nursing home is the environment itself. The typical nursing home patient receives little or no high-intensity light to synchronize circadian rhythms, may be confined or put to bed for long periods, may be subject to little or no daytime stimulation, and may be subjected to noise and light disruptions at night. Transfer from noninstitutional to institutional settings is associated with longer time in bed, increased daytime napping, and earlier bedtimes, even within a period of several months,1 although there are huge differences between facilities in terms of how much time patients are placed in bed during the daytime hours.2 Lower ratios of staff to resident may be a relevant factor,3 but time in bed in the nursing home is a complex issue. Nursing home patients experiencing more pain may spend more time in bed but have poorer sleep.4 A study encompassing 53 nursing homes across the United States showed that facilities placing patients in bed during the daytime were reported to have residents who exhibited lower rates of agitated behavior when compared to facilities that that did not use daytime bedrest,5 which demonstrates the complexity of implementing good sleep hygiene in these environments. Apart from staffing issues, if nursing home personnel believe that their patients “need rest” for fatigue during the daytime hours6 and that such practices reduce disruptive behavior, it may be difficult to convince them otherwise. In the outpatient setting, daytime sleepiness in the dementia patient is seldom viewed as problematic by the caregiver.7 Institutionally based data have linked peak agitation to the time when nursing staff shift (typically 4 pm)8 and imply that staff change is disruptive for patient’s behavior. A broader perspective comes from a nursing home study that based ratings of negative and positive behavior based on observations made in the hours before and after sunset 1551
1552 PART II / Section 17 • Sleep Medicine in the Elderly
and noted that frequencies of both kinds of behavior appeared to increase in the hours before sunset.9 Such more-generalized behavioral activation might represent a manifestation of the wake-maintenance zone in cognitively impaired patients. In the United States, many nursing facilities continue to interpret the Centers for Medicare and Medicaid Services (CMS) guidelines, established in the1987 Omnibus Budget and Reconciliation Act, as providing a mandate for nightly bedchecks and awakenings on a 2-hour basis for all nursing home patients at risk for developing pressure ulcers because of incontinence. The logic is that dementia patients, if not periodically awakened and repositioned and having their bedding changed, would more readily develop erythema and frank bedsores and be subject to their corresponding morbidity.10 However, 66% of incontinent bedridden patients demonstrated spontaneous mobility during the night, both at the shoulder and hip, at rates in excess of one turn per hour,11 thus potentially obviating the need to enforce awakenings in at least some patients. Not surprisingly, such staff-induced nocturnal awakenings have been shown to induce agitation in nursing home patients.1 More-profound levels of dementia, both within and outside of the nursing home setting, are associated with greater daytime sleepiness.12 This appears to be the case for assisted living facilities as well.13 Considerable descriptive evidence, relying upon behavioral observation14 and actigraphy15 in the institutional setting and relying on caregiver report16 in the home setting, suggest that daytime sleepiness and napping might have functional consequences for participation in social activities, occupational therapy, and even independence in selected activities of daily living. Lower amounts of REM sleep at night have been related to higher levels of observed sleep in nursing home patients.17 Actigraphic data also suggest that longer sleep durations per 24-hour period were associated with more-profound dementia in the nursing home,18 these data being compatible with loss of the wake-promoting function of the mammalian suprachiasmatic nucleus.19
TREATMENT Pharmacologic Sedative-Hypnotics Controversy exists over the use of medication for sleep in the nursing home. Injurious falls and hip fracture remain one of the most serious risks ascribed to such medications. Reluctance of many physicians to prescribe certain types or classes of medication was codified with the publication of the consensually derived Beers list of undesirable medications for older patients. The modified Beers list20 includes several older benzodiazepine sedative-hypnotics, consisting of all dosages of flurazepam and temazepam (doses >15 mg) and triazolam (doses >0.25 mg). Both short-half life and intermediate half-life benzodiazepines are discouraged in geriatric patients with a history of syncope or falls. Gamma-aminobutyric acid A (GABAA) selective agonists (zolpidem, zolpidem MR, zaleplon, eszopiclone) were not specified on the list. Diphenhydramine was included, and a study of acutely hospitalized geriatric patients demonstrated an exceptionally high risk for delirium with its
use.21 Anticholinergics have been known for years to cause delirium.22 A Finnish nursing home study suggested that as of 2003, the most commonly misused drug on the Beers list for nursing home patients was temazepam, used at doses greater than 15 mg.23 As of early 2009, there are no published randomized, placecbo-controlled clinical trials of the newer sedative-hypnotics (eszopiclone, ramelteon, sustained-release zolpidem) specifically studying demented, institutionalized patients. Some trials cited in this chapter have included zolpidem and zaleplon. A widely cited meta-analysis24 looked at 24 randomized clinical trials of sedative-hypnotics in elderly persons living independently, in various types of senior living facilities, and in nursing homes; five of the studies used zolpidem or zaleplon encompassing about 15,800 patient nights. The meta-analysis concluded that although sedative hypnotics as a group improved sleep time by an average of about 25 minutes, such medication increased the risks for altered cognition (odds ratio [OR], 4.78) and daytime fatigue or sleepiness (OR, 3.82). The effects on falls and psychomotor impairment (OR, 2.25; 95% confidence interval [CI], 0.93-5.41) did not reach significance; no falls were associated with zolpidem or zaleplon. Of the eight falls occurring across all these trials, none specified the time of day when the fall occurred. Apart from such meta-analyses, most knowledge of potential efficacy and adverse effects of sedative-hypnotics in demented nursing home populations derive from retrospective analyses of various administrative databases. Such data often represent relatively crude summaries of specific times when medications are ingested and when adverse events occur. They also cannot track when and for how long use of a sedative-hypnotic may be successful. For example, apparent lack of efficacy of sleep medications25 or even worse sleep26 with sedative-hypnotics in institutionalized patients have frequently been noted, though other databases suggest that hypnotics may be effective in many patients.27 Wang and colleagues28 examined 1-year risk of hip fracture in association with zolpidem in a retrospective casecontrol study of elderly community-dwelling patients undergoing surgical treatment for a hip fracture. Apparent zolpidem use was associated with nearly double the risk, but the specific ingestion of zolpidem related to the index event (hospital admission date) was inferred on the basis of adequate supply of zolpidem, not documented ingestion of a particular dose at specified time of day. The authors later argued further that residual confounding (i.e., patients most likely to be at risk for hip fracture were those most likely to ingest zolpidem) did not account for their findings,29 but they presented no data on time of drug intake or time of day of fall leading to hospital admission date to clarify their original finding. Although a substantial amount of epidemiologic literature beginning in the late 1980s has demonstrated that psychotropic medications generally (and sedative-hypnotic medications specifically) are associated with increased risk for falls and hip fracture, these observational studies, often derived from either community-dwelling30 or institutionalized31 populations, cannot be considered definitive for several reasons. First, not all population-based studies uniformly have reported such effects,32 implying that the
CHAPTER 136 • Sleep in Independently Living and Institutionalized Elderly 1553
Table 136-1 Prediction of Incident Falls in State of Michigan Nursing Homes (N = 34,163) BASELINE INSOMNIA
OR
95% CL
Not using hypnotics
1.55
1.41-1.71
Using hypnotics
1.32
1.02-1.70
Using hypnotics (implied effective treatment)
1.11
0.94-1.31
CI, confidence interval; OR, odds ratio. Data from Avidan AY, Bries BE, James ML, Szafara KL, Wright GT, Chervin RD. Insomnia and hypnotic use, recorded in the Minimum Data Set as predictors of falls and hip fractures in Michigan nursing homes. J Am Geriatr Soc 2005;53:955-962.
effects may be specific to population, medication, or database. Second, virtually every study fails to account for the time of day the fall or injury occurs. This is highly relevant because such information on timing and dose of medication in relation to when the fall occurred is essential to establish whether a plasma level could reasonably be assumed to be present. An exception to this is the study of Ray and coworkers33 who examined medication dose and half-life and time of day (daytime versus nighttime) as predictors of falls in 2500 Tennessee nursing home patients and showed that acute use of short elimination half-life medications (primarily temazepam, and much smaller numbers using oxazepam, zolpidem, and triazolam) were associated with falls only in the nighttime hours. Avidan and colleagues, using the Minimal Data Set (MDS), an administrative database of Medicare and Medicaid patients, examined successful and unsuccessful use of sedative-hypnotic medication in relation to falls in 34,000 Michigan nursing home patients.27 In these analyses, insomnia (derived from a single item on the MDS) and sedative-hypnotic use were examined as separate predictors of falls. Insomnia per se was associated with increased risk for falls regardless of medication use, and sedativehypnotic use without concurrent insomnia (implying efficacious treatment) was not associated with falls (Table 136-1). Although such use of the MDS has been severely criticized and could not be validated by reference to actigraphic measurements in a separate analysis of about 180 patients,34 the Michigan nursing home data provide a broader perspective for interpretation of administratively derived databases. In that regard, perhaps the most compelling reasons to suspect that falls data may be more parsimoniously interpreted as bedrise episodes associated with an inability to sleep through the night, come from studies of nocturia and incontinence. Both nocturia35 and urge incontinence have been associated with falls,36 though the latter studies also fail to specify the time of day when falls occurred. An Australian study of elderly women demonstrated that daytime sleepiness and urge incontinence independently contributed to the likelihood of falling,37 and in a United States population, daytime sleepiness38 and short nocturnal sleep duration39 were associated with falls. Although interventional studies at the level of health care systems are difficult to implement, a quasiexperimen-
tal study of hip fracture offered some perspective on the implementation of the New York State triplicate benzodiazepine prescription policy for elderly Medicaid enrollees by comparing hip fracture rates over a similar period for comparable Medicaid recipients in New Jersey.40 Although prescriptions showed a dramatic reduction in New York (unlike New Jersey), hip fracture rates showed few changes during that interval and were comparable between states, again raising the possibility that medications are not likely to be the primary cause of such events. Cholinesterase Inhibitors, Antipsychotics, and Stimulants It is well recognized that the most widely used class of medications for the cognitive impairments of AD, the cholinesterase inhibitors, have disrupted sleep as a side effect, which leads to higher than expected concurrent use of sedative-hypnotics.41 Many patients report increased frequency of unpleasant dreaming with this medication class, perhaps reflecting the stimulation of cholinergic systems controlling rapid eye movement (REM) sleep. Memantine, an N-methyl-d-aspartate (NMDA) receptor antagonist, is also approved for moderate to severe cognitive loss in AD, but no studies have specifically reported on its effects on sleep. Some retrospective data analyses derived from the MDS suggest that despite disrupting sleep, cholinesterase inhibitors were associated with lower use of antipsychotics.42 Another study demonstrated that although antipsychotics were not specifically prescribed for sleep in nursing home patients, their withdrawal was associated with lower sleep efficiency as measured with actigraphy.43 Judicious use of antipsychotics in dementia is strongly advised, because this constitutes an off-label use of such drugs. Essentially, promotion of nocturnal sleep by these agents represents an opportunistic use of the side effect of sleepiness (at a rate approaching three times that of placebo as estimated by meta-analysis),44 otherwise cast as an adverse effect. When administered to elderly dementia patients, older-generation antipsychotics (haloperidol, thioridizine)45 and newer atypical antipsychotics (olanzapine, risperidone, quetiapine, aripiprazole) increase risk for sudden death, and the FDA has issued a black-box warning for their use in such populations, the latter supported by meta-analysis of clinical trials46 and by a case-control study involving more than 13,000 matched patient pairs.47 Use of stimulant medication in dementia, targeting the daytime sleepiness and the apathy that characterizes dementia, has been the subject of several small-scale studies in nursing home patients48 and community-dwelling49 AD patients. Results suggested good tolerance and some improvement in apathy. A double-blind, placebo-controlled trial of methylphenidate for AD confirmed these improvements, though some adverse events (restlessness, agitation) were problematic,50 suggesting cautious use of this drug class. There are no published randomized trials with modafinil in institutionalized or noninstitutionalized AD patients, though a small case series in mixed-dementia patients suggested some benefit at 100 to 200 mg.51 Controlled trials in outpatients with PD at doses up to 400 mg have shown only mixed results in increasing daytime alertness.52
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Nonpharmacologic A large number of randomized clinical trials employing nondrug interventions to improve sleep in institutionalized patients have shown mixed success with such approaches. In contrast, multifaceted behavioral treatment programs involving engaged caregivers of dementia patients have shown better rates of success, extending out as long as 6 months subsequent to the intervention.53 The nursing home studies have employed parallel group designs involving hundreds of demented nursing home residents, have incorporated credible control treatments, and have employed a variety of measures attempting to assess sleep, using wrist actigraphy and systematic behavioral observations. Many studies have included secondary outcomes of importance such as mood, functional status, and nurses’ ratings of residents’ behavior. Sloane’s group54 employed relatively high intensity (2500 lux) lights embedded in existing fixtures in common rooms, such as dining areas, in two geriatric facilities for 3 weeks across four lighting conditions: customary, bright light in the morning (7 am to 11 am), bright light in the evening (4 pm to 8 pm), bright light all day (7 am to 8 pm). Sleep durations improved modestly (about 15 minutes) for morning and all-day exposures. The amplitude of wrist actigraphic rhythms did not change substantially, though some changes in phase were noted. Two other studies failed to find markedly beneficial effects of bright light in nursing home patients. Alessi and colleagues55 combined 5 consecutive days of morning outdoor light exposure (documented at >10,000 lux) with an intensive program to limit time in bed during the day, increase daytime physical activity, and reduce nursing home noise and light at night. Effects were dramatic reductions in daytime sleep but no significant change in hours of nighttime sleep or number of awakenings. Dowling and coworkers56 used a much longer treatment period (10 weeks of active treatment), but combined light treatment (1 hour morning exposure at 2500 lux) with 5 mg melatonin. As in the Alessi55 study, the most dramatic effects were seen in reducing daytime sleep, but nighttime sleep did not show differential improvement relative to control condition. Dowling’s group56 demonstrated marked improvements in the actigraphically measured rest–activity rhythm (e.g., amplitude, improved cosine goodness of fit), which the authors interpreted as compatible with functional improvements. The most ambitious attempt at improving sleep in demented nursing home patients was a 3.5-year trial comparing fixture-based light alone (1000 lux administered from 10 am to 6 pm), melatonin alone (2.5 mg mediumfast release), combined light and melatonin versus a dim light (300 lux), and a placebo-control condition.57 Although the study design was straightforward, the analyses were complicated to interpret because residents entered and left the study at various periods; only 7 of 189 residents completed the entire study. Many participants entered the protocol after the baseline period was completed, and only about 30% completed even the 6-month follow-up. Intent-to-treat analyses employing last observation carried forward, an approach of questionable utility in dementia
studies,58 were employed, but analyses were offered only for 3.5- and 1.5-year follow-ups. Given these constraints, the authors’ results were difficult to interpret. For example, light significantly improved sleep duration by 10 minutes and melatonin significantly improved sleep duration by 27 minutes, but the combined interventions did not produce a significant effect on sleep time. Other notable nonsleep outcomes were decreases in mood and greater behavioral withdrawal associated with melatonin and improved mood and cognition with light. The latter extrapolated to an improvement of less than 1 point over 3.5 years on the Mini Mental State Examination (MMSE). Taken together, these results did not suggest dramatic improvements. The melatonin results in particular are difficult to interpret given the large scale (n = 157) multisite National Institutes of Health study of AD outpatients,59 which demonstrated few beneficial effects on sleep of melatonin at a dose of 2.5 mg (sustained release) or 10 mg (immediaterelease) in an 8-week trial using actigraphic measurements. This trial had few drop outs (6%) and showed no change in Hamilton Depression Rating Scale score. Similar negative results were reported in a smaller randomized clinical trial using a single dose of combined 8.5 mg immediate release and 1.5 mg sustained-release melatonin administered for 10 days.60 Perhaps the most intriguing manipulation attempting to improve sleep was an individualized social activity intervention applied daily for 3 weeks in 147 demented nursing home patients.61 The intervention was tailored thoughtfully to the specific background and (often former occupational) interests of the residents and compared to usual nursing home care. Because of broadly defined entry criteria, many patients slept more than 7 hours at baseline (as recorded by actigraph). When analyses were limited to subjects with low baseline sleep efficiencies (<50%), total nocturnal sleep times increased by about 40 minutes and daytime sleep times and nocturnal sleep latencies both decreased by 40 minutes each. A unique aspect of that study was that the cost of such an intervention (if several patients were engaged in an activity at the same time) was estimated at about $10 per patient per day, probably not an unrealistic expense given today’s health care cost burden.
NOCTURNAL WANDERING AND RESTLESS LEGS SYNDROME As a particular form of agitation, wandering, particularly when occurring during the evening and overnight hours, represents a significant safety problem in the care of the aged demented patient and is potentially one of the most troubling symptoms for caregivers,62 though one not always validated by actigraphic measurement of the caregivers’ own sleep.63 So great is the threat to welfare of senior citizens that many communities have implemented a “Safe-Return” program to deal with the problem.64 Alarms and egress warning systems have been implemented in institutional settings and in home environments. The prevalence of nocturnal wandering remains uncertain, though estimates range as high as 52% to 69% at some point in the course of the dementia patient’s illness.65
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Although environmental controls are meaningful, the sleep medicine specialist may offer consultative input at several levels. Obtaining an accurate history of when and how often the episodes occur may be revealing on several fronts. If episodes arise after several hours of sleep, the possibility that the wandering represents an exacerbation of dream-enactment behavior reflecting Parkinsonism or DLB (see Chapters 87 and 91) should be considered. This would lead to treatments such as clonazepam or over-thecounter melatonin, which have been tested as treatments for dream-enactment behavior (though not specifically wandering) in open-label trials (see Chapter 95). No randomized, placebo-controlled clinical trials for wandering have specifically tested the efficacy of newer, prescriptionbased melatonin receptor agonists (ramelteon, tasimelteon, agomelatine). By contrast, wandering behavior commencing in the early evening hours could be a presentation of restless legs syndrome (RLS). The 2002 NIH Development Conference on RLS suggested that RLS in the dementia patient could be manifest as early evening wandering and pacing.66 At least one videographic, observational study of “travel behavior” in nursing home patients demonstrated that such activities increased in frequency between 7 pm and 9 pm67 and were probably independent of shift change, thus lending some credence to this possibility. Recorded PLMS, often a correlate of RLS (see Chapter 90), has been reported to be an independent cause of sleep disruption in community populations,68 and it is common in dementia patients, where it contributes significantly to reductions in total sleep time.69 Both caregiver-reported twitching and restless legs differentiated AD patients from such self-reported symptoms in controls,70 but they might not have generalized to caregiver’s report of “sleep problems” in those patients.71 Use of selective serotonin or noradrenergic reuptake inhibitors or the presence of musculoskeletal pain conditions tended to be related to a periodic leg movement index of more than 15 events per hour in communitydwelling dementia patients,72 and use of antidepressants or antipsychotics was associated with a greater likelihood of past injury from wandering in AD patients.73 Positron emission tomography and single photon emission computed tomography data suggest that AD patients who wander had reduced D2 receptors throughout the caudate and putamen74; these data were compatible with neuroimaging findings in RLS (see Chapter 90). Taken together, these diverse findings are compatible with the idea that wandering in at least some AD patients could represent RLS. Diagnosis may be problematic. It would seem obvious that cognitively compromised dementia patients might not have full language faculties to allow complete verbalization of symptoms so aptly articulated by many patients with RLS. In that situation, careful inquiry should be made into medical risk factors for RLS in such patients, including anemia, kidney disease, neuropathy, and musculoskeletal conditions (see Chapter 90), because these would serve to corroborate a diagnosis of RLS. Another potentially important source of information comes from family members who might reveal a history of lower limb discomfort in the patient (or perhaps, in themselves or other
family members), which might steer the clinician to consider RLS as a basis for the wandering. Wandering dementia patients were reported to be more likely to have used walking as a preferred behavior for coping with stress.75 Before attempting new pharmacologic intervention, careful examination of current medications might yield information. Atypical antipsychotics, often producing at least partial dopamine blockade, are sometimes used as drugs of last resort to control agitated behavior (including wandering) in dementia patients. In the case of a demented patient with medical or genetic risk for RLS, such mediations might worsen, rather than ameliorate, wandering. In this situation, a trial suspension of such medications should be entertained. In the absence of such medication and in the presence of corroborating evidence compatible with RLS (e.g., low serum ferritin), symptomatic treatments for presumed RLS in the dementia patient who wanders in the early evening might be undertaken cautiously, bearing in mind the potential adverse effects of dopamimetics in this population. As in any case of suspected RLS, careful examination of iron markers and use of iron supplementation may be considered. A more-complete description of issues involved in the wandering as a marker of RLS is found elsewhere.76
SLEEP APNEA AND ASSOCIATED MORBIDITIES IN DEMENTIA It has been known for more than 20 years that sleep apnea is relatively common and relatively severe in nursing home patients. Although some of this sleep apnea might represent Cheyne-Stokes–type respiration in sleep as a consequence of heart failure or stroke or might represent occasional cases of purely central apnea, sleep apnea in such populations is primarily obstructive. The prevalence of severe sleep-disordered breathing (SDB) (apnea–hypopnea index [AHI] > 30) in infirm, very old patients residing in nursing homes approximates 20%,77 and pulse oximetry screening indicates an oxygen desaturation index (ODI) of at least 4% more than 5 events per hour in greater than 40% of nursing home patients.78 Even the most casual observer of sleeping patients in a nursing home can grasp how common sleep apnea is in this population.79 The high prevalence undoubtedly reflects the myriad of risk factors that predispose elderly patients in general to high rates of SDB. These can be described generally as the operation of a relatively less stable respiratory control system that leads to interruptions in breathing and a subsequent tendency for upper airway collapse, perhaps accentuated by greater compliance of the upper airway and decreased lung volumes80 and less so the effect of adiposity or high body mass index (see Chapter 3). These somewhat distinctive potential contributing mechanisms are emphasized further by the associations of sleep apnea to measures of frailty,81 an important phenomenon in geriatric medicine, which predicts multiple morbidities82 as well as mortality.83 The observed association between sleep apnea and frailty probably reflects dysfunction of the respiratory pump and upper airway musculature. Whether sleep apnea in aged populations is associated with adverse outcomes has been a matter of considerable debate. Elsewhere in this volume (see Chapters 3 and 134)
1556 PART II / Section 17 • Sleep Medicine in the Elderly
the case has been made that the strength of the associations seen in middle age may only be slightly diminished, if dampened at all, in old age. In addition to cardiovascular outcomes, such as hypertension84 and nondipping of blood pressure,85 some outcomes, such as nocturia,86 urge incontinence or overactive bladder,87 falls,88 poorer physical function,89 behavioral agitation,90 and stroke,91 may be particularly relevant for elderly persons residing in nursing homes. Incident stroke in relation to sleep apnea in a community population appeared more likely in older than younger persons.92 Untreated sleep apnea may be a risk for recurrent stroke,93 and treatment with continuous positive airway pressure (CPAP) can reduce the risk for recurrence.94 Specifically in nursing home populations, nocturnal incontinence may be associated, either biochemically or mechanically, with episodes of sleep apnea,95 and, at least in noninstitutionalized populations, reduction of nocturia episodes was associated with successful treatment of sleep apnea with CPAP.96 Treatment trials for sleep apnea in nursing home patients are nonexistent, and the condition remains grossly underdiagnosed and unrecognized in nursing facilities within the United States.97 If sleep apnea represents a risk for dementia in geriatric patients, it probably does so by virtue of its impact on cardiovascular and cerebrovascular function.98 Although many clinicians who work with dementia patients routinely consider sleep apnea as a cause of dementia99 and others go so far as to add sleep apnea to their rule-out list of causes of AD,100 the role of sleep apnea in late-life dementia is still unsettled. One consideration is that dementia, defined as the decline of multiple cognitive abilities, including memory, that interfere with social or occupational function,101 is a broad diagnosis that encompasses many different conditions (see Chapter 91), and it is conceivable that sleep apnea could be preferentially related to some specific forms of dementia rather than others. For example, some neuropsychological data have suggested that the pattern of cognitive deficits seen in severe obstructive sleep apnea fit better with the constellation of deficits seen in VasD, even more than AD,102 and the International Consensus Criteria for Vascular Dementia considers sleep apnea a recognized cause of dementia in late life.103 However, many patients with clinically diagnosed AD have a substantial number of microvascular lesions when their brains are examined neuropathologically,104 thus blurring the distinction between VasD and AD. Furthermore, analyses from major cohorts, such as the Atherosclerosis Risk in Communities105 study, have all suggested that midlife cardiovascular risk factors predispose to moresevere cognitive loss in late life, such as AD. These data represent long-term follow-ups from 6 to 30 years. If broadly defined cardiovascular disease is a harbinger not only for frank cerebrovascular disease (e.g., VasD, stroke) but also AD in later life, sleep apnea could easily be a mediator or moderator in those associations by virtue of its role in cardiovascular disease in midlife. Although no studies have systematically attempted to treat sleep apnea in demented nursing home patients, one systematic and otherwise heroic clinical trial in noninstitutionalized patients with mild to moderate AD (mean MMSE score, 24.5) provides invaluable guidance and experience on the potential value of initiating such treat-
ments in such cognitively impaired populations. AncoliIsrael and colleagues compared 3 to 6 weeks of CPAP use to placebo CPAP and found rates of adherence not lower than might be expected in noninstitutionalized populations,106 improvements in sleep architecture107 and selfreports of sleepiness,108 but negligible improvement in cognition.109 However, data pooled from the intervention group and the control group (crossed over with 3 weeks of active treatment) showed significant improvement in a composite neuropsychological test score and several individual tests (Trailmaking B, verbal learning), leaving open the possibility that treatment might be beneficial in this domain as well. The study was underpowered for a parallel groups design, and allowing for type I error given the number of psychometrics employed, the results certainly did not indicate dramatic clinical significance. The types of changes seen were no greater and may have even been less than what is typically seen with cholinesterase inhibitors, which themselves have been reported to have modest benefit in treating sleep apnea in Alzheimer’s disease.110 On the other hand, data from this important clinical trial should not be construed as diminishing the value of treating sleep apnea in a demented patient living in the community or in a nursing home. First, preliminary data on a follow-up of five patients using CPAP over an entire year suggested that rate of decline in some functions may be partially ameliorated over a longer exposure to CPAP.111 Additionally, in nondemented patients, numerous other clinical trials have demonstrated unequivocally that sleep apnea treatment is associated with substantial improvement in cognitive function,98 and in view of the brunt of epidemiologic evidence suggesting that vascular disease plays a role in stroke and VasD as well as in AD in late life,105 the modest findings in the cognitive domain require reframing. It may well be that treating sleep apnea in midlife, rather than late life, provides the greatest chance of affecting long-term cognitive function. The clinical trials of therapy with CPAP or oral appliances encompassing decades of treatment that would be required to detect such effects simply do not exist at this time. Weighing the currently available scientific evidence bearing upon whether sleep apnea might represent a causal risk for AD is complex. Together with the equivocal changes in cognition from the clinical trial just cited,106-109 several studies of small numbers of high-functioning, healthy elderly subjects (see reference 112 for a review) and broader population-based studies involving cognitive correlates of snoring,113 polysomnographically defined SDB,114 and brainstem115 and nonbrainstem116 MRI-measured white matter hyperintensities, these negative findings have all been interpreted by some as casting doubt on whether there is any risk conferred by SDB for more-severe forms of cognitive impairment, such as dementia.117 However, such a perspective ignores a diverse matrix of converging studies that provide repeated validation for the presence of an association and offer substantial and plausible evidence for its neuronal substrates. To summarize these findings: 1. In contrast to the aforementioned studies, other epidemiologic data in elderly subjects have shown that sleep apnea–type symptoms (e.g., daytime sleepiness, snoring) are associated with incident cognitive impairments.118
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2. At least two other population-based studies of community-dwelling older persons—the Study of Osteoporotic Fractures (SOF) (in women) and the Osteoporotic Fractures in Men Sleep Study (MrOS)— has demonstrated an association between polysomnographically measured sleep apnea and cognitive impairment.119,120 3. Specifically within a nursing home population (heterogeneous for types of dementias, but probably including sizeable numbers of both AD and VasD patients),112 severity of physiologically measured SDB is modestly associated (r2 effect size of about .21) with severity of cognitive impairment.77 4. Studies comparing caregiver reports about sleep in well-characterized AD outpatients in relation to nondemented controls showed significantly greater endorsements of snoring, irregular breathing in sleep, and daytime napping in the AD patients, all suggesting sleep apnea.71 5. In fully ambulatory middle-aged populations, a broad array of cognitive skills, including executive abilities and memory (typical deficits of dementia patients) but also more subcortically mediated functions such as psychomotor and fine motor speed,98 have been related to sleep apnea, though the absolute level of impairments are not nearly as great as those seen in dementia.112 6. Numerous studies employing structural brain neuroimaging techniques, such as magnetic resonance imaging (MRI), have shown that sleep apnea is associated with lower hippocampal volumes (see reference 121 for review), a key region known to show marked atrophy in AD. Additional studies using even more sensitive diffusion tension imaging (DTI) have suggested reduced volumes in nearby structures such as the mammillary bodies,122 as well as widespread interruption of white matter fiber tracts involving cingulate cortex, corpus callosum, internal capsule, and selected cerebellar nuclei.123 7. Functional neuroimaging studies have suggested enhanced blood oxygen level–dependent (BOLD) activation on fMRI during verbal memory tasks involving activation of left frontal and temporal regions in sleep apnea patients relative to controls124 and absence of activation during working memory tasks in the dorsolateral prefrontal cortex relative to controls,125 an effect that did not resolve with 8 weeks of CPAP treatment. In an uncontrolled study of never-treated sleep apnea patients, increased BOLD activation during a serial addition task requiring working memory was particularly widespread and involved prefrontal cortex, thalamus, basal ganglia, cerebellum, and brainstem.126 These findings are all highly relevant because progressive memory impairment is one of the defining characteristic of dementias, especially AD. 8. Dementia as a concurrent diagnosis of sleep apnea within the limits of a closed health care system (Veterans Administration)127 occurs significantly above chance. 9. Animal models of intermittent hypoxia indicate larger behavioral deficits, hippocampus cell loss, and apoptosis in older, relative to younger, animals, thus suggest-
ing at least one plausible pathophysiologic mechanism for CNS damage.128 10. Among nondementia carriers of the apolipoprotein type 4 (APOE4) allele, the most common genotype predisposing to AD,129 measures of sleep apnea severity were also associated with extent of cognitive impairment,130 a result partially replicated by others131 and one that may be mediated by sleepiness.132 The presence of the APOE4 allele also predicted a stronger relationship between sleep apnea and cognitive impairment in the SOF study.119 The association between sleep apnea and APOE4 appears to be age-dependent (i.e., confined to persons younger than 65 years)133 and might merely represent a coding region in strong linkage disequilibrium with other more-relevant satellite markers.134 However, the APOE4 allele is associated with more guarded prognosis after stroke,135 worse cognitive outcome after coronary artery bypass surgery,136 and poorer recovery from head injury.137 This suggests that even if sleep apnea did not lie on a causal pathway for cognitive impairment in old age, the genotype could still represent a relevant vulnerability for neurobehavioral manifestations of sleep apnea in old age. Genotype was not available in the clinical trial results,106-109 so whether this factor might have affected the largely negative findings on cognition is unknown. How considerations regarding genotypes or specific dementia subtypes would play out in the day-to-day care of the typical nursing home patient, who may be less likely to have undergone genotyping or extensive neuroimaging, are uncertain, though the sleep specialist asked to provide input into the diagnosis or treatment of sleep apnea in such patients should be aware of the many potential causal factors operating here. Ultimately, the clinician undertaking CPAP or oral appliance treatment for sleep apnea in the demented nursing home patient must come to grips with whether the purpose of the intervention is to treat the dementia itself, the excess disability associated with the dementia (e.g., somnolence, nocturia, or incontinence), or both. If treatment is undertaken primarily with the aim of ameliorating the dementia, it should be emphasized to family members that CPAP will probably not represent a “miracle cure.” Realistically, the level of improvement in the cognitive arena may be on a par with that seen with cholinesterase inhibitors. On the other hand, as emphasized repeatedly throughout this chapter, improved alertness and engagement with the environment are far from trivial quality-of-life endpoints for the institutionalized dementia patient and deserve full consideration in treatment planning. Anecdotal AD cases showing substantial cognitive improvement have been noted.112
SUMMARY With the inevitable aging of the population, the likelihood increases that sleep medicine specialists will be asked to offer expertise regarding the care of geriatric patients residing in institutions. To that end, an understanding of the conditions and syndromes that can affect end-of-life care in the broadly defined dementia patient, particularly when these conditions and syndromes involve SDB,
1558 PART II / Section 17 • Sleep Medicine in the Elderly
nocturnal incontinence, falls, agitation, and wandering, can benefit patients and their caregivers. Appropriate and judicious pharmacologic implementation, albeit still limited by lack of trials of newer sedative-hypnotic medications, may be warranted in some cases. Treatments for sleep apnea should also be considered; poor adherence should never be assumed, especially in the presence of an engaged spouse or caregiver. Furthermore, introduction of knowledge at the institutional or staffing level regarding not only specific sleep disorders (sleep apnea, RLS) but also basic sleep hygiene and principles of nonpharmacologic management of inadequate nocturnal sleep, can enhance health and quality of life. Rudimentary understandings of basic principles of chronobiology should also be sought. The sleep and well-being of the institutionalized dementia patient should not be considered beyond the range of care of the sleep medicine specialist.
❖ Clinical Pearl Patients residing in nursing homes can present with many significant sleep-related problems that affect the quality of life of those patients and those who care for them. These issues should not be considered beyond the range of care of the sleep medicine specialist. Consultative advice regarding appropriate medication use, including drug interactions, may be significant when issues arise involving falls, nocturnal agitation and wandering, and daytime sleepiness. Sleep apnea and its treatment should not be considered beyond the realm of possibility for the nursing home patient as long as expectations are clear and warranted. The inevitable aging of the population raises the likelihood that many sleep medicine specialists will be asked to provide input regarding sleep in such patients.
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Women’s Health
Section
Kathryn A. Lee 137 Sex Differences and Menstrual-Related Changes in Sleep and Circadian Rhythms 138 Sleep Disturbances and Sleep-Related Disorders in Pregnancy 139 The Postpartum Period 140 Menopause
Sex Differences and MenstrualRelated Changes in Sleep and Circadian Rhythms
Fiona C. Baker, Louise M. O’Brien, and Roseanne Armitage Abstract There are sex differences in sleep from a very early age. Girls report longer sleeping periods and begin the adolescent decline in slow-wave (delta) activity (SWA) earlier than boys. Women report a poorer sleep quality and have an increased risk for insomnia than do men. However, women have a better sleep efficiency and higher SWA during non-rapid eye movement (NREM) sleep. Sex is an important factor when considering sleep disturbances associated with disorders such as major depressive disorder; depressed men have lower SWA whereas depressed women have lower synchronization between sleep electroencephalographic (EEG) frequency bands compared with healthy controls. These results highlight the importance of sex in sleep and circadian rhythm research studies and have broader implications for women’s health issues relating to these topics. Within groups of women, sleep
SEX DIFFERENCES IN SLEEP FROM INFANCY TO ADULTHOOD Sexual dimorphism describes morphologic differences between the sexes, although it also describes any biological process that differs between men and women. Extensive evidence from fruit flies to humans demonstrates sexual dimorphism in structure, function, and regulation of the brain. Differences between male and female brains are believed to result from the actions of gonadal secretions during a critical period of brain development. Data from animal models show that androgens produced by the testes in fetal and neonatal life induce sex differences in the neural structure and function of the brain, and such sex differences are also apparent in humans. Gonadal secretion is not the only mechanism: Gene expression in neuronal cells also plays a role in sexual dimorphism of the brain before gonadal secretion occurs. There is provocative evidence that even mechanisms of cell death in fetal or newborn brains are not identical between male and female infants.1 Other examples of sexual dimorphism include circadian clock genes, respiratory control, stress responses 1562
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may be affected by variation in reproductive hormones, such as occurs over the menstrual cycle. The menstrual cycle is associated with changes in circadian rhythms and sleep architecture, most notably a blunted amplitude of the body temperature rhythm and increased spindle frequency activity during sleep in the luteal phase compared with the follicular phase. Women with polycystic ovary syndrome are at risk for developing sleep-disordered breathing, which can contribute to insulin resistance and other metabolic abnormalities. Women with severe premenstrual syndrome or dysmenorrhea (painful menstrual cramps) can have transient sleep disturbances or insomnia coupled with their other mood and/or physical symptoms before and during menstruation. Assessment of sleep complaints in women should include an investigation of any association between symptoms and menstrual cycle phase or menstrual-related disorders.
and hypothalamic-pituitary-adrenal axis, density of hypothalamic nuclei and sex hormone receptors in the suprachiasmatic nucleus (SCN), and the action of sex and reproductive hormones on sleep-regulatory mechanisms, all of which have implications for sleep and circadian rhythm regulation. Despite this, research into sex differences in sleep and circadian rhythm regulation lags behind other studies of sex differences in both humans and animal models. The following sections highlight current literature in sleep and circadian rhythms from infancy to adulthood, focusing on differences between the sexes. Major findings are summarized in Table 137-1.
INFANCY In humans, circadian rhythms exhibit a cyclic tendency, with a periodicity of approximately 24 hours. Circadian rhythms undergo a gradual developmental course after birth, strengthening from interaction with a 24-hour light– dark cycle, social cues, and other environmental conditions. In healthy newborns, robust circadian rhythms are usually entrained by 2 to 3 months of age.
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Table 137-1 Sex Differences in Sleep throughout the Life Cycle Objective Measures AGE GROUP
SUBJECTIVE REPORTS
VIDEO
ACTIGRAPHY
POLYSOMNOGRAPHY
Infants
Poor sleepers are more likely to be boys
Girls have a longer sleep period and more quiet sleep than boys
Children
Girls sleep longer than boys
Girls sleep longer than boys
Girls have a higher sleep efficiency than boys
Adolescents
Girls take longer to get to sleep and have more sleep than boys
Girls have a more efficient sleep and fewer awakenings than boys
Girls begin the decline in NREM delta power earlier than boys Depressed boys have greater sleep disturbance than depressed girls
Adults
Women report more sleep difficulties than men Women are more likely to have insomnia than men
Women have better sleep quality and sleep more than men
Women have a shorter sleep latency, better sleep efficiency, and more sleep than men Women have higher delta power during NREM
Boys have more infraslow activity (<0.5 Hz) during sleep than girls
NREM, non–rapid eye movement sleep.
The development of sleep states and circadian rhythms in neonates has been reported in numerous studies, although few have reported on comparisons between the sexes. Of those that have compared male and female infants, findings are contradictory. Some studies using nighttime video recordings of infants find no differences in organization of sleep–wake state,2 but others find that female infants have more mature proportions of quiet sleep and longer sleep periods than male infants have.3 However, based on electroencephalograph (EEG) recordings in healthy infants during the first few months of life, no sex differences in sleep states were found,4 although newborn boys have more infraslow activity (<0.5 Hz) during sleep than newborn girls have,5 supporting the hypothesis that the central nervous system (CNS) of newborn girls is more mature than that of boys. Female infants also have more mature respiration than male infants during the first 6 months of life—possibly related to accelerated CNS maturation.6 In healthy infants, the ratio of nighttime sleep to total sleep becomes progressively greater with age and demonstrates a more-organized pattern of sleep, particularly in female infants. Further, the time course of REM sleep development corresponds with brain maturation,7 and higher proportions of REM sleep, together with a maturational lag in REM sleep, have been reported in infants at risk for sudden infant death syndrome (SIDS),8 a syndrome in which there is a clear male predominance. The evidence linking mutations of circadian clock genes and sleep- and circadian-related disorders is compelling.9 Further, sleep disturbances are important symptoms of many psychiatric disorders. There is increasing evidence that delayed development of circadian rhythms in infancy contributes to differential risk for disease, particularly psychiatric disorders, between male and female infants, as reviewed in the following section.
CHILDHOOD In many studies, the term childhood is not clearly defined and is generally used when referring to any child from infancy through to adolescence. This lack of standardization clearly contributes, at least in part, to inconsistent findings. Even so, the majority of studies investigating sleep in children have not investigated potential sex differences, and of those that have reported results by sex, findings are conflicting. Survey Data Worldwide, several cross-sectional survey-based studies of hundreds of schoolchildren have found that girls report sleeping longer than boys.10,11 However, other large, survey-based, longitudinal studies have failed to find any sex differences in sleep parameters.12 Lack of consistency between findings might result from factors such as cultural or racial differences and the limitations of using questionnaires to investigate sleep. Actigraphy Data Data from actigraph recordings have been more consistent in regard to sex differences in sleep.13,14 Several studies have found that girls sleep more and spend more time in motionless sleep than boys. Minority boys tend to report shorter sleep times than white boys.15 Such findings raise interesting questions about the role of racial background in sleep. Polysomnographic Data Although many reports of sleep in children include polysomnographic (PSG) data, few studies report on the relation of sleep to sex. However, significant sex-by-age-group differences on several PSG measures have been reported in children aged 3 to 8 years.16 Younger girls (ages 3 to 5 years) appear to have higher sleep efficiency, smaller
1564 PART II / Section 18 • Women’s Health
proportion of wake, and a higher proportion of stage 3 sleep than boys of similar age. Among older children (≥6 years), girls appear to have a higher proportion of stage 1 sleep than boys. Despite these significant findings, the effect sizes for sex differences are quite small, and therefore their clinical significance is unclear. Based on measures of the cyclic alternating pattern, which refers to EEG activity characterized by sequences of transient episodes that differ from the background of basal EEG, sex differences have been found, suggesting that girls have greater NREM instability, even when standard EEG criteria showed no sex differences.17 However, another study using similar methodology did not find these sex differences.18 Additional studies relevant to sex differences in children’s sleep include those differentiating healthy children from children with medical problems such as psychiatric disorders. Significant age-related differences in sleep macroarchitecture that vary by sex and disease have been reported.19 Depressed adolescent boys have the most sleep disturbance compared to nondepressed boys, nondepressed girls, and depressed girls. However, differences in sleep macroarchitecture are minimal between depressed and nondepressed girls.19 Pubertal boys and girls in the depressed and nondepressed groups slept significantly less than their prepubertal counterparts. Early-onset depression is associated with a reduction in synchronization of sleep EEG rhythms (temporal coherence) that is stronger in depressed girls than boys.20 Girls with major depressive disorder (MDD) also demonstrate dampened amplitude of circadian rest–activity cycles, even in those who have yet to reach developmental maturity.21 By contrast, dampened circadian amplitude is not evident in depressed boys until adolescence. Together, these findings suggest that there may be a differential developmental influence on sleep in early depression that is dependent on sex.19 Girls at high risk for depression, based on maternal history, but who have yet to experience depression themselves may also show impaired synchronization of sleep EEG rhythms and reduced amplitude of circadian rest– activity cycles.22,23 This finding raises the possibility that it is the initial entrainment of circadian rhythms that is compromised in those with MDD and that this biological rhythm disturbance confers a risk for the future development of MDD. Preliminary evidence from the University of Michigan indicates greater sleep disturbance and slower entrainment of rest–activity cycles in infants from a maternal history of depression.24
ADOLESCENCE Survey Data Adolescence is a period of many changes in sleep patterns, which are under the influence not only of age but also of developmental or pubertal status, as well as changes in sleep schedule. Using questionnaire-based methodologies, several studies have found sex differences in sleep schedules; for example, girls can take longer to get to sleep than boys, boys might sleep longer than girls, or, conversely, boys might have slightly less sleep time than girls, even though they go to bed later and get up later than girls.25 Investigations of insomnia and pubertal development
suggest that boys might have earlier onset of insomnia than girls and that onset of menses may be associated with an increased risk for insomnia.26 This increased risk for insomnia in girls after menarche corresponds with an increased risk for depression,27 which is a risk factor for insomnia. Clearly the relationship among insomnia, depression, and pubertal development is complex because several social and biological changes occur around the onset of menses, which can increase risk for both depression and insomnia. Actigraphy Data In studies using actigraphy, adolescent boys have been found to sleep less, have less-efficient sleep, and awaken earlier than girls, likely related to greater activity levels during the night in boys.28 Measures of total sleep time by actigraphy and PSG are in close agreement for adolescent girls, but actigraphy can underestimate total sleep time in boys, possibly because of the differential pattern of nocturnal movement between girls and boys. Polysomnographic Data In adolescence, a well-described EEG change in sleep is a steep decline in NREM slow-wave (delta) activity (SWA), and data from cross-sectional studies indicate that delta activity declines by about 50% between the ages of 10 and 20 years.29,30 Longitudinal data from cohorts of 9- and 12-year-olds followed up for 4 years suggest that girls begin the steep adolescent decline in SWA earlier than boys, which has been hypothesized to reflect an earlier onset of adolescent synaptic pruning in girls.31 It has long been speculated that sexual maturation and the decline in delta EEG activity in NREM sleep may be causally related. The decline in visually scored slow-wave sleep (SWS) is significantly correlated with increasing Tanner stage, a relationship that is independent of age.32 However, data collected longitudinally has shown that the decline in SWA during NREM sleep in boys and girls between the ages of 12 and 14 years is associated with age but not with pubertal stage.33 Feinberg34 has suggested that the delta decline during adolescence is a component of widespread brain reorganization, of which other manifestations include reductions in brain metabolic rate, decreased plasticity, and the emergence of adult cognitive capacity. It is possible that abnormalities in these maturational brain processes give rise to the emergence of abnormal circuits that cause psychiatric illnesses. In children and adolescents with MDD, significant group-by-age-by-sex interactions for several sleep variables are observed.19 Depressed adolescent boys have the greatest sleep disturbance, and depressed girls do not differ significantly from healthy girls on sleep measures. However, temporal coherence of sleep EEG rhythms (a measure of synchronization of EEG frequencies of the same periodicity), are significantly lower in adolescents with MDD compared to healthy controls, and both sex and age can strongly influence the between-group differences. The lowest temporal coherence may be found among girls with MDD, even in those younger than 13 years.20 Strikingly, almost half of adolescents identified as having the most abnormal coherence values either showed symptoms of depression or met diagnostic criteria within
CHAPTER 137 • Sex Differences and Menstrual-Related Changes in Sleep and Circadian Rhythms 1565
2 years.23 Low temporal coherence represents a more chaotic organization of sleep EEG rhythms, suggesting that early-onset depression is associated with a reduction in synchronization of sleep EEG rhythms that shows a differential maturational course in boys and girls.20 Further, low temporal coherence is evident in adolescent girls at high risk for, but not yet fulfilling criteria for, depression.
ADULTHOOD Survey Data Sex differences in sleep–wake patterns in adults are commonly reported. Men are more likely to nap, and they report more disturbed, lighter sleep than women, particularly in older adulthood.35 However, women have an increased risk for insomnia across different age groups. In 1990 a meta-analysis was conducted on 27 studies addressing sex differences on 31 indices of sleep behavior of adults aged at least 58 years.36 Although no differences in total sleep time were evident, older men tended to show more changes from the patterns of healthy youthful sleep, with small to moderate effect sizes. Such differences included more time in bed, less delta sleep, and shorter REM latency for men. Actigraphy Data Actigraphic assessment of sleep has shown that women exhibit better sleep quality than men,37 with higher sleep efficiency index and lower frequency of transitions between sleep and wakefulness. Women tend to sleep more than men and have shorter sleep-onset latency. Regardless of sex, age affects sleep fragmentation because adults have a strong decline in actual sleep time and sleep efficiency, as well as increased sleep latency as they age. Polysomnographic Data In parallel to actigraphy, PSG data demonstrate better sleep quality in women than men, with shorter sleep onset latency and better sleep efficiency and more time asleep and less time awake. Women have higher delta power relative to men, although there is not a significant age-by-sex interaction,38 suggesting that the process of aging has a similar impact on delta EEG in men and women. It has been argued that sex differences in sleep regulation may be subtle in healthy young adults but that they may become more obvious when the system is challenged, such as in instances of sleep deprivation, stressors, or in diseases associated with immune or hypothalamic-pituitary-adrenal axis abnormalities, such as MDD.39 For example, compared to young men, young women have a greater delta response to the stress of sleep deprivation,40 and sex differences in sleep normally seen in healthy adults become even more magnified when comparing depressed men to depressed women. Men with MDD show lower SWA than women with MDD or men and women without MDD, whereas depressed women show lower temporal coherence than controls.39 These disturbances in sleep microarchitecture that are more apparent in women with MDD might contribute to the increased risk of MDD observed in women.
There may be greater biological flexibility and adaptation among women, reflected as a greater response to a challenge condition. However, it has been hypothesized that women should be less responsive to a challenge in order to preserve sleep, neuroendocrine function, and circadian phase and amplitude.41 Indeed, a review reported that in general, between puberty and menopause, hypothalamic-pituitary-adrenal axis and autonomic responses tend to be lower in women compared to men of same age.42 Findings of sex differences in the neuroanatomy of the suprachiasmatic nucleus and other hypothalamic structures, along with laboratory and clinical data on sleep and circadian rhythms, provides a strong neurophysiologic and neuroanatomic basis for sex differences, which may be relevant for understanding divergent risk factors for neurologic and psychiatric disease in men and women. Although the evidence is strongest for adulthood, emerging data suggest that there is a differential maturational time course in boys and girls that might influence circadian rhythms and sleep–wake cycles. Indeed, the roots of such maturational influences may be evident very early in development. Further longitudinal studies are necessary to determine the time period at which these sex differences emerge and how they are shaped by maturation of sex steroids, neuroendocrine function, gene transcription factors, and environment. When considering potential sex differences in sleep, it is important to be aware of the potential impact on sleep of the menstrual cycle, as discussed in the following section, as well as other stages of a woman’s life cycle, discussed in other chapters.
THE MENSTRUAL CYCLE AND EFFECTS OF OVARIAN HORMONES ON SLEEP AND CIRCADIAN RHYTHMS Female reproductive hormones, specifically estrogen and progesterone, not only regulate reproductive tissue function during the menstrual cycle but also, through their secondary actions in the central nervous system, influence other physiologic processes, such as sleep and circadian rhythms. Conventionally, in a normal menstrual cycle of 28 days, day 1 is identified as the first day of bleeding (menses). Ovulation occurs around day 14, dividing the cycle into two phases: a preovulatory follicular phase and a postovulatory luteal phase (Fig. 137-1).43 Under the control of the hypothalamic–anterior pituitary axis, ovarian follicles grow during the follicular phase, with an associated rise in plasma estradiol. Circulating estradiol levels peak just before ovulation, triggering a surge in secretion of luteinizing hormone (LH) from the anterior pituitary. Ovulation occurs 12 to 16 hours later, around day 14. In the luteal phase, progesterone dominates, being secreted from the ruptured dominant follicle (corpus luteum), together with estradiol. Approximately 14 days after ovulation, if there is no implantation of a fertilized ovum, hormone levels drop precipitously, heralding the onset of menstruation. Ovulatory cycles are typically between 25 and 35 days. Most negative menstrual symptoms are experienced by women during the last few days of the cycle, as progesterone and
1566 PART II / Section 18 • Women’s Health 38.0 Pituitary hormones (mlU.mL–1)
FSH 300
100 Estrogen
Ovarian hormones estrogen (pg.mL–1)
Progesterone
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0 37.0
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37.0 Contraceptives Luteal Follicular Men
36.5
–4
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Time (hours) Figure 137-2 Mean diurnal rhythms in rectal temperature, plotted for 4 hours before lights out and 20 hours thereafter in eight young men (orange), eight young women taking monophasic oral contraceptives (active pill; green) and 15 young women in the midfollicular (blue) and midluteal (red) phases of their ovulatory menstrual cycles. Vertical lines indicate average time in bed. Subjects followed their usual daytime schedules and spent the night in a sleep laboratory (Published with permission from Baker FC, Driver HS. Circadian rhythms, sleep, and the menstrual cycle. Sleep Med 2007;8:613-622.)
Ovulation
Follicular phase
Luteal phase
Days of menstrual cycle
Figure 137-1 Mean daily plasma concentrations of estradiol, progesterone, follicle-stimulating hormone (FSH), and luteinizing hormone (LH) and basal body temperature throughout a typical 28-day ovulatory menstrual cycle. (Adapted from Pocock G, Richards CD. Human physiology: the basis of medicine. New York: Oxford University Press; 1999. p 450.)
estrogen levels decline, and during the first few days of menstruation.44 Circadian Rhythms across the Menstrual Cycle In women, circadian rhythms for hormone secretion, body temperature, and sleep–wake activity are superimposed on the menstrual cycle rhythm. As shown in Figure 137-2, men and women have the most similar temperatures when women are in their follicular phase. In the luteal phase, compared with the follicular phase, body temperature is increased by about 0.4° C, due to the thermogenic action of progesterone secreted from the corpus luteum.45 Most studies have found that the nocturnal decline in body temperature is blunted, reducing the amplitude of the temperature rhythm in the luteal phase compared to the follicular phase.46 Amplitude of the body temperature rhythm is negatively related to the ratio of progesterone to estradiol.47 The literature is inconclusive as to whether the menstrual cycle influences the timing of the peak or the trough of the temperature rhythm, with some studies reporting no change and others reporting a phase delay in the luteal phase compared with the follicular phase.46 Inconsistent results may be attributable to variable control between studies of agents such as ambient light, activity, and posture, which mask the endogenous circadian rhythm.48
A study that applied a modified constant routine protocol to unmask circadian rhythms in women at different menstrual cycle phases48 found no menstrual phase–related difference in phase of the temperature rhythm. There also is no difference in melatonin onset or offset or in duration or acrophase of the melatonin rhythm between the follicular and luteal phases of the menstrual cycle in young women, based on studies that used either a constant routine protocol48 or a multiple nap, ultradian routine.49 However, the amplitude of the melatonin rhythm was blunted in the luteal phase compared to the follicular phase in women following the ultradian routine.49 Findings of a similar dampening of amplitudes for cortisol, thyroid stimulating hormone, and body temperature suggest that amplitude of the endogenous oscillator of the circadian pacemaker is blunted after exposure to ovulatory hormones.49 Indeed, the presence of progesterone and estrogen receptors in the suprachiasmatic nuclei of the hypothalamus50 suggests the possibility that progesterone and estrogen influence circadian rhythmicity directly. Shift Work and Menstrual Rhythms Female shift workers, who work on schedules outside of a regular workday, have disrupted circadian rhythms that could lead to the development of medical problems, including altered reproductive function.51 Female shift workers have more menstrual cycle irregularities, painful menstruation (dysmenorrhea), and longer menstrual cycles compared to non–shift workers.51 Overnight shift workers also have increased risk for breast cancer, possibly because of exposure to artificial light and subsequent melatonin suppression.51 Shift-work nurses who report changes in menstrual function, compared to those who do not, report significantly more sleep disturbances, symptoms of intolerance of shift work, and longer sleep-onset latencies,
CHAPTER 137 • Sex Differences and Menstrual-Related Changes in Sleep and Circadian Rhythms 1567
suggesting an association between sleep disturbances and menstrual irregularities.52 Reproductive health problems associated with shift work could be due to increased stress as well as disrupted rhythms in hormone secretion, particularly luteinizing hormone and follicle-stimulating hormone, that directly influence ovarian hormone secretion.52 Some evidence suggests that menstrual cycle irregularities and extended shift work can lead to fertility problems and increased risk for low-birthweight and preterm babies53; however, a meta-analysis of the literature investigating the association between various working conditions and fetal and maternal health concluded that shift work poses minimal risk to the female reproductive system.54 Sleep across the Menstrual Cycle Surveys and studies based on subjective reports have found that women across a wide age range (aged 18 to 50 years) report more sleep disturbances during the premenstrual week and during the first few days of menstruation than at other times.55 The SWAN (Study of Women’s Health Across the Nation) study, which included women in their late reproductive stage or entering the menopausal transition, reported that trouble sleeping varied with cycle phase, being more likely to occur during the early follicular and late luteal phases of the menstrual cycle.56 Young women (21 ± 3 years) without significant menstrual-associated complaints also report poorer sleep quality around menstruation.57 As discussed later, women who experience severe menstrual cramps or premenstrual symptoms can experience more-significant declines in sleep quality in association with their symptoms. Studies that have investigated sleep objectively with EEG measures have found variable menstrual cycle phase effects on sleep that do not always corroborate findings from subjective sleep studies.44,55,57a One reason for the inconclusive findings from studies of sleep in women across the menstrual cycle is the methodologic challenges for research, including variability in cycle length, presence and timing of ovulation, changes with age, and sampling times during the menstrual cycle.44 Individual studies have generally been performed on a small number of women (<10) and at selected phases of the menstrual cycle. Most studies have found that sleep-onset latency (time from lights out to stage 1 or stage 2 sleep) and sleep efficiency remain stable at different phases of the menstrual cycle in young women.55 Some studies have found increased intermittent awakenings or wake time during the late luteal phase compared with the follicular phase,58,59 which corresponds with women’s reports of poorer subjective sleep quality premenstrually. The most dramatic change in sleep in association with the menstrual cycle is evident from spectral analysis of the sleep EEG. EEG activity in the 14.25- to 15.0-Hz band, which corresponds to the upper frequency range of sleep spindles, is significantly increased in the luteal phase compared with the follicular phase.58,60 An increase in visually scored stage 2 sleep in the luteal phase may also be apparent.60 The increased spindle frequency activity is reminiscent of the effects of the progesterone metabolite, allopregnanolone, on the EEG in rats,61 and might represent an interaction between endogenous progesterone metabolites and gamma-aminobutyric acid A (GABAA)
membrane receptors in the luteal phase.60 Benzodiazepines and barbiturates also exert their sedative effects by binding to the GABAA receptor, but probably at a different site from that to which progesterone metabolites bind.62 Percentage of SWS and SWA in NREM sleep, averaged across the night, do not change,60 suggesting that sleep homeostasis is maintained across the menstrual cycle. The menstrual cycle has some influence on REM sleep. Studies have found that REM sleep has an earlier onset,63 and the percentage of REM sleep tends to be decreased in association with raised body temperature in the luteal phase.44 Women with ovulatory cycles have a shorter REM-onset latency in the luteal phase compared to women with anovulatory cycles.64 In the absence of ovulation, women do not secrete sufficient ovarian hormones or increase their core body temperature and thus do not experience a true luteal phase in the 2 weeks prior to menses. Variation in the timing of REM sleep during the menstrual cycle may be related to altered circadian processes; during the luteal phase, higher core temperature or the dampened amplitude of the temperature rhythm can lower the threshold for earlier REM-sleep onset.63 An analysis of sleep architecture as a function of sleep cycle during the midfollicular phase compared with the midluteal phase of the menstrual cycle in healthy young women has revealed further subtle effects of the menstrual cycle on sleep.44 In the luteal phase compared with the follicular phase, the first sleep cycle and the first REM sleep episode are shorter, and women have less REM sleep in the first and fourth sleep cycles. Also, SWA is significantly higher in the first NREM sleep episode of the luteal phase but is no longer different from follicular phase values by the third episode. EEG activity in the upper spindle frequency range is higher during all NREM sleep episodes in the luteal phase compared with the follicular phase.44 In summary, sleep is remarkably stable across the normal menstrual cycle, despite the large changes in hormone milieu. There are, however, some changes in sleep, most notably an increase in upper spindle frequency activity and a decrease in REM sleep in the luteal phase compared to the follicular phase. Menstrual-related changes in sleep can manifest more in older women and in women with menstrual-associated pain or mood changes, as discussed in the following section. Sleep in Women with Menstrual Cycle Disorders Complaints related to the menstrual cycle—including mood disorders, pain associated with menstruation, and endocrinologic problems such as polycystic ovary syndrome (PCOS)—are common in women. Women who suffer from a menstrual cycle–associated disorder might experience concomitant changes in their sleep; women who have menstrual-related problems are two to three times more likely than other women to report insomnia and excessive sleepiness during the day.65 Polycystic Ovary Syndrome Polycystic ovary syndrome affects 4% to 12% of women of reproductive age.66 Women with PCOS typically present with irregular or absent cycles, androgen excess (evident as hirsutism), and bilateral polycystic ovaries.67 Insulin
1568 PART II / Section 18 • Women’s Health Low apnea risk and no complaint 8% High apnea risk and two complaints 24% High apnea risk and single complaint 32%
Low apnea risk and single complaint 18% High apnea risk and no complaint 18%
Figure 137-3 The frequency distribution of the risk for sleep apnea and sleep complaints in 40 women who have PCOS (Tasali E, Van Cauter E, Ehrmann DA. Relationships between sleep disordered breathing and glucose metabolism in polycystic ovary syndrome. J Clin Endocrinol Metab 2006;91:36-42.)
resistance is also an important component of PCOS,67 and obesity occurs in approximately 50% of cases.68 Medical management of PCOS involves controlling irregular menses with, for example, oral contraceptive pills (OCP); treating hirsutism either by decreasing or blocking androgens or by mechanical means; managing infertility; and managing insulin resistance over the long term.66 The combination of obesity and excess androgen production places women with PCOS at increased risk for sleep-disordered breathing (SDB), hypertension, and cardiovascular disease. Indeed, women with PCOS were found to be 30 times more likely to suffer from SDB than controls.69 Obesity is an important risk factor for SDB, but even when compared with healthy age- and weight-matched controls, women with PCOS are more likely to have SDB during their reproductive years (Fig. 137-3) and are more likely to report excessive daytime sleepiness (80%) than healthy women (27%), even after controlling for body weight.70,70a Increased visceral obesity, common in women with PCOS, may be more closely associated than elevated body mass index with increased risk for SDB.71 Severity of SDB is associated with glucose intolerance and insulin resistance in women with PCOS, suggesting that SDB might contribute to the metabolic abnormalities in these women.70 Given that continuous positive airway pressure (CPAP) therapy leads to an almost immediate improvement in insulin sensitivity in patients with obstructive sleep apnea,72 CPAP therapy is likely to benefit women with PCOS. Premenstrual Syndrome Premenstrual syndrome (PMS) is characterized by emotional, behavioral, and physical symptoms that occur in the premenstrual phase of the menstrual cycle, with resolution at the onset of menses or shortly thereafter. Many women of reproductive age experience some premenstrual symptoms, but up to 18% of women have clinically relevant premenstrual symptoms that they perceive as distressing and that affect daily function.73 Premenstrual dysphoric disorder (PMDD), previously known as late luteal phase dysphoric disorder (LLPD), is
a severe form of PMS that occurs in 3% to 8% of women.73 PMDD is classified as a “depressive disorder not otherwise specified” in the American Psychiatric Association’s Diagnostic and Statistical Manual of Mental Disorders, 4th edition (DSM-IV). A diagnosis of PMDD requires the occurrence of at least five of eleven specified symptoms, of which at least one must be a mood-related symptom during the late luteal phase, for at least two consecutive cycles. One of the specified symptoms is sleep disturbance (insomnia or hypersomnia). Pharmacologic management of severe PMS or PMDD includes selective serotonin reuptake inhibitors (the drug of choice recommended by the American College of Obstetricians and Gynecologists), anxiolytics, and agents that suppress ovulation.74 Nonpharmacologic agents such as calcium supplements, l-tryptophan, and cognitive behavior therapy have also been shown to be effective.74 Women with severe PMS typically report sleep-related complaints such as insomnia, sleep perturbation by body movements and awakenings, disturbing dreams, and poor sleep quality associated with their PMS symptoms.75 They also report sleepiness, fatigue, decreased alertness, and an inability to concentrate during the premenstrual phase.75 Studies using objective PSG recordings have reported traitlike differences in sleep architecture, including more stage 2 sleep, less REM sleep, or decreased incidence of delta (0.3 to 4 Hz) waveforms in NREM sleep in women with severe PMS or PMDD compared to women with minimal symptoms during the follicular and luteal phases, although findings varied between studies.75 However, PSG studies have shown little evidence of nocturnal sleep disturbance that is linked to premenstrual symptoms in the late luteal phase compared with other phases of the menstrual cycle. One study found that women with severe PMS had decreased heart rate variability and decreased highfrequency power, reflecting reduced parasympathetic nervous system activity, during NREM sleep in association with their premenstrual symptoms.76 Reduced parasympathetic modulation during sleep may affect the restorative properties of sleep and the perception of sleep quality in these women.76 Although studies have not been conducted under constant-routine conditions, evidence suggests that women with PMDD have abnormally regulated circadian rhythms. High mean nocturnal temperatures and disturbances in melatonin rhythms and in the timing of the rhythms of cortisol and thyroid-stimulating hormone have been reported in women with severe PMS or PMDD compared with asymptomatic controls.46,77-77b Given these disturbances in circadian rhythmicity in women with PMDD, investigators have explored the possibility of treating PMDD by manipulating the timing of sleep with sleepdeprivation protocols or with light therapy. Appropriately timed light therapy has shown some promise as a treatment strategy for PMDD, possibly by altering nocturnal melatonin secretion78; however, a meta-analysis of clinical trials of bright-light therapy concluded that larger trials are needed to define what role bright-light therapy has in the treatment of PMDD.79 For women with PMDD, sleep deprivation during the symptomatic luteal menstrual cycle phase may be therapeutic. Eight of 10 women responded to sleep deprivation
CHAPTER 137 • Sex Differences and Menstrual-Related Changes in Sleep and Circadian Rhythms 1569
in one study and maintained improved mood after a night of recovery sleep.80 In a follow-up study, partial sleep deprivation had similar positive effects on mood in 60% to 67% of patients, but these effects were only significant after recovery sleep.81 Changes in REM latency and REM density in the first REM sleep period from baseline to recovery nights were significantly correlated with improvement in mood in responders to sleep deprivation.82 The effect of sleep deprivation on mood in women with PMDD differs from that found in patients with MDD, who have improved mood the day following total sleep deprivation but tend to relapse after recovery sleep.83 Dysmenorrhea Dysmenorrhea is defined as painful menstrual cramps of uterine origin. It is the most common gynecologic condition among women of reproductive age, and it is very severe in approximately 10% to 25% of women.84 Primary dysmenorrhea is menstrual pain without organic disease, and secondary dysmenorrhea is associated with conditions such as endometriosis and pelvic inflammatory disease. Menstrual cramps experienced every month significantly affect productivity and quality of life and are associated with a restriction of activity and absenteeism from work and school.84 A PSG study of women with primary dysmenorrhea found that the menstrual cramps were associated with disturbed sleep (poorer subjective sleep quality; lower sleep efficiency; increased time spent awake, moving, and in stage 1 light sleep; and less REM sleep) compared with pain-free phases of the menstrual cycle and compared with women who do not suffer menstrual pain.85 Disturbed sleep, in turn, can exacerbate pain, because sleep deprivation is associated with a decreased pain threshold.86 In most women, dysmenorrhea is effectively treated with analgesics and nonsteroidal antiinflammatory drugs. Alternative therapies such as heat and dietary supplements of thiamine or magnesium have also shown some effectiveness.87 Treatment of nocturnal pain with analgesics alleviates painful cramps and consequently improves sleep quality in women with primary dysmenorrhea.88 Sleep Disorders and Menstrual Cycle Three forms of menstrual-associated sleep disorder— premenstrual insomnia, premenstrual hypersomnia, and menopausal insomnia—were proposed in the 1997 revised edition of the International Classification of Sleep Disorders (ICSD-R). In the second edition of the ICSD (2005) the only gynecologic type of disorder listed is menstrualrelated hypersomnia (recurrent hypersomnia). Premenstrual hypersomnia is a rare disorder characterized by sleepiness occurring in the week before the onset of menses. The patient has no complaints of persistent, excessive sleepiness at other times in the menstrual cycle.75 Patients with premenstrual hypersomnia have been successfully treated with either estrogen or combined OCPs.75 Oral Contraceptives, Body Temperature, and Sleep Oral contraceptives are combined formulations of a lowdose progestin and a synthetic estrogen and are taken by healthy women for long periods of time. OCPs suppress
endogenous reproductive hormones and therefore prevent ovulation so that women taking these preparations do not have ovulatory cycles. Women taking OCPs that contain estrogen and a progestin have raised 24-hour body temperature profiles, with temperature minima occurring at a similar time as in ovulating women in the luteal phase (see Fig. 137-2).46 This body temperature elevation is likely caused by the thermogenic action of progestins contained in the OCP. During the 7-day placebo period of the OCP pack, 24-hour body temperatures remain elevated,89 suggesting that continuous use of synthetic reproductive steroids might have longterm influences on thermoregulation. In contrast, body temperature rapidly decreases as progesterone levels decline before menstruation in women with ovulatory cycles. OCPs also can influence melatonin levels, although findings are inconsistent.46 In one study using a modified constant-routine procedure, researchers found no significant differences in melatonin levels between naturally cycling women and women taking OCPs, although there was a trend in this small sample for increased melatonin levels in the latter part of the night in women taking OCPs.48 Sleep architecture is altered by OCPs. Women taking OCPs have less SWS than do women with natural menstrual cycles.44 Stage 2 sleep is significantly increased during the weeks women are taking active pills compared to the placebo week, and it is significantly higher in women taking active OCPs compared to naturally cycling women in both menstrual cycle phases.89 Other sleep effects reported in OCP users include a shorter REM onset latency and more REM sleep compared to women with natural menstrual cycles.44,90 Exogenous steroid hormones therefore appear to influence sleep differently from the variations in endogenous hormones across the menstrual cycle, possibly because of the greater potency of synthetic steroids. Consideration of OCP use might also be important when comparing healthy women to those with clinical disorders such as depression. The sleep effects of OCPs can compromise sleep differences between healthy and depressed women.90
❖ Clinical Pearls The finding of progesterone and estrogen receptors in the hypothalamus suggests that these hormones might influence circadian rhythmicity and sleep patterns directly. Sex differences in sleep and rhythms may be risk factors for neurologic, immunologic, and psychiatric disease, and the relationship between sleep and psychological health and behavior appears to be strongly influenced by sex. Women are likely to experience a decrease in sleep quality before and during menstruation compared to other phases of their menstrual cycle. In particular, women with severe PMS can experience premenstrual insomnia. Given the high incidence of sleep-disordered breathing and its association with glucose intolerance in women with PCOS, screening for sleep apnea and appropriate treatment with CPAP may be beneficial in these women.
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REFERENCES 1. Renolleau S, Fau S, Charriaut-Marlangue C. Gender-related differences in apoptotic pathways after neonatal cerebral ischemia. Neuroscientist 2008;14:46-52. 2. Anders TF, Halpern LF, Hua J. Sleeping through the night: a developmental perspective. Pediatrics 1992;90:554-560. 3. Goodlin-Jones BL, Burnham MM, Gaylor EE, et al. Night waking, sleep–wake organization, and self-soothing in the first year of life. J Dev Behav Pediatr 2001;22:226-233. 4. Kato I, Scaillet S, Groswasser J, et al. Spontaneous arousability in prone and supine position in healthy infants. Sleep 2006;29: 785-790. 5. Thordstein M, Löfgren N, Flisberg A, et al. Sex differences in electrocortical activity in human neonates. Neuroreport 2006;17: 1165-1168. 6. Hoppenbrouwers T, Hodgman JE, Harper RM, et al. Respiration during the first six months of life in normal infants: IV. Gender differences. Early Hum Dev 1980;4:167-177. 7. Mirmiran M, Maas YG, Ariagno RL. Development of fetal and neonatal sleep and circadian rhythms. Sleep Med Rev 2003;7: 321-334. 8. Cornwell AC, Feigenbaum P, Kim A. SIDS, abnormal nighttime REM sleep and CNS immaturity. Neuropediatrics 1998;29:72-79. 9. Lamont EW, James FO, Boivin DB, et al. From circadian clock gene expression to pathologies. Sleep Med 2007;8:547-556. 10. Epstein R, Chillag N, Lavie P. Starting times of school: effects on daytime functioning of fifth-grade children in Israel. Sleep 1998;21:250-256. 11. Meijer AM, Habekothé HT, Van den Wittenboer GLH. Time in bed, quality of sleep and school functioning of children. J Sleep Res 2000;9:145-153. 12. Thorleifsdottir B, Bjornsson JK, Benediktsdottir B. Sleep and sleep habits from childhood to young adulthood over a 10-year period. J Psychosom Res 2002;53:529-537. 13. Fallone G, Seifer R, Acebo C, et al. How well do school-aged children comply with imposed sleep schedules at home? Sleep 2002; 25:739-745. 14. Sadeh A, Lavie P, Scher A, et al. Actigraphic home-monitoring sleepdisturbed and control infants and young children: a new method for pediatric assessment of sleep–wake patterns. Pediatrics 1991;87: 494-499. 15. Spilsbury JC, Storfer-Isser A, Drotar D, et al. Sleep behavior in an urban US sample of school-aged children. Arch Pediatr Adolesc Med 2004;158:988-994. 16. Montgomery-Downs HE, O’Brien LM, Gulliver TE, et al. Polysomnographic characteristics in normal preschool and early school-aged children. Pediatrics 2006;117:741-753. 17. Lopes MC, Rosa A, Roizenblatt S, et al. Cyclic alternating pattern in peripubertal children. Sleep 2005;28:215-219. 18. Bruni O, Ferri R, Miano S, et al. Sleep cyclic alternating pattern in normal preschool-aged children. Sleep 2005;28:220-230. 19. Robert JJ, Hoffmann RF, Emslie GJ, et al. Sex and age differences in sleep macroarchitecture in childhood and adolescent depression. Sleep 2006;29:351-358. 20. Armitage R, Hoffmann R, Emslie G, et al. Sleep microarchitecture in childhood and adolescent depression: temporal coherence. Clin EEG Neurosci 2006;37:1-9. 21. Armitage R, Hoffmann R, Emslie G, et al. Rest–activity cycles in childhood and adolescent depression. J Am Acad Child Adolesc Psychiatry 2004;43:761-769. 22. Armitage R. Sleep and circadian rhythms in mood disorders. Acta Psychiatr Scand Suppl 2007:104-115. 23. Morehouse RL, Kusumakar V, Kutcher SP, et al. Temporal coherence in ultradian sleep EEG rhythms in a never-depressed, high-risk cohort of female adolescents. Biol Psychiatry 2002;51:446456. 24. Armitage R, Flynn H, Marcus S, et al. Sleep and circadian rest activity cycles in infancy: the role of maternal depression. J Sleep Res 2008;17(Suppl. 1):46. 25. Wolfson AR, Carskadon MA. Sleep schedules and daytime functioning in adolescents. Child Dev 1998;69:875-887. 26. Johnson EO, Roth T, Schultz L, et al. Epidemiology of DSM-IV insomnia in adolescence: lifetime prevalence, chronicity, and an emergent gender difference. Pediatrics 2006;117:247-256.
27. Angold A, Costello EJ, Worthman CM. Puberty and depression: the roles of age, pubertal status and pubertal timing. Psychol Med 1998;28:51-61. 28. Carskadon MA, Wolfson AR, Acebo C, et al. Adolescent sleep patterns, circadian timing, and sleepiness at a transition to early school days. Sleep 1998;21:871-881. 29. Feinberg I. Changes in sleep cycle patterns with age. J Psychiatr Res 1974;10:283-306. 30. Jenni OG, Carskadon MA. Spectral analysis of the sleep electroencephalogram during adolescence. Sleep 2004;27:774-783. 31. Campbell IG, Darchia N, Khaw WY, et al. Sleep EEG evidence of sex differences in adolescent brain maturation. Sleep 2005;28: 637-643. 32. Carskadon MA, Harvey K, Duke P, et al. Pubertal changes in daytime sleepiness. Sleep Breath 1980;2:453-460. 33. Feinberg I, Higgins LM, Khaw WY, et al. The adolescent decline of NREM delta, an indicator of brain maturation, is linked to age and sex but not to pubertal stage. Am J Physiol Regul Integr Comp Physiol 2006;291:R1724-R1729. 34. Feinberg I. Schizophrenia: caused by a fault in programmed synaptic elimination during adolescence? J Psychiatr Res 1982;17:319-334. 35. Middelkoop HAM, Smilde-van den Doel DA, Neven AK, et al. Subjective sleep characteristics of 1,485 males and females aged 50-93: effects of sex and age, and factors related to self-evaluated quality of sleep. J Gerontol A Biol Sci Med Sci 1996;51: M108-M115. 36. Rediehs MH, Reis JS, Creason NS. Sleep in old age: focus on gender differences. Sleep 1990;13:410-424. 37. Jean-Louis G, Mendlowicz MV, Von Gizycki H, et al. Assessment of physical activity and sleep by actigraphy: examination of gender differences. J Womens Health Gend Based Med 1999;8:1113-1117. 38. Carrier J, Land S, Buysse DJ, et al. The effects of age and gender on sleep EEG power spectral density in the middle years of life (ages 20-60 years old). Psychophysiology 2001;38:232-242. 39. Armitage R, Hoffmann RF. Sleep EEG, depression and gender. Sleep Med Rev 2001;5:237-246. 40. Armitage R, Smith C, Thompson S. Sex differences in slow-wave activity in response to sleep deprivation. Sleep Res Online 2001;4: 33-41. 41. Van Cauter E, Leproult R, Kupfer DJ. Effects of gender and age on the levels and circadian rhythmicity of plasma cortisol. J Clin Endocrinol Metab 1996;81:2468-2473. 42. Kajantie E, Phillips DI. The effects of sex and hormonal status on the physiological response to acute psychosocial stress. Psychoneuroendocrinology 2006;31:151-178. 43. Pocock G, Richards CD. Human physiology: the basis of medicine. New York: Oxford University Press; 1999. 44. Driver HS, Werth E, Dijk D-J, et al. The menstrual cycle effects on sleep. Sleep Med Clin 2008;3:1-11. 45. de Mouzon J, Testart J, Lefevre B, et al. Time relationships between basal body temperature and ovulation or plasma progestins. Fertil Steril 1984;41:254-259. 46. Baker FC, Driver HS. Circadian rhythms, sleep, and the menstrual cycle. Sleep Med 2007;8:613-622. 47. Cagnacci A, Arangino S, Tuveri F, et al. Regulation of the 24h body temperature rhythm of women in luteal phase: role of gonadal steroids and prostaglandins. Chronobiol Int 2002;19:721-730. 48. Wright KP Jr, Badia P. Effects of menstrual cycle phase and oral contraceptives on alertness, cognitive performance, and circadian rhythms during sleep deprivation. Behav Brain Res 1999;103: 185-194. 49. Shibui K, Uchiyama M, Okawa M, et al. Diurnal fluctuation of sleep propensity and hormonal secretion across the menstrual cycle. Biol Psychiatry 2000;48:1062-1068. 50. Swaab DF, Chung WCJ, Kruijver FPM. Sex differences in the hypothalamus in the different stages of human life. Neurobiol Aging 2003;24:S1-S16. 51. Shechter A, James FO, Boivin DB. Circadian rhythms and shift working women. Sleep Med Clin 2008;3:13-24. 52. Labyak S, Lava S, Turek F, et al. Effects of shiftwork on sleep and menstrual function in nurses. Health Care Women Int 2002;23: 703-714. 53. Axelsson G, Rylander R, Molin I. Outcome of pregnancy in relation to irregular and inconvenient work schedules. Br J Ind Med 1989;46:393-398.
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54. Bonzini M, Coggon D, Palmer KT. Risk of prematurity, low birthweight and pre-eclampsia in relation to working hours and physical activities: a systematic review. Occup Environ Med 2007;64: 228-243. 55. Manber R, Baker FC, Gress JL. Sex differences in sleep and sleep disorders: a focus on women’s sleep. Int J Sleep Disord 2006;1: 7-15. 56. Kravitz HM, Janssen I, Santoro N, et al. Relationship of day-to-day reproductive hormone levels to sleep in midlife women. Arch Intern Med 2005;165:2370-2376. 57. Baker FC, Driver HS. Self-reported sleep across the menstrual cycle in young, healthy women. J Psychosom Res 2004;56:239-243. 57a. Shechter A, Varin F, Boivin DB. Circadian variation of sleep during the follicular and luteal phases of the menstrual cycle. Sleep 2010;33:647-656. 58. Baker FC, Kahan TL, Trinder J, et al. Sleep quality and the sleep electroencephalogram in women with severe premenstrual syndrome. Sleep 2007;30:1283-1291. 59. Parry BL, Mendelson WB, Duncan WC, et al. Longitudinal sleep EEG, temperature, and activity measurements across the menstrual cycle in patients with premenstrual depression and in age-matched controls. Psychiatry Res 1989;30:285-303. 60. Driver HS, Dijk DJ, Werth E, et al. Sleep and the sleep electroencephalogram across the menstrual cycle in young healthy women. J Clin Endocrinol Metab 1996;81:728-735. 61. Damianisch K, Rupprecht R, Lancel M. The influence of subchronic administration of the neurosteroid allopregnanolone on sleep in the rat. Neuropsychopharmacology 2001;25:576-584. 62. Lancel M. Role of GABAA receptors in the regulation of sleep: initial sleep responses to peripherally administered modulators and agonists. Sleep 1999;22:33-42. 63. Lee KA, Shaver JF, Giblin EC, et al. Sleep patterns related to menstrual cycle phase and premenstrual affective symptoms. Sleep 1990; 13:403-409. 64. Lee KA, McEnany G, Zaffke ME. REM sleep and mood state in childbearing women: sleepy or weepy? Sleep 2000;23:877-885. 65. Strine TW, Chapman DP, Ahluwalia IB. Menstrual-related problems and psychological distress among women in the United States. J Womens Health (Larchmt) 2005;14:316-323. 66. Sheehan MT. Polycystic ovarian syndrome: diagnosis and management. Clin Med Res 2004;2:13-27. 67. Sartor BM, Dickey RP. Polycystic ovarian syndrome and the metabolic syndrome. Am J Med Sci 2005;330:336-342. 68. Dunaif A. Insulin resistance and the polycystic ovary syndrome: mechanism and implications for pathogenesis. Endocr Rev 1997;18: 774-800. 69. Vgontzas AN, Legro RS, Bixler EO, et al. Polycystic ovary syndrome is associated with obstructive sleep apnea and daytime sleepiness: role of insulin resistance. J Clin Endocrinol Metab 2001;86:517-520. 70. Tasali E, Van Cauter E, Ehrmann DA. Polycystic ovary syndrome and obstructive sleep apnea. Sleep Med Clin 2008;3:37-46. 70a. Yang HP, Kang JH, Su HY, et al. Apnea-hypopnea index in nonobese women with polycystic ovary syndrome. Int J Gynaecol Obstet 2009;105:226-229. 71. Fogel RB, Malhotra A, Pillar G, et al. Increased prevalence of obstructive sleep apnea syndrome in obese women with polycystic ovary syndrome. J Clin Endocrinol Metab 2001;86:1175-1180. 72. Harsch IA, Schahin SP, Radespiel-Troger M, et al. Continuous positive airway pressure treatment rapidly improves insulin sensitivity in
patients with obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2004;169:156-162. 73. Halbreich U. The etiology, biology, and evolving pathology of premenstrual syndromes. Psychoneuroendocrinology 2003;28(Suppl. 3):55-99. 74. Rapkin A. A review of treatment of premenstrual syndrome and premenstrual dysphoric disorder. Psychoneuroendocrinology 2003; 28(Suppl. 3):39-53. 75. Baker FC, Lamarche LJ, Iacovides S, et al. Sleep and menstrualrelated disorders. Sleep Med Clin 2008;3:25-35. 76. Baker FC, Colrain IM, Trinder J. Reduced parasympathetic activity during sleep in the symptomatic phase of severe premenstrual syndrome. J Psychosom Res 2008;65:13-22. 77. Parry BL, Martinez LF, Maurer EL, et al. Sleep, rhythms and women’s mood. Part I. Menstrual cycle, pregnancy and postpartum. Sleep Med Rev 2006;10:129-144. 77a. Shechter A, Boivin DB. Sleep, hormones, and circadian rhythms throughout the menstrual cycle in healthy women and women with premenstrual dysphoric disorder. Int J Endocrinol 2010;2010:259345. (Epub). 77b. Parry BL, Meliska CJ, Sorenson DL, et al. Increased sensitivity to light-induced melatonin suppression in premenstrual dysphoric disorder. Chronobiol Int 2010;27:1438-1453. 78. Parry BL, Udell C, Elliott JA, et al. Blunted phase-shift responses to morning bright light in premenstrual dysphoric disorder. J Biol Rhythms 1997;12:443-456. 79. Krasnik C, Montori VM, Guyatt GH, et al. The effect of bright light therapy on depression associated with premenstrual dysphoric disorder. Am J Obstet Gynecol 2005;193:658-661. 80. Parry BL, Wehr TA. Therapeutic effect of sleep deprivation in patients with premenstrual syndrome. Am J Psychiatry 1987;144:808-810. 81. Parry BL, Cover H, Mostofi N, et al. Early versus late partial sleep deprivation in patients with premenstrual dysphoric disorder and normal comparison subjects. Am J Psychiatry 1995;152: 404-412. 82. Parry BL, Mostofi N, LeVeau B, et al. Sleep EEG studies during early and late partial sleep deprivation in premenstrual dysphoric disorder and normal control subjects. Psychiatry Res 1999;85:127-143. 83. Wirz-Justice A, Van den Hoofdakker RH. Sleep deprivation in depression: what do we know, where do we go? Biol Psychiatry 1999;46:445-453. 84. Dawood MY. Dysmenorrhea. Clin Obstet Gynecol 1990;33:168178. 85. Baker FC, Driver HS, Rogers GG, et al. High nocturnal body temperatures and disturbed sleep in women with primary dysmenorrhea. Am J Physiol 1999;277:E1013-E1021. 86. Kundermann B, Krieg JC, Schreiber W, et al. The effect of sleep deprivation on pain. Pain Res Manag 2004;9:25-32. 87. Proctor M, Farquhar C. Diagnosis and management of dysmenorrhoea. BMJ 2006;332:1134-1138. 88. Iacovides S, Avidon I, Bentley A, et al. Diclofenac potassium restores objective and subjective measures of sleep quality in women with primary dysmenorrhea. Sleep 2009;32:1019-1026. 89. Baker FC, Mitchell D, Driver HS. Oral contraceptives alter sleep and raise body temperature in young women. Pflugers Arch 2001;442:729-737. 90. Shine-Burdick R, Hoffmann R, Armitage R. Short note: oral contraceptives and sleep in depressed and healthy women. Sleep 2002;25: 347-349.
Sleep Disturbances and Sleep-Related Disorders in Pregnancy Bilgay Izci Balserak and Kathryn Lee Abstract Most women experience numerous sleep disturbances for the first time in their life during pregnancy, which dramatically changes sleep architecture. Sleep disturbances commence with the onset of pregnancy, and they increase in frequency and duration as pregnancy progresses. The most common sleep disturbances occurring during pregnancy are nausea, vomiting, frequent urination, and anxiety (especially in firsttime or unplanned pregnancies) in the first trimester and backache, fetal movement, abdominal discomfort, leg cramps, frequent urination, shortness of breath, heartburn, and anxiety about delivery and the fetus at the end of the second and into the third trimester. As a result of these disturbances and pregnancy-related changes, women suffer from considerable daytime sleepiness and fatigue. Sleep-related disorders also occur or worsen during pregnancy, such as sleep-disordered breathing (SDB), restless legs syndrome (RLS) and insomnia. SDB, including snoring and sleep apnea, can be
Complaints of sleep disturbances are common during pregnancy, generally commencing with the onset of pregnancy, and increasing in frequency and duration as pregnancy progresses due to pregnancy-related anatomic, physiologic and hormonal changes.1-3 These changes can also cause sleep disorders or exacerbate prepregnancy sleep disorders, both of which can threaten maternal (mental and physical) health and fetal well-being.4-7
PREGNANCY-INDUCED HORMONAL CHANGES AND THEIR EFFECT ON SLEEP Pregnancy brings about significant changes in the maternal endocrine milieu including the gonadal steroids (estrogen and progesterone), pituitary hormones (gonadatropins, prolactin, growth hormone), melatonin, and cortisol.8-10 These hormonal changes not only affect the sleep–wake cycle and sleep structure directly, but they also cause physiologic changes that lead to sleep disturbances (detailed in the later discussion of physiologic changes). The main sex steroids progesterone and estrogen show a 24-hour rhythm at 35 weeks’ gestation. Serum progesterone has a diurnal change, with higher concentrations in the evening.11 The maternal plasma estriol has a phase that is opposite to that of the cortisol rhythm, which is discussed later.9 Progesterone Progesterone significantly increases across pregnancy, with levels 10 to 5000 times higher at term compared to the nonpregnant phase and stage of ovarian cycle.8 Complaints of sleepiness and fatigue may be attributable to increased progesterone during pregnancy.12 Progesterone deactivates the brain and produces soporific and sedating 1572
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induced by pregnancy-related changes in the upper airway, lung mechanics, and the control of breathing. Pregnancyrelated RLS is considered a secondary form of RLS, which has been attributed to low iron and folate level at preconception. Complaints of nocturnal esophageal reflux and sleep-related leg cramps also increase during pregnancy. All these symptoms need to be seriously assessed, particularly in women with obesity and those who develop hypertension because of the potential adverse outcomes for maternal and fetal wellbeing and poor obstetric outcomes such as preeclampsia, intrauterine growth restriction, or long labor. Nonpharmacologic interventions for sleep disturbances and disorders, including lifestyle modifications, should be considered as the first choice. If pharmacologic treatment is needed for severe conditions, medications should be used with caution due to their possible teratogenic effects. Most medications are lacking controlled trials in pregnant women.
effects by activating intracellular progesterone receptors and its metabolites, targeting brain gamma-aminobutyric acid (GABA) receptors.10,13,14 Animal and human studies have demonstrated that progesterone administration decreases the amount of wakefulness and rapid eye movement (REM) sleep and reduces the latency to non-REM (NREM) sleep.10,13-15 On the other hand, progesteroneinduced smooth muscle relaxation can contribute to frequent urination, heartburn, and pregnancy rhinitis, causing nocturnal awakenings.6,13,14,16-18 The increase in levels of progesterone is also believed to raise the body temperature that disrupts sleep quality.19 Estrogen The estrogen level during late pregnancy is approximately 1000 times higher than in the ovulatory premenopausal period.8 Unlike progesterone, estrogen has been reported to have excitatory effects in the nervous system and to selectively decrease REM sleep activation of sleep-active neurons in the ventrolateral preoptic area.20 Increased estrogen concentrations during pregnancy cause vasodilation,8 which can result in edema in the extremities and nasal obstruction.8,18 Cortisol Cortisol starts to increase from the 25th to the 28th week; the most dramatic increase is seen in late pregnancy. Cortisol rapidly returns to normal concentrations after delivery.11 Cortisol has a complex circadian rhythm. It decreases to the lowest level in the early hours of night and increases at the time of morning awakening, reaching its peak at noon.9,11 In pregnant women, this peak is not obvious, probably due to the blunting effect of placental corticotropin (ACTH) on maternal cortisol concentrations.9-11
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A human study of cortisol infusions showed decrements in REM sleep and increases in slow-wave sleep (SWS),10,21 probably due to increased progesterone, which elevates the free cortisol.9 Pregnant women with poor sleep in the third trimester have lower cortisol-to-melatonin ratios than good sleepers as a result of a lower early morning peak in their cortisol levels and a relatively higher concentration of melatonin.14 Melatonin Concentrations of serum melatonin in healthy women display a clear diurnal rhythm in both early and late pregnancy.14,21 However, the circadian melatonin concentration rhythm is lost in preeclamptic women, who have altered blood pressure rhythm.21 Altered rhythm or low levels of melatonin secretion might lead to some pregnancy complications. Serum melatonin levels have been found to be significantly higher during pregnancy and labor than during the postpartum period.21 In singleton pregnancies, nighttime serum melatonin levels steadily increased after 24 weeks of gestation and exhibited significantly higher levels after 32 weeks and around the period of delivery, but they decreased to nonpregnant levels on the second day after delivery.21 In twin pregnancies nighttime melatonin levels were significantly higher after 28 weeks of gestation than normal singleton pregnancies.21 Prolactin Plasma levels of prolactin increase tenfold in pregnant women compared with nonpregnant women.8 Studies showed that SWS is enhanced by prolactin secretion.10,22 Increased maternal SWS has been reported in lactating women compared to nonlactating women, probably due to increased prolactin level, although hormone levels were not measured.22 The type of delivery affects prolactin secretion. The basal level of prolactin rapidly decreases during active labor and reaches its highest level again up to 6 hours after vaginal delivery. This dramatic fluctuation in prolactin is not seen in elective cesarean births.23 Oxytocin Oxytocin has been reported to have a rhythm in late pregnancy, reaching the highest level at night together with the phase of the uterine activity rhythm.9 The rhythm of nocturnal uterine activity can compromise maternal and fetal blood flow and oxygen delivery,14 and contribute to nocturnal awakenings during the third trimester of pregnancy.1-3 The increased incidence of labor and delivery during the evening hours can result from increased maternal plasma oxytocin concentrations at night9,21 and cause significant sleep loss. Growth Hormone The secretion of growth hormone, essential for tissue growth and protein anabolism, is prompted by ghrelin and growth hormone–releasing hormone (GHRH).10 These hormones are closely associated with the onset and maintenance of SWS and play significant roles in sleep regulation.10,22 This suggests that growth hormone secretion and maintenance of SWS are important for fetal development and the mother’s health during pregnancy.
Relaxin Relaxin (primarily secreted by the corpus luteum during pregnancy) increases tenfold during pregnancy. It is associated with remodeling of the connective tissue fibers and inhibiting smooth muscle contractility to prepare the uterus for delivery.8,9 These relaxin-related changes can contribute to sleep-disordered breathing (SDB) due to relaxation of airway muscle, carpal tunnel syndrome due to fluid retention within connective tissue, and low back pain due to ligamentous laxity.8 However, the precise mechanisms for these problems associated with relaxin remain to be clarified. Summary Rhythms and circulation of sex steroids, prolactin. oxytocin, melatonin, cortisol, prolactin, oxytocin, growth hormone, and relaxin during pregnancy have significant effects on sleep during pregnancy. Pregnancy-related changes in hormones and their association with sleep regulation require further study.
PHYSIOLOGIC CHANGES IN PREGNANCY THAT COULD CONTRIBUTE TO SLEEP PROBLEMS In addition to the hormonal changes, pregnancy causes a multitude of anatomic and physiologic changes (Fig. 138-1).8,14,16,17,24,25 These changes are essential to maintain pregnancy, but they can contribute to sleep problems during pregnancy. COMMON SLEEP COMPLAINTS DURING PREGNANCY Each trimester of pregnancy brings its own type of sleep disturbance specific to that trimester. However, some of these disturbances occur across trimesters. First Trimester Fatigue is one of the first symptoms of pregnancy associated with prepregnancy levels of iron, ferritin, and hemoglobin and with younger age.12 Similarly, daytime sleepiness is prevalent (37.5% at 6 to 7 weeks of pregnancy), which is attributable to the somnogenic effect of progesterone and fragmented sleep.3,5,10,13,15,26 Sleep disturbances increase 1.4-fold relative to the prepregnancy period owing to nausea and vomiting, urinary frequency (51%), backache and other physical discomforts (e.g., tenderness and a tingling feeling in the breasts) and altered appetite caused by hormonal changes.1,3,8,27 Elevated anxiety, especially in the case of unplanned pregnancies or the absence of psychosocial support in first-time pregnancies, is common.1,28 Second Trimester Women acclimate to hormonal changes. Sleep disturbances, such as nausea and frequent urination (28.2%) (due to the growing fetus moving above the bladder), also decrease. As a result, energy levels increase and daytime sleepiness decreases.1-3,5,12 However, at the end of the second trimester, irregular uterus contractions
1574 PART II / Section 18 • Women’s Health
Respiratory changes: 1. Engorgement, hypersecretion, and mucosal edema in nose, oropharynx, larynx, and trachea result from progressive ↑ in estrogen and progesterone; ↑ blood and interstitial fluid volumes may lead to a ↓ in pharyngeal and nasal dimensions. 2. Nasal congestion and pregnancy rhinitis are common due to above factors; ↑ with gestational age; ↑ nasopharyngeal resistance may make airway pressure more negative during inspiration. 3. Compensatory ↑ in anterior-posterior diameter of chest and elevation of diaphragm caused by enlarging uterus result in tracheal shortening and progressive ↓ in functional residual capacity (by 20%-25%), expiratory reserve volume (by 33%-40%) and residual volume (by 22%). These alterations can lead to closure of small airways during normal tidal breathing. In late pregnancy, airway closure results in ventilation perfusion mismatch and ↓ gas exchange, especially in supine position. Relaxin-related changes may also contribute to airway closure due to relaxation of airway muscle. 4. Elevated ventilatory drive due to ↑ in progesterone may induce SDB by ↑ diaphragmatic effort leading to negative inspiratory (suction) pressures on hyperemic upper airway. 5. ↑ minute ventilation and tidal volume result in hypocapnia and respiratory alkalosis, causing respiratory instability and episodes of central apnea at sleep onset and during NREM sleep. 6. Frequent awakenings due to sleep disturbances may cause respiratory instability such as periodic breathing during sleep onset. Fragmented sleep and sleep deprivation can also ↓ upper airway muscle activity and ↑ upper airway collapsibility. See text for protective changes related to SDB.
Weight gain and fluid volume: 1. Mean weight gain is 12.5 kg (27.5 lb) between 11-16 kg (24-35 lb) at end of 3rd trimester. Minimum amount of extra fluid in an average woman is 6.5 L during pregnancy. 2. ↑ weight, especially fat deposition within soft tissue neck region, could cause pharyngeal narrowing and SDB. 3. ↑ fluid volume results in ↑ blood volume as well as ↑ uterus and breast size. Cardiovascular changes: 1. ↓ hemoglobin concentration due to ↑ blood volume by 50% from 6-8 wk to 32-34 wk and ↑ plasma volume (40%-50%), with lesser ↑ in red cell volume (20%-30%). 2. ↑ cardiac output in 1st trimester (15%-20%); peaks (50%) at end of 2nd trimester due to ↑ stroke volume and heat rate; 3. ↑ blood flow to uterus and renal system. 4. ↓ total peripheral resistance, thus ↓ blood pressure to nadir at 20 wk; ↑ to prepregnancy level in 3rd trimester. 5. Left ventricular hypertrophy due to upward displacement of diaphragm. Systolic flow murmurs in 90% of women. 6. Compression of inferior vena cava and lower aorta from enlarged uterus and fetal head results in edema (from midpregnancy) in legs and hypotension syndrome while supine. Gastrointestinal tract: 1. ↑ intragastric pressure and displacement of lower esophageal sphincter by gravid uterus. 2. Inhibitory effects of progesterone on gastrointestinal smooth muscle (nausea and vomiting). 3. Deficiencies in iron, folic acid and vitamin B12 may occur. Uro-genital tract: 1. Uterus too large for pelvis by 12 wk, extends to navel by 20 wk, and to lower edge of rib cage by 36 wk. 2. Renal blood flow ↑ ≥50% from baseline in 1st and 2nd trimester. 3. ↑ urination due to smooth muscle relaxation of renal pelvis and bladder compression by growing uterus in 1st and 3rd trimesters.
Musculoskeletal changes: 1. Exaggerated curvature of lower spine to balance ↑ anterior weight of womb. 2. More flexible joints and ligaments in pelvis. 3. ↑ fluid retention within connective tissue. Backache, pelvic pain and leg cramps occur as pregnancy advances and worsen at night leading to insomnia, especially in 3rd trimester. Compression of inferior vena cava and progesterone-induced changes in venous system cause severe hemorrhoids as well as leg and vulvar varicosities.
Figure 138-1 Pregnancy-related changes that can affect sleep. (Modified from American Medical Association, Atlas of the body: changes during pregnancy. Available at: http://www.medem.com/medlb/article_detaillb.cfm?article_ID=ZZZO0MM56JC&sub_ cat=516. Requires paid subscription. Accessed August 10, 2008.)
(Braxton-Hicks), fetal movements, heartburn, and snoring start to disrupt sleep.2,3,8,26 Third Trimester The majority of women typically report restless sleep (30.3%) and multiple nocturnal awakenings (98%) due to the continuation of symptoms that started at the end of the second trimester: frequent urination (47% to 95%),1-3,29 leg cramps, shortness of breath, heartburn, forced body position in bed, backache, joint pain, carpal tunnel symptoms (e.g., numbness), breast tenderness, and itching.1-3,29-31 Women also attribute their sleep loss to internal factors (vivid dreams or nightmares associated with anxiety about labor and delivery, fetus, pregnancy complications, worry about their sleep loss)1,3,5,29,32,33 and external factors such as their children and environmental noise.1-3,29 The incidence of sleep-related disorders such as SDB and restless legs syndrome (RLS) and associated complications increase (discussed later). Daytime sleepiness (up to 65%) and fatigue, associated with less total sleep and low folic acid, have been reported to increase.1-3,5,27,29,34,35
CHANGES IN SLEEP ARCHITECTURE AND SLEEP QUALITY IN NORMAL PREGNANCY Sleep architecture, quality, and quantity are altered by pregnancy due to hormonal changes, physical discomforts, and psychological adjustments.8,9,28 Thus, the majority of women (66% to 97%) report sleep alterations, usually in the form of multiple nocturnal awakenings, becoming more obvious in the third trimester.1-3,27 Studies using objective (e.g., polysomnography [PSG] and actigraphy) and subjective sleep measures (e.g., sleep questionnaires) consistently report that sleep efficiency progressively decreases due to increased nocturnal awakenings after sleep onset.1,2,5,30,36-39 However, the findings from the objective sleep measures are inconsistent, likely because of limited sample sizes, different research methodology, and settings (laboratory or home). It appears that home-recorded PSG results in greater mean total sleep time (TST) and sleep efficiency and shorter sleep-onset latency and fewer minutes awake after sleep onset
CHAPTER 138 • Sleep Disturbances and Sleep-Related Disorders in Pregnancy 1575
compared to laboratory-recorded PSG.40 Sleep during the daytime (naps), which can add to the total 24-hour sleep time, are often not recorded in PSG studies.3,5,39,41,42 First Trimester Sleep starts to change around the 10th week of gestation, showing a polyphasic characteristic with both nighttime sleep and frequent daytime naps.5,36,39 A study using home PSG also revealed an average 34-minute increase in TST, but decreases in sleep efficiency and SWS during the first trimester compared with prepregnancy assessments.36 Another study also found an increased TST and frequent napping in the first trimester.5 Similarly, a survey study reported that the TST significantly increased from 7.8 hours in before pregnancy to 8.2 hours, but subjective sleep quality decreased.2 Second Trimester Sleep becomes monophasic with improvements of subjective and objective sleep parameters, such as better sleep efficiency and less wake after sleep onset (WASO) (Table 138-1), but number of awakenings starts to increase at the end of the trimester.2,5,36,37,39,41 Objective measures of SWS and REM sleep stages are inconsistent.5,36-39 However, a study conducted in a home environment showed that SWS percentage slightly decreased but REM sleep percentage did not change relative to the first trimester.39
Third Trimester In this trimester (see Table 138-1), sleep again shows a polyphasic character with more frequent or longer wake episodes after sleep onset (average, 2.6) and more naps. The mean night sleeping time is reported to be around 7.8 hours with decreased sleep efficiency.2,5,30,36-40,43,44 Women spent more time in sleep stages 1 or 2.5,30,39,45 Most PSG studies reported that SWS decreases when compared to age-matched control women or the same women in previous trimesters (13% to 20%).5,30,36,37,39,43 Spectral analysis of the EEG in NREM sleep also showed a progressive reduction of power density across pregnancy. The largest decrease (30%) occurred in the 14.25- to 15.0-Hz band in the third trimester relative to the first trimester.37 However, a longitudinal study reported a progressive rise in SWS across pregnancy in five women from early to late pregnancy.38 REM sleep (represented either as an absolute number of minutes or as a percentage of TST) has been reported to either remain the same or decrease slightly.36-38,43 REM sleep latency is also highly variable across a number of studies.30,36-39,43 Overall, objective studies are not entirely conclusive but suggest that the structure of sleep in pregnant women is not completely different from that in nonpregnant populations. Pregnant women have more light sleep and less SWS owing to nocturnal awakenings, and they might have
Table 138-1 Sleep Architecture, Complaints, and Daytime Symptoms in Each Trimester and in Labor and Delivery FIRST TRIMESTER
SECOND TRIMESTER
THIRD TRIMESTER
LABOR AND DELIVERY
Monophasic character, ⇓TST (relative to first trimester), ⇑SE, ⇓SWS, ?REM, ⇓WASO
Polyphasic character, ⇑sleep stage1 and 2, ⇓SE, ⇓SWS, ?REM, ⇑WASO, frequent naps
30% of night awake, average 4.5 hr sleep the night before delivery, ⇓TST, ⇓SE, ⇓NREM and REM
Heartburn, onset of snoring, onset of irregular uterus contractions, fetal movements
⇑Urination, irregular uterine contractions, muscle or leg cramps, shortness of breath, heartburn, backache, joint pain, carpal tunnel symptoms, breast tenderness, itching Dreams or nightmares, worry about sleep loss, labor, fetus, birth complications, and life changes Symptoms of SDB, RLS, GER, and complications, e.g., PIH
Pain, anxiety, forceful uterine contractions
⇑ Energy (improved mood), nasal congestion
⇑Fatigue or sleepiness, ⇓ vigilance
Pain, anxiety, forceful uterine contractions
Sleep Pattern Polyphasic character, ⇑TST, ⇓ SE, ⇓SWS (relative to prepregnancy), ⇑WASO, frequent naps Sleep Complains ⇑ Urination, backaches, tenderness and tingling feeling in the breast
Daytime Symptoms Fatigue or sleepiness Morning or evening nausea and vomiting, changes in appetite
GER, gastroesophageal reflux; NREM, non-REM sleep; PIH, pregnancy-induced hypertension; REM, rapid eye movement sleep; RLS, restless legs syndrome; SDB, sleep-disordered breathing; SE, sleep efficiency; SWS, slow-wave sleep; TST, total sleep time; WASO, wake after sleep onset.
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frequent daytime naps, especially if they are not employed outside the home. REM sleep, however, does not change or diminishes only slightly from the first trimester to the third trimester. Labor and Delivery Pain, anxiety, uterine contractions and administration of medications all affect sleep during labor and delivery.5,33,46 The sleep pattern alters and sleep quality decreases as women approach labor and immediately after delivery.5,46 In a descriptive longitudinal study of 35 women, sleep quality deteriorated progressively over the last 5 days of pregnancy and was the lowest on the night before hospital admission.46 Most women experienced spontaneous labor onset with forceful contractions during the night, presumably as a result of the peak of oxytocin level.9,46 There was also a significant relationship between the amount of sleep the night before hospitalization and pain perception in women with spontaneous labor onset. Women who did not experience labor onset had similar patterns of sleep loss. Thus, anxiety in addition to other contributors to sleep disturbance on that night must be considered.46 In a qualitative study of 20 women, all reported that they were unable to sleep once contractions began. As the latent phase of labor becomes prolonged, sleep may become impossible even with sleep aids.33 This can also occur as a result of the concomitant increase in estrogen and decrease in progesterone.20 Parity Differences in sleep characteristics during pregnancy are also influenced by parity (primiparous or multiparous) or the presence of other children living in the home. Studies found that TST, SWS, and REM sleep were not significantly changed by parity in small samples.36,47 However, multiparas had consistently more sleep time but significantly lower sleep efficiency compared to nulliparas during pregnancy due to frequent awakenings.36 This finding, however, was contradicted by a later study using actigraphy.41 Multiparas may be awakened by their child(ren) during the night across pregnancy.1,3 Therefore multiparas might compensate for their disrupted sleep by spending more time in bed. However, it has been noted that during the third trimester, younger women (<30 years) had more TST than older women (>30 years), whose sleep may have been affected by parity or other children’s needs.2 In another study, while sleep efficiency of nulliparas decreased from 90% (third trimester) to 77% (1 month after delivery), sleep efficiency for multiparas did not change significantly (87% in third trimester, 84% 1 month after delivery).47 Energy levels are affected by parity such that nulliparas experienced higher energy levels than did multiparas at all times during pregnancy.12 This suggests that multiparas may be older, have difficulty taking a nap, and have insufficient nocturnal sleep due to other children in the home.3,29 Thus, parity should be controlled in sleep research with pregnant women. In summary, although TST and sleep efficiency progressively decrease during pregnancy regardless of parity, sleep characteristics remain generally constant during pregnancy.
SLEEP-RELATED DISORDERS IN PREGNANCY Primary sleep disorders also occur or worsen during pregnancy. Therefore, clinicians should consider the possibility of sleep disorders, particularly when symptoms are observed, because they have serious consequences for maternal and fetal health. Sleep-Disordered Breathing Sleep-disordered breathing refers to the entire spectrum of breathing disorders during sleep, ranging from intermittent snoring without apnea to the most severe form of SDB, arguably the obesity-hypoventilation syndrome.48 Nighttime features of SDB include snoring, shortness of breath (dyspnea), breathing pauses, and sudden awakenings with choking sensations. Snoring and shortness of breath are common during pregnancy, starting at the end of second trimester. As pregnancy progresses, obstructive sleep apnea (OSA) can also develop, especially in obese women.6,25,43,49 SDB can be attributed to changes in the respiratory system (upper airway, lung mechanics, and control of breathing) during pregnancy. Although some changes cause SDB, others actually protect from it. Potential risk factors for SDB are detailed in Figure 138-1 and include a reduction in upper airway size (due to weight gain, increased fluid volume, nasal congestion etc.), reduced functional residual capacity and residual volume, increased minute ventilation, supine position, and fragmented sleep.4,8,18,34,43,45,48,50-52 The temporal relationship between fragmented sleep and the pathogenesis of SDB in pregnancy requires further study. Active and passive smoking can also contribute to loud snoring and breathing problems during sleep.53 The low incidence of SDB in pregnant women likely results from physiologic changes that can protect them from SDB. High circulating progesterone during pregnancy can protect the upper airway from obstruction, increasing upper airway dilator muscle (genioglossal) activity and its responsiveness to chemical stimuli (CO2) during sleep.48 A right-shifted oxyhemoglobin dissociation curve and increases in heart rate, stroke volume, and cardiac output with reductions in peripheral vascular resistance improve the delivery of oxygen to the placenta and maternal tissues.8,25,48 Also, as pregnancy advances, less time is spent in the supine position during sleep.30,43 This decreases the possibility of adverse respiratory events43,45,48 and of supine hypertensive syndrome.42 Numerous survey studies report that both the severity and frequency of snoring increase steadily during pregnancy.2-4,26,35,54-56,57 However, the prevalence of snoring is variable, ranging from 10.4% to 46% in the third trimester, likely owing to different study designs, reliance on self-reported snoring rather than asking her bed partner, or asking about habitual snoring rather than both habitual and occasional snoring.26,34,35,59 The precise prevalence of OSA during pregnancy is also unknown. Large prospective studies using objective methods are lacking. In one study of 267 women, none had an apnea–hypopnea index (AHI) of 5 or more in their second trimester, but habitual snorers spent between 61% and 92% of TST with snoring.26 Thirteen of these snorers
CHAPTER 138 • Sleep Disturbances and Sleep-Related Disorders in Pregnancy 1577
had abnormal breathing patterns (sustained effort and crescendos) compared to nonsnorers. It has been estimated that more than 10% of pregnant women may be at risk of developing OSA during pregnancy.55 Pregnant women with apnea symptoms have a higher likelihood of gestational hypertensive disorders, gestational diabetes, and unplanned Caesarian sections.55a Normal pregnant women have been reported to exhibit modest oxygen desaturations during sleep, which would be worse in the supine position.26,30,45,58 The mean overnight oxygen saturation (Sao2) in nonpregnant women (98.5%) was significantly higher than the 95% seen in normotensive pregnant women or women with pregnancy-induced hypertension.60 Small PSG studies of healthy pregnant women with or without multiple-gestation pregnancy showed that none had clinically significant OSA.43,53,59 However, case reports and studies of pregnant women with OSA indicate that those with obesity, large neck circumference, abnormal oropharyngeal anatomy, or a small oropharynx are at risk for developing OSA during pregnancy or developing a more severe case of OSA if it is diagnosed before pregnancy.6,43,48,60 However, AHI significantly improves after delivery.6 Diagnosis SDB associated with adverse fetal and maternal outcomes is mentioned later. Because of such outcomes, early diagnosis and treatment of SDB, especially OSA, is important. SDB is likely underdiagnosed during pregnancy because daytime sleepiness is considered a normal part of pregnancy or because women are unwilling to complain about snorting, gasping, or snoring.14 Thus, women without prepregnancy SDB who have predisposing factors require careful surveillance, because SDB can develop with pregnancy progression.4,6,43,55,61 Pregnant women with prepregnancy SDB might also need to be reassessed, particularly after the sixth month of pregnancy, because symptoms can reoccur or worsen with nasal congestion and weight gain.6,63 Sleepiness in pregnant women is not specific to SDB.35 Studies show that snoring pregnant women and preeclamptic women with inspiratory flow limitations (IFLs) do not necessarily demonstrate sleepiness as measured clinically by the Epworth Sleepiness Scale.35,42,57 This may be due to their regular daytime napping or the fact that they describe their sleepiness with words like “unrefreshed,” “fatigue,” or “tired.” Scales measuring fatigue might give more information about sleepiness. Thus, in the clinical setting, questions about SDB should extend beyond simply asking about excessive daytime sleepiness. Objective measures (e.g., multiple sleep latency test (MSLT)) are needed to determine the sleepiness level of women with normal and complicated pregnancies. Women with chronic or gestational hypertension, preeclampsia, gestational diabetes, or a history of infants with unexplained intrauterine growth restriction should be closely evaluated for SDB, especially if they have predisposing factors such as obesity.7,14,42,48,60,62 Women with any of several different problems (Fig. 138-2) should undergo an overnight PSG (with both nasal cannula pressure transducer and thermistor) to measure oxyhemoglobin desaturations, RDI or AHI and IFL index (IFLI).6,7,14,42,48,60,61,62,63 If IFLI is not measured during sleep, abnormal respiratory events would be missed,
especially for preeclamptic women, because most of them experience nonapneic flow limitations during sleep associated with blood pressure surges.7,63 Prevention In all pregnant women, lifestyle modifications and coping strategies can prevent most cases of SDB; these are detailed in Box 138-1.42,48 Treatment In general, there is no consensus about screening and treating SDB in pregnancy. Women with position-dependent SDB, without significant oxyhemoglobin desaturations or hypertensive complications, might benefit from sleeping in the lateral decubitus position.42,45,48 Continuous positive airway pressure (CPAP), especially auto-titrating CPAP, and other therapies have been recommended if a pregnant woman has any condition listed in Figure 138-2.14,42,48,60,61 The main aim of these treatments is to eliminate maternal hypoxemia (oxyhemoglobin saturations of ≤90%) and clinical symptoms and to obtain an RDI of less than 5 events per hour.42 However, this treatment plan is not evidence based. CPAP is a safe, well-tolerated, and preventive therapy with good compliance among pregnant women. It has been shown to abolish inspiratory flow limitations, reduce mean arterial pressure between wake and sleep by 3 mm Hg, reduce severe attacks of dyspnea (shortness of breath), and significantly improve cardiac output, total peripheral resistance during sleep, and nocturnal oxygenation in pregnant women with OSA. It also improve maternal and fetal outcomes for women with preeclampsia risk factors such as chronic hypertension.7,25,49,60,61 Even though these results are from case studies or studies limited by small sample sizes, they are promising and in need of replication. In women with SDB diagnosed before or at the onset of pregnancy, CPAP may need to be recalibrated around 24 weeks of pregnancy.61 In severe cases associated with obesity (especially prepregnancy obesity), multiple gestation (twin pregnancy), and other conditions, bilevel positive airway pressure (BiPAP) ventilation therapy may be more successful than CPAP. Additionally, a combination therapy with CPAP or BiPAP ventilation plus oxygen supplementation would seem to be a more satisfactory treatment option than using one alone.48 A noninvasive treatment has been introduced that abolished IFL by inflating air through an open nasal cannula system, but it is not yet ready for general use.64 Treatment with supplemental oxygen may be considered for pregnant women with SDB who are unable to use therapies such as CPAP, even though its effectiveness is not proved in the pregnant population.14,42 An oral appliance can be an option,65 but its production and fitting sessions can take a long time.14,42 Tracheostomy has been performed in a pregnant woman with OSA, but this case was unusual.62 Summary The severity and prevalence of SDB increases as pregnancy progresses due to pregnancy-induced changes in the upper airway, lung mechanics, and the control of breathing. SDB is more common in the third trimester, especially in women with predisposing factors. CPAP is the treatment of choice.
1578 PART II / Section 18 • Women’s Health
Pregnant woman with new or recurrent symptoms of excessive daytime sleepiness or sleep disturbances
Assess and treat SDB as early as possible to prolong gestation, delay preeclampsia onset and reduce IUGR severity
Assess for RLS/PLMD as early as possible
Assess for parasomnias especially sleepwalking and terrors
Assess for nocturnal gastroesophageal reflux
Examine clinical and pregnancy history: 1) Loud snoring, excessive daytime sleepiness, witnessed apnoeas or choking sensation during sleep in especially women with excessive weight gain 2) Chronic hypertension, gestational hypertension or preeclampsia in especially women with prepregnancy obesity and a large neck size 3) Gestational diabetes and previous unexplained intrauterine growth restriction associated with snoring and obesity 4) Worsening/recurrence of symptoms in women with preexisting OSA
1) Examine clinical and pregnancy history: specific RLS features and RLS in family and previous pregnancy, presence of PLM 2) Evaluate iron, folate and vitamin B12 deficiencies, obtain serum ferritin, ironbinding capacity, folate and B12 levels 3) Screen prepregnancy, diabetes mellitus, thyroid disease, or end-stage renal disease 4) Distinguish from leg cramps, vascular insufficiency, anxiety and neuropathy
Examine clinical history: 1) Previous pregnancy with parasomnias 2) Symptoms concurrent with sleep deprivation, stress, etc.
Examine clinical history: Current complaints and/or any prior history of dyspeptic or refluxtype symptoms
Overnight PSG to determine objective snoring, oxyhemoglobin desaturations, flow limitation events and RDI (AHI and IFLI)
Clinical diagnosis based on the 4 main clinical criteria mentioned in the text. PSG is not necessary. Supportive diagnosis criteria: 1) Positive family history 2) Previous pregnancy with RLS 3) Presence of PLM
If one of them exist: 1) An RDI of 5-30/hr with few/no SaO2 < 90% and clinical symptoms, 2) RDI > 30/hr 3) Recurrent SaO2 < 90% 4) Chronic hypertension and objective evidence of snoring or flow limitation events 5) Gestational hypertension or preeclampsia and objective evidence of snoring or flow limitation events 6) Indication of insufficient treatment in preexisting OSA Treatment: auto-titrating CPAP or recalibration of the CPAP pressure in preexisting OSA or other modality e.g., BiPAP in women with prepregnancy obesity and SDB; main goal is to eliminate maternal hypoxemia, RDI ≥ 5 and clinical symptoms
If available, sleep laboratory monitoring 1) Reduction of risk factors and maximization of the safety of bedroom e.g., night light, door alarm 2) Self-hypnosis and relaxation techniques at bedtime 3) In severe cases, low doses of benzodiazepines can be useful
If mainly indigestion and regurgitation and additionally nausea, vomiting, water brash, chest discomfort, coughing, and choking, sore throat and hoarseness exist 1) Elevating the head of bed and sleeping on left side 2) Avoiding spicy, acidic or fried foods, instead eat small bland meals during the day 3) If these are inadequate, antacids or sucralfate are considered the first-line on-demand drug therapy
1) Replacement of iron (if ferritin <50 ng/mL), folate or vitamin B12 (only in B12 deficiency, intramuscular) 2) Magnesium (intravenous in severe cases) Nonpharmacologic behavioral interventions mentioned in the text Pharmacologic treatment: In severe RLS, opioids/ dopaminergics (preferably category B) only in the 3rd trimester at the lowest effective dosage
Figure 138-2 Management and treatment of sleep-related disorders. AHI, apnea–hypopnea index; BiPAP, bilevel positive airway pressure; CPAP, continuous positive airway pressure; IFLI, inspiratory flow limitation index; IUGR, intrauterine growth retardation; PLM, periodic limb movements; OSA, obstructive sleep apnea; PLMD, periodic limb movement disorder; RDI, respiratory disturbance index; RLS, restless legs syndrome.
Sleep-Related Movement Disorders Sleep-Related Leg Cramps Leg cramps are common, particularly in the second part of pregnancy. It is reported as a primary reason for sleep disruption during pregnancy.3,31,66 Nocturnal leg cramps
increase from 10% before pregnancy to up to 21% in the first trimester, up to 57% in the second trimester, and up to 75% in the third trimester.3,31,66 It is unclear why leg cramps are so common in pregnancy. One possible mechanism is slowed venous return
CHAPTER 138 • Sleep Disturbances and Sleep-Related Disorders in Pregnancy 1579
Box 138-1 Strategies for Managing Sleep Disturbances and Disorders Overweight women should lose weight before pregnancy and control weight gain during gestation. Plan a regular sleep–wake schedule, make sleep a priority, if necessary add naps earlier in the day. Drink lots of fluids during the day, but cut down before bedtime to prevent frequent nocturnal urination. Eat a balanced diet providing magnesium, potassium, calcium and vitamin C (to increase folate absorption from food) and take prenatal folate and iron and vitamin supplements to prevent or decrease leg cramps and RLS. Engage in regular exercise at least 30 minutes a day to control weight, improve circulation, reduce stress, and reduce RLS attacks and leg cramps. Sleep in a left lateral position to improve blood flow to the fetus and to the mother’s body and to increase kidney activity. Use pregnancy or support pillows between the knees, under the abdomen, and behind the back to sleep comfortably. Elevate the head of the bed to prevent or decrease heartburn and snoring. Relieve nasal congestion with nasal saline washes or nasal dilators and avoide active and passive smoking and alcohol to prevent or decrease SDB. Avoid caffeine, spicy, acidic, or fried foods, and eat small meals during the day. Make the bedroom dark, cool, and comfortable and use a nightlight in the bathroom to decrease arousal. Manage low back pain with massage, local heat, and pillow support. Practice relaxation techniques—in particular, breathing techniques—to reduce the contractions and somatic tension. Use stimulus-control techniques; stay in bed only when sleepy. Use sleep restriction (curtail time in bed to restrict actual amount of sleep time) and limit daytime sleep RLS, restless legs syndrome.
due to increased intraabdominal pressure combined with inhibitory effects of progesterone in the venous musculature.67 Another mechanism involves the altered metabolism of calcium, magnesium, and phosphate while fetal bones are developing. There is much anecdotal evidence but few studies on treatment modalities to relieve or prevent cramp attacks. These modalities include leg massage, hyperextension and warm and cold application during cramps, nightly stretching before bedtime, and reducing phosphorous-containing substances like milk and meat.3,14,67 A systematic review of placebo-controlled trials involving 352 women suggested that no benefit was gained by use of calcium alone, sodium chloride alone, or calcium with sodium chloride. One or more of the ingredients in multivitamin and mineral tablets may be beneficial, but only those with magnesium (a mixture of lactate and citrate) have clear evidence of benefit.67
Pregnancy-Related Secondary Restless Legs Syndrome Restless legs syndrome is characterized by an irresistible desire to move the legs in response to uncomfortable sensations in the legs and is relieved by movement. (The syndrome sometimes occurs in the arms.) RLS symptoms are maximal in the evening or at night while at rest.2,65,66,68,69 The diagnosis of RLS depends on four main criteria (detailed in Chapter 90). Pregnancy-related RLS is classified as a secondary form of RLS because pregnancy carries risk factors for RLS.31,69 A preexisting primary RLS is worsened by pregnancy.31,70 Studies show that this syndrome is strongly related to the third trimester of pregnancy and tends to resolve around the time of delivery.31,66,69 Pregnant women have a two to three times higher risk of RLS than the general population. A prevalence rate of RLS in pregnancy ranges from 3% to 30%.2,31,69,71 Variability in these percentages can be attributed to differences in diagnostic criteria, maternal age, and genetic and racial differences in study populations.69,70 The prevalence of RLS in European countries averages around 20%, and it is 11.5% in Japan.2,31,69-71 Prospective studies report that prevalence of RLS increases as pregnancy progresses, particularly at the seventh and eighth months, in women without preconception RLS.2,3,31,66 Most of these epidemiologic studies did not use currently recommended diagnostic criteria. A study using standard diagnostic criteria in Italy found a prevalence of 26.6% of RLS during pregnancy. Among these women, 16.7% had never experienced RLS symptoms before pregnancy, and the mean onset of RLS symptoms was around the sixth month. About 10% had preexisting RLS symptoms, and 15% had symptoms at least three times per week.31 Contrary to previous studies, a study of Japanese women also used the international diagnostic criteria and reported only a 2.9% prevalence of RLS, which increased to more than 6% in the third trimester.70 The association between pregnancy and increased prevalence of RLS is not fully understood. Associated factors for RLS include older age, maternal weight (>79 kg), concomitant SDB, periodic leg movements in sleep (PLMS), and smoking.31,70 RLS is reported more often in pregnant women with positive family history of RLS (30%) compared to women without RLS (1.8%).31,69 Multiparas who experienced RLS in a previous pregnancy may have a higher rate (30% to 38%) in the next pregnancy,31 but they are not likely to experience RLS between pregnancies.2 Iron and folate deficiencies are well-recognized factors associated with RLS in pregnancy.31,66,69 Levels of hemoglobin, ferritin, and vitamin B12 start to fall in the second half of pregnancy, regardless of taking iron and vitamin supplementation, due to fetal growth and hemodilution.31,66 A longitudinal prospective study reported that the women most at risk are those with lower folate levels and serum ferritin at preconception, even though the low level was clinically considered to be within normal limits.66 During pregnancy, women with RLS had lower folate, plasma iron, and hemoglobin values and mean corpuscular volume throughout gestation than those who do not develop RLS.31,66 In addition to these metabolic changes, hypotheses about hormonal changes (prolactin, progesterone, and
1580 PART II / Section 18 • Women’s Health
estrogen) and psychomotor behavior (e.g., sleep deprivation, anxiety) implicated in the etiology of RLS during pregnancy are detailed elsewhere.69 Turkish researchers reported that pregnant women with RLS were more likely to have a lower hemoglobin level, more night cramps, and excessive daytime sleepiness. In that study, only 34% who were taking vitamin and iron supplements had RLS compared to 61% of those not taking supplements.71 PLMS is characterized by rhythmic extension of the big toe and dorsiflexion of the ankle, with occasional flexion at the knee and hip. RLS and PLMS often coexist. Approximately 80% of patients with RLS also have PLMS, but only a small number with PLMS have RLS14,42,71 (see Chapter 90). Studies are lacking on whether PLMS contributes significantly to sleep disruption during pregnancy. In one study, all 10 mothers with a multiple-gestation pregnancy experienced PLMS, and only four developed RLS during pregnancy, suggesting the prevalence of PLMS is even higher than RLS.68 On the other hand, snoring and nocturnal eating also have been found to be more common in pregnant women with RLS.31 These areas require further investigation. RLS symptoms during pregnancy have a significant impact on sleep, resulting in less TST, a longer sleep-onset latency, maintenance insomnia, and excessive daytime sleepiness.31,66,69-71 Further experimental studies are needed to evaluate the relevancy of these hormonal, behavioral, and metabolic factors in pregnancy RLS. For diagnosis of RLS, see Figure 138-2.66,71 Specific symptoms should be sought because women with RLS often report poor sleep quality or difficulty initiating and maintaining sleep, rather than symptoms of RLS.31,69,71 Before conception and in early pregnancy, oral folate is strongly suggested to prevent fetal neural tube defects as is iron supplementation during the second and third trimesters.66,71 Replacement of iron or vitamins is also recommended in the case of a deficiency (see Fig. 138-2).66,71 In general, nonpharmacologic behavioral interventions should be considered as the first choice to relieve symptoms or reduce the number of attacks of RLS.42,66,71 These include cold and hot compresses, leg massage, acupressure, vibration to the affected limbs during symptoms; relaxation techniques, increased mental activity, or regular walking or gentle stretching exercises before bedtime; elimination or restriction of substances and medications invoking symptoms, such as caffeine, alcohol, nicotine, dopamine antagonists, selective serotonin reuptake inhibitors (SSRIs), and antihistamines; good sleep hygiene; and weight management. These interventions, however, have not been well studied. If medication is needed for severe RLS, pharmacologic treatment should be used only during the third trimester and at the lowest effective dosage (Table 138-2 and see Fig. 138-2) owing to their possible teratogenic effects.72,73 Pregnancy-Associated Insomnia Many women (84%) report having one or more symptoms of insomnia at least a few nights each week, and 30% report that they rarely or never get a good night’s sleep during pregnancy.74 Pregnant women can experience some or all of the following: poor sleep quality, difficulty falling asleep, problems maintaining sleep due to multiple noc-
turnal awakenings, waking too early or feeling unrefreshed in the morning, daytime fatigue, irritability, and lack of concentration.3,33,50,65,75,76 Pregnancy-associated insomnia is considered secondary in nature. It can emerge due to pregnancy-related discomforts (delineated earlier). The occurrence of insomnia can be characterized by trimester. The most disturbed sleep with the highest number of nocturnal awakenings occurs during the third trimester.1,2,31 Daytime coping strategies such as napping, spending more time in bed, or increasing caffeine intake also can perpetuate sleep difficulties. It might also be the case that insomnia is actually secondary to a primary sleep disorder that develops or worsens during pregnancy. For example, increased upper airway resistance during pregnancy can cause sleep-maintenance insomnia. Similarly, restless legs can lead to sleep-onset insomnia. Thus, insomnia cannot be treated effectively until the primary condition is resolved or stabilized in pregnancy. Physiologic hyperactivity occurring during pregnancy (elevated heart rate, elevated metabolic rate, increased muscle tension and body temperature) is commonly seen in patients with insomnia.65 In addition to physiologic factors, most women suffer from elevated emotional distress or anxiety, as mentioned earlier.1,28 By the end of the second trimester and into the third trimester, many pregnant women come to realize potentially radical changes in lifestyle trying to balance work and motherhood with a new child, and anxiety about delivery may be accompanied by emotional concerns about the fetus.1,3,31-33,74 Thus, the physiologic hyperactivity combined with cortical arousals associated with anxiety might account for insomnia and daytime sleepiness, especially in women who are prone to insomnia because of trait characteristics.77 Women also might worry about their poor sleep due to experiencing symptoms as mentioned earlier, but the prevalence of psychophysiologic insomnia during pregnancy has not been clearly studied. Only one study reported that around 40% of women worried about their sleep during the first and second trimester, and this increased to 57% at third trimester.3 Polysomnographic features of sleep in third trimester indicate objective insomnia, such as longer sleep latency, increased WASO, decreased sleep efficiency, increased stage 1 and 2 sleep, and some reduction in deep sleep.1,5,30,46 These findings suggest that recurrent awakenings due to discomforts of pregnancy are consistent with the pattern of sleep-maintenance insomnia seen on PSG.5,30 GABA, regulated by sex hormones, can also play a vital role in sleep-initiation and sleep-maintenance insomnia. Although estrogen decreases the number of GABAA receptors, progesterone works against this.10,13 Therefore, increased concentrations of estrogen and progesterone during pregnancy can result in insomnia due to changing GABA function.10,13 The presence of insomnia has a significant impact on quality of life and daytime functioning; its management, therefore, is imperative. However, many women do not seek help because they wish to avoid taking medications. If there is no other reason for insomnia (such as depression, witnessed apneas, RLS), then nonpharmacologic interventions (see Box 138-1) such as cognitive behavior
CHAPTER 138 • Sleep Disturbances and Sleep-Related Disorders in Pregnancy 1581
Table 138-2 Pregnancy Classification of Medications Used for Sleep Disorders CLASSIFICATION
CATEGORY B
CATEGORY C
CATEGORY D
CATEGORY X
Sedatives and Hypnotics (Benzodiazepines) Zolpidem (1)
Zaleplon (1)
Diphenhydramine (1)
Alcohol (Ethanol) D/X (1)
Estazolam (1,2)
Alprazolam (1)
Flurazepam (1,2)
Diazepam (1,4)
Quazepam (1,2)
Lorazepam (1)
Temazepam (1,2)
Midazolam (1)
Triazolam (1,2)
Secobarbital (1) Central Analgesics Clonidine (2) Anticonvulsants Gabapentin (1,2)
Clonazepam (2,4)
Lamotrigine (2)
Carbamazepine (2,4)
Antiparkinsonian Agents (Dopaminergics) Bromocriptine (2)
Carbidopa (2)
Cabergoline (2)
Levodopa (2) Pramipexole (2) Ropinirole (2)
Narcotic Agonist Analgesics (Opioids) Meperidine-B/D (2)
Codeine-C/D (2)
Oxymorphone-B/D (2)
Morphine-C/D (2)
Methadone-B/D (2)
Propoxyphene-C/D (2)
Oxycodone-B/D (2)
Hydrocodone-C/D (2)
Antidepressants and Depressants Sodium oxybate (Xyrem) (4)
Amitriptyline (1,2) Doxepin (1,2) Fluoxetine (3) Imipramine (4) Paroxetine (3,4) Protryptyline (3) Sertraline (4) Trazodone (1,2,4) Venlafaxine (3)
Stimulants Caffeine (3)
Dextroamphetamine (3)
Pemoline (3)
Mazindol (3) Methamphetamine (3) Methylphenidate (3) Modafinil (3)
Numbers refer to the conditions in which medications are used: (1) insomnia, (2) RLS, (3) narcolepsy, (4) parasomnias Category B: Animal studies have not indicated a fetal risk but no controlled studies in pregnant women exist, or animal studies have shown an adverse fetal effect that is not confirmed in controlled studies in women in the first trimester (no evidence in later trimesters). Category C: Animal studies have shown adverse fetal events, but no controlled studies in pregnant women exist, or studies in humans and animals are not available; thus, give if potential benefit outweighs the risk. Category D: Risk to fetus is present, but benefits may outweigh risk if life-threatening or serious disease exists. Category X: Studies in animals or humans show fetal abnormalities; drug contraindicated for pregnant women. B/D: risk factor D if used for prolonged periods or in high doses at term, C/D: risk factor D if used for prolonged periods or in high doses at term, D/X: risk factor X if used in large amounts or for prolonged periods.
1582 PART II / Section 18 • Women’s Health
therapy (CBT) strategies should be the initial therapy and are often effective and durable.77 Alternative herbal or dietary therapies (e.g., chamomile, acupuncture) are also used to aid sleep, but controlled studies are needed to assess the benefits and risks on fetal and maternal health.
Dreams and nightmares may be important indictors of women’s psychological state. This overlooked area requires further study. No special treatments are needed for most parasomnias, except for making the bedroom safe (see Fig. 138-2).79
Nocturnal Gastroesophageal Reflux Gastroesophageal reflux (GER) is experienced by about 25% of pregnant women in each trimester.17,78 The pathophysiology of GER in pregnancy is most likely multifactorial (see Fig. 138-1), but a predominant factor is elevation of hormones, in particular progesterone.16,17,78 Indigestion and regurgitation are common symptoms of nocturnal GER during pregnancy. However, other symptoms include nausea, vomiting, chest discomfort, coughing, choking, sore throat, and hoarseness. Nighttime symptoms of GER can cause esophageal mucosal injury and can affect sleep.16,78 Most (82%) women sleep upright in a chair, especially during the third trimester.31,78 For the diagnosis of GER, a careful history should be obtained, focusing on symptoms.16 Sleeping on the left side is useful, and lifestyle and dietary modifications should be considered (see Box 138-1). When modifications are inadequate, antacids or sucralfate are considered the first-line on-demand drug therapy.16
Narcolepsy Studies reporting associations between pregnancy and narcolepsy are rare. The REM-inhibiting effects of estrogen and, to a minor level, cortisol might prevent pregnant women from developing narcolepsy.14 In narcolepsy with cataplexy, an elective cesarean delivery should be considered due to the potential dangers of cataplectic episodes for both mother and newborn during labor.81 Good sleep hygiene, nutritional supplementation, and a support network are important in the treatment of narcolepsy to ensure adequate nocturnal sleep, adherence to scheduled naps, and fewer work and family responsibilities.42,74,81 Pharmacologic treatment (see Table 138-2) should be used during pregnancy only if it is clearly needed because of a lack of well-controlled studies investigating long-term effects on the fetus.14,73,81
Parasomnias Parasomnias are undesirable physical events or experiences that occur during entry into sleep, within sleep, or during arousals from sleep including abnormal movements, behavior, emotions, perceptions, dreaming, and autonomic nervous system functioning.79 Arousals from any stage of NREM sleep (mostly SWS), sleep deprivation, and stress can predispose to episodes of sleepwalking or a night terror.79 Thus, these episodes may be triggered by pregnancy-induced sleep deprivation and stress, especially in women with genetic disposition and previous history of parasomnia.14,79 Parasomnias in pregnancy are understudied. In one large longitudinal study, sleep paralysis significantly increased in the second half of pregnancy (from 5.8% to 13.2%), but there was a decline in sleepwalking, sleeptalking, hypnagogic hallucinations, and sleep bruxism during pregnancy compared to the 3-month prepregnancy period, especially for primiparas.80 Most (80%) women with a prior pregnancy loss report having dreams associated with anxiety about infants and birth outcomes.19 However, similar types of dreams and nightmares are reported by women without a prior pregnancy loss. Dream recall is equally prevalent among postpartum, pregnant and nonpregnant women (88% to 91%). Pregnant women’s dreams about the unborn child and possibility of birth complications are accompanied by labile emotions. Dreams contain anxiety about the infant and are often accompanied by dream-associated behavior and confusional arousals. Primiparas and multiparas differ in dream recall but not in prevalence of dream-associated behavior.32 Researchers conclude that frequent dreams may be caused by the mother’s intense emotional stress, severe sleep disruption, REM sleep deprivation, or changes in hormone levels. The frequency of dreams increases with gestation.3,29
CONSEQUENCES OF SLEEP PROBLEMS Maternal Complications Studies and case reports of SDB in pregnancy suggest that OSA is associated with gestational hypertension and preeclampsia, gestational diabetes mellitus, pulmonary hypertension, and other cardiovascular diseases.4,7,34,48,63-63b Pregnancy-induced hypertension is a generic term defined as repeated blood pressure recordings higher than 140/90 mm Hg, first diagnosed after 20 weeks’ gestation in previously normotensive women. If it is not accompanied by proteinuria, this condition is called gestational hypertension, but if it includes proteinuria, it is called preeclampsia.7,8 Preeclampsia is described as a pregnancy-specific syndrome of reduced organ perfusion secondary to vasospasm and endothelial activation7,8 and characterized by hypertension with a nondipper pattern also observed in OSA.7 Pregnancy-induced hypertension is associated with maternal and neonatal morbidity and mortality. Most preeclamptic women (59%) snore habitually, likely due to generalized edema. In addition to well-known risk factors of preeclampsia such as hypertension and diabetes,8,42,63 in a recent sample of Scottish women, large neck circumference, high weight gain, and snoring during pregnancy were associated with an increased risk of developing preeclampsia.82 Earlier objective studies also showed that women with preeclampsia experience a narrowing of the upper airway during the daytime likely due to pharyngeal edema4,50 and long episodes of nonapneic airflow limitation during sleep associated with blood pressure surges.7,54,61,83 These abnormal respiratory events occurring during sleep can cause further increases in peripheral vascular resistance and systemic arterial blood pressure, as well as reductions in maternal cardiac output in preeclamptic women, which can then compromise uteroplacental blood flow.7,25 Pathogenesis of preeclampsia remains unclear, but there is growing evidence that the intermittent episodes of
CHAPTER 138 • Sleep Disturbances and Sleep-Related Disorders in Pregnancy 1583
hypoxia and re-oxygenation associated with SDB can be a strong stimulus for oxidative stress.84 These repeated changes in oxygen saturation could be considered analogous to recurrent episodes of placental hypoxia and reperfusion in preeclampsia, which causes endothelial dysfunction as a result of elevated production of oxygen free radicals.84 It has been reported that SDB and endothelial dysfunction occur more often in women with preeclampsia than in women with uncomplicated pregnancies.51 Thus, endothelial dysfunction might underlie intrauterine growth restriction and many of the manifestations of preeclampsia in addition to high blood pressure, such as peripheral vasoconstriction and abnormal regulation of blood vessel tone.7,84 Previous studies using objective measures reported that sleep quality was impaired in preeclamptic women.25,83 Preeclamptic women had markedly altered sleep architecture, with a significant increase in SWS (likely due to cerebral edema and release of cytokines) and a decrease in REM sleep.7 Preeclamptic women also had more frequent naps than healthy pregnant women.83 The evidence suggests that CPAP cannot treat the underlying cause of preeclampsia, but can decrease blood pressure and improve oxygenation. Early CPAP therapy in chronic hypertension or gestational hypertension with SDB may delay preeclampsia onset or lessen its severity.61,63 Thus it potentially allows pregnancy to proceed for longer gestation, ensuring greater fetal maturity at delivery.7,48,49,61,63 However, results of these studies should be interpreted carefully due to their limitations. In order to justify regular use of CPAP in preeclampsia, larger randomized, controlled trials are needed. Fetal Complications Maternal sleep is important for fetal growth and wellbeing, because uteroplacental blood flow and the secretion of neurohormones, especially growth hormone, are at their peak.22,25 Thus, persistent insufficient and fragmented sleep can adversely affect fetal development and well-being.84a Pregnant women might have sleep hypoxemia due to the impact of abnormal respiratory events on maternal cardiorespiratory reserve. Even small declines in maternal oxygenation with uteroplacental insufficiency might endanger oxygen delivery to the fetus. Studies have identified recordable fetal heart decelerations and significant acidosis during apneic episodes associated with maternal desaturation.14,48,49,85 Additionally, a significant correlation is reported between maternal cardiac output during sleep and fetal birth weight in preeclampsia. Snoring has been shown to be a risk factor for lower Apgar scores and intrauterine growth restriction.34 These studies suggest that intermittent maternal hypoxia throughout many weeks of pregnancy can cause fetal growth restriction and other adverse outcomes for a developing fetus.14,48,49,85 Thus SDB, hypertension, preeclampsia, obesity, diabetes mellitus, or other conditions (such as uncontrolled asthma or smoking) can lead to maternal hypoxia and therefore increase the risk of premature delivery, intrauterine growth restriction, low Apgar, score or even infant mortality.14,25,48,63 However, study results can conflict owing to the sample’s severity of SDB, other accompanying disorders (e.g., preeclampsia, diabetes mellitus), obesity, or
mothers with complicated pregnancies who are treated or not treated.14,48 When women with SDB are treated either with nasal CPAP or tracheostomy before the third trimester, they deliver infants with normal birth weight and better Apgar scores.14,48,61,62 In summary, good sleep is essential to optimal fetal health and maternal physical functioning and mental health. Nasal CPAP is a safe and useful treatment of SDB during pregnancy. Early recognition and treatment of SDB can improve maternal and fetal health outcomes.25,48,49,61,63 Pregnancy Complications Sleep quality and quantity may be associated with adverse pregnancy outcomes.86 In a prospective observational study of 131 women in their last month of pregnancy, using both objective and subjective sleep measures, women who slept less than 6 hours at night had longer labor and higher rates (4.5 times) of cesarean delivery (controlling for infant birth weight) than those getting 7 hours or more of sleep.86 Snoring women also have a higher likelihood of requiring an emergency cesarean delivery than nonsnorers.53,63a One mechanism for these adverse outcomes may be an increased perception of pain and discomfort during labor.46,87 A significant relationship has been found between the amount of sleep the night before hospitalization and pain perception in women with spontaneous labor onset. If women have less TST and a higher percentage of awake time on the last night before hospitalization, they feel more pain in labor. Sleep loss before hospitalization also can affect compliance and motivation with interventions and collaboration with health professionals during labor. Thus, excessive sleep debt can interfere with labor progression. Psychosocial Consequences of Insufficient Sleep Accumulated insufficient sleep, fatigue, and hormonal changes can impair women’s mood state, emotional sensitivity, and interpersonal functioning and can trigger physical and psychological stress or depression.1,5,77,87 Insufficient sleep (4 hours) even for 12 consecutive days decreases optimism-sociability (i.e., psychosocial functioning and positive outlook), and has a role in onset or amplification of pain.87 Women with poor sleep throughout many weeks of pregnancy might avoid interpersonal communication or behave in an unusual manner during social interactions. Prospective studies using sleep diaries and questionnaires found that sleep disruption during late pregnancy and before birth and nighttime labor were associated with emotional disturbances in the first few weeks after delivery (see Chapter 139), but sleep, mood, or reproductive hormones were not objectively measured in these studies.44,88 Pregnant women also often complain about difficulties with attention, concentration, memory, and reduced ability to perform daily activities. A meta-analysis of 14 studies involving pregnant and postpartum women matched with controls on behavioral measures of memory concluded that some memory measures, particularly related to executive cognitive control, are significantly impaired.76
1584 PART II / Section 18 • Women’s Health
Persistent insufficient sleep is likely to interfere with a woman’s ability to work efficiently due to a high level of fatigue associated with poor sleep in the third trimester.33,77 Therefore, rates of absenteeism from the workplace might increase, and there is an increased risk for accidents at work, in the home, and while driving an automobile. Mood state, interpersonal functioning, memory, work performance, pain sensitivity, labor duration, and type of delivery can all be affected by sleep disturbance. Because of potential adverse effects on the infant, mother and entire family, these areas require further research. Gestational Diabetes Findings from both epidemiologic and laboratory studies show that chronic partial sleep loss can increase risk of obesity and diabetes by impairing glucose regulation and dysregulating the neuroendocrine control of appetite.89 However, there are no controlled studies investigating these factors during pregnancy. Recent survey studies reported that habitual snoring and short sleep duration are associated with an increased risk of gestational diabetes.63a,89a,89b Another study using both PSG and questionnaires showed that RDI ≥ 15 and longer nap duration are associated with higher glucose levels during pregnancy after adjustment for parity, BMI, and steady night-shift work.90
MANAGEMENT OF SLEEP DISTURBANCES AND SLEEPRELATED DISORDERS Almost all women, especially those who are overweight or obese, have sleep problems at some point during their pregnancy. Much of the stress associated with pregnancy occurs because of uncertainty about whether the problems experienced are normal or not. It is important, then, to educate pregnant women about sleep during pregnancy and provide information about sleep hygiene and other nonpharmacologic alternatives as part of their prenatal care (see Box 138-1). Health professionals who provide care for women should have a high index of suspicion for sleep problems and ask about sleep habits and sleep complaints as well as factors that can contribute to sleep loss. This is especially important to address when women are planning to start a family and they are more aware of initiating healthy behavior. If sleep problems are detected early, women can be referred to sleep experts, and early diagnosis and treatment have the potential for preventing adverse pregnancy outcomes (see Fig. 138-2). Pharmacologic treatment (see Table 138-2) should be used at the lowest effective dosage during pregnancy because of potentiating effects of endogenous progesterone, and it should be used only in severe cases because well-controlled studies on long-term effects for the developing fetus are lacking.14,42,73 The diagnosis and treatment of common sleep-related disorders are highlighted in the flow management chart (see Fig. 138-2) and in related sections in this chapter. Pregnancy may be accompanied by more than one sleep disorder. In this case, a multidirectional therapeutic approach should be considered. Treatment of symptoms
in problems such as snoring, pain, or gastroesophageal reflux should focus on both nighttime and daytime complaints to ensure good-quality sleep.
CONCLUSION Physical and hormonal changes can affect sleep architecture and many organ systems during pregnancy and delivery. These changes cause sleep disturbance with multiple awakenings and daytime fatigue. Pregnant women are predisposed to develop sleep-related disorders (such as SDB and RLS) or worsening of a preexisting disorder. These disorders are associated with several perinatal complications, affect maternal and fetal health outcomes, and need to be assessed and treated as early in the pregnancy as possible and by nonpharmacologic therapy whenever possible. Large longitudinal studies from before pregnancy to after delivery are needed to examine prevalence prospectively, to identify the gestational time of onset of a disorder, and to test interventions for these sleep disorders using objective measures.
❖ Clinical Pearls Good-quality sleep is a necessity for optimal maternal health and fetal development, good pregnancy outcomes, and smooth transition from pregnancy to early motherhood. However, sleep disturbances and sleep-related disorders occur commonly during pregnancy and are associated with increased risk of adverse outcomes. Health care professionals need to educate women about sleep problems and provide information about sleep hygiene during this receptive time in a woman’s life. In the clinical setting, sleep should be accurately assessed and should extend beyond simply asking about sleepiness, especially in overweight women. Early recognition, management, and treatment of these sleep issues are important for improving pregnancy outcomes. However, there is no agreement about practice parameters of how or whom to screen and treat, especially in the case of SDB. Management and treatment should aim to improve sleep using sleep hygiene measures and CBT strategies as a first-line choice, with exceptions for severe cases. In the case of multiple disorders accompanying pregnancy, a multidirectional therapeutic approach should be considered.
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76. Henry JD, Rendell PG. A review of the impact of pregnancy on memory function. J Clin Exp Neuropsychol 2007;29:793803. 77. Espie CA. Understanding insomnia through cognitive modelling. Sleep Med 2007;8(Suppl. 4):S3-S8. 78. Rey E, Rodriguez-Artalejo F, Herraiz MA, et al. Gastroesophageal reflux symptoms during and after pregnancy: a longitudinal study. Am J Gastroenterol 2007;102:2395-2400. 79. Schenck CH, Mahowald MW. Parasomnias from a woman’s health perspective. In: Attarian HP, editor. Sleep disorders in women: a guide to practical management. Totowa, NJ: Humana Press; 2006. 80. Hedman C, Pohjasvaara T, Tolonen U, et al. Parasomnias decline during pregnancy. Acta Neurol Scand 2002;105:209-214. 81. Williams SF, Alvarez JR, Pedro HF, Apuzzio JJ. Glutaric aciduria type II and narcolepsy in pregnancy. Obstet Gynecol 2008;111(2 Pt. 2):522-524. 82. Izci-Balserak B, Venelle M, Liston W, et al. The risk factors of sleep-disordered breathing as predictors of pre-eclampsia. [abstract]. J Sleep Res 2008;17(Suppl. 1):O27. 83. Bachour A, Teramo K, Hiilesmaa V, Maasilta P. Increased plasma levels of inflammatory markers and upper airway resistance during sleep in pre-eclampsia. Sleep Med 2008;9:667-674. 84. Foster GE, Poulin MJ, Hanly PJ. Intermittent hypoxia and vascular function: implications for obstructive sleep apnoea. Exp Physiol 2007;92:51-65. 84a. Chang JJ, Pien GW, Duntley SP, Macones GA. Sleep deprivation during pregnancy and maternal and fetal outcomes: is there a relationship? Sleep Med Rev 2010;14:107-114. 85. Sahin FK, Koken G, Cosar E, et al. Obstructive sleep apnea in pregnancy and fetal outcome. Int J Gynaecol Obstet 2008;100(2): 141-146. 86. Lee KA, Gay CL. Sleep in late pregnancy predicts length of labor and type of delivery. Am J Obstet Gynecol 2004;191(6): 2041-2046. 87. Haack M, Mullington JM. Sustained sleep restriction reduces emotional and physical well-being. Pain 2005;119(1-3):56-64. 88. Wilkie G, Shapiro CM. Sleep deprivation and the postnatal blues. J Psychosom Res 1992;36(4):309-316. 89. Tasali E, Le Proult R, Spiegel K. Reduced sleep duration and quality: relationships with insulin resistance and type 2 diabetes. Prog Cardiovasc Dis 2009;51:381-391. 89a. Facco FL, Grobman WA, Kramer J, et al. Self-reported short sleep duration and frequent snoring in pregnancy: impact on glucose metabolism. Am J Obstet Gynecol 2010;203:142.e1-142.e5. 89b. Qiu C, Enquobahrie D, Frederick IO, et al. Glucose intolerance and gestational diabetes risk in relation to sleep duration and snoring during pregnancy: a pilot study. BMC Womens Health 2010;10:17. 90. Izci-Balserak B, Ratclif S, Pien G. SDB and daytime napping are associated with higher glucose levels in pregnant women. [Abstract 0339]. Sleep 2010;33:A119.
The Postpartum Period Robyn Stremler and Amy R. Wolfson
Abstract The postpartum period is a time when sleep patterns are greatly disturbed. An abrupt drop in placental hormones following birth, along with the unpredictable sleep patterns of the newborn contribute to the postpartum woman’s poor sleep and alteration of her circadian rhythm. Women attempt to counteract sleep loss at night through more frequent naps and sleeping later in the morning. Many women experience considerable daytime sleepiness and fatigue through the first few postpartum months. Additionally, some women develop post-
It is likely that as long as there have been mothers, the experience of sleep disturbance and fatigue in the postpartum has existed. However, sleep is difficult to study during postpartum recovery and the first few months after birth because, not surprisingly, women find it difficult to attend sleep laboratories for study, home polysomnographic monitoring may be intrusive, and sleep data collection, even by actigraphy or questionnaire, may represent a significant burden given the demands of infant care. Sleep disturbance during the postpartum period and its effects on maternal role functioning and mother–infant interactions are not well understood. Confounding factors such as the mother’s age, type of delivery, type of infant feeding, infant temperament, return-to-work issues, prior birth experience, number of other children in the home, and availability of nighttime support from the partner or other members of the family can have an impact on quality and quantity of sleep in new mothers, especially until the infant begins to sleep through the night. Interventions to improve maternal sleep and fatigue in the postpartum are limited, perhaps because of the universal nature of the experience and the belief that disturbed sleep is an unavoidable part of motherhood. In this chapter, we discuss the sleep changes that occur during the postpartum period and the impact of sleep patterns on maternal health during the early months of motherhood. Conclusions are presented within the context of sleep and circadian rhythm disturbances for childbearing women, and the implications for maternal role functioning and maternal-infant interaction are discussed.
PHYSIOLOGIC CHANGES DURING THE POSTPARTUM PERIOD The abrupt drop in hormone levels after the birth of the placenta can affect a new mother’s sleep as much as the 24-hour care she provides for her newborn. The first pregnancy experience has more of an impact on a woman’s postpartum sleep than subsequent pregnancies do (Box 139-1).1 Postpartum women are at risk for anemia (due to blood loss during delivery and increased iron demands of pregnancy), infection (endometritis, urinary tract infection, and mastitis are most common), and thyroid dysfunc-
Chapter
139 partum depression; those who report significant sleep loss and infant sleep problems are more likely to experience depression. Complaints of excessive sleepiness, fatigue, or sleep loss should be evaluated by health care providers because of potential harm to the newborn and relationship to postpartum depression. Evaluation of sleep disturbance and depression should be a part of routine postpartum assessments, and advice related to maximizing sleep in the postpartum should be provided. Pharmacologic options for sleep disturbances should be viewed with caution during lactation because of the risk to infant development.
tion (hypothyroidism). Women who are experiencing high levels of fatigue in the first few months after delivery should be assessed for these risk factors and treated.2
CIRCADIAN RHYTHM AND THE POSTPARTUM PERIOD Although growth hormone, prolactin, melatonin, cortisol, and thyroid-stimulating hormone have a circadian rhythm, little is known about changes that can occur in the postpartum period and their effects on sleep disturbance and daytime sleepiness. Delivery of the placenta results in reduction in estriol and progesterone levels from pregnancy,3 and increases in oxytocin and prolactin are seen. Melatonin levels and patterns of secretion may be altered in postpartum women by increased nighttime light exposure while they provide infant care and decreased daylight exposure due to limited activity outside the home. Changes in melatonin secretion patterns can influence subsequent sleep quality via alterations to circadian rhythms, yet few studies have examined the influence of disruption of circadian rhythm on sleep disturbance or fatigue in the postpartum period. In fact, the most commonly dispensed advice regarding maternal sleep in the postpartum period, the admonishment to “sleep when the baby sleeps,” is counterintuitive to circadian rhythm entrainment. Sleep at night is most restorative when it occurs during usual sleep hours; entraining the mother’s sleep to the infant’s is less ideal than finding ways to more quickly entrain the newborn to sleeping through the middle of the night. A comparison of urinary 6-sulfatoxymelatonin levels and timing of release in women at 4 to 10 weeks after delivey and nonpregnant nulliparous women suggests that postpartum women have higher baseline and lower percentage rise in melatonin levels.4 These differences suggest altered circadian rhythm, and they can contribute to sleep disruption in the postpartum period.4 SLEEP DURING POSTPARTUM RECOVERY For the most part, maternal sleep efficiency is poor on the first night after delivery but begins to improve over the 1587
1588 PART II / Section 18 • Women’s Health Box 139-1 Sleep, Hormone, and Behavior Changes Typical during the Postpartum Period Hormones Abrupt drop in progesterone levels from pregnancy Abrupt drop in estrogen levels from pregnancy Prolactin levels fluctuate with lactation Sleep Patterns and Architecture Sleep is disrupted due to infant care and feeding Sleep is more disrupted for first-time mothers than for experienced mothers Breast-feeding mothers are awake longer during the night in the first month after delivery, but they sleep longer at 3 months postpartum than formulafeeding mothers Tendency to sleep later into the morning hours Increased slow-wave sleep Sleepiness and Sleep Challenges Increased daytime sleepiness Difficulty with sleeping, nap if not employed outside the home Issues of bed-sharing emerge Mental Health Concerns Risk of postpartum depression
following days.5 Being in labor during the night may be related to depressed mood during the first week after delivery (see Postpartum Depression, later).6 Postpartum recovery is generally defined as the first 6 months after delivery, although most women would say that the postpartum period continues from birth until the infant is sleeping through the night with predictable day and night sleeping patterns.7 Maternity leave for employed women is typically only 6 weeks in the United States, whereas in Canada employment leave is for 12 months; these differences in return to employment undoubtedly have effects on mothers and their families’ experiences of sleep and fatigue in the first year, but such comparisons have not been studied. In the early postpartum days, there is a rapid decline in all placental hormones, and 35% to 80% of women experience postpartum distress or blues approximately 3 to 5 days after birth. For most women, the blues are confined to the first 2 weeks after childbirth, but a major episode of postpartum depression can occur at any time during the first 6 months after childbirth.7 About 20% of women develop depression in the postpartum period, a prevalence that is similar to that of women at other stages of life (see Postpartum Depression, later). Both self-report and actigraphy studies have demonstrated that nearly 30% of mothers have disturbed sleep after the birth of their baby and that they experience more nighttime awakenings because of disruptions during the initial postpartum weeks (2 to 4 weeks) in comparison to the end of pregnancy and later postpartum months.8-11 Although total sleep time might change little over this period, a mother’s sleep is far more disrupted and less efficient during these early postpartum weeks than at other points in her life. Women seem to compensate for their sleep disruptions by spending more time napping and
sleeping later in the morning during the first postpartum month.8,9-12 Compared with early in postpartum recovery, awaking and arising times occur earlier at 3 to 4 postpartum months and at 12 to 15 postpartum months,11 presumably because women are returning to work. Researchers have also examined changes in fatigue and lack of energy from pregnancy into the postpartum period, as well as through the year after delivery, through selfreport and physiologic measures such as progesterone levels, thyroid functioning, and iron or other nutrient deficiencies.2,13-15 On the basis of these studies, nulliparas and multiparas do not differ significantly in their perception of fatigue. However, 3 to 6 weeks after delivery is especially fatiguing for first-time mothers, and fatigue levels remain high during the first 3 months after delivery compared with prepregnancy reports.13,15 Postpartum fatigue is associated with reduced sleep time, low hemoglobin, and low levels of ferritin.13 When these measures are taken together, researchers conclude that the level of progesterone is unrelated to fatigue and that social factors, such as employment and family responsibilities, influence perception of fatigue during the postpartum period.13,15 A small number of studies have described sleep architecture in the postpartum period. It appears that mothers, regardless of the number of children, have a significant increase in slow-wave sleep (SWS) and less stage 1 and stage 2 sleep (light sleep) at 1 month after delivery.1,8,13,16-18 This may be caused in part by the action of prolactin (see the section on Breast-Feeding). Interventions to Improve Maternal Sleep Only one randomized, controlled trial has evaluated the effects of a behavioral-educational intervention on maternal sleep. First-time mothers in the intervention group received a 45-minute meeting with a nurse in the immediate postpartum period to discuss sleep information and strategies to improve her sleep and that of her baby, an 11-page booklet, and weekly phone contact to reinforce information and solve problems. Using actigraphy to measure the mother’s and infant’s sleep, women in the intervention group slept 57 minutes more at night, and fewer rated their sleep as a problem at 6 weeks, as compared to women in the control group.19 Breast-Feeding and Formula Feeding Self-reported sleep disturbance and perception of fatigue are unrelated to type of infant feeding, whereas wrist actigraphy measures document more wake time during the night in women who are exclusively breast-feeding at 3 to 4 weeks after the birth.12,20,21 During the first 2 weeks after birth, rapid eye movement (REM) sleep is stable for women who are breast-feeding, but it gradually decreases for women who are not lactating.22 Some families choose to supplement infant feeding with formula in the hope that the infant will be better satiated, settle faster, and sleep longer at night, and parents will achieve more nighttime sleep.23 At 3 months after delivery, however, mothers and fathers of infants who are breast-fed in the evening (6 pm to 12 am) or at night (12 am to 6 am), or both, sleep an average of 37 to 48 minutes more as measured by actigraphy than parents who give infants formula during those same time frames.23 Parents of infants given formula at
night also report more subjective sleep disturbance than parents of infants who are exclusively breast-fed at night. Health care professionals working with pregnant and postpartum women should make parents aware that breastfeeding may in fact increase parental nighttime sleep and should discourage the introduction of formula feeding as a means to promote sleep. For lactating women, basal levels of prolactin are high and there is a burst of prolactin secretion at the onset of each breast-feeding event, regardless of when sleep occurs, and these bursts seem to be of a higher magnitude in the evening than in the morning.24 Both basal levels and bursts of prolactin diminish to prepregnancy levels by about 3 months after delivery. The effect of lactation on sleep patterns of mothers and infants has not been a focus of research, but Blyton and coworkers25 studied women in their home environment with portable polysomnography, and the lactating women had less stage 1 and stage 2 light sleep, fewer arousals, and more SWS, especially in the second half of the night, compared with nonlactating postpartum women. There was no difference in the amount of REM sleep or total sleep time between the two groups.25 Within 24 hours of weaning, prolactin levels return to low basal levels and to the circadian sleep-associated patterns found in healthy adults.26 Bed-Sharing and Room-Sharing Bed-sharing is defined as an infant sleeping in the same bed with the caregiver; previously, this practice was commonly referred to as co-sleeping. Room-sharing refers to sleep situations in which the infant sleeps in the same room as, and in close proximity to, a parent or caregiver but does not occupy the same bed. Although few studies have examined the relationship between bed-sharing or roomsharing and mothers’ sleep–wake patterns, parent–infant bed-sharing has become increasingly common during the postpartum period.27-30 The proportion of usually bedsharing infants in the United States rose from 5.5% in 1993 to 1994 to 12.8% in 1999 to 2000.30 A recent survey in one U.S. state found that over 35% of women report regularly bed-sharing with their infant31 and rates of regular bed-sharing in one Canadian province are estimated at more than 42%.32 Some studies suggest that bed-sharing reduces the risk of sudden infant death syndrome (SIDS) because the bedsharing infant has more arousals due to the mother’s body heat, sounds, oxygen and carbon dioxide exchange, smells, movement, and touch.28 It has been postulated that infants are at risk for dying from SIDS because of their immature neurologic systems and difficulty arousing from sleep to breathe.28 However, greater risks of SIDS or asphyxiation for bed-sharing infants may be posed by overheating, the presence of pillows, comforters, soft surfaces, and multiple bodies, particularly in the case of adults who are smokers, extremely fatigued, intoxicated, or obese.33,34 Room-sharing can decrease risk of SIDS by providing infant proximity to parental cues for arousal, while limiting risks posed by bed-sharing.33,34 Bed-sharing mothers report disrupted, inefficient sleep. In a polysomnographic study, Mosko and colleagues27 demonstrated that bed-sharing had no effect on REM sleep but that it increased the number of arousals and
CHAPTER 139 • The Postpartum Period 1589
modestly reduced SWS, and that it increased stage 1 and stage 2 light sleep in breast-feeding women. Bed-sharing is not necessarily associated with breast-feeding practices or with household crowding.29 Because the trend for infant bed-sharing is on the rise and may be more commonly practiced by low-income women,29-31 the impact of bedsharing or room-sharing on the sleep–wake patterns of the new mother and father, as well as on the infant’s sleep, requires further investigation.
POSTPARTUM HEALTH PROBLEMS ASSOCIATED WITH DISTURBED SLEEP Sleep disorders that can arise during pregnancy, such as sleep-disordered breathing, esophageal reflux, or restless legs syndrome, typically resolve following labor and birth.35 Pharmacologic treatment during lactation for preexisting sleep problems is of great concern because of potential effects on fetal development and on the newborn’s growth and development; see Chapter 138 for a summary of common sleep-related medications and their ratings for potential harm to the fetus or newborn. Severe sleep deprivation in the postpartum period contributes to substantial postpartum weight retention. Women reporting short sleep duration (<5 hours in a 24-hour period) at 6 months after delivery are more than twice as likely to retain at least 5 kg of weight gained during pregnancy at 1 year after delivery.36 Strategies to decrease postpartum obesity should include interventions to increase maternal sleep duration. Postpartum Depression Up to 50% to 60% of all new mothers experience postpartum blues during the first 2 postpartum weeks. The blues manifest as excessive and unpredictable crying episodes and sadness during a time that should be quite joyful. At some point during the first 3 to 6 months after delivery, between 10% and 15% of new mothers experience diagnosable postpartum depression.37,38 Symptoms of postpartum depression are similar to depression experienced at other times of life (see Chapter 130), but they also include difficulty sleeping when the baby sleeps and worrying about hurting the baby.37 Various mechanisms for postpartum depression have been proposed, including the dramatic drop in progesterone and estrogen levels during the first few postpartum days,38 poor supportive relationships, overly high expectations of the baby and motherhood, unexpected difficulties with labor and delivery or postpartum infant care, and a sudden shift in attention from the mother to the baby. These contextual variables, however, have not been shown to be directly related to postpartum depression.37,38 One additional contextual variable that seems obvious but has previously been overlooked is sleep deprivation and disrupted sleep–wake cycles. Sleep deprivation is likely to contribute to postpartum mood changes.8,17,18,22,39 Being in labor during the night and a prior history of sleep disruption at the end of pregnancy can result in a higher incidence of postpartum blues.6,11 Specifically, one study reported that new mothers had increased dysphoric mood during the first postpartum week, but this significant effect
1590 PART II / Section 18 • Women’s Health
was eliminated when “time awake” was controlled for in the analysis.40 The frequency of night awakenings, rather than a change in hormone levels, was related to negative mood at 1 month after delivery, and REM sleep-onset latency was significantly shorter (<60 minutes) for the postpartum women who reported higher levels of depressed mood.39 Mothers who develop elevated depressive symptoms at 2 to 4 weeks after delivery have significantly different sleep schedules or insomnia at the end of their pregnancies compared with nondepressed mothers.11,40a On average, mothers who developed postpartum depressive symptoms reported later rise times, longer naps, and more total sleep at the end of their pregnancies. Postpartum mothers’ increased time awake during the night and poor sleep quality were strongly associated with increased negative daytime mood, or blues, particularly in the first 4 weeks after delivery.11,20,22 Lee and colleagues39 compared sleep patterns for women with positive postpartum affect at 1 month after delivery to women with negative postpartum affect. The positive-mood group had stable sleep times from the last trimester to 1 month after delivery, whereas the negative-mood group reported that they slept 80 minutes less at 1 month after delivery.39 Although Wolfson and colleagues11 did not examine the data in this fashion, the women with clinically significant depressed mood at 2 to 4 postpartum weeks reported more changes in their sleep (e.g., decreased total sleep from the end of pregnancy to early postpartum weeks) than the nondepressed women. Future studies need to examine the impact of changes in sleep patterns from pregnancy to the early postpartum weeks on the possible development of postpartum depression. The effects of infants’ sleep patterns on mothers’ sleep and development of postpartum depression are essential to consider. Postpartum women with no major depressive symptoms at 1 week after delivery were followed to 4 and 8 weeks after delivery to examine relationships among infants’ sleep patterns, mothers’ sleep, and development of depressive symptoms.41 Mothers exhibiting major depressive symptoms at 4 and 8 weeks after delivery were more likely to report less than 6 hours of sleep in a 24-hour period over the previous week and being awakened by their baby three or more times between 10 pm and 6 am. These findings suggest that infant sleep patterns and maternal sleep deprivation and fragmentation are significant contributors to the etiology of postpartum depression. Report of an infant sleep problem when the infant is 6 to 12 months of age is also associated with major depressive symptomatology, even after adjusting for known risk factors such as history of depressive illness.42 Because infant sleep problems in these studies were based on mothers’ reports rather than objective evaluations of infant sleep, the possibility exists that depressed mothers perceive their infant’s sleep more negatively than nondepressed mothers or are more likely to report sleep problems, whether they exist or not. There is evidence, however, that treatment of infants’ sleep problems results in decreased incidence of mothers’ depression. Two randomized, controlled trials of brief behavioral interventions to decrease infant sleep problems significantly decreased mothers’ reports of an infant’s sleep problem and reduced mothers’ symptoms of depression.43,44
Similarly, Wolfson and colleagues demonstrated that parent training focused on developing healthy infant sleep patterns improves parents’ competence and marital satisfaction, and decreases parents’ stress.45 Postpartum depression can have an impact on mother– infant bonding as well as on marital satisfaction and infant development.45 A few women go on to develop postpartum psychosis, of which insomnia is one of the most common symptoms.37,38,46,47 Although women with a history of mental illness are at increased risk for postpartum depression or postpartum psychosis, Coble and colleagues17 followed women until 8 months after delivery and found no differences in sleep architecture between those with a history of mental health problems and controls, and no woman in their study developed postpartum depression. Women with major depression during pregnancy or the postpartum period were found to have more REM sleep than women without a pregnancy-related depressive episode,48 suggesting a greater sleep-related risk for depression. In contrast, in women with a history of mood disorder, less REM sleep was noted early in pregnancy and persisted even at 8 postpartum months in one study,17 and REM sleep was not different during pregnancy or after delivery compared with matched controls.49 Because of the risks of antidepressant drug therapy to the newborn during breast-feeding (see Table 138-1), health care providers hesitate to prescribe medications, and some women refuse pharmacologic therapy or have intolerable side effects that include sedation, disrupted sleep, or insomnia.37,50 For postpartum women, it is recommended that any drug therapy should start with half of the lowest recommended level and be increased slowly in small increments.37 If drug therapy is not a reasonable option, REM sleep deprivation or light therapy may be useful to consider (See Chapters 130 and 149). Women with postpartum depression who were allowed to sleep only from 9 pm to 1 am and kept awake during the second half of the night responded more favorably to this sleep deprivation therapy than women allowed to sleep from 3 am to 7 am.48,51 During postpartum depressive episodes, light treatment may be effective if administered over weeks rather than days.52 ❖ Clinical Pearls If specific sleep disorders such as RLS, sleep apnea, or insomnia developed during pregnancy, these should be evaluated in the postpartum period to determine if the difficulties have resolved. Complaints of excessive sleepiness, fatigue, or sleep loss should be pursued and evaluated by health care providers because of potential harm to the newborn and relationship to anemia, infection, thyroid dysfunction, and postpartum depression. Evaluation of sleep disturbance and depression should be a part of routine postpartum assessments, and advice related to maximizing sleep in the postpartum should be provided. Severe sleep restriction in the postpartum period may contribute to retention of excessive postpartum weight, depressive symptoms, and poor mother–infant interactions, with potential risk to health and safety of the newborn.
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CHAPTER 139 • The Postpartum Period 1591 28. McKenna J, Mosko S, Richard C, et al. Experimental studies of infant–parent co-sleeping: mutual physiological and behavioral influences and their relevance to SIDS (sudden infant death syndrome). Early Hum Dev 1994;38:187-201. 29. Brenner RA, Simons-Morton BG, Bhaskar B, et al. Infant–parent bed sharing in an inner-city population. Arch Pediatr Adolesc Med 2003;157:33-39. 30. Willinger M, Ko C, Hoffman HJ, et al. Trends in infant bed sharing in the United States, 1993-2000. Arch Pediatr Adolesc Med 2003; 157:43-49. 31. Lahr MB, Rosenberg KD, Lapidus JA. Maternal–infant bedsharing: risk factors for bedsharing in a population-based survey of new mothers and implications for SIDS risk reduction. Matern Child Health J 2007;11:277-286. 32. Ateah CA, Hamelin KJ. Maternal bedsharing practices, experiences, and awareness of risks. J Obstet Gynecol Neonatal Nurs 2008;37: 274-281. 33. Canadian Paediatric Society. Recommendations for safe sleeping environments for infants and children. Paediatr Child Health 2004;9:659-663. 34. American Academy of Pediatrics. The changing concept of sudden infant death syndrome: diagnostic coding shifts, controversies regarding the sleeping environment, and new variables to consider in reducing risk. Pediatrics 2005;116:1245-1255. 35. Lee K. Alterations in sleep during pregnancy and postpartum. Sleep Med Rev 1998;2:231-242. 36. Gunderson EP, Rifas-Shiman SL, Oken E, et al. Association of fewer hours of sleep at 6 months postpartum with substantial weight retention at 1 year postpartum. Am J Epidemiol 2008;167:178-187. 37. Wisner KL, Parry BL, Piontek CM. Postpartum depression. N Engl J Med 2002;347:194-199. 38. Bloch M, Schmidt PJ, Danaceau M, et al. Effects of gonadal steroids in women with a history of postpartum depression. Am J Psychiatry 2000;157:924-930. 39. Lee KA, McEnany G, Zaffke ME. REM sleep and mood state in childbearing women: sleepy or weepy? Sleep 2000;23:877884. 40. Salazaro P. Long lasting disturbances in women after childbirth. J Reprod Infant Psychol 1987;5:245-246. 40a. Marques M, Bos S, Soares MJ, et al. Is insomnia in late pregnancy a risk factor for postpartum depression/depressive symptomatology? Psychiatry Res 2010 Jul 16. [Epub ahead of print] 41. Dennis CL, Ross L. Relationships among infant sleep patterns, maternal fatigue, and development of depressive symptomatology. Birth 2005;32:187-193. 42. Hiscock H, Wake M. Infant sleep problems and postnatal depression: a community-based study. Pediatrics 2001;107:1317-1322. 43. Hiscock H, Wake M. Randomised controlled trial of behavioural infant sleep intervention to improve infant sleep and maternal mood. BMJ 2002;324:1062-1065. 44. Hiscock H, Bayer J, Gold L, et al. Improving infant sleep and maternal mental health: a cluster randomised trial. Arch Dis Child 2007;92: 952-958. 45. Wolfson A, Lacks P, Futterman A. The effects of parent training on infant sleeping patterns, parents’ stress and perceived competence. J Consult Clin Psychol 1992;60:41-48. 46. Sharma V, Mazmanian D. Sleep loss and postpartum psychosis. Bipolar Disord 2003;5:98-105. 47. Rohde A, Marneros A. Postpartum psychoses: onset and long-term course. Psychopathology 1993;26:203-209. 48. Frank E, Kupfer DJ, Jacob M, et al. Pregnancy-related affective episodes among women with recurrent depression. Am J Psychiatry 1987;144:288-293. 49. Parry BL, Sorenson DL, Meliska CJ, et al. Hormonal basis of mood and postpartum disorders. Curr Sci 2003;3:230-235. 50. Dennis CL, Stewart DE. Treatment of postpartum depression, part 1: a critical review of biological interventions. J Clin Psychiatry 2004;65:1242-1251. 51. Parry BL, Curran ML, Stuenkel CA, et al. Can critically timed sleep deprivation be useful in pregnancy and postpartum depressions? J Affect Disord 2000;60:201-212. 52. Corral M, Kuan A, Kostaras D. Bright light therapy’s effect on postpartum depression. Am J Psychiatry 2000;157:303-304.
Menopause
Kathryn A. Lee and Karen E. Moe
Abstract Menopause is a normal event in a woman’s life. It is the physiologic centerpiece of a major developmental stage in the normal aging process. Most women now live long enough to become menopausal and can expect to live at least another 30 years beyond their final menstrual period. The number of postmenopausal women in the world is increasing due to longer life expectancy. In the United States, 27% of the population in 2000 consisted of women 45 years of age and older, and the estimate is now at 38%.1 There is accumulating evidence that the hormonal and other biological changes of menopause have health consequences for some women that extend beyond the classic reproductive tissues and functions. In particular, changes in sleep are commonly experienced during and after menopause. Insomnia and
PHASES OF THE MENOPAUSAL TRANSITION Menopause is the anchor point of a woman’s transition to midlife and, because menstrual cycles can be irregular for many reasons, menopause can only be officially declared after 12 months of amenorrhea. Menopause occurs at a mean of 51.4 years of age for Western women, but the range can be as wide as 40 to 58 years of age. For many years, menopause was simply considered a consequence of depleted ovarian follicles (the primary source of estrogen and progesterone). However, it is now clear that it is a transitional process that begins several years before menopause itself, and continues for several years. This perimenopausal developmental transition in a woman’s life is a dynamic process that consists of a series of complex and interactive changes in the endocrine system and central nervous system that occur on a background of aging.2 A menopause staging system has been developed to provide a consistent way to describe this transition in midlife women (Fig. 140-1).3 The early menopausal transition stage is characterized by elevated follicle-stimulating hormone (FSH) and a variable cycle length (more than 7 days’ deviation from normal). FSH levels increase in response to the absence of estrogen and progesterone that would normally provide negative feedback to the hypothalamus to inhibit FSH secretion. The late menopausal transition stage is characterized by two or more skipped menstrual cycles and an interval of amenorrhea (at least 60 days) as well as elevated FSH levels. The postmenopausal period is also divided into stages. The early postmenopause stage is defined as 5 years since the final menstrual period, and is subdivided into two segments: the first 12 months after the final menstrual period and the next 4 years. The late menopause stage starts 5 years after the final menstrual period and continues through the remaining life span. 1592
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140 fatigue are among the most common health complaints of perimenopausal women, including those who are not seeking treatment for menopausal symptoms. This chapter discusses several clinical conditions commonly associated with menopause that can contribute to sleep disruption in middle-aged and older women. Hormone replacement therapy (HRT) has been the treatment of choice for menopausal hot flushes and night sweats, and the effect of these therapies on sleep has been the focus of considerable research. Sleep-disordered breathing is also more prevalent in women after menopause. This may be strongly related to other menopause-related changes, particularly the increased prevalence of obesity. Depression, thyroid disease, and cancer are also more common after menopause. This chapter provides an overview of menopause and discusses these common clinical conditions and their impact on women’s sleep.
Menopause is a universal phenomenon, but the timing of these transitional stages and associated signs and symptoms vary considerably from woman to woman. The age at which menopause occurs is strongly influenced by several factors: smoking, adiposity, race and ethnicity, and reproductive variables such as age at menarche, duration of breast-feeding, and use of oral contraceptives. The vasomotor signs and symptoms associated with menopause, such as hot flushes and night sweats, also vary to such a great extent that they are not specified as one of the staging criteria3 for ascertaining phases of menopause (see Fig. 140-1). The perimenopausal transition for an individual woman arises from a complex interaction of biological, cultural, psychological, and environmental factors. The timing and duration of this midlife transition cannot be easily predicted. Midlife is considered to be between 40 and 60 years of age, but there is no generic midlife woman.4 In addition to the complexity of menopausal stages and hormonal fluctuations, midlife women can be having their first child, have grown children leaving home, and be caring for elderly parents or spouses. All of these scenarios can affect a woman’s sleep during menopause.
NORMAL SLEEP PATTERNS DURING MENOPAUSE Disturbed sleep and daytime fatigue are among the most common complaints of women during the menopausal transition.5,6 Population survey studies of menopause show that sleep problems are more common in perimenopausal and postmenopausal women compared with premenopausal women. The prevalence of sleep disturbance varies widely by culture and from one study to another depending on how the sleep disturbance is defined and measured. As part of menopausal symptoms, trouble sleeping was reported by 54% to 57% of women between 40 and 60 years of age in
Final menstrual period (FMP) 0 –4
–5
Reproductive
Menstrual cycles
Duration of stage
Early
Endocrine
–3
Peak
Late
Variable
Variable to regular
–1
Menopausal transition Early Late* Perimenopause Variable
Regular
Normal FSH
–2
↑ FSH
2 Variable skipped cycle cycles length and an (>7 days interval different of from amenorrhea normal) (60 days)
↑ FSH
+1
+2
Postmenopause Early*
Late
a b Until 1 4 yr demise yr Amen x 12 mo
Terminology
Stages
CHAPTER 140 • Menopause 1593
None
↑ FSH
↑ = elevated *Stages most likely to be characterized by vasomotor symptoms Figure 140-1 Stages of normal reproductive aging in women. The final menstrual period (FMP) is the time in a woman’s life when she has missed 12 consecutive menstrual periods (amenorrhea) (a) and is considered early postmenopausal for the next 4 years (b) before becoming late postmenopausal for the remainder of her life. Before permanent cessation of menstrual cycles, women vary in the duration of their cycles during the stage known as perimenopause. Follicle-stimulating hormone (FSH) is elevated throughout early and late perimenopause because of a lack of adequate levels of ovarian hormones to inhibit secretion of FSH from the hypothalamus. Note that the reproductive stages most likely to see hot flushes and night sweats are late perimenopause and early postmenopause, with wide and unpredictable variations in duration of these stages of normal reproductive aging (Adapted from Soules MR, Sherman S, Parrott E, et al. Executive summary: Stages of Reproductive Aging Workshop [STRAW] Fertil Steril 2001;76:874878).
the Ohio Midlife Women’s Study.6 The large Wisconsin Sleep Cohort Study found that perimenopausal and postmenopausal women were twice as likely to be dissatisfied with their sleep than premenopausal women.7 In the most comprehensive study of U.S. midlife women to date, the Study of Women’s Health Across the Nation (SWAN) has shown that difficulty sleeping is reported by 38% of women between 40 and 55 years of age, with higher levels among late perimenopausal (45.4%) and surgical postmenopausal (47.6%) women.8 Yet longitudinal data from the Penn Ovarian Aging Study would indicate that poor sleep is not necessarily associated with menopausal stage.9 The most common menopausal sleep complaint is difficulty falling asleep, but significant increases in self-reported nighttime awakenings and daytime drowsiness have also been described, even after controlling for confounding factors such as depression and age.4-10
Despite the incidence of insomnia complaints by menopausal women, very few studies have used objective techniques such as polysomnography (PSG) or actigraphy to assess sleep before, during, and after menopause. An actigraph study found that postmenopausal women underestimate their sleep time,11 and studies using PSG have not supported any prominent effect of menopause on sleep.7,12-15 One study may have shed more light on this discrepancy between women’s self-report and PSG findings. When Freedman and Roehrs recorded sleep for 4 nights in the laboratory, the 18 postmenopausal women with hot flushes had more arousals and disrupted sleep, but only in the first half of the night when there was less REM sleep.16 In addition to carefully controlled cooler ambient temperature in the sleep laboratory compared to the home, PSG may be less sensitive in detecting some important unknown element of sleep quality reflected by women’s ratings. Another possibility is that the impact of menopause on objective sleep measures is heterogeneous with a subgroup of women whose objectively measured sleep quality shows a menopause-related decline. This would not be surprising, given the heterogeneity of women’s experiences with hot-flush symptoms. Cultural attitudes and expectations about menopause can also influence women’s experiences and might affect perception of sleep quality.17 One prominent theory of reproductive aging is that menopause results from the aging of multiple pacemakers in the brain and ovaries that control and coordinate a variety of circadian and other rhythms.2 The suprachiasmatic nuclei of the hypothalamus are a primary source of these endogenous rhythms and their synchrony. The sleep–wake cycle is the most visible human circadian rhythm, and it is profoundly influenced by the suprachiasmatic nuclei and by other circadian rhythms, particularly rhythms of body temperature and melatonin secretion. Numerous studies have shown estrogen’s impact on circadian rhythms in female mammals.18 These data suggest that the circadian control of sleep might be changed or compromised with menopause. However, this hypothesis is purely speculative at present. No studies have attempted to distinguish menopause effects on circadian rhythm from the well-known effects of aging per se, and aging is repeatedly found to be associated with a decline in sleep quality regardless of sex.19,20 Although investigators studying midlife women (40 to 60 years of age) usually consider menopausal status when describing women’s health and experiences, the effects of depression and obesity are often ignored, and most sleep effects ascribed to menopause may in fact be due to aging. One approach to this issue is to control the confounding factors, such as age, with statistical techniques and treat age as a covariate.7 Another approach is to report experiences and symptoms for specific narrow age ranges in midlife, such that the specific contributions of age and menopause can be identified.4,12 These techniques might not be entirely successful because there is little overlap between ages of premenopausal and postmenopausal women. In short, sleep disturbance in some midlife women may be related to conditions associated with aging (e.g., thyroid dysfunction, depression, obesity) rather than menopause.
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COMMON CLINICAL CONDITIONS IN MIDLIFE WOMEN Hot Flushes and Night Sweats It has long been suspected that at least some of the selfreported sleep disturbance associated with menopause is secondary to vasomotor symptoms of hot flushes and night sweats. A hot flush (often called a night sweat when it occurs during the night) is a sudden, transient, and recurrent subjective sensation of moderate to intense heat that usually begins in the upper body. It is primarily a thermoregulatory phenomenon21 with the characteristics of a heat dissipation response: peripheral vasodilation, which causes increased heat loss, and increased sweating, which causes evaporative cooling. There is tremendous individual variability in hot flushes, likely a result of the variation in individual thermoneutral zones regulated by the hypothalamus. It is hypothesized that before menopause, when endogenous estrogen still interacts with the sympathetic nervous system, the thermoneutral zone is wider and thus it is easier to regulate body temperature within that zone. With inconsistent estrogen secretion during perimenopausal transition, or with absence of estrogen at menopause, the thermoneutral zone narrows considerably. This also occurs with chronic stress and increased sympathetic activation and has implications for therapeutic approaches to treat vasomotor menopausal symptoms with stress-reduction modalities rather than exogenous estrogen therapy.21 A hot flush typically lasts 3 to 5 minutes, but can be more than 20 minutes in some women. The perceived intensity of the flush can also vary widely, from severely disruptive to mild. Some women have hot flushes 20 or more times every day, whereas others report only 1 or 2 per week.2 The average number of hot flushes was 4.5 during the day and 2.0 per night from a study of women in the Pacific Northwest using self-report.22 Although hot flushes are generally associated with menopause, they are experienced during androgen-suppressive hormone treatment for men with prostate cancer, with use of selective estrogen receptor modulators such as tamoxifen for treatment of estrogen-sensitive breast cancer, and in diabetes or glucose intolerance. Surgical menopause, smoking, obesity, depression, and physical inactivity increase the likelihood of hot flushes.23,24 The prevalence of hot flushes also varies by racial and ethnic group. In the SWAN cohort of 15,000 women, approximately 39% of African Americans experienced hot flushes, compared with 26% of Latin Americans and 24% of whites. Asian Americans had the lowest prevalence (16% for Chinese Americans and 12% for Japanese Americans).23 It is not clear whether differences in the experience of hot flushes are the result of differences in lifestyle stressors, diet, cultural factors, or unidentified biologic factors.17 Hot flushes and night sweats are associated with reduced self-reported sleep quality, and this has been confirmed in a variety of study designs, ethnic groups, and nationalities.25,26 However, little is known about how hot flushes affect objectively measured sleep quality. Only a few studies with very small sample sizes have used PSG and a concurrent objective measure of hot flushes to compare sleep in women with and without hot flushes. They show
that hot flushes disrupt sleep, as indicated by more nocturnal awakenings, lower sleep efficiency, and more sleep stage changes.27,28 Erlik and colleagues also assessed the effect of each nocturnal hot flush on sleep in nine menopausal women; of the 47 objectively measured hot flushes, 45 were associated with an awakening that occurred within 5 minutes before or after the flush.28 Some research suggests that hot flushes are unrelated to PSG sleep quality. Most of these studies relied on self-reports of hot flushes, often for nights other than the PSG nights. This is problematic because women are not always aware of hot flushes that occur during sleep. Freedman and Roehrs recently measured occurrence of hot flushes in relation to PSG awakening and documented that symptomatic women have 1 to 18 flushes during the night (average 5.2 ± 2.9). Some women who thought they were asymptomatic actually had hot flushes during sleep, and one women reported hot flushes and did not have a recorded hot flush while in the laboratory. A majority of awakenings (55%) occurred up to 2 minutes prior to the hot flush, but there was no difference in overall sleep efficiency between the symptomatic (83%) and asymptomatic (87%) groups.29 Upon further analysis, these awakenings occurred during the first part of the night and preceded the hot flush; of the 125 flushes that occurred during the second half of the night, none were during REM sleep, and the asymptomatic group had significantly more REM sleep (48 minutes) than the symptomatic group (35 minutes) during the second half of the night.16 Because thermoregulation is suppressed during REM sleep, these findings provide new information to help with reconciling discrepancies between women’s selfreport of poor sleep associated with vasomotor symptoms and PSG findings of little difference in sleep architecture or wake time. Data from large population studies suggest that some women continue to have hot flushes for many years, even decades, after menopause.30 Hot flushes are not always labeled “hot flushes” by older postmenopausal women because of their previous association with menopause. Rather, they may describe their vasomotor symptoms as waking up during the night “feeling too warm” and feeling the need to throw off bedcovers. Finally, not all women who have menopause-related sleep problems complain of hot flushes.31 This suggests that there are other reasons menopause may be associated with sleep disturbance. Sleep disruption associated with hot flushes may be treated in several ways. HRT has historically been the standard treatment. Although HRT is still recommended for the short-term alleviation of vasomotor symptoms in women who do not have a history of breast cancer or stroke, patients and health care providers are increasingly reluctant to pursue this option because of health risks. Many other options are available.32 Antidepressants that inhibit serotonin reuptake (selective serotonin reuptake inhibitors [SSRIs]; e.g., paroxetine)33 and gabapentin34 have been used with some success. Complementary therapies help some women,32,35 although cohort data on effectiveness has been mixed. Relaxation therapies and stress reduction can improve thermoregulation, and appropriate changes in temperature of the sleeping environment and bedclothes may be helpful because a warm ambient
temperature or elevated body core temperature increases the likelihood of hot flushes.16 Effects of Hormone Replacement Therapy on Sleep Estrogen and progesterone levels fluctuate dramatically during the perimenopause and ultimately decline to very low postmenopausal levels.2 Consequently, estrogen therapy or HRT was commonly prescribed for midlife and older women on a long-term basis in an effort to counter hormone deficiency and protect against osteoporosis, heart disease, and Alzheimer’s dementia. However, the Women’s Health Initiative results abruptly reversed this practice. This national clinical trial showed that use of a common HRT regimen for 1 to 7 years significantly increased the risk of breast cancer, stroke, heart disease, and vascular dementia.36 Women are now being advised to use HRT for only a short time to provide relief from hot flushes and other symptoms during the menopausal transition. Dozens of epidemiologic studies and small clinical trials have shown that estrogen therapy or HRT reduces hot flushes and concurrently improves self-reported sleep quality.37 The size of this effect varies from a significant but clinically small effect38 in some studies to other studies that document alleviation of hot flushes as highly predictive of improvements in sleep.31 PSG studies have generally replicated these findings. In women who were experiencing frequent hot flushes, estrogen therapy decreased the number28,39 and duration39 of nighttime awakenings, increased REM sleep,39-41 and shortened latency to sleep onset.40 However, in studies where many or all of the women had only mild or infrequent hot flushes, neither estrogen therapy42 nor HRT43 had an effect on PSG recorded sleep stages. The PSG studies were based on small groups of less than 20 women. Progesterone Virtually nothing is known about how changes in endogenous progesterone levels during menopausal transition affect sleep. Progesterone given by itself can have acute effects of sleepiness similar to sedative-hypnotic medications. A high clinical dose (300 mg) of micronized progesterone given orally 1.5 hours before bedtime significantly shorted latency to REM sleep and increased non-REM (NREM) sleep in a small group of young men.44 There are also numerous clinical reports and anecdotes about sleepiness as a side effect of progesterone, particularly daytime drowsiness that occurs in a significant percentage of women after taking progesterone in the morning as part of HRT.45 Clinically, women on HRT are often advised to take their progesterone in the evening because of this daytime drowsiness phenomenon.45 There may be significant differences among progestins in their impact on sleep. Montplaisir and colleagues46 found that conjugated equine estrogens (Premarin) plus micronized progesterone significantly improved the sleep of postmenopausal women, whereas the same estrogens plus the synthetic medroxyprogesterone acetate had no effect. This is consistent with emerging evidence of significant differences between progestins in their nonendometrial biological effects.47 For example, unlike medroxyprogesterone acetate, micronized progesterone
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is metabolized to potent neurosteroids such as allopregnanolone and pregnanolone. These neurosteroids interact with the same brain gamma-aminobutyric acid type A (GABAA) receptors as sedative-hypnotic medications, and they are soporific.48 In summary, there have been positive effects of estrogen therapy and HRT on sleep of midlife and older women, independent of the presence or absence of hot flushes. The discrepancy between effects of HRT on self-reports of sleep and PSG measures of sleep remain. Few clinical trials using PSG involved small numbers of subjects, and evidence suggests that analysis should be focused on first and second halves of the night’s sleep. Given the current lack of knowledge and the sobering results of the Women’s Health Initiative study, it would be inappropriate to suggest estrogen therapy or HRT as a treatment for menopauserelated insomnia except when the sleep disturbance is clearly due to frequent and severe hot flushes and other alternatives have been explored. Hormone Withdrawal Because of the results from the Women’s Health Initiative study, many women abruptly discontinued HRT. The number of prescriptions for HRT declined by 66% during the 6-month period after results were published.49 The sleep effects of withdrawal from estrogen therapy and HRT are unknown. At least two studies have shown that abrupt estrogen withdrawal can result in significant hot flushes,50,51 suggesting that there might be sleep consequences to discontinuation of estrogen therapy and HRT. Stress Reactivity One way menopausal hormone changes could influence sleep is through changes in stress reactivity. Stress can disrupt sleep; mild psychological distress or stressors such as daily “hassles” can increase arousals and the subjective experience of sleep disturbance.52 Estrogen therapy reduced sympathetic reactivity to psychological stress in postmenopausal women.53,54 Moe and colleagues55 showed more directly how the relationship between stress reactivity and estrogen levels might affect sleep in postmenopausal women who underwent frequent remote nocturnal blood sampling (a mild stressor) during one night of a sleep study. Those not on estrogen therapy had significantly more disrupted sleep from this mild blood sampling stressor than women on estrogen therapy. They had less total sleep time, more time awake during the night, more episodes of awakenings, a longer latency to the onset of sleep, and less slow-wave sleep. These findings have been replicated in a similar type of study, but with women younger than 50 years to better address the effects of age.14 Apnea, Obesity, and Hypertension Obesity, hypertension, and sleep-disordered breathing (SDB) are strongly associated with one another (See Chapter 105).56 All three are common clinical conditions in postmenopausal women, and considerable research suggests that menopause contributes to these conditions. The well-documented gender gap in prevalence of SDB57 begins to narrow with menopause. Bixler and colleagues58 found a ratio of one woman for every 3.3 men with apnea
1596 PART II / Section 18 • Women’s Health
in their sample of 1741 men and women between 20 and 100 years of age; this ratio fell to one postmenopausal women for every 1.44 men once women were matched with men by age and body mass index (BMI). Sleep-Disordered Breathing Menopause has long been described as a risk factor for SDB.59 Previous studies yielded inconsistent or unconvincing results because of small sample sizes, menopausal status defined by age rather than menstrual history or hormonal assay,13,60 or lack of controls for age, adiposity, and sleep clinic referral bias. However, two large and well-designed population studies now provide strong support for the hypothesis that menopause increases the risk of SDB.58,61 In the first study, Bixler and colleagues performed PSG on 1000 women drawn from a random telephone survey.58 The postmenopausal women had a significantly higher prevalence of SDB compared with the premenopausal women. The prevalence of mild SDB (defined as an apnea– hypopnea index [AHI] between 0 and 15, together with a self-report of moderate or severe snoring) was 3.2% for premenopausal women but 9.7% for postmenopausal women who were not using HRT. The prevalence of more-severe SDB (AHI ≥ 15) was 0.6% for premenopausal women versus 2.7% for postmenopausal women not using HRT. SDB prevalence remained significantly higher for postmenopausal women even after adjusting for known risk factors of age and BMI. In the other study, Young and colleagues examined PSG data collected on 589 middle-aged women participating in the longitudinal Wisconsin Sleep Cohort Study.61 The detailed attention paid to menopausal staging in this study allowed the investigators to determine SDB prevalence and odds ratios for premenopause, perimenopause, and postmenopause. Postmenopausal women were 2.6 times more likely than premenopausal women to have SDB (defined as AHI ≥ 5), and 3.5 times more likely to have more-severe SDB (AHI ≥ 15). The odds of having SDB were not significantly higher for perimenopausal women compared with premenopausal women. However, the data did suggest that the risk for SDB increases throughout the menopausal transition. When women were stratified on years since last menstrual period, there was a significant linear trend toward increased risk for AHI of at least 5 with increasing postmenopause duration up to 5 years. One additional strength of this study was the careful use of multivariate models to adjust for several known risk factors for SDB, particularly age, BMI, smoking, and alcohol use. Despite the inclusion of these potent risk factors in the analyses, menopausal status remained a strong and significant independent risk factor for SDB.61 The mechanism by which menopause increases the risk of SDB is not yet clear. One possibility is the menopauserelated decline in levels of endogenous estrogen or progesterone.59 This hypothesis grew from early work showing that progesterone increases ventilatory drive, but a Cochrane review concluded there was no benefit from progesterone therapy.62 Although several studies have examined the effects of progesterone on ventilation, oxygen saturation, and apneic events, only a few have included female subjects. Postmenopausal women with SDB had improved nocturnal ventilation with exogenous progester-
one administration but no change in the number of apneas or hypopneas.63,64 Menopause and Obesity Menopause transition and the postmenopausal years are characterized by some weight gain. Contrary to widely held belief, this increased weight is likely associated with normal aging and with less physical activity, rather than menopause per se.65 Regardless of etiology, excessive weight is a significant problem for perimenopausal and postmenopausal women, particularly in developed countries. In the United States, more than 37% of midlife women (40 to 59 years of age) are considered obese, with a BMI of 30 or higher.66 Excess weight is a similar problem for women older than 60 years, and more than 35% are considered obese.66 Increased adiposity is a primary risk factor for SDB (see Chapter 105). The prevalence of SDB is highly and positively correlated with excess weight.67 Hypertension The prevalence of hypertension rises sharply with onset of menopause. The etiology of this phenomenon is complex and still under investigation, but two factors strongly associated with hypertension are obesity and SDB, conditions common in perimenopausal and postmenopausal women.68,69 The National Health and Nutrition Examination Survey III (NHANES III) documented a strong association between hypertension and BMI in women.68 For women in midlife, the prevalence of hypertension was approximately 10% when BMI was less than 25, but it rose to 39% when BMI was 30 or higher. For women older than 60 years, hypertension occurred in 52% with a BMI less than 25 but occurred in 72% if BMI was 30 or higher. Midlife women are at increased risk for hypertension and SDB by virtue of their increased risk of obesity rather than hormonal or menopausal factors per se. Metabolic Syndrome The strong association of SDB with obesity, visceral adiposity, and hypertension has led to the suggestion that sleep apnea is a manifestation of the metabolic syndrome (see Chapters 114 and 115).70 The metabolic syndrome is a constellation of closely related symptoms (visceral adiposity, hypertension, insulin resistance, elevated glucose, dyslipidemia) that together convey substantially increased risk of cardiovascular disease.71 Visceral adiposity is first among these symptoms, and it is thought by many to be the major determinant of the metabolic syndrome. These features of the metabolic syndrome become much more common in women as they transition from premenopause to postmenopause.71 Regardless of whether there is any weight gain, the menopausal transition is associated with a decrease in lean body mass and an increase in body fat composition independent of age and total body adiposity. There is also a preferential increase in intraabdominal or visceral deposition of fat relative to other areas of the body.71 It may be due to menopauserelated hormonal changes because HRT decreases the shift to visceral adiposity and can lower serum lipid levels.72,73 Visceral fat’s relationship to SDB is especially strong, and it is believed by some to be the principal culprit leading to SDB.70 Thus, the increased adiposity and visceral fat
associated with menopause places women at increased risk for SDB. Collectively, these data suggest that midlife and older women may have double the risk for SDB compared with younger women because of possibly decreased ventilatory drive resulting from lower progesterone and because of increased visceral adiposity. Hypertension and obesity together in midlife women should be considered risk factors for SDB as well as other serious health problems such as cardiovascular disease and type 2 diabetes. HRT may have some beneficial effects on respiration and visceral adiposity because of its effects on body composition and leptin levels. In epidemiologic population studies, HRT has been associated with a lower prevalence of sleep apnea in postmenopausal women.7,58 This relationship was confirmed in the Sleep Heart Health Study74 even after controlling for well-documented differences (e.g., education level, body weight, health awareness) between women who used HRT and those who did not. It may be premature to conclude that HRT is an effective or desirable treatment for SDB in postmenopausal women without more clinical trials.72,73 The wide variability in responses to HRT among individual women suggests that if these hormones affect SDB, they do so through a specific mechanism that is not common to all cases of SDB. There are also serious health risks associated with using HRT. If it is determined that low endogenous hormone levels play a role in SDB, the relative risks and benefits of HRT compared with other treatment options (e.g., nasal continuous positive airway pressure or surgery; see Chapters 107 and 108) will require thorough consideration for each individual woman. Also, weight loss and exercise (specifically to reduce adiposity) should be strongly considered for any midlife or postmenopausal woman’s SDB treatment plan. Depression Several longitudinal studies have found that depressive symptoms increase during the menopausal transition and then begin to decrease in the years after menopause.75-77 Although these studies controlled for age and other known predictors of depression, it remains unclear whether depression is a menopausal symptom per se or is more highly associated with the metabolic syndrome and SDB. Depression in general has a significant negative impact on sleep (see Chapters 129 and 130), and this is true of depression during menopause. Perimenopausal women have more mood alterations as well as longer and more numerous nocturnal awakenings than premenopausal women.11,18 Also, perimenopausal and postmenopausal women with major depression have been shown to have reduced sleep efficiency and less delta wave sleep than nondepressed women of similar menopausal status and an increased level of melatonin as well as a phase delay in their melatonin secretion18,78 HRT has reduced symptoms of depression and anxiety in perimenopausal and postmenopausal women in some studies,79 leading to the hypothesis that a low estrogen or progesterone level can increase the risk for mood disorders. Moreover, there is a strong relationship between severity of hot flushes and depression in menopausal women.76,78 Results from a large HRT clinical trial that examined depression, vasomotor symptoms, and fatigue in
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2763 postmenopausal women revealed that effects of HRT on these symptoms depended on the presence or absence of hot flushes.80 Women with hot flushes assigned to HRT had fewer depressive symptoms and less fatigue after treatment than those assigned to placebo. Hysterectomy After cesarean delivery, hysterectomy is the second most common surgery for women in the United States.81 The average age at hysterectomy is 40 to 45 years; approximately 37% of women in the United States have had a hysterectomy by 60 years of age. At least half also undergo concurrent bilateral oophorectomy. In these women there is an abrupt cessation of any ovarian hormone secretion and abrupt onset of menopause known as surgical menopause. Disturbed sleep and fatigue are common postoperative symptoms after hysterectomy.82 Women who undergo surgical menopause are more likely to experience hot flushes than women who experience natural menopause. The hot flushes that follow surgical menopause are more severe and continue longer than hot flushes after natural menopause, so most studies exclude surgical menopause from their sample. The SWAN study reported that 38% of women between 40 and 55 years of age reported difficulty sleeping, and the highest prevalence was in the group who had a surgical menopause (47.6%).8 Significant depression or anxiety can also occur after hysterectomy and contribute to sleep problems.82 These findings suggest that women undergoing hysterectomy may be more vulnerable to sleep disruption beyond the immediate postoperative recovery period. Insomnia, daytime sleepiness, and fatigue should be explored and reviewed in the context of these biological and psychological factors so that appropriate treatment strategies can be devised. These may include pharmacologic therapies (antidepressants, short-term sedative-hypnotics, short-term HRT) or nonpharmacologic approaches such as good sleep hygiene and cognitive behavior therapies directed at insomnia or depression. Most studies indicate that hot flushes can be reduced with cognitive behavior therapy and the effect can be maintained over time, but effects on sleep have not been fully investigated.83 Cancer With age, women are more likely to develop cancer of the breast, lung, colon, ovary, gallbladder, or thyroid.84 Persons with cancer commonly experience sleep disturbance.85 As discussed in Chapter 123, the etiology of cancer-related sleep disruption is often complex,86-88 and multiple factors are likely to precipitate sleep problems. These include pain and discomfort, physical effects of the cancer itself, depression and anxiety, and side effects of chemotherapy or radiation treatment (e.g., nausea, vomiting, diarrhea, urinary frequency). In addition to the sleep-disrupting factors commonly experienced by most patients with cancer, women with breast cancer are likely to experience hot flushes.88 Hot flushes are a side effect of chemotherapy-induced ovarian disruption, and they also occur with the use of adjuvant hormone therapy. Women with estrogen receptor–positive tumors are treated with the antiestrogen
1598 PART II / Section 18 • Women’s Health
tamoxifen citrate or aromatase inhibitors (anastrozole, letrozole, exemestane) to prevent endogenous estrogens from stimulating the growth of residual tumors or micrometastases. More than 50% of tamoxifen users experience hot flushes, and the hot flushes associated with the use of these agents are usually more frequent and more severe than hot flushes associated with natural menopause.89 Because standard treatment with adjuvant hormone therapy typically lasts for 5 years, breast cancer survivors are subjected to significant hot flushes and sleep disruption for a considerable period. Although HRT is not indicated for treatment of hot flushes in women with cancer,90 antidepressants (SSRIs such as venlafaxine) and gabapentin have been used with some success.89 Thyroid Dysfunction The prevalence of thyroid disease, particularly hypothyroidism, increases with age and is far higher in women than in men. For midlife women living in iodine-replete areas, the prevalence of impaired thyroid function (i.e., thyroidstimulating hormone [TSH] values outside the euthyroid range) is 9.6%.91 Of these, the majority (6.2%) have elevated TSH, indicating clinical or subclinical hypothyroidism. Because hypothyroidism is typically characterized by tiredness and fatigue, such complaints by perimenopausal and postmenopausal women should be clinically evaluated in light of a TSH level. Women with hypothyroidism may be more likely than euthyroid women to have SDB (see Chapter 125), suggesting that hypothyroidism may also be a risk factor for SDB.92 Midlife and older women with hypothyroidism should also be screened for clinical signs and symptoms that indicate SDB. Neurodegenerative Disorders Sleep disruption can be an early symptom of neurodegenerative disease such as Parkinson’s (see Chapter 87) or Alzheimer’s (see Chapter 91).93 These disorders occur more often in postmenopausal women than in age-matched men. Genetic factors and changes in biological hormone milieu related to menopause can play an important role.94
SUMMARY Menopause as an area of women’s health is a rapidly growing field of clinical practice and research.1 Sleep disruption is one of the most common symptoms reported by midlife and older women, so there is great interest in understanding how menopause affects sleep and how to treat menopausal sleep complaints. Despite major gaps in research on this issue, some clear diagnostic and therapeutic implications are emerging. One of the most important considerations is the interrelationship between menopausal status and aging. There is a tendency to assume a cause-and-effect relationship between menopause and symptoms whose prevalence is linked to menopause. In particular, symptoms tend to be attributed to the hormonal changes that occur as part of menopause. This focus on menopause can obscure the presence of age-related factors associated with sleep complaints. Several common concomitants of aging make midlife women more vulnerable to sleep problems, inde-
pendent of menopause. These include weight gain, reduced physical activity, changes in physiologic stress reactivity, and increased risk of chronic diseases that disturb sleep (e.g., thyroid dysfunction, cancer, surgical menopause, arthritis). Although a woman of menopausal age might attribute the appearance of sleep disturbance to the onset of menopause or “hormone problems,” the symptoms and their treatment should be viewed within the wider context of aging, lack of physical activity, and weight gain. One important example of this is the increased risk of the metabolic syndrome and SDB in midlife and older women. Fatigue or sleep complaints combined with hypertension, thyroid dysfunction, and excessive weight should prompt consideration of snoring and SDB in a clinical evaluation. Likewise, sleep disturbance in a woman younger than the expected age for menopause may be caused by a premature and unexpected perimenopausal transition, and an FSH level should be obtained to evaluate stage of menopause as a possible explanation for her fatigue or sleep complaints. The subjective experience of menopause-related insomnia is well documented. However, the limited research using PSG to investigate this phenomenon has not yet identified specific features of sleep architecture that correspond to these self-reports of poor sleep quality. Thus, PSG may not be of much value in assessing older women’s sleep complaints, except in specific cases when clinical signs and symptoms suggest SDB. It may be more clinically useful to concentrate on a careful clinical interview and assessment that thoroughly explores menopauserelated issues (e.g., hot flushes), aging-related vulnerabilities (e.g., thyroid dysfunction, depression, widowhood, chronic musculoskeletal pain), lifestyle (physical activity, stress, and coping strategies), sleep environment (exposure to light, noise, or violence) and sleep hygiene practices, as well as her expectations of menopause, sleep, and aging. The typical complaint and observations of excessive daytime sleepiness seen with men who have SDB might not be endorsed by older women, as seen in the Sleep Heart Health Study.95 Hot flushes have long been recognized as a possible disruptive influence on sleep during the menopausal transition (Video 140-1). Some women are more likely to experience disruptive hot flushes; the possibility that hot flushes are contributing to insomnia should definitely be explored in women who have undergone surgical menopause or breast cancer treatment or who have abruptly discontinued HRT. Also, hot flushes are popularly assumed to end within a few years after the last menstrual period. However, data from several large studies show that a significant number of postmenopausal women continue to have hot flushes for many years, even decades, after menopause. This possibility should be kept in mind while exploring insomnia complaints with older women, particularly when complaints are accompanied by descriptions of waking up during the night and feeling too warm. Although HRT remains an effective treatment for hot flushes, women and their health care providers are now more reluctant to support its use because of significant health risks. Even women with severe hot flushes may be reluctant to consider HRT, and many women have discontinued their long-term HRT. A growing number of
CHAPTER 140 • Menopause 1599
alternatives to HRT have been identified as successful for at least some women. These include the SSRI class of antidepressants, clonidine, gabapentin, herbal remedies, lifestyle modifications (e.g., exercise, stress reduction, smoking cessation, and weight loss programs), and cognitive behavior therapy.
PITFALLS AND CONTROVERSIES One important challenge for midlife women’s health research is to determine whether changes in sleep and other dimensions of health that occur during and after menopause are directly attributable to menopause rather than to aging.96 This is methodologically difficult and requires creative research designs and analytic methods. Another challenge arises from data suggesting that there may be racial or ethnic differences in menopausal experiences. For example, the prevalence of sleep problems and hot flushes is higher among African American women and lower among Asian American women, compared with other groups.8,23 The nature and implications of these differences have not been adequately explored, and the possible role of cultural differences and expectations has been underinvestigated. There are several unanswered questions about HRT for hot flushes and sleep disturbance in midlife women. There is a clear need for alternative treatments for hot flushes and related insomnia. Determining the etiology of hot flushes and clinical trials97 would help identify possible alternatives. Additional research is needed on the links among obesity, the metabolic syndrome, hypertension, hypothyroidism, and SDB in perimenopausal and postmenopausal women. Older women have an elevated risk of SDB as well as obesity and hypertension because of their age more so than their menopausal status. Because SDB is more commonly found in men, past research on mechanisms and treatments was more focused on men, with very little representation of women in the study samples. There may be significant sex differences in the etiology, expression, and effective treatment modalities for SDB in relation to menopausal status, regardless of age and body weight. ❖ Clinical Pearls Middle-aged women might assume that hormonal changes associated with cessation of menstrual cycles are responsible for any symptoms they experience, and this assumption may obscure other, more likely causes such as weight gain, reduced physical activity, stress, the metabolic syndrome, thyroid dysfunction, cancer, or chronic illness. Postmenopausal women are at increased risk for SDB, and fatigue or sleep complaints combined with hypertension and excessive weight should prompt consideration of snoring and SDB in a clinical evaluation regardless of whether excessive daytime sleepiness is reported. Women younger than the expected age for menopause could have premature menopause, and an FSH level should be obtained to evaluate stage of menopause as a possible explanation for their fatigue or sleep complaint.
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1600 PART II / Section 18 • Women’s Health 28. Erlik Y, Tataryn IV, Meldrum DR, et al. Association of waking episodes with menopausal flushes. JAMA 1981;245:1741-1744. 29. Freedman RR, Roehrs TA. Lack of sleep disturbance from menopausal hot flashes. Fertil Steril 2004;82:138-144. 30. Barnabei VM, Grady D, Stovall DW, et al. Menopausal symptoms in older women and the effects of treatment with hormone therapy. Obstet Gynecol 2002;100:1209-1218. 31. Polo-Kantola P, Erkkola R, Helenius H, et al. When does estrogen replacement therapy improve sleep quality? Am J Obstet Gynecol 1998;178:1002-1009. 32. North American Menopause Society. Estrogen and progestogen use in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause 2010;17(2):242-255. 33. Stearns V, Beebe KL, Iyengar M, et al. Paroxetine controlled release in the treatment of menopausal hot flashes: a randomized controlled trial. JAMA 2003;289:2827-2834. 34. Guttuso T, Kurlan R, McDermott MP, et al. Gabapentin’s effects on hot flashes in postmenopausal women: a randomized controlled trial. Obstet Gynecol 2003;101:337-345. 35. Borrelli F, Ernst E. Alternative and complementary therapies for the menopause. Maturitas 2010;66:333-343. 36. Writing Group for the Women’s Health Initiative. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women’s Health Initiative randomized controlled trial. JAMA 2002;288:2819-2825. 37. MacLennan A, Lester S, Moore V. Oral estrogen replacement therapy versus placebo for hot flushes: a systematic review. Climacteric 2001;4:58-74. 38. Hays J, Ockene JK, Brunner RL, et al. Effects of estrogen plus progestin on health-related quality of life. N Engl J Med 2003;348: 1839-1854. 39. Thomson J, Oswald I. Effect of oestrogen on the sleep, mood, and anxiety of menopausal women. BMJ 1977;2:1317-1319. 40. Schiff I, Regenstein Q, Tulchensky D, et al. Effects of estrogens on sleep and psychological state of hypogonadal women. JAMA 1979; 242:2405-2407. 41. Scharf MB, McDannold MD, Stover R, et al. Effects of estrogen replacement therapy on rates of cyclic alternating patterns and hotflush events during sleep in postmenopausal women: a pilot study. Clin Ther 1997;19:304-311. 42. Polo-Kantola P, Erkkola R, Irjala K, et al. Effect of short-term transdermal estrogen replacement therapy on sleep: a randomized, double-blind crossover trial in postmenopausal women. Fertil Steril 1999;71:873-880. 43. Purdie DW, Empson JAC, Crichton C, et al. Hormone replacement therapy, sleep quality and psychological well-being. Br J Obstet Gynaecol 1995;102:735-739. 44. Friess E, Tagaya H, Trachsel L, et al. Progesterone-induced changes in sleep in male subjects. Am J Physiol 1997;272:E885-E891. 45. de Lignieres B. Oral micronized progesterone. Clin Ther 1999; 21:41-60. 46. Montplaisir J, Lorrain J, Denesle R, et al. Sleep in menopause: differential effects of two forms of hormone replacement therapy. Menopause 2001;8:10-16. 47. Schindler AE. Differential effects of progestins. Maturitas 2003; 46(Suppl. 1):S3-S5. 48. Manber R, Armitage R. Sex, steroids, and sleep: a review. Sleep 1999 22:540-555. 49. Hersh AL, Stefanick ML, Stafford RS. National use of postmenopausal hormone therapy: annual trends and response to recent evidence. JAMA 2004;291:47-53. 50. Simon JA, Mack CJ. Counseling patients who elect to discontinue hormone therapy. Int J Fertil Womens Med 2003;48:111-116. 51. Brunner RL, Aragaki A, Barnabei V, et al. Menopausal symptom experience before and after stopping estrogen therapy in the Women’s Health Initiative randomized, placebo-controlled trial. Menopause 2010 Jun 2. [Epub ahead of print] 52. Shaver JLF, Johnston SK, Lentz MJ, et al. Stress exposure, psychological distress, and physiological stress activation in midlife women with insomnia. Psychosom Med 2002;64:793-802. 53. Saab PG, Matthews KA, Stoney CM, et al. Premenopausal women and postmenopausal women differ in their cardiovascular and neuroendocrine response to behavioral stressors. Psychophysiology 1989;26:270-280.
54. Lindheim SR, Legro RS, Berstein L, et al. Behavioral stress responses in premenopausal and postmenopausal women and the effects of estrogen. Am J Obstet Gynecol 1992;167:1831-1836. 55. Moe KE, Larsen LH, Vitiello MV, et al. Estrogen replacement therapy moderates the sleep disruption associated with nocturnal blood sampling. Sleep 2001;24:886-894. 56. Wolk R, Shamsuzzaman ASM, Somers VK. Obesity, sleep apnea, and hypertension. Hypertension 2003;42:1067-1074. 57. Kapsimalis F, Kryger MH. Gender and obstructive sleep apnea syndrome, part 1. Clinical features. Sleep 2002;25:412-419. 58. Bixler EO, Vgontzas AN, Lin H-M, et al. Prevalence of sleepdisordered breathing in women. Am J Respir Crit Care Med 2001; 163:608-613. 59. Lin CM, Davidson TM, Ancoli-Israel S. Gender differences in obstructive sleep apnea and treatment implications. Sleep Med Rev 2008;12:481-496. 60. Dancy DR, Hanly PJ, Soong C, et al. Impact of menopause on the prevalence and severity of sleep apnea. Chest 2001;120:151-155. 61. Young T, Finn L, Austin D, et al. Menopausal status and sleep-disordered breathing in the Wisconsin Sleep Cohort Study. Am J Respir Crit Care Med 2003;167:1181-1185. 62. Smith I, Lasserson T, Wright J. Drug treatments for obstructive sleep apnoea. Cochrane Database Syst Rev 2002;(2):CD003002. 63. Saaresranta T, Polo-Kantola P, Rauhala E, et al. Medroxyprogesterone in postmenopausal females with partial upper airway obstruction during sleep. Eur Respir J 2001;18:989-995. 64. Wesstrom J, Ulfberg J, Nilsson S. Sleep apnea and hormone replacement therapy: a pilot study and a literature review. Acta Obstet Gynecol Scand 2005;84:54-57. 65. MacDonald HM, New SA, Campbell MK, et al. Longitudinal changes in weight in perimenopausal and early postmenopausal women: effects of dietary energy intake, energy expenditure, dietary calcium intake and hormone replacement therapy. Int J Obes 2003;27:669-676. 66. Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among US adults, 1999-2000. JAMA 2002;288:1723-1727. 67. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea. Am J Respir Crit Care Med 2002;165:1217-1239. 68. Brown CD, Higgins M, Donato KA, et al. Body mass index and the prevalence of hypertension and dyslipidemia. Obes Res 2000;8: 605-619. 69. Dart RA, Gregoire JR, Gutterman DD, et al. The association of hypertension and secondary cardiovascular disease with sleepdisordered breathing. Chest 2003;123:244-260. 70. Vgontzas AN, Bixler EO, Chrousos GP. Metabolic disturbances in obesity versus sleep apnoea: the importance of visceral obesity and insulin resistance. J Intern Med 2003;254:32-44. 71. Carr MC. The emergence of the metabolic syndrome with menopause. J Clin Endocrinol Metab 2003;88:2404-2411. 72. Yuksel H, Odabasi AR, Demircan S, et al. Effects of postmenopausal hormone replacement therapy on body fat composition. Gynecol Endocrinol 2007;23:99-104. 73. Yuksel H, Odabasi AR, Demircan S, et al. Effects of oral continuous 17 beta-estradiol plus norethisterone acetate replacement therapy on abdominal subcutaneous fat, serum leptin levels and body composition. Gynecol Endocrinol 2006;22:381-387. 74. Shahar E, Redline S, Young T, et al. Hormone replacement therapy and sleep-disordered breathing. Am J Respir Crit Care Med 2003; 167:1186-1192. 75. Maartens LWF, Knottnerus JA, Pop VJ. Menopausal transition and increased depressive symptomatology: a community based prospective study. Maturitas 2002;42:195-200. 76. Freeman EW, Sammel MD, Lin H, et al. Associations of hormones and menopausal status with depressed mood in women with no history of depression. Arch Gen Psychiatry 2006;63:375-382. 77. Woods NF, Mariella A, Mitchell ES. Patterns of depressed mood across the menopausal transition: approaches to studying patterns in longitudinal data. Acta Obstet Gynecol Scand 2002;81:623-632. 78. Parry BL, Meliska CJ, Sorenson DL, et al. Increased melatonin and delayed offset in menopausal depression: role of years past menopause, follicle-stimulating hormone, sleep end time, and body mass index. J Clin Endocrinol Metab 2008;93:54-60. 79. Birkhauser M. Depression, menopause and estrogens: is there a correlation? Maturitas 2002;41(Suppl. 1):S3-S8.
80. Hlatky MA, Boothroyd D, Vittinghoff E, et al. Quality-of-life and depressive symptoms in postmenopausal women after receiving hormone therapy. JAMA 2002;287:591-597. 81. Hall MJ, Owings MF. National Hospital Discharge Survey. Advance data from vital and health statistics. DHHS publication no. 20021250. Washington, DC: National Center for Health Statistics; 2002. 82. Kim KH, Lee KA. Symptom experience in women after hysterectomy. J Obstet Gynecol Neonatal Nurs 2001;30:472-480. 83. Tremblay A, Sheeran L, Aranda SK. Psychoeducational interventions to alleviate hot flashes: a systematic review. Menopause 2008;15:193-202. 84. Feuer EJ, Wun LM. DEVCAN: probability of developing or dying of cancer [software]. Version 4.2. Bethesda, Md: National Cancer Institute; 2002. 85. Lee K, Cho M, Miaskowski C, et al. Impaired sleep and rhythms in persons with cancer. Sleep Med Rev 2004;8:199-212. 86. Savard J, Morin CM. Insomnia in the context of cancer: a review of a neglected problem. J Clin Oncol 2001;19:895-908. 87. Davidson JR, MacLean AW, Brundage MD, et al. Sleep disturbance in cancer patients. Soc Sci Med 2002;54:1309-1321. 88. Carpenter JS, Elam JL, Ridner SH, et al. Sleep, fatigue, and depressive symptoms in breast cancer survivors and matched healthy women experiencing hot flashes. Oncol Nurs Forum 2004;31:591-598. 89. Hoda D, Perez DG, Loprinzi CL. Hot flashes in breast cancer survivors. Breast J 2003;9:431-438.
CHAPTER 140 • Menopause 1601 90. Holmberg L, Anderson H, HABITS Steering and Data Monitoring Committees. HABITS (hormonal replacement therapy after breast cancer—is it safe?) a randomised comparison: trial stopped. Lancet 2004;363:453-455. 91. Sowers MF, Luborsky J, Perdue C, et al. Thyroid stimulating hormone (TSH) concentrations and menopausal status in women at the mid-life: SWAN. Clin Endocrinol 2003;58:340-347. 92. Misiolek M, Marek B, Namyslowski G, et al. Sleep apnea syndrome and snoring in patients with hypothyroidism with relation to overweight. J Physiol Pharmacol 2007;58(Suppl. 1):77-85. 93. Gagnon JF, Petit D, Latreille V, et al. Neurobiology of sleep disturbances in neurodegenerative disorders. Curr Pharm Des 2008;14: 3430-3445. 94. Bonomo SM, Rigamonti AE, Giunta M, et al. Menopausal transition: a possible risk factor for brain pathologic events. Neurobiol Aging 2009;30:71-80. 95. Baldwin CM, Kapur VK, Holberg CJ, et al. Associations between gender and measures of daytime somnolence in the sleep heart health study. Sleep 2004;27:305-311. 96. Pinkerton JV, Stovall DW. Reproductive aging, menopause, and health outcomes. Ann N Y Acad Sci 2010;1204:169-178. 97. Barnes S, Kim H. Cautions and research needs identified at the equol, soy, and menopause research leadership conference. J Nutr 2010;140:1390S-1394S.
Methodology
Section
19
Max Hirshkowitz 141 Monitoring and Staging Human Sleep 142 Monitoring Techniques for Evaluating
Suspected Sleep-Disordered Breathing 143 Evaluating Sleepiness 144 Assessment Techniques for Insomnia
145 Neurologic Monitoring Techniques 146 Chronobiologic Monitoring Techniques 147 Actigraphy 148 Gastrointestinal Monitoring Techniques 149 Light Therapy
Monitoring and Staging Human Sleep Sharon Keenan and Max Hirshkowitz
Abstract Polysomnography involves recording a wide assortment of bioparameters while a person sleeps. The electroencephalogram, electrooculogram, and skeletal muscle electromyogram can be summarized according to specific scoring criteria as sleep stages N1, N2, N3, and R (previously called stage 1, 2, 3, 4, and REM). Scoring criteria depend upon EEG bandwidth activity (delta, theta, alpha, and beta), EEG events (vertex sharp waves, sleep spindles, and K complexes), eye movement activity (slow and rapid eye movements), and the level of muscle tone. Stage N3 is characterized by high-voltage slowwave activity. Stage N2 contains sleep spindles and K complexes. Stage N1 has low-voltage, mixed-frequency background,
HISTORY From a behavioral perspective, immobility and reduced environmental responsiveness characterize human sleep. This state stands in contrast to purposeful (presumably) activities and provides the basis for dichotomizing observable living existence as either sleep or wakefulness. Furthermore, sleep and wakefulness cycle in a lawful, orderly fashion. Some rhythms are seasonal, some are daily (circadian), and some occur more than once a day. Changes in sleep cycle duration and composition in response to reduced sleep testify to sleep–wake cycle autoregulation, with a dynamic tension providing overall system homeostasis. Once techniques were developed to transcend observation, electroencephalography (EEG) revealed a complex array of brain activities clustered in a manner strongly suggesting multiple sleep states. All scientific inquiry begins with observation and description. From there it proceeds to classification based ultimately upon measurement. Thus, when Loomis and colleagues1 electroencephalographically recorded their first continuous all-night studies, they faced the daunting task of devising a system to describe sleep patterns in normal healthy human subjects. Thus sleep staging was born. In the original studies, amplified activity derived 1602
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possibly slow eye movements, and vertex sharp waves. If rapid eye movements accompany the low-voltage, mixed-frequency EEG and skeletal muscle tone is low, rapid eye movement (REM or R) sleep is present. Central nervous system arousals also can occur from sleep, either spontaneously or resulting from pathophysiology. Quantitative analysis of sleep stages and CNS arousals provide evidence for, contribute to the definition of, and index the severity of some sleep disorders. Similarly, these measures can provide objective outcome measures for assessing therapeutic interventions. This chapter summarizes recording, digital processing, and scoring techniques used for evaluating brain activity during human sleep and its disturbance by CNS arousals.
from electrodes that were placed on the scalp’s surface at several loci produced ink tracings on paper wrapped around a slowly rotating cylinder. An enormous 8-ft “drum polygraph” enabled all-night sleep recording. One electrode was located near the eye and undoubtedly detected eye movement. However, rapid eye movement (REM) sleep remained unrecognized until Aserinsky published, in part, his University of Chicago doctoral study results 17 years later.2 Aserinsky actually christened them “jerky eye movements” (JEMs) and in the first paper referred to the phenomenon as periodic ocular motility. Perhaps it was the quirkiness of the original commercially available polygraph systems (e.g., Ofner, Beckman, and Grass) with their tendency to polarize electrodes, problematic rechargeable car battery–like systems, and aperiodic (and difficult to predict) recording interference artifacts. Or perhaps it was Loomis’s silence on the matter of eye movements during sleep. In either case, Aserinsky’s pilot work reportedly met with considerable skepticism. Ultimately, however, REM sleep’s discovery, and particularly its correlation with dreaming, altered the course of sleep research for decades.2a The near-exclusive focus on REM sleep, to the point that all other sleep states were considered simply non-REM (NREM), overshadowed
substantial findings (and likely impeded progress) in other sleep research arenas (e.g., neuroendocrinology, physiology, and medicine). The spotlight on REM sleep made electrooculographic (EOG) recording de rigueur when performing sleep studies. Meanwhile, in Lyon, France, Michel Jouvet noted postural difference during sleep in cats.3 These differences correlated with sleep state and reduced skeletal electromyographic (EMG) activity. REM sleep (and, by association, dreaming) coincided with marked hypotonia in descending alpha and gamma motor neurons. The hypotonia induced functional paralysis that was quickly ascribed the purpose of keeping the sleeper from enacting dreamed activities. This sleep state–related EMG alteration added the final compulsory recording component to the procedure now known as polysomnography (PSG). Polysomnography, in addition to brainwave, eye movement, and muscle tone recording, can also assess respiratory, cardiac, and limb movement activity (discussed in detail in other chapters in this volume and elsewhere3a). PSG in its simplest form (including EEG, EOG, and EMG), however, provides the basic information requisite for classifying sleep state and examining sleep processes.
ELECTRODE PLACEMENT AND APPLICATION To make EEG, EOG, and EMG recordings, electrodes are placed on the scalp and skin surfaces. The site must be cleaned and properly prepared to assure good contact and limit electrical impedance to 5000 ohms or less. Scalp electrodes can be affixed with collodion or with electrode paste. Facial electrodes can be applied with double-sided adhesive electrode collars and paper tape. Although prescribed sites for electrode application have changed over the years, the system used to identify location remains the EEG society’s international 10-20 system. In this system, the intersection of lines drawn from the left to right preauricular point, with the midpoint along the scalp between the nasion and inion, serves to landmark the vertex, designated Cz. Other loci can be found by measuring 10% and 20% downward along longitudinal and lateral surfaces. Specific locations are designated with a letter indicating the brain area below the electrode (e.g., C for central lobe, O for occipital lobe, F for frontal lobe) and a number ascribing specific points (odd numbers for the left side, even numbers for the right, and z for midline). EEG electrode placements should be precise; consequently, appropriate measurement techniques must be applied to ensure accuracy. Additionally, EEG amplifiers require calibration at the beginning and end of PSG recording to allow actual waveform amplitude measurements. The classic and amazingly long-lived standardized technique (i.e., the manual produced by the ad hoc committee chaired by Rechtshaffen and Kales) requires a single monopolar central-lobe scalp EEG electrode referenced to a contralateral mastoid electrode (either C3-M2 or C4-M1). This single-channel brainwave recording, when paired with right and left eye EOGs and submentalis EMG, sufficiently reveals brain, eye, and muscle activity for classifying sleep stages.4 As polysomnography evolved from a psychophysiologic research method to a clinical proce-
CHAPTER 141 • Monitoring and Staging Human Sleep 1603
dure, an occipital lead has supplemented centrally derived EEG to provide better visualization of waveforms needed to determine sleep onset and central nervous system (CNS) arousals.5,6 EOG recording capitalizes on the eyes’ cornea–retina potential difference. Strong positive corneal potential fields affect electrodes placed near the eyes’ right and left outer canthi. The recording traces the response to this positive charge moving toward or away from the recording site. Each electrode is referenced to a neutral site, typically over the mastoid behind the ear. Thus, lateral eye movements produce out-of-phase tracings for right and left EOG tracings as the cornea moves toward one electrode and away from the other (provided that two channels are dedicated to tracing eye movements). This arrangement makes eye movements easily differentiable from in-phase frontal lobe EEG activity that is also present when recording from these sites. To discern vertical eye movements, we place the right-side EOG electrode 1 cm above the outer cantus and the left-side electrode 1 cm below (or vice versa). An alternative recording montage devised to enhance vertical eye movement detection entails lowering both recording sites to 1 cm below the outer canthi and referencing each to the middle of the forehead (Fpz). Skeletal muscle activity level is estimated from a pair of electrodes arranged to record submentalis EMG. An electrode placed midline but 1 cm above the mandible’s inferior edge is referenced to another placed 2 cm below and 2 cm to the right (or left). As a precaution, a backup electrode is also attached at the laterally homologous site of the reference electrode. The resulting submentalis EMG recording serves qualitatively (because it is uncalibratable) to provide an overall estimate for muscle activity level. The American Academy of Sleep Medicine (AASM) has published a standardized manual for conducting clinical polysomnography in their accredited sleep disorders centers.7 This AASM standards manual makes recommendations for recording, scoring, and summarizing sleep stages, CNS arousals, breathing, various kinds of movement, and electrocardiographic activity. By bringing instructional guidelines for a range of techniques into a single volume, the AASM manual will strongly influence practice, particularly in North America. Researchers, however, should not feel constrained by these clinical guidelines. New discoveries and future techniques need to continue unshackled by even a de facto standard clinical practice cookbook. AASM specifies recording frontal, central, and occipital monopolar EEG from F4, C4, and O2. The contralateral mastoid (M1) serves as the theoretically neutral reference. Electrodes are placed at F3, C3, and O1 sites (and referenced to M2) to provide redundancy for backup when needed. The AASM manual sanctions the use of midline bipolar recordings for frontal and occipital EEG; however, the AASM frequently asked questions (FAQ) states that frontal bipolar derivations are not appropriate for measuring frontal EEG activity. The FAQ also states that EEG amplitudes can be measured from the C4-M1 derivation. The AASM manual recommends using mastoid-referenced EOG with separate channels for E2 and E1, but it also approves a forehead-referenced alternative montage. Submentalis EMG is recorded in the traditional manner.
1604 PART II / Section 19 • Methodology Table 141-1 Recording Recommendations for Digital Polysomnography Sampling Rate (Hz)* RECORDING CHANNEL
Filter Setting (Hz)
DESIRABLE
MINIMAL
Central EEG (C4-M1)
500
200
0.3
35
Occipital EEG (O4-M1 or Cz-Oz)
500
200
0.3
35
Frontal EEG (F4-M1 or Fz-Cz)
500
200
0.3
35
Left EOG (E1-M2 or E1-Fpz)
500
200
0.3
35
Right EOG (E2-M2 or E2-Fpz)
500
200
0.3
Muscle tone (submental EMG)
500
200
ECG (lead II, modified)
500
200
0.3
70
Airflow sensors at nares and mouth
100
25
0.1
15
25
10
0.1
15
Nasal pressure
100
25
0.1
15
Esophageal pressure
100
25
0.1
15
1
1
Snoring sounds
500
200
Rib cage and abdominal movement
100
25
Intercostal EMG
500
200
Oximetry (ear lobe or finger)
Body position
LOW f
10
HIGH f
35 100
Respiratory Effort 10 0.1 10
100 15 100
*Higher sampling rates increase file storage requirements but provide increased temporal resolution. The tradeoff between fidelity and practicality is a matter of debate. E1, left eye; E2, right eye; ECG, electrocardiogram; EEG, electroencephalogram; EMG, electromyogram; EOG, electrooculogram; f (frequency), Fpz, frontal pole; M, mastoid.
DIGITAL RECORDING REQUIREMENTS The first time a polysomnographic signal was digitized, whether it originated from analogue or digital amplifying circuits, an entirely new set of factors required consideration. The two most important questions to resolve involved specifying amplitude and temporal resolution. Selection of voltage per digital unit (bit) and sampling rate likely had more to do with computer hardware limitations than conceptual considerations. Amazingly, no standard was established for digital polysomnography until publication of the AASM standards manual. The AASM standards manual specifies minimum 12-bit representation for amplitude, providing 4096 units to represent a 2.5-volt regulated current (IREG) range, or its equivalent (Video 141-1). In this manner, even the smallest signals, exceeding the level of electrical noise, can be detected. Temporal resolution during recording depends on sampling rate and ultimately must allow accurate waveform reconstruction, provide enough data to potentially overcome frequency aliasing, and be appropriate for highand low-pass digital filter settings. One size does not fit all: The minimum temporal resolution needed during data acquisition to meet these requirements varies for different bioelectrical signals (Table 141-1). Additional digital specifications involve data selection, display pagination, and calibration. Recorded channels must be selectable, and their calibration must be displayable. The viewable data should provide user-selectable time-frame compression and expansion (ranging from 5 seconds to an entire night shown on a page). Display
screens definition should be at least 1600 × 1200 pixels. Digital polysomnographs should provide the capability to view data as it appeared when it was first recorded and when staging or when each event was marked and classified manually. Accompanying video at a minimum of one frame per second should be synchronized with the polysomnographic display.
EEG BANDWIDTHS, WAVEFORMS, AND OTHER ACTIVITY Bandwidths One approach to differentiating EEG involves separating activity into dominant frequency bandwidths. Delta activity includes brain waves with a frequency less than 4 Hz. Sleep-related delta waves occurring at the low end of the frequency spectrum are called slow waves. Slow waves have high amplitude (≥75 mV) and low frequency (≤2 Hz). Theta activity includes 4- to 7-Hz waves prominent in central and temporal leads. Alpha activity consists of an occipitally prominent 8- to 13-Hz rhythm, and beta waves include the low-amplitude waves at even higher frequencies. Waveforms In addition to ongoing EEG activity oscillating predominantly within one or another of the specific bandwidths, distinct transient waveform events occur. These include vertex sharp waves, K complexes, sleep spindles, and sawtooth theta waves. Vertex sharp waves are sharply contoured, negative-going (upward, as per EEG polarity convention)
waves that stand out from the background activity. As the name implies, they appear prominently in EEGs derived from electrodes placed near Cz. The K-complex begins much like a vertex sharp wave but is immediately followed by a large, usually much slower, positive component. Overall, the K-complex is usually clearest in central and frontal regions and has a duration criterion of 0.5 seconds or more. A sleep spindle is a readily apparent 0.5-second (or longer) burst of 12- to 14-Hz activity generated by the thalamus and thalamocortical pathways. The name derives from its spindlelike shape. A sawtooth wave is a variant of theta activity, with each wave also containing a notch, making it sawtooth-shaped. Other nonpathologic sleep-related waveforms exist (e.g., benign epileptiform transients of sleep [BETS], sensory motor rhythm [SMR], Wicket rhythm [mu rhythm], and positive occipital sharp transients of sleep [POSTS]. These normal variants do not occur consistently during polysomnography. Activity Patterns Sleep EEG also contains dynamic activity patterns not captured by sleep staging schema or identification of individual waveforms. The cyclic alternating pattern (CAP) includes waveform bursts (usually high-amplitude slow, sharp, or polymorphic waves) separated by quiescent periods.8 The pattern’s burst component sometimes includes transient alpha bandwidth components that qualify as CNS arousals and thus can index sleep disturbance. However, a CAP occurring without frank arousals is thought to signify more subtle sleep instability.
SLEEP STAGING RULES AND CENTRAL NERVOUS SYSTEM AROUSALS For more than 40 years, the standardized technique described in A Manual of Standardized Terminology, Techniques and Scoring System for Sleep Stages of Human Subjects4 has provided the unifying methodology for human sleep research. This standardized manual combines elements from various systems that had evolved and provides adequate detail to achieve general use. However, to a large extent, its enormous success stems from the consensus it attained from the multinational, multidiscipline stakeholders composing its development committee. That is, when the committee members returned to their respective laboratories, they used the techniques and taught them to scientists and clinicians in training. Staging, as a summarizing technique, necessarily must define a period over which the summary applies. The standardized manual endorsed 20- and 30-second time domains. This flexibility deferred to extant technology; that is, generally available polygraph machine paper chart drive speeds. Over time, the 30-second epoch won out because it provided enough detail to see waveforms (EEG standards dictate minimal paper speed of 10 mm/sec to ensure ability to discern individual EEG waveforms); at 10 mm/sec, one epoch fit on a standard 30-cm wide paper fan-fold polygraph page; and one 1000-page box of polygraph paper would hold a complete recording (or two if one also recorded on the back).
CHAPTER 141 • Monitoring and Staging Human Sleep 1605
Sleep Staging Rules Wakefulness (stage W) in a relaxed subject with eyes closed is differentiated from sleep by the presence of alpha EEG activity in 50% or more of the epoch (Fig. 141-1). Poorly defined alpha EEG complicates determination of sleep onset. Stage 1 winds up being largely defined by exclusion; that is, it is a low-voltage, mixed-frequency background EEG devoid of sleep spindles and K-complexes, minimal slowwave activity, cessation of blinking, absence of saccadic eye movements, and alpha activity less than 50% of the epoch duration (Fig. 141-2). Stage 1 sleep may, but does not
C4/M1
O2/M1
E2/M2
E1/M2
Chin EMG Figure 141-1 Stage wake (W), eyes closed. This example demonstrates a classic wake pattern, with alpha rhythm in the EEG and EOG. Alpha activity is most prominent in the occipital channel. The chin EMG displays normal muscle tone associated with relaxed wakefulness. (From Butkov N. Atlas of clinical polysomnography, 2nd ed. Medford, Ore: Synapse Media; [in press].)
C4/M1
O2/M1
E2/M2
E1/M2 Chin EMG Figure 141-2 Stage 1 sleep (N1). The onset of N1 is identified by the disappearance of alpha rhythm, replaced by relatively low voltage mixed-frequency EEG with a prominence of theta activity in the range of 4 to 7 Hz. The chin EMG remains tonic, although it can attenuate slightly with sleep onset. (From Butkov N. Atlas of clinical polysomnography, 2nd ed. Medford, Ore: Synapse Media; [in press].)
1606 PART II / Section 19 • Methodology
C4/M1 C4/M1 O2/M1
O2/M1
E2/M2 E2/M1 E1/M2 E1/M2 Chin EMG Figure 141-3 Stage 2 sleep (N2). Stage N2 is identified by the presence of K-complexes and/or sleep spindles against a background of mixed-frequency EEG. The chin EMG displays normal muscle tone, as expected during NREM sleep. (From Butkov N. Atlas of clinical polysomnography, 2nd ed. Medford, Ore: Synapse Media; [in press].)
necessarily, include vertex sharp waves, background activity slowing, and slow eye movements. Stage 2 characteristics include sleep spindles and Kcomplexes (Fig. 141-3) occurring on a low-voltage, mixedfrequency background EEG and minimal (<20% of the epoch) slow-wave activity. Slow-wave sleep (stages 3 and 4 sleep) contains delta EEG activity (recorded from a monopolar central derivation) with a 75-mV or greater amplitude enduring for 20% or more of an epoch (Fig. 141-4). Stage 3 is scored when the duration of slow waves composes 20% to 50% of the epoch and stage 4 is scored when duration reaches 50% or more. REM sleep is scored when saccadic eye movements occur during epochs with low-voltage, mixed-frequency EEG in association with a very low level of submentalis EMG activity (Fig. 141-5). Epochs with low-voltage, mixedfrequency EEG and continuing low-level submentalis EMG (without eye movements) falling between epochs of REM sleep (with eye movements) are also scored as REM sleep. Epochs falling before or after (and contiguous with) clear REM sleep that have comparable EEG and EMG features but lack rapid eye movements are scored as REM sleep until an arousal, EMG level increase, or resumption of K-complexes or sleep spindles occurs. These smoothing rules gloss over minor transitions on the supposition that REM sleep represents a persistent central nervous system (CNS) organizational state distinct from wakefulness and NREM sleep. In 2007, the AASM standards manual provided revised criteria for scoring sleep stages. Changes are summarized in Table 141-2. Essentially, changes include standardizing epoch length at 30 seconds; combining stages 3 and 4 sleep and applying amplitude criteria for slow waves to frontal EEG activity; revising terminology (R for REM sleep, N1 for NREM stage 1, N2 for NREM stage 2, N3 for NREM stages 3 and 4, and W for wakefulness); and simplifying smoothing rules. Some changes are controversial.9-14
Chin EMG Figure 141-4 Slow-wave sleep (N3). In this example, highamplitude slow waves occupy greater than 50% of the epoch. By the Rechtchaffen and Kales criteria, this epoch is scored as stage 4. By the revised AASM criteria, this epoch is scored as N3. (From Butkov N. Atlas of clinical polysomnography, 2nd ed. Medford, Ore: Synapse Media; [in press].)
C4/M1
O2/M1
E2/M1 E1/M2 Chin EMG Figure 141-5 REM sleep. During REM sleep, chin muscle tone drops to the lowest level of the recording. REM sleep is identified by the presence of rapid eye movements in combination with relatively low-voltage mixed-frequency EEG and low-chin EMG. (From Butkov N. Atlas of clinical polysomnography, 2nd ed. Medford, Ore: Synapse Media; [in press].)
Central Nervous System Arousal Scoring Sleep staging fails to represent brief CNS arousals because it summarizes EEG, EOG, and EMG activity over a 30-second time domain. Increasing clinical application of polysomnographic technique heightened the need to appreciate sleep fragmentation; consequently, a scoring system for arousals was developed6 under the auspices of the American Sleep Disorders Association (later to become the AASM). Abrupt 3-second (or longer) EEG frequency increases to theta, alpha, or beta (but not to sleep spindles) are considered biomarkers for CNS activation. The arousals most often entail emergent occipital EEG alpha activity. To qualify as an arousal, 10 seconds of sleep must precede the event. In REM sleep, activity must increase in submentalis EMG leads for at least 1 second (Fig. 141-6). The 3-second duration represents the minimum duration
CHAPTER 141 • Monitoring and Staging Human Sleep 1607
Table 141-2 Comparison of Traditional and AASM (2007) Sleep Stage Scoring Systems PARAMETER
R&K CLASSIFICATION CRITERIA
AASM CLASSIFICATION CRITERIA
Epoch length
15 or 30 seconds, user’s choice
30 seconds, mandated
Stage nomenclature
Wakefulness, stage 1 sleep, stage 2 sleep, stage 3 sleep, stage 4 sleep, REM sleep, movement time
Stages W, N1, N2, N3, and R
Wakefulness
EEG alpha activity for ≥50% of an epoch
Same
Slow-wave sleep
EEG slow-wave activity for ≥50% of the epoch for stage 4 sleep or ≥20% of the epoch for stage 3 sleep
Same, except that stages 3 and 4 are combined to N3
Stage 2 sleep
Sleep spindles or K-complexes; EEG slow-wave activity for <20% of the epoch
Same
Stage 1 sleep
Low-voltage, mixed-frequency activity; possibly vertex sharp waves; possibly slow eye movements; no sleep spindles or K-complexes; EEG alpha activity for <50% of the epoch
Same
REM sleep
Low-voltage, mixed-frequency EEG activity; very low submental EMG activity; possibly saw tooth EEG theta activity; at least one unequivocal rapid eye movement
Same
Movement time
Polysomnographic activity obscured to the point of not being readable for more than 50% of the epoch; the preceding epoch is scored as stage 1, 2, 3, 4, or REM sleep
This epoch classification is eliminated
Smoothing rules
When an epoch is classified as a particular stage but is surrounded by epochs lacking unique features (e.g., a sleep spindle, slow-rolling eye movements, or CNS arousal) and would otherwise have been scored as stage 1 sleep, the classified epoch scoring is generalized to the surrounding epochs (but only for 3 minutes). These smoothing rules apply to stage 2 and REM sleep.
Same, except that there is no 3-minute limit to the generalization
AASM, American Academy of Sleep Medicine; CNS, central nervous system; EEG, electroencephalogram; EMG, electromyogram; R&K, Rechtchaffen and Kales; REM, rapid eye movement.
E1-M2
E1-M2
E2-M1
E2-M1
F4-M1
F4-M1
C4-M1
C4-M1
O2-M1
O2-M1
EMGSM
EMGSM
A
B
Figure 141-6 Arousals from NREM(A) and REM(B) sleep. A, A paroxysmal burst of high-amplitude slow activity appears near the center of the epoch. The distribution of the electrical field changes associated with this event can be seen reflected in the other EEG channels but with (expected) decreased amplitude. There is little or no change in the EMG channel in association with this event. It is common to see K-complex activity evoked by auditory stimuli. B, An increase in EMG activity is noted on the EMG and almost simultaneously in the E2-M1 channel. This is followed by a brief generalized presentation of EMG artifact throughout the EEG and EOG channels. Prior to the event there is evidence of REM sleep: low-voltage, mixed-frequency EEG, rapid eye movements, and very low EMG. After the event, the EMG channel shows an increased tone, and the EEG background activity is low voltage and fast. There is a continuation of EMG artifact on the EEG channels after the short burst. These data, especially the burst of alpha activity seen in the O2-M1 channel, are consistent with a possible transition to wake from REM sleep (Courtesy of Max Hirshkowitz, PhD, DABSM).
1608 PART II / Section 19 • Methodology
that could be reliably scored by visual inspection (among the task force members). Events of shorter duration likely also have clinical significance. The AASM standards manual endorsed this scoring technique and simplified the original 11 rules to a single statement with two explanatory notes.
SUMMARIZING NORMAL SLEEP The sleep stage pattern across the night can be represented diagrammatically (Fig. 141-7). In healthy young adults, stage R accounts for approximately 20% to 25% of total sleep time, stage N2 accounts for 50%, N3 accounts for 12.5% to 20%, and N1 accounts for the remainder. In normal sleepers, wakefulness might account for 5% to 10% of the time in bed. Stage R typically does not appear until approximately 90 minutes after sleep onset, after
R W N1 N2 N3 Time 21:00
22:00
23:00
00:00
01:00
02:00
03:00
04:00
05:00
Figure 141-7 Normal sleep histogram illustrating sleep macroarchitecture (stages) for a young adult.
which it reoccurs every 90 to 120 minutes in distinct episodes. These episodes increase in duration as the night progresses; therefore, the first half of the sleep session contains less REM sleep than the second half. By contrast, slow-wave activity (stage N3) predominates in the first third of the night. Age-matched sleep bears great similarity in men and women; however, women might have slightly better preserved stage N3 with advancing age. Sleep can be quantitatively summarized, and Table 141-3 provides definitions for commonly used parameters.
AMBIGUOUS SLEEP STAGES AND SLEEP QUALITY Sleep stage scoring was developed to summarize EEG, EOG, and EMG correlates of normal sleep. Under normal circumstances, particular events cluster the vast majority of the time. By contrast, this tight coupling tends to loosen when patients rebound from sleep deprivation; sustain brain injury; are afflicted with sleep, medical, neurologic, psychiatric, or sleep disorders; or ingest psychoactive substances. The resulting intrusion, translocation, or migration of specific EEG, EOG, or EMG activity, characteristic of one stage into another, produces ambiguous epochs that are difficult to classify according to the usual scoring rules. This departure from normal processes can provide qualitative evidence of an underlying sleep dysfunction.
Table 141-3 Parameters Derived from Sleep Staging and CNS Arousal Scoring PARAMETER
NOTATION
AASM Recommended Parameters Lights out clock time L-out Lights on clock time Total sleep time Total recording time Sleep latency
L-on TST TRT SLAT
REM sleep latency Wake after sleep onset Sleep efficiency Time in each stage Sleep stage percentages
RLAT WASO SEI MW, M1, M2, M3, MR P1, P2, P3, PR
Number of CNS arousals CNS arousal
NArsls CNS AI
Other Useful Parameters Latency to persistent sleep
LTPS
Latency to unequivocal sleep
LUS
Sleep-period time Number of REM episodes Number of awakenings Wake index Sleep fragmentation index Number of stage shifts Stage shift index Latency to arising
SPT NREME NWake WI SFI NShifts SSI LTA
CNS, central nervous system; REM, rapid eye movement [sleep].
EXPLANATION The clock time (in hh:mm) that the subject was instructed to allow himself or herself to fall asleep The clock time (in hh:mm) that the subject was awakened Minutes scored as stage N1, N2, N3, or R Elapsed time from L-out to L-on (in minutes) Elapsed time from L-out to first epoch of stage N1, N2, N3, or R (in minutes) Elapsed time in minutes from SLAT to first epoch of stage R Minutes scored as stage W from first sleep epoch to L-on TST as a percentage of TRT Minutes scored as W, N1, N2, N3, and R (individually) Time scored as N1, N2, N3, and REM as a percentage of TST (individually) The number of CNS arousals The number of CNS arousals scored per hour of TST Elapsed time (in minutes) from L-out to first of 10 consecutive minutes of sleep Elapsed time (in minutes) from L-out to first epoch of N2, N3, or R or to three consecutive (or more) epochs of N1 If N1 is followed by an epoch of N2, N3, or R, LUS is calculated from L-out to the first epoch of N1 Minutes from first to last epoch scored as N1, N2, N3, or R Number of stage R occurrences Number of stage W occurrences Number of awakenings per hour of TST Number of awakenings and CNS arousals per hour of TST Number of stage transitions during TRT Number of stage transitions per hour of TRT Duration of final stage W if it was ongoing when L-on occurred
CHAPTER 141 • Monitoring and Staging Human Sleep 1609
Perhaps the most common ambiguities accompany pharmacotherapy. Gamma-aminobutyric acid A (GABAA) and benzodiazepine receptor agonists generally increase spindle activity in the EEG. These pharmacologically induced spindles typically are of higher frequency (16 to 18 Hz), often of longer duration, occur more frequently (higher density), and can appear not only in N2 but also in other stages of sleep and even in wakefulness. Another commonly noted drug effect involves serotonin agonist augmentation of eye movement activity. In some persons, rapid eye movements occur at sleep onset, in stage N2, and stage N3, making the scoring of REM sleep a challenge. The phenomenon is so common that many sleep specialists refer to it as Prozac eyes (referring to fluoxetine, the prototypical selective serotonin reuptake inhibitor). Another serotonin agonist–provoked sleep alteration involves elevated muscle activity during REM sleep. In some cases, these medications produce a loss of atonia, permitting attempted dream enactments (i.e., iatrogenic REM Sleep behavior disorder [RBD]). Individual PSG epochs during these events do not meet usual stage classification criteria. Similar REM sleep ambiguities occur in idiopathic, Parkinson’s disease–related, and posttraumatic stress disorder–related RBD. Patients suffering from neurodegenerative diseases or brain insult can manifest an overall erosion of EEG sleep events. This includes reduced sleep spindles, K-complexes, and slow-wave activity. We also sometimes observe this in patients with sleep apnea, heart failure, and metabolic disorders. The resulting nearly featureless sleep EEG can be difficult to score according to normal staging rules. By contrast, another very different scoring problem can occur in patients with severely fragmented sleep produced by obstructive apnea. In these patients, a continual cycle of falling asleep, airway collapse, struggle to breathe, awakening, and falling asleep occurs. Thus, the patient remains in a transition state that does not fit well into any sleep stage category. It was once proposed that this pattern be scored as t-sleep. In some persons, copious EEG alpha activity permeates ongoing background activity. In sleep states marked by low-amplitude, mixed-frequency activity, alpha bursts meeting criteria for CNS arousal can be scored as such (alpha intrusion). However, when slow waves characterize the dominant ongoing background EEG activity and the alpha coincides with delta, arousals are not scored. This alpha-delta sleep sometimes accompanies pain syndromes, but it appears to lack specificity. A related phenomenon, also ascribed to pain, involves K-complex bursts followed by EEG alpha activity. Many sleep specialists consider K-alpha a variety of the CAP.
unrefreshed or who have difficulty initiating or maintaining sleep can be assayed for sleep integrity, quantity, and quality using polysomnography. Human sleep is a brain process. Pathophysiologies such as increased airway resistance and leg movements produce CNS arousals that fragment and destroy the fabric of sleep. Disorders often alter sleep patterns and overall architecture. Treatments may promote return to normal. Quantitative analysis through staging and arousal scoring objectively documents sleep disruption and provides a severity index for sleep disorders.
❖ Clinical Pearl Sleep staging and CNS arousal scoring provide important clinical information about sleep-related brain process. Ultimately, persons who awaken sleepy or
REFERENCES 1. Loomis AL, Harvey N, Hobart GA. Cerebral states during sleep, as studied by human brain potentials. J Exp Psychol 1937;21:127-144. 2. Aserinsky E, Kleitman N. Regularly occurring periods of eye motility, and concomitant phenomena, during sleep. Science 1953;118: 273-274. 2a. Dement W, Kleitman N. Cyclic variations in EEG during sleep and their relation to eye movements, body motility, and dreaming. Electroencephalogr Clin Neurophysiology 1957;9:673-690. 3. Jouvet M. Neurophysiology of the states of sleep. Physiol Rev 1967;47:117-177. 3a. Hirshkowitz M, Kryger MH. Diagnostic methods. In: Kryger MH, editor. Atlas of clinical sleep medicine. Philadelphia: Elsevier; 2010. 4. Rechtschaffen A, Kales A. A manual of standardized, techniques and scoring system for sleep stages in human subjects. Washington DC: NIH Publication No. 204, US Government Printing Office; 1968. 5. AASM Standards of Practice Committee. Littner MR, Kushida C, Wise M, Davila DG, et al. Practice parameters for clinical use of the multiple sleep latency test and maintenance of wakefulness test. An American Academy of Sleep Medicine Report. Sleep 2005; 28:113-121. 6. Bonnet M, Carley D, Carskadon M, Easton P, et al. EEG arousals: scoring rules and examples. ASDA report. Sleep 1992;15:173-184. 7. Iber C, Ancoli-Israel S, Chesson A, Quan SF for the American Academy of Sleep Medicine. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. 1st ed. Westchester, Ill: American Academy of Sleep Medicine; 2007. 8. Terzano MG, Parrino L, Smerieri A, Chervin R, et al. Atlas, rules, and recording technique for scoring of cyclic alternating pattern (CAP) in human sleep. Sleep Med 2002;3:187-199. 9. Moser D, Anderer P, Gruber G, et al. Sleep classification according to AASM and Rechtschaffen & Kales: effects on sleep scoring parameters. Sleep 2009;32:139-149. 10. Danker-Hopfe H, Anderer P, Zeitlhofer J, et al. Interrater reliability for sleep scoring according to the Rechtschaffen & Kales and the new AASM standard. J Sleep Res 2009;18:74-84. 11. Parrino L, Ferri R, Zucconi M, Fanfulla F. Commentary from the Italian Association of Sleep Medicine on the AASM manual for the scoring of sleep and associated events: for debate and discussion. Sleep Med 2009;10:799-808. 12. Grigg-Damberger MM. The AASM scoring manual: a critical appraisal. Curr Opin Pulm Med 2009;15: 540-549. 13. Novelli L, Ferri R, Bruni O. Sleep classification according to AASM and Rechtschaffen and Kales: effects on sleep scoring parameters of children and adolescents. J Sleep Res 2010;19:238-247. 14. Miano S, Paolino MC, Castaldo R, Villa MP. Visual scoring of sleep: A comparison between the Rechtschaffen and Kales criteria and the American Academy of Sleep Medicine criteria in a pediatric population with obstructive sleep apnea syndrome. Clin Neurophysiol 2010;121:39-42.
Monitoring Techniques for Evaluating Suspected Sleep-Disordered Breathing Max Hirshkowitz and Meir H. Kryger Abstract Assessment of sleep-disordered breathing represents the most common application of laboratory and home sleep studies. Numerous techniques can provide objective measures of breathing, identify breathing abnormalities, and detect physiologic alterations produced by abnormal respiratory events. Recording techniques, measurement criteria, data acquisition systems, operational paradigms, and the setting where data are collected (home or laboratory) can vary significantly. Over the past 3 decades, some common procedures have evolved and become commonplace in clinical sleep laboratories. In 2007, the American Academy of Sleep Medicine (AASM) published guidelines for laboratory-based techniques for record-
DEFINITIONS Abnormal breathing during sleep can take several different forms, arises from differing etiologies, and goes by many names, including sleep apnea, sleep apnea–hypopnea syndrome, sleep-disordered breathing (SBD), sleep-related breathing disorder (SRBD), periodic breathing, CheyneStokes respiration, and hypoventilation (Box 142-1). SRBDs associated with neurologic lesions are described elsewhere in this volume. Some terms distinguish between different types of sleep-related breathing impairments; others are synonymous. SDB events include episodes of apnea, hypopneas, respiratory effort–related arousals, oxygen desaturations, and snore arousals. The criteria for designating a breathing event as an apnea episode is defined fairly consistently. By contrast, definitions of hypopnea vary widely. Part of the difficulty stems from the fact that a hypopnea episode during sleep (or wakefulness) is not intrinsically abnormal—it is merely a shallow breath. However, a hypopnea that occurs during sleep and is associated with significant oxyhemoglobin desaturation or a central nervous system arousal is deemed pathophysiologic. Another difficulty arises because recording techniques for indexing airflow are uncalibrated and thus qualitative. The airflow signal magnitude from thermistors, thermocouples, capnographs, and nasal pressure transducers correlate poorly with tidal volume. Consequently, operational definitions for hypopnea based on a percentage decrease of flow signal use arbitrary cutpoints (upon which there exists considerable disagreement). Similarly, even though oximetry provides quantitative indices, a desaturation event’s pathophysiologic threshold remains a matter of disagreement, with some setting the criteria at 3% and others requiring drops of 4% or more. Finally, respiratory-related and snore-related arousals certainly seem irrefutably abnormal (because they compromise sleep integrity); however, there are issues concerning detection reliability. 1610
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142
ing sleep-related breathing, method of scoring, and terminology as part of their standardized sleep manual. Additional proposals concerning home sleep testing were published subsequently. Recommendations were based on expert opinion, consensus panels, and published evidence. However, some proposals remain controversial and hotly debated. Evaluating breathing during sleep has become a component of standard medical practice. Diagnostic methods largely reflect AASM recommendations, but local medical resources and research needs also influence specific procedures. The AASM manual does not provide illustrative examples for the spectrum of sleep-related breathing disorders; however, examples are given in Section 13.
Apnea and hypopnea episodes can be further categorized as obstructive, central, or mixed based on the presence or absence of respiratory effort during the entirety or some part of the breathing event. Sleep-disordered breathing severity can be based on a clinical dimension (e.g., sleepiness), event frequency (e.g., number of events per hour), or magnitude of the consequence (e.g., degree of oxyhemoglobin desaturation). Table 142-1 provides examples for dimensionally classifying severity of SDB. There is no general agreement about assigning severity descriptors to indices of SDB; however, two schemes are commonly used. In the first (the liberal) classification, an apnea–hypopnea index (AHI) between 5 and 15 is mild, between 15 and 30 is moderate, and greater than 30 is severe. In the second (the conservative) classification, an AHI between 10 and 20 is mild, between 20 and 50 is moderate, and greater than 50 is severe.1
METHODS TO DETECT AIRFLOW In general, airflow cessation or near cessation for 10 seconds or more constitutes a sleep apnea episode. Although the American Academy of Sleep Medicine (AASM) manual recommends a thermal sensor to document apnea and a nasal pressure sensor to detect hyponea,2 other methods provide reliable assessment. Occasionally, unidirectional occlusion occurs, with no airflow during attempted inspiration but tiny puffs of expiration. Fully quantitative airflow determination requires pneumotachography. Alternatively, a body box could be used; however, such an approach is unsuitable for sleep studies. Semiquantitative measures are attainable using calibrated inductance plethysmography; however, most clinical evaluations rely on qualitative nasal-oral thermography and nasal pressure to minimize the patient’s discomfort, reduce costs, and simplify acquisition of data. Airflow can also be measured
CHAPTER 142 • Monitoring Techniques for Evaluating Suspected Sleep-Disordered Breathing 1611
Box 142-1 Sleep-Related Breathing Events, Disorder Classifications, and Parameters Apnea (A): The complete or near-complete cessation of breathing for ≥10 sec in an adult Oxyhemoglobin desaturation (ODE): A decrease in blood oxygen saturation. Usually, the magnitude must be ≥3% to distinguish it from signal noise Hypopnea (H): A reduction in (but not cessation of) ventilation. To be clinically significant, the hypopnea must be associated with an oxyhemoglobin desaturation event or a CNS arousal Desaturating hypopnea (DH): A hypopnea with a ≥4% ODE (also known as a Medicare hypopnea) Respiratory effort–related arousal (RERA): A CNS arousal terminating obstructive breathing events that do not meet the criteria for apnea or hypopnea Obstructive apnea or hypopnea episodes (OA or OH): Breathing events caused by obstruction or reduced upper airway patency Central apnea or hypopnea episodes (CA or CH): Breathing events caused by absent or reduced respiratory effort (i.e., decreased output to inspiratory muscles from CNS respiratory control centers) Mixed apnea or hypopnea episodes (MA or MH): Breathing events with both obstructive and central features. Many laboratories consider mixed events obstructive Periodic breathing (PB): A regularly repeating pattern in which normal or increased ventilation alternates with decreased or absent ventilation
Central sleep apnea syndromes (CSAS): These syndromes includes primary central sleep apnea, Cheyne-Stokes breathing pattern, high-altitude periodic breathing, central sleep apnea due to medical condition not Cheyne-Stokes, and central sleep apnea due to drug or substance* Obstructive sleep apnea syndromes (OSAS): These syndromes include obstructive sleep apnea and obesity hypoventilation syndrome (see sleep-related hypoventilation syndromes). Primary snoring is a normal variant of an obstructive airway process Sleep-related hypoventilation or hypoxemic syndromes (SRHS): These syndromes include sleep-related nonobstructive alveolar hypoventilation, idiopathic congenital central alveolar hypoventilation, sleep-related hypoventilation or hypoxemia due to medical condition, pulmonary parenchymal or vascular pathology, lower airways obstruction, or neuromuscular and chest wall disorders (including obesity hypoventilation syndrome) Apnea index (AI): The number of apnea episodes per hour of sleep Apnea–hypopnea index (AHI): The number of apnea and hypopnea episodes per hour of sleep Oxygen desaturation index (ODI): The number of ODE events per hour of sleep Respiratory disturbance index (RDI): The number of apneas, hypopneas, and RERAs per hour of sleep.
*Opiate and other sedatives are known to depress respiration by blunting respiratory drive. CNS, central nervous system.
qualitatively by detecting chemical differences between ambient and expired air (e.g., capnography). Pneumotachography Several types of pneumotachographs based on different physical principles are in use: differential pressure airflow transducers, ultrasonic flow meters, and hot-wire anemometers. The discussion is limited here to the most widely used technique: the differential pressure flow transducer. In this technique, airflow directed through a cylinder exits through a small resistive field, usually composed of small parallel tubes or a grill promoting laminar flow. The pressure drop across this resistive field is measured using a differential manometer. When flow is laminar, the relationship between the pressure differences and flow is linear. Changes in gas density, viscosity, and temperature alter the pressure–flow relationship. To prevent condensation on the resistive element requires heating; therefore, calibration should be conducted when the pneumotachograph is heated. After correcting for errors introduced by alterations in these physical factors, the flow signal is integrated to determine volume. Pneumotachography accurately and quantitatively measures airflow volume. The patient usually wears a facemask, the equipment can be bulky and large, and the procedure is usually uncomfortable. Therefore, its routine use for overnight assessment of SDB is problematic. In awake subjects, such invasive devices can increase tidal volume and reduce respiratory rate. Nonetheless, some
positive airway pressure machines have built-in pneumotachographs and can be used to monitor airflow and ventilation. Cardiogenic oscillations can also be detected to provide a possible marker for central apnea.3 Thermistors and Thermocouples Exhaled air is usually warmer than ambient temperature. Air in the lungs is warmed by core body heat, thereby creating a temperature difference between air entering and exiting the respiratory system. Consequently, measuring temperature fluctuation at the nares and in front of the mouth provides a simple surrogate measure of airflow. Measurement is possible using thermistors. Thermistors are thermally sensitive variable resistors that produce voltage alterations when connected in a lowcurrent (but constant-current) circuit. Low current minimizes the tendency for the thermistor to heat itself. Thermistors maximize sensing area while minimizing sensor size and mass. Small temperature changes can produce large resistance changes that can in turn be transduced with a bridge amplifier. Care must be taken to ensure the thermistor remains below body temperature (i.e., it must not rest on the skin); otherwise, expired air will not be warmed and no resistance change will occur. In such a case, inspiratory activity and a respiratory pause will not be differentiable. Thermocouples also sense temperature change but use a different approach. Different metals expand at different rates when heated. In a calibrated system, this difference
1612 PART II / Section 19 • Methodology Table 142-1 Severities of Obstructive Sleep Apnea Syndrome DIMENSION
MILD
MODERATE
SEVERE
Sleepiness or unintended sleep episodes
During activities requiring little attention (e.g., watching television)
During activities requiring some attention (e.g., business meeting)
During activities requiring active attention (e.g., driving)
Sleep-related obstructive breathing events per hour
5-15
15-30
>30
01:41:30
Left side
Mean SaO2: N/A
Window 51 (120 sec)
EEG EOG
EOG EMG
Legs
THERMISTOR Rib Abdomen NASAL CANNULA SaO2
Figure 142-1 A 120-second section from a nocturnal polysomnogram in a subject undergoing simultaneous recording with a conventional thermistor and with a nasal cannula used for recording pressure. In this subject, there is nothing in the thermistor tracing to suggest a respiratory event, and there is only a suggestion of a movement in the rib and abdominal inductance plethysmographic tracings. However, in the nasal cannula tracing, the end of one hypopnea and the beginning of another are easily detected. Notice the plateaus (chopped off tops) of the pressure traces during hypopnea. EEG, electroencephalogram; EMG, electromyogram; EOG, electrooculogram; SaO2, oxygen saturation in arterial blood (Courtesy of Dr. David Rappaport, New York University, NY).
can be transduced to voltage alterations displayable on polygraph systems. Like thermistors, thermocouples are placed in the path of airflow in front of the nares and mouth, where expired air heats the sensor and increases its resistance. The transduced signal reflects oscillation between exhaled warm air and cooled inhaled air, thus providing a trace roughly corresponding to respiratory airflow.
greater sensitivity for detecting subtle flow limitations than nasal–oral thermography (Fig. 142-1) when persons breathe through the nose.5 Airflow limitation manifests as pressure trace plateauing during inspiration. A direct current (DC) amplifier provide optimal interface; however, long time-constant alternating current (i.e., a very slowly coupled signal) can suffice. By contrast, rapid coupling can create artifact (Fig. 142-2).
Nasal Airway Pressure During inspiration, airway pressure is negative relative to atmosphere. By contrast, expiration produces a relatively positive pressure in the airway. The resulting alteration in nasal airway pressure can provide a surrogate estimate of airflow and correlates favorably with pneumotachographically recorded signals.4 The nasal pressure signal also offers
Expired Carbon Dioxide Sensing Air leaving the lungs has a much higher concentration of CO2 than ambient air. There is always a large CO2 difference between air entering and exiting the respiratory system. Thus, measuring CO2 in front of the nose and mouth can detect expiration, and an infrared analyzer can be used to determine its concentration. Measuring CO2
Flow (DC)
Flow (AC) Long time constant
Flow (AC) Short time constant
CHAPTER 142 • Monitoring Techniques for Evaluating Suspected Sleep-Disordered Breathing 1613
0
5
10
15
20
25
30
Time (seconds) Figure 142-2 A, flow limitation event recorded from the nasal cannula measuring pressure simultaneously amplified by three different amplifiers. The bottom signal is from a direct current (DC) amplifier with no filtering. The top two signals are from alternating current (AC) amplifiers with low-frequency filters, with time constants of 1.6 (top) and 5.3 (middle). The short time-constant filter (top) causes the flow signal to decay to baseline rapidly during a period of relatively constant flow (flow limitation plateau). The longer time-constant filter (middle) provides reasonably good reproduction of these constant flows.
offers several advantages compared with thermistor, thermocouple, and nasal pressure recordings. In some patients, the end-of-breath CO2 concentration provides evidence of elevated end-tidal Pco2. The catheters sampling CO2 typically entrain some room air, making the measured CO2 lower than actual end-tidal Pco2. Therefore, an elevated CO2 indicates that true Pco2 is even higher, thereby providing a noninvasive technique (merely sampling the air stream) for detecting hypoventilation. The shape of the expired CO2 curve can also offer useful information. When a patient’s baseline expired CO2 curve shows a clear-cut plateau, the loss of this plateau (or the curve’s becoming smaller or dome shaped) indicates a change in breathing pattern, usually a reduction in expiratory volume. During central apnea, a low-volume catheter system set at its most rapid response time can show cardiogenic oscillations in the CO2 signal. These oscillations result from small volume displacements caused by the beating heart.6 These heartbeat-synchronized oscillations signify a wideopen upper airway (Fig. 142-3). Infants and children with upper airway obstruction can severely hypoventilate during sleep without observable apnea or hypopnea. Measuring expired CO2 provides evidence for hypoventilation not detectable using thermistors or thermocouples.6
because a patient’s airway can completely occlude during inspiration but release small puffs on expiration (detectable by thermistor or CO2 analyzer). Such events are erroneously categorized as hypopneas or even normal (unobstructed breathing). Figure 142-4 illustrates the problem. Airflow is recorded simultaneously with a CO2 analyzer and a pneumotachograph. During the obstructive apnea, periods of expiratory airflow occur (recorded by the pneumotachograph and the CO2 analyzer) in the absence of inspiratory flow (obvious in the pneumotachograph recording and unclear in the CO2 recording). Without the information from the pneumotachograph, the recording from the CO2 analyzer would be interpreted as evidence of uninterrupted inspiratory and expiratory airflow.
Cautionary Note Concerning Qualitative versus Quantitative Airflow Measures The vast majority of clinical sleep evaluations use qualitative measures of airflow for detecting SDB events. Extreme care must be taken when classifying respiratory activity
Rib Cage and Abdominal Motion Measuring rib cage and abdominal movement represents the most common technique for assessing respiratory effort in laboratory sleep studies. Rib cage and abdominal movement can be measured with a variety of techniques,
METHODS TO DETECT RESPIRATORY EFFORT Qualitative airflow measures and devices monitoring expired gases cannot reliably differentiate between prolonged inspiration, central apnea, and obstructive apnea. Therefore, airflow is typically recorded in conjunction with measures of respiratory effort. The differential patterns of airflow and respiratory effort are commonly used to categorize apnea and hypopnea events as central, obstructive, or mixed.
1614 PART II / Section 19 • Methodology EMG EEG EOG(R) EOG(L) ECG SaO2
RC
ABD
HR 5 sec PCO2
Figure 142-3 Cardiogenic oscillations in CO2 are seen in the bottom channel in this example of central apnea. The presence of these oscillations, synchronous with the heartbeat, proves that the upper airway is patent. ABD, abdominal (movement); EEG, electroencephalogram; ECG, electrocardiogram; EMG, electromyogram; EOG, electrooculogram; HR, heart rate; RC, rib cage (movement); SaO2, oxygen saturation in arterial blood.
including strain gauges, inductance plethysmography, and piezoelectric transducers. To determine whether respiratory effort is present, a single uncalibrated abdominal movement sensor will suffice. Strain gauges are sealed elastic tubes filled with an electrical conductor through which an electric current is passed. When length is constant, current and resistance are constant. Stretching the strain gauge lengthens and narrows the cross-sectional area of the fixed-volume conductor. This produces a proportional increase in electrical resistance. Current varies inversely to the length of the gauge, thereby becoming an index of gauge length. A Whetstone bridge amplifier transduces this change to voltage so it can be displayed as a tracing showing rib cage or abdominal expansion (depending upon where it is placed). Inductance pleythysmography electronically measures changes in the cross-sectional area of the rib cage and abdominal compartments by determining changes in inductance. Inductance is a property of electrical conductors characterized by the opposition to a change of current flow in the conductor. Transducers are placed around the rib cage and abdomen—the physiologic equivalent of conductors. Each transducer consists of an insulated wire sewn into the shape of a horizontally oriented sinusoid and onto an elasticized band. Piezoelectric transducers are yet another method used to detect movement. These sensors can be placed on the rib cage and abdomen and are sensitive to changes in length.
ERROR IN DETECTING APNEA Expired CO2
10 sec
Increasing
Respitrace (abdomen) inspiration
Airflow inspiration
Figure 142-4 An example of the limitations of noninvasive airflow detection. Top, Airflow is detected with the CO2 analyzer. Middle, Respiratory inductance plethysmograph (RIP). Bottom, Airflow measured with a pneumotachograph. With each apnea-related expiratory deflection documented by the pneumotachograph (arrows, bottom), there is a sustained shift in the baseline of the RIP. This suggests an incremental decrease in functional residual capacity resulting from absent inspirations with continued small expiratory puffs. If only the top two tracings were available, this pattern would have been mistakenly called hypoventilation or hypopnea, when it is clearly total occlusion on inspiration. (From West P, Kryger MH. Sleep and respiration: terminology and methodology. Clin Chest Med 1985;6:706.)
CHAPTER 142 • Monitoring Techniques for Evaluating Suspected Sleep-Disordered Breathing 1615
During normal breathing, the major inspiratory muscles produce rib cage expansion and a downward movement of the diaphragm. These movements cause the pressure around and in the lung to become negative (relative to atmospheric pressure). The pressure gradient between ambient air and the lung draws air through the airways into the alveoli. Thus, a change in lung volume is the sum of the volume changes of the structures surrounding the lungs, the rib cage, and the abdomen.7 Other respiratory muscles (e.g., intercostal, sternocleidomastoid) also play a role in stabilizing the thoracic cage. Some clinicians erroneously interpret the abdominal and rib cage motion changes as implying separate activities of abdominal and thoracic respiratory muscles, but this is not the case. Virtually all the changes in abdominal and rib cage volumes (including paradoxical motion) can be explained by changes in the respiratory muscles directly inserting onto the thoracic cage. Paradoxical motion of the rib cage and abdomen can result from several changes, including loss of tone of the diaphragm, loss of tone of the other respiratory muscles, or upper airway obstruction (complete or partial). The mechanisms underlying this asynchronous motion of rib cage and abdomen are described in Box 142-2. Regardless of the pattern or its underlying mechanism, rib cage and abdominal movement reflect effort to breathe. Respiratory Muscle Electromyography One of the older techniques for detecting respiratory effort entail recording intercostal muscle electromyographic (EMG) activity (Fig. 142-5). These uncalibrated recordings are made using standard surface electrodes placed in pairs in the intercostal space on the right anterior chest. Attaining an optimal signal requires practice, patience, and skill; recordings are prone to artifact, especially artifact from the electrocardiogram (ECG). Intercostal EMG recordings, when recorded properly, can be extremely valuable for differentiating central, obstructive, and mixed SBD events. Furthermore, although signals are not calibrated, cascading increases in respiratory effort are readily apparent from recordings. Pleural Pressure Some sleep centers use esophageal pressure to index inspiratory effort. In our experience, most patients undergoing all-night polysomnography find esophageal balloons unacceptable. However, the thin water-tip or catheter-tip piezoelectric transducers are better tolerated. Esophageal pressure measurements are especially helpful to to verify central apnea or hypopnea episodes with high certainty and to detect subtle SDB events. In what is sometimes called upper airway resistance syndrome, the classic findings include pleural pressure becoming progressively more negative until an arousal (sometimes associated with an audible snort) occurs (Fig. 142-6). After arousal, the pleural pressure swings temporarily decrease, to be followed by the next cycle of increased swings and arousal. Sometimes the central nervous system (CNS) activation falls short of AASM duration criteria for arousal. However, it should be noted that the AASM’s 3-second rule was designed to improve scoring reliability for visually detecting spontaneous arousals. Electroencephalographic (EEG) changes of shorter duration are conceptually
Box 142-2 Paradoxical Motion of the Rib Cage and Abdomen Loss of Diaphragm Tone When the diaphragm ceases to contract and becomes flaccid, it merely reacts to pressure changes around it instead of generating pressure changes. In this situation, when the other respiratory muscles contract, the rib cage is enlarged, and pleural pressure becomes negative, sucking the diaphragm into the chest. This condition results in an increase in rib cage volume and a reduction in abdominal volume. Loss of Accessory Respiratory Muscle Tone When the accessory muscles lose tone, the rib cage, particularly the upper part of the rib cage, becomes unstable. When the diaphragm then contracts, the negative intrathoracic pressure causes the unstable part of the thorax to be sucked in during inspiration. Partial Upper Airway Obstruction With partial upper airway obstruction, the diaphragm must generate very strong negative pressures for inspiration to occur. As the diaphragm contracts, it both pushes out the abdomen and creates great negative intrathoracic pressure. This highly negative intrathoracic pressure can overcome the mechanisms maintaining chest wall stability (accessory muscle tone and rigidity of the cage) and cause the least stable portions of the rib cage to move inward with inspiration. This inward movement of the rib cage is a problem mainly in the very young, who have a pliable rib cage. Complete Upper Airway Obstruction (Obstructive Apnea) With complete upper airway obstruction, there is no movement of air into the lungs. Because the volume change is zero, the volume change of the abdomen (caused by diaphragmatic contraction) is equal and opposite in direction to the volume change of the rib cage. This volume change is a pathognomonic finding in obstructive sleep apnea.
thought to represent CNS arousals, as are spectral analysis indices of alpha power loading, even when it is difficult to see on the raw data tracing. Ten (or more) negative pleural pressure swings per hour with accompanying arousals in a sleepy patient who has an adequate sleep schedule, does not affirm ancillary symptoms associated with narcolepsy, does not have significant neurologic or psychiatric conditions, and does not meet diagnostic criteria for sleep apnea is presumptive evidence of upper airway resistance syndrome. Static Charge–Sensitive Bed The static charge–sensitive bed technology has been evaluated in sleep disorders.8 The transducer is part of a thin mattress that responds to the slightest movement. Output from the bed is exquisitely sensitive and can even detect heartbeat as a ballistocardiogram. Respiratory signal amplitude differs with body position changes; however, output is otherwise stable.
1616 PART II / Section 19 • Methodology
BASELINE
CPAP 15 cm H2O LE-Fp RE-Fp C3-A2 O1-A2 Chin EMG L + R ant. tibialis R intercostal EMG ECG Airflow Thoracic movement
Abdominal movement Respitrace sum Figure 142-5 Surface respiratory (R intercostal) muscle EMG in sleep apnea. Left, The respiratory EMG is dramatically increased. Right, This signal is reduced on nasal continuous positive airway pressure (CPAP). ECG, electrocardiogram; EMG, electromyogram (Courtesy of Dr. J. Catesby Ware, East Virginia Medical School, VA).
Digital Video Digital video is now a common feature of computerized polysomnography. Although recordings are widely used to evaluate parasomnias and seizures, they can be helpful when assessing SRBDs. When properly synchronized with the polysomnogram, ambiguous and difficult-to-interpret polysomnographic events often become obvious. For example, it is easy to recognize a small dip in arterial oxygen saturation (Sao2) as a significant SDB event when it is followed by oxygen resaturation after an audible snort, a repetitive moving forward of the jaw, an arching of the neck, or a closing of a gaping mouth. It is particularly helpful in children, whose polysomnographic recordings may be difficult to interpret (Fig. 142-7). The Sao2 dip, without the other visual information, would quite likely be missed, ignored, or dismissed as artifact. We find video recordings particularly useful in thin persons who might not have oxygen desaturation with their abnormal respiratory events. Furthermore, showing the sleep study video to patients can be very effective for promoting understanding of the problem and an appreciation of its severity.
METHODS TO DETECT CHANGES IN LUNG VOLUME An assortment of techniques are available not only to measure respiratory movement but also to estimate tidal
volume. These measures can provide semiquantitative information concerning presumed airflow while also documenting respiratory effort. When attempting to use these devices to gauge ventilation, calibration is crucial. Inaccuracies may be introduced by movements, changes in body position, and shifting in placement of the recording device. In sleep laboratories, strain gauges, inductance plethysmography, and impedance pneumography are sometimes used to measure volume changes. Other techniques include magnetometers, body plethysmography, canopy with neck seal, barometric method, and pneumotachography; however, these are seldom used in a clinical setting. Strain Gauges, Inductance Plethysmography, and Piezoelectric Transducers In principle, length-sensitive devices can be used qualitatively to detect breathing abnormalities. If properly calibrated, these devices can be used quantitatively to measure dynamic volume changes.9 Normally, the enlargement of the thorax and the outward movement of the abdominal wall occur together; that is, they are in phase. For a given change in lung volume, one can thus quantify a change in rib cage volume and abdominal volume. For a given breath, the relative contributions of the rib cage and abdominal compartments also can be determined.
CHAPTER 142 • Monitoring Techniques for Evaluating Suspected Sleep-Disordered Breathing 1617
C3/A2
LOC/A2
Arousal
ROC/A1 Chin EMG
Stage 2
ECG Left anterior tibialis Right anterior tibialis Snoring sensor
–100%
Oximetry –50%
Esophageal pressure
Pes scale (cm H2O) 0 –10 –20 –30
Respiratory effort—chest Respiratory effort—abdomen
Figure 142-6 Esophageal pressure in the upper airway resistance syndrome. The esophageal pressure swing was greatest just before the arousal. ECG, electrocardiogram; EMG, electromyogram; LOC, left outer canthus; ROC, right outer canthus. (From Butkov N. Atlas of clinical polysomnography. Ashland, Ore: Synapse Media; 1996. p. 224.)
Figure 142-7 Synchronized digital video can be extremely helpful, as in this example in which a child with retrognathia slept with his neck arched and his mandible thrust forward (arrow). This resulted in an unoccluded upper airway. The conventional PSG recording missed that a significant sleep breathing problem was present. (From Banno K, Al Sabbagh A, Delaive K, et al. Experience in using split-day studies for suspected obstructive sleep apnea syndrome. Respir Med 2005; 99:1334-1339.)
To properly quantify actual volume changes, the transducers must be calibrated against an independent volumemeasuring system. In practice, two length-measuring devices are required for measuring changes in lung volume: one for the rib cage and one for the abdomen. The rib cage device is placed at the level of the axilla, and the abdominal
device is placed just superior to the iliac crest. If it is assumed that the fractional contributions of the abdomen and the rib cage are constant, then changes in lung volume can be measured by calibrating transducers sensitive to rib cage and abdominal displacement. Once the transducers are calibrated, the sum of the rib cage and abdominal excursions will describe volume changes. Unfortunately, the relative rib cage and abdominal contributions can change with posture and muscle tone occurring in sleep. Additional factors to consider include migration of the device from its original site caused by movement and device deformability. These factors can adversely affect the accuracy and stability of the original volume calibration. Nonetheless, calibrated inductance plethysmography has been suggested as a sensitive method for detecting subtle SDB events exemplified by the upper airway resistance syndrome.10 The following have been described: Snoring can lead to asynchrony between rib cage and abdomen, with increased thoracic breathing and increased breathing cycle time taken up by inspiration; before arousal, one can detect evidence of flow limitation; and arousals can lead to increased variation of respiratory cycle time and increased tidal volume. Impedance Pneumography Impedance defines the combined effects of two previously discussed properties of an electrical conductor: resistance and inductance. In physical terms, when impedance pneumography is used, the conductor is the thorax. Impedance is measured by applying a small current across the thorax using a pair of electrodes placed at the site of maximal thoracic excursion. Transthoracic impedance changes reflect variations in the amount of conductive materials (liquids, including interstitial fluid, blood and lymph, and tissue) and nonconductive material (air) between the electrodes. The conductive and nonconductive materials affect the total impedance differently. Increased air in the lung increases impedance, and increased fluid in the thorax decreases impedance. A recording of the volume of air exchanged and the total of impedance changes can allow the differentiation of airrelated and fluid-related changes in impedance. If total impedance is recorded in a single channel, changes related to air volume and fluid are measured. Impedance alterations in obstructive apnea are complex. During apnea, lung volume decreases, whereas the negative intrathoracic pressure most likely temporarily pools blood in the pulmonary circulation. For these reasons, a precise measurement of respiratory volume and pattern might not be possible.11 Rate-adapting cardiac pacemakers using transthoracic impedance to drive ventilation have been used to screen for obstructive sleep apnea.12
METHODS TO DETECT PHYSIOLOGIC CONSEQUENCES Blood Gas Changes Oxyhemoglobin desaturation represents an important clinical consequence of SDB. However, directly measuring blood oxygen with an indwelling arterial catheter during sleep is highly invasive. Intermittent sampling also fails to
1618 PART II / Section 19 • Methodology
detect the incidence and severity of hypoxemia, which is now known to be highly variable in sleep. Pulse Oximetry Noninvasive technologies allow continuous Sao2 monitoring,13 and pulse oximetry is the standard technique for recording oxyhemoglobin desaturations during sleep. Pulse oximeters determine Sao2 spectrophotoelectrically using a two-wavelength light transmitter and a receiver placed on either side of a pulsating arterial vascular bed (usually a finger, a toe, an ear, or the nose). Alternatively, in reflectance pulse oximetry, the light transmitter and receiver are on the same surface. The light transmitted into the vascular bed is scattered, absorbed, and reflected. The amplitude of light detected in particular spectrums by the receiver depends on the magnitude of the change in arterial pulse, the wavelengths transmitted through the arterial vascular bed, and the oxygen saturation of arterial hemoglobin (deoxygenated blood is bluer). These devices are sensitive only to pulsating tissues; consequently, venous blood, connective tissue, skin pigment, and bone theoretically do not hamper determination of Sao2. Accurate measurement, however, requires a minimal pulse amplitude. Dyshemoglobinemias can cause problems. Correct alignment of the light transmitter and receiver is critical to ensure proper operation of pulse oximeters. If the sensor is applied to a digit, that digit must be immobilized. Significant bending of the digit can compromise detection of pulsatile flow and thereby preclude determination of Sao2. Although all pulse oximeters are based on similar technology, their response characteristics differ across manufacturers, as a function of sensor placement, according to the approach used to minimize movement artifact, and due to programming.14 Indeed, the same brand and model of a device can have different software versions that perform differently. Reflectance oximeters must contend with weaker pulse signals because much less light is reflected back to the sensor; therefore, these devices are more sensitive to changes in blood pressure and to motion artifacts. Differences in response characteristics and effect of sensor location cannot be overemphasized (Fig. 142-8) because some oximeters appear to be completely insensitive to hypoxemia episodes clearly detected by other devices—thereby compromising diagnostics and therapeutics (Fig. 142-9). Reviewing specific oximeters goes beyond the scope of this chapter; nonetheless, generalizations about sensor location, instrument filtering and sampling rates, and potential pitfalls are worth noting. Sensor Location In our experience, the preferred sensor location in adults is the earlobe. Poor perfusion can be enhanced by applying a trace amount of vasodilator (e.g., nonylic acid vanillylamide and nicotinic acid, Finalgon ointment [Boehringer Ingelheim, Ridgefield, CT]). Technicians must take care to avoid contact with the eyes because it is a powerful cutaneous vasodilator. When the ear site is not usable, reflectance pulse oximeter sensors placed on the forehead or another well-perfused surface will suffice. Recording from the ear also reduces circulator delay (compared to the
HR HP
95
A
95
Mean = 66±11 Min = 48 Max = 107 Mean = 91.5±3.5 Min = 81 Max = 96 Mean = 90.5±4.5 Min = 79 Max = 99 Mean = 90.5±5.75 Min = 70 Max = 100 Mean = 90±3.25 Min = 81 Max = 95 Mean = 94.5±3.5 Min = 84 Max = 100 Mean = 91.5±3.25 Min = 84 Max = 97
81 81
B
96
C
93
D
94
E
85 93 84
70 83
Figure 142-8 Heart rate (HR) and arterial oxygen saturation (SaO2) during 5 minutes in a patient with sleep apnea. HP, Hewlett Packard oximeter; A to E, five different pulse oximeters. The scales for the six oximeters are identical. The numbers on the tracings represent the instantaneous SaO2 measured during the peak and trough of an apneic episode. The numbers to the right of the figure are the mean, standard deviation, and minimum and maximum values for HR and SaO2 for the six oximeters. Note that C and D do not track SaO2, and that E has numerous artifacts.
HR 95
HP 95 89
A B C D E
95 87
84
Mean = 44±5 Min = 36 Max = 66 Mean = 92±2 Min = 84 Max = 95 Mean = 95±1.25 Min = 92 Max = 98 Mean = 97.5±1.75 Min = 94 Max = 100 Mean = 94±1 Min = 92 Max = 96 Mean = 95.5±1.5 Min = 91 Max = 98 Mean = 95±1 Min = 93 Max = 97
Figure 142-9 Heart rate (HR) and arterial oxygen saturation (SaO2) during 5 minutes in a patient with sleep apnea and bradycardia. Tracings are taken from six oximeters, as described in Figure 142-8. In this example, three apneic episodes are missed entirely by all the pulse oximeters. This patient’s problem would have been missed entirely by pulse oximetry screening.
finger). This becomes especially important for associating a respiratory event with its subsequent oxyhemoglobin desaturation in patients with congestive heart failure. Instrument Filtering and Sampling Rate Most pulse oximeters filter the signal, and some filter algorithms use the heart rate. The degree of filtering is inversely related to heart rate; therefore, brief, mild hypoxemic episodes may be missed during periods of very low heart rates because they are filtered more strongly. During
CHAPTER 142 • Monitoring Techniques for Evaluating Suspected Sleep-Disordered Breathing 1619
polysomnographic recording, filtering should be minimized (i.e., set oximeter to the fastest response or the highest sampling rate, or both) to reduce missing transient oxyhemoglobin desaturation events.15 Potential Problems Because pulse oximeters use two wavelengths of light to estimate Sao2, they cannot distinguish three or more hemoglobin species. In the presence of carboxyhemoglobin (as in heavy smokers, whose carboxyhemoglobin level can reach 10% to 20%), Sao2 is overestimated.16 In the presence of a rising methemoglobin concentration, oximetry-determined Sao2 will plateau at about 85%, regardless of whether true saturation is much higher or lower.17 Because light is transmitted through tissue, pigment in the skin can degrade oximeter performance and produce incorrect “probe-off” or “perfusion-low” errors.18 Technologists should not assume plug-compatible probes are interchangable. Although probe connectors from one manufacturer might fit another brand’s equipment, wiring may be incompatible and can severely burn a patient if used all night.19 Finally, pressure-related injuries to the digits can also occur. Transcutaneous Oxygen and Carbon Dioxide Partial pressure of arterial oxygen (Pao2) estimated from the skin’s surface depends on oxygen flux through the skin, local oxygen consumption, and the skin’s diffusion barrier.20 This measurement technique is most commonly used in neonates, whose skin is thin. Accurate measurement of transcutaneous Po2 (Po2tc) requires maximal dilation of the local vasculature in the upper dermis. This is achieved by heating (to 43° C); however, heating shifts the oxyhemoglobin dissociation curve to the right, increases the resistance of the skin stratum corneum to oxygen permeation, increases the metabolic rate of the dermal tissue, and increases the rate of cutaneous blood flow. The shift in the oxyhemoglobin dissociation curve and the increase in metabolic rate effectively cancel each other out, leaving permeability and flow as the dependent factors in correlating Po2tc and Pao2. An important advantage of heating is that the amount of blood present is maximal, and Po2tc is therefore unaffected by small changes in blood supply to the tissue. The Po2tc may be misinterpreted when the state of blood flow is unknown. When flow and Pao2 are adequate, Po2tc reflects Pao2. Under conditions of compromised flow and adequate Pao2, Po2tc will change with flow. If Sao2 and flow are compromised, Po2tc tracks oxygen delivery. Transcutaneous measurement accuracy also depends on correct sensor application. To convert Po2tc measurements to Pao2 values precisely, a calibration curve for each subject is required, thereby making it too labor intensive for routine clinical practice. In most laboratories, Po2tc serves to track, in relative terms, arterial oxygenation status. Device responsiveness is too slow for tracking rapid blood gas changes associated with brief SDB events (<30 seconds) because oxygen diffuses slowly across the skin. The conditions governing transcutaneous Pco2 measurement are remarkably similar to those described for Pao2. Although transcutaneous blood gas determinations are of
greatest value in neonates and young children, Pco2tc is useful for assessing hypoventilation in adults. Central Nervous System Arousals and Awakenings Awakenings and CNS arousals provide critical information concerning sleep disturbance and fragmentations. Standardized scoring derives from electroencephalographic activity, preferably recorded from occipital sites. CNS arousals often take the form of bursts of alpha (7 to 13 Hz) activity, and the term EEG speeding is sometimes used to describe the event. When scored visually, a 3- to 15-second burst of alpha activity in non–rapid eye movement (NREM) sleep is considered an arousal. During rapid eye movement (REM) sleep, when alpha bursts can be an ongoing part of background activity, the alpha intrusion must be accompanied by increased muscle tone. In any sleep stage, bursts exceeding 15 seconds are scored as frank awakenings (the epoch is scored as wake). The reason the committee selected a lower limit of 3 seconds was not because they thought shorter bursts did not represent arousals but rather because bursts shorter than 3 seconds were not reliably identified across scorers when traces were reviewed visually. At the time the rule was developed, it was fully expected that computerized scoring would be able to identify shorter and more subtle events with adequate replicability. The CNS arousal, as a clinically significant parameter of sleep, has both face and empirical validity. Face validity derives from the principle that disturbed or fragmented sleep is less restorative than undisturbed or consolidated sleep. Indeed, it can be empirically demonstrated that disrupted sleep is associated with tiredness, fatigue, and sleepiness. As a pathophysiologic consequence of obstructive sleep apnea, the arousal is thought to play a special role. Presumably resulting from respiratory effort, the arousal returns ventilation to voluntary control so that the airway can be dilated, and then breathing resumes. However, some controversy exists about resumption of breathing after an obstructive event without an arousal and about the presence of arousals at the termination of central events. The role of the autonomic nervous system, especially sympathetic activation, is an area of active research.21 Blood Pressure Changes Clinical laboratories do not routinely record sleep-related blood pressure; thus, the techniques described in the following paragraph primarily apply to research settings. Many pulse oximeters can also track pulse pressure (a magnitude index of pulsation occurring at the oximetry sensor site). Pulse transit time (PTT) represents the time interval from heart beat (ECG R wave) to its pulse recorded in the periphery. Negative pleural pressure provokes a blood pressure drop and in so doing lengthens PTT. Thus, techniques to calculate blood pressure changes from PPT have been developed.22 The progressive increase in pleural pressure during obstructive apnea correlates with rising oscillations in PTT amplitude. During central apnea, this does not occur. Thus, it has been suggested that PTT might provide an opportunistic estimate of inspiratory effort and therefore provide a means to differentiate obstructive from central apnea.23
1620 PART II / Section 19 • Methodology
Automatic self-inflating arm-cuff sphygmomanometers have long been available but are problematic for routine clinical use in the sleep laboratory (unless you need a protocol to intentionally produce sleep disturbance related to cuff inflation). By contrast, continuous measurement of blood pressure during sleep can be obtained using a miniature finger cuff.24 One current system designed for this application (Finapres Medical Systems, Amsterdam) obtains data alternately from adjacent fingers to minimize risk of digit injury. Additionally, it automatically performs hydrostatic correction for arm movement; however, finger flexion artifacts remain. Nonetheless, the technique provides an acceptable method for continuously measuring mean blood pressure. Autonomic Nervous System Activation Although autonomic nervous system changes underlie heart rate and blood pressure changes, they can be difficult to measure. Direct measurement of sympathetic motor neurons during sleep is difficult and invasive, making it mostly of interest to researchers. Alternatively, photoplethysmography is noninvasive and can detect vasoconstrictive response in extremity blood flow; however, it is very prone to artifact. A better approach involves using tonometric measurement of segmental pulsatile flow. A commercially available device (Watch-PAT, Itamar Medical, Boston, Mass.) uses an inflatable bladder mounted inside a housing worn on the fingertip that incorporates a pulse volume sensor. Vasoconstriction associated obstructive SDB events can be reliably detected by this device. This tonometer’s sensitivity and specificity for detecting SDB in patients with an AHI of 20 or more were 90.9% and 84.2%, respectively.25 Cardiopulmonary Coupling Cardiopulmonary coupling uses a single-channel ECG recording to extract signal features modulated by breathing.26 Respiration induces small alterations in heart rate and amplitude variations in R-wave amplitude. Using computerized frequency domain analysis, a high-frequency component can be isolated that represents variations in breathing-induced vagal sinus pressure heart rate. A lowfrequency component can be extracted that provides data about interbreath intervals. By examining a weighted composite of these data (increased variability and the envelope of amplitude change), time-domain periods (usually 2 to 10 minutes) with breathing pauses can be discerned by examining coherence and cross-power spectrums. To minimize error, the system must identify ectopic beats, identify and exclude missed R waves, and reject ECG contaminated by movement artifact. In general, normal breathing loads high-frequency bands, and SDB events masses in lowfrequency troughs.
HOME SLEEP TESTING In addition to standard attended polysomnography, the AASM defines three categories of unattended overnight sleep recordings.27 Table 142-2 summarizes the procedures required for each level of categorization. Recording channel selection has some flexibility; however, AASM
(and Medicare) requires home sleep-testing equipment to meet level III criteria when used to diagnose SDB. Level III recordings achieve equivalence with “cardiorespiratory sleep studies” by including channels for airflow, respiratory effort, cardiac rhythm, and blood oxygen saturation. The bioparameters recorded by specific commercially available, self-contained, level III devices vary depending upon the manufacturer and user-defined protocols. Cardiopulmonary home sleep-testing devices, in the proper hands, can reliably confirm the diagnosis in patients with high pretest probabilities for SDB. Home sleep testing can rule in but not rule out a SRBD because it is less sensitive than attended laboratory polysomnography. To succeed diagnostically and economically, home sleep testing requires proper patient selection, appropriate portable recorder application, study interpretation by a qualified sleep specialist, readily available access to laboratory polysomnography (when needed after a negative test or continuing problems notwithstanding treatment), and systematic follow-up. The Center for Medicare and Medicaid Services (CMS) recently approved home sleep testing for diagnosing sleep apnea,28 local coverage determination (LCD) contractors are beginning to rule that home sleep testing is reasonable and necessary, and reimbursement G-codes and fee schedules are emerging. Nocturnal oximetry alone is generally not recommended due to its poor diagnostic accuracy.29 Unattended studies are more prone to data loss due to uncorrected technical failures (for example, electrode detachment) and patient tampering. Consequently, only patients with a high clinical suspicion for SRBD should be referred for home sleep testing. Additionally, level III studies can be used for patients who, for a variety of reasons, cannot be studied in the sleep laboratory. Patients with symptoms suggesting sleep disorders other than SRBD (e.g., sleep paralysis, cataplexy, sleepwalking, or dream enactment with injury) should be referred for laboratory evaluation. Additionally, if the patient has multiple sleep disorders in addition to SRBD, these disorders will likely remain undetected by home sleep testing. Thus, when symptom presentation is mixed, pretest probability is low, or treatment response is suboptimal, the appropriate referral is for full, attended laboratory assessment. Also, on clinical follow-up, patients with residual sleep-related symptoms (e.g., sleepiness, insomnia, fatigue) should be referred for further assessment. It was inevitable that positive airway pressure (PAP) systems with data collection capability would develop. Although the information gathered focuses primarily on therapeutic adherence and adequacy of treatment, it was no surprise when clinicians began using self-titrating machines (also called auto-PAP) for diagnosis. With such systems, a patient is sent home for an empirical clinical trial with PAP, with or without prior laboratory or home sleep test diagnostic assessment. The machine monitors breathing (airflow patterns, vibration, pressure oscillation) and adjusts pressure to optimize flow curves. If the machine detects apnea or finds it necessary to maintain positive pressure to preserve optimal flow, airway resistance or obstruction is inferred. However, we often encounter clinical problems in patients who were initially assumed to have SDB based
CHAPTER 142 • Monitoring Techniques for Evaluating Suspected Sleep-Disordered Breathing 1621
Table 142-2 Laboratory and Home Sleep Study Classifications LEVEL
DESIGNATION
DESCRIPTION
I
Attended laboratory polysomnography
Conducted in a sleep laboratory Includes recordings of EEG, EOG, EMG-SM, airflow, respiratory effort, ECG, SaO2, EMG-AT Technologist in attendance
II
Unattended polysomnography
Usually conducted in the patient’s home but sometimes recorded in a hospital bedroom or care unit Includes recordings of EEG, EOG, EMG-SM, airflow, respiratory effort, ECG, SaO2, EMG-AT No technologist in attendance
III
Unattended cardiopulmonary recording
Usually conducted in the patient’s home but sometimes recorded in a hospital bedroom or care unit Usually four or more channels, including airflow, respiratory effort, ECG, SaO2, and/or snoring sounds No technologist in attendance
IV
Unattended single- or dual-channel recording
Usually conducted in the patient’s home but sometimes recorded in a hospital bedroom or care unit Usually records one or two channels, typically ECG and SaO2 No technologist in attendance
ECG, electrocardiogram; EEG, electroencephalogram; EMG-AT, electromyogram anterior tibialis; EMG-SM, electromyogram submentalis; EOG, electrooculogram.
on an auto-PAP trial. Some of these patients had severe nasal obstructions that were not appreciated, and consequently they could not tolerate the CPAP. Some patients slept with their mouths wide open and therefore the selftitrating process failed. Patients with severe respiratory disease (e.g., chronic obstructive pulmonary disease, kyphoscoliosis) sometimes hyperinflated and experienced severe dyspnea with auto-PAP and actually needed bilevel PAP or home ventilation. Other auto-PAP–diagnosis failures included patients ultimately found to have central apnea and those with upper airway abnormalities that actually required a different modality of treatment (e.g., an oral appliance or surgical excision of tonsils and adenoids). These cases emphasize that self-titrating CPAP machines are not diagnostically useful in all patient subgroups. Using this mixed therapeutic-diagnostic mode as the sole “test” produces significant problems in some patients.
STANDARDS OF PRACTICE AND CLINICAL PRACTICE GUIDELINES The AASM has developed guidelines for evaluating SRBDs using attended laboratory polysomnography2 or home sleep testing.30 These recommendations were developed largely in the interest of standardizing sleep medicine practice in AASM-accredited sleep disorders centers. Task forces constructed these guidelines using evidence-based medicine techniques (when possible) and systematic expert panel consensus following the Rand Appropriateness Method. There are serious misconceptions about the AASM’s guidelines. Researchers on the cutting edge of SDB inquiry may consider the methods described in the standardized manual simplistic and inadequate, and they are probably correct, at least with regard to their research. However, these standards were not designed to guide scientific
endeavor attempting to extend the frontiers of knowledge. These AASM recommendations set forth a practical primer for pragmatic practitioners; that is, a clear-cut clinical cookbook. It establishes a much-needed minimum methodologic standard for diagnosing SDB. It also provides procedural details to inform third-party insurers what they are supposedly paying for and allows regulators to conduct quality control and verify claims. Attended Laboratory Polysomnography The key physiologic parameters required to assess SDB include airflow, respiratory effort, blood oxygenation, and sleep disturbance. AASM standardized technique currently mandates recording airflow with a thermal sensor placed at the nose and mouth and a nasal pressure transducer. Respiratory effort can be recorded with an esophageal manometer, chest and abdominal inductance plethysmographs, or intercostal EMG. Blood oxygenation is recorded with a pulse oximeter set to average over 3 seconds. Conceptually, airflow cessation for at least two respiratory cycles during sleep constitutes a sleep apnea episode (which on average is a ≥10-second arrest in ventilation). The operational definition requires a 10-second (or longer) 90% drop (or greater) in the nasal or oral airflow channel’s peak-to-trough amplitude persisting for at least 90% of the event’s duration. The classification of an apnea episode as central, obstructive, or mixed is based on whether respiratory effort is absent, present throughout, or present only part of the time airflow has ceased. In the strictest sense, a hypopnea is merely a shallow breath. However, when a hypopnea provokes significant oxygen desaturation or a CNS arousal it can adversely affect sleep, wakefulness, and health. Traditionally, sleep experts defined a hypopnea as a shallow breath associated with oxygen desaturation, CNS arousal, or both. However, CMS split the definition to include only events associated
1622 PART II / Section 19 • Methodology
with significant drops (≥4%) in blood oxygen concentration. This change reduced the AHI’s capability to identify SRBD because patients with good lung function and brisk arousal reflexes seldom desaturate enough to meet CMS criteria. The official AASM operational definition differs slightly from the one mandated by CMS. AASM’s recommended definition for hypopnea requires at least a 10-second 30% drop in nasal pressure signal amplitude (compared to baseline) persisting for at least 90% of the event’s duration and associated with a 4% or greater drop in oxygen saturation. However, the AASM standardized manual offers alternative criteria conforming more to traditional definition recognizing either an oxygen desaturation or CNS arousal. Even though I am inclined to prefer the alternative criteria, having two definitions for a single term is ill advised because it creates ambiguity, confusion, and miscommunication. To obviate this logistic difficulty, many clinicians classify airflow-limited respiratory events terminated by CNS arousal (but failing to meet the AASM and CMS ≥ 4% drop in oxygen saturation criterion) as falling into the category of respiratory effort–related arousals (RERAs), defined as an arousal-terminated breath sequence of at least 10 seconds and characterized by nasal pressure signal flattening or increasing respiratory effort. This, unfortunately, partially corrupts the traditional definition for RERA, but it provides a simple and unambiguous way to calculate the summary variables that are used to formulate treatment plans and that are required by some insurers. In this scheme, apnea index is the number of apneas per hour of sleep, AHI is the number of apneas and hypopneas (as per the AASM recommended definition) per hour of sleep, and respiratory disturbance index (RDI) is the number of apneas, the number of hypopneas (using the alternative criteria), and the number of events meeting AASM-defined criteria for RERAs per hour of sleep. The recording, scoring, and summarization techniques were developed for attended continuous all-night polysomnography. However, many laboratories conduct split-night diagnostic and pressure-titration studies. In a split-night procedure, sleep-related breathing is evaluated during a 2-hour or longer baseline period (using identical methods). When treatment-threshold for positive airway pressure therapy is reached, titration commences. (Treatment thresholds vary depending on the insurance carrier, and some carriers no longer require a full 2-hour diagnostic baseline.) Reportedly, this approach is acceptable for approximately 80% of patients.31 Split-day studies have also been conducted. Banno and colleagues32 found the procedure useful for diagnosis and titration in patients with prominent sleepiness (Epworth Sleepiness Scale scores > 16). Mask fit problems, pressure leaks, difficulty sleeping, disorientation in the middle of the night when positive airway pressure is applied, and initial difficulty adjusting to the mask can compromise split-night studies. If optimal pressure is not attained until the last hour of titration, the patient might not appreciate positive airway pressure’s full therapeutic benefit. By contrast, if optimal pressure is reached during the first 2 hours of a full-night titration,
the remaining 5 or more hours may be judged as the best night of sleep the patient has had in years. High perceived benefit is the first, and perhaps the most important, step on the road to therapeutic acceptance and utilization. Home Sleep Testing AASM provides clinical guidelines using unattended portable monitors to diagnose SDB in adults.30 The guideline stipulates that a sleep medicine board-certified or boardeligible clinician must first supervise and review a clinical sleep evaluation. Home sleep testing is an option only for patients with a high pretest probability for moderate to severe SDB. Patients with comorbid conditions that can compromise the accuracy of home sleep testing should be excluded (e.g., moderate to severe pulmonary disease, neuromuscular disease, congestive heart failure), as should patients with suspected other dyssomnias, parasomnias, and circadian rhythm disorders. Home sleep testing may also be used to assess patients who cannot have, or for whom it is unsafe to have, laboratory polysomnography. Finally, home sleep testing is recommended for outcome follow-up after weight loss, oral appliance fitting, and airway surgery. Recordings should minimally include airflow, respiratory effort, and oxyhemoglobin saturation. Flow should ideally be measured with nasal–oral thermistors and with a nasal pressure transducer; effort should be determined preferably using inductance plethysmography; and Sao2 should be recorded using an oximeter with a rapid sampling and averaging rate. The recording device must provide full signal disclosure for scoring and review and is subject to the same scoring criteria established for laboratory polysomnography. Finally, testing, scoring, and interpretation should be performed by appropriately credentialed professionals working in an AASM-accredited sleep medicine program. Evaluations with negative or technically inadequate home sleep testing results should be repeated using standard laboratory polysomnography. Automatic Scoring Accuracy represents the central issue for automatic scoring. Automatic scoring tends toward unreliability in complicated patients.33 Uncertainty about scoring accuracy can be framed in terms of confidence and trust. Confidence can be increased by objective and appropriate system validation. Scoring accuracy varies between manufacturers and even within a particular manufacturer’s system across different models or software versions. Much like a car, systems can perform differently depending who is driving (i.e., for different users on identical systems). Thus, scoring accuracy can differ within and between laboratories. Therefore, the AASM requires each laboratory to maintain documented validation trials, an adequately descriptive procedure manual, and quality control practices to ensure data integrity (for computerized and manual scoring). A well-conceived approach should scrutinize performance in different situations: with different patient groups, in the presence of various artifacts, and when processing suboptimal signals. Regular reliability testing and validation must be an ongoing process for data obtained with standard polysomnography and portable monitoring systems.
CHAPTER 142 • Monitoring Techniques for Evaluating Suspected Sleep-Disordered Breathing 1623
CONCLUSION Although attended comprehensive polysomnography remains the gold standard for diagnosis of the broad spectrum of sleep breathing disorders, it is likely that home sleep testing will have an important role in the diagnosis of uncomplicated obstructive sleep apnea in adults. Use of home sleep testing remains controversial because different issues are important to different stakeholders. Some of the issues are: 1) what technology should be used34,35; 2) economics and reimbursement36; 3) access36; 4) which patients should be evaluated with portable technology37; 5) the sleep field remains too focused on diagnosis and not enough on management.38,39 In the end, we have to remember that the goal of the testing is to establish a correct diagnosis, a small but critical initial step in the management of a patient with a chronic illness. ❖ Clinical Pearl Detecting SDB events and classifying each as obstructive, central, or mixed requires measures of airflow, respiratory effort, and oxyhemoglobin saturation. Patients with a high pretest probability for SDB should be evaluated using either attended laboratory polysomnography or a portable monitor in the home; however, home tests tend to be less sensitive diagnostically. Standardized guidelines developed by the AASM were developed to advance clinical practice and should not be construed as an impediment to advancing scientific inquiry.
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13. Taylor MB, Whitwam JG. The accuracy of pulse oximeters: a comparative clinical evaluation of five pulse oximeters. Anaesthesia 1988;43:229-232. 14. Hannhart B, Haberer JP, Saulnir C, Laxenaire MC, et al. Accuracy and precision of 14 pulse oximeters. Eur Respir J 1991;4:115-119. 15. Davila DG, Richards KC, Marshall BL, O’Sullivan PS, et al. Oximeter performance: the influence of acquisition parameters. Chest 2002;122:1654-1660. 16. Barker SJ, Tremper KK, Hufstedler S. The effects of carbon monoxide inhalation on pulse oximetry and transcutaneous Po2. Anesthesiology 1987;66:677-679. 17. Tremper KK, Barker SJ. Pulse oximetry. Anesthesiology 1989;70: 98-106. 18. Ries AL, Prewitt LM, Johnson JJ. Skin color and ear oximetry. Chest 1989;96:287-290. 19. Murphy KG, Secunda JA, Rockoff MA. Severe burns from a pulse oximeter. Anesthesiology 1990;73:350-352. 20. Lubbers DW. Theoretical basis of the transcutaneous blood gas measurements. Crit Care Med 1981;9:721-733. 21. Levy P, Pepin J. Sleep fragmentation: clinical usefulness of autonomic markers. Sleep Med 2003;4:489-491. 22. Pitson DJ, Stradling JR. Value of beat-to-beat blood pressure changes, detected by pulse transit time, in the management of the obstructive sleep apnoea syndrome. Eur Respir J 1998;12:685-692. 23. Argod J, Pepin JL, Levy P. Differentiating obstructive and central sleep respiratory events through pulse transit time. Am J Respir Crit Care Med 1998;158:1778-1783. 24. Mateika JH, Slutsky AS, Hoffstein V. The effect of snoring on mean arterial blood pressure during non-REM sleep. Am Rev Respir Dis 1992;145:141-152. 25. Ayas NT, Pittman S, MacDonald M, White DP. Assessment of a wrist-worn device in the detection of obstructive sleep apnea. Sleep Med 2003;4:435-442. 26. Thomas RJ, Mietus JE, Peng CK, Gilmartin G, et al. Differentiating obstructive from central and complex sleep apnea using an automated electrocardiogram-based method. Sleep 2007;30:1756-1769. 27. Chesson AL, Berry RB, Pack A. Practice parameters for the use of portable monitoring devices in the investigation of suspected obstructive sleep apnea in adults. Sleep 2003;26:907-913. 28. Centers for Medicare and Medicaid Services. Proposed decision memo for continuous positive airway pressure (CPAP) therapy for obstructive sleep apnea (OSA) 2007. Accessed April, 2010. https:// www.cms.hhs. gov/mcd/viewdraftdecisionmemo.asp?id=204. 29. Hussain SF, Fleetham JA. Overnight home oximetry: can it identify patients with obstructive sleep apnea–hypopnea who have minimal daytime sleepiness? Respir Med 2003;97:537-540. 30. Collop NA, Anderson WM, Boehlecke B, Claman D, et al. Clinical guidelines for the use of unattended portable monitors in the diagnosis of obstructive sleep apnea in adult patients. J Clin Sleep Med 2007;3:737-747. 31. Iber C, O’Brien C, Schluter J, Davies S, et al. Single night studies in obstructive sleep apnea. Sleep 1991;14:383-385. 32. Banno K, Al Sabbagh A, Delaive K, Higami S, et al. Experience in using split-day studies for suspected obstructive sleep apnea syndrome. Respir Med 2005;99:1334-1339. 33. George CF, Kryger MH. When is an apnea not an apnea? Am Rev Respir Dis 1985;131:485-486. 34. Campbell AJ, Neill AM. Home set-up polysomnography in the assessment of suspected obstructive sleep apnea. J Sleep Res 2010 Jun 16. [Epub ahead of print] 35. Choi JH, Kim EJ, Kim YS, et al. Validation study of portable device for the diagnosis of obstructive sleep apnea according to the new AASM scoring criteria: Watch-PAT 100. Acta Otolaryngol 2010;130:838-843. 36. Ayas NT, Fox J, Epstein L, et al. Initial use of portable monitoring versus polysomnography to confirm obstructive sleep apnea in symptomatic patients: an economic decision model. Sleep Med 2010; 11:320-324. 37. Joo BE, Seok HY, Yu SW, et al. Prevalence of sleep-disordered breathing in acute ischemic stroke as determined using a portable sleep apnea monitoring device in Korean subjects. Sleep Breath 2010 Jan 23. [Epub ahead of print] 38. Gay PC, Selecky PA. Are sleep studies appropriately done in the home? Respir Care 2010;55:66-75. 39. Collop NA. Home sleep testing: it is not about the test. Chest 2010;138:245-246.
Evaluating Sleepiness
Chapter
Max Hirshkowitz, Aliya Sarwar, and Amir Sharafkhaneh
Abstract Excessive sleepiness, although central to sleep medicine practice, remains a poorly defined concept. In clinical practice, assessment usually involves self-report; however, objective measures are available. This chapter covers the conceptual framework positing the three faces of sleepiness: that is, introspective, physiologic, and manifest. We also review the
OVERVIEW Excessive sleepiness affects not just the sleepy person but also the person’s family, coworkers, and society at large. Excessive sleepiness during work activities represents a serious, potentially life-threatening condition. When a person can no longer maintain vigilance, has significant response slowing, and begins lapsing into sleep, sleepiness becomes dangerous. Dangerous sleepiness, however, embodies a composite outcome from an increased physiological drive to sleep and a failure of the alerting system to stave off that drive. Thus, the overall level of sleepiness (and conversely, alertness) reflects a dynamic balance between systems with opposing functions. It is generally agreed that sleep regulation involves two processes: circadian and homeostatic. The way these processes alter self-reported, biological, and behavioral sleepiness measures is well characterized. By contrast, alerting processes are more poorly understood. Activation via dopaminergic, noradrenergic, adenosinergic, and histaminergic pathways provides the basis of pharmacologic attempts to enhance wakefulness. Sympathetic activation provides central nervous system stimulation that can usually temporarily counteract sleepiness. This allows a person to awaken and respond in emergencies and is likely an adaptive survival mechanism. Nonetheless, with increasing interest in sleep disorders, we need more sensitive, operationalized, well-validated metrics for conducting research and for clinically assessing patients. This chapter focuses on clinical assessment; therefore, three specific measurement issues merit special attention. The first issue highlights the differential utility of measures appropriate for within-subject versus between-subjects comparisons. For example, many reliable measures of sleepiness can detect changes in before-and-after experimental designs. However, case-by-case examination can reveal instances in which the initial value for one person exceeds the final value for another. Consequently, although the measure can provide a superb metric for assessing change, it does not automatically qualify as useful for determining whether the patient in your office is sleepy. The second issue concerns self-report. With increasing frequency, sleep specialists are being asked to make assessments for regulatory and judicial purposes. Testing parameters rise to new heights in such situations. Unlike research circumstances where self-interest is fairly neutral, possible 1624
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indications and techniques for evaluation procedures considered standard practice. This includes the Epworth Sleepiness Scale (introspective), the multiple sleep latency test (physiologic), and the maintenance of wakefulness test (manifest). Other assessment procedures, their relative merits, and their limitations are reviewed. Finally, a few practical considerations and conclusions are discussed.
primary and secondary gain must be assumed to color selfreport. Some people may be inclined to exaggerate or to minimize a disclosed sleepiness level to avoid losing a license or to obtain compensation. The third issue, validation of the sleepiness test, largely depends on daytime measures. The commonly used term excessive daytime sleepiness (EDS) underscores this point. Normative values for self-reported and physiologically based sleepiness metrics rely mainly on data collected during the day. When clinical necessity requires nighttime assessment (for example, in shift workers), the choices of validated instruments mostly involve vigilance tests for manifest sleepiness. Although physiologic techniques are readily adaptable and can detect nighttime drops in alertness in normal persons and in persons with sleep disorders, our understanding of what degree of sleepiness is pathologic during the night has yet to be established. In other words, how sleepy must one be for sleepiness to be considered abnormal at 4:00 am? Or to be considered excessive at 4:00 am? Or be considered dangerous at 4:00 am? In fact, although answers to these three questions might not differ at noon, they likely differ at 4:00 am! Carskadon and Dement1 proposed a useful conceptualization for characterizing sleepiness. They considered sleepiness along three dimensions: physiologic, manifest, and introspective. Physiologic sleepiness refers to the underlying biological drive to sleep; consequently, the primary index is the speed with which a person falls asleep. Manifest sleepiness includes behavioral signs of sleepiness, inability to volitionally remain awake, and performance deficit on psychomotor or cognitive tasks. The underlying process involves transformation of the underlying sleepiness to outward behavioral signs and abilities. The failure in ability also depends on the sleepiness overwhelming the opposing system that maintains wakefulness. Finally, introspective sleepiness (when unbiased by a person’s motives) represents the person’s selfassessment of his or her internal state. Although the manifest and introspective measures can stem from the same underlying drive state, individual differences modify the measurable phenomena. The Carskadon-Dement model provides an organizational device for understanding differences between sleepiness measures. If sleepiness were a single measurable core phenomenon, rather than a composite output of multiple sleep and alertness mechanisms, one would
expect equivalence between measures. However, different tests for sleepiness often produce varying results because they index quite different (although related) phenomena. The best concordance usually emerges at the extremes. When all sleepiness dimensions are at nadir (no sleepiness) or when sleepiness reaches its zenith (maximum sleepiness), all measures agree. Thus, most of the time it is illogical to use physiologic, manifest, and introspective sleepiness measures interchangeably; it also misses the important differences between them.
PHYSIOLOGIC SLEEPINESS Multiple Sleep Latency Test Background Sleepiness can be considered a physiologic drive state (i.e., a cousin to hunger, thirst, and libido). Therefore, the rapidity with which a person falls asleep represents the drive’s intensity. This relationship between sleepiness and sleep onset provides the foundation for the multiple sleep latency test (MSLT).2 That sleep deprivation hastens sleep onset (decreases sleep latency) on subsequent sleep opportunities is well documented with MSLT and provides considerable face validity for the procedure. Also, according to current theory, homeostatic sleep drive builds across the normal waking day but is opposed by an increasing circadian-dependent drive for alertness. This dynamic tension maintains alertness at a relatively stable level throughout the day. In the evening, the homeostatic sleep drive that has been increasing as a function of prior wakefulness approaches maximum. However, the homeostatic drive is met and offset by ever-increasing circadian-dependent alertness until the circadian drive precipitously declines. The homeostat then asserts itself and sleep onset occurs. In a series of elegant studies, the effects of age, partial sleep deprivation, and disorders of excessive somnolence were well characterized on MSLT sleep latency.3-5 Data relating homeostatic influences and sleepiness derive directly from MSLT studies.6 Circadian influence also manifests as shorter MSLT latencies on midafternoon test sessions for persons not fully rested or maximally sleepy. Methodology MSLT is the most widely used technique to scientifically assess physiologic sleepiness. In its traditional form, MSLT involves a series of nap opportunities (four to six) presented at 2-hour intervals beginning approximately 2 hours after initial (morning) awakening (for details, see reference 7). To appreciate the prior night’s sleep quantity and quality, the patient undergoes attended laboratory polysomnography the night before testing. A careful history of sleep habits, schedule, and drug use in the past month is essential (a sleep diary should be obtained). A clinical MSLT should not be conducted during drug withdrawal (especially from stimulants or from medications that suppress REM sleep), while sedating medications are pharmacologically active, or after a night of profoundly disturbed sleep. Persons undergoing an MSLT are instructed to allow themselves to fall asleep or to not to resist falling asleep.
CHAPTER 143 • Evaluating Sleepiness 1625
Box 143-1 Multiple Sleep Latency Test Recording Montage: Physiologic Activity Recorded Left or right central EEG (C3 or C4) Left or right occipital EEG (O1 or O2) Left horizontal or oblique EOG Right horizontal or oblique EOG Vertical EOG Submentalis (chin) EMG Electrocardiogram Respiratory flow, as needed Respiratory sounds, as needed EEG, electroencephalogram; EMG, electromyogram; EOG, electrooculogram;
Subjects are tested under standardized conditions in their street clothes and are not permitted to remain in bed between nap test sessions. Similarly, subjects should not engage in vigorous pretest activity because it will alter test outcome.8 Obtaining reliable results depends critically on using standardized test conditions and techniques.9 Sleep rooms must be dark and quiet during testing. Electroencephalographic (EEG; central and occipital), electroocculographic (EOG; left and right eye), and electromyographic (EMG; submentalis) parameters used to score sleep stages and detect sleep onset must be recorded during test sessions. MSLT guidelines also call for monitoring respiratory flow and sounds in patients known to snore (Box 143-1). Two protocols exist for conducting the MSLT; one designed for research and the other for clinical assessment (Fig. 143-1). The research protocol minimizes accumulated sleep by awakening the person when unequivocal sleep onset occurs. Criteria for unequivocal sleep requires either three consecutive 30-second epochs of stage N1 sleep or a single 30-second epoch of stage N2, N3, or R (REM). The MSLT clinical version attempts to index sleepiness and to detect abnormal REM sleep tendency characteristic in patients with narcolepsy. Therefore, test sessions continue for 15 minutes after sleep onset occurs. The clinical version of the MSLT reliably distinguishes patients with narcolepsy from control subjects based on REM sleep appearing in during test sessions (Table 143-1). Short sleep latency and REM appearing on two or more MSLT naps confirms diagnosis, especially in patients with cataplexy, sleep paralysis, or hypnagogia (or hypnapompia). In both the research and clinical versions, the test session is terminated after 20 minutes if no sleep onset occurs. Sleep latency is defined as the elapsed time from the start of the test to the first 30-second epoch scored as sleep. Sleep latency in normal adult control subjects ranges from 10 to 20 minutes. Traditionally, clinicians classified mean sleep latency on MSLT of 5 minutes or less as pathological sleepiness.10 Utility The MSLT can objectively document treatment response11 and residual physiologic sleepiness12 in patients independent of whether they self-reported sleepiness after treatment. MSLT’s sensitivity to physiologic sleepiness makes
1626 PART II / Section 19 • Methodology
helps rule out pharmacologically induced sleepiness. The availability of a specific cutpoint value characterizing pathological sleepiness and the well-defined test standardization made MSLT the test of choice for assessing sleepiness for many years.
No smoking
No vigorous activity
Prepare for bed
Biocalibration
–30 min
–15 min
–10 min
–5 min
SSS
Assume comfortable position
–45 sec
–30 sec
Lightsout
1st epoch any sleep
1st epoch unequivocal sleep
1st epoch REM sleep
T0
T1
T2
T3
0
“Please lie quietly, keep your eyes closed and try to fall asleep”
–5 sec
0
Test session termination rules: Experimental protocol: End at T2 Clinical protocol: End at T1 + 15 min Either version, if no sleep occurs: T0 + 20 min Figure 143-1 Specific procedures for multiple sleep latency test (MSLT) nap opportunities. REM, rapid eye movement; SSS, Stanford Sleepiness Scale.
Table 143-1 Multiple Sleep Latency Test Results PARAMETER
PATIENTS WITH NARCOLEPSY
CONTROL SUBJECTS
N (male/female)
57 (33/24)
17 (6/11)
Age (SD) in years
43.3 (12.3)
33.4 (9.9)
Percent who slept
99.0
63.5
3.0 (2.7)
13.4 (4.0)
Minimum
0.6
4.8
Maximum
14.1
20
REM score
3.5
0
Sleep latency mean (SD)
REM, rapid eye movement.
it especially useful for detecting persistent sleepiness in patients with occult comorbid sleep disorders, ineffective treatment, poor adherence to a therapeutic regimen, or concomitant soporific medication. As a technique to demonstrate a person’s underlying sleepiness, the MSLT has the advantage of being a direct, objective, quantitative approach. It is generally thought that under normal circumstances nonsleepy persons cannot make themselves fall asleep. By contrast, a sleepy person (if not overwhelmingly sleepy) can remain awake. Thus, false-positive tests (MSLT indicating sleepiness when the person is not sleepy) are theoretically minimal. Polysomnography documents the prior night’s sleep quality and quantity, and if significant sleep disruption or disturbance occurs, the MSLT can be rescheduled. Drug screening
Standards of Practice Parameters In 2005, the American Academy of Sleep Medicine (AASM) published new practice parameters for the clinical use of MSLT.13 These standards, guidelines, and options were developed on the basis of a comprehensive evidence-based medicine review process and a systematic protocol for expert consensus.14 The conclusions can be summarized as follows: • The MSLT is indicated as part of the clinical evaluation for patients with suspected narcolepsy. • The MSLT may be helpful for clinical assessment of patients with suspected idiopathic hypersomnia. • The MSLT is not indicated for routine evaluation of obstructive sleep apnea. • The MSLT is not indicated for routine reevaluation of patients with sleep apnea treated with positive airway pressure therapy. • The MSLT is not indicated for routine clinical assessment of insomnia, circadian rhythm disorders, or dyssomnia associated with medical, psychiatric, or neurologic disorders (other than narcolepsy and idiopathic hypersomnia). Other Measures of Physiologic Sleepiness Pupillography Pupil stability and size are affected by exposure to light and by a person’s arousal level. In a darkened room, a person’s pupils dilate to improve vision by widening the aperture for light to enter. However, if the person begins to fall asleep, parasympathetic activation constricts pupillary diameter. Sleepiness also provokes pupil size instability and alters the magnitude and speed of papillary constriction in response to a flash of light. These alterations reflect the autonomic nervous system balance changes associated with sleep and wakefulness. Several researchers and clinicians use pupillography to measure sleep tendency and evaluate narcolepsy.15,16 Although pupillography would seem a very attractive approach to objectively measure sleepiness, several barriers continue to impede its clinical utility. First, it is not an easily mastered procedure. Second, it remains difficult to compare one patient to another and designate a clinical cutpoint for sleepiness. Finally, normative data are not currently available. Electroencephalography Computerized quantitative analyses of EEG waveform features seem an obvious approach to the assessment of central nervous system arousal level. In essence, EEG (in conjunction with EOG and EMG) markers of sleep onset quantify sleepiness on the MSLT. It would be reasonable to expect that subtle waveform patterns (microarchitecture) could provide a sensitive metric. Just before sleep onset marked by alpha EEG disappearance, alpha frequency decreases and its amplitude increases. Additionally, it has long been thought that EEG delta activity could
potentially index sleepiness because it increases in response to experimental sleep deprivation.16 Some researchers believe the EEG cipher lies not in examining resting EEG spectral content but rather EEG responsiveness to sensory input. On the theory that sleepiness evokes altered neurologic reactivity, event-related potential (ERP) techniques have been applied in attempts to objectively measure sleepiness. Although these approaches hold promise, the lack of technique standardization and the absence of normative data limit their clinical application. In addition, the high degree of between-subject variation makes it difficult to compare results between persons. Finally, continuous EEG measures might not be as sensitive to episodes of sleepiness as continuous observation by a trained observer. Several investigators report that continuous EEG identified fewer episodes of sleepiness and was less predictive of performance lapses than continuous video monitoring revealing eyelid drooping and closure.17
MANIFEST SLEEPINESS Manifest sleepiness encompasses observable signs and measurable behavior indicating a person is either sleepy or is about to fall asleep, is in the process of falling asleep, or has fallen asleep. Observable signs can include yawning, ptosis (upper eyelid drooping), and head bobbing. These signs, however, are not specific to sleepiness; for example, ptosis may be neurogenic (as in oculomotor nerve palsy) or myotonic (as in myasthenia gravis), and head bobbing can signify cysts in the third ventricle. By contrast, EEGEOG-EMG recordings can objectively determine if a person is falling, or has fallen, asleep during controlled test sessions. Such test results are quite specific and provide the basis for the maintenance of wakefulness test (MWT). Finally, response slowing and lapsing during vigilance tests offer evidence for sleepiness, inattention, or both.18 Maintenance of Wakefulness Test Background The procedures for conducting the MWT are similar to those used for the MSLT.14 The most significant difference is that rather than instructing the subject to not resist sleep, you instruct the subject to attempt to remain awake. In this manner, the MWT is used to assess a person’s capability to, as the name implies, maintain wakefulness. The subject’s task is to resist being overwhelmed by sleepiness. To a large extent, the MWT evaluates the magnitude of sleepiness in relationship to the underlying wakefulness system’s functioning. If the wakefulness system fails, sleepiness becomes manifest. This laboratory situation parallels circumstances in which sleep onset occurs inadvertently while a person remains passively sedentary in a nonstimulating environment. The MWT gauges the potential threat of inappropriately and nonvolitionally lapsing into sleep; that is, dangerous sleepiness. The promise of potentially identifying dangerous sleepiness has attracted the attention of regulatory agencies. With growing interest in sleepiness and public safety, the demand for tests to assess sleepiness has increased. Indeed, the Federal Aviation Administration recognizes the MWT as a means to determine whether noncommercial pilots
CHAPTER 143 • Evaluating Sleepiness 1627
may be licensed after treatment for sleep apnea.19 Trucking companies and safety officers for companies with high-risk processes are beginning to follow suit, especially as the liability for and financial costs of accidents increase. However, the MSLT and the MWT do not correlate well in patients complaining of excessive sleepiness.20,21 Patients who fall asleep when not resisting it (as on MSLT) often can remain awake if they desire because underlying neurophysiologic mechanisms for maintaining alertness are distinct from those regulating and coordinating sleep. Methodology In the MWT, the subject’s only task is to remain awake. The subject sits in a dimly lit but not totally darkened room and attempts to remain awake. Dressed in street clothing and situated on the bed with a bolster pillow, the subject is not permitted to read, watch television, or engage in other activities. During testing, EEG, EOG, and EMG parameters used to discern sleep and wakefulness are recorded. Like the MSLT, test sessions are scheduled at 2-hour intervals, beginning approximately 2 hours after awakening from the previous night’s sleep. Test sessions are terminated when unequivocal sleep occurs (either three consecutive 30-second epochs of N1 or a single 30-second epoch of N2, N2, or REM sleep). Sleep latency for each test session, regardless of unequivocal sleep determination, is determined by the first epoch of sleep. The average sleep latency across tests is calculated, and the recording may be assessed for microsleep (3- to 10-second) occurrences. In studies comparing MWT and MSLT sleep latencies, as expected, subjects took longer to fall asleep when instructed to remain awake than when told not to resist sleep. Unlike the MSLT, polysomnography on the prior night is not required. The reason for this difference stems from the test’s utility to demonstrate ability to remain awake. If one can maintain wakefulness, how he or she slept the night before is not important. Important factors include stimulant use and coffee consumption; therefore, MSLT often requires urinalysis or blood chemistry, or both. For many years, MWT lacked standardization. Consequently, researchers and clinicians employed a wide variety of protocols. The MWT test session duration ranged from 20 to 60 minutes, with the longer tests attempting to avoid ceiling effects. An additional, but related, hurdle for using MWT clinically was the absence of normative data. However, this situation has changed.22 Normative data gathered by a consortium of sleep disorders centers established a range for expected values. The raw data from this project was provided for additional analysis by the AASM standards of practice committee. The results enabled MWT to ascend to the status of preferred clinical tool for objectively indexing alertness. Clinical utility of MWT has been demonstrated for evaluating treatment outcomes in patients with narcolepsy and sleep-related breathing disorders. Also, MWT measures can detect improvement in treated patients who continue to be physiologically sleepy; thus, MWT is sometimes used to extend MSLT’s sensitivity range.23 Nonetheless, MWT changes induced by acute versus chronic sleep deprivation, age, time of testing, and drugs remain grist for researchers’ mills.
1628 PART II / Section 19 • Methodology
Standards of Practice Parameters The AASM developed practice parameters for using the MWT clinically. These standards are based on an evidence-based literature review14 and expert opinion (when data were inadequate). MWT testing is indicated for assessing persons whose inability to remain alert constitutes a safety hazard. It is also indicated for determining pharmacotherapeutic response in patients with narcolepsy or idiopathic hypersomnia. Clinicians are cautioned that although falling asleep rapidly on MWT logically seems a powerful indicator for dangerous sleepiness, there is little direct evidence linking MWT sleep latency to real-world accidents. Thus, clinical evaluation must integrate MWT findings with signs and symptoms, history, and treatment adherence. Specific recommendations include conducting four 40-minute trials. MWT is indicated for evaluating a person’s ability to remain awake when personal or public safety is at stake. Based on statistical analysis of normative data, a mean sleep latency of less than 8 minutes is abnormal. Scores between 8 and 40 (the maximum value) are of uncertain significance. The mean sleep latency for presumed-normal volunteer subjects was 30.4 minutes. The ability to remain awake for the entire 40 minutes on all four test sessions (which is the upper limit of the 95% confidence interval) provides the strongest evidence for normal alertness. Nonetheless, clinical judgment is critical because even completely normal values do not guarantee safety. Vigilance Tests Manifest sleepiness can be measured using a variety of tests requiring simple psychomotor responding; that is, signaldetection tasks. Such tests are called vigilance tests because they test a person’s ability to remain heedfully vigilant. Typically (but not always) these tests attempt to mimic the tedious, palling situation of watching for blips on a radar screen or for ships on the horizon.24 Loss of vigilance, when faced with a nonstimulating task, is particularly relevant for patients with disorders of sleep and arousal. Theoretically, a vigilance test measures arousal or attention, or both. As with the MWT, performance can only be as good as ability. Although a person could fake bad, faking good is not possible if her or she cannot remain alert. Arousal and attention have traditionally been difficult to tease apart, making nonsleepy patients with attention deficits potential test confounders. Usually, sleepiness and inattention coexist; therefore, it is not surprising that long, experimenter-paced, monotonous tasks taxing a person’s endurance are sensitive to sleep loss, sleep disruption, and circadian variation. The landmark studies, collectively referred to as the Walter Reed experiments (named for the institute where they were conducted), documented the effects of sleep deprivation on performance.25 From these pioneering studies, it became clear that increasing duration of prior wakefulness and time-on-task provoked response slowing and lapsing (for an excellent review, see reference 26). A variety of vigilance tests exist; however, the psychomotor vigilance test (PVT) developed by Dinges and colleagues is probably the most commonly used today.27,28 The PVT is a visual signal detection test, approximately
10 minutes long, administered either by computer or by a hand-held display-and-response unit. Response latencies to visual target stimuli are recorded. Response slowing and lapsing correlation with the Stanford Sleepiness Scale (SSS) and the MSLT provide evidence for convergent validity. Additionally, PVT results have been reported for a variety of subject groups, including normal controls, sleep-deprived volunteers, and patients with major sleep disorders. Some PVT normative data are limited; however, between-subject comparisons for assessing the clinical level of sleepiness can be difficult to evaluate. The other vigilance test used to assess sleepiness in current literature is the Oxford Sleep Resistance (OSLER) test.29,30 The testing paradigm mimics MWT but uses a visual signal detection task rather than EEG-EOG-EMG monitoring. The test uses four 40-minute test sessions, during which visual target signals are presented. Subjects are instructed to respond to each signal with a simple button press. A test session is terminated either after 40 minutes or after significant response lapsing (which is considered a failure to maintain wakefulness). OSLER has been validated against MWT test results, but specific normative data supporting clinical cutpoint scores is not currently available.
INTROSPECTIVE SLEEPINESS Introspective sleepiness is measured using self-administered questionnaires. In this section we describe the most prominent instruments used in sleep research laboratories and clinics. Some of these questionnaires request the person to make a prediction about their behavior (e.g., how likely are you to doze off when …) or judge their feelings over some time interval of the recent past (e.g., in the past month). By contrast, other instruments involve momentary assessment and want to know how you feel right now. In general, questionnaires evaluating longer time domains (e.g., in the past month) are more useful clinically than those focused on momentary assessments. By contrast, momentary assessment instruments are more sensitive to variations in the level of sleepiness, making them more useful for investigating circadian oscillation or druginduced alterations in sleepiness. Ultimately, introspective sleepiness relies on self-report. On the positive side, it is only through self-report that one can hope to know what another is feeling. However, selfdisclosed information is modified by one’s ability to recognize internal states, one’s memory, one’s tendency to minimize or exaggerate feelings, and one’s underlying agenda. Epworth Sleepiness Scale The Epworth Sleepiness Scale (ESS) is the most widely used clinical instrument for evaluating sleepiness. This specialized, validated, eight-item, pencil-and-paper instrument was developed by Murray Johns at the Epworth Hospital in Melbourne, Australia.31 ESS questions a person about his or her expectation of “dozing” in differing circumstances. Dozing probability is designated as none (0), slight (1), moderate (2), or high (3) for eight hypothetical situations shown in Table 143-2.
CHAPTER 143 • Evaluating Sleepiness 1629
Table 143-2 The Epworth Sleepiness Scale Items QUESTION
HYPOTHETICAL SITUATION TO BE RATED
Table 143-3 The Stanford Sleepiness Scale Items CODE
SCALE STATEMENTS
1
Feeling active and vital, alert, wide awake
2
Functioning at a high level, but not at peak, able to concentrate
Sitting inactive in a public place (e.g., a theater or a meeting)
3
Relaxed, awake, not at full alertness, responsive
4
As a passenger in a car for an hour without a break
4
A little foggy, not at peak, let down
5
5
Lying down to rest in the afternoon when circumstances permit
Foggy, beginning to lose interest in remaining awake, slowed down
6
6
Sitting and talking to someone
Sleepy, prefer to be lying down, fighting sleep, woozy
7
Sitting quietly after a lunch without alcohol
7
Almost in reverie, sleep onset soon, lost struggle to remain awake
8
In a car, while stopped for a few minutes in traffic
1
Sitting and reading
2
Watching television
3
ESS’s popularity stems in part from its simplicity, brevity, and validation. Johns established reliability and validity using 54 patients with sleep apnea (before and after continuous positive airway pressure therapy) and 104 medical students.32,33 Student controls had a mean score of 7.6. Patients with sleep apnea had a mean score of 14.3 at baseline that declined to 7.4 after treatment. In another study, normative values were gathered from 942 patients waiting at outpatient clinics (e.g., dermatology, audiology, and ophthalmology clinics) and 1120 healthy people attending health fairs or community health lectures. The mean ESS total score for these two groups were 8.1 and 5.2, respectively.34 Based on this study and subsequent work in our clinic, we categorize ESS scores ranging from 0 to 8 as normal, 9 to 12 as mild, 13 to 16 as moderate, and greater than 16 (an order of magnitude above high normal) as severe. ESS differs from other tests in that respondents are not asked about how they feel but rather to make a probability judgment about their own behavior. In this manner, persons completing the ESS are indirectly rating their sleep drive and may explain why ESS correlates (albeit weakly) with MSLT sleep latency (an objective index of sleep drive). ESS’s main disadvantage is its questionable utility when it is readministered within a brief time interval. Its sensitivity to age, acute sleep disturbance or deprivation, and drugs needs further research. Stanford Sleepiness Scale and Karolinska Sleepiness Scale For many years, the Stanford Sleepiness Scale (SSS) represented the standard measure of introspective sleepiness.35 Persons taking the SSS choose one of seven statements to describe their self-assessed current state (choices are shown in Table 143-3). The SSS is a momentary assessment scale and can detect sleepiness as it waxes and wanes over the course of a day. Advantages include its brevity, its ease of administration, and its ability to be administered repeatedly. Experimentally induced sleep deprivation increases SSS scores; however, normative data do not exist, making it difficult to use for clinical decision making or comparisons between persons.
The Karolinska Sleepiness Scale (KSS) is quite similar to the SSS and consists of a nine-point scale ranging from 1, “very alert,” to 9, “very sleepy, great effort to stay awake or fighting sleep.” Scores of 7 or above are considered pathologic. The KSS is becoming increasingly popular for evaluating sleepiness in drug trials, flight crews, oil-rig workers, train engineers, and professional drivers. Its brevity, validation against EEG and behavioral parameters,36 and its now-proven sensitivity to sleepiness put KSS on equal footing with the SSS. Pictorial Sleepiness Scale Maldonado and colleagues37 developed a nonverbal sleepiness scale for testing young children and poorly educated adults. They had subjects rank order seven cartoon faces depicting sleepiness. Rankings were transformed to approximate linearity, and two cartoons were eliminated. The resulting five-picture scale was re-ranked by a different group of subjects to verify order for a final scale. Finally, a validation test indicated significant correlation with KSS and SSS using a mix of normal adults, patients with sleep apnea, shift workers, and school children. Whether this scale will gain popularity remains to be seen. Profile of Mood States Although principally designed to assess mood, the Profile of Mood States (POMS) has often been used in sleep research.38 The original test design intended a dimension for sleepiness, but it was eliminated because the factor proved to be not independent. The “sleepiness” items are the Vigor (negative), Confusion, and Fatigue scales. To a lesser extent, sleepiness emerged on Depression and Anger scales. The Confusion scale elevates more in response to severe sleepiness and the Vigor scale appears sensitive to partial sleep deprivation.39 Thus, early on, psychometricians found sleepiness a composite of other, more elemental and independent dimensions of mood. That difficulty lingers on as some researchers heedlessly view sleepiness as a unitary factor.
PRACTICAL ISSUES AND CONCLUSIONS Before sleepiness is assessed, several questions should be considered, including whether the goal is to establish the
1630 PART II / Section 19 • Methodology Table 143-4 Comparison between Tests for Evaluating Sleepiness TEST NAME
NORMATIVE DATA
POSSIBLE TO FAKE SLEEPINESS
POSSIBLE TO FAKE ALERTNESS
Physiologic Sleepiness MSLT* Pupillography EEG
Yes No No
No No No
Yes† Unknown Unknown
Manifest Sleepiness MWT* Vigilance and performance
Yes No
Yes‡ Yes§
No No
Self-Report ESS SSS POMS
Yes No Yes
Yes Yes Yes
Yes Yes Yes
*Standard protocol described in an American Academy of Sleep Medicine Practice Parameter: Test involves 4 to 6 test sessions per day, at 2-hour intervals. Test sessions are sometimes scheduled at shorter intervals (e.g., for children); however, this practice is not recommended by the authors. † Assuming that the subject is not overwhelmingly sleepy, attempting to remain awake can undermine the test result. ‡ Assuming that the subject is physiologically sleepy, not attempting to remain awake will make it appear that overwhelming sleepiness is present. § Intentionally not attending or responding to the task can make a person appear sleepy. EEG, electroencephalogram; ESS, Epworth Sleepiness Scale; MSLT, multiple sleep latency test; MWT, maintenance of wakefulness test; POMS, Profile of Mood States; SSS, Stanford Sleepiness Scale.
presence of sleepiness, the absence of sleepiness, or changes in sleepiness. Is testing being conducted for clinical assessment, research, or legal purposes? Is there selfinterest involved as part of a primary or secondary agenda? With increasing frequency, sleep specialists are providing expert opinions in legal matters involving accidents and disability claims. Expert witnesses are often pressured to render opinions concerning fitness for duty. In such cases, objective testing is crucial. Furthermore, a normal test result does not guarantee fitness for duty. Table 143-4 shows some characteristics of the tests described in this chapter. Ideally, physiologic, manifest, and introspective sleepiness should be assessed. In general, if a person claims to be sleepy and the goal is to demonstrate sleepiness, the MSLT is likely the best confirmatory test. If a person claims not to be sleepy and the goal is to demonstrate an ability to remain awake (as when there are concerns about ability to operate a motor vehicle), the MWT has certain advantages.40,41 For clinical purposes, self-reported measures combined with MSLT have long been the sine qua non for establishing sleepiness. Sometimes, however, in cases involving severe sleepiness, the MWT can demonstrate improved alertness after treatment, whereas the MSLT shows little or no change. Such persons continue to be pathologically sleepy, but they are not overwhelmed by it during the brief testing interval. The relationship between this pattern of change and performance or behavior requires further study. The dangers posed by excessive sleepiness are becoming increasingly apparent. The National Commission on Sleep Disorders Research catalogued a substantial list of sleeprelated industrial and transportation accidents. Long ago, Kleitman proposed sleepiness as resulting from accumulation of blood-borne hypnotoxins; however, such substances
have not been identified. Nonetheless, the search continues for sleep-inducing peptides (descendents of the hypothesized hypnotoxins). Unfortunately, no convenient or reliable blood test for sleepiness exists. Therefore, one or a combination of the evaluation techniques described in this chapter can be used and interpreted with respect to the underlying physiologic drive for sleep, the subjective, internalized consequence of that drive, and the behavioral manifestations.
❖ Clinical Pearl Measuring sleepiness in a clinical setting is not a simple matter. Testing for physiologic and manifest sleepiness has become standardized in the MSLT and MWT. The MSLT is indicated for evaluating narcolepsy and idiopathic hypersomnia, and the MWT is indicated for testing ability to remain awake when safety is at stake. Sleepiness testing must always be viewed within a larger context of a patient’s clinical history and examination findings.
REFERENCES 1. Carskadon MA, Dement WC. Daytime sleepiness: quantification of behavioral state. Neurosci Biobehav Rev 1987;11:307-317. 2. Carskadon MA, Dement WC. The multiple sleep latency test: what does it measure? Sleep 1982;5:S67-S72. 3. Carskadon MA, Dement WC. Cumulative effects of sleep restriction on daytime sleepiness. Psychophysiology 1981;18:107-113. 4. Carskadon MA, Harvey K, Duke P, et al. Pubertal changes in daytime sleepiness. Sleep 1980;2:453-460. 5. Mitler MM, Nelson S, Hajdukovic R. Narcolepsy: diagnosis, treatment, and management. Psychiatr Clin North Am 1987;10:593-606. 6. Richardson GS, Carskadon MA, Orav EJ, et al: Circadian variation in sleep tendency in elderly and young adult subjects. Sleep 1982;5: S82-S94.
7. Carskadon MA, Dement WC, Mitler MM, et al: Guidelines for the multiple sleep latency test (MSLT): a standard measure of sleepiness. Sleep 1986;9:519-524. 8. Bonnet MH, Arand DL. Sleepiness as measured by modified multiple sleep latency testing varies as a function of preceding activity. Sleep 1998;21:477-483. 9. Roehrs TA, Carskadon MA. Standardization of method: essential to sleep science. Sleep 1998;21:445. 10. Carskadon MA, Dement WC. Cumulative effects of sleep restriction on daytime sleepiness. Psychophysiology 1981;18:107-113. 11. U.S. Modafinil in Narcolepsy Study Group (USMNSG): randomized trial of modafinil for the treatment of pathological somnolence in narcolepsy. Ann Neurol 1998;43:88-97. 12. Zorick F, Roehrs T, Conway W, et al: Effects of uvulopalatopharyngoplasty on the daytime sleepiness associated with sleep apnea syndrome. Bull Eur Physiopathol Respir 1983;19:600-603. 13. Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for clinical use of the multiple sleep latency test and the maintenance of wakefulness test. Sleep 2005;28:113-121. 14. A review by the MSLT and MWT Task Force of the Standards of Practice Committee of the American Academy of Sleep Medicine. The clinical use of the MSLT and MWT. Sleep 2005;28:123-144. 15. Schmidt HS, Fortin L. Electronic pupillography in disorders of arousal. In: Guilleminault C, editor. Sleeping and waking disorders: indications and techniques. Menlo Park, Calif: Addison-Wesley; 1982. p. 127-143. 16. Borbely AA, Baumann F, Brandeis D, Strauch I, et al. Sleep deprivation: effect on sleep stages and EEG power density in man. Electroencephalogr Clin Neurophysiol 1981;51:483-493. 17. Dinges DF, Mallis MM. Managing fatigue by drowsiness detection: can technological promises be realized? Third International Conference on Fatigue in Transportation. Coping with the 24-hour society. Fremantle, Western Australia, February 9-13, 1998. 18. Franzen PL, Siegle GJ, Buysse DJ. Relationships between affect, vigilance, and sleepiness following sleep deprivation. J Sleep Res 2008;17(1):34-41. 19. Federal Aviation Administration (FAA). Sleep apnea evaluation specifications. Federal Aviation Administration specification letter dated October 6, 1992. Washington, DC: U.S. Department of Transportation; 1992. 20. Sangal RB, Thomas L, Mitler MM. Disorders of excessive sleepiness: treatment improves ability to stay awake but does not reduce sleepiness. Chest 1992;102:699-703. 21. Sullivan SS, Kushida CA. Multiple sleep latency test and maintenance of wakefulness test. Chest. 2008;134(4):854-861. 22. Doghramji K, Mitler MM, Sangal RB, Shapiro C, et al. A normative study of the maintenance of wakefulness test (MWT). Electroencephalogr Clin Neurophysiol 1997;103:554-562. 23. Mitler MM, Miller JC. Methods of testing for sleepiness. Behav Med 1996;21:171-183. 24. Baulk SD, Biggs SN, Reid KJ, van den Heuvel CJ, et al. Chasing the silver bullet: measuring driver fatigue using simple and complex tasks. Accid Anal Prev 2008;40(1):396-402.
CHAPTER 143 • Evaluating Sleepiness 1631 25. Lubin A. Performance under sleep loss and fatigue. In: Kety SS, Evarts EV, Williams HL, editors. Sleep and altered states of consciousness. Baltimore: Williams & Wilkins; 1967. p. 506513. 26. Dinges DF, Kribbs NB. Performing while sleepy: effects of experimentally induced sleepiness. In: Monk TM, editor. Sleep, sleepiness and performance. Chichester, England: John Wiley & Sons; 1991. p. 97-128. 27. Kribbs NB, Pack AI, Kline LR, Getsy JE, et al. Effects of one night without nasal CPAP treatment on sleep and sleepiness in patients with obstructive sleep apnea. Am Rev Respir Dis 1993;147: 1162-1168. 28. Doran SM, Van Dongen HP, Dinges DF. Sustained attention performance during sleep deprivation: evidence of state instability. Arch Ital Biol 2001;139:253-267. 29. Bennett LS, Stradling JR, Davies RJ. A behavioural test to assess daytime sleepiness in obstructive sleep apnoea. J Sleep Res 1997;6: 142-145. 30. Krieger AC, Ayappa I, Norman RG, Rapoport DM, et al. Comparison of the maintenance of wakefulness test (MWT) to a modified behavioral test (OSLER) in the evaluation of daytime sleepiness. J Sleep Res 2004;13(4):407-411. 31. Johns MW. A new method for measuring daytime sleepiness: the Epworth Sleepiness Scale. Sleep 1991;14:540-545. 32. Johns MW. Reliability and factor analysis of the Epworth Sleepiness Scale. Sleep 1992;15:376-381. 33. Hirshkowitz M, Gokcebay N, Iqbal S, Zebrak A, et al. Epworth Sleepiness Scale and sleep-disordered breathing: replication and extension. Sleep Res 1995;24:249. 34. Sharafkhaneh A, Hirshkowitz M. Contextual factors and perceived self-reported sleepiness: a preliminary report. Sleep Med 2003;4: 327-331. 35. Hoddes E, Zarcone V, Smythe H, Phillips R, et al. Quantification of sleepiness: a new approach. Psychophysiology 1973;10:431-436. 36. Kaida K, Takahashi M, Akerstedt T, Nakata A, et al. Validation of the Karolinska sleepiness scale against performance and EEG variables. Clin Neurophysiol 2006;117(7):1574-1581. 37. Maldonado CC, Bentley AJ, Mitchell D. A pictorial sleepiness scale based on cartoon faces. Sleep 2004;27(3):541-548. 38. McNair DM, Lorr M, Droppleman LF. Manual of the profile of mood states. San Diego: Educational and Industrial Testing Service; 1992. 39. Horne J. Dimensions to sleepiness. In: Monk TM, editor. Sleep, sleepiness and performance. Chichester, England: John Wiley & Sons; 1991. p. 169-196. 40. Philip P, Sagaspe P, Taillard J, et al. Maintenance of wakefulness test, obstructive sleep apnea syndrome, and driving risk. Ann Neurol. 2008;64(4):410-416. 41. Pizza F, Contardi S, Mondini S, et al. Daytime sleepiness and driving performance in patients with obstructive sleep apnea: comparison of the MSLT, the MWT, and a simulated driving task. Sleep 2009;32(3):382-391.
Assessment Techniques for Insomnia Arthur J. Spielman, Chien-Ming Yang, and Paul B. Glovinsky
This chapter is both a primer on how to evaluate insomnia and a reference guide to the array of assessment tools currently available. We first review major theories of the origins and maintenance of insomnia to highlight the importance of keeping a comprehensive formulation in mind as details are gathered. We then review essential data-gathering techniques, including self-administered questionnaires, sleep logs, the initial interview, and other clinical sources. Using sleep logs, we depict common insomnia subtypes and apply the 3P1,2 model that categorizes case material into predisposing, precipitating, and perpetuating factors. The resulting analyses demonstrate how clinical case material may be organized to enhance understanding of insomnia and target its treatment. This chapter discusses various methods by which clinicians evaluate the complaint of insomnia (for an additional perspective see Chapter 77). Although insomnia is extremely common, it can still be a difficult problem to evaluate, let alone to treat, because it is a symptom of a wide variety of disorders, has a number of different manifestations, and often follows a variable course. The clinician must avoid focusing on the particulars of last night’s sleep problem and instead address the major factors underlying the symptom. The methods discussed here have evolved to address this challenge. Although few investigators will apply this list exhaustively, a working knowledge of these methods will prove very helpful when the clinician is confronted with the inconstancy and persistence of insomnia. Certain methods of assessment are beyond the scope of this chapter. We omit specialized techniques that have been developed to assess sleep disturbance in children, and we forgo discussion of assessments that have been devised to further research protocols, even though some of these techniques have been proposed as potentially useful in the clinical setting. Our aim is to address the needs of the practicing clinician rather than listing all esoteric research methodologies. Finally, we do not cover the various methods of assessing daytime sleepiness, which is a major complaint of only a subgroup of insomniac patients (see Chapter 143).
MODELS OF THE PATHOGENESIS OF INSOMNIA The assessment of any disorder is typically directed toward identifying the factors producing and maintaining the condition, as well as toward gauging a person’s predisposition to the disorder. Although this model is often applied to insomnia, the fit is not always comfortable. Despite careful inquiry, the cause and pathogenesis of a substantial proportion of insomnia cases often remain unsettled. By contrast, the characteristics and consequences of a par1632
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144
ticular case of insomnia, as well as factors maintaining the disturbance, can usually be well delineated. Effective treatments for insomnia target these features. The clinician therefore often works on multiple levels, addressing current maladaptations while building a case for pathogenesis that can direct longer-term treatment interventions. With this in mind, we briefly review the major models proposing mechanisms responsible for the insomnia disorders. Psychiatric and Psychological Conditions Insomniacs, clinicians, and normally good sleepers have long recognized the close connection between psychological distress and poor sleep. Correlative research has shown that excessive anxiety, depression, and severe psychopathology are associated with sleep disturbance.3-7 A series of studies has delineated personality patterns associated with insomnia, and a theory has been put forward that internalization of conflicts produces physiologic arousal in vulnerable persons.8,9 Concomitant helplessness has also been identified as a key contributing factor.10-12 Organic factors associated with psychiatric conditions or acute states that promote wakefulness or impair sleep have also been identified; these factors include the lack of cortisol suppression, enhanced cholinergic mechanisms, and reduced slow-wave sleep (see Section 10).13-15 The findings from six studies showing that insomnia is a risk factor for developing depression has reminded clinicians not to reflexively attribute insomnia to depression.16-20 Notwithstanding the recent International Classification of Sleep Disorders, 2nd edition, Diagnostic and Coding Manual (ICSD-2) nosology, it is the current consensus of the field to describe insomnia in the presence of depression as “comorbid insomnia,”21 conveying the understanding that insomnia may be either secondary to or independent of depression. Two studies bearing on this issue show that successful treatment of major depression does not completely relieve insomnia: Sleep disturbance and fatigue were the most common residual symptoms after successful treatment of depression.22 Although sleep quality improves with treatment of depression, sleep remains disturbed compared to normal controls.23 Learned Insomnia and the Vicious Circle Experiencing poor sleep night after night promotes an association between sleeplessness and both activities preceding bedtime and the setting where sleep is being sought.24 Once these connections are established, bedtime rituals and the bedroom itself become cues for poor sleep. Worries about sleeplessness that gather force as the night approaches then become a self-fulfilling prophecy. Animal studies showing classic conditioning of sleep and wakefulness support this learning model of insomnia.25,26
Physiologic Arousal A global reduction in metabolism as well as relative deactivation of a broad range of other physiologic processes are hallmarks of the transition to sleep. It is therefore not surprising that heightened physiologic arousal, indexed by such changes as increased body temperature, heart rate, fast EEG activity, and muscle tension, is incompatible with sleep.27-29 Patients may be unaware of their hyperarousal, posing a problem for the diagnostician. Furthermore, there is not yet a clinically practical, valid, and objective method of assessing arousal. Inadequate Sleep Hygiene Aspects of everyday living have long been known capable of promoting or preventing sleep.30 It is common knowledge that keeping regular bedtimes and avoiding caffeine in the evening enhances the likelihood of good-quality sleep. On the other hand, conventional wisdom can be misleading. For example, many people, insomniac or not, believe that alcohol promotes sleep. In fact, although the sedating properties of alcohol can hasten sleep onset, subsequent sleep may be more disrupted. Similarly, some persons make the mistake of trying to “tire themselves out” with strenuous activity before bedtime, leading to hyperarousal instead of sleep. Practices of good and poor sleep hygiene have been the subject of systematic focus.1,31,32 It has been found that they are often jettisoned in the pursuit of short-term relief. For example, napping and caffeine may be deployed against the effects of sleep loss, only to lead to more difficulties sleeping the next night. Cognitive Factors: Arousal and Beliefs The buzz of an overactive mind can block sleep onset or can awaken the sleeper.33-37 Sometimes insomnia can be readily attributed to worries and cares, but benign planning and reflections on the day or jumping from one uncompleted thought to another can also cause sleeplessness. Because substantial mental processing occurs subconsciously, the irritating thought might not even be available for scrutiny. The poor sleeper also learns to anticipate the daytime consequences of insomnia, such as cloudy consciousness, fatigue, and irritability, leading to a fresh round of worry and arousal. Anticipatory anxiety resulting from past insomnia has become the cause of future sleep disturbance, completing the vicious circle. Beliefs and self-attribution can also act like self-fulfilling prophecies. The insomniac patient who assumes that mild sleep loss eventually leads to an impaired immune system, disease, and even death has greatly raised the stakes on falling asleep. Similarly, labeling oneself an insomniac may be a depressing thought that is damaging to the self. The label itself becomes worrisome and interferes with sleep. Primary Sleep Disorders Polysomnography (PSG) has illuminated physiologic processes taking place under cover of dark. Such monitoring has revealed that some persons with insomnia complaints have arousals induced by sleep-disordered breathing; in others, brief arousals or awakenings are triggered by periodically occurring movements.37,38 Less commonly, other
CHAPTER 144 • Assessment Techniques for Insomnia 1633
medical problems such as nocturnal seizures and cardiac arrhythmias may be confined to sleep and therefore initially manifest as sleep disorders. Sleep Disorders Secondary to Medical Conditions Trouble sleeping can also be the result of the pain, discomfort, and pathophysiology associated with medical conditions (see Section 10). Such secondary insomnia does not always remain linked to the patient’s illness. The patient may be taking medications that interfere with sleep, or a learned association can develop between sleeplessness and bedroom cues. The patient might spend too much time in bed to “rest and get healthy,” leading to a weakening of the circadian sleep–wake cycle, or might begin using hypnotic medication on a regular basis and then have difficulty stopping because of anticipatory anxiety and the physiologic effects of withdrawal. Regardless of the specific route, troubled sleep initiated by medical illness can readily lead to chronic insomnia. Circadian Rhythm Disorders Discovery of endogenous timing mechanisms regulating biological and behavioral processes has enhanced understanding of normal and abnormal sleep.39-40 Although the periodic occurrence of the sleep–wake cycle reflects this endogenous pacemaker, its expression has been shown to be susceptible to the timing, duration, and intensity of time cues. The ability of the most salient time cue, bright light, to shift the times of sleep onset and offset has suggested that aberrant clock mechanisms or poorly timed cue delivery may be implicated in some insomnia disorders. Predisposing, Precipitating, and Perpetuating Factors A simple conceptual model, known as the 3P model, organizes the multiple determinants of insomnia just reviewed into predisposing, precipitating, and perpetuating factors (Figs. 144-1 and 144-2).1,2 Clinical evaluation of all three components allows treatment to address the current conditions producing and sustaining the insomnia as well as a person’s vulnerability to future bouts of sleep disturbance. A recent line of work has investigated whether there is a trait of stress-related vulnerability to insomnia.41-43 One questionnaire predicts which persons without a current complaint of insomnia are prone to develop insomnia in stressful situations. This nine-item Likert-type questionnaire, the Ford Insomnia Response to Stress Test, has been shown to predict trouble sleeping on the first night in the sleep laboratory and increased difficulty falling asleep when administered caffeine.42,43 In terms of precipitating factors, one study examined the relationship between life stresses and the triggering of insomnia.44 It found that sleep in younger persons is more prone to disturbance due to work or school stress, and sleep in older adults is more sensitive to stress associated with health. Finally, perpetuating factors have long been a major focus of the evaluation of insomnia (see Chapter 77 for a list of assessments for perpetuating factors). Historically, arousal was one of the first domains attracting attention for evaluation and treatment. The multiple facets of sleep hygiene have also been
1634 PART II / Section 19 • Methodology PRECIPITATING/PERPETUATING FACTORS CONTRIBUTING TO INSOMNIA OVER TIME
PREDISPOSING FACTORS CONTRIBUTING TO INSOMNIA OVER TIME
Insomnia threshold
Perpetuating Precipitating
Insomnia severity
Insomnia severity
Precipitating
Perpetuating
Insomnia threshold Predisposing
Predisposing Time Figure 144-1 Conceptual model of the development of chronic insomnia and the changing factors that play a role over the course of the disorder. In this particular case, at the onset of the insomnia, precipitating factors predominate. When the insomnia becomes chronic, perpetuating factors become the main feature contributing to the sleep disturbance. (Adapted from Spielman AJ, Caruso L, Glovinsky PB. A behavioral perspective on insomnia. Psychiatr Clin North Am 1987;10:541-553). This depiction of the 3P model was improved by the contribution of Max Hirshkowitz, PhD. We acknowledge his help in making the changes over time look dynamic and dimensional rather than fixed and categorical.
a central focus. With the ascendance of the cognitive view of insomnia and its treatment, beliefs and attitudes, worry, attentional bias, sleep effort, and safety behavior have all become key issues to assess. In Figure 144-1 we illustrate the maintenance of chronic insomnia by perpetuating factors. In this case, predisposing factors such as hyperarousal or susceptibility to depression do not figure prominently. Loss of a job precipitates a bout of sleeplessness. As our patient with new insomnia begins to cope with unemployment, this factor plays less of a role. He speaks to colleagues, lines up interviews, and believes his prospects are good. Determined to be at his best, he tries to get more sleep by spending more time in bed, and he drinks more coffee to maintain acuity. He begins to worry about how his sleep problem will affect his performance at interviews. Eventually the contribution of the precipitating factor is barely present. Perpetuating factors of poor sleep hygiene and worry about sleeplessness are now the main reasons the sleep problem persists. In Figure 144-2 the person has a strong predisposition to insomnia. He is generally hyperaroused, overreactive to challenges, and a night owl. He often has trouble falling asleep and attaining an adequate amount of sleep. Although precipitating factors such as interpersonal conflicts, money problems, and health concerns trigger exacerbations of the sleep problem, the main ingredient producing the insomnia remains his underlying predisposition.
ASSESSMENT METHODS OF SLEEP DISORDERS CENTERS To obtain a sense of evaluation procedures for insomnia, we conducted a quasirandom telephone survey of 40 sleep
Time Figure 144-2 The conceptual model of insomnia applied to a case in which predisposing factors are prominent and are the single most important determinant of the insomnia. Precipitating factors episodically activate the predisposing factors (Adapted from Spielman AJ, Caruso L, Glovinsky PB. A behavioral perspective on insomnia. Psychiatr Clin North Am 1987;10:541-553).
disorders centers for the first version of this chapter. At the time of the fourth edition of this book, this sample represented more than 10% of the centers certified by the American Sleep Disorders Association. We learned that a majority of centers used structured rating scales and questionnaires as adjuncts in the evaluation of patients complaining of insomnia. More than two thirds of the centers send questionnaires to the patient before the initial visit. Although virtually all centers use sleep logs, only about one third of patients fill out a sleep log before the sleep consultation. About three fourths of centers formally evaluate some of their patients for depression, whereas fewer than half evaluate their patients for anxiety. Although only a handful of centers use a separate instrument to assess beliefs and attitudes about sleep, this domain is often measured in sleep questionnaires. Two thirds of patients fill out a sleep and medical history questionnaire, and a similar percentage are evaluated by the clinician with the use of a semistructured interview. Half of the insomniac patients have an evaluation by a psychologist or psychiatrist. After the initial consultation, a fourth of patients undergo nocturnal PSG. In the four centers that use actigraphy, only about 10% of patients receive this type of evaluation. Unfortunately, most of the sleep logs, sleep history questionnaires, and semistructured interviews are unpublished and are unique to each center. The lists that follow include published and unpublished methods. We refer to an instrument as published when the reference includes either a blank questionnaire or all the items, responses, and scoring necessary for use. Scales referred to as available on request can be purchased or obtained from the authors. The material in the tables is listed by date, except for Table 144-3 (assessment of specific causes), which groups according to categories.
CHAPTER 144 • Assessment Techniques for Insomnia 1635
Table 144-1 Sleep Quality Questionnaires* SCALE NAME (SOURCE)
NO. OF ITEMS
FORMAT
Published Pittsburgh Sleep Quality Index61 (pp. 298-213)
24
Severity and frequency ratings Mainly symptom checklists
Global Score Composed of a Number of Categories Insomnia Severity Index51
7
Frequency, severity ratings Mainly symptom checklists
Available on Request Insomnia Symptom Questionnaire81
13
Visual analogue scales
*All scales assess the quality and adequacy of sleep. None survey etiologic factors.
Questionnaires, Diaries, and Logs Some of the best methods for obtaining a balanced, comprehensive overview of a complaint of persistent insomnia involve having patients fill out retrospective questionnaires, inventories of current status, and prospective sleep diaries or logs. Retrospective Instruments A main benefit of adopting a guided retrospective approach to the assessment of insomnia is that it aids in forming an accurate picture of the sleep disturbance. Provided prompts to recognition memory as opposed to relying solely on recall, the patient is helped to gain a broader perspective on the problem. There is less need to focus only on those aspects that, in the judgment of the patient, would justify clinical attention. A systematic review of available assessment instruments and recommendations for a standard evaluation of insomnia for research studies has been published.45
SLEEP AND MEDICAL HISTORY QUESTIONNAIRES There are two types of sleep history questionnaire. One assesses the adequacy and quality of sleep, and the other, more comprehensive type also includes a survey of potential etiologic factors (Table 144-1). Most useful if filled out by the patient before the first visit, sleep and medical history questionnaires can broach potentially sensitive topics for the patient’s consideration in privacy, while also giving notice that the inquiry will necessarily be a broad one if the patient’s complaint is to be adequately addressed. Questionnaires also have the benefit of introducing the long view and of moving the patient from the role of hapless victim of the vagaries of sleep into that of a coinvestigator.32,33 Committing his or her experience to paper gives the patient the opportunity for reflection and revision common to all writing processes, which fosters a more-considered and more-reliable assessment.
These methods do generate problems. The most obvious is that they often take a fair amount of the clinician’s time to review. One such example is the venerable Cornell Medical Index, which contains 195 items, yielding a comprehensive survey.46 In addition to reviewing the patient’s past medical history and current symptoms, it is essential to carefully consider the effects of all medications administered over the course of the insomnia disorder. This is partly accomplished with the sleep diary (see later), which asks the patient to list medication use. However, because the patient starts filling out the diary after the evaluation has begun, it does not yield information on the effect of drugs during the development of the insomnia. The clinical interview is the best way to weave together the features of medication use (e.g., type, amount, time of administration, frequency, side effects, withdrawal effects on discontinuation, and degree of drug tolerance) with other treatments and coping strategies in order to gauge the effects of these approaches on sleep. There are subtle problems associated with the use of questionnaires. They can create a false sense, on the part of both patient and clinician, that the inquiry has been comprehensive. There is a danger that in the interests of expediency, the clinician may choose not to cover the same ground as the questionnaire. Alternatively, due to the patient’s positive response bias, the clinician may be obliged to follow up more intensively than would be otherwise necessary merely to rule out various diagnostic possibilities, and the interview will be prolonged. In other cases, patients simply are not capable of providing a faithful account by these means. However, even when a welldesigned questionnaire is completed accurately, there is ample opportunity for confusion. For these reasons, leaving the history taking to the form is tantamount to leaving out the history altogether. Rather than being misused in this way, questionnaires are properly used to structure the ensuing inquiry, to serve as an outline, and to guarantee that attention will be paid to all relevant areas as well as to the particular flags raised by the patient’s responses.
PSYCHOPATHOLOGY AND PERSONALITY QUESTIONNAIRES Although insomnia can result from a wide array of medical, environmental, and chronobiological conditions, the high prevalence of psychopathology in patients with insomnia makes careful attention to this domain particularly important. Specific disorders such as depression, anxiety disorder, chaotic personality organizations, and psychoses can play a direct role in the genesis of insomnia. Even when overt psychopathology is not present, certain types of personality configuration can predispose toward insomnia. For example, detail-oriented perfectionists might not allow themselves a respite from the day’s challenges, instead bringing these into bed for further reflection. Persons with ruminative personalities can become caught in a cycle of misgivings or strategizing rather than settling into sleep. Screening for psychopathology and personality typing are readily accomplished through the use of assessment instruments (Table 144-2). A large number of tests have
1636 PART II / Section 19 • Methodology Table 144-2 Assessment of Psychopathology and Personality SCALE NAME (SOURCE)
FORMAT
SCALE DESCRIPTION
20
Clinician rating of severity based on patient interview Four levels of severity description Four-point frequency ratings
Semistructured interview for depression Clinician needed for administration Assesses depressive state with a cognitive emphasis Depression survey
Available on Request Symptom Checklist Revised85
90
Five-point frequency ratings
Profile of Mood Scales86
65
Five-point severity ratings
State-Trait Anxiety Inventory50
40
Four-point severity ratings
Psychiatric symptoms and descriptions Norms for different samples Nine primary symptom dimensions and three global indices Narrative interpretation may be obtained Adjectives that describe mood states Norms published Separate scales measure current and long-standing anxiety
Published Hamilton Rating Scale of Depression82 (pp. 61-62) Beck Depression Inventory (pp. 561-571) I83, II49 Self-Rating Depression Scale84 (p. 65)
NO. OF ITEMS 21 21
been developed that permit valid inferences to be drawn about a patient’s psychological makeup. Some cast a wide net and are useful in characterizing a broad range of pathology47; others have a more specific focus. In any case, the use of psychological assessments does not relieve the clinician of responsibility for evaluating the patient’s mental status. Often, clinical judgment is confirmed and treatment can proceed with greater assurance, whereas at other times, discrepancies between these forms of assessment can lead to fruitful new avenues of inquiry. Two instruments—the Beck Depression Inventory48,49 and the Spielberger State-Trait Anxiety Scale50—deserve mention, because they are in widespread use in sleep disorders centers, are relatively easy to administer and interpret, and target the most common types of psychopathology associated with insomnia: depression and anxiety. Because they offer a quick assessment of the intensity of depression or anxiety, these scales allow rapid intervention in patients who may be at risk for serious psychological distress. When choosing a scale, the clinician must become familiar with the content of the items that yield the scaled score, because different instruments can focus on different aspects of a disorder. For example, one depression scale might emphasize the biological features of the disturbance, whereas another might focus on cognitive abnormalities. As with all questionnaires, these inventories are susceptible to response bias on the part of the patient. Some people tend to deny or minimize, others aim to give the clinician what he or she is thought to expect, others are careless in responding, and still others harbor some motivation to exaggerate their symptoms.
INVENTORIES OF COGNITIVE AND SOMATIC AROUSAL Cognitive style often determines whether a person is predisposed to develop insomnia. Although everyone must deal with some degree of stress in their lives, there is a great deal of variation in how this coping is accomplished. Some lucky souls can literally “sleep on it” when confronted with a problem, but many people obsess over
issues until they are too aroused to fall asleep. When the particular problem to be overcome is lack of sleep, the consequences can be especially pernicious. Several authors have described a vicious circle in which concern over the possibility of not sleeping, underscored by previous experience, leads to hyperarousal as evening approaches, reaching such a peak that by bedtime, sleep is truly impossible.5,33,51 Many patients insist with bewilderment that there is nothing particularly upsetting that they are dealing with in their lives. Their thoughts range initially over all sorts of seemingly trivial issues, eventually gravitating to the fact that sleep is not occurring. It may in fact be that the contents of one’s thoughts do not necessarily lead directly to arousal; rather, the problem might lie with the thought process itself. Half-completed thoughts, racing, and the repetition of themes might represent operating characteristics of a mind that is temporarily incapable of sleep. One reason hyperarousal so effectively forestalls sleep is that once it is triggered, baseline conditions of arousal are not reestablished for a long time. It has been noted that the response to a perceived threat is rapid, which makes sense from an evolutionary perspective, whereas the “fall time” to a level of calm that would be conducive to sleeping is prolonged.52 Several inventories gauge the extent to which cognitive and somatic hyperarousal are interfering with sleep (Table 144-3). Muscle tension, psychomotor agitation, and heart pounding are reported by some insomnia patients, and the role of treatments based on dearousal suggests that an assessment of this domain is relevant to a comprehensive evaluation of sleep disturbance. Sleep-related beliefs are commonly identified via the Dysfunctional Beliefs and Attitudes about Sleep Scale. The original version contains 30 items regarding beliefs about the consequences of sleep loss, control and expectation of sleep, sleep need, attribution of insomnia, and sleep-promoting activities.51 Three short versions with 753 or 1054,55 items were developed for research and clinical purposes. By targeting the tendency to catastrophize the consequences of poor sleep and fostering instead a more detached, dispassionate attitude,
CHAPTER 144 • Assessment Techniques for Insomnia 1637
Table 144-3 Assessment of Specific Causes SCALE NAME (SOURCE)
NO. OF ITEMS
FORMAT
SCALE DESCRIPTION
Morningness– Eveningness56 (pp. 100-103)
19
Four-point severity ratings
Feeling and functioning best rhythm Time of day ratings
Munich ChronoType Questionnaire87
23+
Mainly fill in the blank
Feeling and functioning best rhythm Development and family assessed
Sleep Hygiene Awareness and Practice Scale12 (pp. 75-76)
31+
Frequency and effect on sleep ratings
Activities, practices, and circumstances of the day that affect sleep
Sleep-related Behaviours Questionnaire88
58
Five-point ratings
Safety behavior
Presleep Arousal Scale89 (p. 266)
16
Five-point severity ratings
Assesses cognitive and somatic arousal at bedtime
Sleep Disturbance Questionnaire90 (p. 153)
12
Five-point severity ratings
Assesses sleep hygiene and cognitive and somatic arousal
Ten-point scale
Surveys dysfunction about sleep-related and performance-related cognition
Dysfunctional Beliefs and Attitudes about Sleep Scale53,54,55
30,10,7
examination of beliefs and attitudes about sleep can help interrupt the vicious circle of insomnia. The clinician should be aware, however, of the potential for confrontation that can occur by implying that a patient’s beliefs are “faulty” or “unrealistic.”
ASSESSMENT OF SLEEP HYGIENE AND PREFERRED SLEEP PHASE The nature of the hours spent before bedtime often determines whether sleep will come easily. The amount of physical activity, bed rest, and light exposure obtained during the day affect one’s propensity for sleep, the timing of that sleep, and its quality. Exposure to dreadful evening news stories, extended periods of reading in bed, and other aspects of poor sleep hygiene ultimately prove counterproductive, whereas regular bedtimes and an evening buffer period in which to wind down from the day’s events will over time be beneficial. Several authors have developed scales that assess these factors (see Table 144-3). The timing of the propensity for sleep and activity differs among individuals, often on a constitutional basis. Understanding the circadian tendency of patients can help in the formulation of behavioral strategies to align and maintain their endogenous circadian phase with work and school demands. Disposition toward a morning lark or a night owl pattern is assessed by a number of circadiantyping scales (see Table 144-3).56,57 SLEEP DISTURBANCE, WAKE DISTURBANCE, AND FATIGUE The Patient-Reported Outcomes Measurement Information System (PROMIS) is a collaboration between the National Institutes of Health and primary research sites at six American universities.57 The principal aim of PROMIS is to develop standardized item banks and questionnaires to assess, from the perspective of the patient, both baseline status and the outcomes of interventions for a broad range
of chronic illness. The PROMIS program is currently in its first 5-year development cycle. Its initial focus has been coverage of five specific domains: pain, fatigue, emotional distress, physical function, and social function. To date, several groups of calibrated items directly applicable to insomnia research and to sleep research in general have been developed with the use of item response theory, including items covering sleep disturbance, wake disturbance, and fatigue.
PROSPECTIVE SLEEP DIARIES Retrospective instruments have the advantage of being able to quickly summarize events occurring over a long period. However, they inevitably introduce distortion due to the collapse and distillation of information. Memories are often incomplete or selective. In the case of insomnia, there is a natural tendency to focus on the worst experiences and perhaps to amplify their importance. These pitfalls can be countered through the use of a prospective sleep diary or sleep log (Table 144-4). Sleep logs have an intuitive appeal, are user friendly, and allow prospective monitoring of target behavior. Filling out a sleep log directs the patient’s attention to aspects of behavior that might otherwise be overlooked. Some sleep logs present information in a graphic format that allows the clinician to quickly survey and appreciate patterns in large amounts of data. On the other hand, more-precise information is obtained from fill-in-the-grid or question-type formats. A work group of experts in the field is in the process of developing a sleep diary that, it is hoped, can serve as a standard format.58 This group has decided to use a question-type format, based on the need to gather precise information for research purposes. Because our aim is to guide clinicians in the evaluation of insomnia we recommend a graphical format (see later). Sleep logs do have potential drawbacks. Some obsessive patients feel compelled to provide such accurate and complete information that the very act of logging clock times of various events interferes with sleep. Even in less-extreme
1638 PART II / Section 19 • Methodology Table 144-4 Sleep Diaries* SCALE NAME (SOURCE) Published Sleep Diary51 (p. 210) Pittsburgh Sleep Diary† (pp. 113-114) Sleep Log91 (p. 140)
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Five-point severity ratings Fill in the blanks Five-point frequency ratings Visual analogue scales Fill in the blanks Graphical depiction of sleep over time Five-point severity ratings Fill in the blanks
Friday Saturday
Graphical depiction of sleep over time Fill in the blanks
*All diaries assess sleep pattern and quality as well as presleep activities and practices. † Spielman AJ, Glovinsky PB. The diagnostic interview and differential diagnosis for complaints of insomnia. In Pressman MR, Orr WC, editors. Understanding sleep: the evaluation and treatment of sleep disorders. Washington, DC: American Psychological Association; 1997. p. 125-160. ‡ Metrodesign Associates/Charles Pollak, MD, 90 Clinton Street, Homer, NY 13077, 1989.
Into bed
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Figure 144-3 Delayed sleep phase syndrome. Complaint: very hard to fall asleep, easier to fall asleep if bedtime is later, hard to wake in the morning, late to school, sleeps late on weekends. Predisposing factor: late night type, rebellious adolescent. Precipitating factor: start of school in the fall with an early start time. Perpetuating factor: late wake-up time on weekends.
Case 2
cases, the act of logging information on a night-by-night basis often works against the therapeutic goal of instilling in the patient a longer view toward the sleep disturbance. This tendency may be countered by drawing attention to week-to-week changes shown on the logs, as opposed to focusing on nightly variations. Case Illustrations The following cases illustrate the use of sleep logs (based on actual cases but redrawn for clarity) in assessing and treating insomnia. They also demonstrate how application of the predisposing, precipitating, and perpetuating model of insomnia enhances understanding of the disorder. Case 1 Figure 144-3 shows the key features of delayed sleep phase syndrome. Before the onset of her sleep problems, this 16-year-old was a late-night type, but she did not have trouble falling asleep by 11 PM and getting up early for school. During the summer she began to fight with her parents over staying out late; her bedtime drifted to 1 AM and her rising time to 10 AM or later. When school resumed in the fall, she needed to get up at 6 AM to make her bus. In November she was still complaining of trouble falling asleep whenever she went to bed before 1 AM, and she had difficulty getting up in the morning. She was habitually late for school and slept in on the weekends. Groggy in the morning, she would become progressively more alert through the day, except for a dip in alertness around 4 PM. She got a second wind in the evening, and was not in the least bit sleepy at her former 11 PM bedtime.
The patient depicted in Figure 144-4 is depressed as a result of the miscarriage of her first pregnancy. She is spending too much time in bed, which is also contributing to her sleeping difficulties. In bed for 10 hours, she is achieving only 6 hours of fragmented sleep. Treatment required addressing both the insomnia’s triggering event, her miscarriage, as well as the perpetuating factor, excess time in bed.
Case 3 Bed was the hub of evening activity for the patient depicted in Figure 144-5. When she turned the lights off around 11 PM, she often had trouble falling asleep. Habitual association of the bed with waking activities conditioned her insomnia. The bed was no longer a clear signal for falling asleep, but instead it was perpetuating the sleep-onset problem.
Case 4 Never a good sleeper, the patient portrayed in Figure 144-6 developed a medication strategy to prevent the development of drug tolerance. He used a different sleep medication each night at bedtime, and he usually took a second dose during the night. He felt desperate for sleep and unable to function if he did not get an adequate amount nightly. The onset of insomnia in early life often suggests a weak sleepgenerating system. Hypnotic dependence was apparent in this patient’s case, as was his preoccupation with sleep.
CHAPTER 144 • Assessment Techniques for Insomnia 1639
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Figure 144-4 Depression and inadequate sleep hygiene. Complaint: trouble falling and staying asleep; onset after miscarriage. Predisposing factor: unknown. Precipitating factors: postpregnancy depression and hormonal changes. Perpetuating factor: too much time in bed.
Trying to sleep after getting into bed
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Figure 144-5 Psychophysiologic insomnia or inadequate sleep hygiene. Complaint: mainly trouble falling asleep; snacks, talks on phone, watches television, and reads in bed; stays in bed during awakenings. Predisposing factor: unknown. Precipitating factor: started to come home early after quitting second job in the evening. Perpetuating factor: engages in sleep-incompatible activities in bed.
Case 5 Figure 144-7 depicts a pattern of short sleep on weekdays and catch-up sleep on weekends. This somewhat agitated and overly stressed man was physiologically and cognitively hyperaroused. He was not able to wind down properly during weekday evenings. However, the discharge of his sleep debt on weekends was also perpetuating his poor weekday sleep pattern.
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The patient with the variable sleep schedule depicted in Figure 144-8 was quite reactive physiologically. She had a robust startle response to loud noises, and her heart often raced during the day. She woke up abruptly in the middle of the night and had great difficulty going back to sleep. She felt she needed to seize sleep whenever she could get it and therefore avoided plans that might interfere with her sleep. Case 7 Figure 144-9 depicts a log of consistently solid sleep that was truncated after 4 hours. Wide awake in the middle of the night, the patient found that getting out of bed, working on his computer, and eating helped him get back to sleep for an hour or so in the morning. He did not use an alarm in the morning so that he could capture the last drop of sleep. This patient never required much sleep and was always an early riser. These traits predisposed him to early-morning awakenings. Perpetuating factors included conditioned arousal secondary to working on the computer and eating in the middle of the night, variable arising time, and allowing too much time for sleep.
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Figure 144-6 Insomnia associated with dependence on hypnotics. Complaint: light sleeper since childhood, can’t sleep without medication; must sleep in order to function. Predisposing factor: possible weak central nervous system sleep drive. Precipitating factor: none. Perpetuating factors: dependence on hypnotics, cognitive distortions, overly focused on sleep.
Recommendations for a Standard Research Assessment of Insomnia An expert panel of 25 insomnia researchers was convened to review existing insomnia assessment tools and develop a consensus regarding what would constitute essential and recommended components of insomnia assessment in
1640 PART II / Section 19 • Methodology Midnight
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Figure 144-7 Inadequate sleep hygiene or psychophysiologic insomnia. Complaint: too little sleep; hard-driving businessman, catches up on sleep on weekends. Predisposing factor: hyperarousal. Precipitating factor: unknown. Perpetuating factors: unequal distribution of sleep across 7 days, irregular wake-up time.
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Figure 144-8 Irregular sleep–wake schedule. Complaint: “I can’t depend on my sleep, I wake up abruptly, I try to sleep whenever I can.” Predisposing factors: robust autonomic arousal response, dependent personality. Precipitating factor: started freelance work, irregular work schedule. Perpetuating factors: irregular sleep–wake schedule, napping at different times of day for long periods of time, too much time in bed, overconcern about sleep.
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Figure 144-9 Psychophysiologic insomnia. Complaint: trouble staying asleep, long awakening after 3 to 4 hours of solid sleep during which he works on the computer, gets refreshing sleep in the morning. Predisposing factor: significant morning type, short sleeper. Precipitating factor: unknown. Perpetuating factors: variable morning rise time, too much time in bed, awakenings have become conditioned and associated with activating tasks.
research settings.45 This panel was charged with specifying both instruments to employ and reporting guidelines. Their effort responded to the problem that varying methodologies and differing inclusionary and exclusionary criteria were hampering the ability to compare insomnia research results and pool data for meta-analyses. Standardized assessments were suggested for three domains: the diagnosis of insomnia and comorbid conditions, sleep measurements, and waking correlates and consequences of insomnia. The panel concluded that the diagnosis of insomnia should be made through a clinical history and questionnaires that yield ICSD-2 diagnoses. The potential usefulness of several published semistructured interviews was noted, although to date these were still seen to await sufficient documentation of reliability and validity. The employment of recently developed research diagnostic criteria for insomnia59 was also recommended as essential in research settings. Comorbid medical and psychiatric disorders should be assessed through clinical histories and well-validated instruments. Specifically, the use of the structured clinical interview for the Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision (DSM-IV-TR)60 was recommended for psychiatric evaluation. Sleep measurement should include the assessment of global insomnia symptoms through instruments such as the Pittsburgh Sleep Quality Index61 and the Insomnia Severity Index62 as well as a 1- or 2-week sleep diary. Finally, evaluation of the waking correlates and consequences of insomnia was seen to be aided by a number of
psychometrically validated instruments. Some of these specifically consider the precursors or consequences of insomnia, such as the Dysfunctional Beliefs and Attitudes About Sleep Scale51 or the Ford Insomnia Response to Stress Test.42 Given their relatively narrow focus, they are seen as quite useful in selected settings but not required for routine clinical assessment. Other instruments have established their utility in a broad variety of clinical settings, such as the Fatigue Severity Scale,63 the Beck Depression Inventory-II,49 the State-Trait Anxiety Inventory50 and the Medical Outcomes Study Short Form-36 (SF36).64 These are seen as essential in documenting the waking consequences of insomnia. Initial Consultation Questionnaires and prospective logs certainly have their role in the assessment of insomnia, but it is in the face-to-face setting of the consultation that the clinician’s skills and knowledge find full expression. Questionnaires do not ask follow-up questions. They cannot achieve the degree of nuance that is often necessary to decide, for example, whether episodes of awakening with gasping and palpitations likely represent a nocturnal anxiety attack or an apneic disturbance. They cannot probe for further examples or establish context. It is up to the clinician, too, to recognize internal inconsistencies in a patient’s history and encourage a more-accurate reconstruction. Finally, in consultation there might arise facets of the history that were not previously apparent to the patient and that would likely be wholly overlooked on a questionnaire. The consultation interview is critical for establishing the trust and working alliance that will be necessary to carry the patient successfully through the treatment phase, especially when that treatment might involve changes in habits or lifestyle that are difficult to implement. The clinician must demonstrate caring, openness, and an ability to listen and understand, while bearing in mind that the patient is by definition in distress and likely to focus more on extreme experiences to garner aid. A standard history-taking format usually serves well to elicit the essential features of insomnia. However, an empirical study has shown that a clinician who is not a sleep specialist asks few pertinent questions of the insomnia patient.65 The skilled clinician starts close to the patient’s experience, allowing opportunity to expound the gist of the presenting problem with sufficient idiosyncratic detail to ensure that the experience does not fit too neatly and quickly into a preconceived diagnostic category—a potential pitfall for both patient and clinician. As these details emerge, the clinician develops hypotheses regarding the genesis of the insomnia and the factors that are maintaining it. These hypotheses are then tested via further questioning. For example, if it appears that a sleep-onset difficulty relates to concerns about performance at work, the clinician might ask about patterns in the severity of the disturbance and find that it is exacerbated on Sunday night, whereas the patient has experienced some asymptomatic periods during vacations. After a working formulation has been established and a preliminary differential reached, the clinician generally
CHAPTER 144 • Assessment Techniques for Insomnia 1641
performs a survey of the various domains potentially bearing on the problem, such as the past medical history, family history, current psychosocial context, and so on. Even when the clinician is fairly certain of the cause of a patient’s insomnia and confident of an appropriate course of treatment, it still is important to piece together a comprehensive picture of the background conditions from which the disturbance evolved. There may be other ancillary or independent problems that also require attention. Several semistructured interviews have been developed to guide the evaluation of insomnia (Table 144-5). They have the advantage of cueing the clinician to cover relevant domains, and they include a survey of sleep hygiene practices. As with the use of any interview framework, the skilled clinician will be alert to instances where departures from the guide must be made to fully follow up on the patient’s experience. Duke Structured Interview for Sleep Disorders The report of the working group of the American Academy of Sleep Medicine charged with developing research diagnostic criteria for insomnia noted that “variable insomnia definitions have encumbered studies concerning the pathophysiology, clinical characteristics, and treatment of this form of sleep disturbance.”59 The Duke Structured Interview for Sleep Disorders represents a comprehensive
Table 144-5 Semistructured Sleep Interviews* SCALE NAME (SOURCE) Published Structured Sleep History Interview12 (pp. 66-69) Insomnia Interview Schedule51 (pp. 195-198) CCNY Insomnia Interview79 (pp. 421-426)
NO. OF ITEMS 53+
77
41+
Available on Request Duke 30+ Structured Interview for Sleep Disorders66
FORMAT Open-ended questions
Open-ended questions Yes/no Severity ratings Fill in the blanks Open-ended questions Symptom checklists Severity ratings Rating of the degree to which factors covary with sleep disturbance Diagnostic entities linked to particular questions Lists of comorbidities Branch-tree logic Rate four choices Past/present Derives DSM-IV-TR or ICSD-2 diagnostic codes
*All interviews survey a wide range of symptoms and etiologic factors. CCNY, City College of New York; DSM-IV-TR, Diagnostic and Statistical Manual of Mental Disorders, 4th edition, text revision; ICSD-2, International Classification of Sleep Disorders, 2nd ed: Diagnostic and Coding Manual.
1642 PART II / Section 19 • Methodology
approach toward systematizing the elicitation of clinical information, with an aim to more reliably classify patients with regard to the major sleep disorders and their subtypes.66 The Duke interview is organized in a series of modules that function as decision trees. It directs the proceedings to various branches representing sleep-related diagnostic categories based on the text revision of the DSM-IV (DSM-IV-TR),60 and their equivalents (or more finegrained subtypes) from the ICSD-2.21 The interviewer is supplied the order of question presentation, along with specific wording (or a list of alternatives when a range of responses would indicate a positive response). Most critically, the interviewer is given explicit criteria to consider for every question when evaluating patient responses with one of four possible scores—insufficient information; absent (no); subthreshold (uncertain); threshold (yes)— both at the present time and in the past. These scores are then transferred to a scoring table, which links the scores to specific items within the structured interview to the various diagnostic categories. Finally, a ranking table is used to determine which specific DSM-IV-TR or ICSD-2 diagnostic codes appear most applicable to the response pattern elicited. The use of a structured interview, whether the Duke version or another of the handful of published examples, yields clear benefits in terms of standardization, comprehensiveness, and documentation of the response pattern that warranted a particular diagnosis. In the clinic, it also poses special challenges in terms of maintaining a therapeutic alliance with insomnia patients. The interview might represent the patient’s first meeting with a sleep specialist, perhaps after several encounters with generalists whose take on sleep was considered perfunctory. Patients might understand on an intellectual level that accurate diagnosis is certainly in their best interests, but they also will want to leave the consultation feeling that their idiosyncratic histories have been fully appreciated, that their particular concerns have registered, that the reassurance they are hearing is not of the blanket variety. Thus the successful use of a structured interview in clinical settings may in fact require more rather than less expertise. A physical examination has been recommended for the standard assessment of insomnia by a number of evidencebased review papers.67,68 The physical examination might detect disorders comorbid with insomnia. We are unaware of any empirical demonstration of the diagnostic yield of this evaluation. Testing and Referrals Sleep specialists in almost all cases accumulate information from the broad categories just covered: retrospective questionnaires, prospective logs, and interviews. Referrals for testing or evaluation by another specialist are generally made more judiciously, based on the information gathered during the evaluation process. Sometimes the history will be sufficiently strong to warrant PSG testing to confirm or rule out physiologic disturbance during sleep, such as sleep apnea or periodic limb movement disorder, before any treatments are applied. Similarly, further clinical evaluation may be indicated if the history suggests psy-
chiatric disturbance or specific disorders, such as hyperthyroidism or cardiac arrhythmia, that may be accompanied by insomnia. In other cases, testing or referral to a specialist takes place after a poor response to initial treatment is documented, to widen the base of potentially helpful information. Nocturnal Polysomnogram The nocturnal PSG is the standard objective measure of sleep (see Chapter 141). Since the 1970s, a large body of research and clinical experience has accumulated regarding both normal sleep parameters and variants seen in disordered sleep. Evaluation with PSG allows the clinician to objectively compare the patient’s sleep characteristics with normative data and with data gathered within various clinical populations to clarify the diagnosis. The PSG is also helpful in uncovering covert disorders, such as periodic limb movement disorder, that might otherwise escape detection, especially if there is no bed partner available to observe sleep. In addition to characterizing sleep, PSG affords the clinician several indices of arousal that can prove especially helpful in characterizing and addressing cases of insomnia. These include such measures as the percentage of non– rapid eye movement (NREM) stage 1 (N1) transitional sleep, the number of transient arousals, the number of stage changes across the record, and the intrusion of alpha wave activity into deeper sleep. PSG also allows the clinician to compare objective parameters—such as total sleep time or the number of awakenings exceeding a specified duration—with the patient’s subjective estimate of these same parameters. Sometimes, a large discrepancy between objective parameters and their corresponding subjective estimates characterizes the core of the presenting problem.69,70 The nocturnal PSG does have drawbacks. One is its expense, reflecting both its labor-intensive character and the investment in costly technology. A consequence of this expense is that only one or two nights of data are typically obtained, resulting in a very limited sample of sleep. Given the increased night-to-night variability of sleep typically seen in insomnia, this can result in a biased estimate. The effect of sleeping in a sleep laboratory can also result in an inaccurate representation of the patient’s sleep, either exaggerating sleep difficulties— the classic “first night effect”71—or, paradoxically, resulting in better sleep than that typically obtained at home—the “reverse first-night effect.”72 This latter effect can occur when associations have been established between the insomniac patient’s bedroom environment and the experience of sleeping poorly. These maladaptive cues are missing from the sleep laboratory, so sleep is improved there. Because of these drawbacks, nocturnal PSG is not indicated as a first-line diagnostic tool for assessing insomnia according to American Academy of Sleep Medicine guidelines.73 Actigraphy Actigraphy is a relatively low-cost method of estimating sleep parameters, such as total sleep time and the timing and duration of prolonged awakenings (see Chapter 147).25,74-77 An actigraph is a device that records gross
motor movements. Not much bigger than a wristwatch, it is attached to a limb and can be worn day or night without interfering with normal sleep or daily functioning. It can record motor activity (or in the case of sleep, the lack thereof) across many days and nights, employing various sampling rates. The collected data are usually downloaded to a computer for analysis. The cost-effectiveness of actigraphy allows multiple nights of sampling, avoiding the sampling error associated with the nocturnal PSG. However, it can overestimate the amount of sleep obtained in insomniac patients who do not move much during the night, even when they are awake. Furthermore, the various actigraphs available commercially have not been standardized. They have different sensitivities to the detection of movement and differing algorithms for converting raw data points into estimates of sleep and wakefulness. Laboratory Urinalysis and Blood Work Analyses of urine and blood samples routinely conducted by commercial laboratories at the behest of physicians in general medical practice can also prove helpful in assessing selected patients complaining of insomnia with clinical evidence of comorbid medical conditions. Levels of thyroid-stimulating hormone and follicle-stimulating hormone and blood count profiles will help in evaluating whether hyperthyroidism, menopause, or infection is playing a role in the sleep disturbance. A survey of the methods used to assess the numerous medical conditions associated with insomnia is beyond the scope of this chapter (see Section X). We will comment on tests pertinent to the assessment of the conditions of restless legs syndrome (RLS) and periodic limb movement disorder (PLMD). Although the pathophysiology of these conditions is still under investigation, a subset of patients might have reduced iron stores or vitamin B12 levels; the former can be assessed by obtaining ferritin levels.78 Obtaining a set of blood panels on every insomnia patient is not recommended because of the low yield; however, when there is sufficient reason to suspect an underlying medical cause of insomnia, and testing proves negative, blood panels allow behavioral interventions to be applied with more confidence and persistence. Commonplace Technologies Ubiquitous devices such as telephone answering machines or digital watches can be helpful in assessing insomnia. Patients complaining that they “get no sleep at all, or at best, just 1 or 2 hours” can be instructed to call on an hourly basis into a telephone answering machine equipped with a time stamp when they are unable to sleep. This provides an objective record of at least intermittent wakefulness across the night and may be useful in cases of sleep state misperception, also known as paradoxical insomnia. Digital watches that have an hourly chime function can be used to cue the patient to rate alertness or mood. Audiotape or videotape recordings can be useful as screening tools in cases where sleep-maintenance difficulties are suspected of being secondary to a physiologic disturbance such as sleep apnea.
CHAPTER 144 • Assessment Techniques for Insomnia 1643
Trial Treatment as Assessment There are times when even a thorough evaluation yields only provisional understanding of a patient’s complaint of insomnia. In these cases, the most expeditious means of verifying that supposition may be through the application of a trial treatment. Of course, reasoning that a diagnostic impression is correct because improvement follows treatment is not necessarily valid; just because a cold improves after a few days of drinking chamomile tea does not mean that chamomile deficiency caused the cold in the first place. Similarly, good sleep hygiene practices are helpful for all sleepers, not just those whose sleep difficulties stem specifically from poor sleep hygiene. Therefore, if poor sleep hygiene is suspected as a causative factor, instruction in better practices can efficiently treat those who are correctly targeted, while not doing harm to those whose insomnia arises from other causes. Another condition that deserves mention in this regard is sleep-maintenance insomnia due to suspected PLMD during sleep.21 Very often, this condition responds to treatment with dopamine agonists or opioid drugs. These drugs are not of general benefit in other types of sleepmaintenance insomnia; therefore, if a patient with suspected PLMD shows a positive response to these drugs, this response can usually be taken as indirect evidence that PLMD was the underlying culprit. Note that a positive response to one of the sedative-hypnotic medications, which can also be helpful in treating cases of insomnia due to PLMD, would not yield information regarding the presence of PLMD. This class of drug would be expected to benefit many different types of insomnia whether it is due to PLMD or not. Other Reviews For those interested in further reading on this topic, we recommend a chapter we have written79 and two publications of the American Academy of Sleep Medicine that review the evaluation of chronic insomnia.73,80
SUMMARY Very few medical or psychological disorders are associated with as diverse an array of diagnostic procedures as those summarized here in connection with the assessment of insomnia. This heterogeneity mirrors the multiple facets of the complaint, which range through physical discomfort, psychological distress, cognitive deficiencies, behavior impairment, and social disruption. Full evaluation of the complaint requires a multidimensional approach because those aspects of the sleep disorder that are most salient or distressing to the patient—and the facets where it might prove most amenable or recalcitrant to treatment—vary among individual patients. The clinician who is prepared to meet a complaint of insomnia on its own terms, drawing from the range of diagnostic methods described in this chapter, will come to a more complete understanding of the problem and be better able to formulate effective recommendations for its treatment.
1644 PART II / Section 19 • Methodology ❖ Clinical Pearls The factors that increase risk for insomnia and those that trigger the onset of an episode are typically not the same as factors that maintain the disorder once it is established. Even if predisposing factors cannot be readily altered and precipitating factors are never positively identified, substantial relief from insomnia may be attained by addressing perpetuating factors. Evaluation of insomnia is a multitiered process. It should virtually always make use of prospective sleep diaries and specialized questionnaires. A faceto-face clinical consultation is required to follow up responses on these instruments in order to articulate idiosyncratic features of the problem, establish a therapeutic alliance, and inform treatment decisions. Although overnight PSG may be beneficial, especially in cases where covert sleep disorders are suspected, it is not considered a front-line diagnostic tool for insomnia.
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National Institute of Mental Health Epidemiologic Catchment Area Program. Acta Psychiatr Scand 1991;84(1):1-5. 20. Livingston G, Blizard B, Mann A. Does sleep disturbance predict depression in elderly people? A study in inner London. Br J Gen Pract 1993;43(376):445-448. 21. American Academy of Sleep Medicine. International classification of sleep disorders. 2nd ed. Diagnostic and coding manual. Westchester, IL: American Academy of Sleep Medicine; 2005. 22. Nierenberg AA, Keefe BR, Leslie VC, et al. Residual symptoms in depressed patients who respond acutely to fluoxetine. J Clin Psychiatry 1999;60(4):221-225. 23. Fava M, McCall WV, Krystal A, et al. Eszopiclone co-administered with fluoxetine in patients with insomnia coexisting with major depressive disorder. Biol Psychiatry 2006;59(11):1052-1060. 24. Bootzin RR, Rider SP. Behavioral techniques and biofeedback for insomnia. In: Pressman MR, Orr WC, editors. Understanding sleep: the evaluation and treatment of sleep disorders. Washington, DC: American Psychological Association; 1997. p. 315-338. 25. Sterman MD, Clemente CD, Wyricka W. Forebrain inhibitory mechanisms: conditioning of basal forebrain induced EEG synchronization and sleep. Exp Neurol 1963;7:404-417. 26. Sterman MB, Szymusiask R, McGinty D. Quantitative analysis of basal forebrain stimulation effects: sleep induction, sleep conditioning, and state distribution. Paper presented at the Fifth International Congress of Sleep Research, July 1987, Copenhagen, Denmark. 27. Bonnet MH, Arand DI. 24-Hour metabolic rate in insomniacs and matched normal sleepers. Sleep 1995;19:581-588. 28. Freedman R, Sattler HI. Physiological and psychological factors in sleep-onset insomnia. Abnorm Psychol 1982;91:380-389. 29. Johns MW, Gay MP, Masterton JP, et al. Relationship between sleep habits, adrenocortical activity and personality. Psychosomat Med 1971;3:499-508. 30. Kleitman N. Sleep and wakefulness. Chicago: University of Chicago Press; 1939. 31. Hauri P. The sleep disorders. 2nd ed. Kalamazoo, Mich: Upjohn; 1982. 32. Hauri PJ. Consulting about insomnia: a method and some preliminary data. Sleep 1993;16:344-350. 33. Espie CA. The psychological treatment of insomnia. New York: Wiley; 1991. 34. Hauri P, Linde S. No more sleepless nights. New York: John Wiley; 1990. 35. Monroe LJ. Psychological and physiological differences between good and poor sleepers. J Abnorm Psychol 1967;72:255-264. 36. Torsvall L, Akerstedt T. Disturbed sleep while being on-call: an EEG study of ship’s engineers. Sleep 1988;11:35-38. 37. Guilleminault C, Eldridge F, Dement WC. Insomnia, narcolepsy, and sleep apneas. Bull Physiopathol Respir 1972;8:1127-1138. 38. Symonds CP. Nocturnal myoclonus. J Neurol Neurosurg Psychiatry 1953;16:166-171. 39. Moore-Ede MC, Czeisler CA, Richardson GS. Circadian timekeeping in health and disease, I: basic properties of circadian pacemakers. N Engl J Med 1983;309:469-476. 40. Moore-Ede MC, Czeisler CA, Richardson GS. Circadian timekeeping in health and disease, II: clinical implications of circadian rhythmicity. N Engl J Med 1983;309:530-536. 41. Bonnet M, Arand DL. Situational insomnia: in the situation or in the patient? Sleep (Suppl.) 2002;25:A32-A33. 42. Drake C, Richardson G, Roehrs T, et al. Vulnerability to stressrelated sleep disturbance and hyperarousal. Sleep 2004;27(2): 285-291. 43. Drake C, Jefferson C, Roehrs T, Roth T. Stress-related sleep disturbance and polysomnographic response to caffeine. Sleep Med 2006;7:567-572. 44. Bastien CH, Vallieres A, Morin CM. Precipitating factors of insomnia. Behav Sleep Med 2004;2;50-62. 45. Buysse DJ, Ancoli-Israel S, Edinger JD, et al. Recommendations for a standard research assessment of insomnia. Sleep 2006;29(9): 1155-1173. 46. Brodman K, Erdmann AJ Jr, Lorge I, et al. The Cornell Medical Index: an adjunct to medical interview. JAMA 1949;140:530-534. 47. Butcher JN, Dahlstrom WG, Graham JR, et al. MMPI-2: Minnesota Multiphasic Personality Inventory-2: manual for administration and scoring. Minneapolis: University of Minnesota Press; 1989. 48. Beck AT, Ward CH, Mendelson M, et al. An inventory for measuring depression. Arch Gen Psychiatry 1961;4:561-571.
49. Beck AT, Steer RA, Ball R, Ranieri W. Comparison of Beck Depression Inventories-IA and -II in psychiatric outpatients. J Pers Assess 1996;67:588-597. 50. Spielberger CD, Gorsuch RL, Lushene R, et al. The State-Trait Anxiety Inventory for Adults. Palo Alto, Calif: Mind Garden; 1983. 51. Morin CM. Insomnia: Psychological assessment and management. New York: Guilford Press; 1993. 52. Hauri PJ. Personal communication, 1985. 53. Morin CM, Espie CA. Insomnia: a clinical guide to assessment and treatment. New York: Kluwer Academic/Plenum Publishers; 2003. 54. Espie CA, Inglis SJ, Harvey L, Tessier S. Insomniacs’ attributions. psychometric properties of the Dysfunctional Beliefs and Attitudes about Sleep Scale and the Sleep Disturbance Questionnaire. J Psychosom Res 2000;48(2):141-148. 55. Edinger JD, Wohlgemuth WK. Psychometric comparisons of the standard and abbreviated DBAS-10 versions of the dysfunctional beliefs and attitudes about sleep questionnaire. Sleep Med 2001; 2(6):493-500. 56. Horne JA, Ostberg O. A self-assessment questionnaire to determine morningness-eveningness in human circadian rhythms. Int J Chronobiol 1976;4:97-110. 57. Patient-Reported Outcomes Measurement Information System. Available at: http://www.nihpromis.org/default.aspx. 58. Carney CE, Ancoli-Israel S, Buysse DJ, et al. An update from the Sleep Log Standardization Workgroup. Presented as part of a symposium at the Sleep 2008 meeting, Baltimore, June 2008. 59. Edinger JD, Bonnet MH, Bootzin RR, et al. Derivation of research diagnostic criteria for insomnia: report of an American Academy of Sleep Medicine Work Group. Sleep 2004;27(8):1567-1596. 60. First MB, Gibbon M, Spitzer RL, Williams JBW. Structured clinical interview for DSM-IV Axis I Disorders SCID I: clinician version, administration booklet. Washington, DC: American Psychiatric Press; 1997. 61. Buysse DJ, Reynolds CF, Monk TH, et al. The Pittsburgh Sleep Quality Index (PSQI): a new instrument for psychiatric research and practice. Psychiatry Res 1989;28:193-213. 62. Bastien CH, Vallieres A, Morin CM. Validation of the insomnia severity index as an outcome measure for insomnia research. Sleep Med 2001;2:297-307. 63. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. Application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol 1989;46:1121-1123. 64. Ware JE, Snow KK, Kosinski M. SF-36 Health Survey: manual and interpretation guide. Boston, MA: Health Institute, New England Medical Center; 1993. 65. Everitt DE, Avoran J. Clinical decision-making in the evaluation and treatment of insomnia. Am J Med 1990;89:357-362. 66. Carney CE, Edinger JD, Olsen MK, et al. Inter-rater reliability for insomnia diagnoses derived from the Duke Structured Interview for Sleep Disorders. Presented at Sleep 2008, meeting, Baltimore. 67. Chesson A, Hartse CW, McDowell A, et al. Practice parameters for the evaluation of chronic insomnia. Sleep 2000;23(2):1-5. 68. Schutte-Rodin S, Broch L, Buysse D, et al. Evaluation and management of chronic insomnia in adults: an American Academy of Sleep Medicine clinical guideline. J Clin Sleep Med 2008;4:487-504. 69. Frankel BL, Coursey RD, Buchbinder R, et al. Recorded and reported sleep in chronic primary insomnia. Arch Gen Psychiatry 1976;33:615-623.
CHAPTER 144 • Assessment Techniques for Insomnia 1645 70. McCall WV, Edinger JD. Subjective total insomnia: an example of sleep state misperception. Sleep 1992;15:71-73. 71. Agnew HW Jr, Webb WB, Williams RL. The first night effect: an EEG study of sleep. Psychophysiology 1966;2:263-266. 72. Hauri PJ, Olmstead EM. Reverse first night effect in insomnia. Sleep 1989;12:97-105. 73. Standards of Practice Committee of the American Academy of Sleep Medicine. Practice parameters for the evaluation of chronic insomnia. Sleep 2000;23:237-241. 74. Hauri PJ, Wisbey J. Wrist actigraphy in insomnia. Sleep 1992; 15:293-301. 75. Jean-Louis G, von Gizycki H, Zizi F, et al. Determination of sleep and wakefulness with the actigraph data analysis software (ADAS). Sleep 1996;19:739-743. 76. Sadeh A, Hauri PJ, Kripke D, et al. The role of actigraphy in the evaluation of sleep disorders. Sleep 1995;18:288-302. 77. Standards of Practice Committee of the American Sleep Disorders Association. Practice parameters for the use of actigraphy in the clinical assessment of sleep disorders. Sleep 1995;18:285-287. 78. Early C, Sun E, Chen C, et al. Iron relation to periodic leg movements and sleep disturbance in patients with the restless legs syndrome. Sleep 1998;21(Suppl.):142. 79. Spielman AJ, Anderson MW. The clinical interview and treatment planning as a guide to understanding the nature of insomnia: the CCNY insomnia interview. In: Chokroverty S, editor. Sleep disorders medicine: basic science, technical considerations, and clinical aspects, 2nd ed. Boston: Butterworth-Heinemann; 1998. p. 385-426. 80. Sateia MJ, Doghramji K, Hauri PJ, et al. Evaluation of chronic insomnia. Sleep 2000;23:243-308. 81. Spielman AJ, Saskin P, Thorpy MJ. Treatment of chronic insomnia by restriction of time in bed. Sleep 1987;10:45-56. 82. Hamilton M. A rating scale for depression. J Neurol Neurosurg Psychiatry 1960;23:56-62. 83. Beck AT, Epstein N, Brown G, et al. An inventory for measuring clinical anxiety. J Consult Clin Psychol 1988;56:893-897. 84. Zung WWK. A self-rating depression scale. Arch Gen Psychiatry 1965;12:63-70. 85. Derogatis LR. SCL-90-R: administration, scoring, and procedures manual. Baltimore: Clin Psychometrics Res; 1977. 86. McNair DM, Lorr M, Droppleman LF. EDITS manual for the Profile of Mood States. San Diego: Educational and Industrial Testing Service; 1981. 87. Roenneberg T, Wirz-Justice A, Merrow M. Life between clocks: daily temporal patterns of human chronotypes. J Biol Rhythms 2003;18(1):80-90. 88. Ree MJ, Harvey AG. Investigating safety behaviours in insomnia: the development of the Sleep-Related Behaviours Questionnaire (SRBQ). Behaviour Change 2004;21:26-36. 89. Nicassio PM, Mendlowitz DR, Fussell JJ, et al. The phenomenology of the pre-sleep state: the development of the pre-sleep arousal scale. Behav Res Ther 1985;23:263-271. 90. Espie CA, Brooks DN, Lindsay WR. An evaluation of tailored psychological treatment of insomnia. J Behav Ther Exp Psychiatry 1989;20:143-153. 91. Monk TH, Reynolds CF III, Kupfer DJ, et al. The Pittsburgh Sleep Diary. J Sleep Res 1994;3:111-120.
Neurologic Monitoring Techniques Beth A. Malow
Abstract Patients with nocturnal spells present a unique challenge to the sleep specialist and the sleep laboratory. Although standard polysomnography (PSG) provides valuable information about the stage of sleep from which spells emerge and the time of the spell relative to sleep onset, the characterization of these spells is enhanced by video and extended electroencephalogram (EEG; 12 or more channels, and sometimes 21 or more). Addition of video and an extended EEG to the standard PSG is essential for precise definition of nocturnal spells, including epileptic seizures, rapid eye movement (REM) sleep behavior disorder, and arousal disorders. The video component provides information on the behavioral and motor manifestations of the nocturnal spell. The EEG might show a rhythmic evolving discharge characteristic of an epileptic seizure, or it might show interictal epileptiform discharges that occur apart from epileptic seizures. Lack of an EEG change, however, does not exclude some
Nocturnal spells often present diagnostic problems in sleep medicine because the history alone might not provide sufficient information to differentiate among the various diagnostic possibilities. Standard polysomnography (PSG) is helpful in defining the state and stage of sleep from which such nocturnal spells emerge, but it has limitations in diagnosis because behavioral analysis often is not included and the number of channels devoted to electroencephalography (EEG) is limited. These shortcomings are especially pertinent to the evaluation of suspected nocturnal epileptic seizures, which are defined by behavioral and motor manifestations in addition to EEG criteria.1 Both behavioral and EEG analyses are critical for characterizing epileptic seizures and for distinguishing them from parasomnias. The behavioral and EEG manifestations of nocturnal spells caused by parasomnias, neurologic disorders, and psychiatric disorders can be characterized more precisely by combining standard PSG with video recordings and extensive (12 or more channels) EEG montages.2 This chapter emphasizes the methodology and indications for video-EEG PSG (VPSG) in the diagnosis of nocturnal events. The methodology and roles of routine EEG, shortterm continuous video-EEG monitoring (STM), longterm continuous video-EEG monitoring (LTM), and ambulatory monitoring are addressed.
METHODOLOGY Technical Aspects of Electroencephalography The EEG measures the difference in electrical potential between pairs of electrodes placed on the scalp. These signals, reflecting synchronous postsynaptic potentials in 1646
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145
types of epilepsy, particularly those of frontal lobe origin. The movement artifact usually associated with nocturnal seizures can also obscure the EEG. A stereotyped series of movements on the video is highly suggestive of epileptic seizures, even in the absence of EEG changes. Pitfalls in the interpretation of recorded events are common; the inexperienced interpreter might mistakenly identify an artifact as EEG activity characteristic of seizures or parasomnias. A clinician who is in doubt about an EEG-PSG pattern should consult a trained electroencephalographer. Apart from artifacts, many other normal physiologic variants may be mistaken for epileptic activity. Sophisticated digital video and EEG-PSG computer systems facilitate the acquisition, review, and storage of large quantities of data, with synchronization of behavioral manifestations and the EEG-PSG. Depending on the clinical situation, a daytime EEG, an ambulatory EEG, daytime short-term monitoring, 1 or 2 nights of polysomnography, or long-term (several days and nights) monitoring may be indicated.
large groups of neurons, are amplified and filtered to produce an analog or digital recording.3 The international 10-20 system of EEG electrode placement is customarily used, in which the 10-20 refers to 10% and 20% of the distances between standard cranial landmarks (Fig. 145-1).4,5 Each electrode site is identified with a letter representing the underlying region of the brain and with a number indicating a specific position above that region, with odd numbers indicating the left hemisphere and even numbers indicating the right hemisphere (e.g., T3 represents a left midtemporal electrode). Each recording channel is derived from the signals from a pair of electrodes, and several pairs of electrodes, or derivations, are combined to form a montage. Montages may be either referential or bipolar. In referential montages, one of the electrodes in each pair is connected to a common electrode (e.g., channel 1: Fp1-A1; channel 2: F7-A1; channel 3: T3-A1; channel 4: T5-A1; channel 5: O1-A1). In bipolar montages, there is no common electrode. Bipolar montages are usually arranged in a chain with the same electrode in adjacent derivations (e.g., channel 1: Fp1-F7; channel 2: F7-T3; channel 3: T3-T5; channel 4: T5-01). The EEG montages used in a combined EEG-PSG study depend on the clinical indication and the number of channels available for recording (Table 145-1). The channels suggested in this text are in addition to those recommended by the American Academy of Sleep Medicine (AASM) for the scoring of sleep stages.6 Physicians and technicians involved in the use of EEG monitoring techniques require a solid knowledge of the principles of EEG recording and interpretation. Additional information regarding EEG methodology is available in a standard EEG text.7
CHAPTER 145 • Neurologic Monitoring Techniques 1647
Table 145-1 Sample Attended Electroencephalographic Montages Nasion
NUMBER OF AVAILABLE CHANNELS
Fp2
Fp1 F7
F8 F4
F3
Left A1
T3
8
Fz
C3
Cz
C4
T4
Fp1-F7, F7-T3, T3-T5, T5-O1, Fp2-F8, F8-T4, T4-T6, T6-O2, F3-C3, F4-C4
12
Fp1-F7, F7-T3, T3-T5, T5-O1, Fp2-F8, F8-T4, T4-T6, T6-O2, F3-C3, C3-P3, F4-C4, C4-P4
14
Fp1-F7, F7-T3, T3-T5, T5-O1, Fp2-F8, F8-T4, T4-T6, T6-O2, F3-C3, C3-P3, P3-O1, F4-C4, C4-P4, P4-O2
16
Fp1-F7, F7-T3, T3-T5, T5-O1, Fp2-F8, F8-T4, T4-T6, T6-O2, Fp1-F3, F3-C3, C3-P3, P3-O1, Fp2-F4, F4-C4, C4-P4, P4-O2
18
Fp1-F7, F7-T3, T3-T5, T5-O1, Fp2-F8, F8-T4, T4-T6, T6-O2, Fp1-F3, F3-C3, C3-P3, P3-O1, Fp2-F4, F4-C4, C4-P4, P4-O2, Fz-Cz, Cz-Pz
24
Fp1-F7, F7-T3, T3-T5, T5-O1, Fp2-F8, F8-T4, T4-T6, T6-O2, Fp1-F3, F3-C3, C3-P3, P3-O1, Fp2-F4, F4-C4, C4-P4, P4-O2, Fz-Cz, Cz-Pz, T1-T3, T3-C3, C3-Cz, Cz-C4, C4-T4, T4-T2
Right A2
P6
T5
T6 O1
O2 Inion
Figure 145-1 Standard international 10-20 electrode placement: Electrodes are placed at 10% or 20% of the distances between standard cranial landmarks (From Keenan SA. Polysomnographic technique: an overview. In: Chokroverty S, editor. Sleep disorders medicine. Boston: Butterworth-Heinemann; 1994. p. 84).
Computerized digital EEG-PSG systems facilitate the review of large amounts of EEG-PSG data by displaying scoring and event information in a format that allows the user to, for example, click on the stage or event of interest and bring up the corresponding EEG-PSG. The recording may be viewed at a variety of display settings. Filters, sensitivities, and montages may be adjusted to characterize events of interest and to help distinguish abnormalities from artifacts or normal variants. For example, certain montages can more easily identify and distinguish artifacts from interictal epileptiform discharges (IEDs), defined as epileptic activity occurring between seizures. Digital EEG enhances the detection and review of IEDs by allowing for remontaging, changing the display settings that influence temporal resolution, and isolating specific channels for review (Fig. 145-2). For example, by altering the display settings, synchronous delta or theta activity characteristic of non–rapid eye movement (NREM) arousal disorders may be more easily distinguished from spike-wave activity or an evolving ictal (seizure) pattern characteristic of an epileptic seizure disorder. Several digital EEG-PSG systems share a common platform with epilepsy monitoring systems, allowing data obtained during a PSG to be analyzed by IED detection programs. Conversely, a study performed in the epilepsymonitoring unit can be enhanced via the addition of electrooculogram (EOG) and chin electromyogram (EMG) electrodes to score sleep and determine the stage of sleep that precedes a particular event. This can be diagnostic in the case of distinguishing dissociative events, which rarely
F7-T3, T3-T5, T5-O1, F8-T4, T4-T6, T6-O2, F3-C3, F4-C4
10
Pz P3
MONTAGE
occur during sleep,8 from epileptic seizures, which can occur during sleep or wakefulness. Daytime Electroencephalography Daytime EEG is used to look for IEDs, which support the diagnosis of a seizure disorder in many clinical settings.7 In addition to the electrodes listed earlier, central (Fz, Cz, Pz) and ear (A1, A2) electrodes are included. Nasopharyngeal electrodes, although used in the past, are not recommended because they are uncomfortable, are prone to artifact, and rarely provide additional information. The activating techniques of hyperventilation and intermittent photic stimulation are routinely performed and can bring out focal asymmetries or epileptiform activity. Although seizures are not uniformly recorded during a routine EEG, focal IEDs or generalized spike-and-wave discharges may be observed and can assist in the classification of an epileptic syndrome as partial or generalized. The location of IEDs, which can be determined with the use of an extended EEG montage, can clarify the nature of the epilepsy syndrome and its prognosis.9 For example, benign epilepsy of childhood with centrotemporal spikes has an excellent prognosis (Fig. 145-3). In contrast, some temporal lobe IEDs may be refractory to medical treatment, and the patients can become candidates for epilepsy surgery. Daytime studies performed while the patient is asleep for at least a portion of the recording increase the yield of finding abnormalities, because in many patients, IEDs are more common in drowsiness and NREM sleep. Stage N2 sleep is usually, but not always, recorded on the routine
Fp1-F7 F7-T3 T3-T5 T5-O1 Fp1-F3 F3-C3 C3-P3 P3-O1 Fp2-F4 F4-C4 C4-P4 P4-O2 Fp2-F8 F8-T4 T4-T6 T6-O2 LOC-A1 ROC-A1 Chin1-Chin3 C3-A1 C4-A1 O1-A1 O2-A1 LAT1-RAT1 Nasal-Oral Thor1-Thor2 Abd1-Abd2 Pes SaO2 A A1-EKG
Fp1-F7
F7-T3
T3-T5
T5-O1
Fp1-F3
F3-C3
C3-P3
P3-O1
B Figure 145-2 Use of different montages to enhance the review of interictal epileptiform discharges (IEDs). A, Left temporally dominant IEDs (arrows) on an extended EEG montage that are not apparent in the central-to-ear channels (asterisk). B, Digital EEG allows the interpreter to select the relevant left temporal and parasagittal channels for review. The arrows highlight IEDs with phase reversals (asterisks) at T3 and F3, indicating maximal negativity at these electrodes, which defines the approximate location of the epileptic region. Both are 30-second epochs. Calibration symbol at bottom right, 100 µV.
CHAPTER 145 • Neurologic Monitoring Techniques 1649
F7-Fp1 Fp1-Fp2 Fp2-F8 F7-F3 F3-Fz Fz-F4 F4-F8 A1-T3 T3-C3 C3-Cz Cz-C4 C4-T4 T4-A2 T5-P3 P3-Pz Pz-P4 P4-T6 T5-O1 O1-O2 O2-T6 Figure 145-3 Runs of interictal epileptiform discharges with a centrotemporal dominance in benign epilepsy of childhood with centrotemporal spikes. The bipolar montage readily demonstrates peak negativity at the C4 and T4 electrodes. Such localization is not possible with EEG montages commonly used with standard polysomnography (PSG). Calibration symbol, 500 µV, 1 sec. (From Malow BA. Sleep and epilepsy. Neurol Clin 1996;14:774.)
EEG, whereas stage N3 sleep and REM sleep are rarely recorded. When the routine EEG does not show IEDs and the physician has a high suspicion for seizures, a sleepdeprived EEG improves the yield of finding epileptiform activity, at least in part because sleep is more likely to be recorded. Analog EEG recordings use a variety of montages to display ongoing brain activity, whereas digital EEG recordings permit the viewing of a segment of EEG in a variety of montages and speeds, which can help distinguish an IED from an artifact. Video-Electroencephalography Polysomnography When the history does not allow the physician to diagnose nocturnal spells associated with complex movements and behavior, recording of the sleep-related event in question might allow definitive diagnosis. VPSG, which combines video recording with an extended EEG montage and with other standard PSG physiologic monitoring, is useful in characterizing unusual behavior and movements during
sleep. Diagnostic considerations for patients with complex actions at night can include epileptic seizures, NREM arousal disorders, REM sleep behavior disorder (RBD), rhythmic movement disorder, or psychiatric disorders such as panic disorder or dissociative disorder. Episodes associated with these disorders have specific clinical features as discussed in Chapters 92 and 94 to 96. Events recorded with VPSG are reviewed to characterize the motor and behavioral manifestations of the event and the EEG-PSG features, including the stage of sleep preceding the event, the time of the event relative to sleep onset, and EEG patterns occurring during the event or between events. Video recordings that are synchronized with digital EEG-PSG recordings allow review of the event in question by clicking on the epoch of interest. The time-locked video can then be reviewed second by second along with the EEG-PSG. Infrared cameras are useful for recording nighttime events. Movable cameras can be mounted in a patient’s room and display close-ups or full-body views.
1650 PART II / Section 19 • Methodology
Double cameras are useful for focusing on the face while simultaneously monitoring the body. During recorded events, the technologist should interact with the patient to test for level of consciousness and ability to perform commands. The stage of sleep from which the spells emerge and the time of the spell relative to sleep onset provide useful diagnostic information. For example, the actions accompanying the NREM arousal disorders arise from stage N3 or sometimes stage N2 sleep, usually in the first third of the sleep period (see Chapter 94), whereas those associated with RBD emerge from REM sleep, most commonly in the last third of the sleep period (see Chapter 95). Epileptic seizures are more common during NREM sleep than during REM sleep (see Chapter 92).10 Rhythmic movements associated with rhythmic movement disorder usually occur during sleep–wake transitions, and dissociative episodes emerge from wakefulness. Nocturnal panic attacks occur from NREM sleep, usually at the transition from Stage N2 to N3.11 Specific EEG patterns associated with nocturnal spells are discussed in the section Relative Indications, Advantages, Disadvantages, and Limitations. If complex partial seizures are a diagnostic consideration, the EEG montage should emphasize the use of electrodes placed over the temporal lobes (e.g., F7, T1, T3, T5). If benign childhood epilepsy with centrotemporal spikes is a consideration, the montage should include the parasagittal region (e.g., C3, C4). The specific montage that is used depends on the number of channels available for EEG. Sample montages for 8, 10, 12, 14, 16, 19, and 24 channels are shown in Table 145-1. The following montage of 16 electrodes in anterior-toposterior chains provides excellent coverage for suspected seizures: • Left temporal: Fp1-F7, F7-T3, T3-T5, and T5-O1 • Left parasagittal: Fp1-F3, F3-C3, C3-P3, and P3-O1 • Right parasagittal: Fp2-F4, F4-C4, C4-P4, and P4-O2 • Right temporal: Fp2-F8, F8-T4, T4-T6, and T6-O2. This montage allows the evaluation of interictal and ictal activity during sleep. Two additional anterior temporal electrodes, T1 and T2, may be added because they are particularly useful for detecting anterior temporal IEDs. In one study comparing abbreviated EEG montages with a standard 18-channel bipolar montage, seizures were more readily distinguished from arousal patterns using 7and 18-EEG channel montages as compared with 4-channel EEG records.12 Short-Term and Long-Term Monitoring When the history suggests frequent daytime spells or spells occurring during daytime naps, STM, a video-EEG recording typically performed in an EEG or sleep laboratory for 6 to 8 hours during the day, may be helpful. The value of such studies for assessing patients with strictly nocturnal spells, however, is limited. Occasionally, STM is useful if sleep attacks—spells of diminished responsiveness due to sleepiness—are included in the differential diagnosis of daytime spells. Unfortunately, one or two nights of monitoring in the sleep laboratory is not always sufficient to capture and characterize spells. LTM, an extension of STM that allows
continuous recordings for up to several weeks, is used mainly for patients with known or suspected seizures.13 For patients who are taking antiepileptic medications, these drugs may be tapered and discontinued during LTM; intermittent sleep deprivation also is commonly used to facilitate spells. Because frequent seizures or status epilepticus can occur in epileptic patients discontinuing medication, LTM is generally performed in a hospital setting, usually a specialized epilepsy-monitoring laboratory. Eye movement leads and chin electromyographic leads may be added to the standard EEG electrodes to stage sleep. Semiinvasive sphenoidal electrodes, placed in the subtemporal fossa to record from the inferior temporal region and adjacent areas of the inferior frontal lobe, are usually reserved for patients who have previously diagnosed epilepsy refractory to medication trials and who are undergoing evaluation for epilepsy surgery. These leads are generally not required when the goal of monitoring is to identify EEG activity consistent with seizures or parasomnias rather than to precisely characterize an epileptic focus. Even though sphenoidal electrodes can increase the number of IEDs recorded, the detection of IEDs from a sphenoidal electrode alone rarely occurs, particularly if ear, T1, and T2 electrodes are used.14 In addition, although ictal patterns from sphenoidal electrodes can appear earlier and be better developed than those from surface electrodes, EEG seizure patterns are generally evident in both surface and sphenoidal electrodes.15 Even if additional electrodes are used, the lack of scalp or sphenoidal ictal activity during a clinical event does not exclude a seizure, particularly if awareness is preserved during the clinical event (e.g., a simple partial seizure) or if the event originates in the frontal lobe. Ictal activity may be apparent only with intracranial electrodes, such as depth electrodes that penetrate the brain parenchyma, subdural strips, and subdural grids.16 These invasive electrodes, which are rarely used in the diagnosis of nocturnal spells because of the risks of infection and hemorrhage, are generally reserved for patients who require localization of epileptic foci before surgical resection and in whom scalp recordings are inconclusive. If an ictal pattern is not recorded but clinical seizures are highly suspected based on the history and stereotyped behavioral spells recorded on videotape, an empirical trial of an antiepileptic medication may be appropriate. Ambulatory Monitoring Ambulatory monitoring combines the extended recording time of VPSG with the convenience of recording in a patient’s home. Several commercial products allow patients to go home with 12 or more channels of EEG electrodes and a recording device, which sometimes includes video monitoring. Ambulatory recording systems may use analog or digital recorders. Patients and their bed partners are instructed to keep an activity log to document events. The indications for ambulatory monitoring in the differential diagnosis of nocturnal events are not established. This monitoring technique appears promising for evaluating interictal epileptiform activity during sleep. Depending on the sophistication of the video recordings, ambulatory monitoring can identify some cases of epileptic
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seizures, NREM arousal disorders, RBD, rhythmic movement disorder, panic disorder, and dissociative disorder.
ARTIFACTS AND PITFALLS Artifacts, which are common during sleep-related spells recorded with any of these modalities, must be distinguished from interictal and ictal epileptiform activity and from EEG activity associated with parasomnias. Although artifacts can obscure the EEG and make diagnosis more difficult, they are sometimes helpful; for example, head or body rocking artifact may be diagnostic of rhythmic movement disorder, and rhythmic myogenic artifact may support bruxism (Fig. 145-4). Other examples of frequently encountered artifacts include those caused by head tremor, eye movements, and tongue movements (glossokinetic artifact). Associated rhythmic activities can resemble ictal EEG patterns. Pitfalls in interpreting recorded events are common; the inexperienced interpreter can mistakenly identify an artifact as EEG activity characteristic of seizures or parasomnias. When the clinician is in doubt about an EEG-PSG pattern, a trained electroencephalographer should be consulted. Apart from artifacts, many other normal physiologic variants may be mistaken for epileptic activity; these include positive occipital sharp transients of sleep (see Fig. 145-4); frequent and sharply contoured vertex waves, particularly in young patients (Fig. 145-5); sawtooth waves; benign epileptiform transients of sleep; wicket spikes; and rhythmic temporal theta of drowsiness.17
RELATIVE INDICATIONS, ADVANTAGES, DISADVANTAGES, AND LIMITATIONS Although VPSG and other neurologic monitoring techniques can be useful in diagnosing nocturnal events, the incremental cost of these techniques over standard PSG necessitates that specific indications be met. Unfortunately, no standards exist for determining when to choose a specific monitoring technique, and the reliability and validity of the monitoring techniques described here have not been formally studied. Consensus guidelines for interpretation have not been developed. In addition, the role of ambulatory EEG in monitoring parasomnias is not well defined. The indications, advantages, disadvantages, and limitations outlined here are based on my experiences and the experiences of others. Video-Electroencephalography Polysomnography Indications for VPSG include suspected sleep-related epileptic seizures, suspected NREM arousal disorders, RBD, or suspected dissociative disorder. Suspected Sleep-Related Epileptic Seizures Although some epileptic seizures can be diagnosed on the basis of history (e.g., generalized tonic–clonic activity witnessed by a reliable observer), most events occurring frequently and suspected to be complex partial seizures are best confirmed with VPSG monitoring, especially if they
F7-T3 T3-T5 T5-O1 F3-C3 C3-P3 P3-O1 F4-C4 C4-P4 P4-O2 P8-T4 T4-T6 T6-O2 LAT RAT EKG
Chewing movements
Moving jaw
100 µV 3 seconds
L EOG-A2 R EOG-A1 Chin EMG C3-A2 N/O Air Flow EfforT Figure 145-4 Artifacts resembling interictal epileptiform activity. Chewing movements produced by bruxism cause rhythmic activity with superimposed myogenic artifact in the EEG channels, bearing a superficial resemblance to generalized spike-wave discharges. The arrows identify posterior occipital sharp transients of sleep (POSTS), normal features of NREM stage 1 sleep that appear sharply contoured and may be mistaken for pathologic occipital sharp waves at the standard polysomnograph (PSG) paper speed of 10 mm/sec.
1652 PART II / Section 19 • Methodology
Fp1-F7
F7-T3 T3-T5 T5-O1 Fp1-F3 F3-C3 C3-P3 P3-O1 Fp2-F4 F4-C4 C4-P4 P4-O2 Fp2-F8
F8-T4 T4-T6 T6-O2 LAT1-RAT1 Nasal-Oral Thor1-Thor2 Abd1-Abd2 LOC-A1 ROC-A2 Chin1-Chin2 C3-A2 C4-A1 O1-A2 O2-A1 A2-EKG1 SaO2 Figure 145-5 Sharply contoured vertex waves in a 6-year-old child. Although these physiologic waves resemble abnormal epileptiform activity, their morphology and distribution distinguish them from pathologic discharges. Compare with Figure 145-2. Thirtysecond epoch. Calibration symbol at bottom right, 100 µV.
include the features of thrashing, kicking, hyperventilating, head rocking, screaming, or subtle arousals from sleep observed in parasomnias or dissociative disorders. The advantage of VPSG over conventional PSG or EEG without video in suspected epileptic seizures is the ability to analyze stereotyped activities, characteristic of epileptic seizures, in association with ictal EEG activity. Figure 145-6 shows a recording with an extended EEG
montage of an epileptic seizure, illustrating a clear evolution of activity. Apart from recording epileptic seizures, PSG with an expanded EEG montage allows sampling of IEDs throughout the night. The IEDs associated with partial epilepsy are usually more prevalent in sleep, especially delta NREM sleep, than in wakefulness.18,19 Therefore, occasionally, IEDs missed on a routine daytime EEG are detected on an overnight recording.20
Case 1 A 34-year-old woman with a remote history of daytime complex partial seizures presented with nightly nocturnal spells. Her husband reported that within 45 minutes of falling asleep she aroused, sat up, appeared frightened, breathed rapidly, looked around the room with a blank, wide-eyed stare, and then returned to sleep. These episodes were stereotyped and lasted less than 1 minute. She responded almost immediately and did not recall the episodes. The differential diagnosis includes an NREM arousal disorder, dissociative episodes, or epileptic seizures. Nocturnal panic disorder is unlikely because she does not recall the episodes. RBD is possible, but it would be unusual in a young woman, usually does not cause stereotyped behavior, and rarely occurs soon after sleep onset.
Because the history was insufficient for diagnosis and because the spells were occurring nightly, VPSG was performed, during which the patient had several stereotyped spells occurring from all stages of NREM sleep. These spells were associated with ictal discharges beginning over the right temporal lobe and consisting of rhythmic theta activity that increased in frequency and decreased in amplitude. She was treated for complex partial seizures with carbamazepine, and the spells resolved. If this patient had been on antiepileptic medication chronically and had spells that were less frequent (e.g., once a week), an alternative approach would have been LTM with tapering of medications to promote occurrence of seizures.
CHAPTER 145 • Neurologic Monitoring Techniques 1653
F7-T3 T3-T5 T5-O1 F3-C3 C3-P3 P3-O1 F4-C4 C4-P4 P4-O2 F8-T4 T4-T6 T6-O2
100 µV 3 seconds
Chin EMG L EOG-A2
A
R EOG-A1
F7-T3 T3-T5 T5-O1 F3-C3 C3-P3 P3-O1 F4-C4 C4-P4 P4-O2 F8-T4 T4-T6 T6-O2
100 1second µv
Chin EMG L EOG-A2
B
R EOG-A1
Figure 145-6 Partial seizure beginning during NREM sleep. A, recorded at 10 mm/sec paper speed. Clinically, the seizure began with an abrupt arousal, followed by turning of head and eyes to the left and movements of the arms beneath the bedclothes. On EEG, an initial reduction in voltage is followed by a progressive increase in the amplitude of the ictal discharge over the left hemisphere, with spread to the right hemisphere derivations. The underlined activity from the F3-C3 derivation appears to be muscle artifact; however, in B, at 30 mm/sec paper speed, it is clear that the same underlined segment is the initial focal surface representation of the ictal discharge. Additional polysomnographic measures recorded on channels 16 to 21 are not shown. (Modified from Aldrich MS, Jahnke B. Diagnostic value of video-EEG polysomnography. Neurology 1991;41:1060-1066.)
Suspected NREM Arousal Disorders Although confusional arousals, sleepwalking, and sleep terrors often can be diagnosed on the basis of history, VPSG is indicated if behavioral features are atypical or stereotyped, multiple nightly episodes occur, onset is in adulthood, or spells do not respond to a trial of medications. An advantage of VPSG in the diagnosis of NREM arousal disorders is the combination of video to characterize the event of interest, sleep scoring channels to deter-
mine the stage of sleep involved, and an extended EEG montage to exclude ictal EEG activity characteristic of epileptic seizures. The VPSG can capture a confusional arousal, night terror, or sleepwalking episode arising out of delta NREM (stage N3 sleep) accompanied by synchronous delta activity (Fig. 145-7). Alternatively, the VPSG recorded during an NREM arousal event might show asynchronous delta or theta activity, synchronous theta activity, a drowsy
1654 PART II / Section 19 • Methodology
F7-T3 T3-T5 T5-O1 F3-C3 C3-P3 P3-O1 F4-C4 C4-P4 P4-O2 P8-T4 T4-T6 T6-O2 LAT RAT
100 µV 3 seconds
EKG L EOG-A2 R EOG-A1 Chin EMG C3-A2 N/O Airflow Effort
Figure 145-7 Arousal from delta NREM sleep in a child with an NREM arousal disorder. Note synchronous delta activity during arousal from delta NREM sleep, associated with a tonic increase in chin electromyogram (EMG) and left anterior tibialis (LAT) and right anterior tibialis (RAT) EEG. In contrast to the EEG of an epileptic seizure, the delta activity does not evolve in amplitude or frequency.
pattern, or nonreactive alpha activity. Apart from clinical events, the EEG can show synchronous delta during arousals from N3 sleep, a nonspecific finding that is more common in patients with arousal disorders than in healthy subjects.21 Case 2 A 4-year-old girl had near-nightly episodes of screaming loudly about 1 hour after falling asleep. During these episodes, her parents found her agitated and inconsolable. On rare occasions, she got out of bed and wandered out of her room. She was amnestic for these spells. An older sibling had had similar spells. Because the history is compelling for night terrors, evaluation with VPSG is not necessary. If any atypical features were present (e.g., automatisms or stereotyped behavior, multiple nightly episodes, or onset in adulthood) or if symptoms did not respond to treatment, a VPSG would be warranted.
Suspected REM Sleep Behavior Disorder Although the definitive diagnosis of RBD may be suspected based on the history, definitive diagnosis requires capturing a behavioral event on a video recording or demonstrating abnormal muscle tone or excessive limb movements during REM sleep (see Chapter 94). The advantage of VPSG is that video is combined with sleep staging to
identify REM, and an extended EEG montage is used to exclude ictal EEG activity. Suspected Dissociative Disorder Dissociative episodes and other psychogenic spells occur during wakefulness, although the patient might appear to be asleep and might believe that he or she is asleep.8 Because the manifestations of dissociative episodes can be quite bizarre and include thrashing, screaming, or bicycling movements, it is often impossible to distinguish these spells from epileptic seizures or parasomnias based on the history alone. When nocturnal psychogenic episodes are suspected, VPSG is advantageous in documenting the behavior of the patient, the presence of waking background EEG preceding the onset of the spells, and the absence of ictal EEG activity. The major disadvantage of VPSG in the evaluation of suspected epileptic seizures, parasomnias, and dissociative disorders is the cost of the study. Additional technologist time is needed to place an extended EEG montage and to continuously observe patients throughout the study. In addition, physicians must review each spell to assess behavior and EEG patterns. The VPSG also has limitations. The EEG recorded during a spell might not demonstrate an abnormality. Because epileptic seizures can lack surface EEG correlates, the absence of surface ictal EEG activity does not ensure that an epileptic seizure has not occurred. In addition, it can be difficult to differentiate an ictal EEG seizure pattern
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(which consists of rhythmic activity that evolves in frequency and amplitude) from the synchronous delta or theta activity or diffuse alpha activity occurring during an NREM arousal disorder. The best-developed portion of the ictal EEG pattern may be rhythmic delta or theta without a clear evolution, seizures can have bilateral onsets, seizures can arise from delta NREM sleep, and muscle or movement artifact can obscure the EEG. Two consecutive nights of VPSG are often scheduled so if no events are captured on the first night, the second night is available for study. Case 3 A 32-year-old man developed spells of unresponsiveness associated with asynchronous jerking movements of all four extremities for up to 30 minutes. These spells occurred nightly during sleep and rarely during the day. When they occurred during the day, he recalled portions of the spells and stated that he could hear people around him but that he could not respond. His wife could shake him out of the spells, and then he would regain full alertness. Based on the history of prolonged spells with bilateral extremity jerking and preserved consciousness, a dissociative episode was likely, although occasionally, epileptic seizures, especially of frontal lobe origin, manifest with bilateral jerking movements of the extremities and rapid return to full alertness. Depending on the relative frequency of the nocturnal and daytime spells, VPSG, STM, or LTM may be appropriate. In this case, because of the relative frequency of nocturnal spells, VPSG was performed. It documented an awake background preceding and during the spell, with an absence of ictal EEG activity, characteristic of a dissociative disorder. After psychiatric evaluation and treatment, the frequency of the spells decreased.
Daytime Electroencephalography The advantage of daytime EEG over VPSG, standard PSG, or any of the other monitoring techniques is its brief recording time and low cost. The disadvantage is that spells, particularly sleep-related spells, are rarely captured. When the history is highly suggestive of epileptic seizures, a routine EEG can demonstrate epileptic activity as supportive evidence of epilepsy. However, IEDs are not the equivalent of epileptic seizures and may be present in patients without epilepsy, such as occurs in relatives of patients with benign childhood epilepsy with centrotemporal spikes. Conversely, patients with epilepsy might not have IEDs during EEG recordings. In addition, patients with epilepsy can have coexisting parasomnias. Therefore, in the absence of a compelling history, the occurrence of abnormal interictal epileptiform activity should not be used by itself to definitively diagnose nocturnal spells as epileptic seizures. Short-Term and Long-Term Monitoring The advantages of STM and LTM over routine EEG are a longer recording time and simultaneous video monitoring. In patients with exclusively sleep-related spells, VPSG
is preferred over STM because the recording is performed during sleep. In patients with a mixture of daytime and sleep-related spells, STM is sometimes appropriate. LTM is an alternative in patients in whom antiepileptic medication taper or discontinuation is planned. Medication taper or discontinuation is especially useful in facilitating seizure activity in epileptic patients with infrequent spells (e.g., once a week or less). The disadvantages of LTM are the cost of inpatient hospitalization and the need for a specialized epilepsy-monitoring laboratory. The limitations of LTM are similar to those of PSG in that spells might lack EEG correlates or might not occur even over many days of monitoring. Ambulatory Monitoring Outpatient monitoring of sleep has been employed to manage patients and to perform research studies.22 The advantage of ambulatory monitoring is the convenience of recording in a patient’s home and the lack of need for continuous monitoring by a technologist. Cost varies, but it is usually lower than that of a recording in a sleep laboratory. A major disadvantage of ambulatory monitoring relates to the fidelity of the recording in the absence of a technologist. If electrodes become detached, ground wires break, or conductive media become dry during the study, adjustments cannot be made. In addition, most systems use a reduced number of channels, thereby limiting the information provided, although technologic advances should increase the capability for expanded montages. Furthermore, in contrast to the other monitoring techniques, the patient is not under constant observation and a technologist is not present. Consequently, interactions with the patient, which are critical for evaluating the level of consciousness, are not possible, and the interpretation of rhythmic activities that resemble ictal discharges may be difficult in the absence of an assessment of behavior and consciousness. The addition of synchronized video recordings to ambulatory monitoring has potential for facilitating correlation between EEG activity and clinical events.
❖ Clinical Pearl The clinician should consider performing video-EEG in suspected cases of nocturnal seizures and parasomnias such as REM sleep behavior disorder or NREM arousal disorders. The video may be as helpful as the EEG in documenting stereotyped behavior typical of epileptic seizures.
REFERENCES 1. Commission on Classification and Terminology of the International League against epilepsy: proposal for revised clinical and electrographic classification of epileptic seizures. Epilepsia 1981;22: 489-501. 2. Aldrich MS, Jahnke B. Diagnostic value of video-EEG polysomnography. Neurology 1991;41:1060-1066. 3. Epstein CM. Technical aspects of EEG: an overview. In: Wyllie E, editor. The treatment of epilepsy: principles and practices. Philadelphia: Lea & Febiger; 1993. p. 202-210. 4. Jasper H. The 10-20 electrode system of the International Federation. Electroencephalogr Clin Neurophysiol 1958;10:370-375.
1656 PART II / Section 19 • Methodology 5. Keenan SA. Polysomnographic technique: an overview. In: Chokroverty S, editor. Sleep disorders medicine. 2nd ed. Boston: Butterworth-Heinemann; 1999. p. 151-169. 6. Iber C, Ancoli-Israel S, Chesson A Jr, Quan SM. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. Westchester, IL: American Academy of Sleep Medicine; 2007. 7. Ebersole JS, Pedley TA. Current practice of clinical electroencephalography. 3rd ed. Philadelphia: Lippincott Williams & Wilkins; 2003. 8. Thacker K, Devinsky O, Perrine K, et al. Nonepileptic seizures during apparent sleep. Ann Neurol 1993;33:414-418. 9. Burgess RC, Iwasaki M, Nair D. Localization and field determination in electroencephalography and magnetoencepalography. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. Philadelphia: Lippincott Williams & Wilkins; 2006. p. 141-168. 10. Malow B. Sleep and epilepsy. Neurol Clin 2005;23(4):1127-1147. 11. Mellman T, Uhde T. Electroencephalographic sleep in panic disorder. Arch Gen Psychiatry 1989;46:178-184. 12. Foldvary N, Caruso AC, Mascha E, et al. Identifying montages that best detect electrographic seizure activity during polysomnography. Sleep 2000;23:211-229. 13. Cascino GD. Recognition of potential surgical candidates and videoelectroencephalographic evaluation. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. Philadelphia: Lippincott Williams & Wilkins; 2006. p. 993-1008.
14. Sperling MR, Engel J Jr. Sphenoidal electrodes. J Clin Neurophysiol 1986;3:67-73. 15. King DW, So EL, Marcus R, et al. Techniques and applications of sphenoidal recording. J Clin Neurophysiol 1986;3:51-65. 16. Benbadis SR, Wyllie E, Bingaman WE. Intracranial electroencephalography and localization studies. In: Wyllie E, editor. The treatment of epilepsy: principles and practice. Philadelphia: Lippincott Williams & Wilkins; 2006. p. 1059-1068. 17. Drury I. Epileptiform patterns of children. J Clin Neurophysiol 1989;6:1-39. 18. Sammaritano M, Gigli GL, Gotman J. Interictal spiking during wakefulness and sleep and the localization of foci in temporal lobe epilepsy. Neurology 1991;41:290-297. 19. Malow BA, Lin X, Kushwaha R, et al. Interictal spiking increases with sleep depth in temporal lobe epilepsy. Epilepsia 1998;39: 1309-1316. 20. Malow BA, Selwa LM, Ross DA, et al. Lateralizing value of interictal spikes on overnight sleep-EEG studies in temporal lobe epilepsy. Epilepsia 1999;40:1587-1592. 21. Blatt I, Peled R, Gadoth N, et al. The value of sleep recording in evaluating somnambulism in young adults. Electroencephalogr Clin Neurophysiol 1991;78:407-412. 22. Romigi A, Izzi F, Marciani MG, et al. Pregabalin as add-on therapy induces REM sleep enhancement in partial epilepsy: a polysomnographic study. Eur J Neurol 2009;16:70-75.
Chronobiologic Monitoring Techniques John H. Herman
Abstract This chapter serves as an introduction to fundamental methodologies in circadian rhythm research. Exciting advances have occurred in techniques for measuring circadian rhythms. We are on the threshold of being able to measure circadian rhythm period length from saliva gathered from a subject or patient; now able to measure circadian rhythm period length, phase, and amplitude from genes extracted from a subject or patient’s forearm. These are remarkable advances considering that the earliest studies of circadian rhythm properties required that the subject live in a cave for several weeks (and the results were grossly inaccurate). Although methods can be described to measure the circadian rhythm properties of
BASIC CONCEPTS AND TERMINOLOGY The purpose of chronobiological monitoring techniques in humans is to measure biological and behavioral properties of circadian rhythms, to better understand normal and abnormal clocks that control human alertness and sleepiness. Chronobiology research is based on the assumption that a given organism contains within it a core mechanism or clock for generating rhythmic expression of physiologic parameters. The fluctuations in any biological or behavioral parameter that display an approximately 24-hour periodicity are assumed to be the direct or indirect consequence of an underlying pacemaker that has its own inherent and autonomous periodicity. The internal clock has a variety of properties that are indirectly studied in circadian rhythm research by examining output variables. These include amplitude, or the quantity of change in a parameter that occurs from apogee to nadir by measuring variables such as temperature, cortisol, or cognitive problem solving; period length (or tau), or the temporal duration of one complete circadian cycle under free-running conditions; phase, or the relation of the internal clock to the environment, such as sunrise and morning awakening; rate of change, or the rapidity with which a circadian parameter switches from its active to dormant or dormant to active modes; and the duration of the active period relative to the duration of the dormant period. Chronobiological techniques have evolved to measure each of these variables, how they may be manipulated, and how they are interrelated. The process by which the internal clock stays in synchrony with the environment is called entrainment. Stimuli, such as light, that bring about entrainment are called zeitgebers. The circadian mechanism is always subject to the influences of masking. Masking is the ability of an external variable, such as light, sound, or physical activity, to alter a behavioral or physiologic parameter without affecting the core pacemaker.
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single-celled organisms, worms, flies, or mammalian organs, this chapter concentrates exclusively on methodologies applicable to mammalian and, most specifically, human research. This chapter examines controversies and unresolved issues, and critically evaluates varying chronobiological protocols. Major advances include standardized measurement of human circadian period length from melatonin and the wider dissemination of less invasive and more-standardized kits for measuring salivary melatonin. A melatonin phaseresponse curve similar to the well-accepted phase-response curve to light has been established. We now also have the capacity to estimate circadian rhythms from genes extracted from human fibroblast cells, leukocytes, or blood cells.
The distinction between entrainment and masking is not clearly defined. Exposure to daily sunlight, for example, entrains us to our local time zone and masks our internal clock from expressing its endogenous rhythm. In animals, masking influences may be removed by placing the animal in continuous light or dark conditions. As simple and straightforward as it would seem to be to measure the period length of the human circadian rhythm, the field of circadian rhythms research has undergone continual upheaval as methodologic errors have been repeatedly revealed and new paradigms designed to correct them. In humans, for example, there have been continued corrections of the period length of the free-running circadian rhythm length, or period, which is now estimated at slightly greater than 24 hours, 24.18 hours being the most recent value.1 In addition to a core pacemaker, each circadian system has input and output components. Input components are principally responsive to photic information but respond to a variety of stimuli, each of which is manipulated in circadian studies to examine the effect on output variables such as the sleep-wake cycle, temperature, or behaviors such as reaction time or problem-solving ability.
METHODOLOGIC QUESTIONS IN THE FIELD OF CIRCADIAN RHYTHMS During the preceding 5 decades, various estimates have placed the human circadian period length anywhere from 13 to 65 hours.2 Also, greater interindividual inconstancy in circadian variables in humans had been observed than that observed in other mammals. These findings showed a disparity between humans and nonhuman mammals, in which circadian rhythms are remarkably stable from day to day. In humans, there have been continued corrections of the period length of the circadian rhythm of activity, which has been most recently estimated at slightly greater 1657
1658 PART II / Section 19 • Methodology
than 24 hours, with a precision not that different from our mammalian relatives. Disagreements continue over which stimuli are capable of acting as zeitgebers to entrain or shift circadian rhythms. Initially, only bright light was considered to be capable of shifting the timing of circadian rhythms.3 Subsequently, light of moderate intensity was described as being capable of shifting circadian rhythms,4 and, most recently, studies now maintain that ordinary room light is capable of inducing a circadian shift.5,6 Some authors have claimed that extraocular light is capable of influencing circadian rhythms. One study demonstrated that behind-the-knee (popliteal region) bright light is capable of inducing shifts in circadian timing,7 but there have been multiple failures to replicate this finding.8-11 As chronobiology research progressed, a series of modifications of experimental design successively eliminated some masking artifacts and external zeitgebers that previously introduced artifact.1 The field has also been inundated by controversy over what constitutes a zeitgeber, or a stimulus capable of entraining a circadian rhythm. There is evidence that nonphotic stimuli are capable of entraining individuals.12 Exercise,13,14 social activity,15 feeding schedule,16 ambient temperature,17 napping in darkness,18 administration of melatonin,19 and knowledge of time of day or night20 each has the capacity to entrain human and nonhuman subjects. Some studies suggest a major role for such nonvisual zeitgebers,12 whereas other studies imply a more modest role.21 The extent to which melatonin is capable of shifting circadian rhythms was controversial until recently.22 Another area of research involves separating behavioral and biological properties of circadian rhythms from other physiologic processes. Many behavioral and biological phenomena are influenced by the sleep-wake cycle, or the duration of prior wakefulness. This is known as the homeostatic model, which describes an increasing pressure to sleep with increased duration of wakefulness and a decreased pressure to sleep with increased duration of sleep.23 Circadian rhythm studies must separate variance in a biological or behavioral parameter into homeostatic and circadian components; that is, they must identify what portion of the parameter’s variance is circadian and what portion is homeostatic.24,25 Neither the circadian nor the homeostatic models can explain in a compelling manner why humans are most wide awake in the hour or two preceding sleep and sleepiest in the hour after morning awakening. An additional area of continued controversy is what biological metric is best used to approximate the properties of the underlying core pacemaker, such as period length. Core body temperature24 and melatonin26 secretory profiles have been used in most studies. Some research uses dim-light melatonin onset as the marker of the beginning of a new circadian cycle, others use dim-light melatonin offset,26 and many use the temperature nadir. However, there is no obvious point that can be identified as the minimum of temperature or the onset of melatonin secretion. Temperature fluctuates from moment to moment, and the minimum or maximum must be extracted mathematically. Melatonin rises gradually after sunset, and an arbitrary level must be selected to denote onset or offset. In addition, it must be emphasized that extracting
circadian rhythm data relies on mathematical criteria and data analytic techniques selected in each experimental protocol.1 The amount of information uncovered in the past few decades in the field of circadian rhythm research has been truly astounding and includes the identification of basic anatomy, novel photoreceptors, and genetic mechanisms. The field has not accepted specific definitions in the areas of contention listed previously, nor has it accepted a single chronobiological monitoring technique as being the gold standard. Various studies using different experimental paradigms have contributed to the turbulence in this field. This chapter briefly reviews the various paradigms recently used in circadian rhythm research and discusses the strengths and weaknesses of each. This chapter does not present an in-depth description of the details of each model, but the reader is directed to a few key references in which a fuller exposition is offered.
PARADIGMS Fixed Light-Dark Schedules, Double Plotted The most common model for animal studies of circadian variables and activity schedule consists of placing the animal in a cage with a running wheel and subjecting the animal to a fixed schedule of light and dark. The running wheel’s turns are counted continuously. Typically, the animal’s running behavior on the wheel is plotted as a vertical or horizontal line per unit time, or wheel turns per unit time. These counts are plotted successively for 24 hours, yielding a visual representation of when and how much the animal ran that day. Successive days are stacked, enabling the reader to visually appreciate changes in the timing of activity that occurred during the experiment. The entire plot is duplicated side by side, called double plotting, because seeing the image next to itself enables the reader to appreciate what happened in the experiment more readily. For example, if the animal’s principal expression of wheel-running activity drifts from before to after midnight, double plotting allows the reader to more easily follow the continuity of changed running wheel times. Drinking or feeding may be plotted in the same manner. Protocols are labeled as LL (constant light), LD (fixed light-dark schedule, most commonly 12 hours light and 12 hours dark), or DD (constant darkness). Constant dim light is sometimes used in such protocols, or light dim enough to prevent suppression of the rat’s or hamster’s secretion of melatonin. In some studies the LD period length may be longer than or shorter than 24 hours, and as short as 1 hour in some studies. The DD paradigm has been successful in demonstrating the remarkable consistency of a given species’ free-running activity rhythm in constant darkness or dim light, successfully elucidating the period length of its biological clock.1 Often, the timing of light and dark are abruptly changed to measure the animal’s reaction, which can take several days to adapt. Such paradigms are at the core of much genetic research, in which normal (wild-type) animals (+/+) are compared with heterozygous (+/−, −/+)
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Circadian phase (Melatonin midpoint = 22 h) Figure 146-1 Accurately identifying the effect that light and melatonin have on advancing or delaying circadian timing is at the core of much circadian rhythm research. The magnitude of the phase advances (falling asleep and awakening earlier, represented by positive numbers) and delays (falling asleep and awakening later, represented by negative numbers) are plotted against the center of the period of light exposure relative to the core body temperature minimum at 0 h. The filled circles represent data from plasma melatonin, and the open circle represents data from salivary melatonin in one subject from whom blood samples were not acquired. The solid curve is a harmonic function fitted through all of the data points. Light’s phase-delaying effect increases as it approaches the temperature minimum, then it flip-flops in the 6-hour period surrounding the temperature minimum to a maximum phase-advancing effect 6 hours after the temperature minimum. (From Khalsa SB, Jewett ME, Cajochen C, Czeisler CA. A phase response curve to single bright light pulses in human subjects. J Physiol 2003;549(Pt 3):945-52.)
or homozygous (−/−) knockouts. Studies reveal genetic phenotypes (behavioral expression) because knockout animals display altered periodicity, diminished rhythmicity, or lack of any circadian rhythm in running, feeding, or drinking behavior. The obvious strength of the fixed light-dark schedule with activity monitoring is its ability to accurately and economically measure an animal’s rest-activity schedule. Alterations in rest-activity schedules after genetic knockouts have become the basis for a standard genotype– phenotype model. Weaknesses of this design include its inability to examine complex interactions that would occur in more natural circumstances that could have an impact on the circadian system. If only light, dark, or light versus dark are studied, then all effects appear to be a function of the animal’s illumination schedule. The paradigm is subject to overly simple interpretation, the implications of which are discussed later. Entrained 24-Hour Studies In entrained 24-hour studies, subjects live in laboratory conditions with constant bedtime, wakeup time, meal time, and timed activities. Subjects are aware of time of day and are not isolated from normal zeitgebers such as light from windows. This protocol is used to study biological or behavioral parameters such as hormone secretory profiles or cognitive processes under constant conditions. Often, indwelling catheters with recurrent blood draws are used in such studies.
Phase-Shifting Protocols One of the most experimentally robust findings in the area of circadian rhythm research is the capacity of zeitgebers such as bright light to change the time of day at which the circadian system switches from its active or day mode to its dormant or night mode. This is referred to as a phase shift. It is similar to jet lag or shift work in the real world. Many studies have examined the capacity of light of varying intensities and durations to alter the timing of sleep, melatonin secretion, or the temperature nadir. These studies share in common a baseline in which environmental light is controlled but typically is similar to the timing of natural environmental light. Often the baseline consists of dim light (ranging from about 70 lux, equivalent to romantic restaurant lighting, to as low as 1.5 lux, similar to the light from a candle) in different studies. In the experimental condition, light is then delivered to the subject in what would normally be the dark or night portion of the circadian rhythm.27 Light is delivered for the same duration but at a different time during this experimental condition for 1 or several days. In some studies there is then a subsequent condition in which the subject is in constant dim light or in a constant routine (described later). Circadian variables such as wheel running in rodents and hamsters, the timing of sleep, or the timing of melatonin secretion are monitored during each condition.1-3 The magnitude of the change in a circadian variable after the altered timing of light is measured. A phase response curve (see Fig. 146-1) shows the magnitude of response to light exposure (typically 1 to 3 hours) at different times throughout the circadian cycle in changing the timing of a circadian output variable.28 Most studies show circadian rhythm shifts in response to light occurring only if the light is delivered at specific times, typically at or near normal hours of darkness, and indicate that mammals are not responsive to bright light administered during normal hours of daylight.29 Other studies claim there is no dead zone and that bright light delivered at any hour, including normal daylight hours, has a phase-shifting effect.30 Time-Isolation Protocols Animals may be kept in total darkness or in light dim enough to have no effect on their circadian timing mechanism. Humans have typically been isolated in an environment free of time cues, such as an underground facility or an internal suite of rooms in an enclosed bunker. Great pains are taken not to give subjects any clues as to time, including double-door entry chambers and randomized schedules for technicians interacting with subjects. In such studies, for many years, subjects were permitted to turn off their room lights and retire when they wished and awaken when they wished. Subjects were instructed not to nap. One of the more unexpected findings in circadian rhythm research is that the subjective sense of sleepiness, or the wish to sleep, is at its minimum at the normal time of sleep initiation and that sleepiness is greatest at the normal time of awakening.31-35 This propensity to be alert at the normal hour of onset of sleep has bedeviled studies attempting to assess the period length of the human circadian clock using time-isolation protocols. Under
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conditions of time isolation, a variety of studies showed great variability in human sleep-wake cycle length, unlike studies in any other mammal. Studies showed sleep-wake cycles as long as 36 hours and great day-to-day variability in both sleep and wake duration.36 Subjects who remained in time-isolation conditions for a sufficient interval developed desynchrony between their temperature rhythm and their sleep-wake cycle. Under normal conditions, the temperature minimum occurs somewhat after the middle of the sleep period. In subjects in temporal isolation protocols, the interval from one temperature minimum to the next has a cycle length of 24 to 25 hours, but the interval between sleep initiation on successive nights would be longer, meaning that the temperature minimum can stray elsewhere in the sleep-wake schedule.37 The time-isolation protocol is no longer employed because results from these studies are widely disparate from those of circadian rhythm studies of all other mammalian species. In disregarding this experimental approach, a basic attribute of human behavior is being ignored: Most persons appear to prefer a sleep-wake schedule longer than 24 hours, when allowed. This perhaps unique human preference for longer wake and sleep episodes has been overlooked in the circadian rhythm field’s fervor to produce human data as similar as possible to that from other mammals, invertebrates, and plants. Forced-Desynchrony Protocols In forced-desynchrony protocols, subjects are scheduled for rest-activity cycles anywhere from every 20 minutes to 28 hours. In such studies, core body temperature, melatonin, or both are monitored continuously. Subjects live in dim light during the active part of their rest-activity cycle and in darkness during scheduled sleep episodes. Dim light is defined as a level from 1 to 70 lux in various studies. Under such conditions, the endogenous circadian pacemaker, as measured by dim light melatonin onset or temperature rhythm, displays a stable period and is unable to follow the scheduled 28-hour (or 20-minute) sleepwake cycle. The temperature rhythm then becomes desynchronized from the imposed sleep-wake schedule. The 20-minute sleep-wake cycle is referred to as the ultrashort sleep schedule.38 In forced-desynchrony protocols, subjects are placed in a sound-attenuated and windowless room in which they have no access to any timepiece for the duration of the study. The contacts with staff members are limited and the staff is trained not to transmit any information about the time of day. In such studies, technicians have only brief contact with the subjects to announce the moments for rising, meals, showering, testing, and going to bed. Subjects watch videos, listen to music, or engage in their own preference of leisure activities. In some studies, subjects are allowed caffeine-containing beverages in the scheduled morning. In forced-desynchrony protocols, subjects spend two thirds of their time in light or waking conditions and one third of their time in dark or sleep conditions—for example, 60 minutes of activity and 30 minutes of scheduled sleep in a 90-minute day, and 18.66 hours of activity and 9.33 hours of scheduled sleep in a 28-hour day paradigm. In all forced-desynchrony protocols, from 20-minute
to 28-hour cycles, the scheduled day cycle length is outside the range of entrainment of the human circadian clock (under dim-light conditions).39 Under such conditions, the circadian clock becomes unmasked as it continues to oscillate at its near-24-hour intrinsic period despite sleep permitted only on the 28-hour schedule (Fig. 146-2). Constant-Routine Protocols The constant-routine protocol requires the subjects to remain in a semirecumbent posture throughout the constant-routine experimental phase, typically 24 to 48 hours, sometimes continuously awake. During constant routine, the subject remains in temporal isolation in dim light. Subjects are fed their normal caloric and liquid intake in 24 equally divided portions. Food and beverages are at room temperature. In such studies, salivary melatonin samples may be acquired hourly, core body temperature may be monitored continuously, and psychometric testing may be administered at hourly intervals. Blood samples may be drawn at hourly intervals through an indwelling intravenous catheter. Constant-routine protocols eliminate the effects of activity, light-dark cycles, sleep, and meals on temperature, enabling a more accurate estimate of the period length of the hypothetical “master clock” in the suprachiasmatic nucleus (SCN).40 Other chapters in this book adequately provide the evidence that the SCN is the body’s master clock, synchronizing the clock cells throughout the body. Long-Nights Protocol In the long nights protocol, subjects have an enforced dark period longer than the permitted light period. Such studies have been used in adults and adolescents. This protocol reveals an aspect of the human circadian rhythm that is typically ignored: the capacity of humans to adapt to an extended dark period with enforced immobility. Historically, humans in temperate zones of the northern and southern hemispheres obviously spent approximately half of the year with dark periods exceeding light periods. Society has used artificial light to impose permanent light conditions similar to the long days of summer, to which humans are capable of entraining. The long nights protocol reverses the circumstances, testing the ability of the human circadian system to adapt to short days (10 hours) and long nights (14 hours) (Fig. 146-2). Such studies have revealed increased total sleep time, increased duration of cortisol suppression, increased duration of melatonin secretion, increased duration of temperature suppression, and decreased daytime sleepiness under these conditions.41 During long nights, subjects spend some of this time awake, typically after rapid eye movement (REM) sleep periods.42 In this manner, the portion of the time spent with the body geared for sleep is increased and the time spent with the body geared to be awake is decreased (see Fig. 146-2). This demonstrates an aspect of adaptability in the human circadian system that is not revealed in other circadian protocols. Phase Shifting of Gene Expression Protocol A sizeable percentage of all employees work at a time not in keeping with their biological clocks. Numerous studies
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Figure 146-2 The left portion of the figure shows subjects in a 16-hour day and an 8-hour night (LD 16 : 8), equivalent to mid-summer at a latitude of 39 degrees (Washington, DC). The right portion of the figure shows a 10-hour day and 14-hour night, which occurs in mid-winter at the same latitude. The circadian pacemaker imposes a pattern of neuroendocrine secretion influenced by the length of daylight. A, In summer and winter, the pattern of melatonin secretion is characterized by distinct diurnal and nocturnal periods with relatively discrete transitions between them. Melatonin is either at high levels (biological night) or virtually absent (biological day). C, In humans, diurnal periods of absence of melatonin secretion, and falling levels of cortisol alternate with nocturnal periods of active melatonin secretion and high and rising levels of cortisol. The timing and duration of endocrine secretion are matched to the timing and duration of solar day and night. The pacemaker adjusts the duration of the biological day and night to match seasonal variation in the duration of sunlight. After humans have been chronically exposed to long nights (right), the duration of melatonin secretion and rising levels of cortisol is longer than it is after they have been chronically exposed to short nights. B, The paradox described in this chapter: Subjects are sleepiest when they wake up and most wide awake when closest to bed time (as measured by the Stanford Sleepiness Scale). Also notice that subjects are far sleepier during short nights compared to long nights. This means that the introduction of artificial light has increased sleepiness of our population as a whole.(From Wehr TA. Effect of seasonal changes in daylength on human neuroendocrine function. Horm Res 1998; 49(3-4):118-124.)
have shown that virtually all of these night- or grave-shift workers maintain their daytime peak and nocturnal drop in circadian activity, probably due to light exposure during and surrounding their hours of sleep and jumping back to a normal day–night sleep schedule on days off. This has been recognized as a health risk, increasing the likelihood of suffering a number of chronic illnesses.
The following study describes a protocol for flipping circadian rhythm activity to peak in the nocturnal work hours of night-shift employees. One of the techniques used to measure phase shift was measurement of circadian genes in blood cells. This study examined clock gene expression in peripheral blood mononuclear cells (PBMCs) in comparison to melatonin and cortisol secretion. In a laboratory study, five subjects awakened, worked, and slept 10 hours later than they normally would. Subjects were exposed to very bright white light of 6000 lux, equivalent to being outdoors in the shade on a sunny day, during their night shifts. They were restricted to dim light after night shifts, and slept in total darkness for 8 hours, beginning two hours after the night shift. Following 9 days on the night schedule, melatonin and cortisol secretory rhythms adapted to the shifted schedule. Gene expression of HPER1 and HPER2 in blood also shifted to the night-work schedule. This study is significant for two reasons: First, it conclusively demonstrates that proper light exposure completely shifts circadian activity to a night-shift schedule, and second, it shows that the underlying biology of these shifts can be measured with traditional hormonal sampling or with genes extracted from peripheral blood.43 Measuring Circadian Rhythms with Salivary Melatonin A commonly employed technique in human circadian research is measurement of melatonin in blood or saliva. Measuring melatonin levels in blood was first accomplished in 1978,44 and its suppression by the presence of bright light was soon demonstrated.45 The evening rise in blood levels of melatonin, called dim light melatonin onset (DLMO), and the decline in blood levels of melatonin, called dim light melatonin offset (DLM offset) are standard techniques for measuring duration of the human circadian period in the various experimental protocols described earlier. More recently, melatonin salivary assays have been substituted for blood draws in measuring the timing of DLMO and DLM offset. This noninvasive procedure permits a clinician or investigator to indirectly measure circulating melatonin levels, which may be consecutively plotted to estimate time of melatonin onset and offset, thereby determining a subject’s or patient’s circadian phase.46 Salivary melatonin correlates directly with sleep propensity and inversely with core body temperature.47 Collection of Saliva During the sampling period, subjects typically avoid heavy exercise. Samples are taken under controlled light conditions to avoid light inhibition of melatonin: 250 to 300 lux for daytime and less than 50 lux for nighttime. Saliva is collected by placing a wool swab in the mouths of subjects and having them chew for 5 minutes. Saliva samples may be acquired once or multiple times over a 24-hour period.48 Salivary Melatonin and Cortisol Assay Melatonin in saliva is measured by a direct radioimmunoassay (RIA). Various kits are manufactured in North America and Europe and are specially made for the quantitative determination of melatonin in saliva. The cross-reactivity of the assay for closely related chemical
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Figure 146-3 A normal subject wearing an actigraphy watch. The shaded box indicates where sleep most likely occurred. It is generated by software developed by the actigraph manufacturer, described in Chapter 145. Days 11 and 12 are most likely weekends because the subject sleeps later.(Permission granted by and copyright ©2009 Koninklijke Philips Electronics NV.)
structures is less than 1%. The sensitivity of the assay is approximately 1 ng/L.49 Statistics in Salivary Melatonin Studies To characterize the salivary melatonin profile for a given subject, the periodic function may be fitted to a set of data points using the baseline cosine function. The peak height (amplitude), acrophase, and duration of secretion are then calculated and may be subjected to further calculations or common statistical analysis. Standardized procedures for measuring DLMO and DLM offset have been published, including guidelines for collecting and analyzing urinary, salivary, and plasma melatonin, to help clinicians and researchers to determine which technique of measuring melatonin is most appropriate for their particular needs. It is hoped this will facilitate the comparison of data between laboratories.49 Another study showed that salivary estimation of DLMO is consistent when gathered from normal subjects and those who meet criteria for delayed sleep phase syndrome in the International Classification of Sleep Disorders, 2nd edition (ICSD-2), occurring in each approximately 10.75 hours before wakeup time.50 Another study established a phase-response curve for melatonin, or a measurement of effect size as related to time of administration. This study found the greatest phase advance approximately 6 hours before the habitual hour of sleep onset and the greatest phase delay soon after habitual
wakeup time. This study found a “dead-zone,” lasting from shortly before sleep onset to mid-sleep, a period that encompasses the time when melatonin is most typically administered to patients.51
ACTIGRAPHY Actigraphy is comprehensively reviewed in Chapter 147. Actigraphy is a relatively noninvasive method of monitoring human rest–activity cycles. It is used in circadian rhythm research and in clinical sleep disorders centers. Clinically helpful for quantifying and diagnosing various sleep disorders, it is extremely valuable for providing objective data confirming a suspected circadian rhythm disorder. Typically, the patient wears the actigraph for 1 to 3 weeks and then returns to have the data uploaded. The plot of active versus quiescent periods visually displays each of the circadian rhythm disorders, the degree of phase shift, and the consistency of the sleep-wake pattern. One is able to visually display the normal timing and continuity of sleep in a normal adult (Fig. 146-3). Advanced sleep phase disorder consistently shows an early bed and rising time (Fig. 146-4). Delayed sleep phase disorder usually shows the patient’s enforced wakeup time on weekdays and delayed wakeup and sleep onset on weekends (Fig. 146-5). In delayed sleep phase disorder, the difference between the timing of sleep on work days and nonwork days quantifies the magnitude of the disorder. Free-running sleep disorder
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Figure 146-4 This figure displays typical features of advanced sleep phase disorder: The subject begins sleep by as early as 7:00 PM and as late as 10:00 PM. The subject awakens anywhere from 3:00 AM to 5:45 AM. The subject takes lengthy naps on two of the mornings, suggesting insufficient sleep. (Permission granted by and copyright ©2009 Koninklijke Philips Electronics NV.)
shows an incremental delay in the onset of sleep and wakeup time (Fig. 146-6).
MEASURING CIRCADIAN RHYTHM PARAMETERS IN GENE EXPRESSION A new method for measuring circadian rhythms has evolved recently. It is well known that most cells contain genes that express proteins in a manner similar to gene expression in the suprachiasmatic nucleus. Studies have shown that different organs express gene products in a circadian manner, in vitro or in vivo, and each organ has its own rhythm of gene expression. It is believed that the suprachiasmatic nucleus acts as the conductor or organizer of the expression of gene products throughout the body. What follows is a brief description of the methodology and some applications of the technique of studying circadian rhythms from blood, organs, or muscle fibroblasts. The expression of clock genes in peripheral leukocytes is believed to reflect the circadian clock system. Per1 and Per2 demonstrate circadian oscillations in mRNA expression in mouse leukocytes, and these rhythms are virtually abolished in Cry1-Cry2 double knockout mice whose circadian rhythms are abolished.52 In human leukocyte clock genes, only PER1 exhibits a robust circadian rhythm, making this gene a candidate for human investigation.52 The suprachiasmatic nuclei are believed to synchronize biological rhythms in peripheral tissues. In humans, blood
is the most accessible tissue source. Various investigators have examined clock gene expression in human peripheral blood mononuclear cells (PBMCs). Clock genes in peripheral blood and in peripheral organs have been found to express circadian rhythms.53 The liver, kidney, and spleen express the most clock genes: Per1, Per2, Cry1, Cry2, Reverb-α, Clock, and Bmal1 in a rhythmic manner. Clock genes are examined simultaneously in peripheral tissues in rodents or humans every 4 hours for 24 hours in synchronized light–dark conditions using real-time polymerase chain reaction (PCR) assays. This study showed that different tissues expressed different genes to different extents. For example, Bmal1 and Cry1 are more abundant in the thymus, Per1, Cry1, and Cry2 are more abundant in the testis, and Cry2 and Per2 are expressed at a lower level in the kidney, spleen, and thymus. All genes tested are less abundant in peripheral blood. Of all peripheral tissues, the greatest circadian changes occur in the liver and kidney.54 Of all circadian clock genes, PER1, PER2, and PER3 are most rhythmically expressed in human blood samples.54 One study claimed to be able to measure both circadian period and chronotype (owl versus lark) from genes from human blood.55 The most interesting development in measuring circadian rhythms has been the study of human and mouse fibroblasts. Most cells express circadian clock genes similar to those of the suprachiasmatic nucleus. One is able to engineer a lentiviral circadian reporter gene that permits
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DAY 8 2002-01-07 Figure 146-5 A subject with delayed sleep phase disorder. Sleep apparently begins about 2:00 AM or later and wakeup is as late as noon. On days 3, 4, 5, and 8, there are periods of inactivity between noon and 2:00 PM suspicious for drowsiness. (Permission granted by and copyright ©2009 Koninklijke Philips Electronics NV.)
characterization of circadian rhythms from forearm skin biopsies, because the selected cell glows proportional to gene expression as measured by a light meter. Several findings have emerged from these studies. First, the circadian period mean of gene expression from fibroblasts, 24.5 hours, is approximately the same as it is in behavioral (wheel running) and physiologic studies (melatonin secretion) of mice and humans.56 However, the range of rhythms of human fibroblasts (from 23.5 hours to 26 hours) is greater than what is observed in human behavioral studies (23.9 to 24.5 hours).1 In mice, the fibroblast period length correlates with the period length of wheel running.56 A recent study in human volunteers examined the fibroblast period length of larks and owls, or morning and evening chronotypes.57 Morning types had significantly shorter fibroblast period lengths than evening types. Some of the morning types and evening types turned out to have normal period lengths, 24.5 hours ± 0.5 hours. In these subjects, a greater amplitude of the fibroblast gene signal was linked to more evening-type behavior. This novel finding suggests that the amplitude of circadian gene activity in addition to the cell’s period length influences chronotype.57 As described above, researchers transfect cells with luciferase (glowing) to measure circadian period length of fibroblasts taken from mice and humans. Transfected cells glow in proportion to gene activity. Using a photo-multiplier tube, one is able to measure the gene’s activity over time, revealing that it glows in a sine wave–like circadian
pattern. Peak to peak or trough to trough luminance demonstrates the gene’s period length. Trough-to-peak luminance demonstrated the gene’s circadian amplitude. The position of peak activity in the luminance cycle, early versus late, revealed the phase (owl versus lark) of peak activity. Moreover, the transfected cells continued to glow in vivo for more than 20 cycles, showing little degradation. Fibroblasts were selected because they are easily obtained and their genetic period has been found to be similar to that of the mouse’s SCN.58 In both mice and humans, with different circadian behavior, fibroblast luminance characteristics correlated closely with the individual from whom the genes were taken. In mice, gene luminescence period length is similar to the period of wheel running in the same animals: If the mouse’s clock genes are mutated to shorten, lengthen, or abolish the circadian period of wheel running, a similar effect is observed in the luminescence characteristics of the fibroblasts taken from these mice.58 Another study of dermal fibroblasts from normal humans and persons with bipolar disorder found that the amplitude of the clock gene’s circadian rhythm was damped in persons with bipolar disorder.59 An interesting application of the fibroblast technique was the extraction of fibroblasts from pregnant mouse dams in a forced-feeding protocol when food was only available during the dam’s biological night. As expected, the dams developed a secondary feeding rhythm while maintaining their normal day–night circadian rhythm. The pups were sacrificed shortly before birth, and fibroblast analysis showed the pups’ most active
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Figure 146-6 The rest–activity pattern in individual with free-running or nonentrained type circadian rhythm disorder. This disorder most typically occurs in blinded persons whose biological circadian rhythms are not entrained or masked by conventional time. The time of sleep onset does not follow an orderly progression, suggesting that social factors might contribute to the variance. (Permission granted by and copyright ©2009 Koninklijke Philips Electronics NV.)
time, from a gene transcription perspective, was when the mother fed, and not during her biological day, as measured by the mother’s wheel-running activity and by her fibroblast gene activity.60
FUTURE DIRECTIONS Imagine a school-age child who is asleep first through third periods every day. Imagine the child being sent to the school nurse who obtains saliva or a hair follicle and has a circadian rhythm analysis performed. Results show the child has a longer than normal circadian cycle length but also show that the phase of peak circadian activity is late in his or her cycle. A note is sent to the parents describing the child’s owl-like propensities to be asleep in morning classes along with instructions on how this may be corrected in 1 or 2 weeks. The child returns to the nurse 2 weeks later and is no longer falling asleep in class. The nurse obtains a second biological sample, and analysis shows the same long cycle length, but the phase of peak activity has advanced by several hours. This is a not so far-fetched as it might sound. New techniques of genetic analysis of circadian rhythms could be used to diagnose and treat persons with inappropriate bouts of sleepiness or wakefulness. As circadian rhythm monitoring techniques continue to advance, it is likely that they will move out of the laboratory and become an everyday tool.
Current methods for assessing circadian pacemaker properties are indirect. In the future, our current experimental techniques will probably be viewed as clever but rudimentary. Temperature is an indirect output of the core pacemaker, and melatonin is also indirectly related to it. Genetic advances in chronobiological technique could allow measurement of gene transcription or translation products that are direct outputs of the circadian pacemaker. Studies employing techniques such as functional magnetic resonance imaging could make it possible to directly monitor the functional activity of neuronal assemblies with purported pacemaker activity, such as the suprachiasmatic nuclei, which, after all, is the heart of the matter.
DISCUSSION Methodologies in circadian rhythm research are rapidly evolving, and this is one of the more exciting fields in biological research. Much has been learned about the circadian pacemaker in humans, its inputs and outputs, and the factors that affect circadian rhythms. The protocols described in this chapter are continually being refined: Additional controls are incorporated to eliminate unintended factors that could have masking effects. These protocols are complex and require sophisticated laboratories with extensive time-isolated floor space and equipment. Much of the data have been gathered from
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young male subjects, and little is yet known concerning sex effects. Each of the protocols has advantages and disadvantages. Forced-desynchrony studies must have a major impact in disrupting the emotional well-being of subjects, who live continuously in a timeless environment, have no contact with the outside world, are awakened at various times throughout the night and day, are permitted to sleep only at times when sleeping is unlikely, and have meals at times when one would not be hungry. In countries where physical torture is not permitted, circumstances similar to forced desynchrony are used to interrogate prisoners of war. It is possible that the results from forced desynchrony protocols are affected by the unusual and unsustainable nature of the experimental conditions. The long nights protocol reveals great flexibility in the human capacity to adapt to long periods of darkness, both biologically and behaviorally. It reveals biological changes, such as longer cortisol suppression and decreased daytime sleepiness, that could prove advantageous in certain populations, such as children, narcoleptic patients, or patients with affective disorders. Little is yet known about this chronobiological approach. Chronobiology research in humans appears to be searching for experimental protocols that minimize any differences between humans, other animals, and plants. Rodent studies have become the gold standard to which human circadian research aspires. Rodent and human studies maximize stability of period length and minimize variability. If gathering phenotypic information for genetic studies is the goal, it is understandable that maximal stability and minimal variance are sought. But something about what makes us human is lost when we abandon paradigms that show individual variance in preferred day length, and exclude individuals who prefer to remain awake and asleep for extended periods. ❖ Clinical Pearl Much of human biology and behavior fluctuates with a temporal period close to the 24-hour cycle of day and night. Defining the properties of human circadian rhythms requires complex experimental paradigms that are at the heart of chronobiological research. Studies following these paradigms now show the endogenous circadian pacemaker to have a period length of 24.18 hours, similar to that of many mammals. Human circadian rhythms are flexible and can adapt, for example, to very long (14-hour) nights by suppressing cortisol longer, secreting melatonin longer, and dropping temperature for a moreextended period. Using saliva, researchers and clinicians now measure circadian rhythm parameters in subjects and patients by constructing melatoninexpression profiles. New genetic studies that measure circadian rhythms in humans from tissue or blood is one of the hottest topics in biological research.
REFERENCES 1. Czeisler CA, Duffy JF, Shanahan TL, et al. Stability, precision, and near-24-hour period of the human circadian pacemaker. Science 1999;284:2177-2181.
2. Weitzman ED, Czeisler CA, Zimmerman JC, Ronda JM. Timing of REM and stages 3 + 4 sleep during temporal isolation in man. Sleep 1980;2:391-407. 3. Czeisler CA, Allan JS, Strogatz SH, et al. Bright light resets the human circadian pacemaker independent of the timing of the sleep– wake cycle. Science 1986;233:667-671. 4. Boivin DB, Duffy JF, Kronauer RE, Czeisler CA. Sensitivity of the human circadian pacemaker to moderately bright light. J Biol Rhythms 1994;9:315-331. 5. Boivin DB, Czeisler CA. Resetting of circadian melatonin and cortisol rhythms in humans by ordinary room light. Neuroreport 1998;9:779-782. 6. Waterhouse J, Minors D, Folkard S, et al. Light of domestic intensity produces phase shifts of the circadian oscillator in humans. Neurosci Lett 1998;245:97-100. 7. Campbell SS, Murphy PJ. Extraocular circadian phototransduction in humans. Science 1998;279:396-399. 8. Lushington K, Galka R, Sassi LN, et al. Extraocular light exposure does not phase shift saliva melatonin rhythms in sleeping subjects. J Biol Rhythms 2002;17:377-386. 9. Lindblom N, Hatonen T, Laakso M, et al. Bright light exposure of a large skin area does not affect melatonin or bilirubin levels in humans. Biol Psychiatry 2000;48:1098-1104. 10. Lindblom N, Heiskala H, Hatonen T, et al. No evidence for extraocular light induced phase shifting of human melatonin, cortisol and thyrotropin rhythms. Neuroreport 2000;11: 713-717. 11. Hebert M, Martin SK, Eastman CI. Nocturnal melatonin secretion is not suppressed by light exposure behind the knee in humans. Neurosci Lett 1999;274:127-130. 12. Klerman EB, Rimmer DW, Dijk DJ, et al. Nonphotic entrainment of the human circadian pacemaker. Am J Physiol 1998;274: R991-R996. 13. Baehr EK, Fogg LF, Eastman CI. Intermittent bright light and exercise to entrain human circadian rhythms to night work. Am J Physiol 1999;277:R1598-R1604. 14. Redlin U, Mrosovsky N. Exercise and human circadian rhythms: what we know and what we need to know. Chronobiol Int 1997; 14(2):221-229. 15. Duffy JF, Kronauer RE, Czeisler CA. Phase-shifting human circadian rhythms: influence of sleep timing, social contact and light exposure. J Physiol (Lond) 1996;495:289-297. 16. Mistlberger RE. Circadian food anticipatory activity: formal models and physiological mechanisms. Neurosci Biobehav Rev 1994;18: 1-25. 17. Herzog ED, Huckfeldt RM. Circadian entrainment to temperature, but not light, in the isolated suprachiasmatic nucleus. J Neurophysiol 2003;90:763-770. 18. Buxton OM, L’Hermite-Baleriaux M, Turek FW, van Cauter E. Daytime naps in darkness phase shift the human circadian rhythms of melatonin and thyrotropin secretion. Am J Physiol 2000;278: R373-R382. 19. Lockley SW, Skene DJ, James K, et al. Melatonin administration can entrain the free-running circadian system of blind subjects. J Endocrinol 2000;164:R1-R6. 20. Mills JN. Circadian rhythms during and after three months in solitude underground. J Physiol (Lond) 1964;174:217. 21. Waterhouse J, Minors D, Folkard S, et al. Lack of evidence that feedback from lifestyle alters the amplitude of the circadian pacemaker in humans. Chronobiol Int 1999;16:93-107. 22. Arendt J. Complex effects of melatonin. Therapie 1998;53:479-488. 23. Borbely AA, Achermann P. Sleep homeostasis and models of sleep regulation. J Biol Rhythms 1999;14:557-568. 24. Akerstedt T, Hume K, Minors D, Waterhouse J. Experimental separation of time of day and homeostatic influences on sleep. Am J Physiol 1998;274:R1162-R1168. 25. Van Dongen HP, Dinges DF. Investigating the interaction between the homeostatic and circadian processes of sleep–wake regulation for the prediction of waking neurobehavioural performance. J Sleep Res 2003;12:181-187. 26. Lewy AJ, Cutler NL, Sack RL. The endogenous melatonin profile as a marker for circadian phase position. J Biol Rhythms 1999;14: 227-236. 27. Reebs SG, Mrosovsky N. Large phase-shifts of circadian rhythms caused by induced running in a re-entrainment paradigm: the role of pulse duration and light. J Comp Physiol [A] 1989;165: 819-825.
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28. Rosenwasser AM, Dwyer SM. Circadian phase shifting: relationships between photic and nonphotic phase response curves. Physiol Behav 2001;73:175-183. 29. Minors DS, Waterhouse JM, Wirz-Justice A. A human phaseresponse curve to light. Neurosci Lett 1991;133:36-40. 30. Jewett ME, Rimmer DW, Duffy JF, et al. Human circadian pacemaker is sensitive to light throughout subjective day without evidence of transients. Am J Physiol 1997;273:R1800-R1809. 31. Webb WB, Agnew HW. Sleep efficiency for sleep–wake cycles of varied length. Psychophysiology 1975;12:637-641. 32. Weitzman ED, Nogeire C, Perlow M, et al. Effects of a prolonged 3-hour sleep–wake cycle on sleep stages. plasma cortisol, growth hormone and body temperature in man. J Clin Endocrinol Metab 1974;38:1018-1030. 33. Carskadon MA, Dement WC. Sleep studies on a 90-minute day. Electroencephalogr Clin Neurophysiol 1975;39:145-155. 34. Carskadon MA, Dement WC. Distribution of REM sleep on a 90-minute sleep wake schedule. Sleep 1980;2:309-317. 35. Dijk D, Czeisler C. Paradoxical timing of the circadian rhythm of sleep propensity serves to consolidate sleep and wakefulness in humans. Neurosci Lett 1994;166:63-68. 36. Weitzman ED, Moline ML, Czeisler CA, Zimmerman JC. Chronobiology of aging: temperature, sleep–wake rhythms and entrainment. Neurobiol Aging 1982;3:299. 37. Aschoff J, Wever R. Spontaneous period of human sleep without zeitgebers. Naturwissenschaften 1962;49:337-342. 38. Shochat T, Luboshitzky R, Lavie P. Nocturnal melatonin onset is phase locked to the primary sleep gate. Am J Physiol 1997;273: R364-R370. 39. Wyatt JK, Cecco AR, Czeisler CA, Dijk DJ. Circadian temperature and melatonin rhythms, sleep, and neurobehavioral function in humans living on a 20-h day. Am J Physiol 1999;277:R1152-R1163. 40. Dijk DJ, Duffy JF, Czeisler CA. Circadian and sleep/wake dependent aspects of subjective alertness and cognitive performance. J Sleep Res 1992;1:112-117. 41. Wehr TA, Aeschbach D, Duncan WC. Evidence for a biological dawn and dusk in the human circadian timing system. J Physiol (Lond) 2001;535:937-951. 42. Barbato G, Barker C, Bender C, Wehr TA. Spontaneous sleep interruptions during extended nights: relationships with NREM and REM sleep phases and effects on REM sleep regulation. Clin Neurophysiol 2002;113:892-900. 43. James FO, Cermakian N, Boivin DB. Circadian rhythms of melatonin, cortisol, and clock gene expression during simulated night shift work. Sleep 2007;30(11):1427-1436. 44. Lewy AJ, Markey SP. Analysis of melatonin in human plasma by gas chromatography negative chemical ionization mass spectrometry. Science 1978;201(4357):741-743.
45. Lewy AJ. Effects of light on human melatonin production and the human circadian system. Prog Neuropsychopharmacol Biol Psychiatry 1983;7(4-6):551-556. 46. Carskadon MA, Labyak SE, Acebo C, Seifer R. Intrinsic circadian period of adolescent humans measured in conditions of forced desynchrony. Neurosci Lett 1999;260:129-132. 47. Wehr TA, Aeschbach D, Duncan WC. Evidence for a biological dawn and dusk in the human circadian timing system. J Physiol 2001;535(Pt. 3):937-951. 48. Fei GH, Liu RY, Zhang ZH, Zhou JN. Alterations in circadian rhythms of melatonin and cortisol in patients with bronchial asthma. Acta Pharmacol Sin 2004;25:651-656. 49. Benloucif S, Burgess HJ, Klerman EB, et al. Measuring melatonin in humans. J Clin Sleep Med 2008;4(1):66-69. 50. Wyatt JK, Stepanski EJ, Kirkby J. Circadian phase in delayed sleep phase syndrome: predictors and temporal stability across multiple assessments. Sleep 2006;29(8):1075-1080. 51. Burgess HJ, Revell VL, Eastman CI. A three pulse phase response curve to three milligrams of melatonin in humans. J Physiol 2008; 586(2):639-647. 52. Fukuya H, Emoto N, Nonaka H, et al. Circadian expression of clock genes in human peripheral leukocytes. Biochem Biophys Res Commun 2007;23;354(4):924-928. 53. Liu S, Cai Y, Sothern RB, Guan Y, Chan P. Chronobiological analysis of circadian patterns in transcription of seven key clock genes in six peripheral tissues in mice. Chronobiol Int 2007;24(5):793-820. 54. Kusanagi H, Hida A, Satoh K, et al. Expression profiles of 10 circadian clock genes in human peripheral blood mononuclear cells. Neurosci Res 2008;61(2):136-142. 55. Teboul M, Barrat-Petit MA, Li XM, et al. [Circadian clock gene expression in human peripheral blood mononuclear cells] Pathol Biol (Paris) 2007;55(3-4):208-210. 56. Brown SA, Fleury-Olela F, Nagoshi E, et al. The period length of fibroblast circadian gene expression varies widely among human individuals. PLoS Biol 2005;3(10):e338. 57. Brown SA, Kunz D, Dumas A, et al. Molecular insights into human daily behavior. Proc Natl Acad Sci U S A 2008;105(5):1602-1607. 58. Yoo SH, Yamazaki S, Lowrey PL, et al. PERIOD2::LUCIFERASE real-time reporting of circadian dynamics reveals persistent circadian oscillations in mouse peripheral tissues. Proc Natl Acad Sci U S A 2004;101(15):5339-5346. 59. Yang S, Van Dongen HP, Wang K, et al. Assessment of circadian function in fibroblasts of patients with bipolar disorder. Mol Psychiatry 2009;14(2):143-155. 60. Ohta H, Xu S, Moriya T, Iigo M, et al. Maternal feeding controls fetal biological clock. PLoS ONE 2008;3(7):e2601.
Actigraphy
Katie L. Stone and Sonia Ancoli-Israel
Abstract Wrist actigraphy technology is based on the fact that during sleep there is little movement and during wake there is increased movement. Wrist actigraphy has the advantages of being well tolerated and noninvasive, being cost-efficient, allowing the recording of sleep in natural environments, recording behavior that occurs both during the night and during the day, and recording for long time periods (e.g. days to weeks). Although it is not a replacement for EEG or PSG recordings, there are times when actigraphy provides clear advantages for data collection. Actigraphy is particularly useful for studying persons who cannot tolerate polysomnography (whether performed in the laboratory or at home), such as patients with complaints of insomnia, small children, or the elderly. It may provide a more accurate estimate of typical sleep durations by providing an opportunity for patients to adhere more closely to their scheduled sleep and wake times. Furthermore, data are typically averaged over several nights, providing a more accurate representation of usual sleep patterns. Actigraphy is also becoming an important tool in research settings, including observational studies as well as random-
The gold standard for evaluating sleep is polysomnography (PSG), with a minimum of electroencephalogram (EEG), electrooculogram (EOG), and submentalis electromyogram (EMG) recordings. Other physiologic variables are added depending on the patient’s sleep complaints (e.g., respiration, heart rate, tibialis muscle activity, oximetry). A PSG, therefore, allows the collection of detailed information. The EEG, EOG, and EMG records can be scored for stages of sleep (rapid eye movement [REM, R] and non-REM [NREM] stages N1, N2, N3), total sleep time, total wake time, sleep-onset latency, and percentage of time in REM versus NREM sleep. This information is very important for certain types of evaluations; however, the recording process can disturb a patient’s sleep and is often very costly to record and to score. In addition, the PSG typically provides data about sleep episodes during the time of recording, which often is 6 to 10 hours long. Because recordings are generally made during the major sleep period, little information is available about daytime waking or napping behavior. There are some instances when it is not essential to know the specific stage of sleep nor the status of other physiologic variables; only information on whether the person is awake or asleep is needed. Actigraphy, much less expensive than a PSG, allows 24-hour recordings of activity from which wake and sleep can be scored. Actigraphs (or actimeters) record limb movement. Traditionally, the actigraph is placed on a wrist, although sometimes activity from the leg is recorded. The data collected are displayed on a computer and are examined for activity and inactivity and analyzed for wake 1668
Chapter
147 ized trials in which actigraphy may be used to examine efficacy in clinical outcome. The newer scoring algorithms have great accuracy in determining variables that are most important in insomnia, such as improved ability to detect wake versus sleep, sleep latency, awakenings during the night, and total sleep time. Actigraphy is particularly superior to sleep logs in detecting brief arousals during the night. It can also be used for the evaluation and clinical diagnosis of circadian rhythm disorders. The ability to detect movement holds promise for the potential utility of actigraphy in identification of sleep disorders characterized by frequent movements, such as periodic limb movements in sleep and sleep apnea. The ability to measure for long time periods makes actigraphy particularly useful in situations where long-term changes in sleep are of interest. Actigraphy is reliable and valid for detecting sleep in normal populations, but it is less reliable for detecting specific sleep disturbances. It is a useful adjunct to the routine evaluation of insomnia, circadian rhythm disorders, and excessive sleepiness, and it is helpful in the diagnosis of periodic limb movements in sleep and restless legs syndrome. It is also useful in special populations such as children or demented elderly patients.
and sleep. This chapter reviews the major areas where actigraphy can be used, tips for using actigraphy successfully, and limitations of its use.
HISTORY OF WRIST ACTIGRAPHY Wrist actigraphy technology is based on the fact that during sleep there is little movement and during wake there is increased movement. Activity monitors have been around for many years.1 With the advent of microprocessors and miniaturization, most contemporary actigraphs have a movement detector (such as an accelerometer) and sufficient memory to record for long time periods. The only time the actigraph needs to be removed by the patient is during bathing or swimming, although many of the models now available are water resistant, thus allowing nearly continuous 24-hour recordings for several days or weeks. Newer models are the size of a wristwatch and collect digitized data. Physical movement is generally sampled several times per second and stored in 1-minute epochs, although sampling and epoch rates can be set by the clinician or investigator. The three ways signals can be digitized are time above threshold (TAT), zero crossing mode (ZCM) and digital integration mode (DIM) (Fig. 147-1).2 TAT mode counts the amount of time per epoch that the motion signal is above a given threshold. However, neither the amplitude of the signal nor the acceleration of the movement are reflected in this strategy. The ZCM method counts the number of times per epoch that the signal crosses zero. In this strategy, once again neither the amplitude nor the
CHAPTER 147 • Actigraphy 1669
TIME ABOVE THRESHOLD
A ZERO CROSSING
B DIGITAL INTEGRATION
C Figure 147-1 Three methods of deriving activity counts in actigraphy. A, Time above threshold derives the amount of time per epoch that the activity is above some defined threshold (line). B, Zero crossing counts the number of times the activity reaches zero (solid baseline). C, Digital integration calculates the area under the curves represented by red shading. (Reprinted with permission from Ancoli-Israel S, Cole R, Alessi CA, Chambers M, Moorcroft WH, Pollak C. The role of actigraphy in the study of sleep and circadian rhythms. Sleep 2003;26: 342-392.)
acceleration are taken into account, and high-frequency artifact could potentially be counted as movement. DIM, on the other hand, samples the accelerometry output signal at a high rate and then, for each epoch, calculates the area under the curve. This reflects the amplitude and acceleration of the signal, but it does not reflect duration or frequency of the signal. In studies comparing the three methodologies, DIM was best for identifying movement amplitude, followed by TAT and ZCM.3 Some newer actigraphs use more than one method, thus decreasing the deficits of each method alone. Once data are digitized, computer algorithms are used to automatically score wake and sleep and provide the user with summary statistics. These computer algorithms generally supply information on total sleep time, percentage of time spent asleep, total wake time, percentage of time spent awake, number of awakenings, time between awakenings, and sleep onset latency.2,4 The use of actigraphy in sleep disorders medicine has gained popularity. Research has examined the reliability of activity versus EEG for distinguishing wake from sleep. Results vary depending on the populations studied and on the actigraph and scoring software used. Most studies have agreed that actigraphy estimates of total sleep time correlate well with corresponding PSG data, particularly in normal sleep, where reliability coefficients have ranged from 0.89 to 0.98.2,5,5a Correlations are somewhat lower for severely disturbed sleep. For example, in patients in sleep disorders clinics, reliability ranged from 0.78 to 0.88.6,7 In infants and in children, the reliability ranges from 0.90 to 0.95.8,9 Actigraphy has been compared to sleep and wake EEG in demented nursing home patients.10 Correlations with total sleep time were 0.91 for averaged activity (i.e.,
the average activity recorded per minute) and 0.81 for maximum activity (i.e., the maximum activity recorded per minute). Given the problems with obtaining EEG recordings in this setting, actigraphy offers a relatively accurate and more feasible alternative in these patients. A multicenter study of 68 community-dwelling older women (mean age, 82 years) participating in the Study of Osteoporotic Fractures examined the reliability of estimates of total sleep time based on all three modes of actigraphy data collection (ZCM, TAT, and DIM) compared with unattended in-home EEG. Results showed that estimates based on DIM mode were most highly correlated with EEG, with a reliability coefficient of 0.76.11 However, in study involving similar methods in a sample of 181 adolescents, TAT mode performed best in terms of agreement with EEG, but overall agreement was modest (0.41). However, further analysis revealed better concordance in girls than in boys (0.66 versus 0.31) and among those without sleep-disordered breathing (0.55).12 Reliability of estimated sleep time from actigraphy varies considerably depending on the device used, the setting, and the specific population being studied. In addition, although total sleep time generally correlates well with EEG, the actigraph data do not necessarily correlate well on a minute-by-minute basis, particularly if sleep is very disturbed. Most studies agree that with correct use, the actigraph is reliable for certain populations. Actigraphs with different algorithms are now commercially available; therefore, reliability has become a major question. Ideally, each actigraph needs its own reliability studies, and results from one population might not generalize to other populations. However, it has been demonstrated that even those algorithms based on different mathematical principles result in similar reliability.5 In general, validation studies for normal subjects show more than 90% agreement when compared with EEG.13 However, to date, there has been no head-to-head comparison between different actigraphs; therefore, no conclusion can be drawn about which method of collecting and scoring data more closely approximates data from PSG.2 Wrist actigraphy records continuously for long time periods; therefore, activity occurring both during the night and during the day can be studied. For example, collecting nighttime and daytime information for long time periods is particularly useful when examining sleep of patients complaining of insomnia: It economically allows one to see if there is a pattern of difficulty sleeping. The sleep of patients with complaints of insomnia can vary from night to night and is easily disturbed by novel environments. The actigraph therefore has the potential of being well suited for examining sleep over several nights in the patient’s home environment. Compared to a sleep diary, the resulting data are similar, but superior, because the data are continuous and objective rather than discrete and self-reported. Another advantage of collecting data over long periods is the ability to examine the circadian rhythms of the sleep or activity cycle, particularly in studies of patients with sleep–wake schedule disorders (e.g., jet lag, shift work, and advanced or delayed sleep phase). Most commercial software now analyzes circadian rhythms, including the computation of the mesor (mean of the rhythm), the amplitude
1670 PART II / Section 19 • Methodology
(peak of the rhythm) and the acrophase (time of the peak of the rhythm). These analyses need 5 to 7 days of data collection to be most accurate. Several adaptations and alternative methods of circadian rhythm analyses in humans have been proposed.14 The wrist actigraph may be particularly valuable for studying persons who would have difficulty sleeping in a sleep laboratory or sleeping with the wires associated with traditional PSG, such as insomnia patients, children, and demented elderly persons. With actigraphy, patients are studied in their natural environment. In the demented elderly, it has been shown that the traditional recording process disturbs sleep. In addition, the EEG in demented elderly often makes it difficult to distinguish wake from sleep.15 Actigraphy therefore avoids both these problems and enables the recording of sleep–wake activity in an easy, unobtrusive manner. Some actigraphs record other parameters in addition to activity, such as ambient light, skin temperature, and sound. These additional features enhance the capabilities of actigraphy to allow clinical and investigational studies of circadian rhythms in the home environment. Most actigraphs also have optional event buttons that the subject can push when he or she turns out the lights or needs to note other events. The addition of an actigraphs’ concurrent recording of light is particularly useful in determining lights-out, as well as observing the beginning of morning light as the sun begins to rise. Light measurements are also very helpful in studies of advanced and delayed sleep phase because they help determine the amount and duration of light a person is normally exposed to. For example, several studies using activity monitors that also record light exposure have found that normal elderly are exposed to only 58 minutes of bright light per day,16 Alzheimer’s patients living at home are exposed to 30 minutes of bright light a day,17 and nursing home patients are exposed to only 1.7 minutes.18 These data are useful in understanding the changes that occur in sleep in these populations and can be used to devise treatment programs.
APPLICATIONS OF WRIST ACTIGRAPHY Because actigraphy is unobtrusive, and as mentioned, can record for multiple days and nights, it is a useful tool for evaluating insomnia, particularly because insomnia symptoms can vary from night to night. In addition, the use of actigraphy eliminates laboratory effects because patients can be recorded sleeping in their own beds in their own homes. However, the convenience of actigraphy must be weighed against its reliability and validity versus polysomnography.2 The American Academy of Sleep Medicine (AASM) published recommendations on the use of actigraphy in clinical assessment of sleep disorders.19 They concluded that actigraphy is reliable and valid for detecting sleep in normal healthy adult populations and in patients in whom certain sleep disorders are suspected, such as advanced sleep phase syndrome, delayed sleep phase syndrome, and shift work disorder. Additionally, when polysomnography is not available, actigraphy may be useful
to estimate total sleep time in patients with obstructive sleep apnea. Additionally, in patients with insomnia, the use of actigraphy is recommended for characterizing circadian rhythms and sleep–wake patterns. They also concluded that actigraphy is useful in special populations such as children or elderly populations, who might have reduced tolerance to PSG. Insomnia Several studies have used actigraphy to evaluate sleep in the patient with insomnia, yet few of the studies validated the actigraphy findings with PSG. In a large insomnia sample, a high concordance was demonstrated between actigraphic estimates of total sleep time and measures of sleep fragmentation as compared with PSG.20 However, estimates of sleep onset latency were much less reliable. Furthermore, it is noted that there is little standardization of actigraphy devices and scoring methods across studies, so that the findings of this particular study are not sufficient to support a blanket recommendation on the use of actigraphy to assess sleep among persons with insomnia. Another study reported that actigraphy tended to underestimate total sleep time, sleep efficiency, and sleep onset latency, and it tended to overestimate sleep onset latency. However, actigraphy was more accurate than the sleep diary when compared to PSG.21 Although actigraphy cannot determine the etiology of insomnia, it can help evaluate the severity. In patients with insomnia, the most difficult distinctions for the actigraph to recognize are the transitions between sleep and wake and the ultra short sleep–wake cycles. In patients with insomnia comorbid with circadian rhythm disturbances, actigraphy can detect alterations in sleep phase. Sleep Apnea It is clear that actigraphy cannot determine the presence or absence of breathing abnormalities. However, because patients with sleep apnea have more disrupted sleep and thus more body movements, several studies have been conducted on the efficacy of wrist activity in recognizing patients with sleep apnea. One study showed that compared to controls, those with sleep apnea had significantly higher movement and fragmentation indices.22 Once treatment was begun, activity recordings showed decreased indices, indicating successful treatment. Activity measures of sleep have also been shown to successfully differentiate patients with sleep apnea from those with insomnia and from controls.8 In general, the conclusion from studies is that actigraphy may be capable of distinguishing normal patients from those with moderate or severe sleep apnea, particularly because actigraphy is more sensitive than sleep logs in identifying brief awakenings. However, it is unlikely that a distinction could be made between the different types of sleep disorders that all cause brief arousals.2 The real value of actigraphy in sleep apnea is in combination with stand-alone devices, recording equipment that is used to screen for sleep apnea and that does not have measures of wake or sleep. The addition of an actigraph to such a recording would allow one to determine if all respiratory events actually occurred during sleep. In an update, the Standards of Practice Committee of the AASM concluded
that actigraphy is indicated for assessing total sleep time among patients with sleep apnea when PSG is not available.19 Periodic Limb Movements in Sleep PLMS is generally evaluated by measuring EMG from the tibialis muscle. Because the leg movement is the primary characteristic of this disorder, the ability of actigraphy to measure movement is thought to be an advantage. One study found high reliability between tibialis EMG and actigraphy for the number of leg movements per hour of sleep.23 Another study that compared alternative placements of actigraphy for assessment of PLMS in comparison with PSG found that actigraphic PLM evaluation at the base of the big toe provided good validity.24 Because PLMS can greatly vary from night to night, actigraphy can offer advantages because multiple nights can easily be recorded. Actigraphy has also been useful in assessing efficacy of treatment.25 More research is needed to determine optimal procedures for detecting PLMS using actigraphy. Treatment Effects Actigraphy is particularly appropriate in the study of treatment effects because it can identify changes over time. Because actigraphy is less invasive and less expensive than PSG, it is a promising device for assessing treatment effects. Furthermore, single-night measures of sleep (which are often all that is feasible with PSG) might not accurately reflect habitual behavior.26 Actigraphy has also been used to successfully measure the effects of drug and behavioral treatments, suggesting that actigraphy can be used as a screening device in some patients before the more expensive PSG is ordered. It also can be used for follow-up once treatment has begun or to evaluate changes in sleep over the course of the treatment period. Circadian Rhythms Actigraphy allows the study of rhythms occurring over many days; it is therefore well suited for the study of circadian rhythms. Activity is a valid marker of entrained PSG sleep phase and correlates strongly with entrained endogenous circadian phase.2 It is also useful in identifying sleep that has been disturbed by circadian rhythm changes. Actigraphy has been used to study circadian rhythms in cancer patients27 and in demented elderly persons.28 Studies have also examined sleep schedules of adolescents,29 shift workers,30 flight crews,31 and jet lag.32 There are a variety of methodologies for analyzing circadian parameters of activity,33-35 but no studies have compared one methodology to another, and to date, no one standard methodology has been accepted. Pediatrics More and more studies have been published that have used actigraphy in children, particularly in those with behavioral, psychiatric, or neurologic problems. Actigraphy has been used successfully to characterize the sleep of infants,36 of developmental differences,37 and of children with autism38 and to demonstrate differences in sleep between children with depression, abused children, and normal children.39 One study used wrist activity to study treatment
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effects on the sleep patterns of 50 infants whose parents complained of sleep disturbances in their children.40 Objective activity recordings were compared to parental reports. The activity records showed that percentage sleep increased and the number of awakenings during the night decreased with behavioral treatments. By examining data from each successive night, it was determined that most changes occurred during the first night of intervention. In addition, parents’ subjective reports significantly differed from objective actigraphy on quality of sleep, with parents reporting fewer awakenings during the night. The presence of objective measures allows the evaluation of activity during sleep that would otherwise be missed by observation alone. Actigraphy has also been used to assess sleep and wake in children with sleep-disordered breathing. For example, one study compared actigraphic estimates of sleep and wake to PSG on an epoch-by-epoch basis, using various activity thresholds, and reported overall very high predictive values and sensitivity for detecting sleep (all >90%) but much lower predictive values and sensitivity for detecting wake.41 In a study of preschoolers with and without autism, poor agreement was found using actigraphy for detecting nocturnal awakenings compared with video observations.42 Although actigraphy offers many advantages as a means to quantify sleep and wake in children, results may be less reliable for detecting awakenings, and validation studies are needed for the specific device to be used and for the specific population of children to be studied. Geriatrics At the other end of the age spectrum, actigraphy has been used to study sleep–wake patterns of the elderly. The elderly are particularly susceptible to sleep complaints secondary to circadian rhythm changes, sleep-disordered breathing, PLMS, medical illness, and medication use.43 Although some of these complaints may be examined in the laboratory, the elderly are often more set in their ways, need to stay home to take care of a spouse, or just find it more comfortable to sleep in their own beds. In many large studies of older adults, actigraphy represents the only viable option for obtaining objective measures of sleep. Many studies tend to rely on self-report of sleep duration, but this can quite inaccurate in older populations, and particularly among those with poor cognition and functional disabilities.44 Using actigraphy, studies have shown that sleep in nursing home patients is extremely fragmented, with most patients never sleeping for a full hour and never awake for a full hour throughout the 24-hour day.45 Actigraphy was then used to show that a light treatment trial consolidated sleep but did not improve agitation in this population.34,46 Measures of sleep using actigraphy have been incorporated into several large epidemiologic studies of older adults. In this situation, standardization of techniques across multiple clinic sites is essential. In one such study of older women participating in the multicenter Study of Osteoporotic Fractures, excellent agreement was reported between an expert scorer and a second scorer when both followed standardized scoring procedures.47 Further details
1672 PART II / Section 19 • Methodology
are provided in the section Epidemiologic Studies of Sleep. Other Medical Conditions and Populations Actigraphy is increasingly used in clinical research in populations where it would be difficult to conduct PSG studies. Actigraphy has been used to study sleep and circadian rhythms in women in menopause,48 in older schizophrenia patients,49 in patients with cirrhosis,50 in patients with coronary artery disease,51 and in patients with cancer.52-54 Epidemiologic Studies of Sleep Actigraphy is useful for studying sleep in large populations, particularly when recording in the laboratory might be cost-prohibitive and might also jeopardize the compliance rate of subjects. Ancoli-Israel and Kripke, along with their colleagues,55,56 used actigraphy to determine wake and sleep patterns in large samples of elderly (n = 426) and middle-aged (n = 355) subjects. Measurements were used to determine prevalence of sleep apnea and PLMS (these were recorded with additional sensors). Many of these volunteers would have been less willing to participate if they had been required to sleep in the laboratory. Since the turn of the century, several other large observational studies have incorporated measures of sleep using actigraphy. In the multicenter Study of Osteoporotic Fractures, actigraphy was performed in nearly 3000 older women, and in the multicenter study Outcomes of Sleep Disorders in Older Men (MrOS), actigraphy data were collected in more than 3000 older men. Using actigraphy in these populations helped identify the relationship between poor sleep and increased risk of falls,57 poor cognitive function,58 and poor physical performance and functional limitations.59,60 Actigraphy has also been used to obtain objective measures of sleep characteristics in early to middle-aged men and women in the Coronary Artery Risk Development in Young Adults (CARDIA) study.26
TRICKS OF THE TRADE Actigraphs are traditionally placed on the wrist of the nondominant hand. However, two groups of investigators have shown that either wrist can be used. Both found that although activity levels were different between the two hands, agreement rates with PSG were essentially the same for data collected from both hands.9 In studies on babies, actigraphs have also been placed on the baby’s leg.61 Most actigraphs come with bands similar to plastic watch bands. For persons who might be sensitive to such bands or who find it uncomfortable to wear them for long time periods, bands made of terry cloth and hook-and-loop tape (Velcro) can be customized. To discourage patients from removing the bands, the two Velcro-type straps can be reversed, with one opening from right to left and the other from left to right. Some investigators use locked hospital bands to keep actigraphs on difficult populations. These techniques have worked to keep even the most diligent patient from removing the band. These techniques also work with young children.
Patients wearing actigraphs should be asked to keep an actigraph log. They should note information about daily time to bed, time out of bed, and any unusual activity or times when the device is removed (such as for showers or swimming). This information is extremely helpful for editing and analyzing data. When data are collected in 1-minute epochs and for more than 1 week, it is prudent to download data every week to minimize data loss. In units with batteries that need to be replaced, battery levels should be checked when initializing the device and again during downloading. Batteries with levels below 90% of the original battery voltage should be discarded because they are likely to fail. The battery life is approximately 30 days. In our laboratory, a battery log is kept that records the battery number, date activity monitor was initialized, date the data were downloaded, total number of days the battery had been used, and the starting and ending battery level. When actigraphy is used in large samples and with multiple examiners administering the instructions and downloading the data, it is strongly recommended that standardized protocols be developed and that centralized training and certification be incorporated into the overall data quality assurance plan. With devices that also record light, it is extremely important that the light sensor not be covered by the person’s sleeve. The sleeve can be tucked under the actigraph or pinned up to ensure it does not occlude the light sensor. Because the angle of the wrist differs from the angle of the eye, the lux reading from a light sensor might differ from ambient illumination. Some devices have external light sensors, in addition to the internal sensor, which can be clipped to a collar and might give more exact readings. All activity and light monitors should be checked on a regular basis to determine if calibration is needed. In patients with sensitive skin, the bands can be removed for a few minutes each day to prevent pressure sores. The time the device is removed, the time it is replaced, and whether or not the person was awake while it was removed should be noted on the log. This information is needed during the data-editing process.
EDITING ACTIGRAPHY DATA Different software packages are available for scoring the rest–activity data and inferring sleep–wake. Data are edited on a computer screen with the use of the daily sleep log. Time intervals that the device is removed should be manually changed to wake only if the investigator is sure that the person was awake (for example, in the shower); otherwise, these data points should be marked as missing data. Lack of movement scored as sleep when the device was removed for especially vigorous activity can also be manually changed to wake. For example, in a study of adolescents, some subjects removed the actigraph during football or volleyball practice. No activity was recorded during that time period; however, it was clear that the subjects were awake.62 If there is no information on the log about the activity during the time the device was removed, that time period should be scored as missing data. Figure 147-2 shows examples of two actigraph outputs.
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Figure 147-2 A, Four days of unscored output from the SleepWatch-0 (Ambulatory Monitoring, Inc., Ardsley, N.Y.). B, Four days of unscored output from Actiwatch (Mini Mitter, a Respironics Company, Bend, Ore.).
LIMITATIONS The actigraph user needs to be aware of the limitations of these devices.2 When compared to PSG, actigraphy is fairly valid and reliable in healthy normal subjects. It is best at estimating total sleep time. As sleep becomes more disturbed, the actigraph becomes less accurate. In general, actigraphy can overestimate sleep and underestimate wake, particularly during the day.
SUMMARY Wrist activity has the advantages of being cost-efficient, allowing the recording of sleep in natural environments, recording behavior that occurs both during the night and during the day, and recording for long time periods. Although it is not a replacement for EEG or PSG recordings, there are times when actigraphy provides clear advantages for data collection.
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Actigraphy is particularly useful for studying persons who cannot tolerate sleeping in the laboratory; for example, patients with complaints of insomnia, small children, or the elderly. It can provide a more accurate estimate of typical sleep durations by providing an opportunity for patients to adhere more closely to their scheduled sleep and wake times. Actigraphy is also becoming an important tool in follow-up studies and for examining efficacy in clinical outcome. Actigraphy has some value in the assessment of sleep disorders, although it does not necessarily distinguish between different sleep disorders. The newer scoring algorithms have great accuracy in determining variables that are most important in insomnia, namely, improved ability to detect wake versus sleep, sleep latency, awakenings during the night, and total sleep time. Actigraphy is particularly superior to sleep logs in detecting brief arousals during the night. It can also be used for the evaluation and clinical diagnosis of circadian rhythm disorders. The ability to detect movements hold promise in the identification of sleep disorders characterized by frequent movements, such as PLMS, sleep apnea, or REM sleep behavior disorders. The ability to measure for long time periods makes actigraphy particularly useful in situations where long-term changes in sleep are of interest. ❖ Clinical Pearl Actigraphy is reliable and valid for detecting sleep in normal populations, but it is less reliable for detecting disturbed sleep. It is a useful adjunct to the routine evaluation of insomnia, circadian rhythm disorders, and excessive sleepiness, and it helps in the diagnosis of periodic limb movements in sleep and restless legs syndrome. It is useful in special populations such as children and the demented elderly. Actigraphy is becoming a valuable tool for studying sleep in large-scale epidemiologic studies.
Acknowledgments Research reported in this chapter is supported by NIA AG08415, AG026720, NCI CA112035, NHLBI HL071194, and the Research Service of the Veterans Affairs San Diego Healthcare System. REFERENCES 1. Tryon WW. Activity measurement in psychology and medicine. New York: Plenum Press; 1991. 2. Ancoli-Israel S, Cole R, Alessi CA, et al. The role of actigraphy in the study of sleep and circadian rhythms. Sleep 2003;26:342-392. 3. Gorny SW, Spiro JR. Comparing different methodologies used in wrist actigraphy. Sleep Rev 2001;Summer:40-42. 4. Sadeh A, Acebo C. The role of actigraphy in sleep medicine. Sleep Med Rev 2002;6:113-124. 5. Cole RJ, Kripke DF, Gruen W, et al. Automatic sleep/wake identification from wrist activity. Sleep 1992;15:461-469. 5a. Weiss AR, Johnson NL, Berger NA, Redline S. Validity of activitybased devices to estimate sleep. J Clin Sleep Med 2010;6:336-342. 6. Hauri PJ, Wisbey J. Wrist actigraphy in insomnia. Sleep 1992; 15(4):293-301. 7. Verbeek I, Arends J, Declerck G, Beecher L. Wrist actigraphy in comparison with polysomnography and subjective evaluation in insomnia. In: Coenen AML, editor. Sleep–wake research in the Netherlands. ed 5. Leiden: Dutch Society for Sleep–Wake Research; 1994, p. 163-170.
8. Sadeh A, Alster J, Urbach D, Lavie P. Actigraphically based automatic bedtime sleep–wake scoring: validity and clinical applications. J Ambulatory Monitoring 1989;2(3):209-216. 9. Sadeh A, Sharkey KM, Carskadon MA. Activity-based sleep–wake identification: an empirical test of methodological issues. Sleep 1994;17:201-207. 10. Ancoli-Israel S, Clopton P, Klauber MR, et al. Use of wrist activity for monitoring sleep/wake in demented nursing home patients. Sleep 1997;20:24-27. 11. Blackwell T, Redline SS, Ancoli-Israel S, et al. Comparison of sleep parameters from actigraphy and polysomnography in older women: the SOF study. Sleep 2008;31:283-291. 12. Johnson NL, Kirchner HL, Rosen CL, et al. Sleep estimation using wrist actigraphy in adolescents with and without sleep disordered breathing: a comparison of three data modes. Sleep 2007;30: 899-905. 13. Sadeh A, Hauri PJ, Kripke DF, Lavie P. The role of actigraphy in the evaluation of sleep disorders. Sleep 1995;18:288-302. 14. Marler MR, Martin JL, Gehrman PR, Ancoli-Israel S. The sigmoidally-transformed cosine curve: a mathematical model for circadian rhythms with symmetric non-sinusoidal shapes. Stat Med 2006;25: 3893-3904. 15. Bliwise DL. Review: sleep in normal aging and dementia. Sleep 1993;16:40-81. 16. Espiritu RC, Kripke DF, Ancoli-Israel S, et al. Low illumination by San Diego adults: Association with atypical depressive symptoms. Biol Psychiatry 1994;35:403-407. 17. Campbell SS, Kripke DF, Gillin JC, Hrubovcak JC. Exposure to light in healthy elderly subjects and Alzheimer’s patients. Physiol Behav 1988;42:141-144. 18. Ancoli-Israel S, Kripke DF. Now I lay me down to sleep: the problem of sleep fragmentation in elderly and demented residents of nursing homes. Bull Clin Neurosci 1989;54:127-132. 19. Morgenthaler T, Alessi C, Friedman L, et al. Practice parameters for the use of actigraphy in the assessment of sleep and sleep disorders: an update for 2007. Sleep 2007;30:519-529. 20. Lichstein KL, Stone KC, Donaldson J, et al. Actigraphy validation with insomnia. Sleep 2006;29:232-239. 21. Vallieres A, Morin CM. Actigraphy in the assessment of insomnia. Sleep 2003;26:902-906. 22. Aubert-Tulkens G, Culee C, Rijckevorsel KH, Rodenstein DO. Ambulatory evaluation of sleep disturbance and therapeutic effects in sleep apnea syndrome by wrist activity monitoring. Am Rev Respir Dis 1987;136:851-856. 23. Kazenwadel J, Pollmacher T, Trenkwalder C, et al. New actigraphic assessment method for periodic leg movements (PLM). Sleep 1995;18:689-697. 24. Kemlink D, Pretl M, Sonka K, Nevsimalova S. A comparison of polysomnographic and actigraphic evaluation of periodic limb movements in sleep. Neurol Res 2008;30:234-238. 25. Collado-Seidel V, Kazenwadel J, Wetter TC, et al. A controlled study of additional sr-l-dopa in l-dopa–responsive restless legs syndrome with late-night symptoms. Neurology 1999;52:285-290. 26. Knutson KL, Rathouz PJ, Yan LL, et al. Intra-individual daily and yearly variability in actigraphically recorded sleep measures: the CARDIA study. Sleep 2007;30:793-796. 27. Mormont MC, Waterhouse J, Bleuzen P, et al. Marked 24-h rest/ activity rhythms are associated with better quality of life, better response and longer survival in patients with metastatic colorectal cancer and good performance status. Clin Cancer Res 2000;6: 3038-3045. 28. Gehrman PR, Marler M, Martin JL, et al. The timing of activity rhythms in patients with dementia is related to survival. J Gerontol Med Sci 2004;59A:1050-1055. 29. Carskadon MA, Acebo C, Richardson GS, et al. An approach to studying circadian rhythms of adolescent humans. J Biol Rhythms 1997;12:278-289. 30. Lavie P, Tzischinsky O, Epstein R, Zomer J. Sleep–wake cycles in rotating shift work: effects of changing from phase advance to phase delay rotation. Isr J Med Sci 1992;28(8-9):636-644. 31. Buck A, Tobler I, Borbely AA. Wrist activity monitoring in air crew members: a method for analyzing sleep quality following transmeridian and north–south flights. J Biol Rhythms 1989;4(1):93-105. 32. Lavie P. Effects of midazolam on sleep disturbances associated with westward and eastward flights: evidence for directional effects. Psychopharmacology (Berlin) 1990;101(2):250-254.
33. Martin J, Marler MR, Shochat T, Ancoli-Israel S. Circadian rhythms of agitation in institutionalized patients with Alzheimer’s disease. Chronobiol Intl 2000;17:405-418. 34. Ancoli-Israel S, Martin JL, Kripke DF, et al. Effect of light treatment on sleep and circadian rhythms in demented nursing home patients. J Am Geriatr Soc 2002;50:282-289. 35. van Someren E, Swaab DF, Colenda CC, et al. Bright light therapy: improved sensitivity to its effects on rest–activity rhythms in Alzheimer’s patients by application of nonparametric disorder. Chronobiol Int 1999;16:505-518. 36. Sadeh A, Dark I, Vohr BR. Newborns’ sleep–wake patterns: the role of maternal, delivery and infant factors. Early Hum Dev 1996;44: 113-126. 37. Sadeh A, Raviv A, Gruber R. Sleep patterns and sleep disruptions in school-age children. Dev Psychol 2000;36:291-301. 38. Hering E, Epstein R, Elroy S, et al. Sleep patterns in autistic children. J Autism Dev Disord 1999;29:143-147. 39. Glod CA, Teicher MH, Hartman CR, Harakal T. Increased nocturnal activity and impaired sleep maintenance in abused children. J Am Acad Child Adolesc Psychiat 1997;36:1236-1243. 40. Sadeh A. Assessment of intervention for infant night waking: parental reports and activity-based home monitoring. J Consult Clin Psychol 1994;62(1):63-68. 41. Hyde M, O’Driscoll DM, Binette S, et al. Validation of actigraphy for determining sleep and wake in children with sleep disordered breathing. J Sleep Res 2007;16:213-216. 42. Sitnick SL, Goodlin-Jones BL, Anders TF. The use of actigraphy to study sleep disorders in preschoolers: some concerns about detection of nighttime awakenings. Sleep 2008;31:395-401. 43. Ancoli-Israel S. Sleep problems in older adults: putting myths to bed. Geriatrics 1997;52:20-30. 44. van den Berg JF, van Rooij FJ, Vos H, et al. Disagreement between subjective and actigraphic measures of sleep duration in a populationbased study of elderly persons. J Sleep Res 2008;17(3):295-302. 45. Pat-Horenczyk R, Klauber MR, Shochat T, Ancoli-Israel S. Hourly profiles of sleep and wakefulness in severely versus mild–moderately demented nursing home patients. Aging Clin Exp Res 1998;10: 308-315. 46. Ancoli-Israel S, Gehrman PR, Martin JL, et al. Increased light exposure consolidates sleep and strengthens circadian rhythms in severe Alzheimer’s disease patients. Behav Sleep Med 2003;1:22-36. 47. Blackwell T, Ancoli-Israel S, Gehrman PR, et al. Actigraphy scoring reliability in the study of osteoporotic fractures. Sleep 2005;28: 1599-1603.
CHAPTER 147 • Actigraphy 1675 48. Baker A, Simpson A, Dawson D. Sleep disruption and mood changes associated with menopause. J Psychosomatic Res 1997;43:359-369. 49. Martin J, Jeste DV, Caligiuri M, et al. Actigraphic estimates of circadian rhythms and sleep/wake in older schizophrenia patients. Schizophr Res 2001;47:77-86. 50. Cordoba J, Cabrera J, Lataif L, et al. High prevalence of sleep disturbance in cirrhosis. Hepatology 1998;27:339-345. 51. Redeker NS, Wykpisz E. Effects of age on activity patterns after coronary artery bypass surgery. Heart Lung 1998;28:5-14. 52. Ancoli-Israel S, Moore P, Jones V. The relationship between fatigue and sleep in cancer patients: a review. Eur J Cancer Care 2001; 10:245-255. 53. Berger AM. Patterns of fatigue and activity and rest during adjuvant breast cancer chemotherapy. Oncol Nurs Forum 1998;25:51-62. 54. Mormont MC, De Prins J, Levi F. Assessment of activity rhythms by wrist actigraphy: preliminary results in 30 patients with colorectal cancer. Biol Rhythm Res 1995;6:423. 55. Ancoli-Israel S, Kripke DF, Klauber MR, et al. Sleep disordered breathing in community-dwelling elderly. Sleep 1991;14(6):486-495. 56. Kripke DF, Ancoli-Israel S, Klauber MR, et al. Prevalence of sleep disordered breathing in ages 40-64 years: A population-based survey. Sleep 1997;20:65-76. 57. Stone KL, Ancoli-Israel S, Blackwell T, et al. Poor sleep is associated with increased risk of falls in older women. Arch Intern Med 2008;168:1768-1775. 58. Blackwell T, Yaffe K, Ancoli-Israel S, et al. Poor sleep is associated with impaired cognitive function in older women: the study of osteoporotic fractures. J Gerontol Med Sci 2006;61:405-410. 59. Goldman SE, Stone KL, Ancoli-Israel S, et al. Poor sleep is associated with poorer physical performance and greater functional limitations in older women. Sleep 2007;30:1317-1324. 60. Dam TL, Ewing SK, Ancoli-Israel S, et al. Association between sleep and physical function in older men: the Osteoporotic Fractures in Men Sleep Study. J Am Geriatr Soc 2008;56:1665-1673. 61. Gershoni-Baruch R, Epstein R, Tzischinsky O, et al. Actigraphic home-monitoring of the sleep pattern of in vitro fertilization children and their matched controls. Dev Med Child Neurol 1994;36: 639-645. 62. Israel SL, Ancoli-Israel S. Light exposure, sleep and delayed sleep phase in middle-school adolescents. Sleep Res 1997;26:159.
Gastrointestinal Monitoring Techniques William C. Orr and Chien Lin Chen Abstract Symptoms suggesting unexplained arousals from sleep resulting in complaints of insomnia or daytime sleepiness may well have nocturnal gastroesophageal reflux (GER) as an underlying contributing factor. In addition, nocturnal GER may be the cause of exacerbations from bronchial asthma and repeated pulmonary infections as a result of pulmonary aspiration of refluxed gastric contents. For most clinical circumstances, 24-hour ambulatory pH studies with careful documentation of the sleeping interval are suitable and allow a reasonable assessment of waking GER and sleep-related GER, as well as acid contact time (ACT) during the total interval and the sleep
Gastroesophageal reflux (GER) is a common problem associated with considerable morbidity.1 Studies have shown the highest incidence of esophagitis, as well as the most severe complications (erosion and stricture), to be associated with recumbent reflux that occurs during sleep, a situation permitting prolonged acid mucosal contact.2,3 This is presumably the result not only of an incompetent lower esophageal sphincter (LES) but also of an inability to effectively clear the refluxed material. Poor clearance of acid from the esophagus and subsequent acid neutralization have been documented to be impaired during sleep.4,5 GER may be viewed as consisting of two components: the retrograde flow of gastric contents through the antireflux barrier at the esophagogastric junction and the return of the acid gastric juice to the stomach and subsequent neutralization of the distal esophagus to a pH of 4 (i.e., esophageal acid clearing). The critical parameter in determining the extent of GER, and its potential damage to the esophageal mucosa, is the percentage of time the esophagus is exposed to a pH lower than 4. In view of the previous research documenting the importance of sleep-related GER in the pathogenesis of reflux esophagitis, it is important to determine the percentage of acid contact time (ACT) at night, as well as during the day. Postprandial reflux has been shown to be physiologic, and when confined to the postprandial interval, it is considered benign.6 In determining the clinical significance of GER, it is important to assess the 24-hour pattern (see Chapter 127). Twenty-four-hour patterns of GER can be evaluated with commercially available devices. Two types of pH studies are described here: ambulatory pH studies in which sleep monitoring does not occur and inlaboratory pH studies that include simultaneous pH monitoring with polysomnography (PSG). More recent developments include techniques that allow the assessment of both acidic and nonacidic reflux via impedance measurement.
AMBULATORY pH MONITORING Ambulatory esophageal pH monitoring can be accomplished by using commercially available pH probes and 1676
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interval. When patients present with unexplained extraesophageal symptoms, such as chronic cough, uncontrolled nocturnal wheezing, or repeated pulmonary aspiration, dual pH monitoring can provide unique data concerning the role of GER in the pathogenesis of these symptoms. Impedance monitoring of the esophagus now allows the assessment of nonacidic reflux and the proximal migration of refluxant to the level of the upper esophageal sphincter. In the majority of instances, ambulatory studies provide adequate information for clinical management. In certain circumstances, however, more precise information may be needed concerning specific responses to reflux or infused acid, necessitating a complete polysomnographic evaluation.
portable data-acquisition devices. The techniques are similar to those in Holter monitoring; the patient is intubated with either a glass- or antimony-tipped pH electrode, the output of which is attached to a small recorder (3.5-inch wide × 7.25-inch long × 1-inch deep) that recorder patient wears either at the waist with a belt or across the shoulder with a shoulder strap. Our laboratory specifically conducted a validation study of one of these units, which included simultaneous monitoring of input to the computer system and polygraphic tracing of the pH. Although this was not an ambulatory study, because the patient had to be tethered to a recording device, there was excellent agreement between the computer-detected reflux events and those detected by visual inspection from the paper tracing.7 The decision to use antimony or glass electrodes depends on a variety of factors; each has advantages and disadvantages. The glass electrode is somewhat more accurate and linear across a large pH range, whereas the antimony electrode is somewhat more durable. From a clinical standpoint, there is little difference between the two with regard to the accuracy of data collected. These commercially available devices have internal calibration techniques that should be performed before every intubation. For the best readings, the pH probe is placed 5 cm above the proximal border of the manometrically determined LES. The LES must be determined manometrically, which can be somewhat inconvenient because it can require two separate intubations (the first to determine the LES location and the second to insert the pH probe). However, a pH probe has been developed to allow the site of the LES to be determined and the pH probe to be placed with a single intubation. Data have shown that an approximation of the ideal site can be accomplished by using pH determinations only. This method requires placing the pH probe distally until a clearly acidic (approximately 1.5 to 2.5) pH is established (indicating that the pH probe is in the stomach) and then slowly withdrawing the probe until the pH rises to approximately 4. At that point, the pH probe is most likely out of the stomach and in the esophagogastric junction. The
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probe is then withdrawn 5 to 7 cm above this level and affixed at that point. Although not as accurate as the manometric method of determination, for clinical purposes this is an acceptable placement method. It should be recognized, however, that this method has been shown to be most problematic with regard to accuracy in patients who actually have substantial GER and most accurate in normal volunteers.8 Thus, whenever feasible, the manometric method should be used to locate the LES for accurate pH probe placement. With the increasing clinical interest in establishing GER as the cause of a variety of extraesophageal symptoms such as bronchial asthma, chronic cough, laryngopharyngitis, and pulmonary aspiration, dual pH probe monitoring has become substantially more popular. It entails monitoring at least two sites in the esophagus: one at the standard site in the distal esophagus (placed as described earlier) and one in the more proximal esophagus. The exact location in the more proximal esophagus varies from the midesophagus to the pharynx, and there is little in the way of currently accepted standard as to the proximal probe placement. Studies have shown that proximal esophageal and pharyngeal acid exposure effectively discriminates persons with posterior laryngitis.9 A study by Jacob and colleagues10 has shown that supine (primarily during sleep) proximal acid exposure best discriminates patients with laryngeal symptoms from those with reflux esophagitis and normal persons.10 These data suggest that some proximal acid exposure has clinically significant correlates. Dual pH probe monitoring assumes additional clinical significance in reviewing data from Koufman, who has shown in an animal model that even minute amounts of acid exposure can create cancerous lesions in the larynx.11 In addition, numerous studies have shown that patients with aerodigestive symptoms such as chronic cough and pulmonary aspiration have greater proximal esophageal and pharyngeal acid exposure.10,12,13 Although much work needs to be done to assess the importance of, and specific parameters relating to, proximal esophageal acid exposure in the pathogenesis of extraesophageal symptoms of reflux, it is clear that the trend is moving increasingly toward use of dual pH monitoring. Once the intubation has been accomplished, the patient is instructed concerning the operation of the dataacquisition system. Patients may be given special dietary instructions to avoid acidic foods; however, our preference is not to have the patient adopt a special diet. GER and heartburn are both significantly affected by dietary intake; therefore a more accurate clinical picture of the frequency and severity of GER can be obtained if patients eat their usual meals. The patient completes a log to document significant events. The patient is instructed to indicate the start and end time of meals, time of going to sleep and waking up, time of taking medication, and time of occurrence of clinical symptoms. The patient is instructed to return to the laboratory approximately 24 hours from the time of departure. On returning to the laboratory, the patient is extubated and the data are downloaded into a computer system that analyzes a variety of reflux parameters over the total recording interval. These parameters include number of reflux episodes, average duration of the reflux episodes,
longest reflux episode, percentage of ACT, and a summary of these events according to upright (primarily waking) and supine (primarily sleeping) postures. The computer printout summarizes the timing of meals, sleep, and clinical symptoms as well. This information allows one to determine the relationship of symptoms to episodes of GER. A technique for monitoring pH via wireless telemetry is also now available. The Medtronic Bravo pH monitoring system is approved in the United States. This pH system involves attaching a radiotelemetry pH capsule to the mucosal wall of the esophagus using a prepackaged assembly that incorporates both a delivery system and the pH capsule. The capsule is oblong (6 × 5.5 × 25 mm) and contains a well (4 mm in diameter by 3.5 mm deep) for delivery, antimony pH electrode and reference electrode, and an internal battery and transmitter. The pH capsule sends a data signal to the external receiver via radiofrequency telemetry. Using endoscopic measurement, the pH probe is positioned 6 cm above the squamocolumnar junction, which approximates the placement method targeting a position 5 cm proximal to the upper margin of LES that is typically used in conventional pH recordings.14 The wireless pH monitoring system has demonstrated usefulness by successfully recording up to 2 days in 89% of all enrolled subjects.15 The Bravo system has been shown to have minimal impact on daily acidity and diet. It is a viable option for patients who are unwilling or unable to undergo conventional pH studies using a transnasally placed pH electrode and who will be undergoing endoscopy or part of an evaluation for acid reflux disease. The power of the wireless pH recording system in distinguishing esophagitis patients from controls has been demonstrated to be comparable with previous results using a conventional pH monitoring system.15-17 In fact, the discriminative power of the wireless pH study is comparable using data from the first 24-hour recording, but the sensitivity is more improved using data from the worse day of the 48-hour recording. It takes advantage of the observation that esophageal acid exposure can exhibit day-to-day variability.18 The comparable ability of the wireless pH system was also observed in discriminating endoscopy negative gastroesophageal reflux disease (GERD) from controls. However, in this patient population, there was no significant improvement in sensitivity or specificity using data from the worse day of the 48-hour recording.15 This is likely due to the fact that excessive acid exposure is one of the several pathophysiologic factors contributing to nonerosive GERD (NERD) in which hypersensitivity to acid reflux and symptoms can occur without pathologic acid reflux.19 Although more work is needed related to analyzing symptoms, the wireless pH monitoring system using 48-hour recording may be particularly beneficial in the diagnosis of NERD by increasing the possibility of documenting the association between symptoms and reflux over a longer duration of recording. Multichannel intraluminal impedance (MII) has been introduced as a new technique to study esophageal motility, and the reflux of gastric contents (acidic and nonacidic) based on differences in conductivity to alternating current of intraluminal content.20 Impedance is the average electric resistance between two adjacent electrodes and is measured using a specialized catheter with a 2.1-mm diameter
1678 PART II / Section 19 • Methodology
consisting of a series of cylindrical electrodes that make up measuring segments, each 2 cm long, corresponding to one recording channel. The impedance between the two electrodes is inversely proportion to the electrical conductivity and the cross-sectional area of the material through which the current must travel. If a highly conductive bolus arrives at the measuring segment (saliva), impedance will decrease, and the opposite occurs with a resistive bolus (air). Additionally, increasing the luminal diameter (arrival of bolus into the measuring segment) results in an impedance drop, whereas a luminal narrowing (contraction wave) causes an impedance increase. Studies have indicated that MII can be used as a discriminative test of esophageal function evaluating bolus transport.21 It has been shown that combining MII with esophageal manometry (MIIEM) allows simultaneous measurement of intraesophageal pressure and bolus movement.22 These data suggest that MII-EM is a more sensitive tool in assessing esophageal function compared to standard manometry because impedance can distinguish different bolus transit pattern. The use of MII allows determination of the direction of bolus movement within the esophagus. Progression of impedance changes from distal to proximal indicates retrograde bolus movement as found in GER. It allows prolonged monitoring and detection of bolus volume presence independent of the chemical (pH) composition, as well as the proximal migration of the refluxant. In combined MII-pH, the pH sensor is used to define whether the refluxant is acid or nonacid based on predefined criteria. Combined manometry pH impedance has been used to study the patterns of gas and liquid reflux in adults or patients with GERD.23-25 Using this approach in subjects in the sitting position, Sifrim and colleagues have shown that patients with reflux disease had more acid reflux, less nonacid reflux, and higher proportion of pure liquid reflux compared with healthy subjects.24-25 Intraluminal impedance is able to detect small volumes of liquid reflux of more neutral pH that are not detected by the traditional pH sensor. Combined impedance with pH monitoring allows the detection of most reflux episodes: very acid (pH <4), moderately acid (pH 4 to 6), and nonacid (pH 6 to 7). A pH drop below 4 usually indicates acidic GER. All other reflux events could be categorized as nonacidic reflux. The pathophysiologic relevance of nonacidic reflux in GERD is still unknown, but previous data suggest that it does not play a role in the development of esophageal mucosal damage because of no difference in the patterns of nonacidic reflux between patients with reflux disease and healthy controls.26 However, it might be more important as a cause of persistent symptoms in patients taking acidsuppressant therapy27 or in patients with endoscopy-negative reflux disease. The nonacidic reflux episodes in the most proximal impedance segment have been shown to be less than that of traditional acid reflux episodes both in patients with reflux disease and controls, suggesting a smaller volume of liquid refluxant.28
POLYSOMNOGRAPHIC RECORDING In certain circumstances, a PSG recording during pH monitoring may be desirable. For example, there may be specific interest in the possibility that a patient is having
sleep-related reflux and pulmonary aspiration. In addition, nocturnal recordings of reflux or the clearance time of externally infused acid might identify persons who are at high risk for pulmonary aspiration. Such persons are specifically identified by prolonged clearance of spontaneous reflux or infused acid associated with poor arousal responses from sleep. It may be clinically useful to note whether reflux itself is triggered by periodic arousal responses as a result of disturbed sleep. Such a relationship (sleep-related reflux preceded by a brief arousal response) has been reported.29 Similar findings have been reported with actigraphy.29a Electrode placement is as described for ambulatory studies. A reference lead is placed on the ventral surface of the forearm or the forehead. The reference lead and the pH probe should always be recorded through an electrical isolation box attached to the pH meter. Any commercially available pH meter is suitable, but it must have an external output to allow polygraphic recording. The output needs to be in a range of 0 to 1 V for most direct-current (DC) amplifiers. This measurement is made simultaneously with the standard polygraphic measurements for monitoring sleep (i.e., electroencephalogram, electrooculogram, electromyogram, electrocardiogram). Reflux is defined by a drop in the pH of the distal esophagus below a level of 4. Clearance is arbitrarily defined by a return of the esophageal pH to 4. The time between the drop in the pH below 4 and its return to 4 is referred to as the clearing duration or clearance interval. A pH of 4 has been arbitrarily chosen as the criterion to determine a reflux event because the esophageal pH level is routinely between 5.5 and 6.5. Thus, for the pH to drop below 4, it is assumed that the electrode must be in contact with acid. There is little if any peptic activity associated with a pH of 4, although such activity increases logarithmically as the pH decreases below 4. With regard to evaluating esophageal function during sleep, we have chosen to focus on the patient’s ability to clear infused acid from the esophagus. This method has several advantages. First, spontaneous reflux during sleep— even in symptomatic patients with esophagitis—is relatively infrequent and unpredictable. Second, important parameters such as when the event occurs and the volume of the refluxant are uncontrolled with spontaneous reflux. Our method was designed to evaluate reflux by simulating an event using a controlled infusion of a specified volume at a specific point in time (waking versus a particular stage of sleep). Although this method does not allow the study of the effects of physiologic reflux, it does allow the control of the other critical factors. Although acidity per se does not necessarily damage the mucosa, we assume that the arousal response from sleep is the result of the afferent stimulus caused by the low pH. Volume is an important parameter in producing arousal responses, and it is therefore important to take this variable into consideration in evaluating reflux during sleep. For example, studies in our laboratory have shown that acid clearance and arousal responses are markedly altered by the volume infused into the esophagus.30 Other obvious advantages of performing sleep studies relate to the determination of important responses to esophageal acidification such as polygraphic arousal responses and swallowing
CHAPTER 148 • Gastrointestinal Monitoring Techniques 1679
Esophageal pH
Infusion of acid 7 6 5 4 3 2 1
Acid clearing duration
Submental EMG EEG Asleep
Arousal from sleep
Asleep
Figure 148-1 Schematic representation of the acid infusion paradigm. As with spontaneous gastroesophageal reflux, the duration of acid clearing is determined as the time from the drop in pH below 4 until the pH reaches 5 (in some studies the value is 4). EEG, electroencephalogram; EMG, electromyogram.
responses. These are important parameters with regard to acid clearance (assuming normal esophageal motor function) that cannot be assessed via 24-hour ambulatory studies. The schematic diagram in Figure 148-1 illustrates the parameters that are obtained from a single infusion of a controlled volume of acid. The acid clearance time is determined as the interval of time elapsing between the drop in pH to 4 or lower until the pH returns to 4. The arousal response latency is the elapsed time from a pH drop to 4 until polygraphic evidence of an arousal response. The latency to the first swallow is defined as the elapsed time from the drop in pH to 4 until the first swallow, defined as a transient burst of muscle activity from the submental electromyogram recording. Studies in our laboratory have determined normal parameters for these measures.4,5
CLINICAL INTERPRETATION GERD is a complex multifactorial disorder involving not only physiologic mechanisms that determine the retrograde flow of acid contents from the stomach into the esophagus but also anatomic aspects of mucosal resistance.1,31 Current diagnostic methodology confines itself only to evaluating GER and mucosal esophageal ACT. Important aspects of the pathogenesis of esophagitis, such as hydrogen ion back diffusion, constituents of the acid contents of the stomach (i.e., pepsin, bile salts, and pancreatic enzymes), and esophageal mucosal potential difference are not routinely available for evaluation in patients. However, the 24-hour ambulatory pH study allows one to assess a number of parameters thought to be important in the development of esophagitis. Clinically, the most important parameters relate to the total percentage of ACT, percentage of ACT in the upright
and supine positions, longest reflux episode, and number of reflux episodes longer than 5 minutes. The assessment of each of these parameters and the extent to which they occur in the waking state versus sleep are all clinically relevant. Normal parameters for reflux events have been published in a number of sources and have been reviewed by de Caestecker.32 Clinical interpretation of these studies is, to a large extent, subjective. However, most experts agree that the most important parameter is ACT. For a normal person, total ACT is generally between 4% and 6%. At or above 8% is considered a clinically significant elevation in ACT. If the majority of ACT occurs in the sleeping interval or if the sleeping ACT exceeds 4% to 5%, however, the clinical impact is considerably greater. In interpreting differences between upright (waking) and the sleeping interval it has been shown that recumbent but awake is not different from upright in terms of the percentage of acid contact time noted.33 The researchers concluded that the acidreflux events in the recumbent-awake period are more similar to the upright period than to the recumbent asleep period. It was suggested that the state of consciousness (awake versus asleep) is physiologically more critical for 24-hour esophageal monitoring analysis than body position. This clinical difference occurs because patients who are susceptible to sleep-related reflux have prolonged acid clearance associated with episodes of reflux during sleep, and such episodes are thought to be more damaging to the esophageal mucosa than short waking episodes, even if they are more numerous.3,6 With regard to pH studies that are conducted as part of a PSG evaluation, several variables are clinically important. First, the occurrence of spontaneous GER needs to be documented by identifying each time the esophageal pH drops below 4. The length of the subsequent arousal latency response is also significant. For example, an arousal response that is delayed beyond 2 to 3 minutes might indicate some alteration in arousal mechanisms. A prolongation of the arousal latency or the acid clearance time suggests that the patient may be at risk for pulmonary aspiration. It is not fully understood whether nonacidic mucosal contact, being more neutral pH, would also induce a similar arousal response. To address these questions, we examined the occurrence of acidic and nonacidic reflux during sleep under conditions of powerful acid suppression using impedance and pH measurement techniques.34 Acidic reflux events were significantly decreased with proton pump inhibitor (PPI) treatment as compared to placebo. Nonacid reflux events were more common with PPI treatment as compared to placebo, but this result was not statistically significant. Under conditions of powerful acid suppression, the ratio of nonacidic to acidic events was significantly greater with PPI treatment, although proximal migration of acidic versus nonacidic reflux events was not significantly different. Our study documents a trend for increasing nonacidic reflux during sleep subsequent to powerful acid suppression. The findings indicate that the esophagus is equally responsive to acidic and nonacidic reflux events in terms of both eliciting arousal responses and preventing significant proximal migration. Also of considerable clinical significance is the association of multiple short awakenings
1680 PART II / Section 19 • Methodology
with repeated reflux events, which might suggest that fragmented sleep may be contributing to a complaint of daytime sleepiness. We have investigated GERD patients with and without nighttime heartburn. All participants had to undergo simultaneous recordings of 24-hour esophageal pH and polysomnography.35 It was noted that overall acid contact time was significantly greater in patients with nighttime heartburn than in those without nighttime heartburn. Despite a significant difference noted regarding these reflux parameters, no difference could be identified for any objective sleep parameter by an overnight polysomnographic study. This study suggests that nighttime heartburn is associated with excessive GER. These data collectively indicate that sleep-related GER indicates a more-severe form of GERD and deserves more attention in daily clinical practice. The inconsistency between subjective and objective sleep measures may be partially explained by the fact that a transnasal pH catheter can induce discomfort that can influence the quality and duration of sleep, one of the major outcomes measures of the study. Similarly, we have demonstrated an improvement in subjective but not objective measures of sleep after treatment with a PPI in a group of symptomatic GERD patients.36 As with the ambulatory studies, the percentage of time the esophageal pH is below 4 is relevant, as is the number of spontaneous episodes of reflux. Normal persons rarely have reflux during sleep; thus, the spontaneous occurrence of GER during sleep is an important clinical event. Having more than two or three episodes a night is clinically significant, particularly if any one of these events is associated with prolonged ACT (longer than 5 to 10 minutes). An acid exposure time exceeding 4% to 5% during sleep probably represents a clinically significant finding, and nocturnal acid suppression would be an appropriate approach to treatment. There are minimal normative data with regard to proximal acid exposure. Because there is no standardization with regard to the placement of the proximal probe, it is impossible to describe normative values across a large population of patients. In general, this is done within each laboratory, where a standardized procedure is used. Most useful information with regard to normative data in the proximal esophagus is described in a review article by Richter.37 In general, most studies in which control data have been collected describe proximal acid contact time in normal persons to be between 0 and 1%.33
❖ Clinical Pearl Esophageal pH monitoring may be helpful in explaining arousals from sleep that result in complaints of insomnia or daytime sleepiness, because sleeprelated GER may be an underlying contributing factor. In addition, sleep-related GER may be the cause of exacerbations from bronchial asthma and repeated pulmonary infections as a result of pulmonary aspiration of refluxed gastric contents, which can be acidic or nonacidic, and nonacidic reflux can be detected via impedance monitoring.
REFERENCES 1. Richter JE, Bradley LA, Castell DO. Esophageal chest pain: current controversies in pathogenesis, diagnosis and therapy. Ann Intern Med 1989;110:66-78. 2. Johnson LF, DeMeester TR. Twenty-four-hour pH monitoring of the distal esophagus, a quantitative measure of gastroesophageal reflux. Am J Gastroenterol 1974;62:325-332. 3. Johnson LF, DeMeester TR, Haggitt RC. Esophageal epithelial response to gastroesophageal reflux, a quantitative study. Am J Dig Dis 1978;23:478-509. 4. Orr WC, Robinson MG, Johnson LF. Acid clearing during sleep in the pathogenesis of reflux esophagitis. Dig Dis Sci 1981;26:423. 5. Orr WC, Johnson LF, Robinson MC. The effect of sleep on swallowing, esophageal, peristalsis, and acid clearance. Gastroenterology 1984;86:814-819. 6. DeMeester TR, Johnson LF, Guy JJ, et al. Patterns of gastroesophageal reflux in health and disease. Ann Surg 1976;184:459-470. 7. Allen M, Woodruff D, Robinson MG, et al. Validation of an ambulatory esophageal pH monitoring system. Am J Gastroenterol 1988;83:287-290. 8. Klauser AG, Schindlbeck NE, Muller-Lissner SA. Esophageal 24-pH monitoring: is prior manometry necessary for correct positioning of the electrode? Am J Gastroenterol 1990;85:1463-1467. 9. Shaker R, Milbrath M, Ren J, et al. Esophagopharyngeal distribution of refluxed gastric acid in patients with reflux laryngitis. Gastroenterology 1995;109:1575-1582. 10. Jacob P, Kahrilas PJ, Herzon G. Proximal esophageal pH-metry in patients with “reflux laryngitis.” Gastroenterology 1991;11: 305-310. 11. Koufman JA. The otolaryngologic manifestations of gastroesophageal reflux disease (GERD): a clinical investigation of 225 patients using ambulatory 24-hour pH monitoring and an experimental investigation of the role of acid and pepsin in the development of laryngeal injury. Larynoscope 1991;101:1-78. 12. Patti MG, Debas HT, Pellegrini CA. Esophageal manometry and 24-hour pH monitoring in the diagnosis of pulmonary aspiration secondary to gastroesophageal reflux. Am J Surg 1992;163:401406. 13. Paterson WG, Murat BW. Combined ambulatory esophageal manometry and dual-probe pH-metry in evaluation of patients with chronic unexplained cough. Dig Dis Sci 1994;39:1117-1125. 14. Kahrilas PJ, Lin S, Chen J, Manka M. The effect of hiatus hernia on gastro-oesophageal junction pressure. Gut 1999;44:476-482. 15. Pandolfino JE, Richter JE, Ours T, et al. Ambulatory esophageal pH monitoring using a wireless system. Am J Gastroenterol 2003;98: 740-749. 16. Johnson F, Joelsson B, Isberg PE. Ambulatory 24-hour intraesophageal pH-monitoring in the diagnosis of gastroesophageal reflux disease. Gut 1987;28:1145-1150. 17. Matioli S, Pilotti V, Spangaro M, et al. Reliability of 24-hour home esophageal pH monitoring in diagnosis of gastroesophageal reflux. Dig Dis Sci 1989;34:71-78. 18. Wiener GJ, Morgan TM, Copper JB, et al. Ambulatory 24-hour esophageal pH monitoring. Reproducibility and variability of pH parameters. Dig Dis Sci 1988;33:1127-1133. 19. Shi G, Bruley des Varannes S, Scarpignato C, et al. Reflux related symptoms in patients with normal oesophageal exposure to acid. Gut 1995;37:457-464. 20. Silay J. Intraluminal multiple electric impedance procedure for measurements of gastrointestinal motility. J Gastrointest Motil 1991;3:151-162. 21. Srinivasan R, Vela MF, Katz PO, et al. Esophageal function testing using multichannel intraluminal impedance. Am J Physiol Gastrointest Liver Physiol 2001;289:G457-G462. 22. Tutuian R, Vela MF, Balaji NS, et al. Esophageal function testing with combined multichannel intraluminal impedance and manometry: multicenter study in healthy volunteers. Clinical Gastroenterol Hepatol 2003;1:174-182. 23. Sifrim D, Silny J, Holloway RH, Janssens JJ. Patterns of gas and liquid reflux during transient lower oesophageal sphincter relaxation: a study using intraluminal electrical impedance. Gut 1999; 44:47-54. 24. Sifrim D, Holloway R. Transient lower esophageal sphincter relaxations: how many or how harmful? Am J Gastroenterol 2001;96: 2529-2532.
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25. Sifrim D, Holloway R, Silny J, et al. Composition of the postprandial refluxate in patients with gastroesophageal reflux disease. Am J Gastroenterol 2001;98:647-655. 26. Sifrim D, Holloway R, Silny J, et al. Acid, non-acid, and gas reflux in patients with gastroesophageal reflux disease during ambulatory 24-hour pH impedance recordings. Gastroenterology 2001;120: 1588-1598. 27. Vela MF, Camacho-Lobato L, Srinivasan R, et al. Simulatneous intraesophageal impedance and pH measurement of acid and nonacid gastroesophageal reflux: effect of omeprazole. Gastroenterology 2001;120:1599-1606. 28. Sifrim D, Tack J, Lerut T, Janssens J. Transient lower esophageal sphincter relaxations and esophageal body muscular contractile response in reflux esophagitis. Dig Dis Sci 2000;45:1293-1300. 29. Dent J, Dodds WJ, Friedman RH, et al. Mechanism of gastroesophageal reflux in recumbent asymptomatic human subjects. J Clin Invest 1980;65:256-267. 29a. Allen L, Poh CH, Gasiorowska A, et al. Increased oesophageal acid exposure at the beginning of the recumbent period is primarily a recumbent-awake phenomenon. Aliment Pharmacol Ther 2010. [Epub ahead of print] 30. Orr WC, Robinson MG, Johnson LF. The effect of esophageal acid volume on arousals from sleep and acid clearance. Chest 1991;99: 351-354.
31. Johnson LF, Harmon JW. Experimental esophagitis in a rabbit model: clinical relevance. J Clin Gastroenterol 1986;8(Suppl. 1): 26-44. 32. de Caestecker JS. Twenty-four-hour oesophageal pH monitoring: advances and controversies. Neth J Med 1989;34:S20-S39. 33. Dickman R, Shapiro M, Malagon IB, et al. Assessment of 24-h oesophageal pH monitoring should be divided to awake and asleep rather than upright and supine time periods. Neurogastroenterol Motil 2007;19:709-715. 34. Orr WC, Craddock A, Goodrich S. Acidic and non-acidic reflux during sleep under conditions of powerful acid suppression. Chest 2007;131:460-465. 35. Chen CL, Robert JT, Orr WC. Sleep symptoms and gastroesophageal reflux. J Clin Gastroenterol 2008;42:13-17. 36. Orr WC, Goodrich S, Robert JT. The effect of acid suppression on sleep parameters and sleep related gastroesophageal reflux. Aliment Pharmacol Ther 2005;21:103-108. 37. Richter JE. Ambulatory esophageal pH monitoring. Am J Med 1997;103:130S-134S.
Light Therapy
Michael Terman and Jiuan Su Terman
Abstract The susceptibility of the circadian system to selective phase shifting by timed light exposure has broad implications for the treatment of sleep phase and depressive disorders. Light therapies have been developed to normalize the patterns of delayed sleep phase disorder (through circadian phase advances) and advanced sleep phase disorder (through circadian phase delays). Physicians and patients need to be cognizant of the daily intervals when light exposure—and darkness—can facilitate or hamper adjustment to the desired circadian phase. The critical intervals lie at the edges of the subjective night, which coincide with the tails of the nocturnal melatonin cycle, but can be inferred clinically through a morn-
Exposure of the eyes to light of appropriate intensity and duration, at an appropriate time of day, can have marked effects on the timing and duration of sleep and on the affective and physical symptoms of depressive illness.1 Here we review and evaluate delivery systems and the application of light therapy for circadian rhythm sleep disorders including delayed sleep phase disorder (DSPD), advanced sleep phase disorder (ASPD), and free running (or non–24-hour) sleep disorder. The most extensive clinical trials have focused on wintertime recurrence of major depression (seasonal affective disorder) [SAD]. We also cover light therapy for nonseasonal depressions (recurrent, chronic, bipolar), including combination treatment with sleep deprivation (wake therapy) and antidepressant medication. Light therapy holds promise in treating several clinical disorders.1a-1f
LIGHT DELIVERY Apparatus Light Boxes Many of the early research studies used a standard 60-cm by 120-cm (2-foot by 4-foot) fluorescent ceiling unit, with a plastic prismatic diffusion screen, placed vertically on a table about 1 meter (3 feet) from the user. A bank of fluorescent lamps—full spectrum or cool white—provided approximately 2500-lux illuminance. Smaller, more lightweight units have become commercially available; however, specific design features of marketed light boxes have most often not been clinically tested. Factors include lamp type (output intensity and spectrum), filter, ballast frequency (for fluorescent lamps), size and positioning of radiating surface, heat emission, and so on. One clinically tested model (Fig. 149-1) illustrates modifications in second-generation apparatus, including smaller size, portability, raised and downwardtilted placement of the radiating surface to reduce glare, height adjustment relative to the patient’s head, a smooth polycarbonate diffusion screen with maximal ultraviolet (UV) filtering, and high-output fluorescent lamps (non1682
Chapter
149 ingness–eveningness questionnaire or habitual sleep timing. The schedule of light exposure might have to be continually adjusted during treatment as the subjective night shifts gradually in the desired direction. The treatment strategy for seasonal and nonseasonal depression is similar. In winter depression, the size of circadian rhythm phase advances correlates with the degree of mood improvement, and the optimal timing of light therapy must be specified relative to the patient’s circadian clock rather than solar time. Apart from its use as a monotherapy, light therapy in outpatient and inpatient trials indicates that it accelerates remission of nonseasonal depression in conjunction with antidepressant and mood-stabilizing medication.
glaring 4000-Kelvin color temperature) driven by highfrequency solid-state ballasts. The combination of elements in this configuration yields a maximum illuminance of approximately 10,000 lux with the patient seated in a position with the eyes about 30 cm (1 foot) from the screen. With the direction of gaze downward toward the work surface, such a configuration provides pleasant illumination suitable for reading and, despite illuminance far higher than in normal home lighting, is generally well tolerated (see Adverse Effects of Bright Light Exposure, later). The presentation of light from above eye level is supported by a study showing enhancement of melatonin suppression with directional illumination of the lower retina.2 As the apparatus becomes miniaturized, however, the field of illumination narrows, and even small changes in head position can substantially reduce the intensity of light that reaches the eyes. Clinicians should seek documentation of the safety and effectiveness of any apparatus under consideration. Home construction of such an apparatus is discouraged because of the danger of excessive irradiation affecting the eyes and eyelids. Claims for the specific efficacy of any particular lamp type or spectral distribution, although commonly made, need to be questioned. Unfortunately, systems have been marketed that provide excessive visual glare, exposure of naked bulbs, direct intense illumination from below the eyes (“ski slope” effect), and intentionally augmented short-wavelength blue and UV radiation. The earliest light therapy trials used full-spectrum white fluorescent light at high color temperature with increased blue and near-UV radiation, in an attempt to approximate the spectral distribution of skylight relative to standard fluorescent sources. UV, however, was shown to be unnecessary for the antidepressant effect,3 leading to the use of alternative light sources and light boxes with UV filters to reduce exposure hazard to the eyes and skin. Claims that blue light is selectively therapeutically active4 have not yet been substantiated. Full-spectrum lighting is tolerable at 2500 lux, but aversive glare is excessive at 10,000 lux, the dose designed
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rior to postawakening light therapy at 10,000 lux administered between 6:00 am and 6:30 am (which may have been too early for these phase-delayed patients). Terman’s group11 conducted a controlled trial of naturalistic dawn simulation ending at individually selected wake up times and found similar rates of improvement to postawakening bright light therapy, and both methods were superior to low-density negative air ions, a nonphotic placebo. The average posttreatment phase advance of dim light melatonin onset was 0.58 hours, in contrast to a small delay shift of 0.19 hours under placebo (2-tailed t-test, P = .001).11a The effectiveness of dawn simulation may depend on the presentation of diffuse, broad-field illumination that reaches the sleeper in varying postures. Such efficacy has not been demonstrated for commercial “light alarm clocks,” which have small directional fields. Adequate apparatus remains an active focus of industrial research and development.
Figure 149-1 Table-mounted, tilted, height-adjustable, 10,000lux, UV-filtered, diffused 4000-Kelvin fluorescent light system. (Photograph courtesy of the Center for Environmental Therapeutics, http://www.cet.org.)
to reduce average session duration from 2 hours to 30 minutes.5 Softer white light with lower color temperature (3000 to 4000 Kelvin) works as well. Both the clinician and consumer must be vigilant in the selection of apparatus. Criteria are reviewed on the therapy Web page of the nonprofit Center for Environmental Therapeutics, http:// www.cet.org. Dawn Simulators Dawn simulation methodology provides a major contrast to bright light therapy. A microprocessor-controlled lighting device delivers a mimic of gradual twilight transitions found outdoors in the spring or summer. A laboratory study of healthy young adults demonstrated that the addition of simulated, naturalistic dawn exposures blocked the delay drift of circadian rhythms under dim light–dark cycles, when subjects were awakened to view the signal.6 For clinical use, relatively dim dawn signals are presented to the patient while asleep, when the eyes are adapted to the dark and the circadian system is most susceptible to phase advances (see Timing of Morning Light Exposure, later). The initial open-label studies of dawn simulation found an antidepressant response; normalization of hypersomnic, phase-shifted, and fractionated sleep patterns; phase advances of the melatonin cycle; and truncation of melatonin production after simulated sunrise.7-9 Avery and colleagues10 conducted a 6-week controlled clinical trial of sigmoid light-onset ramps (which differ from the curvilinear acceleration of naturalistic dawns) rising to 250 lux between 4:30 am and 6:00 am, which were significantly more antidepressant than dim red control signals rising to 0.5 lux. The treatment was supe-
Safety of Bright Light for the Eyes Ophthalmologic evaluations of unmedicated patients with normal oculoretinal status have thus far shown no obvious acute light-induced pathology or long-term sequelae.12 Although the intensity of bright light treatment falls well within the low outdoor daylight range, the exposure conditions differ from those outdoors, and prolonged use entails far greater cumulative light exposure than is normally experienced by urban dwellers and workers.13,14 There remains a risk of direct retinal photoreceptor and pigment epithelium damage, drug photosensitization, and acceleration of age-related macular degeneration to visible spectral components above the UV range up to about 500 nm (blue light).15-17 Although wavelengths from ∼450 to 500 nm preferentially suppress nocturnal melatonin production18 and enhance circadian phase shifting,19 the selective therapeutic benefit of such light has yet to be ascertained. Nevertheless, manufacturers have marketed a variety of blue-light devices. Because the blue-light hazard is magnified at wavelengths below 450 nm, ideally these should be completely filtered out, although commercial fluorescent apparatus has yet to do so. Clinical studies of phase shifting20 and antidepressant effect21 with blue light thus far have shown no advantage over broad-spectrum white light, which remains the standard. White light, of course, includes a blue component, though in lower relative proportion than from narrow-band or blue-supplemented sources. The potential adverse effects of concentrated shortwavelength radiation suggest that clinical implementation for long-term treatment is problematic.22 At the opposite end of the light spectrum, ocular exposure to infrared illumination, which makes up about 90% of the output of incandescent lamps, poses risk of damage to the lens, cornea, retina, and pigment epithelium.23 Thus, despite being marketed for light therapy, incandescent lamps are contraindicated. Light-box diffusion filters vary widely in shortwavelength transmission (for examples, see reference 24). Transmission curves should be demanded of manufacturers and compared with published standards. Normal clouding of the lens and ocular media that begins in middle
1684 PART II / Section 19 • Methodology
age, as well as formation of cataracts, serves to exacerbate perceptual glare that can make high-intensity light exposure quite uncomfortable.24 Furthermore, both UV and short-wavelength blue light can interact with photosensitizing medications—including many standard antidepressant, antipsychotic, and antiarrhythmic agents, as well as common medications such as tetracycline—to promote or accelerate retinal pathology, whether acute, or slow and cumulative.23 In one reported case, a patient received combination treatment with clomipramine and full-spectrum fluorescent light. After 5 days, the patient had reduced contrast sensitivity, foveal sensitivity, and visual acuity and central scotomas and lesions, fortunately with only minor residual aftereffects in contrast sensitivity and scotoma 1 year after discontinuation.25 Filtered glasses are available (see Resources, later) that eliminate transmission of short-wavelength blue light while maximizing exposure above the range of primary circadian photoreception (>535 nm), reducing glare, enhancing visual acuity and subjective brightness,26 and minimizing the risk of drug photosensitization. Such protection is clinically useful to forestall circadian rhythm phase delays and melatonin suppression27 when patients are exposed to ambient light, especially before sleep, with increased risk of initial insomnia. Although there are no definite contraindications for bright light treatment other than the retinopathies, research studies have routinely excluded patients with glaucoma or cataract. Some of these patients have used light therapy effectively in open treatment; this should be done, however, only with ophthalmologic monitoring. A simple eye checkup is advised for all new patients, for which a structured examination chart has been designed (see Resources, later).28 The examination has occasionally revealed preexisting ocular conditions that should be distinguished from potential consequences of bright light treatment. Adverse Effects of Bright-Light Exposure If evening light is timed too late, the patient can develop insomnia and hyperactivity. If morning light is timed too early, the patient can awaken prematurely, well before light onset, and be unable to resume sleep. These problems are responsive to timing and dose (duration and intensity) adjustments during treatment of circadian sleep phase disorders and mood disorders. The emergence of side effects relates in part to the parameters of light exposure, including intensity, duration, spectral content, and method of exposure (diffuse or focused; direct or indirect; forward, upward, or downward angle of incidence relative to the eyes). Thus far, side effects have been assessed primarily in patients with seasonal and nonseasonal mood disorders, and information is lacking for sleep disorders without mood disturbance. The earliest clinical trials of 2500-lux full-spectrum fluorescent light therapy for winter depression noted infrequent side effects of hypomania, irritability, headache, and nausea.29,30 Such symptoms often subside after several days of treatment. If persistent, they can be reduced or eliminated by decreasing the dose. Rarely have patients discontinued treatment due to side effects.
Two cases of induced manic episodes have been reported in drug-refractory nonseasonal unipolar depressives beginning after 4 to 5 days of light treatment.31 A few cases of light-induced agitation and hypomania have been noted, also in patients with nonseasonal depression.32 A patient with seasonally recurrent brief depressions developed rapid mood swings after light overexposure (far exceeding 30 minutes per day at 10,000 lux),33 and a patient who had unipolar winter depression and similar exposure showed his first manic episode34; both patients required discontinuation and medication. We had one bipolar patient with winter depression who became manic after the use of light and was given lithium as an effective countermeasure; almost all patients using mood stabilizers have responded to light therapy without mania. However, some have switched into mixed states with early morning light exposure, which was resolved by moving treatment to midday.35 Three cases of suicide attempt or ideation, also occurring in patients with winter depression, were reported within 1 week of standard early-evening bright-light treatment, and the patients required hospitalization.36 A 42-item side-effect inventory was administered to 30 patients with winter depression after treatment with unfiltered full-spectrum fluorescent light at 2500 lux for 2 hours daily.37 Other than for one case of hypomania, there were no clinically significant side effects. Patients given evening light (the timing relative to bedtime was unspecified) reported initial insomnia. Mild visual complaints included blurred vision, eyestrain, and photophobia. Of specific interest is the side-effect profile for patients using a downward-tilted fluorescent light box protected by a smooth diffusion screen (see Fig. 149-1), with 30-minute daily exposures at 10,000 lux, because this method has had widespread application. A study of 83 patients with winter depression who were evaluated for 88 potential side effects38 identified a small number of emergent symptoms at a frequency of 6% to 16%, including nausea, headache, jumpiness or jitteriness, and eye irritation.39 These results must be weighed against the improvement of other patients who showed similar symptoms at baseline but became asymptomatic after light treatment: All symptoms, except nausea, showed greater improvement than exacerbation, which forces attention to the risk-to-benefit ratio. Indeed, emergence of symptoms might have reflected the natural course of the depression in nonresponders to light, rather than a specific response to light exposure.
CASE MANAGEMENT, TIMING, AND DOSING Monitoring of Patients Light treatment is typically self-administered at home on a schedule recommended by the clinician. To the extent that the timing of light exposure is important to obtain a therapeutic effect, patient adherence is a sine qua non. The patient and clinician need to work together to find the optimum dosing–timing combination. At the Columbia clinic, the two talk by telephone after the first 3 days of treatment, although the patient is expected to report any side effects the same day they are experienced. Patients maintain a daily sleep, mood, and energy log (download-
Timing of Morning Light Exposure The thrust of recent clinical trials (see Seasonal Affective Disorder, later) leads to the recommendation that patients with winter depression initially be given morning light shortly after awakening. The dose of 10,000 lux for 30 minutes5,41 appears to be most efficient. A similar strategy applies to patients with DSPD, with evening light for
ASPD, but longer exposure duration up to 60 minutes may been needed. Although intensities as low as 2500 lux can also be effective, they require longer exposure,42,43 and to accommodate such treatment in the morning most patients would have to wake far earlier than their habitual wake up time, with a risk of counterproductive circadian phase delays. The advantage of morning light appears to lie in circadian rhythm phase advances, which can be measured as shifts in the time of nocturnal melatonin onset.44 The magnitude of the antidepressant response varies with the magnitude of phase advances. In a protocol with 10,000-lux treatment for 30 minutes on habitual awakening, the magnitude of antidepressant response was negatively correlated with the interval between dim-light melatonin onset (DLMO) and treatment time (r = −0.38, P = .01).45 The greatest improvement was seen with light therapy 7.5 hours after DLMO, which produced a 2.7-hour phase advance over 3 weeks. Overall, light therapy given 7.5 to 9.5 hours after melatonin onset yielded twice the remission rate (80% versus 38%) of light given 9.5 to 11.0 hours after DLMO.46 Clock time per se should not be used to schedule morning light administration, because the baseline DLMO—our metric for circadian time—spans a 7-hour range. Unfortunately, a phase diagnostic based on melatonin assays is not readily available in clinical practice. The melatonin assay remains primarily a research tool, with high cost and slow turnaround time, although user-friendly clinical kits are becoming available. To provide the clinician a basis to readily specify treatment time, a quick, approximate solution lies in the relation between melatonin onset and the Horne-Östberg Morningness–Eveningness Questionnaire (MEQ)47 score, which for unmedicated winter depression patients are strongly correlated (r = −0.73; Fig. 149-2). Healthy subjects without depression show a similar relationship.48 One thus can schedule morning light exposure at individually determined circadian times by estimating the time of melatonin onset from the MEQ score, a strategy that 01 n = 69 r = –0.73 P <.0001 y = 25.9 – 0.09x
24 Salivary melatonin onset at 3 pg/mL (clock time)
able in hard copy or PC formats),40 which they are asked to email or fax before subsequent scheduled contacts. This information is essential for tracking sleep-phase changes in response to the treatment, and adjusting the dose or timing. Patients with depression also complete a hard copy or online symptom rating scale (see Resources, later). With the personalized feedback presented online, this exercise also teaches patients to track their status independently, in preparation for self-management of light therapy after the initial period of guided treatment. In contrast with structured research studies, the motivation and adherence of patients in open treatment can be problematic. Despite an agreement to awaken for light treatment at a specific hour, patients might ignore the alarm, considering additional sleep to be the priority of the moment, and might delay or skip treatment. The initial evaluation should explicitly cover the patient’s weekly schedule of major activities, early morning and late evening commitments, dinner times, regularity of work hours, coordination with partner’s sleep schedule, pattern of late nights out, and so on. Such factors can adversely interact with the treatment regimen, and it may be important to reset priorities. Patients often attempt to test whether improvement can be achieved without rigid compliance, and they might quit if treatment is managed too rigidly. Adolescents often promise adherence without following through, yielding to social peer pressure and norms. Indeed, the behavioral investment in a maintenance regimen of light therapy is considerable, far exceeding that of pharmacotherapy (which, of course, has its own adherence issues). For hypersomnic or DSPD patients who are unable to wake when instructed, light exposure initially should be scheduled at the time of habitual awakening and then edged earlier across days toward the target interval. Some depressed hypersomnic patients compensate for earlier wake up times with earlier bedtimes or napping, but others are comfortable with less sleep as the antidepressant effect sets in. Clinical experience suggests that most such patients could not sustain earlier awakening without the use of light to phase-advance their circadian rhythms. Variability in the sleep pattern, if it occurs, can yield important information for determining the course of treatment. Continual adjustments in scheduling, although labor intensive for the clinician, often succeeds. Our strategy has been to encourage the adherence to a recommended light exposure schedule but to consider the obtained sleep pattern as a dependent measure that often reflects changes in mood state, sleep need, and circadian rhythm phase. Rarely do we set a patient’s bedtime (rise time is linked to the light schedule); rather, we ask the patients to go to bed once they are sleepy. In this way, we have a better handle on circadian clock phase as it changes in response to treatment.
CHAPTER 149 • Light Therapy 1685
23 22 21 20 19 18 17 30
40
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80
Morningness-Eveningness score Figure 149-2 Correlation of Morningness–Eveningness (MEQ) score and dim-light melatonin onset (DLMO) in a group of 69 patients with winter depression. A 10.2-point difference in MEQ score corresponds to a 1-hour difference in DLMO. Solid line, linear regression; dashed lines, DLMO within 1 hour of the MEQ predictor.
1686 PART II / Section 19 • Methodology
facilitates circadian rhythm phase advances and the antidepressant response. Given the spread of DLMOs around the regression line (see Fig. 149-2), there is a risk that light will be scheduled too early, which might lead to premature awakening or counterproductive phase delays. The MEQbased recommendation maximizes the chance that the patient will receive light in the window of 7.5 to 9.5 hours after DLMO. With a target time of 8.5 hours after DLMO, most patients (44/69, or 64% in our sample) will be captured in this window (± 1 hour) and 66/69 (96%) will receive light within ± 2 hours. A list of recommended initial light exposure times, derived from the regression of the MEQ score on melatonin onset for 8.5 hours after DLMO, is shown in Table 149-1 (An online version of the MEQ,49 which has been used successfully for more than 6 years, automatically returns the recommended light exposure interval to the user.) This schedule is a best-guess solution, and prompt timing adjustments may be needed. For example, if the circadian phase estimate were too early, a patient might report an uncontrollable urge to resume sleep for several hours after treatment (unintended phase delay), or sleeponset insomnia beyond habitual bedtime, in which case light exposure should be moved later to bring the session into the 7.5 to 9.5 hour post-DLMO range. Similarly, if the patient suddenly starts waking up hours earlier than expected, the session should be moved later. On the other hand, with light exposure later than 9.5 hours after DLMO,
Table 149-1 Timing of Morning Light Therapy* Based on Morningness–Eveningness Score MEQ SCORE 16-18
START TIME 08:45
19-22
08:30
23-26
08:15
27-30
08:00
31-34
07:45
35-38
07:30
39-41
07:15
42-45
07:00
46-49
06:45
50-53
06:30
54-57
06:15
58-61
06:00
62-65
05:45
66-68
05:30
69-72
05:15
73-76
05:00
77-80
04:45
81-84
04:30
85-86
04:15
*Start of 10,000-lux, 30-minute session, approximately 8.5 hours after estimated melatonin onset. Bold indicates the range confirmed in clinical trials. MEQ, Horne-Östberg Morningness–Eveningness Questionnaire. Data from Terman M, Terman JS. Light therapy for seasonal and nonseasonal depression: efficacy, protocol, safety, and side effects. CNS Spectr 2005;10:647-663.
there might be inadequate response. If 5 days of treatment shows no sign of improvement, the light should be moved earlier. The MEQ solution is not diagnostic of circadian phase.50 For example, as shown in Fig. 149-2, it is possible for individual evening types (score below 42) and morning types (score above 58) to share the same DLMO.51 Another source of error, of course, lies in the DLMO measure itself.48 The MEQ algorithm offers the clinician an intelligent starting point that varies substantially from patient to patient, minimizing the problem of inappropriate treatment times, which would otherwise often be too early or too late. According to this algorithm, treatment often begins earlier than habitual wake up time, depending on the patient’s sleep duration. (Beyond the DLMO, the MEQ score is significantly correlated with sleep onset and offset derived from sleep logs of 1 week or longer.) For example, a short sleeper, whose bedtime is at midnight and who awakens at 6 am, would start treatment on habitual awakening. In contrast, a longer sleeper, with onset at 11:30 pm and awakening at 7:30 am, would need to wake up 1 hour earlier, at 6:30 am. For every half hour of sleep beyond 6 hours, awakening for light treatment is 15 minutes earlier than habitual wake up time—up to 1.5 hours earlier for a sleep duration of 9 hours. Although the algorithm is based on winter depression data, it has been applied successfully to patients with nonseasonal unipolar and bipolar depression52 and moderate delayed sleep phase. However, for DSPD patients going to sleep after 2 am, night shift workers, or the retired elderly, several questions on the MEQ will be difficult or impossible to answer, and timing decisions should be based on a pretreatment sleep log instead. Additionally, the MEQ score may be distorted by masking effects of hypnotic medication, compromising its usefulness as a circadian phase estimator.
INDICATIONS FOR TREATMENT Circadian Rhythm Sleep Disorders Delayed Sleep Phase Disorder Patients with DSPD have difficulty initiating sleep before 2 to 7 am, with commensurate difficulty awakening in the morning (for a review and discussion of the relationship with circadian rhythm phase, see reference 53). The problem is often exacerbated by light exposure during the night, even at normal room light levels, which can induce and maintain circadian rhythm phase delays. Similarly, forced early awakening and exposure to light can induce phase delays rather than advances. Once awake on their delayed schedule, most patients exhibit normal alertness and energy, but others report difficulties for several hours after awakening and spurts of energy after midnight. Often patients with DSPD show comorbid mood and personality disorders. Morning light therapy can directly normalize the timing of the sleep episode without the need for progressive daily delays into the desired phase position,54 an arduous procedure now rarely used. In one study, patients with DSPD were given 2 hours of early-morning light treatment at 2500 lux and light restriction after 4:00 pm.55 Both the
CHAPTER 149 • Light Therapy 1687
T.W., ° 32 YR, BEGIN 16 JUL 88
12 13 14 15 16 17 18 19 20 21 22 23 24 01 02 03 04 05 06 07 08 09 10 11 12 Time of day (hr)
Figure 149-3 Self-report sleep and light therapy record for Patient T.W. (delayed sleep phase disorder). Green bars, sleep episodes on successive days (top to bottom); sun symbols, 15-minute intervals of 10,000-lux light exposure. Pretreatment baseline, 11 days (see Case 1 in the text).
body temperature rhythm and daily cycle of sleep-onset latencies showed phase advances, with an increase in morning alertness within 1 week. These effects were not obtained with the use of a dim light control. The cases presented here, accompanied by sleep records, relate the experiences of three patients using morning light alone, morning light following progressive phase delays, or morning light in conjunction with evening low-dose melatonin. Case 1: DSPD Phase Advances with Postsleep Light Patient T.W. (Fig. 149-3) was a male, age 32 years, a freelance writer. He reported a lifelong history of DSPD with variable sleep onset averaging 5:00 AM and occasional hypersomnic episodes lasting 11 to 12 hours. Although not depressed when he sought help, he also reported experiencing subsyndromal symptoms of winter depression. The treatment consisted of gradually shifting light exposure earlier across days, beginning at 10:30 AM, a time of typical spontaneous awakening. The patient monitored his level of sleepiness and time of awakening to determine the rate of shift. He was able to achieve successively earlier wake-up times over a period of 2 weeks while light-treatment sessions were advanced from 10:30 AM to 7:30 AM, but even at that point he could not fall asleep before 2:30 AM. However, when the treatment session was further advanced to 7 AM—an unprecedented time of awakening for this patient—sleep onset abruptly jumped approximately 2 hours earlier. The sleep episode stabilized at about 1:15 AM to 6:30 AM with light treatment on awakening. After several months, the patient reported having increased light duration from 30 minutes (at 10,000 lux) to 45 or 60 minutes to enhance daytime energy. He also reported a relapse when discontinuing treatment twice within the next year. He selfmanaged his readjustments and reported the remission of depressed mood in the winter.
When morning light treatment fails to induce and maintain the desired phase advance, the patient may undergo a schedule of successive delays in the sleep episode until the desired target phase is achieved, usually within a week. The patient then attempts to keep sleep–wake timing consistent. As delay chronotherapy was originally applied,54 the shifting sleep episodes were couched in darkness. It followed that the timing of light exposure changed during and after the phase adjustment. By the end of the procedure, the patient begins to receive a normalized pattern of daily light exposure that serves to maintain the target phase. Early morning light therapy can forestall further drifting toward the original delayed sleep phase, which is a large risk. Additionally, presleep light exposure can be used to expedite the daily phase delays, with a switch to postsleep light exposure during maintenance treatment.
Case 2: DSPD Progressive Delays with Presleep Light Followed by Stabilization with Morning Light Patient S.P., male, age 47 years, experienced a delayed sleep pattern that had been present since childhood. Although he was groggy on awakening, afternoon and evening energy levels were high, and he could work productively at those times. On nights when he used a benzodiazepine hypnotic, he could sometimes advance sleep onset by a few hours, which he considered trivial. An attempt was then made to phase advance the sleep episode with the use of 10,000-lux, 30- to 45-minute light exposures on awakening. Despite intense effort over a 1-week trial, the patient could not be awakened before 12:30 PM, making successively earlier treatment sessions impossible. An alternative course of chronotherapy was then attempted. The patient was instructed to delay successive sleep episodes by 2 hours, in conjunction with 1-hour light treatment sessions ending 2 hours before bedtime (a procedure intended to facilitate successive phase delays). However, he refused to enter bed until ready to fall asleep, resulting in daily delays that varied between 1 and 5 hours. After 6 days, the presleep light was discontinued, with the instruction to substitute light exposure for 2 hours at 6 AM in an attempt to halt the delay drift. In the next weeks, the patient was able to maintain sleep onset between 11 PM and midnight and to awaken by 7:30 AM or earlier. The resilience of the adjustment was tested on the occasion of two late-night parties after which the desired sleep pattern was easily recaptured. Subsequently, however, the patient discontinued treatment and resumed his former schedule, citing family stresses that he preferred to escape by sleeping during the day.
With the identification of phase-shifting properties of exogenous melatonin in humans,56 we have the prospect of an enhanced protocol for treatment of DSPS. Melatonin can be used to phase-advance the cycle with a dosing regimen57 distinct from its use close to bedtime
1688 PART II / Section 19 • Methodology
as a soporific agent (which remains controversial).58,59 The phase response curve to melatonin is approximately opposite to that for light. Thus, morning light and evening melatonin both serve to promote phase advances. In the present application, melatonin is administered in low, physiologic doses (0.1 to 0.3 mg) several hours before bedtime (earlier than endogenous pineal melatonin onset). Because it is not soporific, the patient can continue normal evening activities. However, once the melatonin is ingested, the patient must avoid inappropriate, countervailing ambient light until bedtime, which could induce phase delays and inhibit the onset of pineal melatonin production. Additionally, melatonin is a suspected retinal photosensitizer,23 which mandates cautionary eye protection. An alternative to dark goggles,60 which would constrain evening activities, is blue-blockers (see Resources, later) that maintain clear visibility while blunting retinal circadian photoreception. Melatonin has been used as monotherapy to halt the free-running cycle of totally blind people,61 in which case there is no interaction with light exposure. Clinically, we have found melatonin especially useful for DSPS in conjunction with postsleep light therapy. Although light monotherapy can be effective for DSPS (e.g., Case 1), the advancing schedule is especially difficult for patients who are not falling asleep until early morning. Adding melatonin 4 to 6 hours before current sleep onset and moving light exposure and melatonin ingestion gradually earlier— as an ensemble—can expedite progress. Once sleep has stabilized, melatonin might maintain the pattern after discontinuation of light therapy, with spontaneous exposure to early morning postsleep light. Case 3: DSPD Phase Advances with Evening Melatonin and Blue Blockers and Postsleep Light Patient J.M. (Fig.149-4) is male, age 28 years, and an accomplished scholar. He had experienced extreme delayed sleep phase disorder since adolescence. It was aggravated in recent years, with sleep onset around 7 AM and waking around 3 PM. The distinct downside for him was the inability to collaborate with colleagues during the normal workday. He resisted hypnotic medication but intermittently used alcohol to fall asleep a few hours earlier. The phase-advancing strategy combined three chronotherapeutic methods: 0.2 mg controlledrelease melatonin62 in the evening, blue-blocking (400 to 535 nm) glasses until sleep onset, and 1 hour of light therapy at 10,000 lux upon awakening. Melatonin was initially taken too early (about 7 hours before sleep onset) because the patient insisted he was ready to fall asleep earlier; after stabilization, the delay to sleep was about 4 to 5 hours. He followed a 1- to 3-day schedule of 30-minute advances in wakeup time and light therapy, based on his level of confidence that he would not oversleep. Sleep onset remained spontaneous throughout. He achieved the goal of sleep from 11:30 PM to 7 AM in about 2 weeks and expressed incredulity that this could happen.
Mild Sleep Phase Delay (Initial Insomnia) The common problem of chronic sleep-onset insomnia that falls short of DSPD but also entails difficulty arising and low morning alertness, is readily treatable with postsleep light, leading to rapid adjustment. Many patients with such insomnia do not respond to hypnotic medication and are not depressed.
Case 4: Mild Sleep-Phase Delay Counteracted by Postsleep Morning Light Patient J.B., male, age 34 years, could rarely fall asleep before 1:30 AM or wake up in time for a normal workday. Although he was allowed to work from midmorning into the evening, he was handicapped by low alertness until midafternoon and headaches at a computer terminal during the late afternoon. Light treatment began with 10,000-lux exposures at 8 AM for 30 minutes, with no effect in advancing sleep onset for several days. When the session was advanced to 7:30 AM, sleep onset immediately advanced by about 1 hour. However, several days of terminal insomnia followed, with awakenings before 6 AM, signaling an overdose. Reducing the treatment duration to 15 minutes at 7:30 AM alleviated this problem, with sleep onset maintained around midnight. This regimen was continued, with effortless awakening accompanied by improved morning alertness and complete remission of the headache.
Advanced Sleep Phase Disorder Advanced sleep phase disorder, in which sleep onset occurs in the evening with awakening well before dawn, would seem to provide a counterpart to DSPD, treatable with late evening light, but such treatment has not been extensively investigated. Light presented in the first part of the subjective night is known to elicit phase delays in the onset of nocturnal melatonin secretion44 and the decline of body temperature,63 which might promote later sleep onset. Case 5: ASPD Counteracted by Presleep Evening Light The experience of a 38-year-old woman with a lifetime history of ASPD64 illustrates the potential use— and limitations—of evening light treatment. Patient K.W. was a mildly hypomanic high achiever, without seasonal pattern, who typically fell asleep at about 9:00 PM and woke up between 2 AM and 4 AM, a pattern that led to marital stress. She could remain awake for occasional late-evening engagements by compensating with delayed time of arising at 5 AM to 6 AM. At baseline, she exhibited an early melatonin onset, at about 7:45 PM. Light exposure at 2500 lux for up to 2 hours beginning at 8 PM barely affected sleep phase or melatonin onset, whereas light exposure beginning at 9 PM succeeded in maintaining sleep onset at about 11 PM and wakeup time between 4 AM and 5 AM, which was accompanied by a 1-hour delay in melatonin onset.
CHAPTER 149 • Light Therapy 1689
J.M., ° 28 YR, BEGIN 18 OCT 07
AAAAAA AAAA AAAAA 5 day trip
M
M
M
M
Blue blockers
M M M M
| Sleepy /emergency AAA
M M M
M M M M M
M M M M (forgot M) M M M M
12
13
14
15
16
17
18
19
20
21
22
23
24
01
02
03
04
05
06
07
08
09
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12
Time of day (hr) Figure 149-4 Self-report sleep and light therapy record Patient J.M. (delayed sleep phase disorder). Green bars, sleep episodes on successive days (top to bottom); sun symbols, 15-minute intervals of 10,000-lux light exposure; red bars, blue-blocking glasses; A, alcohol; M, 0.2 mg controlled-release melatonin; dashes, gap in record. Pretreatment baseline, 13 days (see Case 3 in the text).
Although ASPD is not strictly age-related, it is more prevalent among the elderly, whose early rise time is a common cause of concern. Campbell and colleagues65 compared the effects of evening bright-light exposure (>4000 lux for 2 hours) with a dim red-light control in elderly subjects with histories of sleep maintenance insomnia. The bright light group showed improved sleep efficiency; after 12 days of treatment, nighttime wakefulness decreased by about 1 hour. Despite this benefit, most subjects declined to continue treatment, given the long exposure sessions and glare discomfort. These drawbacks might be corrected with shorter exposures to higher intensity light in a glare-free configuration (see Apparatus, earlier). Free-Running Sleep Disorder When sleep phase does not stabilize but continually shifts later relative to clock time, the pattern resembles the free run seen in normal subjects under conditions of temporal isolation without day and night cues. However, in freerunning sleep disorder, despite the presence of such cues, a failure of entrainment is evidenced by a hypernychthemeral66 sleep pattern. Some patients with DSPD break into transient hypernychthemeral patterns, which suggests that
free-running sleep disorder and DSPD are associated disorders of varying severity.67 To halt the delay drift, light therapy is introduced when the subjective and objective nights coincide. Case 6: Free-Running Sleep Halted by Morning Light Patient B.C., male, age 31 years, showed a sleep–wake cycle length averaging 25 hours over approximately 13 years preceding treatment.68 He was unemployed and socially withdrawn and refused to attempt to sleep when alert. Treatment began when sleep onset had drifted to midnight. The patient was exposed to light of 4000 to 8000 lux for about 2.5 hours on awakening. The free run immediately decelerated, and the sleep interval was maintained at approximately 1:30 AM to 8:15 AM for several weeks. In the long run, however, the sleep pattern continued to drift at a period of about 24.08 hours, a problem that might have been corrected with increased light dose, adjunctive evening melatonin treatment, or both.
1690 PART II / Section 19 • Methodology
Depressive Disorders Seasonal Affective Disorder Patients with SAD experience annually recurrent mood disturbance often accompanied by increased appetite for carbohydrates, weight gain, daytime fatigue and loss of concentration, anxiety, and increased sleep duration. The appetitive and sleep symptoms are considered atypical, in contrast with the poor appetite, weight loss, and early awakening seen in melancholic depression. For a set of diagnostic and clinical assessment instruments, see Resources (later) and the discussion by Terman and colleagues.69 Most light therapy studies have focused on parameters that influence treatment response, such as time of day, duration of exposure, intensity, and wavelength. The original regimen tested at the National Institute of Mental Health used 2500-lux full-spectrum illumination in 3-hour sessions in the morning and the evening.29 A cross-center analysis of more than 25 studies that included 332 patients70 summarized the results for dual daily sessions at 2500 lux for 2 hours; single morning, midday, and evening sessions; brief sessions (30 minutes); and lower light intensity (<500 lux). One week of morning bright-light treatment produced a significantly higher remission rate (53%) than did evening (38%) or midday (32%) treatment. Dual daily sessions provided no benefit over morning light alone. All three bright-light regimens were more effective than the dim-light controls; only morning (or morning plus evening) light was superior to the brief light control. Two subsequent studies increased light intensity to 10,000 lux, substituting lower color-temperature light for full-spectrum, in 30- to 40-minute exposure sessions, with remission rates of approximately 75%, matching the most successful 2500-lux, 2-hour studies.5,71 At these short durations, both dim light (400 lux) and lower-level bright light (3000 lux) were significantly less effective. Three large controlled clinical trials have clarified the specific action of antidepressant light relative to placebo and the influence of exposure time of day. Eastman’s group42 administered light in the morning or evening, and an inert placebo (an inactive negative-ion generator), to parallel groups. Although all groups showed progressive improvement over 4 weeks, patients administered morning light were most likely to show remissions, exceeding the placebo rate. Lewy’s group43 conducted a crossover study of morning and evening light. Although there was no placebo control, morning light proved to be more effective than evening light. Terman’s group41 performed both crossover and balanced parallel-group comparisons, which included nonphotic control groups that received negative air ions at a low or high concentration. Morning light produced a higher remission rate than evening light and the putative placebo, low-density ions. However, the response to evening light also exceeded that for placebo. Indeed, in the trials of Lewy’s group43 and Terman’s group,41 a minority of patients responded preferentially to evening light. Figure 149-5 compares morning and evening light therapy and its relation to the sleep cycle for a representative patient with SAD who received 10,000-lux light treatment in 30-minute sessions. Treatment timing was
S.H., ° + 37 YR, BEGIN 4 NOV 88
D
D
R
12 13 14 15 16 17 18 19 20 21 22 23 24 01 02 03 04 05 06 07 08 09 10 11 12 Time of day (hr)
Figure 149-5 Self-report sleep and light therapy record for Patient S.H. (winter depression), who first received a trial of evening light (5:00 PM), then morning light (6:30 AM). Green bars, sleep episodes on successive days (top to bottom); sun symbols, 15-minute intervals of 10,000-lux light exposure; D, depression at clinical evaluation; R, remission at clinical evaluation. Pretreatment baseline, 17 days (see Case 7 in the text).
determined according to the patient’s reported sleep habits and daily commitments. The patient was urged to maintain consistent sleep times whether on or off treatment, waking up shortly before the time planned for morning treatment and keeping free a block of time for evening treatment at least 2 hours before bedtime in order to avoid light-induced initial insomnia. However, sleep timing showed considerable variability depending in part on the time of treatment and treatment response. Case 7: Differential Antidepressant Response to Evening and Morning Light Therapy for Winter Depression Patient S.H. (see Fig. 149-5), female, age 37 years, became depressed every winter, with middle insomnia and oversleeping on weekends. During the course of early-evening light treatment at 5 PM, sleep onset was gradually delayed, with reduced nighttime awakening. She remained depressed. In contrast, under morning light treatment at 6:30 AM, sleep onset returned to the baseline pattern, sleep interruptions were largely eliminated, and the depression remitted.
The generally poor response to evening light appears to be correlated with delayed sleep onset, time of arising relative to baseline, or both. By contrast, morning light usually serves to truncate morning sleep. Some patients conserve sleep duration by going to bed earlier, but many do not and feel fine with sleep shortened by about 30 minutes. Although the common symptom of interrupted sleep is often eliminated under effective treatment, initial, middle, or terminal insomnia sometimes emerges. The insomnia could signal light overdose that can be dealt with by reduc-
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Nonseasonal Unipolar Depression M ONOTHERAPY WITH L IGHT Beyond its established application for winter depression, light therapy for nonseasonal depression appears both safe and effective. Kripke77 compared several controlled trials in terms of the relative benefit of light versus placebo and found light therapy for as little as 1 week produced improvement within the range of classic antidepressant drug studies of 4 to 16 weeks. For example, Yamada and colleagues78 gave 7 days of light therapy to 27 inpatients with nonseasonal major depression and obtained a benefit of 24% over a dim-light placebo. However, morning or evening exposure times showed no difference, nor did phase shifts of body temperature relate to clinical improvement. Wirz-Justice and colleagues79 used a ceiling-light installation at 3000 to 4000 lux in a 10-day open-label trial with 28 unmedicated hospitalized patients, with improvement greater than 50% in half the cases. Goel and colleagues80 gave 5 weeks of morning light therapy (10,000 lux, 60 minutes) to outpatients with chronic major depression. The remission rate was 50%, and a control group given low-density negative-air ionization as placebo showed negligible improvement.
an early review, see reference 81). This combination strategy has seen widespread clinical use in Europe with hospitalized patients.82 One such study by Beauchemin and colleagues83 demonstrated benefit among inpatients with either unipolar or bipolar depression who were given 10,000-lux illumination in 30-minute morning sessions, with less improvement at 2500 lux. Benedetti and colleagues52 administered citalopram 40 mg to 21 MDD inpatients (and 9 with bipolar depression) with or without morning green-light therapy for the first 2 weeks, using a deactivated ionizer as placebo. Treatment was scheduled according to the MEQ algorithm (see Timing of Morning Light Exposure, earlier). The active combination was more effective within 1 week, supporting the light augmentation strategy. Martiny and colleagues conducted large-scale outpatient trial that combined 10,000-lux or 50-lux light therapy with standard sertraline 20 mg.84 Both remission rate and speed of improvement were greater under the active light condition. The advantage of combination treatment has been inconsistent, however. For example, in a blinded trial of 29 inpatients with nonseasonal recurrent MDD, Prasko and colleagues85 found 64% improvement in rating scale scores after 3 weeks of morning light treatment (5,000 lux, 2 hours; n = 9), which was not significantly different from groups receiving imipramine 150 mg or the combination of light with imipramine. One needs to consider the flip-side argument—whether medication is always needed as an adjunct to light. In a case series of treatment-refractory inpatients with MDD, Terman’s group86 added light therapy to tranylcypromine at the highest tolerable dose, when the drug alone had produced insufficient improvement. Two patients who showed remission under this combination, and continued with home treatment after discharge, experienced relapse within 2 days of skipping light therapy sessions, yet recovered within 2 to 4 days of resumption. The necessity of drug treatment could be questioned. A Cochrane meta-analysis87 has confirmed the therapeutic utility of bright light boxes (but not other exposure methods) for nonseasonal unipolar depression, noting that results were strongest in combination with drugs. With more selective screening of high-quality studies, Even and colleagues88 have endorsed light therapy for nonseasonal depression, but only as an adjuvant. They urged refinement of homogeneous MDD subgroups that might respond to light monotherapy on the basis of circadian rhythm characteristics. Going a step further, Neumeister and colleagues89 combined light with drugs and a single session of late-night sleep deprivation90 (wake therapy) at the start of treatment and achieved marked improvement in 1 day and benefit over a dim light control within 1 week. Combined light and wake therapy can be self-administered at home to MDD patients who are able to self-manage it. Loving and colleagues91 used this method in a group for whom standard antidepressants and psychotherapy were inadequate, and achieved a remission rate of 43%.
C OMBINATION T REATMENT Several investigators have combined light with drugs and found accelerated improvement relative to drugs alone (for
Nonseasonal Bipolar Depression The light therapy strategy for bipolar depression is similar to that for MDD, although clinicians must be vigilant
ing light intensity or duration (see Adverse Effects of Bright Light Exposure, earlier) or by scheduling evening sessions earlier or morning sessions later. In clinical practice, many SAD patients are treated with antidepressant drugs, light therapy, or both. Antidepressants and light are compatible. Some patients seek to taper or discontinue drugs after starting light therapy, and others need both to relieve the depression. An advantage of light is its faster course of improvement, often within a week. Yet relapse is likely upon discontinuation of light therapy during the winter.72 Martiny and colleagues73 used 1 week of light therapy (5000 lux, 2 hours/day) as a booster toward quick improvement, which was maintained with citalopram 40 to 60 mg for 15 weeks, but relapse was more common in patients who received placebo drug. Subsyndromal Seasonal Depression The phenomenology of subsyndromal winter depression, or winter doldrums, is similar to that of SAD, though it falls short of major depressive disorder (MDD) criteria. However, the presence and severity of atypical neurovegetative symptoms (including difficulty awakening and food cravings) can be similar to those in winter depression, as can fatigability (leading to characterization as a seasonal anergic syndrome).74 The prevalence of winter doldrums is about three times higher than that of SAD, and its burden should not be minimized. Clinical trials have demonstrated significant improvement with bright light therapy75 as well as dawn simulation.76 For bright light, optimum light scheduling and dose appear to be similar for subsyndromal winter depression and SAD; in other words, the lower severity of depressed mood does not imply that a lower light dose will be sufficient to relieve symptoms.
1692 PART II / Section 19 • Methodology
about emergence of manic or mixed states, even with mood stabilizers. Colombo and colleagues92 administered three cycles of wake therapy over 1 week in patients who were either stabilized on lithium or were medication free. Subgroups also received 30-minute morning light therapy at 2500-lux white or 150-lux red or normal ambient room illumination at 80-lux. Patients receiving bright-light therapy with or without lithium showed sustained, incremental improvement without mood reversals following sleep deprivation. The lithium-alone group showed similar improvement, but without lithium or bright light there was minimal overall improvement, with distinct reversals after sleepdeprivation nights. This study underscores the advantage of light therapy in sustaining and enhancing the transient benefit of wake therapy. In a follow-up study, Benedetti and colleagues93 combined wake therapy, morning light therapy, lithium, and antidepressants for inpatients with bipolar depression. Of 27 patients with histories of drug resistance, 44% responded during 1 week of acute intervention, and nonresistant patients showed 70% success. Patients were followed for 9 months at home on their usual medications (without light treatment), and the relapse rate differed significantly for drug-resistant (83%) and nonresistant (43%) subgroups. Although this study does not isolate light therapy as the critical intervention, it underscores the effectiveness of the chronotherapeutic combination with wake therapy in acutely reversing the depressive episode even in resistant cases. A case series of drug-resistant bipolar patients who continued light therapy at home with sustained benefit86 points to the need for and utility of long-term maintenance treatment. In an instructive pilot study of light therapy during depressed phases of rapid-cycling bipolar disorder, Lei benluft and colleagues94 were struck by increasingly labile mood when 10,000-lux light was administered in the morning for up to 60 minutes, whereas midday presentation was effective. Sit and colleagues35 studied nine women with longstanding nonseasonal bipolar I or II disorder in which mood stabilizers controlled manic phases, but antidepressants did not relieve depressed phases. Light duration was flexibly dosed between 15 and 45 minutes to maximize improvement while minimizing side effects. Three of four patients beginning 7000-lux morning bright-light therapy experienced disruptive mixed states forcing discontinuation, but the fourth showed a full, sustained response. The next five patients used midday light without such disruption, with success in three cases. One midday nonresponder who switched to morning light then responded. Clearly, despite the impressive initial results, the dosing and timing of light therapy for bipolar depression needs further scrutiny. Though dawn simulation has not yet been tested in bipolar depression, it is a milder intervention that might especially suit this population. In a retrospective chart review of 187 inpatients with bipolar depression,95 those who occupied east-facing rooms with direct natural dawn illumination were discharged 3.7 days earlier than those facing west. No such benefit was found for patients with MDD, however.
Other Indications Practice parameters or meta-analytic endorsement of light therapy for circadian sleep phase disorders96,97 and seasonal98 and nonseasonal depression87,88 are now in place. Other indications for light therapy might emerge in the future. See reviews46,86 of clinical trials of light therapy for antepartum depression, premenstrual dysphoric disorder, geriatric depression,98a bulimia nervosa, adult attentiondeficit/hyperactivity disorder, dementia, and Parkinson’s disease.
TOWARD AN INTEGRATED CHRONOTHERAPEUTICS Three main applications of light therapy have emerged: light therapy alone, combination of light therapy with antidepressant and mood-stabilizing drugs, combination of light therapy with other chronotherapeutic methods to accelerate and maintain treatment response, and combination of all three types of therapy (light, medication, and chronotherapy). The range of chronotherapeutic methods beyond light therapy includes sleep deprivation, or wake therapy; wake therapy followed by sleep phase-advance therapy, in which bedtime is moved earlier, with maintained wakefulness at the end of the night; low-dose melatonin administered several hours before scheduled bedtime, to facilitate circadian rhythm phase advances; and blue-light restriction in the evening (alone or in conjunction with melatonin) to forestall phase delays or in the morning to promote phase delays. Blue-light restriction and melatonin administration in the evening derive from laboratory studies27,99 and clinical experience, with clinical trials still pending. Light monotherapy is a potent tool for treating the circadian rhythm sleep disorders, though patients with extreme delayed sleep phase appear to respond most rapidly to a combination of postsleep light in coordination with physiological-dose melatonin 4 to 6 hours before sleep onset, with light restriction (in the short-wavelength range below ∼535 nm) until bedtime. For patients already using hypnotic drugs, the chronotherapeutic regimen should be introduced before attempting to taper and discontinue the drug. Although tapering can require weeks to months, it can begin as soon as the patient reports onset of sleepiness before taking the sleeping pill. Light monotherapy for depression has been best demonstrated for treatment of seasonal affective disorder, for which complete clinical remission with normalization of hypersomnia is often obtained within a week. Clearly, light alone should be the first course of treatment for patients with SAD. For those already using antidepressants, light can be added and the drug subsequently tapered, even to discontinuation. Combining light with drugs may be more effective for treating nonseasonal depression, even though light monotherapy works in individual cases, notably in patients with drug resistance whose main issue is circadian phase maladjustment. For hospitalized patients with depression, a chronotherapeutic combination in conjunction with ongoing medication appears very promising, with the prospect of unprecedented rapid, maintained remission and shorter hospital stay. The protocol combines multiple nights
CHAPTER 149 • Light Therapy 1693
of wake therapy with interspersed recovery sleep,93,100 earlier bedtime and rise time for recovery sleep (sleep phase advance),101 and initiation of daily light therapy after the first night of sleep deprivation. Timing of all the chronotherapeutic procedures—not only light—is anchored individually to the patient’s assumed circadian phase position, as inferred from the MEQ, habitual sleep schedule, or both.102
RESOURCES The nonprofit Center for Environmental Therapeutics (http://www.cet.org) offers the following materials for clinicians and patients: • A 10,000-lux light box: tilted, height-adjustable, 4000Kelvin fluorescent with polycarbonate filter diffuser • Blue-blockers: short-wavelength filtered fitover or nonfitover glasses • Clinical instruments: the Columbia Clinical Assessment Tools packet, including rating scales and structured eye examination chart • Self-rating instruments: downloadable or automated assessments of morningness–eveningness (MEQ-revised with American idiom and categorical scoring),49 seasonality and depression, with personalized feedback. The Society for Light Treatment and Biological Rhythms (http://www.sltbr.org) offers a continuing medical education course associated with its annual scientific meeting and hosts a lively listserv for members. ❖ Clinical Pearl Appropriately timed artificial light exposure can correct sleep-phase maladjustment and counteract seasonal and nonseasonal depression. The clinician’s tasks are to determine the interval of the individual patient’s subjective night and to schedule light at its end for phase advances or at its beginning for phase delays.
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Index 1697
Index
Page numbers followed by f indicate figure(s); t, table(s); b, box(es).
A
AASM. See American Academy of Sleep Medicine (AASM) Abdominal motion, 1613-1615 Abdominal pain, 318 Abilify. See Aripiprazole Abuse of benzodiazepines, 911 misuse vs., of drugs, 519 Acceptability, of insomnia treatment protocols, 894-896 Accident prediction, 755-756 Accident risk, 753-754 Acebutolol, 552t Acetazolamide, 1148, 1411 Acetylcholine (ACH) in dreaming, 566 in sleep control, 79, 239f ACH. See Acetylcholine (ACH) Acid secretion, gastric, 313-314 nocturnal, 1452-1453 Acromegaly, 1435-1437 ACTH. See Adrenocorticotropic hormone (ACTH) Actigraphy applications of, 1670-1672 in children, 1671 in chronobiologic monitoring, 1662-1663 editing data in, 1672 in elderly patients, 1671-1672 history of, 1668-1670 in insomnia, 846-847, 884-885, 1642-1643, 1670 limitations of, 1673 in periodic limb movements in sleep, 1671 in sexual dimorphism of sleep in adolescents, 1564 in sexual dimorphism of sleep in adulthood, 1565 in sexual dimorphism of sleep in children, 1563 in sleep apnea, 1670-1671 Activity, sleep deprivation and, 55 Acute disseminated encephalomyelitis, 1070 Acute encephalitides, 1070-1071 Acute intermittent porphyria, 426 Acute mountain sickness (AMS), 275 Acute phase response (APR), to inflammatory challenge, 281-282 Acute sleep deprivation activity and, 55 age and, 57 alcohol and, 56 ambient temperature and, 55-56 arousals and, 55-57 autonomic changes in, 59-60 behavioral effects of, 54-59 biochemical changes in, 60 body temperature and, 59-60 caffeine and, 56 circadian rhythm and, 54-55 clinical changes in, 60-61 cortisol in, 292f in Drosophila, 153 drugs and, 56 EEG in, 59, 63-64 exercise and, 61 fragmentation as, 61-62 gene expression in, 60 glucose in, 292f group effects in, 57 growth hormone in, 292f imaging studies in, 59 immune function and, 60 insulin and, 61
Acute sleep deprivation (Continued) interest and, 56-57 light and, 55 motivation and, 56-57 neurologic changes in, 59 noise and, 55 overview of, 54 pain and, 60-61 personality and, 57-58 physiologic effects of, 59-61 posture and, 56 prolactin in, 292f psychopathology and, 57-58 recovery of performance after, 62-63 recovery sleep after, 62-64 repeated, 57 sensitivity to, 57 sleep homeostasis and, 435 stimulants and, 56 test characteristics and types in, 58-59 thyroid stimulating hormone in, 292f total, 54-59 weight control and, 61 AD. See Alzheimer’s disease (AD) ADA. See Adenosine deaminase (ADA) Adaptation to chronic sleep deprivation, 68 to high altitude, 277-278 Adaptive inactivity, 126-127 Adenosine in Drosophila, 157-158 in sleepiness, 45 as sleep-promoting, 87-88 Adenosine deaminase (ADA), 179 ADHD. See Attention deficit hyperactivity disorder (ADHD) Adherence, to insomnia treatment protocols, 894-896 Adhesive forces, in pharyngeal airway, 1154-1155 Adjusted neck circumference (ANC), 1175 Adjustment sleep disorder, 680, 840t ADNFE. See Autosomal dominant nocturnal frontal lobe epilepsy (ADNFE) Adolescents chronic fatigue syndrome in, 1429 cognitive therapy for insomnia in, 899 fibromyalgia in, 1429 sexual dimorphism of sleep in, 1564-1565 sleepiness in, 721 stimuli response in sleeping, 127 Adrenergic uptake inhibition, 940 Adrenocorticotropic hormone (ACTH) in corticotropic axis, 293-294 overview of, 293t Adulthood, sexual dimorphism of sleep in, 1565 Advanced sleep phase syndrome (ASPS), 166, 475-476 clinical features of, 475 diagnosis of, 476 epidemiology of, 475-476 familial, 166, 187-188 genetics in, 451 light therapy for, 1688-1689 melatonin and, 425 pathogenesis of, 476 treatment of, 476 Aerophagia, 1325 Afferent nerve fibers, 348-349 African Americans, insomnia in, 832 African sleeping sickness, 1070 Afternoon shift work, 785
Age and aging architecture of sleep and, 27-30, 28t arousals and, 29, 29t chronologic vs. physiologic, 27 circadian rhythms and, 30-32, 372-373, 414-415 cognitive therapy for insomnia and, 899-900 dream content and, 590 endocrine function and, 303-306 growth hormone axis and, 303-304 insomnia in, 32-33, 695, 830-831, 833 latency and, 27-28 melatonin and, 425-426 napping and, 36 neural circulatory response to sleep and, 232-233 pain perception and, 1445 in Parkinson’s disease, 980 periodic leg movements in sleep and, 34 phase shift in, 31 pituitary-adrenal axis in, 304-305 pituitary-gonadal axis in, 305-306 poor sleep in, 32-33 prolactin in, 304 sleep deprivation and acute, 57 sleep-disordered breathing and, 34-36 sleep regulation changes in, 1545-1546 sleep stage distribution and, 22-24 slow wave sleep and, 29-30, 30f stage distribution and, 28-29 subjective, 27 testosterone in, 305-306 upper airway resistance and, 35 Aggression, psychotic dream-related, 1124 Agitation, in dementia patients, 1044-1045 Agomelatine, 543t-545t Agoraphobia, 1474b. See also Panic disorder Agrypnia excitata, 1091 Airflow detection methods, 1610-1613 Airflow resistance, 255 Airway, upper anatomy, 259-261, 1153 in sleep apnea, 1160-1164 collapsing forces in, 263-265 dilating forces in, 264-265 dynamic properties of, 1153-1157 effects of sleep on, 262-263 elastic forces in, 259-260 examination in obstructive sleep apnea, 1214-1215 function, 1153 jaw position and, 1155-1156 muscles, 259, 260f, 264f effect of sleep on, 265 myopathy, 1162-1164 neck position and, 1155-1156 opening muscles, 254 physiology, 259-261 resistance age and, 35 arousal from, 252-253, 253f syndrome, 1212-1213 in snoring, assessment of, 1175 stabilizing forces in, 265 as Starling resistor, 262-263 static properties of, 1153-1157 stimulation, 1226-1227 Airway cooling, 1295 Airway morphology, as diagnostic tool, 673 Airway negative-pressure reflex, 354-355 Airway occlusion, 252
1697
1698 Index Airway resistance age and, 35 arousal from, 252-253, 253f Alcohol apnea and, 705 benzodiazepines and, 489 nightmares and, 1109-1110 obstructive sleep apnea and, 1221-1222, 1516 periodic limb movements in sleep and, 1516 sleep deprivation and, 56 sleep stage distribution and, 23-24 sleep-wake alterations with, 1515-1517 snoring and, 1177 Alexithymia, 1116-1118 Alleles, 152-153. See also Gene(s) Allergens, asthma and, 1295 Almitrine, 277, 1303 Alodorm. See Nitrazepam Alpha agonists, 552 ALS. See Amyotrophic lateral sclerosis (ALS) Alternative therapy, for insomnia, 926 Altitude acclimatization to, 274 chemosensory mechanisms and, 274 hypocapnia and, 272-273 hypoxia and, 272-273 increased ventilation at, 269 long-term adaptation to, 277-278 mechanisms of breathing at, 272 periodic breathing at, 271-276 physiologic adjustment to, 269-271 sleep disturbances at, 269-271 syndromes, 275 treatment for periodic breathing at, 276-277 Alveolar hypoventilation, 1148 Alveolar hypoxia-hypercapnia, 1371 Alzheimer’s disease (AD) circadian rhythm and, 426 EEG in, 1039 obstructive sleep apnea and, 1038 overview of, 1038 polysomnography in, 1038-1039 REM sleep in, 1039 sleep problems in, 1038 Amantadine, 549-551 Ambien. See Zolpidem Ambient temperature sleep deprivation and, 55-56 sleep stage distribution and, 23 Ambiguous sleep stages, 1608-1609 Ambulatory monitoring, 1650-1651 American Academy of Sleep Medicine (AASM), 12, 17b, 931-932 American Narcolepsy Association, 12 American Sleep Disorders Association, 721 Amitriptyline, 493t-494t, 497, 543t-545t, 917t-919t, 921, 1495t Amoxapine, 543t-545t, 546-547 Amphetamines, 532t-533t absorption of, 512 abuse of, 519-520, 1518-1519 anatomic substrates mediating, 518 chemical structure of, 511, 512f drug interactions with, 520 historical perspective with, 510-511 inactivation of, 512 indications for, 519 misuse of, 519-520 molecular targets of action of, 512-515 for narcolepsy, 941b, 964 neurotoxicity of, 519 norepinephrine and, 519 presynaptic modulation of dopaminergic system with, 515-518 side effects of, 519 for sleepiness in dementia patients, 1043t structure-activity relationships in, 511-512 toxicology of, 519 d-amphetamine sulfate, 513t Amphibians, 120 AMS. See Acute mountain sickness (AMS) Amygdala, 210 Amyotrophic lateral sclerosis (ALS), 661, 662f, 1017-1018 Anafranil. See Clomipramine
ANC. See Adjusted neck circumference (ANC) Anemia, restless legs syndrome and, 1030 Angina, 1355-1357 Angiotensin II converting enzyme, 1188-1189 Animals, rapid eye movement sleep in, 8 Anorectal function, 319-320 Antibodies, sleep deprivation and, 286 Anticataplectics, 941b Anticipation, 816 Anticonvulsants, 489, 924, 1033 Antidepressants, 542-547 adrenergic uptake inhibition and, 940 anticataplectic effects of, 940 effects on sleep and waking, 543t-545t, 1496 for insomnia, 921-923 mechanisms of action, 542-545 for narcolepsy, 965 obstructive sleep apnea and, 1224-1225 pharmacokinetic properties of sedating, 493t polysomnographic effects of sedating, 494t receptor pharmacology of sedating, 493t sedating, 494-500, 921-923 sleep stage distribution and, 23-24 tricyclic, 493t, 495-498, 1495t effects on sleep, 497-498, 543t-545t, 545 for insomnia, 921 for panic disorder, 1476 pharmacodynamics of, 497 pharmacokinetics of, 495-497 receptor pharmacology of, 497 side effects of, 498 Antiepileptics, 49, 549, 550t-551t Antihistamines, 553 effect on sleep, 502 as hypnotics, 487, 501-502, 924-925 pharmacodynamics of, 501-502 pharmacokinetics of, 501 receptor pharmacology of, 501-502 sleepiness and, 49 specific agents, 501 Antihypertensives, sleepiness and, 49-50 Antiparkinsonian drugs, 549-551 Antipsychotics, 504-505, 547, 548t, 923, 1505-1507 Anxiety disorders controversies with, 1483-1484 in elderly patients, 1526 pitfalls with, 1483-1484 polysomnography in, 1473 prevalence of, 1473 Anxiolytics, 489, 547-549 Apnea(s), sleep. See also Congenital central hypoventilation syndrome (CCHS) ; Sleepdisordered breathing (SDB) actigraphy in, 1670-1671 cardinal manifestations of, 651-653 central acromegaly in, 1435-1437 alveolar hypoventilation for, 1148 arterial carbon dioxide tension and, 1142 carbon dioxide for, 1411-1412 cardiac pacing for, 1410 cardiovascular function and, 1404-1406 clinical features of, 1146-1148 CPAP and, 1234 diagnostic evaluation of, 1148 epidemiology of, 1146 heart failure and, 1403-1404 clinical presentation of, 1406-1407 treatment of, 1408-1412 idiopathic, 1144-1149 mechanisms of, 1403-1404 medications for, 1148-1149 neurologic disorders and, 1145 pathophysiology of, 1141-1146 sleep-onset, 1143-1144 in stroke, 997f treatment of, 1148-1149 types of, 681t-683t ventilatory control stability and, 1142-1143 in children, 705 complex, 1145-1148, 1245 definition of, 1282b in diastolic heart failure, 1402 dreaming and, 606-608
Apnea(s), sleep (Continued) in elderly people, 705 epidemiology of, 702-708 fragmentation in, 62 heart disease and, 705-706 in high altitudes, 273 menopause and, 1595-1596 in nursing home patients, 1555-1557 obstructive, 684 airway morphology studies in diagnosis of, 673 alcohol and, 1221-1222, 1516 Alzheimer’s disease and, 1038 amyotrophic lateral sclerosis and, 661, 662f angiotensin II converting enzyme in, 1188-1189 antidepressants and, 1224-1225 apolipoprotein E in, 193, 1188 appliances for, 1165-1167 arrhythmias in, 1376-1377 associated medical disorders in, 1279 atrial fibrillation and, 1377-1378 attention and, 1197 barbiturates and, 1222-1223 bariatric surgery for, 1287 behavioral factors in, 1279 behavioral interventions for, 1219-1223 body position and, 1221 bradyarrhythmias and, 1377 cardiac pacing for, 1228 cardiac resynchronization therapy for, 1228 cardinal manifestations of, 652-653 cardiopulmonary examination in, 662 cardiovascular function and, 1404 chronic obstructive pulmonary disease and, 1289 circadian rhythm and, 1186-1187 clinical course of, 1284 clinical examination in, 1213-1216 clinical features in, 1279-1280 clinical signs and symptoms in, 1207-1212 clinical values of symptoms in diagnosis, 671t cognitive problems in assessment of, 1194-1196 effects of treatment on, 1201 epidemiology of, 1194 etiology of, 1199-1201 legal aspects of, 1201-1203 medical aspects of, 1201-1203 processing and, 1196-1198 combination therapy for, 1227-1228 common clinical problems in management of, 1287-1290 coronary artery disease and clinical course in, 1397 elimination of, 1395-1396 epidemiology of, 1393-1396 pathogenesis of, 1396-1397 prevalence of, 1393-1394 CPAP for, 1165 craniofacial factors in, 658, 1184-1185 daytime signs and symptoms of, 1210-1212 definitions in, 1207 in dementia patients, 1044 diabetes and, 306 diagnosis of, 1280-1284 diastolic heart failure and, 1375-1376 discovery of, 10 diurnal blood pressure and, 1384-1385 in Down syndrome, 194 dreaming and, 606-608 driving risk in, 1288 early observation of, 5-6 edema and, 1160-1161 in elderly patients body position and, 1540 cardiovascular disease and, 1539 clinical consequences of, 1537-1539 clinical manifestations in, 1536-1537 cognition and, 1538-1539 CPAP for, 1539-1540 driving and, 1540 epidemiology of, 1536 gender and, 1536 nocturia and, 1537-1538 obesity and, 1536
Apnea(s), sleep (Continued) oral appliances for, 1540 pathophysiology of, 1537 pharmacologic treatment for, 1540 presentation of, 1536-1537 stroke and, 1539 treatment of, 1539-1540 vs. younger patients, 1537t endocrine considerations in, 1223 endocrine function and, 303 in end stage renal disease patients, 1467-1469 epidemiology of, 1206-1207, 1278-1279 estrogen and, 1223 evolution of, 706-708 executive functions and, 1197-1198 familial aggregation of, 1187-1188 fat distribution and, 1161-1162 gender and, 1164, 1215-1216, 1280 genetic analyses in, 1188-1190 genetic analyses of, 1188-1190 genetics of, 193, 1164, 1279 goiter in, 659f heart failure and, 1374-1376 clinical presentation of, 1406-1407 treatment of, 1407-1408 hemodynamic effects in, 1373-1378 history in evaluation of, 666-668, 669t-670t home studies in diagnosis of, 672-673 hypertension and, 1381-1388 clinical relevance of, 1387-1388 in population subgroups, 1384 hypnotics and, 1222 hypothyroidism and, 1223, 1438 intermediate phenotypes of, 1183-1184 leptin signaling and, 1189-1190 mandibular micrognathia in, 659f mandibular retrognathia in, 659f in Marfan syndrome, 194 mechanical therapy for, 1226-1228 memory in, 1196-1197 modafinil in, 534 molecular genetic studies in, 1188-1190 myopathy in, 1162-1164 narcotics and, 1222 nasal dilators for, 1226 nasal factors in, 658 nasopharyngeal airway stents for, 1226 neck circumference in, 658-660, 1214 neurological examination in, 661 nighttime signs and symptoms in, 1207-1210 obesity and, 306, 659f, 702-703, 1161-1162, 1184, 1214, 1339-1340 occurrence of, 704t oral appliances for, 1287 oromaxillofacial surgery for, 1287 oxygen for, 1223-1224 palatal implants for, 1287 palate in, 661f pathogenesis of, 1279 obesity and, 1340-1341 pharmacologic interventions for, 1223-1226 pharynx examination in, 660 phenotype, 1183 phenotype of, 1183 phosphodiesterase-5 inhibitors and, 1223 physical examination in, 658-662, 668-671 polycystic ovary syndrome and, 306-307 polysomnography in diagnosis of, 671, 1280 in pregnancy, 1576-1577 prevalence of, 1278-1279 prevention of, 1284 progesterone and, 1223 protriptyline and, 1224-1225 as pulmonary hypertension cause, 1388-1389 pulmonary hypertension mechanisms in, 1389-1390 quality of life and, 1198-1199 questionnaires in evaluation of, 666-668, 669t-670t risk factors for, 1213, 1278-1279 segregation analysis in, 1188 serotoninergic pathways in, 1189 serotonin uptake inhibitors and, 1225 sleep deprivation and, 1220-1221
Index 1699 Apnea(s), sleep (Continued) sleepiness in, 1280 sleep-onset REM periods in, 24 smoking cessation for, 1220 snoring in, 1279-1280 stimulants and, 1225 in stroke, 997f surgery for, 1167, 1286-1287 sympathetic activation in, 234 testosterone and, 1223 tongue in, 659f tonsil examination in, 660-661, 662f tracheostomy for, 12-13, 1287 treatment of, 1284-1287 types of, 681t-683t upper airway stimulation for, 1226-1227 ventilatory control patterns and, 1185-1186 weight loss for, 1165, 1219-1220 prevalence of, 702-703 primary, 684 sleep-inducing situations for patients with, 47t in systolic heart failure, 1401-1402 threshold, 273 upper airway anatomy differences in, 1160-1164 Apneic threshold, 273 Apolipoprotein E (APOE), 14, 1188 Apomorphine, 549-551 Appetite regulation, 297-298 Appliances, oral cardiovascular outcomes with, 1270 clinical outcomes with, 1268-1271 clinical protocol for, 1273-1274 comparison of designs in, 1270-1271 compliance issues in, 1272-1273 complications with, 1272 contraindications for, 1273 CPAP vs., 1271 for daytime sleepiness, 1269-1270 future directions in, 1274-1275 indications for, 1273 long-term follow up in, 1274 mandibular repositioning, 1266 mechanism of action in, 1266-1268 neurocognitive outcomes with, 1270 for obstructive sleep apnea, 1165-1167, 1287 in elderly patients, 1540 overview of, 1266 posttreatment assessment in, 1274 pretreatment assessment in, 1273 quality of life and, 1270 selection of, 1273-1274 side effects of, 1272 for snoring, 1178, 1269 surgery vs., 1271 for teeth grinding, 1135-1136 titration protocol in, 1274 treatment outcome predictors with, 1271-1272 types of, 1266 Application, of electrodes, 1603 APR. See Acute phase response (APR) Architecture, sleep age and, 27-30, 28t chronic sleep deprivation and, 69 genes for, 178-179 genotype-dependent differences in, 175 oral contraceptives and, 1569 in pregnancy, 1574-1576 in stroke patients, 1008-1010 testosterone and, 1437 Aripiprazole, 548t, 1497t Armodafinil, 56, 964 indications for, 520 mechanism of action of, 521-522 pharmacokinetics of, 520 side effects of, 520-521 Arousal(s) age and, 29, 29t autonomic responses associated with, 231-232, 1371-1373 from bronchial irritation, 253-254 confusional, 655, 1077 delineation of systems for, 77-78 deprivation and, 55-57 disorders of clinical course of, 1080
Apnea(s) (Continued) clinical features of, 1077-1078 diagnosis of, 1079 differential diagnosis of, 1079 epidemiology of, 1076 pathogenesis of, 1076-1077 pitfalls and controversies, 1080 risk factors for, 1076 treatment of, 1079-1080 epilepsy and disorders of, 1054 histamine in, 157 from hypercapnia, 252, 253f hypothalamus in, 201 from inspiratory resistance increase, 252-253, 253f from isocapnic hypoxia, 252, 253f physiologic, 1633 respiratory response, 252-254 scoring, 1606-1608 serotonin in, 78 ventilatory response to, 254 wake-on, REM-off, 78-79 wake-on, REM-on, 79 Arousal-retrieval model of dream recall, 604 Arrhythmias in epilepsy, 1057 in obstructive sleep apnea, 1376-1377 ventricular, 221-222, 1363-1364, 1377 Arrhythmogenesis, 220-223, 1363 Arterial baroreflex, 227 Arterial blood pressure control of, 218 in sudden infant death syndrome, 218 Arterial carbon dioxide tension, 1142 Arterial tone, peripheral, 230 Arthritis, 1526 Ascending arousal system, 569-570 Ascending reticular system, 5, 5f Aserinsky, Eugene, 7, 92 ASPS. See Advanced sleep phase syndrome (ASPS) Assisted coughing techniques, 1323-1324 Association of Sleep Disorders Centers, 12 Associative networks, 630-631 Asthma, nocturnal airway cooling and, 1295 airway in, 1294 airway narrowing mechanisms in, 1297 allergens and, 1295 autonomic function and, 1297 bronchial hyperreactivity and, 1295-1296 catecholamines and, 1297 cortisol and, 1297 death from, 1298 diagnosis of, 1298 gastroesophageal reflux and, 1295 hormones and, 1297 hypoxemia in, 1298 incidence of, 1294 inflammation in, 1297 mucociliary clearance and, 1295 obesity and, 1296 parasympathetic nervous system and, 1297 pathogenesis of, 1294-1296 sleep disturbance in, 1297-1298 sympathetic nervous system and, 1297 treatment of, 1298-1299 Asystole, nocturnal, 1364 Atenolol, 552t Atomoxetine, 522, 543t-545t, 941b, 963 Atrial fibrillation, 1364-1366, 1377-1378 Atrial natriuretic peptide, in water and electrolyte balance, 298 Attended laboratory polysomnography, 1621-1622 Attention in obstructive sleep apnea, 1197 in occupational medicine, 423-424 Attention deficit hyperactivity disorder (ADHD), 537, 1029-1030 Atypical parkinsonism, 981 Auditory response, in sleep onset, 19 Automatic behavior, 654, 728-730 Autonomic nervous system arousals and, responses in, 231, 1371-1373 in arrhythmogenesis, 222-223 cardiovascular arterial baroreflex in, 227
1700 Index Autonomic nervous system (Continued) functions of, 226-227 role of, 226 sleep-related changes in, 230-232 changes during sleep, 227-230 in diabetes mellitus, 233-234 disordered sleep and, 233-234 hypoxemia-hypercapnia and, 1371 periodic leg movements in sleep and, responses in, 231-232 in sleep, 1353-1355 Autosomal dominant nocturnal frontal lobe epilepsy (ADNFE), 1056-1057 Average volume-assured pressure support (AVAPS), 1022 Aviation safety, 720, 760 Awakening, false, 1112-1113 Awakening headache, 1065-1066
B
Bacterial challenge, sleep changes in, 284-285 Balance electrolyte, 298 water, 298 Bandwidths, 1604 Barbiturates, obstructive sleep apnea and, 1222-1223 Bariatric surgery, 1287, 1341-1344 benefits of, 1344-1345 complications of, 1345-1346 procedures of, 1343-1344 risks of, 1345-1346 Baroreflex, arterial, 227, 229 Basal metabolic rate, respiratory control and, 254-255 Basal sleep need, 67-68 Bat, big brown, 136 BC. See Bötzinger Complex (BC) Bed-sharing, with newborn children, 1589 Behavior automatic, 654, 728-730 daytime sleepiness and, 46 neuroethologic approach to, 729-730 prescriptions, for insomnia, 885-888 in sleep onset, 18-19 in substance abuse, 1514-1515 total sleep deprivation and, 54-59 Behavioral drug dependence, 1512 Behavioral interventions, for obstructive sleep apnea, 1219-1223 Behavioral seizures, 1056-1057 Behavioral treatment, of insomnia, 824 Behavioral treatment, of narcolepsy, 961 Benefit, sleep, 984 Benign nocturnal alternating hemiplegia of childhood, 1102 Benign sleep myoclonus of infancy, 687 Benzodiazepines. See also Hypnotics abuse of, 911 alcohol and, 489 for altitude-related breathing problems, 277 amnestic effects of, 910 as antiepileptics, 550t-551t for anxiety disorders, 547 cognitive effects of, 911-912 in comorbid insomnia, 907-908 dependence on, 490 discontinuation effects of, 910-911 dose range, 906t duration of action in, 905 in early hypnotic efficacy studies, 10 effectiveness of, 905-910 efficacy of, 905-910 elimination half-life, 906t fall risk and, 911-912 as first-line hypnotics, 905 for generalized anxiety disorder, 1478 idiosyncratic behavioral effects of, 912 mechanism of action of, 483-485 metabolism of, 906t mortality risk with, 912 in older patients, 911-912 overdose of, 489 pharmacokinetics of, 487-488
Benzodiazepines (Continued) for primary insomnia, 906-907 prolactin and, 295 receptor binding specificity in, 906t REM sleep and, 489 residual effects of, 910 for restless legs syndrome, 1033, 1034t safety of, 910-912 sleep latency and, 489, 906 sleep-related eating disorder and, 912 sleep stage distribution and, 23-24 somnambulism and, 912 in substance abuse patients, 927 tolerance of, 906-907 types of, 905 withdrawal, REM sleep and, 23-24 Bereavement, 1526 Bereavement dreams, existential, 1123 Berger, Hans, 4 Berlin Questionnaire, 652t Bernoulli effect, 1157 Beta-adrenergic receptor blockage, 221-222 Beta antagonists, 551-552, 552t Betaxolol, 1110t Biliopancreatic diversion (BPD), 1343 Biliopancreatic diversion with duodenal switch (BPDDS), 1343 Binswanger’s disease, 1041 Biological stress, psychosocial vs., 814 Bipolar disorder, 1494-1497, 1525-1526 Birds, 112, 119-120, 128-129, 132-133 Bizarreness, in dreams, 588, 598-601 Blindness circadian rhythm and, 425 dreams in, 591 Blood flow aging and, 232-233 cerebral, metabolism relationship with, 255 coronary artery, 220 day-night changes in, 230 obstructive sleep apnea and, 1373-1378 by parasympathetic nervous system, 226-227 in sleep, 1353-1355 Blood gases abnormalities in, 1370-1373 effect of sleep on, 262-265 monitoring of changes in, 1617-1618 Blood pressure arterial baroreflex and, 227 cardiopulmonary reflexes and, 227 control of, 218 CPAP treatment and, 1385-1387 diurnal, obstructive sleep apnea and, 1384-1385 monitoring, 1619-1620 sleep loss and, 233 in sudden infant death syndrome, 218 variability, 227-229 Bmal1 gene, 143, 145, 147t Body mass, sleep duration and, 128 Body position, obstructive sleep apnea and, 1221 Body temperature circadian regulation of, 323-324 core, 323-324 hibernation and, 330-331 melatonin and, 324 in REM sleep, 92-93 sleep deprivation and, 59-60, 328-329 sleep onset and, 86, 87f Borbély, Alexander, 112-113 Bötzinger Complex (BC), 238f BPD. See Biliopancreatic diversion (BPD) BPDDS. See Biliopancreatic diversion with duodenal switch (BPDDS) Bradyarrhythmias, 1377 Brain, electrical activity of, 4-5 Brain infarction, sleep apnea and, 706 Brain plasticity, 342-343 Brainstem, lower, 77 Brainstem reticular formation, medial, 99-100 Brain tumors, 1071 Breast cancer, 424 Breast-feeding, 1588-1589 Breathing. See Apnea(s); Respiration; Sleepdisordered breathing (SDB); Upper airway; Ventilation
Bremer, Frederick, 4 Bromocriptine, 549-551 Bronchial hyperreactivity, 1295-1296 Bronchial irritation, arousal from, 253-254 Bronchopulmonary reflex, 355-356 Broughton, Roger, 726 Brugada syndrome, 1367 Brumination, 127 Bruxism, sleep, 353, 655-656, 663-664 behavioral treatment strategies for, 1135 catecholamines and, 1131 clinical features of, 1132-1133 diagnostic evaluation of, 1133-1135 in electromyography, 1134b epidemiology of, 1128-1129 etiology of, 1128 familial disposition in, 1131 genes in, 1131 iatrogenic, 1129b local factors in, 1131-1132 neurochemistry and, 1131 occlusal appliances for, 1135-1136 palliative management for, 1135b pathophysiology of, 1129-1132 pharmacologic management for, 1136-1137 pitfalls and controversies in, 1137 risk factors for, 1128-1129 salivary flow and, 1132 secondary, 1129b in sleep laboratory, 1133-1134 stress and, 1130 tooth equilibration in, 1136 treatment of, 1135-1137 types of, 1129b BTBD9 gene, 191 Buccinator crest, 264f Buccinator muscle, 264f Bupropion, 522, 543t-545t, 546, 1495t Burnout, 736-737, 817-818 Buspirone, 549
C
Cabergoline, 549-551 Caffeine abuse, 1517-1518 alerting effects, 528 for cognitive improvement in sleep loss, 810 for excessive daytime sleepiness, 513t in history, 527 mechanism of, 528 in popular ingestibles, 529t-530t side effects of, 528-530 sleep deprivation and, 56 as stimulant, 522-523 tolerance, 528-530 withdrawal, 528-530 Cage exchange model of insomnia, 851b, 860-862 Calcium-binding proteins, in suprachiasmatic nucleus, 379 Calgary Police Service, 806 Cancer brain, 1071 in elderly patients, 1528 fatigue in differential diagnosis of, 1420 epidemiology of, 1417 pathogenesis of, 1418-1419 treatment of, 1419-1420 hormone-dependent, 424 insomnia and, 830t-831t, 1416-1417 in menopausal women, 1597-1598 sleep disruption in behavioral therapy for, 1419 differential diagnosis of, 1420 epidemiology of, 1416-1417 pathogenesis of, 1418 pharmacotherapy for, 1419 treatment of, 1419 Candida albicans, 284-285 Cannon, W. B., 112-113 CAPD. See Continuous ambulatory peritoneal dialysis (CAPD) Carbachol, 99, 1110t
Carbamazepine, 550t-551t, 1043t, 1497t Carbon dioxide for central sleep apnea, 1411-1412 sensing of expired, 1612-1613 transcutaneous, 1619 Carbonic anhydrase inhibitors, 276-277 Cardiac medications, sleep-disrupting effects of, 1367-1368 Cardiac pacing, for obstructive sleep apnea, 1228 Cardiac resynchronization therapy, 1228 Cardiac transplantation, 1409 Cardiomyotrophin-like cytokine (CLC), 146 Cardiopulmonary coupling, 1620 Cardiopulmonary parasomnias, 1101 Cardiopulmonary reflexes, 227 Cardiorespiratory homeostasis, 217-218 Cardiorespiratory interactions, 216-218 Cardiovascular autonomic nervous system arterial baroreflex in, 227 disordered sleep and, 233-234 functions of, 226-227 role of, 226 sleep-related changes in, 230-232 Cardiovascular disease economic costs of, 1349 obstructive sleep apnea and, in elderly patients, 1539 overview of, 1349 sleep medicine and, 717-718 snoring and, 1174 Cardiovascular drugs, 551-553 Cardiovascular events, nocturnal, 1355-1360 Cardiovascular function central sleep apnea and, 1404-1406 cerebellum and, 217 chronic sleep deprivation and, 73 insular cortex and, 217 obstructive sleep apnea and, 1404 in pregnancy, 1574f in REM sleep, 216 sleep-state control of, 215-216 Caregiving, by older adults, 1530-1531 Carskadon, Mary, 12 Carvedilol, 552t Case-control study information, 186b Casein kinase 1, 145 Cataplexy cardinal manifestations of, 653 epilepsy and, 1052 in genetic disorders, 194 hypocretin deficiency in, 943 muscle tone and, 101, 958 in narcolepsy, 957-958 sleep-onset REM periods and, 9 Catathrenia, 655, 689, 1098-1099 Catecholamines asthma and, 1297 bruxism and, 1131 systemic, 230 Catechol-O-methyltransferase (COMT), 181 Caton, Richard, 4 Cat preparations, 4-5 CBT. See Cognitive behavioral therapy (CBT); Core body temperature (CBT) CCHS. See Congenital central hypoventilation syndrome (CCHS) Celexa. See Citalopram Cenesthopathic feelings, 958-959 Central fatigue, 1422 Central nervous system, melatonin in disorders of, 426 Central pattern generators, 729-730 Central sleep apnea in acromegaly, 1435-1437 alveolar hypoventilation and, 1148 arterial carbon dioxide tension and, 1142 breathing control and, 1141-1142 carbon dioxide for, 1411-1412 cardiac pacing for, 1410 cardiovascular function and, 1404-1406 clinical features, 1146-1148 CPAP and, 1234 diagnostic evaluation of, 1148 epidemiology of, 1146
Index 1701 Central sleep apnea (Continued) heart failure and, 1403-1404 clinical presentation of, 1406-1407 treatment of, 1408-1412 idiopathic, 1144-1149 mechanisms of, 1403-1404 medication for, 1148-1149 neurological disorders and, 1145 pathophysiology of, 1141-1146 sleep-onset, 1143-1144 in stroke, 997f treatment of, 1148-1149 types of, 681t-683t ventilatory control stability and, 1142-1143 Cephalometric imaging, 1252 Cerebellum, in cardiorespiratory function, 217 Cerebral blood flow-metabolism relationship, 255 Cerebral infarction, sleep apnea and, 706 Cerebrospinal fluid (CSF) hypocretin levels, in narcolepsy, 946-949, 948t, 950b, 951t Cerebyx. See Fosphenytoin Cerveau isolé, 4-5 Cessation of dreaming, 1116 Cetaceans, 118, 133-135 C-Fos mapping, 80-81 Chalder fatigue scale, 1426 Chaos theory, 229 Characterization, functional, 185b Charcot-Marie-Tooth (CMT) disease, 1070 Charcot-Wilbrand syndrome, 1005 Charles Bonnet syndrome, 568t, 569, 1005 Chemoreflexes, 227, 356-358 Chest compliance, 260b Cheyne, John, 1400 Cheyne-Stokes respiration, 1145, 1147, 1149 Chiari malformation, 1072 Chief complaint, 641-644 Children actigraphy and, 1671 amphetamines for, 511 cardinal manifestations of sleep disorders in, 656-657 chronic fatigue syndrome in, 1429 cognitive therapy for insomnia in, 899 fibromyalgia in, 1429 headache in, 1066 narcolepsy treatment in, 961b, 966 restless legs syndrome in, 1029-1030 attention-deficit/hyperactivity disorder and, 1029-1030 diagnosis of, 1029 prevalence of, 1029 sexual dimorphism of sleep in, 1563-1564 sleep apnea in, 705 slow wave sleep in, 22 snoring in, 705 stimulants in, 537 Chloral hydrate, 495t-496t, 504 for insomnia, 917t-919t, 925 for insomnia in dementia patients, 1043t Chlordiazepoxide, 10, 484t Chlorpromazine, 548t Choate, Rufus, 725-726 Chocolate, 529t-530t Cholinergic cell groups, 100 Chronic fatigue syndrome (CFS) in adolescents, 1429 in children, 1429 clinical assessment of, 1425-1426 clinical course of, 1430 clinical features in, 1424-1425 controversies with, 1429-1430 diagnosis of, 1424b, 1425-1427 EEG in, 1430-1433 epidemiology of, 1423 fatigue in, 1425 idiopathic hypersomnia vs., 975-976 pathogenesis of, 1423-1424 polysomnography in assessment of, 1426-1427 treatment of, 1427-1429 Chronic kidney disease (CKD) breathing disorders in, 1466-1467 definition of, 1463b definition of terms in, 1462 epidemiology of sleep disturbances in, 1463-1464
Chronic kidney disease (CKD) (Continued) hemodialysis in, 1462 insomnia in, 1464-1465 periodic limb movements in, 1466 restless legs syndrome in, 1465-1466 treatment terminology in, 1462 Chronic obstructive pulmonary disease (COPD) cardiac dysrhythmias and, 1301 definition of, 1299 in elderly patients, 1527 functional residual capacity in, 1300 hemodynamics and, 1301 hypnotics in, 1304 hypoventilation in, 1299-1300 hypoxemia in, 1299-1301 lung volume reduction surgery for, 1303 medroxyprogesterone for, 1303 obstructive sleep apnea and, 1289, 1301 polycythemia and, 1301 protriptyline for, 1303 sleep studies in, 1302-1303 theophylline for, 1303 treatment of, 1303-1304 ventilation-perfusion mismatching in, 1300-1301 Chronic paroxysmal hemicrania, 1065 Chronic sleep deprivation adaptation to, 68 cardiovascular effects in, 73 cognitive effects of, 70-72 core vs. optimal sleep in, 68 driving and, 72 effects of, 69-72 endocrine effects of, 73, 298-301 glucose and, 300 growth hormone in, 300 immune function and, 73 incidence of, 67 individual differences in responses to, 72 leptin in, 300 metabolic effects of, 73, 298-301 mood in, 72 on Multiple Sleep Latency Test, 70 obesity and, 300-301 obstructive sleep apnea and, 1220-1221 oculomotor responses in, 70 physiologic effects of, 73 sleep architecture and, 69 sleep need and, 67-68 sleep propensity and, 69-70 thyroid stimulating hormone in, 300 two-process model predictions of, 68-69 waking EEG in, 70 Chronobiologic monitoring actigraphy in, 1662-1663 basic concepts in, 1657 future directions in, 1665 methodologic questions in, 1657-1658 paradigms in, 1658-1662 terminology in, 1657 Chronobiology, 6 Chronotherapy, 473-475 for advanced sleep phase syndrome, 1688-1689 apparatus for, 1682-1683 boxes in, 1682-1683 case management, 1684-1686 for circadian disorders, 1686-1689 dawn simulators in, 1683 for delayed sleep phase disorder, 1686-1688 delivery of, 1682-1684 for depressive disorders, 1690-1692 for free-running disorder, 1689 indications for, 1686-1692 in nursing homes, 1554 patient monitoring in, 1684-1685 safety in, 1683-1684 for seasonal affective disorder, 1690-1691 timing in, 1685-1686 Cigarettes, obstructive sleep apnea and, 1220 Circadian oscillators, 394-398 Circadian rhythm. See also Suprachiasmatic nucleus (SCN) across lifespan, 372-373 activity and, 371-372 as activity consolidation mechanism, 365 on actogram, 364f, 1671
1702 Index Circadian rhythm (Continued) adaptive significance of, 365 in aging, 30-32, 414-415 of airway caliber, 1294 Alzheimer’s disease and, 426 arousal states and, 371-372 artifacts in study of, 446-448 blindness and, 425 body temperature and, 86, 323-324 chronobiology and, 6 cognitive performance measures in study of, 445 cryptochromes and, 144 daytime sleepiness and, 48-49 diencephalon and, 77 disorders, 685 in dementia patients, 1044 endogenous, 425-426 genes in, 698 genetic models of, 460 idiopathic hypersomnia vs., 976-977 insomnia and, 1633 light therapy for, 1686-1689 melatonin and, 423-425 overview of, 470 prevalence of, 698 in traumatic brain injury, 1068 underrecognized, 470 dreaming and, 578-583 in Drosophila, 153-156 endocrine function and, 291-292, 383-384 environmental influences on, 366-372 eveningness in study of, 448-449 exercise and, 407-408 feedback pathways in, 413 in fetus, 372 forced desynchrony protocol in, 449-450 forebrain and, 76-77 gene expression patterns and, 465 genes for, 139 genetic factors underlying, 187-188 genetic regulation of, 170-171 genetics of individual differences in, 451 homeostasis and, 435-436 homeostasis vs., 116-118 hormonal variation with, asthma and, 1297 hypertension and, 424 influence of, on physiology, 402-404 integration of, 86 interindividual variability in, 448 Kleitman protocol and, 408-409 light and, 366-368, 404-407, 471 lower brainstem in, 77 masking in study of, 446 measurement of, 364-365 menstrual cycle and, 1565-1569 metabolism and, 466-467 mid-afternoon dip and, 446 morningness in study of, 448-449 multiple oscillator nature of, 394-398 nature of, 363-364 neurobehavioral functions in, 409-410 nonphotic input in, 407-408 norepinephrine in, 79 obstructive sleep apnea and, 1186-1187 ovarian hormones and, 1565-1569 pain perception in, 1444 parameters, 364-365 in gene expression, 1663-1665 performance deficits and, 740 performance monitoring and, 775-776 Per genes in, 177 period of, 413-414 photic entrainment and, 366-368 physiologic regulation and, 463-464 in postpartum period, 1587 practice effect in study of, 446-448 properties of, 141-142 proteins in, 147 protein synthesis in, 142 resonance of, with light-dark cycle, 457-458 salivary melatonin and, 1661-1662 shift work and, 785-786 sleep and wake vs., 449-451 sleep deprivation and, 54-55, 435, 449 sleep stage distribution and, 23
Circadian rhythm (Continued) sleep structure and, 412-413 social cues and, 372 in stroke patients, 1010 suprachiasmatic nucleus and, 141 thalamus and, 77 thyroid stimulating hormone and, 403-404 as true clock, 365 ultradian days and, 450-451 vision and, 380-381 Circulation aging and, 232-233 cerebral, metabolism relationship with, 255 coronary artery, 220 day-night changes in, 230 obstructive sleep apnea and, 1373-1378 by parasympathetic nervous system, 226-227 in sleep, 1353-1355 Circumference of neck, in sleep apnea, 658-660 Citalopram, 543t-545t, 1495t CKD. See Chronic kidney disease (CKD) CLC. See Cardiomyotrophin-like cytokine (CLC) Clinical practice, early development of, 11-12 Clinical practice guidelines definition of, 931 for insomnia development of, 932-936 diagnosis in, 934 evaluation section of, 933-934 pharmacologic therapies in, 935-936 treatment in, 934-936 monitoring in, 1621-1623 national clearinghouse for, 931 role of, 931-932 systematic review in, 931 Clock, circadian. See Circadian rhythm Clock genes, 117, 139, 141-142, 147t, 464-465 input regulation, 146-147 negative elements in identification of, 143-144 output regulation, 146 positive elements in identification of, 142-143 Clomipramine, 543t-545t, 941b, 1495t Clonazepam, 484t, 1043t, 1091-1092 Clozapine, 548t, 1043t Cluster headaches, 1065 CMT. See Charcot-Marie-Tooth (CMT) disease Cocaine, 512, 1518-1519 Coccagna, Giorgio, 10 Cockroaches, 120-121 Coffee, 529t-530t Coffin-Lowry syndrome, 950 Cognition benzodiazepine use and, 911-912 caffeine and, 810 chronic sleep deprivation and, 70-72 daytime sleepiness and, 51 dextroamphetamine and, 811 insomnia and, 33 modafinil and, 810-811 obstructive sleep apnea and, in elderly patients, 1538-1539 pharmacologic strategies for improvement of, in sleep loss, 810-811 in sleep apnea, problems with assessment of, 1194-1196 effects of treatment on, 1201 epidemiology of, 1194 etiology of, 1199-1201 legal aspects of, 1201-1203 medical aspects of, 1201-1203 processing and, 1196-1198 social, dreams and, 571 Cognitive behavioral therapy (CBT) for generalized anxiety disorder, 1478 for insomnia, 824, 866-867, 871t-878t for panic disorder, 1476 for social phobia, 1479 Cognitive inventories, 1636-1637 Cognitive performance measures, 445 Coke, Sir Edward, 725 Cold-sensitive neurons (CSNs), 86 Collapsing forces, in upper airway, 263-265 Colonic function, 319-320 Comorbidities, sleep architecture and, 29 Complaint, chief, 641-644
Complementary and alternative therapies, for insomnia, 869, 926 Complex sleep apnea, 1145-1148, 1245 Compliance, chest, 260b COMT. See Catechol-O-methyltransferase (COMT) Confabulation, 567-569 Confusional arousals, 655, 1077 Congenital central hypoventilation syndrome (CCHS), genetics of, 193-194 Congestive heart failure, 1145, 1359 Connectivity, cortical, 563-564 Consciousness components of, 727t as continuum, 728-729 in dreaming, 727-728 evolution of thought on, 726-728 waking, 726-727 Consolidation, 119 Constant-routine protocols, 1660 Continuity, sleep, 119, 1504 Continuity hypothesis of dreaming, 604-605 Continuous ambulatory peritoneal dialysis (CAPD), definition of, 1462, 1463b Continuous positive airway pressure (CPAP), 1285-1286 adherence issues with, 1239-1241, 1288 airflow in, 1238-1239 autotitrating, 1241 blood pressure changes after, 1385-1387 in cardiorespiratory failure patients, 1236 central apnea and, 1234 in decompensated patients, 1236 dreaming and, 608 effects of, 1165 in elderly patients, 1539-1540 in end stage renal disease patients, 1468 failure management, 1241-1245 first night with, 1235-1236 health outcomes with, 1245 heart failure and, 1245, 1409-1410 interface, 1238 mode of action, 1233-1234 nasal congestion with, 1238 oral appliances vs., 1271 practical aspects of, 1234-1237 pressure level in, 1238-1239 problems with, 1237-1239 pulmonary artery pressure changes after, 1390 side effects of, 1237-1239 for snoring, 1178 in stroke patients, 1001t-1002t Contraceptives, oral, 1569 Control, in genetic research, 185b Conversion hysteria, 1102 Cooling, airway, 1295 Core body temperature (CBT), 323-324 Core sleep, optimal vs., 68 Coronary artery blood flow regulation, 220 Coronary artery disease incidence of, 1395 obstructive sleep apnea and elimination of, 1395-1396 epidemiology of, 1393-1396 prevalence of, 1393-1394 Coronary endothelial dysfunction, 1370-1371 Cortex, insular, 217 Cortical connectivity, 563-564 Corticosteroid rhythm, 384 Corticosteroids, 554 Corticosteroid secretion disorders, 1438-1439 Corticotropic axis, 293-294 Cortisol action of, 293t asthma and, 1297 in pregnancy, 1572-1573 in sleep deprivation, 292f Cost-effectiveness analysis, 676-677 Coughing, assisted, 1323-1324 Coupling, EEG, 231 Cows, 118 Cramps, 1101 Craniofacial morphology, in obstructive sleep apnea, 1184-1185 Craniovertebral junction malformation, 1072 Creutzfeldt-Jakob disease (CJD), 1042
Index 1703
Cricoid cartilage, 264f Cricopharyngeus muscle, 264f Cricothyroid ligament, 264f Cricothyroid muscle, 264f Cry genes, 144-146, 147t Cryptochromes, 144 CSF. See Cerebrospinal fluid (CSF) CSNs. See Cold-sensitive neurons (CSNs) Cushing’s syndrome, 649, 1438-1439 Cymbalta. See Duloxetine Cytokines in acute phase response, 281-282 proinflammatory, 88 sleep deprivation and, 285
D
DA. See Dopamine (DA) Dalmane. See Flurazepam DAT. See Dopamine transporter (DAT) Dawn simulators, 1683 Daytime electroencephalography, 1647-1649 Daytime sleepiness adaptation to, 44 adenosine in, 45 alerting drugs and, 50 antiepileptics and, 49 antihistamines and, 49 antihypertensives and, 49-50 assessment of, 45-47 behavioral functioning and, 46 cardinal manifestations of, 650 central nervous system pathologies and, 50 circadian rhythm and, 48-49 clinical assessment of, 47 clinical significance of, 50-51 cognition and, 51 in dementia patients, 1044 determinants of, 47-50 dopaminergic agonists and, 50 drugs for, 513t early measurement of, 12 in end stage renal disease, 1464 epidemiology of, 42-43, 698-700 evaluation of, 674-675 fatigue vs., 49-50 gamma-aminobutyric acid and, 45 history in evaluation of, 674 idiopathic hypersomnia and, 970 introspective, 1628-1629 in limited populations, 42 in Maintenance of Wakefulness Test, 46, 674-675 manifest, 1627-1628 on MRI, 44-45 in Multiple Sleep Latency Test, 42-43, 43f, 45-47, 674-675 in myotonic dystrophy, 50 in narcolepsy, 957 nature of, 43-45 neural substrates of, 44-45 neurochemistry in, 45 in obstructive sleep apnea, 1210-1212, 1280 oral appliances for, 1269-1270 overview of, 1624-1625 in Parkinson’s disease, 50, 984-986 treatment of, 989-990 physical examination in, 674 physical findings in, 650 physiologic, 1625-1627 as physiological need state, 43-44 polysomnography in evaluation of, 674 presentation of, 643-644 public health significance of, 50-51 quality of sleep and, 48 quantification of, 45-46 quantity of sleep and, 47-48 recognition of clinical significance of, 12 in representative populations, 42-43 risk factors for, 43 sedating drugs and, 49-50 snoring and, 1173 treatment of, 513t
Death sleep vs., 3 snoring and sudden, 706 Debt, sleep, 67 Dec genes, 146 Decision analysis, 676-677 Declarative memory, 336, 339-340, 633-634 Deep sleep. See Slow wave sleep (SWS) Definitions of sleep, 16 Delayed sleep phase syndrome (DSPS), 472-475 clinical features of, 472 diagnosis of, 473 epidemiology of, 472 genetics in, 166, 451 light therapy for, 1686-1688 melatonin and, 425, 474-475 pathogenesis of, 472-473 treatment of, 473-475 Deletion, targeted gene, 169-170 Delta sleep. See Slow wave sleep (SWS) De Mairan, Jean Jacques d’Ortous, 6 Dementia frontotemporal, 1042 in Huntington’s disease, 1041-1042 insomnia in, 1042-1043 with Lewy bodies, 1040-1041 in nursing home patients antipsychotic use in, 1553 associated morbidities in, 1555-1557 cholinesterase inhibitor use in, 1553 hypnotic use in, 1552-1553 light therapy in, 1554 melatonin in, 1554 overview of, 1551 restless legs syndrome in, 1554-1555 sleep apnea in, 1555-1557 sleep integrity and, 1551-1552 stimulant use in, 1553 treatment of sleep problems in, 1552-1554 wandering in, 1554-1555 in Parkinson’s disease, 1040 in progressive supranuclear palsy, 1039-1040 treatment of sleep disorders in patients with, 1042-1045 vascular, 1041 Dementia, snoring and, 706 Depakene. See Valproic acid Depakote. See Sodium valproate Depression. See also Mood disorders diagnosis of, 1474b dreams in, 622 menopause and, 1597 nonseasonal unipolar, 1691 in older adults, 1525-1526 postpartum, 1589-1590 REM sleep in, 212 seasonal, 1690-1691 stimulants for, 511 treatment of, 1494, 1495t Depression, insomnia and, 32 Deprivation, sleep acute activity and, 55 age and, 57 alcohol and, 56 ambient temperature and, 55-56 arousals and, 55-57 autonomic changes in, 59-60 behavioral effects of, 54-59 biochemical changes in, 60 body temperature and, 59-60 caffeine and, 56 circadian rhythm and, 54-55 clinical changes in, 60-61 cortisol in, 292f in Drosophila, 153 drugs and, 56 EEG in, 59, 63-64 exercise and, 61 in fatigue risk management, 761-762 fragmentation as, 61-62 gene expression in, 60 glucose in, 292f group effects in, 57 growth hormone in, 292f
Deprivation, sleep (Continued) imaging studies in, 59 immune function and, 60 insulin and, 61 interest and, 56-57 light and, 55 motivation and, 56-57 neurologic changes in, 59 noise and, 55 overview of, 54 pain and, 60-61 personality and, 57-58 physiologic effects of, 59-61 posture and, 56 prolactin in, 292f psychopathology and, 57-58 recovery of performance after, 62-63 recovery sleep after, 62-64 repeated, 57 sensitivity to, 57 sleep homeostasis and, 435 stimulants and, 56 test characteristics and types in, 58-59 thyroid stimulating hormone in, 292f total, 54-59 weight control and, 61 bipolar disorder and, 1496-1497 body temperature and, 328-329 chronic adaptation to, 68 cardiovascular effects in, 73 cognitive effects of, 70-72 core vs. optimal sleep in, 68 driving and, 72 effects of, 69-72 endocrine effects of, 73, 298-301 ghrelin in, 300 glucose and, 300 growth hormone in, 300 immune function and, 73 incidence of, 67 individual differences in responses to, 72 leptin in, 300 metabolic effects of, 73, 298-301 mood in, 72 on Multiple Sleep Latency Test, 70 obesity and, 300-301 obstructive sleep apnea and, 1220-1221 oculomotor responses in, 70 physiologic effects of, 73 sleep architecture and, 69 sleep need and, 67-68 sleep propensity and, 69-70 thyroid stimulating hormone in, 300 two-process model predictions of, 68-69 waking EEG in, 70 circadian rhythm and, 449 cytokines and, 285 imaging of, 208-209 immune function and, 285-286 as mood disorder treatment, 1496 pain and, 351 in police officers, 802-806 posttraining, 337 sleep homeostasis and, 432-433 slow wave activity and, 117, 432-433 Desipramine, 543t-545t, 941b, 1495t Desvenlafaxine, 543t-545t, 1495t Desyrel. See Trazodone Detoxification, sleep as, 88-89 Dextroamphetamine, 811, 1043t Diabetes, 1439-1440 in elderly patients, 1527 gestational, 1584 insomnia and, 830t-831t loss of diurnal variation in autonomic function in, 233-234 obstructive sleep apnea and, 306, 1331-1332 in sleep medicine, 718 Diagnostic studies, 645-646 Dialysis hemodialysis, definition of, 1462, 1463b peritoneal, definition of, 1462 restless legs syndrome and, 1466 Diapause, 127
1704 Index Diaphragm, 260f Diary, sleep, 843-844, 884, 885f-886f prospective, 1637-1643 Diastolic heart failure, 1375-1376, 1400 sleep apnea in, 1402 Diazepam, 484t in early hypnotic efficacy studies, 10 Dickens, Charles, 5-6 Diencephalon, 77 Diffuse esophageal spasm, 1101 Digastric muscle, 264f Digital recording requirements, 1604 Dilantin. See Phenytoin Dilating forces, in upper airway, 264-265 Dilators, nasal, 1177-1178, 1226 Dimorphism, sexual, 1562 Diphenhydramine, 487, 495t, 917t-919t, 924-925 Diurnal blood pressure, obstructive sleep apnea and, 1384-1385 Diurnal preference candidate genes for, 175-178 genotype-dependent differences in, 175 in twin studies, 188 Diversity of sleep, 129-130 Divorce, dreams and, 622-623 Dolphins, 118, 133-135 Donepezil, 1043t, 1110t Dopamine (DA) dreaming and, 567 in Drosophila, 157 reuptake inhibitors, 543t-545t, 546 in sleep control, 79, 239f Dopaminergic agonists, sleepiness and, 50 Dopamine transporter (DAT), 513-514 Doral. See Quazepam Dormancy, in plants, 126 Dormonoct. See Loprazolam Dorsal respiratory group (DRG), 237, 238f Dorsolateral prefrontal executive association cortex, 572 Down syndrome, obstructive sleep apnea in, 194 Doxepin, 493t-494t, 497, 543t-545t, 917t-919t, 921, 1495t Doxylamine, 487, 495t, 917t-919t, 925 Dreams and dreaming acetylcholine and, 566 age and content of, 590 in alexithymia, 1117-1118 analysis methods for, 595-598 analysis of content of, 587-588 arousal-retrieval model of recall, 604 association with behavioral state, 563-565 associative networks in sleep and, 630-631 bizarreness in, 588, 598-601 in blind subjects, 591 in brain imaging, 205-206, 625 cessation of, 1116 characterizations of, 597t in Charcot-Wilbrand syndrome, 1005 circadian factors in, 578-583 classification of, 595 confabulation in study of, 567-569 consciousness in, 727-728 continuity hypothesis of, 604-605 continuous positive airway pressure and, 608 cortical connectivity and, 563-564 declarative memory and, 631-632 “default mode” networks and, 565-566 definition of, 585 in depression, 622 divorce and, 622-623 dopamine and, 567 emotion and, 571, 588, 633-634 in epilepsy, 1122 episodic memory and, 629-630 excessive, 1118 existential bereavement, 1123 fast oscillations and, 563 frequency in analysis of, 596 frequency of, 576 in Freud, 6 hallucinations in study of, 568t Hall/Van de Castle coding system for, 587 impossibility in, 600t impoverished, 1116-1118
Dreams and dreaming (Continued) improbability in, 600t incorporation of waking events into, 632-633 insomnia and, 605-606 intensity in analysis of, 596 intensive care unity delirious, 1124 interpretation of, 6 as interruptions, 3-4 in laboratory vs. home setting, 589 length of, 576 limbic structures and, 571 logs, 586 lucid, 1113 memory consolidation and, 628-629 memory processing in, 571 memory systems and, 629-630 migraine, 1123 mood regulation function of, 620-625 in parasomnias, 625 movement related to, 655 narcolepsy and, 608-609 neural activation and, 565 neurochemistry of, 566-567 neurocognitive model of, 634-635 neuronal network model for phenomenology of, 569-572 neuropsychiatric syndromes in study of, 567-569 normative content in, 589-591 novelty in, 600t in Parkinson’s disease, 1121t, 1122 pathologic, 1113 phasing activity and, 564-565 postpartum infant peril, 1123-1124 prevalence in analysis of, 596 prodromal cardiac, 1123 in psychotherapy, 624-625 psychotic aggression related to, 1124 quality of reports of, 576-578 quantitative findings on content of, 588-592 questionnaires, 586-587 reality confusions, 1123-1124 as reality simulation, 595, 601-602 recall of, 578-583, 604 recurrent, 1110, 1118-1123 REM sleep behavior disorder and, 1087-1088 repetitive content in, 1118-1123 replicative trauma, 613-614, 1122-1123 report collection methods, 585-587 reports from laboratory awakenings, 588-589 restless legs syndrome and, 609 resurgence in study of, 561, 562f seizures and, 1054 serotonin and, 567 simulation in, 561 sleep apnea and, 606-608 sleep-dependent factors in, 578-583 sleep disorders affecting, 1107t sleep laboratories in study of, 586 sleep-onset REM periods and, 565 sleep stages and content of, 629 in sleep-wake transition, disturbances in, 1111-1113 slow oscillations and, 563 social cognition and, 571 spirituality and, 3-4 stress adaptation and, 614-615 stress and content of, 614, 623 in stroke patients, 1004-1006 structural coherence in, 598 in surgical patients, 621 talking in sleep during, 1112 thalamocortical relay centers and, 570-571 traumatic brain injury and, 1068 treatment of disturbed, 1124-1125 ultradian factors in, 576-578 waking experience and, 604-605 well-being and content of, 590-591 DreamThreat rating scale, 587-588 DRG. See Dorsal respiratory group (DRG) Driving drowsy associated risks in, 769-771 chronic sleep deprivation and, 72 future considerations in, 772-773 license regulations and, 771-772
Driving drowsy (Continued) obstructive sleep apnea and, 1288 in elderly patients, 1540 occupational medicine and, 735 prevalence of, 769-771 public health and, 718-720 rest/activity patterns in, 769-770 risk evaluation for, 771 sleep disorders and, 770-771 Driving license regulations, 771-772 Drosophila, 121, 129-130 adenosine in, 157-158 advantages of, 151 cellular basis of sleep in, 154 circadian rhythm in, 153-156 dopamine in, 157 epidermal growth factor in, 156-157 GAL4/UAS system in, 154 gamma aminobutyric acid in, 157-158 as genetic model, 151-152 G protein-coupled receptors in, 157 growth factors in, 156-157 heat-shock proteins in, 156 immune response in, 156 local field potentials in, 153 membrane excitability in, 156 monitoring of, 152, 152f monoaminergic arousal pathways in, 157 mushroom bodies in, 155 nervous system of, 151-152 neural circuits in sleep-wake regulation of, 154-155 pars intercerebralis in, 155 signal transduction in, 156-157 sleep deprivation in, 153 as sleep model, 152-153 sleep pharmacology in, 155-158 unfolded protein response in, 156 Drosophila Activity Monitoring System, 152, 152f Drosophila model of insomnia, 851b, 858-860 Drug dependence behavioral, 1512 physiological, 1512 sleep medicine and, 1512-1513 types of, 1512 Drug ingestion daytime sleepiness and, 50 sleep deprivation and, 56 sleep stage distribution and, 23-24 Drugs antidepressant, 542-547 effects on sleep and waking, 543t-545t mechanisms of action, 542-545 sedating, 493t, 494-500 pharmacokinetic properties of, 493t polysomnographic effects of, 494t receptor pharmacology of, 493t sleep stage distribution and, 23-24 tricyclic, 493t, 495-498 effects on sleep, 497-498, 543t-545t, 545 pharmacodynamics of, 497 pharmacokinetics of, 495-497 receptor pharmacology of, 497 side effects of, 498 antiepileptic, 49, 549, 550t-551t antiparkinsonian, 549-551 antipsychotic, 504-505, 547, 548t anxiolytic, 489, 547-549 for bruxism, 1136-1137 cardiovascular, 551-553 sleep disrupting effects of, 1367-1368 for central sleep apnea, 1148-1149 for cognitive improvement in sleep loss, 810-811 headache-causing, 1066 hypnotic (See also Benzodiazepines) adverse reactions to, 489 antidepressants as, 493t, 494-500 antihistamines as, 501-502 clinical effects of, 487 dependence on, 490 under development, 486t effects on sleep of, 489-490 future, 490
Drugs (Continued) mechanism of action, 483-487 neuroanatomic considerations with, 485-486 neurotransmitters and, 486-487 overview of, 483 pharmacokinetics of, 487-489 pharmacologic properties of, 489 prolactin and, 295, 295f respiratory effects of, 489 serotonin receptor antagonists as, 500 sleepiness and, 49-50 sleep-wake regulation model relevant to, 492-494 use of, 483 hypolipidemic, 552 for insomnia, 824-825 in dementia patients, 1043t for narcolepsy, 941b, 961-966 for obesity-hypoventilation syndrome, 1312 for pain, 553-554 for restless legs syndrome, 1032-1033 for sleep quality improvement, 811-812 stimulant abuse of, 519-520 amphetamines absorption of, 512 abuse of, 519-520 anatomic substrates mediating, 518 chemical structure of, 511, 512f drug interactions with, 520 historical perspective with, 510-511 inactivation of, 512 indications for, 519 misuse of, 519-520 molecular targets of action of, 512-515 neurotoxicity of, 519 norepinephrine and, 519 presynaptic modulation of dopaminergic system with, 515-518 side effects of, 519 structure-activity relationships in, 511-512 toxicology of, 519 in children, 537 definition of, 510 for depression, 511 drug holidays from, 538 future, 523-524 history of, 527-528 insufficient sleep and, 537 military applications of, 537 recommendations with, 538-539 sleep deprivation and, 56 sleepiness and, 50 summary of, 532t-533t treatment planning with, 538-539 uses of, 537 Drug seeking, 1520-1521 Drunkenness, sleep, 655, 1076-1077 DSPS. See Delayed sleep phase syndrome (DSPS) DU. See Duodenal ulcer (DU) Duality, of sleep, 9 Duchenne’s muscular dystrophy, 1019 Duke Structured Interview for Sleep Disorders, 1641-1642 Duloxetine, 543t-545t, 553, 1428, 1495t Duodenal ulcer (DU) gastric acid secretion and, 313 nocturnal acid secretion in, 1452-1453 Duration, sleep, 21 body mass and, 128 correlates of, 127-129 factors in, 694 genes contributing to, 178 genotype dependent differences in, 175 health outcomes in, 694-695 hypertension and, 33 life expectancy and, 51 as lifestyle factor, 694 regulation of, 113-115 social factors in, 694 variability of, 694 Dyslipidemia, obstructive sleep apnea and, 1332, 1335 Dysmenorrhea, 1569 Dystonia, nocturnal paroxysmal, 192-193
Index 1705 E
Early morning shift work, 785 Eating, sleepiness after, 318-319 Eating disorder, nocturnal, 663, 912, 1077 Ecstasy, 1520 EDS. See Excessive daytime sleepiness (EDS) Education, in insomnia treatment, 889 Education status, insomnia and, 832-833 EEG. See Electroencephalogram (EEG) Effexor. See Venlafaxine Efficacy, potency vs., 511 EGF. See Epidermal growth factor (EGF) Ekborn’s syndrome. See Restless legs syndrome (RLS) Elastic forces, in upper airway, 259-260 Elderly patients. See also Age and aging actigraphy in, 1671-1672 anxiety disorders in, 1526 arthritis in, 1526 benzodiazepine use in, 911-912 bereavement in, 1526 bipolar disorder in, 1525-1526 cancer in, 1528 cardiac risk in, 1359-1360 caregiving by, 1530-1531 chronic obstructive pulmonary disease in, 1527 cognitive therapy for insomnia in, 900 depression in, 1525-1526 diabetes in, 1527 endocrine disorders in, 1527 gastroesophageal reflux disease in, 1527 geriatric syndromes in, 1531-1532 grief in, 1526 heart disease in, 1527 hospitalized, sleep in, 1531 increase in, 1524 insomnia in comorbidities with, 1546 consequences of, 1545 diagnosis of, 1547 epidemiology of, 1544 etiology of, 1545-1547 evaluation of, 1547 medications and, 1546 periodic limb movements in sleep and, 1546-1547 pharmacologic treatment of, 1548-1549 restless legs syndrome and, 1547 risk factors, 1544 sleep-disordered breathing and, 1546 treatment of, 879, 1547-1549 kidney disease in, 1527-1528 medications affecting sleep in, 1528-1530 medication use in, 1524 in nursing homes antipsychotic use in, 1553 associated morbidities in, 1555-1557 cholinesterase inhibitor use in, 1553 hypnotic use in, 1552-1553 light therapy in, 1554 melatonin in, 1554 overview of, 1551 restless legs syndrome in, 1554-1555 sleep apnea in, 1555-1557 sleep integrity and, 1551-1552 stimulant use in, 1553 treatment of sleep problems in, 1552-1554 wandering in, 1554-1555 obstructive sleep apnea in body position and, 1540 cardiovascular disease and, 1539 clinical consequences of, 1537-1539 clinical manifestations in, 1536-1537 cognition and, 1538-1539 CPAP for, 1539-1540 driving and, 1540 epidemiology of, 1536 gender and, 1536 nocturia and, 1537-1538 obesity and, 1536 oral appliances for, 1540 pathophysiology of, 1537 pharmacologic treatment for, 1540 presentation of, 1536-1537 stroke and, 1539
Elderly patients (Continued) treatment of, 1539-1540 vs. younger patients, 1537t pain in, 1526 palliative care in, 1531 psychiatric conditions and sleep in, 1525-1526 sleep apnea among, 705 substance abuse in, 1530 urologic problems in, 1527-1528 Electrical activity of brain, 4-5 gastric, 314-315 in respiratory motorneurons, 242 Electrode placement and application, 1603 Electroencephalogram (EEG) in Alzheimer’s disease, 1039 artifacts, 1651 bandwidths, 1604 in cat preparations, 4-5 in chronic fatigue syndrome, 1430-1433 in chronic sleep deprivation, waking, 70 in circadian rhythm studies, 448 coupling, 231 in Creutzfeldt-Jakob disease, 1042 daytime, 1647-1649 electrode use in, 1603 in fibromyalgia, 1430-1433, 1445 genes contributing to, 180-181 genetic factors in, 188 genotype-dependent differences in, 175 as heritable trait, 179 history of use, 4 homeostatic marker on waking, 434 homeostatic mechanisms in, 116 in Huntington’s disease, 1041-1042 long-term, 1650 in mood disorders, 1479 non-REM sleep on, 16 onset on, 18, 18f pitfalls, 1651 in progressive supranuclear palsy, 1039-1040 in recovery sleep, 63-64 REM sleep on, 92-93 in sleep deprivation, 59 in sleepiness evaluation, 1626-1627 spindles on, 84 technical aspects of, 1646-1647 thalamic-cortical interactions and, 82-86 in torpor, 331 in twin studies, 184 waveforms, 1604-1605 Electrolyte balance, 298 Electromyogram (EMG) electrode use in, 1603 REM sleep on, 92-93 respiratory muscle, 1615 in sleep onset, 17-18 Electrooculogram (EOG), 7 electrode use in, 1603 onset on, 18 EMG. See Electromyogram (EMG) Emotion dreaming and, 571, 588 in episodic memory, 339-340 in sleeping brain, 633-634 Emotional system, ventral, 210-211 Encéphale isolé, 4 Encephalitides, acute, 1070-1071 Encephalitis lethargica, 1070-1071 Encephalomyelopathy, subacute necrotizing, 1018 Endocrine function in age-related sleep alterations, 303-306 appetite regulation in, 297-298 chronic sleep deprivation and, 73 circadian rhythm and, 291-292, 383-384 corticotropic axis in, 293-294 disorders of, sleep disturbances in, 306-307 electrolyte balance and, 298 glucose regulation in, 296-297 gonadal axis in, 296 growth hormone axis in, 292-293 hormones in, 293t insomnia and, 303 modulation of, 291-292 obstructive sleep apnea and, 303
1706 Index Endocrine function (Continued) prolactin in, 295-296 quality of sleep and, 301-303 sleep homeostasis and, 291-292 thyroid axis in, 294 water balance and, 298 Endogenous analgesia, dysfunctional, 1445 End stage renal disease (ESRD) CPAP in, 1468 definition of, 1462, 1463b sleepiness in, 1464 sleep-related breathing disorders in, 1467-1469 Energy drinks, 529t-530t Ensam. See Selegiline transdermal Entrainment melatonin and, 471 nonphotic, 368-372, 471 photic, 366-368, 471 Enuresis, 1054, 1099 Environment circadian rhythm and, 366-372 idiopathic hypersomnia and, 969-970 in occupational medicine, 734 EOG. See Electrooculogram (EOG) Ephedrine, 510, 527 Epidermal growth factor (EGF), 156-157 Epiglottis, 1158f Epilepsy arousal disorders and, 1054 arrhythmias and, 1057 autosomal dominant nocturnal frontal lobe, 1056-1057 behavioral, 1056-1057 cardiopulmonary manifestations of, 1057 cataplexy and, 1052 diagnostic evaluation of, 1058-1059 dream repetition in, 1122 dreams and, 1054 enuresis and, 1054 epidemiology of sleep problems with, 1048-1049 historical aspects of, 1048 hypersomnia in, 1052 incidence of, 1048-1049 insomnia and, 1053 narcolepsy and, 1052 nightmares vs., 1052 nocturnal frontal lobe, genetics of, 192-193 nocturnal panic attacks and, 1057 parasomnias and, 1054-1055 pathogenesis of sleep problems in, 1049-1050 periodic hypersomnia and, 1052-1053 periodic limb movements disorder and, 1055 posttraumatic stress disorder and, 1055 psychogenic dissociative states and, 1057 REM sleep behavior disorder and, 1054 respiratory dyskinesias in, 1057 rhythmic movement disorder and, 1054-1055 in sleep, 1055-1057 sleep-disordered breathing and, 1053 sleep-related, 687 sleep starts vs., 1050-1052 treatment of, 1059 types of, 1049 Episodic memory, 339-340, 629-630 Epworth Sleepiness Scale, 651t, 1426, 1628-1629 Equilibration, tooth, 1136 Erection, sleep-related painful, 1092 Error risk, 753-754 Erythromycin, 1110t Escherichia coli, 284-285 Escitalopram, 543t-545t, 1495t Eskin, Arnold, 142 Esophageal acid clearance, 1454-1457 Esophageal function, 315-317 Esophageal spasm, diffuse, 1101 Esophageal sphincter lower, 315-316 upper, 315-316 Espresso, 529t-530t ESRD. See End stage renal disease (ESRD) Estazolam, 484t dose range, 906t elimination half-life, 906t metabolism of, 906t Estimation, of sleep times, 748
Estradiol action of, 293t Estrogen obstructive sleep apnea and, 1223 in oral contraceptives, 1569 in pregnancy, 1572 Eszopiclone, 484t, 488 for comorbid insomnia, 907-908 dose range, 906t elimination half-life, 906t metabolism of, 906t Etavil. See Amitriptyline Ethnicity, insomnia and, 832-833 Ethosuximide, 550t-551t Evaluation, patient chief complaint in, 641-644 diagnostic studies in, 645-646 in excessive sleepiness, 643-644 family history in, 644 history in, 641-644 in insomnia, 643 in insomnia clinical practice guidelines, 933-934 medical history in, 644 medication use in, 644 physical examination in, 645 review of systems in, 642t, 645 social history in, 644-645 symptom types in, 642 Eveningness, 448-449 Evening shift work, 785 Event-related potentials (ERPs), 448 Examination, physical, 645 in narcolepsy, 662-663 in parasomnias, 663 in restless legs syndrome, 663 in sleep apnea, 658-662, 668-671 in snoring, 1174-1175 Excessive daytime sleepiness (EDS) adaptation to, 44 adenosine in, 45 alerting drugs and, 50 antiepileptics and, 49 antihistamines and, 49 antihypertensives and, 49-50 assessment of, 45-47 behavioral functioning and, 46 cardinal manifestations of, 650 central nervous system pathologies and, 50 circadian rhythm and, 48-49 clinical assessment of, 47 clinical significance of, 50-51 cognition and, 51 in dementia patients, 1044 determinants of, 47-50 dopaminergic agonists and, 50 drugs for, 513t early measurement of, 12 in end stage renal disease, 1464 epidemiology of, 42-43, 698-700 evaluation of, 674-675 fatigue vs., 49-50 gamma-aminobutyric acid and, 45 history in evaluation of, 674 idiopathic hypersomnia and, 970 introspective, 1628-1629 in limited populations, 42 in Maintenance of Wakefulness Test, 46 manifest, 1627-1628 on MRI, 44-45 in Multiple Sleep Latency Test, 42-43, 43f, 45-47, 674-675 in myotonic dystrophy, 50 in narcolepsy, 957 nature of, 43-45 neural substrates of, 44-45 neurochemistry in, 45 in obstructive sleep apnea, 1210-1212, 1280 oral appliances for, 1269-1270 overview of, 1624-1625 in Parkinson’s disease, 50, 984-986 treatment of, 989-990 physical examination in, 674 physical findings in, 650 physiologic, 1625-1627 as physiological need state, 43-44
Excessive daytime sleepiness (EDS) (Continued) polysomnography in evaluation of, 674 presentation of, 643-644 public health significance of, 50-51 quality of sleep and, 48 quantification of, 45-46 quantity of sleep and, 47-48 recognition of clinical significance of, 12 in representative populations, 42-43 risk factors for, 43 sedating drugs and, 49-50 snoring and, 1173 treatment of, 513t Excessive dreaming, 1118 Excessive sleep, life expectancy and, 51 Excitability membrane, 156 oromotor, 1130 Executive functions, obstructive sleep apnea and, 1197-1198 Exercise circadian rhythm and, 407-408 sleep deprivation and, 61 Existential bereavement dreams, 1123 Expert witness, sleep medicine professional as, 731 Expired carbon dioxide sensing, 1612-1613 Exploding head syndrome, 1065, 1100 Expression studies, gene, 151-152 External oblique muscle, 260f Exxon Valdez, 719 Eye movements, in REM sleep, 93
F
Face, somatosensory pathway from, 350f Facioscapulohumeral muscular dystrophy, 1019-1020 Fain v. Commonwealth, 726 Falls, benzodiazepine use and, 911-912 False awakening, 1112-1113 Familial advanced sleep phase syndrome (FASPS), 166, 187-188 Family history, 644 FASPS. See Familial advanced sleep phase syndrome (FASPS) Fast oscillations, 563 Fatal familial insomnia (FFI) in brain imaging, 212 genes in, 181, 194 overview of, 687 Fatigue in cancer patients differential diagnosis of, 1420 epidemiology of, 1417 pathogenesis of, 1418-1419 treatment of, 1419-1420 cardinal manifestations of, 650 central, 1422 daytime sleepiness vs., 49-50 measurement of, 1426 modeling, 745-746 in multiple sclerosis, 1069 performance tasks in assessment of, 1426 physical, 1422 polysomnography in assessment of, 1426-1427 in pregnancy, 1573 risk management challenges in, 765-766 changing roles in, 765-766 dynamics in, 761-763 individual differences in, 762 knowledge gaps in, 765 regulation in, 764-765 safety management systems in, 764 sleep deprivation in, 761-762 task type in, 762 theoretical framework for, 760-761 risk of errors/accidents in, 753-754 sleepiness and, 754-755 sleepiness vs., 1422 in stroke patients clinical features of, 1003-1004 pathophysiology of, 1006 types of, 1422 Fatigue effects, 740-742
Fatty liver disease, obstructive sleep apnea and, 1332, 1336 Feedback pathways, in circadian system, 413 Feeding, as entrainment, 369-370 Felbamate, 550t-551t Felbatol. See Felbamate Female sex hormones, 1438 Fetus, circadian rhythm in, 372 FFI. See Fatal familial insomnia (FFI) Fiberoptic nasopharyngolaryngoscopy, 1251 Fibromyalgia, 687 in adolescents, 1429 in children, 1429 clinical assessment of, 1425-1426 clinical course of, 1430 clinical features in, 1424-1425 controversies with, 1429-1430 diagnosis of, 1424b, 1425-1427 duloxetine for, 1428 EEG in, 1430-1433, 1445 epidemiology of, 1423 fatigue in, 1425 milnacipran for, 1428 pathogenesis of, 1423-1424 polysomnography in assessment of, 1426-1427 pramipexole for, 1428 pregabalin for, 1428 restless legs syndrome and, 1030 sleep disturbances in, 1423-1424 treatment of, 1427-1429 “Fight or flight” response, 814 First responders, 736 duration of deployments, 801t prevalence of sleep loss, mortality, and morbidity with, 799-800 Fish, 120 Fisher, Charles, 9 Fixed action patterns, 729-730 Flexion reflex, 352 Flow, turbulent, 260b Flunitrazepam, 484t Fluoxetine, 543t-545t, 941b, 1110t, 1495t Flurazepam, 484t dose range, 906t elimination half-life, 906t metabolism of, 906t Fluvoxamine, 543t-545t Follicle-stimulating hormone (FSH) action of, 293t Forced desynchrony protocol, 31, 449-450, 1660 Forces collapsing, in upper airway, 263-265 dilating, in upper airway, 264-265 elastic, in upper airway, 259-260 stabilizing, in upper airway, 265 surface adhesive, in pharyngeal airway, 1154-1155 Forebrain, isolated, 76-77 Forensic sleep medicine automatic behavior and, 728-730 clinical guidelines in, 730-731 development of, 730 history of, 725-726 legal thought in, evolution of, 725-726 role of specialist in, 731 testimony in, 731 Fos labeling, 100-101 Fosphenytoin, 550t-551t Fractal analysis, 229 Fragmentation, sleep as deprivation, 61-62 disorders and, 62 sleep stage distribution and, 24 FRC. See Functional residual capacity (FRC) Free running disorder (FRD) clinical features of, 476 diagnosis of, 477 epidemiology of, 476 light therapy for, 1689 pathogenesis of, 477 treatment of, 477-478 Freud, Sigmund, 6 Friedman palate classification, 661f Frontotemporal dementia (FTD), 1042
Index 1707 Fruit fly, 121, 129-130 adenosine in, 157-158 advantages of, 151 cellular basis of sleep in, 154 circadian rhythm in, 153-156 dopamine in, 157 epidermal growth factor in, 156-157 GAL4/UAS system in, 154 gamma aminobutyric acid in, 157-158 as genetic model, 151-152 G protein-coupled receptors in, 157 growth factors in, 156-157 heat-shock proteins in, 156 immune response in, 156 local field potentials in, 153 membrane excitability in, 156 monitoring of, 152, 152f monoaminergic arousal pathways in, 157 mushroom bodies in, 155 nervous system of, 151-152 neural circuits in sleep-wake regulation of, 154-155 pars intercerebralis in, 155 signal transduction in, 156-157 sleep deprivation in, 153 as sleep model, 152-153 sleep pharmacology in, 155-158 unfolded protein response in, 156 FSH. See Follicle-stimulating hormone (FSH) FTD. See Frontotemporal dementia (FTD) Functional characterization, 185b Functional residual capacity (FRC) in chronic obstructive pulmonary disease, 1300 definition of, 260 in REM sleep, 255 Fungal infection, 284-285
G
GABA. See Gamma-aminobutyric acid (GABA) GABAergic. See Gamma-aminobutyric acid-ergic (GABAergic) neurons Gabapentin, 495t-496t, 550t-551t, 553 for insomnia, 503, 917t-919t, 924 for restless legs syndrome, 1043t Gabitril. See Tiagabine Gaboxadol, 503-504 GAD. See Generalized anxiety disorder (GAD) ; Glutamic acid decarboxylase (GAD) GAHMS. See Genioglossus advancement-hyoid myotomy suspension (GAHMS) Galantamine, 1043t GAL4/UAS system, 154 Gamma-aminobutyric acid (GABA) in Drosophila, 157-158 glutamic acid-decarboxylase and, 79 hypocretin and, 105 in lesion studies of REM sleep, 98 in respiration, 245 sleepiness and, 45, 49 in suprachiasmatic nucleus, 379 Gamma-aminobutyric acid-ergic (GABAergic) neurons, 152 Gamma-hydroxybutyrate (GHB), 495t, 505, 527-528, 532t-533t, 535-536, 942 Gases, blood abnormalities in, 1370-1373 effect of sleep on, 262-265 monitoring of changes in, 1617-1618 Gastric motility, 314-315 Gastrin-releasing peptide (GRP), 377-379 Gastroesophageal reflux disease (GERD), 315-317, 687, 1295, 1453-1458, 1527 pH monitoring in, 1676-1678 in pregnancy, 1582 Gastrointestinal function acid secretion in, 313-314 esophageal function in, 315-317 historical aspects in study of, 312-313 motor aspect of, in sleep, 314-315 overview of, 312 polysomnography in, 1678-1679 in pregnancy, 1574f swallowing in, 315-317
Gastrointestinal monitoring clinical interpretation of, 1678-1679 pH monitoring in, 1676-1678 Gastrointestinal parasomnias, 1101 Gastrointestinal symptoms, nocturnal, 1452 Gélineau, Jean Baptiste Edouard, 5 Gender insomnia and, 695, 831-833, 832t obstructive sleep apnea and, 1164, 1215-1216, 1280 REM sleep behavior disorder and, 1085 sleep differences with, 1562 Gene(s) in advanced sleep phase syndrome, 451 alleles of, 152-153 for architecture, 178-179 Bmal1, 143, 145, 147t bruxism and, 1131 BTBD9, 191 in circadian rhythm differences, 451 clock, 117, 139, 141-142, 147t input regulation, 146-147 negative elements in identification of, 143-144 output regulation, 146 positive elements in identification of, 142-143 Cry, 144-146, 147t Dec, 146 in delayed sleep phase syndrome, 451 for diurnal preference, 175-178 for duration, 178 for EEG patterns, 180-181 expression patterns, 465 expression studies, 151-152 in familial advanced sleep phase syndrome, 187-188 Homer1, 154 in hypersomnias, 192 in idiopathic hypersomnia, 969-970 immediate early, 161-164 in insomnia, 192, 833 in Kleine-Levin syndrome, 192 knockouts, 168-171 Meis1, 186 methodological limitations in study of, 185-187, 185b in multiple sclerosis, 1068-1069 in narcolepsy, 188-190, 944-946 in neuromuscular diseases, 1016 in nocturnal frontal lobe epilepsy, 192-193 obstructive sleep apnea and, 1164, 1279 in parasomnias, 192 Per, 139, 143-144, 177, 188 period, 143-144 Rab3a, 147 rapid response, 161-162 for REM sleep, 178-179 in restless legs syndrome, 190-192, 1031 sleep, 147-148 for slow wave sleep, 178-179 in Smith-Magenis syndrome, 194 targeted deletion of, 169-170 timeless, 144-145 Gene expression, sleep deprivation and, 60 Generalized anxiety disorder (GAD), 1477-1478 Genetic model for circadian disorder research, 460 Drosophila as, 151-152 Genioglossus advancement-hyoid myotomy suspension (GAHMS), 1256-1258 Genioglossus muscle, 265, 1158f Geniohyoid, 1158f Genotyping quality control, 186b GERD. See Gastroesophageal reflux disease (GERD) Geriatrics. See Elderly patients Geriatric syndromes, 1531-1532 Gestational diabetes, 1584 GH. See Growth hormone (GH) GHB. See Gamma-hydroxybutyrate (GHB) Ghrelin action of, 293t energy balance and, 297-298 in sleep deprivation, 300 GHRH. See Growth hormone-releasing hormone (GHRH)
1708 Index Glu. See Glutamate (Glu) Glucose hypoxemia and, 1334-1335 obstructive sleep apnea and, 1332-1335 regulation, 296-297 in sleep deprivation, 292f, 300 Glucose intolerance, obstructive sleep apnea and, 1331-1332 Glutamate (Glu) hypocretin and, 105 in REM sleep, 99 in sleep control, 79 Glutamic acid decarboxylase (GAD), 81 Glutaminergic compounds, 524 Glutathione, oxidized (GSSR), 88 Glycine, inhibitory respiratory influence, 245 Goiter, in obstructive sleep apnea, 659f Golgi, Camillo, 4 Gonadal axis, 296 G protein-coupled receptors (GPCR), in Drosophila, 157 Gravity, pharyngeal airway and, 1156 Grief, 1526 Grinding teeth, 353, 655-656, 663-664 behavioral treatment strategies for, 1135 catecholamines and, 1131 clinical features of, 1132-1133 diagnostic evaluation of, 1133-1135 in electromyography, 1134b epidemiology of, 1128-1129 etiology of, 1128 familial disposition in, 1131 genes in, 1131 iatrogenic, 1129b local factors in, 1131-1132 neurochemistry and, 1131 occlusal appliances for, 1135-1136 palliative management for, 1135b pathophysiology of, 1129-1132 pharmacologic management for, 1136-1137 pitfalls and controversies in, 1137 risk factors for, 1128-1129 salivary flow and, 1132 secondary, 1129b in sleep laboratory, 1133-1134 stress and, 1130 tooth equilibration in, 1136 treatment of, 1135-1137 types of, 1129b Groaning, sleep-related, 655, 689, 1098-1099 Group treatment, of insomnia, 890-892 Growth factors, in Drosophila, 156-157 Growth hormone (GH), 88 action of, 293t axis, 292-293, 303-304 in chronic sleep deprivation, 300 disorders, 1435-1437 in onset of sleep, 292-293 in pregnancy, 1573 in sleep deprivation, 292f Growth hormone-releasing hormone (GHRH), 88, 292 GRP. See Gastrin-releasing peptide (GRP) GSSR. See Oxidized glutathione (GSSR) Guidelines, clinical practice definition of, 931 for insomnia development of, 932-936 diagnosis in, 934 evaluation section of, 933-934 pharmacologic therapies in, 935-936 treatment in, 934-936 monitoring in, 1621-1623 national clearinghouse for, 931 role of, 931-932 systematic review in, 931 Guillerminault, Christian, 11-12
H
HA. See Histamine (HA) Halcion. See Triazolam Hall and Van de Castle coding system, 587
Hallucinations in dream study, 568t, 569 hypnagogic, 1107t cardinal manifestations of, 653-654 genetics of, 192 as normal, 1098 terrifying, 1111-1112 hypnopompic, 653-654, 1098 in narcolepsy, 958-959 in stroke patients, 1004-1006 Hallucinogen intoxication, 568t Hallucinogens, 1520 Haloperidol, 548t HAPE. See High-altitude pulmonary edema (HAPE) Hazardous workplaces, 721 HD. See Huntington’s disease (HD) Headache(s) on awakening, 1065-1066 in children, 1066 in chronic paroxysmal hemicrania, 1065 cluster, 1065 diagnostic workup in, 1066-1067 differential diagnosis in, 1066-1067 drugs causing, 1066 in hemicrania horologica, 1065 hypnic, 1065, 1100-1101 insomnia and, 1066 management of, 1067 migraine, 1064-1065 morning, 653 as parasomnias, 1100-1101 sleep effect on, 1064 stage-specific, 1064-1066 vascular, 1100 Head trauma, 1067-1068 Health care workers, 720-721 Hearing, in sleep onset, 19 Heart, blood flow regulation to, 220 Heart disease in elderly patients, 1527 insomnia and, 830t-831t sleep apnea and, 705-706 Heart failure central sleep apnea and, 1403-1404, 1408-1412 congestive, 1145, 1359 diastolic, 1375-1376, 1400 sleep apnea in, 1402 epidemiology of, 1400-1401 obstructive sleep apnea and, 1374-1376 oxygen therapy in, 1411 polysomnography in, 1406-1407 sex and, 1402-1403 sleep apnea in, 1401-1402 systolic, 1374-1375, 1401-1402 treatment of sleep-related breathing disorders in, 1407-1412 Heart rate surges, 218-219 Heart rate variability, 227-229 Heart rhythm neural maintenance of, 220-222 sleep-state dependent changes in, 218-220 Heart rhythm pauses, 219-220 Heat-shock proteins (HSPs), 156 Hemicrania horologica, 1065 Hemiplegia of childhood, benign nocturnal alternating, 1102 Hemodialysis definition of, 1462, 1463b restless legs syndrome and, 1466 Herbal remedies history of, 926 for insomnia, 926 safety of, 926 Herbivores, 118 Heritability of narcolepsy, 188-189 of restless legs syndrome, 190 of sleep EEG, 179 Hibernation, 118-119, 127, 330-331 Hiccup, sleep, 1101 Hierarchical control model, 86-87 High altitude acclimatization to, 274 chemosensory mechanisms and, 274 hypocapnia and, 272-273
High altitude (Continued) hypoxia and, 272-273 increased ventilation at, 269 long-term adaptation to, 277-278 mechanisms of breathing at, 272 periodic breathing at, 271-276 physiologic adjustment to, 269-271 sleep disturbances at, 269-271 syndromes, 275 treatment for periodic breathing at, 276-277 High-altitude pulmonary edema (HAPE), 275 Hippocampal rhythms, 342-343 Histamine (HA) antagonists, 553 in Drosophila arousal, 157 in REM sleep, 107 in sleep control, 79, 239f Histaminergic H3 antagonists, 523 History of actigraphy, 1668-1670 family, 644 in hypersomnolence evaluation, 674 in obstructive sleep apnea evaluation, 666-668, 669t-670t in patient evaluation, 641-644 sleep, 842-844 of sleep monitoring, 1602-1603 social, 644-645 History of sleep study, 4-5 History of sleep theories, 3-4 HIV. See Human immunodeficiency virus (HIV) HLA. See Human leukocyte antigen (HLA) HMS Advocate v. Fraser, 726 HO. See Horne-Ostberg (HO) diurnal preference scores Hobson, J. Allan, 3 Holland, Jerome, 11 Homeostasis cardiorespiratory, 217-218 definition of, 431 electrolyte, 298 sleep, 112 circadian rhythm and, 435-436 circadian rhythm vs., 116-118 definition of, 112, 431 deprivation and, 432-433 duration in, 113-115 endocrine function and, 291-292 in fatigue modeling, 746 in fruit flies, 152-153 genetic regulation of, 170, 188 intensity in, 113-115 marker on EEG, 434 non-REM vs. REM, 433-434 origins of, 112-113 REM sleep in, 116 slow waves in, 431-433 water, 298 Homer1 gene, 154 Home sleep testing, 1620-1621 Home studies, 672-673 Hormone(s), 293t adrenocorticotropic in corticotropic axis, 293-294 overview of, 293t dependent cancer, 424 female sex, 1438 follicle-stimulating action of, 293t growth, 88 action of, 293t axis, 292-293, 303-304 in chronic sleep deprivation, 300 disorders, 1435-1437 in onset of sleep, 292-293 in pregnancy, 1573 in sleep deprivation, 292f growth hormone-releasing, 88, 292 luteinizing action of, 293t in gonadal axis, 296 ovarian, 1565-1569 in pregnancy, 1572-1573 receptors, nuclear, 465-466 replacement therapy, 1595
Hormone(s) (Continued) thyroid stimulating action of, 293t circadian rhythm and, 403-404 in sleep deprivation, 292f, 300 in thyroid axis, 294 thyrotropin-releasing, 523-524 Hormone-dependent cancer, 424 Hormone receptors, nuclear, 465-466 Horne-Ostberg (HO) diurnal preference scores, 188 Horses, 118 Hospitalized older adults, sleep in, 1531 Hot flashes, in menopause, 1594-1595 “H” reflex, 8 HSPs. See Heat-shock proteins (HSPs) Human immunodeficiency virus (HIV), sleep changes in, 282-283 Human leukocyte antigen (HLA), in narcolepsy, 189, 944-945 Hunter, John, 1400 Hunter-Cheyne-Stokes breathing, 1400 Huntington’s disease (HD) dementia in, 1041-1042 EEG in, 1041-1042 sleep disturbances in, 1041 Hygiene, sleep, 680-683, 867b, 869, 888, 1220-1221, 1507, 1633 Hyoglossus muscle, 264f Hyoid bone, 264f Hyoid myotomy and suspension, 1258-1259 Hypercapnia arousal from, 252, 253f chemoreflexes and, 227 ventilatory response to, 251-252 Hypercapnic respiratory failure, 1144 Hypernychthermal syndrome. See Free running disorder (FRD) Hypersomnia(s). See also specific hypersomnias of central origin, 684-685 in epilepsy, 1052 genetics of, 192 idiopathic associated features in, 971 chronic fatigue syndrome vs., 975-976 circadian disorders vs., 976-977 clinical course of, 978 clinical features of, 970-971 diagnosis of, 971-974 differential diagnosis of, 974-977 environmental factors in, 969-970 epidemiology of, 969 excessive daytime sleepiness in, 970 genetics of, 969-970 history of, 969 hypersomnia of medical origin vs., 977 Multiple Sleep Latency Test in, 971-974 narcolepsy vs., 974 neurochemistry of, 970 neurophysiology in, 970 nocturnal sleep in, 970-971 pathogenesis of, 969 periodic hypersomnia vs., 977 pitfalls with, 978 polysomnography in, 971, 974 prevention of, 978 psychiatric hypersomnia vs., 975 restless legs syndrome vs., 976 sleep-disordered breathing syndromes vs., 974 substance abuse vs., 977 treatment of, 977 overview of, 689 periodic, 1052-1053 posttraumatic, 1068 in schizophrenia, 1508 in stroke clinical features of, 1002-1003 pathophysiology of, 1006 treatment of, 1008 types of, 681t-683t Hypertension insomnia and, 830t melatonin and, 424 menopause and, 1595-1596 nocturnal, 1358-1359
Index 1709 Hypertension (Continued) obstructive sleep apnea and, 1381-1388 clinical relevance of, 1387-1388 epidemiologic evidence for, 1381-1384 in population subgroups, 1384 pulmonary, 1388-1390 CPAP and, 1390 mechanisms in obstructive sleep apnea patients, 1389-1390 obstructive sleep apnea as cause of, 1388-1389 sleep-disordered breathing and, 35 sleep duration and, 33 snoring and, 705 Hypnagogic hallucinations, 1107t cardinal manifestations of, 653-654 genetics of, 192 as normal, 1098 terrifying, 1111-1112 Hypnic headaches, 1065, 1100-1101 Hypnic jerks, 687, 1098, 1111 Hypnic myoclonia, 19 Hypnogenic system, 81-82 Hypnopompic hallucinations, 653-654, 1098 Hypnotics. See also Benzodiazepines abuse of, 1519-1520 adverse reactions to, 489 antidepressants as, 493t, 494-500 antihistamines as, 501-502 in chronic obstructive pulmonary disease, 1304 clinical effects of, 487 dependence on, 490 under development, 486t effects on sleep of, 489-490 future, 490 mechanism of action, 483-487 neuroanatomic considerations with, 485-486 neurotransmitters and, 486-487 in nursing home patients, 1552-1553 obstructive sleep apnea and, 1222 overview of, 483 pharmacokinetics of, 487-489 pharmacologic properties of, 489 prolactin and, 295, 295f respiratory effects of, 489 safety of, 910-912 serotonin receptor antagonists as, 500 sleepiness and, 49-50 sleep-wake regulation model relevant to, 492-494 use of, 483, 698 “Hypnotoxin” theory, 4 Hypocapnia effects of, 1371 at high altitudes, 272-273 Hypocretin, 103-105 antagonists, 504 based-therapies, 523 deficiency, 943 in narcolepsy, 189, 938, 942-944 in narcolepsy therapy, 951 in progressive supranuclear palsy, 1039 in sleep control, 79, 239f system, 940, 942-943 transmission in sleep regulation, 943-944 Hypolipidemic drugs, 552 Hypopharynx, 1158f Hypopnea, definition of, 1282b Hypothalamic arousal networks, 209-210 Hypothalamic-pituitary-adrenal (HPA) axis, 1445-1446, 1493 Hypothalamus, in arousal, 201 Hypothalamus, posterior (PH), in sleep control, 80-81 Hypothyroidism obstructive sleep apnea and, 1223, 1438 sleep quality in, 1438 Hypoventilation, in chronic obstructive pulmonary disease, 1299-1300 Hypoventilation syndrome, 684 congenital central, genetics of, 193-194 types of, 681t-683t Hypoxemia, myocardial effects of, 1370 Hypoxemic syndromes, 681t-683t, 684 Hypoxia chemoreflexes and, 227
Hypoxia (Continued) in high altitudes, 272-273 isocapnic, arousal from, 252, 253f ventilatory response to, 251 Hysterectomy, 1597 Hysteria, conversion, 1102
I
Iatrogenic bruxism, 1129b IBS. See Irritable bowel syndrome (IBS) Idiopathic central sleep apnea, 1144-1149 Idiopathic CNS hypersomnolence, 50 Idiopathic hypersomnia associated features in, 971 chronic fatigue syndrome vs., 975-976 circadian disorders vs., 976-977 clinical course of, 978 clinical features of, 970-971 diagnosis of, 971-974 differential diagnosis of, 974-977 environmental factors in, 969-970 epidemiology of, 969 excessive daytime sleepiness in, 970 genetics of, 969-970 history of, 969 hypersomnia of medical origin vs., 977 Multiple Sleep Latency Test in, 971-974 narcolepsy vs., 974 neurochemistry of, 970 neurophysiology in, 970 nocturnal sleep in, 970-971 pathogenesis of, 969 periodic hypersomnia vs., 977 pitfalls with, 978 polysomnography in, 971, 974 prevention of, 978 psychiatric hypersomnia vs., 975 restless legs syndrome vs., 976 sleep-disordered breathing syndromes vs., 974 substance abuse vs., 977 treatment of, 977 Idiopathic insomnia, 840t Idiopathic nightmares, 1106-1111 IEGs. See Immediate early genes (IEGs) IGL. See Intergeniculate leaflet (IGL) IL-1. See Interleukin-1β (IL-1) Imaging, brain dreams in, 625 of insomnia, 209-211 in mood disorders, 1493 non-REM sleep in, 201-204 in performance deficit measurement, 739-740 REM sleep in, 205-206 of sleep deprivation, 208-209 of sleep-wake cycle regulation, 206-208 types of, 201 Imipramine, 543t-545t, 941b, 1495t Immediate early genes (IEGs), 161-164 Immune function acute phase response in, 281-282 cytokines in, 281-282 in Drosophila, 156 interferons in, 283-284 narcolepsy and, 944-945 pathogen-associated molecular patterns in, 282-283 regulatory molecules in, 286-288 sleep deprivation and, 285-286 acute, 60 chronic, 73 Imovane. See Zopiclone Impedance pneumography, 1617 Implants, palatal, 1180 Impossibility, in dreams, 600t Impoverished dreaming, 1116-1118 Improbability, in dreams, 600t Inactivity, adaptive, 126-127 Inadequate sleep hygiene, 680-683 Indiplon, 824 Inductance plethysmography, 1614, 1616-1617 Industrial revolution, 716 Inertia, sleep, 746, 1076-1077
1710 Index Infancy benign sleep myoclonus of, 687 sex differences in sleep in, 1562-1563 sleep-onset REM periods in, 24 Infant peril dreams, postpartum, 1123-1124 Infarction, brain, sleep apnea and, 706 Infectious challenge acute phase response in, 281-282 sleep changes after, 282-285 Inflammation, chronic sleep deprivation and, 73 Influenza, sleep changes in, 283 Injection snoreplasty, 1179 Insects, diapause in, 127 Insomnia actigraphy in, 846-847, 884-885, 1642-1643, 1670 in African Americans, 832 age and, 695, 830-831, 833 in aging, 32-33 amitriptyline for, 917t-919t, 921 anticonvulsants for, 924 antidepressants for, 921-923 antihistamines for, 501-502, 924-925 antipsychotics for, 504-505, 923 assessment of, 822-823, 1634-1635 behavioral treatment of, 824, 866-867 behaviors perpetuating, 649 biological findings in, 823-824 body systems and, 649 cancer and, 830t-831t, 1416-1417 Cano-Saper model of, 851b cardinal manifestations of, 647-649 chloral hydrate for, 495t-496t, 504, 917t-919t, 925 classification of, 680-683 clinical assessment of, 838-847 clinical practice guidelines for development of, 932-936 diagnosis in, 934 evaluation section of, 933-934 pharmacologic therapies in, 935-936 treatment in, 934-936 coding of, 840t cognition and, 33 cognitive factors in, 1633 cognitive therapy for, 868-869, 871t-878t comorbid, 687-689, 695-697, 907-908 comorbidities in, 829-830, 830t, 834, 844-845 complementary and alternative therapies for, 869, 926 consequences of, 33 cultural context of, 842 current sleep in, 842-843 definition of, 827, 828b, 850 in dementia patients, 1042-1043 demographics of, 830-833 depression and, 32 developmental context of, 842 diabetes and, 830t-831t diagnosis of, 822-823, 838 diagnostic flow chart for, 648f diary for, 843-844, 884, 885f-886f diphenhydramine for, 495t, 917t-919t, 924-925 doxepin for, 917t-919t, 921 doxylamine for, 917t-919t, 925 dreaming and, 605-606 Drosophila model of, 851b, 858-860 early observations of, 5 education in treatment of, 889 education status and, 832-833 in elderly patients comorbidities with, 1546 consequences of, 1545 diagnosis of, 1547 epidemiology of, 1544 etiology of, 1545-1547 evaluation of, 1547 medications and, 1546 periodic limb movements in sleep and, 1546-1547 pharmacologic treatment of, 1548-1549 restless legs syndrome and, 1547 risk factors, 1544 sleep-disordered breathing and, 1546 treatment of, 879, 1547-1549 endocrine function and, 303 epidemiology of, 649, 695-698, 822, 823b, 827-833
Insomnia (Continued) epilepsy and, 1053 ethnicity and, 832-833 evaluation of, 675-676, 828 fatal familial, 687 in brain imaging, 212 genes in, 181, 194 future directions in, 825 gabapentin for, 495t-496t, 503, 917t-919t, 924 gamma-hydroxybutyrate for, 495t gender and, 695, 831-833, 832t generalized anxiety disorder and, 1477-1478 genetics of, 192, 833 group treatment of, 890-892 headache and, 1066 heart disease and, 830t-831t herbal remedies for, 926 history in, 647-648 hyperarousal and, 833 hypertension and, 830t in ICSD-2, 840t idiopathic, 840t imaging of, 209-211 initial consultation for, 1641 initiating factors in, 649 interview for, 842-844 in kidney disease, 1464-1465 learned, 1632 life events and, 834 melatonin for, 495t-496t, 916-921 in menopause, 908, 909f, 1438 mirtazapine for, 917t-919t, 922-923 models of pathogenesis of, 1632-1634 modifiable risk factors for, 833-834 neurocognitive model of, 851b, 853-855 nocturia and, 33 non-benzodiazepine drugs for, 495t nontraditional providers in treatment of, 892 occurrence of, 696t olanzapine for, 917t-919t, 923 ontazapine for, 495t pain and, 649, 830t-831t paradoxical, 680, 840t in Parkinson’s disease, 981-982, 984-985 pathophysiology of, 823-824 patient perception in, 647 perpetuating factors, 846, 1633-1634 pharmacologic treatment of, 824-825, 917t-919t, 927 (See also Benzodiazepines; Hypnotics) in pinealectomy patients, 426 polysomnography in, 846 precipitating factors, 1633-1634 predisposing factors, 1633-1634 pregabalin for, 503, 924 pregnancy-associated, 1580-1582 presentation of, 643 prevalence of, 828-829, 829t, 831t primary, 680-683 problem-solving in treatment of, 889 psychiatric conditions and, 32, 829-830, 844-845, 1632 psychobiological inhibition model of, 855-858 psychological comorbidities in, 834 psychological treatments for, 867b, 891t psychophysiologic, 680, 840t questionnaire for, 843 quetiapine for, 495t, 917t-919t, 923 quick assessment guide for, 839b-840b ramelteon for, 917t-919t, 920 relaxation training for, 867b, 868 research criteria, 687-689 research measures for, 841t restless legs syndrome and, 845 retrospective assessment in, 828 as risk factor, 834-835 risk factors, 833-835 rodent model of, 860-862 in schizophrenia, 1507-1508 seasonal differences in, 695 secondary, 683 shift work and, 786 sleep-disordered breathing and, 32, 34f sleep disorders comorbid with, 845 sleep history in, 842-844 sleep hygiene education for, 867b, 869, 888
Insomnia (Continued) sleep logs for, 675 sleep restriction in treatment of, 867, 867b, 886-888, 887f sleep symptoms of, 827 social context of, 842 socioeconomic status and, 832-833 sodium oxybate for, 917t-919t static risk factors for, 833 stimulus control model of, 850-851 stimulus control therapy for, 867-868, 887f, 888 stress and, 834 in stroke patients clinical features of, 1004 pathophysiology of, 1006-1007 treatment of, 1008 testing in, 846-847 3P model of, 851-853 tiagabine for, 495t-496t, 503, 917t-919t, 924 timing of, 649 transient, 834 in traumatic brain injury, 1068 trazodone for, 917t-919t, 922 treatment acceptability in, 894-896 treatment adherence in, 894-896 treatment efficacy evidence in, 869-870 treatment guideline development for, 825 treatment of, 495t-496t, 823b, 824-825, 851b, 866-869 in Parkinson’s disease, 989 treatment outcomes in, 847, 869-881 tricyclic antidepressants for, 921 trimipramine for, 917t-919t, 921 types of, 681t-683t urinalysis in, 1643 urinary problems and, 830t-831t valerian for, 495t-496t, 502-503, 926 vicious circle of, 1632 wake symptoms of, 827 worry and, 889 written behavioral prescriptions for, 885-888 Inspiratory resistance, increased, arousal from, 252-253, 253f Instability, wake-state, 754-755 Insulin action of, 293t sleep deprivation and, 61 Insulin resistance obesity and, 1439-1440 obstructive sleep apnea and, 1331-1332 Insulin secretion rates (ISR), 292f Integrity, sleep, nursing homes and, 1551-1552 Intensity, sleep regulation of, 113-115 slow waves and, 431 Intensive care unit dream delirium, 1124 Intercostal muscles, 260f Interest, sleep deprivation and, 56-57 Interferons, 283-284 Intergeniculate leaflet (IGL), 381-382 Interleukin-1β (IL-1), 88, 286-288 Interstitial lung disease clinical features of, 1315 definition of, 1314-1315 diagnosis of, 1315 epidemiology of, 1314-1315 pathogenesis of, 1315 respiratory mechanics in, 1315 treatment of, 1315-1316 Interview, for insomnia assessment, 842-844 Intestinal motility, 317-319, 1458-1459 Intratentorial strokes, 1009-1010 Intrathoracic pressure, negative, 1373 Introspective sleepiness, 1628-1629 Invertebrates, 120-122 Iron, restless legs syndrome and, 1032 Irregular sleep-wake rhythm (ISWR) clinical features of, 478 diagnosis of, 479 epidemiology of, 478 pathogenesis of, 478 treatment of, 479 Irritable bowel syndrome (IBS), 318, 1458-1459 Irritation, bronchial, arousal from, 253-254 Isocapnic hypoxia, arousal from, 252, 253f
Index 1711
Isocarboxazid, 1495t Isolated forebrain, 76-77 Isolated sleep paralysis (ISP), 1112 ISR. See Insulin secretion rates (ISR) ISWR. See Irregular sleep-wake rhythm (ISWR)
J
Jerks, hypnic, 1098, 1111 Jet lag, 791-793 circadian rhythm and, 424-425 sleep-onset REM periods in, 24 Johnson, Carl, 457 Jouvet, Michel, 8
K
Kadish, Sanford, 725 Karolinska Sleepiness Scale, 1629 Keppra. See Levetiracetam Kidney disease, chronic breathing disorders in, 1466-1467 definition of, 1463b definition of terms in, 1462 in elderly patients, 1527-1528 epidemiology of sleep disturbances in, 1463-1464 hemodialysis in, 1462 insomnia in, 1464-1465 periodic limb movements in, 1466 restless legs syndrome in, 1465-1466 treatment terminology in, 1462 Kidney transplantation, 1466, 1469 Kleine-Levin syndrome (KLS) epilepsy and, 1052-1053 genetics of, 192 Kleitman, Nathaniel, 4, 6-7, 7f, 92, 408, 409f Kleitman protocol, 408-409 Klonopin. See Clonazepam KLS. See Kleine-Levin syndrome (KLS), genetics of Knockouts, 168-171 Kryger, Meir, 5-6 Kyphoscoliosis clinical features of, 1313 definition of, 1312 diagnosis of, 1313-1314 epidemiology of, 1312 pathogenesis of, 1312-1313 respiratory mechanics in, 1313 treatment of, 1314
L
Labetalol, 552t Laboratories, sleep in dream research, 586 in restless legs syndrome diagnosis, 1027-1028 Lamictal. See Lamotrigine Lamotrigine, 550t-551t, 1497t Laparoscopic adjustable gastric banding procedure, 1343 Laryngeal reflex, 355-356 Laser-assisted uvuloplasty (LAUP), 1179 Latency, sleep. See also Deprivation, sleep age and, 27-28 benzodiazepines and, 489, 906 in schizophrenia, 1504 Lateral pterygoid plate, 264f LAUP. See Laser-assisted uvuloplasty (LAUP) Lavie, Peretz, 5-6 Law, 725 Learned insomnia, 1632 Learning. See also Memory motor, 340-341 onset of sleep and, 20 perceptual, 340 perceptual-motor, 341-342 sequence, 341-342 Legal thought, 725-726 Leg cramps, in pregnancy, 1578-1579 Legs. See Periodic limb movements in sleep (PLMS); Restless legs syndrome (RLS)
Leigh’s disease, 1018 Length, sleep. See Duration, sleep Leptin action of, 293t appetite regulation and, 297 in chronic sleep deprivation, 300 signaling in obstructive sleep apnea, 1189-1190 LES. See Lower esophageal sphincter (LES) Levator veli palatini muscle, 264f, 1158f Levetiracetam, 550t-551t Levodopa, for restless legs syndrome, 1032-1033, 1043t Lewy bodies, dementia with, 1040-1041 Lexapro. See Escitalopram LFPs. See Local field potentials (LFPs) LH. See Luteinizing hormone (LH) Librium. See Chlordiazepoxide Licensure, driving, 771-772 Life expectancy, excessive sleep and, 51 Light circadian amplitude and, 368 circadian period and, 367-368 circadian phase and, 366-367 circadian rhythm and, 404-407 in delayed sleep phase syndrome treatment, 473-474 dose-response curve to circadian phase-resetting effects of, 406-407 entrainment by, 366-368, 471 melatonin secretion and, 404-406 phase response curves to, 406 pineal melatonin rhythm and, 406 sleep deprivation and, 55 Light boxes, 1682-1683 Light-dark cycle, 457-458 Light therapy for advanced sleep phase syndrome, 1688-1689 apparatus for, 1682-1683 boxes in, 1682-1683 case management, 1684-1686 for circadian disorders, 1686-1689 dawn simulators in, 1683 for delayed sleep phase disorder, 1686-1688 delivery of, 1682-1684 for depressive disorders, 1690-1692 for free-running disorder, 1689 indications for, 1686-1692 in nursing homes, 1554 patient monitoring in, 1684-1685 safety in, 1683-1684 for seasonal affective disorder, 1690-1691 timing in, 1685-1686 Limbic structures, dreaming and, 571 Lisuride, 549-551 Lithium, 547, 1497t “Living high, training low,” 275-276 Local field potentials (LFPs), 153 Locomotor centers, 1076 Logs dream, 586 sleep, 675, 884 Long-nights protocol, 1660 Long sleeper, 687 Loprazolam, 484t Loramet. See Lormetazepam LORETA. See Low-resolution electromagnetic tomography (LORETA) Lormetazepam, 484t Lower esophageal sphincter (LES), 315-316 Low-resolution electromagnetic tomography (LORETA), 1433 Lucid dreaming, 1113 Luciferase, 142 Lugaresi, Elio, 10, 10f Lunesta. See Eszopiclone Lung compliance, 260b Lung disorders, restrictive interstitial lung disease as, 1314-1316 kyphoscoliosis as, 1312-1314 obesity as, 1308-1310 obesity-hypoventilation syndrome as, 1310-1312 Lung volume monitoring, 1616-1617 Lung volume reduction surgery, 1303 Lung volumes, 259-262
Luteinizing hormone (LH) action of, 293t in gonadal axis, 296 Lymphocytes, sleep deprivation and, 285-286 Lyrica. See Pregabalin
M
Machado-Joseph disease, 1069-1070 MacNish, Robert, 3 “Maggie’s Law,” 718-719 Magnetic resonance imaging (MRI) sleep deprivation on, 59 sleepiness on, 44-45 slow wave sleep on, 204f Magou, Horace, 5 Maintenance, sleep, 1504 Maintenance of Wakefulness Test (MWT), 46, 675, 959-960, 1627-1628 Male hormonal disorders, 1437-1438 Malingering, 1102 Maltase deficiency myopathy, 1019 Mammals, sleep regulation in, 112-119 Mandible, 264f Mandibular micrognathia, in obstructive sleep apnea, 659f Mandibular osteotomy, 1256-1258 Mandibular retrognathia, in obstructive sleep apnea, 659f Manic episode, 1474b MAO inhibitors. See Monoamine oxidase (MAO) inhibitors Maprotiline, 543t-545t, 546-547 Marfan syndrome, obstructive sleep apnea in, 194 Marijuana, 1520 Maritime safety, 719 Masking of circadian rhythmicity in studies, 446 entrainment and, 368-369 Mass, sleep duration and, 128 Massachusetts v. Tirrell, 725-726 Maxillary mandibular osteotomy, 1259-1260 Mazindol, 513t, 522 MBs. See Mushroom bodies (MBs) MCI. See Mild cognitive impairment (MCI) Mechanical ventilation, in neuromuscular diseases, 1021 Medial brainstem reticular formation, 99-100 Median preoptic nucleus (MnPN), 80-81 Medical review criteria, 932b Medicine, sleep awareness of, 717-721 cardiovascular disease and, 717-718 challenge of, 717 education on, 717-721 forensic automatic behavior and, 728-730 clinical guidelines in, 730-731 development of, 730 history of, 725-726 legal thought in, evolution of, 725-726 role of specialist in, 731 testimony in, 731 importance of, 716 metabolism in, 718 occupational, 423-424 burnout in, 736-737 environment in, 734 fatigue in, 734-735 fatigue modeling in, 749-750 overview of, 734 performance deficits in circadian rhythm and, 740 imaging in, 739-740 nature of, 738 nonspecificity of, 742 prediction modeling of, 742-743 time on task and, 740-742 performance monitoring in, 736 pharmacology in, 736 risk management in, 735 stress in, 736-737 Medroxyprogesterone, 277, 1303 Medullary respiratory neurons, 237
1712 Index Meis1 gene, 186 Melanopsin, 146-147 Melatonin action of, 293t advanced sleep phase syndrome and, 425 in aging, 425-426 in blindness, 425 cancer and, 424 delayed sleep phase syndrome and, 425, 474-475 in disorders of circadian rhythm, 423-425 effects on sleep, 500-501 entrainment of circadian rhythm and, 471 hypertension and, 424 as hypnotic, 487, 500-501 for insomnia, 495t-496t, 916-921 in dementia patients, 1043t jet lag and, 424-425 migraine and, 426 mood disorders and, 426 in nursing home patients, 1554 pharmacodynamics of, 500 pharmacokinetics of, 500 photic suppression of, 404-406 in pinealectomy patients, 426 pineal rhythm, 406 in pregnancy, 1573 receptor effects of, 500, 916-920 receptors, 421-422 for REM sleep behavior disorder in dementia patients, 1043t in rest-activity cycle, 422-423 salivary, 1661-1662 secretion, 422 serotonin and, 420-421 shift work and, 423-424 side effects of, 501 in Smith-Magenis syndrome, 194, 426 synthesis of, 420-422 in thermoregulation, 324 Melatonin receptor agonists, 500-501 Membrane excitability, 156 Memory in confabulation, 567 declarative, 336, 339-340, 631-632 in dreams, 571 dreams and systems of, 629-630 emotions and, 339-340 episodic, 339-340, 629-630 hippocampal rhythms and, 342-343 motor learning and, 340-341 nondeclarative, 336, 340-342 obstructive sleep apnea and, 1196-1197 perceptual learning and, 340 perceptual-motor learning and, 341-342 perceptual priming and, 342 plasticity, 342-343 ponto-geniculo-occipital waves and, 342 posttraining sleep deprivation in study of, 337 posttraining sleep modifications in study of, 337-338 REM sleep and, 107 semantic, 339 sequence learning and, 341-342 sleep onset in, 19-20, 20f slow wave sleep and, 30, 343 spindles and, 343 study methods in research on, 337-339 systems, 336-337 within-sleep stimulations in study of, 338-339 Menopause cancer in, 1597-1598 common clinical conditions in, 1594-1598 depression and, 1597 hormone replacement therapy in, 1595 hot flashes in, 1594-1595 hypertension and, 1595-1596 insomnia in, 908, 909f, 1438 metabolic syndrome and, 1596-1597 neurodegenerative disorders in, 1598 night sweats in, 1594-1595 obesity and, 1595-1596 phases of, 1592 progesterone in, 1595 sleep apnea in, 1595-1596 sleep patterns in, 1592-1593
Menopause (Continued) stress reactivity in, 1595 thyroid dysfunction in, 1598 Menstrual cycle, 1565-1569 disorders in, 1567-1569 Mental illness insomnia and, 32, 829-830 sleep deprivation and, 57-58 Mental protuberance, 1158f Metabolic disorders, 1069-1070 Metabolic dysregulation, 424 Metabolic rate, respiratory control and, 254-255 Metabolic syndrome definition of, 1439 menopause and, 1596-1597 obstructive sleep apnea and, 1332, 1335-1336 Metabolism of benzodiazepines, 906t cerebral blood flow relationship with, 255 chronic sleep deprivation and, 73, 298-301 circadian rhythm and, 466-467 disorders of, sleep disturbances in, 306-307 glucose, obstructive sleep apnea and, 1332-1335 hibernation and, 330-331 quality of sleep and, 301-303 in REM sleep, 107 glucose, 203f in sleep medicine, 718 in slow wave sleep, glucose, 203f Methamphetamine, 510, 941b. See also Amphetamines Methamphetamine HCl, 513t Methodology in genetic studies, limitations of, 185-187, 185b sleep medicine, 17b Methylenedioxymethamphetamine (MDMA), 1520 Methylphenidate, 511-512, 513t, 532t-533t, 941b, 1043t, 1519 Metoprolol, 552t MFI-20. See Multidimensional Fatigue Inventory (MFI-20) Mianserin, 543t-545t Microarray studies, 153-154 Microneurography, 229-230 Micturition, in Parkinson’s disease, 986t MID. See Multiinfarct dementia (MID) Mid-afternoon dip, 446 Midbrain raphe nuclei, 382-383 Migraine, 1064-1065 melatonin and, 426 serotonin and, 1064-1065 therapeutic effect of sleep on, 1064-1065 Migraine dreams, 1123 Migrating motor complex (MMC), 317-318 Mild cognitive impairment (MCI), 27 Military, 736 duration of deployments in, 801t field training, 778 prevalence of sleep loss, mortality, and morbidity with, 799-800 stimulants in, 537 Milnacipran, 543t-545t, 1428 Mind-body dilemma, 725 Minute ventilation, 260-261, 260b Mirtazapine, 493t-494t, 499-500, 543t-545t, 546, 917t-919t, 922-923, 1495t Misuse, abuse vs., 519 MMC. See Migrating motor complex (MMC) M’Naghten Rules, 725 MnPN. See Median preoptic nucleus (MnPN) Moaning, sleep-related, 655, 689, 1098-1099 Moclobemide, 543t-545t Modafinil, 56, 513t, 532t-533t, 941b abuse, 535 alerting effects of, 534 for cognitive improvement in sleep loss, 810-811 dependence, 535 for excessive daytime somnolence in dementia patients, 1043t in history, 527 indications for, 520 mechanism of action in, 521-522, 534 for narcolepsy, 963-964 in neuromuscular diseases, 1020 in obstructive sleep apnea, 534
Modafinil (Continued) pharmacokinetics of, 520 in schizophrenia, 1508 shift work and, 534 side effects of, 520-521, 535 tolerance, 535 withdrawal, 535 Modeling, fatigue, 745-746 Modulation, presynaptic, in respiratory motorneurons, 242-243 Moebius syndrome, 950 Molecular genetic studies, in obstructive sleep apnea, 1188-1190 Monitoring. See also specific modalities ambulatory, 1650-1651 chronobiologic actigraphy in, 1662-1663 basic concepts in, 1657 future directions in, 1665 methodologic questions in, 1657-1658 paradigms in, 1658-1662 terminology in, 1657 gastrointestinal clinical interpretation of, 1678-1679 pH monitoring in, 1676-1678 home, 1620-1621 pH, 1676-1678 sleep, history of, 1602-1603 of sleep-disordered breathing abdominal motion in, 1613-1615 airflow detection methods in, 1610-1613 definitions in, 1610 expired carbon dioxide sensing in, 1612-1613 lung volume in, 1616-1617 nasal airway pressure in, 1612 pleural pressure in, 1615 pneumotachography in, 1611 respiratory effort detection in, 1613-1616 respiratory muscle electromyography in, 1615 rib cage motion in, 1613-1615 static charge-sensitive bed in, 1615 thermistors in, 1611-1612 thermocouples in, 1611-1612 Monoamine-containing cells, 100 Monoamine oxidase (MAO) inhibitors, 107, 543t-545t, 545, 1495t Monoaminergic arousal pathways, in Drosophila, 157 Monotremes, 130-132 Mood chronic sleep deprivation and, 72 dreams as method for regulating, 620-625 in parasomnias, 625 Mood disorders. See also Depression classification of, 1488 clinical course of, 1498 clinical features of, 1476-1477 controversies with, 1498 diagnosis of, 1488 EEG in, 1479 epidemiology of, 1474 genetic polymorphisms in, 1493 hypothalamic-pituitary-adrenal axis in, 1493 melatonin and, 426 neuroimaging in, 1493 neurotransmitter imbalance in, 1481-1483 pathogenesis of, 1474-1476 pitfalls with, 1498 polysomnography in, 1478-1479 prevention of, 1498 risk factors, 1474 sleep complaints in, 1477-1478 treatment of, 1494-1498 with sleep deprivation, 1496 Mood stabilizers, 1497t Morgan, Thomas Hunt, 151 Morning headache, 653 Morningness, 448-449 Morphology studies, as diagnostic tool, 673 Motility gastric, 314-315 intestinal, 317-319, 1458-1459 Motivation, sleep deprivation and, 56-57 Motor function, gastrointestinal, 314-315 Motor learning, 340-341
Index 1713
Motorneurons respiratory control of, 240-241 determinants of activity in, 241-243 electrical properties of, 242 medullary, 237 neuromodulation of, 243-245 presynaptic modulation in, 242-243 respiratory-related inputs to, 241-242 tonic inputs to, 241-242 Mouth, somatosensory pathways from, 350f Movement disorders, sleep-related, 686-687 MS. See Multiple sclerosis (MS) MSLT. See Multiple Sleep Latency Test (MSLT) MSNA. See Muscle sympathetic nerve activity (MSNA) Mucociliary clearance, 1295 Multidimensional Fatigue Inventory (MFI-20), 1426 Multiinfarct dementia (MID), 1041 Multiple sclerosis (MS), 1068-1069 Multiple Sleep Latency Test (MSLT), 12 background of, 1625 chronic sleep deprivation on, 70 daytime sleepiness in, 42-43, 43f, 45-47 in hypersomnolence evaluation, 674-675 in idiopathic hypersomnia, 971-974 methodology of, 1625 in narcolepsy diagnosis, 675, 948t, 959 utility of, 1625-1626 variations of, 675 Munchausen’s syndrome, 1102 Munich ChronoType Questionnaire, 698 Muscimol, 98 Muscles in cataplexy, 958 in eye movements of REM sleep, 93 pharyngeal, 1157-1160 respiratory, 260f, 264f effect of sleep on, 265 electromyography of, 1615 tonic and respiratory-related activity in, 243 in upper airway anatomy, 259 upper airway–opening, 254 Muscle sympathetic nerve activity (MSNA), 229-230 Muscle tone control, 101-103 Muscular diseases, 994-998 Muscular dystrophy, obstructive sleep apnea and, 661 Mushroom bodies (MBs), in Drosophila sleep-wake regulation, 155 Mutagenesis, 168-171 MWT. See Maintenance of Wakefulness Test (MWT) Myasthenia gravis, obstructive sleep apnea and, 661, 662f Mylohyoid muscle, 264f Myocardial infarction nocturnal, 1358 sleep disturbances after, 1357-1358 time of day and, 718 Myocardial ischemia, nocturnal, 1355-1357 Myocardium, effects of hypoxemia on, 1370 Myoclonia, hypnic, 19, 687 Myoclonus, propriospinal, 1100 Myopathy, upper airway, 1162-1164 Myorelaxants, 489 Myotonic dystrophy, 998-999 narcolepsy and, 950 sleepiness and, 50 Mysoline. See Primidone
N
NA. See Noradrenaline (NA) NAD. See Nicotinamide adenine dinucleotide (NAD) Nadolol, 552t Napping aviation industry and, 720 in older people, 36 Naproxen, 1110t Naps, slow wave sleep in, 432 Narcolepsy amphetamine for, 941b, 964 animal models of, 939-940
Narcolepsy (Continued) antidepressants for, 965 armodafinil for, 964 atomoxetine for, 941b, 963 behavioral approaches to treatment of, 961 cataplexy in, 957-958 cenesthopathic feelings in, 958-959 in children, 961b, 966 clinical features of, 957-959 clomipramine for, 941b definition of, 938, 957 desipramine for, 941b diagnosis of, 959-961 diagnostic procedures for, 948t dreaming and, 608-609 early clinic for, 9 early observation of, 5 environmental factors in, 944 epidemiology of, 701-702 epilepsy and, 1052 evaluation of sleepiness in, 959-960 familial aspects of, 944 fluoxetine for, 941b genetics of, 188-190, 944-946 hallucinations in, 958-959 heritability of, 188-189 history of, 957 in history of amphetamines, 510-511 human leukocyte antigen in, 189, 944-945 hypocretin and, 103-105, 189, 938, 942-944 hypocretin in therapy for, 951 idiopathic hypersomnia vs., 974 imipramine for, 941b immune system and, 944-945 Maintenance of Wakefulness Test in, 959-960 methamphetamine for, 941b methylphenidate for, 941b modafinil for, 941b, 963-964 motor processing and, 354 Multiple Sleep Latency Test in, 959 onset of, 959 paralysis in, 958 pemoline for, 941b pharmacologic treatments of, 941b, 961-966 pharmacology of, 940-942 physical examination in, 662-663 polysomnography in diagnosis of, 960 posttraumatic, 1068 in pregnancy, 1582 protriptyline for, 941b REM sleep and, 103-105 REM sleep behavior disorder and, 1084 secondary, 949-950 selegiline for, 941b, 963 sleep disruption in, 959 sleepiness in, 957 sleep-onset REM periods in, 24 sleep stage distribution and, 24 sodium oxybate for, 941b, 942, 961-963 stimulants for, 964 in syndromic associations of likely genetic origin, 950 treatment of, 961-966 in twin studies, 944 types of, 939t venlafaxine for, 941b Narcotics, obstructive sleep apnea and, 1222 Nardil. See Phenelzine Nasal airway pressure, 1612 Nasal dilators, 1177-1178, 1226 Nasal reconstruction, 1255 Nasopharyngeal airway stents, 1226 Nasopharyngolaryngoscopy, fiberoptic, 1251 Nasopharynx, 1158f National Commission for Sleep Disorders Research, 722 National Guideline Clearinghouse (NGC), 931 National Sleep Foundation, 13 NE. See Norepinephrine (NE) Nebivolol, 552t Neck circumference, in sleep apnea, 658-660, 1175, 1214 Need, sleep, 67-68 Nefazodone, 493t-494t, 498-499, 543t-545t, 1495t Negative intrathoracic pressure, 1373
Negative-pressure reflex, 354-355 Negative pressure ventilation, 1321 Nerve fibers, primary afferent, 348-349 Nervous system autonomic arousals and, responses in, 231, 1371-1373 in arrhythmogenesis, 222-223 cardiovascular arterial baroreflex in, 227 functions of, 226-227 role of, 226 changes during sleep, 227-230 in diabetes mellitus, 233-234 disordered sleep and, 233-234 hypoxemia-hypercapnia and, 1371 periodic leg movements in sleep and, responses in, 231-232 in sleep, 1353-1355 central, melatonin in disorders of, 426 parasympathetic asthma and, 1297 circulation control by, 226-227 sympathetic asthma and, 1297 microneurographic recording of, 229-230 in obstructive sleep apnea, activation of, 234 NET. See Norepinephrine transporter (NET) Neurobiology of sleep, overview of, 239-240 Neurochemical agents, sleep-promoting, 87-89 Neurocognitive model of dream construction, 634-635 Neurocognitive model of insomnia, 851b, 853-855 Neurodegenerative diseases, 1017-1020, 1069-1070, 1598 Neuromodulation of respiratory motorneurons, 243-245 of respiratory neurons, 247 Neuromuscular disease clearance problems in, 1017 clinical features in, 1017-1020 definition of, 1016 diagnostic evaluation in, 998-999 epidemiology of, 1016 genetics in, 1016 mechanical ventilation in, 1021 pathophysiology of sleep disturbances in, 1017 treatments in, 999 Neuromuscular junction impairments, 994 Neuronal observation, 95-96 Neurons, respiratory control of, 246-247 neuromodulation of, 247 in non-REM sleep, 246 in REM sleep, 246-247 as varying in strength, 246 Neurontin. See Gabapentin Neuropathies, restless legs syndrome and, 1030 Neuropeptide system, hypocretin, 942-943 Neurotensin (NT), 377 Neurotransmitter release patterns, 95 Neurotransmitters. See also specific neurotransmitters in mood disorders, 1481-1483 in suprachiasmatic nucleus, 377-379 NFLE. See Nocturnal frontal lobe epilepsy (NFLE) NGC. See National Guideline Clearinghouse (NGC) Nicotinamide adenine dinucleotide (NAD) biosynthesis, 466 Nicotine, 1518. See also Tobacco Niemann-Pick disease type C (NPC), 194, 950, 1070 Nightmare(s), 655 alcohol and, 1109-1110 chronicity, 1109 coping style, 1109 definition of, 1106-1107 distress, 1109 drugs and, 1109-1110 familial pattern in, 1108 frequency of, 1107-1108 historical aspects in, 1106-1107 idiopathic, 1106-1111 pathophysiology of, 1108-1109 personality and, 1109 polysomnographic correlates of, 615 prevalence of, 1107-1108 recurrent, 1110
1714 Index Nightmare(s) (Continued) replicative-trauma, 613-614 seizures vs., 1052 treatment of, 1110-1111 treatment of posttraumatic, 616-617 Night sweats, 1101-1102, 1594-1595 Night terrors, 654-655 Night work, 423-424, 456, 458-460, 463, 736 Nitrazepam, 484t, 1110t Nitric oxide synthase (NOS1), 191-192 Nociceptors, 348-349 Nocturia in elderly patients with obstructive sleep apnea, 1537-1538 insomnia and, 33 Nocturnal angina, 1355-1357 Nocturnal asystole, 1364 Nocturnal cardiovascular events, 1355-1360 Nocturnal eating disorder, 663 Nocturnal frontal lobe epilepsy (NFLE), genetics of, 192-193 Nocturnal gastrointestinal symptoms, 1452 Nocturnal hemodialysis, definition of, 1463b Nocturnal myocardial infarction, 1358 Nocturnal myocardial ischemia, 1355-1357 Nocturnal noninvasive positive pressure ventilation aerophagia in, 1325 alarms in, 1324-1325 clinical severity in selection of, 1318-1320 complication management in, 1325 continuous, 1320-1321 contraindications for, 1321 full-face masks in, 1322 indications for, 1318-1321, 1320t initiation of, 1324 interfaces in, 1321-1323 nasal dryness in, 1325 nasal interfaces, 1321-1322 negative pressure vs., 1321 in neuromuscular disease, 1021-1022 oral interfaces in, 1322 oronasal masks in, 1322 outcomes of, 1325-1328 rhinitis in, 1325 settings of, 1324 technical considerations for, 1321-1325 ventilators in, 1323 Nocturnal paroxysmal dystonia (NPD), 192-193, 1056-1057 Nocturnal peritoneal dialysis (NPD), definition of, 1462, 1463b Noise, sleep deprivation and, 55 Nomenclature, sleep medicine, 17b Nonalcoholic fatty liver disease, obstructive sleep apnea and, 1332, 1336 Nondeclarative memory, 336, 340-342 “Nondippers,” 1358-1359 Non-24-hour sleep-wake syndrome. See Free running disorder (FRD) Noninvasive negative pressure ventilation, 1321 Noninvasive positive pressure ventilation (NPPV) aerophagia in, 1325 alarms in, 1324-1325 clinical severity in selection of, 1318-1320 complication management in, 1325 continuous, 1320-1321 contraindications for, 1321 full-face masks in, 1322 indications for, 1318-1321, 1320t initiation of, 1324 interfaces in, 1321-1323 nasal dryness in, 1325 nasal interfaces, 1321-1322 negative pressure vs., 1321 in neuromuscular disease, 1021-1022 oral interfaces in, 1322 oronasal masks in, 1322 outcomes of, 1325-1328 rhinitis in, 1325 settings of, 1324 technical considerations for, 1321-1325 ventilators in, 1323 Nonphotic entrainment, 368-372, 471
Non-rapid eye movement (NREM) sleep airflow resistance in, 255 cardiovascular function control in, 215-216 cardiovascular physiologic responses to, 230-231 cycle of, 21 on electroencephalogram, 16 hemodynamic parameter modification in, 202t, 203 homeostatic regulation of, 433-434 in imaging studies, 201-204 metabolic parameter modification in, 202t, 203f neurobiology of, 240 respiratory neuron activity in, 246 in schizophrenia, 1504 stages of, 16, 17b, 17f stimuli processing in, 204-205 thalamocortical circuits in, 82, 83f Nonseasonal unipolar depression, 1691 Nonsteroidal antiinflammatory drugs (NSAIDs), 554 Noradrenaline (NA), in sleep control, 239f Norepinephrine (NE) amphetamines and, 519 in REM sleep, 107 reuptake inhibitors, 543t-545t, 546, 965 in sleep control, 79 Norepinephrine transporter (NET), 513-514 Normative content, in dreams, 589-591 Norrie disease, 194, 950 Nortriptyline, 543t-545t, 1495t NOS1. See Nitric oxide synthase (NOS1) Novelty, in dreams, 600t NPC. See Niemann-Pick disease type C (NPC) NPD. See Nocturnal peritoneal dialysis (NPD) NPPV. See Noninvasive positive pressure ventilation (NPPV) NREM. See Non-rapid eye movement (NREM) sleep NSAIDs. See Nonsteroidal antiinflammatory drugs (NSAIDs) NT. See Neurotensin (NT) Nuclear hormone receptors, 465-466 Nursing home patients, demented antipsychotic use in, 1553 associated morbidities in, 1555-1557 cholinesterase inhibitor use in, 1553 hypnotic use in, 1552-1553 light therapy in, 1554 melatonin in, 1554 overview of, 1551 restless legs syndrome in, 1554-1555 sleep apnea in, 1555-1557 sleep integrity and, 1551-1552 stimulant use in, 1553 treatment of sleep problems in, 1552-1554 wandering in, 1554-1555 Nutrient sensors, 465-466
O
Obesity asthma and, 1296 bariatric surgery for, 1341 definition of, 1308 diagnosis of, 1309 as endocrine disorder, 1439-1440 epidemiology of, 1308, 1339 insulin resistance and, 1439-1440 lung volume and, 261 menopause and, 1595-1596 obstructive sleep apnea and, 306, 659f, 702-703, 1161-1162, 1184, 1214, 1339-1340 in police, 805t as restrictive lung disorder, 1308-1310 sleep-disordered breathing and, 34-35 in sleep medicine, 718 sleep times and, 300-301 snoring and, 702-703 treatment of, 1309-1310 Obesity-hypoventilation syndrome, 1310-1312 clinical features of, 1311 definition of, 1310 diagnosis of, 1311 drug therapy for, 1312 epidemiology of, 1310 oxygen therapy for, 1312 pathogenesis of, 1310-1311
Obesity-hypoventilation syndrome (Continued) treatment of, 1311-1312 weight loss for, 1311-1312 Obsessive-compulsive disorder (OCD), 1480-1481 Obstructive sleep apnea syndrome (OSAS), 684 airway morphology studies in diagnosis of, 673 alcohol and, 1221-1222, 1516 Alzheimer’s disease in, 1038 amyotrophic lateral sclerosis and, 661, 662f angiotensin II converting enzyme in, 1188-1189 antidepressants and, 1224-1225 apolipoprotein E in, 193, 1188 appliances for, 1165-1167 arrhythmias in, 1376-1377 associated medical disorders in, 1279 atrial fibrillation and, 1377-1378 attention and, 1197 barbiturates and, 1222-1223 bariatric surgery for, 1287, 1341-1344 behavioral factors in, 1279 behavioral interventions for, 1219-1223 body position and, 1221 bradyarrhythmias and, 1377 cardiac pacing for, 1228 cardiac resynchronization therapy for, 1228 cardinal manifestations of, 652-653 cardiopulmonary examination in, 662 cardiovascular function and, 1404 chronic obstructive pulmonary disease and, 1289, 1301 circadian rhythm and, 1186-1187 clinical course of, 1284 clinical examination in, 1213-1216 clinical features in, 1279-1280 clinical signs and symptoms in, 1207-1212 clinical values of symptoms in diagnosis, 671t cognitive problems in assessment of, 1194-1196 effects of treatment on, 1201 epidemiology of, 1194 etiology of, 1199-1201 legal aspects of, 1201-1203 medical aspects of, 1201-1203 processing and, 1196-1198 combination therapy for, 1227-1228 common clinical problems in management of, 1287-1290 coronary artery disease and clinical course in, 1397 elimination of, 1395-1396 epidemiology of, 1393-1396 pathogenesis of, 1396-1397 prevalence of, 1393-1394 CPAP for, 1165 craniofacial factors in, 658, 1184-1185 daytime signs and symptoms of, 1210-1212 definitions in, 1207 in dementia patients, 1044 diabetes and, 306, 1331-1332 diagnosis of, 1280-1284 diastolic heart failure and, 1375-1376 discovery of, 10 diurnal blood pressure and, 1384-1385 in Down syndrome, 194 dreaming and, 606-608 driving risk in, 1288 dyslipidemia and, 1332, 1335 early observation of, 5-6 edema and, 1160-1161 in elderly patients body position and, 1540 cardiovascular disease and, 1539 clinical consequences of, 1537-1539 clinical manifestations in, 1536-1537 cognition and, 1538-1539 CPAP for, 1539-1540 driving and, 1540 epidemiology of, 1536 gender and, 1536 nocturia and, 1537-1538 obesity and, 1536 oral appliances for, 1540 pathophysiology of, 1537 pharmacologic treatment for, 1540 presentation of, 1536-1537
Obstructive sleep apnea syndrome (OSAS) (Continued) stroke and, 1539 treatment of, 1539-1540 vs. younger patients, 1537t endocrine considerations in, 1223 endocrine function and, 303 in end stage renal disease patients, 1467-1469 epidemiology of, 1206-1207, 1278-1279 estrogen and, 1223 evolution of, 706-708 executive functions and, 1197-1198 familial aggregation of, 1187-1188 fat distribution and, 1161-1162 fatty liver disease and, 1332, 1336 gender and, 1164, 1215-1216, 1280 genetic analyses of, 1188-1190 genetics of, 193, 1164, 1279 glucose intolerance and, 1331-1332 glucose metabolism and, 1332-1335 goiter in, 659f heart failure and, 1374-1376 clinical presentation of, 1406-1407 treatment of, 1407-1408 hemodynamic effects in, 1373-1378 history in evaluation of, 666-668, 669t-670t home studies in diagnosis of, 672-673 hypertension and, 1381-1388 clinical relevance of, 1387-1388 epidemiologic evidence for, 1381-1384 in population subgroups, 1384 hypnotics and, 1222 hypothyroidism and, 1223, 1438 insulin resistance and, 1331-1332 intermediate phenotypes of, 1183-1184 leptin signaling and, 1189-1190 mandibular micrognathia in, 659f mandibular retrognathia in, 659f in Marfan syndrome, 194 mechanical therapy for, 1226-1228 memory in, 1196-1197 metabolic syndrome and, 1332, 1335-1336 modafinil in, 534 molecular genetic studies in, 1188-1190 myopathy in, 1162-1164 narcotics and, 1222 nasal dilators for, 1226 nasal factors in, 658 nasopharyngeal airway stents for, 1226 neck circumference in, 658-660, 1214 neurological examination in, 661 nighttime signs and symptoms in, 1207-1210 obesity and, 306, 659f, 702-703, 1161-1162, 1184, 1339-1340 occurrence of, 704t oral appliances for, 1287 oromaxillofacial surgery for, 1287 oxygen for, 1223-1224 palatal implants for, 1287 palate in, 661f pathogenesis of, 1279 obesity and, 1340-1341 pharmacologic interventions for, 1223-1226 pharynx examination in, 660 phenotype, 1183 phosphodiesterase-5 inhibitors and, 1223 physical examination in, 658-662, 668-671 polycystic ovary syndrome and, 306-307 polysomnography in diagnosis of, 671, 1280 in pregnancy, 1576-1577, 1582 prevalence of, 1278-1279 prevention of, 1284 progesterone and, 1223 protriptyline and, 1224-1225 as pulmonary hypertension cause, 1388-1389 pulmonary hypertension mechanisms in, 1389-1390 quality of life and, 1198-1199 questionnaires in evaluation of, 666-668, 669t-670t risk factors for, 1213, 1278-1279 segregation analysis in, 1188 serotoninergic pathways in, 1189 serotonin uptake inhibitors and, 1225 sleep deprivation and, 1220-1221 sleepiness in, 1280 sleep-onset REM periods in, 24
Index 1715 Obstructive sleep apnea syndrome (OSAS) (Continued) smoking cessation for, 1220 snoring in, 1279-1280 steatohepatitis and, 1336 stimulants and, 1225 in stroke, 997f surgery for, 1167, 1286-1287 sympathetic activation in, 234 testosterone and, 1223 tongue in, 659f tonsil examination in, 660-661, 662f tracheostomy for, 12-13, 1287 treatment of, 1284-1287 types of, 681t-683t upper airway stimulation for, 1226-1227 ventilatory control patterns and, 1185-1186 weight loss for, 1165, 1219-1220 Occlusal appliances, for bruxism, 1135-1136 Occupational medicine, 423-424 burnout in, 736-737 environment in, 734 fatigue in, 734-735 fatigue modeling in, 749-750 overview of, 734 performance deficits in circadian rhythm and, 740 imaging in, 739-740 nature of, 738 nonspecificity of, 742 prediction modeling of, 742-743 time on task and, 740-742 performance monitoring in, 736 pharmacology in, 736 risk management in, 735 stress in, 736-737 OCD. See Obsessive-compulsive disorder (OCD) Octopamine, 129-130, 157 Ocular measures, in circadian rhythm studies, 448 Olanzapine, 495t, 504, 548t, 917t-919t, 923, 1043t, 1497t Older people, napping in, 36 Olfactory response, in sleep onset, 19 Ondine’s curse. See Congenital central hypoventilation syndrome (CCHS) Onset, of sleep, 17-20 auditory response in, 19 behavioral concomitants of, 18-19 central sleep apnea in, 1143-1144 definition of, 17-18 on electroencephalogram, 18, 18f electromyogram in, 17-18 on electrooculogram, 18 growth hormone pulse in, 292-293 hypnic myoclonia in, 19 learning and, 20 meal ingestion and, 318-319 meaningful stimuli response in, 19 memory near, 19-20, 20f olfactory response in, 19 visual response in, 19 Opioids, 553-554, 1033, 1034t, 1519 Optimal sleep, core sleep vs., 68 Oral appliances cardiovascular outcomes with, 1270 clinical outcomes with, 1268-1271 clinical protocol for, 1273-1274 comparison of designs in, 1270-1271 compliance issues in, 1272-1273 complications with, 1272 contraindications for, 1273 CPAP vs., 1271 for daytime sleepiness, 1269-1270 future directions in, 1274-1275 indications for, 1273 long-term follow up in, 1274 mandibular repositioning, 1266 mechanism of action in, 1266-1268 neurocognitive outcomes with, 1270 for obstructive sleep apnea, 1165-1167, 1287 in elderly patients, 1540 overview of, 1266 posttreatment assessment in, 1274 pretreatment assessment in, 1273 quality of life and, 1270
Oral appliances (Continued) selection of, 1273-1274 side effects of, 1272 for snoring, 1178, 1269 surgery vs., 1271 for teeth grinding, 1135-1136 titration protocol in, 1274 treatment outcome predictors with, 1271-1272 types of, 1266 Oral contraceptives, 1569 Orexin (OX) antagonists, 504 in sleep control, 79, 239f Oromaxillofacial surgery, 1287 Oromotor excitability, 1130 OSAS. See Obstructive sleep apnea syndrome (OSAS) Oscillations fast, 563 slow, 84-86, 85f, 113-115, 563 Oscillators, circadian, 394-398 Otarids, 135 Ovarian hormones, 1565-1569 OX. See Orexin (OX) Oxcarbazepine, 550t-551t, 1497t Oxidative stress, sleep as protection from, 88-89 Oxidized glutathione (GSSR), 88 Oxybutynin, 1529 Oxygen for chronic obstructive pulmonary disease, 1303 for heart failure patients, 1411 for obesity-hypoventilation syndrome, 1312 for obstructive sleep apnea, 1223-1224 Oxytocin, 1573
P
Pain abdominal, 318 aging and, 1445 circadian variation in perception of, 1444 clinical evaluation of, 1446-1448 definition of, 1442 diagnosis of sleep problems with, 1446-1448 in elderly patients, 1526 epidemiology of, 1443-1444 hypothalamic-pituitary-adrenal axis and, 1445-1446 insomnia and, 649, 830t-831t medications, 553-554 modulation of, 350-351 neurobiology of, 553 pathogenesis of sleep problems with, 1444-1446 perception in sleep, 1444 quality of sleep and, 351 sensory processing related to, 351 sleep and, 1442-1444 sleep deprivation and, 60-61, 351 treatment of sleep problems with, 1448-1449 visceral vs. somatic, 1443 Painful erections, sleep-related, 1092 Palatal implants for obstructive sleep apnea, 1287 for snoring, 1180 Palate, in obstructive sleep apnea, 661f Palliative care, in elderly patients, 1531 Pamelor. See Nortriptyline PAMPs. See Pathogen-associated molecular patterns (PAMPs) Panic attacks, nocturnal, 1057, 1102 Panic disorder clinical features of, 1474 cognitive behavioral therapy for, 1476 diagnosis of, 1475b epidemiology of, 1474 sleep features in, 1474-1476 treatment of, 1476-1477 tricyclic antidepressants for, 1476 PaO2, ventilation and, 250 Paradoxical insomnia, 680, 840t Parahippocampal gyrus, 203-204 Paralysis, sleep cardinal manifestations of, 653 genetics of, 192
1716 Index Paralysis, sleep (Continued) isolated, 1112 in narcolepsy, 958 as normal, 1098 Parasites, 126-127 Parasomnia overlap syndrome, 1090-1091 Parasomnias, 685-686. See also specific parasomnias cardinal manifestations of, 654-656 cardiopulmonary, 1101 central nervous system, 1100-1101 epidemiology of, 708-709 epilepsy and, 1054-1055 evaluation for suspected, 676 gastrointestinal, 1101 genetics of, 192 miscellaneous, 1098-1100 mood regulation function of dreaming in, 625 overview of, 689-690 physical examination in, 663 in pregnancy, 1582 prevalence of, 708t in schizophrenia, 1508 secondary, 1100-1102 in stroke patients clinical features of, 1004 pathophysiology of, 1006-1007 treatment of, 1008 Parasympathetic nervous system asthma and, 1297 circulation control by, 226-227 Parietal lobe, inferior, 572 Parkinson, James, 981 Parkinsonism assault and defense dreams in, 1118-1122 atypical, 981 definition of, 980-981 Parkinson’s disease abnormal movements during sleep in, 982-984 age in, 980 clinical features of, 981-984 dementia in, 1040 diagnosis of sleep problems in, 986-988 dream content themes in, 1121t dreams in, 1122 drugs for, 549-551 epidemiology of sleep disorders in, 984-985 historical aspects of, 981 insomnia in, 981-982, 984-985 treatment of, 989 nocturnal sleep problems in, 986t pathogenesis of sleep problems in, 985-986 REM sleep behavior disorder in, 982-986 treatment of, 989 sleep benefit in, 984 sleep disturbances in, 980-981 sleepiness in, 50, 549, 984-986 treatment of, 989-990 stridor in, 984 treatment of sleep problems in, 988-990 urinary problems in, 986t Parnate. See Tranylcypromine Paroxetine, 543t-545t, 1495t Pars intercerebralis (PI), 155 Passive state, sleep as, 3-4 Passouant, Pierre, 5-6 PAT. See Peripheral arterial tone (PAT) Pathogen-associated molecular patterns (PAMPs), 282-283 Pathology early observations of, 5-6 sleep stage distribution and, 24 Patient evaluation chief complaint in, 641-644 diagnostic studies in, 645-646 in excessive sleepiness, 643-644 family history in, 644 history in, 641-644 in insomnia, 643 medical history in, 644 medication use in, 644 physical examination in, 645 review of systems in, 642t, 645 social history in, 644-645 symptom types in, 642 Pattern, of sleep, 20-21
Pauses, in heart rhythm, 219-220 Paxil. See Paroxetine PCOS. See Polycystic ovary syndrome (PCOS) PDF. See Pigment dispersing factor (PDF) Pediatrics. See Children Peduncular hallucinosis, 568t Pemoline, 511-512, 513t, 532t-533t, 941b PEP. See Preejection period (PEP) Peptide histidine isoleucine (PHI), 377 Perceptual learning, 340 Perceptual-motor learning, 341-342 Perceptual priming, 342 Performance deficits circadian rhythm and, 740 imaging in, 739-740 nature of, 738 nonspecificity of, 742 prediction modeling of, 742-743 time on task and, 740-742 Performance measures, 932b Performance modulation, 746 Performance monitoring, workplace, 736, 777-778 Per gene, 139, 143-144, 147t, 177, 188 Pergolide, 549-551 Period, circadian, 413-414 Period genes, 143-144 Periodic hypersomnia, 1052-1053 Periodic limb movements in sleep (PLMS). See also Restless legs syndrome (RLS) actigraphy in, 1671 in aging, 34 alcohol and, 1516 autonomic responses associated with, 231-232 cardinal manifestations of, 656 in dementia patients, 1044 in elderly patients with insomnia, 1546-1547 epilepsy and, 1055 in kidney disease patients, 1466 in Parkinson’s disease, 982-984 schizophrenia and, 1507 sensorimotor processing and, 353-354 sleep laboratories and, 1027-1028 Peripheral arterial tone (PAT), 230 Peristalsis, 314-315 Peritoneal dialysis continuous ambulatory, definition of, 1462, 1463b definition of, 1462 nocturnal, definition of, 1462, 1463b Personality questionnaires, 1635-1636 sleep deprivation and, 57-58 PGD2. See Prostaglandin D2 (PGD2) PGO. See Ponto-geniculo-occipital (PGO) waves PH. See Hypothalamus, posterior (PH) pH apnea generation and, 273 monitoring, ambulatory, 1676-1678 Pharyngeal constrictor muscle, 264f Pharyngeal muscles, 1157-1160 Pharyngobasilar fascia, 264f Pharynx examination of, in obstructive sleep apnea, 660 obstruction during sleep, 1165 upstream resistance within, 1157 Phase shift, aging and, 31 Phase shifting of gene expression protocol, 1660-1661 Phase-shifting protocols, 1659 Phenelzine, 543t-545t, 1495t Phenobarbital, 550t-551t Phenotype, sleep as, 139 Phenylpropanolamine, 554-555 Phenytoin, 550t-551t PHI. See Peptide histidine isoleucine (PHI) Phosphatase receptor type delta (PTPRD), 191-192 Phosphodiesterase-5 inhibitors, 1223 Photic entrainment, 366-368, 471 Physical examination, 645 in excessive daytime sleepiness, 674 in narcolepsy, 662-663 in parasomnias, 663 in restless legs syndrome, 663 in sleep apnea, 658-662, 668-671 in snoring, 1174-1175 Physical fatigue, 1422
Physicians in training, performance studies of, 778-779 Physiologic drug dependence, 1512 Physiology, clock regulation of, 463-464 PI. See Pars intercerebralis (PI) PIA. See Pontine inhibitory area (PIA) Pick’s disease, 1042 Pictorial sleepiness scale, 1629 Piezoelectric transducers, 1614, 1616-1617 Pigment dispersing factor (PDF), 155 Pindolol, 552t Pinealectomy, 426 Pineal melatonin rhythm, 406 Piribedil, 549-551 Pittendrigh, Colin, 141-142 Pittsburgh Sleep Quality Index, 1426 Pituitary-adrenal axis, 304-305 Pituitary gland, 293t Pituitary-gonadal axis, 305-306 PK2. See Prokinectin 2 (PK2) Placement, of electrodes, 1603 Plants, dormancy in, 126 Plasma renin, in water and electrolyte balance, 298 Plasticity, memory and, 342-343 Plethysmography, inductance, 1614, 1616-1617 Pleural pressure, 1615 PLMS. See Periodic limb movements in sleep (PLMS) PMS. See Premenstrual syndrome (PMS) Pneumography, impedance, 1617 Pneumotachography, 1611 POA. See Preoptic area (POA) Police, 736 management of sleep deprivation in, 802-806 obesity among, 805t prevalence of sleep loss, mortality, and morbidity with, 799-800 Poliomyelitis, 1018 Polycystic ovary syndrome (PCOS), 306-307, 1567-1568 Polyneuropathies, 994 Polysomnography in Alzheimer’s disease, 1038-1039 in anxiety disorders, 1473 attended laboratory, 1621-1622 as diagnostic tool, 671-672 in excessive daytime sleepiness evaluation, 674 in fatigue assessment, 1426-1427 in heart failure, 1406-1407 in idiopathic hypersomnia, 971, 974 in insomnia, 846 in insomnia treatment evaluation, 870 insurance recognition of, 11-12 modified forms of, 672 in mood disorders, 1478-1479 in narcolepsy diagnosis, 960 in obstructive sleep apnea, 1280 in pH monitoring, 1678-1679 in schizophrenia, 1504-1505 in sexual dimorphism of adolescents, 1564 in sexual dimorphism of adulthood, 1565 in sexual dimorphism of children, 1563-1564 in snoring, 1175-1176 video-electroencaphlography, 1649-1655 POMS. See Profile of Mood States (POMS) Pontine inhibitory area (PIA), 101-102 Ponto-geniculo-occipital (PGO) spikes, 93 Ponto-geniculo-occipital (PGO) waves, 16, 342, 564 Population stratification, 185b Porphyria, acute intermittent, 426 Portable recordings, 672-673 Position of body, obstructive sleep apnea and, 1221 Posterior hypothalamus (PH), in sleep control, 80 Postpartum infant peril dreams, 1123-1124 Postpartum period bed-sharing in, 1589 circadian rhythm in, 1587 depression in, 1589-1590 physiologic changes in, 1587 sleep-disturbing health problems in, 1589-1590 sleep in, 1587-1589 Postprandial sleepiness, 318-319 Posttraining sleep deprivation, 337 Posttraining sleep modifications, 337-338 Posttraumatic hypersomnia, 1068
Posttraumatic narcolepsy, 1068 Posttraumatic stress disorder (PTSD) as anxiety disorder, 1481-1483 clinical features of, 1481 content themes in dreams in, 615 definition of, 613 diagnosis of, 613, 1482b dreaming in, 1118 epidemiology of, 1481 epilepsy and, 1055 impoverished dreaming in, 1118 polysomnographic correlates of nightmares in, 615 replicative trauma dreams in, 613-614, 1122-1123 stress and, 816 treatment of, 613 treatment of nightmares in, 616-617 Posture lung volume and, 261 sleep deprivation and, 56 Potency, efficacy vs., 511 Practice effect, 446-448 Prader-Willi syndrome (PWS), 194, 950 Pramipexole, 549-551, 1043t, 1428 Prazosin, 552-553 Pre-Bötzinger complex, 237-238 Prediction, of accidents, 755-756 Preeclampsia, 1582-1583 Preejection period (PEP), 229 Pregabalin, 503, 550t-551t, 553, 924, 1428 Pregnancy cardiovascular changes in, 1574f changes in, affecting sleep, 1574f complications, 1583 cortisol in, 1572-1573 diabetes (gestational) in, 1584 estrogen in, 1572 fatigue in, 1573 gastroesophageal reflux in, 1582 gastrointestinal changes in, 1574f growth hormone in, 1573 hormonal changes in, 1572-1573 insomnia in, 1580-1582 leg cramps in, 1578-1579 melatonin in, 1573 musculoskeletal changes in, 1574f narcolepsy in, 1582 oxytocin in, 1573 parasomnias in, 1582 preeclampsia in, 1582-1583 progesterone in, 1572 prolactin in, 1573 psychosocial consequences of sleep problems in, 1583-1584 relaxin in, 1573 respiratory changes in, 1574f restless legs syndrome in, 1579-1580 sleep architecture in, 1574-1576 sleep complaints in, 1573-1574 sleep-disordered breathing in, 1576-1577, 1582 sleep quality in, 1574-1576 sleep-related disorders in, 1576-1582 Premenstrual dysphoric disorder (PMDD), 1568 Premenstrual syndrome (PMS), 1568-1569 Preoptic area (POA) hypnogenic system, 81-82 lesions, 76-77 sleep-promoting system, 80 suprachiasmatic nucleus of, 86 thermoregulation and, 86 ventrolateral, 80-81 Pressure blood arterial baroreflex and, 227 cardiopulmonary reflexes and, 227 control of, 218 CPAP treatment and, 1385-1387 diurnal, obstructive sleep apnea and, 1384-1385 monitoring, 1619-1620 sleep loss and, 233 in sudden infant death syndrome, 218 variability, 227-229 nasal airway, 1612 pleural, 1615
Index 1717 Presynaptic modulation, in respiratory motorneurons, 242-243 Primary afferent nerve fibers, 348-349 Primary insomnia, 680-683 Primary sleep apneas, 684 Primidone, 550t-551t Priming, perceptual, 342 Prioritization, of sleep, 717 Pristiq. See Desvenlafaxine PRL. See Prolactin (PRL) Problem-solving, in insomnia treatment, 889 Prodromal cardiac dreams, 1123 Profile of Mood States (POMS), 1629 Progestational agents, 277 Progesterone in menopause, 1595 obesity-hypoventilation syndrome and, 1312 obstructive sleep apnea and, 1223 in pregnancy, 1572 Progestin, 1569 Progression, of sleep, 20-25 generalizations in, 21-22 length in, 21 pattern in, 20-21 Progressive supranuclear palsy (PSP) dementia in, 1039-1040 EEG in, 1039-1040 Proinflammatory cytokines, 88 Project Sleep, 721 Prokinectin 2 (PK2), 146 Prolactinoma, 1438 Prolactin (PRL) action of, 293t age and secretion of, 304 benzodiazepines and, 295 in pregnancy, 1573 secretion, 295-296 in sleep deprivation, 292f Propensity, sleep, chronic sleep deprivation and, 69-70 Propranolol, 552t Propriospinal myoclonus, 1100 ProSom. See Estazolam Prostaglandin D2 (PGD2), 88 Protein(s) calcium-binding, in suprachiasmatic nucleus, 379 heat-shock, 156 Protozoans, 126 Protriptyline, 543t-545t, 941b, 1224-1225, 1303, 1495t Prozac. See Fluoxetine Pruritus, 1101 Pseudoephedrine, 554-555 Pseudoreplication, 185b PSP. See Progressive supranuclear palsy (PSP) Psychiatric conditions. See also specific conditions in elderly patients, 1525-1526 insomnia and, 32, 1632 sleep deprivation and, 57-58 Psychobiological inhibition model of insomnia, 855-858 Psychogenic dissociative states, 1057, 1102 Psychomotor vigilance test (PVT), 738 Psychopathology questionnaires, 1635-1636 Psychophysiologic insomnia, 680, 840t Psychosocial stress, biological vs., 814 Psychotherapeutic drugs, 542-549. See also specific drugs and classes Psychotherapy, dreams in, 624-625 Psychotic dream-related aggression, 1124 Pterygoid hamulus, 264f Pterygomandibular raphe, 264f PTPRD. See Phosphatase receptor type delta (PTPRD) PTT. See Pulse transit time (PTT) Public health daytime sleepiness and, 50-51 promotion of, 721-722 sleep in, 721-722 transportation safety and, 718-720 Pulmonary arteriolar vasoconstriction, 1371 Pulmonary complications, in gastroesophageal reflux, 1457-1458 Pulmonary edema, high-altitude, 275
Pulmonary hypertension, 1388-1390 CPAP and, 1390 mechanisms in obstructive sleep apnea patients, 1389-1390 obstructive sleep apnea as cause of, 1388-1389 Pulse oximetry, 1618-1619 Pulse transit time (PTT), 230 Pupillography, 1626 PVT. See Psychomotor vigilance test (PVT) PWS. See Prader-Willi syndrome (PWS)
Q
QT-interval prolongation, 1364 QTL. See Quantitative trait locus (QTL) analysis Quality, sleep daytime sleepiness and, 48 endocrine function and, 301-303 in hypothyroidism, 1438 metabolic function and, 301-303 pain and, 351 in pregnancy, 1574-1576 Quality-control, genotyping, 186b Quality of life obstructive sleep apnea and, 1198-1199 oral appliances and, 1270 shift work and, 786-787 Quality standards, 932b Quantitative trait locus (QTL) analysis, 156, 167f, 168-171 Quantity, sleep, daytime sleepiness and, 47-48 Quazepam, 484t dose range, 906t elimination half-life, 906t metabolism of, 906t Questionnaires dream, 586-587 in hypersomnolence evaluation, 674 for insomnia, 843 medical history, 1635 for obstructive sleep apnea evaluation, 666-668, 669t-670t personality, 1635-1636 psychopathology, 1635-1636 sleep, 1635 Quetiapine, 484t, 495t, 504, 548t, 1497t for insomnia, 917t-919t, 923 for insomnia in dementia patients, 1043t Quota, sleep, 112
R
Rab3a gene, 147 Rabies, 282-283 Radiofrequency ablation (RFA) for snoring, 1179-1180 for tongue base obstruction, 1261 Radiofrequency volumetric tissue reduction (RFVTR), 1286-1287 Railroad safety, 719 Ramelteon, 484t, 489, 501, 824, 917t-919t, 920 Ramón y Cajal, Santiago, 4 Raphe nuclei, midbrain, 382-383 Rapid eye movement (REM) sleep alcohol ingestion and, 23-24 in Alzheimer’s disease, 1039 in animals, 8 arrhythmogenesis in, 1363 behavior disorder, 663, 708 acute vs. chronic, 1085 assault dreams in, 1118-1122 case studies, 1086 clinical course of, 1092 clinical features of, 1086-1088 clonazepam for, 1091-1092 defense dreams in, 1118-1122 in dementia patients, 1044 diagnosis of, 1088-1091 differential diagnosis of, 1089-1090 dopaminergic abnormalities in, 1085 dream enacting in, 1119t-1120t dreams and, 1087-1088 epidemiology of, 1083-1084
1718 Index Rapid eye movement (REM) sleep (Continued) epilepsy and, 1054 extrapyramidal disease and, 1083-1084 idiopathic, 1087 male predominance of, 1085 narcolepsy and, 1084 in Parkinson’s, 982-986, 989 pathogenesis of, 1084-1086 prevention of, 1092 risk factors, 1083-1084 treatment of, 1091-1092 variations on, 1090-1091 benzodiazepines and, 489 in birds, 132-133 cardiorespiratory function and, 216-217 cardiovascular physiologic responses to, 230-231 cells with activity selective for, 100 characteristics of, 92-93 cholinergic cell groups in, 100 circadian rhythm and, 23 coronary blood flow in, 220 cycle of, 21 definition of, 16 in depression, 212 discovery of, 6-7, 92 duality of sleep and, 9 on EEG, 92-93 on electromyogram, 92-93 electrooculograms in, 7 energy consumption in, 107 eye movements in, 93 Fos labeling in, 100-101 functional residual capacity in, 255 functions of, 105-108 gamma-aminobutyric acid in, 98 generation mechanisms, 93-101 genes for, 178-179 glutamate in, 99 heart rate in, 216 heart rate surges in, 218-219 heart rhythm pauses in, 219-220 hemodynamic parameter modification in, 202t homeostatic regulation of, 116, 433 hypocretin and, 103-105 localized lesion studies of, 98 medial brainstem reticular formation in, 99-100 memory and, 107 metabolic parameter modification in, 202t, 203f modeling of, 440 monoamine-containing cells and, 100 muscle tone control in, 101-103 narcolepsy and, 103-105 neurobiology of, 240 neuronal activity in, 99-101 phasic, 16, 17f pitfalls in, 1092 in recovery sleep, 63 regulation of, 433 reorganization of regional brain function in, 205-206 respiratory neuron activity in, 246-247 in schizophrenics, 1504 sinus arrest in, 1092 sleep-onset, cataplexy and, 9 as stimulation of brain, 107 stimulation studies of, 99 temperature of environment and, 23 thalamocortical circuits in, 82, 83f thermoregulation in, 92-93 tonic, 16 transection studies of, 96-98 transmitter release in, 99-101 types of, 16, 17b ventricular arrhythmias in, 222 Rapid response genes, 161-162 RAS. See Reticular activating system (RAS) RBD. See Rapid eye movement (REM) sleep, behavior disorder Reactive oxygen species (ROS), 88-89 Reality-dream confusions, 1123-1124 Reality simulation, in dreaming, 561, 595, 598-602 Rebound, sleep, 135-136 Reboxetine, 522, 543t-545t, 546 Recordings, portable, 672-673
Recovery sleep, 62-64 Rectal function, 319-320 Rectus abdominis, 260f Reflex(es) airway negative-pressure, 354-355 arterial baroreflex, 227, 229 bronchopulmonary, 355-356 cardiopulmonary, 227 chemoreflexes, 227, 356-358 “H,” 8 laryngeal, 355-356 respiratory, 354-358 somatic, processing of, 352-353 withdrawal, 352 Regina v Parks, 726 Regulation, sleep. See also Homeostasis, sleep age-related changes in, 1545-1546 genetic basis of, 181 hypocretin transmission in, 943-944 imaging of, 206-208 interactive mathematical models of, 436t intermediate-level network models of, 438t models of, 436-440 neuronal architecture models of, 437t sleep, in mammals, 112-119 three-process model of, 436t two-process model of, 436-440, 436t ultradian variation model of, 436t Reindeer, 132 Relaxation training, 867b, 868 Relaxin, 1573 REM. See Rapid eye movement (REM) sleep Remeron. See Mirtazapine Repetitive dream content, 1118-1123 Reptiles, 120 Resistance airflow, 255, 261 airway age and, 35 arousal from, 252-253, 253f syndrome, 1212-1213 Starling model of, 263 Respiration. See also Ventilation at altitude acclimatization to, 274 chemosensory mechanisms and, 274 hypocapnia and, 272-273 hypoxia and, 272-273 increased ventilation at, 269 long-term adaptation to, 277-278 mechanisms of breathing at, 272 periodic breathing at, 271-276 physiologic adjustment to, 269-271 sleep disturbances at, 269-271 syndromes, 275 treatment for periodic breathing at, 276-277 chemoreflexes and, 227 Cheyne-Stokes, 1145, 1147, 1149 cycle, 260-261 excitatory influences in, 244-245 factors in control of, 254-255 glycine in, 245 inhibitory influences in, 245 medullary neurons, 237 metabolic rate and, 254-255 motorneuron activity determinants in, 241-243 motorneuron control in, 240-241 neurobiology of, 237-239 neuronal connections in, 238-239 pre-Bötzinger complex in, 237-238 in pregnancy, 1574f rhythm control in sleep, 254 Respiratory dyskinesias, 1057, 1101 Respiratory failure, hypercapnic, 1144 Respiratory homeostasis, 217-218 Respiratory interactions, 216-218 Respiratory motorneurons control of, 240-241 determinants of activity in, 241-243 electrical properties of, 242 medullary, 237 neuromodulation of, 243-245 presynaptic modulation in, 242-243 respiratory-related inputs to, 241-242 tonic inputs to, 241-242
Respiratory muscles, 260f effect of sleep on, 265 electromyography of, 1615 tonic and respiratory-related activity in, 243 in upper airway anatomy, 259 Respiratory neurons control of, 246-247 neuromodulation of, 247 in non-REM sleep, 246 in REM sleep, 246-247 as varying in strength, 246 Respiratory reflexes, 354-358 Rest consolidation, 119 Restless legs syndrome (RLS) anemia and, 1030 anticonvulsants for, 1033 benzodiazepines for, 1033, 1034t BTBD9 gene in, 191 burden of, 1027 cardinal manifestations of, 656 in children, 1029-1030 attention-deficit/hyperactivity disorder and, 1029-1030 diagnosis of, 1029 prevalence of, 1029 clinical course of, 1027 clinical diagnosis of, 1027 clinical management of, 1033-1034 in dementia patients, 1044 diagnosis of, 1027-1029 dopamine agonists for, 1033, 1034t dopamine precursors for, 1034t dopaminergic medications for, 1032-1033 dreaming and, 609 in elderly, 33-34 with insomnia, 1547 epidemiology of, 708, 1026-1027 etiology of, 1031-1032 fibromyalgia and, 1030 genetics of, 190-192, 1031 genome-wide associations in, 190-192 heritability of, 190 idiopathic hypersomnia vs., 976 incidence of, 33-34 insomnia and, 845 iron levels and, 1032 in kidney disease patients, 1465-1466 kidney transplantation and, 1466 levodopa for, 1032-1033 linkage studies, 190 medical investigation of, 1030-1031 Meis1 gene in, 186 motor manifestations of, 1026-1027 neural substrates in, 1031 neuropathies and, 1030 neurotransmitter dysfunctions in, 1031-1032 nitric oxide synthase in, 191-192 in nursing home patients, 1554-1555 opioids for, 1033, 1034t overview of, 686-687 pathophysiology of, 1031-1032 pharmacologic treatment of, 1032-1033 phosphatase receptor type delta in, 191-192 physical examination in, 663 in pregnancy, 1579-1580 prevalence of, 707t schizophrenia and, 1507 secondary, 1030 sensorimotor processing and, 353-354 sensory manifestations of, 1026-1027 severity assessments in, 1028-1029 sleep disturbances with, 1027 sleep laboratory diagnosis of, 1027-1028 in stroke patients, 1004 suggested immobilization test in, 1028 treatment of, 1032-1034 uremia and, 1030 Restoril. See Temazepam Restriction, sleep, 867, 887f adaptation to, 68 cardiovascular effects in, 73 cognitive effects of, 70-72 core vs. optimal sleep in, 68 driving and, 72 effects of, 69-72
Index 1719
Restriction, sleep (Continued) endocrine effects of, 73 immune function and, 73 incidence of, 67 individual differences in responses to, 72 as insomnia treatment, 867b, 886-888 metabolic effects of, 73 mood in, 72 on Multiple Sleep Latency Test, 70 oculomotor responses in, 70 physiologic effects of, 73 sleep architecture and, 69 sleep need and, 67-68 sleep propensity and, 69-70 two-process model predictions of, 68-69 waking EEG in, 70 Restrictive lung disorder(s) interstitial lung disease as, 1314-1316 kyphoscoliosis as, 1312-1314 obesity as, 1308-1310 obesity-hypoventilation syndrome as, 1310-1312 Reticular activating system (RAS), 77-78 Reticular system, ascending, 5, 5f Retina, suprachiasmatic nucleus and, 380-381, 392-393 Retinohypothalamic tract (RHT), 380-381, 392-393 Retroglossal oropharynx, 1158f Retropalatal oropharynx, 1158f Review of systems, 642t, 645 RFA. See Radiofrequency ablation (RFA) RFVTR. See Radiofrequency volumetric tissue reduction (RFVTR) RHT. See Retinohypothalamic tract (RHT) Rhythmic movement disorder (RMD), 655, 1054-1055, 1099-1100 Rib cage motion, 1613-1615 Ribonucleic acid (RNA), virus-associated double stranded, 283 Risk, of errors and accidents with sleepiness, 753-754 Risk management challenges in, 765-766 changing roles in, 765-766 dynamics in, 761-763 individual differences in, 762 knowledge gaps in, 765 in occupational sleep medicine, 735 regulation in, 764-765 safety management systems in, 764 sleep deprivation in, 761-762 task type in, 762 theoretical framework for, 760-761 Risperdal. See Risperidone Risperidone, 504, 548t, 1043t, 1497t Ritamserin, 532t-533t Rivastigmine, 1043t RLS. See Restless legs syndrome (RLS) RMD. See Rhythmic movement disorder (RMD) Roffwarg, Howard, 12 Rohypnol. See Flunitrazepam Ropinirole, 549-551 ROS. See Reactive oxygen species (ROS) Rotating-shift work, 785 Rotifers, 126 Rotigotine, 549-551 Roux-en-Y gastric bypass (RYGB), 1343 Ruminants, 118 Rumination, 816 RYGB. See Roux-en-Y gastric bypass (RYGB)
S
Sabril. See Vigabatrin Safety of light therapy, 1683-1684 transportation, 718-720 Saint Denys, Hervey de, 335 Salivary flow, 1132 Salivary melatonin, 1661-1662 SAQ. See Sleep Assessment Questionnaire (SAQ) Scalenes, 260f Schizophrenia antipsychotics for, 1505-1507 clinical course of, 1503 comorbid psychiatric illness in, 1507
Schizophrenia (Continued) controversies in, 1508-1509 diagnosis of, 1502 epidemiology of, 1501-1502 hyperarousal in, 1507-1508 hypersomnia in, 1508 insomnia in, 1507-1508 modafinil in, 1508 non-REM sleep in, 1504 parasomnias in, 1508 pathogenesis of, 1503 periodic limb movements in sleep and, 1507 polysomnography in, 1504-1505 prevention of, 1503 REM sleep in, 1504 restless legs syndrome and, 1507 risk factors, 1501-1502 sleep hygiene in, 1507 sleep latency in, 1504 sleep-related complaints in, 1503-1504 sleep-related features in, 1503-1505 slow-wave sleep in, 1505 treatment of, 1505-1508 SCN. See Suprachiasmatic nucleus (SCN) Scorpions, 122 SDB. See Sleep-disordered breathing (SDB) Seals, eared, 135 Seasonal affective disorder (SAD), 1690-1691 Secondary bruxism, 1129b Secondary insomnia, 683 Secondary narcolepsy, 949-950 Secondary parasomnias, 1100-1102 Secondary restless legs syndrome, 1030 Sedatives. See Hypnotics Seed dormancy, 126 Segregation analysis, in obstructive sleep apnea, 1188 Seizures arousal disorders and, 1054 arrhythmias and, 1057 autosomal dominant nocturnal frontal lobe, 1056-1057 behavioral, 1056-1057 cardiopulmonary manifestations of, 1057 cataplexy and, 1052 diagnostic evaluation of, 1058-1059 dreams and, 1054 enuresis and, 1054 epidemiology of sleep problems with, 1048-1049 historical aspects of, 1048 hypersomnia in, 1052 incidence of, 1048-1049 insomnia and, 1053 narcolepsy and, 1052 nightmares vs., 1052 nocturnal frontal lobe, genetics of, 192-193 nocturnal panic attacks and, 1057 parasomnias and, 1054-1055 pathogenesis of sleep problems in, 1049-1050 periodic hypersomnia and, 1052-1053 periodic limb movements disorder and, 1055 posttraumatic stress disorder and, 1055 psychogenic dissociative states and, 1057 REM sleep behavior disorder and, 1054 respiratory dyskinesias in, 1057 rhythmic movement disorder and, 1054-1055 in sleep, 1055-1057 sleep-disordered breathing and, 1053 sleep-related, 687 sleep starts vs., 1050-1052 treatment of, 1059 types of, 1049 Selective serotonin reuptake inhibitors (SSRIs), 543t-545t, 545-546, 965, 1494, 1495t Selegiline, 513t, 522, 532t-533t, 941b, 963 Selegiline transdermal, 543t-545t Self simulation, in dreaming, 561 Semantic memory, 339 Sensorimotor pathways, 352 Sensorimotor processes, modulation of, 352-354 Sensors, nutrient, 465-466 Sensory pathways, 348-350 Sensory processing afferent nerve fibers in, 348-349 modulation of, 348-351 narcolepsy and, 354
Sensory processing (Continued) of pain, 351 periodic limb movements in sleep and, 353-354 restless legs syndrome and, 353-354 Sequence learning, 341-342 Seroquel. See Quetiapine Serotonin in control of sleep, 78 dreaming and, 567 melatonin and, 420-421 migraine and, 1064-1065 in obstructive sleep apnea, 1189 in REM sleep, 107 Serotonin-norepinephrine reuptake inhibitors (SNRIs), 0, 1495t Serotonin receptor antagonists, 500 Sertraline, 543t-545t, 1495t Serzone. See Nefazodone Sex, heart failure and, 1402-1403 Sex hormone disorders, 1437-1438 Sexual dimorphism, 1562 Sexual disorders, sleep-related, 689-690, 1077-1078 SHHS. See Sleep Heart Health Study (SHHS) Shift work, 456, 736 accidents and, 786 afternoon, 785 circadian rhythm and, 458-460, 463, 785-786 early morning, 785 evening, 785 health effects of, 787 individual and, 804 insomnia and, 786 melatonin and, 423-424 menstruation and, 1566-1567 modafinil and, 534 morbidity associated with, 786-787 night, 784-785 organization and, 804-806 prevalence of, 784-787 productivity and, 786-787 quality of life and, 786-787 rotating, 785 types of, 784-785 Shift work sleep disorder (SWSD), 423-424, 736, 787-791, 792t Shipping safety, 719 Short sleeper, 687 Sickness, sleeping, 1070 Signal transduction, in Drosophila, 156-157 Simulation, in dreaming, 561, 595, 598-602 Sinequan. See Doxepin Sinus arrest, REM sleep-related, 1092 Sirtuins, 466 SIT. See Suggested immobilization test (SIT) Sleep. See also Non-rapid eye movement (NREM) sleep ; Rapid eye movement (REM) sleep behavioral definition of, 16 definitions of, 16 diversity of, 129-130 duality of, 9 history of theories on, 3-4 in modern society, 716-717 as passive state, 3-4 Sleep Assessment Questionnaire (SAQ), 1426 Sleep-disordered breathing (SDB), 683-684. See also specific disorders in acromegaly, 1435-1437 in aging, 34-36 in amyotrophic lateral sclerosis, 1017-1018 contraindications for surgery in, 1250 in end stage renal disease, 1467-1469 epidemiology of, 702-708 epilepsy and, 1053 hypertension and, 35 idiopathic hypersomnia vs., 974 indications for surgery in, 1250 insomnia and, 32, 34f in kidney disease patients, 1466-1467 kidney transplantation and, 1469 lung volume in, 1616-1617 in menopause, 1595-1596 monitoring of abdominal motion in, 1613-1615 airflow detection methods in, 1610-1613 definitions in, 1610
1720 Index Sleep-disordered breathing (SDB) (Continued) expired carbon dioxide sensing in, 1612-1613 nasal airway pressure in, 1612 pleural pressure in, 1615 respiratory effort detection in, 1613-1616 rib cage motion in, 1613-1615 static charge-sensitive bed in, 1615 obesity and, 34-35 obstructive cephalometric imaging in evaluation of, 1252 clinical evaluation for surgery in, 1251-1252 evidence-based medicine issues in, 1252-1253 historical perspective in, 1250 nasopharyngolaryngoscopy in evaluation of, 1251 pretreatment recommendations for surgery in, 1250-1251 rationale for surgery in, 1250 two-phased surgical protocol for, 1252-1253 outcomes in, 35-36 in pregnancy, 1576-1577, 1582 respiratory muscle electromyography in, 1615 risk factors for, 34-35 in schizophrenia, 1508 in stroke, 993-1000 after, 995t-996t clinical features of, 994-998 clinical significance of, 999 diagnosis of, 999-1000 pathophysiology of, 998-999 symptoms of, 994 treatment of, 1000 as stroke risk factor, 993-994 in traumatic brain injury, 1068 upper airway resistance and, 35 ventilatory control instability and, 35 Sleep Heart Health Study (SHHS), 28-29, 28t Sleep history, sleep stage distribution and, 22-23 Sleepiness, daytime adaptation to, 44 adenosine in, 45 alerting drugs and, 50 antiepileptics and, 49 antihistamines and, 49 antihypertensives and, 49-50 assessment of, 45-47 behavioral functioning and, 46 cardinal manifestations of, 650 central nervous system pathologies and, 50 circadian rhythm and, 48-49 clinical assessment of, 47 clinical significance of, 50-51 cognition and, 51 in dementia patients, 1044 determinants of, 47-50 dopaminergic agonists and, 50 drugs for, 513t early measurement of, 12 in end stage renal disease, 1464 epidemiology of, 42-43, 698-700 evaluation of, 674-675 fatigue vs., 49-50 gamma-aminobutyric acid and, 45 history in evaluation of, 674 idiopathic hypersomnia and, 970 introspective, 1628-1629 in limited populations, 42 in Maintenance of Wakefulness Test, 46 manifest, 1627-1628 on MRI, 44-45 in Multiple Sleep Latency Test, 42-43, 43f, 45-47, 674-675 in myotonic dystrophy, 50 in narcolepsy, 957 nature of, 43-45 neural substrates of, 44-45 neurochemistry in, 45 in obstructive sleep apnea, 1210-1212, 1280 oral appliances for, 1269-1270 overview of, 1624-1625 in Parkinson’s disease, 50, 984-986 treatment of, 989-990 physical examination in, 674 physical findings in, 650
Sleepiness, daytime (Continued) physiologic, 1625-1627 as physiological need state, 43-44 polysomnography in evaluation of, 674 presentation of, 643-644 public health significance of, 50-51 quality of sleep and, 48 quantification of, 45-46 quantity of sleep and, 47-48 recognition of clinical significance of, 12 in representative populations, 42-43 risk factors for, 43 sedating drugs and, 49-50 snoring and, 1173 treatment of, 513t Sleeping sickness, 1070 Sleep-onset REM periods (SOREMPs) benzodiazepine withdrawal and, 23-24 cataplexy and, 9 dreaming and, 565 in infancy, 24 in jet lag, 24 in narcolepsy, 24 in sleep apnea syndromes, 24 Sleepwalking, 1077 benzodiazepine use and, 912 genetics of, 192 manifestation of, 654 “Sleepwalking defense”, 725-726 Slow oscillations, 84-86, 85f, 113-115, 563 Slow-wave activity (SWA) daily time course of, 115-116 deprivation and, 117 on functional MRI, 204f global time course of, 432 homeostasis and, 113, 431 imaging of, 203 intensity of sleep and, 431 memory and, 343 naps and, 432 parahippocampal gyrus in, 203-204 ultradian dynamics of, 433 Slow-wave sleep (SWS) age and, 22-24, 29-30, 30f in children, 22 in core sleep, 68 definition of, 21 distribution of, 21 genes for, 178-179 glucose metabolism in, 203f memory and, 30 in older persons, 25b in recovery sleep, 63 in schizophrenia, 1505 sleep deprivation and, 432-433 sleep history and, 22-23 sleep homeostasis and, 431 thalamocortical circuits and, 84 Smell, in sleep onset, 19 Smith-Magenis syndrome genetics of, 194 melatonin and, 426 Smoking cessation, for obstructive sleep apnea, 1220 Snoreplasty, injection, 1179 Snoring, 650-651, 702-708. See also Obstructive sleep apnea syndrome (OSAS) alcohol and, 1177 cardiovascular disease and, 1174 clinical features in, 1174-1176 clinical history in, 1174 daytime sleepiness and, 1173 definition of, 1172 diagnostic assessment of, 1174-1176 epidemiology of, 1173 health effects of, 1173-1174 historical perspective in, 1172 injection snoreplasty for, 1179 laboratory investigations in, 1175-1176 laser-assisted uvuloplasty for, 1179 lifestyle modification for, 1177 measurement of, 1172-1173 nasal dilators for, 1177-1178 nasal surgery for, 1178 in obstructive sleep apnea, 1279-1280
Snoring (Continued) palatal implants for, 1180 pathophysiology of, 1172-1173 pharmacologic treatments for, 1177 pharyngeal surgery for, 1178-1180 physical examination in, 1174-1175 polysomnography in, 1175-1176 positional training for, 1177 radiofrequency ablation for, 1179-1180 surgery for, 1178-1180 tonsillectomy for, 1180 treatment of, 1176-1180 upper airway assessment in, 1175 uvulopalatopharyngoplasty for, 1179 weight loss for, 1177 SNRIs. See Serotonin-norepinephrine reuptake inhibitors (SNRIs) Social cognition, dreams and, 571 Social cues, circadian rhythm and, 372 Social factors, circadian rhythm and, 415 Social history, 644-645 Social phobia, 1478-1479 Socioeconomic status, insomnia and, 832-833 SOD. See Superoxide dismutase (SOD) Sodium oxybate, 505, 532t-533t, 535-536, 917t-919t, 941b, 942, 961-963 Sodium valproate, 1497t Soft drinks, 529t-530t Somatic pain, 1443 Somatic reflexes, processing of, 352-353 Somnambulism, 1077 benzodiazepine use and, 912 genetics of, 192 manifestation of, 654 Somniloquy, 654, 687, 1100, 1112 Sonata. See Zaleplon SOREMPs. See Sleep-onset REM periods (SOREMPs) Sotalol, 552t Spectral analysis, 229 Sphincter, esophageal lower, 315-316 upper, 315-316 Spielman model of insomnia, 851b Spinal cord disease, 994-998, 1071-1072 Spindles, 84 memory and, 343 thalamic activity associated with, 203 ultradian dynamics of, 433 Spirituality, dreams and, 3-4 SSRIs. See Selective serotonin reuptake inhibitors (SSRIs) SSS. See Stanford Sleepiness Scale (SSS) Stabilizing forces, in upper airway, 265, 811-812 Staging rules, 1605-1608 Standards of practice, 1621-1623 Standards of quality, 932b Stanford Sleepiness Scale (SSS), 12, 45, 959, 1426, 1629 Stanford University sleep clinic, 11-12 Staphylococcus aureus, 284 Starling resistance model, 262-263 Starts, sleep, 687, 1050-1052, 1098, 1111 Static charge-sensitive bed, 1615 Status dissociatus, 1091 Steatohepatitis, nonalcoholic, 1336 Steele-Richardson-Olszewski syndrome. See Progressive supranuclear palsy (PSP) Stents, nasopharyngeal airway, 1226 Sternocleidomastoid, 260f Stimulants abuse of, 519-520 amphetamines absorption of, 512 abuse of, 519-520 anatomic substrates mediating, 518 chemical structure of, 511, 512f drug interactions with, 520 historical perspective with, 510-511 inactivation of, 512 indications for, 519 misuse of, 519-520 molecular targets of action of, 512-515 neurotoxicity of, 519
Stimulants (Continued) norepinephrine and, 519 presynaptic modulation of dopaminergic system with, 515-518 side effects of, 519 structure-activity relationships in, 511-512 toxicology of, 519 in children, 537 definition of, 510 for depression, 511 dopaminergic transmission and, 941-942 drug holidays from, 538 future, 523-524 history of, 527-528 insufficient sleep and, 537 military applications of, 537 for narcolepsy, 941b, 964 obstructive sleep apnea and, 1225 recommendations with, 538-539 sleep deprivation and, 56 sleepiness and, 50 sleep-wake alterations in, 1517-1519 summary of, 532t-533t treatment planning with, 538-539 uses of, 537 Stimulation studies, of REM sleep, 99 Stimuli, chemical, ventilatory response to, 252 Stimuli processing, in non-REM sleep, 204-205 Stimulus control model of insomnia, 850-851 Stimulus control therapy, 867-868, 887f, 888 Stokes, William, 1400 Strain gauges, 1616-1617 Stratification, population, 185b Stress cross-sectional connection with sleep, 814-815 dream content and, 614 dreams after presleep, 623 insomnia and, 834 measurement of, 818 morbidities with, 817 in occupational medicine, 736-737 posttraumatic stress disorder and, 816 prospective connection with sleep, 815-816 psychosocial vs. biological, 814 Stridor, in Parkinson’s disease, 984 Stroke circadian rhythm and, 1010 definition of, 993 dreaming and, 1004-1006 fatigue in clinical features of, 1003-1004 pathophysiology of, 1006 hallucinations in, 1004-1006 history of sleep problems in, 993 hypersomnia in clinical features of, 1002-1003 pathophysiology of, 1006 treatment of, 1008 incidence of, 993 insomnia in clinical features of, 1004 treatment of, 1008 intratentorial, 1009-1010 obstructive sleep apnea in, 997f in elderly patients, 1539 parasomnias in clinical features of, 1004 pathophysiology of, 1006-1007 treatment of, 1008 prevention of, 993 restless legs syndrome and, 1004 risk factors for, 993 sleep architecture changes in, 1008-1010 sleep-disordered breathing in/after, 993-1000, 995t-996t clinical features of, 994-998 clinical significance of, 999 diagnosis of, 999-1000 pathophysiology of, 998-999 symptoms of, 994 treatment of, 1000 sleep-wake disturbances in, 1000-1010 clinical features of, 1002-1006 clinical significance of, 1007-1008
Index 1721 Stroke (Continued) diagnosis of, 1008 epidemiology of, 1000-1002 pathophysiology of, 1006-1007 supratentorial, 1009 Styloglossus muscle, 264f Stylohyoid ligament, 264f Stylohyoid muscle, 264f Styloid process, 264f Stylopharyngeus muscle, 264f Substance abuse and dependence, 1512 alcohol in, 1515-1517 amphetamines in, 1518-1519 behavioral mechanisms in, 1514-1515 cocaine in, 1518-1519 diagnosis of, 1513b drug seeking behavior in, 1520-1521 in elderly patients, 1530 hypnotics in, 1519-1520 incidence of, 1512 marijuana in, 1520 neurobiological mechanisms in, 1515 opioids in, 1519 sleep-wake alterations in, 1515-1520 stimulants in, 1517-1519 understanding, 1513-1515 Substance-induced sleep disorder, diagnosis of, 1514b Subsyndromal seasonal depression, 1691 Sudden infant death syndrome (SIDS), 1366 blood pressure regulation and, 218 respiratory control and, 215 Sudden unexplained nocturnal death syndrome (SUNDS), 1367 Suggested immobilization test (SIT), 1028 Sullivan, Colin, 12-13 SUNDS. See Sudden unexplained nocturnal death syndrome (SUNDS) Superoxide dismutase (SOD), 88-89 Suprachiasmatic nucleus (SCN), 113, 141 ablation of, 456-457 anatomy of, 376-377 calcium-binding proteins in, 379 connectivity in, 378 cytoarchitecture of, 376-377 gamma-aminobutyric acid in, 379 gastrin-releasing peptide in, 378-379 identification of, as pacemaker, 402 inputs, 379-383, 393-394 intergeniculate leaflet and, 381-382 intrinsic organization of, 376-378 as master pacemaker, 390-394 midbrain raphe nuclei and, 382-383 neuroanatomy of, 391-392 neurotransmitter roles in, 378-379 neurotransmitters synthesized in, 377-378 outputs, 383-385 peripheral oscillators and, 385 in preoptic area, 86 retina and, 380-381, 392-393 vasoactive intestinal polypeptide in, 378 Supratentorial strokes, 1009 Surface adhesive forces, in pharyngeal airway, 1154-1155 Surges, in heart rate, 218-219 SWA. See Slow wave activity (SWA) Swallowing, 315-317, 1101 Sweats, night, 1101-1102 SWS. See Slow wave sleep (SWS) SWSD. See Shift work sleep disorder (SWSD) Sympathetic nervous system asthma and, 1297 microneurographic recording of, 229-230 in obstructive sleep apnea, activation of, 234 Sympathomimetic alerting agents abuse, 531-534 alerting effects of, 530-531 dependence, 531-534 mechanism of, 530 side effects of, 531 tolerance, 531-534 weaning from, 537-538 Symptom types, in patient evaluation, 642 Systemic catecholamines, 230
Systemic features of sleep disorders, 656 Systolic heart failure, 1374-1375, 1401-1402 sex and, 1402-1403
T
Tachyarrhythmias, ventricular, 221 Tachycardia-bradycardia oscillations, 1376-1377 Talking, in sleep, 654, 687, 1100, 1112 Targeted gene deletion, 169-170 Tassinari, C. Alberto, 10 TBI. See Traumatic brain injury (TBI) Tea, 529t-530t Technology, 716-717 Teeth grinding, 353, 655-656, 663-664 behavioral treatment strategies for, 1135 catecholamines and, 1131 clinical features of, 1132-1133 diagnostic evaluation of, 1133-1135 in electromyography, 1134b epidemiology of, 1128-1129 etiology of, 1128 familial disposition in, 1131 genes in, 1131 iatrogenic, 1129b local factors in, 1131-1132 neurochemistry and, 1131 occlusal appliances for, 1135-1136 palliative management for, 1135b pathophysiology of, 1129-1132 pharmacologic management for, 1136-1137 pitfalls and controversies in, 1137 risk factors for, 1128-1129 salivary flow and, 1132 secondary, 1129b in sleep laboratory, 1133-1134 stress and, 1130 tooth equilibration in, 1136 treatment of, 1135-1137 types of, 1129b Tegretol. See Carbamazepine Temazepam, 484t dose range, 906t elimination half-life, 906t metabolism of, 906t Temperature ambient sleep deprivation and, 55-56 sleep stage distribution and, 23 body circadian regulation of, 323-324 core, 323-324 hibernation and, 330-331 melatonin and, 324 in REM sleep, 92-93 sleep deprivation and, 59-60, 328-329 sleep onset and, 86, 87f Tendinous arch, 264f Tensor veli palatini muscle, 264f, 265, 1158f Terazosin, 552-553 Terrifying hypnagogic hallucinations (THHs), 1111-1112 Terrors, sleep, 654-655, 1077 Testimony, 731 Testosterone action of, 293t in aging, 305-306 obstructive sleep apnea and, 1223 sleep apnea and, 1437 sleep architecture and, 1437 Tetrahydrocannabinol (THC), 1520 TGF-α. See Transforming growth factor α (TGF-α) Thalamic-cortical interactions, 82-86 Thalamocortical relay centers, 570-571 Thalamus, 77 dorsal, 727 spindles and, 203 THC. See Tetrahydrocannabinol (THC) Theophylline, 277, 555, 1303, 1411 Thermistors, 1611-1612 Thermocouples, 1611-1612 Thermoregulation, 86, 92-93. See also Body temperature
1722 Index THHs. See Terrifying hypnagogic hallucinations (THHs) Thioridazine, 548t Thiothixene, 1110t Thought records, 889-890 3P model of insomnia, 851-853 Thyrohyoid membrane, 264f Thyrohyoid muscle, 1158f Thyroid axis, 294 Thyroid cartilage, 264f Thyroid disorders, 1438, 1598 Thyroid stimulating hormone (TSH) action of, 293t circadian rhythm and, 403-404 in sleep deprivation, 292f, 300 in thyroid axis, 294 Thyrotropin. See Thyroid stimulating hormone (TSH) Thyrotropin-releasing hormone (TRH), 523-524 Tiagabine, 495t-496t, 503, 550t-551t, 824-825, 917t-919t, 924 TIAs. See Transient ischemic attacks (TIAs) Time, circadian rhythm and, 365 Time-isolation protocols, 1659-1660 Timeless gene, 144-145 Time on task effects, 740-742 Timing, genotype-dependent differences in, 175 Timolol, 552t TIM protein, 144-145 Tindal, Sir Nicholas, 725 Tinnitus, 1101 TLC. See Total lung capacity (TLC) TNF-α. See Tumor necrosis factor alpha (TNF-α) Tobacco, obstructive sleep apnea and, 1220 Tofranil. See Imipramine Tolerance, benzodiazepine, 906-907 Tone, peripheral arterial, 230 Tongue base obstruction, 1256-1260 biting, 1102 in obstructive sleep apnea, 659f Tonic inputs, to respiratory motorneurons, 241-242 Tonsillectomy, 1180 Tonsils, examination of in obstructive sleep apnea, 660-661, 662f Tooth equilibration, 1136 Topamax. See Topiramate Topiramate, 550t-551t Torpor, 127, 331 Total lung capacity (TLC) definition of, 260 Total sleep deprivation, 54-59 Tracheal tug, 1156 Tracheostomy, for obstructive sleep apnea, 12-13, 1287 Tracheotomy, 1254-1255 Train drivers, 780-781 Transcutaneous oxygen and carbon dioxide, 1619 Transforming growth factor α (TGF-α), 146 Transient insomnia, 834 Transient ischemic attacks (TIAs), 993 Transplantation cardiac, 1409 kidney sleep-related breathing disorders and, 1469 kidney, restless legs syndrome and, 1466 Transportation safety, 718-720, 735. See also Driving drowsy Transection studies, of REM sleep, 96-98 Transection technique, 94 Transversus abdominis, 260f Tranylcypromine, 1495t Traumatic brain injury (TBI), 1067-1068 circadian rhythm disorders in, 1068 dreams and, 1068 hypersomnia in, 1068 insomnia in, 1068 narcolepsy in, 1068 sleep-disordered breathing in, 1068 Trazodone, 484t, 493t-494t, 498-499, 543t-545t, 546, 1495t for insomnia, 917t-919t, 922 for insomnia in dementia patients, 1043t TRH. See Thyrotropin-releasing hormone (TRH) Triazolam, 484t
Triazolam (Continued) dose range, 906t duration of action of, 905 metabolism of, 906t nightmares and, 1110t prolactin and, 295f Trichotillomania, 1101 Tricyclic antidepressants, 493t, 495-498, 1495t effects on sleep, 497-498, 543t-545t, 545 for insomnia, 921 for panic disorder, 1476 pharmacodynamics of, 497 pharmacokinetics of, 495-497 receptor pharmacology of, 497 side effects of, 498 Trileptal. See Oxcarbazepine Trimipramine, 493t-494t, 543t-545t, 917t-919t, 921 Triptans, 554 Trucking industry, 719 Trypanosoma brucei, 284-285, 1070 TSH. See Thyroid stimulating hormone (TSH) Tug, tracheal, 1156 Tumor necrosis factor alpha (TNF-α), 286-288 Tumors, brain, 1071 Turbulent flow, 260b Twin studies diurnal preference in, 188 EEG patterns in, 184 of narcolepsy, 944
U
UARS. See Upper airway resistance syndrome (UARS) UAS. See Upstream activating sequence (UAS) UES. See Upper esophageal sphincter (UES) Ulcer, duodenal gastric acid secretion and, 313 nocturnal acid secretion in, 1452-1453 Ultradian days, 450-451 Ultradian factors in dreaming, 576-578 Unfolded protein response (UPR), 156 Unihemispheric sleep, 118, 133 Unihemispheric slow waves (USW), 133-135 Upper airway anatomy, 259-261, 1153 in sleep apnea, 1160-1164 collapsing forces in, 263-265 dilating forces in, 264-265 dynamic properties of, 1153-1157 effects of sleep on, 262-263 elastic forces in, 259-260 examination in obstructive sleep apnea, 1214-1215 function, 1153 gravity and, 1156 jaw position and, 1155-1156 muscles, 259, 260f, 264f effect of sleep on, 265 myopathy, 1162-1164 neck position and, 1155-1156 opening muscles, 254 physiology, 259-261 resistance age and, 35 arousal from, 252-253, 253f syndrome, 1212-1213 in snoring, assessment of, 1175 stabilizing forces in, 265 as Starling resistor, 262-263 static properties of, 1153-1157 stimulation, 1226-1227 Upper airway resistance syndrome (UARS), 1212-1213 Upper esophageal sphincter (UES), 315-316 UPPP. See Uvulopalatopharyngoplasty (UPPP) UPR. See Unfolded protein response (UPR) Upstream activating sequence (UAS), 154 Uremia, restless legs syndrome and, 1030 Urinalysis, 1643 Urinary problem(s) in elderly patients, 1527-1528 with obstructive sleep apnea, 1537-1538 enuresis as, 1054, 1099 insomnia and, 33, 830t-831t in Parkinson’s disease, 986t
USW. See Unihemispheric slow waves (USW) Uvulopalatal flap, 1256 Uvulopalatopharyngoplasty (UPPP), 1167, 1179, 1255-1256, 1256f, 1286 Uvuloplasty, laser-assisted, 1179
V
Valerian, 495t-496t, 502-503, 926 Validity, in genetic research, 186b Valium. See Diazepam Valproic acid, 550t-551t, 1043t Vascular dementia, 1041 Vascular headaches, 1100 Vascular theories of sleep, 4 Vasoactive intestinal polypeptide (VIP), 377-378 Vasopressin in suprachiasmatic nucleus, 379 in water and electrolyte balance, 298 Venlafaxine, 543t-545t, 941b, 1495t Ventilation. See also Respiration added resistance and, 252 airway occlusion and, 252 at altitude, 269 arousal effect on, 254 central sleep apnea and, 1141-1142 chemical stimuli response, 252 clinical sequelae of abnormal responses in, 255-256 hypercapnic response, 251-252 hypoxic response, 251 mechanical information in, 250 minute, 260-261, 260b noninvasive positive pressure aerophagia in, 1325 alarms in, 1324-1325 clinical severity in selection of, 1318-1320 complication management in, 1325 continuous, 1320-1321 contraindications for, 1321 full-face masks in, 1322 indications for, 1318-1321, 1320t initiation of, 1324 interfaces in, 1321-1323 nasal dryness in, 1325 nasal interfaces, 1321-1322 negative pressure vs., 1321 oral interfaces in, 1322 oronasal masks in, 1322 outcomes of, 1325-1328 rhinitis in, 1325 settings of, 1324 technical considerations for, 1321-1325 ventilators in, 1323 PaO2 and, 250 physiology of control of, 250-252 Ventilatory control instability, 35 Ventilatory control patterns, 1185-1186 Ventilatory control stability, 1142-1143 Ventral emotional system, 210-211 Ventral respiratory group (VRG), 237, 238f Ventricular arrhythmias, 221-222, 1363-1364, 1377 Ventrolateral preoptic area (VLPO), 79-81, 152-153 Verapamil, 1110t Video-electroencephalography polysomnography, 1649-1655 Vigabatrin, 550t-551t Vigilance tests, 1628 VIP. See Vasoactive intestinal polypeptide (VIP) Viral challenge, sleep changes after, 282-284 Virus-associated double stranded RNA, 283 Visceral pain, 1443 Vision. See also Blindness circadian rhythm and, 380-381, 392-393 in sleep onset, 19 Visual association cortex, 572 Visual hallucinosis, 568t Vivactil. See Protriptyline VLPO. See Ventrolateral preoptic area (VLPO) Vogel, Gerald, 9 Volumes, lung, 259-260 VRG. See Ventral respiratory group (VRG)
Index 1723 W
Wakefulness neurobiology of, 239-240 subjective experience of, 536-537 Wake-on, REM-off arousal systems, 78-79 Wake-on, REM-on arousal systems, 79 Wake-promoting medications. See Stimulants Wake-state instability, 754-755 Waking consciousness, 726-727 Walrus, 133 Wandering, in dementia patients, 1044, 1554-1555 Warm-sensitive neurons (WSNs), 86, 87f Water balance, 298 Waveforms, EEG, 1604-1605 Weight loss for obesity-hypoventilation syndrome, 1311-1312 for obstructive sleep apnea, 1165, 1219-1220 sleep deprivation and, 61 snoring and, 1177 Wellbutrin. See Bupropion Whales, 133-135 Withdrawal reflex, 352 Witness, sleep medicine professional as, 731 Women circadian rhythm in, 1565-1569 menopausal cancer in, 1597-1598 common clinical conditions in, 1594-1598 depression and, 1597 hormone replacement therapy in, 1595 hot flashes in, 1594-1595 hypertension and, 1595-1596 insomnia in, 908, 909f, 1438 metabolic syndrome and, 1596-1597 neurodegenerative disorders in, 1598 night sweats in, 1594-1595 obesity and, 1595-1596 phases of, 1592
Women (Continued) progesterone in, 1595 sleep apnea in, 1595-1596 sleep patterns in, 1592-1593 stress reactivity in, 1595 thyroid dysfunction in, 1598 pregnant cardiovascular changes in, 1574f changes in, affecting sleep, 1574f complications, 1583 cortisol in, 1572-1573 diabetes (gestational) in, 1584 estrogen in, 1572 fatigue in, 1573 gastroesophageal reflux in, 1582 gastrointestinal changes in, 1574f growth hormone in, 1573 hormonal changes in, 1572-1573 insomnia in, 1580-1582 leg cramps in, 1578-1579 melatonin in, 1573 musculoskeletal changes in, 1574f narcolepsy in, 1582 oxytocin in, 1573 parasomnias in, 1582 preeclampsia in, 1582-1583 progesterone in, 1572 prolactin in, 1573 psychosocial consequences of sleep problems in, 1583-1584 relaxin in, 1573 respiratory changes in, 1574f restless legs syndrome in, 1579-1580 sleep architecture in, 1574-1576 sleep complaints in, 1573-1574 sleep-disordered breathing in, 1576-1577, 1582 sleep quality in, 1574-1576 sleep-related disorders in, 1576-1582 sexual dimorphism of sleep and, 1562 Workplace performance monitoring, 736
World simulation, in dreaming, 561 Worry, insomnia and, 889 WSNs. See Warm-sensitive neurons (WSNs)
Yeast, 126
Y
Z
Zaleplon, 277, 484t dose range, 906t duration of action of, 905 elimination half-life, 906t metabolism of, 906t protein binding of, 488-489 Zarontin. See Ethosuximide “Z drugs,” 488-489 Zeitgebers, 366-372 Zion, Libby, 720-721 Ziprasidone, 548t, 1497t Zoloft. See Sertraline Zolpidem, 484t for altitude-related sleep problems, 277 bioavailability of, 488 for comorbid insomnia, 907 dose range, 906t duration of action of, 905 elimination half-life, 906t for insomnia in dementia patients, 1043t mechanism of, 488 metabolism of, 906t prolactin and, 295f Zonegran. See Zonisamide Zonisamide, 550t-551t Zopiclone, 484t bioavailability of, 488 metabolites of, 488
